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a method of determining the quality of contact between a remotely navigated medical device and a cyclically moving anatomical structure includes measuring movement of the device , and processing the measured movement of the device to determine the contact between the device and the moving anatomical structure . | remote navigation systems have been used in recent years in the interventional treatment of various medical conditions such as , for example , cardiac arrythmias . an example of remote navigation system for conducting remote medical navigation procedures is the niobe ® magnetic navigation system available from stereotaxis inc ., st . louis , mo . this system allows the user to orient the distal end of a compatible device in a selected direction through the application of a magnetic field from one or more external source magnets , and selectively advance the medical device in the selected direction . these magnetic navigation systems allow for fast and easy navigation of a device through a subject &# 39 ; s body . other types of remote navigation systems could employ mechanical systems , electrostrictive systems , hydraulic systems , and pneumatic systems for remotely orienting the distal end of a medical device . often , during the use of a medical device navigated with a remote navigation system , it is useful to determine the extent of contact of the medical device with an anatomical organ such as the heart . such a measure can be useful in further enhancing contact so that the medical procedure , for example intracardiac radio - frequency ablation , can be better performed . embodiments of the present invention provide for enhanced remote control of remote medical device using real time location data . in accordance with one embodiment , when a catheter or other device is in contact with a structure such as a cardiac wall , the position is monitored in real time , and through analysis of the tip location data , it is possible to estimate the periodicities of the cardiac cycle and of the respiration cycle . the resulting identified periodicity can be used to gate the navigation system for respiration , for instance during targeting . the remote navigation system interfaces with a localization system that determines real - time location data and provides it to the remote navigation system . the localization system can be an electromagnetic localization system ( such as the carto ™ system manufactured by biosense webster inc .) or an electric field - based localization system ( such as the navx ™ system manufactured by st . jude medical ), or be based on other modalities such as ultrasound localization . the remote navigation system can use the real - time device location data that it receives from the localization system in several ways . in particular , the present invention discusses methods of determining and enhancing contact stability based on such real - time location data ( as generally used here , “ location data ” can be a combination of positional and orientational data ). fig6 illustrates in schematic form a remote navigation system for performing a remote navigation interventional procedure . as shown there , a patient 110 is positioned within a remotely actuated , computer controlled interventional system 100 . an elongated navigable medical device 120 having a proximal end 122 and a distal end 124 is provided for use in the interventional system 100 and the medical device is inserted into a blood vessel of the patient and navigated to an intervention volume 130 . a means of applying force or torque to advance or orient the device distal end 124 is provided , as illustrated by actuation block 140 comprising a component 142 capable of precise proximal device advance and retraction and a tip deflection component 144 . the actuation sub - system for tip deflection may be one of ( i ) a robotically controlled mechanical pull - wire system ; ( ii ) a magnetic system , consisting of external magnets for applying a magnetic field and at least one magnet in the distal portion of the interventional device for steering the device in response to the applied magnetic field ; ( iii ) an electrostrictive system ; ( iv ) a magnetostrictive system ; ( v ) a hydraulic or pneumatic system ; or ( vi ) other navigation system as known in the art . for illustration of a preferred embodiment , in magnetic navigation a magnetic field externally generated by magnet ( s ) assembly 146 orients a small magnetically responsive element ( not shown ) located at or near the device distal end 124 . real time information is provided to the physician by an imaging sub - system 150 , for example an x - ray imaging chain comprising an x - ray tube 152 and a digital x - ray detector 154 , to facilitate planning and guidance of the procedure . additional real - time information such as distal tip position and orientation may be supplied by use of a three - dimensional ( 3d ) device localization sub - system such as comprising one or more electromagnetic wave receivers located at the device distal end ( not shown ), and associated external electromagnetic wave emitters ( not shown ); or other localization device with similar effect such as an electric field - based localization system that measures local fields induced by an externally applied voltage gradient . in the latter case the conducting body of a wire within the device itself carries the signal recorded by the tip electrode to a proximally located localization system . the real - time location information provided by the localization sub - system can be used for device contact assessment and control , as described further below . the physician provides inputs to the navigation system through a user interface ( uif ) sub - system 160 comprising user interfaces devices such as keyboard 162 , mouse 164 , joystick 166 , display 168 , and similar input or output devices . display 168 also shows real - time image information acquired by the imaging system 150 and localization information acquired by the three - dimensional localization system . uif sub - system 160 relays inputs from the user to a navigation sub - system 170 comprising 3d localization block 172 , feedback block 174 , planning block 176 , and controller 178 . navigation control sequences are determined by the planning block 176 based on inputs from the user , and also possibly determined from pre - operative or intra - operative image data and localization data from a localization device and sub - system and processed by localization block 172 , and alternatively or additionally real - time imaging or additional feedback data processed by feedback block 174 . the feedback block 174 can in some cases include one or more of the various contact estimation and optimization methods described in the following . the navigation control sequence instructions are then sent to controller 178 that actuates interventional device 120 through actuation block 140 to effect device advance or retraction and tip deflection . other navigation sensors might include an ultrasound device or other device appropriate for the determination of distances from the device tip to surrounding tissues , or for tissue characterization . further device tip feedback data may include relative tip and tissue positional information provided by a local intra - operative imaging system , and predictive device modeling and representation . such device feedback in particular enables remote control of the intervention . in closed - loop implementations , the navigation sub - system 170 automatically provides input commands to the device advance / retraction 142 and tip orientation 144 actuation components based on feedback data and previously provided input instructions ; in semi closed - loop implementations , the physician fine - tunes the navigation control , based in part upon displayed information and possibly other feedback data , such as haptic force feedback . control commands and feedback data may be communicated from the user interface 160 and navigation sub - system 170 to the device and from the device back to navigation sub - system 170 and the user through cables or other means , such as wireless communications and interfaces . additionally , fig6 schematically shows “ remote navigation interventional procedure ” block 180 that performs specific functions in various embodiments of the present invention . block 180 applies to magnetic navigation system such as that illustrated in fig6 , and more generally to any medical navigation device and actuation method that also comprises contact sensing / estimation and enhancement , as described in this disclosure . in accordance with another embodiment of this invention , real - time tip location data can also be used to estimate the qualitative extent of contact with an anatomical structure . the inventors have discovered that a catheter with a soft shaft ( such as magnetic catheters ) that is engaged in wall contact will tend to maintain tip contact at a fixed location relative to the cardiac wall during motion of the wall , since the shaft can easily buckle or deform to permit this . accordingly , the extent of motion of the tip over the cardiac cycle will be largest when contact is very consistent . this is illustrated in fig1 a and 1b , where in fig1 a , the medical device 20 is in good contact and remains in contact with the moving anatomical surface 22 during the entire cycle . thus midway through the cycle , the medical device 20 ′ is still in contact with the surface 22 ′, and the device 20 has a total displacement d 1 corresponding to the movement of the surface 22 . as shown in fig1 b where the medical device is not in good contact , the tip loses contact with the anatomical surface . at the start of the cycle the tip 20 is in contact with anatomical surface 22 , and midway through the cycle medical device 20 ′ loses contact with the surface 22 , and the device has a total displacement d 2 that is less than the total movement of the surface 22 . the motion of the medical device is such that d 1 & gt ; d 2 , so that greater device motion corresponds to better contact , and this can be used in several ways to estimate the quality of contact of the device with the anatomical structure . one way of estimating the quality of contact is using the oscillation amplitude . the oscillation of the difference [ x real − x gated ] can be tracked over a few cardiac cycles , where the three dimensional vectors are defined such that x gated is always the most recent gated location ( gated to the cardiac cycle ) and x real is the realtime location . if the contact is good , the distal tip of the device moves with the movement of the surface , and the graph of the oscillation shows a relatively smooth and continuous movement ( as shown in fig2 a ). if contact is temporarily lost for a portion of time between successive cycles , the amplitude of the oscillation will display a “ truncated ” or flat behavior over such time intervals ( as shown in fig2 b ), where the catheter location will stay relatively constant , and this can be detected from signal analysis to assess stability of contact . another way of estimating the quality of contact is using positional covariance . if x mean is the mean location over a cardiac cycle , set x =( x − x mean ) and form the 3 × 3 covariance matrix c with entries c ij =& lt ; x i x j & gt ; where the average & lt ; & gt ; is taken over a cardiac cycle ( or over several cycles ). let a , b and c be the eigenvectors of c , with corresponding eigenvalues e a , e b , e c . these eigenvectors and eigenvalues define the covariance ellipsoid associated with the motion of the catheter tip ( as shown in fig3 ). a soft catheter that maintains good contact with a given target location on the cardiac wall over the cardiac cycle will have larger values of ( e a , e b , e c ) than a catheter that is in inconsistent / unstable contact ; thus for example , d =( e a + e b + e c ) can be used as a measure of contact . alternative measures based on the eigenvalues of the positional covariance matrix can also be constructed . thus , alternatively or in addition to the measure d given above , the difference between maximum and minimum eigenvalues ( e max − e min ) can be used as a measure of contact ; in some situations a larger eigenvalue difference can represent greater relative motion along one direction , thus characterizing the local cardiac wall motion . for example the cardiac ventricles exhibit expansion and contraction in volume together with a strong twisting wall motion ; this leads to a local wall motion pattern that can be generally termed an elongated approximate ellipse . a catheter tip in stable contact with such a cardiac wall location would move with the cardiac wall through the cardiac cycle . to enhance contact between the medical device and the tissue , the surface normal n to the cardiac wall can be used in order to torque the device tip into the wall . for example , with a magnetic navigation system , the magnetic field can be rotated about an axis defined by v = t × n in order to push the device tip into the wall , where t is the device tip orientation . in this case , let a be the eigenvector of c that has the largest dot product with n ({ right arrow over ( v )} 1 in fig4 ); then a can be used in some cases place of n to define the axis of rotation v . while this is useful in magnetic navigation , it can also be exploited with other navigation systems . another way of estimating the quality of contact is using orientational covariance . if t mean is the mean tip orientation over a cardiac cycle , and t =( t − t mean ), a covariance matrix m can be formed with entries m ij =& lt ; m i m j & gt ; ( average taken over a cardiac cycle ), and as with the positional covariance matrix discussed above , the eigenvalues and eigenvectors of m can be used to assess extent of contact . analogously to the contact measures based on positional covariance eigenvalues , various measures based on the orientational covariance eigenvalues such as the magnitude of the summed eigenvalues , or the difference between maximum and minimum eigenvalues , can be used to assess stability of cardiac contact . another method of measuring contact stability is to perform a frequency analysis of catheter tip motion . the frequency spectrum of the motion of a catheter tip that is in firm contact with the cardiac wall will have a dominant peak at the frequency of the cardiac cycle . thus , the ratio of the peak ( maximum , or dominant frequency ) in the fourier transform of the catheter tip location over a period of time to the next smaller peaks ( the sub - dominant peaks ) in the frequency spectrum can provide a measure of contact and can in a sense be interpreted as a signal - to - noise ratio . the frequency spectrum of the tip position will have to be obtained in general from motion over multiple cardiac cycles , and can be obtained from applying the fourier transform to the tip position data . the amplitude of the heart rate frequency should be greater with more consistent contact and less with less consistent myocardial contact . more consistent contact should be conveyed by a greater signal - to - noise ratio as the tip moves with the myocardium , and vice - versa . filtering the tip position data prior to implementing these algorithms can be implemented as a preprocessing step and can lead to improved quantification of contact stability . of course , it will be important to apply the filter at least several beats prior to the cardiac cycle being analyzed to allow the transient effects of the filter to decay sufficiently . other measures based on the frequency spectrum such as the spread in frequency between specified peak threshold values , or a variety of other such possible measures that can be determined by those skilled in the art can also be used without limitation and the specific examples of measures detailed here are provided for illustrative purposes only . another way of estimating the quality of contact is using perturbation . a control variable of the navigation system ( for example magnetic field direction , or catheter insertion length ) can be perturbed or changed by a small amount , and the resulting change in a contact measure ( such as one of the eigenvalue - based measures discussed above ) can be determined . thus for instance if contact is found to be enhanced by a small amount , a larger change in the same sense of the corresponding control variables can be applied to further enhance contact . as shown in fig5 a , the tip orientation { right arrow over ( t )} 1 is determined with a particular control value , for example the applied magnetic field { right arrow over ( b )} 1 . as shown in fig5 b , the control variable is changed , for example from { right arrow over ( b )} 1 to { right arrow over ( b )} 2 , and the resulting changing in tip orientation { right arrow over ( t )} 2 is evaluated , to determine the control variable that provides the optimum , or at least the local maximum , contact . another way of estimating the quality of contact is using unipolar voltage : if unipolar intracardiac ecg voltage information is available in real - time , its magnitude can be used to sense proximity to the wall . in particular , its behavior over a cardiac cycle or a several cycles can be analyzed as in the methods above ( except that voltage values would be used instead of positional data ) in order to assess stability , with the difference that the variation in voltage will be the smaller when contact is better . still another way of estimating the quality of contact is using a mapped mechanical model . a cardiac mechanical motion model is constructed by mapping over a “ coarse ” set of cardiac wall locations with a localized mapping catheter , so that the range of wall motion at every map point is recorded at each of these locations . then the range of mechanical motion at intermediate points can be estimated , for example by interpolation . when the catheter is later placed at such an intermediate location , the range of motion as seen in the real - time location data can be compared with the expected range of motion in order to assess quality of contact , so that the closer the actual range is to the expected range , the better the contact quality . while one method of remote actuation involving applied magnetic fields has been described for illustrative purposes , other methods of remote actuation can be involved in the remote navigation control , such as mechanical operation using a set of motorized pull - wires , electrostrictive actuation , hydraulic actuation , and various other actuation schemes known to those skilled in the art . in one embodiment the directly actuated device can be a hollow sheath that carries through it another device or devices . thus the various embodiments of this invention provide for the improved control , and in particular for enhanced measure of contact , and thus control of contact , of a remote medical navigation system . any method of remote navigation can be implemented . likewise a variety of contact measures can be constructed by those skilled in the art according to the concepts taught in this invention . these and other features and advantages will be in part apparent , and in part pointed out hereinafter , and the scope of the invention is limited only by the appended claims . | US-16369308-A |
an imaging method places an object upon a background pattern of regular repetitive marks and records a 2d image that is then processed for determining where in the image the repetitive marks are interrupted by the object , thereby indirectly determining the edge of the object . multiple 2d images from different perspectives are used to create a 3d image of the object . when the object is a human food , individual bar codes and imaged foot dimensions can be cross - referenced to manufactured shoe sizes for accurate ordering of correctly sized footwear . | an embodiment of the invention is described with reference to the figures using reference designations as shown in the figures . referring to fig1 a human foot as shown is disposed on a patterned floor plane and in front on a patterned back plane . the patterned floor plane and back plane have , in the preferred form , a checkerboard print , only part of which is shown for convenience , but the print preferably extends over a field of view ( fov ) of a camera . the checkerboard print is partially shown for convenience to be alternative square block of white and cross hair blocks , the later of which is actually printed as solid blocks . the field of view angularly extends from the focusing camera so as to capture in the fov the human foot features desired to be imaged . the patterned print of the background plane and the floor plane extends throughput the fov . targets are used to provide relative reference points to the checkerboard prints so as to reference displacement of the human foot relative to the blocks of the checkerboard print . the camera focuses upon the checkerboard pattern to image the foot and the checkerboard print area to capture the fov image . the camera provides a digital image to a computer processing means that processes the digital image . the image is captured by the camera as a two - dimensional ( 2d ) image containing the reference target points , and the checkerboard of alternating blocks having patterned regularity that is interrupted by the presence of the human foot . the computer is further used to control the position of the camera through a camera position range by actuating a motor so as to capture a plurality of desired 2d images at differing focusing angular views . the computer processes the plurality of captured 2d images into a 3d image of the outermost periphery of the foot resulting in outermost 3d dimensions of the human foot . a bar code identification card is disposed within a bar code cardholder also position within the camera fov . the bar code of the bard code card is a code that uniquely identifies the human foot to a particular human being so that the computer processes can cross reference the particular human being to the respective 3d image and the resulting 3d dimensions of the foot . the computer can further store data cross referencing shoe sizes of a particular shoe manufacturer to the 3d dimensions of the 3d image so that the computer can determine the appropriate shoe size of the particular manufacturer for the particular feet of the particular human being . by cross - referencing the identification card to the bar code to the peripheral size and shape of the measured foot to the inside cavity dimensions and shape of the footwear . referring to fig1 , and 3 , and more particularly to fig2 and 3 , an alternative dual imaging embodiment may be used to concurrently capture 2d images of a pair of human feet , a left foot and a right foot . the two feet are disposed on a double patterned floor plane with the camera capturing a pair of respective 2d images for the respective feet . as shown , there is a single camera traversing the vertical range , having two fovs extending horizontal . the camera captures left and right images through two respective left and right fovs . the camera can be a single camera that views from one perspective fov then is pivoted 180 degrees or two cameras vertically translated by the motor in tandem to view both perspective fov at the same time . the camera and the patterned floor and back planes function in combination as a scanning mechanisms that in effect scans through scanner sweep ranges that are fovs of the camera . the patterned floor plane is divided into respective left and right halves , each having a respective pair of referencing targets . vertically extending and opposing left and right backplanes are used to image the vertical height features of the respective human feet . the vertically extending back planes also contain targets , not shown . all of the targets are used to provide reference points for referencing the positions of the blocks within the planes to a known location in advance of imaging . the bi - directional imaging camera is shown to traverse the vertical camera position range . left and right top cameras are shown to have fovs extending downward towards the respective pattern floor plane halves to image the outside periphery of the respective feet , and more particularly the forefoot of the feet extending towards and to almost the heel . the heels of the respective feet are shown to be disposed in respective heels cups for proper positioning of the feet on the respective patterned floor planes halves . the camera may be an exemplar charged - complex - device ( ccd ) sensor imaging means used to capture a 2d image and output the captured image in digital form . the image is captured preferably through the sequential scanning of ccd detectors . conventional ccd cameras may be used for imaging in the preferred form . the image comprising the subject foot and background checkerboards is focused by a lens of the camera onto a silicon chip ccd x - y array of light detectors representing respective x - y pixels . a ccd controller of the camera raster - scans the x - y detectors . when each pixel detector is scanned , an analog value of the light intensity is provided and represents the light intensity for a respective pixel at a particular x - y coordinate in the x - y area . the ccd imaging means is fed a clock pulse that advances through each pixel detector by row and by column in a raster scan so that an output of the ccd sensor is provided for each pixel by row and by column , serially , one at a time , until sequencing through all the pixels of the captured image . the camera captures the black and white blocks of the checkerboard as well as the imaged foot . each block is captured as two or more pixels having the same substantial output analog value . during image area capturing , the camera generates an analog value of the returned light for each pixel . in the preferred form , monochrome gray - scale image processing is used . for simplicity in constructing a body contour , the white of black imaging through gray - scale conversion is suitable , through other color schemes could be used as well . an analog output for the ccd sensor has a dynamic range between zero and full scale , such as five volts , for spanning the gray - scale values between black to gray - scale values to white . the output of the ccd sensor may be coupled to level detector , not shown , that is set to one half of the full scale value , such as 2 . 5 volts , for digitizing the ccd gray - scale analog output into a data stream of zero and one bits for computer image processing . anytime a pixel is sensed from below medium gray to black , the output of the comparator would be below the one half of full scale and the pixel would be digitized a zero bit , and , anytime a pixel is sensed from medium gray to white , the output of the comparator would be detected above 2 . 5 volts and the pixel would be digitized as a one bit . when the ccd sensor includes an analog to digital converter ( dac ), such as an 8 bit dac , then the most significant bit of the dac output would be the center value of the gray - scale and this most significant bit is the digitized zero or one bit output to the computer processing means . even though a ccd with a dac built on - board provides digital outputs representing the whole dynamic range of the output intensity sensed , only the halfway point is needed to discern an edge of an object . yet , the computer image processing could process a multiple bit output of the gray scale or color scale for enhanced image processing . in the preferred form , only edge detection is required and only zero and one digital bit intensity resolution is required . imaging processing operates upon pixel digitization . each white or black block of the checkerboard pattern is processed by sensing at least four pixels , two pixel in each of the x rows and y columns . along each row or column , each block on the checkerboard is determined by at least two pixels having the same value . a corresponding digital pulse train from the camera is provided to the image processing computer during the raster scan of the image . the pulse train provides a sequence of transitions that occur every block transition when transiting between black and white blocks . the pixel pulse train would include transition levels of alternating zero and one values along each column and row of the captured image , and the computer processing can recognize the pattern of transitions in the pulse train to determine which receive transition corresponds to which image block . the length between the transitions indicates the number of like zero or one digitized plane . a limited amount of variations in pulse widths between transition for each block includes an inherent tolerance of +/− one pixel . each block of the checkerboard pattern is not imaged at a perfect right angle , and hence the detected image will naturally have a progression in the number of pixels per block across the rows and across the columns . the checkerboard pattern and the resulting captured image will provide a progressive number of pixels per blocks greater than two pixels per block to cause the progression of pixels per block to vary in a progressive manner . the progression of the number of pixels per block may cover a large range across the entire row or column of the captured image . for example , in the case of the floor checkerboard pattern , in the near field , at one extreme , the number of pixels per blocks may be three , and in the far field , at another extreme , the number of pixels per blocks may be seven , with the number of pixels per blocks progressively increasing from the near field to the far field along a column or row of pixels . for another example , in the case of the back plane checkerboard pattern , or in the case of the floor checkerboard panel image by an over had camera , from a center located block , the range number of pixels per block may be at minimum , such as three pixels per block , progressively increasing towards blocks located at the edge of the checkerboard . computer image processing can detect regular block pixel lengths , and can determine the progression in block pixel lengths . for example , a series of transitions of three pixels per blocks followed by a series of transitions of four pixels per blocks , indicates a natural progressive increase in the number of pixels per block , and would not thereby indicate an interruption of the pixelized image of the checkerboard . the computer image processing can recognize when the block pixel lengths have increase or decreased in a progressive manner across rows and columns of the captured image . when a transition from a first block pixel length is followed by a transition of a second block pixel length , the change should be within the +/− one pixel tolerance , allowing for the average progressive change in the block pixel length through a row and column . the error in digitization is at least +/− one pixel accounting for the edge of block . the +/− one pixel error can be compensated for by smoothing to provide an enhanced contour image . the +/− one pixel errors tend to render the object smaller then the actual size because the interruption will occur after the edge is encountered when scanning the checkerboard blocks towards the foot edge . the block error that can be tolerated and compensated through smoothing is typically twice the block size . the average block error can be partially compensated by subtracting one block from the block count to the encountered edge . when a change in block pixel length , that is the pixel duration between transitions , exceeds the +/− one pixel tolerance , the computer image processing can recognize this abrupt change as an interruption in the progressive block pixel length . the computer processes can detect this abrupt change in the transition period indicating an interruption in the progression of the block pixel length so as to then indicate and determine when the checkerboard pattern has been interrupted by the presence of the body part being imaged . hence , each block is digitized into a number of pixels per block for each square block , and this number progressively increases or decreases across rows and columns in the fov . each block is positioned at a predetermined distance from the checkerboard pattern target . the checkerboard target preferably has a unique pixel definition , such as a very large square block , recognized as such by the image processing computer . the target can be replaced by simple edge checkerboard detection , by referencing the start of the checkerboard pattern at the edge of the checkerboard . the checkerboard edge then providing a reference point , as does the target , to the remaining blocks for block position count determination . block position count determination is achieved by counting the number of the blocks from the reference point , be it a special target or a checkerboard edge , or other suitable image reference . hence , the image processing computer receives the pixel pulse train and determines , while counting the blocks in both the rows and columns , at what x - y block position in the checkerboard the block pixel length has been abruptly interrupted , thereby providing the x - y block interruption position indicating a detected edge of the imaged foot . when the order of alternative blocks , that is , the order of alternating transitions of a number of pixels per block +/− one pixel is disrupted , this disruption indicates that the foot edge interrupts the image of the checkerboard pattern . the disruption in the predetermined order of transitions is recognized as an abrupt interruption of the image of the alternating white and black blocks of alternating transition of the number of pixels per block +/− one pixel . the disruptions of the foot edge appear as truncated or extended number of pixels of the alternating transition . for example , a transition between one to three pixels in duration , in the two pixels per block range , indicates an abrupt interruption of the transition pulse train , and thereby indicating an abrupt interruption of the image checkerboard pattern by the presence of the edge of the human foot . the image processing computer determines the interruption location along each row and column and the checkerboard for each 2d image . with multiple 2d images , the computer processes can indirectly determines the periphery of the imaged human foot disposed in front of the checkerboard . referring to all of the figures , and more particularly to fig4 a , 4 b and 4 c , the vertically traversing imaging camera capture images at various vertical positions to generate multiple 2d images . as indicated in fig4 a , 4 b and 4 c , the vertical imaging camera captures images at various vertical positions , y 1 , y 2 and y 3 . the captured imaged include the checkerboard patterned of the floor and black planes . the checkerboard pattern is interrupted by the presence of the foot at respective block positions . in fig4 a , for vertical camera positions y 1 , y 2 , and y 3 , the floor plane checkerboard pattern is interrupted at x 1 , x 2 , and x 3 horizontal floor plane block positions , respectively , and the back plane checkerboard pattern is interrupted at x 4 , x 5 and x 6 vertical back plane block positions , respectively . to measure the outside periphery of a foot as viewed from the top of the forefoot , the top left and right cameras are used in the over head above the forefoot about midway between the toe and the front of the leg for the longest foot expected to ever be measured when the foot is against the back heel - cup . the fov of the over head camera would then cover as far back to the heel as possible , adequate to measure the forefoot of the shortest foot to be measured . the heel cup could be moved slidably forward for very small feet into the fov of the over head camera . the over head camera does not measure the heel periphery because the ankle and leg will shadow the hell cup , but additional cameras could be used to image the heel if desired . the important part of the foot to image is the part of the forefoot in front of the ankle . to image the side of the foot to capture the outline of the instep requires that the camera be placed on the medial side of the foot and with a back plane of the checkerboard pattern extending vertically on the lateral side of the foot . the foot instep is disposed at a particular gap distance from the vertical checkerboard back plane while the camera is vertically positioned at a particular elevation for each capture 2d image . various instep heights will not be accurately measured by a single 2d image because of angular position errors resulting from differing foot gap distances and at a particular camera elevation . because the instep height of the feet will significantly vary for different feet , it is necessary to compensate for the angular error . elevating the camera by motor control to varying elevations enable the capturing of multiple 2d images to adequately image the instep . when the camera takes multiple 2d images at respective multiple vertical heights , the number of pattern row and column blocks counted down from the top will change . through triangulation computer processing , the actual height of the instep can be calculated from the plurality of 2d images . the more 2d images taken , the more accurately the instep height calculation will be . the arch height on the medial side of the foot is an important arch dimension used to build an arch support . the arch height can be imaged by the camera taking the plurality of 2d images . by positioning the camera with reference to the floor at various elevations , and taking multiple images of the arch area , the camera will image the floor plane checkerboard pattern at various respective angles . the floor plane checkerboard pattern is imaged to the extend not blocked by the presence of the foot . the presence of the foot will interrupt the regularity of the imaged background pattern blocks . the arch height and position of the foot determines the extend of uninterrupted checkerboard pattern imaging . the higher the arch of the foot is , the more checkerboard blocks will be counted under the arch from the target position . to adequately determine the contour of the arch , the camera is moved incrementally vertically while taking multiple 2d images . as the camera moves upward , fewer floor plane horizontal blocks will be counted because the rising arch will interrupt imaging of the floor plane blocks in varying amounts . the digitized 2d image information is fed to the image processing computer that in turn calculates the arch height and approximate configuration shape by performing a series of triangulation calculations . as the vertical position of the camera is increased , the number of horizontal floor blocks counted is decreased because of the interruption of the captured image by the presence of the foot . at the lowest y 1 camera position , the farthest position under the arch will be seen at the largest number of blocks imaged and counted . in the exemplar form , when the camera is positioned at the y 1 elevation , the value that represents the lowest line of sight is the y 1 , x 3 line that relates to the largest number of horizontal blocks from the camera to the x 3 position at y 1 number of blocks in elevation . the number of horizontal blocks can be determined from the number of horizontal blocks from the reference point that is in turn at a predetermined number of horizontal blocks from the camera . this means that x 1 number of horizontal blocks is seen under the foot when the camera is at the y 1 vertical position of y 1 number of blocks high . the horizontal values of x blocks for other lines of sight at respective camera elevations can be also determined during imaging . with three captured images at respective increasing vertical positions , a virtual imaging triangle is create for triangulation computation purposes providing three intersecting points designated ( ax , ay ), ( bx , by ), and ( cx , cy ). the segment between ( bx , by ) and ( cx , cy ) forms the hypotenuse of a virtual triangle having a center point that is the closest approximation of the actual contour point on the arch which is determined to be the edge location . by moving the camera along the vertical dimension , additional virtual lines can be create and additional virtual triangles can be created , the center of each hypotenuse representing the closest approximation contour points of the edge of the rising arch as viewed from the vertical position . more than three images provide center points that will describe the contour of the arch along a cross section of the foot for constructing the 3 - d image and dimensions of the arch . it may now be apparent that the same triangulation calculation method can be used to describe the instep of the foot . the difference being that in instead of counting the blocks on the floor plane checkerboard pattern , the camera focuses on the vertical back plane checkerboard pattern on the lateral side of the foot where the foot is positioned between the camera and the vertical back plane . the processing requires that the vertical height position of the camera positional range exceed the highest instep height . the higher the camera can be moved with reference to the highest part of the instep determines the amount of the lateral side of foot that can be seen by the camera and hence how far down the lateral side of the foot can be measured . by using this imaging method , it is possible to describe the top of the instep at any longitudinal block position between the toe and the heel as an arc over the top of the instep where the peak position of the arc is known with relation to the lateral and medial sides of the foot . the general outside shape of the leading and falling sides of the arc are discernable and calculable within the angle of the fov of the camera . while the preferred embodiment is directed towards imaging a foot , the same method can be applied to imaging an entire human body , or any arbitrary object . for full body imaging , a larger vertical plane of checkerboard pattern is used . the camera views a section of area at a time depending on the number of pixels in the ccd camera and the focused fov . the size of the section is determined by the size of the checkerboard blocks and the number of pixels per block . because the body will be some distance from the vertical checkerboard plane , the camera will need to assume several locations both horizontal and vertical so that the same method of triangulation calculation can be used to produce the curved edges of the human body being measured . a group of two sets of images may be taken , for example , a first set of images are of the back of the person with the back of the person facing the camera , and a second set of images are of the side of a person with the side of the person facing the camera . this group of images would provide 2d image information to reconstruct the 3d profile of a person . to expedite imaging , at increase costs , a plurality of cameras could be placed vertically and staggered from each other so that all of the cameras move in unison when actuating the motor . the cameras could be driven by another motor that moves the camera in the same plane as the checkerboard back plane from one side to the other such as left side to and from to right side . as the cameras move from one side to the other , the body will block the checkerboard pattern at various amounts depending on the line of sight , and the triangulation calculation would produce the body contour image . more than one camera may be used along the vertical direction to cover the full height of a tall person . the person may be sectioned into elevation bands wherein a plurality of images is taken . the number of bands is determined by the size of the checkerboard blocks and the number of pixels imaged in each block . the person being imaged may further stand on a rotating platform that rotates the vertical axis of the person so that for each stop position of the platform , the camera / s perform a sweep to capture the number of blocks hidden by the shadow of the body of the periphery of the body . the peripheries at a number of rotational positions are thus measured and recorded to build a series of dimensions for a number of elevation on the body and for a multiplicity of points around the body . the computer can then use best curve fitting algorithms to smooth between the points to produce a full body 3 - d image with accurate dimensions . for full body scanning , the person would modestly wear snug fitting clothes to display the actual body contours . in may further be apparent , that other imaging system configurations could be used to take advantage of indirect imaging processing using the background checkerboard pattern . furthermore , the block could be rectangles or other shapes to meet desired accuracy in each x - y dimension . the camera should be replaced with a single line ccd sensor such as a typical desk scanner and then moved across bands as scanned line images sequentially . the checkerboard pattern could be replaced with a wall of checkerboard physical bumps that would enable a laser to scan the physical checkerboard pattern as sequential group of regular depth changes interrupted by the edge of the object when the transition ordered sequence is abruptly interrupted . the laser would be moved or the laser beam reflected across bands of imaged lines . each foot can be imaged , one foot at a time to reduce the number of camera used and checkerboard required . suitable lighting means is used to reduce shadows to provide equal and adequate imaging of all of the blocks on the checkerboard . the blocks could be colors other then just black and white , to provide enhanced calculated positions without the use of a target . the interruptions could be computed from the edge of the checkerboard rather than from the target so that the target is not used , but in either case , a relative reference point is needed to determine the distance from a known point to the point of image interruption . overprinted colors could be used to increase resolution or improve the edge detection depending on the color and physical configuration of the object to measure . the camera movement is preferably linear for simplicity , however , moving the elements in an arc that somewhat follows the contour of the object to be measured could be used for enhanced resolution and increased area coverage . the regular pattern of the checkerboard squares may be progressively dimensioned to compensate for the progression in angular error with the distance from the lens so that all of the resulting transition outputs have the same number of pixels per blocks . the checkerboard could also incorporate specific pattern interruptions that are sensed by the computer as targets for position accuracy check or other detection or verification reasons . such purposeful interruptions could be used to calibrate the camera field and pixel organization or linearity . without a foot in place , the camera can observe all of the alternating blocks across the entire fov . the camera can be used to check the cleanliness of the checkerboard pattern and then for use for calibration of the light intensity for readjusting the medium gray - scale point that differentiates white from black blocks . when the checkerboard is soiled by dirt or body oils , the orderly progressive sequence of blocks could be interrupted thus indicating that the pad needs to be cleaned during calibration testing . for compensation during use prior to cleaning , the light intensity may be increased to compensate for the reduction in white block reflection due to being soiled when it becomes slightly less then pure white . to properly adjust the light source to optimize the sensor detection and to compensate for light source variations due to power fluctuations and bulb life and to some degree to compensate for the cleanliness of the imaging checkerboard pattern , each sensor fov which also includes a light source to illuminate the fov includes a series of increasing gray density blocks in a specified location not ever covered by the object being measured . the light reflected from the different gray density blocks is proportional to the intensity of the light source . the power applied to the light source is controlled by a light dimmer controlled by the computer which in turn receives light intensity values from the camera for the blocks in question . the dimer controls the power applied to the light bulb so that the intensity is adjusted to provide a zero or one output for a specified pair of gray density blocks . this light adjustment is then used for the balance of the measurement session . this assures that the light level is accurately controlled at all time . as may now be apparent , the imaging system can be used to image any arbitrary object other than human feet or body part , as long as the object interrupts the imaged background pattern . those skilled in the art can make enhancements , improvements , and modifications to the invention , and these enhancements , improvements , and modifications may nonetheless fall within the spirit and scope of the following claims . | US-56284300-A |
a wallet organization system and apparatus relating to wallet card differentiating tabs is disclosed . the tabs are configured to adhere to conventional cards contained in wallets with at least one adhesive surface . the tabs are equipped with a label which may be customized via included personalization , as well as a variety of colors , helping users rapidly differentiate between layered cards in a wallet , and provide for easy removal of the target card in need of removal from the wallet for use . a bendable portion of the tabs facilitates the use of wallet cards within magnetic strip readers and atms without removal of the tabs from the cards . the adhesive is configured to be reusable and durable . | the present invention generally comprises a wallet organization system oriented around the use of tabs ( 10 ). the tabs ( 10 ) of the present invention are preferably equipped with a label ( 20 ), a first adhesive surface ( 30 ) and a second adhesive surface ( 40 ). each of the tabs ( 10 ) of the present invention are removable , repositionable and also bendable in specific portions to retain the utility of the card . the adhesive covering of the first adhesive surface ( 30 ) and the second adhesive surface ( 40 ) is configured to be ink - proof , and as such , will not lift ink when the tab ( 10 ) is repositioned on a card . the second adhesive surface ( 40 ) is not necessarily present on all embodiments of the tab ( 10 ) of the present invention . the tab ( 10 ) of the present invention is applied to a card by pressing the adhesive portion on the first adhesive surface ( 30 ) ( and the second adhesive surface ( 40 ) if needed ) of the tab firmly onto the desired location on the card . the body portion of the tab ( 10 ) is made of a transparent film preferably composed of acetate and a mylar film material . these materials are employed as they are durable and stable , as well as non - tearing and non - yellowing in quality . the present invention is a high quality product to purchase by consumers , as it is durable , may be used and reapplied multiple times , and is attractive and unique for use in wallets . the tab ( 10 ) of the present invention are preferably equipped with ribbed tips ( 90 ), which are preferably made of a rubber , silicone , or similar gripping material . the ribbed tips ( 90 ) are configured to facilitate the removal of the cards with the fingertips of the user , providing comfort as well as traction for the removal of the target card . the ribbed tips ( 90 ) of the present invention are preferably fashioned of a durable plastic material base . the ribbed tips ( 90 ) each have a raised , ribbed edge for easy finger - gripping and retrievablility . the ribbed tips ( 90 ), as well as the tab ( 10 ) itself are preferably equipped with the glow - in - the - dark element ( 100 ) of the present invention . a label ( 20 ) of the tab ( 10 ) preferably includes a variety of specific pastel colors , consisting of blue , pink , yellow , green , and gray , helping to facilitate decorating and personalizing the tabs ( 10 ) to the taste of the user . the tabs ( 10 ) also expedite differentiation between all wallet cards and photos for ease of reference via personalization . this makes the present invention appealing to those who would find it fun in being creative with personalizing their tabs ( 10 ) for their wallet cards . additionally , the present invention also comes with available adhesive letters , numbers and specific design logos which the consumer can use to personalize the tabs attached to their wallet cards . these customization options are configured to adhere to the label ( 20 ) portion of each tab ( 10 ) of the present invention . the adhesive at the bottom of the tab ( 10 ) is made of removable and reusable , double - sided adhesive material that can be used again and again on surfaces of all wallet cards . it is also photo - safe and great for use with photographs in photo albums . the adhesive material on the first adhesive surface ( 30 ) and the second adhesive surface ( 40 ) can be used repetitively , and is preferably strong enough to support up to 0 . 6 pounds , making the present invention a highly durable product for long - term use by the consumer . additionally , most embodiments of the present invention are equipped with a glow - in - the - dark element ( 100 ), which is preferably embedded into various portions of the tab ( 10 ), including , but not limited to the label ( 20 ), the body , and the ribbed tips ( 90 ) of the present invention . the glow - in - the - dark element ( 100 ) is preferably built - in to the mold of the plastic , and is not a glow - in - the - dark paint . however , some embodiments of the present invention may employ a glow - in - the - dark paint for light use . the glow - in - the - dark element ( 100 ) of the present invention enables use of the present invention in dark room settings , or outdoors at night . the glow - in - the - dark element ( 100 ) is configured to illuminate in the dark , which facilitates the rapid location and identification of the needed card . additionally , the glow - in - the - dark element ( 100 ) enables the location of a card if it has been dropped on the floor inside a dark room , or outdoors at night . the preferred embodiment of the present invention preferably is available in three primary sizes and forms including : a ) the swiper tab ( 50 ): the swiper tab ( 50 ) is the standard sized tab ( 10 ) of the three primary embodiments , and is configured to be placed anywhere on the front surface of wallet cards . the swiper tab ( 50 ) is specifically made for use with wallet cards that require swiping in atm swiping machines , such as debit cards , credit cards , gift cards , driver licenses and the like . this will allow the secured information in the magnetic strip on the rear of the card to be read by conventional atm machines in order to expedite account access . additionally , the swiper tab ( 50 ) has a bendable section near the bottom of the tab directly above the first adhesive surface ( 30 ). with the swiper tab ( 50 ) of the present invention attached to the wallet card , the consumer folds down the bendable label ( 20 ) section of the tab while holding their card in the hand before swiping it in the machine , without removing the tab ( 10 ) from the card during this process . this allows the card to be swiped in the machine with full accessibility , and without interruption . once the card is swiped , the label ( 20 ) may be bent back into place . a film extension ( 80 ) extends from the first adhesive portion ( 30 ) to the label ( 20 ) portion , providing for a place from which the label ( 20 ) may be bent out of the way to swipe the card at point - of - sale terminals . the first adhesive portion ( 30 ) of the swiper tab ( 50 ) may also be equipped with a logo or marking . it should be noted that the only occasion that the swiper tab ( 50 ) must be removed from the card is when it is necessary to insert a card into the bank vault of an atm , and upon removing the tab following this process , the user may simply place the tab ( 10 ) back into position on the card . the adhesive on the first adhesive surface ( 30 ) and second adhesive surface ( 40 ) on the tab ( 10 ) is preferably of such durable quality that the tab may be removed , repositioned , and placed back onto the card numerous times , and can be used repeatedly this way for several years . thus , the present invention is preferably durable , making it a wise and usable product to purchase by the consumer for its function and quality . b ) the big buddy tab ( 60 ) is the larger size tab disclosed in fig2 , and is configured to be placed on the back surface of all other wallet cards that do not require any swiping , such as all business cards and photos , or other types of ids that are not to be swiped in a machine . c ) the tight fit tab ( 70 ) is the smallest size tab , which is disclosed in fig3 . the tight fit tab ( 70 ) is configured to adhere to a card to be placed in a slim - line , narrow , or otherwise tight - fitting card slot or pocket of a wallet . as such , the tight fit tab ( 70 ) is similar in body size and use to the big buddy tab ( 60 ), with the exception that the label ( 20 ) portion is smaller , providing for the use of the tight fit tab ( 70 ) in tight spaces where the card slots leave no room to accommodate the big buddy tab ( 60 ). the tight fit tab ( 70 ) may be affixed to the long or short sides of the card , and is equipped with a smaller label ( 20 ) portion , while still providing ample space to grip the tight fit tab ( 70 ). the tight fit tab ( 70 ) is preferably red in color , easily differentiating it from other tabs ( 10 ). the label ( 20 ), disposed at the top or tip portion of the tab , is shaped differently for each of the three primary embodiments of the present invention . for example , the swiper tab ( 50 ) has a round label portion , thereby giving the total appearance of the tab ( 10 ) a shape similar to that of a pawn chess piece . special instructions for use of all three types of tab ( 10 ) of the present invention include : 1 ) when removing the tab ( 10 ) from the surface of the card , the adhesive portion is to be peeled off slowly and gently from its surface , and the user should avoid pulling the tab straight out from the surface . this preserves the stickiness of the adhesive section of the tab . the present invention may lose its adhesive efficacy with repetitive use and / or exposure to dust particles to the first adhesive surface ( 30 ) and / or second adhesive surface ( 40 ) on either embodiment of the present invention . to resolve this issue , the tabs ( 10 ) may be gently washed on the first adhesive section ( 30 ) and second adhesive portion ( 40 ) of the tab with soapy water , rinse , air - dry , and reuse . the preferred measurements of the three embodiments of the present invention are preferably as follows : a ) the smaller swiper tab ( 50 ) preferably measures three inches in height , and two centimeters in width . the first adhesive section ( 30 ) for this tab is also preferably two centimeters in width and one and a half centimeters in height . b ) the larger big buddy tab ( 60 ) preferably measures four centimeters in height and two inches in width . the second adhesive section ( 40 ) for this tab ( 10 ) is also preferably two inches in width and one centimeter in height . the big buddy tab ( 60 ) preferably has a curved label portion , similar in shape to a bread slice . c ) the low - profile tight fit tab ( 70 ) preferably measures three centimeters in height , with a variable width according to the needs of the user . the tight fit tab ( 70 ) preferably has a curved label ( 20 ) portion , similar in shape to a low - profile bread slice . the first adhesive section ( 30 ) of the tight fit tab ( 70 ) is preferably two inches in width and one centimeter in height . additionally , a “ wallet buddy ” logo is preferably featured on the front or rear of the label ( 20 ) of the present invention . the logo is preferably disposed on the front surface of the label for customers who do not wish to personalize their tabs ( 10 ). it should be noted that the ribbed tips ( 90 ) of the swiper tabs ( 50 ) of the present invention is preferably 0 . 2 cm in width , and 0 . 2 cm in height ( thickness ). in the larger big buddy tab ( 60 ), the ribbed grip area of the ribbed tips ( 90 ) is preferably 4 . 5 cm in width , and 0 . 2 cm in height . additionally , the ribbed grip area of the ribbed tip ( 90 ) of the tight - fit buddy tab ( 70 ) is preferably 4 . 0 cm in width and 0 . 2 cm in height . however , it is envisioned that alternate embodiments of the present invention may employ differing dimensions of the ribbed tips ( 90 ), so long as portions of the ribbed tips ( 90 ) are raised such that they extend outwards from the tips . similarly , it is envisioned that the pattern of the ribbing of the ribbed tips ( 90 ) may vary in order to facilitate access to the wallet cards without a direct line of sight . alternate embodiments of the ribbed tips ( 90 ) can assist sight - impaired individuals in wallet card identification and location as well . having illustrated the present invention , it should be understood that various adjustments and versions might be implemented without venturing away from the essence of the present invention . further , it should be understood that the present invention is not solely limited to the invention as described in the embodiments above , but further comprises any and all embodiments within the scope of this application . the foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description . they are not intended to be exhaustive or to limit the present invention to the precise forms disclosed , and obviously many modifications and variations are possible in light of the above teaching . the exemplary embodiment was chosen and described in order to best explain the principles of the present invention and its practical application , to thereby enable others skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated . | US-201615183176-A |
a camera apparatus can be mounted on an endoscope to enable a picture to be taken of the interior of a coeliac cavity . the apparatus comprises a detecting device which detects whether the apparatus is or is not mounted on an endoscope . when the apparatus is mounted , the detecting device operates to supply power to an electrical circuit of the apparatus which requires energization only during a photographing operation , which power may be drawn from either an internal battery or an external power supply , thus minimizing the power dissipation of the internal battery . | referring to fig1 there is shown a camera apparatus 1 for an endoscope according to one embodiment of the invention , which is illustrated as mounted on an eyepiece assembly 2a of an endoscope 2 . the camera apparatus 1 internally houses detecting means 4 which detects that the apparatus 1 is mounted on the endoscope 2 , an electrical control device 5 which includes the essential parts of a control mechanism for the camera apparatus 1 , and a connection terminal 6 for connection with an external power source . the terminal 6 is located so as to mate with a supply output terminal 7 which is disposed on the part of the eyepiece assembly 2a of the endoscope , so that when the camera apparatus 1 is mounted on the eyepiece assembly 2a , both terminals 6 , 7 mate with each other to establish an electrical interconnection . the output terminal 7 is connected through a light source connection tube 2b of the endoscope 2 with a supply terminal 8 which is provided on the part of a connector assembly 2c , which is in turn adapted to be connected with a feed terminal 11 electrically connected to a power supply 10 of a light source unit 9 whenever the connector assembly 2c is connected to the light source unit 9 . in this manner , when the camera apparatus 1 is mounted on the endoscope 2 , it is fed from the power supply 10 of the light source unit 9 , in addition to the internally housed battery 3 . referring to fig2 which shows the electrical control device 5 in more detail , it essentially comprises a film winding motor 21 , a motor control circuit 22 , a shutter release electromagnet 23 , a control circuit 24 associated with the electromagnet 23 , a data entry light emitting assembly 25 , a control circuit 26 associated with the light emitting assembly 25 and formed by a decoder , a driver and the like , detection and display means 27 which includes a film speed sensor and a battery checker associated with the battery 3 , a control circuit 28 associated with the detection and display means 27 , a sequence control circuit 29 , a display 30 which is used to provide an external indication of the number of film frames and the date when a picture is taken , and a control circuit 31 associated with the display and formed by a decoder , a driver and the like . the battery 3 is connected to a number of components including detecting means 4 and the sequence control circuit 29 directly , to the motor control circuit 22 , the electromagnet control circuit 24 , the light emitting assembly control circuit 26 , the control circuit 28 associated with the detection and display means and the sequence control circuit 29 through the detecting means 4 , and also connected through a series combination of the sequence control circuit 29 and its connected display control circuit 31 to the display 30 . the sequence control circuit 29 is connected to the motor control circuit 22 , the electromagnet control circuit 24 , the light emitting assembly control circuit 26 and the control circuit 28 associated with the detection and display means , respectively . the connection terminal 6 is connected to the motor 21 , the electromagnet 23 , the light emitting assembly 25 and the detection and display means 27 through their respective control circuits 22 , 24 , 26 , 28 , respectively . the detection and display means 27 is also connected to the sequence control circuit 29 . in operation , when the camera apparatus 1 is not mounted on the endoscope 2 , the battery 3 is connected to only the display 30 and the display control circuit 31 through the sequence control circuit 29 . the display 30 provides a display of the number of film frames and the date in accordance with an output from the display control circuit 31 . when the camera apparatus 1 is mounted on the endoscope 2 , the detecting means 4 detects that it is mounted , and effects a switching operation to connect the battery 3 to other control circuits 22 , 24 , 26 and 28 . in addition , the detecting means 4 produces a signal indicative of the fact that the camera apparatus 1 is mounted on the endoscope 2 , which signal is applied to the sequence control circuit 29 . as the control circuits 22 , 24 , 26 and 28 are activated , the power from the power supply 10 ( see fig1 ) which is now supplied through the connection terminal 6 is fed to the motor 21 , the electromagnet 23 , the light emitting assembly 25 and the detection and display means 27 at the same time as the camera apparatus 1 is mounted on the endoscope 2 . as a consequence , in response to a photographing operation such as the depression of a shutter release button , not shown , the sequence control circuit 29 controls the individual control circuits 22 , 24 , 26 and 28 , causing a film winding operation by the motor 21 , or causing the electromagnet 23 to effect a shutter release operation . fig3 and 4 show the general arrangement and an electrical circuit of a camera apparatus for endoscope which is constructed according to another embodiment of the invention . as shown , a camera apparatus 41 is adapted to be mounted on an endoscope 42 of hard type , the eyepiece assembly 42a of which is not provided with a power terminal . thus the camera apparatus 41 is essentially the same as that shown in fig1 and 2 except that connection terminals for connection with an external power supply are not provided . hence , corresponding parts are designated by like reference numerals without repeating their description . the apparatus 41 operates in quite the same manner as the camera apparatus 1 except that the motor 21 , the electromagnet 23 , the light emitting assembly 25 and the detection and display means 27 are fed from the internal battery 3 . fig5 shows a specific example of detecting means 4 which may be preferably used in the camera apparatus 1 or 41 shown in fig1 to 4 . the detecting means 4a comprises a detecting terminal 43 connected to the battery 3 ( see fig1 and 3 ) and a detecting terminal 44 connected to the sequence control circuit 29 and the individual control circuits 22 , 24 , 26 and 28 ( see fig2 and 4 ), both of which are disposed in that portion of the camera apparatus 1 or 41 which is adapted to mate with the eyepiece assembly of the endoscope . when the camera apparatus 1 or 41 is mounted on the endoscope 2 or 42 , both detecting terminals 43 , 44 of the detecting means 4a are short - circuited by an electrically conductive member 45 which is disposed on the eyepiece assembly 2a and 42a of the endoscope to feed the individual control circuits 22 , 24 , 26 and 28 from the battery 3 . the detecting means 4a also transmits a mounting detected signal to the sequence control circuit 29 . fig6 a and 6b show another form of detecting means 4b . detecting means 4b comprises a light emitting element 46 such as a light emitting diode which is disposed in the eyepiece assembly 2a or 42a of the endoscope 2 or 42 in combination with a light receiving element 47 such as a photodiode or phototransistor which is disposed in the mating portion of the camera apparatus 1 or 41 . in this manner , it provides a photoelectric detection of the mounting of the camera apparatus 1 or 41 onto the endoscope 2 or 42 . more specifically , in addition to the elements 46 and 47 , the detecting means 4b includes a light shield member 48 which is disposed forwardly of the light emitting element 46 on the endoscope , preventing an external leakage of light therefrom when the camera apparatus 1 is not mounted on the endoscope , and another light shield member 49 disposed forwardly of the light receiving element 47 in order to prevent the element 47 from operating in response to an extraneous light such as natural light when the apparatus is not mounted on the endoscope 2 or 42 . it will be noted from fig6 b that the light shield members 48 , 49 retract from their positions located forwardly of the elements 46 , 47 whenever the camera apparatus 1 or 41 is mounted on the endoscope 2 or 42 to leave the elements 46 , 47 in opposing relationship . because no electrical contact is used , the detecting means 4b affords the advantage that a more stable operation is achieved as compared with detecting means 4a , free from the problem of poor contact between or the formation of rust on terminals and conductive members . fig7 and 8 show a camera apparatus for an endoscope according to a further embodiment of the invention . the camera apparatus 51 is a modification of the camera apparatus 1 shown in fig1 and 2 in that the direct detection of a mounting of the apparatus onto the endoscope 2 by detecting means 4 is replaced by a switch circuit formed by a relay circuit which is operated by power from the external power supply 10 which is fed through the connection terminal 6 whenever the apparatus is mounted on the endoscope 2 . consequently , the camera apparatus 51 is similar to the camera apparatus 1 in that the detecting means 4 is replaced by a switch circuit 54 which is connected to the connection terminal 6 . other parts are designated by like reference characters , and hence will not be described . it should be understood that the switch circuit 54 may be formed by a semiconductor switching element . it will be appreciated that the camera apparatus 51 functions in the same manner as the camera apparatus 1 of fig1 and 2 . fig9 shows a specific electric circuit of the electrical control device shown in fig2 . in the electrical circuit shown , the electromagnet control circuit 24 comprises or circuit or 1 , switching transistor q 1 , a pair of resistors r 1 , r 2 and diode d 1 . the transistor q 1 comprises an npn transistor having its collector connected through the electromagnet 23 to a supply bus e 1 which is in turn connected to the connection terminal 6 , its emitter connected to a common ground line e 0 connected to a ground terminal which is not shown in fig2 and its base connected through resistor r 1 to the output of or circuit or 1 , respectively . a bias resistor r 2 is connected across the base and emitter of the transistor q 1 . the electromagnet 23 is shunted by diode d 1 , which serves to suppress a counter electromotive force developed across the electromagnet 23 as the latter is deenergized . or circuit or 1 is connected between a supply bus e 2 and the ground line e 0 . the bus e 2 is adapted to feed an operating voltage during a photographing operation , and is connected to the battery 3 through the detecting means 4 . or circuit has its one input connected to the output of timer circuit tm 2 which controls the duration during which the electromagnet 23 remains energized to allow a mirror shutter , not shown , disposed within the camera apparatus 1 out of a taking light path . the other input of or circuit is connected to the output of timer circuit tm 4 which controls the duration during which the electromagnet 23 is energized to allow the mirror shutter to move down into the taking light path . timer circuit tm 2 has its input connected to the output of timer circuit tm 1 which controls the timing when the energization of the electromagnet 23 is initiated to thereby allow the mirror shutter to move up . timer circuit tm 4 has its input connected to the output of timer circuit tm 3 which controls the timing when the electromagnet 23 is energized in order to allow the mirror shutter to move down . both timer circuits tm 1 and tm 3 have their input connected in common to one end of a shutter release switch sw 1 through a waveform shaping buffer circuit 41 , to be described later . the motor control circuit 22 comprises and circuit and 1 , switching transistor q 2 , three resistors r 3 - r 5 , noise suppressing capacitor c 1 and diode d 2 . the transistor q 2 comprises an npn transistor having its collector connected to the supply bus e 1 through the motor 21 , its emitter to the ground lines e 0 and its base to the output of and circuit and 1 through resistor r 4 . a bias resistor r 5 is connected across the base and emitter of the transistor q 2 . the diode d 2 serves suppressing a counter electromotive force developed upon interruption of the energization of the motor 21 , and hence is connected in shunt therewith . and circuit and 1 is connected across the bus e 2 and the ground line e 0 , and has its one input connected to the junction between resistor r 3 and capacitor c 1 which are connected in series across the buses e 2 , e 0 . as mentioned previously , the purpose of capacitor c 1 is to suppress noises , and it also prevents a malfunctioning of the motor 21 when the power is initially turned on . when the bus e 2 is connected to the battery 3 , the capacitor maintains an &# 34 ; l &# 34 ; level at one input of and circuit and 1 for a given time interval , and supplies an &# 34 ; h &# 34 ; level at the same input terminal subsequently , thus preventing the input from inadvertently assuming an &# 34 ; l &# 34 ; level . the other input of and circuit and 1 is connected to the output of timer circuit tm 6 which controls the duration during which the motor 21 is driven in order to wind up a film . the input of timer circuit tm 6 is connected to the output of timer circuit tm 5 which controls the timing when the motor 21 begins to be driven . the input of timer circuit tm 5 is connected to one end of shutter release switch sw 1 through the waveform shaping buffer circuit 41 . the light emitting assembly control circuit 26 comprises a switching circuit 26a which turns on or off the power supply to the light emitting assembly 25 , a decoder driver circuit 26b ( see fig1 ) for driving a pair of light emitting elements 25a , 26b used for the entry of the number of film frames , and a buffer circuit 26c ( see fig1 ) for driving four light emitting elements 25c - 25f for the entry of the date when a picture is taken . the switching circuit 26a comprises a pair of and circuits and 2 , and 3 , a pair of transistors q 3 , q 4 and four resistors r 6 - r 9 . the transistors q 3 , q 4 comprise an npn and a pnp transistor . the transistor q 3 has its emitter connected to the bus e 1 , its collector connected to individual light emitting elements 25a - 25f ( see fig1 ) which are disposed in a luminescent display 42 , and its base to the collector of the other transistor q 4 through resistor r 0 . resistor r 9 is connected between the collector of the transistor q 4 and the emitter of the transistor q 3 . the transistor q 4 has its emitter connected to the ground line e 0 and its base connected through resistor r 6 to the output of and circuit and 2 and also connected through resistor r 7 to the output of the other and circuit and 3 . a bias resistor r 8 is connected across the base and emitter of the transistor q 4 . and circuit and 2 has its one input connected to the output of timer circuit tm 8 which causes the light emitting elements 25 ( 25a - 25f ) to emit light for an increased length of time , and has its other input connected to one end of a film speed establishing switch sw 2 through a combination of polarity inverting inverter in 3 and diode d 3 . and circuit and 3 has its one input connected to the output of timer circuit tm 9 which causes the light emitting assembly 25 to emit light for a reduced length of time , and its other input connected through diodes d 3 to one end of the film speed establishing switch sw 2 . timer circuits tm 8 and tm 9 have their input connected in common to the output of timer circuit tm 7 which controls the timing when the light emitting assembly 25 begins to emit light . the input of timer circuit tm 7 is connected to one end of shutter release switch sw 1 through the waveform shaping buffer circuit 41 . the film speed establishing switch sw 2 has its other end connected to the ground line e 0 while one end is connected through resistor r 10 to the cathode of light emitting diode 27a which operates as a film speed detection and display means . the combination of the switch sw 2 and resistor r 10 constitutes a control circuit 28a for the light emitting diode 27a , which has its anode connected to the bus e 1 . whenver the bus e 1 is connected to the external power supply 10 and the switch sw 2 is closed , the light emitting diode 27a is illuminated to provide an indication externally of the camera apparatus 1 that the film used is of a low speed . the fact that the light emitting diode 27a is not illuminated indicates that the film used is of a high speed . it is to be noted that the film speed establising switch sw 2 is automatically operated in response to the detection of a film speed indicating mark on the film used . the inverter in 3 has its input connected to the anode of diode d 3 and functions to invert a switch sw 2 signal that is fed to the other input of and circuit and 3 before it is supplied to the other input of and circuit and 2 . this prevents and circuits and 2 and and 3 from being enabled simultaneously , selecting either a long or a short duration during which the light emitting assembly 25 emits light for purpose of data entry . the buffer circuit 41 which has its output connected to the input of timer circuits tm 1 , tm 3 , tm 5 and tm 7 comprises a series combination of a pair of inverters in 1 and in 2 which is connected across the buses e 2 and e 0 . the input of the buffer circuit 41 is connected to the junction between the shutter release switch sw 1 and resistor r 20 connected in series across the buses e 2 , e 0 , thus effecting a waveform shaping , by the double inversion , of the switch sw 1 close signal which occurs as a shutter release button ( not shown ) is depressed . timer circuit tm 1 to tm 9 have an identical circuit arrangement , which is illustrated in fig1 . as shown , it comprises a time delay producing , integrated circuit ic 1 ( for example , ha17555 manufactured by hitachi mfg ., co . or ne555 manufactured by signestics , inc . ), three capacitors c 2 - c 4 and three resistors r 11 - r 13 , all of which constitute together a monostable multivibrator . integrated circuit ic 1 has eight terminals t 1 - t 8 including a ground ( gnd ), trigger , output , reset , control voltage , threshold , discharge and supply ( vcc ) terminal . trigger terminal t 2 is connected with one end of a differentiating capacitor c 2 which has its other end connected to the input of timer circuits tm 1 - tm 9 . the trigger terminal t 2 is also connected with supply bus e 2 through a resistor r 11 which forms a differentiator together with capacitor c 2 . output terminal t 3 represents the output terminal of timer circuits tm 1 - tm 9 for connection with a succeeding circuit . output terminal t 3 is also connected to ground line e 2 through resistor r 13 . reset terminal t 4 is connected to ground line e 2 together with supply terminal t 8 . control voltage terminal t 5 is connected to the ground line e 0 through a stabilizing capacitor c 3 . threshold terminal t 6 is connected to the line e 0 through a timing capacitor c 4 while discharge terminal t 7 is connected to the line e 2 through a timing resistor r 10 . it will be noted that the both terminals t 6 and t 7 are connected to each other . ground terminal t 1 is connected to the ground line e 0 . in response to a negative trigger pulse applied to the trigger terminal t 2 , each of timer circuits tm 1 to tm 9 produces an output of &# 34 ; h &# 34 ; level , whereby capacitor c 4 is charged with a time constant determined by its combination with resistor r 12 . when the voltage across capacitor c 4 reaches the threshold voltage , it discharges , returning the output to &# 34 ; l &# 34 ; level . it should be noted that timer circuits tm 1 - tm 9 have individual time constants t 1 - t 9 of different suitable values through a combination of suitable values for the capacitor c 4 and resistor r 12 ( see fig1 ). returning to fig9 the detection and display means 27 and its associated control circuit 28 include portions 27b and 28b which are utilized to check the voltage of the internal battery 3 . at this end , these portions are connected across a supply bus e 3 , which is connected to the positive terminal of battery 3 , and the common ground line e 0 . the control circuit portion 28b comprises a comparator cp 1 , a zener diode zd 1 which provides a constant voltage , three resistors r 15 - r 17 and a manual switch sw 3 . the switch sw 3 is connected in series with resistors r 15 and r 16 across the buses e 3 and e 0 . the series combination of resistors r 15 and r 16 is shunted by a series circuit of resistor r 7 and zener diode zd 1 and also by comparator cp 1 . comparator cp 1 has its one input connected to the junction between resistors r 15 and r 16 and its other end connected to the junction between resistor r 17 and zener diode zd 1 . the output of comparator cp 1 represents the output of the control circuit portion 28b , which is connected through a resistor r 18 to the cathode of light emitting diode 27b which represents detection and display means . diode 27b has its anode connected to the bus e 3 . these portions operate in response to the closure of the manual switch sw 3 . specifically , the supply voltage of the internal battery which is applied to the control circuit portion 28b through the switch sw 3 is divided by voltage divider resistors r 15 and r 16 and then applied to one input of the comparator cp 1 . zener diode zd 1 provides a given voltage at its cathode which is applied to the other input of comparator cp 1 , which then compares the supply voltage against the latter . when the applied voltage exceeds the given voltage , comparator cp 1 is turned on to cause an illumination of light emitting diode 27b , indicating that a supply voltage above the given value is available from the internal battery . if the supply voltage is less than the given voltage , comparator cp 1 remains off , whereby the failure of light emitting diode 27b to illuminate indicates that the internal battery 3 is exhausted . a detection circuit which detects the number of film frames is connected across the buses e 3 and e 0 . it comprises a detecting switch sw 4 , an inverter in 4 which serves as a buffer to prevent a chattling of the switch sw 4 , a capacitor c 5 and resistor r 19 . the series circuit of resistor r 19 and capacitor c 5 as well as the inverter in 4 are connected across the buses e 3 and e 0 , and the capacitor c 5 is shunted by the switch sw 4 . the inverter in 4 has its input connected to the junction between the resistor r 19 and capacitor c 5 , and its output is connected to the input of a first digit counter 43a which counts the number of frames , as shown in fig1 . the detection circuit detects marks such as perforations which are formed in the photographic film in order to permit a number of film frames to be detected . the detecting switch sw 4 is closed for each frame , and provides an input to the inverter in 4 . the input signal is shaped and inverted by the inverter in 4 , and is fed to the input of the counter 43a . the luminescent display 42 shown in fig9 is illustrated in more detail in fig1 . it includes the light emitting assembly 25 ( 25a , 25b ) and its associated control circuit 26 ( 26a , 26b , 26c ), the display 30 ( 30a , 30b ) and its associated control circuit 31 , a timing integrated circuit ic 2 which operates to produce the date when a picture is taken , and film frame counting counters 43a , 43b . the light emitter assemblies 25a , 25b are formed by six light emitting elements 25a - 25f such as light emitting diodes which are adapted to display numerals in seven segments . each of the light emitting elements 25a - 25f is connected to the bus e 1 through transistor q 3 in the switching circuit 26a . the elements 25a - 25f are driven by the external power supply 10 for illumination . two of these elements , 25a , 25b , form light emitting assembly 25a which is used for entry of the number of film frames while the remaining four elements 25c - 25f form together the light emitting element 25b which is used for entry of the photographing date . the elements 25a , 25b are connected to respective decoder drivers 26a , 26b through seven input lines which control the illumination of each of the seven segments . the decoder drivers 26a , 26b are connected to a first digit and a second digit counter 43a , 43b through four lines which transmit a single decimal digit . the first digit counter 43a has a carry signal line which is connected to the input of the second digit counter 43b . these counters 43a , 43b are connected across the buses e 3 and e 0 , and thus is normally energized by the internal battery 3 . the decoder drivers 26a , 26b are connected across the buses e 2 and e 0 , and hence are rendered into operative condition upon application of a voltage thereto from the internal battery 3 whenever the camera apparatus 1 is mounted on the endoscope 2 . the light emitting elements 25c - 25f are connected to respective buffers 26c - 26f through seven input lines which control the illumination of respective segments . the buffers 26c - 26f are connected to the timing integrated circuit ic 2 through respective seven lines which are utilized to input a decode signal . the integrated circuit ic 2 is connected across the buses e 3 and e 0 and is hence normally fed from the internal battery 3 to continue counting the time . the buffers 26c - 26f are connected across the buses e 2 and e 0 , and hence are fed from the internal battery whenever the camera apparatus 1 is mounted on the endoscope 2 . it is to be noted that the elements 25c , 25d represent the month while the elements 25e , 25f represent the day . the display 30 ( 30a , 30b ) is formed by six display elements 30a - 30f , which represent liquid crystal elements , for displaying numerals in seven segments as is well known . each of the display elements 30a - 30f is connected to the bus e 3 through the timing integrated circuit ic 2 , whereby it is normally fed from the internal battery 3 to provide an indication on the exterior of the camera apparatus 1 . two of these display elements , 30a , 30b , form the display unit 30a for indicating the number of film frames while the remaining four display elements 30c - 30f form the display unit 30b which indicates the photographing date . the display elements 30a , 30b are connected to decoder drivers 31a , 31b through seven input lines which control the seven individual segments . these decoder drivers 31a , 31b are connected to the first digit and the second digit counter 43a , 43b through four lines which transmit a single decimal digit , these counters counting the number of film frames . the decoder drivers 31a , 31b are connected across the buses e 3 and e 0 , and are normally fed from the internal battery 3 . on the other hand , the display elements 30c - 30f are directly connected to the timing integrated circuit ic 2 through seven input lines which control the seven segments , respectively . the display elements 30c , 30d represent the month while the display elements 30e , 30f represent the day . the timing integrated circuit ic 2 is formed by a complementary metal - oxide - semiconductor large scale integrated circuit ( cmos - lsi ) which is used for liquid crystal driver clock , and is connected across the supply lines e 3 and e 0 , whereby it is normally fed from the internal battery 3 to effect the timing function and also driving the display elements 30c - 30f . the above description covers a specific form of an electrical circuit which is contained in the electrical control device 5 shown in fig2 . referring to the timing chart shown in fig1 , the operation of the electrical control device 5 will be described briefly together with the operation of the camera apparatus 1 . initially when the camera apparatus 1 is mounted on the endoscope 2 , the detecting means 4 detects that the camera apparatus 1 is mounted , feeding the bus e 2 and the various circuits connected therewith from the internal battery 3 . at the same time , the connection terminal 6 is brought into electrical contact with the output terminal 7 of the power supply , so that the bus e 1 as well as the various circuits connected therewith are fed from the external power supply 10 , rendering the camera apparatus 1 to be capable of taking a picture . when a shutter release button is depressed to close the shutter release switch sw 1 , the resulting signal is shaped by the buffer 41 to be applied to respective timer circuits tm 1 , tm 3 , tm 5 and tm 7 . in response to the signal applied , these timer circuits tm 1 to tm 7 are triggered , producing an &# 34 ; h &# 34 ; level output , causing a delay operation of these timer circuits to be initiated for respective intervals of t 1 , t 3 , t 5 and t 7 . as indicated in fig1 , these time delays are chosen such that t 1 & lt ; t 7 & lt ; t 3 & lt ; t 5 , so that after the time delay of t 1 , timer circuit tm 1 is initially turned off , thus producing an &# 34 ; l &# 34 ; level output . in response to this output signal , the succeeding timer circuit tm 2 initiates to operate , producing an &# 34 ; h &# 34 ; level output for a time interval of t 2 . this output signal is fed through or circuit or 1 to turn transistor q 1 on . thereupon , the electromagnet 23 is energized to cause the mirror shutter to bounce up , initiating an exposure of a film to an image from an object being photographed . then timer circuit tm 7 is turned off after the time delay of t 7 , causing the succeeding timer circuits tm 8 and tm 9 to operate , which therefore produce output signals of an &# 34 ; h &# 34 ; level . if the film speed presetting switch sw 2 remains open at this time , the other input to and circuit and 2 will be &# 34 ; l &# 34 ; level while the other input to and circuit and 3 will be an &# 34 ; h &# 34 ; level , so that transistor q 4 is turned on by and circuit and 3 for the time interval t 9 which is determined by timer circuit tm 9 . if the switch sw 2 is closed , the other input to and circuit and 2 will be an &# 34 ; h &# 34 ; level while the other input to and circuit and 3 will be an &# 34 ; l &# 34 ; level , so that the transistor q 4 will be turned on through and circuit and 2 for the time interval t 8 which is determined by timer circuit tm 8 . when the transistor q 4 is turned on , this also renders transistor q 3 conductive , so that the light emitting assembly 25 is fed from the external power supply 10 , causing the individual light emitting elements 25a - 25f to emit light , allowing a digital entry onto the film to take place . the time interval determined by timer circuits tm 8 and tm 9 is determined so that t 8 & gt ; t 9 , as indicated in fig1 , so that the data entry onto a film having a higher speed takes place when the switch sw 2 is opened while the data entry onto a film having a lower speed takes place when the switch is closed . when timer circuit tm 3 is turned off after the time interval of t 3 , the succeeding timer circuit tm 4 begins to operate , producing an output of an &# 34 ; h &# 34 ; level for the time interval of t 4 . this output signal is fed through or circuit or 1 to turn transistor q 1 on , whereby the electromagnet 23 is energized . this causes mirror shutter to move down into the taking light path from its upper position , whereby the exposure of the film to the image from an object being photographed is terminated . subsequently , timer circuit tm 5 is turned off after the time delay of t 5 , whereby the succeeding timer circuit tm 6 begins to operate , producing an output of an &# 34 ; h &# 34 ; level for the time interval of t 6 . this signal is fed through and circuit and 1 to turn transistor q 2 on , whereby the motor 21 is fed from the external power supply 10 . during the time interval of t 6 , the motor 21 continues to be driven , effecting a film winding operation . in this manner , a series of operations which are required to take a picture and including the upward movement of the mirror shutter , the exposure of the film , the data entry , the downward movement of the mirror shutter and the film winding operation are electrically controlled in an automatic manner . it should be noted that the electrical circuit of the electrical control device shown in fig9 to 11 can be directly applied to the camera apparatus 41 of fig3 and 4 and to the camera apparatus 51 of fig7 and 8 , by slightly modifying the connection of the bus e 1 with the power supply . specifically , when it is applied to the camera apparatus 41 , the bus e 1 is connected through the detecting means 4 to the internal battery 3 . in the case of the camera apparatus 51 , the bus e 1 may be connected through the relay circuit 54 , acting as detecting means , to the connection terminal 6 . in this manner , a desired function for the electrical circuit of the electrical control device can be obtained . while in the described embodiments , the detecting means comprises a pair of detection terminals and a conductive member , a combination of light emitting and light receiving element or a relay circuit , any other conventional means such as microswitch or pressure - sensitive element may be used instead . it should be understood that the electrical circuits shown in fig9 to 11 are exemplary only , and that the invention is not limited to the electrical circuit shown or any other circuit similar thereto . | US-12751580-A |
an ophthalmic solution is disclosed comprising an aqueous solution of polyvinyl alcohol , hydroxyethyl cellulose , polyvinylpyrrolidone , and , optionally , hydroxypropyl methylcellulose . the ophthalmic solution is used in treating dry eye syndrome due to insufficient tear production in humans and mammals , and as an ocular lubricant for inflamed eyes . | the polyvinyl alcohol used in the ophthalmic solution of this invention may be either fully hydrolyzed or partially hydrolyzed material having average molecular weight ranging from 2 , 000 to 125 , 000 . it is preferred to use polyvinyl alcohol having an average molecular weight of about 125 , 000 . the polyvinyl alcohol used in the composition described herein is sold by the monsanto company under the trademark gelvatol ®. it is to be understood , however , that the invention is not limited to the use of any specific polyvinyl alcohol , and that any equivalent polyvinyl alcohol of pharmaceutical grade can be used to achieve equivalent results . the hydroxyethyl cellulose used in the ophthalmic solution of this invention is a hydroxyethyl ether of cellulose , produced by treating cellulose with sodium hydroxide and reacting with ethylene oxide . each anhydroglucose unit in the cellulose molecule has three reactive hydroxyl groups . the number substituted is known as the &# 34 ; degree of substitution .&# 34 ; it is preferred to use an hydroxyethyl cellulose having a degree of substitution of about 2 . 5 . the hydroxyethyl cellulose used in the compositions described herein is sold by the hercules company under the trademark natrosol ®. it is to be understood , however , that the invention is not limited to the use of any particular hydroxyethyl cellulose and that any equivalent hydroxyethyl cellulose of pharmaceutical grade can be used to achieve similar results . the polyvinylpyrrolidone used in the compositions of this invention is a linear polymer of 1 - vinyl - 2 - pyrrolidinone groups having a molecular weight of 10 , 000 to 40 , 000 . such materials are sold by gaf corporation under the trademark plasdone ®. it is to be understood , however , that the invention is not limited to any specific polyvinylpyrrolidone , and that any equivalent polyvinylpyrrolidone of pharmaceutical grade may be used to achieve equivalent results . the hydroxypropyl methylcellulose used in the compositions of this invention is a propylene glycol ether of methylcellulose . suitable material is sold by the dow chemical company under the trademark methocel ®. it is to be understood , however , that the invention is not limited to any specific hydroxypropyl methylcellulose , and that any equivalent hydroxypropyl methylcellulose may be used to achieve equivalent results . the ophthalmic solutions of this invention preferably contain a buffer salt to control the ph . any pharmaceutically acceptable buffer system may be used . a preferred buffer system is a mixture of monobasic and dibasic sodium phosphate in the proportions to produce the desired ph . the ophthalmic solution may have a ph between 6 . 0 and 8 . 0 . a preferred ph range is 7 . 0 - 7 . 8 and a most preferred range is 7 . 4 - 7 . 8 . the ophthalmic solutions of this invention are preferably isotonic with the fluids of the mammalian eye , that is , they should have the same osmotic pressure . the tonicity may be adjusted by adding sodium chloride until the total concentration of salts in the solution and its osmotic pressure matches that of the ocular fluids . the ophthalmic solutions of this invention preferably contain a preservative to prevent bacterial growth . pharmacologically acceptable preservatives such as phenylmercuric nitrate , thimerosal , and benzalkonium chloride may be used in concentrations of about 0 . 001 to 0 . 02 % by weight . the ophthalmic solutions of this invention may be prepared simply by dispersing the polymers directly in water or an isotonic buffer solution . they may also be made by first preparing stock solutions of the polymers , mixing the stock solutions in the proper proportions and diluting this with water or buffer to produce the desired concentrations . the following examples are intended to illustrate the practice of this invention without limiting its scope . all percentages are by weight . stock solutions of the polymer ingredients were prepared by dissolving the predetermined quantities of the polymer in enough water to produce 1 liter of stock solution having the following concentrations : ______________________________________polyvinylpyrrolidone ( plasdone c - 15 ) 6 % polyvinyl alcohol ( gelvatol 20 - 60 ) 6 % hydroxyethyl cellulose ( natrosol 250 g ) 2 % ______________________________________ stock solutions of the phosphate buffer were prepared by dissolving 6 . 9 grams of monobasic sodium phosphate in 1 liter of water and titrating with 1n sodium hydroxide solution until the desired ph was attained . stock solutions of the preservatives were prepared by dissolving 0 . 08 grams in 1 liter of distilled water . an ophthalmic solution was prepared by mixing the stock solutions in the following proportions : ______________________________________hydroxyethyl cellulose ( 2 % solution ) 12 . 5 mlpolyvinylpyrrolidone ( 6 % solution ) 12 . 5 mlpolyvinyl alcohol ( 6 % solution ) 12 . 5 mlphenylmercuric nitrate ( 8x concentrate ) 12 . 5 mlisotonic phosphate buffer ( 8x concentrate ) 12 . 5 mlwater , sufficient to make 100 ml______________________________________ viscosity of the ophthalmic solution was measured with a hoeppler viscometer ( falling ball ) or epprecht rheomat - 15 ( a cup and bob rotational viscometer ). the ophthalmic solution had a viscosity of 5 . 2 centipoises and a surface tension of 42 . 6 dynes / cm . the ph was 7 . 6 ± 0 . 2 . by the procedure of example i , an ophthalmic solution was prepared having the following composition : ______________________________________hydroxyethyl cellulose ( natrosol 250 gr ) 1 . 2 % polyvinylpyrrolidone ( plasdone c - 15 ) 2 . 0 % polyvinyl alcohol ( gelvatol 20 - 90 bp ) 2 . 0 % thimerosal 0 . 001 % disodium edetate 0 . 01 % ______________________________________ by the procedure of example i , an ophthalmic solution was prepared having the following composition : ______________________________________hydroxyethyl cellulose ( natrosol 250 mr ) 0 . 65 % polyvinyl alcohol ( gelvatol 20 - 90 bp ) 0 . 50 % polyvinylpyrrolidone ( plasdone c - 15 ) 1 . 50 % benzalkonium chloride 0 . 01 % disodium edetate 0 . 1 % ______________________________________ by the procedure of example i , an ophthalmic solution was prepared having the following composition : ______________________________________hydroxyethyl cellulose ( natrosol 250 gr ) 1 . 2 % polyvinylpyrrolidone ( plasdone c - 15 ) 2 . 0 % polyvinyl alcohol ( gelvatol 20 - 90 bp ) 0 . 5 % benzalkonium chloride 0 . 01 % disodium edetate 0 . 01 % ______________________________________ by the procedure of example i , an ophthalmic vehicle was prepared having the following composition : ______________________________________hydroxyethyl cellulose ( natrosol 250 gr ) 0 . 5 % hydroxypropyl methylcellulose ( methocel hg 65 ) 0 . 4 % polyvinyl alcohol ( gelvatol 20 - 90 bp ) 0 . 5 % polyvinylpyrrolidone ( plasdone c - 15 ) 1 . 0 % benzalkonium chloride 0 . 01 % disodium edetate 0 . 01 % ______________________________________ by the procedure of example i , an ophthalmic solution was prepared having the following composition : ______________________________________hydroxyethyl cellulose ( natrosol 250 gr ) 0 . 8 % polyvinylpyrrolidone ( plasdone c - 15 ) 1 . 5 % polyvinyl alcohol ( gelvatol 20 - 90 bp ) 0 . 5 % hydroxypropyl methylcellulose ( methocel hg65 ) 0 . 4 % benzalkonium chloride 0 . 01 % disodium edetate 0 . 01 % ______________________________________ by the procedure of example i , an ophthalmic solution was prepared having the following composition : ______________________________________hydroxyethyl cellulose ( natrosol 250 kr ) 0 . 8 % polyvinylpyrrolidone ( plasdone c - 15 ) 1 . 5 % polyvinyl alcohol ( gelvatol 20 - 90 bp ) 0 . 5 % benzalkonium chloride 0 . 01 % disodium edetate 0 . 01 % ______________________________________ by the procedure of example i , an ophthalmic solution was prepared having the following composition : ______________________________________polyvinyl alcohol ( gelvatol 20 - 90 bp ) 0 . 5 % hydroxyethyl cellulose ( natrosol 250 kr ) 0 . 8 % polyvinylpyrrolidone ( plasdone c - 15 ) 1 . 5 % benzalkonium chloride 0 . 005 % disodium edetate 0 . 01 % ______________________________________ this example illustrates the tear film break - up times ( but ) measured for the ophthalmic solutions of this invention . four male rhesus monkeys were selected for testing . the four monkeys weights 5 . 9 , 6 . 0 , 7 . 3 , and 7 . 7 kgs , respectively . the monkeys were maintained on a standard commercial diet , but were starved on the day of testing . each monkey was anesthetized and maintained with vetalar ® ( ketamine hydrochloride , 100 mg / ml ) by intramuscular injection into the thigh . once anesthetized , each monkey was immobilized to facilitate their handling by securing their hands and feet , and then wrapping their body in a cloth towel . each restrained monkey was placed in a seated position in front of a zeiss slit lamp . the head was supported on the chin rest and the eyes were aligned for observation . the eyelids of one eye were held open for topical instillation of one 10 μl drop of normal saline containing 0 . 125 % sodium fluorescein . the lids were manually blinked twice in order to uniformly distribute the fluorescein and then held open for a control but measurement . the resultant tear film was scanned with a broad beam slit in a darkened room , using a cobalt blue filter , until the first dry spot appeared . the dry spot manifested itself as a black area , ( round , oval or streak - shaped ) in the fluorescent yellowish - green precorneal film . a laboratory stop watch was started immediately after the last blink and was stopped as soon as a break was observed in the tear film . this procedure was alternated between the right and left eyes until three control but values were measured for each eye . immediately after the control but measurements were determined , the same four monkeys were employed to test one ophthalmic solution . no more than one formulation was tested on any single day . three but values for each ophthalmic vehicle were measured for each eye by employing the same methodology as described for the control , normal saline solution . the three saline control but values for each eye were averaged and the three tear substitute but values for each eye were averaged . the mean ± s . e . of the eight eyes treated with normal saline and the mean ± s . e . of the same eight eyes treated with tear substitute were determined . a one - tailed t - test was performed to determine whether the ophthalmic vehicle was more effective than the normal saline in prolonging tear film but . the measured values of tear film break - up time ( but ) are listed in table i ( s . e . = standard error ). in these tests , the but for the normal saline controls range from 8 to 12 seconds . table i______________________________________solution ofexample but ± ( s . e .) ( seconds ) ______________________________________i 15 . 6 ± 2 . 5ii 29 . 2 ± 3 . 7iii 20 . 7 ± 1 . 4iv 28 . 1 ± 3 . 0v 23 . 8 ± 2 . 2vi 30 . 3 ± 1 . 8vii 30 . 5 ± 2 . 8viii 18 . 6 ± 1 . 8______________________________________ | US-83933277-A |
methods and apparatus are provided for measuring contrast sensitivity . in one method , a person is presented with a test pattern having several test areas . in a first test cycle , one of the test areas contrasts with the other test areas . the person being tested indicates which test area the person perceives as contrasting with the other test areas . this is repeated a number of times for the other test areas , with the level of contrast staying the same but with a different test area becoming the contrasting test area . in subsequent cycles , these steps are repeated , with decreasing levels of contrast . the contrasting test area may , for example , appear as a solid , as a pattern such as two contrasting vertical bars , or as an animation such as a sinusoidal frequency grating . | fig1 depicts a test pattern , or test panel , in accordance with one embodiment of the invention . a test area 5 in the center of the test pattern is substantially square . four test areas are disposed around test area 5 : upper left - hand corner 1 , upper right - hand corner 3 , lower left - hand corner 7 , and lower right - hand corner 9 ( which may be referred to as test areas 1 , 3 , 7 , and 9 respectively ). horizontal bands 4 and 6 extend from test area 5 to the left and right edges , respectively , of the test pattern . vertical bands 2 and 8 extend from test area 5 to the top and bottom edges , respectively , of the test pattern . bands 2 , 4 , 6 , and 8 serve to separate the test areas from each other ( except where test areas 1 , 3 , 7 , and 9 meet the corners of test area 5 ) and may be referred to as nontest areas 2 , 4 , 6 , and 8 , respectively . any of areas 1 - 9 may also be loosely referred to as a quadrant . fig1 may also be described as consisting of a 3 by 3 matrix . considering the rows from top to bottom and the columns from left to right : in row 1 , columns 1 and 3 are test areas and column 2 is a nontest area ; in row 2 , column 2 is a test area and columns 1 and 3 are nontest areas ; and in row 3 , columns 1 and 3 are test areas and column 2 is a nontest area . a test session for measuring contrast sensitivity using the test pattern of fig1 includes a number of cycles . in any one cycle , there is a level of contrast between the quadrants . preferably , one quadrant is relatively dark and the other eight quadrants are relatively light . with each successive cycle the brightness ( darkness or lightness ) of one or more of the quadrants will change , such that there is a change ( preferably a decrease ) in the level of contrast between the relatively dark quadrant ( s ) and the relatively light quadrant ( s ). each cycle consists of one or more sets of displays that use variations of the test pattern of fig1 , with one or more quadrants darker than one or more other quadrants . one example of a cycle consisting of six display sets is shown in fig2 , with the next two cycles shown in fig3 and 4 . in this example , one test area is darker than the other eight quadrants ; with each successive cycle the darker test area will become lighter , while all other quadrants of the test panel will become darker . thus with each successive cycle the contrast between the darker test area and the other quadrants decreases . one preferred test session consists of up to 20 cycles . to help establish a fixation point for the person being tested while he or she is looking at the display , one of the test areas — preferably test area 5 — may include a letter , number , symbol , ideogram , icon , sign , shape , figure , picture , or any other image . preferably the image used is a single letter ( although multiples or combinations of images could be used ) and may change or repeat with each display set . ( for example , the image used may be selected randomly or in a predetermined sequence from the 26 letters a - z .) with this flexibility , the patient may be literate in any language , or illiterate . also preferably included are the crossing lines shown , for example , in fig1 — horizontally below row 1 and above row 3 , and vertically to the right of column 1 and to the left of column 3 — to provide guidance to assist fixation , with the person being tested instructed to keep looking at the area in the center where all the lines cross . one preferred test session , in which the dark test area appears as a solid , proceeds as follows . as shown in fig2 , in the first cycle one brightness value b d for a dark test area is set to a darkest value ( e . g ., absolute black ) and another brightness value b l for the other , relatively light quadrants is set to a least - dark value ( e . g ., absolute white ) for use during the session . the first display set will have one test area dark and the other eight quadrants light ; in the subsequent display sets , the test area that had been dark will become light and another of the other four test areas will become dark , with no test area repeating as the dark area . the sixth display set repeats one of the earlier display sets in the cycle so that the patient cannot deduce which test area will next be dark . for each of the first five display sets , the test area that is dark may be predetermined ( for example , by a software - programmed sequence ) or may be determined randomly , so long as no test area is dark a second time . the repeated sixth display set also may be predetermined ( for example , by a software - programmed selection ) or may be determined randomly . specifically , for the six display sets shown in fig2 a - 2f : in the first set test area 7 is dark ; in the second set test area 3 is dark ; in the third set test area 5 is dark ; in the fourth set test area 1 is dark ; in the fifth set test area 9 is dark ; and the sixth set repeats the fourth set . in each of these display sets , the dark test area is at a darkest value ( b d = absolute black ) and the other test areas and the other eight quadrants are at a lighter value ( b l = absolute white ). in subsequent cycles , there is a progressively lower contrast between the relatively dark test area and the eight other quadrants that are relatively light . preferably , at the start of each subsequent cycle , the brightness value b d ( for the dark test areas ) is set to a less - dark value than in the previous cycle , while the brightness value b l ( for the light quadrants ) is set to a more - dark value than in the previous cycle . accordingly , fig3 depicts a second cycle , with six display sets shown in fig3 a - 3f : in the first set test area 1 is dark ; in the second set test area 5 is dark ; in the third set test area 9 is dark ; in the fourth set test area 7 is dark ; in the fifth set test area 3 is dark ; and the sixth set repeats the second set . in each of these display sets , the dark test area is at a less - dark value compared with that in the first cycle ( e . g ., b d = 98 % of absolute black ) and the other quadrants are at a less - lighter value compared with that in the first cycle ( e . g ., b l = 10 % of absolute black ). in an alternative example , the other quadrants remain at the same value as in the first cycle ( e . g ., b l = absolute white ). fig4 depicts the third cycle , with six display sets shown in fig4 a - 4f : in the first set test area 9 is dark ; in the second set test area 3 is dark ; in the third set test area 1 is dark ; in the fourth set test area 5 is dark ; in the fifth set test area 7 is dark ; and the sixth set repeats the first set . in each of these display sets , the dark test area is at a less - dark value compared with that in the second cycle ( e . g ., b d = 95 % of absolute black ) and the other quadrants are at a less - lighter value compared with that in the second cycle ( e . g ., b l = 15 % of absolute black ). in an alternative example , the other quadrants remain at the same value as in the first cycle ( e . g ., b l = absolute white ). in a second example of a test session according to the invention , contrast decreases in each cycle by having the light areas get gradually darker . again , in this test session &# 39 ; s first cycle , one brightness value b d is set to a darkest value ( e . g ., absolute black ) and another brightness value b l is set to a least - dark value ( e . g ., 10 % of absolute black ) for use during the session . in the first cycle , one test area in each display set will be dark ( b d = absolute black ) and the other four test areas will be light ( b l = absolute white ). but at the start of each subsequent cycle , the first value remains constant ( b d = absolute black ), while the second value is set to a higher darkness value than in the previous cycle ( e . g ., in cycle no . 2 , b l = 15 % of absolute black ; in cycle no . 3 , b l = 18 % of absolute black , and so on ). in a third example of a test session according to the invention , in which the dark test area appears as an animation of a sinusoidal frequency grating , display sets include no letter or other image in test area 5 , as shown in fig5 . in addition , in the first cycle , one test area will contain vertical bars of two contrasting shades of gray , with the other test areas being the lighter of the two shades . in each display set as shown in fig5 a - 5f , the test area that contains the contrasting vertical bars preferably undergoes the following animated transition : it will first appear as a solid gray tone throughout the given test area , then for approximately ⅓ of a second it will appear as the contrasting grayscale bars , the lighter of the grayscales being the same shade as seen in the initial solid gray tone , then it will revert to the initial solid gray tone and remain that way until a mouse click is made . in a fourth example of a test session according to the invention , in which the dark test area appears as a pattern of two contrasting brightnesses , display sets include no letter or other image in test area 5 . in addition , as shown in fig6 , in the first cycle , one test area will contain two contrasting shades of gray — one darker and one lighter — with the other eight quadrants having that same lighter shade of gray throughout every set in the first cycle ( as shown in fig6 a - 6f ) and in every subsequent cycle of the session ( not shown ). in this example of the test , the maximum of number cycles is 10 . the progression of contrast through the 10 cycles is represented in fig6 g , a graph in which the test cycle number is plotted along one axis and brightness according to a standard computer grayscale designation ( ranging from 0 for absolute black to 255 for absolute white ) is plotted along a second axis . while the background grayscale level remains at 222 for each of the up to 10 cycles , the contrasting grayscale level for each cycle is as presented in table 1 : in this example , the level of contrast in the first cycle is one for which inability of the patient to perceive it will signify that the patient &# 39 ; s contrast sensitivity has deteriorated to the degree that further testing will be unlikely to serve any benefit to the patient . the rate of change in contrast is greatest in the early cycles , and least in the later cycles , for the purpose of enabling the test to detect at essentially the earliest instance subtle , but diagnostically significant , changes in the patient &# 39 ; s contrast sensitivity over time . fig7 is a flowchart for a computer - based system for administering a contrast sensitivity test according to one embodiment of the invention . preferably , this embodiment is accessible to operators and test subjects over the world wide web via a web browser . preferably , an operator — typically a doctor or technician — will assist a patient to whom the test will be administered . for example , the operator ensures that the patient is positioned in front of a computer monitor appropriately , including the correct distance from the monitor . the operator may also determine if it is possible or desirable for the patient to operate a computer by , for example , clicking a mouse button to provide input to the computer system . if it is not possible or desirable for the patient to do so , the operator may provide instructions to the patient such as these : “ you will see a series of grayscale test panels appear on the screen . in each panel , one of five different areas will be darker than the others . the central area will contain an alphabet letter . throughout the test , maintain focus on the letter in the central area , even if you think the darkened area is likely to be elsewhere . say out loud the alphabet letter that will appear in the central area each time a new test screen appears , then tell me which area is the dark area , and i ( the operator ) will register the result by clicking on that area with the mouse . the letter in the central area may change after a click or it may repeat .” alternately , if the technician believes that the patient has the capacity , the technician may instruct the patient to click on the test area displayed on the monitor that is dark . as shown in fig7 a , processing by the computer system begins at block 501 . the system may require a login by an operator with privileges authorizing the operator to run the system and administer the contrast sensitivity test . the system at block 503 calibrates a computer screen that will be used to administer test . preferably , the calibration is initiated by an operator going to a screen - calibration page ( e . g ., by clicking a web link ) that depicts the display of fig1 . the system permits the operator to account for variations in the size and screen resolution of different computer monitors by adjusting the width of the display grid . the screen - calibration page may specify the correct width . the system at block 505 permits inputting of data identifying a patient to be tested . the computer system preferably includes a central database that can store data , including the patient - identifying data . instead of entering complete identifying data for a patient , previously entered data may be retrieved ( e . g ., by the operator entering the patient &# 39 ; s name and birth date ) from the central database , another data - storage device , or another computer system ( e . g ., a hospital &# 39 ; s computerized patient records ). proceeding to block 507 , the system generates a new display set . the system processing indicated at block 507 includes accessing , generating , and keeping track of data as necessary to determine the current cycle and display set . for a test session implemented according to the preferred session described above and depicted partially in fig2 - 4 , the system will access or generate data on the darkness value for dark test areas , which of test areas 1 - 4 or test area 5 will be relatively dark , what image will be displayed in test area 5 , and any other display data . in this example , when the system first proceeds to block 507 to produce the first display set of the first cycle of the test session , the display set depicted in fig2 a is presented to the patient on the computer monitor . at block 509 , the system inputs and processes response data from the patient , indicating which test area the patient perceived to be the dark area . typically this will be entered by the operator or by the patient . at block 511 , the system determines whether the required number of display sets has been completed . if not , processing returns to block 507 ; if so , processing continues to block 513 , where a summary of the test results is displayed . preferably this includes a score based on the number of cycles in which the patient answers correctly for all display sets in a cycle . for instance , a patient who provides correct answers for all the display sets in 18 of 20 cycles would receive a score of 90 %. the system next proceeds to block 515 to receive as input operator instructions . when input is received , the system proceeds via jump point a ( block 516 ) to block 517 shown in fig7 b . if at block 517 the system determines the operator input indicated that the test results should be registered , then the system proceeds to block 519 to register the test results ( preferably by storing the results in a database on a server computer ), and the system then returns via jump point b ( block 514 ) to block 515 . otherwise , the system proceeds to block 521 . if the at block 521 the system determines that operator input indicated that a new test session should be started , then the system proceeds via jump point c ( block 506 ) to block 507 . otherwise , the system proceeds to block 523 . if at block 523 the system determines that the operator input indicated that a new test session for a new patient should be started , then the system proceeds via jump point d ( block 504 ) to block 505 . otherwise , the system proceeds to block 525 . if at block 525 the system determines that the operator input indicated that a calibration be performed , then the system proceeds via jump point e ( block 502 ) to block 503 . otherwise , the system proceeds to block 527 and processing ends . in another example of a test session according to the invention , up to 20 cycles are possible , but the computer system will not necessarily go through all of them . the system is implemented to provide that , so long as the patient is answering correctly for all the display sets in a cycle , the test progresses at a doubled rate by skipping the next cycle . in this case , the skipped display sets would be counted as “ correct ” answers . in this example it is preferable that the system resume presenting every cycle as soon as the patient makes one error during a cycle . it is also preferable that the test session continues until the patient has incorrectly identified , at least once , each of the five test areas , or until the patient reaches the end of the 20 th cycle . for instance , let us say that during cycle nos . 1 , 3 , and 5 the patient makes no mistakes ; during cycle no . 7 the patient incorrectly identifies test area 3 ; during cycle no . 8 the patient incorrectly identifies test area 5 ; during cycle no . 9 the patient incorrectly identifies test areas 1 , 7 , and 9 ( in whatever order ). in this example , the test session will end after cycle no . 9 is completed ; cycle nos . 1 - 6 will be scored as correct , and cycle nos . 7 - 20 will be scored as incorrect , for a final score of 6 out of 20 ( 30 %). taking another instance , in which the patient makes no mistakes until the 13 th cycle : let us say that the patient first makes a mistake concerning test area 1 during the 13 th cycle , then makes mistakes concerning test areas 1 and 5 ( in either order ) during the 14 th cycle , and then make mistakes concerning test areas 1 , 3 , 5 , 7 , and 9 ( in whatever order ) during the 15 th cycle . in this case , by the end of the test session the patient will have been presented with cycle nos . 1 , 3 , 5 , 7 , 9 , 11 , 13 , 14 , and 15 . for this patient , 12 answers would be scored correct for cycle nos . 1 - 12 , and 8 answers would be scored incorrect for cycle nos . 13 - 20 , for a final score of 12 out of 20 ( 60 %). it is preferred in this example that the last four cycles ( nos . 17 - 20 ) will always be presented — i . e ., that the doubled rate ends once the patient begins cycle no . 17 — so long as mistakes have not been made for all five test areas . for instance , a patient who makes no mistakes throughout the entire test session will have been presented with cycle nos . 1 , 3 , 5 , 7 , 9 , 11 , 13 , 15 , 17 , 18 , 19 , and 20 . for another instance , a patient who makes no mistakes through the 17 th cycle , then makes mistakes concerning test areas 1 , 3 , 5 , and 7 ( in whatever order ) during the 18 th cycle , and then makes a mistake concerning test area 9 during the 19 th cycle , the patient will have been presented with cycle nos . 1 , 3 , 5 , 7 , 9 , 11 , 13 , 15 , 17 , 18 , and 19 . in this example of a test session , whether a patient &# 39 ; s answer is correct or incorrect is preferably determined as follows . in a given display set , if the patient responds by identifying as dark a test area that is not in fact the dark test area , the next display set in that cycle will repeat the set just presented . if the patient fails again to correctly identify the dark test area , the display set is registered as incorrectly answered . if on the second presentation of the same display set the patient correctly identifies the dark test area , then the same set appears a third time , and the patient &# 39 ; s third click defines the set as correct or incorrect . it is still the case that five different display sets and a sixth , dummy set is presented during the cycle , although each of the six display sets could be presented up to three times . in another example of a test session according to the invention , up to 10 cycles are possible . so long as the patient is answering correctly for all the display sets in a cycle , the test progresses at a doubled rate by skipping the next cycle , but cycle nos . 6 - 10 are always presented , so long as there is at least one test area that the patient has not yet mistaken . in addition , if the patient makes a mistake during one cycle that follows a skipped cycle , the test proceeds to complete that one cycle and then regresses to the skipped cycle . for instance , a patient who makes no mistakes in cycle no . 1 is presented next with cycle no . 3 . if no mistakes are made , the patient is then presented with cycle no . 5 . let us say that here the patient makes a mistake concerning test area 7 ; test area 7 in cycle no . 5 is then scored as incorrect and the patient is presented with cycle no . 4 . if , say , the patient makes a mistake concerning test area 1 , then test area 1 in cycle no . 4 is scored as incorrect . the patient is then presented with a second instance of cycle no . 5 . whatever the patient &# 39 ; s responses , test area 7 in cycle no . 5 remains scored as incorrect . let us say that the patient again makes a mistake concerning only test area 7 . the patient is then presented with cycle nos . 6 - 10 . let us say that no mistake is made until cycle no . 10 , when the patient makes mistakes concerning test areas 1 , 3 , and 9 ( in whatever order ), and the patient makes no mistake throughout the test session for test area 5 . the score for any test area equals the lowest cycle number in which a mistake occurred for that test area , minus 1 , times 2 . for a test area where no mistake is made , the score is 20 ( 10 times 2 ). ( multiplication by 2 provides that the highest possible test score will be 100 .) scoring in this example is shown in table 2 . adding the scores for the five test areas , for this patient the final score is 70 ( or 70 %). as those skilled in the art will recognize , numerous variations are possible for many aspects of the invention , such as the appearance of the contrasting quadrants , the number of cycles , the number of display sets , the sequence in which display sets are presented , whether and when display sets are repeated , the way that contrast between test areas is displayed , whether there is contrast between nontest areas or between test and nontest areas , how correct or incorrect answers are determined , the score or measurement of contrast sensitivity based upon data from the test session , and the way that operator or patient input is received . in particular , contrast between any one or more quadrants with any other one or more quadrants can be achieved in a variety of ways . the examples described here — including a test area that appears as a solid , as a pattern such as vertical bars , or as an animation such as a sinusoidal frequency grating — are merely illustrative . a computer system according to the invention may be implemented using a variety of hardware ( including processors , memories , storage devices , and storage media ), software ( including operating systems , databases , and web - based applications ), configurations ( including a single unit , multiple units , networks , and client / server arrangements ), and other elements . the scope of the invention is defined by the claims . | US-79902810-A |
this invention relates to an abuse deterrent dosage form of opioid analgesics , wherein an analgesically effective amount of opioid analgesic is combined with a polymer to form a matrix . | the present invention includes an abuse deterrent formulation for reducing the potential for one or more of a ) parenteral abuse , b ) inhalation ( e . g ., intranasal abuse ), and / or c ) oral abuse of a drug , typically an opioid analgesic type drug , for satisfaction of a physical or psychological dependence . in one embodiment , the present invention deters parenteral abuse by providing a pharmaceutical composition which includes an analgesic with one or more gel forming agents such that upon contact with a solvent ( e . g ., water ), the agents swell by absorbing the solvent thereby 1 ) entrapping the drug in a gel matrix and / or 2 ) reducing or preventing a significant amount of the opioid analgesic from being drawn into a syringe . in one embodiment , the present invention deters inhalation abuse by providing a pharmaceutical composition which includes a therapeutically active pharmaceutical ( e . g ., an analgesic ), with one or more mucous membrane , mucosa or mucosal tissue irritants ( collectively referred to as mucous membrane irritants ). in one embodiment , the mucosal tissue is nasal passageway tissue . upon contact with a mucous membrane , the irritants induce temporary pain and / or irritation of the membranes and / or tissues to thereby deter abuse . for example , if inhaled by snorting , the mucous membrane in the nasal passageway will be irritated and result in pain to the individual . in one embodiment , the present invention provides a pharmaceutical composition which includes an analgesic with one or more emetics , such that after oral consumption of more than a typically prescribed amount of the dosage form , emesis is induced . in one embodiment , two or more of the abuse deterrents can be combined into one composition according to the present invention . the present invention describes formulations which have abuse deterrent properties as described herein . examples of specific oral solid dosage forms containing morphine , hydrocodone and oxycodone were evaluated using suitable analytical test methods , such as uv / vis spectrophotometry . in the evaluation , dosage forms were crushed and contacted with a small amount of water ( about a teaspoon or tablespoon ). after attempting to dissolve the dosage form , the resultant material was drawn into a syringe , volume was measured and opioid content was quantitated . as shown in fig1 , almost 100 % of the opioid can be extracted from standard formulations . comparatively , as shown in fig2 , an abuse deterrent formulation of the present invention for the same opioids , provides a significantly lower percentage of extractable opioid . as shown in fig1 , approximately 93 %, 103 % and 99 % of the opioid analgesic drugs contained in a dosage form were recoverable using the above described techniques . comparatively , as shown in fig2 , using an abuse deterrent polymer of the present invention , only 9 %, 5 %, and 6 % of the opioid analgesic drugs were recoverable . in another embodiment , the present invention is a pharmaceutical composition that includes an opioid analgesic , one or more gel forming agents , and one or more mucous membrane irritants or nasal passageway tissue irritants . in another embodiment , the present invention includes a pharmaceutical composition , which includes an analgesic , one or more gel forming agents and one or more emetics as described herein . in another embodiment , the present invention includes a pharmaceutical composition , which includes an opioid analgesic , one or more mucous membrane irritants or nasal passageway tissue irritants and one or more emetics as described herein . in one particular embodiment , the present invention includes a pharmaceutical composition which includes an analgesic , one or more gel forming agents , one or more mucous membrane irritants and / or nasal passageway tissue irritants , and one or more emetics . each of the components of the pharmaceutical composition of the present invention are described in more detail below . any drug , therapeutically acceptable drug salt , drug derivative , drug analog , drug homologue , or polymorph can be used in the present invention . in one embodiment , the drug can be orally administered . in certain embodiments , drugs susceptible to abuse are used . drugs commonly susceptible to abuse include psychoactive drugs and analgesics , including but not limited to opioids and drugs that can cause psychological and / or physical dependence on the drug . a drug for use in the present invention can be one or more of the following : alfentanil , amphetamines , buprenorphine , butorphanol , carfentanil , codeine , dezocine , diacetylmorphine , dihydrocodeine , dihydromorphine , diphenoxylate , diprenorphine , etorphine , fentanyl , hydrocodone , hydromorphone , β - hydroxy - 3 - methylfentanyl , levo - α - acetylmethadol , levorphanol , lofentanil , meperidine , methadone , methylphenidate , morphine , nalbuphine , nalmefene , o - methylnaltrexone , naloxone , naltrexone , oxycodone , oxymorphone , pentazocine , pethidine , propoxyphene , remifentanil , sufentanil , tilidine and tramodol , salts , derivatives , analogs , homologues , polymorphs thereof , and mixtures of any of the foregoing . in one embodiment , a pharmaceutical composition of the present invention includes one or more opioids such as hydrocodone , morphine and oxycodone and / or salts thereof , as the therapeutically active ingredient . typically when processed into a suitable dosage form , as described in more detail below , the drug can be present in such dosage forms in an amount normally prescribed , typically about 0 . 5 to about 25 percent on a dry weight basis , based on the total weight of the formulation . with respect to analgesics in unit dose form , such an amount can be typically from about 5 , 25 , 50 , 75 , 100 , 125 , 150 , 175 or 200 mg . more typically , the drug can be present in an amount from 5 to 500 mg or even 5 to 200 mg . in other embodiments , a dosage form contains an appropriate amount of drug to provide a therapeutic effect . as described above , the present invention can include one or more gel forming agents . the total amount of gel forming agent is typically about 3 to about 40 percent on a dry weight basis of the composition . suitable gel forming agents include compounds that , upon contact with a solvent ( e . g ., water ), absorb the solvent and swell , thereby forming a viscous or semi - viscous substance that significantly reduces and / or minimizes the amount of free solvent which can contain an amount of solublized drug , and which can be drawn into a syringe . the gel can also reduce the overall amount of drug extractable with the solvent by entrapping the drug in a gel matrix . in one embodiment , typical gel forming agents include pharmaceutically acceptable polymers , typically hydrophilic polymers , such as hydrogels . in some embodiments , the polymers exhibit a high degree of viscosity upon contact with a suitable solvent . the high viscosity can enhance the formation of highly viscous gels when attempts are made by an abuser to crush and dissolve the contents of a dosage form in an aqueous vehicle and inject it intravenously . more specifically , in certain embodiments the polymeric material in the present invention provides viscosity to the dosage form when it is tampered . in such embodiments , when an abuser crushes and dissolves the dosage form in a solvent ( e . g ., water or saline ), a viscous or semi - viscous gel is formed . the increase in the viscosity of the solution discourages the abuser from injecting the gel intravenously or intramuscularly by preventing the abuser from transferring sufficient amounts of the solution to a syringe to cause a desired “ high ” once injected . suitable polymers include one or more pharmaceutically acceptable polymers selected from any pharmaceutical polymer that will undergo an increase in viscosity upon contact with a solvent . preferred polymers include polyethylene oxide , polyvinyl alcohol , hydroxypropyl methyl cellulose and carbomers . in preferred embodiments , the polymers include : in some embodiments , the polymer includes polyethylene oxide . the polyethylene oxide can have an average molecular weight ranging from about 300 , 000 to about 5 , 000 , 000 , more preferably from about 600 , 000 to about 5 , 000 , 000 , and most preferably at least about 5 , 000 , 000 . in one embodiment , the polyethylene oxide includes a high molecular weight polyethylene oxide . in one embodiment , the average particle size of the polyethylene oxide ranges from about 840 to about 2 , 000 microns . in another embodiment , the density of the polyethylene oxide can range from about 1 . 15 to about 1 . 26 g / ml . in another embodiment , the viscosity can range from about 8 , 800 to about 17 , 600 cps . the polyethylene oxide used in a directly compressible formulation of the present invention is preferably a homopolymer having repeating oxyethylene groups , i . e ., —(— o — ch 2 — ch 2 —) n —, where n can range from about 2 , 000 to about 180 , 000 . preferably , the polyethylene oxide is a commercially available and pharmaceutically acceptable homopolymer having moisture content of no greater than about 1 % by weight . examples of suitable , commercially available polyethylene oxide polymers include polyox ®, wsrn - 1105 and / or wsr - coagulant , available from dow chemicals . in some embodiments , the polyethylene oxide powdered polymers can contribute to a consistent particle size in a directly compressible formulation and eliminate the problems of lack of content uniformity and possible segregation . in one embodiment , the gel forming agent includes polyvinyl alcohol . the polyvinyl alcohol can have a molecular weight ranging from about 20 , 000 to about 200 , 000 . the specific gravity of the polyvinyl alcohol can range from about 1 . 19 to about 1 . 31 and the viscosity from about 4 to about 65 cps . the polyvinyl alcohol used in the formulation is preferably a water - soluble synthetic polymer represented by —(— c 2 h 4 o —) n —, where n can range from about 500 to about 5 , 000 . examples of suitable , commercially available polyvinyl alcohol polymers include pva , usp , available from spectrum chemical manufacturing corporation , new brunswick , n . j . 08901 . in one embodiment , the gel forming agent includes hydroxypropyl methyl cellulose ( hypromellose ). the hydroxypropyl methyl cellulose can have a molecular weight ranging from about 10 , 000 to about 1 , 500 , 000 , and typically from about 5000 to about 10 , 000 , i . e ., a low molecular weight hydroxypropyl methyl cellulose polymer . the specific gravity of the hydroxypropyl methyl cellulose can range from about 1 . 19 to about 1 . 31 , with an average specific gravity of about 1 . 26 and a viscosity of about 3600 to 5600 . the hydroxypropyl methyl cellulose used in the formulation can be a water - soluble synthetic polymer . examples of suitable , commercially available hydroxypropyl methylcellulose polymers include methocel k100 lv and methocel k4m , available from dow chemicals . in one embodiment , the present invention includes carbomers . the carbomers can have a molecular weight ranging from 700 , 000 to about 4 , 000 , 000 , 000 . the viscosity of the polymer can range from about 4000 to about 39 , 400 cps . examples of suitable , commercially available carbomers include carbopol 934p nf , carbopol 974p nf and carbopol 971p nf , available from noveon pharmaceuticals . following the teachings set forth herein , other suitable gel forming agents can include one or more of the following polymers : ethyl cellulose , cellulose acetate , cellulose acetate propionate , cellulose acetate butyrate , cellulose acetate phthalate and cellulose triacetate , cellulose ether , cellulose ester , cellulose ester ether , and cellulose , acrylic resins comprising copolymers synthesized from acrylic and methacrylic acid esters , the acrylic polymer may be selected from the group consisting of acrylic acid and methacrylic acid copolymers , methyl methacrylate copolymers , ethoxyetlryl methacrylates , cyanoetlryl methacrylate , poly ( acrylic acid ), poly ( methaerylic acid ), methacrylic acid alkylamide copolymer , poly ( methyl methacrylate ), polymethacrylate , poly ( methyl methacrylate ) copolymer , polyacrylamide , aminoalkyl methacrylate copolymer , poly ( methacrylic acid anhydride ), and glycidyl methacrylate copolymers . any of the above described polymers can be combined together or combined with other suitable polymers , and such combinations are within the scope of the present invention . in one embodiment , the abuse deterrent , gel forming agent can prevent less than or equal to about 95 %, 94 %, 70 %, 60 %, 54 %, 50 %, 45 %, 40 %, 36 %, 32 %, 30 %, 27 %, 20 %, 10 %, 9 %, 6 %, 5 % or 2 % of the total amount of drug in a dosage form from being recovered from a solvent in contact with a dosage form of the present invention . as shown in fig3 , formulations a3 , b3 , c3 , d3 and e3 reduce the amount of drug extractable or recoverable from a dosage for of the present invention . specifically , formulation a3 provides for recovery of 26 . 77 % of the total amount of drug in the dosage form , formulation b3 provides for recovery of 31 . 8 % of the total amount of drug in the dosage form , formulation c3 provides for recovery of 35 . 75 % of the total amount of drug in the dosage form , formulation d3 provides for recovery of 35 . 8 % of the total amount of drug in the dosage form , and formulation e3 provides for recovery of 42 . 5 % of the total amount of drug in the dosage form . in fig3 , all five formulations a3 through e3 are compared with a standard dosage form of oxycontin , which provided for recovery of 98 . 6 % of the total amount of drug in the dosage form . the five formulations a3 through e3 are set forth in examples 14 through 18 , respectively . it should be noted that the above described formulations also have dissolution profiles as determined by the usp 2 - paddle method , as shown in fig4 . in particular , for formulations a3 through e3 , about 50 % to about 82 % of each formulation dissolves after about 15 minutes and about 80 % to about 95 % dissolves after 90 minutes . fig4 further includes the dissolution profile of formulation f3 . with respect to fig4 , the composition of formulation f3 is set forth in example 19 . the above described gel forming agents can be further optimized as necessary or desired in terms of viscosity , molecular weight , etc . as described above , the present invention can include one or more mucous membrane irritants and / or nasal passageway tissue irritants . in one embodiment , suitable mucous membrane irritants and / or nasal passageway tissue irritants include compounds that are generally considered pharmaceutically inert , yet can induce irritation . such compounds include , but are not limited to surfactants . in one embodiment , suitable surfactants include sodium lauryl sulfate , poloxamer , sorbitan monoesters and glyceryl monooleates . other suitable compounds are believed to be within the knowledge of a practitioner skilled in the relevant art , and can be found in the handbook of pharmaceutical excipients , 4th ed . ( 2003 ), the entire content of which is hereby incorporated by reference . in one embodiment of the present invention , the irritant can be present in amount of from 1 to 20 percent by weight on a solid basis , preferably 1 to 10 percent by weight on a solid basis . in another embodiment , the amount of irritant can be present in an amount of 5 to 15 percent by weight . in another embodiment , the irritant can be present in an amount of at least 5 percent by weight . in yet another embodiment , the irritant can be present in an amount from 1 to 5 percent by weight . in another embodiment , the amount of irritant can be present in an amount from 1 to 3 percent by weight . in certain embodiments , the irritant can deter abuse of a dosage form when a potential abuser tampers with a dosage form of the present invention . specifically , in such embodiments , when an abuser crushes the dosage form , the irritant is exposed . the irritant discourages inhalation of the crushed dosage form by inducing pain and / or irritation of the abuser &# 39 ; s mucous membrane and / or nasal passageway tissue . in one embodiment , the irritant discourages inhalation ( e . g ., via snorting through the nose ) by inducing pain and / or irritation of the abuser &# 39 ; s nasal passageway tissue . in one embodiment , the present invention includes one or more mucous membrane irritants to cause irritation of mucous membranes located anywhere on or in the body , including membranes of the mouth , eyes and intestinal tract . such compositions can deter abuse via oral , intra - ocular or rectal or vaginal routes . the above - described irritants can be further optimized as necessary or desired in terms of concentration , irritation severity , etc . as described above , the present invention can include one or more emetics or emesis inducing agents . preferably , the emetic is a pharmaceutically acceptable inert excipient that only induces emesis after a certain threshold amount is ingested . in another embodiment , the emetic can be a pharmaceutically active emetic . in one embodiment , the amount of emetic present in a pharmaceutical composition of the present invention can be tied directly to the amount of drug in the pharmaceutical composition . thus , by controlling the quantity of the emetic compound in the pharmaceutical composition , emesis can be avoided if normal prescription directions are followed . however , if an overdosage occurs by ingesting more than a prescribed quantity of a drug in a pharmaceutical composition of the present invention , the amount of ingested emetic can exceed the threshold amount necessary to induce emesis . in some embodiments , the threshold amount of emetic for inducing emesis can be reached when the normal prescription directions are inappropriately increased by factors of 2 , 3 , 4 , 5 , 6 , 7 , or 8 times , or more . thus , in some embodiments , the amount of emetic present in a pharmaceutical composition of the present invention is an amount such that the amount of emetic ingested does not exceed the threshold amount necessary for inducing emesis until a subject ingests 2 , 3 , 4 , 5 , 6 , 7 , or 8 or more times the amount of drug normally prescribed . in some embodiments , emesis can preclude death or serious illness in the subject . in one embodiment , the emetic includes zinc sulfate . zinc sulfate is an excipient , which can induce emesis when more than about 0 . 6 to 2 . 0 gm is ingested , typically more than about 0 . 6 gm . in one embodiment , a pharmaceutically acceptable inert excipient which can induce emesis ( e . g ., zinc sulfate ) can be present at about 5 to 60 percent by weight on a solid basis , or about 5 to 40 percent by weight on a solid basis or about 5 to 25 percent by weight on a solid basis more typically about 5 to 10 percent by weight on a solid basis . accordingly , pharmaceutical compositions of the present invention can be easily designed to induce emesis if a prescribed dosage is exceeded and / or if prescription directions are not followed for dosage forms containing a composition of the present invention . in some embodiments of the present invention , a dosage form can include about 0 . 01 , 0 . 05 , 0 . 1 , 0 . 15 , 0 . 2 , 0 . 25 , 0 . 3 , 0 . 35 , 0 . 4 , 0 . 45 , 0 . 5 , 0 . 55 , 0 . 6 , 0 . 65 , 0 . 7 , 0 . 75 , 0 . 8 , 0 . 85 , 0 . 90 , 0 . 95 , 1 . 0 grams of a pharmaceutically acceptable inert excipient which can induce emesis ( e . g ., zinc sulfate ) or pharmaceutically active emetic . in another embodiment , the present invention includes an inert excipient which can induce emesis ( e . g ., zinc sulfate ) or pharmaceutically active emetic in an amount that is a summation of two or more of the above described amounts . in another embodiment , the present invention can include 1 , 2 , 3 , 4 , or 5 times , or more , of the above described amounts of pharmaceutically acceptable inert excipient which can induce emesis ( e . g ., zinc sulfate ) or a pharmaceutically active emetic . typically , suitable embodiments of the present invention include from about 0 . 1 gm to about 2 . 0 gm of zinc sulfate . in other embodiments the present invention can include about 0 . 6 to less than about 2 . 0 gm of zinc sulfate . for example , in one embodiment , if a practitioner desires to create a dosage form that will induce emesis only after four or more dosage forms are ingested , the amount of zinc sulfate in each dosage form should not exceed about 0 . 19 gm . thus , if three dosage forms are ingested , the amount of emetic is 0 . 57 gm , which is less than a typical threshold amount of the particular emetic . however , if a fourth dosage form having 0 . 19 gm . of zinc sulfate is ingested , the amount of emetic exceeds the threshold amount , and emesis is induced . the above - described emetics can be further optimized as necessary or desired in terms of concentration in the pharmaceutical composition , etc . other suitable emetics can include one or more of cephaeline , methyl cephaeline , psychotrine , o - methylpsychotrine , ammonium chloride , potassium chloride , magnesium sulfate , ferrous gluconate , ferrous sulfate , aloin , and emetine . the present invention can also optionally include other ingredients to enhance dosage form manufacture from a pharmaceutical composition of the present invention and / or alter the release profile of a dosage forming including a pharmaceutical composition of the present invention . some embodiments of the present invention include one or more pharmaceutically acceptable fillers / diluents . in one embodiment , avicel ph ( microcrystalline cellulose ) is a filler used in the formulation . the avicel ph can have an average particle size ranging from 20 to about 200 μm , preferably about 100 μm . the density ranges from 1 . 512 - 1 . 668 g / cm 3 . the avicel ph should have molecular weight of about 36 , 000 . avicel ph effectiveness is optimal when it is present in an amount of from about 10 to 65 percent , by weight on a solid basis , of the formulation . typical fillers can be present in amounts from 10 to 65 percent by weight on a dry weight basis . other ingredients can include sugars and / or polyols . other ingredients can also include dibasic calcium phosphate having a particle size of about 75 to about 425 microns and a density of about 0 . 5 to about 1 . 5 g / ml , as well as calcium sulfate having a particle size of about 1 to about 200 microns and a density of about 0 . 6 to about 1 . 3 g / ml and mixtures thereof . further , lactose having a particle size of about 20 to about 400 microns and a density of about 0 . 3 to about 0 . 9 g / ml can also be included . in some embodiments of the invention , the fillers which can be present at about 10 to 65 percent by weight on a dry weight basis , also function as binders in that they not only impart cohesive properties to the material within the formulation , but can also increase the bulk weight of a directly compressible formulation ( as described below ) to achieve an acceptable formulation weight for direct compression . in some embodiments , additional fillers need not provide the same level of cohesive properties as the binders selected , but can be capable of contributing to formulation homogeneity and resist segregation from the formulation once blended . further , preferred fillers do not have a detrimental effect on the flowability of the composition or dissolution profile of the formed tablets . in one embodiment , the present invention can include one or more pharmaceutically acceptable disintegrants . such disintegrants are known to a skilled artisan . in the present invention , disintegrants can include , but are not limited to , sodium starch glycolate ( explotab ®) having a particle size of about 104 microns and a density of about 0 . 756 g / ml , starch ( e . g ., starch 21 ) having a particle size of about 2 to about 32 microns and a density of about 0 . 462 g / ml , crospovidone ® having a particle size of about 400 microns and a density of about 1 . 22 g / ml , and croscarmellose sodium ( ac - di - sol ) having a particle size of about 37 to about 73 . 7 microns and a density of about 0 . 529 g / ml . the disintegrant selected should contribute to the compressibility , flowability and homogeneity of the formulation . further the disintegrant can minimize segregation and provide an immediate release profile to the formulation . in some embodiments , the disintegrant ( s ) are present in an amount from about 2 to about 25 percent by weight on a solid basis of the directly compressible formulation . in one embodiment , the present invention can include one or more pharmaceutically acceptable glidants , including but not limited to colloidal silicon dioxide . in one embodiment , colloidal silicon dioxide ( cab - o - sil ®) having a density of about 0 . 029 to about 0 . 040 g / ml can be used to improve the flow characteristics of the formulation . such glidants can be provided in an amount of from about 0 . 1 to about 1 percent by weight of the formulation on a solid basis . it will be understood , based on this invention , however , that while colloidal silicon dioxide is one particular glidant , other glidants having similar properties which are known or to be developed could be used provided they are compatible with other excipients and the active ingredient in the formulation and which do not significantly affect the flowability , homogeneity and compressibility of the formulation . in one embodiment , the present invention can include one or more pharmaceutically acceptable lubricants , including but not limited to magnesium stearate . in one embodiment , the magnesium stearate has a particle size of about 450 to about 550 microns and a density of about 1 . 00 to about 1 . 80 g / ml . in one embodiment , magnesium stearate can contribute to reducing friction between a die wall and a pharmaceutical composition of the present invention during compression and can ease the ejection of the tablets , thereby facilitating processing . in some embodiments , the lubricant resists adhesion to punches and dies and / or aid in the flow of the powder in a hopper and / or into a die . in an embodiment of the present invention , magnesium stearate having a particle size of from about 5 to about 50 microns and a density of from about 0 . 1 to about 1 . 1 g / ml is used in a pharmaceutical composition . in certain embodiments , a lubricant should make up from about 0 . 1 to about 2 percent by weight of the formulation on a solids basis . suitable lubricants are stable and do not polymerize within the formulation once combined . other lubricants known in the art or to be developed which exhibit acceptable or comparable properties include stearic acid , hydrogenated oils , sodium stearyl fumarate , polyethylene glycols , and lubritab ®. in certain embodiments , the most important criteria for selection of the excipients are that the excipients should achieve good content uniformity and release the active ingredient as desired . the excipients , by having excellent binding properties , and homogeneity , as well as good compressibility , cohesiveness and flowability in blended form , minimize segregation of powders in the hopper during direct compression . in another embodiment , the present invention can include an opioid antagonist in addition to the other ingredients , or as a substitute for one of the other abuse deterrent ingredients of a formulation of the present invention . suitable antagonists are described above . one particular antagonist includes naloxone . as described above , typically naloxone has no action when taken orally , and will not interfere with the pharmacologic action of an opioid agonist . however , when given by injection naloxone can have profound antagonistic action to opioid agonists . an appropriate antagonist can be used in combination with one or more of gel forming agents , mucous membrane irritants and / or nasal passageway tissue irritants , or emetics in the present invention . an appropriate antagonist can also be used as a substitute for one or more of gel forming agents , mucous membrane irritants and / or nasal passageway tissue irritants , or emetics in the present invention . suitable opioid receptor antagonists can include but are not limited to the antagonists described in u . s . pat . nos . 6 , 559 , 159 and 6 , 375 , 957 , the entire content of which are hereby incorporated by reference . a pharmaceutical composition of the present invention including one or more drug components , one or more of gel forming agents , mucous membrane irritants and / or nasal passageway tissue irritants , and emetics , and optionally other ingredients , can be suitably modified and processed to form a dosage form of the present invention . as referred to herein and in fig5 a , 5 b , 5 c and 6 , an “ abuse deterrent composition ” or “ adc ” ( labeled “ 40 ” in these figures ) includes a composition having one or more gel forming agents and / or mucous membrane irritants and / or nasal passageway tissue irritants , and / or emetics according to the teachings set forth herein . in this manner , an abuse deterrent composition can be layered onto , coated onto , applied to , admixed with , formed into a matrix with , and / or blended with a drug and optionally other ingredients , thereby providing a therapeutic composition of the present invention . as shown in fig5 a , an abuse deterrent composition can be combined with a drug and / or opioid analgesic ( e . g ., hydrocodone ) in one or more layered dosage forms . according to the present invention , drug 50 can be a layer on or near the surface ( i ) of adc 40 of the present invention , or sandwiched between two or more distinct layers ( ii and iii ) of adc 40 of the present invention . in other embodiments , drug 50 can be a coating ( iv ) on adc 40 . drug 50 can be any of the pharmaceutically active ingredients ( e . g ., opioids ) described herein and can be combined with other excipients , e . g . disintegrants including but not limited to sodium starch glycolate or explotab ®. as shown in fig5 b an abuse deterrent composition 40 of the present invention can be combined with drug 50 , e . g ., hydrocodone , in a blended mixture . in such embodiments , drug 50 and adc 40 can be evenly mixed . as shown in fig5 c abuse deterrent composition 40 of the present invention can be combined with drug 50 , e . g ., hydrocodone , in a blended mixture with other ingredients 60 , e . g ., a disintegrant . fig6 shows one embodiment of the present invention for making a dosage form of the present invention . specifically , a first step ( step 1 ) of fig4 shows drug 50 combined with abuse deterrent composition 40 of the present invention . adc 40 can contain one or more gel forming agents and / or mucous membrane irritants and / or nasal passageway tissue irritants , and / or emetics according to the teachings set forth herein . in a second step ( step 2 ), the combination of drug 50 and adc 40 can then be blended with other ingredients 60 , e . g . disintegrants and lubricants , to form a mix 100 . lastly , in a third step ( step 3 ) combination 100 can then be processed using conventional practices 110 , e . g ., compression , into a suitable unit dosage form 120 , e . g . tablets . suitable formulations and dosage forms of the present invention include but are not limited to powders , caplets , pills , suppositories , gels , soft gelatin capsules , capsules and compressed tablets manufactured from a pharmaceutical composition of the present invention . the dosage forms can be any shape , including regular or irregular shape depending upon the needs of the artisan . compressed tablets including the pharmaceutical compositions of the present invention can be direct compression tablets or non - direct compression tablets . in one embodiment , a dosage form of the present invention can be made by wet granulation , and dry granulation ( e . g ., slugging or roller compaction ). the method of preparation and type of excipients are selected to give the tablet formulation desired physical characteristics that allow for the rapid compression of the tablets . after compression , the tablets must have a number of additional attributes such as appearance , hardness , disintegrating ability , and an acceptable dissolution profile . choice of fillers and other excipients typically depend on the chemical and physical properties of the drug , behavior of the mixture during processing , and the properties of the final tablets . adjustment of such parameters is understood to be within the general understanding of one skilled in the relevant art . suitable fillers and excipients are described in more detail above . the manufacture of a dosage form of the present invention can involve direct compression and wet and dry granulation methods , including slugging and roller compaction . however , in the present invention , it is preferred to use direct compression techniques because of the lower processing time and cost advantages . accordingly , and as described further below , a directly compressible pharmaceutical composition of the present invention can be designed following the teachings set forth herein that can deter one or more of a ) parenteral abuse of a drug , b ) inhalation abuse of a drug , and c ) oral abuse of a drug . such compositions and dosage forms are formed according to the present invention are described . steps for making the compositions or dosage forms include the step of providing one or more drugs and / or analgesics described above and an amount of a gel forming polymer having a desired molecular weight or viscosity as described above , and / or providing a nasal tissue irritant , and / or providing an emetic in the amounts as described above . by controlling the molecular weight and / or viscosity of the gel forming polymer , and / or by controlling the amount of mucous membrane irritant and / or nasal tissue irritant such that nasal tissue irritation occurs if the composition is inhaled ( e . g . snorting ), and / or by controlling the amount of emetic such that emesis ensues if more than a prescribed amount of the analgesic is consumed , a therapeutic composition suitable for use to deter drug abuse can be formed . the compositions according to the present invention can deter abuse of the analgesic by ( 1 ) forming a viscous substance upon contact with a solvent such that the substance and analgesic cannot be easily drawn into a syringe and / or ( 2 ) by inducing mucous membrane irritation and / or nasal tissue irritation if the composition is inhaled , and / or ( 3 ) by inducing emesis if more than a prescribed amount of the analgesic is consumed . the present invention can be used to manufacture immediate release , and controlled drug release formulations . controlled release formulations can include delayed release and extended release oral solid dosage preparations . examples 25 ( formulation a7 of fig7 ), 26 ( formulation b7 of fig7 ) and 27 ( formulation c7 of fig7 ) provide embodiments of the invention that can provide controlled release of a drug . the release profiles of the controlled release dosage forms of the present invention are shown in fig7 . the dosage forms in fig7 include hydrocodone bitartrate ( hcbt ) as an active . as shown in fig7 , about 80 to 95 % of the drug in a controlled release dosage form of the present invention is released after about 10 hours , as compared to an immediate release dosage form ( a conventional dosage form ) which is at least 75 % dissolved after about 45 minutes . other opioid formulations having an extended effect , which can be modified to further include one or more of the abuse deterrent compositions of the present invention , are described in u . s . pat . no . 6 , 572 , 885 , the entire content of which is hereby incorporated by reference . certain aspects of the present invention may be better understood as illustrated by the following examples , which are meant by way of illustration and not limitation . a direct compression formulation , as shown in table 1 , for an immediate release opioid analgesic , e . g . hydrocodone bitartrate , tablet having 5 mg of hydrocodone bitartrate was formed by weighing each component separately and mixing the hydrocodone bitartrate and the polymer in a v - blender for about 5 to 10 minutes at low shear conditions or in a high shear blender by mixing 2 to 5 minutes . the other formulation excipients were added to the above blend excepting the lubricant and mixed at the same rate for additional 5 to about 10 minutes . finally , the lubricant , magnesium stearate was added to the formulation and blended at the same rate for an additional 3 to 5 minutes . this polymeric matrix containing the drug and other excipients was further compressed on a rotary tablet press to form pharmaceutically acceptable tablets . the tablets were monitored for weight , hardness , thickness and friability . the tablets were tested for assay , release characteristics ( in - vitro dissolution method ) and abuse deterrent properties . samples of the tablets were subjected to dissolution testing using usp apparatus 2 ( u . s . pharmacopoeia , xxvi , 2003 ), speed 50 rpm at 37 ° c ., in purified water as dissolution medium for a period of 90 minutes . the acceptable dissolution criterion is not less than 75 percent of the drug dissolved in 45 minutes . to evaluate abuse deterrent properties of the formulation a method has been developed that mimics the street abuser &# 39 ; s method for abuse . ( i ) the tablets are crushed and the resulting powder is placed into table / teaspoon . ( ii ) measured amount of water is added to the spoon . contents of the spoon are heated for about 1 to 2 minutes . ( iii ) contents of the spoon are withdrawn using a syringe equipped with a needle . ( iv ) the volume of the sample removed from the spoon is measured and the contents of the syringe are tested for the active , using a suitable analytical test method such as uv / vis spectrophotometry . as shown by table 2 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 31 percent . as shown by table 3 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 11 percent . as shown by table 4 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 6 . 5 percent . as shown by table 5 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 17 percent . as shown by table 6 , a direct compression formulation of oxycodone hydrochloride immediate release formulation including a dosage of 5 mg of oxycodone hydrochloride was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 70 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 9 percent . as shown by table 7 , a direct compression formulation of morphine sulfate immediate release formulation including a dosage of 20 mg of morphine sulfate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 16 percent . as shown by table 8 , a direct compression formulation of morphine sulfate immediate release formulation including a dosage of 20 mg of morphine sulfate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 12 percent . as shown by table 9 , a direct compression formulation of morphine sulfate immediate release formulation including a dosage of 40 mg of morphine sulfate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 15 percent . as shown by table 10 , a direct compression formulation of morphine sulfate immediate release formulation including a dosage of 40 mg of morphine sulfate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 6 percent . as shown by table 11 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 7 . 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 5 percent . as shown by table 12 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 10 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 9 . 5 percent . as shown by table 13 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 27 percent . as shown by table 14 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution showed about 62 % of the drug dissolved in 45 minutes . the drug extracted by the abuse - test method was about 26 . 77 percent . as shown by table 15 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution showed about 72 % of the drug dissolved in 45 minutes . the drug extracted by the abuse - test method was about 31 . 8 percent . as shown by table 16 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution showed about 75 % of the drug dissolved in 45 minutes . the drug extracted by the abuse - test method was about 35 . 75 percent . as shown by table 17 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution showed about 82 % of the drug dissolved in 45 minutes . the drug extracted by the abuse - test method was about 35 . 8 percent . as shown by table 18 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution showed about 79 % of the drug dissolved in 45 minutes . the drug extracted by the abuse - test method was about 42 . 5 percent . as shown by table 19 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 54 percent . as shown in table 20 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 60 percent . as shown by table 21 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 94 percent . as shown in table 22 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 70 percent . as shown in table 23 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 33 percent . as shown in table 24 , a direct compression formulation of hydrocodone bitartrate immediate release formulation including a dosage of 5 mg of hydrocodone bitartrate was prepared and tested using the blending conditions and procedure as stated in example 1 . an in - vitro dissolution criterion of nlt 75 % of the drug dissolved in 45 minutes was met . the drug extracted by the abuse - test method was about 85 percent . as shown by table 28 , a direct compression formulation of oxycodone hydrochloride immediate release formulation including a dosage of 5 mg of oxycodone hydrochloride was prepared using the blending conditions and procedure as stated in example 1 . as shown by table 29 , a direct compression formulation of oxycodone hydrochloride immediate release formulation including a dosage of 5 mg of oxycodone hydrochloride was prepared using the blending conditions and procedure as stated in example 1 . it will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the invention shown in the specific embodiments without departing form the spirit and scope of the invention as broadly described . further , each and every reference cited above is hereby incorporated by reference as if fully set forth herein . | US-65736007-A |
a transcutaneous electrical nerve stimulation apparatus having stimulus electrical pulses modulated in time and intensity to stimulate afferent nerves and cause the release of endogenous opiates which suppress pain . an astable pulse generator provides a first train of pulses at a selected repetition rate . a monostable pulse generator connected to receive the first train of pulses supplies a second pulse train having the frequency of the first train . the width of the pulses of the first train is varied over a predetermined range . a second monostable pulse generator connected to pulse amplifiers receives the first and second train of pulses and provides a supply pulse to the patient . adjustable pulse modulators connected to the second pulse generators function to simultaneously increase the repetition rate of the first train of pulses and decrease the second train of pulses . | fig1 is a diagram of how strength - duration curves would appear for a different class of nerves if all were plotted on the same coordinates . here stimulus intensity increases along the vertical axis and pulse width increases along the horizontal axis . curve a shows the path of modulation in which the pulse width is varied , the amplitude remaining constant . curve b shows the path of modulation in which amplitude increases with pulse width . this is the preferred modulation to maximize the recruitment with time of various classes of nerves , thereby increasing sensory input to the biological system . curve c shows the path of modulation in which amplitude decreases with pulse width . turning now to fig2 the curves are plotted which show the variation of the perception or subjective awareness of stimulation intensity on the vertical axis with rate decrease and pulse amplitude and pulse width on the horizontal axis increase . curve d corresponds to curve b of fig1 and shows that as the pulse amplitude and pulse width increase , the intensity perceived by the patient also increases . curve e shows that if the pulse rate changes , amplitude and pulse width remaining the same , the patient perceives a decrease in stimulus intensity . curve f shows that when the rate decreases , as intensity and pulse width increase , no great change in stimulus is sensed by the patient . the rate changes are encoded at the synaptic level as the integral , or time average , of the number of pulses per second . thus , an increase in pulses per second is experienced as an increase in intensity . the subjective intensity versus rate function is a non - linear s - shaped curve . stimulus intensity changes are encoded as changes in recruitment of the number of nerve fibers . this is a complex function approximately describing an s - shaped curve . in view of the above , if we increase rate , and also increase pulse width and amplitude simultaneously , we will have a double increase in input energy . this results in an intolerable sensation . this perceived increase in time average intensity is undesirable . instantaneous sensation of changes in energy is highly desirable , if there is an avoidance of accommodation and adaption . accommodation is the adjustment of nerves to a constant stimulus such that the stimulus is no longer perceived by the organism . the accommodation to a belt , wrist watch , or glasses , is a common example of this phenomenon . nerve action potentials are no longer propagated . adaption is an adjustment at the perception levels to a stimulus , even though accommodation has not taken place . an example of adaption is the distraction phenomenon , whereby an individual fails to notice pain from an injury due to a stronger sensory input from another source . it is important to avoid both accommodation and adaption to the stimulus if one is to override pain . the stimulator device and method of the present invention accomplishes this in the following manner . the method includes the varying of the input at the synaptic level via rate modulation to give instantaneous variation in information to the central nervous system , thus , avoiding adaption . the variation of the input of the pulse width changes the class of nerve fiber and number recruitment . this avoids accommodation . the variation in intensity changes the number of fibers and class a , b , and c recruitment . this results in the avoiding of adaption and accommodation . the invention accomplishes all of the above in a simple , straight forward , economical manner . the method and apparatus accomplishes the improved control of pain , while increasing the tolerance to high levels of stimulation , by affecting the changes in perceived intensity of stimulus in a manner such that no unpleasant increases in time average energy are perceived . the present invention provides stimuli having variations in the pulse amplitude , pulse width , and pulse rate necessary to accomplish the result of curve f . as shown in fig3 a pair of patient treatment units 20 and 21 are shown as energizing pairs of electrodes 22 and 23 . each unit comprises a pulse amplifier and pulse - width - to - amplitude converter . the units are energized through conductors 24 and 25 from monostable pulse generators 26 and 27 , respectively , having individual manual amplitude controls 30 and 31 for adjustment by the patient . generators 26 and 27 are triggered through conductors 32 and 33 from an astable pulse generator 34 having a manual rate control 35 for adjustment by the patient . generators 26 and 27 are controlled through conductors 36 and 37 by a modulation pulse generator and control 40 , which also controls generator 34 through a conductor 41 . latching of control 40 is accomplished by a switch 42 actuated with control 35 by a mechanical connection 43 . turning now to fig4 astable pulse generator 34 is shown to comprise a regenerative comparator , further referred to as a schmitt trigger 50 , a capacitor 51 , and feed back resistors 52 and 53 , the former being variable by an adjusting knob 54 and comprising manual adjustment 35 of fig4 . monostable pulse generator 26 is shown to comprise an inverter 60 , a capacitor 61 , and a variable resistor 62 connected through a switch 63 to a positive bus 64 energized from the positive terminal of a battery 65 having its negative terminal grounded . a filter capacitor 66 is provided . switch 63 and resistor 62 are actuated by a common knob 67 and constitute adjustment 30 of fig3 . pulse amplifier 20 comprises a capacitor 70 , a mosfet ( field effect transistor ) 71 , and a transformer 72 having a primary winding 73 shunted by a capacitor 74 and connected to bus 64 , and a secondary winding 75 connected to electrodes 22 . monostable pulse generator 27 is shown to comprise a schmitt trigger 80 , a capacitor 81 , and a variable resistor 82 connected through a switch 83 to positive bus 64 . switch 83 and resistor 82 are actuated by a common knob 87 and constitute adjuster 31 of fig3 . pulse amplifier 21 comprises a capacitor 90 , a mosfet 91 , and a transformer 92 having a primary winding 93 shunted by a capacitor 94 and connected to bus 64 , and a secondary winding 95 connected to electrodes 23 . modulation generator 40 comprises a schmitt trigger 100 , a capacitor 101 connected to bus 64 through switches 63 and 83 in parallel , and a feed back resistor 102 . it is connected to generator 26 through a resistor 103 , a diode 104 , and conductor 36 , and to generator 27 through a resistor 105 , a diode 106 , and conductor 37 . modulation generator 40 also comprises a diode 110 , a pair of schmitt triggers 111 and 112 , a pair of mosfets 113 and 114 , a coupling resistor 115 , a coupling capacitor 116 , and a programmable unijunction transistor 117 powered through a pair of resistors 120 and 121 . a modulation mode selector switch 122 is associated with transistor 117 , and is actuated with knob 54 by a mechanical connection 123 as a part of manual adjustment 35 . a visual monitoring circuit 130 is shown to comprise a light emitting diode 131 energized from battery 65 through switches 63 and 83 in parallel under the control of a mosfet 132 an a current limiting resistor 133 . input circuitry for mosfet 132 has a common resistor 134 and includes a diode 135 connected to schmitt trigger 60 and a diode 136 connected to schmitt trigger 80 . in use , switch 122 is closed to inhibit modulation as will be described below , the circuit is energized to provide continuous stimulation to assist in placing one or both pairs of electrodes 22 and 23 on the patient &# 39 ; s body in optimum positions , one or both of switches 63 and 83 being closed for this purpose , and monitoring circuit 130 giving indication of correct operation of the stimulator . after the electrodes are positioned , switch 122 is opened and the character of the stimuli is adjusted at will by operating controls 30 , 31 , and 35 . schmitt trigger 50 with capacitor 51 and resistors 52 and 53 comprises astable pulse generator 34 and sets the basic pulse rate by the setting of resistor 52 . the output rectangular pulses from generator 34 are supplied to capacitors 61 and 81 , which , along with variable resistors 62 and 82 , respectively , produce differentiated pulses in the form of positive and negative spikes . negative going spikes are supplied to the inputs of schmitt triggers 60 and 80 . schmitt triggers are known to exhibit a hysteresis phenomenon , which enables electric circuits comprising schmitt trigger 60 , variable resistor 62 , and capacitor 61 to form a monostable pulse generator 26 . generator 26 has an output rectangular pulse having its width determined by variable resistor 62 and capacitor 61 . in the same way , schmitt trigger 80 , with capacitor 81 and variable resistor 82 , form another monostable generator 27 . schmitt trigger 100 with capacitor 101 and resistor 102 comprises a second astable pulse generator for setting the basic rate of change of modulation for the stimulator . transistor 117 is switched to latch in the modulation mode via diode 110 , once it is selected by switch 122 . when the switch is momentarily actuated , transistor 117 turns on and latches until power is removed , reverse biasing diode 110 and allowing capacitor 101 to charge . this is periodically switched by schmitt trigger 100 to produce a second train of pulses which are communicated through resistor 103 and diode 104 to schmitt trigger 60 , and through resistor 105 and diode 106 to schmitt trigger 80 . when the output pulse of schmitt trigger 100 is at a high level , resistor 103 is in effect placed in parallel with resistor 62 . the reduced resistance of the parallel combination causes capacitor 61 to charge more rapidly , resulting in switching of schmitt trigger 60 sooner so that the width of the pulses from schmitt trigger 60 is reduced . when the output of the schmitt trigger 100 is at a low level , diode 104 is reverse biased , since its anode is now at ground and its cathode is at supply voltage through resistor 62 . this results in the output pulses of schmitt trigger 60 increasing in width to a preset value determined by the setting of resistor 62 . thus , as schmitt trigger 100 switches between high and low outputs , the pulse width alternates between wider and narrower . this variation in pulse width is amplified by transistor 71 and transformer 72 . the parameters of transformer 72 are such that as the output pulse width varies from wide to narrow , the output pulse amplitude varies from high to low , so that the stimulus to the patient fluctuates periodically in intensity and pulse width . an action similar to that just described for schmitt trigger 60 also occurs for schmitt trigger 80 and affects the output of patient unit 21 . a second sequence of events occurs to vary the pulse rate of generator 34 . when the output of schmitt trigger 100 goes to a high level , the signal is conveyed to schmitt trigger 112 whose output goes to a low level . if transistor 113 is turned on , which is the case when transistor 117 is on and a low signal is supplied to schmitt trigger 111 , then the output pulse of schmitt trigger 112 can be communicated through transistor 113 to turn transistor 114 off . when schmitt trigger 100 goes to a low level , schmitt trigger 112 has a low input and a high output . transistor 113 is on transmitting the high level to transistor 114 to turn it on , thus connecting capacitor 116 in parallel with capacitor 51 of generator 34 and suddenly lowering the rate of pulses from schmitt trigger 50 . when schmitt trigger 100 returns to a high level , capacitor 116 is disconnected from schmitt trigger 50 which resumes its former rate of pulses . as pointed out above , when the output of schmitt trigger 100 is high , the pulse width is decreased and the amplitude is reduced . this occurs simultaneously with the increase in the pulse repetition rate . in one embodiment of the invention the output voltage varied between 0 and 60 volts , the pulse width range was 0 to 400 micro - seconds , the pulsing rate was from 1 to 100 pulses per second , the modulation rate was 1 cycle per second , and the changes during modulation were 0 to 40 percent amplitude , 0 to 60 % pulse width , and 10 to 40 % phase rate change . from the above it will be evident that the invention comprises a stimulator in which pulse repetition rate varies between two levels , the variation being accompanied by changes in the pulse width and amplitude , so that an increase in the average pulse energy due to increase in repetition rate is counteracted by a simultaneous decrease due to individual pulses being reduced in width and amplitude . numerous characteristics and advantages of the invention have been set forth in the foregoing description , together with details and structure of the function of the invention , and the novel features thereof are pointed out in the appended claims . the disclosure , however , is illustrative only , and changes may be made in detail , especially in matters of shape , size , and arrangement of parts , within the principle of the invention , to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed . | US-49036183-A |
this disclosure relates generally to methods and pharmaceutical compositions useful in treating pulmonary hypertension . in one embodiment , for example , the disclosure provides a method for treating pulmonary hypertension comprising administering a therapeutically effective dose of a carbonic anhydrase inhibitor to a patient in need of treatment . the disclosure finds utility in the fields of medicine and pharmacology . | before describing the present invention in detail , it is to be understood that unless otherwise indicated , this invention is not limited to particular formulations , active and inactive agents , modes of administration , or methods of treatment or use , as such may vary . it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only , and is not intended to be limiting . it must be noted that , as used in this specification and the appended claims , the singular forms “ a ,” “ an ” and “ the ” include plural referents unless the context clearly dictates otherwise . thus , for example , “ an active agent ” refers not only to a single active agent but also to a combination of two or more different active agents , “ a dosage form ” refers to a combination of dosage forms as well as to a single dosage form , and the like . unless defined otherwise , all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains . although any methods and materials similar or equivalent to those described herein may be useful in the practice or testing of the present invention , preferred methods and materials are described below . specific terminology of particular importance to the description of the present invention is defined below . when referring to an active agent , applicants intend the term “ active agent ” to encompass not only the specified molecular entity but also its pharmaceutically acceptable , pharmacologically active analogs , including , but not limited to , salts , esters , amides , prodrugs , conjugates , active metabolites , and other such derivatives , analogs , and related compounds . the terms “ treating ” and “ treatment ” as used herein refer to reduction in severity and / or frequency of symptoms , elimination of symptoms and / or underlying cause , prevention of the occurrence of symptoms and / or their underlying cause , and improvement or remediation of damage . thus , “ treating ” a patient as described herein encompasses prevention of pulmonary hypertension in a susceptible individual as well as treatment of a clinically symptomatic individual by inhibiting or causing regression of disease . by the terms “ effective amount ” and “ therapeutically effective amount ” of a compound of the invention is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect . the term “ dosage form ” denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve a therapeutic effect with a single administration . when the formulation is a tablet or capsule , the dosage form is usually one such tablet or capsule . the frequency of administration that will provide the most effective results in an efficient manner without overdosing will vary with the characteristics of the particular active agent , including both its pharmacological characteristics and its physical characteristics , such as hydrophilicity . the term “ controlled release ” refers to a drug - containing formulation or fraction thereof in which release of the drug is not immediate , i . e ., with a “ controlled release ” formulation , administration does not result in immediate release of the drug into an absorption pool . the term is used interchangeably with “ nonimmediate release ” as defined in remington : the science and practice of pharmacy , nineteenth ed . ( easton , pa . : mack publishing company , 1995 ). in general , the term “ controlled release ” as used herein includes sustained release and delayed release formulations . the term “ sustained release ” ( synonymous with “ extended release ”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time , and that preferably , although not necessarily , results in substantially constant blood levels of a drug over an extended time period . the term “ delayed release ” is also used in its conventional sense , to refer to a drug formulation which , following administration to a patient , provides a measurable time delay before drug is released from the formulation into the patient &# 39 ; s body . by “ pharmaceutically acceptable ” is meant a material that is not biologically or otherwise undesirable , i . e ., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained . when the term “ pharmaceutically acceptable ” is used to refer to a pharmaceutical carrier or excipient , it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the inactive ingredient guide prepared by the u . s . food and drug administration . “ pharmacologically active ” ( or simply “ active ”) as in a “ pharmacologically active ” derivative or analog , refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree . the invention involves administration of a carbonic anhydrase inhibitor to a patient afflicted with pulmonary hypertension , generally secondary pulmonary hypertension . carbonic anhydrase inhibitors are generally imidazoles ( such as imidazole per se ), imidazole derivatives , sulfonamides ( such as topiramate ), and sulfonylureas ( such as zonisamide ). any carbonic anhydrase inhibitor may be advantageously employed in conjunction with the present invention . examples of suitable carbonic anhydrase inhibitors include , without limitation , acetazolamide ( diamox ™), brinzolamide , diclofenamide , dichlorphenamide ( daranide ™), dorzolamide , furosemide , imidazole , methazolamide ( neptazane ™), phenylalanine , topiramate , and zonisamide . carbonic anhydrase inhibitors also include selective inhibitors of the cyclooxygenase - 2 enzyme (“ cox 2 inhibitors ”), such as such as celecoxib , valdecoxib , rofecoxib , etoricoxib , and the like . preferred carbonic anhydrase inhibitors for use in conjunction with the present invention include , without limitation , acetazolamide , brinzolamide , diclofenamide , dichlorphenamide , dorzolamide , furosemide , imidazole , methazolamide , phenylalanine , topiramate , zonisamide , celecoxib , valdecoxib , rofecoxib , and etoricoxib , with acetazolamide , zonisamide , and topiramate particularly preferred . the oral daily dose of topiramate effective to treat pulmonary hypertension according to the method of the invention is generally in the range of about 10 mg to about 400 mg , preferably in the range of about 50 mg to about 250 mg , and optimally in the range of about 75 mg to about 225 mg . the daily dose may be undivided , such that carbonic anhydrase inhibitor is administered once a day , or the daily dose may be divided into two to four individual doses . preferably , the topiramate is administered in sustained release form , as will be discussed infra , either once or twice daily to achieve a daily dosage in the aforementioned ranges . it will be appreciated that the daily dose of topiramate as well as other carbonic anhydrase inhibitors normally represents on the order of 25 % to 200 %, more generally 25 % to 100 %, and most typically 25 % to 75 %, of the daily dose known and / or prescribed for previously known indication ( s ) ( as set forth , for example , in the physicians &# 39 ; desk reference ), using the same mode of administration . in a preferred embodiment , the dosage of the carbonic anhydrase inhibitor is increased gradually at the outset of therapy , generally over a period of about three to ten weeks , more usually over a period of about three to about eight weeks , starting with a relatively low initial dose ( on the order of 10 mg to 40 mg topiramate , preferably 15 mg to 35 mg topiramate , for instance ), in order to reduce the likelihood of undesirable side effects . with topiramate , for example , a representative dosage regimen is as follows : administration of about 25 mg daily for about the first 5 - 7 days of treatment ; administration of about 50 mg daily for the next 5 - 7 days ; administration of about 75 mg daily for about the next 5 - 7 days ; administration of about 100 mg daily for the next 5 - 7 days ; and , subsequently , ongoing administration of a daily maintenance dose in the ranges specified earlier herein . administration of the active agent may be carried out using any appropriate mode of administration . thus , administration can be , for example , oral , parenteral , transdermal , transmucosal ( including rectal , vaginal , and transurethral ), sublingual , by inhalation , or via an implanted reservoir in a dosage form . the term “ parenteral ” as used herein is intended to include subcutaneous , intravenous , and intramuscular injection . depending on the intended mode of administration , the pharmaceutical formulation may be a solid , semi - solid or liquid , such as , for example , a tablet , a capsule , a caplet , a liquid , a suspension , an emulsion , a suppository , granules , pellets , beads , a powder , or the like , preferably in unit dosage form suitable for single administration of a precise dosage . suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature , e . g ., in remington : the science and practice of pharmacy ( easton , pa . : mack publishing co ., 1995 ). for those compounds that are orally active , oral dosage forms are generally preferred , and include tablets , capsules , caplets , solutions , suspensions and syrups , and may also comprise a plurality of granules , beads , powders , or pellets that may or may not be encapsulated . preferred oral dosage forms are tablets and capsules . as noted above , it is especially advantageous to formulate compositions of the invention in unit dosage form for ease of administration and uniformity of dosage . the term “ unit dosage forms ” as used herein refers to physically discrete units suited as unitary dosages for the individuals to be treated . that is , the compositions are formulated into discrete dosage units each containing a predetermined , “ unit dosage ” quantity of an active agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier . the specifications of unit dosage forms of the invention are dependent on the unique characteristics of the active agent to be delivered . dosages can further be determined by reference to the usual dose and manner of administration of the ingredients . it should be noted that , in some cases , two or more individual dosage units in combination provide a therapeutically effective amount of the active agent , e . g ., two tablets or capsules taken together may provide a therapeutically effective dosage of the carbonic anhydrase inhibitor , such that the unit dosage in each tablet or capsule is approximately 50 % of the therapeutically effective amount . tablets may be manufactured using standard tablet processing procedures and equipment . direct compression and granulation techniques are preferred . in addition to the active agent , tablets will generally contain inactive , pharmaceutically acceptable carrier materials such as binders , lubricants , disintegrants , fillers , stabilizers , surfactants , coloring agents , and the like . capsules are also preferred oral dosage forms for those carbonic anhydrase inhibitors that are orally active , in which case the active agent - containing composition may be encapsulated in the form of a liquid or solid ( including particulates such as granules , beads , powders or pellets ). suitable capsules may be either hard or soft , and are generally made of gelatin , starch , or a cellulosic material , with gelatin capsules preferred . two - piece hard gelatin capsules are preferably sealed , such as with gelatin bands or the like . see , for example , remington : the science and practice of pharmacy , cited earlier herein , which describes materials and methods for preparing encapsulated pharmaceuticals . oral dosage forms , whether tablets , capsules , caplets , or particulates , may , if desired , be formulated so as to provide for controlled release of the carbonic anhydrase inhibitor , and in a preferred embodiment , the present formulations are controlled release oral dosage forms . generally , the dosage forms provide for sustained release , i . e ., gradual , release of the carbonic anhydrase inhibitor from the dosage form to the patient &# 39 ; s body over an extended time period , typically providing for a substantially constant blood level of the agent over a time period in the range of about 4 to about 12 hours , typically in the range of about 6 to about 10 hours . in a particularly preferred embodiment , there is a very gradual increase in blood level of the drug following oral administration of the dosage form containing the carbonic anhydrase inhibitor , such that peak blood level ( generally about 50 - 200 μg / ml for topiramate , about 1 - 5 μg / ml for zonisamide , or about 10 - 35 μg / ml for acetazolamide ), is not reached until at least 4 - 6 hours have elapsed , with the rate of increase of blood level drug approximately linear . in addition , in the preferred embodiment , there is an equally gradual decrease in blood level at the end of the sustained release period . generally , as will be appreciated by those of ordinary skill in the art , sustained release dosage forms are formulated by dispersing the active agent within a matrix of a gradually hydrolyzable material such as a hydrophilic polymer , or by coating a solid , drug - containing dosage form with such a material . hydrophilic polymers useful for providing a sustained release coating or matrix include , by way of example : cellulosic polymers such as hydroxypropyl cellulose , hydroxyethyl cellulose , hydroxypropyl methyl cellulose , methyl cellulose , ethyl cellulose , cellulose acetate , and carboxymethylcellulose sodium ; acrylic acid polymers and copolymers , preferably formed from acrylic acid , methacrylic acid , acrylic acid alkyl esters , methacrylic acid alkyl esters , and the like , e . g . copolymers of acrylic acid , methacrylic acid , methyl acrylate , ethyl acrylate , methyl methacrylate and / or ethyl methacrylate ; and vinyl polymers and copolymers such as polyvinyl pyrrolidone , polyvinyl acetate , and ethylene - vinyl acetate copolymer . preferred sustained release dosage forms herein are composed of the acrylate and methacrylate copolymers available under the tradename “ eudragit ” from rohm pharma ( germany ). the eudragit series e , l , s , rl , rs , and ne copolymers are available as solubilized in organic solvent , in an aqueous dispersion , or as a dry powder . preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate , such as the eudragit l and eudragit s series polymers . particularly preferred such copolymers are eudragit l - 30d - 55 and eudragit l - 100 - 55 ( the latter copolymer is a spray - dried form of eudragit l - 30d - 55 that can be reconstituted with water ). the molecular weight of the eudragit l - 30d - 55 and eudragit l - 100 - 55 copolymer is approximately 135 , 000 da , with a ratio of free carboxyl groups to ester groups of approximately 1 : 1 . the copolymer is generally insoluble in aqueous fluids having a ph below 5 . 5 . another particularly suitable methacrylic acid - methyl methacrylate copolymer is eudragit s - 100 , which differs from eudragit l - 30d - 55 in that the ratio of free carboxyl groups to ester groups is approximately 1 : 2 . eudragit s - 100 is insoluble at ph below 5 . 5 , but unlike eudragit l - 30d - 55 , is poorly soluble in aqueous fluids having a ph in the range of 5 . 5 to 7 . 0 . this copolymer is soluble at ph 7 . 0 and above . eudragit l - 100 may also be used , which has a ph - dependent solubility profile between that of eudragit l - 30d - 55 and eudragit s - 100 , insofar as it is insoluble at a ph below 6 . 0 . it will be appreciated by those skilled in the art that eudragit l - 30d - 55 , l - 100 - 55 , l - 100 , and 5 - 100 can be replaced with other acceptable polymers having similar ph - dependent solubility characteristics . other preferred eudragit polymers are cationic , such as the eudragit e , rs , and rl series polymers . eudragit e100 and e po are cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylates ( e . g ., methyl methacrylate ), while eudragit rs and eudragit rl polymers are analogous polymers , composed of neutral methacrylic acid esters and a small proportion of trimethylammonioethyl methacrylate . a particularly preferred dosage form according to the invention contains in the range of about 10 mg to about 400 mg topiramate , preferably in the range of about 50 to about 250 mg topiramate , most preferably in the range of about 75 mg to about 225 mg topiramate , and is formulated using eudragit rs , eudragit rl , or a blend of eudragit rs and eudragit rl , to provide sustained release over a time period in the range of about 4 to about 12 hours , typically in the range of about 6 to about 10 hours , following oral administration of the dosage form to a patient . such formulations can be made using conventional means known to those of ordinary skill in the art , for example by coating active agent particles with the sustained release polymer ( s ) and either loading the coated particles into a capsule or compressing the coated particles into a tablet using tabletting excipients and a tablet press . preparations according to this invention for parenteral administration include sterile aqueous and nonaqueous solutions , suspensions , and emulsions . injectable aqueous solutions contain the active agent in water - soluble form . examples of nonaqueous solvents or vehicles include fatty oils , such as olive oil and corn oil , synthetic fatty acid esters , such as ethyl oleate or triglycerides , low molecular weight alcohols such as propylene glycol , synthetic hydrophilic polymers such as polyethylene glycol , liposomes , and the like . parenteral formulations may also contain adjuvants such as solubilizers , preservatives , wetting agents , emulsifiers , dispersants , and stabilizers , and aqueous suspensions may contain substances that increase the viscosity of the suspension , such as sodium carboxymethyl cellulose , sorbitol , and dextran . injectable formulations are rendered sterile by incorporation of a sterilizing agent , filtration through a bacteria - retaining filter , irradiation , or heat . they can also be manufactured using a sterile injectable medium . the active agent may also be in dried , e . g ., lyophilized , form that may be rehydrated with a suitable vehicle immediately prior to administration via injection . the active agent may also be administered through the skin using conventional transdermal drug delivery systems , wherein the active agent is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin . in such a structure , the drug composition is contained in a layer , or “ reservoir ,” underlying an upper backing layer . the laminated structure may contain a single reservoir , or it may contain multiple reservoirs . in one embodiment , the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery . alternatively , the drug - containing reservoir and skin contact adhesive are present as separate and distinct layers , with the adhesive underlying the reservoir which , in this case , may be either a polymeric matrix as described above , or it may be a liquid or hydrogel reservoir , or may take some other form . transdermal drug delivery systems may in addition contain a skin permeation enhancer . in addition to the formulations described previously , the active agent may be formulated as a depot preparation for controlled release of the active agent , preferably sustained release over an extended time period . these sustained release dosage forms are generally administered by implantation ( e . g ., subcutaneously or intramuscularly or by intramuscular injection ). although the present compositions will generally be administered orally , parenterally , transdermally , or via an implanted depot , other modes of administration are suitable as well . for example , administration may be transmucosal , e . g ., rectal or vaginal , preferably using a suppository that contains , in addition to the active agent , excipients such as a suppository wax . transmucosal administration also encompasses transurethral administration , as described , for example , in u . s . pat . nos . 5 , 242 , 391 , 5 , 474 , 535 , and 5 , 773 , 020 to place et al . formulations for nasal or sublingual administration are also prepared with standard excipients well known in the art . the pharmaceutical compositions of the invention may also be formulated for inhalation , e . g ., as a solution in saline , as a dry powder , or as an aerosol . in another embodiment of the invention , the method of treating the patient involves administering at least one additional active agent , i . e ., in addition to the carbonic anhydrase inhibitor . the additional active agent may be , for example , a sympathomimetic amine , a type v phosphodiesterase inhibitor , and / or an endothelin antagonist . in some cases , the additional active agent will reduce the quantity of the carbonic anhydrase inhibitor needed to achieve a therapeutic effect , e . g ., a sympathomimetic amine such as phentermine or bupropion can reduce the minimum effective amount of a carbonic anhydrase inhibitor such as topiramate , zonisamide , or acetazolamide . sympathomimetic amines , including the catecholamines , are amine drugs that mimic the actions of drugs that activate the sympathetic nervous system , such as epinephrine and norepinephrine . sympathomimetic amines thus include amphetamine , benzphetamine , bupropion , chlorphentermine , colterol , diethylpropion , dopamine , dobutamine , ephedrine , epinephrine , epinine , ethylnorepinephrine , fenfluramine , fenoldapam , hydroxyamphetamine , ibopamine , isoetharine , isoproterenol , mephentermine , metaproterenol , metaraminol , methoxamine , methoxyphenamine , midodrine , norepinephrine , phendimetrazine , phenmetrazine , phentermine , phenylephrine , phenylethylamine , phenylpropanolamine , prenalterol , propylhexedrine , protokylol , ritodrine , terbutaline , tuaminoheptane , tyramine , and acid addition salts thereof , either organic or inorganic . common acid addition salts of some of the aforementioned sympathomimetic amines include , without limitation , dobutamine hydrochloride , epinephrine bitartrate , ethylnorepinephrine hydrochloride , fenoldopam mesylate , hydroxyamphetamine hydrobromide , isoproterenol hydrochloride , mephentermine sulfate , metaraminol bitartrate , methoxamine hydrochloride , norepinephrine bitartrate , phenylephrine hydrochloride , and terbutaline sulfate . preferably , the sympathomimetic amine is phentermine , chlorphentermine , or bupropion , with phentermine and bupropion particularly preferred . in an exemplary embodiment , the carbonic anhydrase inhibitor administered is topiramate and the sympathomimetic amine administered is phentermine , wherein the daily dose of topiramate is as given above for the monotherapeutic regimen , and the corresponding daily dose of phentermine that is co - administered is such that the weight ratio of the daily dose of topiramate to the daily dose of phentermine is in the range of about 2 . 5 : 1 to about 20 : 1 , typically in the range of about 5 : 1 to about 20 : 1 . in another exemplary embodiment , the carbonic anhydrase inhibitor administered is topiramate and the sympathomimetic amine administered is bupropion , wherein the daily dose of topiramate is as given above for the monotherapeutic regimen , and the corresponding daily dose of bupropion that is co - administered is such that the weight ratio of the daily dose of topiramate to the daily dose of bupropion is in the range of about 1 : 5 to about 3 : 1 , preferably in the range of about 1 : 4 to about 2 : 1 , most preferably in the range of about 1 : 4 to about 1 . 5 : 1 when the method of the invention involves combination therapy , i . e ., wherein a secondary agent such as a sympathomimetic amine is co - administered with a carbonic anhydrase inhibitor , the agents may be administered separately , at the same or at different times of the day , or they may be administered in a single composition . in the former case , it is generally preferred that the sympathomimetic amine be administered later in the day than the carbonic anhydrase inhibitor , particularly when the amine drug acts as a cns stimulant and could interfere with sleep . in the latter case , each agent can be administered in an “ immediate release ” manner or in a “ controlled release manner .” when the additional active agent is a sympathomimetic amine , for instance , any dosage form containing both active agents , i . e ., both the carbonic anhydrase inhibitor and the sympathomimetic amine , can provide for immediate release or controlled release of the sympathomimetic amine , and either immediate release or controlled release of the carbonic anhydrase inhibitor . it is preferred , however , that the carbonic anhydrase inhibitor be in controlled release form , as described supra with respect to carbonic anhydrase inhibitor monotherapy . as an example , a combination dosage form of the invention for once - daily administration might contain in the range of about 50 mg to about 400 mg topiramate , preferably about 50 mg to about 250 mg topiramate , and optimally about 50 mg to about 150 mg topiramate , in controlled release ( e . g ., sustained release ) form , and either phentermine in immediate release form , or bupropion in controlled release form , with the additional active agent present in an amount that provides a weight ratio of topiramate to phentermine , or a weight ratio of topiramate to bupropion , specified as above . in other formulations of the invention , two or more additional active agents , which may or may not be in the same class of drug ( e . g ., sympathomimetic amines ), can be present in combination , along with the carbonic anhydrase inhibitor . in such a case , the effective amount of either or each individual additional active agent present will generally be reduced relative to the amount that would be required if only a single added agent were used . specific examples of such once - daily formulations include the following : as may be deduced from the foregoing , representative topiramate / phentermine formulations typically contain 100 mg to 200 mg topiramate and : 100 mg to 300 mg bupropion ; 10 mg to 15 mg phentermine ; or 100 mg to 300 mg bupropion and 5 mg to 10 mg phentermine . the additional active agent may also be a type v phosphodiesterase inhibitor , administered with the carbonic anhydrase inhibitor , or with both the carbonic anhydrase inhibitor and a sympathomimetic amine . examples of type v phosphodiesterase inhibitors include , without limitation , avanafil , sildenafil , tadalafil , zaprinast , dipyridamole , vardenafil and acid addition salts thereof . avanafil , described in u . s . pat . no . 6 , 656 , 935 , is particularly preferred . in an exemplary embodiment , the carbonic anhydrase inhibitor administered is topiramate and the type v phosphodiesterase inhibitor administered is avanafil , tadalafil , or sildenafil , wherein the daily dose of topiramate is as given above for the monotherapeutic regimen , and the corresponding daily dose of avanafil that is co - administered is such that the weight ratio of topiramate to avanafil is in the range of about 3 : 1 to about 1 : 3 , typically in the range of about 2 : 1 to about 1 : 2 . for sildenafil , which is approximately twice as potent as avanafil , the corresponding daily dose co - administered with topiramate is in the range of about 6 : 1 to about 1 : 1 . 5 , typically about 4 : 1 to about 1 : 1 . for tadalafil , which is a still more potent phosphodiesterase inhibitor , the daily dose when co - administered in combination with topiramate according to the method of the invention is in the range of about 36 : 1 to about 4 : 1 , typically in the range of about 24 : 1 to about 6 : 1 . the additional active agent may also be an endothelin receptor antagonist , e . g ., bosentan , sitaxsentan , or ambrisentan , with bosentan preferred . combination therapy involving a carbonic anhydrase inhibitor and either avanafil or bosentan will generally involve administration of a single dosage form that contains in the range of about 50 mg to about 400 mg topiramate , optimally about 50 mg to about 150 mg topiramate , in sustained release form , and avanafil or bosentan , also preferably in sustained release form . when the additional active agent is avanafil , the amount in the dosage form will generally be such that the weight ratio of topiramate to avanafil provided will be in the range of about 3 : 1 to about 1 : 3 , preferably about 2 : 1 to about 1 : 2 , as noted above . with bosentan , the preferred weight ratio of topiramate to bosentan is in the range of about 0 . 5 : 1 to about 2 : 1 . in the method of the invention , the carbonic anhydrase inhibitor is administered to a person suffering from pulmonary hypertension , either primary pulmonary hypertension or secondary pulmonary hypertension . the carbonic anhydrase inhibitor is administered alone or in combination with one or more additional active agents , within the context of a dosing regiment as described above . it has also been found that the carbonic anhydrase inhibitor alleviates or otherwise treats certain causes of pulmonary hypertension , primarily secondary pulmonary hypertension , such as sleep apnea and chronic obstructive pulmonary disease . it has additionally been found that administration of a carbonic anhydrase inhibitor according to the present invention improves the patient &# 39 ; s cardiac index ( or cardiac output ). further , it has been found that administration of a carbonic anhydrase inhibitor alleviates or otherwise treats certain adverse physiological conditions in addition to pulmonary hypertension , conditions that are often present in patients afflicted with pulmonary hypertension , usually , but not necessarily , with secondary pulmonary hypertension . one such condition is congestive heart failure . accordingly , the invention further encompasses methods of treating congestive heart failure , sleep apnea , and chronic obstructive pulmonary disease using a carbonic anhydrase inhibitor , optionally in combination with one or more additional active agents , at doses and in formulations as described above . all patents , patent applications , and publications mentioned herein are hereby incorporated by reference in their entireties . however , where a patent , patent application , or publication containing express definitions is incorporated by reference , those express definitions should be understood to apply to the incorporated patent , patent application , or publication in which they are found , and not to the remainder of the text of this application , in particular the claims of this application . it is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof , that the foregoing description as well as the examples that follow , are intended to illustrate and not limit the scope of the invention . it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention , and further that other aspects , advantages and modifications will be apparent to those skilled in the art to which the invention pertains . a 26 year - old female with obesity and elevated lipids exhibited a heart murmur , shortness of breath out of proportion to her weight and age , low blood pressure , and leg edema . she underwent an echocardiogram , which showed mitral regurgitation of 1 - 2 + and mild elevation in pulmonary artery pressure of 36 mm hg . she was 66 ″ tall , weight 282 lbs , bmi 46 , initial bp 118 / 80 . she had 2 + edema of both ankles , clear lungs , and a systolic murmur along the left sternal border , grade ii / vi . she was started on atorvastatin 10 mg daily as well as bupropion 150 mg daily and topiramate 200 mg daily along with a low fat , low carbohydrate diet and exercise . two weeks after the start of her weight loss program she reported that her exercise tolerance was markedly improved and previous chest pressure and shortness of breath on exertion were gone . she lost weight continuously on the program and 4 months later had lost 20 lbs . a repeat echocardiogram taken 2 weeks after the start of treatment showed only 1 + mitral regurgitation and normal pulmonary pressures . after six months , the patient temporarily discontinued the medications . within a few days , even though her weight was the same , her chest pressure and shortness of breath on exertion returned . on resumption of the treatment , the symptoms resolved within a few days . the second patient was a 57 year - old female with obesity , hypothyroidism , hypertension , valvular heart disease , elevated cholesterol and depression . her medications were levothyroxine 50 mcg daily , metoprolol 50 mg daily , venlafaxine 37 . 5 mg daily , progesterone 100 mg daily , esterified estrogens 1 . 25 mg daily , and methyltestosterone 2 . 5 mg daily . she was 63 ″ tall , weight 178 lbs , bmi 32 , initial bp 120 / 78 . she had trace edema of both ankles and a systolic murmur of i / vi along the left sternal border . an echocardiogram obtained nine months before obesity treatment because of her heart murmur and edema showed mild mr , moderate tr and pulmonary hypertension with a pressure of 39 mm hg noted . a comment on the report stated that this was a slight increase in pulmonary pressure compared with an echocardiogram taken seven months earlier . she was treated with phentermine 15 mg daily and topiramate 200 mg daily along with a low fat , low carbohydrate diet and exercise . metoprolol was discontinued after four months due to low blood pressure . eight months after treatment started , her weight was 165 lbs , bp was 122 / 76 , and she had no edema . a repeat echocardiogram 1 month later ( nine months on treatment for obesity ) showed that the pulmonary artery pressure was 33 mm hg and the tricuspid regurgitation was now rated as mild . no mr was seen . the third patient was a 62 year - old female with obesity , hypertension , elevated cholesterol , heart murmur and dyspnea on exertion . her medications were atorvastatin 10 mg daily , captopril 12 . 5 mg daily , trazodone 50 mg daily , spironolactone 50 mg daily , and bupropion 150 mg daily . she was 64 ″ tall , weight 319 lbs , bmi 55 , initial bp 148 / 76 . she had a systolic murmur of i / vi loudest along the left sternal border . an echocardiogram showed mild tricuspid regurgitation , normal lv size and function with probable mild pulmonary hypertension . she was treated with phentermine 15 mg daily and topiramate 200 mg daily along with a low fat , low carbohydrate diet and exercise . she was instructed to stop both the spironolactone and captopril since this weight loss treatment results in marked lowering of blood pressure in most patients . three weeks later , before significant weight loss had occurred , a repeat echocardiogram showed no findings of pulmonary hypertension . blood pressure one week later was 140 / 86 and weight 317 lbs . the fourth patient was a 56 year - old female with obesity , sleep apnea on cpap , known pulmonary hypertension with pa pressure estimated at 76 mm hg by echocardiogram , valvular heart disease ( mild - moderate tricuspid and mitral regurgitation ), depression and hypertension . she smoked just under half pack of cigarettes per day and was a co2 retainer by abg &# 39 ; s with a pco2 of 54 mm hg on room air . she was short of breath with minimal exertion . her baseline medications were furosemide 80 mg daily , potassium chloride 20 meq daily , lisinopril 10 mg daily , carvedilol 25 mg bid , escitalopram 10 mg daily , alprazolam 0 . 5 mg tid , and nightly oxygen . she was 68 ″ tall , weight 284 lbs , bmi 43½ , initial bp 122 / 76 . she had 1 + edema of both lower legs and was short of breath on exertion . she was treated with aspirin 81 mg coated daily , bupropion 300 mg daily , topiramate 100 mg daily , phentermine 5 mg daily , along with a low fat , low carbohydrate diet and light exercise . by the first 4 weeks of follow - up , she had lost 17 lbs and was breathing much better . four months into the treatment she was clinically markedly improved and able to exercise normally without shortness of breath . she was still smoking cigarettes occasionally . she had lost 38 lbs . her blood pressure was 110 / 70 on only lisinopril 10 mg daily . furosemide and carvedilol had been gradually discontinued due to improved edema , blood pressure , and breathing . an echocardiogram performed at three months into the program was mostly unchanged from her prior echocardiogram except that the pulmonary artery pressure was reported as normal . this change was consistent with her clinical picture . the fifth patient was a 70 year - old female with obesity , diabetes , hypertension , hypothyroidism , elevated cholesterol , copd , and pulmonary hypertension . an echocardiogram 2 years previously showed mild lvh , mild - moderate tricuspid regurgitation , mild rvh , and elevated pulmonary artery pressure of 45 - 50 mm hg . she had stopped smoking 1 ppd about 10 years previously . her baseline medications were verapamil 240 mg daily , losartan - hctz 50 - 12 . 5 daily , levothyroxine 0 . 125 mg daily , pulmicort 200 mg 2 puffs twice daily , foradil powder 12 mg twice daily , metformin 500 mg twice daily , atorvastatin 10 mg daily , fluticasone nasal spray 50 mcg 2 puffs daily and vitamins . she was short of breath with minimal exertion . she was 67 ″ tall , weight 228 lbs , bmi 36 , initial bp 138 / 70 . she was treated with phentermine 15 mg daily and topiramate 100 mg daily . three years into treatment , her fasting glucose is 106 off metformin compared with 114 on metformin at baseline , her blood pressure is 115 / 60 on valsartan 80 mg daily and diltiazem cd 120 mg daily ( changed from verapamil because of constipation ). her weight has been stable for six months in the low 180 &# 39 ; s . a follow - up echocardiogram 30 months into treatment showed normal pulmonary pressures . she was also symptomatically much better and exercising more without shortness of breath . these five patients showed a surprising improvement in pulmonary hypertension , with marked improvement in symptoms in two patients even before significant time had elapsed , and symptomatic improvement in all patients . in addition to treatment with topiramate , a carbonic anhydrase inhibitor , these patients were also subject to a low fat , low carbohydrate diet and weight loss program that typically resulted in mild diuresis and lower blood pressures . however , the improvement in pulmonary pressures appeared to be independent of weight loss in these patients . the procedure of example 1 is repeated with a patient exhibiting similar symptoms with respect to pulmonary hypertension , except that 25 mg zonisamide is substituted for the topiramate . substantially the same results are expected . the procedure of example 1 is repeated with a patient exhibiting similar symptoms with respect to pulmonary hypertension , except that 50 mg zonisamide is substituted for the topiramate . substantially the same results are expected . the procedure of example 1 is repeated with a patient exhibiting similar symptoms with respect to pulmonary hypertension , except that 100 mg zonisamide is substituted for the topiramate . substantially the same results are expected . the procedure of example 1 is repeated with a patient exhibiting similar symptoms with respect to pulmonary hypertension , except that 100 mg acetazolamide is substituted for the topiramate . substantially the same results are expected . the procedure of example 1 is repeated with a patient exhibiting similar symptoms with respect to pulmonary hypertension , except that 250 mg acetazolamide is substituted for the topiramate . substantially the same results are expected . the procedure of example 1 is repeated with a patient exhibiting similar symptoms with respect to pulmonary hypertension , except that 500 mg acetazolamide is substituted for the topiramate . substantially the same results are expected . the procedures of examples 2 through 5 are repeated with patients exhibiting similar symptoms with respect to pulmonary hypertension , except that the following are substituted for the amount of topiramate given : 25 mg , 50 mg , and 100 mg zonisamide ; and 100 mg , 250 mg , and 500 mg acetazolamide . substantially the same results are expected . sustained release dosages in the form of gelatin capsules were prepared with a target dose of 15 mg phentermine and 100 mg topiramate per capsule . phentermine beads were prepared using 20 / 25 mesh sugar spheres nf and a drug layering solution containing components selected from phentermine , methocel ® e5 ( hypromellose , produced by the dow chemical company ), and water . topiramate beads were prepared using a spheronized core , a cr coating , and an enteric coating . the spheronized core contained components selected from topiramate , avicel ® ph102 ( microcrystalline cellulose , supplied by fmc biopolymer ), and methocel ® a15lv ( methylcellulose , produced by the dow chemical company ). the cr coating solution contained components selected from eudragit ® rspo ( less permeable , amino methacrylate copolymer , supplied by degussa pharma polymers , germany ), eudragit ® rlpo ( more permeable , amino methacrylate copolymer , supplied by degussa pharma polymers , germany ), glycerol monostearate , isopropyl alcohol , and acetone . the enteric coating solution contained components selected from eudragit ® s100 ( copolymer of methacrylic acid and methyl methacrylate , supplied by degussa pharma polymers , germany ), glycerol monostearate , isopropyl alcohol , and acetone . weight percentages ( theoretical — not measured ) for the final compositions are summarized in tables 1 - 3 . dosages in the form of gelatin capsules were prepared with a target dose of 100 mg topiramate per capsule . topiramate beads were prepared using a spheronized core , an optional cr coating , and an optional enteric coating . the spheronized core contained components selected from topiramate , avicel ® ph102 , and methocel ® a15lv . the cr coating solution contained components selected from ethylcellulose ( ethocel premium standard 10 ), povidone k - 30 , ethanol ( absolute sd3a ), eudragit ® rlpo ( more permeable ), glycerol monostearate , isopropyl alcohol , and acetone . the enteric coating solution contained components selected from eudragit ® s100 , eudragit ® l100 - 55 , glycerol monostearate , isopropyl alcohol , and acetone . weight percentages ( theoretical — not measured ) for the final compositions are summarized in tables 4 - 8 . table 4 describes capsules containing spheronized topiramate beads without a cr coating and without an enteric coating . tables 5 and 6 describe capsules containing spheronized topiramate beads with a cr coating but without an enteric coating . tables 7 and 8 describe capsules containing spheronized topiramate beads with an enteric coating but without a cr coating . dosages in the form of gelatin capsules were prepared with a target dose of 100 mg topiramate per capsule . spheronized topiramate beads were prepared using components selected from topiramate , methocel ° a15lv , acdisol ®, avicel ° ph102 , and lactose monohydrate . weight percentages ( theoretical — not measured ) for the final compositions are summarized in tables 9 - 10 . in addition to the dosage forms described in tables 9 - 10 , a capsule was prepared containing 100 wt % topiramate ( target fill weight = 100 . 0 mg ). | US-201314025051-A |
broadly defined adhesive latex formula s exhibiting antimicrobial properties . such formulations comprise certain antimicrobial compounds , such as , preferably , metal - containing ion - exchange and / or zeolite compounds , are provided . the inventive latex formulations must also exhibit substantially uniform characteristics in order to provide a functionally and aestheticially pleasing formulation for utilization within any number of applications . in order to provide such an inventive latex formulation , it has been found that compounding of all the base ingredients must be undertaken prior to the final thickening step , which ultimately produces the desired latex . the specific method of producing such formulations is also encompassed within this invention . | it is thus an object of the invention to provide a simple manner of producing an effective adhesive latex comprising , as the sole antimicrobial agent , at least one inorganic silver - based ion - exchange compound or zeolite compound . another object of the invention is to provide an antimicrobial adhesive latex exhibiting a substantially uniform appearance and possessing no voc content . accordingly , this invention encompasses an adhesive latex fomulation comprising at least one polymer constituent , at least one thickening agent ( in order to provide a latex having a viscosity of , preferably , at least 4 , 000 cps at 25 ° c . and at 1 atmosphere ), and at least one inorganic silver - based antimicrobial agent selected from the group consisting of silver - based ion - exchange compounds , silver - based zeolites , silver - based glasses , and any mixtures thereof , wherein said formulation does not include any voc ( due to the absence of any organic bactericide compounds , primarily ). this invention also encompasses a method of producing such an antimicrobial adhesive latex formulation comprising the steps of ( a ) providing a polymer constituent , compounding said polymer constituent with an inorganic silver - based antimicrobial agent ( as noted above ) and a thickener , simultaneously , until the resultant composition exhibits a viscosity of , preferably , at least 4 , 000 cps at 25 ° c . and at 1 atmosphere . the term adhesive latex is intended to encompass any thickened formulation of already - made polymer constituents which possesses a viscosity of at least viscosity of , preferably , at least 125 , 000 cps at 25 ° c . and at 1 atmosphere and which also exhibits an affinity for different surfaces which results in the ability to create a stationary interaction between the latex and the target surface without the needed presence of any other adhesive initiators , additives , compounds , or other compositions . such latices are well known throughout the pertinent art ( such as within u . s . pat . no . 5 , 736 , 591 ) and may be utilized within any variety of applications which require extremely thick adhesives , including , without limitation , carpet backings , sealant compositions ( for ceramic tiles , for example ), and the like . the term polymer constituent is intended to encompass any polymeric material capable of being in latex form . such constituents thus include , without limitation , olefins , acrylics , urethanes , vinylidene chlorides , vinyl acetates , vinyl pyridines , aromatics , silicones , and any copolymers thereof . most preferably , the latex is a styrene butadiene rubber ( sbr ) latex , a polyurethane latex , a vinylidene chloride latex , a polyvinylidene chloride latex , a carboxylated sbr latex , and the like . such polymer constituents within this invention include , without limitation , and preferably , hpl 8455na ( a vinylidene chloride ) from dow , and reichold r101 ( sbr rubber ). the amount of polymer constituent present within the inventive latex ranges from about 10 to about 65 % by weight of the total composition . preferably , this amount is from about 20 to about 60 %; more preferably from about 25 to about 50 %; most preferably from about 30 to about 50 %. it is common for such pre - prepared polymer constituents to include biocide agents solely for the purpose of preserving such compounds upon long - term storage . such latices arc preferably of high solids content to provide high adhesive properties . as such , the latex should be , as noted above , of rather high viscosity in order to stabilize the solid compounds in composition . such a viscosity , as measured at 25 ° c . and at 1 atmosphere pressure , is at least 4 , 000 cps ; preferably between about 4 , 500 and 25 , 000 cps ; more preferably from about 5 , 000 cps to about 15 , 000 cps ; and most preferably from about 5 , 000 cps to about 12 , 000 cps . the necessary thickener added to the polymer constituent is thus of prime importance . a thickener such as polyacrylate salt ( sodium for example ) is highly preferred , although any standard latex thickening agents may be utilized for this purpose . the amount of thickener is highly dependent on the desired target viscosity . generally , then , the amount should be from about 0 . 005 to about 5 % by weight of the total latex formulation ; preferably from about 0 . 01 to about 3 %; more preferably from about 0 . 015 to about 1 %; and most preferably from about 0 . 02 to about 0 . 5 %. the term inorganic silver - based antimicrobial material is intended to encompass any such silver - conatining solid compound which is primarily inorganic in nature ( some organic component is permitted , although the primary antimicrobial portion must be inorganic ), is a solid at standard temperature and pressure , and which exhibits antimicrobial activity . preferably , such material is a silver - based ion - exchange compound , a silver - based zeolite , or a silver - based glass , and any combinations thereof the preferred silver - based ion exchange material is an antimicrobial silver zirconium phosphate available from milliken & amp ; company , under the tradename alphasan ®. other potentially preferred silver - containing solid inorganic antimicrobials in this invention is a silver - substituted zeolite available from sinanen under the tradename zeomic ® aj , or a silver - substituted glass available from ishizuka glass under the tradename ionpure ®, may be utilized either in addition to or as a substitute for the preferred species . other possible compounds , again without limitation , are silver - based materials such as amp ® t558 and microfree ®, both available from dupont , as well as jmac ®, available from johnson matheny . generally , such a metal compound is added in an amount of from about 0 . 00001 to 10 % by total weight of the particular latex composition ; preferably from about 0 . 001 to about 5 %; more preferably from about 0 . 01 to about 1 %; and most preferably from about 0 . 1 to about 1 . 0 %. other possible components within the inventive latex composition include water , ( as a diluent ), fillers , such as calcium carbonate ( to provide strength and hardness to the latex , as well as to fill any “ empty spaces ” for a uniform strength dispersion ), flame retardants , such as antimony oxide , available from great lakes chemical , emulsifiers and / or surfactants ( to provide more effective interaction with target surfaces and / or to provide foaming for easier application to target surfaces ). of these components , the fillers are generally added in large amounts within such latex formulations for the strength and hardness purposes . as noted above , such an inventive comprises no organic bactericide compounds and thus does not include any appreciable voc content originating from the antimicrobial component . this is of vital importance to ensure that utilization of such a latex does not result in the release of environmentally and / or physically hazardous organics , particularly upon exposure to high temperatures ( e . g ., above about 100 ° c .). the inventive adhesive latex is preferably compounded with all of the required components simultaneously added together in order to provide the most uniform product , from both appearance and physical performance perspectives . thus , simultaneous compounding of the polymer constituent , thickener , and silver - based inorganic antimicrobial agent are required ( as well as the other potential additives ) for this purpose . adding such solid antimicrobial agents after compounding is extremely difficult without the production of highly undesirable discolorations ( e . g ., darkening , particularly if high temperatures are utilized for further processing ). the particular silver - based inorganic antimicrobial agent should exhibit an acceptable log kill rate after 24 hours in accordance with the aatcc test method 100 - 1983 . such an acceptable level log kill rate is tested for staphylococcus aureus or klebsiella pneumoniae of at least 0 . 1 increase over baseline . alternatively , an acceptable level will exist if the log kill rate is greater than the log kill rate for non - treated ( i . e ., no solid inorganic antimicrobial added ) latices ( such as about 0 . 5 log kill rate increase over control , antimicrobial - free latices ). preferably these log kill rate baseline increases are at least 0 . 3 and 0 . 3 , respectively for s . aureus and k . pneumoniae ; more preferably these log kill rates are 0 . 5 and 0 . 5 , respectively ; and most preferably these are 1 . 0 and 1 . 0 , respectively . of course , the high end of such log kill rates are much higher than the baseline , on the magnitude of 5 . 0 ( 99 . 999 % kill rate ). any rate in between is thus , of course , acceptable as well . however , log kill rates which are negative in number are also acceptable for this invention as long as such measurements are better than that recorded for correlated non - treated latices . in such an instance , the antimicrobial material present within the latex at least exhibits a hindrance to microbe growth . the preferred embodiments of these alternatives fabric treatments are discussed in greater detail below . examples of particularly preferred compounds within the scope of the present invention are set forth below . the preferred inventive adhesive latices were compounded in accordance with the table below with all of the components admixed together . the resultant viscosity of each of these compositions are listed as ranges . the resultant compounded formulation exhibited a viscosity of approximately 5 , 500 cps . the resultant compounded formulation exhibited a viscosity of approximately 5 , 500 cps . the antimicrobial material tested was alphasan ® rc 5000 and rc 7000 and , for comparison purposes , durotex 5000 ( an isothiazoline - based bactericide from rohm and haas ). the resultant latices were then utilized as carpet backing components during the production of carpet tiles which involved combining at least three carpet components together , namely the face fibers ( e . g ., pile fibers ), the primary backing fabric ( through which the face fiber is introduced ), and the secondary backing fabric or a polyurethane foam backing or an olefinic - based resin the adhesive latex was introduced to the side of the primary backing fabric prior to with the secondary backing . upon introduction the latex strongly adhered to the backing and , upon said subsequent contact , with the secondary backing . the resultant was a strongly integrated article as desired , the face fibers were then coated and into separate preparations of microbes , namely , s . aureus and k . pneumoniae . after an exposure of 24 hours , the carpet was then tested for log kill rates of such microbes in accordance with aatcc test method 100 - 1993 . the results for each of the formulations noted above , in combination with the specific antimicrobial agents as noted above , are in tabular form below : there are , of course , many alternative embodiments and modifications of the present invention which are intended to be included within the spirit and scope of the following claims . | US-65452900-A |
a residue handling system for an agricultural combine including a residue chopper that provides enhanced air flow for evenly distributing crop materials onto a crop field . a hub and blade assembly accurately positions flail blades and resists fatigue stresses . each flail blade includes an outer portion that is angled longitudinally away from a plane transverse to the axis of rotation . in a mated blade pair embodiment , the leading edges of the paired flail blades may be closer to each other than the trailing edges , or vice versa . also , the leading edges of the flail blade pair may be the same distance away as the trailing edges of the pair , beneficially directing discharge sideways in a preferred common direction . the assembly includes a mounting support post that has a width substantially equal to the distance between two mated blades . the mated blades are installed directly against the sides of the mounting support , without spacer bushings , using only three connector elements . | referring to the drawings , and particularly to fig1 a portion of a rotary combine is shown generally at 10 . the combine portions 10 includes a feeder assembly 20 and a rotary threshing assembly 22 . the rotary threshing assembly 22 includes a rotor 26 and a rotor housing 28 . crop materials travel rearwardly through the rotary threshing assembly 22 and are threshed by a series of threshing elements attached to the exterior of the rotor 26 . along the bottom side of the rotor housing 28 are perforated concaves 30 which allow grain heads and other fine materials to pass through , and out of , the rotary threshing assembly 22 . larger material pieces such as crop stalks continue rearwardly through and are discharged out the rear end of the rotary threshing assembly 22 . the grain heads and other fine materials are directed to a series of sieves 32 . a drive mechanism ( not shown ) effects a constant back and forth motion between the sieves 32 . as the crop materials pass through the sieves 32 , they further separate the grain from the unwanted chaff and fine and light materials . a cleaning fan 34 located forward of the sieves 32 blows air rearwardly through the sieves , thus helping to separate the grain from the fine and light materials . the cleaning fan 34 air also drives the unwanted fine and light materials out the rear end of the sieves 32 . the distribution of unwanted crop materials onto the cleared field as the combine 10 travels across the field is effected by a residue chopper 41 embodying features of the invention . the chopper 41 chops the crop stalks into a finer residue material , mixes the chopped crop stalks with the chaff fine materials , and distributes the mixed residue evenly across the crop field . the residue chopper 41 is oriented transversely of the combine to the rear of the threshing assembly 22 . referring now to fig2 the residue chopper 41 includes housing 42 mounted in the combine body 12 and elongated transversely of the body . the housing 42 encloses a rotatable hub and blade assembly 49 , including a hub 48 to which flail blades 50 are pivotally attached , preferably in mated pairs . the hub and blade assembly 49 is viewed from one end in fig2 which shows it rotating in a counter - clockwise direction . the housing 42 has front entrance 44 through which both crop stalks and chaff fine materials enter . it also has a rear exit 46 where chopped materials exit . to aid in spreading the exiting crop materials evenly across the field , vanes 47 are attached to the rear end of the combine body 12 near the rear exit 46 . the vanes 47 are angled outwardly so that the crop materials which exit the system 40 are redirected to cover a wide swath pattern . optimally , the width of the swath pattern is equal to the width of the header assembly 18 . to spread the crop materials over a swath of this width , the crop materials have to contact the vanes 47 at a high velocity . in order to achieve this high velocity , a large amount of air flow must be driven at a high speed through the housing 42 . the system 40 of the present invention accelerates the stream of air received from the cleaning fan 34 so as to produce an air flow speed of up to sixty miles per hour at the exit 46 . referring now to fig3 in the hub assembly 49 a plurality of flail blades 50 are pivotally attached to a hub 48 in pairs 51 , arranged in a row spaced along the length of the hub 48 . in turn , four such rows are displaced 90 ° from each other around the hub 48 . drive means ( not shown ), which are well known to those skilled in the art , rotate the assembly 49 . referring additionally to fig4 and 5 , each flail blade 50 includes a flat inner mounting portion 54 lying in the plane of blade rotation , which is transverse to the axis of the hub 48 . the outer portion 56 of the flail blade 50 is angled away from the plane of rotation of the blade . the blades 50 are pivotally connected to the hub 48 in a manner hereinafter discussed . a preferred method of manufacturing the flail blade 50 is by bending a single piece of metal so that an intermediate portion 58 is bent in a smooth transition between the outer portion 56 and the inner portion 54 . in the illustrated blade , 50 , the outer portion 56 is flat , both longitudinally and transversely . therefore , as the hub 48 rotates each radial line along its forward surface 60 travels along a different plane . although the invention envisions employing a variety of blade 50 angles , a preferred configuration has a flat outer portion 56 which is angled five degrees from the plane of blade rotation so that its projected frontal area is twelve millimeters wide . in an alternative configuration , the flat outer portion 56 is angled thirty - five degrees from the plane of blade rotation so that its projected frontal area is twenty - four millimeters wide . the specific angle of the outer portion 56 in a flail blade can be tailored to optimize the cutting action , i . e . fine or coarse , and the effect on exiting air flow velocity of the system 40 . the flail blades 50 are preferably attached to the hub 48 in mated pairs 51 , as has been pointed out . in the arrangement seen in fig3 - 5 , the leading edges 62 of the outer portions 56 on mated flail blades are relatively close to each other . the trailing edges 64 of the outer portions 56 on the mated blades , on the other hand , are relatively further from each other . a v - shape pocket is formed between , and behind , the outer portions 56 of the mated blades . as the hub 48 rotates , the forward surfaces 60 of the outer portions 56 compress the air in front of the blades 50 , driving air forward . also , a pressure drop is created in the pocket formed behind the rear surfaces 61 of the outer portions 56 of each pair of blades 50 , causing the rotating blades to draw air from the rear . referring to fig2 attached to the base of the housing 42 , in fixed relationship , are a series of knives 43 ( only one shown ). the knives 43 extend upwardly , inside the housing 42 , between mated pairs of flail blades 50 . a scissor - like cutting action results as each flail blade 50 passes by a knife 43 . the cutting action chops the crop materials into a finer residue . the knife blades 43 are all mounted in one , downwardly removable cassette 70 . the number of knife blades 43 , and their placement , can then be easily changed , based on the angle and width of the flail blades 50 , in order to achieve a variety of fine or coarse cutting actions . preferably , the leading edge 62 of each blade 43 is sharpened , as at 63 , to enhance the scissor action . this is accomplished by relieving the leading edge 62 to a surface that it lies in the plane of blade 50 rotation , or is angled from this plane , so that this surface actually undercuts the forward surface 60 . the blade 50 mounting support includes a mounting post 72 for each pair of blades 50 fixed to the hub 48 . each post 72 comprises a rectangular cross - section tube extending radially away from the hub 48 . each tube includes front and back walls 74 and 75 , and left and right side walls 76 and 77 . the outside width of the tube in each mounting post 72 is substantially the same as the desired distance between the mounting surfaces 52 of a mated pair of flail blades 50 . thus , the mounting surfaces 52 of the flail blades 50 seat flush against the exterior surfaces of the side walls 76 and 77 . referring to fig6 as well as fig5 the mated pair of blades 50 are pivotally mounted on the support post 72 with a hollow pin 78 . the pin 78 extends through the inner portions 54 of the flail blades 50 and the mounting support side walls 76 and 77 . the pin 78 has a cap 79 at one end and an internally threaded bore 80 extending into the other end . a bolt 81 having a head 82 and a threaded shaft 83 is inserted through a washer 84 into the bore 80 . the threaded shaft 83 is received in the threaded bore 80 . the bolt 81 can easily be tightened with a wrench , acting on the head 82 . in order to provide maximum contact area between the flail blade 50 and the mounting support 72 , and to allow pivoting clearance between the inner portion 54 of the flail blade and the hub 48 , the innermost edge of the flail blade is formed in a segmentally circular shape around the pivot axis of the bolt 78 . this is best seen in fig4 . the flail blades 50 are more accurately positioned in the present invention because spacer bushings , which are commonly used in prior art systems , are not required . additionally , a greater area of surface contact and , thus , support is possible between the flail blade mounting surface and the mounting support side walls 76 and 77 . because the flail blades are positioned more accurately , a more effective scissor action is made possible because each knife 43 may be positioned closer to the spaced flail blades 50 than is possible with prior art mounting systems . the tubular configuration of the mounting post 72 is also stronger than the simple tang mounts prevalent in the prior art . therefore , the mounting post 72 can better resist fatigue stresses , stresses that cause tang mounts to break . in the first form of blade assembly 49 which has been described , the leading edges 62 of mated blades 50 are relatively close to each other while the trailing edges 64 are relatively further apart . in a second form of blade assembly , seen in fig7 just the opposite is true . in this form , the trailing edges 164 of mated blades 150 are relatively close to each other while the leading edges 162 are relatively further apart . in a third form of hub and blade assembly 249 embodying features of the present invention , as seen in fig8 the leading edges 262 and trailing edges 264 of the mated blades 250 are equidistant from each other . the outer portions 256 of each blade 250 in a mated pair are angled at anywhere between five degrees and thirty - five degrees from a plane transverse to the axis of rotation of the hub 248 . referring now to fig9 another hub and blade assembly 349 embodying features of the invention is illustrated . the assembly 349 utilizes a combination of blade forms which produce a particularly advantageous result ; serving both to enhance air flow through the chopper housing and the spreading of exiting crop materials across the field . as seen in fig9 the hub and blade assembly 349 includes a hub 348 . six rows of mated pairs 351 of blades 350 are mounted on the hub 348 ( 60 ° displayed from each other ). each row contains five evenly spaced pairs 351 of blades 350 . each row of blade pairs 351 also includes three different blade 350 arrangements , 350 a , 350 b and 350 c . in fig9 in the uppermost blade row illustrated , each blade pair 351 a is constructed and arranged according to the first form of the invention . the blade pair 351 b is constructed and arranged according to one variation of the third form of the invention . each blade pair 351 c is constructed and arranged according to another variation of the third form of the invention . insofar as variations of the third form of blade pairs 351 b and 351 c are concerned , it will be seen that the variation resides in the direction of inclination of the outer portions 356 of the blades 350 in question . the blades 350 in the pairs 351 b have both outer blade portions 356 inclined ( in the same direction ) so as to drive air axially outwardly of the hub 38 , as well as rearwardly . similarly , the blades 30 in the pairs 31 c have outer blade portions 356 inclined ( in the same direction ) so as to drive air axially outwardly , as well as rearwardly . each row - of blade pairs 351 has at least one , and sometimes as many as three , pairs 351 a ( the pairs 351 are staggered in different rows ). each has , in addition , at least one pair 351 each of 350 b and 350 c blade configurations . the effect of this construction is to effect a powerful rearward and laterally outward flow of air from the system 40 . spreading of crop material is further enhanced by this arrangement . while a preferred embodiment of the invention has been described , it should be understood that the invention is not so limited , and modifications may be made without departing from the invention . the scope of the invention is defined by the appended claims , and all devices that come within the meaning of the claims , either literally or by equivalence , are intended to be embraced therein . | US-77609101-A |
a hockey stick safety cover for disposing over the blade and contiguous shaft portion of a hockey stick for providing cushion to reduce the danger of using a hockey stick with a hard blade . the safety cover includes a single length or block of soft extruded plastic foam having a slit disposed along the length for receiving and completely covering the hockey stick blade and the contiguous shaft portion . the soft foam deforms around the slit to receive and surround the blade and contiguous shaft portion . the soft foam also provides a cushioned exterior for reducing the impact of the hockey stick on persons or property . the light weight of the foam does not seriously impair the user &# 39 ; s ability to manipulate the stick . | we disclose a hockey stick safety cover 10 for covering a hard hockey stick 12 of the type having a shaft and a blade 14 attached thereto to reduce the threat of the hockey stick 12 causing injury to person or property . the blade 14 forms a predetermined angle with a contiguous shaft portion 16 . the blade 14 has a length , a height and a thickness . the safety cover 10 comprises a block 18 of homogeneous solid material having a length , height and thickness greater than the blade 14 and a receiving slit 20 defining two opposing faces 22 disposed along the length for receiving the entire blade 14 and contiguous shaft portion 16 into the material , the slit 20 being narrower than the thickness of the blade 14 . the assembly is characterized by the material being flexible to allow the opposing faces 22 to deform to receive the hockey stick blade 14 and contiguous shaft portion 16 , to allow the faces 22 to close completely around the inserted blade 14 and contiguous shaft portion 16 and to provide cushion to reduce the impact of the blade 14 and the contiguous shaft 16 on persons and objects . the block 18 comprises soft plastic foam , preferably polyethylene foam sold under the trademark ethofoam . this foam is extremely inexpensive to produce . it is extruded in sheets which can be procured &# 34 ; off - the - shelf .&# 34 ; it need not be pre - molded to the desired shape since it can easily be cut into the desired shape . for example , one can acquire a plank - shaped sheet of foam polyethylene , use a table saw or other suitable machine or tool and cut the plank into the desired shape by cutting the plank to the desired length , rounding one end of the plank , cutting a &# 34 ; v &# 34 ; shaped notch , and cutting the slit 20 along one side of the plank . this material is also well adapted for the present purpose since it combines firmness with softness , and durability with light weight . the block 18 includes a shaft end 24 for disposing over the contiguous shaft portion 16 and an oppositely disposed blade end 26 for disposing over the blade 14 . the block 18 also includes a bottom side 28 for contacting the hockey playing surface , which can be a gym floor , a patch of grass , a street or an ice rink . the block 18 further includes an oppositely disposed top side 30 . the bottom and top sides 28 , 30 are spaced apart by a mass of the foam material having a front 32 for contacting a hockey puck or ball and an oppositely disposed and spaced apart rear 34 . it is along the top side 30 that the slit 20 is cut . the block 18 is also cut to have a rounded end . the positioning and size of the slit 20 is very important . the slit 20 should extend from the shaft end 24 toward the blade end 26 , but should not reach the blade end 26 . in other words , the slit 20 will appear along the shaft end 24 , but not along the blade end 26 . also , the slit 20 should extend from the top side 30 toward the bottom side 28 , but should not reach the bottom side 28 . thus , no slit 20 will appear along the bottom side 28 . the slit 20 should extend deep enough into the block 18 to receive the entire hockey blade 14 . in other words , the depth of the slit 20 should exceed the height of the blade 14 . this allows the blade 14 to be completely covered by the block 18 . the slit 20 should also be deep enough so that there is at least one half inch of foam above and below the blade 14 of the hockey stick to provide sufficient cushion . this means that the slit 20 should come no closer to the bottom side 28 than one half inch , and that the slit 20 should be at least one half inch deeper than the height of the blade 14 . also , the slit 20 should be positioned roughly halfway between the front 32 and rear 34 of the block 18 so that there is adequate cushion covering the front and rear of the hockey blade 14 . this cushion is also preferably 1 / 2 &# 34 ;- 5 / 8 &# 34 ;. one way to visualize the positioning of the slit 20 is as follows : if the slit 20 extended fully through the block 18 it would divide the block 18 into two symmetric halves . however , in the preferred embodiment , the slit 20 does not extend fully though the block 18 . the block 18 should also be cut to include a &# 34 ; v &# 34 ; shaped notch 36 disposed between the shaft end 24 and the blade end 26 and adjacent the shaft end 24 . the notch 36 includes first and second spaced apart surfaces 38 converging at a vertex 40 disposed adjacent the bottom side 28 . the surfaces 38 form an acute angle which should roughly equal the acute angle supplementary to the obtuse angle formed by the blade 14 and the contiguous shaft portion 16 of the hockey stick 12 . the blade end 26 of the block 18 generally covers the hockey stick blade 14 , while the shaft end 24 of the block 18 generally covers the contiguous shaft portion 16 . the block 18 is also cut to have a rounded blade end 26 . the safety cover 10 should include fastening means 42 for fastening the safety cover 10 to the hockey stick 12 . preferably , the fastening means 42 includes tape 44 for winding around the safety cover 10 after the safety cover is disposed over the blade 14 and the contiguous shaft portion . the tape 44 should exert a squeezing force to force the faces 22 together to completely surround the blade 14 and contiguous shaft portion 16 . the tape 44 can be any suitable tape , though common plastic or cloth sports tape is the preferred variety . other fastening means 42 such as hook and loop fasteners sold under the trademark velcro may be used to the same end . to attach the safety cover 10 on the stick 12 , the blade 14 is disposed in the receiving slit 20 at the blade end 26 of said safety cover 10 . the material adjacent the slit 20 should deform or compress slightly to receive the blade 14 . the shaft end 24 of the cover 10 pivots with respect to the blade 14 end about the vertex 40 of the &# 34 ; v &# 34 ; notch 36 so that the shaft portion fits in the receiving slit 20 at the shaft end 24 and so that the first and second surfaces 38 touch . when the first and second surfaces 38 touch , and the angle between them is closed , the shape of the cover 10 should resemble the portions of the hockey stick 12 which it covers . if the angle defined by the surfaces 38 is not properly chosen , the shape of the cover 10 will not match that of the stick portions . also , just as the material deforms to receive the blade 14 , the material deforms to receive the shaft . since the shaft is usually thicker than the blade 14 , the material in the shaft end 24 actually deforms more than the material in the blade end 26 in order to fully receive the shaft into the block 18 . once the blade 14 and contiguous shaft portion 16 is inserted into the block 18 , tape 44 should be wound around the block to force the opposing faces 22 together to close the slit 20 and seal the blade 14 and contiguous shaft 16 within the block 18 . the invention has been described in an illustrative manner , and it is to be understood that the terminology which has been used is intended to be in the manner of words of description rather than words of limitation . obviously , many modifications and variations are possible in light of the above teachings . it is therefore to be understood that within the scope of the appended claims wherein reference numerals are merely for convenience and are not to be in any way limiting , the invention may be practiced otherwise than as specifically described . | US-81386191-A |
an apparatus for receiving energy through space and storing the received energy on a chip includes an antenna for receiving the energy , a converter circuit for converting the received energy , and a storage device for storing the converted energy , the antenna , converter circuit and storage device being formed on the chip . associated methods of use of the apparatus are also disclosed . | the present invention provides an apparatus for harvesting and storing energy on a chip . the energy source for the apparatus may include radio frequency ( rf ) energy , either ambient rf energy or rf energy transmitted to the apparatus by a dedicated source using microwave energy , laser energy , sound energy , nuclear energy , ocean wave energy , deep space energy and wind energy . with reference to fig5 an apparatus generally designated 500 in accordance with the invention may include an antenna 510 coupled to a voltage doubler 520 formed on a semiconductor chip ( not shown ). antenna 510 may include an antenna having an effective antenna size greater than a physical antenna size for use on the chip . voltage doubler 520 may provide a means for getting a high dc output voltage from a remote ac source . a storage device 530 may be coupled to the voltage doubler 520 to provide a means for storing the output voltage . storage device 530 may include a capacitor . in an exemplary application , a micro - pump 540 may be powered by the apparatus 500 . in use , the apparatus 500 may be encapsulated by a gel capsule 600 as shown in fig6 . apparatus 500 may include a charge carrying means for carrying a positive charge to provide adsorption of cholesterol 610 and fatty acids 620 from a patient &# 39 ; s gastrointestinal ( gi ) tract into the gel capsule 600 . in this manner a plasma cholesterol level of a patient may be lowered . the reduction in plasma fatty acids may also find application in weight reduction practices . those skilled in the art will appreciate that the apparatus 500 may alternatively carry a negative charge to provide adsorption of positively charged ions and molecules . with reference to fig7 , the apparatus 500 may include an electrode 700 for providing electrical stimulation . in use the apparatus 500 having the electrode 700 may be used to provide electrical stimulation to muscles and nerves . a piezoelectric device 800 as shown in fig8 may be coupled to the apparatus 500 to provide for vibration and / or heating . piezoelectric device 800 may provide vibrational stimulation to muscles and tissues . with reference to fig9 , a pump 900 may be coupled to the apparatus 500 to provide for pumping of drugs and other materials . a device for detecting the binding of a molecule 1010 to an antibody 1000 may include a signaling means having moveable member 1020 coupled to the apparatus 500 . movement of the moveable member 1020 may provide a signal to the apparatus 500 of the binding of the molecule 1010 . an artificial cell 1100 may include the apparatus 500 implanted in a cell 1110 . the artificial cell 1100 may include synthetic cells similar to bacteria that are not truly alive . with reference to fig1 , the apparatus 500 may be coupled to a drug delivery device 1200 . with reference to fig1 , the apparatus 500 may be coupled to an artificial organ 1300 . the apparatus 500 may be used to power a variety of devices outside of a body . examples are shown in fig1 for use in computer devices , fig1 for use as a switching means in space technology , computers , and explosives , fig1 for use in power tools , motors , and automobiles , fig1 for use in space technology , fig1 for use in speakers , audio systems , and home theatre systems , fig1 for use in irrigation and fertilization triggered by a signal from the apparatus 500 , fig2 for use in triggering explosives , and fig2 for use in remote listening devices . the present invention advantageously provides for an apparatus for harvesting and storing energy on a chip . the apparatus may be used as a power source for a plurality of devices , a signaling means , a switching means and a charge carrying means . the apparatus may be implanted in or administered to a human or an animal for treating or preventing a disease including parkinson &# 39 ; s disease , dystonia , epilepsy , depression , alzheimer &# 39 ; s disease , huntington &# 39 ; s disease , prion disease , down &# 39 ; s syndrome , autism , jacob creutzfeldt disease , neuropathic and back pain , cancer , stroke related movement disorders , urinary incontinence , cardiovascular disease , and chronic headache . the present invention further provides for a container kit including a plurality of containers , each container having a unit dose of the apparatus of the invention . each container may include a dose for oral delivery and include a tablet , a gel and a capsule having the apparatus of the invention . containers may be adapted for parenteral delivery and include a depot product , a syringe , an ampoule and a vial having the apparatus of the invention . containers may further be adapted for topical delivery and include a patch , a medipad , an ointment and a cream having the apparatus of the invention . with regard to these diseases , the term “ treating ” means that devices of the invention can be used in humans with existing disease . the devices of the invention will not necessarily cure the patient who has the disease but will delay or slow the progression or prevent further progression of the disease thereby giving the individual a more useful life span . the term “ preventing ” means that that if the devices of the invention are administered to those who do not now have the disease but who would normally develop the disease or be at increased risk for the disease , they will not develop the disease . in addition , “ preventing ” also includes delaying the development of the disease in an individual who will ultimately develop the disease or would be at risk for the disease due to age , familial history , genetic or chromosomal abnormalities , and / or due to the presence of one or more biological markers for the disease . by delaying the onset of the disease , devices of the invention will have prevented the individual from getting the disease during the period in which the individual would normally have gotten the disease or reduce the rate of development of the disease or some of its effects but for the administration of devices of the invention up to the time the individual ultimately gets the disease . preventing also includes administration of the devices of the invention to those individuals thought to be predisposed to the disease . in a preferred aspect , the devices of the invention are useful for slowing the progression of disease symptoms . in another preferred aspect , the devices of the invention are useful for preventing the further progression of disease symptoms . in treating or preventing the above diseases , the devices of the invention are administered in a therapeutically effective amount . the therapeutically effective amount will vary depending on the particular device used and the route of administration , as is known to those skilled in the art . in treating a patient displaying any of the diagnosed above conditions a physician may administer a device of the invention immediately and continue administration indefinitely , as needed . the many features and advantages of the invention are apparent from the detailed specification , and thus , it is intended by the appended claims to cover all such features and advantages which fall within the true spirit and scope of the invention . further , since numerous modifications and variations will readily occur to those skilled in the art , it is not desired to limit the invention to the exact construction and operation illustrated and described , and accordingly , all suitable modifications and equivalents may be resorted to , falling within the scope of the invention . | US-2733504-A |
disclosed is footwear , such as a sandal , having an outsole , an insole , and an upper . the upper is attached to the outsole and / or the insole and is meant to hold the foot in place when the sandal is worn . the outsole includes a bottom surface and a sidewall extending upwardly from the bottom surface to provide an area of insertion for the insole . the insole is comprised either partially or fully of a gel or gel - like substance and is placed within the gel insole receiving area of the outsole . the gel insole can be manufactured within the gel insole receiving area or manufactured separately and placed within the gel insole receiving area . | fig1 is a representation of an outsole ( 110 ) and an insole ( 120 ). the outsole ( 110 ) has a front end ( 130 ) and a rear end ( 140 ); a left side ( 150 ) and a right side ( 160 ). the outsole ( 110 ) also has an inner wall ( 170 ), a perimeter wall ( 175 ), an inner bottom ( 180 ), and an outer bottom ( not shown ). the outsole ( 110 ) can be composed of a polymer block copolymer , or other durable material . examples of such material include sbs rubber , plastic , and foam to name a few . such materials used in the outsole ( 110 ) provide durability , traction , support , and some cushion to the user of the sandal . in some embodiments , the material chosen for the outsole ( 110 ) can be chosen to withstand significant contact with rough ground surfaces such as concrete , dirt , grass , carpet , stone , wood , and asphalt . the outsole ( 110 ) is generally formed such that the insole ( 120 ) is able to rest in the space formed by the combination of the inner wall ( 170 ) and inner bottom ( 180 )— protected further by the perimeter wall ( 175 ) and outer bottom ( not shown ). this insole receiving area ( 170 / 180 ) can provide a protective environment into which a comfortable insole ( 120 ) may be manufactured directly or into which a comfortable insole ( 120 ) may be placed once it has been manufactured separately . the insole ( 120 ) has a front end ( 185 ) and a rear end ( 190 ) and may be composed , for example , of a solid polymer gel , a viscoelastic polymer gel , a semi - liquid “ squishy ” polymer gel , or some combination of the above . the primary purpose of using a polymer gel material for the insole ( 120 ) is to provide comfort and relief to tired and sore feet . in some embodiments , the material used for the insole ( 120 ) is thick enough to provide outstanding comfort , yet thin enough to provide a high level of support . throughout the remainder of this application , the insole will be referred to as a single layer of polymer gel or gel - like material ( 120 ); however , a multiple layer insole ( 190 ) could also be used . as shown in fig2 , a solid or viscoelastic polymer gel / other solid material used to form the insole may be completely or partially exposed to the air ( 210 ) or contained in / covered with a cloth , rubber , nylon , plastic , vinyl , foam , or other type of material covering ( 220 ) to provide the insole with desired characteristics such as added comfort , traction , durability , protection , design , and / or styling . referring to fig3 , a semi - liquid or “ squishy ” polymer gel ( 310 ) can be contained in some kind of container or pouch ( 320 ) to keep the material enveloped within the insole while the sandal is in use . this container ( 320 ) would preferably be composed of a plastic , rubber , or some other material capable of housing a liquid or semi - liquid substance without being prone to excessive damage which would allow the liquid to escape . for example , the material can be durable enough to hold the liquid without being ruptured or damaged by various amounts of pressure caused by the foot or other stress factors that could affect the semi - liquid or “ squishy ” polymer gel container ( 320 ). also , as illustrated in fig3 , the container holding the semi - liquid or “ squishy ” polymer gel ( 320 ) could be completely exposed to the air ( 320 ) or contained in / covered with cloth , rubber , nylon , plastic vinyl , foam , or some other type of material covering ( 330 ). one purpose of the cover ( 330 ) is to provide desired characteristics such as added comfort , traction , durability , protection , design , and / or styling — similar to the application described for a solid or viscoelastic polymer gel application ( see fig2 ). referring to fig4 , a semi - liquid or “ squishy ” gel ( 410 ) may be enclosed in a one - piece pouch ( 420 ) or in a pouch with several internal gates or boundaries ( 430 ). said gates could be formed vertically , horizontally , or in any number of directions or combination of directions . these gates or boundaries can be strategically placed within the pouch ( 420 / 430 ) to prevent excess amounts of gel from moving to any one area of the insole when pressure is applied to the pouch ( 420 / 430 ) under the weight of the user . for example , the gates can be placed so as to form several square inch enclosures , each of which would be filled with gel ( 440 ). in some embodiments , the gel can be free to move within its own square inch area , but not beyond . thus , regardless of the amount of pressure being applied to the insole , the gel would maintain a relatively even distribution throughout the greater insole . as in other application , this conglomerate of pouches formed by the internal gates could be completely or partially exposed to the air ( 440 ) or contained in / covered with cloth , rubber , nylon , plastic , vinyl , foam , or some other type of material covering ( 450 ) to provide desired characteristics such as added comfort , traction , durability , protection , design , and / or styling . fig5 provides a top plan illustration of an additional application in which the insole ( 520 / 530 ) could be produced using several separate gel pouches ( 510 ) placed side - by - side within the entire gel insole receiving area of the outsole ( 520 ) rather than being produced in a one - piece pouch that is separated by internal gates as shown in fig4 . this conglomerate of individual polymer gel packets could be packaged individually ( 540 ) and placed within the gel receiving area of the outsole ( 520 ), or packaged in a larger container or pouch ( 550 ) which would be placed in the gel receiving area of the outsole ( 520 ) for additional security , durability , and / or stability . as in applications described in fig2 , 3 , and 4 , this conglomerate of pouches could be completely or partially exposed to the air ( 210 ) or contained in / covered with cloth , rubber , nylon , plastic , foam , or some other type of material covering ( 220 ) to provide desired characteristics such as added comfort , traction , durability , protection , design , and / or styling . the insole ( 530 ) is not restricted to one specific type of polymer gel . just as different parts of the foot have different sensitivities , a combination of solid or viscoelastic gel and semi - liquid or “ squishy ” polymer gel can be used in the insole ( 530 ). one purpose of using different materials for different areas of the foot is to provide additional comfort and support to specific areas of the foot prone to soreness , fatigue , or excessive irritation from blisters or other foot issues cased by cleats . if several different types of gel are used , the “ squishy ” portion of the gel insole ( 530 ) can be contained in a special cloth , nylon , plastic , or rubber package as previously explained and shown in fig4 ( 410 / 420 ). the package can then be integrated into the solid gel insole ( 530 ) base . the semi - liquid gel can be strategically placed in areas of the insole ( 530 ) that house portions of the foot requiring special attention . fig6 shows one such area of the foot which , in some embodiments , can potentially require special attention — the arch ( 610 ). in this instance , the base of the insole can be comprised of a solid or viscoelastic polymer gel ( 620 ). a special semi - liquid or “ squishy ” polymer gel pocket can be assigned to the area of the insole that touches the arch of the foot ( 610 ). fig7 illustrates another potential area of sensitivity in the foot that could need special attention — the heel ( 710 ). in this instance , the base of the insole can be comprised of a solid or viscoelastic polymer gel ( 720 ). a special semi - liquid or “ squishy ” polymer gel pocket can be assigned to the area of the insole that touches the heel of the foot ( 710 ). likewise , the ball of the foot is an area that often causes athletes and other active people pain . as shown in fig8 , in this embodiment , the base of the insole can be comprised of a solid or viscoelastic polymer gel ( 820 ). a special semi - liquid or “ squishy ” polymer gel pocket can be assigned to the area of the insole that touches the ball of the foot ( 810 ). in addition to limiting the “ squishy ” polymer gel to one area of sensitivity as discussed in the previous three paragraphs , any combination of these three areas of sensitivity could be supplied with the semi - liquid or “ squishy ” gel . fig9 gives one example . in this embodiment , the base of the insole could be comprised of a solid or viscoelastic polymer gel ( 910 ). the area of the insole that touches the arch ( 910 ) and the ball ( 930 ) of the foot can contain the semi - liquid or “ squishy ” polymer gel material . similarly , as shown in fig1 , a semi - liquid or “ squishy ” polymer gel can be applied to the arch of the foot ( 1010 ) and the heel of the foot ( 1020 ), both of which would benefit from the semi - liquid or “ squishy ” gel pockets . the rest of the insole can be comprised of a solid or viscoelastic polymer gel ( 1030 ). fig1 shows that the heel of the foot ( 1110 ) and the ball of the foot ( 1120 ) constitute another possible combination area for the semi - liquid or “ squishy ” gel pocket application . the remaining part of the insole can be comprised of the solid or viscoelastic polymer gel material ( 1130 ). as illustrated schematically in fig1 , an insole covering all three of the previously mentioned areas of the foot ; the arch ( 1210 ), the heel ( 1220 ), and the ball of the foot ( 1230 ), can be formed using the semi - liquid or “ squishy ” polymer gel material in one single application . the rest of the insole can be formed using a solid or viscoelastic polymer gel ( 1240 ). referring now to fig1 , a solid or viscoelastic polymer gel can be used for the base of the insole ( 1310 ) and the semi - liquid or “ squishy ” polymer gel can be applied in small pockets throughout the insole in a uniform manner ( 1320 ) to create additional comfort or other desired characteristics . these semi - liquid gel pockets can also be spread through the insole strategically or randomly to provide added comfort and to enhance the sandal &# 39 ; s appearance and marketability through specific design cues ( 1330 ). for example , the gel pockets can be made to look like shapes , objects , letters , numbers , or any variety of possible pictures of symbols ( 1340 ). as illustrated in fig1 , in addition to an insole comprised completely of a polymer gel substance ( 1410 ), an insole comprised of a polymer gel , integrated or combined with another material such as cloth , rubber , plastic , or foam could also apply ( 1420 ). one purpose of a partially gel / partially rubber , cloth , foam , plastic , or other material insole ( 1420 ) is to add comfort , structure , stability , traction , durability , protection , support , and / or unique design to the sandal . similar to the solid gel base insole application previously discussed , several applications can be used with a base comprised of rubber , plastic , foam , or some other non - polymer gel material for the insole . for example , fig1 shows how a polymer gel , solid or “ squishy ” ( 1520 / 30 / 40 ), can be strategically placed in or on areas of the rubber , plastic , foam , or other material base insole ( 1510 ) in such a way as to provide additional padding , massage , comfort , and relief from stress to the foot . as seen in fig1 , one such area of the insole where gel can be applied within the rubber , plastic , foam , or other material base ( 1510 ) is area of the insole where the arch of the foot would rest ( 1520 ). another possible area of the insole where the gel could be applied within the rubber , plastic , foam , or other material base insole ( 1510 ) is the part of the foot where the heel would rest ( 1530 ). yet another area within the rubber , plastic , foam , or other material base insole ( 1510 ) where a solid or “ squishy ” polymer gel could be applied is the area of the insole where the ball of the foot would rest ( 1540 ). as discussed earlier in this application , any combination of these three areas of the foot : the arch ( 1520 ), the heel ( 1530 ), and the ball ( 1540 ), can be used as areas where the gel would rest within the larger base insole made of such materials as plastic , rubber , foam , or some other materials ( 1510 )— similar to the options show with the semisolid or solid viscoelastic polymer gel base in fig7 - 13 . for example , the area of the insole where the heel ( 1530 ) and the ball of the foot ( 1540 ) rest could contain a solid or semi - liquid “ squishy ” polymer gel with the rest of the insole being composed of plastic , rubber , foam , or some other material ( 1510 ). likewise , the area of the insole where the arch ( 1520 ) and the heel ( 1530 ) rest can contain solid or “ squishy ” polymer gel with the rest of the insole being composed of plastic , rubber , foam , or some other material ( 1510 ). the area of the insole where the arch ( 1520 ) and the ball of the foot ( 1540 ) will rest can contain solid or “ squishy ” polymer gel with the rest of the insole being composed of the foot , the arch ( 1520 ), the heel ( 1530 ), and the ball ( 1540 ) can contain the solid or “ squishy ” polymer gel — placed within the larger base of the insole made of a plastic , rubber , foam , or some other durable material ( 1510 ). one purpose of the gel in these embodiments would be to provide additional comfort and support to specific areas of the foot prone to soreness , fatigues , or excessive irritation from blisters or other foot issues caused by cleats . fig1 illustrates another embodiment using an sbs rubber , plastic , foam , or some other material base ( 1610 ) combined with a solid or “ squishy ” polymer gel ( 1620 ). in this embodiment , the gel ( 1620 ) can be provided throughout the larger insole made of plastic , rubber , foam , or some other durable material ( 1610 ) in a uniform manner to create additional comfort or to enhance the sandal &# 39 ; s appearance through specific design cues ( 1620 ). fig1 also shows that these gel pockets can be distributed strategically or randomly throughout the insole with the primary purpose of providing comfort and relaxation to specific pressure points located in the foot ( 1630 ). a strategic or random distribution of gel pockets within the sbs rubber , plastic , foam , or other material base insole ( 1610 / 20 / 30 ) can also be made with the dual purpose of providing desired design and styling as well as outstanding comfort . continuing with fig1 , many possible insole designs can achieve a strategically or randomly distributed gel applications . for example , the gel pockets can be scattered throughout the sbs rubber , plastic , foam , or other material base , and made to look like objects , shapes , letters , numbers , or any of a variety of possible pictures , or symbols ( 1640 ). once the material and design of the insole have been determined , at least four recommended manufacturing techniques can be used . other manufacturing techniques known to those of skilled in this field could also be used . shown in fig1 , one of these methods involves the gel insole ( 1710 ) manufactured as a separate ( to the outsole ( 1720 )) piece and subsequently placed in the insole receiving area ( 1730 / 1740 ) created by the inner side wall ( 1730 ) and inner bottom ( 1740 ) of the outsole ( 1720 ). this independent ( from the outsole ( 1720 )) insole ( 1710 ) can then be sewn to the perimeter wall ( 1750 ) and / or bottom ( not shown ) of the outsole ( 1720 ) or attached to the inner side wall ( 1730 ) and / or inner bottom ( 1740 ) of the outsole ( 17200 ) with an adhesive substance such as glue . this method of manufacturing can be carried out by a single entity or split into two or more entities . fig1 shows another manufacturing technique that can be applied to the sandal , protective material ( 1820 ) into which the insole ( 1810 ) can be placed . once combined , this newly created insole ( 1830 ) could then be sewn to the perimeter wall ( 1840 ) and / or bottom ( not shown ) of the outsole ( 1850 ) or attached to the inner side wall ( 1860 ) and / or inner bottom ( 1870 ) with an adhesive substance such as glue . fig1 shows that if a semi - liquid or “ squishy ” polymer gel ( 1910 ) is chosen for a portion ( or all ) of the insole ( 1930 ), the area formed by the inner side wall ( 1940 ) and inner bottom ( 1950 ) of the outsole ( 1920 ) can act as a receptacle for this gel , thus forming an insole ( 1930 ) integrated into the outsole ( 1920 ). in this instance , the gel ( 1920 ) can be placed directly into the outsole receiving area ( 1940 / 1950 ) and then be covered by a plastic , rubber , vinyl , or some other suitable , durable material or combination of materials ( 1960 ). this covering ( 1960 ) can protect the gel and prevent it from seeping out of the gel receiving area ( 1940 / 1950 ) of the outsole ( 1920 ). as mentioned earlier in this application , a semi - liquid or “ squishy ” gel insole ( 1930 ) solution would likely include gates or boundaries so the gel would not move significantly to any one area when pressure from the foot or body is applied to the insole ( see fig4 and 5 ). as shown in fig2 , the polymer gel insole ( 2010 ) can be simply manufactured as one piece within the sbs rubber , plastic , vinyl , or other material base outsole ( 2020 ). this solution would probably work best with a partial gel - based insole ( 2010 ) rather than with a completely gel base insole ( 2010 )— especially if a “ squishy ” polymer gel is being used for a portion of the insole ( 2010 ). also , a solid or viscoelastic gel insole ( 2010 ) would likely be easier than a semi - liquid or “ squishy ” gel insole ( 2010 ) to manufacture as part of the complete combined sole of the sandal . fig2 illustrates an embodiment of a sandal ( 2110 ) according to the invention . the sandal ( 2110 ) is comprised of an outsole ( 2120 ), an insole ( 2130 ), and an upper ( 2140 ). the upper ( 2140 ) is preferably attached to the perimeter wall ( 2150 ) of the outsole ( 2120 ) on both sides . the upper ( 2140 ) can be sewn , glued , or otherwise attached to the inner side wall ( 2160 ) and / or perimeter wall ( 2150 ) of the outsole ( 2120 ). the upper ( 2140 ) can be constructed of one or more pieces depending on the desired functionality of the sandal . a one - piece upper ( 2140 ) can provide more stability and security to the foot . a two - piece ( or more ) upper ( 2140 ) can provide a tighter , more customized fit to the individual foot . the upper ( 2140 ) can be comprised of any material deemed sturdy enough to support the foot during use . the upper ( 2140 ), combined with the insole ( 2130 ), provides a receiving area for the foot . the upper ( 2140 ), combined with the insole ( 2130 ), provides a receiving area for the foot . the upper ( 2140 ) is intended to help keep the foot in place while the sandal is in use . | US-54926509-A |
a hip - joint prosthesis includes a shaft which is configured to be inserted into the femur and whose surface has an osteoinductive finish . this finish is provided exclusively in the metaphyseal portion of the shaft and laterally from the line delineating the maximum antero - posterior dimension of the shaft cross section . this ensures a better involvement of the metaphyseal spongiosa in the flow of forces , without compromising the ability to perform follow - up surgery on the prosthesis . | the hip prosthesis according to fig1 comprises a joint head 1 , and a neck 2 which has a shaft 3 . the latter has a diaphyseal portion 4 to be anchored in the diaphysis of the bone , and a metaphyseal portion 5 to be anchored in the metaphysis of the bone . the diaphyseal portion is dimensioned such that it ensures primary anchoring of the shaft in the diaphysis of the femur . the person skilled in the art will see , from looking at fig1 , how the prosthesis will lie in the bone , and he or she will therefore also know where the border 8 between the diaphyseal and metaphyseal portions of the prosthesis lies . whereas the diaphyseal portion 4 of the shaft can bear on the strong cortical bone of the diaphysis and effect primary anchoring there , the metaphyseal portion lies mainly in the spongy bone tissue of the metaphysis . fig2 shows a location 7 having the greatest dimension of the shaft 3 in the ap direction ( antero - posterior ). the connection of the locations of maximum ap dimension is shown in fig2 as line 7 . this extends the entire length of the prosthesis . for the invention , only its extent in the metaphyseal portion 5 is of interest . laterally from this line , the surface of the shaft in the illustrative embodiment in fig3 is composed exclusively of surface areas in which the surface normal has a component oriented in the lateral direction . this means that it is not possible , by conventional means , to obtain a connection between these surfaces and the bone which is able to take up medially directed prosthesis forces . these forces in fact presuppose a tensile connection between these surface areas and the bone . in the illustrative embodiments according to fig4 or fig5 , undercut surface areas are also present laterally from the location or line 7 , in which undercut surface areas the surface normal has no component oriented in the lateral direction . however , the laterally directed surface portions also predominate here . according to the invention , a part 6 of the shaft surface lying in the metaphyseal portion ( that is to say above the line 8 ) and laterally from the line 7 is finished with an osteoinductive substance . this is shown by stippling in the drawing . the finish is preferably contained in a layer of osteoconductive material such as hydroxyapatite . by means of this finish , it is possible to strengthen the connection between the surface areas in question and the bone tissue in such a way that it is able to transmit tensile forces . this means that the tension trajectories in the spongy bone tissue are involved in the take - up of forces and are accordingly not broken down . in the illustrative embodiment in fig1 , the area finished according to the invention includes a projection 9 which lies in the trochanteric area of the metaphysis . such trochanteric projections are customary for improving the anchoring of the shaft in the bone tissue and for preventing the shaft from turning relative to the bone . a surface configuration promoting the connection to the bone can also be provided in the other areas of the shaft 3 , i . e . medially from the line 7 and distally from the line 8 , for example a coating with hydroxyapatite or calcium phosphate . however , it should contain no osteoinductive components there , because otherwise the removal of the prosthesis shaft from the bone in the event of follow - up surgery is made very difficult . fig2 shows that the projection 13 has a considerable thickness in the antero - posterior direction . its anterior and posterior surface areas 6 are therefore set back from the central area in which the spongy bone substance is in many cases depleted , and they are situated in a more compact area closer to the cortical bone . hence , the likelihood of a good connection between the bone surface and the bone substance is further enhanced . fig5 shows the cross - sectional shape of the projection 9 in sectional direction v - v , which also corresponds approximately to the direction of insertion . if the hollow space , which has been prepared by means of a rasp ( fig7 ) in order to receive the prosthesis , is slightly smaller than the prosthesis shape , the insertion of this wedge shape into the bone causes a displacement of bone substance and , as a result , an increase in the pressure exerted on the prosthesis surface by the bone substance . in this way too , a rapidly growing and intimate union of the prosthesis surface with the bone is promoted . to ensure that the intimate connection between the surface of the trochanteric projection and the bone is not problematic in the event of follow - up surgery , the projection 9 can be detachable from the shaft 3 ( fig6 ). for example , it can be connected to the shaft 3 by means of screws or other connecting means and can be detached from said shaft 3 before the shaft is removed from the bone . the projection can then be more easily released from the bone surrounding it and connected to it . the surface finish according to the invention is not limited to the prosthesis shape shown in fig1 and 2 . examples of other cross - sectional shapes are shown in fig3 and 4 . reference number 7 there designates the cross - sectional point of maximum thickness in the ap direction , laterally from which the invention permits an osteoinductive finish of the prosthesis surface . | US-201113084249-A |
securing devices secure the position of protective pads on the arms of a user of the protective pads . a first strap and a second strap are placed over the head with the head of the user passing in between the first and second strap . the first and second straps connect to a third strap at a first connection point . at a second connection point opposite from the first connection point a fourth strap connects to the first and second straps . the third and fourth straps each connect to an attachment device . the attachment devices connect to the protective pads of the wearer . each one of the straps can each be adjustable to accommodate wearers of varying dimensions . the attachment devices can be detachable from the protective pads so that the wearer can utilize the securing device in conjunction with protective pads that the wearer already has . | embodiments include protective pad securing devices and associated methods for wearing and attaching securing devices to a variety of protective pads . certain embodiments of securing devices include various features such as the construction of the straps , means to allow for adjusting the length of the straps , the means used to connect the straps , and means to attach the embodiments to protective pads . certain embodiments of securing devices connect the first and second straps directly to the third and fourth straps while others connect the first and second straps to the third and fourth straps with the use of connectors . certain embodiments connect the attachment means directly to the third and fourth straps while others secure the attachment means by the use of additional attachment devices . certain embodiments allow for the distance between the first connection point and the second connection point of a strap to be adjusted . fig1 - 5 show various views of illustrative embodiments of a securing device . the securing device 100 of fig1 and 2 includes a first strap 101 , a second strap 102 , a third strap 105 and a fourth strap 106 . the width and length of the straps 101 , 102 , 105 and 106 can be of any width and length to provide for effectively securing pads about the wearer &# 39 ; s arms . particular dimensions of the wearer &# 39 ; s body , such as the width of the wearer &# 39 ; s shoulders , the diameter of the wearer &# 39 ; s neck , the location of the pads about the wearer &# 39 ; s arms , and the girth of the wearer &# 39 ; s chest will influence the required length for each one of the straps . one manner of fitting the securing device to the wearer &# 39 ; s body can be to construct the straps with excessive length and to provide means to adjust the distance between the connections of the straps that can provide for an effective apparatus . once the apparatus has been placed on the wearer &# 39 ; s body the distance between the connections of the straps can be adjusted to provide for proper functioning of the mechanism . another manner of fitting the securing device to the wearer &# 39 ; s body can be to measure the necessary dimensions of the user &# 39 ; s body , the location of the pads to be secured , and then adjust the locations of connections of the straps to provide for proper function of the mechanism . once the proper adjustments have been made the securing device can be placed on the wearer &# 39 ; s body . a further manner of fitting the securing device to the wearer can be to measure the necessary dimensions of the user &# 39 ; s body , the location of the pads to be secured , and then to construct the dimensions of the apparatus according to the measurements of the wearer &# 39 ; s body . once the securing device has been constructed with the proper dimensions the securing device can be placed on the wearer &# 39 ; s body . the first strap 101 and the second strap 102 as shown in fig1 are located adjacent to each other . both the first strap 101 and the second strap 102 feature a first connection point 118 and 122 and a second connection point 120 and 124 . the first connection point 118 and 122 of the first strap 101 and the second strap 102 are substantially opposite from the second connection point 120 and 124 of the first strap 101 and the second strap 102 . the third strap 105 connects to the first connection point 118 of the first strap 101 and the first connection point 122 of the second strap 102 at a first connection point 126 of the third strap 105 . the fourth strap 106 connects to the second connection point 120 of the first strap 101 and the second connection point 124 of the second strap 102 at a first connection point 128 of the fourth strap 106 . the third strap 105 and fourth strap 106 both feature a second connection point 130 and 132 . the second connection point 130 and 132 of each strap 105 and 106 is substantially opposite of the first connection point 126 and 128 of each strap 105 and 106 . the pad securing device as shown in fig2 includes at least two attachment means to secure protective pads placed about a wearer &# 39 ; s arms . a first attachment means 107 for allowing manual attachment and detachment of the third strap 105 to a protective pad 114 connects to the second connection point 130 of the third strap 105 . a second attachment means 108 for allowing manual attachment and detachment of the fourth strap 106 to a protective pad 115 connects to the second connection point 132 of the fourth strap 106 . one example of an attachment means would be a suspender clip , well known in the art to hold up trousers . alternative attachment means can also be used such as but not limited to a clasp , clamp , hook , clip , or hook and loop straps ( e . g . velcro ® straps ) that facilitate the proper function of the apparatus . using such attachment means allows the wearer to attach his own set of protective pads to the third and fourth straps 105 and 106 . the location of the connection points for each strap is a function of distance where the location of each connection point for a particular strap should be located according to the particular dimensions of the wearer &# 39 ; s body and where the location of connection points allows for proper functioning of the apparatus . in an embodiment , as shown in fig1 , the first strap 101 can be worn around the wearer &# 39 ; s chest while the second strap 102 can be worn laying below the back of the wearer &# 39 ; s neck and across the wearer &# 39 ; s shoulders . in the alternative , the second strap 102 can be worn around the wearer &# 39 ; s chest and the first strap 101 can be worn across the wearer &# 39 ; s shoulders . the first connection point 126 of the third strap 105 can be located near a first shoulder joint of the wearer &# 39 ; s and the first connection point 128 of the fourth strap 106 can be located near a second shoulder joint of the wearer &# 39 ; s . the third strap 105 , as shown in fig2 , can extend in a substantially parallel direction to a first arm of the wearer and down to engage the first protective pad 114 placed about a first elbow of the wearer . the fourth strap 106 can extend in a substantially parallel direction to a second arm of the wearer and down to engage the second protective pad 115 placed about a second elbow of the wearer . the protective pads can be placed about other locations of the wearer &# 39 ; s arms other than the elbows . the manner in which the straps are connected at each connection point can vary . in one embodiment , the connections between the straps can be accomplished by the straps attaching directly to each other . the connection between the straps can be accomplished by various means such as stitching , rivets , adhesive , snaps , staples , buttons or any other equivalent means . the individual straps can also be connected to each other at the connection points with a first connector 103 and a second connector 104 as shown in fig1 and 2 . an embodiment of the second connector 104 is shown in detail in fig4 . as shown in fig4 , the second connector 104 can connect to the second connection point 120 of the first strap 101 , the second connection point 124 of the second strap 102 , and the first connection point 128 of the fourth strap 106 . as shown in fig1 , the first connector 103 can connect to the first connection point 118 of the first strap 101 , the first connection point 122 of the second strap 102 , and the first connection point 126 of the third strap 105 . the first connector 103 and the second connector 104 , in an embodiment as shown in fig1 , can each be in the form of bar slide connectors . the connectors 103 and 104 can each also include a first aperture and a second aperture where the first strap 101 and the second strap 102 pass through the first aperture of each connector , the third strap 105 passes through the second aperture of the first connector 103 , and the fourth strap 106 passes through the second aperture of the second connector 104 . additional embodiments of the connectors 103 and 104 can be used . other embodiments of the connectors 103 and 104 can be in the form of simple structures such as each connector comprising a ring . an embodiment of the connectors can also take more complex forms , such as each connector including more than two apertures , such as where there is an aperture dedicated to each strap on each connector . in an embodiment , as shown in fig1 and 2 , the distance between the first connection point of a strap and the second connection point of a strap can be adjusted . the distance between the first connection point 118 and the second connection point 120 of the first strap 101 can be adjusted . similarly , the distance between the first connection point 122 and the second connection point 124 of the second strap 102 can be adjusted . the distance between the first connection point 126 and the second connection point 130 of the third strap 105 can be adjusted . furthermore , the distance between the first connection point 128 and the second connection point 132 of the fourth strap 106 can be adjusted . in an embodiment as shown in fig1 and 2 , a wafer , such as 109 , or 111 , can be provided to allow for the location of a connection point , such as 118 , 120 , 122 or 124 , to be adjusted . each wafer can be attached and detached from points along the strap that the wafer is used upon . each wafer can have a first side and a second side . each side of the wafer can be constructed of a material that allows the wafer to attach to a strap by pressing with adequate force against the strap and to be detached from the strap by adequate force pulling the wafer away from the strap . this capability of detaching and reattaching allows for the points that a wafer attaches to a strap to be moved back and forth along the strap . the detach and reattach capability can be accomplished by each side of the wafer being constructed of a fastener , such as a hook type fastener . the surface of each one of the straps can provide for the looped surface for the hooked wafer to detach from a strap and then again attach to the strap ( e . g . velcro ® fasteners ). this detaching and reattaching of the wafers to the straps can be described as detachably attaching . alternative means , that may or may not include wafers , can be used to allow for adjusting the locations of the connection points and to provide for the capability of detachably attaching . these alternative means can include but are not limited to clasps , clamps , hooks , clips , buttons , or snaps that are placed about the straps 101 , 102 or on one or both sides of the wafers 109 , 111 that allow the connection points to vary . in an embodiment , shown in detail in fig3 , a first wafer 109 can be used to connect the first strap 101 to the first connector 103 at the first connection point 118 of the first strap 101 . the first strap 101 can include a first end section and a mid - section . the first end section can be separated from the mid - section by the first strap 101 passing through the first connector 103 and the first end section extending from the first connector 103 such that the first end section attaches to the first side of the first wafer 109 and the second side of the first wafer 109 attaches to the mid - section of the first strap 101 . the point at where the first strap 101 passes through the first connector 103 is the first connection point 118 of the first strap 101 . the first wafer 109 can also be used to connect the second strap 102 to the first connector 103 at the first connection point 122 of the second strap 102 , as shown in fig1 . the second strap 102 can include a first end section and a mid - section . the first end section can be separated from the mid - section by the second strap 102 passing through the first connector 103 and the first end section extending from the first connector 103 such that the first end section attaches to the first side of the first wafer 109 and the second side of the first wafer 109 attaches to the mid - section of the second strap 102 . the point at where the second strap 102 passes through the first connector 103 is the first connection point 122 of the second strap 102 . it can be appreciated that a separate wafer can be used to connect the second strap 102 to the first connector 103 at the first connection point 122 of the second strap 102 , rather than the first strap 101 and the second strap 102 sharing the first wafer 109 at their first connection point 118 and 122 . the first wafer 109 can abut against the first connector 103 such that the first connection point 118 of the first strap 101 and the first connection point 122 of the second strap 102 are locked in place about the first connector 103 . a second wafer 111 can be used to connect the first strap 101 to the second connector 104 at the second connection point 120 of the first strap 101 , as shown in fig2 . the first strap 101 can include a second end section . the second end section can be separated from the mid - section by the first strap 101 passing through the second connector 104 and the second end section extending from the second connector 104 such that the second end section attaches to the first side of the second wafer 111 and the second side of the second wafer 111 attaches to the mid - section of the first strap 101 . the point at where the first strap 101 passes through the second connector 104 is the second connection point 120 of the first strap 101 . the second wafer 111 can also be used to connect the second strap 101 to the second connector 104 at the second connection point 124 of the second strap 102 , as shown as fig2 . the second strap 102 can include a second end section . the second end section can be separated from the mid - section by the second strap 102 passing through the second connector 104 and the second end section extending from the second connector 104 such that the second end section attaches to the first side of the second wafer 111 and the second side of the second wafer 111 attaches to the mid - section of the second strap 102 . the point at where the second strap 102 passes through the second connector 104 is the second connection point 124 of the second strap 102 . the second wafer 111 can abut against the second connector 104 such that the second connection point 120 of the first strap 101 and the second connection point 124 of the second strap 102 are locked in place against the second connector 104 . it can be appreciated that a separate wafer can be used to connect the second strap 102 to the second connector 104 at the second connection point 122 of the second strap 102 , rather than the first strap 101 and the second strap 102 sharing the second wafer 111 at their second connection point 120 and 124 . as shown in fig2 , the distance between the first connection point 118 and the second connection point 120 of the first strap 101 can be adjusted by altering where the second wafer 111 attaches to the second end section of the first strap 101 . to decrease the distance between the first connection point 118 and the second connection point 120 , the point of attachment of the second wafer 111 to the second end section of the first strap 101 can be moved further away from the end of the first strap 101 . to increase the distance between the first connection point 118 and the second connection point 120 , the point of attachment of the second wafer 111 to the second end section of the first strap 101 can be moved closer to the end of the first strap 101 . in a similar fashion , the distance between the first connection point 122 and the second connection point 124 of the second strap 102 can be adjusted by altering where the second wafer 111 attaches to the second end section of the second strap 102 as shown in fig2 . it can be appreciated that the distance between the first connection point 118 and the second connection point 120 of the first strap 101 can also be adjusted by altering where the first wafer 109 attaches to the first end section of the first strap 101 . similarly , the distance between the first connection point 122 and the second connection point 124 of the second strap 102 can be adjusted by altering where the first wafer 109 attaches to the end section of the second strap 102 . the distance between the first connection point 118 and the second connection point 120 of the first strap 101 can also be adjusted by altering where the second wafer 111 is attached to the mid - section of the first strap 101 , as shown in fig2 . the distance between the first connection point 118 and the second connection point 120 can be increased by moving the point of attachment of the second wafer 111 to the mid - section of the first strap 101 closer to the second connector 104 . the distance between the first connection point 118 and the second connection point 120 can be decreased by moving the point of attachment of the second wafer 111 to the mid - section of the first strap 101 further away from the second connector 104 . likewise , as illustrated in fig2 , the distance between the first connection point 122 and the second connection point 124 of the second strap 102 can be adjusted by altering where the second wafer 111 is attached to the mid - section of the second strap 102 . it can be appreciated that the distance between the first connection point 118 and the second connection point 120 of the first strap 101 can also be adjusted by altering where the first wafer 109 is attached to the mid - section of the first strap 101 . similarly , the distance between the first connection point 122 and the second connection point 124 of the second strap 102 can be adjusted by altering where the first wafer 109 is attached to the mid - section of the second strap 102 . as illustrated in fig2 , a third wafer 110 can be used to attach the loose end of the second end section of the first strap 101 to the mid - section of the first strap 101 . a fourth wafer 116 can be used to attach the loose end of the second end section of the second strap 102 to the mid - section of the second strap 102 . it can be appreciated that additional wafers can be used to connect the loose end of the first end section of the first strap 101 to the mid - section of the first strap 101 and to attach the loose end of the first end section of the second strap 102 to the mid - section of the second strap 102 . the distance between the two connection points 118 and 120 of the first strap 101 can be adjusted independently of the distance between the two connection points 122 and 124 of the second strap 102 . furthermore , the distance between the first connection point of a strap can be adjusted independently of the second connection point of a strap . as stated above , other attachment devices such as but not limited to detachable buckles , clips , clamps , snaps , buttons and hooks can be used in place of the wafers 109 and 111 to connect the first strap 101 and the second strap 102 to the first connector 103 and the second connector 104 and still provide adjustability for each connection point and to provide for detachably attaching the straps . additional mechanisms can be used to connect the third strap 105 and the fourth strap 106 to the attachment means 107 and 108 . as shown in fig2 , the use of hook and loop fasteners can be used to allow for the distance between the first connection point 126 and the second connection point 130 of the third strap 105 to be adjusted . in a similar fashion , as shown by fig2 , the use of hook and loop fasteners can be used to allow for the distance between the first connection point 128 and the second connection point 132 of the fourth strap 106 to be adjusted . other means can be used to allow the distance between the first connections points 126 and 128 to be varied from the second connection points 130 and 132 . examples of these means include but are not limited to straps configured with buttons , snaps , hooks , buckles , clips or clamps . fig5 illustrates an embodiment that allows for the distance between the first connection point 126 and the second connection point 130 of the third strap 105 to be adjusted . the third strap 105 can further include a first end section and a second end section . the first end section of the third strap 105 can be separated from the second end section by the first end section passing through the first connector 103 and extending from the first connector 103 such that the first end section is adjacent to the second end section . where the third strap passes through the first connector 103 is the location of the first connection point of the third strap 126 . a fifth strap 112 can include a first end section and a second end section . the first end section can be separated from the second end section by the first end section passing through the first attachment means 107 and extending from the first attachment means 107 such that the first end section is adjacent to the second end section . the first end section of the fifth strap 112 can attach to the first end section of the third strap 105 and the second end section of the fifth strap 112 can attach to the second end section of the third strap 105 . the point of attachment between the third strap 105 and the fifth strap 112 forms the second connection 130 of the third strap 105 . the distance between the first connection point 126 and the second connection point 130 of the third strap 105 can be adjusted by varying where the fifth strap 112 and the third strap 105 attach to each other . if the end sections of the fifth strap 112 are attached to the end sections of the third strap 105 such that there is an increased amount of overlap between the end sections of the two straps then the distance between the two connection points 126 and 130 is shortened . likewise , if the straps 105 and 112 are attached to each other with a lessened amount of overlap then the distance between the connection points 126 and 130 is increased . an embodiment , as shown in fig2 , also allows for the distance between the first connection point 128 and the second connection point 132 of the fourth strap 106 to be adjusted . the fourth strap 106 can include a first end section and a second end section . the first end section can be separated from the second end section by the first end section passing through the second connector 104 and extending from the second connector 104 such that the first end section is adjacent to the second end section . where the fourth strap 106 passes through the second connector 104 is the location of the first connection point 128 of the fourth strap 106 . a sixth strap 113 can include a first end section and a second end section . the first end section can be separated from the second end section by the first end section passing through the second attachment means 108 and extending from the second attachment means 108 such that the first end section is adjacent to the second end section . the first end section of the sixth strap 113 can attach to the first end section of the fourth strap 106 and the second end section of the sixth strap 113 can attach to a second end section of the fourth strap 106 . the point of attachment between the fourth strap 106 and the sixth strap 113 forms the second connection point 132 of the fourth strap 106 . the distance between the first connection point 128 and the second connection point 132 of the fourth strap 106 can be adjusted by varying where the sixth strap 113 and the fourth strap 106 attach to each other . if the end sections of the sixth strap 113 are attached to the end sections of the fourth strap 106 such that there is an increased amount of overlap between the end sections of the two straps then the distance between the two connection points 128 and 132 is shortened . likewise , if the straps 106 and 113 are attached to each other with a lessened amount of overlap then the distance between the connection points 128 and 132 is increased . in the embodiment as shown in fig2 , the fifth strap 112 and sixth strap 113 can be constructed of a hooked fastener material while the third strap 105 and fourth strap 107 can be constructed of a looped fastener material such that at each point where the fifth strap 112 attaches to the third strap 107 and the sixth 113 strap attaches to the fourth strap 108 a hook and loop fastening is formed ( e . g . velcro ® straps ). the use of the hook and loop fastening allows the straps to be attached , detached , and attached again repeatedly . this detaching and reattaching of the straps to each other can be described as detachably attaching . it can be appreciated that one example of a hook and loop fastening the fifth strap 112 and the sixth strap 113 can be constructed of a looped fastener , and the third strap 105 and the fourth strap 107 constructed of a hooked fastener . other means of detaching and reattaching of the straps may be used , such as but not limited to clasps , clamps , hooks , clips , buttons , or snaps . it will be appreciated that each one of the straps of fig1 and 2 can be composed of any desired material that facilitates the proper functioning of the apparatus . in an embodiment , the straps 101 , 102 , 105 and 106 can be composed of an elastic material . certain materials such as lycra , neoprene , and spandex can be employed in the construction of the straps . in an embodiment , the straps 101 , 102 , 105 and 106 can be composed of a non - elastic material such as nylon or polypropylene . in another embodiment , in place of flat straps , for one or more of the straps 101 , 102 , 105 and 106 , straps of varying cross sections , such as straps with a circular or an elliptical cross section can be used . certain examples of straps not having a flat cross section can include cord , rope or custom formed webbing . the straps 101 , 102 , 105 and 106 can also be composed of a perforated material or material including slots or other types of venting to allow better airflow through the apparatus . furthermore , the width of the straps 101 , 102 , 105 and 106 relatively to each other can vary . the first strap 101 can be of a greater or lesser width than the second strap 102 . the third strap 105 and fourth strap 106 can be of a greater or lesser width than either the first strap 101 or second strap 102 depending upon a particular application . additionally , the third strap 105 can be of a greater or lesser width than that of the fourth strap 106 . while various embodiments of a sports apparatus have been shown and described , it will be understood by those skilled in the art that various other changes in the form and details can be made therein without departing from the spirit and scope of the disclosed invention embodiments . | US-24626108-A |
an underwater antenna assembly suitable for subsurface rfid tag interrogation in flowing water such as a river . in preferred embodiments , the antenna interrogates rfid tags implanted in aquatic species . the antenna resides in an elongate antenna housing whose cross - sectional shape is preferably a hydrodynamic teardrop shape . a first end of the housing is linked to a pivoting mechanism such that when the pivoting mechanism is held substantially stationary with respect to the water flow , the second end of the housing is free to rotate generally about the first end in a substantially vertical plane parallel to the water flow direction . the length of the antenna housing is advantageously selected to enable the antenna to monitor for signals across substantially the entire water depth . | fig1 illustrates one example of a top - end pivoting embodiment of the vertically - oriented antenna arrays disclosed herein . it will be seen on fig1 that the array 100 is deployed in moving water ( such as a stream or river ) with a nominal direction of water flow as indicated by arrow wf . each antenna comprises an elongate antenna housing 101 having a hydrodynamic teardrop shape in cross - section . the advantageous hydrodynamics of the hydrodynamic teardrop shape are discussed above in the first paragraph of the “ summary ” section of this disclosure . this inventive disclosure is not limited , however , to antenna housings with a teardrop shape in cross - section . in other embodiments ( not illustrated ), the antenna housing &# 39 ; s cross - sectional shape may also be round , ovate , oblong , square or another shape befitting the installation conditions and antenna windings . the external shell of antenna housing 101 is made of non - ferrous materials such as , without limitation , plastics , rubber , fiberglass , carbon fiber or resins . antenna housing 101 may also be coated on the outside with materials or resins selected to increase durability or protect against abrasion . each antenna on fig1 is suspended from a support cable 102 at its top ( water surface ws ) end . the support cable 102 may be suspended from any suitable anchoring points , such as , for example , anchors on the shore or on banks of a river , or permanent concrete structures in the water itself . in preferred embodiments , the support cable 102 on fig1 will be understood to be disposed substantially perpendicular to the direction of water flow wf , so that each antenna remains substantially in the vertical plane of water flow wf , although the inventive material disclosed herein is not limited in this regard . the support cable 102 may be deployed at other angles with respect to the direction of water flow wf , per user selection , and swivel structure in the pivot assemblies 103 ( as described further below ) enables each antenna nonetheless to remain substantially in the vertical plane of water flow wf . the support cable 102 may be made from any conventional metallic or non - metallic construction . in fig1 , the support cable 102 is illustrated as located above the water surface ws . however , the inventive material disclosed herein is not limited in this regard . other embodiments ( not illustrated ) may deploy the support cable 102 below the surface of the water at user - selected depths . such other embodiments ( not illustrated ) may also set the support cable 102 at other user - selected orientations and anchor points . fig1 also illustrates the support cable 102 being available to support one or more power and / or communications cables 105 addressing each of the antennas . such power and / or communications cables 105 connect the antennas to a power supply , a transceiver and other hardware that may be located elsewhere , such as on the shore , within the antenna housing 101 , or nearby underwater . each antenna may receive a separate power and / or communications cable 105 , or alternatively a single power and / or communications cable 105 may be attached to one end of the array 100 and pass through to neighboring antennas . fig1 further illustrates each antenna suspended from the support cable 102 by its own pivot and swivel assembly 103 . in current embodiments , the design and construction of the pivot and swivel assemblies 103 is conventional , although in future embodiments it may be inventive . as noted above , the swivel structure in the pivot and swivel assemblies 103 allows each antenna to remain oriented substantially in the vertical plane of water flow wf . the pivot structure in the pivot and swivel assemblies 103 leaves the antenna free to rotate about the support cable 102 . each hanging antenna may thus deflect responsive to temporary ( or momentary ) bursts of force or impact placed upon it by events such as seasonally high water flows , turbulence , or passing or accumulating debris . such deflection will be understood to be primarily by rotating about the support cable 102 in the vertical plane of water flow wf . however , in preferred embodiments , each pivot and swivel assembly 103 is also sufficiently articulated to permit its corresponding antenna to deflect in other planes as well . counterweights 107 are also illustrated on fig1 at the basal ( riverbed s ) end of each antenna . these counterweights 107 operate to cause the antennas to tend to return to a vertical or angled ( parallel to flow , deflected downstream ) rest position after momentary deflection by , for instance , passing or accumulating debris . alternatively a portion of the antenna housing 101 may be flooded with water to create a neutrally buoyant antenna , requiring little ( if any ) further counterweighting . it will be appreciated from fig1 that an array of antennas may be dimensionally configured by user selection of the lengths of the antennas and the spacing along the support cable at which each one is fixed . rfid charge and read zones crz are thus created between the antennas that extend nominally the entire length of antennas ( as shown on fig1 ). when the length of antennas is selected to be long enough , the entire depth of the water column potentially becomes available for rfid tag detection and interrogation . rfid charge and read zones crz will be only temporarily compromised while antennas deflect , and will be restored when the antennas return to their substantially vertical or angled ( parallel to flow , deflected downstream ) rest position . top - end pivoting antenna embodiments , such as illustrated on fig1 , are useful where basal - end pivoting embodiments , such as illustrated on fig2 through 4 , are not possible or desirable . for example , basal - end pivoting embodiments may not be suitable at or near engineered water project infrastructure such as concrete fishways , dam spillways , penstock or other turbine entryways , sluice gates , or canals . such environments tend to operate in higher water velocities , and may further present logistical challenges in physically accessing the riverbed or bottom in order to anchor and service a basal - end pivoting embodiment . fig2 through 4 illustrate one example of a basal - end pivoting embodiment of the vertically - oriented antenna arrays disclosed herein . it will be understood on fig2 , that the array 200 is deployed in moving water ( such as a stream or river ) with a nominal direction of water flow wf . as on fig1 , each antenna on fig2 also comprises an elongate antenna housing 201 having a hydrodynamic teardrop shape in cross - section . the advantageous hydrodynamics of the hydrodynamic teardrop shape are discussed above in the first paragraph of the “ summary ” section of this disclosure . this inventive disclosure is not limited , however , to antenna housings with a teardrop shape in cross - section . in other embodiments ( not illustrated ), the antenna housing &# 39 ; s cross - sectional shape may also be round , ovate , oblong , square or another shape befitting the installation conditions and antenna windings . the external shell of antenna housing 201 is made of non - ferrous materials such as , without limitation , plastics , rubber , fiberglass , carbon fiber or resins . antenna housing 201 may also be coated on the outside with materials or resins selected to increase durability or protect against abrasion . turning momentarily to fig3 and 4 , fig3 illustrates an antenna assembly from fig2 in isolation , comprising an antenna housing 201 , a housing cap 203 and an antenna base 207 . common features illustrated on fig2 through 4 share the same reference numeral . fig4 is a cross - section of fig3 as shown on fig3 , and illustrates the hydrodynamic teardrop - shaped profile of the antenna housing 201 as described in the preceding paragraph with reference to fig2 , and earlier in this disclosure in the first paragraph of the “ summary ” section . for the avoidance of doubt , the hydrodynamic teardrop - shaped profile illustrated on fig4 is symmetric about a centerline axis h - h as illustrated . returning to fig2 , each antenna housing 201 in fig2 is connected to an antenna base 207 . pivot and swivel mechanisms 205 are in hinged connection with each antenna base 207 . in current embodiments , each pivot and swivel mechanism 205 is anchored to the riverbed or ground bottom s by conventional anchoring technology 202 , although future embodiments may include inventive anchoring technology . in preferred embodiments , each pivot and swivel assembly 205 is anchored to the bottom s in spaced relationship , per user selection , in a line that runs perpendicular to the direction of water flow , so that each antenna may remain substantially in the vertical plane of water flow . the inventive material disclosed herein , however , is not limited in this regard . in other embodiments ( not illustrated ), pivot and swivel assembly anchoring may be in other angles or shapes with respect to the direction of water flow , per user selection . swivel structure on the pivot and swivel assembly 205 ( as described further below ) enables each antenna nonetheless to remain substantially in the vertical plane of water flow . as discussed elsewhere in this disclosure , the hinged connection between the antenna base 207 and the upper portion of the pivot and swivel assembly 205 may , in some embodiments , be further restrained by torsion springs set to return the antenna to a vertical or angled ( parallel to flow ) rest position after deflection . fig2 also illustrates power and communications cables 204 being brought along the river bed or ground bottom s to address and serve each antenna . connection and anchoring of the power and communication cables 204 may be by any conventional waterproof method so that electrical signals and communications in the cables are not compromised . as on fig1 , the power and communications cables 204 on fig2 connect the antennas to a power supply , a transceiver and other hardware that may be located within the antenna housing 201 , the housing cap 203 , the antenna base 207 or elsewhere , such as on the shore or nearby underwater . each antenna may receive a separate power and / or communications cable 204 , or alternatively a single power and / or communications cable 204 may be attached to one end of the array 200 and pass through to neighboring antennas . current embodiments of the pivot and swivel assemblies 205 illustrated on fig2 are of conventional design and manufacture , although future embodiments may include inventive technology . a lower portion of each pivot and swivel assembly 205 is anchored to the bottom s . the lower portion is in vertical swivel connection with an upper portion , so that when an antenna is attached to the upper portion , the antenna is free to swivel about a vertical axis . the upper portion is further disposed to receive an antenna base 207 via a generally horizontal hinged connection . when an antenna is in hinged connection ( via its antenna base ) to the upper portion of a corresponding pivot and swivel assembly , the antenna is free to pivot about the hinge 206 , and so essentially becomes free to pivot about the bottom s ( or other substantially horizontal plane at which the pivot and swivel assembly 205 may be anchored ). fig3 illustrates the antenna base 207 in isolation , and shows the antenna base &# 39 ; s portion of the hinged connection to the upper portion of a corresponding pivot and swivel assembly 205 . fig3 also illustrates the axis of pivot p about which the antenna is free to rotate . it will be understood from viewing fig2 and 3 together that a conventional pin or axle 206 may be used to form a hinged connection between the antenna base 207 and the upper portion of a corresponding pivot and swivel assembly 205 that permits multi - axial movement . as noted above , the swivel structure in the pivot and swivel assemblies 205 leaves each antenna free to remain oriented substantially in the vertical plane of water flow . the pivot structure in the pivot and swivel assemblies 205 leaves the antenna free to rotate about the river bed s ( or other substantially horizontal plane of anchoring ). each antenna may thus deflect responsive to temporary ( or momentary ) bursts of force or impact placed upon it by seasonally high water flows , or turbulence , or passing or accumulating debris . such deflection will be understood to be primarily by rotating about the river bed s ( or other substantially horizontal plane of anchoring ) in the vertical plane of water flow . however , as illustrated on fig2 and 3 , each pivot and swivel assembly 205 provides independent pivot structure and swivel structure to permit its corresponding antenna to deflect in multiple planes . it will be appreciated that although current embodiments of pivot and swivel assembly 205 are illustrated on fig2 and 3 , future embodiments may also provide partial or full articulation at the antenna base 207 connection to the pivot and swivel assembly 205 . such articulation will enhance the ability of the antenna to deflect in multiple planes . housing caps 203 are also illustrated on fig2 and 3 at the top ( water surface ws ) end of each antenna . in some embodiments , these caps 203 may physically house each antenna &# 39 ; s transceiver , thereby isolating them from electromagnetic interference generated by the antenna coil itself . the caps 203 further provide a construction seal for the top ( water surface ws ) end of the antenna housing 201 . when sealed by the cap 203 and at the antenna base 207 , the air core antenna assembly ( which is buoyant ) operates to cause the antenna to tend to return to a vertical or angled ( parallel to flow , deflected downstream ) rest position after momentary deflection by , for instance , passing or accumulating debris . plastic and other buoyant materials used in the construction of the antennas , and torsion springs within the basal pivot and swivel mechanisms 205 will also be understood to assist the antennas to tend to return such vertical rest or angled position . a user - selected amount of buoyancy for any embodiment of the vertical antenna system may be controlled by a variety of mechanisms , including flooding portions of each antenna housing 201 with water or filling the lower end thereof with a pourable solid material such as silica sand . similar to disclosure above with reference to fig1 , it will be appreciated from fig2 that an array of antennas 200 may be dimensionally configured by user selection of the lengths of the antennas and the spacing along the bottom at which each one is anchored . rfid charge and read zones crz are thus created between the antennas that extend nominally the entire length of antennas ( as shown on fig2 ). when the length of antennas is selected to be long enough , the entire depth of the water column potentially becomes available for rfid tag detection and interrogation . rfid charge and read zones crz will be only temporarily compromised while antennas deflect , and will be restored when the antennas return to their substantially vertical or angled ( parallel to flow ) rest position . although the inventive material in this disclosure has been described in detail along with some of its technical advantages , it will be understood that various changes , substitutions and alternations may be made to the detailed embodiments without departing from the broader spirit and scope of such inventive material as set forth in the following claims . | US-201313925597-A |
new and useful phenylalkylcarbohydroxamic acids are disclosed of the formula ## str1 ## wherein : r is selected from the group consisting of alkoxy of one to six carbon atoms , alkenyloxy of two to six carbon atoms , alkyl of one to six carbon atoms , and benzyloxy ; r 1 and r 2 are each selected from the group consisting of hydrogen , alkoxy of one to six carbon atoms , alkenyloxy of two to six carbon atoms , alkyl from one to six carbon atoms , and benzyloxy ; r 3 and r 4 are selected from the group consisting of hydrogen or alkyl of one to six carbon atoms ; r 5 is hydrogen or r 5 together with r 3 or r 4 represent methylene ; and n signifies the number 0 or 1 , and non - toxic salts thereof , which novel compounds exert a pronounced inhibition of blood platelet aggregation and accelerate the disaggregation of platelet aggregates already formed . | the hydroxamic acids according to the present invention are prepared in a way which is generally known for the preparation of hydroxamic acids . the most usual method for the preparation of the hydroxamic acids concerned consists of the reaction of a carboxylic acid with the general formula : ## str3 ## or an ester , acid halide or anhydride thereof , where r , r 1 , r 2 , r 3 , r 4 , r 5 and n have the meanings assigned above , with hydroxylamine . see example i incorporated herein by reference . the condensation of the free acid according to formula ii with hydroxylamine is preferably performed in the presence of a dehydrating agent , for example a carbodi - imide such as dicyclohexylcarbodi - imide . in the condensation of an ester according to formula ii with hydroxylamine use is preferably made of a lower aliphatic ester of from one to six carbon atoms such as the methyl , ethyl , isopropyl , propyl , butyl , pentyl , or hexyl ester . ( see example i and ii ). the starting compounds according to the general formula ii and the esters , acid halides and anhydrides derived from these compounds are known . they may be prepared in obvious ways known to those skilled in the art . for example , acids of formula ii where n is 0 , and r 3 and r 4 represent hydrogen may be prepared by catalytic reduction of the corresponding cinnamic acid derivative . compounds according to formula ii in which n is 0 or 1 , and at least one of r 3 and r 4 represents hydrogen , may be prepared by a wittig reaction ( at from about - 20 ° c . to about 80 ° c . and at a pressure of about 0 . 5 atm to about 1 . 5 atm ) of the appropriate wittig reagent with a benzaldehyde or phenylalkylketone ( derived for example from acetophenone ), substituted in the phenyl nucleus , followed by catalytic reduction of the unsaturated compound obtained at a temperature of from about - 20 ° c . to about 120 ° c . and a pressure from about 1 atm to about 10 atm . compounds according to formula ii in which both r 3 and r 4 represent an alkyl group may for example be prepared by ( a ) halogenating a 1 , 1 - dialkylbenzyl alcohol substituted in the phenyl nucleus ( for example , a 2 - phenylisopropyl alcohol substituted in the phenyl nucleus ), ( b ) converting the halide thus obtained into the corresponding nitrile with the aid of potassium or sodium cyanide , ( c ) subsequently hydrolysing the nitrile to the corresponding carboxylic acid ( after which the carboxylic acid is reduced to the corresponding alcohol with , for example , lithium aluminium hydride and the entire procedure is repeated again once or twice ). compounds according to formula ii , in which r 3 and r 5 together represent a methylene group , may for example be prepared by reacting a styrene derivative ( substituted in the phenyl nucleus ) with diazo - acetic ester or by reacting a cinnamic - ester derivative or a β , γ - unsaturated butyric acid ester derivative with diazo - methane . by an alkyl group in the definition of r , r 2 , r 3 and r 4 is meant a branched or straight - chain alkyl group with from one to six carbon atoms , such as methyl , ethyl , propyl , isopropyl , butyl , isobutyl , tert . butyl , amyl , iso - amyl tert . amyl , hexyl and isohexyl . the alkyl part of the alkoxy group as meant in the definition of r , r 1 and r 2 has the same significance . by an alkenyloxy group in the definition of r , r 1 and r 2 is meant an unsaturated hydrocarbon residue with two to six carbon atoms , such as vinyl , allyl , β - allyl , iso - allyl , 1 - butenyl , 2 - butenyl , 3 - butenyl , iso - butenyl , 2 - methylallyl , 1 - pentenyl and 3 , 3 - dimethylallyl groups . the compounds according to the invention may be administered by the oral , rectal or parentereal routes in pharmaceutically effective amounts , preferably in a daily dosage of from about 0 . 01 to about 100 mg per kg body weight . when mixed with suitable excipients , the compounds according to the invention may be compressed to give solid formulations such as pills , dragees , tablets or suppositories . examples of suitable excipients are lactose , starch , magnesium stearate , etc . optionally mixed with the usual pharmaceutical excipients , they may also be processed to give capsules . with the aid of suitable liquids , the compounds may furthermore be used as injection preparations in the form of sterile solutions , emulsions or suspensions . compounds according to the invention which are preferably used are those compounds according to the general formula i , in which ( a ) r 3 , r 4 and r 5 are hydrogen , or ( b ) r 3 is methyl and r 4 and r 5 are hydrogen , or ( c ) r 3 + r 5 is methylene and r 4 is hydrogen , are particularly valuable . among these preferred compounds , those compounds which contain one further substituent in the para - position , in particular an alkoxy , alkenyloxy or benzyloxy group , are particularly preferred . a particularly valuable compound is the compound 3 -( 3 , 4 - dimethoxyphenyl ) propionohydroxamic acid . the compounds according to the general formula i may be converted into pharmaceutically acceptable non - toxic salts . these salts which are also numbered among the compounds of the invention are prepared by reacting the acid of formula i with a suitable alkaline substance , such as an alkalimetalhydroxide . the sodium salts of the acids of formula i are preferred . preparation of 3 -( 3 , 4 - dimethoxyphenyl ) propiono - hydroxamic acid . a solution of 8 . 44 g powdered 88 % koh ( 132 . 6 mmol ) by weight in 25 ml methanol is added to a solution previously obtained by dissolving 6 . 15 g hydroxylamine hcl ( 88 . 4 mmol ) in 40 ml methanol at 50 ° c . after standing for 3 minutes in an ice - bath , the resultant kcl is filtered off and the filtrate is added to 10 . 0 g methyl 3 -( 3 , 4 - dimethoxyphenyl ) propionate . after stirring for 20 hours at room temperature , solvent is removed by evaporation without increasing the temperature and the residue is neutralized with 6 n hcl . extraction with ethyl acetate , evaporation to dryness and crystallization of the residue from chloroform - hexane gives 7 . 70 g 3 -( 3 , 4 - dimethoxyphenyl ) propionohydroxamic acid . repeated crystallization from chloroform - hexane gives a substance of analytical purity with a melting point of 105 °- 106 ° c . ; rf in toluene - ethanol ( 8 : 2 )= 0 . 45 ( on sio 2 ). generally , this condensation reaction may take place at a temperature of from about - 20 ° c . to about 100 ° c . and at a pressure of from about 0 . 5 atm to about 5 atm . ( a ) 13 . 1 g methyl 3 -( 3 - methoxy - 4 - hydroxyphenyl ) propionate ( 62 . 4 mmol ) is dissolved in 150 ml dry n , n - dimethylformamide ( dmf ). after addition of 4 . 0 g 88 % koh ( 62 . 7 mmol ) to this solution , the whole is stirred for 30 minutes , after which 7 . 55 g allyl bromide ( 62 . 4 mmol ) in 120 ml dry dmf is added dropwise over a 30 - minute period . after stirring for 11 / 2 hours at room temperature , the reaction mixture is poured out into 1700 ml saturated nacl solution . extraction with ethyl acetate , evaporation to dryness and chromatography on 150 g silica gel with tolueneethyl acetate ( 95 : 5 ) as eluent gives 12 . 4 g methyl 3 -( 3 - methoxy - 4 - allyloxyphenyl ) propionate as an oil . rf in toluene : ethyl - acetate ( 85 . 15 )= 0 . 5 on sio 2 . ( b ) 12 . 4 g methyl 3 -( 3 - methoxy - 4 - allyloxyphenyl ) propionate is treated with hydroxylamine at conditions corresponding to that described in example i . the yield of 3 -( 3 - methoxy - 4 - allyloxyphenyl ) propionohydroxamic acid is 11 . 5 g . crystallization from a methanol - toluene mixture gives an analytically pure sample of melting point 94 °- 95 ° c . the following compounds are prepared in a way corresponding to that described in example i : 3 -( 3 - benzyloxy - 4 - methoxyphenyl ) propionohydroxamic acid ; rf in methylene chloride : methanol ( 85 : 15 )= 0 . 58 on sio 2 ; in order to illustrate that the inhibition of platelet aggregation is coupled to the compounds of formula i , test results of a number of related hydroxamic acids in the so - called &# 34 ; in - vivo screen filtration &# 34 ; test are given in this example . in this test the effects of the compounds to be tested on aggregation of platelets induced in - vivo by adenosine - 5 &# 39 ;- diphosphate ( adp ) are determined . the circulation of blood through the aorta of normal rats , ( which have already been treated for 5 days with the substance being tested ( or placebo )), is diverted to the outside of the body through a plastic tube . the plastic tube is attached to a micro - filter system ( 20 μ ) containing heparin . the blood pressure in front of and behind this filter can be recorded at any desired time . by injecting an adp solution immediately before the filter , platelet aggregation is induced at that point . aggregates of platelets then partially block the filter system , causing a change in pressure across the filter . two variables are measured : ( a ) the change in pressure across the filter ( hereinafter aggregation index ) and ( b ) the time necessary for the original pressure gradient to be restored ( hereinafter normalisation time ). the changes in aggregation index and normalization time are expressed as percentages of the values found for the rats treated with placebo . the compounds 1 to 7 inclusive are hydroxamic acids claimed and are according to the invention . __________________________________________________________________________ ## str4 ## % change inscreen filtration testno . a r r . sub . 1 r . sub . 2 dosage ( oral ) aggregation index normalisation__________________________________________________________________________ time1 . ch . sub . 2ch . sub . 2 och . sub . 3 och . sub . 3 h 5 × 50 mg / kg - 23 - 242 . ch . sub . 2ch . sub . 2 och . sub . 3 h och . sub . 3 5 × 50 mg / kg - 21 - 153 . ch . sub . 2ch . sub . 2 och . sub . 3 h h 5 × 50 mg / kg - 6 - 28 ## str5 ## och . sub . 3 och . sub . 3 h 5 × 50 mg / kg - 10 - 425 . ch . sub . 2ch . sub . 2ch . sub . 2 och . sub . 3 och . sub . 3 h 5 × 50 mg / kg - 8 - 19 ## str6 ## och . sub . 3 och . sub . 3 h 5 × 50 mg / kg - 22 - 377 . ch . sub . 2ch . sub . 2 och . sub . 3 och . sub . 2 c . sub . 6 h . sub . 5 h 5 × 50 mg / kg - 24 - 288 . ch . sub . 2ch . sub . 2 h och . sub . 3 h 5 × 50 mg / kg - 1 + 49 . ch . sub . 2ch . sub . 2 och . sub . 3 oh h 5 × 50 mg / kg + 10 - 310 . chch och . sub . 3 och . sub . 3 h 5 × 100 mg / kg - 2 0 ch . sub . 2 och . sub . 3 och . sub . 3 h 5 × 50 mg / kg + 3 - 1__________________________________________________________________________ | US-85914277-A |
an instrument for chemical spectroscopy with imaging capabilities . a lightsource produces an array of light beams , each of which is made up of a plurality of discrete wavelengths . the array of light beams are modulated by an interferometer , then directed through a sample to an array of detectors . the sample may be a chemical mixture or a body part . an array of laser or light - emitting diodes provides light at the desired wavelengths and high intensity . the set of wavelengths is selected for a particular kind of analysis , and a specific set of possible absorbing species to be detected . the different wavelengths are guided optically into a single lightbeam , or an array of lightbeams . this light is then directed through the sample and onto a detector . the lightsource and detector , or lightsource alone , may be rastered if necessary to form an image . individual lightbeams in an array may be modulated , polarized , or both so as to improve resolution . the signal from the detector undergoes a fast fourier transform to produce a near - infrared absorption spectrum as a function of wavelength . the absorption spectra can be used to produce an image of the spacial distribution of detected species within the sample . either the lightsource or detectors can be placed on the end of a probe or catheter for imaging through the wall of a hollow sample . | fig1 a shows the manner in which light scattering affects an image projected through a turbid sample . initially the photon trajectories are ballistic , but after multiple scattering takes place the trajectories can be described as diffusive . the light intensity is attenuated not only by scattering but also by absorption . once past the ballistic region , photon trajectories bloom outward from the central axis . the light diffuses outward at a constant rate , for a given distance along the axis . thus a diffusive cone of light propagates through the sample for each original point . fig1 b shows the cross section of the diverging cone of light as it propagates through the sample . photons emerging from the other side of a turbid sample still may contain much information about the original image . this information is contained in the photon exit position , exit angle , absorption probability , and net pathlength . ( if the original light was polarized , the residual polarization may also be of some use .) the distributions of each parameter can be used to improve the resolution of the projected image . the image resolution can be improved by selecting only the central part of each distribution , especially of the pathlength distribution . this in effect selects only a narrow bloom , or amount of outward diffusion . fig1 c shows the resolution gain for 99 % signal attenuation by three techniques . the graph shows that the pathlength distribution remains quite narrow compared to the other distributions , and offers the best increase in resolution in exchange for signal attenuation . fig2 shows a scanning system constructed in accordance with the principles of the present invention . the lightsource 10 , in this case an ild array , and the detector 12 are depicted as square arrays that provide a square image . the detector arrays have very small acceptance apertures provided by a collimator or modulator 14 , in order to discriminate against scattered light . the lightsource 10 requires a controller 16 , power 16 , and possibly cooling until such time as very high efficiencies can be achieved with ilds ( perhaps using microcavities ). a piezoelectric assembly 18 can move the ftir mirror 20 at 30 hertz , since relatively small path differences must be achieved in precise increments . a stack of piezoelectric layers can be controlled in series , in order to use relatively low voltages to achieve net displacements on the order of a millimeter . other mirrors 13 , beam - splitters 11 , lenses , and fiberoptic lightguides may be used as passive optical elements in the design . ultimately , the information on the sample 15 is passed through signal processing 17 and the image shown on display 17 . fig3 shows a matched lightsource 22 and detector array 24 . a lightguide 26 , either fiberoptic or hollow metal , is used to mix the colors from different types of ilds into a multichromatic lightbeam with a relatively small divergence . alternative schemes could use lenses , mirrors , or integrated fiberoptics for mixing if these prove less expensive . a 100 × 100 array that uses 20 different colors would require 200 , 000 ilds . the simplest approach at present to generating and mixing the photons seems to be to use 20 separate arrays of vcsel diodes , each array producing one wavelength of photons . these vertically emitting diodes must be spaced sufficiently far apart to permit the emitted beams to be easily directed into specific lightguides . microlenses or microlens arrays may be useful in reducing the divergence of emitted photons from each diode . at present 32 × 32 addressable ild arrays have been produced . with advances in photonics it may be possible to fabricate 100 × 100 arrays , or even arrays with 200 , 000 ilds in which 100 × 100 sub - arrays of 20 different wavelengths are included . however , the simplest and cheapest approach may be to combine separate , monochromatic arrays of ilds . reliability issues are also significant - diodes are active elements with finite lifetimes or values for mean - time - between - failure ( mtbf ). another alternative is to use linear arrays of more traditional side - emitting ild structures . square arrays can be fabricated by combining such linear arrays . suitable power , cooling , and control must also be provided to permit reliable operation . in this example , twenty different wavelengths are assumed to be necessary to provide nine different plsr factors for a particular analysis . the lightsource and detector arrays can be removed and replaced with new arrays with wavelengths better suited to other samples and analyses . the software algorithm used to modulate the lightbeams and to process the resulting data would also have to be changed , to match the new arrays . the collimator or modulator 28 array directs light that has been transmitted through the sample 23 , but not scattered 25 , to the appropriate detector 30 . several parallel arrays of apertures may be used for this purpose , along with beamstops to minimize reflection and lenses to magnify dispersion . each detector 30 receives a ftir signal , which must be converted with a fft algorithm , evaluated for the intensities at the twenty wavelengths , and analyzed for concentrations with multivariate calibration . ( the prior arts of software and hardware for rapid digital signal processing of large arrays of video data is already highly developed , and finds many applications in other fields .) fig4 shows the use of a modulation scheme to increase the image resolution , at the cost of a decrease in the signal - m - noise ratio . either a linear array or a square array may be used , the linear array requiring a linear raster in order to obtain a two - dimensional image . in this case an ild array 31 with 20 wavelengths , each with 100 × 100 ild &# 39 ; s is shown . two individual arrays 33 are drawn as 10 × 10 arrays . a cross - section of the array 33 gives the intensity profile . the profile differs with modulation and without modulation . modulation improves the peak - to - peak separation and the peak - to - valley difference in an intensity profile . the modulation scheme may be positional , pathlength - based , or both depending on the thickness of the sample and the degree of light - scattering . positional modulation would involve switching neighboring lightbeams 33 on and off . pathlength - based modulation would involve switching on and off or modulating each lightbeam , as well as gating the detector or sampling the detector signal with a small phase offset . fig5 graphically illustrates an algorithm for identifying a metabolite concentration . the specific algorithm for a given sample and kind of analysis determines the choice of wavelengths in the lightsource 50 , shown here as an ild array . the ir spectrum from the lightsource 50 is modulated by an interferometer to create an ftir spectrum , which is passed through the sample 52 . the ftir spectrum of the light passing through the sample is received by the detector array 54 and the signal is subjected to a fast fourier transfer analysis to obtain the ir spectrum . the ir spectrum is subjected to a plsr analysis to determine the concentration of metabolites within each pixel of the sample 52 , which is displayed as an image of the metabolite concentration on the display 56 . the algorithm is represented in terms of vectors and matrices , corresponding to the plsr factor , for the respective multivariate calibration . the spectral information from the unknown and calibration samples is digitized to form the numerical matrices d and c . the matrix equation d = cs + e then is solved using multivariate calibration analysis ( such as the plsr approach ). graphically , the column or row vectors of the matrix c are projected by multivariate regression onto those of the matrix d . the coefficients of the resultant matrix are the calculated concentrations of the metabolites at each pixel . fig6 illustrates a process of scanning a body part 32 . the diodes 34 provide photons of wavelengths absorbed by oxyhemoglobin and skin . concentrations would be displayed according to a color scheme which effectively presents the dam to the desired audience . for example , higher oxyhemoglobin concentrations might be shown in brighter shades of red , and lower in darker shades of blue , to communicate the connotations of arterial and venous blood . such concentrations would be calculated from intensity ratios for a given pixel . absolute intensities would denote the optical thickness of the sample and might be shown in shades of grey . the scanning process illustrated here is a fast one , in which power and control are supplied to the interferometer and square lightsource 36 and , after passing through a collimator or modulator , detector arrays 38 are used to acquire the image with the best possible s / n ratio . this information is then processed by the fft and digital array processors 37 to create an image of blood flow in the sample on display 39 . mirrors , beam - splitters , lenses , and fiberoptic lightguides may be used as passive optical elements if the design . in order to permit real - time imaging , the s / n ratio must be sufficiently high to define a point or neighborhood on the calibration coordinates , for each pixel in the image every 0 . 03 seconds . low concentrations or species that absorb light weakly may still require time - averaging for accurate and precise quantification , and thus might be displayed as running averages over longer time intervals . fig7 illustrates one possible external appearance of the embodiment depicted in fig6 . the components of the invention are lightweight and compact , so that a practical embodiment may actually be portable . fig8 illustrates an alternate embodiment for imaging hollow body structures . the lightsource 40 is incorporated into a fiberoptic probe 46 or the body of an endoscope . the probe 46 with the lightsource 40 is inserted into a hollow body structure 44 or other sample with an internal cavity to illuminate the structure 44 from the inside . the detector 42 can be placed externally to the structure 44 for detecting the photons that pass through the structure 44 . this embodiment may offer even greater resolution for imaging the walls of hollow organs or other structures by shortening the pathlength of the light and therefore the degree of scattering . in some applications it may be advantageous to reverse the positions of the lightsource 40 and the detector 42 such that the lightsource 40 is external and the detector 42 is internal to the sample 44 . also fiberoptic extensions of the lightsource 40 and the detector 42 might be used to permit endoscopy . perhaps the most widespread , immediate , practical application of the invention would be to mammography and to pediatrics . three or four wavelengths should suffice to image vascularized tumors in both fatty and fibrous tissues , for example . images with resolutions on the order of 1 mm probably can be obtained through collimation and pathlength selection . this roughly 10 - fold improvement in spatial resolution opens up a very wide range of new applications ( such as in obstetrics ). the present practice of mammography screening by x - rays makes use of ionizing radiation which is known to be carcinogenic , and may itself be responsible for about 0 . 2 % of breast cancer . similar concerns about cancer must be raised in pediatric situations ( e . g . esolutions on the order of 1 mm probably can be obtained through collimation and pathlength selection . this roughly 10 - fold improvement in spatial resolution opens up a very wide range of new applications ( such as in obstetrics ). the present practice om mamography screening by x - rays makes use of ionizing radiation which is known to be carcinogenic , and may itself be responsible for about 0 . 2 % of breast cancer . similar concerns about cancer must be raised in pediatiric situations ( e . g . in screening for bronchial pneumonia , a very common childhood occurrence ). among existing non - invasive analytical techniques , only magnetic resonance imaging ( mri ) offers a similar combination of chemical specificity and spatial resolution without ionizing radiation . most of the components of the present invention are quickly becoming cheaper and more reliable , t a pace that is driven by related mass technologies ( optical communication , photonic computing , and electro - optical devices ). it seems very unlikely that mri machines will become affordable in price or compact in size ( e . g . potable or even desk - top analytical units ) in the near future , whereas the present invention offers exactly this prospect in the near term . the illustrative embodiments have shown scanning protocols in which the lightsource and detector are rastered in parallel planes in order to obtain spatially - resolved distributions of concentration in two dimensions . many other geometries are possible , and may be better suited to particular measurements or samples . these methods may be extended to three dimensions for tomography of internal structures or to obtain solid models of molecular distributions , for example by rotating the sample about an axis perpendicular to the direction of the transmitted lightbeams . in addition , more finely focused beams may be used for microscopy , and more defocused beams may be used to obtain larger fields of view . triangulation might be used to better image objects deep within the sample . finally , signals in thin samples may be sufficiently intense to obtain data with sufficient rapidity to display real - time images . several possible ild arrays have been described . the use of integrated lightguides on a planar surface is another possible arrangement , in which silica or other materials are deposited in such a way as to channel and multiplex light from several individual ild emitters to a single output port or lens . such planar monolithic technology for photonics is possible , but higher packing densities require higher conversion efficiencies and lower power consumption . a single ild typically consumes more than 10 mw of power at present and have efficiencies no greater than 10 %. the ideal of direct conversion would be to produce little or no thermal energy . the prices of optoelectronic components and of computer processors are likely to continue decreasing in the future , making an optimized design for transillumination an increasingly cost - effective analytical method . further research in the field of chemometry will provide additional algorithms and candidates for analysis by near - infrared spectroscopy . thus the present invention should continue to be a useful and versatile tool . four frequencies are fundamental to this invention : that of the light wavelengths , the modulation frequency , the interferometer cycling frequency , and the frequency at which a useful image can be formed . the frequency of light with wavelengths from 1 to 10 microns is about 10 15 to 10 16 hz . the modulation frequency is necessarily in the 10 8 to 10 9 hz region , in order to measure changes in phase . the interferometer may cycle at 10 2 hz or less , slower rates enjoying more time averaging but susceptible to greater 1 / f noise . the rate at which useful images can be formed depends on the sample thickness . in thin samples , it might be useful to introduce a fifth frequency - modulation of the lightbeam at the same frequency as some time - variant process in the sample in schlieren and stroboscopic methods of measurement . one of the more noticeable biological frequencies suited to nirs is that of the pulse . thus it may be possible to locate and resolve aneurysms or other dynamic cardiovascular anomalies even in thick samples , by time - averaging a strobed image . due to the long exposure times required for the best results , flexible designs with fiberoptics could be used to minimize discomfort . this would compare favorably with present methods that use uncomfortable compression protocols and seek to minimize net exposure . a small lightsource array or detector array could also be used to advantage in endoscopy , to provide better resolution with a relatively non - invasive procedure . past in vivo applications of transillumination have included dentistry , laparoscopy , opthalmology , pediatrics , and veterinary medicine . for very thin biological samples in which ballistic photons remain plentiful , it might be possible to acquire images in real - time . increased spatial resolution requires higher total doses . near - infrared photons pose less of a hazard than higher energy photons or ionizing radiation , since the main effect is heating of the sample . skin bums have reportedly been the main hazard associated with traditional methods of laparoscopy . the rate of power absorption is much more significant than the total dose . in many cases , moreover , most of the absorption will occur before the light has penetrated halfway through the sample . this suggests that some advantages in the form of more uniform heat - dissipation ( and higher acceptable light intensities ) might be realized in a three - dimension scanning arrangement in which the lightsource / detector rotates about the sample . it also seems possible to use image - enhancement algorithms , so that the signal from all wavelengths is combined to provide the best net spatial resolution . thus 16 wavelengths give a 4fold increase in s / n for resolution . application of stroboscopic techniques also can be used to improve spatial resolution , by allowing better focus and the application of time - averaging to features that otherwise would change at the pulse rate . polarized light and polarization filters can also be used to measure phenomena such as optical rotation , fluorescence depolarization , and so on . these may require single wavelengths and different geometries ( e . g . a detector array facing the sample but at right angles to the transmitted light ). many other spectroscopic and scanning techniques are part of the prior art , and may be adapted to the present invention in order to better measure particular samples or phenomena . the increased resolution and chemical specificity offered by the present invention suggests a wide range of new applications . although the illustrative embodiments show several examples of this invention , it is to be understood that various modifications and substitutions for the illustrative diodes , optical guides , filters , and detectors may be made by those skilled in the relevant art without departing from the novel spirit and scope of the present invention . | US-10138993-A |
a table and improved hinge mechanism therefor . a table top having extension leaves secured to opposite edges of top by hinges . hinge including a pivot member , a slide member , a pivot pin and an extension spring operate to permit extension leaves to be oriented in three positions , horizontal and even with the table top , vertically upward , and vertically downward . when in the horizontal orientation , tongue is engaged within channel . to reorient the extension leaves , tongue is withdrawn from channel against the spring and may be pivoted on the pin . | a table according to the invention as shown in perspective in fig1 comprises a wheel support 10 , a table top 11 tiltably secured to support 10 by a suitable mechanism and a pair of extension leaves 13 and 14 secured to the opposite edges 15 and 16 of top 11 by locking hinges 17 , 17a , 17b , and 17c . support 10 , as shown in greater detail in fig2 - 3 , includes a pair of posts 100 , 101 interconnected by a cross member 102 . a pair of longitudinal rails 103 and 104 are secured below top 11 in any suitable fashion . a tilting mechanism of the type shown in u . s . pat . no . 3 , 437 , 058 issued to bue is used to permit movement of top 11 from a horizontal use position to a vertical storage position . rails 103 and 104 are provided with shaped elongated slots 105 . a rod 106 is secured at the tops of post 100 and 101 to extend laterally beyond and into slots 105 . arms 107 and 110 are pivoted to rails 103 and 104 at 111 and 112 , and the posts 100 and 101 at 113 and 114 , all respectively . the distance between pivots 111 and 113 is greater than the distance from pivot 113 to the upper end of slot 105 as seen in fig3 so that when the table top is tilted in the direction of arrow 114 , slots 105 move past rod 106 , until the rod finally settles in a notch 116 at the end of the slot . in the storage position of the parts shown in solid lines in fig3 first ends of slots 105 rest on rod 106 . when the parts are tilted in the direction of arrow 116 , slots 105 slide on rod 106 , until the rod finally seats in notches 116 at the second ends of the slots : the geometry of the mechanism prevents further tilting of the table from the horizontal use position shown in broken lines in fig3 . for resetting the table to its storage position the top is slightly lifted , to enable movement of rod 106 out of notches 116 . extension leaves 13 and 14 are attached to table top 11 by four identical locking hinges 17 , 17a , 17b , 17c . the details of hinge 17 are shown in fig5 - 7 . hinge 17 comprises a pivot member 20 , a slide member 21 , a pivot pin 22 , and an extension spring 23 . member 20 includes a plate 24 having a flat mounting surface 25 . the outer edge 26 of member 20 is turned away from surface 25 as a beveled lip 27 . a pair of laterally spaced walls 30 and 31 extend transversely away from mounting surface 25 , and are joined at a site spaced from the mounting plate by a cross member 32 . walls 30 and 31 extend longitudinally beyond lip 27 , and are provided with aligned holes 33 , 34 to receive pivot pin 22 . plate 24 , walls 30 and 31 , and cross member 32 define a longitudinal channel 35 , of known transverse dimensions extending parallel and orthogonal to the mounting surface . slide member 21 comprises a mounting plate 40 having a mounting surface 41 . a tongue 43 extends transversely away from mounting surface 41 , and extends longitudinally beyond plate 40 . tongue 43 has working edges 44 and 45 , and is provided with a stop shoulder 46 and a longitudinal slot 47 extending between closed ends 50 and 51 , for traversal by pin 22 . a further pin 52 extends from tongue 43 at a site remote from slot 47 , and spring 23 engages pins 22 and 52 at its ends , to draw members 20 and 21 toward one another , the assembly being secured by cotter pins 53 and 54 . a spaced pair of hinges 17 as shown in detail in fig5 - 8 are installed at each edge of the table , with pins 22 parallel to the edge and channels 35 perpendicular thereto . mounting plate 24 is secured under the table top by fasteners 55 , in such a position that surface 25 and lip 27 project beyond the edges 15 and 16 . member 21 is secured under the extension leaf by fasteners 56 so that when the edges of the top and leaf are in abutment tongue 43 is received in channel 35 with shoulder 46 engaging cross member 32 and pin 22 passing through hole 33 , slot 47 , and hole 34 . if the table top and leaf are of the same thickness , surfaces 25 and 41 are coplanar . spring 23 is secured at the ends to pins 22 and 52 , and cotter pins 53 and 54 are inserted . as best shown in fig1 and 2 , a rub rail 57 is secured to the under surface of each leaf by fasteners 60 , being formed to pass over the pair of hinges 17 , 17a or 17b , 17c for each leaf . these rub rails , which may be constructed from straps of steel or other protective material , function as guards for protecting both the hinges and any walls or other objects which might be contacted by the table in motion . in the arrangement of parts shown in fig6 and 7 and at the right of fig2 leaf 13 is resiliently urged into edge - to - edge contact with top 11 by springs 23 , and pivotal movement of the leaf about pivot pins 22 is prevented by contact of tongue edges 44 with plates 24 and tongue edges 45 with cross members 32 . if it is desired to drop leaf 13 , the leaf is drawn to the right , extending spring 23 , until pin 22 engages the end 50 of slot 47 . tongue surfaces 44 and 45 are now clear of channel 35 and the leaf is enabled to pivot downwardly to the position shown in fig9 . springs 23 need not be strong enough to support the weight of the leaf , which can simply hang on pins 22 . restoration of leaf 13 to its extended position is accomplished simply by pivoting the leaf upwardly , until tongues 43 can enter channels 35 , the operation then being completed with the assistance of springs 32 , and the leaf being guided into position by engagement of lips 27 with the undersurface of the leaf . when it is desired to move leaf 13 into the &# 34 ; side rail &# 34 ; position shown in fig8 the leaf is first drawn outwardly as directed above to release tongues 43 from channels 35 , then pivoted upwardly to the desired position , and then allowed to settle until its edge contacts the projecting portions of plates 24 . here the force of springs 23 is acting to hold the leaf against plate 24 . ends 50 of tongues 43 are now lower than plates 24 and cross members 32 , so that edges 44 of the tongues prevent movement of the leaf about pins 22 in either direction . this position of leaf 14 is shown at the left in fig1 and 2 , and both leaves are in this position in fig4 . fig1 also illustrates leaf 13 in phantom lines in the upward position . it is clear that rub rails 35 are the most lateral portions of the table , and prevent contact of hinges 17 with walls , doorframes , and other surfaces past which the table is being moved . to remove the leaf from this position , it is lifted slightly until surface 44 disengages cross member 32 , and may then be pivoted into any other desired position . it should be understood that the present invention may be suitable for use in connection with any table - like surface where drop - leaves are desirable . of particular interest is its use in connection with room service tables used in hotels for delivery of food to hotel rooms . one of the requisites for room service tables is that they occupy minimum space when not in use : for this purpose table 11 is arranged to tilt into a vertical storage position . fig2 and 3 show that top 11 can be tilted into the storage position regardless of the positions of leaves 13 and 14 , although the relative position of fig3 is that in which the least storage space for the table is required . in addition , as a room service table , the ability to fold the leaves upwardly , as in fig3 is of significant aid in maintaining plates on the table when the table is rapidly wheeled down hotel corridors . the rub rails 57 further aid in protecting the corridor walls from sustaining extensive damage of the type which would otherwise be caused by scraping of the hinges along the wall when wheeled down a corridor . numerous characteristics and advantages of the invention have been set forth in the foregoing description , together with details of the structure and function of the invention ; the novel features thereof are pointed out in the appended claims . the disclosure , however , is illustrative only , and changes may be made in detail , especially in matters of shape , size , and arrangement of parts , within the principle of the invention , to the full extent intended by the broad general meaning of the terms in which the appended claims are expressed . | US-16175081-A |
a film - forming siloxane composition having excellent adherent and lubricating properties comprising a reactive component having a combination of three siloxane polymers chemically crosslinked , and a non - reactive component dispersed therein . substrates are dipped or otherwise coated with the compositions , at which time they are cured quickly under heat to a durable , adherent lubricating surface which is dry to the touch . of particular advantage is the use of these films on hypodermic needles , razor blades , catheters and the like . | the first siloxane polymer of the reactive component is present in amounts of about 3 % to about 35 % by weight of the total film - forming composition ; and preferably in amounts of about 10 % to about 30 % weight percent . this polymer corresponds to the following structural formulae : ## str3 ## wherein r is alkyl c 1 - 20 , haloalkyl , aryl , haloaryl , cycloalkyl , silacyclopentyl , aralkyl and mixtures thereof ; x is about 60 to about 1000 , and preferably about 200 to about 320 ; and y is about 3 to about 25 . copolymers and mixtures of these polymers are also contemplated . it is preferred that a mixture of siloxane polymers selected from the formulae i and / or ii be used in the reactive component . most preferably this mixture comprises a mixture of two different molecular weight vinyldimethylsilyl terminated polydimethylsiloxane polymers , wherein one of the polymers has an average molecular weight of about 5 , 000 to about 25 , 000 and preferably about 16 , 000 , and the other polymer has an average molecular weight of about 30 , 000 to about 75 , 000 and preferably about 38 , 000 . the lower molecular weight siloxane is generally present in amounts of about 20 % to about 80 %, and preferably about 60 % by weight of this mixture ; and the higher molecular weight siloxane is present in amounts of about 80 % to about 20 %, and preferably about 40 % by weight of this mixture . the second siloxane polymer of the reactive component is present in amounts of about 0 . 3 to about 5 . 5 % by weight of the total composition and preferably in amounts of about 0 . 5 to about 4 . 0 %, and comprises : ## str4 ## wherein p is about 8 to about 12 and preferably about 10 . the final requirement of the reactive component is a siloxane chain - extending polymer having two or more terminal hydrogen groups . these compounds correspond to the formula iv below and are generally present in the reactive component in amounts of about 2 . 5 % to about 50 %, and preferably about 5 % to about 40 % by weight of the reactive component . wherein p is about 140 to about 170 and preferably about 150 to about 160 . preferably a mixture of these polymers is also used comprising two different molecular weight materials . for example , a preferred embodiment incorporates about 2 % to about 5 % by weight of the mixture of a trimethyl silyl terminated polymethylhydrogensiloxane having an average molecular weight of about 400 to about 7 , 500 , and preferably about 1900 , in admixture with about 98 % to about 95 % of a dimethylhydrogen silyl - terminated polymethylhydrogensiloxane having an average molecular weight of about 400 to about 37 , 000 and preferably about 12 , 000 . the three required siloxane polymers of the reactive component are present in relative weight ratios of about 0 . 2 : 5 : 1 to about 2 : 20 : 1 and preferably about 0 . 4 : 5 : 1 to about 1 . 5 : 16 : 1 . in these ratios , an adherent , fast curing film is obtained with the added advantage that it is optically clear and free of cloudiness or opaque appearance . the reactive component has a viscosity ranging from about 100 to about 100 , 000 centistokes and an average molecular weight per crosslink of about 5 , 000 to about 75 , 000 . the mole ratio of vinyl groups to hydrogen groups in the reactive component is about 0 . 010 : 1 to about 0 . 20 : 1 . the mole ratio of hydrogen groups of the crosslinking polymer to hydrogen groups of the chain - extending polymer is about 5 . 0 : 1 to about 20 : 1 . the non - reactive component of the inventive compositions is responsible for the lubricating properties of the resultant films and coatings . this component comprises a siloxane polymer having an average molecular weight of about 1900 to about 100 , 000 , and preferably about 5 , 000 to about 100 , 000 . generally , this corresponds with a viscosity of about 20 to about 300 , 000 centistokes ( cstks ). the non - reactive component is present in amounts of about 10 % to about 90 %, and preferably about 70 % to about 80 % by weight of the total composition . the non - reactive component generally corresponds to compounds of formula v : ## str5 ## wherein r is alkyl c 1 - 20 , haloalkyl , aryl , haloaryl , cycloalkyl , silacyclopentyl , aralkyl and mixtures thereof ; and z is about 20 to about 1 , 800 . preferably , the non - reactive component has the following formula : ## str6 ## wherein z is about 70 to about 1800 and preferably about 70 to about 1 , 350 . the non - reactive polymer viscosity and the weight ratio of the non - reactive component to the reactive component are the two most significant variables influencing the properties of the final coatings and films . when applied to a hypodermic needle as a coating , the penetration , drag , retract and adhesion to needle - surface are affected by these variables . generally , the lower viscosity compositions cure to better lubricating films and coatings . additionally , better lubricating properties are also obtained in the resultant films and coatings if the weight ratio of the non - reactive lubricating component to reactive component is increased . penetration forces are lowest when the ratio of the crosslinker ( the second siloxane polymer of the reactive component ) to the chain extender is lowest . the weight ratio of the reactive component to the non - reactive component is preferably about 20 : 80 to about 30 : 70 . the inventive compositions are useful on a variety of materials and substrates such as metal and plastics and in applications where dry lubrication is required . the inventive compositions have excellent adherent properties when cured and if used in the proper thickness may serve as relatively permanent lubricative films . curing of the reactive portion can be accomplished by conventional methods well known in the art . for example , heat curing via oven or radio frequency ( rf ) are useful methods as well as the use of gamma radiation . any mechanism which will initiate the hydrosilylation reaction is a useful curing technique . in the case of oven curing , temperatures should range from about 150 ° to about 180 ° c . and residence time in the oven is generally about 30 to about 40 seconds , depending on the precise formulation . if rf techniques are used , the coil should conduct enough heat to obtain a substrate surface temperature of about 180 ° to about 240 ° c . at these temperatures , only about 2 to about 4 seconds are required for cure . this technique is particularly useful on hypodermic needles , catheters and cutting edges where production costs can be lowered significantly . if gamma radiation techniques are used , the need for hydrosilylation initiating catalyst is eliminated , since the radiation will start the cure . this technique has the advantage of sterilizing as well , which is useful in medical applications . the inventive compositions can be partially cured to attach them to the substrate , and then fully cured at a later time . for example , air drying will permit partial cure . the compositions are initially fluid and can be applied directly to the substrate in any suitable manner , for example by dipping , brushing or spraying . the exact thickness of the coating does not appear to be critical and very thin coatings , e . g ., one or two microns exhibit effective lubricating properties . while not necessary for operability , it is desirable that the thickness of the coating be substantially uniform throughout . the inventive compositions can be applied from an inert , solvent carrier , such as non - toxic chlorinated or fluorinated hydrocarbons . for example , 1 , 1 , 2 - trichloro - 1 , 2 , 2 - trifluoroethane , freon and the like are useful . conventional hydrocarbon solvents such as alkanes , toluene , petroleum ether and the like are also useful in applications where toxicology is not considered important . the compositions when cured have two distinct properties which are related to the two distinct components . the reactive component gives the cured product its surface adherent properties , allowing the film to coat and stick to the substrate . chemical attraction of the hydrogen functionality on the crosslinked film to the oxides and hydroxyl groups on the substrate surface are believed to be primarily responsible for the adhesion , although some physical adhesion may also be occurring . the adhesion thus provides a definite advantage in that they do not wipe off and remain on the substrate without creep or migration over long periods of storage time . the films are dry to the touch and are less likely to trap dust and dirt as the prior art compositions . fig1 is a diagramatic illustration of the probable chemical configuration of the cured film of the invention on a substrate . as previously stated , the non - reactive component provides the lubricating property to the film . lubrication is experienced on the non - adherent surface of the film , that is , on the exposed side . without wishing to be bound to any one theory , the non - reactive polymer chains are believed to fit within the voids of the cured reactive component . fig1 provides an illustration of the probable chemical configuration of the cured film on a substrate . chains labelled &# 34 ; a &# 34 ; represent the siloxanes of the reactive component having vinyl functionality . those labelled &# 34 ; b &# 34 ; represent siloxanes of the reactive component having hydrogen functionality . the substrate is depicted as a metal surface where metal oxides ( mo ) and metal hydroxyl groups ( moh ) are present . chemical bonds can be seen between the functional groups of the reactive components and the oxide and hydroxyl groups of the substrate . the chains labelled &# 34 ; c &# 34 ; represent the non - reactive component , which can be seen to be physically entrapped within the voids of the reactive chains . to prepare the inventive compositions , appropriate quantities of the three siloxanes required for the reactive component are mixed along with a catalyst solution . it is preferred that the vinyldimethylsilyl terminated pdms polymers be mixed together first , followed by addition of the catalyst and finally the second and third siloxanes , e . g ., the cross - linker and chain - extender . mixing takes place for five to fifteen minutes at room temperature . this reactive portion is then combined with the non - reactive polymer and mixed for about five minutes at room temperature . the mixture is then diluted with a solvent , for example 1 , 1 , 2 - trichloro - 1 , 2 , 2 - trifluoroethane to prepare a 4 weight % solids concentration . the fluid mixture is then ready to be applied to a substrate by one of the aforementioned techniques , and subsequently cured to a film . the films and coatings of the instant invention have an average molecular weight per crosslink of about 5 , 000 to about 110 , 000 and preferably about 15 , 000 to about 37 , 000 . the most preferred composition of the instant invention is a composition containing the following siloxane polymers : reactive component ## str7 ## wherein x is about 200 to about 500 ; ## str8 ## wherein x is about 8 to about 12 ; ## str9 ## wherein x is about 160 ; and non - reactive component ## str10 ## wherein z is about 70 to about 1 , 350 . this preferred composition has been found to be especially useful and effective in coating hypodermic needles . the following examples serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention . all percentages are by weight of the total composition unless otherwise specified . this example is intended to show the criticality of process conditions and materials used in the preparation of the coating formulations . six formulations were prepared according to the procedure below and needles were coated therefrom . all of the formulations in table i were prepared according to the following procedure . a homogenous solution of the vinyldimethylsilyl terminated polydimethylsiloxane polymers was prepared by mixing 1 , 000 centistoke and 10 , 000 centistoke polymers for 3 - 5 minutes . to this solution was added chloroplatinic acid catalyst in a sufficient amount to catalyze the silane to vinylsilane addition reaction , and the solution was mixed for about 3 - 5 minutes . a separate homogenous solution of the crosslinker and chain - extender was prepared at room temperature by mixing for 3 - 5 minutes . the vinyl functional polymer solution was added to the crosslinker / chain - extender solution ( hydrogen functional solution ) and mixed for 3 - 5 minutes . to this reactive polymer solution was added the non - reactive silicone polymer and the combined sample is mixed for 3 - 5 minutes at room temperature . samples of the inventive coating compositions were diluted with 1 , 1 , 2 - trichloro - 1 , 2 , 2 - trifluoroethane to a concentration of 4 wt .% solids . table i__________________________________________________________________________coating formulations ( weight %) ingredients a b c d e f__________________________________________________________________________a . reactive component vime . sub . 2 siloxane polymer . sup . ( 1 ) 4 . 5 10 . 8 8 . 4 21 1 . 2 14 vime . sub . 2 siloxane polymer . sup . ( 2 ) 10 . 5 7 . 2 3 . 6 9 1 . 8 21 crosslinker . sup . ( 3 ) 1 . 75 1 . 5 . 9 1 . 5 . 875 . 75 chain - extender . sup . ( 4 ) 33 . 25 10 . 5 17 . 1 18 . 5 6 . 125 14 . 25b . non - reactive component weight % lubricative polymer / viscosity . sup . ( 5 ) ## str11 ## ## str12 ## ## str13 ## ## str14 ## ## str15 ## ## str16 ## __________________________________________________________________________ ## str17 ## ## str18 ## ## str19 ## ## str20 ## ## str21 ## this example is intended to demonstrate by comparative tests the advantages the inventive compositions have over the prior art . the tests were specifically designed to compare the lubrication properties of the inventive compositions against the prior art . each of the compositions in table i was used as a coating material for clean stainless steel , 16 gauge hypodermic needles . five needle samples were used for each composition . the needles coated with the inventive compositions ( a - f ) were mechanically disposed 19 mm ( 3 / 4 &# 34 ;) deep and withdrawn at a rate of about 12 mm / sec . the comparative compositions of the prior art ( g - h ) were similarly dipped and withdrawn at the rate of about 6 mm / sec . certain of the control needles were dipped 19 mm ( 3 / 4 &# 34 ;) deep in 4 wt % solution of the commercial version of the composition described in the aforementioned u . s . pat . no . 3 , 574 , 673 . other control needles were dipped similarily in a 4 wt % solution of 12 , 500 centistoke dow corning 360 fluid . the control polymer solutions all used 1 , 1 , 2 - trichloro - 1 , 2 , 2 - trifluoroethane as the solvent . coating of all the needles was done using a machine which controlled the rate of dipping and withdrawal . the thickness of the coating is related to the speed of withdrawal of the substrate . in the case of needles , an optimum speed for obtaining a coating with the highest degree of lubricity was chosen through routine experimentation and experimental modeling . generally , the faster the substrate is withdrawn from the fluid composition , the thicker the resultant coating . this would be expected since there would be less time for the fluid to run off the substrate . speeds of withdrawal for all formulations tested were chosen to maximize the degree of lubricity . the speeds for the control formulations were the conventional rates used for high speed assembly - line coating . the speeds for maximizing lubricity of the inventive compositions was determined to be about 12 . 7 mm / sec ; and was about 6 . 35 mm / sec for the control compositions . thus , the respective rates were previously determined by routine experimentation to be the appropriate ones for obtaining a coating with the highest degree of lubricity . the coated needles were then tested for penetration , drag , retract and catheter / needle adhesion . a natural isoprene rubber , astm d - 2000 type aa was used as a test membrane through which the needles were pierced . the force required for the 16 gauge needles to pierce a 1 / 16 &# 34 ;× 1 × 11 / 8 membrane was recorded as the penetration value . the membrane was held by a clamp assembly at a 45 ° angle and the penetration and withdrawal was performed by a model 1122 instron tensile machine . a fresh , unpierced membrane was used for each measurement . for purposes of this invention , the drag force is defined as the force required to slide the needle surface through the punctured membrane when inserting the needle through the membrane . that is , it is the functional force between the needle and the membrane after the needle has punctured the membrane and is continued to be moved in relation to the membrane . the retract force is the force required to slide the needle surface through the membrane when withdrawing the needle . the catheter / needle adhesion force is the force required to separate the catheter from the needle at their point of adhesion . turning to table ii , it is clear that the inventive compositions a - f demonstrated significantly lower values for the force required to penetrate the skin , drag through the skin and for retraction , then the two commercially available silicone lubricants shown . the values for catheter / needle adhesion indicated acceptable lubricating properties such that the needle can be easily separated from the catheter when the needle is withdrawn from the catheter to needle assembly . it is apparent that the inventive compositions have excellent adherent properties on the substrate to which they are applied , yet are non - tacky and do not transfer to adjacent surfaces . rather , these adjacent surfaces easily slide over the coated surface due to the lubricating properties of the inventive compositions . the inventive compositions may be employed as coating on a variety of materials and substrates , thereby imparting their lubricating effects . it is apparent that the inventive compositions exhibit improved lubricity over the prior art . table ii______________________________________ catheter / needle penetration drag retract adhesion______________________________________needles coatedwith coating : a 242 37 37 120b 257 44 41 95c 246 18 22 57d 270 45 44 158e 288 20 41 70f 262 56 56 97 g * 282 76 82 189 h ** 297 29 48 114______________________________________ * comparative composition from u . s . pat . no . 3 , 574 , 073 ( dow corning mdx4 - 4159 commercial needle lubricant ) ** trimethylsilyl terminated pdms ( dow corning medical grade 360 fluid silicone ) the invention being thus described , it will be obvious that the same may be varied in many ways . such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the claims . | US-80420985-A |
a mechanism for supporting and permitting selected adjustment of the position of a headrest relative to the back of a chair comprises a body , a first pivotable connection , a second pivotable connection and a selectively releasable locking mechanism . the first pivotable connection is near the first end of the body , adapted to connect to the chair and to allow pivoting of the body relative to the chair . the second pivotable connection is near the second end of the body , adapted to connect to the headrest and to allow pivoting of the headrest relative to the body . the selectively releasable locking mechanism is configured to retain the body in selected angular positions relative to the chair and relative to the headrest by clamping together interleaved plate members in frictional contact and to allow for one - handed actuation . | referring to the drawings , and first more specifically to fig1 , at 10 as indicated generally a headrest with a cushion 11 supported above a chair back 12 such as would be used in a dental or other medical style chair to support a patient . the headrest is supported above the chair back 12 by adjustment and support mechanism indicated generally at 14 constructed according to an embodiment of the invention . an elongate slide post , or bar , 18 would be attached to the back of chair 12 by a frictional holding mechanism which allows major raising and lowering of the headrest mechanism . this allows approximate positioning of the headrest but is inconvenient for finer adjustment once the patient is in the chair . the adjustment and support mechanism 14 for the headrest according to the invention includes an elongate housing , or mounting body , 22 . referring to fig3 - 5 , the housing has a selected length l , a selected height h , and a selected width w which are best adapted to provide the operational advantages of the present device . for example , the width w is greater than height h so that appropriate operating mechanism may be accommodated within the housing while still providing a low profile height h to allow patient &# 39 ; s head on the headrest to be placed as close to the operator &# 39 ; s lap as possible . the support mechanism 14 is show in fig3 - 5 in a substantially horizontal orientation which it may assume when a patient is laid back in the chair . the housing 22 has a substantially planar top wall 24 , a substantially planar bottom wall 26 , spaced therefrom , and a pair of opposed spaced apart side walls 28 , 30 . the top , bottom and side walls define an enclosure which houses the major portion of the operating components of the apparatus . a headrest mounting bracket 34 having a pair of bracket arms 34 a , 34 b is pivotally connected through pivot connection , or rod , 36 adjacent one end of housing , or body , 22 . pivot connection 36 is spaced outwardly from a central region of housing 22 toward said one end . pivot connection 36 has an axis 36 a which extends laterally , or widthwise , of housing 22 . headrest bracket 34 also has a lever arm portion 34 c thereon which extends laterally from pivot connection 36 . a crossplate , or guide plate , 38 extends across outer edge portions of bracket arms 34 a , 34 b and is secured , as by welding , thereto or is cast as a single element with bracket arms 34 a , 34 b . the crossplate has opposed outer edge , or margin , portions 38 a , 38 b which project laterally outwardly beyond bracket arms 34 a , 34 b and a central portion 38 c as best seen in fig2 and 5 . as best seen in fig2 , cushion 11 of headrest 10 may have a shallow curved configuration to comfortably cradle a patient &# 39 ; s head , indicated generally at 40 in dashed line in fig2 . a connector plate , or member , 44 may be secured to the back of cushion 11 and , as best seen in fig2 , and has a shallow curved configuration which conforms to , or is complementary to , the curved configuration of cushion 11 . connector plate 44 has laterally spaced apart parallel guide rail portions 46 , 48 extending longitudinally of the connector plate and forming channels , or guideways , 46 a , 48 b adapted to slidably receive edge margin portions 38 a , 38 b , respectively , of crossplate 38 therein . channels 46 a , 48 b act as guideways to mount connector plate 44 on headrest bracket 34 and permit translational sliding movement relative thereto . explaining further , a sliding fit is provided between edge margins 38 a , 38 b and channels 46 a , 48 b permitting the headrest connector plate 44 and the headrest cushion connected thereto to be slid along crossplate 38 toward and away from chair back 12 . to improve the operation of this translational sliding movement , appropriate materials may be interposed between edge margin portions 38 a , 38 b and channels 46 a , 48 b to provide a selected sliding fit therebetween . the fit should be such that an operator or patient may easily slide the headrest up or down to produce the most convenient or comfortable position desired . a layer of a material such as delrin ( produced by e . i . dupont de nemours ) has been found to work well as an interface in the channels between edge margin portions 38 a , 38 b and channels 46 a , 48 b . this , or other material appropriate to provide the desired sliding fit , may be applied either to edge margin portions 38 a , 38 b or to the interiors of channels 46 a , 48 b . referring still to fig2 , a cavity 42 is formed in central section 38 c of crossplate 38 facing toward connector plate 44 . a friction plate 47 , which may be in the form of a block of nylatron ( produced by polymer corporation ) is situated in cavity 42 with a spring 49 biasing it outwardly toward connector plate 44 . the biasing force of spring 49 urging friction plate 47 outwardly and against connector plate 44 serves to produce a selected frictional holding of the connector plate relative to the crossplate such that the headrest cushion will be held in a selected position once it is placed as desired by the user . a back support bracket 50 to which post 18 is secured , as by welding or other means , is pivotally connected to housing 22 through a pivot connection , or rod , 52 adjacent the end of housing 22 opposite bracket 34 . pivot connection 52 is spaced outwardly from a central region of housing 22 toward the opposite end . the pivot connection 52 has an axis 52 a which extends laterally , or widthwise , of housing 22 . bracket 50 includes a pair of laterally spaced bracket arms 50 a , 50 b . bracket arms 50 a , 50 b project outwardly from their associated end of housing 22 through openings defined in housing 22 , as do bracket arms 34 a , 34 b , at the opposite end of the housing . bracket 50 has a lever arm portion indicated generally at 50 c which projects laterally of pivot connection 52 . a plurality of elongate substantially planar parallel plate members , or fingers , also referred to herein as friction plates , 56 are disposed in a set . they are pivotally connected adjacent their outer set of ends at a pivot connection 58 , or rod , 58 to lever arm 34 c of bracket 34 . the axis 58 a of the pivot connection extends transversely , or widthwise , of housing 22 . remainder portions of plate members 56 extend longitudinally through a major portion of the interior of the enclosure provided by housing 22 toward the opposite end of the housing . elongate slots 56 a are formed in plates 56 extending longitudinally thereof . these slots extend toward the opposite , or inner , ends of plates 56 spaced from the end portion connected to pivot connection 58 . plate members 56 and their respective slots 56 a are aligned transversely , or widthwise , of housing 22 . a plurality of elongate parallel substantially planar plate members , or fingers , also referred to as friction plates , 62 are disposed in a set with their outer ends pivotally connected at a pivot connection , or rod , 64 extending transversely , or widthwise , of housing 22 . the axis 64 a of pivot connection 64 extends transversely , or widthwise , of housing 22 . plates 62 are connected to lever arm 50 c in a region spaced from pivot connection 52 for bracket 50 . remainder portions of plate members 62 extend longitudinally through the enclosure of housing 22 toward the end occupied by bracket 34 . plate members 62 have elongate longitudinally extending slots 62 a formed therein which extend to a region adjacent their inner ends . plate members 62 and their respective slots 62 a are aligned transversely , or widthwise , of housing 22 . as best seen in fig5 , the inner end portions of the sets of plate members , fingers , 56 and 62 are interleaved in a mid - region of housing 22 . in the interleaved region portions of slots 56 a , 62 a are aligned . an elongate rod portion 68 of a locking , or clamping , mechanism indicated generally at 70 , extends laterally and slidably through aligned portions of slots 56 a , 62 a . rod portion 68 assists in maintaining alignment of the plate members as they move within the housing . rod 68 has an enlarged cylindrical head portion 68 a received in a cavity 72 formed in side wall 28 . the opposite end portion 68 b of rod 68 extends into a throughbore 74 in side wall 30 . an enlarged bearing member , or portion , 76 secured to rod 68 is mounted for reciprocating movement in the direction of arrow 78 and is positioned to bear against a laterally outwardly facing side of one of the plate members . in fig5 , it bears against an outer facing surface of a plate member 56 . rod 68 and member 76 are held against movement longitudinally of housing 22 . a plurality of stacked spring washers , or bellville springs , indicated generally at 80 are interposed between side wall 28 of the housing and bearing member 76 . these urge the bearing member away from wall 28 and into forceful bearing contact with the plate members . this forces the interleaved portions of the plate members into clamping engagement between bearing member 76 and the inner , or abutment , surface 30 a of side wall 30 . the forceful clamping of bearing member 76 against the interleaved portions of fingers 56 , 62 clamps them into frictional locking engagement such that they are held in the position shown . since the outer end portions of the plate members 56 , 62 are connected to bracket members 34 , 50 , this frictional locking will hold the brackets in their given positions , thus holding the adjustment mechanism in position relative to slide bar support 18 and holding headrest 10 in selected angular position relative to housing 22 . depending upon the particular operating requirements , including the number , size , and surface finish of the plate members 56 , 62 and the clamping force that can be applied to them , it may be desirable in some situations to interpose washers or other thin separating structures between adjacent plate members 56 , 62 at least in the area of their overlap where the clamping force is applied . such a washer 90 or separating structure is shown schematically in , e . g ., fig7 . in practice , any washer 90 or other separating structure can be quite thin , e . g ., even 10 % or less of the thickness of the plate members 56 , 62 . release mechanism including a lever 84 is provided to release the frictional clamping force and allow the plate members , or fingers , to move longitudinally relative to the housing and relative to each other to permit rotation of and changing of the angularity of brackets 34 and 50 relative to housing 22 . the elongate lever 84 is pivotally connected at 86 to housing 22 and has an engaging projection 88 thereon closely adjacent pivot connection 86 . when the lever is in the position illustrated in solid outline in fig5 , it has substantially no effect on the clamping mechanism and thus the clamping mechanism frictionally locks the plate members in position . swinging of the lever member to the dashed outline position illustrated in fig5 , causes projection 88 to engage end portion 68 b of rod 68 and force the rod and bearing member 76 away from clamping engagement with the plate members against the biasing force of springs 80 . when the clamping force is thus released by swinging movement of the lever , the plate members are released allowing relative sliding movement therebetween . this permits rotational swinging of bracket 34 and bracket 50 relative to housing 22 to change the angular position of headrest 10 . release of lever 84 returns the mechanism to its locked up position . the range of pivotal movement of brackets 34 , 50 and the commensurate longitudinal shifting of their associated fingers 56 , 62 , respectively , are illustrated in fig3 and 4 . explaining operation of the apparatus , the operator initially places headrest slide support , or rod , 18 in a selected position relative to the back rest . when a patient , or user , enters the chair , the operator may depress lever 84 easily with one - handed operation due to its significant mechanical advantage provided by the long lever arm to release the clamping lock of the fingers . with the clamping lock thus released , the angular positions of portions of the assembly may be easily adjusted to conform to the patient . release of the lever returns the mechanism to a locked position . when the user , or patient , is seated in the chair their back rests against the plane of the user - engaging surface of the chair back . when the clamping mechanism is released , housing 22 may be swung rearwardly or forwardly about its pivot axis 52 to swing the headrest relative to the plane of the user - engaging surface of the chair back . at the same time , the angle of head rest support bracket 34 may be swung about its pivot axis 36 to a selected angular position relative to housing 22 . this is all permitted by longitudinal movement of plate members 56 , 62 within the housing when the clamping mechanism is released . in this way , the headrest may be positioned as desired for the most comfortable disposition for the user and convenient positioning for the operator . similarly , once the patient is situated , the slide mechanism connected to the back of the headrest allows the headrest to be easily slid up and down relative to the chair back to obtain desired vertical positioning . fig6 a , 6b , 6 c , 6 d and 6 e are schematic side views showing the headrest 10 in various positions to illustrate further its range of motion and use . in fig6 a , the headrest 10 is shown in a compact state with the slide bar support 18 retracted and the headrest positioned to overlap an upper edge of the chair back 12 . in the illustrated implementation , the chair back 12 has curved cross - section terminating in side edges that curve outwardly from the center back area , as shown in the figures . with the headrest 10 in the compact state , the mechanism 14 ( which can have a generally enclosed housing ) is generally aligned with the slide bar 18 in the illustrated implementation . in fig6 b , the slide bar support 18 has been extended to position the headrest 10 away from the chair back 12 . in addition , the head rest 10 has been translated in the direction of arrow b relative to the mechanism 14 . in fig6 c , the mechanism 14 has been adjusted to position the head rest 10 outward from the plane of the slide bar support 18 . in the illustrated implementation , the head rest 10 has been maintained generally parallel to the slide bar support 18 . in fig6 d , the slide bar support 18 has been partially retracted and the head rest 10 has been translated in the direction of arrow b relative to its position in the compact state . in addition , the mechanism 14 has been adjusted to position the headrest 10 at an angle relative to the slide bar support . in fig6 e , the slide bar support 18 is in approximately the same position as shown in fig6 d . the mechanism 14 has been pivoted to position the head rest 10 generally parallel to the slide bar support 18 and spaced outwardly from the plane of the chair back 12 . fig6 f shows the one - handed operation capability in more detail . specifically , fig6 f shows an operator &# 39 ; s left hand depressing the lever 84 , thereby releasing the locking mechanism to allow its body and the headrest 10 attached to the body to be repositioned within the ranges as shown schematically by the arrows in the figure . fig7 a , 7b and 7 c show an alternative embodiment of the head rest support mechanism . fig7 a is similar to fig5 in that the internal elements of the mechanism 10 are shown , but it is viewed from the opposite side and schematically depicts an arrangement where the pivot connections 36 , 52 are reversed from the relative positions shown in fig5 . in other words , the pivot connection 52 that connects to the slide bar support is positioned closer to the top wall 24 ( fig7 b ) than as shown in fig5 . similarly , the pivot connection 36 that connects to the cross plate 38 is spaced closer to the bottom wall 26 ( fig7 b ) than as shown in fig5 . for convenience of illustration , only two plate members 56 and three plate members 62 are shown in fig7 a and 7c , but of course any number of plate members can be provided depending upon operating requirements . as described above , washers 90 can be provided between adjacent plate members 56 , 62 , particularly in the area of the rod 68 . fig8 a , 8b and 8 c show an alternative embodiment similar to fig7 a - 7c , except the linkage includes an additional link 91 ( fig8 b ). the link 91 may be comprised of multiple link members 92 ( fig8 a and 8c ), similar to the plate members 56 , 62 . the link members 92 have slots 93 that connect the link 91 and allow it to move relative to a stationary pivot 95 . from right to left in fig8 b , the pivot connection 52 to the slide bar support 18 is stationary or grounded , the pivot connection 64 between the slide bar support 18 and the plate members 62 is free to move , the pivot connection 68 at the inner ends of the plate members 62 to the inner ends of the plate members 56 is stationary , the pivot connection 94 at the outer ends of the plate members 56 to the link 91 is free to move , the pivot connection 58 connecting the other end of the link 91 and the cross plate 38 is free to move , and the pivot connection 36 to the cross plate 38 is fixed . movement of the link 91 is constrained by the stationary pivot 95 and the length of the slots 93 . the addition of the link 91 provides additional degrees of freedom in positioning the cross plate , and thus the head rest 10 , relative to the chair back attached to the support rod at 18 . although not illustrated , other embodiments employing additional links are also possible . fig9 a , 9b and 9 c show an alternative embodiment similar to fig7 a - 7c , except that the pivot connections 36 , 52 are each positioned closest to the same side of the housing , in this case the bottom wall 26 , and the two sets of plate members 56 , 62 have been replaced by a single set of plate members 56 with curved slots 97 . the curved slots constrain the motion of the plate members 56 relative to the pivot connection 68 . in this embodiment , the positions of the slide bar support 18 and the cross bar 38 are not independent of each other . although the embodiment of fig9 a - 9c provides less freedom in positioning the headrest 10 compared to other embodiments in this application , the additional ability to translate the headrest 10 relative to the mechanism allows for sufficient flexibility of positioning for many situations . fig1 a , 10b and 10 c show an alternative embodiment similar to fig7 a - 7c , except that the locking mechanism 70 is positioned coaxially with the pivot connection 52 for the slide bar support 18 , rather than between the pivot connections 36 , 52 as shown in fig7 a and 7b . of course , in another variation it would also be possible to position the locking mechanism coaxially with the pivot connection 36 . as illustrated , the plate members 62 are constrained only to pivot and , unlike the embodiment of fig7 a and 7b , they cannot translate relative to the locking mechanism 70 . fig1 a , 11b and 11 c show an alternative embodiment similar to fig7 a - 7c , except that in addition to the locking mechanism 70 , there is a second , separate locking mechanism 71 . also , there is a set of plate members 63 , which are generally stationary in this example , that are interleaved at one set of their ends with the plate members 56 adjacent the pivot connection 36 , and at the opposite set of their ends with the plate members 62 adjacent the pivot connection 52 . of course , the single set of plate members 63 could be replaced by two shorter sets , with each of the shorter sets having one end interleaved . as shown in fig1 a and 11b , the locking mechanisms 70 , 71 can be positioned coaxially with the pivot connections 36 , 52 , respectively . with the embodiment of fig1 a and 11b , adjusting the position relative to the cross plate 38 and adjusting the position relative to the slide bar support 18 requires actuation of the separate locking mechanisms . the actuator handles may be positioned to allow for one - handed actuation of both locking mechanisms 70 , 71 , such as shown in fig1 a . fig1 a and 12b show an alternative embodiment similar to fig4 and 5 , except that there are single pivots at the ends and the interleaved plate members have complimentary curved slots where they overlap in the area of the release mechanism . specifically , the plate members 56 connected to the cross plate 38 are pivotable about the single pivot connection 36 , and the plate members 62 connected to the slide bar support 18 are pivotable about the single pivot connection 52 . the plate members 56 , 62 have complimenting curved slots 65 , 67 , respectively , positioned near their inner ends . the slots 65 , 67 overlap as shown and define the pivot ranges . the slots 65 , 67 receive and allow the plate members 56 , 62 to move relative to the locking mechanism 70 . although the embodiment of fig1 a and 12b as illustrated may provide slightly less freedom in positioning the headrest 10 compared to other embodiments , particularly those with more pivots , the mechanism provides sufficient flexibility of positioning for many situations . in addition , the positions of the pivots , the lengths of the plate members and the slots and other geometrical relationships can be adapted as necessary to yield a sufficient range of motion . the configuration of housing 22 and the operating mechanism mounted therein for permitting adjustment of the headrest and locking such in a selected position , has a relatively thin profile , or height h , allowing the patient &# 39 ; s head to be placed closely adjacent the operator &# 39 ; s lap . further , the enclosed housing provides a protective casing for the operating mechanism which permits ease of operation , cleaning , and positioning . other advantages include the ability to configure the assembly to default to a locked position so the head rest does not move unexpectedly , the ability to operate the mechanism with one hand and while the mechanism is covered , such as with plastic or other sterile covering , the ability to adjust the position while the patient is occupying the chair , and the ability to accommodate patients of all sizes , including children . in the illustrated embodiments , the selective locking into desired positions for use of the headrest is achieved using a locking mechanism that releasably secures interleaved plate members in place relative to each other . other mechanisms are also possible , including but not limited to belt arrangements and locking members with nesting cone - or hemispherical - shaped elements . it would also be possible to provide the a powered locking force with fluid , electricity , magnetism , etc . while preferred embodiments have been described herein , it should be apparent to those skilled in the art that variations and modifications are possible without departing from the spirit of the invention . | US-11487605-A |
in accordance with the present invention , there are provided a class of compounds which are capable of selectively modulating processes mediated by peroxisome proliferator activated receptor - gamma . the identification of such compounds makes possible the selective intervention in ppar - γ mediated pathways , without exerting inadvertent effects on pathways mediated by other ppar isoforms . | in accordance with the present invention , there are provided methods for modulating process ( es ) mediated by peroxisome proliferator activated receptor - gamma ( ppar - γ ), said method comprising conducting said process ( es ) in the presence of at least one ppar - γ - selective prostaglandin or prostaglandin - like compound or precursor thereof . ppar - γ - selective prostaglandins or prostaglandin - like compounds contemplated for use in the practice of the present invention include members of the prostaglandin - j 2 family of compounds ( e . g ., prostaglandin - j 2 , δ 12 - prostaglandin - j 2 or 15 - deoxy - δ 12 , 14 - prostaglandin - j 2 ) members of the prostaglandin - d 2 family of compounds ( e . g ., prostaglandin - d 2 ), or precursors thereof , as well as compounds having the structure i : ## str1 ## wherein : a is selected from hydrogen or a leaving group at the α - or β - position of the ring , or a is absent when there is a double bond between c . sup . α and c . sup . β of the ring ; x is an alkyl , substituted alkyl , alkenyl , substituted alkenyl , alkynyl or substituted alkynyl group having in the range of 2 up to 15 carbon atoms ; and y is an alkyl , substituted alkyl , alkenyl , substituted alkenyl , alkynyl or substituted alkynyl group having in the range of 2 up to 15 carbon atoms . as employed herein , the term &# 34 ; leaving group &# 34 ; refers to functional groups which can readily be removed from the precursor compound , for example , by nucleophilic displacement , under e 2 elimination conditions , and the like . examples include hydroxy groups , alkoxy groups , tosylates , brosylates , halogens , and the like . as employed herein , &# 34 ; lower alkyl &# 34 ; refers to straight or branched chain alkyl groups having in the range of about 1 up to 4 carbon atoms ; &# 34 ; alkyl &# 34 ; refers to straight or branched chain alkyl groups having in the range of about 1 up to 12 carbon atoms ; &# 34 ; substituted alkyl &# 34 ; refers to alkyl groups further bearing one or more substituents such as hydroxy , alkoxy ( of a lower alkyl group ), mercapto ( of a lower alkyl group ), halogen , trifluoromethyl , cyano , nitro , amino , carboxyl , carbamate , sulfonyl , sulfonamide , and the like . as employed herein , &# 34 ; cycloalkyl &# 34 ; refers to cyclic ring - containing groups containing in the range of about 3 up to 8 carbon atoms , and &# 34 ; substituted cycloalkyl &# 34 ; refers to cycloalkyl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; alkenyl &# 34 ; refers to straight or branched chain hydrocarbyl groups having at least one carbon - carbon double bond , and having in the range of about 2 up to 12 carbon atoms and &# 34 ; substituted alkenyl &# 34 ; refers to alkenyl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; alkynyl &# 34 ; refers to straight or branched chain hydrocarbyl groups having at least one carbon - carbon triple bond , and having in the range of about 2 up to 12 carbon atoms , and &# 34 ; substituted alkynyl &# 34 ; refers to alkynyl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; aryl &# 34 ; refers to aromatic groups having in the range of 6 up to 14 carbon atoms and &# 34 ; substituted aryl &# 34 ; refers to aryl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; alkylaryl &# 34 ; refers to alkyl - substituted aryl groups and &# 34 ; substituted alkylaryl &# 34 ; refers to alkylaryl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; arylalkyl &# 34 ; refers to aryl - substituted alkyl groups and &# 34 ; substituted arylalkyl &# 34 ; refers to arylalkyl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; arylalkenyl &# 34 ; refers to aryl - substituted alkenyl groups and &# 34 ; substituted arylalkenyl &# 34 ; refers to arylalkenyl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; arylalkynyl &# 34 ; refers to aryl - substituted alkynyl groups and &# 34 ; substituted arylalkynyl &# 34 ; refers to arylalkynyl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; aroyl &# 34 ; refers to aryl - carbonyl species such as benzoyl and &# 34 ; substituted aroyl &# 34 ; refers to aroyl groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; heterocyclic &# 34 ; refers to cyclic ( i . e ., ring - containing ) groups containing one or more heteroatoms ( e . g ., n , o , s , or the like ) as part of the ring structure , and having in the range of 3 up to 14 carbon atoms and &# 34 ; substituted heterocyclic &# 34 ; refers to heterocyclic groups further bearing one or more substituents as set forth above . as employed herein , &# 34 ; halogen &# 34 ; or &# 34 ; halo &# 34 ; refers to fluoro substituents , chloro substituents , bromo substituents or iodo substituents . in a presently preferred aspect of the present invention , &# 34 ; x &# 34 ; of formula i is selected from : each r is independently selected from h , lower alkyl , substituted lower alkyl , hydroxy , lower alkoxy , thioalkyl , halogen , trifluoromethyl , cyano , nitro , amino , carboxyl , carbamate , sulfonyl or sulfonamide , each m &# 39 ; falls independently in the range of 0 up to 12 , with the proviso that the total chain length of the alkenyl moiety does not exceed 15 carbon atoms , each m &# 34 ; falls independently in the range of 0 up to 12 , with the proviso that the total chain length of the alkynyl moiety does not exceed 15 carbon atoms , and those of skill in the art can readily identify numerous groups which satisfy the requirement that z be a polar , heteroatom - containing ( i . e ., o , n , s , or the like ) substituent . thus , z can be selected from cyano , nitro , amino , carbamate , or a substituent having the structure : -- ch 2 or &# 39 ;, wherein r &# 39 ; is selected from h , alkyl , alkenyl , alkynyl , acyl , aryl , or the like ; -- c ( o ) r &# 34 ;, wherein r &# 34 ; is selected from h , alkyl , substituted alkyl , alkoxy , alkylamino , alkenyl , substituted alkenyl , alkynyl , substituted alkynyl , aryl , substituted aryl , aryloxy , arylamino , alkylaryl , substituted alkylaryl , arylalkyl , substituted arylalkyl , heterocyclic , substituted heterocyclic or trifluoromethyl , -- co 2 r &# 39 ;&# 34 ;, wherein r &# 39 ;&# 34 ; is selected from h , alkyl , alkenyl , alkynyl , or the like ; -- sr &# 39 ;, -- s ( o ) r &# 39 ;, -- s ( o ) 2 r &# 39 ; or -- s ( o ) 2 nhr &# 39 ;, wherein each r &# 39 ; is as defined above , especially preferred compounds employed in the practice of the present invention are those wherein &# 34 ; x &# 34 ; of formula i is each r is independently selected from h , lower alkyl , substituted lower alkyl , hydroxy , alkoxy ( of a lower alkyl group ), halogen , trifluoromethyl , amino , carboxyl or sulfonyl , m falls in the range of 1 up to 6 , and z is selected from -- ch 2 oh , -- ch 2 oac , -- co 2 h , -- co 2 me or -- co 2 et . in another preferred aspect of the present invention , &# 34 ; y &# 34 ; of formula i is selected from : each r &# 39 ; is independently selected from h , lower alkyl , substituted lower alkyl or a leaving group , n &# 39 ; falls in the range of 2 up to 12 , and especially preferred compounds contemplated for use in the practice of the present invention include those wherein &# 34 ; y &# 34 ; of formula i is selected from : z &# 39 ; is selected from h , lower alkyl or substituted lower alkyl , and presently most preferred compounds for use in the practice of the present invention include those wherein &# 34 ; y &# 34 ; of formula i is wherein each r is selected from h , lower alkyl or substituted lower alkyl , n is 1 , n &# 39 ; falls in the range of about 2 up to 6 , and z &# 39 ; is selected from h or lower alkyl ; or those wherein &# 34 ; y &# 34 ; of formula i is wherein each r is selected from h , lower alkyl or substituted lower alkyl , r &# 39 ; is selected from h , lower alkyl , or an hydroxy group , n is 1 , n &# 39 ; falls in the range of about 2 up to 6 , and z &# 39 ; is selected from h or lower alkyl . referring to the structural formulae set forth above , prostaglandin - d 2 ( pg - d2 ) is described by formula i ( as set forth above ), wherein a is 9 -- oh , y is iv , each r is hydrogen , r &# 39 ; is hydroxy , z is -- co 2 h , m is 3 , z &# 39 ; is methyl , n is 1 and n &# 39 ; is 4 ; prostaglandin - j 2 ( pg - j2 ) is described by formula i , wherein a is absent , y is iv , each r is hydrogen , r &# 39 ; is hydroxy , z is -- co 2 h , m is 3 , z &# 39 ; is methyl , n is 1 and n &# 39 ; is 4 ; δ 12 - prostaglandin - j 2 ( δ 12 - pg - j2 ) is described by formula i , wherein a is absent , y is iii , each r is hydrogen , r &# 39 ; is hydroxy , z is -- co 2 h , m is 3 , z &# 39 ; is methyl , n is 1 and n &# 39 ; is 4 ; 15 - deoxy - δ 12 , 14 - prostaglandin - j 2 ( 15 - deoxy - δ 12 , 14 - pg - j2 ) is described by formula i , wherein a is absent , y is ii , each r is hydrogen , z is -- co 2 h , m is 3 , z &# 39 ; is methyl , n is 1 and n &# 39 ; is 4 . the above - described compounds can be readily prepared using a variety of synthetic methods , as are well known by those of skill in the art . for example , many of the above - described compounds can be prepared chemically or enzymatically , from the naturally occurring precursor , arachidonic acid . as employed herein , the term &# 34 ; modulate &# 34 ; refers to the ability of a modulator for a member of the steroid / thyroid superfamily to either directly ( by binding to the receptor as a ligand ) or indirectly ( as a precursor for a ligand or an inducer which promotes production of ligand from a precursor ) induce expression of gene ( s ) maintained under hormone expression control , or to repress expression of gene ( s ) maintained under such control . as employed herein , the phrase &# 34 ; processes mediated by pparγ &# 34 ; refers to biological , physiological , endocrinological , and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the ppar - γ - selective prostaglandin or prostaglandin - like compounds described herein . modulation of such processes can be accomplished in vitro or in vivo . in vivo modulation can be carried out in a wide range of subjects , such as , for example , humans , rodents , sheep , pigs , cows , and the like . ppar - γ - selective prostaglandin or prostaglandin - like compounds contemplated for use in the practice of the present invention can be employed for both in vitro and in vivo applications . for in vivo applications , the invention compounds can be incorporated into a pharmaceutically acceptable formulation for administration . those of skill in the art can readily determine suitable dosage levels when compounds contemplated for use in the practice of the present invention are so used . in accordance with another embodiment of the present invention , there is provided a method of testing compound ( s ) for the ability to regulate the transcription - activating effects of a peroxisome proliferator activated receptor - gamma ( ppar - γ ), said method comprising assaying for changes in the level of reporter protein present as a result of contacting cells containing said receptor and reporter vector with said compound ; wherein said reporter protein - encoding dna segment is operatively linked to said promoter for transcription of said dna segment , and wherein said hormone response element is operatively linked to said promoter for activation thereof . hormone response elements contemplated for use in the practice of the present invention are composed of at least one direct repeat of two or more half sites separated by a spacer of one nucleotide . the spacer nucleotide can be selected from any one of a , c , g or t . each half site of response elements contemplated for use in the practice of the invention comprises the sequence each n is independently selected from a , t , c , or g ; and with the proviso that at least 4 nucleotides of said -- rgbnnm -- sequence are identical with the nucleotides at corresponding positions of the sequence -- aggtca --. response elements employed in the practice of the present invention can optionally be preceded by n x , wherein x falls in the range of 0 up to 5 . presently preferred response elements contain at least one copy ( with one , two or three copies most common ) of the minimal sequence : as noted above , the minimal sequence can optionally be flanked by additional residues , for example , as in the sequence : in a preferred embodiment of the present invention , only the ligand binding domain of pparγ is utilized , in combination with the dna binding domain of gal4 protein , for the identification of pparγ ligands or ligand - precursors . this allows one to avoid possible background signal caused by the potential presence of endogenous pparγ in the host cells used for the assay . the dna binding domain of the yeast gal4 protein comprises at least the first 74 amino acids thereof ( see , for example , keegan et al ., science 231 : 699 - 704 ( 1986 )). preferably , the first 90 or more amino acids of the gal4 protein will be used , with the first 147 amino acid residues of yeast gal4 being presently most preferred . the gal4 fragment employed in the practice of the present invention can be incorporated into any of a number of sites within the pparγ receptor protein . for example , the gal4 dna binding domain can be introduced at the amino terminus of the pparγ receptor protein , or the gal4 dna binding domain can be substituted for the native dna binding domain of the pparγ receptor , or the gal4 dna binding domain can be introduced at the carboxy terminus of the pparγ receptor protein , or at other positions as can readily be determined by those of skill in the art . thus , for example , a modified receptor protein can be prepared which consists essentially of amino acid residues 1 - 147 of gal4 , plus the ligand binding domain of pparγ ( i . e ., containing the ligand binding domain only of said receptor ( i . e ., residues 163 - 475 of seq id no : 1 ), substantially absent the dna binding domain and amino terminal domain thereof ). identification methods according to the present invention involve the use of a functional bioassay system , wherein the modified receptor and a reporter plasmid are cultured in suitable host cells in the presence of test compound . evidence of transcription ( e . g ., expression ) of reporter gene is then monitored to determine the presence of an activated receptor - ligand complex . accordingly , the functional bioassay system utilizes two plasmids : an &# 34 ; expression &# 34 ; plasmid and a &# 34 ; reporter &# 34 ; plasmid . the expression plasmid can be any plasmid which contains and is capable of expressing dna encoding the desired form of pparγ receptor protein ( i . e ., intact receptor or gal4 chimeric receptor as described hereinabove ), in a suitable host cell . the reporter plasmid can be any plasmid which contains an operative ppre or gal4 response element , as appropriate , functionally linked to an operative reporter gene . exemplary ppres have been described in detail hereinabove . exemplary gal4 response elements are those containing the palindromic 17 - mer : 5 &# 39 ;- cggaggactgtcctccg - 3 &# 39 ; ( seq id no : 6 ), such as , for example , 17mx , as described by webster et al ., in cell 52 : 169 - 178 ( 1988 ), as well as derivatives thereof . additional examples of suitable response elements include those described by hollenberg and evans in cell 55 : 899 - 906 ( 1988 ); or webster et al . in cell 54 : 199 - 207 ( 1988 ). exemplary reporter genes include chloramphenicol transferase ( cat ), luciferase ( luc ), beta - galactosidase ( β - gal ), and the like . exemplary promoters include the simian virus ( sv ) promoter or modified form thereof ( e . g ., δsv ), the thymidine kinase ( tk ) promoter , the mammary tumor virus ( mtv ) promoter or modified form thereof ( e . g ., δmtv ), and the like [ see , for example , mangelsdorf et al ., in nature 345 : 224 - 229 ( 1990 ), mangelsdorf et al ., in cell 66 : 555 - 561 ( 1991 ), and berger et al ., in j . steroid biochem . molec . biol . 41 : 733 - 738 ( 1992 )]. the plasmids pgmcat , pghcat , ptk - gal p 3 - luc , δmtv - gal p 3 - luc , δmtv - gal p 3 - cat , and the like , are examples of reporter plasmids which contain an operative hormone responsive promoter / enhancer element functionally linked to an operative reporter gene , and can therefore be used in the above - described functional bioassay ( see example 2 for details on the preparation of these plasmids ). in pgmcat , the operative hormone responsive promoter / enhancer element is the mtv ltr ; in pghcat it is the functional portion of the growth hormone promoter . in both pgmcat and ghcat the operative reporter gene is the bacterial gene for chloramphenicol acetyltransferase ( cat ). as used herein in the phrase &# 34 ; operative response element functionally linked to an operative reporter gene &# 34 ;, the word &# 34 ; operative &# 34 ; means that the respective dna sequences ( represented by the terms &# 34 ; ppre ,&# 34 ; &# 34 ; gal4 response element &# 34 ; and &# 34 ; reporter gene &# 34 ;) are operational , i . e ., work for their intended purposes ; the word &# 34 ; functionally &# 34 ; means that after the two segments are linked , upon appropriate activation by a ligand - receptor complex , the reporter gene will be expressed as the result of the fact that the &# 34 ; ppre &# 34 ; or &# 34 ; gal4 response element &# 34 ; was &# 34 ; turned on &# 34 ; or otherwise activated . in practicing the above - described functional bioassay , the expression plasmid and the reporter plasmid are co - transfected into suitable host cells . the transfected host cells are then cultured in the presence and absence of a test compound to determine if the test compound is able to produce activation of the promoter operatively linked to the ppre or gal4 response element of the reporter plasmid . thereafter , the transfected and cultured host cells are monitored for induction ( i . e ., the presence ) of the product of the reporter gene sequence . any cell line can be used as a suitable &# 34 ; host &# 34 ; for the functional bioassay contemplated for use in the practice of the present invention . thus , in contrast to the requirements of prior art assay systems , when gal4 chimerics are employed , there is no need to use receptor - negative cells in carrying out the invention process . since the modified receptor employed in the practice of the present invention is the only species in the test cell which is capable of initiating transcription from a gal4 response element , the expression of native receptor by the test cell does not contribute to background levels . thus , the invention bioassay can be made to be very selective . cells contemplated for use in the practice of the present invention include transformed cells , non - transformed cells , neoplastic cells , primary cultures of different cell types , and the like . exemplary cells which can be employed in the practice of the present invention include schneider cells , cv - 1 cells , hutu80 cells , f9 cells , ntera2 cells , nb4 cells , hl - 60 cells , 293 cells , hela cells , yeast cells , and the like . preferred host cells for use in the functional bioassay system are cos cells and cv - 1 cells . cos - 1 ( referred to as cos ) cells are monkey kidney cells that express sv40 t antigen ( tag ); while cv - 1 cells do not express sv40 tag . the presence of tag in the cos - 1 derivative lines allows the introduced expression plasmid to replicate and provides a relative increase in the amount of receptor produced during the assay period . cv - 1 cells are presently preferred because they are particularly convenient for gene transfer studies and provide a sensitive and well - described host cell system . the above - described cells ( or fractions thereof ) are maintained under physiological conditions when contacted with physiologically active compound . &# 34 ; physiological conditions &# 34 ; are readily understood by those of skill in the art to comprise an isotonic , aqueous nutrient medium at a temperature of about 370 ° c . in accordance with another embodiment of the present invention , there is provided a method of screening for antagonists of pparγ receptor proteins , said method comprising ( i ) increasing concentrations of at least one compound whose ability to inhibit the transcription activation activity of pparγ agonists is sought to be determined , and ( i ) exogenous dna which expresses intact pparγ or a modified form of pparγ , wherein the modified form of pparγ contains the dna binding domain of gal4 , and ( ii ) a ppre or gal4 response element , respectively , operatively linked to a reporter gene ; and thereafter assaying for evidence of transcription of said reporter gene in said cells as a function of the concentration of said compound in said culture medium , thereby indicating the ability of said compound to inhibit activation of transcription by pparγ agonists . media employed for such culturing may include agonist for the receptor being tested , or the receptor may be constitutive ( i . e ., not require the presence of agonist for activation ), or a fixed concentration of agonist can be added to the media employed for such testing . the above - described assays of the present invention have low background and a broad dynamic range . in accordance with yet another embodiment of the present invention , there is provided a method for preventing obesity , said method comprising administering to a subject in need thereof an amount of a peroxisome proliferator activated receptor - gamma ( ppar - γ ) antagonist effective to block cell differentiation to produce lipid - accumulating cells . as employed here , &# 34 ; obesity &# 34 ; refers generally to individuals who are at least about 20 - 30 % over the average weight for his / her age , sex and height . technically , &# 34 ; obese &# 34 ; is defined , for males , as individuals whose body mass index is greater than 27 . 8 kg / m 2 , and for females , as individuals whose body mass index is greater than 27 . 3 kg / m 2 . those of skill in the art recognize that there are numerous cell types which are capable of differentiation to produce &# 34 ; lipid - accumulating cells ,&# 34 ; such as , for example , mesenchymal cells ( e . g ., fibroblasts ). as employed herein , the phrase &# 34 ; amount . . . effective to block cell differentiation &# 34 ; refers to levels of compound sufficient to provide circulating concentrations high enough to effect activation of pparγ . such a concentration typically falls in the range of about 10 nm up to 2 μm ; with concentrations in the range of about 100 nm up to 200 nm being preferred . in accordance with a particular embodiment of the present invention , compositions comprising at least one prostaglandin or prostaglandin - like compound ( as described above ), and a pharmaceutically acceptable carrier are contemplated . exemplary pharmaceutically acceptable carriers include carriers suitable for oral , intravenous , subcutaneous , intramuscular , intracutaneous , and the like administration . administration in the form of creams , lotions , tablets , dispersible powders , granules , syrups , elixirs , sterile aqueous or non - aqueous solutions , suspensions or emulsions , and the like , is contemplated . for the preparation of oral liquids , suitable carriers include emulsions , solutions , suspensions , syrups , and the like , optionally containing additives such as wetting agents , emulsifying and suspending agents , sweetening , flavoring and perfuming agents , and the like . for the preparation of fluids for parenteral administration , suitable carriers include sterile aqueous or non - aqueous solutions , suspensions , or emulsions . examples of non - aqueous solvents or vehicles are propylene glycol , polyethylene glycol , vegetable oils , such as olive oil and corn oil , gelatin , and injectable organic esters such as ethyl oleate . such dosage forms may also contain adjuvants such as preserving , wetting , emulsifying , and dispersing agents . they may be sterilized , for example , by filtration through a bacteria - retaining filter , by incorporating sterilizing agents into the compositions , by irradiating the compositions , or by heating the compositions . they can also be manufactured in the form of sterile water , or some other sterile injectable medium immediately before use . in accordance with still another embodiment of the present invention , there is provided a method for treating diabetes , said method comprising administering to a subject in need thereof an amount of a peroxisome proliferator activated receptor - gamma ( ppar - γ ) agonist effective to lower the blood glucose level of said subject . as employed herein , the phrase &# 34 ; amount . . . effective to lower blood glucose levels &# 34 ; refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect . such a concentration typically falls in the range of about 10 nm up to 2 μm ; with concentrations in the range of about 100 nm up to 200 nm being preferred . the invention will now be described in greater detail by reference to the following non - limiting examples . a basic vector useful for the generation of gal4 - receptor fusion proteins is called pcmx - gal4 ( see seq id no : 2 ). this vector encodes gal4 dna binding domain , followed by a polylinker sequence useful in the cloning . the parental expression vector pcmx has been described by umesono et al ., in cell 65 : 1255 - 1266 ( 1991 ), and the gal4 portion of pcmx - gal4 is derived from plasmid psg424 , described by sadowski and ptashne , in nucleic acids res . 17 : 7539 ( 1989 ). in general , gal4 - receptor ligand binding domain fusions are prepared by taking advantage of mutant receptor cdna clones , such as gr - rar chimera [ see , for example , giguere et al ., in nature 330 : 624 - 629 ( 1987 )]. these mutant receptor cdnas encode common xhoi sites at the end of the dna binding domain , as described by giguere et al ., supra . to do so , a new pcmx - gal4 vector was prepared which encodes a compatible sali site in the polylinker sequence ( there is an xhoi site in the gal4 sequence ): this allows efficient transfer of the receptor ligand binding domain to gal4 dna binding domain . through this method , a number of chimeric species have been generated , including gal4 - pparγ , containing residues 163 - 475 of pparγ ( see seq id no : 1 ). if mutants of the type referred to above are not available for the construction of gal4 - containing chimerics , one may simply look for any convenient restriction enzyme site within or downstream of the dna binding domain of the receptor of interest ( i . e ., within about the first 30 amino acid residues downstream of the conserved gly - met residues of the dna binding domain , i . e ., within 30 residues of the last two residues shown in seq id no : 1 ), and utilize the carboxy terminal sequences therefrom . various reporter constructs are used in the examples which follow . they are prepared as follows : tk - luc : the mtv - ltr promoter sequence was removed from the mtv - luc plasmid described by hollenberg and evans in cell 55 : 899 - 906 ( 1988 ) by hindiii and xhoi digest , and cloned with the hindiii - xhoi fragment of the herpes simplex virus thymidine kinase gene promoter (- 105 to + 51 with respect to the transcription start site , m , isolated from plasmid pblcat2 , described by luckow & amp ; schutz in nucleic acids res . 15 : 5490 ( 1987 )) to generate parental construct tk - luc . ptk - ppre3 - luc : three copies of double - stranded peroxisome proliferator response element ( ppre ) oligonucleotides ( see seq id no : 3 ) were cloned upstream of the tk promoter of tk - luc at the sali site . ptk - mh100x4 - luc : four copies of double - stranded mh100 oligonucleotides , encoding a gal4 binding site , were cloned upstream of the tk promoter of tk - luc at the hindiii site . cmx - βgal : the coding sequence for the e . coli β - galactosidase gene was isolated from plasmid pch110 [ see hall et al ., j . mol . appl . genet . 2 : 101 - 109 ( 1983 )] by hindiii and bamhi digest , and cloned into pcmx eucaryotic expression vector [ see umesono et al ., supra ]. cv - 1 cells are co - transfected with cmx - gal - pparγ and ptk - mh100x4 - luc at a ratio of about 100 ng of receptor - encoding dna per 10 5 cells . the usual amounts of dna per 10 5 cells are 100 ng of cmx - gal - pparγ , 300 ng of ptk - mh100x4 - luc , and 500 ng of cmx - βgal . typically , transfections are performed in triplicate . the plates are then incubated for 2 - 3 hours at 370 ° c . the cells are washed with fresh medium . fresh medium containing one concentration of a serial dilution of agonist is added to each well . a typical agonist dilution series extends from 10 - 5 m through 10 - 11 m . a solvent control is performed for each agonist . the cells are incubated at 37 ° c . for 1 - 2 days . the cells are rinsed twice with buffered saline solution . subsequently , cells are lysed , in situ , by adding 200 μl of lysis buffer . after 30 minutes incubation at room temperature , 40 μl aliquots of cell lysate are transferred to 96 - well plates for luciferase reporter gene assays and μ - galactosidase transfection controls [ see heyman et al ., cell 68 : 397 - 406 ( 1992 )]. the data are expressed as relative light units ( rlus ) per o . d . unit of μ - galactosidase per minute . the triplicates are averaged for each concentration and plotted ( see fig1 ) as fold induction induced by a standard dose ( 10 μm ) of agonist . effector plasmid , reporter plasmid , and μ - galactosidase control plasmid are co - transfected into cv - 1 cells at a ratio of about 1 : 3 : 5 , using a liposome - mediated method , employing n -{ 2 -( 2 , 3 )- dioleoyloxy ) propyl - n , n , n - trimethyl ammonium methyl sulfate } ( i . e ., dotap , boehringer mannheim ) according to the manufacturer &# 39 ; s instructions in dulbecco &# 39 ; s modified eagle &# 39 ; s medium ( dmem ) with 10 % delipidated hormone - depleted fetal calf serum . after about 2 - 3 hours , the cells are washed with dmem and an appropriate prostaglandin is added to the media to the final molar concentration indicated in fig2 . after 24 - 48 hours of incubation , the cells are rinsed with phosphate buffered saline ( ph 7 . 2 ) and lysed . aliquots are assayed for luciferase and μ - galactosidase activity . luciferase activity is normalized to optical density units of μ - galactosidase per minute of incubation . the data are expressed in fig2 as fold induction over the same construct incubated in solvent alone . review of fig2 reveals that pgd2 and pgj2 families of compounds are functional modulators of pparγ . while the invention has been described in detail with reference to certain preferred embodiments thereof , it will be understood that modifications and variations are within the spirit and scope of that which is described and claimed . __________________________________________________________________________ # sequence listing - & lt ; 160 & gt ; number of seq id nos : 7 - & lt ; 210 & gt ; seq id no 1 & lt ; 211 & gt ; length : 2005 & lt ; 212 & gt ; type : dna & lt ; 213 & gt ; organism : mus musculus & lt ; 220 & gt ; feature :& lt ; 221 & gt ; name / key : cds & lt ; 222 & gt ; location : ( 352 )...( 1776 )- & lt ; 400 & gt ; sequence : 1 - atcgaatccc gcgccccagg cgctgccgct ctgagtgcga cgggccccgc ct - # ggccggcc 60 - ggaggacgcg gaagaagaga cctggggcgc tgcctggggt attgggtcgc gc - # gcagtgag 120 - gggaccgagt gtgacgacaa ggtgaccggg ctgaggggac gggctgagga ga - # agtcacac 180 - tctgacagga gcctgtgaga ccaacagcct gacggggtct cggttgaggg ga - # cgcgggct 240 - gagaagtcac gttctgacag gactgtgtga cagacaagat ttgaaagaag cg - # gtgaacca 300 # atg gtt 357cattttt aaaaacaaga ctacccttta ctgaaattac c # met val # 1 - gac aca gag atg cca ttc tgg ccc acc aac tt - # c gga atc agc tct gtg 405asp thr glu met pro phe trp pro thr asn ph - # e gly ile ser ser val # 15 - gac ctc tcc gtg atg gaa gac cac tcg cat tc - # c ttt gac atc aag ccc 453asp leu ser val met glu asp his ser his se - # r phe asp ile lys pro # 30 - ttt acc aca gtt gat ttc tcc agc att tct gc - # t cca cac tat gaa gac 501phe thr thr val asp phe ser ser ile ser al - # a pro his tyr glu asp # 50 - att cca ttc aca aga gct gac cca atg gtt gc - # t gat tac aaa tat gac 549ile pro phe thr arg ala asp pro met val al - # a asp tyr lys tyr asp # 65 - ctg aag ctc caa gaa tac caa agt gcg atc aa - # a gta gaa cct gca tct 597leu lys leu gln glu tyr gln ser ala ile ly - # s val glu pro ala ser # 80 - cca cct tat tat tct gaa aag acc cag ctc ta - # c aac agg cct cat gaa 645pro pro tyr tyr ser glu lys thr gln leu ty - # r asn arg pro his glu # 95 - gaa cct tct aac tcc ctc atg gcc att gag tg - # c cga gtc tgt ggg gat 693glu pro ser asn ser leu met ala ile glu cy - # s arg val cys gly asp # 110 - aaa gca tca ggc ttc cac tat gga gtt cat gc - # t tgt gaa gga tgc aag 741lys ala ser gly phe his tyr gly val his al - # a cys glu gly cys lys115 1 - # 20 1 - # 25 1 -# 30 - ggt ttt ttc cga aga acc atc cga ttg aag ct - # t att tat gat agg tgt 789gly phe phe arg arg thr ile arg leu lys le - # u ile tyr asp arg cys # 145 - gat ctt aac tgc cgg atc cac aaa aaa agt ag - # a aat aaa tgt cag tac 837asp leu asn cys arg ile his lys lys ser ar - # g asn lys cys gln tyr # 160 - tgt cgg ttt cag aag tgc ctt gct gtg ggg at - # g tct cac aat gcc atc 885cys arg phe gln lys cys leu ala val gly me - # t ser his asn ala ile # 175 - agg ttt ggg cgg atg cca cag gcc gag aag ga - # g aag ctg ttg gcg gag 933arg phe gly arg met pro gln ala glu lys gl - # u lys leu leu ala glu # 190 - atc tcc agt gat atc gac cag ctg aac cca ga - # g tct gct gat ctg cga 981ile ser ser asp ile asp gln leu asn pro gl - # u ser ala asp leu arg195 2 - # 00 2 - # 05 2 -# 10 - gcc ctg gca aag cat ttg tat gac tca tac at - # a aag tcc ttc ccg ctg1029ala leu ala lys his leu tyr asp ser tyr il - # e lys ser phe pro leu # 225 - acc aaa gcc aag gcg agg gcg atc ttg aca gg - # a aag aca acg gac aaa1077thr lys ala lys ala arg ala ile leu thr gl - # y lys thr thr asp lys # 240 - tca cca ttt gtc atc tac gac atg aat tcc tt - # a atg atg gga gaa gat1125ser pro phe val ile tyr asp met asn ser le - # u met met gly glu asp # 255 - aaa atc aag ttc aaa cat atc acc ccc ctg ca - # g gag cag agc aaa gag1173lys ile lys phe lys his ile thr pro leu gl - # n glu gln ser lys glu # 270 - gtg gcc atc cga att ttt caa ggg tgc cag tt - # t cga tcc gta gaa gcc1221val ala ile arg ile phe gln gly cys gln ph - # e arg ser val glu ala275 2 - # 80 2 - # 85 2 -# 90 - gtg caa gag atc aca gag tat gcc aaa aat at - # c cct ggt ttc att aac1269val gln glu ile thr glu tyr ala lys asn il - # e pro gly phe ile asn # 305 - ctt gat ttg aat gac caa gtg act ctg ctc aa - # g tat ggt gtc cat gag1317leu asp leu asn asp gln val thr leu leu ly - # s tyr gly val his glu # 320 - atc atc tac acg atg ctg gcc tcc ctg atg aa - # t aaa gat gga gtc ctc1365ile ile tyr thr met leu ala ser leu met as - # n lys asp gly val leu # 335 - atc tca gag ggc caa gga ttc atg acc agg ga - # g ttc ctc aaa agc ctg1413ile ser glu gly gln gly phe met thr arg gl - # u phe leu lys ser leu # 350 - cgg aag ccc ttt ggt gac ttt atg gag cct aa - # g ttt gag ttt gct gtg1461arg lys pro phe gly asp phe met glu pro ly - # s phe glu phe ala val355 3 - # 60 3 - # 65 3 -# 70 - aag ttc aat gca ctg gaa tta gat gac agt ga - # c ttg gct ata ttt ata1509lys phe asn ala leu glu leu asp asp ser as - # p leu ala ile phe ile # 385 - gct gtc att att ctc agt gga gac cgc cca gg - # c ttg ctg aac gtg aag1557ala val ile ile leu ser gly asp arg pro gl - # y leu leu asn val lys # 400 - ccc atc gag gac atc caa gac aac ctg ctg ca - # g gcc ctg gaa ctg cag1605pro ile glu asp ile gln asp asn leu leu gl - # n ala leu glu leu gln # 415 - ctc aag ctg aat cac cca gag tcc tct cag ct - # g ttc gcc aag gtg ctc1653leu lys leu asn his pro glu ser ser gln le - # u phe ala lys val leu # 430 - cag aag atg aca gac ctc agg cag atc gtc ac - # a gag cac gtg cag cta1701gln lys met thr asp leu arg gln ile val th - # r glu his val gln leu435 4 - # 40 4 - # 45 4 -# 50 - ctg cat gtg atc aag aag aca gag aca gac at - # g agc ctt cac ccc ctg1749leu his val ile lys lys thr glu thr asp me - # t ser leu his pro leu # 465 - ctc cag gag atc tac aag gac ttg tat tagcaggaa - # a gtcccacccg1796leu gln glu ile tyr lys asp leu tyr # 475 - ctgacaacgt gttccttcta ttgattgcac tattattttg agggaaaaaa at - # ctgacacc1856 - taagaaattt actgtgaaaa agcatttaaa aacaaaaagt tttagaacat ga - # tctatttt1916 - atgcatattg tttataaaga tacatttaca atttactttt aatattaaaa at - # taccacat1976 # 2005 aaaa aggaattcc - & lt ; 210 & gt ; seq id no 2 & lt ; 211 & gt ; length : 475 & lt ; 212 & gt ; type : prt & lt ; 213 & gt ; organism : mus musculus - & lt ; 400 & gt ; sequence : 2 - met val asp thr glu met pro phe trp pro th - # r asn phe gly ile ser # 15 - ser val asp leu ser val met glu asp his se - # r his ser phe asp ile # 30 - lys pro phe thr thr val asp phe ser ser il - # e ser ala pro his tyr # 45 - glu asp ile pro phe thr arg ala asp pro me - # t val ala asp tyr lys # 60 - tyr asp leu lys leu gln glu tyr gln ser al - # a ile lys val glu pro # 80 - ala ser pro pro tyr tyr ser glu lys thr gl - # n leu tyr asn arg pro # 95 - his glu glu pro ser asn ser leu met ala il - # e glu cys arg val cys # 110 - gly asp lys ala ser gly phe his tyr gly va - # l his ala cys glu gly # 125 - cys lys gly phe phe arg arg thr ile arg le - # u lys leu ile tyr asp # 140 - arg cys asp leu asn cys arg ile his lys ly - # s ser arg asn lys cys145 1 - # 50 1 - # 55 1 -# 60 - gln tyr cys arg phe gln lys cys leu ala va - # l gly met ser his asn # 175 - ala ile arg phe gly arg met pro gln ala gl - # u lys glu lys leu leu # 190 - ala glu ile ser ser asp ile asp gln leu as - # n pro glu ser ala asp # 205 - leu arg ala leu ala lys his leu tyr asp se - # r tyr ile lys ser phe # 220 - pro leu thr lys ala lys ala arg ala ile le - # u thr gly lys thr thr225 2 - # 30 2 - # 35 2 -# 40 - asp lys ser pro phe val ile tyr asp met as - # n ser leu met met gly # 255 - glu asp lys ile lys phe lys his ile thr pr - # o leu gln glu gln ser # 270 - lys glu val ala ile arg ile phe gln gly cy - # s gln phe arg ser val # 285 - glu ala val gln glu ile thr glu tyr ala ly - # s asn ile pro gly phe # 300 - ile asn leu asp leu asn asp gln val thr le - # u leu lys tyr gly val305 3 - # 10 3 - # 15 3 -# 20 - his glu ile ile tyr thr met leu ala ser le - # u met asn lys asp gly # 335 - val leu ile ser glu gly gln gly phe met th - # r arg glu phe leu lys # 350 - ser leu arg lys pro phe gly asp phe met gl - # u pro lys phe glu phe # 365 - ala val lys phe asn ala leu glu leu asp as - # p ser asp leu ala ile # 380 - phe ile ala val ile ile leu ser gly asp ar - # g pro gly leu leu asn385 3 - # 90 3 - # 95 4 -# 00 - val lys pro ile glu asp ile gln asp asn le - # u leu gln ala leu glu # 415 - leu gln leu lys leu asn his pro glu ser se - # r gln leu phe ala lys # 430 - val leu gln lys met thr asp leu arg gln il - # e val thr glu his val # 445 - gln leu leu his val ile lys lys thr glu th - # r asp met ser leu his # 460 - pro leu leu gln glu ile tyr lys asp leu ty - # r465 4 - # 70 4 - # 75 - & lt ; 210 & gt ; seq id no 3 & lt ; 211 & gt ; length : 546 & lt ; 212 & gt ; type : dna & lt ; 213 & gt ; organism : saccharomyces cerevisiae & lt ; 220 & gt ; feature :& lt ; 221 & gt ; name / key : cds & lt ; 222 & gt ; location : ( 35 )...( 544 )- & lt ; 400 & gt ; sequence : 3 - gggagaccca agcttgaagc aagcctcctg aaag atg aag cta c - # tg tct tct atc 55 # met lys leu leu ser ser ile # 5 1 - gaa caa gca tgc gat att tgc cga ctt aaa aa - # g ctc aag tgc tcc aaa 103glu gln ala cys asp ile cys arg leu lys ly - # s leu lys cys ser lys # 20 - gaa aaa ccg aag tgc gcc aag tgt ctg aag aa - # c aac tgg gag tgt cgc 151glu lys pro lys cys ala lys cys leu lys as - # n asn trp glu cys arg # 35 - tac tct ccc aaa acc aaa agg tct ccg ctg ac - # t agg gca cat ctg aca 199tyr ser pro lys thr lys arg ser pro leu th - # r arg ala his leu thr # 55 - gaa gtg gaa tca agg cta gaa aga ctg gaa ca - # g cta ttt cta ctg att 247glu val glu ser arg leu glu arg leu glu gl - # n leu phe leu leu ile # 70 - ttt cct cga gaa gac ctt gac atg att ttg aa - # a atg gat tct tta cag 295phe pro arg glu asp leu asp met ile leu ly - # s met asp ser leu gln # 85 - gat ata aaa gca ttg tta aca gga tta ttt gt - # a caa gat aat gtg aat 343asp ile lys ala leu leu thr gly leu phe va - # l gln asp asn val asn # 100 - aaa gat gcc gtc aca gat aga ttg gct tca gt - # g gag act gat atg cct 391lys asp ala val thr asp arg leu ala ser va - # l glu thr asp met pro # 115 - cta aca ttg aga cag cat aga ata agt gcg ac - # a tca tca tcg gaa gag 439leu thr leu arg gln his arg ile ser ala th - # r ser ser ser glu glu120 1 - # 25 1 - # 30 1 -# 35 - agt agt aac aaa ggt caa aga cag ttg act gt - # a tcg ccg gaa ttc ccg 487ser ser asn lys gly gln arg gln leu thr va - # l ser pro glu phe pro # 150 - ggg atc cgt cga cgg tac cag ata tca gga tc - # c tgg cca gct agc tag 535gly ile arg arg arg tyr gln ile ser gly se - # r trp pro ala ser # 165 # 546val ala arg - & lt ; 210 & gt ; seq id no 4 & lt ; 211 & gt ; length : 169 & lt ; 212 & gt ; type : prt & lt ; 213 & gt ; organism : saccharomyces cerevisiae - & lt ; 400 & gt ; sequence : 4 - met lys leu leu ser ser ile glu gln ala cy - # s asp ile cys arg leu # 15 - lys lys leu lys cys ser lys glu lys pro ly - # s cys ala lys cys leu # 30 - lys asn asn trp glu cys arg tyr ser pro ly - # s thr lys arg ser pro # 45 - leu thr arg ala his leu thr glu val glu se - # r arg leu glu arg leu # 60 - glu gln leu phe leu leu ile phe pro arg gl - # u asp leu asp met ile # 80 - leu lys met asp ser leu gln asp ile lys al - # a leu leu thr gly leu # 95 - phe val gln asp asn val asn lys asp ala va - # l thr asp arg leu ala # 110 - ser val glu thr asp met pro leu thr leu ar - # g gln his arg ile ser # 125 - ala thr ser ser ser glu glu ser ser asn ly - # s gly gln arg gln leu # 140 - thr val ser pro glu phe pro gly ile arg ar - # g arg tyr gln ile ser145 1 - # 50 1 - # 55 1 -# 60 - gly ser trp pro ala ser val ala arg 165 - & lt ; 210 & gt ; seq id no 5 & lt ; 211 & gt ; length : 13 & lt ; 212 & gt ; type : dna & lt ; 213 & gt ; organism : mus musculus - & lt ; 400 & gt ; sequence : 5 # 13 - & lt ; 210 & gt ; seq id no 6 & lt ; 211 & gt ; length : 23 & lt ; 212 & gt ; type : dna & lt ; 213 & gt ; organism : mus musculus - & lt ; 400 & gt ; sequence : 6 # 23cacg ttc - & lt ; 210 & gt ; seq id no 7 & lt ; 211 & gt ; length : 17 & lt ; 212 & gt ; type : dna & lt ; 213 & gt ; organism : saccharomyces cerevisiae - & lt ; 400 & gt ; sequence : 7 # 17 g__________________________________________________________________________ | US-46537595-A |
the invention relates to a method of reducing skin pigmentation . the method includes the steps of providing an h3 antagonist configured to prevent histamine from connecting to an h3 receptor , thereby preventing the h3 receptor from initiating melanin production ; adding the h3 antagonist to a cosmetic product ; and applying the cosmetic product to a user &# 39 ; s skin . | skin pigmentation is determined by the amount of melanin in the skin . melanin is produced by dermal melanocytes . melanogenesis is the process that leads to the formation of melanin . it is initiated in melanosomes , the special organelles of melanocytes , with the oxidation of l - tyrosine to l - dopa ( l - 3 , 4 - dihydroxyphenylalanine ) and then to dopaquinone , which is catalyzed by tyrosinase . overproduction of melanin can cause hyperpigmentation leading to melisma , freckles , age - spots , and liver spots . it is well known that h1 , h2 , and h3 are receptors in inflammatory pathways of the human body . it has been shown that h1 and h2 antagonist by - products are suitable for reducing pigmentation in the skin , i . e ., age spots or sun damage , by blocking the h1 and h2 pathways . however , until now , it has been assumed that h3 antagonist by - products would not be suitable for the same use . through experimentation , it has been found that h3 antagonists such as impentamine dihydrobromide ; lodophenpropit ; ( r )-(-)- a - methylhistamine dihydrobromide ; conessine ; and imetit dihydrobromide are in fact suitable for use as a by - product in cosmetics to reduce or eliminate pigmentation in a users skin . melanin inhibition studies were conducted using several h3 antagonists to assess their ability to inhibit melanin synthesis . fig1 - 3 show the results for conessine , impentamine dihydrobromide , and lodophenpropit . the assays utilized mouse melanoma cells ( b16f10 cell line ) which are very efficient at producing melanin . various inhibitors and enhancers of melanin synthesis were added to the cultured cells along with experimental samples . the melanin present in the cells was extracted and had an absorbance at 400 nm , which can be quantitated through optical density measurements . the greater the inhibition exhibited by the sample , the lower the optical density value due to the lack of melanin present . the results of the assays were analyzed and compared to known melanin inhibitors , such as arbutin and ascorbic acid 2 - glucoside ( aa2g ). the b16f10 murine melanocytes were seeded into 24 - well tissue culture plates and allowed to grow to confluency in complete dmem . solutions of h3 antagonists , arbutin , alpha - melanocyte stimulating hormone ( a - msh ), and aa2g were prepared in complete dmem . complete dulbeco &# 39 ; s modified eagle media ( dmem ) was used as the untreated control . additionally , the individual components of the h3 antagonists , yeast peptide and plant extract , were also analyzed for melanogenic effects . cells were treated for 72 hours . for the inhibition assay , the media was removed from the wells and the monolayers were washed with phosphate buffered saline ( pbs ). naoh was added to each well and 100 μl of each solution were added to a 96 - well plate in duplicate . the plate was measured by optical density readings at 400 nm . as shown in fig1 - 3 , each of the h3 antagonists was capable of inhibiting melanin production . the h3 antagonist by - product of the present invention is a fermented plant extract ( the terms h3 antagonist by - product and fermented plant extract are to be appreciated as referring to the same by - product ). the by - product is typically used in leave - on products such as serums , lotions , cremes , etc . the by - product could be in liquid or powder form and is mixed with or added to a cosmetic company &# 39 ; s existing product to allow a user to apply the cosmetic product to skin as usual . as skin is exposed to ultraviolet radiation , the inflammatory pathway releases histamine . this histamine binds with receptor binding sites and causes the production of melanin . the h3 antagonist by - product of the current invention prevents histamine from connecting to h3 receptors by connecting itself to the receptor . because the h3 antagonist by - product does not talk to the receptor like histamine does , the h3 antagonist by - product prevents the receptor from initiating melanin production . fig4 shows the results of a melanin inhibition assay comparing the h3 antagonist by - product of the current invention with aa2g , arbutin , and α - msh . as shown , the h3 antagonist by - product was effective as a melanin inhibitor . fig5 and 6 show additional results of the melanin inhibition assay comparing concentrations of the h3 antagonist by - product to aa2g , arbutrin , and kojic acid . again , the h3 antagonist by - product was shown to be effective as a melanin inhibitor . the h3 antagonist by - product of the current invention is produced using a fermentation process . in general , the fermentation process includes the steps of : 1 . providing feedstock ; 2 . processing the feedstock ( i . e ., macerating , etc . ); 3 . fermenting the feedstock using yeast or suitable bacteria ; 4 . using a solvent to extract the antagonist and any other beneficial components / compounds ; and 5 . filtering to clarify solution and remove any remaining feedstock material . more particularly , the h3 antagonist by - product is manufactured using vitis vinifera which is macerated and fermented with yeast . fermentation media is comprised of ammonium sulfate , magnesium sulfate , disodium phosphate , and yeast autolysate . an antimicrobial compound or product is added and then the solution is filtered . see fig7 for more detailed steps . it was found in testing that the fermenting process produces a more potent h3 antagonist by - product . assays for tyrosinase inhibition and melanin inhibition were performed . as discussed above , tyrosinase is one of the causes of hyperpigmentation , and over - production of dermal melanin pigment , leading to melasmas , freckles , age - spots , and liver spots . tyrosinase is a key enzyme in melanin biosynthesis , involved in determining the color of mammalian skin and hair . tyrosinase &# 39 ; s main application is to identify new potent tyrosinase inhibitors in the cosmetic industry . tyrosinase is a copper - containing monooxygenase that is widely distributed in nature . the enzyme catalyzes the first two reactions of melanin synthesis , the hydroxylation of l - tyrosine to 3 , 4 - dihydroxyphenylalanine , l - dopa , and the oxidation of l - dopa to dopaquinone . this quinine is a highly reactive compound and can polymerize spontaneously to form melanin . a tyrosinase inhibition assay was conducted for the fermented plant extract ( fermented h3 antagonist by - product ) and its individual components — peptide from yeast and plant extract . the assay was based on the conversion of l - tyorosine into a dopachrome complex by tyorsinase . the dopachrome complex has an abosorbance at 490 nm and can be quantitated through optical density measurements . the greater the inhibition exhibited by the sample , the lower the optical density value due to the lack of l - tyrosine conversion . for the inhibition assay , 10 μl of test material and controls were combined with 170 μl of 1 mm l - tyrosine and 20 μl 1000 u / ml mushroom tyrosinase in a 96 - well microtitre plate . the plate was placed in a synergy h1 reader set to 37 ° c . and optical density measurements were taken every 20 minutes at 490 nm . the results were analyzed and compared to known tyrosinase inhibitors , kojic acid and arbutrin — market standard skin lightening ingredients . see fig8 and 9 . as shown , the fermented plant extract was able to inhibit tyrosinase compared to the positive control , kojic acid . additionally , the h3 antagonist by - product of the current invention was compared to its individual components — peptide from yeast and plant extract . as shown in fig1 , the fermented plant extract outperformed the peptide from yeast and non - fermented plant extract individually and exhibited a synergetic effect . as discussed above , skin pigmentation is determined by the amount of melanin in the skin which is produced by dermal melanocytes . in addition to the melanin inhibition study comparing the fermented plant abstract to aa2g , arbutin , α - msh , and kojic acid , a melanin inhibition study was conducted to compare the fermented plant extract with its individual components — peptide from yeast and plant extract — to assess their ability to inhibit melanin synthesis . the melanin assay was conducted using the same methodogies as discussed above with respect to h3 antagonists , in general . as shown in fig1 , the fermented plant extract was able to inhibit melanin production by 93 . 58 % when using the product at a 0 . 1 % concentration . the inhibition activity increased as the concentration increased . further , the fermented plant extract outperformed the peptide from yeast and plant extract components and showed a synergistic antimelanogenic effect . the fermented plant extract was also evaluated in its ability to lighten skin in - vivo . to test this , subjects applied a lotion containing 5 . 0 % fermented plant extract to their selected hyperpigmentation once a day for four weeks . photos were taken twice a week during the four week study . as shown in fig1 a - 12c and 13 a - 13 c , the fermented plant extract visibly lightened dark spots on the subjects in less than 14 days of application — with even greater improvement after 4 weeks . the foregoing has described and h3 antagonist by - product , its manufacture , and method of using by - product to reduce pigmentation in skin . while specific embodiments of the present invention have been described , it will be apparent to those skilled in the art that various modifications thereto can be made without departing from the spirit and scope of the invention . accordingly , the foregoing description of the preferred embodiment of the invention and the best mode for practicing the invention are provided for the purpose of illustration only and not for the purpose of limitation . | US-201514666864-A |
an apparatus and method for providing instructional help , at multiple levels of sophistication , in a learning application includes assistance in the form to at least two optional levels of sophistication . the user can select any level of sophistication according to desire or need . the levels allow for flexibility in learning relative to the person involved , the amount of previous knowledge the person has about the subject matter , the differences in how different people learn . in one embodiment , the assistance is contained in programming on a cd - rom which is used in an interactive computerized system . | to assist in a better understanding of the present invention , one form the invention could take will now be described in detail . reference will sometimes be taken to the drawings , which were summarized immediately above . reference numerals or letters are used to indicate certain parts or locations in the drawings . the same reference numerals or letters will be used to indicate the same parts and locations throughout the drawings unless otherwise indicated . in the description of this preferred embodiment , the environment and context of the learning application will be with respect to a computer - based , interactive software program to teach individuals the rules and regulations about using what is called a purchase card . this purchase card is essentially a credit card or debit card . authorized personnel for a company or organization can use the card to make acquisitions on behalf of the company or organization , but certain procedures must be followed . such cards have been used in businesses and are being used in such organizations as certain agencies of the government . such cards usually have restrictions as to when they can be used , who can use them , etc . therefore , there is a considerable amount of essentially rules and regulations that must be mastered to correctly use the cards . incorrect use can result in significant problems , and therefore good training is a necessity . however , good training also needs to be efficient training in terms of time on behalf of authorized personnel that will use the cards . therefore , in the preferred embodiment , training in use of the purchase card will be accomplished using an interactive computerized learning station . [ 0066 ] fig1 depicts such a learning station . a personal computer ( pc ) 10 includes a monitor 12 and a keyboard 14 . a cd - rom drive / player 16 is operatively connected to computer 10 , such as is well known in the art . training is facilitated by a user placing a cd - rom 18 into drive 16 , and operating computer 10 to install and run the programming on cd 18 . cd 18 has audio - visual content and helps the user learn about the purchase card and its rules and regulations . following is further description of a system according to the present invention . a multimedia instructional application is often developed from an information model . this information model is a graphical representation of how , and at what stage , instructional text and graphics will be presented to the user . fig2 shows a specific information model that has been found to be particularly effective . here , the “ huh ” and “ tell me more ” levels of sophistication are shown juxtaposed at various stages of the application . as illustrated in the drawing , after information on a particular topic is presented , then the program asks the user a series of questions on the topic . after the user answers correctly , then the program advances to the next topic . the user can access the “ huh ” or “ tell me more ” help at various stages : ( 1 ) at the beginning of the program , when the context of the application is explained , ( 2 ) when the user is presented with instructional text ( information ), ( 3 ) in response to a question presented by the program , and ( 4 ) after selecting a right or wrong answer to a question . in a preferred embodiment of the invention , the two - levels of sophistication are incorporated into a multimedia computer software application . multimedia in the computer context generally refers to the selection and arrangement of text , graphics , and sound that appeals to and stimulates the human senses . a multimedia software applications for use with an operating system that employs a graphical user interface ( gui ) is preferred . examples of guis commonly used in the industry include windows 95 , windows nt and the apple macintosh user interface , and the up - coming wide - spread use of web browsers . there exists a myriad of different multimedia software development tools suitable for creating and maintaining a help or tutorial program employing two - level sophisticated help . asymmetric toolbook ® is a particularly valuable and facile development tool . asymmetric toolbook ® and other similar development tools speed development time by providing a “ work bench ” that allows the developer to create and arrange the windows , dialog boxes , text , graphics , audio clips , etc ., as desired without having to resort to the task of writing time - consuming and cumbersome code in computer languages such as visual basic and c ++. as an example , the developer can insert a data field or list box , all common objects used in a gui environment , by choosing the appropriate object and then drawing that object in the desired location using a mouse or other drawing aid . once the object is fixed on the screen , the development tool provides the logic that enables the object to function in the graphical environment . multimedia applications often contain multiple screens or windows of text , data , and graphics . these screens or windows are sometimes referred to as pages , with the entire help or tutorial application constituting a book . links are created between different pages of the book to give the application much of its flow and functionality . an illustration is best shown in fig3 - 5 . if in response to the information presented in fig3 the user selects ( clicks on ) the appropriate button or selection , for example “ huh ”( using a peripheral mouse or other input device ), then the “ huh ” explanation as shown in fig4 appears along with the accompanying voice . the development tool allows the user to specify the text , picture , button , etc . to serve as the link , as well as the areas which are being linked . in the preferred embodiment , when “ huh ?” is selected , the text shown in fig4 appears on the right side of the screen while an older man , in a rough , gravelly or husky voice , vocalizes those words . the voice is a caricature ; like a wise but gruff grandfather , or world - wise , cut - to - the - chase person . when “ tell me more ” is selected , not only do the words on the right side of fig5 appear , but a women in a calm , direct , authoritative , but patient and assuring voice , vocalizes those words . the voice is a caricature ; like a respected , instructive professor . it is to be understood that the use of the identifiers “ huh ?” and “ tell me more ” are arbitrary . other identifiers can be used . if in response to the information presented in fig3 the user selects “ tell me more ”( using a peripheral mouse or other input device ), then the “ tell me more ” explanation as shown in fig5 appears along with the accompanying voice . the development tool allows the user to specify the text , picture , button , etc . to serve as the link , as well as the areas which are being linked . because more sophisticated logic is often required to control or enhance an application , toolbook ® is designed for use with a particular scripting language . a scripting language is a high level programming language that gives the developer more control over the functionality of the application . one skilled in the art can quickly and easily write short routines to enhance the application . during the testing and development stage , the source file is edited that runs under toolbook ®. however , once the application has been modified and debugged into its preferred form , the source file is compiled into an executable file that can run independently of toolbook ®. this executable file , as well as other data and install files , can then be digitally fixed on a cd rom or other data storage device and provided to the end user for installation on a particular platform . as shown in fig1 the multimedia application is intended for use on a ibm - compatible personal computer having at least 8 megabytes of ram , twenty megabytes of free hard disk space , and a quad - speed cd - rom . multimedia applications using two - levels of sophisticated instruction or help can also be developed for other platforms , such as apple macintosh operating system or unix , as well as web or internet type environments . it is to be understood that the above description of the preferred embodiment is not intended to and does not limit the scope of the present invention . variations obvious to those of ordinary skill in the art are included herein . the claims define the scope of the invention . for example , in the preferred embodiment , the two levels of sophistication are defined by ( a ) the type of voice and ( b ) the type of language . other types of differentiation can be used to provide the two levels of sophistication . moreover , the preferred embodiment is described relative to an interactive , cd - rom based program on a computer . the concept of two levels of sophistication can apply to other learning environments , books , audio , video , and web . additionally , below are examples of a variety of different ways in which different levels of sophistication , according to the meaning ascribed herein , can be applied to the invention : audio — with any of the graphic , text and / or video options itemized below graphic — with any of the text , audio and / or video options itemized above and below text — linked to other text to provide a pre - defined path through the subject that is delivered from a consistent and defined view text — stand alone , linked to other text boxes , or linked to case histories and / or examples to provide a comprehensive and sequential walk - through of a practical application , process , or procedure from a consistent and defined view video — with any of the itemized graphic , text and / or audio options above in the preferred embodiment the difference in level of sophistication is not only the words used for each “ huh ?” and each “ tell me more ”, but also the nature of the voice used to announce the words . specifically , “ huh ?” words are voiced by a bottom - line type of character ( in this case an older man , brusque , gravelly voice , no - non - sense , get to the bottom line ). in comparison , the “ tell me more ” words are voiced by a professorial type of character ( in this case a woman , professional , calm , sophisticated , authoritative , provide context and substance ). additionally , the invention contemplates that more than two levels of sophistication can be used . for example , there can be customizable characters , dependent characters , and independent characters . it is to be understood that the “ character ” used with a “ level of sophistication ” can provide subtle benefits to the assistance given to the user . the user can almost subconsciously identify a level of sophistication to the character , which almost subconsciously assists the user in the learning process . it is to be understood also that the invention can be tailored to the individualized needs of a company or organization , or of particular persons or to particular subject matter . there can also be what can be called “ zoom capability ”, for example , “ tell me mores ” inside “ tell me mores ”, etc . there could also be what will be called a “ customized teacher ”, where one picks whose voice is wanted as the main line voice and then can listen to that view as the main view . voices could appear on the right side of the screen . in other words , if one wanted a “ bottom line ” to be taught , one could just call in the lecturer when wanted , pertaining to that view . this would call for screen reconfiguration on the fly . also , the help system according to the invention could be associated with things other than information to be learned by reading and / or listening to textual material . it could also be used with tests . the user could answer a test question and have available multiple levels of sophistication of explanation about the question , the right answer , the wrong answer , etc . in certain situations , the multiple level of sophistication help system can be implemented where some of the time only one help option is available , but at other times multiple levels are available . this would be another way to mix and vary the help options to keep the interest of the user . non - computerized applications are possible . for example in book form training materials , multiple levels of sophistication help could be placed at one side of the page next to the information being learned , or could be placed at other portions of the book , or in other books or booklets that are cross - referenced to the main book . also , the invention can be used with customizable targets . for example , if a section of the information being learned involves using a purchase card , and a specific subsection of the information is directed to how to actually make a purchase , a customizable target might be the topic of how to purchase a particular product , such as for example , software . this could be done with varying levels of sophistication . | US-7573002-A |
disclosed herewith is drug repurposing efforts that lead to the discovery of prior non - antibiotic drugs can be used in clinical applicable ranges to treat patients of bacterial infection . these repurposed drug can be used either alone or in combination with traditional antibiotic drugs to treat bacterial strains that may develop or already have developed drug resistance . | while the concepts of the present disclosure are illustrated and described in detail in the figures and the description herein , results in the figures and their description are to be considered as exemplary and not restrictive in character ; it being understood that only the illustrative embodiments are shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected . unless defined otherwise , the scientific and technology nomenclatures have the same meaning as commonly understood by a person in the ordinary skill in the art pertaining to this disclosure . for the purposes of promoting an understanding of the principles of the present disclosure , reference will now be made to the embodiments illustrated in the drawings , and specific language will be used to describe the same . it will nevertheless be understood that no limitation of the scope of this disclosure is thereby intended . infections caused by gram - positive drug - resistant pathogens are still a leading cause of mortality . three species — methicillin - resistant staphylococcus aureus ( mrsa ), streptococcus pneumoniae and vancomycin - resistant enterococcus ( vre )— are responsible annually for at least 84 % of the antibiotic - resistant bacteria mortality in the united states alone . drug development is a time - consuming , costly , and high - risk venture given few compounds successfully make it through stringent regulatory requirements to the marketplace . collectively , this points to a critical need for the identification of novel strategies to develop antibiotics to deal with this challenging health issue . one strategy which warrants more attention for identifying new antimicrobials is drug repurposing . repurposing existing approved drugs permits companies to bypass much of the preclinical work and early stage clinical trials required for new compounds thus cutting into the cost associated with bringing a drug to the marketplace . in response to the pressing need to develop novel antimicrobials to circumvent the scourge of antimicrobial resistance , drug - repurposing efforts are deployed to identify non - antibiotic drugs exhibiting bactericidal activity and they have gained some ground ; however , these identified drugs possess high minimum inhibitory concentration ( mic ) values that cannot be achieved clinically . for the purpose of this disclosure , a mic within clinical achievable range is deemed as clinical applicable range to kill the bacterium at issue . depending on the strain of the bacterium and the fda - approved drug being investigated , this clinical applicable range may be about sub - micromolar to about nanomolar . this high mic value is a major impediment to repurposing these drugs as antimicrobial agents . the objective of this disclosure is to identify non - antibiotic drugs with potent antimicrobial activity within an applicable clinical range . this is done by first screening fda approved drug library to identify groups of drugs that show antimicrobial effect as hit compounds . then using the hit compounds with their clinical applicable range to test their in vitro and / or in vivo effect on several multi - drug resistant pathogens , for example , methicillin - resistant s . aureus ( mrsa ), vancomycin - resistant s . aureus ( vrsa ), and vancomycin - intermediate s . aureus ( visa ). a library , containing 727 fda approved drugs and small molecules , was screened against eskape pathogens ( enterococcus faecium , staphylococcus aureus , klebsiella pneumoniae , acinetobacter baumannii , pseudomonas aeruginosa , and enterobacter cloacae ). drugs that showed antimicrobial activity in an applicable clinical range were further tested in vitro and in vivo in an infected mouse model . the initial screening identified 24 non - antibiotic drugs and clinical molecules active against gram - positive pathogens including methicillin - resistant s . aureus ( mrsa ) and vancomycin - resistant enterococcus ( vre ) isolates . two non - antibiotic drugs showed activity against gram - negative pathogens . among the active non - antibiotic drugs , ebselen ( eb ) and 5 - fluoro - 2 ′- deoxyuridine ( fdurd ), showed bactericidal activity , in an applicable clinical range , against multi - drug - resistant staphylococcus isolates including mrsa , vancomycin - resistant s . aureus ( vrsa ), and vancomycin - intermediate s . aureus ( visa ). the minimum inhibitory concentration at which 90 % of clinical isolates of s . aureus were inhibited ( mic 90 ) was found to be 0 . 25 and 0 . 0039 mg / l for eb and fdurd , respectively . treatment with eb orally significantly increased mice survival in a lethal model of septicemic mrsa - infection by ( 60 %) compared to that of control . fdurd oral and intraperitoneal treatment significantly enhanced mouse survival by 60 % and 100 %, respectively , in a lethal model of septicemic mrsa - infection compared to that of control . these data encourage screening and repurposing of non - antibiotic drugs and clinical molecules to treat multidrug - resistant bacterial infections . in an intensive search and subsequent study for antimicrobial activity in an applicable clinical range among non - antimicrobial drugs , at least three drugs , ebselen ( eb ), auranofin , and 5 - fluoro - 2 ′- deoxyuridine ( fdurd ), have been identified with potent antibacterial activities against gram - positive pathogens , including highly multidrug - resistant clinical isolates of s . aureus , with mic values in an applicable clinical range . these drugs showed antibacterial activity against clinical isolates of methicillin - resistant s . aureus ( mrsa ), vancomycin - resistant s . aureus ( vrsa ), and vancomycin - intermediate s . aureus ( visa ) with mic values in submicromolar concentrations . additionally , at least some of these drugs showed significant levels of protection against a lethal model of septicemic mrsa - infection in mice . it should be appreciated that while the present disclosure focuses on identifying non - antibiotic drugs with potent antimicrobial activity , such reference is not intended to be limiting in nature , as the methods described herein can also be applied to identifying non - antibiotic drugs with potent antifungal activity and anti - anthrax activity . repurposing drugs , with well - characterized toxicology and pharmacology , to find new applications outside the scope of the original medical indication is a novel way to reduce both the time and cost associated with antimicrobial innovation . these identified fda approved drugs can be applied to infected patient for 1 ) killing intracellular and persistent mrsa , 2 ) disrupting adherent staphylococcal biofilms , 3 ) suppressing toxin production and key virulence factors , 4 ) reducing excessive host - inflammatory responses associated with these toxins , 5 ) significantly reducing both the bacterial load and levels of the pro - inflammatory cytokines in mrsa skin lesions , and 6 ) enhancing wound healing . in addition , these drugs have many advantageous qualities including ; a ) they are fda - approved and clinically safe molecules , b ) orally bioavailable , c ) possess potent bactericidal activity in a clinically achievable range , d ) exhibit very low frequency of bacterial resistance , e ) demonstrate a synergistic activity with conventional antibiotics , and f ) possess a novel mechanism of action . to date , no fda - approved drug has been repurposed to treat bacterial infections in clinical relevant range . the non - antibiotic drugs that showed antimicrobial activity serve as untapped reservoir for new antibiotic leads that could lead to identification of new targets which will guide the future development of improved antimicrobial agents . the library we screened represents only 7 % of the total drugs known to clinical medicine . finding hits in a clinical range illustrates the potential to identify more drugs with potent antimicrobial activity and encourage the screening of all clinical compounds to complement current antibiotics . the disclosure herein further provides that repurposing auranofin and ebselen to treat bacterial infections has the potential to produce significant impact that leapfrog the drug development process and save years of expensive research . both drugs has significant promise to be repurposed as a novel antibacterial for treatment of both superficial and invasive infections . auranofin is currently approved for long - term treatment of unresponsive rheumatoid arthritis . auranofin &# 39 ; s oral bioavailability and reduced associated side effects offer significant advantages over traditional injectable gold drugs . the emergence of new anti - rheumatoid drugs with fewer side effects and faster activity has resulted in the decline of oral gold therapy clinically . nevertheless , there has been considerable research efforts employed to identify alternative therapeutic applications for auranofin , particularly in the area of infectious diseases . the fact that auranofin , a fda - approved gold compound used for treating rheumatoid arthritis , recently has been granted orphan - drug status from the fda for treatment of human amebiasis , further validates the herein disclosed antimicrobial repurposing approach for auranofin . eskape pathogens vancomycin resistant e . faecium atcc 700221 ( vre ), mrsa usa300 , carbapenemase ( kpc )- producing bla kpc + k . pneumoniae atcc baa - 1705 , multi - drug - resistant a . baumannii atcc baa - 1605 , p . aeruginosa atcc 15442 , and e . cloacae atcc baa - 1143 were used for the initial screening . clinical isolates of methicillin - sensitive s . aureus ( mssa ), mrsa , vrsa , visa , and s . epidermidis are described in table 1 . the nih clinical collections 1 and 2 ( http :// www . nihclinicalcollection . com ) containing 727 fda approved drugs and small molecules previously used in human clinical trials with known safety profiles were screened against eskape pathogens . the library was initially screened at a single concentration of 16 μm to identify “ hit ” non - antibacterial drugs . once the antimicrobial activity of the drugs was confirmed , we determined their mics and minimum bactericidal concentrations ( mbcs ) according to the clinical and laboratory standards institute ( clsi ). drugs were selected that showed potent antimicrobial activity in an applicable clinical range for further screening and testing in vitro and in vivo in an infected mouse model . animal procedures were approved by the purdue university animal care and use committee ( pacuc ) ( protocol no . 1311000988 ). eight - week - old female balb / c mice ( harlan laboratories , indianapolis , ind .) were used for this study . mice were rendered neutropenic by treatment with cyclophosphamide intraperitoneally ( ip ) 150 and 100 mg / kg at four days and one day before infection , respectively . neutropenic mice were inoculated ip with 8 × 10 8 mrsa usa200 . at one hour after infection , the mice were divided into five groups ( n = 10 per group ), and two groups were treated orally with either eb 30 mg / kg or fdurd 25 mg / kg . two groups were treated ip with either eb 30 mg / kg or fdurd 25 mg / kg . one group was used as a control with no treatment . treatment was continued once daily for two more days ( animals received three doses total ). mortality was monitored four times daily for six days , and the cumulative percent survival was determined . the data were subjected to statistical analysis using kaplan - meier survival curves . a log rank test was performed for 95 % confidence intervals by graphpad prism 6 . 0 ( graphpad software , la jolla , calif .). example 1 . in vitro antimicrobial activity from screening of fda - approved drug library in this example , we identified and validated drugs that are active against gram - positive pathogens mrsa and vre in clinical relevant range . initial screening identified 24 non - antibiotic drugs and clinical molecules active against gram - positive pathogens mrsa and vre ( table 2 ). among the active non - antimicrobial drugs against mrsa identified in the nih clinical collections , eb and fdurd showed potent bactericidal activity in a nano - molar ( clinically achievable ) range . both drugs demonstrated potent bactericidal activity against clinical multi - drug - resistant staphylococcus isolates . the mic at which 90 % of s . aureus isolates were inhibited ( mic 90 ) was found to be 0 . 25 and 0 . 0039 mg / l for eb and fdurd , respectively ( table 1 ). only two non - antibiotic drugs showed activity against gram - negative pathogens ( table 2 ). eb oral treatment , but not ip , significantly increased mice survival ( 60 %) compared to that of control ( fig1 a ). fdurd oral and ip treatment significantly enhanced mouse survival by 60 % and 100 %, respectively , compared to that of control ( fig1 b ). it is well established that currently approved antimicrobials are losing the battle in the fight against multidrug - resistant pathogens . without a doubt , novel antimicrobials and novel approaches to develop them are urgently needed ; however , new antimicrobials are becoming increasingly difficult to develop . repurposing fda - approved drugs , with well - characterized toxicology and pharmacology , to find new applications outside the scope of the original medical indication is a novel way to reduce both the time and cost associated with antimicrobial innovation . whole - cell screening assays of non - antibiotic drugs and clinical safe molecules in the nih clinical collections against eskape pathogens revealed several non - antibiotic drugs with antimicrobial activity ( table 2 ). many drugs with antimicrobial activities were unexpected because their clinical indications are unrelated to treatment of microbial infections . among the active non - antimicrobial drugs against mrsa , eb and fdurd showed potent bactericidal activity in a nano - molar ( clinically achievable ) range . both drugs demonstrated potent bactericidal activity against clinical multi - drug - resistant staphylococcus isolates , including linezolid - resistant s . aureus , vrsa , visa , and mrsa . additionally , the activities of eb and fdurd exceeded those determined for vancomycin and linezolid . furthermore , they exhibited strong antimicrobial activity against other important gram - positive pathogens , including vre and methicillin - resistant s . epidermidis . eb , an organoselenium compound , is considered clinically safe but without proven use . it has been widely studied for its anti - inflammatory , anti - atherosclerotic , and antioxidative properties . independent of its anti - inflammatory effect , eb also has been shown to exhibit antimicrobial activity in vitro . it inhibits the thioredoxin reductase enzyme in escherichia coli , and it inhibits the antigen 85 ( ag85 ) complex in mycobacterium tuberculosis . however , clinical applications and the underlying mechanism of action for its antibacterial activity against s . aureus still remain unclear . in this study , we have established that treatment with eb orally , but not ip , significantly increased mice survival ( 60 %) in a lethal model of septicemic mrsa - infection compared to that of control ( fig1 a ). eb is rapidly absorbed from the gastrointestinal tract , and it maintains a plasma concentration of 2 . 91 mg / l with 30 mg / kg dose ( according to increase in selenium concentration in the blood of 0 . 84 ± 0 . 1 mg / l − 1 ), several - fold higher than mic 90 . higher doses or multiple doses might be required to achieve 100 % protection . furthermore , the recognized anti - inflammatory response of eb , combined with the potent antimicrobial activity , make it an excellent candidate for topical treatment of mrsa skin infections . fdurd is an anticancer drug used to treat colorectal cancers . fdurd inhibits thymidylate synthase ( a key enzyme in dna synthesis ) and acts as a nucleoside analog that impairs the metabolism and structure of nucleic acids . the antimicrobial activity of nucleoside analog against s . aureus has been demonstrated in vitro . fdurd oral and ip treatment significantly enhanced mouse survival in a lethal model of septicemic mrsa - infection by 60 % and 100 %, respectively , compared to that of control ( fig1 b ). the bioavailability of oral fdurd is unpredictable , which probably contributed to a lower protection rate compared to an ip route . while fdurd shows preclinical promise as a medication for the treatment of mrsa infections , the therapeutic dose can be reduced significantly to avoid drug - associated toxicity . the achieved plasma concentration of the drug after receiving a therapeutic dose is estimated to be more than a thousand - folds higher than the required mic 90 against mrsa . example 3 . bactericidal activity of auranofin and ebselen against a range of gram - positive clinical isolates in this example , we demonstrated that auranofin and ebselen have potent bactericidal activity against drug - resistant staphylococcus isolates , including methicillin - resistant staphylococcus aureus ( mrsa ), vancomycin - intermediate s . aureus ( visa ), vancomycin - resistant s . aureus ( vrsa ) and linezolid - resistant s . aureus . furthermore , they exhibited strong antimicrobial activity against other important gram - positive pathogens , including vancomycin - resistant enterococcus ( vre ), streptococcus pneumonia , methicillin - resistant s . epidermidis , and bacillus anthracis . the mics at which 90 % of mrsa isolates were inhibited ( mic 90s ) were 0 . 125 μg / ml and 0 . 25 μg / ml for auranofin and ebselen , respectively ( table 3 ). mics of auranofin and ebselen against g + ve pathogens are several fold lower than the clinically achievable blood concentration of the drugs of 2 . 37 μg / ml for auranofin and 2 . 91 μg / ml for ebselen . we are using the guidelines of the clinical and laboratory standards institute ( clsi ) to identify mics . example 4 . bactericidal activity of auranofin and ebselen against a range of gram negative clinical isolates in this example , we showed that auranofin and ebselen demonstrated bactericidal activity , in a clinical range , against g − ve pathogens , including metallo - β - lactamase ( ndm - 1 ), carbapenemase ( kpc ) resistant k . pneumonia , and colistin - resistant p . aeruginosa isolates from colistin - treated cystic fibrosis patients , when the intrinsic resistance mechanism conferred by the outer membrane ( om ) had been artificially compromised ( table 4 ) by sub - inhibitory concentrations of polymyxin b nonapeptide or colistin ( nano molar range that did not inhibit growth of the bacteria ). this study indicates that the targets of auranofin and ebselen are present in g − ve bacteria and it can be combined , in a clinical range , with other approved drugs that cause leakage in the om to sensitize g − ve pathogens . mics of auranofin and ebselen against g - ve pathogens are several fold lower than the clinically achievable blood concentration of the drugs of 2 . 37 μg / ml for auranofin and 2 . 91 μg / ml for ebselen . biofilms are a major contributing factor to lack of healing of chronic wounds , as the matrix - embedded bacteria are recalcitrant to antibiotics and host immune response , rendering them extremely challenging and costly to treat . auranofin and ebselen were superior in reducing adherent biofilms of both s . aureus and s . epidermidis when compared to conventional antibiotics ( linezolid 256 μg / ml ( 128 × mic ), mupirocin 16 μg / ml ( 128 × mic ), vancomycin 128 μg / ml ( 128 × mic ), and rifampicin 0 . 5 μg / ml ( 16 × mic ) ( fig2 ) example 6 . topical auranofin and ebselen prove superior to conventional antimicrobials in mrsa skin infection in this example , we compared auranofin and ebselen with other conventional antimicrobials in mrsa skin infection and concluded that these two drugs are superior to other available conventional drugs . since the clinical severity of bacterial skin infections is driven by the excess host pro - inflammatory cytokines rather than by bacterial burden , the recognized anti - inflammatory response of auranofin and ebselen combined with the potent antimicrobial , killing intracellular mrsa , and antibiofilm activities , should provide great advantage in the treatment of bacterial skin infection and wound healing . in this example , we evaluated auranofin and ebselen in a mouse - model of staphylococcal skin infection . seven groups of balb / c mice ( n = 5 ) were inoculated with mrsa usa300 ( 4 . 3 × 10 9 cfu / ml ) intradermally . 48 hours after infection and formation of open wound , four groups were treated topically with 20 mg of 2 % ebselen , 2 % auranofin , 2 % mupirocin or 2 % fluidic acid in petroleum jelly ( ointment — skin protectant ). two groups were treated orally with either linezolid or clindamycin ( 25 mg / kg ). the last group received the vehicles alone ( petroleum jelly ). all groups were treated twice a day for 5 days . auranofin and ebselen significantly reduced the bacterial load and auranofin was superior to traditional antimicrobial agents currently utilized for topical treatment ( fig3 ). example 7 auranofin and ebselen reduce inflammatory cytokines induced by mrsa skin infection in this example , we investigated the immunomodulatory activity of auranofin and ebselen in a topical application against mrsa skin infection in mice . auranofin and ebselen significantly reduced the levels of the pro - inflammatory cytokines tumor necrosis factor - α ( tnf - α ), interleukin - 6 ( il - 6 ), interleukin - 1 beta ( il - 1β ), and monocyte chemo attractant protein - 1 ( mcp - 1 ) ( fig4 and data not shown for il - 1β or mcp - 1 ). these cytokines are thought to play a greater role in the severity of s . aureus skin infections more than the size of the bacterial burden and can lead to an infection persisting for a longer time period . therefore , the ability of auranofin and ebselen reduces the production of these cytokines in the infected mice , indicating the clinical relevance of these drugs if used for antimicrobial treatment . in this example we investigated if auranofin and ebselen possess intracellular anti - staphylococcal activity . fig5 shows that treatment with auranofin and ebselen was superior in reducing intracellular mrsa when compared to conventional antibiotics ( vancomycin and linezolid ) in j774a . 1 cells . some extracellular pathogens such as s . aureus are also capable of invading and surviving within the mammalian host cells . survival of s . aureus within host cells may provide a reservoir relatively protected from antibiotics , thus enabling long - term colonization of the host and explaining clinical failures and relapses after antibiotic therapy . moreover , treatment of intracellular stage with antimicrobials is very challenging because most antibiotics do not actively pass through cellular membranes . therefore , clinical failures of drug of choice , such as vancomycin , to cure s . aureus pneumonia have exceeded 40 % and have been attributed mainly to poor intracellular penetration of the drug and consequently to the failure to kill intracellular mrsa in alveolar macrophages . in addition , intracellular persistence of s . aureus constitutes a potent virulence components for various skin diseases such as impetigo and folliculitis . hence , finding antimicrobials that possess both extra - and intracellular activity would be an optimum strategy to treat such invasive intracellular s . aureus infections . auranofin and ebselen fulfill such optimization treatment of invasive intracellular s . aureus infections . in this example we tested whether the inhibition of protein synthesis by auranofin and ebselen lead to inhibition of virulence factors and toxin production in mrsa . antimicrobials that suppress translation in s . aureus markedly suppress expression of virulence factors and the formation of toxins such as α - hemolysin ( hla ), toxic shock syndrome toxin - 1 ( tsst - 1 ), and panton - valentine leucocidin ( pvl ) that will lead to better treatment outcomes . we tested the effect of auranofin and ebselen after 1 hour incubation with mrsa usa300 - 0114 on production of these important toxins hla and pvl by elisa and found that auranofin and ebselen significantly suppressed toxin production in mrsa ( fig6 ). in this example we showed that auranofin and ebselen do not affect mitochondria protein synthesis . due to concern about the possible mitochondrial toxicities associated with many antibacterial protein synthesis inhibitors such as linezolid and chloramphenicol , we tested the effect of auranofin and ebselen on mitochondrial protein synthesis directly within the mammalian cells . in - cell elisa was performed in j774a . 1 cells treated with auranofin , ebselen , and control antimicrobials ( chloramphenicol and ampicillin ) for three days to detect the levels of two proteins ( subunit i of complex iv ( cox - i ), which is mitochondrial dna ( mtdna )- encoded , and the 70 kda subunit of complex ii ( sdh - a ), which is nuclear dna ( ndna )- encoded . ebselen and auranofin had no significant inhibition ( less than 10 %) of mitobiogenesis , similar to the effect of ampicillin , which does not interfere with mitochondrial protein synthesis process ( fig7 ) ( only ebselen data shown ). these results provide valuable information about these drugs safety profile and the lack of interference with mammalian protein synthesis and mitobiogenesis . example 11 . synergistic activities of auranofin and ebselen with conventional antibiotics in vitro and in cell culture in this example we showed that auanofin and ebselen may be combined with conventional antibiotics to achieve synergistic effect . with the rapid emergence of multidrug - resistant strains , monotherapy with single antibiotic has become less effective . therefore , alternative strategies such as combinational therapy have been used in the healthcare setting to improve the morbidity associated with mrsa infections and to reduce the likelihood of emergence of resistant strains . to ascertain whether auranofin and ebselen have the potential to be combined with conventional antimicrobials such as linezolid , clindamycin , vancomycin , ciprofloxacin , erythromycin , rifampicin , gentamicin , mupirocin , fusidic acid , retapamulin and daptomycin against multiple mrsa and vrsa strains , we evaluated the synergistic activity in in - vitro and in infected cell culture assay . auranofin and ebselen were found to exhibit a synergistic relationship with most of the tested conventional antimicrobials in vitro against all tested strains ( with few exceptions such as vrsa5 strain ) ( data not shown but available ). in infected cell cultures , clindamycin , erythromycin , and rifampicin showed synergistic activity when combined with auranofin and ebselen and significantly reduced intracellular mrsa when compared to monotherapy . identifying antibiotics that can be synergistically paired with auranofin and ebselen can potentially prolong the clinical utility of these antibiotics , reduce the likelihood of emergence of resistant strains , and supplement current therapies . in this example , we showed that auranofin can be combined with other antibiotics to treat persister s . aureus . persister s . aureus , bacteria that presumably enter a dormant state to survive antibiotic treatment , are very challenging to target . moreover , no treatment strategy has been established , despite the high mortality associated with persistent mrsa infections . the effect of auranofin and conventional antibiotics ( linezolid , retapamulin and vancomycin ) on s . aureus persister cells that demonstrated tolerance to ciprofloxacin was investigated as described previously in this example . when treated with ciprofloxacin , mrsa usa300 in exponential growth phase produces a biphasic killing pattern that results in surviving persister cells ( fig8 ). subsequent addition of conventional antimicrobials such as linezolid and retapamulin had minimal impact in reducing the number of planktonic persisters . however , treatment with auranofin resulted in complete eradication of planktonic persister cells after 48 h , a result that is comparable with vancomycin ( fig8 ) in this example , in view of our results demonstrating potent antimicrobial in - vitro and in mrsa skin infection ( above ), we moved forward with a preliminary in - vivo experiment in a mouse model of mrsa systemic infection to ensure the feasibility of repurposing these two drugs systemically . for mrsa systemic infection , neutropenic female balb / c mice were inoculated ip with 1 × 10 9 mrsa usa300 . at 1 h after infection , the mice were divided into five groups ( n = 10 per group ) and four groups were treated orally with linezolid 25 mg / kg , auranofin 0 . 125 and 0 . 25 mg / kg ( dose approved for treatment of juvenile rheumatoid arthritis in children ( 68 - 70 ) and ebselen 30 mg / kg . one group was used as a control with no treatment . treatment was continued once daily for two more days . all drugs significantly increased mice survival ( 60 % ebselen , 40 % and 80 % oral auranofin ) compared to that of control ( fig9 ). in a non - lethal mrsa infection mice model ( 2 × 10 7 cfu mrsa usa300 ip ), two doses of oral auranofin ( 0 . 25 mg / kg ) significantly reduced the bacterial load in the liver and spleen , comparable to linezolid ( 25 mg / kg ) ( fig1 ). in this example we examined the effect of auranofin and ebselen on incorporation of radioactive precursors into macromolecules in s . aureus . for auranofin : dna , protein and cell wall synthesis inhibition were detected with a clear dose - dependent disruption at concentrations significantly below the mic ( 0 . 25 ). whereas no significant effect was observed on the lipid and rna synthesis up to 4 × mic ( dose response fig1 ). ebselen primarily inhibited dna and protein synthesis at 1 × the mic ( data not shown but available ). in this example , we tested the effects of the two drugs on bacterial , mammalian and mitochondrial protein - synthesis . for bacterial protein - synthesis inhibition , we used e . coli cellular extracts in a transcription and translation assay that monitors protein production via luciferase readout . as expected from mms and proteomics results , auranofin and ebselen strongly inhibited bacterial translation process ( fig1 ). auranofin and ebselen , exhibited ic 50 of 0 . 038 μg / ml and 0 . 25 μg / ml , respectively . these results confirm mms and proteomics results and indicate that both drugs act by a favorable mechanism of action and inhibit bacterial protein synthesis and inhibit toxin production . both drugs did not inhibit translation in mammalian protein synthesis in a rabbit reticulocyte lysate system ( fig1 ) or mitobiogenesis ( above ) those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above . the implementations should not be limited to the particular limitations described . other implementations may be possible . | US-201615380648-A |
a portable combination cooking and storage unit having : a housing having at top , a bottom , a front , a back and two sides , and at least one access door at the front ; at least two stackable removable grilling trays containable within the housing ; at least one removable storage tray containable within the housing ; wherein each of the at least two removable grilling trays have at least one burner , a cooking grid proximate the at least one burner , and at least one burner control for controlling fuel to the at least one burner . | the figures contained herein are protected under copyright by copyright holder robert john thorndyke . referring now to fig1 and 2 , there is provided a portable combination cooking , grilling , warming , cooling and storage unit 10 in the shape of a box container ( other shapes suitable to accommodate the following may also be used ). the front 20 of the unit includes a first access door 21 and a second access door 22 . access door 21 is hinged at one side of the unit 10 . access door 22 is hinged at the bottom of the unit 10 . the first access door 21 is larger and located above the second access door 22 . located on the front access door 21 is a temperature gauge 23 for measuring the internal temperature of the unit 10 , although the temperature gauge 23 may located at other areas of the unit . also located on the front access door 21 is a locking mechanism 30 to ensure the unit 10 is secure when being transported . in this embodiment , the locking mechanism 30 is a latch type mechanism , however any suitable locking mechanism may be used herein . referring now to fig2 , both the first and second access doors 21 , 22 are open and an empty unit 10 is show . inside the unit 10 are as series of spaced apart tray supports . in this embodiment the spaced apart tray supports are shelves 40 , although any suitable support may be used herein . on one side 50 of the unit 10 are three shelves 40 spaced apart from each other . one the opposing side 60 of the unit 10 are three shelves 40 spaced apart from each other to complement the shelves 40 of side 50 and to provide for either a grilling tray 70 and / or storage tray 80 and / or burner tray 90 to be substantially level when in the unit 10 . each of the shelves 40 runs substantially the length of each side 50 and 60 . in this embodiment , each of the shelves 40 are “ l ” shaped but may be of any shape to accommodate the trays 70 , 80 and / or 90 . in this embodiment , the shelves 40 are secured in place along the inside walls of the unit by rivets but may also be secured in place by welding , spot welding and combinations thereof or the like as understood by a person skilled in the art . the spacing 41 between shelves 40 at each side 50 and 60 is such that it accommodates the facile insertion and removal of either a grilling tray 70 , storage tray 80 and / or burner tray 90 . referring now to fig3 and 4 , there is provided an open view of the unit 10 depicting the grilling trays 70 and storage tray 80 in the unit 10 . in fig3 , the secondary access door 22 is in the closed position . in fig4 , the secondary access door 22 is in the opened position and the burner tray 90 is seen . as can best be seen in fig5 , the storage tray 80 comprises a substantially square bottom 81 , two side walls 82 , a back wall 83 and a front wall 84 forming a chamber within the storage tray 80 . at the top end of each wall 82 , 83 , 84 there is a flange 85 running along the length of each wall , for strengthening the tray 80 . the front 84 of tray 80 includes a handle 86 and two hooks 87 saddling said handle 86 . the hooks 87 are used to wrap a portion of a fuel hose ( not shown ) when the trays 70 and 80 are in storage in the unit 10 . the storage tray 80 may be used to store food in the unit and when used in combination with a burner tray 90 , items in the storage tray 80 may be cooked and / or kept warm in the unit 10 . in practice , for keeping food warm , storage tray 80 is placed in the unit above burner tray 90 . burner tray 90 is preferably placed at the inside bottom of the unit 10 . access door 21 is kept closed during the cooking or warming process . access door 22 may also be kept closed and when adjustment of temperature in the unit 10 is required , access door 22 may be opened to adjust the temperature of burner tray 90 . an alternative is to keep items in the unit cool and / or cold by placing ice in the storage tray 80 and placing the storage tray 80 on an upper shelf and placing food items to be kept cool / cold beneath storage tray 80 , preferably on the bottom of the unit 10 , although food items may be placed above the storage tray 80 . in either instance , both doors 21 , 22 may be kept closed and the unit 10 acts as a cooler for storage of food items . referring now to fig6 and 7 , there is provided a grilling tray 70 . grilling tray 70 comprises a bottom 71 , two side walls 72 , a back wall 73 and a front wall 74 , forming a chamber within the grilling tray 70 . at the top of the back wall 73 , two side walls 72 and front wall 74 , there is a flange 75 running along the length of each wall , for strengthening the tray 70 and concentrating heat in the chamber of the grilling tray 70 . the flange being less wide at the front wall 74 than the flange at the back wall 73 and two side walls 72 . the opening formed by the flange 75 allows for support of a removable cooking grid 100 . the cooking grid 100 is a mesh type grid to allow support of the item to be cooked and / or grilled while allowing heat to contact the item to be cooked . the cooking grid in this instance , is a perforated basket 101 with a flange 102 at the front and back of the basket 101 to allow for support of the basket 101 on the flange 75 at the front 75 and back 73 walls . the cooking grid 100 further comprises a shield 110 which runs along the bottom of said cooking grid 100 and is aligned to sit a predetermined distance above the burner 120 . in this embodiment , the shield 110 is rectangular in shape and is narrower than the cooking grid 100 such that the shield 110 reduces the likelihood of food particles and liquids , such as liquids produced during the cooking and / or grilling process from making contact with the burner 120 ( which could result in flare ups ) while allowing for heat to contact the item to be cooked . in this instance , the shield 110 is connected to the cooking grid 100 by a pair of screw connectors 111 each being proximate an opposite end of the shield 110 . referring now to fig7 , a burner 120 is seen in a grilling tray 70 with the cooking grid 100 removed . the burner 120 is a conventional gas burner used in cooking units and know to persons of ordinary skill in the art . when the cooking grid 100 is removed from said grilling tray 70 , the grilling tray 70 may be used as a heat source ( or as a burner tray 90 or 140 ) at the bottom of the unit 10 to keep items warm in the storage tray 80 when inserted above the grilling tray 70 . given the shelves 40 are at various heights in the unit 10 , the user may select the appropriate level to place the grilling tray 70 to keep items warm . grilling tray 70 may also be used to store a griddle 141 ( see fig8 ) when not in use . griddle 141 is placed above the burner 120 and the cooking grid 100 is placed above the griddle 141 and the tray 70 is then placed inside the unit 10 for storage and transportation . referring now to fig8 , there is shown three grilling trays 70 side by side to allow for cooking various items simultaneously . the trays 70 are each connected to a fuel source 71 , such as a fuel tank , by fuel passageways 72 , such as appropriate hoses . in this manner , depending on the item being cooked , the user will adjust the individual burner control 130 to regulate the heat to each grilling tray 70 . if desired , the user can also use a side burner tray 140 ( see fig1 ) to cook items in a pot or pan ( not shown ) or griddle 141 on a grilling tray 70 . fig9 depicts the unit 10 with an optional telescopic spaced apart handle 180 connected to the back wall 24 of the unit 10 . the handle 180 has proximate the bottom 181 thereof a pair of wheels 182 to facilitate moving the unit 10 along a surface . the handle 180 and wheels 182 are made of a material that is light and also resistant to heat . the handle may be integral to the unit 10 or it may be removable to facilitate cleaning as well as storage of the unit 10 . although not shown in the figures , the unit 10 may also be used as an ice box to keep items cold . in this instance , the used would place ice in the storage tray 80 and place the storage tray 80 containing the ice on a shelf above the items to be kept cold . fig1 depicts a typical burner control 130 , which includes a burner handle 140 , a fuel inlet connection 150 and a fuel outlet connection 160 . each connection 150 and 160 may be quick connects or any suitable connector as understood by a person skilled in the art . fig1 depicts a perspective view of the unit 10 with a rotisserie shaft receiver 170 on each side wall 50 and 60 . this allows for receiving a rotisserie shaft ( not shown ) and using the unit 10 as a rotisserie oven . the receiver 170 also includes a bracket 171 to allow the unit 10 to receive a rotisserie motor ( not shown ). the unit is preferably made of stainless steel , aluminum and other materials listed herein or combinations thereof such that structural integrity and safety of the unit 10 is not compromised as many changes can be made to the preferred embodiment without departing from the scope thereof ; it is intended that all matter contained herein be considered illustrative and not in a limiting sense . | US-201715417288-A |
mechanisms and methods to install upper restrictive barriers onto existing pull - out shelves to prevent or decrease the likelihood of the shelf contents from falling over the back or sides of the shelf . | fig1 a , 1 b , 1 c and 1 d relate to the first embodiment corresponding to provisional application 61 / 908 , 188 . 1 . the sliding shelf , front , back , sides , and bottom , are existing elements of a conventional sliding shelf unit . 2 . sliding shelves are built in random lengths and widths , and this invention will accommodate units from 12 . 0 inches to 22 . 5 inches ( 30 . 5 cm to 57 . 2 cm ) in length and 12 . 0 inches to 30 . 0 inches ( 30 . 5 cm to 76 . 2 cm ) in width . standard two rail system can accommodate an 8 - inch ( 20 . 3 - cm ) sliding - shelf space . a three rail system can accommodate up to an 11 - inch ( 27 . 9 - cm ) space . 3 . element 115 ( also referred to herein as a containment member )— telescoping rail of metal or rigid material , to accommodate shelf varying widths and lengths . 4 . drawings for this embodiment are : fig1 a , fig1 b , fig1 c , and fig1 d . fig1 a is a top oblique view of a sliding shelf and a rail containment system 101 . 1 . existing sliding shelf , elements 103 front , 105 bottom , 107 side , and 109 back . 2 . element 111 ( also referred to herein as a containment - member support )— rail standard — is attached to the shelf sides and back , every four to six inches , with screws , and holds the rails in place . 3 . element 113 — self tapping , # 8 , ½ inch lath screws , attach rail standards 111 to sides and back of sliding shelf . 4 . element 115 — telescoping rail of metal or rigid material , to accommodate shelf varying widths and lengths . 5 . element 117 — rail end cap of rubberized or plastic material , to close off the ends of the rails , and eliminate sharp edges . fig1 b is an enlargement oblique view of the top left rear corner of the containment shelf and rail containment system 101 . 1 . existing sliding shelf , elements 103 front , 105 bottom , 107 side , and 109 back . 2 . element 111 — rail standard — is attached to the shelf sides and back , every four to six inches ( 10 to 15 cm ), with screws , and holds the rails in place . 3 . element 113 — self tapping , # 8 , ½ inch lath screws , attach rail standards 111 to sides and back of sliding shelf . 4 . element 115 — telescoping rail of metal or rigid material , to accommodate shelf varying widths and lengths . 5 . element 117 — rail end cap of rubberized or plastic material , to close off the ends of the rails , and eliminate sharp edges . fig1 c is a front enlargement view of a rail standard in rail containment system 101 . fig1 d is a side enlargement view of the rail standard of fig1 c . 1 . existing sliding shelf , elements 105 bottom , 107 side , and 109 back . 2 . element 111 — rail standard is a metal or rigid material , approximately ⅛ inch in thickness , by ⅞ inch in width , by 8 . 0 inches in height ( taller standards may hold up to three rails ; for example , a first containment member , a second containment member , and a third containment member ). 3 . element 113 — self tapping , # 8 , ½ inch lath screws , attach rail standards 111 ( for example , a first containment - member support , a second containment - member support , and a third containment - member support ) to sides and back of sliding shelf . 4 . element 115 — telescoping rail of metal or rigid material , to accommodate shelf varying widths and lengths . the outside diameter of these rails may be up to ½ inch in diameter . 5 . element 119 — rail cradle is a metal stamping , or molded protrusion from the rail standard 111 material , made to hold the telescoping rails . the rails can have a thin plasticized material wrapped around the rails at the location of the cradles to provide flexibility when snapping the rail into the cradle . a thicker plasticized material will be wrapped around the inner telescoping rail , to accommodate a snug fitting into the standard size cradle . fig2 a , fig2 b , fig2 c , and fig2 d relate to the second embodiment corresponding to provisional application 61 / 965 , 331 . 1 . the sliding shelf , front , back , sides , and bottom , are existing elements of a conventional sliding shelf unit . 2 . sliding shelves are built in random lengths and widths , and this invention will accommodate units from 12 . 0 inches to 22 . 5 inches in length and 12 . 0 inches to 30 . 0 inches in width . standard system can accommodate an 8 inch high sliding shelf space . an 11 . 0 inch containment panel can accommodate up to a 12 inch high space . 3 . element 135 — containment panel can have elongated screw hole channels to allow panel sliding movement , to accommodate shelf varying widths and lengths . 4 . drawings for this embodiment are : fig2 a , fig2 b , fig2 c , and fig2 d . fig2 a is a top oblique view of a sliding shelf and a rigid panel containment system 201 . 1 . existing sliding shelf , elements 103 front , 105 bottom , 107 side , and 109 back . 2 . element 135 — is a rigid material , approximately ⅛ inch in thickness that may be opaque or transparent . this material is attached to the shelf sides and back , every four to six inches ( 10 to 15 cm ), with screws 113 , and holds the material in place . elongated screw hole channels allow for panel sliding movement , to accommodate shelf varying widths and lengths . 3 . element 113 — self tapping , # 8 , ½ inch lath screws , attach containment panels 135 to sides and back of sliding shelf . 4 . element 131 — edge cap is a rigid plasticized material forming a u channel that has an approximate inside dimension of ¼ inch in width by ½ inch legs . this cap clips together the containment panels 135 and filler strips 133 to reinforce the containment panel 135 edges , while at the same time , eliminating sharp edges . material can accommodate cutting to various lengths with a razor knife or similar . 5 . element 133 — filler strip is an approximate ¾ inch strip of containment panel 135 material , used under the edge cap 131 , at places where overlapping panels do not occur . this strip provides a second thickness to accommodate the snap - on edge cap 131 . the filler strip 133 has an etched grove every ½ inch of its length , to accommodate selecting the approximate length by utilizing snap breaking joints . the filler strip 133 is held in place with a mastic type material of rubberized or plastic material . filler strip 133 material is also used in 2 . 0 inch lengths to provide double wall thickness at screw locations , where only a single inside ( closest to the center of the shelf ) containment panel 135 exists . fig2 b is an enlargement oblique view of the top right rear corner of the containment shelf and containment system 201 , as viewed along line 2 b of fig2 a . 1 . existing sliding shelf , elements 103 front , 105 bottom , 107 side , and 109 back . 2 . element 135 — is a rigid material , approximately ⅛ inch in thickness that may be opaque or transparent . this material is attached to the shelf sides and back , every four to six inches , with screws , and holds the material in place . elongated screw hole channels allow for panel sliding movement , to accommodate shelf varying widths and lengths . 3 . element 113 — self tapping , # 8 , ½ inch lath screws , attach containment panels 135 to sides and back of sliding shelf . 4 . element 131 — edge cap is a rigid plasticized material forming a u channel that has an approximate inside dimension of ¼ inch in width by ½ inch legs . this cap clips together the containment panels 135 and filler strips 133 to reinforce the containment panel 135 edges , while at the same time , eliminating sharp edges . material can accommodate cutting to various lengths with a razor knife or similar . 5 . element 133 — filler strip is an approximate ¾ inch wide strip of containment panel 135 material , used under the edge cap 131 , at places where overlapping panels do not occur . this strip provides a second thickness to accommodate the snap - on edge cap 131 . the filler strip 133 has an etched groove every ½ inch of its length , to accommodate selecting the approximate length by utilizing snap breaking joints . the filler strip 133 is held in place with a mastic type material of rubberized or plastic material . filler strip 133 material is also used in 2 . 0 inch lengths to provide double wall thickness at screw locations , where only a single inside ( closest to the center of the shelf ) containment panel 135 exists . fig2 c is a top cross - section view of containment system 201 , as viewed along line 2 c of fig2 a . 1 . existing sliding shelf , elements 103 front , 105 bottom , 107 side , and 109 back . 2 . element 135 — is a rigid material , approximately ⅛ inch in thickness that may be opaque or transparent . this material is attached to the shelf sides and back , every four to six inches , with screws , and holds the material in place . elongated screw hole channels allow for panel sliding movement , to accommodate shelf varying widths and lengths . 3 . element 113 — self tapping , # 8 , ½ inch lath screws , attach containment panels 135 to sides and back of sliding shelf . 4 . element 133 — filler strip is an approximate ¾ inch wide strip of containment panel 135 material , used at places where overlapping panels do not occur . the filler strip 133 has an etched grove every ½ inch of its length , to accommodate selecting the approximate length by utilizing snap breaking joints . filler strip 133 material is used in 2 . 0 inch lengths to provide double wall thickness at screw locations , where only a single inside ( closest to the center of the shelf ) containment panel 135 exists . fig2 d is a front cross - section view of containment system 201 , as viewed along line 2 d of fig2 a . 1 . existing sliding shelf , elements 103 front , 105 bottom , 107 side , and 109 back . 2 . element 135 — is rigid material , approximately ⅛ inch in thickness that may be opaque or transparent . this material is attached to the shelf sides and back , every four to six inches , with screws , and holds the material in place . elongated screw hole channels allow for panel sliding movement , to accommodate shelf varying widths and lengths . 3 . element 113 — self tapping , # 8 , ½ inch lath screws , attach containment panels 135 to sides and back of sliding shelf . 4 . element 131 — edge cap is a rigid plasticized material forming a u channel that has an approximate inside dimension of ¼ inch in width by ½ inch legs . this cap clips together the containment panels 135 and filler strips 133 to reinforce the containment panel 135 edges , while at the same time , eliminating sharp edges . material can accommodate cutting to various lengths with a razor knife or similar . 5 . element 133 — filler strip is an approximate ¾ inch wide strip of containment panel 135 material , used under the edge cap 131 , at places where overlapping panels do not occur . this strip provides a second thickness to accommodate the snap - on edge cap 131 . the filler strip 133 has an etched grove every ½ inch of its length , to accommodate selecting the approximate length by utilizing snap breaking joints . the filler strip 133 is held in place with a mastic type material of rubberized or plastic material . filler strip 133 material is also used in 2 . 0 inch lengths to provide double wall thickness at screw locations , where only a single inside ( closest to the center of the shelf ) containment panel 135 exists . sliding shelves are typically manufactured in random sizes to fit in existing cabinetry space shelf width and length measurements . typically , the side and back heights of these sliding shelves is 2¼ inches — plus or minus . custom manufacturers can offer increased wall heights during the initial manufacturing process . this product is produced to retro - fit existing sliding shelves that have not been manufactured with extended walls . typical wall heights contribute to materials tipping and falling off the shelves . this invention is to solve these tipping and falling item problems . back to dimensions — the third dimension is to measure the height of the cabinetry space to determine the height and type of products that can be placed on these shelves . if the major problem is to solve the tipping and falling condition , then the first embodiment corresponding to provisional application 61 / 908 , 188 — the telescoping rail system solves the problem . if the shelf is to contain horizontally stacked items , and the sliding of these items causes problems — then the second embodiment corresponding to provisional application 61 / 965 , 331 — the containment panel system works better . this application also solves the item tipping and falling problem . both product applications have a standard height of 8 inches from shelf bottom to top of containment . higher containment levels can be produced for both products , to bring the rail system up to 11 inches and the panel system up to 12 inches . materials for the first embodiment corresponding to provisional application 61 / 908 , 188 — telescoping rail system 101 . a . telescoping rail 115 — stainless steel , steel , other metals , fiberglass , rigid plastic and other high tensile materials . b . rail standard 111 — stainless steel , coated steel , other metals , rigid plastic and other high tensile materials . c . rail end cap 117 — stretchable vinyl material with ½ inch inside length and diameter to fit over the ends of the rail . d . screws 113 — zinc coated , 8 - gauge , ½ inch length phil mod truss , lath screws . materials for the second embodiment corresponding to provisional application 61 / 965 , 331 — containment panel system 201 . a . containment panel 135 — 0 . 125 inch thick polycarbonate , 0 . 125 inch thick acrylic sheet , materials in clear or colored , 8 inch high × 12 inch long and 8 inch high × 10 inch long typical panels , 12 inch high panels available . all panels are predrilled , and elongated screw hole channels allow for panel sliding movement , to accommodate shelf varying widths and lengths . b . edge cap 131 — c - line slide &# 39 ; n grip plastic binding bars , 11 × ¼ inches , cut and shaped for vertical and horizontal ells sections . c . filler strip 133 — same material as the containment panel , ¾ × 12 inch pieces with scoring every ½ inch to allow for break - off lengths . filler strips at screw location , for maintaining double thickness , are ¾ × 2 inch dimensions with predrilled screw holes . d . screws 113 — zinc coated , 8 - gauge , ½ inch length phil mod truss , lath screws . assembly for the first embodiment corresponding to provisional application 61 / 908 , 188 — telescoping rail system 101 . a . measure the inside of the existing sliding shelf . shelf rail standards 111 , to be installed four to six inches center to center . shorter length and width shelves will have sides and or back lengths that may have three rail standards 111 as close as four inches center to center . using a pencil , mark rail standard 111 locations , beginning 2¼ inches from each inside corner , to the center of the first rail standard . divide the remaining distance by 6 , and increase to the next whole number . divide the remaining length by this whole number , to get the spacing for the rail segment . example for a 30 inch back width shelf — 30 minus 4½ ( 2¼ inches from each corner ), equals 25½ inches , divided by 6 is 4¼ . increase to next whole number is 5 . twenty - five and one half inches divided by 5 is a 5 . 1 inch spacing for this back section . measure the shelf sides and repeat the same process to obtain spacings . mark all spacings for rail standards 111 on the shelf bottom , immediately adjacent to the shelf sides and back sections . b . install rail standards 111 at all spacing marks . hold a rail standard 111 in place , lining up the space marking with the center of the rail standard 111 , and mark the bottom drill hole . drill at the bottom hole and install the rail standard ( with the rail cradle protrusion to the outside of the shelf ) with a screw . snug up the screw to hold the rail standard 111 in place . plumb the rail standard 111 to vertical using any 90 degree angle item ( like a deck of cards , credit card , note pad , small square , etc .). mark , drill , and install screw in upper rail standard hole . check for vertical 90 degrees , and tighten both screws . complete this process for the remaining rail standard 111 installations . c . lay out rails next to all three shelf walls . for side sections , partially insert a smaller diameter rail into a large one . install rail end caps on each end ( smaller end cap onto smaller rail , and larger cap onto larger rail end ). lay the side sections into the rail cradles 119 , of the shelf standards 111 , with the larger diameter rail toward the front of the shelf . assemble the shelf back wall rails ( three rail sections will have a small diameter rail on each end ). two rail sections will be the same as the side wall sections . install rail end caps 117 as necessary , and lay the back rails into the back rail standard 111 rail cradles 119 ( two section rails can have the small diameter at either end of the back section ). d . extend the telescoping rails to be flush with the back side of the pull out shelf front . extend corner telescoping rails to meet at the corners . pencil - mark each rail at the center of the rail cradle 119 . e . remove one side rail assembly . two thicknesses of cradle tape are supplied . use the thin tape and wrap one revolution over each pencil marking on the large diameter rails . do the same for the small diameter rails — using the thick tape . reinstall the side rail assembly , by pressing it down to the bottom of each receiving cradle . repeat the same process for the other side and back of the shelf . assembly for the second embodiment corresponding to provisional application 61 / 965 , 331 containment panel system . a . measure the inside of the existing sliding shelf . twelve inch deep shelves require only one side 8 inch × 12 inch containment panel 135 . twelve and a half to 22½ inch depth requires two containment panels 135 . twelve inch wide shelves require only one 8 inch × 12 inch containment panel . twelve and a half to 20 . 0 inch require 2 containment panels 135 ( 1 - 8 × 12 and 1 - 8 × 10 inch ). twenty to 22 inch widths require 2 containment panels 135 ( 2 - 8 × 12 inch ). twenty - two to 30 inch widths require 3 containment panels 135 ( 2 - 8 × 12 and 1 - 8 × 10 inch ). b . measure the inside depth of sliding drawer . if the side dimension is 14½ inches or more , install 8 × 12 side panel at the right rear corner , using the 8 inch side as the panel height . drill and install the upper screw hole 2¼ inches from the corner . hold up the second panel ( panel closest to the middle of the slide out shelf ), against and touching the back of the pull out shelf front 103 . pencil mark proposed screw holes , in the double thickness portion , 2 inches from the overlap , and evenly along the side panel every 4 to 6 inches . attach glue side of 2 inch long filler strips 133 to the outside ( closest to the pull out shelf side 107 ) of the panel at screw locations where the inside panel is single thickness . drill and install one screw at a location close to the midpoint of where the panels overlap . this will hold both panels in place while you drill and install the remaining screws at marked points , using the predrilled panel holes as a guide . repeat the same installation on the opposite pull out shelf side 107 . c . for side depths of less than 14½ inches and more than 12½ inches — temporarily install corner side panel using the top screw hole 2 inches from the corner . hold up the second 8 × 12 inch panel and pencil mark screw holes and attach filler strips 133 , as described in 4 . b . ( above ). remove screw holding the first panel . hold up both panels and drill and install a screw at a marked hole near the midpoint of the double thickness area . this will hold both panels in place until all screws are installed . repeat the same installation on the opposite pull out shelf side 107 . d . for back panel installation where the back dimension is less than 14½ inches and more than 12½ inches — start the right rear corner , hold the first panel against the pull out shelf back 109 , with the end touching the installed side panel and repeat the steps contained in 4 . c . above . e . for back panel installation where the dimension is less than 22 inches and more than 14½ inches — start the first 8 × 12 panel against the pull out shelf back 109 right rear corner . drill and install the upper screw hole 2¼ inches from the corner . hold up the second 8 × 12 panel ( panel closest to the middle of the slide out shelf ), against and touching the left rear corner . pencil mark proposed screw holes at the mid point of the double thickness portion , and evenly along the back panel every 4 to 6 inches . attach glue side of 2 inch long filler strips to the outside ( closest to the pull out shelf back 109 ) of the inside panel at screw locations where the inside panel is single thickness . drill and install one screw at a location close to the midpoint of the panel . this will hold both panels in place while you drill and install the remaining screws at marked points , using the predrilled panel holes as a guide . f . for back panel installation where the dimension is less than 30 inches or more than 24 inches — install an 8 × 12 panel against the pull out shelf back 109 in each corner . drill and install the upper screw hole 2¼ inches from each corner . center the third 8 × 10 panel in the gap between the first two panels . pencil mark all screw hole locations and install filler strips as necessary in the gap between the first two panels . attach glue side of 2 inch long filler strips to the outside ( closest to the pull out shelf back 109 ) of the panel . drill and install one screw at a marked location close to the midpoint of the panel . this will hold all panels in place while you drill and install the remaining screws at marked points , using the predrilled panel holes as a guide . g . before you install the top and front edge cap 131 , additional filler strips must be installed to provide a gripping surface for the edge cap 131 . all areas along the edge cap 131 , must receive filler strips to make the edge a double thickness . starting on the side panel at the right rear corner of the sliding shelf — this single section will receive a filler strip 133 , on the side closest to the sliding shelf center . hold the break - off strip against the single panel and mark the length with a pencil . if this mark falls in between break - off points , go to the next shortest break - off point on the strip and ( using two pliers ) break the strip at that location . that will allow the strip to fit into the gap . install the glue side to the inside of the corner side panel . moving toward the front of the sliding shelf , repeat the measurement , break off , and glue attachment for the strip on the outside of the second panel . then repeat the measurement , brake - off , and glue attachment for the vertical front strip . move to the other side and repeat the same procedure . now move to the back right corner of the shelf , and repeat the measurement , break - off , and glue and attach the strip on the inside of the first panel attached to the back of the shelf . then repeat the measurement , brake - off , and glue attachment for the intire horizontal strip . as you move toward the shelf left back corner , alternate sides ( when there are two or three back panels ) when applying filler strips 133 . h . when all filler strips are installed , there should be a continuous double thickness of containment panels 135 and filler strips 133 , all along the top of the containment panels 135 , and from the top of the front two containment panels 135 , down to the top of the pull out shelf front . i . begin installing edge caps 131 . use the ell edge cap 131 consisting of the vertical and horizontal angle — to be applied to the front two corners of the containment panels . measure the distance from the top of the front two containment panels 135 , down to the top of the pull out shelf front . using a razor knife , carefully cut the ell edge cap 131 , to the measurement . install edge cap 131 , starting at the top of the pull out shelf front . spread the bottom corner legs of the edge cap , and insert it over the containment panel 135 , and filler strip 133 , at the bottom of the vertical section . gently apply pressure on the back of the edge cap 131 , as you move up the edge cap . when the edge cap is fully seated on the vertical portion of the panel , gently apply pressure on the back of the edge cap 131 , as you move horizontally toward the rear corner of the shelf . when this edge cap is fully seated , install the horizontal ell edge cap 131 on the back corners , using the same procedure . there will be gaps between the ell edge caps 131 on the tops of the panels on the sides and back of the shelf . measure the gap distance , and ( using a razor knife ) carefully cut and install a section of straight edge cap 131 , to the measurement . two straight sections of edge cap 131 may be required on the back panels of wide shelves . apply pressure to all edge cap 131 sections to complete the installation . | US-201414537900-A |
a shelf or hanger mounting bracket which comprises an inner bracket body having one end provided with projections configured for locking engagement with vertically extending slits in a wall - mounted upright mounting rail and an ornamental outer sleeve comprising a locking system enabling the sleeve to be continuously adjustable over a range of positions so that it can be adjusted to lie flush with the mounting wall . the locking system employs a latching member pivotally mounted on the forward end of the inner bracket body having a locking end slantingly engaging the confronting interior wall surface of the sleeve so that forward retracting movement of the sleeve cannot occur as long as the locking end is held in contact with this sleeve surface . slipping rearward movement towards the wall readily occurs . in the preferred form of the invention the latching member has a release end extending forwardly of the pivot and having sufficient weight that the locking end is continually forced into engagement with the sleeve inner surface . an aperture in the bottom of the sleeve permits insertion of a pencil or similar object to bear against the release end so as to raise it , thereby rotating the locking end out of engagement , permitting limited withdrawal of the sleeve so that the bracket assembly can be removed from the mounting rail . | this invention relates to display hardware , in particular to brackets which can support shelving or garment supporting hangers from slotted uprights or rails . mounting systems for wall - mounted display hardware typically include horizontally spaced vertical uprights or rails generally mounted within vertical recesses in a mounting wall . horizontally extending brackets having a pair of vertically spaced hooked extensions at the rear thereof are mounted within selected pairs of short vertically spaced outwardly facing slots formed in the outer faces of these uprights . the brackets are inserted into the upright slots by angling the hooked extension - carrying ends of the brackets in a downward direction at the time of insertion into the upright slots . the brackets are then pivoted downward and dropped onto the uprights to cause the hooked extensions to interlock with the upright slots . if the brackets are designed to support shelving , they are provided at the front ends thereof with upwardly extending shelf engaging fingers to receive the forward ends of the shelving . these brackets are commonly plate - like brackets which are unattractive . to provide a more attractive bracket design , there has heretofore been developed a bracket design made in two pieces . one piece is an inner bracket body having an appearance very similar to that of the rear half of a conventional , thin , plate - like . bracket , and thus includes a pair of vertically spaced hooked extensions at the rear end thereof . the inner bracket body is covered by an outer ornamental sleeve , also sometimes referred to as an outer tubular member , having a rear portion telescoping over the inner bracket body and a front portion projecting forwardly thereof . at the front end of this outer sleeve are shelf - receiving fingers if the bracket is to support shelving . the rear edge or face of this outer ornamental sleeve is desirably configured to be flush with the outer surface of the mounting wall to eliminate any unsightly gaps between the outer ornamental sleeve and the mounting wall . however , when the outer sleeve has this flush relationship to the mounting wall , the bracket cannot be pivoted for insertion or removal of the bracket from the slotted uprights . it was therefore necessary to design the outer sleeve so that it is initially movable along the inner bracket body so it can be withdrawn from the rear end of the bracket body when the bracket body is inserted into or removed from the upright slots . after removal or re - insertion of the bracket inner body into the outer sleeve is pushed rearwardly where to bring it flush around the mounting wall surface . some form of securing means , such as set screws or locking bolts , are then used to secure the sleeve against outward withdrawal of the sleeve . while various locking systems have been provided to permit two telescoping members to be adjustable , one with respect to the other , and then locked in place in their adjustable positions , these locking systems have not been heretofore utilized in a bracket construction such as that described for a variety of reasons . in the first place , most of these locking systems do not permit a continuous progressive adjustment between the telescoping members , necessary to permit the outer sleeve in the bracket construction described to be mounted exactly flush with the mounting wall surface . a common locking system is one having an outwardly urged pin on the inner member which can be snapped into position in any one of a number of vertically spaced horizontal slots in the outer telescoping member . in the second place , these locking systems which did provide for a progressive continuous adjustment were generally too complicated and expensive for incorporation into the bracket constructions described , or required use of set screws or locking bolts to fix the position of the outer member . set screws or locking bolts are not desirable because they take a special tool , namely a screw driver or allen wrench , to lock the sleeve in place , and the need to tighten or release a screw or nut is an inconvenient means for releasing and locking the outer sleeve to the inner bracket body . there has thus been a need for a simple , inexpensive and reliable means for locking and unlocking the outer sleeve from the inner bracket body in the bracket construction described , which did not require the use of a special tool to lock and unlock the outer sleeve from the inner bracket body , and which permitted a continuous progressive adjustment of the position of the outer sleeve over the inner bracket body . according to a feature of the invention , a shelf or hanger mounting bracket preferably comprises an inner bracket body and an ornamental outer sleeve , sometimes referred to as an outer tubular member , with a unique means for enabling the sleeve to be continuously progressively adjustable over at least a limited range of positions , so that it can be telescopingly slid over the inner bracket body to an innermost position where the rear face of the outer sleeve lies flush with the mounting wall . to this end , the present invention provides a unique one - way releasable sliding latching member carried on the inner bracket body . the latching member can be an elongated member or bar which is pivotable on the inner bracket body . the latching member has a locking end edge portion inclined toward the inner surface of the sleeve and an opposite release end . the latching member is also preferably configured to be asymmetrically disposed about the pivot point of the member so that the weight of its release end portion will cause the locking edge portion of the latching member to be gravity - urged into contact with the interior surface of the sleeve . to this end , the release end of the latching member , which is on one side of the pivot point of the latching member , is much heavier than the locking end portion so that gravity will cause the release end of the locking member to be urged towards the upwardly facing surface of the bottom of the outer sleeve . an optional weight may be affixed to the release end to augment this action . the locking end portion contains an edge angled in a direction to make locking engagement with the closely facing inner surface of the sleeve , so that this locking edge prevents the outer sleeve from being moved forwardly away from its innermost position where it is flush against the outer surface of the mounting wall . the sleeve has a hole in the bottom thereof which is located opposite the position of the heavier release end of the latching member . the hole is sized to receive a pencil or other similarly thin article which can be pushed upwardly to raise the release end of the latching member . this drops the locking end of the release member from engagement with the outer sleeve , permitting the outer sleeve to be moved forwardly away from the mounting wall surface so that the inner bracket body can be removed from , or replaced back into engagement with , the wall - mounted upright , involved . the locking end of the latching member will engage the outer sleeve at an angle such that it will not arrest the sleeve from movement to a rearward direction after it is brought into flush engagement with the mounting wall surface . it is therefore not necessary to utilize a pencil to maintain the release end of the latching member in a raised position when it is desired to move the outer sleeve into its rearwardmost flush position with the mounting wall surface involved . according to a related feature of the invention , the inner bracket body is configured as a single plate - shaped member having a v - shaped cutout at the forward end thereof . the remainder of the forward end of the inner bracket body thus forms an upwardly extending finger . the latching member is configured as a generally strap - shaped element having a slot therealong intermediate the locking and release ends thereof configured to engagingly receive the aforementioned finger . the latching member is thus pivotally mounted about the apex of the v - shaped slot . according to a further related feature of the invention , the inner bracket body is provided with outwardly extending protrusions on either major face thereof , the lengths of the protrusions being chosen so that they closely confront the major inner faces of the outer , tubular member to serve as alignment guides . similarly placed protrusions may optionally be provided on the outer tubular member of the inner end thereof and disposed to arrestingly engage the protrusions on the inner body member to prevent accidental total withdrawal of the inner body member from the outer tubular member during handling . similarly , the width of the generally strap - shaped latching member is preferably slightly less than the distance between the confronting major interior wall surfaces to provide a similar aligning effect of the latching member with respect to the inner body to insure that the latching member is freely pivotable thereon . thus , an inexpensive 3 - piece assembly is provided which will allow the outer tubular member of a shelf bracket assembly to be easily and reliably retained in a flush position against the mounting surface , and which may easily be released for retraction to allow remounting without the use of special tools or fasteners . there is known in the art a form of floor mountable upright display stand for hanging garments or the like , this stand having an upright outer tubular member affixed to a base and having an inner telescoping member which can be raised to various heights . a locking mechanism permitting a continuously adjustable range of heights is provided in the form of a latching member held loosely captive at the lower end of the inner member , which is urged by its own weight against lower support shoulders so as to be completely disengaged from the inner wall surfaces of the outer tubular member . if , however , the inner member is accelerated downward , then under the influence of inertial forces the latching member will rise into engagement with an upper supporting shoulder configured to rotatingly urge the ends of the latching member into arresting engagement with the aforementioned interior wall surfaces . the inner member is thus locked at a chosen height . release is secured simply by moving the inner member upwards , at which time the latching member drops back to its lower position , disengaging from the inner wall surfaces . it will be appreciated that such a system uses inertial effects arising from acceleration to secure the locking condition , whereas the locking system of the present invention requires no such acceleration , the latching member being engaged with the outer sleeve at all times during rearward motion of the outer tubular member . other features and advantages of the invention will become apparent upon making reference to the specification , claims and drawings to follow . fig1 is a perspective view of a shelf support bracket assembly for supporting a shelf . fig2 is a perspective exploded view of one of the shelf support elements shown in fig1 . fig3 - 5 are partly cut - away side views of one of the elements shown in fig1 during insertion , when locked , and during removal thereof respectively . fig6 is a cross sectional view of an assembled support assembly . fig7 is a partially cut - away detail view of the assembly showing a locking mechanism for securing the support assembly together . fig8 is a partially cut - away view of one end of the bracket assembly . fig9 is a perspective view of a hanger support bracket assembly . fig1 shows an inexpensive shelf support assembly bracket 120 for supporting a shelf 122 . a pair of such assemblies 120 are shown in fig1 . the support bracket assemblies 120 shown in fig1 are configured for downwardly sloping orientation ; however , they may equally well be configured as horizontally disposed shelf support assemblies . referring particularly to fig2 each support assembly 120 includes a generally planar strap - shaped bracket inner body 124 having upper and lower shoulders 126 with an inner or locking end 130 thereon , and further having transversely extending notch 132 adjacent the lower shoulder 128 . the shoulders 126 , 128 and the notch 132 are configured for inserting locking engagement into a mounting rail 134 having slots 136 therein , the mounting rail , 134 being adapted to mounting to a wall 137 and having preferably an ornamental molding 138 disposed on either side thereof . an ornamental tubular outer member 140 configured as a sleeve having a generally rectangular central passage 142 extending axially therealong is configured in the embodiment shown with an inner sleeve end 144 configured for flush engagement with the wall 137 , or alternatively the molding 138 when the sleeve is slid fully over the inner body 124 . centering is preferably accomplished by means of centering tabs 146 extending outwardly from the major faces of the inner body 134 . end caps 145 ( fig1 ) are provided at the outer ends 147 of the sleeve 140 to prevent the shelf 122 from sliding off the support assemblies 120 . the sleeve 140 is automatically secured against withdrawal by a specially configured latching member 148 configured preferably from bent planar stock and having an extended portion forming a release end 150 ( preferably augmented by an attached strap - shaped weight 151 ) and a sharply angled portion at the other end thereof forming a locking end 152 having a blade edge 154 at the end thereof . intermediate the locking end 152 and the release end 150 there is a slot 156 provided running lengthwise along the arcuate region joining the locking end 152 and the release end 150 . a v - shaped slot 158 is provided proximate to the outer end 160 of the inner body 124 by a forwardly angled slot face 159 , joining and confronting perpendicular slot face 161 at a slot lengthwise extending wall face 163 . the space between the outer end 160 and the slot 158 is thus configured as a finger 167 extending into the slot 156 . as shown in fig3 - 5 the latching member 148 is thus pivotally secured to the outer end 160 of the inner body 124 when emplaced thereon by the engagement of the slot end face 165 of the latching member 148 with the joining wall portion 163 . in particular it will be noted in fig3 - 5 that the length of the locking end 152 is chosen so that when engaged with the upper interior wall surface 162 of the sleeve 140 it is disposed at an angle thereto . thus , as shown in fig3 the sleeve may readily slide past the blade edge 154 as it is moved toward the locking end 130 of the inner body 124 during assembly . final engagement flush with the molding 138 is shown in fig4 . to assist in alighment , the width of the latching member 148 is preferably slightly less than the interior wall separations of the sleeve 140 . if one next attempts to withdraw the sleeve 140 , it will be seen that the blade edge 154 will be pivotally driven into hard engagement with the interior wall surface 164 , preventing such withdrawal . in the preferred form of the invention this effect is augmented by reducing the effective length of the blade edge 154 by providing an arcuate cut - out 164 therein to shorten the effective bearing surface of the blade edge . a tool passage 166 is provided in a lower portion of the sleeve 140 to allow insertion of a tool such as a pencil 168 to urge the release end 150 upward to withdraw the blade edge 154 from contact , thus allowing the sleeve to be withdrawn ( fig5 ). only a slight retraction of the sleeve 140 is necessary to provide sufficient clearance between the sleeve end 144 and the molding 138 to allow the assembly 140 to be rotated to disengage the inner body 124 from the mounting rail 134 . spring biasing means may equally well be employed to urge the blade edge 154 into similar engagement with the sleeve wall 162 ; however , this adds to the number of parts in the assembly . optional inwardly extending tabs 145 may be provided extending from the major inner faces of the sleeve 140 to confrontingly arrestingly engage the centering tabs 146 to prevent accidental total withdrawal of inner body 124 from the sleeve 140 during handling of the assembly . fig9 shows a modified assembly 175 adapted for hanging garments on display , the modified sleeve 177 having a number of hooks 179 downwardly depending therefrom . the end cap 181 does not have the projecting edge of the previous embodiment , since shelf retention is not necessary . all other part numbers have been kept the same in the previous embodiment because their functions are identical . thus , a simple inexpensive assembly has been provided which will allow the sleeve to be locked in close flush engagement with the mounting surface without employing such customary alternatives as sliding ratchets , extra securing screws or similar fastening methods well known in the art . while the invention has been described with reference to a preferred embodiment , it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the broader aspects of the invention . also , it is intended that broad claims not specifying details of a particular embodiment disclosed herein as the best mode contemplated for carrying out the invention should not be limited to such details . furthermore , while , generally , specific claimed details of the invention constitute important specific aspects of the invention in appropriate instances even the specific claims involved should be construed in light of the doctrine of equivalents . | US-83610692-A |
an auto - cleaning marination filter for a poultry injector system including an outer housing having a liquid inlet and outlet , a screen that allows passage of liquids and impedes passage of solid particles , and a wiper surrounded by said screen for removing solid particles attached to the screen by reverse flow of the liquid through a gap in the wiper . | with reference to fig1 - 4 , the preferred embodiments of the present invention may be described . the auto - cleaning filter 19 of the present invention includes an outer filter housing 1 and a filter screen 10 . the outer filter housing 1 and filter screen 10 are preferably cylindrical . the cylindrical filter screen 10 allows the liquid brine to pass through its perforations , but collects any solids against its surface . fig2 shows a sectional view illustrating the internal components of the auto - cleaning filter 19 . on the inside surface of the cylindrical screen 10 is a wiper 8 that is attached to a tube 2 . the wiper 8 is continuously moved or stroked with the tube 2 to the top of the screen 10 and then with the tube 2 to the bottom of the screen 10 by pneumatic cylinders 4 attached to tube 2 below valve 3 . this cycle is repeated continuously so the wiper 8 is constantly moving inside the cylindrical surface of the screen 10 . the filter 19 has a brine inlet 5 on the bottom of the housing 1 and a brine outlet 7 on the side of the housing 1 . brine is pumped through the inlet 5 and into the space 12 created between the tube 2 and the screen 10 . the brine mixture then moves through the screen 10 into the space 13 created between the outside surface of the screen 10 and the outer filter housing 1 . as the brine flows through the screen 10 , the solid particles within the brine mixture are trapped on the inner surface of the screen 10 while the liquid flows through the screen 10 . the liquid brine then moves out of the filter 19 through the filter outlet 7 attached to the outer filter housing 1 . the wiper 8 has a top half and a bottom half that are separated slightly to create a gap 9 between them . this gap provides a passage to the inside of the tube 2 on which the wiper 8 is connected . the tube 2 extends out of the filter housing 1 . as shown in fig2 , a sealed cap 11 is attached to the top of the outer filter housing 1 and receives the tube 2 as it exits the outer filter housing 1 . the cap 11 prevents leakage of brine . at the top of the tube 2 , there is a valve 3 that opens and closes . opening the valve causes the brine to flow through the screen in the opposite direction ( i . e . from outside the screen to inside the screen ) as described above . the opposite flow of the brine is only permitted in the area surrounding the gap 9 formed in the wiper . the brine in the space 13 between the outside surface of the screen 10 and the outer filter housing 1 flows through the screen 10 and the gap 9 in the wiper . the brine then moves into the tube 2 and out of an outlet port 6 on the valve 3 on the filter 19 . as this occurs , the reverse flowing brine will clean the solid particles off the inside of the screen 10 and flush them out through the valve outlet port 6 . the valve outlet port 6 is connected to a hose that will transport the brine and the solid mixture back to an open screen 15 where the solids will be carried out by an auger and the brine will be re - used . in operation , the brine inside the filter 19 will always be at a certain system pressure , which will be determined by the requirements of the operation . when the valve 3 on the filter 19 opens , the pressure through the tube 2 and in the gap 9 between the wiper 8 will drop substantially compared to the system pressure . this causes the brine to back flow in this gap 9 area only , thus cleaning a small spot on the filter each time the valve 3 opens . as this is repeated when the wiper is in different locations , the filter screen 10 will stay much cleaner than a standard system without any internal cleaning system . fig4 shows a representative drawing of a complete filter system used to filter the brine on a product injector system . in this system , brine will be pulled from a brine tank 14 into a pump 34 through a pump inlet 31 , and discharged from a pump outlet 32 and into the inlet 5 of the auto - cleaning filter 19 . from there , the brine exits the auto - cleaning filter 19 through the outlet port 7 . the brine may then flow into a backup in - line filter 18 . this is an optional filter to catch any solid particles that may have made it through the auto - cleaning filter . if utilized , the brine will travel into the backup filter 18 through an inlet port 27 on the backup filter 18 and then through an internal screen and out of the outlet port 26 on the backup filter 18 . the backup filter 18 is cleaned manually when clogged , but by using the auto - cleaning filter upstream of it , the cleaning should be minimal . after the brine exits the backup filter 18 , it flows through a valve ( not shown ) and into the injector head of the injector 16 through an inlet port 24 . the brine flows through the head , enters the injection needles 25 extending downwardly from the head , and is then discharged through the bottom of the needles 25 into the product 33 , such as poultry carcasses , that are on top of a perforated belt 17 . any excess brine that is not retained in the product 33 will flow through the perforated belt 17 and down into the lower body 20 of the injector 16 . the brine then drains out of the lower body 20 through a drain port 21 and into an open screen solid separating rotary filter 15 through the inlet side 22 of the filter 15 . the open screen solid separating rotary filter 15 has a screen with an internal auger system that rotates to push solids out the discharge end 23 and let the brine fall through the screen and back into the brine tank 14 . this cycle then continues as previously described . the brine mixture that is created as the wiper cleans the screen in the auto - cleaning filter is discharged through the exit port 6 of the auto - cleaning filter . this is reintroduced into the brine system by plumbing this line in with the drain port 21 from the lower injector body 20 . the brine mixture is discharged by the open screen rotary filter 15 where the brine will flow through the filter and back into the brine tank 14 to be reused . the present invention has been described with reference to certain preferred and alternative embodiments that are intended to be exemplary only and not limiting to the full scope of the present invention . | US-201414211725-A |
the present invention relates to novel stable aqueous suspension concentrate or aqueous flowable compositions of the low - melting dinitroaniline pesticide , pendimethalin , alone or in combination with secondary pesticide melting at temperatures greater than 70 ° c . or pesticides which are water soluble . additionally are provided methods for preparing the compositions of the invention . | preferred compositions of the invention comprise on a weight to volume basis , about 5 . 0 % to 50 . 0 % pendimethalin ; about 0 % to 50 . 0 % of one or more secondary pesticide ( s ) having a melting point greater than 70 ° c . or being water soluble ; about 3 . 0 % to 30 . 0 % of coformulants , such as surfactants , dispersing agents , wetting agents , antifreezing agents , antifoaming agents , thickening agents , gums , preservatives and 20 . 0 % to 92 . 0 % water . pesticides suitable for use in the composition of the present invention include ureas , triazines , imidazolinones , alone or in combination , amongst just a few . fungicides , insecticides and plant growth regulators which have melting points greater than 70 ° c . and / or possess physical properties which are amenable to the preparation of aqueous suspension concentrate compositions also may be used in the compositions of the present invention . additionally , water - soluble pesticides , such as difenzoquat , amine salts , alkali or alkali metal salts of ioxynil , bromoxynil , phenoxy acetic acids , and imidazolinyl carboxylic acids such as 2 -( 4 - isopropyl - 4 - methyl - 5 - oxo - 2 - imidazolin - 2 - yl )- 3 - quinolinecarboxylic acid and the like may readily be incorporated into the stable aqueous suspension concentrate compositions of this invention . preferred higher melting ( greater than 70 ° c .) components for use in the aqueous suspension compositions of the invention containing pendimethalin include : isoproturon , [ n , n - dimethyl - n &# 39 ;-( 4 -( 1 - methylethyl ) phenyl ) urea ]; linuron , [ n -( 3 , 4 - dichlorophenyl )- n &# 39 ;- methoxy - n &# 39 ; methyl urea ]; metoxuron , [ n &# 39 ;-( 3 - chloro - 4 - methoxyphenyl ) n , n - dimethylurea ]; chlortoluron , [ n &# 39 ;-( 3 - chloro - 4 - methyl - phenyl )- n , n - dimethylurea ]; atrazine , [ 2 - chloro - 4 - ethyl - amino - 6 - isopropylamino - 1 , 3 - 5 - triazine ]; imidazolinone herbicides such as 2 -( 4 - isopropyl - 4 - methyl - 5 - oxo - 2 - imidazolin - 2 - yl )- 3 - quinolinecarboxylic acid and water soluble salts thereof , and the isomeric mixture of methyl 6 -( 4 - isopropyl - 4 - methyl - 5 - oxo - 2 - imidazolin - 2 - yl )- m - toluate and methyl 2 -( 4 - isopropyl - 4 - methyl - 5 - oxo - 2 - imidazolin - 2 - yl ) toluate . other secondary active components include terbutylazine , 2 - tert - butylamino - 4 - chloro - 6 - ethylamino - 1 , 3 , 5 - triazine and metolachlor , 2 - chloro - 6 &# 39 ;- ethyl - n -( 2 - methoxy - 1 - methylethyl ) acet - o - toluidide . surfactants ( including dispersing agents and / or wetting agents ) suitable in the aqueous suspension compositions of the invention containing solid pendimethalin include : ethylene oxide / propylene oxide condensates ; alkyl , aryl - and aryl , arylethoxylates and derivatives thereof ; lignosulfonates ; cresol - and naphthaleneformaldehyde condensates and sulfonates ; polycarboxylates and derivatives thereof ; and mixtures thereof . in general , anionic polymerics , such as cresol formaldehyde condensates and their sulfonates , naphthalene formaldehyde condensates and their sulfonates and lignosulfonates have been found to minimize crystal formation during storage and as such , are most preferred . suspending agents such as polysaccharide gums like xanthan gum , guar gum ; gum arabic and cellulose derivatives , and the like are suitable for addition to the hot emulsion in amounts of about 0 . 02 % to 3 . 0 %, on a weight to volume basis . these aid in stabilizing the emulsion of a desired droplet size by increasing the viscosity of the emulsion from an initial viscosity of about 100 cps to about 1 , 000 cps or greater prior to cooling . preservatives to prevent microbial spoiling of the compositions of the invention are included as necessary . one example is a 38 % solution of formaldehyde . other preservatives include methyl and propyl parahydroxybenzoate , 2 - bromo - 2 - nitro - propane - 1 , 3 - diol , sodium benzoate , glutaraldehyde , o - phenylphenol , benzisothiazolinones , 5 - chloro - 2 - methyl - 4 - isothiazolin - 3 - one , pentachlorophenol , 2 - 4 - dichlorobenzylalcohol , mixtures thereof and others known to those in the art . siliconic antifoaming agents are useful in the present compositions . antifreezing agents such as ethylene glycol , propylene glycol , other glycols , glycerine or urea may then be added to the resulting aqueous suspension concentrate compositions . additional surfactants , preservatives and thickening agents , such as clays , precipitated silicas , polyvinyl alcohol , polyvinylpyrrolidone , polyacrylamides and the like , may then be added , as can higher melting active components or a suspension concentrates containing other active components . stable aqueous suspension concentrate compositions of pendimethalin may be prepared by : emulsifying molten pendimethalin in hot water ( 50 ° c . to 80 ° c .) containing a surfactant and antifoaming agent to achieve the desired droplet size . then a suspending agent is added . the resulting hot emulsion is cooled and agitated , allowing the molten material to solidify . the resulting composition may then be milled , if desired , or additional higher melting active components and coformulants , such as antifreezing agents , surfactants , thickeners , preservatives and the like or a preformed suspension concentrate containing one or more active component and coformulants is added . the aqueous suspension concentrate compositions containing pendimethalin in combination with higher melting or water soluble components may then be subjected to additional milling , if desired . the above method of preparation lends itself to a variety of optional processing steps , such as ( 1 ) molten emulsion followed by cooling with no further processing ; ( 2 ) molten emulsion followed by cooling and optionally adding other active components and coformulants and then milling ; ( 3 ) molten emulsion in the presence of higher melting active components with concurrent milling followed by cooling ; ( 4 ) molten emulsion concurrently milled and cooled , then mixing to allow crystallization and standing (&# 34 ; aging &# 34 ;) with or without secondary active components and a second milling . alternatively , the molten pendimethalin may be dispersed at ambient temperature in a water solution of coformulants , containing if desired , other higher melting active components , followed by milling . surprisingly , stable aqueous suspension concentrate compositions of pendimethalin , alone or in combination with other active pesticidal components may be prepared by the above methods containing , on a weight to volume basis : these compositions do not form large , elongated crystals after being processed . therefore , processing and manufacturing is not halted because of the crystal growths . further , the compositions are stable without sedimentation of active component in these large ( 3000 micron ) crystals and most importantly , the application of these compositions results in an even dispersibility of active component . the following examples further illustrate the present invention but are not limitative thereof . preparation of stable aqueous suspension concentrate compositions of pendimethalin , alone or in combination with other higher melting herbicides an aqueous solution containing surfactants and antifoaming agents at temperatures 50 ° c . to 80 ° c . is prepared . then , the molten pendimethalin ( 60 ° c . to 80 ° c .) is added and agitated sufficiently to obtain an emulsion having an average droplet size of about 2 microns to 10 microns . this stabilized emulsion is cooled to ambient temperature , allowing the pendimethalin to solidify , whereupon the desired additional coformulants or active components ( antifreezing agents , suspending agents , surfactants , pesticides ) are added to the resulting aqueous suspension of solid pendimethalin . the resulting aqueous composition is milled to achieve the desired average particle size of suspended particles of less than 20 microns , preferably less than 5 microns ; and finally , additional thickening agents , preservatives , or surfactants , as desired , are admixed with the aqueous composition . this is then packaged as the aqueous suspension composition . utilizing the above procedure yields the stable aqueous suspension concentrate compositions listed in table i . table i__________________________________________________________________________ examplecomposition 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15__________________________________________________________________________pendimethalin 26 . 0 26 . 0 23 . 6 20 . 0 12 . 5 26 . 0 26 . 0 26 . 0 26 . 0 26 . 0 20 . 0 20 . 0 26 . 0 23 . 6 40 . 0 ( unstabilized ) isoproturon 26 . 0 26 . 0 23 . 6 -- 37 . 5 -- 26 . 0 26 . 0 26 . 0 26 . 0 -- -- 26 . 0 23 . 6 -- chlorotoluron -- -- -- 30 . 0 -- -- -- -- -- -- 30 . 0 30 . 0 -- -- -- isomeric mixture of -- -- -- -- -- 12 . 5 -- -- -- -- -- -- -- -- -- methyl - 6 -( 4 - isopropyl - 4 - methyl - 5 - oxo - 2 - imidazolin - 2 - yl )- . sub .-- m - toluene andmethyl 2 -( 4 - iso - propyl - 4 - methyl - 5 - oxo - 2 - imidazolin - 2 - yl - toluatena . sup .+ cresol - 5 . 0 -- 5 . 0 -- -- 5 . 0 -- -- -- -- -- -- -- -- -- formaldehydecondensatena . sup .+ cresol - -- 3 . 0 -- 3 . 0 3 . 0 -- 3 . 0 3 . 0 3 . 0 3 . 0 3 . 0 3 . 0 3 . 0 7 . 0 5 . 0formaldehydesulphonated - condensatena . sup .+ lauryl sulphate 0 . 5 0 . 5 0 . 5 0 . 5 0 . 5 -- 0 . 5 0 . 5 -- -- -- -- 0 . 5 -- -- ca . sup .++ lignosulphonate -- -- -- -- -- 2 . 0 2 . 0 -- -- -- -- -- -- -- -- alkyl phenol -- -- -- -- -- 6 . 0 -- -- -- -- -- -- -- -- -- ethoxylateurea 8 . 0 8 . 0 8 . 0 8 . 0 8 . 0 8 . 0 -- -- 8 . 0 -- 8 . 0 -- 10 . 0 8 . 0 -- precipitated silica 2 . 0 2 . 0 2 . 0 2 . 0 2 . 0 2 . 0 2 . 0 2 . 0 2 . 0 2 . 0 -- 2 . 0 2 . 0 2 . 0 -- xanthan gum 0 . 1 0 . 1 0 . 1 0 . 1 0 . 1 0 . 1 0 . 1 0 . 1 0 . 1 0 . 1 0 . 2 0 . 12 0 . 12 0 . 1 0 . 2formaldehyde 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 0 . 25 0 . 5 0 . 25 0 . 25 0 . 25 0 . 538 % sol . sup . nsiliconic antifoam 0 . 1 0 . 2 0 . 5 0 . 25 0 . 5 0 . 75 0 . 2 0 . 2 0 . 2 0 . 2 0 . 2 0 . 2 0 . 2 0 . 2 0 . 2ethylene glycol -- -- -- -- -- -- 8 . 0 8 . 0 -- 8 . 0 -- 8 . 0 -- -- 8 . 0ethylene oxide / pro - -- -- -- -- -- -- -- -- -- 2 . 0 2 . 0 2 . 0 -- -- -- pylene oxidecondensatewater qs qs qs qs qs qs qs qs qs qs qs qs qs qs qs__________________________________________________________________________ examplecomposition 16 17 18 19 20 21 22 23__________________________________________________________________________pendimethalin 26 . 0 20 . 0 20 . 0 20 . 0 20 . 0 20 . 0 26 . 0 26 . 0isoproturon 26 . 0 -- -- -- -- -- 26 . 0 26 . 0chlorotoluron -- 30 . 0 30 . 0 30 . 0 30 . 0 30 . 0 -- -- urea 8 . 0 -- -- -- -- -- -- 10 . 0siliconic antifoam 0 . 2 0 . 4 0 . 5 0 . 5 0 . 5 0 . 5 0 . 4 0 . 5xanthan gum 0 . 2 0 . 05 -- -- -- 0 . 05 -- 0 . 1formaldehyde 38 % 0 . 5 0 . 125 -- -- -- 0 . 125 -- 0 . 25solutionprecipitated silica -- 2 . 5 2 . 0 -- -- 2 . 0 2 . 7 2 . 0na . sup .+ naphthalene - for - 1 . 5 -- -- -- -- -- -- -- maldehyde conden - satena . sup .+ oleoyl methyl 1 . 5 1 . 0 -- -- -- -- -- -- taurideethylene oxide - propylene -- 5 . 5 2 . 0 2 . 0 2 . 0 3 . 6 6 . 0 -- oxide copolymerethylene glycol -- 8 . 0 8 . 0 8 . 0 8 . 0 8 . 0 8 . 0 -- na . sup .+ cresol - formal - -- -- 3 . 0 3 . 0 3 . 0 -- -- -- dehyde sulphonatecondensatena . sup .+ carboxymethyl -- -- 0 . 5 -- -- -- -- -- cellulosepolyvinylalcohol -- -- -- 2 . 0 -- -- -- -- polyvinylpyrrolidone -- -- -- -- 2 . 0 -- -- -- na . sup .+ lignosulphonate -- -- -- -- -- 2 . 0 -- -- china clay -- -- -- -- -- -- 1 . 3 -- calcium chloride -- -- -- -- -- -- 1 . 3 -- na . sup .+ polyacrylate -- -- -- -- -- -- -- 2 . 0propoxylated alkyl - -- -- -- -- -- -- -- 3 . 0aryl ethoxylatewater sufficient water to total 100 % __________________________________________________________________________ preparation of stable aqueous suspension concentrate compositions of pendimethalin , alone or in combination with other active components an aqueous solution containing surfactant ( s ) and antifoaming agents is prepared at a temperature of 50 ° c . to 80 ° c . then , the molten pendimethalin ( 60 ° c . to 80 ° c .) is added to the aqueous solution while agitating sufficiently to obtain an emulsion having an average droplet size of about 2 microns to 10 microns . sufficient suspending agent is added to this to stabilize the thus - formed emulsion , and this is cooled to ambient temperature , allowing the pendimethalin to solidify , whereupon the additional coformulants , as desired , are admixed to the emulsion . this can then be packaged . further , a suspension of a pesticide having a melting point greater than 70 ° c . is prepared and milled to a suitable average particle size ( i . e . less than 20 microns , preferably less than 5 microns ) or an aqueous solution containing the desired amount of a water - soluble pesticide is prepared . either one of these is then admixed with the suspension concentrate composition of pendimethalin prepared hereinabove . finally , additional thickening agents , preservatives or surfactants , as desired , are added , and this is then packaged as the mixed aqueous suspension concentrate composition . utilizing the above procedure yields the stable aqueous suspension concentrate compositions listed in table ii . table ii__________________________________________________________________________ examplecomposition 24 25 26 27 28__________________________________________________________________________pendimethalin ( unstabilized ) 23 . 6 23 . 6 23 . 6 23 . 6 23 . 6isoproturon 23 . 6 23 . 6 23 . 6 23 . 6 23 . 6na . sup .+ cresol - formaldehyde sulphonated condensate -- 3 . 0 4 . 1 3 . 0 4 . 3na . sup .+ cresol - formaldehyde condensate 5 . 0 -- -- -- -- alkylphenol ethoxylate -- -- -- -- 8 . 0na . sup .+ oleoyl methyl tauride -- 0 . 65 -- -- -- na . sup .+ lauryl sulphate 0 . 5 -- -- 0 . 5 -- urea 8 . 0 8 . 0 8 . 0 -- -- ethylene glycol -- -- -- 8 . 0 -- blend of polyalkylene glycol ether and poloxy - -- -- 0 . 7 -- -- ethylene alkylaryl ethersiliconic antifoam 0 . 25 0 . 5 0 . 5 0 . 5 0 . 5silica 2 . 0 2 . 0 -- 2 . 0 -- xanthan gum 0 . 1 0 . 1 0 . 2 0 . 1 0 . 1formaldehyde 38 % soln 0 . 25 0 . 25 0 . 5 0 . 25 0 . 3water qs qs qs qs qs__________________________________________________________________________ examplecomposition 29 30 31 32 33__________________________________________________________________________pendimethalin ( unstabilized ) 20 . 0 20 . 0 20 . 0 26 . 0 30 . 0chlorotoluron 30 . 0 30 . 0 -- -- -- isomeric mixture of methyl 6 -( 4 - isopropyl - 4 - methyl - -- -- 12 . 5 12 . 5 -- 5 - oxo - 2 - imidazolin - 2 - yl )- . sub .-- m - toluate and methyl 2 -( 4 - isopropyl - 4 - methyl - 5 - oxo - 2 - imidazolin - 2 - yl )- toluateammonium 2 -( 4 - isopropyl - 4 - methyl - 5 - oxo - 2 - imidazo - -- -- -- -- 5 . 0lin - 2 - yl )- 3 - quinolinecarboxylic acid ( solution ) na . sup .+ cresol - formaldehyde sulphonated condensate 3 . 0 3 . 6 -- -- -- na . sup .+ cresol - formaldehyde condensate -- -- 5 . 0 3 . 0 -- triethanolamine salt of polyarylethoxylate -- -- -- 1 . 3 -- phophatena . sup .+ lignosulphonate -- -- -- -- 4 . 0ca . sup .++ lignosulphonate -- -- 2 . 0 -- -- alkylphenol ethoxylate -- -- 8 . 0 6 . 0 -- na . sup .+ lauryl sulphate 0 . 5 -- -- -- -- urea 8 . 0 8 . 0 8 . 0 -- -- ethylene glycol -- -- -- 5 . 0 8 . 0siliconic antifoam 0 . 5 0 . 1 0 . 5 0 . 4 0 . 5silica 2 . 0 0 . 1 2 . 0 2 . 0 0 . 75xanthan gum 0 . 1 0 . 2 0 . 1 0 . 1 0 . 1formaldehyde 38 % soln 0 . 25 0 . 5 0 . 25 0 . 25 0 . 25glacial acetic acid ( to ph 7 . 4 ) -- -- -- -- blend of polyalkylene glycol ether and polyoxy - -- 0 . 55 -- -- -- ethylene alkylaryl etherwater qs qs qs qs qs__________________________________________________________________________ examplecomposition 34 35 36 37 38 39__________________________________________________________________________pendimethalin ( unstabilized ) 33 . 0 40 . 0 40 . 0 40 . 0 40 . 0 33 . 0na . sup .+ cresol - formaldehyde sulphonated condensate -- 4 . 2 -- -- -- -- na . sup .+ cresol - formaldehyde condensate -- -- 4 . 7 -- -- 4 . 2triethanolamine salt of polyarylethoxylate 3 . 4 -- -- -- -- -- phosphatena . sup .+ lignosulphonate -- -- -- 4 . 8 -- -- urea -- -- -- -- -- 13 . 3ethylene glycol 8 . 0 8 . 0 -- -- 5 . 0 -- siliconic antifoam 0 . 1 0 . 5 0 . 9 0 . 3 1 . 0 0 . 3xanthan gum 0 . 1 0 . 1 0 . 1 0 . 1 0 . 2 0 . 16formaldehyde 38 % soln 0 . 25 0 . 25 0 . 25 0 . 25 0 . 5 0 . 4polycarboxylate derivative -- -- -- -- 3 . 0 -- water qs qs qs qs qs qs__________________________________________________________________________ examplecomposition 40 41 42 43 44__________________________________________________________________________pendimethalin ( unstabilized ) 27 . 3 30 . 0 27 . 3 30 . 0 30 . 0atrazine 18 . 2 20 . 0 18 . 2 20 . 0 20 . 0na . sup .+ cresol - formaldehyde sulphoanted condensate 3 . 4 1 . 65 3 . 4 1 . 65 1 . 65triethanolamine salt of polyarylarylethoxylate -- -- -- 1 . 9 1 . 9phosphateurea 5 . 8 -- -- -- 5 . 0ethylene glycol -- 5 . 6 5 . 2 5 . 0 -- blend of polyalkylene glycol ether and 1 . 34 1 . 26 1 . 2 -- -- polyoxyethylene alkylaryl ethersiliconic antifoam 0 . 9 0 . 35 0 . 9 0 . 16 0 . 16silica -- 0 . 5 -- 0 . 4 0 . 4xanthan dum 0 . 2 0 . 1 0 . 2 0 . 1 0 . 1formaldehyde 38 % soln 0 . 5 0 . 25 0 . 5 0 . 25 0 . 25water qs qs qs qs qs__________________________________________________________________________ an aqueous dispersion of surfactants , antifoaming and antifreezing agents , containing , if desired , a solid active component having a melting point greater than 70 ° c ., is prepared or a water soluble active component is prepared at ambient temperatures . the molten pendimethalin ( 60 ° c . to 80 ° c . ), with or without additional surfactants , is then added to the agitated aqueous mixture . this resulting aqueous mixture is milled to achieve the desired average particle size of suspended solids , less than 20 microns , preferably less than 5 microns , and additional thickening agents , suspending agents , preservatives , antifreezing agent and surfactants , as desired , are admixed to the milled composition . this is then packaged as the resulting stable aqueous suspension concentrate composition . utilizing the above procedure yield the stable aqueous concentrate compositions listed in table iii . table iii______________________________________ examplecomposition 45 46______________________________________pendimethalin ( unstabilized ) 26 . 0 26 . 0isoproturon 26 . 0 26 . 0na . sup .+ cresol - formaldehyde sulphonated condensate 3 . 0 -- polyarylarylpolyoxyethylene phosphate , acid form -- 5 . 0siliconic antifoam 0 . 2 0 . 2xanthan gum 0 . 2 0 . 12formaldehyde 38 % solution 0 . 5 0 . 5ethanediol ( ethylene glycol ) 8 . 0 -- water qs qs______________________________________ preparation of stable aqueous suspension concentrates of pendimethalin via the method of the invention versus the method of milling while cooling an emulsion ( method e ) an aqueous suspension concentrate composition of pendimethalin was prepared according to examples 1 - 23 , method a . as a comparision , a suspension concentrate of pendimethalin was prepared according to the description of epo application 033291 . 2 . a mixture of hot - water ( 575 cc ), ethylene glycol ( 50 g ) and an anionic surface - active agent ( a mixture of the monophosphate and the diphosphate of tristyrylphenol with a polyoxyethylene of 18 oxyethylene units , neutralized with triethanolamine , marketed under the tradename of soprophor fl ® by rhone - poulenc ) ( 50 g ) is vigorously agitated while 400 g of pendimethalin are added . this is then ground in a dyno mill with a jacket for rapid cooling , resulting in a mixture leaving the mill at 24 ° c . and having a particle size of 98 % less than 5 microns , indicating the formation of a suspension concentrate . a xanthan gum biopolymer of a heteropolysaccharide type ( 1 . 5 g ), produced by fermentation of xanthomonas campestris on carbohydrates ( tradename rhodopol xb 23 marketed by rhone - poulenc ), is added . table iv summarizes the stability observations of the two compositions . the milling method does not avoid the appearance of elongated crystals even upon two short periods of storage , one three day storage at 15 ° c . and one three day storage at 28 ° c . table iv__________________________________________________________________________method a - method of the invention method e - milling while cooling * composition % w / v result composition % w / v result__________________________________________________________________________pendimethalin 40 ( 1 ) after six weeks pendimethalin 40 two tests : at 28 ° c ., 95 % of ( 1 ) large crystals the particles particle size have an average up to 80 × 5 particle size of microns ap - less than 15 × 4 peared after microns . thre days at 15 ° c . and also when stored at three days at 28 ° c . suspending agent suspending agentxanthan gum 0 . 02 xanthan gum 0 . 15 ( added prior ( added afterto cooling ) milling and cooling ) surfactants surfactantssulfonated cresol 4 . 0 mixture of mono 5 . 0formaldehyde and di phosphatecondensate of tristyrylphenol neutralized with triethanolamine ( soprophor ® fl ) polyethoxylated - 3 . 0polymethylmeth - acrylateantifreeze antifreezeurea 5 . 0 ethylene glycol 5 . 0antifoamsiliconic 0 . 5preservativebenzisothiazolone 0 . 1__________________________________________________________________________ ® trademark of soprosoie , division of rhonepoulenc . * particle size found in initial suspension concentrate composition is 98 % less than five ( 5 ) microns . an aqueous suspension concentrate composition of pendimethalin with a secondary pesticide was prepared according to examples 1 - 23 containing the following components : ______________________________________ (% w / v ) formula x formula y______________________________________pendimethalin 23 . 6 20 . 0isoproturon 23 . 6 -- chlorotoluron -- -- na cresol - formaldehyde 4 . 1 4 . 14sulphonated condensatesurfactantpolycarbonate -- 1 . 64surfactantblend of polyalkylene 0 . 71 -- glycol ether andpolyoxyethylene alkylaryl etherurea 8 . 0 8 . 0xanthan gum 0 . 2 0 . 230 % siliconic antifoam 0 . 5 0 . 3benzisothiazolinone -- 0 . 033methyl paraben 0 . 1 -- propyl paraben 0 . 05 -- water to 100 % 100 % ______________________________________ a hot emulsion of molten pendimethalin is prepared as in examples 1 - 23 wherein hot pendimethalin is added to the hot solution of surfactant whilst mixing at high shear . the temperature is 50 ° c . to 80 ° c . with a particle size of 2μ to 5μ . the hot emulsion is then miled through a dyno - mill and exits as a shattered crystalline form ( temperature into mill is about 65 ° c ., and temperature exiting is about 20 ° c . to 25 ° c .). this mixture is allowed to &# 34 ; age &# 34 ; to allow orange polymorph crystal conversion . following conversion , usually 0 . 5 to 48 hours , a second milling in a dyno - mill occurs . ( in the event another active pesticide is added , it is added into the aging period stage ). once milled a second time , final coformulants are added . ______________________________________ concentrate______________________________________ % w / vpendimethalin technical 40 . 0soprophor ® fl surfactant 5 . 0silnaolapse ® 500 0 . 5propylene glycol 7 . 0water to 100 % this is formulated into the following : 8 / 1concentrate from above 1000rodopol 2 % gel 70water to 100 % % w / vconcentrate from above 75 . 0atrazine technical 20 . 0soprophor ® fl 1 . 25propylene glycol 1 . 25water to 100 % ______________________________________ | US-39592589-A |
the system and method of the invention pertains to an mr - guided breast biopsy procedure , specifically as to real - time tracking and navigation of a biopsy device . more particularly , the system utilizes a diagnostic imaging modality such as magnetic resonance imaging to locate lesions in a human breast while utilizing an inertial measurement unit to track advancement of a biopsy device in real - time . the invention simplifies the workflow of mri - guided breast biopsies , shortens the time needed to perform the biopsy , decreases cost , and increases accuracy . this is achieved by enabling real - time visualization of the biopsy device as it advances towards the targeted lesion . | various embodiments will be better understood when read in conjunction with the appended drawings . it should be understood that the various embodiments are not limited to the arrangements and instrumentality shown in the drawings . embodiments of tracking technologies for the biopsy device have been designed to work in the strong , inhomogeneous fringe field of the mri magnet . the desired tracking range is about 20 cm × 20 cm × 50 cm ; tracking is intended to give positioning of the surgical instrument with an accuracy of better than about 2 mm . one tracking approach is based on a set of 3 - axis hall - effect - gyroscope - accelerometer sensors : respectively , sensors / transducers yield varying output voltages in response to the different magnetic fields sensed , as well as for different accelerations and angular velocities . other motion processing technology may be utilized as well , and such sensors implemented in various arrangements and combinations . biopsies are performed in a region of inhomogeneous magnetic field where a unique relationship exists between the three components of the magnetic field and position . while the hall - effect sensors can provide the three components of the magnetic field in the instrument &# 39 ; s frame of reference , the gyroscope and accelerometer provide the instrument &# 39 ; s orientation , hence enabling full position determination . this is the first time when an inertial measurement unit ( imu ) is used for high accuracy tracking in a surgical setting , benefitting from the unique advantage offered by the strong , position - dependent magnetic field . real - time tracking of the biopsy tool of the invention utilizes imu sensors , an inexpensive solution that does not clutter the room with additional hardware . embodiments of the invention employ an imu ( e . g . similar , in principle , to that utilized in plane or missile tracking ) for high accuracy position determination in a surgical application . this approach may also utilize high precision mapping of the magnetic field in the biopsy region for each individual scanner if the simulated maps do not correspond to the field measured in real life . a technique known as simultaneous localization and mapping ( slam ) may also be used to refine mapping of the magnetic field in the biopsy region for each individual scanner , such as when the simulated maps do not correspond to the field measured in real life . in one embodiment of the invention , the improved mr - guided breast biopsy procedure is reduced from prior 30 - 60 min procedures to duration of about 15 minutes or less , and with greater accuracy . fig2 ( a ) depicts the workflow 222 of a breast biopsy procedure as currently known in the art . because the imaging is performed in the mri magnet , and the biopsy performed outside the magnet ( i . e . essentially blindly ), a lot of back and forth steps are utilized to confirm by imaging that the biopsy procedure is performed at the designated location , i . e . where the lesion appeared on the images . fig2 ( b ) depicts a schematic to compare workflow 200 in the present invention as utilized with technology of the invention , in contrast to the inefficiencies as listed in the prior workflow 222 . in fig2 , the systems of 30 - 60 minute duration ( e . g . fig2 ( a ) ) include the following steps : ( la ) the radiologist identifies the biopsy location on the interventional ( mri ) images ( e . g . often on compressed post - contrast images ); ( 2 a ) the grid and sub - grid entry point are defined by automated software on a computer screen in the control room ; ( 3 a ) the entry point is then physically identified by the radiologist in the scanner room , with the depth of penetration manually adjusted on the introducer ; ( 4 a ) the stylet is then advanced orthogonally through the grid to about the desired location , then replaced with the plastic obturator ; ( 5 a ) the patient is re - imaged to confirm appropriate location of the tip of the obturator ; ( 6 a ) the patient is removed from the scanner , the obturator is replaced with biopsy device and the biopsy then taken ; and ( 7 a ) the biopsy device is replaced with the obturator , followed by the patient re - entering the magnet for re - imaging confirmation , e . g . another image then taken to visually confirm that the lesion was sampled at an appropriate biopsy location . in one embodiment of the improved method , as shown in fig2 ( b ) , workflow 200 illustrates a simplified procedure for biopsy . with real - time tracking of the surgical instrument , the prior back and forth steps are no longer needed . an embodiment of the method includes as follows : ( 1 b ) a patient is imaged to find a lesion , such that the radiologist defines a biopsy point on compressed post - contrast images ( 240 ); ( 2 b ) the patient is removed from the magnet and a coarse grid entry point is then identified , representing the entry point for a biopsy device ( 250 ); and ( 3 b ) the biopsy device is advanced to a target lesion , the device visualized in real - time , such that the biopsy is taken when the tip of the biopsy device reaches the target lesion and ensures that the biopsy is taken from the target lesion ( 260 ). this reduces procedure time and expense , while also facilitating more efficient patient care . embodiments of the invention provide the interventional radiologist with real - time visualization of his / her actions during a biopsy procedure . fig3 presents an illustration of the physical changes in hardware implemented in the biopsy setup for the real - time tracking system 300 , including connectivity and the role of each component . specifically , fig3 illustrates a system 300 where a computer 302 receives data in real - time from both an mri scanner 304 and the tracking sensors 305 which are attached to the surgical instrument 306 , both separate from the biopsy workstation 308 by way of the mri screening room enclosure 310 . near the mri scanner 304 are a display monitor 312 and a compression grid 314 . the biopsy location is in the fringe field 315 of the mri magnet 304 . the biopsy workstation 308 receives mri images from the host computer 302 ; acquires sensor data from the sensor combination , imu 305 , attached to the surgical instrument 306 ; transforms sensor data streams into position locators using a computer algorithm 309 ; and then registers , reformats , and sends three - dimensional ( 3d ) images to the in - room display 312 for visualization . the sensor combination ( imu ) is a mini - scale device attached at a distal or proximal end of the instrument . for exemplary purposes , the device is a box attached to the inside hollow tube body 311 of the instrument 306 ( e . g . a stylet 306 ). the imu may be positioned with the instrument to be tracked in various manners , including direct attachment of sensors to the body or tip of the instrument , internal or external to the tube body 311 , or integral therewith . in one aspect , the biopsy workstation sends desired information ( e . g ., real - time display of biopsy advancement ) to the display monitor 312 located in the mri screen room enclosure 310 . as depicted , the biopsy workstation 308 and the host computer 302 include separate respective processors . in another aspect , the processor of the host computer 302 may be included in the biopsy workstation 308 , or part of the host computer of the scanner can perform the steps as described . as depicted in fig4 , the actions of the computer processor 302 , which can be the computer processor of the host computer , or a separate processor placed in a separate computer , are defined in a flow chart schematic to demonstrate the methodology of the real - time tracking system 300 . initially , images are acquired and imported ( 321 ) into the system . the surgical target is identified . for exemplary purposes , and not limitation , the surgical target is a breast lesion to be biopsied . data is acquired ( 324 ) from imu sensors which are attached to a surgical instrument . the sensor information is converted into position using a computer algorithm ( 325 ). then , using the pre - acquired images at 321 and the computed algorithm to define position , the position of the surgical instrument on the pre - acquired images is displayed in real - time ( 327 ) during the duration of the interventional procedure . assuming breast immobility during the biopsy procedure , the motion of the biopsy device is followed in real - time and displayed on the previously acquired images . aspects of the invention first confirm immobilization of a patent &# 39 ; s breast during biopsy and then obtain tracking data in the fringe field of the mri magnet . during confirmation of breast immobility during a biopsy procedure , pixel displacement as a function of position is recorded using non - rigid image registration between a first ( contrast ) series and a last series in the biopsy exam . the average displacement over the breasts of four separate patients during the biopsy procedure was about 0 . 8 mm with higher displacements around the biopsy site , up to about 3 . 5 mm displacements . in another example , the 9 - gauge biopsy tools have about 4 mm diameters , and larger displacements around the biopsy site are therefore expected . the low displacement , especially with the use of 9 - gauge biopsy tools with diameters of about 4 mm , confirmed a rigid geometry assumption and usefulness of real - time monitoring of the surgical instrument during a biopsy procedure , while assuming that the breast anatomy remains fixed . thus , tracking instruments with high precision , over a relatively large region , in a strong , inhomogenous background magnetic field proves beneficial . the solution includes implementing a set of accelerometers , gyroscopes , and hall - effect sensors to allow real - time tracking one embodiment of a real - time mri tracking system is illustrated in the image of fig5 . in the system 500 , in the fringe field 501 of an mri scanner 502 , an rf breast coil 504 is positioned adjacent a translation stage 506 . as shown , an imu 508 is attached to the translation stage 506 which is endowed with an optical encoder 511 . for example , the translation stage enables motion in three dimensions ; each of the dimensions has a “ ruler ” such that a laser scans the ruler as it moves . in this implementation , the translation stage and optical encoder are used to validate the position determination reported by the imu in comparison with the position determination reported by the optical encoder . it is to be understood , however , that this was done for validation purposes . in the clinical implementation , once the precision of the imu of reporting position is confirmed ( e . g ., during the development stage ), the translation stage and the optical encoder are removed . in embodiments of the invention , the imu sensors are attached to the clinical instrument using a snap - on box , for example . any number of attachment mechanisms may be implemented including adhering the imu to an internal or external side wall of the instrument , implementing a pre - molded box ( e . g . injection molding with the instrument ) during manufacture to position the imu , or any other method as known in the art to integrate the imu with the instrument . in one aspect , the translation stage is used for accuracy in providing a reference from the optical encoder . a simulated magnetic field map of a 3t mr scanner indicates background fringe fields of 100 - 300g , and field gradients of 4 - 7 g / cm ( depending on the axis ) in the general area where breast biopsies are performed . the spatially varying features of the field are used to establish a correspondence between position and magnetic field measurements . unfortunately , fringe field measurements alone cannot fully determine position ; thus , the orientation of the sensors ( e . g ., direction cosine matrix ) is utilized to relate the instrument &# 39 ; s frame of reference back to the laboratory frame where the map of the magnetic field exists . to track position and pose of the instrument with high accuracy and at a high update rate , a sensor combination of gyroscopes , accelerometers and magnetometers , an inertial measurement unit ( imu ), is installed at the distal end of an instrument . ( see fig3 . imu 305 is attached to surgical instrument 306 .) the instrument may be any surgical instrument , catheter , probe , or instrument for medical or other purposes , such use and capability defined within a field of use . the imus are small mems devices , magnetic field compatible , and are used for different purposes in the mri environment . for exemplary purposes , sub - degree precision has recently been shown for attitude tracking control of a handheld instrument using an imu , and now further encompasses position tracking as described herein . the algorithmic approach for optimal fusion of sensor measurements and use of the pre - mapped magnetic field is based on probabilistic techniques . such techniques were applied with great success to similar problems , such as human motion tracking , indoor localization of wireless devices , and mobile robot navigation . for this problem , an occupancy grid map of the environment is correlated with measurements obtained from a laser range finder . in one case , a set of magnetic sensors are analogous to the laser range finder , since the measurements are directly correlated to position . the magnetic field map is analogous to the occupancy grid map . the goal of the algorithm is to estimate the state of the system comprising : position , velocity , acceleration , and angular velocities with respect to the laboratory frame . to model drift and bias in some elements of the imu , the state vector may be extended in other inertial navigation applications . the basis for the solution comprises in a two - step recursive algorithm , known as bayes &# 39 ; filter . in bayes &# 39 ; general form , the filtering process has two main steps , prediction and update . for prediction , the probability density function associated with the state at iteration k , a . k . a . belief ( bel ( x k )), is estimated from the previous estimate ( bel ( x k - 1 )), using bel ( x k )= ƒ k - 1 ( bel ( x k - 1 )). in this probabilistic framework , the state and its associated uncertainty are propagated through the non - linear function ƒ k - 1 derived from the kinematics associated with the sensor configuration . for the update step , the probability of obtaining measurements z k given the state x k , p ( z k | x k ), is used to correct the prediction generated in previous step ( bel ( x k )), through bel ( x k )= ηp ( z k | x k ) bel ( x k ). to update the predicted state , 1 ) the magnetic map , which relates magnetometer measurements with the instrument &# 39 ; s position and 2 ) the inertial measurements , which relate to the instrument &# 39 ; s orientation and motion are considered . furthermore , the probabilistic nature of p ( z k | x k ) allows for incorporating measurement noise and map errors , in a similar way range finder and occupancy grid map errors are accounted for in mobile robot navigation . considering the non - linear relationships of the application , a sampled representation of belief ( particle filter ) enables assessment of the performance bounds of the algorithm and error budgets . to reduce computational demand , parametric representations are evaluated , such as unscented kalman filtering . generic implementations of these algorithms in optimal estimation libraries have been developed for this application , as well as multiple others . while the use of a simulated fringe field map for positioning could be utilized , for greater accuracy the fringe fields are mapped in the biopsy region using an automated , mr compatible translation stage on mri scanners , and compared to the simulated field maps . if the simulated field enables accurate sensor localization , this map is preserved as the standard ; otherwise , the measured maps are set as a reference . in the latter case , a limited set of ( corner ) measurements may be performed and used to interpolate the fields . in addition , the stability of measurements of the sensors attached to the surgical instrument may be affected by the mechanical instabilities created in the mri room ( such as the motion of nearby elevators ). the sensors enable correction through field referencing . if the measurements are sensitive to disturbances , other sensors may be added to the compression grid , for example , to enable correction for such effects . one embodiment , as shown in fig6 , displays the magnetic field reported by the imu magnetometer [ sensors ] 508 and the position reported by the optical encoder 511 of the translation stage 506 as a function of time , while moving the translation stage over about 8 cm . this confirms a direct relationship between the field reported by the sensor and position ; this graph indicates that measurements of millimeter precision are achievable . once a map of the background field in the biopsy space is uploaded in the biopsy workstation , the magnetic field measurement translates to position . in order for the advancement of the biopsy tool to be displayed on the previously acquired mri images , a common reference frame needs to be established for the lesion and the biopsy tool . the lesion is visualized on the mri images . these images are displayed in the patient reference frame , which depends on the landmark location . the biopsy tool is visualized in the laboratory frame , which can have identical orientation ( angles ) as the patient reference frame , but is offset in all three directions versus the patient frame . fiducial ( s ) embedded in the compression grid 314 , visible in the mri images and accessible during real time biopsy instrument tracking , enable superposition of data acquired in these two ( 2 ) frames of reference . an initial calibration step , ( e . g ., the contact between the tip of the tracked biopsy tool and these fiducials ) determines the transformation matrix that links the two reference frames . the fiducials can have the form of liquid - filled vials . correction for susceptibility induced magnetic field changes may be implemented in order to increase the accuracy of localizing the fiducial versus the lesion . in another aspect , an optical tracking or rfid based tracking may be utilized . optical tracking , however , is difficult in this situation , as the radiologist &# 39 ; s hand can come between the instrument and the source of light / detector . rfid based tracking also uses a transmitter , and is usually not very accurate . the invention disclosed herein provides a solution to resolve issues around performing a biopsy blindly . as a biopsy device advances toward a lesion in real time , the biopsy device can now be visualized in relation to the location of the lesion , and tracked in real - time . this methodology not only enhances accuracy but also shortens the procedure time . the various embodiments may be implemented in connection with different types of systems including a single modality imaging system and / or the various embodiments may be implemented in or with multi - modality imaging systems . the system is illustrated as an mri imaging system and may be combined with different types of medical imaging systems , such as a computed tomography ( ct ), positron emission tomography ( pet ), a single photon emission computed tomography ( spect ), as well as an ultrasound system , or any other system capable of generating images , particularly of a human . moreover , the various embodiments are not limited to medical imaging systems for imaging human subjects , but may include veterinary or non - medical systems for imaging animals and primates . it should be noted that the particular arrangement of components ( e . g ., the number , types , placement , or the like ) of the illustrated embodiments may be modified in various embodiments . different numbers of a given module or unit may be employed , a different type or types of a given module or unit may be utilized , a number of modules or units ( or aspects thereof ) may be combined , a given module or unit may be divided into plural modules ( or sub - modules ) or units ( or sub - units ), a given module or unit may be added , or a given module or unit may be omitted . it should be noted that the various embodiments may be implemented in hardware , software or a combination thereof . the various embodiments and / or components , for example , the modules , or components and controllers therein , also may be implemented as part of one or more computers or processors . the computer or processor may include a computing device , an input device , a display unit and an interface , for example , for accessing the internet . the computer or processor may include a microprocessor . the microprocessor may be connected to a communication bus . the computer or processor may also include a memory . the memory may include random access memory ( ram ) and read only memory ( rom ). the computer or processor further may include a storage device , which may be a hard disk drive or a removable storage drive such as a solid state drive , optical drive , and the like . the storage device may also be other similar means for loading computer programs or other instructions into the computer or processor . use of a robot in the magnet and / or to perform the biopsy under mr imaging guidance may also be implemented . in other embodiments , various tissues in other parts of the human or animal body can be imaged . as used herein , the term “ computer ,” “ controller ,” and “ module ” may each include any processor - based or microprocessor - based system including systems using microcontrollers , reduced instruction set computers ( risc ), application specific integrated circuits ( asics ), logic circuits , gpus , fpgas , and any other circuit or processor capable of executing the functions described herein . the above examples are exemplary only , and are thus not intended to limit in any way the definition and / or meaning of the term “ module ” or “ computer .” the computer , module , or processor executes a set of instructions that are stored in one or more storage elements , in order to process input data . the storage elements may also store data or other information as desired or needed . the storage element may be in the form of an information source or a physical memory element within a processing machine . the set of instructions may include various commands that instruct the computer , module , or processor as a processing machine to perform specific operations such as the methods and processes of the various embodiments described and / or illustrated herein . the set of instructions may be in the form of a software program . the software may be in various forms such as system software or application software and which may be embodied as a tangible and non - transitory computer readable medium . further , the software may be in the form of a collection of separate programs or modules , a program module within a larger program or a portion of a program module . the software also may include modular programming in the form of object - oriented programming . the processing of input data by the processing machine may be in response to operator commands , or in response to results of previous processing , or in response to a request made by another processing machine . as used herein , the terms “ software ” and “ firmware ” are interchangeable , and include any computer program stored in memory for execution by a computer , including ram memory , rom memory , eprom memory , eeprom memory , and non - volatile ram ( nvram ) memory . the above memory types are exemplary only , and are thus not limiting as to the types of memory usable for storage of a computer program . the individual components of the various embodiments may be virtualized and hosted by a cloud type computational environment , for example to allow for dynamic allocation of computational power , without requiring the user concerning the location , configuration , and / or specific hardware of the computer system . it is to be understood that the above description is intended to be illustrative , and not restrictive . for example , the above - described embodiments ( and / or aspects thereof ) may be used in combination with each other . in addition , many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope . dimensions , types of materials , orientations of the various components , and the number and positions of the various components described herein are intended to define parameters of certain embodiments , and are by no means limiting and are merely exemplary embodiments . many other embodiments and modifications within the spirit and scope of the claims will be apparent to those of skill in the art upon reviewing the above description . the scope of the invention should , therefore , be determined with reference to the appended claims , along with the full scope of equivalents to which such claims are entitled . in the appended claims , the terms “ including ” and “ in which ” are used as the plain - english equivalents of the respective terms “ comprising ” and “ wherein .” moreover , in the following claims , the terms “ first ,” “ second ,” and “ third ,” etc . are used merely as labels , and are not intended to impose numerical requirements on their objects . this written description uses examples to disclose the various embodiments , and also to enable a person having ordinary skill in the art to practice the various embodiments , including making and using any devices or systems and performing any incorporated methods . the patentable scope of the various embodiments is defined by the claims , and may include other examples that occur to those skilled in the art . such other examples are intended to be within the scope of the claims if the examples have structural elements that do not differ from the literal language of the claims , or the examples include equivalent structural elements with insubstantial differences from the literal languages of the claims . | US-201514671252-A |
the present invention relates generally to methods of inducing contraceptive or abortive effects via modulation of levels of circulating hormones via administration of an enzyme , pharmaceutical compositions achieving such effects , antibody substances immunoreactive to said enzyme and related substances , and methods for screening for the predisposition of spontaneous abortions | among its advantages , the present invention provides ( 1 ) a novel method of inducing abortion or preventing nidation by the reduction of progesterone levels via administration of 20α - hsd , ( 2 ) novel methods for screening for individuals predisposed to spontaneous abortions , and ( 3 ) antibody substances immunoreactive with 20α - hsd and 20α - hydroxyprogesterone . example 1 describes the isolation and characterization of rat luteal cdna encoding 20α hsd . example 2 is directed to the expression and purification of recombinant or non - naturally occurring 20α - hsd from bacterial and / or insect cell expression systems . example 3 sets forth the characterization of the recombinant 20α - hsd produce in example 2 . example 4 relates to antibodies to 20α - hsd and to progesterone metabolites . example 5 is directed to methods for screening for individuals predisposed to spontaneous abortions . example 6 is related to the anti - reproductive effect of recombinant 20α - hsd during pregnancy . the following examples are illustrative of the processes and products of the present invention but are not to be construed as limiting . the isolation and characterization of cdna ( rat corpus luteum ) encoding for 20α - hsd described herein was described by mao et al . [ biochem . biophys . res . comm . 201 ( 3 ): 1289 - 1295 ( 1994 )]. in sum , a λ zap ii rat cdna library was screened using both an antibody to rat 20α - hsd and a rabbit 20α - hsd cdna . further , a full length cdna was isolated and sequenced . in addition , the isolated cdna was used to examine the tissue specific expression of 20α - hsd and the role of prolactin on the abundance of 20α - hsd mrna . an oligo ( dt ) primed cdna expression library made from corpus luteum mrna of day 7 hypophysectomized pregnant rats was constructed in λ zap ii ( stratagene , la jolla , calif .). the library was initially screened with rat 20α - hsd antiserum [ albarracin et al ., endocrinology , 129 : 1821 - 1830 ; ( 1991 ) and albarracin et al ., endocrinology 134 : 2453 - 2460 ; ( 1994 )] using the pico - blue immunoscreening kit ( stratagene , la jolla , calif .). approximately 5 × 10 5 phages were screened . positive plaques were isolated and rescreened by standard filter hybridization with rabbit 20α - hsd cdna [ lacy et al ., molecular endocrinology 7 : 58 - 66 ( 1993 )] labeled with 32 p . filters were prehybridized , hybridized ( 10 6 cpm / ml ) in a 2 × pipes buffer containing 50 % formamide , 0 . 5 % sds and 100 μg / ml salmon sperm dna for 12 - 16 hours at 42 ° c ., washed twice in 2 × ssc and 0 . 1 % sds at room temperature for 15 minutes , twice in 0 . 2 × ssc and 0 . 1 % sds at 42 ° c . for 15 minutes , and finally twice in 0 . 1 × ssc and 0 . 1 % sds at 42 ° c . for 15 minutes . secondary and tertiary screenings were performed until all plaques were positive . nine of the 33 positive clones were isolated . pbluescript sk (-) containing the insert was excised in vivo by r408 helper phage to produce pbluescript double - stranded phagemids . 20α - hsd cdna was sequenced using the sequenase kit ( united states biochemical , inc ., cleveland , ohio ). the sequence was extended by a primer - directed dideoxy sequencing approach with sequence specific oligonucleotide primers ( national bioscience , plymouth , minn .). two clones were completely sequenced and the cdna sequence was determined from both strands . dna and deduced amino acid sequence analysis was performed using the fasta program [ pearson and lipman , proc . natl . acad . sci . usa , 85 : 2444 - 2448 ( 1988 )] with genbank ® and pir ® databases , respectively . the prosite [ bairoch , nucleic acids res ., 20 : 2013 - 2018 ( 1992 )] program was used to identify protein patterns or motifs in the protein sequence . a full length 1233 bp 20α - hsd cdna was isolated and the complete nucleotide sequence is shown as seq id no . 1 with the deduced amino acid sequence presented as seq id no . 2 . the 20α - hsd cdna ( seq id no . 1 ) contained an open reading frame of 969 nucleotides , a single in - frame atg initiation codon , a stop codon at nucleotide 1015 and a poly ( a + ) stretch at the 3 &# 39 ; end . the deduced amino acid sequence ( seq id no . 2 ) of the protein was shown to be composed of 323 amino acids , having a molecular weight of 37 , 268 daltons . further , the amino acid composition deduced from the cdna matched that obtained from an amino acid analysis performed on the purified 20α - hsd previously reported by albarracin et al . [ endocrinology 134 ( 6 ): 2453 - 2460 ( 1994 )]. as it has been previously reported that 20α - hsd is prolactin regulated ( id . ), the isolated 20α - hsd cdna was used to examine the tissue specific expression of 20α - hsd and the role of prolactin in the abundance of 20α - hsd mrna . for these studies , holtzman pregnant rats were hypophysectomized on day 3 and treated with either prolactin ( niaddk oprl - 18 , 125 μg , twice daily ) or with vehicle ( control ). on day 7 , corpus luteum and various other tissues ( brain , decidua , ovary , and uterus ) were obtained for analysis . total rna from the harvested tissues was isolated by the method of chomzynski and sacchi [ anal . biochem . 162 : 156 - 159 ( 1984 )] and equal aliquots ( 20 μg ) were electrophoresized and transferred to nylon membranes , or slot blotted onto genescreen ( dupont , wilmington , del .) membrane . rna was prehybridized for 16 hours at 42 ° c . in 40 % formamide , 6 × ssc , 5 × denhardt &# 39 ; s , 20 mm nah 2 po 4 , 0 . 2 % sds and 100 μg / ml salmon sperm dna . hybridization was completed in the same solution with the addition of 32 p - labeled rat 20α - hsd cdna ( 10 6 cpm / ml ) at 42 ° c . for 12 - 16 hours . blots were washed twice in 05 .× ssc and 0 . 1 % sds ( 15 minutes , room temperature ), twice in 0 . 2 × ssc and 0 . 1 % sds ( 15 minutes , 42 ° c . ), twice in 0 . 2 × ssc and 0 . 1 % sds ( 15 minutes , 56 ° c .) and twice in 01 .× ssc and 0 . 1 % sds ( 15 minutes , 56 ° c .). northern analysis revealed that the rat 20α - hsd cdna specifically hybridized to a single 1 . 2 kb 20α - hsd mrna transcript in corpora lutea and that prolactin pretreatment markedly reduced expression of 20α - hsd mrna correlating perfectly with earlier results seen with the enzyme [ albarracin et al ., endocrinology , 129 : 1821 - 1830 ( 1991 ) and albarracin et al ., endocrinology 134 : 2453 - 2460 ( 1994 )]. although 20α - hsd was detected in both the corpus luteum and whole ovaries of hypophysectomized pregnant rats , levels in the ovary were lower than in the isolated corpus luteum due to the fact that non - luteal tissues of the pregnant rat do not express 20α - hsd [ id .]. hybridization analysis performed on the corpus luteum of intact rats clearly indicated that the 20α - hsd gene is not expressed in corpus lutea that are actively secreting progesterone , but increases markedly after the corpus luteum undergoes luteolysis . in addition to the specific examples demonstrated below , other prokaryotic and eukaryotic expression systems may be used to express a non - naturally occurring 20α - hsd protein . [ see current protocols in molecular biology , eds . ausubel et al ., wiley and sons , new york , 16 . 12 . 1 - 16 . 14 . 13 ( 1996 ) and u . s . pat . no . 5 , 594 , 104 , incorporated herein by reference ]. standard procedures of dna manipulation and transfection were used to construct plasmids and expression vectors [ sambrook et al ., molecular cloning : a laboratory manual , cold spring harbor laboratory press , cold spring harbor , n . y . ( 1989 )]. more particularly , a dna fragment of 1 . 2 kb containing the entire coding region of 20α - hsd was removed from pbluescript vector by ecori and xhoi digestion . the purified ecori - xhoi fragment was then ligated into the ecori and xhoi cloning sites of the pgex - 4t - 2 vector ( pharmacia , piscataway , n . j . ), which is a glutathione - s - transferase ( gst ) fusion protein expression vector . the construct was then transfected into a bacterial host , e . coli dh5α . although other bacterial hosts may be used . the correct orientation of the translational reading frame for gst - 20α - hsd fusion protein was confirmed by dna sequencing . 200 μl of overnight culture containing the expression vector described above ( e . coli dh5α transfected with gst - 20 - hsd cdna ) was inoculated into 200 ml fresh , prewarmed 2 × ytg medium ( 16 g / l tryptone , 10 g / l yeast extract and 5 g / l nacl ) containing 100 mg / ml of ampicillin . the culture was incubated at 37 ° c . with shaking until an absorption reading between 1 . 2 and 2 . 0 at 600 nm was achieved . subsequently , isopropyl - β - d - thiogalactopyranoside ( iptg ) was added to a final concentration of 01 nm . the incubation was continued for an additional 4 hours . the culture was centrifuged and the pelleted bacteria were resuspended in pbs / triton x - 100 , sonicated and mixed gently at room temperature for 30 minutes . the suspension was then centrifuged at 1200 × g for 10 minutes . the supernatant containing recombinant 20α - hsd - gst fusion protein was further processed to obtain pure 20α - hsd using standard protocols [ hakes and dixon , anal . biochem . 202 : 293 - 298 ( 1992 )]. briefly , a 50 % slurry of glutathione sepharose 4b beads was mixed with supernatant ( approximately 2 ml of the 50 % slurry of beads to each 100 ml supernatant ) and agitated at room temperature . at the end of the incubation , the beads were collected by centrifugation and washed several times with 10 volumes of pbs . after final centrifugation , the glutathione beads ( approximately 2 ml ) with bound 20α - hsd - gst fusion protein were resuspended in 1 bed volume of pbs and digested with 500 cleavage units of bovine plasma thrombin at room temperature for 16 hours . after thrombin cleavage of the fusion protein , the beads with bound gst were separated from the recombinant 20α - hsd protein by centrifugation at 10 , 000 × g for 10 minutes at 4 ° c . typically , 500 μg of recombinant 20α - hsd was obtained from 200 ml of bacterial cell culture . c . insect cells : construction of a 20α - hsd cdna - containing baculovirus transfer vector ; transfection and isolation of recombinant baculovirus the expression and purification of recombinant 20α - hsd from insect cells described herein was previously undertaken and demonstrated by mao et al . [ endocrinology , 138 ( 1 ): 182 - 190 ( 1997 )]. a vector containing rat luteal 20α - hsd cdna clone was digested with xhoi and blunt ended with klenow dna polymerase . thereafter , a 20α - hsd cdna fragment was excised using bamh1 . the resulting 1 . 2 kb fragment was then inserted into the pbluebaciii vector to create pbluebaciii - 20α - hsd . the cdna insert of 20α - hsd is located immediately downstream of the polyhedrin promotor . the correct orientation of 20α - hsd cdna in pbluebaciii - 20α - hsd was analyzed by dna sequencing and was shown to be correct . recombinant baculovirus , acnpv [ autographa californica nuclear polyhidrosis virus ; in vitrogen , inc ., san diego , calif .] containing the 20α - hsd sequence under the transcriptional control of the polyhedrin promotor was produced by in vivo homologous recombination via the method of webb and summer [ technique 2 : 173 - 188 ( 1990 )]. in order to express 20α - hsd , 2 μg of the pbluebaciii - 20α - hsd vector described above were mixed with 1 mg of linearized wild type acnpv viral dna and co - transfected into spodoptera frugiperda [ sf - 9 ; in vitrogen , inc ., san diego , calif . insect cells by cationic liposome - mediated gene transfer according to the protocol suggested by the manufacturer . after 120 hours post - infection , the medium was collected , centrifuged , diluted 10 to 10 , 000 - fold and then used to infect a fresh monolayer of sf - 9 cells . to facilitate the identification of viral plaques , a layer of 0 . 625 % agarose containing 75 μg / ml x - gal ( 5 - bromo - 4 - chloro - 3 - inolyl - β - d glactopyranoside was applied to the transfected cells . after 6 - 8 days , recombinant viruses , designated acnpv - 20α - hsd , were detected by the formation of blue plaques . several blue plaques were picked and subjected to three cycles of plaque purification until cells with inclusion bodies were not detected . after purification , several strains of recombinant acnpv &# 39 ; s were obtained . sf - 9 insect cells were maintained in grace &# 39 ; s medium ( gibco brl products , gaithersburg , md .) supplemented with 10 % fetal bovine serum , supplemented with yeastolate ( 3 . 3 g / l ), lactalbumin hydrolysate ( 3 . 3 g / l ; intermedia ), gentamycin ( 50 μg / ml ; sigma chemical co ., st . louis , mo .) and fungizone ( 2 . 5 μg / ml ; gibco brl products , gaithersburg , md .) in monolayer or suspension culture . the sf - 9 cells were seeded at a density of 2 - 2 . 5 × 10 6 per 60 mm dish or 9 × 10 6 cells per 75 cm 2 flask in grace &# 39 ; s medium . after the cells were attached , the medium was removed and a volume of virus inoculum sufficient to infect the cells ( in log phase of growth ) at a multiplicity of 3 or 4 to 1 was added . after incubation at 27 ° c . for 1 . 5 hours , the inoculum was replaced with fresh grace &# 39 ; s medium and incubated at 27 ° c . for up to 5 days ; infected insect cells were collected and used for purification of recombinant 20α - hsd . recombinant 20α - hsd was purified by the combination of procedures described by noda et al . [ biochim biophys . acta . 1079 : 112 - 118 ( 1986 )] and de la llosa - hermier et al . [ biochimie 784 : 1117 - 1120 ( 1992 )]. in brief , the culture was centrifuged and the resulting pellet was resuspended in 30 ml of homogenization buffer containing 10 mm potassium phosphate buffer ( ph 8 . 0 ), 1 mm edta and 10 mm dithiothreitol ( buffer a ), homogenized in a potter - elvehjem homogenizer at 4 ° c . the homogenate was sonicated and centrifuged for 10 minutes at 1 , 000 × g to remove nuclei , unbroken cells and cell debris . the supernatant from the low speed spin was centrifuged for 1 hour at 100 , 000 × g and the resultant supernatant was loaded onto a deae - cellulose column ( 1 . 6 × 10 cm ) that had been previously equilibrated with buffer a . the columns was eluted with a 120 ml liners gradient of nacl ( 0 - 500 mm ) in the equilibration buffer . the fractions containing the enzyme activity ( detected by spectrophotometric assay method , described below ) were pooled , concentrated and dialyzed against buffer a . after dialysis , the sample was applied to a 1 . 2 × 12 cm matrex gel green dye affinity column [ gibco brl , gaithersburg , md .] pre - equilibrated with buffer a . the active fractions were combined , concentrated by ultrafiltration dialyzed against buffer a and further purified by affinity chromatography on red - sepharose ( 1 . 2 × 10 cm ). the enzyme was eluted from the column in buffer a containing 1 mm nadph . fractions containing the enzyme were combined , concentrated and dialyzed against buffer a containing 20 % glycerol before storage at - 80 ° c . the characterization and analysis of the non - naturally occurring ( recombinant ) 20α - hsd from a bacterial expression system or an insect expression system described herein was previously reported by mao et al . [ endocrinology , 138 ( 1 ): 182 - 190 ( 1997 )]. immunoblotting of expressed recombinant 20α - hsd ( either from the bacterial or insect expression systems ) was performed using the polyclonal 20α - hsd anti - rat antibody [ albarracin et al . endocrinology , 134 ( 1 ): 2453 - 2460 ( 1994 )]. the fusion protein expressed in either e . coli or sf9 cells ( see example 2 , above ) were subjected to sds - page under reducing conditions on a gel containing 7 . 5 % polyacrylamide and then transferred to a nitrocellulose membrane . after transfer , the blots were blocked with 3 % bsa and then probed with the anti - 20α - hsd antibody or pre - immune serum . the immunoreactive proteins were visualized using alkaline phosphatase conjugated anti - rabbit igg as a secondary antibody . results indicated a protein form of having a molecular mass of approximately 37 kda . this result agreed with the calculated molecular mass of the encoded protein [ mao et al ., biochem . biophys . res . com . 201 : 1289 - 1295 ( 1994 )] and with the native enzyme detected in the corpus luteum [ albarracin et al ., endocrinology 134 : 2453 - 2460 ( 1994 )]. enzyme activity of the recombinant 20α - hsd was determined by the rate of conversion of [ 1 - 2 3 h ]- 20α - hydroxy - pregn - 4 - ene - 3 - one ( 20α - hydroxprogesterone ) to [ 1 , 2 3 h ] progesterone in the presence of nadph as described by jones & amp ; hsueh [ j . biol . chem . 256 : 1248 - 1254 ( 1981 )]. enzyme activity was measured in this manner due to the fact that in an in vitro setting the reaction may be reversed , i . e . conversion of 20α - hydroxyprogesterone to progesterone . the assay mixtures ( 0 . 05 ml ) contained 100 μm [ 1 , 2 3 h ] hydroxyprogesterone [ dupont - new england nuclear research products , boston mass .] ( approximately 1 × 10 6 dpm ), 0 . 1 m tris - hcl , ph 8 . 0 ; 0 . 5 mm dithiothreitol , 1 mm edta , 10 mm nicotinamide , 300 μm nadp and from about 0 . 025 to about 2 . 5 μg of purified recombinant 20α - hsd , prepared as described above . following incubation at 37 ° c . for 30 minutes , the [ 3 h ] progesterone content of each sample was determined after isolation by thin layer chromatography isolation . one unit of enzyme activity is defined as that amount of enzyme catalyzing the formation of 1 nmol of [ 3 h ] progesterone / minute from [ 1 , 2 3 h ] hydroxyprogesterone . specific activity is expressed as units / min / mg protein . the protein concentration was determined by the bradford method using bovine serum albumin [ sigma chemical co , st . louis , mo .] as the standard [ bradford , anal . biochem . 72 : 248 - 254 ( 1976 )]. in some cases , enzyme activity was also determined spectrophotometrically either by measuring the reduction of nadp or oxidation of nadph [ mori et al ., j . steroid biochem . 11 : 1443 - 1449 ( 1979 ); pongsawasdi et al ., biochim biophys . acta . 799 : 51 - 58 ( 1984 ); noda et al ., biochim biophys . acta . 1079 : 112 - 118 ( 1991 )]. the purified preparation of non - naturally occurring 20α - hsd from the bacterial expression system showed high levels of enzymatic activity . more particularly , the average specific activity of the purified preparations was 332 ± 47 nmol / min / mg protein , and activity was concentration ( enzyme protein ) and time dependent . enzyme activity was not detected using the gst - 20α - hsd fusion protein alone . sf - 9 cells infected with the recombinant baculovirus ( see example 1 , parts c - d ) containing 20α - hsd cdna ( acnpv / 20α - hsd ) were assayed for 20 - α - hsd activity as a function of days post - infection . results indicated enzyme activity in the total cell lysates was maximal ( 750 - 893 pmol / min / mg protein ) at 2 days post - infection , with a steady and substantive decline in 20α - hsd activity between days 3 - 6 . since the cdna and predicted amino acid sequence of the rat luteal 20α - hsd is related to bovine lung pgf 2 α synthase and aldose / aldehyde reductase ( pgf 2 α synthase : 75 % nucleotide identity and 69 % amino acid identity , aldose / aldehyde reductase : less than 50 % nucleotide sequence homology , [ mao et al . biochem . biophys . res . comm . 201 : 1289 - 1295 , 1994 ; miura et al . biochem . j . 299 : 561 - 567 , 1994 and lacy et al . mol . endocrinol . 7 : 58 - 66 , 1993 ], analysis was conducted to see whether recombinant 20α - hsd was active as a aldose / aldehyde reductase and / or prostaglandin endoperoxide synthase . to test for prostaglandin endoperoxide synthase type catalytic activity of recombinant 20α - hsd , both cyclooxygenase activity ( which converts arachidonic acid into the hydroperoxide , pgg 2 ) and peroxidase activity ( which reduces pgg 2 and other hydroperoxides to the corresponding alcohol , such as pgh 2 ) were measured . the cyclooxygenase assay was performed by following the conversion of [ 3 h ] arachidonic acid [ dupont - new england nuclear research products , boston , mass .] to [ 3 h ] phg 2 and [ 3 h ] phe2 [ mitchell et al . proc . natl . acad . sci . usa 90 : 11693 - 11697 , 1994 ]. peroxidase activity was measured by monitoring the oxidation of n , n , n &# 39 ;, n &# 39 ;, tetramethyl - p - phenylenediamine at 611 nm [ iwata et al ., arch . biochem . biophys . 282 : 70 - 77 ( 1990 )]. neither peroxidase not cyclooxygenase activity was detected in the purified preparations recombinant 20α - hsd from either expression systems . aldo - keto reductase activity of the recombinant 20α - hsd was assayed spectrophotometrically by measuring the rate of oxidation of nadph at 340 nm at 37 ° c . using a saturating concentration of benzaldehyde , 2 - nitrobenzaldehyde , d , l - glyceraldehyde methylgloxal , 9 , 10 - phenanthrequinone or d - galactose [ azhar et al ., biochemistry 26 : 7047 - 7057 ( 1987 )]. as shown in table 1 ( data from 20α - hydroxyprogesterone is shown for comparison purposes only ), the purified recombinant 20α - hsd proteins were quite active against the general substrates of aldose / aldehyde reductase . more particularly , 20α - hsd reduced benzaldehyde , 4 - nitrobenzaldehyde , and d , l - glyceraldehyde very efficiently . maximal activity was noted with either benzaldehyde or d , l - glyceraldehyde , although these results were only approximately a third of the activity observed with 20α - hydroxyprogesterone . further , the activities of 20α - hsd produced in bacterial and insect cells were similar . table 1______________________________________aldose / aldehyde reductase activity of recombinant 20α - hsd 20α - hsd activity ( nmol / min / mg protein ) expressed insubstrate e . coli sf - 9 cells______________________________________20α - hydroxyprogesterone ( 100 μm ) 327 258 benzaldehyde ( 250 μm ) 122 81 4 - nitrobenzaldehyde ( 1 mm ) 103 89 . sub . d , l - glyceraldehyde ( 250 mm ) 115 96 methylglyoxal ( 1 mm ) 67 50 9 , 10 - phenanthrenquinone ( 100 μm ) 48 32 . sub . d - galactose ( 400 mm ) 65 45______________________________________ results are the means of duplicate determinations from three separate experiments . as potential sites for phosphorylation by serine / threonine and tyrosine kinase have been previously identified [ mao et al . biochem . biophys . res . com . 201 : 1289 - 1295 ], evaluations were undertaken to test the possibility that phosphorylation modulates 20α - hsd activity . purified recombinant 20α - hsd ( of the bacterial expression system ) was incubated with various protein kinases after an initial incubation with alkaline phosphatase ( to ensure that the protein was in a non - phosphorylated state ) and subsequently assayed for 20α - hsd activity . more particularly , purified bacterially expressed recombinant 20α - hsd was first incubated in 500 ml 20 nm tris - hcl ( ph 8 ), 1 mm mgcl 2 , 1 mg / ml bsa , 0 . 5 mm dithiothreitol , and 60 u alkaline phosphatase coupled to agarose beads for 30 min . at 30 ° c . after centrifugation , the supernatant containing 20α - hsd was used as a substrate in various in vitro kinase assays . the protein kinase a ( pka ), protein kinase c ( pkc ) and insulin receptor - associated tyrosine kinase activities were measured as described previously [ raz et al ., biochem . j . 269 : 603 - 607 ( 1990 ), azhar et al ., am j . physiol , 260 : e1 - e7 ( 1991 )]. src kinase ( p60 src ) activity was assayed as described by simonson and herman [ simonson et al ., j . biol chem ., 268 : 9347 - 9357 ( 1993 )]. to test the relationship between phosphorylation and alteration of 20α - hsd activity , aliquots of 20α - hsd ( 1 - 2 μg ) were incubated with 25 mm pipes , ph 6 . 8 , containing 10 mm mg acetate , 100 μm atp [ γ 32 p ] atp [ amersham , arlington heights , ill .] to monitor phosphorylation , and egta ( 0 . 5 mm ) plus purified rat liver pkc ( 4 μg ; 10 u ) or pkc , phosphatidylserine ( 250 μg / ml ), diolein ( 10 μg / ml ), plus cacl 2 , and 250 μm atp ( or [ γ 32 p ] atp ) to monitor phosphorylation and the catalytic subunit of pka ( 10 u ) for 60 min . at 30 ° c . reactions without atp were performed under identical conditions . the catalytic activities of phosphorylated and non - phosphorylated forms of 20α - hsd were determined radiochemically as described above . after treatment with various kinases ( pkc , pka , insulin receptor tyrosine kinase , src kinase ( p 60src )), the recombinant 20α - hsd was assayed for activity . the results indicated that the recombinant 20α - hsd was readily phosphorylated by in vitro incubation with purified pka or pkc in the presence of [ γ - 32 p ] atp . phosphoamino - acid analysis of phosphorylated 20α - hsd confirmed the [ 32 p ] phosphorylation was restricted to serine and threonine residues , and label was found predominantly on serine residues . in contrast , members of the tyrosine kinase family , including src kinase and insulin - receptor - associated tyrosine kinase , failed to phosphorylate 20α - gsd . however , all kinases tested rapidly phosphorylated their respective substrates ( pkc : histone iiis ; pka : histone v ; insulin receptor tyrosine kinase : polyglu : tyr ( 4 : 1 ); src kinase : cdc2 ( 6 - 20 ) peptide ). also when the recombinant 20α - hsd was phosphorylated with pkc in the presence of atp - mg 2 + , diacylglycerol , and phosphatidylserine , 20α - hsd activity was unaffected . further , 20α - hsd was not significantly affected by phosphorylation with pka . taken together , these results suggest that phosphorylation of 20α - hsd is not essential for catalytic activity . to determine substrate specificity of recombinant 20α - hsd , the oxidation / reduction of several steroid substrates was also studied . assays were as described above in example 3 , part b , i . e . reduction of nadp or oxidation of nadph [ mori et al ., j . steroid biochem . 11 : 1443 - 1449 ( 1979 ); pongsawasdi et al ., biochim biophys . acta . 799 : 51 - 58 ( 1984 ); noda et al ., biochim biophys . acta . 1079 : 112 - 118 ( 1991 )]. results shown in table 2 indicate that the recombinant 20α - hsd not only reduced progesterone and 17α - hydroxyprogesterone , but also oxidized 20α - hydroxyprogesterone . however , compared to 20α - hydroxyprogesterone , 20α - hsd activity toward 17α - hydroxyprogesterone was lower , and its activity with progesterone was relatively higher . further , the recombinant 20α - hsd did not act on corticosterone or 5α - dihydrotestosterone . table 2______________________________________substrate specificity of recombinant 20 - α - hsd recombinant 20α hsd activity ( nmol / min / mg protein ) expressed insubstrate e . coli sf - 9 cells______________________________________progesterone 459 352 20α - hydroxyprogesterone 321 250 17α - hydroxyprogesterone 97 85 corticosterone nd nd______________________________________ the enzyme activity was measured spectrophotometrically . the data are expressed as the mean of duplicate determinations from three separate experiments . nd , not detected . since the 20α - hsd contains a putative n - glycosylation site [ mao et al ., biochem . biophys . res . comm . 201 ( 3 ): 1289 - 1295 ( 1994 )] experiments were conducted to determine whether glycosylation was required for catalytic activity . a comparison of the catalytic parameters of a non - glycosylated ( recombinant 20α - hsd from bacteria ) and glycosylated ( recombinant 20α - hsd from insects cells ) forms of 20α - hsd . specifically , kinetic constants were determined with 20α - hydroxyprogesterone as a substrate and nadp as a cofactor . the results obtained with different amount of 20α - hydroxyprogesterone ( 1 - 100 μm ) and a fixed concentration of nadp ( 1 mm ) using bacterially expressed recombinant enzyme indicate that enzyme activity reached a saturation level around 10 μm 20α - hydroxyprogesterone . the data were transformed into a reciprocal lineweaver - burk plot to calculate the k m and maximum velocity ( v max ) values . the initial velocity experiments were also performed under conditions where nadp concentrations varied ( 1 - 1000 μm ) at a fixed saturating concentration of 20α - hydroxyprogesterone ( 100 μm ). the maximal 20α - hsd activity was obtained with about 100 μm nadp . similar data were obtained using the purified preparations of 20α - hsd expressed in insect cells . kinetic parameters obtained from bacteria and insect cell - derived 20α - hsd are summarized in table 3 . the calculated k m values of bacterially expressed enzyme for 20α - hydroxyprogesterone and nadp were 5 . 9 and 9 . 5 μm , respectively , the corresponding values for baculovirus - expressed 20α - hsd were 5 . 8 and 9 . 6 μm , respectively . thus , the enzyme preparations from two different sources had similar values . however , the recombinant 20α - hsd expressed in e . coli had v max values that were 20 - 30 % higher than those of the recombinant 20α - hsd expressed in insect cells and when measured using similar assay conditions . these results suggest that glycosylation of 20α - hsd may not be required for the expression of catalytic activity . table 3______________________________________steady state kinetic parameters of recombinant 20α - hsd recombinant 20a - hsd expressed inparameters e . coli sf - 9 cells______________________________________mean specific activity ± se ( nmol / min - mg 332 ± 47 259 ± 36 protein ) k . sub . m , 20α - hydroxyprogesterone ( μm ) 5 . 9 5 . 8 k . sub . m , nadp ( μm ) 9 . 5 9 . 6 v . sub . max , 20α - hydroxyprogesterone ( nmol / min - mg 347 265 protein ) v . sub . max , nadp ( nmol / min - mg protein ) 334 259______________________________________ in still another embodiment , the present invention provides antibodies immunoreactive with a 20α - hsd . in a preferred embodiment the antibody specifically binds to a 20α - hsd having an amino acid sequence set out in seq id no . 2 . preferably , an antibody of the invention is a monoclonal antibody . means for preparing and characterizing antibodies are well known in the art [ see , e . g ., antibodies &# 34 ; a laboratory manual , harlow et al ., cold spring harbor laboratory , ( 1988 )]. briefly , polyclonal antibodies are prepared by immunizing an animal with an immunogen comprising a polypeptide of the present invention , and collecting antisera from that immunized animal . a wide range of animal species can be used for the production of antisera . typically an animal used for production of anti - antisera is a rabbit , a mouse , a rat , a hamster or a guinea pig . because of the relatively large blood volume of rabbits , a rabbit is a preferred choice for production of polyclonal antibodies . antisera collected from the rabbit may be affinity purified according to methods well known to those of ordinary skill in the art ( harlow et al ., supra ). as is well known in the art , a given polypeptide may vary in its immunogenicity . it is often necessary therefore to couple the immunogen ( e . g ., a polypeptide or polynucleotide of the present invention ) with a carrier . exemplary and preferred carriers are keyhole limpet hemocyanin ( klh ) and bovine serum albumin ( bsa ). other albumins such as ovalbumin , mouse serum albumin or rabbit serum albumin can also be used as carriers . means for conjugating a polypeptide to a carrier protein are well known in the art and include glutaraldehyde and m - maleimidobenzoyl - n - hydroxysuccinimide ester . as is also well known in the art , immunogenicity to a particular immunogen can be enhanced by the use of non - specific stimulators of the immune response known as adjuvants . exemplary and preferred adjuvants include complete freund &# 39 ; s adjuvant , incomplete freund &# 39 ; s adjuvants and aluminum hydroxide adjuvant . the amount of immunogen used of the production of polyclonal antibodies varies inter alia , upon the nature of the immunogen as well as the animal used for immunization . a variety of routes can be used to administer the immunogen ( e . g ., subcutaneous , intramuscular , intradermal , intravenous and intraperitoneal ). the production of polyclonal antibodies is monitored by sampling blood of the immunized animal at various points following immunization and assaying for antibody levels . when a desired titer of antibodies is obtained , the immunized animal can be bled and the serum isolated and stored . antibodies may then be isolated from the serum by methods well known in the art . a monoclonal antibody of the present invention can be readily prepared through use of well - known techniques such as those exemplified in u . s . pat . no . 4 , 196 , 265 , herein incorporated by reference . typically , a technique involves first immunizing a suitable animal with a selected antigen ( e . g ., a polypeptide or polynucleotide of the present invention ) in a manner sufficient to provide an immune response . rodents such as mice and rats are preferred animals . spleen cells from the immunized animal are then fused with cells of an immortal myeloma cell . where the immunized animal is a mouse , a preferred myeloma cell is a murine ns - 1 myeloma cell . the fused spleen / myeloma cells are cultured in a selective medium to select fused spleen / myeloma cells from the parental cells . fused cells are separated from the mixture of non - fused parental cells , for example , by the addition of agents that block the de novo synthesis of nucleotides in the tissue culture media . exemplary and preferred selection agents are aminopterin , methotrexate and azaserine . aminopterin and methotrexate block de novo synthesis of both purines and pyrimidines , whereas azaserine blocks only purine synthesis . where aminopterin or methotrexate is used , the media is supplemented with hypoxanthine and thymidine as a source of nucleotides . where azaserine is used , the media is supplemented with hypoxanthine . this culturing provides a population of hybridomas from which specific hybridomas are selected . typically , selection of hybridomas is performed by culturing the cells by single - clone dilution in microtiter plates , followed by testing the individual clonal supernants for reactivity with antigen - polypeptides . the selected clones can then be propagated indefinitely to provide the monoclonal antibody . by way of specific example , to produce an antibody according to the present invention , mice are typically injected intraperitoneally with between about 1 - 200 μg of an antigen comprising a polypeptide of the present invention . b lymphocyte cells are stimulated to grow by injecting the antigen in association with an adjuvant such as complete freund &# 39 ; s adjuvant ( a non - specific stimulator of the immune response containing killed mycobacterium tuberculosis ). at some time ( e . g ., at least two weeks ) after the first injection , mice are boosted by injection with a second dose of the antigen mixed with incomplete freund &# 39 ; s adjuvant . a few weeks after the second injection , mice are tail bled and the sera titered by immunoprecipitating against radiolabeled antigen . preferably , the process of boosting and titering is repeated until a suitable titer is achieved . the spleen of the mouse with the highest titer is removed and the spleen lymphocytes are obtained by homogenizing the spleen with a syringe . typically , a spleen from an immunized mouse contains approximately 5 × 10 7 to 2 × 10 8 lymphocytes . mutant lymphocyte cells known as myeloma cells are obtained from laboratory animals in which such cells have been induced to grow by a variety of well - known methods . myeloma cells lack the salvage pathway of nucleotide biosynthesis . because myeloma cells are tumor cells , they can be propagated indefinitely in tissue culture , and are thus denominate immortal . numerous cultured cells lines of myeloma cells from mice and rats , such as murine ns - 1 myeloma cells , have been established . myeloma cells are combined under conditions appropriate to foster fusion with the normal antibody - producing cells from the spleen of the mouse or rat injected with the antigen / polypeptide of the present invention . fusion conditions include , for example , the presence of polyethylene glycol . the resulting fused cells are hybridoma cells . like myeloma cells , hybridoma cells grow indefinitely in culture . hybridoma cells are separated from unfused myeloma cells by culturing in a selection medium such as hat media ( hypoxanthine , aminopterin , thymidine ). unfused myeloma cells lack the enzymes necessary to synthesize nucleotides from the salvage pathway because they are killed in the presence of aminopterin , methotrexate , or azaserine . unfused lymphocytes also do not continue to grow in tissue culture . thus , only cells that have successfully fused ( hybridoma cells ) can grow in the selection media . each of the surviving hybridoma cells produces a single ( monoclonal ) antibody . these cells are then screened for the production of the specific antibody immunoreactive with an antigen / polypeptide of the present invention by well known methods . single cell hybridomas are isolated by limiting dilutions of the hybridomas . the hybridomas are serially diluted many times and , after the dilutions are allowed to grow , the supernatant is tested for the presence of the monoclonal antibody . the clones producing that antibody are then cultured in large amounts to produce an antibody of the present invention in convenient quantity . in yet another embodiment , antibodies may also be produced , by the methods described supra , against 20α - hydroxprogesterone ( the metabolite of progesterone reduction by 20α - hsd ) and progesterone ( the natural substrate of 20α - hsd ). the present invention also relates to diagnostic applications , wherein individuals are screened for the predisposition to spontaneous abortions . as discussed previously , it is possible that a significant number of spontaneous abortions are due to early expression of 20α - hsd . therefore , in one embodiment , circulating levels of 20α - hsd are determined ( e . g ., for those individuals at - risk for spontaneous abortions ). specifically , antibodies ( of example 4 ) may be used to quantify circulating levels of 20α - hsd . a certain percentage of the population of women predisposed to spontaneous abortions may be expected to have higher levels of 20α - hsd , as compared to normal subjects . 20α - hsd levels may be determined by such well known techniques [ e . g . enzyme - linked immunosorbent assay ( elisa )) as set forth in current protocols in molecular biology , eds . ausubel et al ., wiley interscience , ( 1997 )]. in a second embodiment , circulating levels of 20α - hydroxprogesterone ( the metabolite of progesterone reduction by 20α - hsd ) are determined ( e . g ., for those individuals at - risk for spontaneous abortions ). determination of the circulating levels of 20α - hydroxyprogesterone , is an indirect determination of the levels of 20α - hsd , i . e ., one would expect higher levels of 20αhydroxyprogesterone in individuals with increased expression of 20α - hsd , as compared to normal subjects . specifically , antibodies ( of example 4 ) may be used to quantify circulating levels of 20α - hydroxprogesterone . 20α - hydroxyprogesterone levels may be determined by such well known techniques [ e . g . enzyme - linked immunosorbent assay ( elisa )) as set forth in current protocols in molecular biology , eds . ausubel et al ., wiley interscience , ( 1997 )]. in a third embodiment , circulating levels of progesterone ( the natural substrate of 20α - hsd ) are determined ( e . g ., for those individuals at - risk for spontaneous abortions ). determination of the circulating levels of progesterone , would be an indirect determination of the levels of 20α - hsd , i . e ., one would expect low levels in individuals with increased expression of 20α - hsd , as compared to normal subjects specifically , antibodies ( of example 4 ) may be used to quantify circulating levels of progesterone . progesterone levels may be quantified by such well known techniques [ e . g . enzyme - linked immunosorbent assay ( elisa )) as set forth in current protocols in molecular biology , eds . ausubel et al ., wiley interscience , ( 1997 )]. briefly , in one version of an elisa assay ( i . e ., antibody - sandwich elisa ), unlabeled capture antibody to the antigen of interest , i . e ., 20α - hsd , 20α - hydroxprogesterone , or progesterone is bound to the bottom of a microplate well ; unbound capture antibody is removed by washing the microplate . a solution ( e . g . serum or plasma ) containing an unknown amount of antigen ( i . e ., 20α - hsd , 20α - hydroxprogesterone , or progesterone ) is added for a set incubation time - period . after binding of the antigen to the antibody , unbound antigen is washed out and a second enzyme - labeled antibody directed against the antigen is added . unbound enzyme - labeled antibody is removed by washing and a substrate to the enzyme is added . once the enzyme has acted upon the substrate , a color will develop . standard colorimetric techniques and analysis are employed to determine levels of the antigen ( i . e ., microtiter plate reader ). those of skill in the art will readily recognize that other forms of the elisa may be used to quantify levels of circulating 20α - hsd , 20α - hydroxprogesterone , or progesterone ( e . g ., direct competitive elisa ). further , in order to determine the normal and abnormal range of levels ( of 20α - hsd 20α - hydroxprogesterone , or progesterone , levels will be determined ( by the method described herein ) in normal ( not at - risk for spontaneous abortions ) individuals . levels will be determined in both pregnant and non - pregnant individuals , at various ages , and at various stages of the menstrual cycle . also contemplated with the above embodiments of methods of screening for individuals predisposed to spontaneous abortions are diagnostic kits for the determination of serum levels of 20α - hsd , 20α - hydroxyprogesterone , or progesterone . the diagnostic kits may comprise a known amount of antibody substance immunologically reactive to the substance or enzyme of interest , buffers , diluents , label for the detection of the substance of interest , and directions for the use of said diagnostic kit . the aim of these experiments was to determine whether administration of recombinant 20α - hsd to pregnant animals would lead to interruption in pregnancy . although the following is exemplified by administration of rats , those of skill in the art will readily appreciate that other mammals may be treated in the same manner . pregnant sprague - dawley rats were treated with purified 20α - hsd produced by a bacterial expression system ( see example 1 ) to assess the effect of the enzyme on ( 1 ) progesterone levels and ( 2 ) the possible termination of pregnancy . more particularly , animals were divided into two treatment groups ( 7 rats per group : 6 receiving treatment , 1 control ) and were injected ( intraperitoneally ) with the purified recombinant 20α - hsd and an eqimolar dose of nadph . injections were administered on day 8 of pregnancy and continued for 72 hours . group 1 received intraperitoneal injections of the purified 20α - hsd ( 167 μg with an equimolar dose of nadph ) every 4 hours , continuing for 72 hours . group 2 received intraperitoneal injections of the purified 20α - hsd ( 250 μg with an equimolar dose of nadph ) every 6 hours , continuing for 72 hours . the control treatment groups received an equal amount of gst alone with an eqimolar dose of nadph . blood samples were collected every 12 hours via jugular veins . serum progesterone levels were determined by standard radioimmunoassay techniques [ gibori et al ., endocrinology 100 : 1483 - 1495 ( 1977 )]. administration of 20α - hsd caused a marked decrease in circulating progesterone and termination of pregnancy within 72 hours of treatment . specifically , administration of 20α - hsd caused serum progesterone levels to decline significantly within 48 hours after beginning treatment in group 1 ( 4 hour treatments ). further , serum progesterone levels significantly declined after 60 hours in group 2 ( 6 hour treatments ). administration under the group 1 protocol ( 4 hour injections ) caused spontaneous abortions . more specifically , vaginal bleeding was noted prior to the 72 hour end point and laparoscopy ( at the 72 hour end point to check for fetal ) confirmed the abortive effects . 5 animals aborted totally , with 2 animals partially aborting . animals treated with gst and nadph did not show a similar decrease in circulating progesterone levels or termination of pregnancy . as discussed above , although rats were used to exemplify use of 20α - hsd as , those of skill in the art will readily appreciate that other mammals , including humans , may be treated in a similar manner . specifically , a pharmaceutical composition comprising the 20α - hsd and a pharmaceutically acceptable carrier , diluent and / or adjuvant may be administered to a mammal ( including a human ) to reduce circulating levels of progesterone and thereby inhibit the maintenance of pregnancy and / or preventing implantation leading to pregnancy . although the present invention has been described in terms of preferred embodiments , it is intended that the present invention encompass all modifications and variations that occur to those skilled in the art upon consideration of the disclosure herein , and in particular those embodiments that are within the broadest proper interpretation of the claims and their requirements . all literature cited herein is incorporated by reference . __________________________________________________________________________ # sequence listing - - - - ( 1 ) general information : - - ( iii ) number of sequences : 2 - - - - ( 2 ) information for seq id no : 1 : - - ( i ) sequence characteristics : ( a ) length : 1233 base - # pairs ( b ) type : nucleic acid ( c ) strandedness : single ( d ) topology : linear - - ( ii ) molecule type : cdna - - ( ix ) feature : ( a ) name / key : cds ( b ) location : 46 .. 1014 - - ( xi ) sequence description : seq id no : 1 : - - ggcacgagag aaagcgactc ttctagggaa gagcagcatc tgaga atg - # aat tcc 54 - # - # met asn s - # er - # - # 1 - - aaa att cag aag atg gag tta aac gat ggt ca - # c tcc atc cct gta ctg102 lys ile gln lys met glu leu asn asp gly hi - # s ser ile pro val leu 5 - # 10 - # 15 - - ggc ttt ggc acc tat gca acc gaa gag aat ct - # c aga aaa aag tct atg150 gly phe gly thr tyr ala thr glu glu asn le - # u arg lys lys ser met 20 - # 25 - # 30 - # 35 - - gag tcc acg aaa ata gct ata gat gtt ggg tt - # c cgc cat att gat tgt198 glu ser thr lys ile ala ile asp val gly ph - # e arg his ile asp cys 40 - # 45 - # 50 - - tct cac ttg tac cag aat gaa gaa gag ata gg - # t cag gcc att gta agc246 ser his leu tyr gln asn glu glu glu ile gl - # y gln ala ile val ser 55 - # 60 - # 65 - - aag att gaa gat ggc act gtg aaa agg gaa ga - # t ata ttc tat act tca294 lys ile glu asp gly thr val lys arg glu as - # p ile phe tyr thr ser 70 - # 75 - # 80 - - aag ctt tgg tca act tcc cat cgt cca gag tt - # g gtc aga ccc agc ttg342 lys leu trp ser thr ser his arg pro glu le - # u val arg pro ser leu 85 - # 90 - # 95 - - gaa aat tca ctg agg aaa ctt aat ttg gac ta - # t gta gac ctc tat ctc390 glu asn ser leu arg lys leu asn leu asp ty - # r val asp leu tyr leu 100 1 - # 05 1 - # 10 1 -# 15 - - att cat ttc ccg gta tct ctg aag cca ggg ga - # t gag ctt tta cctcaa 438 ile his phe pro val ser leu lys pro gly as - # p glu leu leu pro gln 120 - # 125 - # 130 - - gat gag cat gga aac tta ata ctt gac aca gt - # g gat ctc tgc gac acc486 asp glu his gly asn leu ile leu asp thr va - # l asp leu cys asp thr 135 - # 140 - # 145 - - tgg gag gcc atg gag aag tgt aag gat gca gg - # a ttg gcc aag tcc atc534 trp glu ala met glu lys cys lys asp ala gl - # y leu ala lys ser ile 150 - # 155 - # 160 - - ggg gtg tcc aac ttt aac cgc agg cag ctg ga - # g aag atc ctg aat aag582 gly val ser asn phe asn arg arg gln leu gl - # u lys ile leu asn lys165 - # 170 - # 175 - - ccg ggg ctc aag cac agg cct gtg tgc aac ca - # g gta gaa tgc cat ctt630 pro gly leu lys his arg pro val cys asn gl - # n val glu cys his leu 180 1 - # 85 1 - # 90 1 -# 95 - - tat ctc aac cag agc aag ctg ctc gct tac tg - # c aag atg aat gacatc 678 tyr leu asn gln ser lys leu leu ala tyr cy - # s lys met asn asp ile 200 - # 205 - # 210 - - gtt ctg gtt gcc tat ggt gcc ctg gga act ca - # g aga tac aaa tac tgt726 val leu val ala tyr gly ala leu gly thr gl - # n arg tyr lys tyr cys 215 - # 220 - # 225 - - att aat gaa gat acc cca gtt ctc ttg gat ga - # t ccc att ctt tgt acc774 ile asn glu asp thr pro val leu leu asp as - # p pro ile leu cys thr 230 - # 235 - # 240 - - atg gca aag aag tac aag cgg act cca gcc ct - # g att gcc ctt cgc tac822 met ala lys lys tyr lys arg thr pro ala le - # u ile ala leu arg tyr245 - # 250 - # 255 - - cag ctg gag cgt ggg att gtg acc cta gtc aa - # g agt ttc aat gag gag870 gln leu glu arg gly ile val thr leu val ly - # s ser phe asn glu glu 260 2 - # 65 2 - # 70 2 -# 75 - - aga atc aga gag aac ctg cag gtc ttt gat tt - # c cag ttg gct tcagat 918 arg ile arg glu asn leu gln val phe asp ph - # e gln leu ala ser asp 280 - # 285 - # 290 - - gac atg gaa att tta gat aac ctg gac aga aa - # t ctt cgg tac ttt cct966 asp met glu ile leu asp asn leu asp arg as - # n leu arg tyr phe pro 295 - # 300 - # 305 - - gct aat atg ttt aag gct cac cct aac ttt cc - # a ttc tct gat gaa tac 1014 ala asn met phe lys ala his pro asn phe pr - # o phe ser asp glu tyr 310 - # 315 - # 320 - - taagatggca gccctagcca tgagttctgc tcgaagctcc tttgtgtgat gc -# tcgactct 1074 - - cagaggccaa taatacaaca cactgactcc aatccatact gcttagcaac tc -# acccccag 1134 - - tttgagctgt gtctgtacat cggggagcaa attcactaaa ttttcctgct tt -# tctgtaaa 1194 - - taaataaaaa tattttgctt caaaaaaaaa aaaaaaaaa - # - # 1233 - - - - ( 2 ) information for seq id no : 2 : - - ( i ) sequence characteristics : ( a ) length : 323 amino - # acids ( b ) type : amino acid ( d ) topology : linear - - ( ii ) molecule type : protein - - ( xi ) sequence description : seq id no : 2 : - - met asn ser lys ile gln lys met glu leu as - # n asp gly his ser ile 1 5 - # 10 - # 15 - - pro val leu gly phe gly thr tyr ala thr gl - # u glu asn leu arg lys 20 - # 25 - # 30 - - lys ser met glu ser thr lys ile ala ile as - # p val gly phe arg his 35 - # 40 - # 45 - - ile asp cys ser his leu tyr gln asn glu gl - # u glu ile gly gln ala 50 - # 55 - # 60 - - ile val ser lys ile glu asp gly thr val ly - # s arg glu asp ile phe 65 - # 70 - # 75 - # 80 - - tyr thr ser lys leu trp ser thr ser his ar - # g pro glu leu val arg 85 - # 90 - # 95 - - pro ser leu glu asn ser leu arg lys leu as - # n leu asp tyr val asp 100 - # 105 - # 110 - - leu tyr leu ile his phe pro val ser leu ly - # s pro gly asp glu leu 115 - # 120 - # 125 - - leu pro gln asp glu his gly asn leu ile le - # u asp thr val asp leu130 - # 135 - # 140 - - cys asp thr trp glu ala met glu lys cys ly - # s asp ala gly leu ala 145 1 - # 50 1 - # 55 1 -# 60 - - lys ser ile gly val ser asn phe asn arg ar - # g gln leu glu lysile 165 - # 170 - # 175 - - leu asn lys pro gly leu lys his arg pro va - # l cys asn gln val glu 180 - # 185 - # 190 - - cys his leu tyr leu asn gln ser lys leu le - # u ala tyr cys lys met 195 - # 200 - # 205 - - asn asp ile val leu val ala tyr gly ala le - # u gly thr gln arg tyr210 - # 215 - # 220 - - lys tyr cys ile asn glu asp thr pro val le - # u leu asp asp pro ile 225 2 - # 30 2 - # 35 2 -# 40 - - leu cys thr met ala lys lys tyr lys arg th - # r pro ala leu ileala 245 - # 250 - # 255 - - leu arg tyr gln leu glu arg gly ile val th - # r leu val lys ser phe 260 - # 265 - # 270 - - asn glu glu arg ile arg glu asn leu gln va - # l phe asp phe gln leu 275 - # 280 - # 285 - - ala ser asp asp met glu ile leu asp asn le - # u asp arg asn leu arg290 - # 295 - # 300 - - tyr phe pro ala asn met phe lys ala his pr - # o asn phe pro phe ser 305 3 - # 10 3 - # 15 3 -# 20 - - asp glu tyr__________________________________________________________________________ | US-85383997-A |
a dispenser for dispensing a paper sheet from a paper roll having a core . the dispenser can have a spindle made of two separate sleeves . the sleeves are inserted in opposite ends of the core and frictionally retained therein . a support is rotatably mounted in one sleeve to support the roll . a brake member is rotatably mounted in the other sleeve and selectively cooperates therewith to brake rotation of the roll on the support . | the dispenser 1 as shown in fig1 and 2 is used to dispense a sheet 3 of paper , such as towelling , from a roll 5 . the roll 5 is formed by winding the sheet 3 in a coil on a core 9 . the core 9 is preferably made of cardboard . the dispenser 1 has a spindle means 11 , a support 13 , and a brake member 15 . in the preferred embodiment of the invention , the spindle means 11 , as shown in fig2 and 3 , consists of two cylindrical sleeves 17 , 19 . both sleeves 17 , 19 are sized to fit snugly , normally non - rotatably , within the core 9 of the paper roll 5 . the first sleeve 17 is adapted to be inserted into the core 9 from one end 21 of the core , and second sleeve 19 is adapted to be inserted into the core 9 from the other end 23 of the core . both sleeves 17 , 19 can have longitudinal slots 25 , 27 formed in their bodies 29 , 31 and spaced apart about their periphery . the slots 25 , 27 make sleeves 17 , 19 slightly more flexible , allowing the sleeves 17 , 19 to more easily fit into cores having small variations or tolerances in their inner diameter . the first sleeve 17 as shown in fig3 and 4 has a narrow lateral flange 33 at its outer end that abuts the end 21 of the core 9 when the sleeve is inserted into the core . the body 29 of the first sleeve 17 , adjacent its inner end 35 , is angled inwardly to present a conical entry surface 37 making it easy to insert the sleeve into a core . the first sleeve 17 has a central circular opening 39 in its inner end 35 , defined by circular edge 41 . the second sleeve 19 as shown in fig3 and 5 has a short , cylindrical extension 43 at its outer end that is slightly larger in diameter than the body 31 of the sleeve . a stop flange 45 is formed at the junction of the extension 43 and the sleeve body 31 which stop flange abuts against the end 23 of the core 9 when the sleeve 19 is inserted into the core . the outer end of the extension 43 has braking means 47 thereon . the braking means 47 can be in the form of serrated teeth 49 formed in the outer edge of the extension 43 , the teeth pointing outwardly in a direction parallel to the longitudinal axis of the sleeve 19 . the second sleeve 19 is angled inwardly adjacent its inner end 51 to provide an outer conical entry surface 53 and an inner camming surface 55 . a central , circular opening 57 is formed in the inner end 51 , defined by circular edge 59 . the support 13 for the dispenser 1 , as shown in fig3 and 6 , comprises a relatively large cylindrical base 61 having a tubular axle 63 projecting axially from one side 65 of the base 61 . the base 61 is adapted to sit on its opposite side 67 on a flat surface to support the roll of paper in an upright position . the axle 63 of the support 13 is sized to closely fit within the first sleeve 17 , while being rotatable therein . the outer portion of the axle 63 is angled inwardly as shown at 71 . a short tubular section 73 , smaller in diameter than the main body of the axle 63 , projects axially from the inwardly angled portion 71 and terminates in the outer end 75 of the axle 63 . the tubular section 73 has an outwardly directed rib 77 adjacent its outer end 75 . the rib 77 has a conical entry surface 79 . the smaller , outer diameter &# 34 ; d &# 34 ; of the entry surface 79 is slightly smaller than the diameter of the opening 39 in the inner end 35 of the first sleeve 17 while the larger inner diameter &# 34 ; d &# 34 ; of the entry surface 79 is larger than the opening 39 . the diameter of the tubular section 73 is slightly smaller than the diameter of opening 39 . two slots 83 extend longitudinally inwardly from the outer end 75 of the axle , past the angled portion 71 , into the main body of the axle 63 . the slots 83 are equally spaced apart and form somewhat resilient fingers 85 in the outer portion of the axle 63 . the resilient fingers 85 form means for use in rotatably connecting the first sleeve 17 to the support 13 as will be described . the brake member 15 , as shown in fig3 and 7 , has a generally cylindrical head 91 with an axle 93 projecting axially from one side 95 of the head 91 . the axle 93 of the brake member 15 is sized to closely fit within the second sleeve 19 while being rotatable therein . the outer portion of the axle 93 is angled inwardly as shown at 97 . a short , tubular section 99 projects axially from the angled portion 97 and terminates in the outer end 101 of the axle 93 . the tubular section 99 is slightly smaller in diameter than the opening 57 in the second sleeve 19 . a rim 103 extends outwardly from the tubular section 99 adjacent the outer end 101 . the rim 103 is larger in diameter than the opening 57 in the second sleeve 19 . four slots 105 extend longitudinally inwardly from the outer end 101 of the axle 93 well into the main body of the axle . the slots 105 are equally spaced - apart and form four resilient fingers 107 in the axle 93 . the resilient fingers 107 form means for detachably connecting the second sleeve 19 to the brake member , and also provide spring means for use in the brake as will be described . brake means 111 are provided on the brake member 15 that cooperate with the brake means 47 on the second sleeve 19 . the brake means 111 comprise a collar 113 formed about the axle 93 adjacent the one side 95 of the cylindrical head 91 . serrated teeth 115 are formed in the collar 113 pointing in a direction parallel to the longitudinal axis of the axle 93 and away from the head 91 . the serrated teeth 115 are formed to interlock with the serrated teeth 49 on the second sleeve 19 . the base 61 of the mounting 13 can be provided with three equally spaced - apart openings 117 adjacent its peripheral edge 119 as shown in fig2 and 3 . the openings 117 can be used to permanently mount the mounting 13 and thus the dispenser , with screws ( not shown ) on a horizontal or vertical surface . the openings 117 can also be used to receive short posts 125 . the posts have a narrow base 127 and taper very slightly upwardly from the base so that each post can be wedged tightly in an opening 117 . when tightly wedged in the opening the base 127 of the posts 125 extend just below the base 61 of the mounting 13 to provide foot pads for the mounting 13 . the base 127 of the posts can be coated with non - slip material , or the posts can be made from non - slip material to prevent the dispenser from sliding . each post 125 extends a short distance above the base 61 when wedged in the opening and also extends up the side of a full roll of paper when the dispenser is assembled . the posts prevent the paper from unwinding . to assemble the dispenser 1 , the first sleeve 17 is mounted on the support 13 by sliding the sleeve 17 over the axle 63 until the rib 77 passes through the opening 39 in the sleeve . the entry surface 79 on the rib 77 cams the resilient fingers 85 inwardly as the surface passes the edge 41 of the opening 39 . once the rib 77 passes the edge 41 , the fingers 85 spring back and the rib 77 overlies the inner end 35 of the first sleeve 17 connecting the support 13 to the sleeve . the sleeve 17 , with its flange 33 resting on the base 61 of the support 13 , is rotatable on the support . the brake member 15 is connected to the second sleeve 19 by inserting its axle 93 through the sleeve until the rim 103 passes through the opening 57 in the sleeve . in passing through the sleeve 19 , the inner cam surface 55 on the sleeve adjacent its inner end 51 cams the resilient fingers 107 inwardly until the rim 103 passes the edge 59 . the fingers 107 then spring back and the brake member 15 is held in place , connected to the sleeve 19 , by the edge 59 of the sleeve resting adjacent the reduced tubular portion 99 of the axle 93 between the rim 103 and the angled , camming surface 97 . the brake member 15 is rotatable in the sleeve 19 and in the position described , the brake means 111 on the axle 93 are longitudinally separated from the brake means 47 on the sleeve 19 as shown in fig8 . the dispenser 1 is now readied for use by inserting the sleeve 17 which is mounted on the support 13 into one end of the core 9 of the paper roll 5 and inserting the sleeve 19 which is mounted on the brake member 15 into the other end of the core . the assembled dispenser 1 , carrying the roll 5 , can be placed on a table or other support resting on base 61 . it can be permanently fastened to the support with screws through the holes 117 in base 61 if desired . a length of paper sheet can be pulled off the roll with one hand while the other hand holds the head 91 of the brake member 15 to stabilize the dispenser 1 . the roll 5 rotates freely on the axles 63 , 93 via the sleeves 17 , 19 which are frictionally held in the core , as the paper is pulled off . when the desired amount of paper has been pulled off , the head 91 of the brake member 15 is pushed toward the support 13 . the head 91 is prevented from rotating while being pushed and when pushed , the braking teeth 115 on the axle 93 interlock with the braking teeth 49 on the sleeve 19 to stop the sleeve , and thus the roll 5 , from further rotation . the braking is instantaneous . the piece of paper can now be torn off the roll . as the brake member 15 is being pushed toward the support 13 , the cam surface 97 on the axle 93 rides against the edge 51 of the sleeve 19 camming the resilient fingers 107 inwardly as shown in fig9 . when the pushing pressure against the brake member 15 is released , after tearing off the sheet , the resilient fingers 107 spring back and , via cam surface 97 , move the brake member 15 axially away from the support member 13 thereby separating the teeth 49 , 115 and thus releasing the brake . the resilient fingers 107 act as a return spring , returning the brake member 15 to its released position . the roll 5 is again freely rotatable on the support 13 . the head of the brake member 15 can be pushed with the forearm or elbow of a person wishing to use the dispenser if the hands are too dirty to operate it . the base of the mounting 13 can be adapted to be hung on a wall with the towel roll horizontal . the head 91 of the brake member 15 can be provided with an opening 121 therein as shown in fig3 . the opening 121 forms an integral handle 123 in the head . the handle 123 allows the assembled dispenser to be easily carried about . the top of brake member 15 can be closed off with a cap 129 which can be embossed or printed with a logo or trade mark for identification purposes . | US-65118491-A |
a process for treating hair involving contacting the hair with a composition containing : a cationic surfactant component comprising : a quaternized fatty acid amidoamine ; and optionally , a non - quaternized fatty acid amidoamine ; and optionally , a conditioning agent selected from the group consisting of a fatty alcohol , a fatty alcohol polyglycol ether , and mixtures thereof . | the present invention relates to the use of quaternized fatty acid amidoamines for the production of cosmetic preparations . it has surprisingly been found that quaternized fatty acid amidoamines , preferably those which contain non - quaternized components from their production , satisfy the desired requirement profile . the preparations are transparent during production and do not cloud , even in the event of storage . both silicone oils and antidandruff agents can be stably incorporated even in relatively high concentrations and are not secreted again , even after storage for 4 weeks at 40 ° c . the treated hair shows excellent softness and is easier to comb — in some cases more so than in the prior art . quaternized fatty acid amidoamines are known substances which may be obtained in known manner , for example by reaction of fatty acids with polyfunctional amines and subsequent quaternization of the free amine functions . substances preferably used correspond to formula ( i ): in which r 13 is a linear or branched , saturated or unsaturated acyl group containing 6 to 22 carbon atoms , r 14 and r 15 independently of one another represent hydrogen , an optionally hydroxysubstituted alkyl group containing 1 to 4 carbon atoms , r 16 is an alkyl group containing 1 to 4 carbon atoms , a is a linear or branched alkylene group containing 2 to 4 carbon atoms , n is 1 or 2 and x represents halide , alkyl sulfate or alkyl phosphate . with regard to the fatty acids , the cationic compounds may be derived from caproic acid , caprylic acid , 2 - ethylhexanoic acid , capric acid , lauric acid , isotridecanoic acid , myristic acid , palmitic acid , palmitoleic acid , stearic acid , isostearic acid , oleic acid , elaidic acid , petroselic acid , linoleic acid , linolenic acid , elaeostearic acid , arachic acid , gadoleic acid , behenic acid and erucic acid and technical mixtures thereof , quaternized fatty acid amidoamines based on coconut oil fatty acids being preferred . other preferred cationic compounds are those of which the amide component is derived from ethylenediamine , propylenediamine , diethylenetriamine , dipropylenetriamine , aminoethyl ethanolamine and , in particular , n , n - dimethyl aminopropylamine and mixtures thereof . with regard to the choice of the fourth substituent at the amine nitrogen , there is a preference for methyl or chloride . overall preference is attributed to quaternized fatty acid amidoamines which combine the individual structural features mentioned as preferred . a preferred embodiment of the invention is characterized by the use of quaternized fatty acid amidoamines which still partly contain non - quaternized starting materials so that , ultimately , mixtures of quaternized and non - quaternized fatty acid amidoamines in a ratio by weight of 99 . 9 : 0 . 1 to 10 : 90 are used . however , a ratio of 75 : 25 to 25 : 75 and , more especially , 60 : 40 to 40 : 60 has proved to be particularly advantageous from the performance perspective because synergistic increases in performance are observed with ratios in those ranges . in another preferred embodiment of the invention , the quaternized fatty acid amidoamines are used together with fatty alcohols and / or fatty alcohol polyglycol ethers . for example , particularly stable emulsions and creams for treating and , more particularly , conditioning the hair can be obtained in this way . the fatty alcohols or fatty alcohol polyglycol ethers preferably correspond to formula ( ii ): in which r 5 is a linear or branched alkyl and / or alkenyl group containing 6 to 22 and preferably 12 to 18 carbon atoms and m is 0 or a number of 1 to 20 and preferably 10 to 15 . typical examples are caproic alcohol , caprylic alcohol , capric alcohol , lauryl alcohol , myristyl alcohol , cetyl alcohol , stearyl alcohol , isostearyl alcohol , oleyl alcohol , elaidyl alcohol , petroselinyl alcohol , arachyl alcohol , gadoleyl alcohol , behenyl alcohol and erucyl alcohol and technical mixtures thereof such as , for example , cocoalcohol or cetearyl alcohol and ethylene oxide addition products thereof . the fatty acid amidoamines on the one hand and the fatty alcohols or fatty alcohol polyglycol ethers on the other hand may be used in a ratio by weight of 90 : 10 to 10 : 90 and are preferably used in a ratio by weight of 35 : 65 to 50 : 50 . as mentioned at the beginning , a particular concern of the invention is the stable incorporation of silicone oils and antidandruff agents which , normally , are very difficult to incorporate in emulsions and have a tendency to separate out in the event of prolonged storage , particularly under the influence of temperature . suitable silicone oils are , for example , dimethyl polysiloxanes , methylphenyl polysiloxanes , cyclic silicones and amino -, fatty acid -, alcohol -, polyether -, epoxy -, fluorine -, glycoside - and / or alkyl - modified silicone compounds which may be both liquid and resin - like at room temperature . other suitable silicone oils are simethicones which are mixtures of dimethicones with an average chain length of 200 to 300 dimethylsiloxane units and hydrogenated silicates . a detailed overview of suitable volatile silicones can be found in todd et al . in cosm . toil . 91 , 27 ( 1976 ). the silicone oils may be used in quantities of 1 to 20 and preferably 5 to 15 % by weight , based on the preparations . suitable antidandruff agents are pirocton olamin ( 1 - hydroxy - 4 - methyl - 6 -( 2 , 4 , 4 - trimethylpentyl )- 2 -( 1h )- pyridinone monoethanolamine salt ), baypival ® ( climbazole ), ketoconazol ® ( 4 - acetyl - 1 -{ 4 -[ 2 -( 2 , 4 - dichlorophenyl ) r - 2 -( 1h - imidazol - 1 - ylmethyl )- 1 , 3 - dioxylan - c - 4 - ylmethoxyphenyl }- piperazine , ketoconazole , elubiol , selenium disulfide , colloidal sulfur , sulfur polyethylene glycol sorbitan monooleate , sulfur ricinol polyethoxylate , sulfur tar distillate , salicylic acid ( or in combination with hexachlorophene ), undecylenic acid , monoethanolamide sulfosuccinate na salt , lamepon ® ud ( protein / undecylenic acid condensate ), zinc pyrithione , aluminium pyrithione and magnesium pyrithione / dipyrithione magnesium sulfate . the antidandruff agents may be used in quantities of 0 . 1 to 2 % by weight and are preferably used in quantities of 0 . 5 to 1 . 5 % by weight , based on the preparations . the present invention also relates to the use of the quaternized fatty acid amidoamines for the production of hair care preparations , more particularly hair conditioners , preferably those in the form of emulsions , which are , in particular , hair creams that may contain the cationic surfactants in quantities of 1 to 30 , preferably 2 to 20 and more particularly 5 to 15 % by weight , based on the preparations . finally , the present invention relates to the use of the quaternized fatty acid amidoamines for the production of hair care preparations , more particularly those in the form of emulsions . these cosmetic preparations which may be produced using the cationic mixtures may additionally contain mild surfactants , oil components , emulsifiers , pearlizing waxes , consistency factors , thickeners , superfatting agents , stabilizers , polymers , fats , waxes , lecithins , phospholipids , biogenic agents , uv protection factors , antioxidants , deodorizers , antiperspirants , film formers , swelling agents , insect repellents , self - tanning agents , tyrosine inhibitors ( depigmenting agents ), hydrotropes , solubilizers , preservatives , perfume oils , dyes and the like as further auxiliaries and additives . suitable surfactants are anionic , nonionic , cationic and / or amphoteric or zwitterionic surfactants which are normally present in the preparations in quantities of about 1 to 70 , preferably 5 to 50 and more particularly 10 to 30 % by weight . typical examples of anionic surfactants are soaps , alkyl benzenesulfonates , alkanesulfonates , olefin sulfonates , alkylether sulfonates , glycerol ether sulfonates , α - methyl ester sulfonates , sulfofatty acids , alkyl sulfates , fatty alcohol ether sulfates , glycerol ether sulfates , fatty acid ether sulfates , hydroxy mixed ether sulfates , monoglyceride ( ether ) sulfates , fatty acid amide ( ether ) sulfates , mono - and dialkyl sulfosuccinates , mono - and dialkyl sulfosuccinamates , sulfotriglycerides , amide soaps , ether carboxylic acids and salts thereof , fatty acid isethionates , fatty acid sarcosinates , fatty acid taurides , n - acylamino acids such as , for example , acyl lactylates , acyl tartrates , acyl glutamates and acyl aspartates , alkyl oligoglucoside sulfates , protein fatty acid condensates ( particularly wheat - based vegetable products ) and alkyl ( ether ) phosphates . if the anionic surfactants contain polyglycol ether chains , they may have a conventional homolog distribution although they preferably have a narrow - range homolog distribution . typical examples of nonionic surfactants are fatty alcohol polyglycol ethers , alkylphenol polyglycol ethers , fatty acid polyglycol esters , fatty acid amide polyglycol ethers , fatty amine polyglycol ethers , alkoxylated triglycerides , mixed ethers and mixed formals , optionally partly oxidized alk ( en ) yl oligoglycosides or glucuronic acid derivatives , fatty acid - n - alkyl glucamides , protein hydrolyzates ( particularly wheat - based vegetable products ), polyol fatty acid esters , sugar esters , sorbitan esters , polysorbates and amine oxides . if the nonionic surfactants contain polyglycol ether chains , they may have a conventional homolog distribution , although they preferably have a narrow - range homolog distribution . typical examples of cationic surfactants are quaternary ammonium compounds , such as dimethyldistearyl ammonium chloride for example , and esterquats , more particularly quaternized fatty acid trialkanolamine ester salts . typical examples of amphoteric or zwitterionic surfactants are alkylbetaines , alkylamidobetaines , aminopropionates , aminoglycinates , imidazolinium betaines and sulfobetaines . the surfactants mentioned are all known compounds . information on their structure and production can be found in relevant synoptic works , cf . for example j . falbe ( ed . ), “ surfactants in consumer products ”, springer verlag , berlin , 1987 , pages 54 to 124 or j . falbe ( ed . ), “ katalysatoren , tenside und mineralöladditive ( catalysts , surfactants and mineral oil additives )”, thieme verlag , stuttgart , 1978 , pages 123 - 217 . typical examples of particularly suitable mild , i . e . particularly dermatologically compatible , surfactants are fatty alcohol polyglycol ether sulfates , monoglyceride sulfates , mono - and / or dialkyl sulfosuccinates , fatty acid isethionates , fatty acid sarcosinates , fatty acid taurides , fatty acid glutamates , α - olefin sulfonates , ether carboxylic acids , fatty acid glucamides , alkylamidobetaines , amphoacetals and / or protein fatty acid condensates , preferably based on wheat proteins . suitable oil components are , for example , guerbet alcohols based on fatty alcohols containing 6 to 18 and preferably 8 to 10 carbon atoms , esters of linear c 6 - 22 fatty acids with linear or branched c 6 - 22 fatty alcohols or esters of branched c 6 - 13 carboxylic acids with linear or branched c 6 - 22 fatty alcohols such as , for example , myristyl myristate , myristyl palmitate , myristyl stearate , myristyl isostearate , myristyl oleate , myristyl behenate , myristyl erucate , cetyl myristate , cetyl palmitate , cetyl stearate , cetyl isostearate , cetyl oleate , cetyl behenate , cetyl erucate , stearyl myristate , stearyl palmitate , stearyl stearate , stearyl isostearate , stearyl oleate , stearyl behenate , stearyl erucate , isostearyl myristate , isostearyl palmitate , isostearyl stearate , isostearyl isostearate , isostearyl oleate , isostearyl behenate , isostearyl oleate , oleyl myristate , oleyl palmitate , oleyl stearate , oleyl isostearate , oleyl oleate , oleyl behenate , oleyl erucate , behenyl myristate , behenyl palmitate , behenyl stearate , behenyl isostearate , behenyl oleate , behenyl behenate , behenyl erucate , erucyl myristate , erucyl palmitate , erucyl stearate , erucyl isostearate , erucyl oleate , erucyl behenate and erucyl erucate . also suitable are esters of linear c 6 - 22 fatty acids with branched alcohols , more particularly 2 - ethyl hexanol , esters of c 18 - 38 alkylhydroxycarboxylic acids with linear or branched c 6 - 22 fatty alcohols ( cf . de 197 56 377 a1 ), more especially dioctyl malate , esters of linear and / or branched fatty acids with polyhydric alcohols ( for example propylene glycol , dimer diol or trimer triol ) and / or guerbet alcohols , triglycerides based on c 6 - 10 fatty acids , liquid mono -, di - and triglyceride mixtures based on c 6 - 18 fatty acids , esters of c 6 - 22 fatty alcohols and / or guerbet alcohols with aromatic carboxylic acids , more particularly benzoic acid , esters of c 2 - 12 dicarboxylic acids with linear or branched alcohols containing 1 to 22 carbon atoms or polyols containing 2 to 10 carbon atoms and 2 to 6 hydroxyl groups , vegetable oils , branched primary alcohols , substituted cyclohexanes , linear and branched c 6 - 22 fatty alcohol carbonates such as , for example , dicaprylyl carbonate ( cetiol ® cc ), guerbet carbonates based on fatty alcohols containing 6 to 18 and preferably 8 to 10 carbon atoms , esters of benzoic acid with linear and / or branched c 6 - 22 alcohols ( for example finsolv ® tn ), linear or branched , symmetrical or nonsymmetrical dialkyl ethers containing 6 to 22 carbon atoms per alkyl group such as , for example , dicaprylyl ether ( cetiol ® oe ), ring opening products of epoxidized fatty acid esters with polyols and / or aliphatic or naphthenic hydrocarbons , for example squalane , squalene or dialkyl cyclohexanes . suitable emulsifiers are , for example , nonionic surfactants from at least one of the following groups : products of the addition of 2 to 30 mol ethylene oxide and / or 0 to 5 mol propylene oxide onto linear c 8 - 22 fatty alcohols , c 12 - 22 fatty acids , alkyl phenols containing 8 to 15 carbon atoms in the alkyl group and alkylamines containing 8 to 22 carbon atoms in the alkyl group ; alkyl and / or alkenyl oligoglycosides containing 8 to 22 carbon atoms in the alk ( en ) yl group and ethoxylated analogs thereof ; adducts of 1 to 15 mol ethylene oxide with castor oil and / or hydrogenated castor oil ; adducts of 15 to 60 mol ethylene oxide with castor oil and / or hydrogenated castor oil ; partial esters of glycerol and / or sorbitan with unsaturated , linear or saturated , branched fatty acids containing 12 to 22 carbon atoms and / or hydroxycarboxylic acids containing 3 to 18 carbon atoms and adducts thereof with 1 to 30 mol ethylene oxide ; partial esters of polyglycerol ( average degree of self - condensation 2 to 8 ), polyethylene glycol ( molecular weight 400 to 5000 ), trimethylolpropane , pentaerythritol , sugar alcohols ( for example sorbitol ), alkyl glucosides ( for example methyl glucoside , butyl glucoside , lauryl glucoside ) and polyglucosides ( for example cellulose ) with saturated and / or unsaturated , linear or branched fatty acids containing 12 to 22 carbon atoms and / or hydroxycarboxylic acids containing 3 to 18 carbon atoms and adducts thereof with 1 to 30 mol ethylene oxide ; mixed esters of pentaerythritol , fatty acids , citric acid and fatty alcohol according to de 1165574 ps and / or mixed esters of fatty acids containing 6 to 22 carbon atoms , methyl glucose and polyols , preferably glycerol or polyglycerol , the addition products of ethylene oxide and / or propylene oxide with fatty alcohols , fatty acids , alkylphenols or with castor oil are known commercially available products . they are homolog mixtures of which the average degree of alkoxylation corresponds to the ratio between the quantities of ethylene oxide and / or propylene oxide and substrate with which the addition reaction is carried out . c 12 / 18 fatty acid monoesters and diesters of adducts of ethylene oxide with glycerol are known as lipid layer enhancers for cosmetic formulations from de 20 24 051 ps . alkyl and / or alkenyl oligoglycosides , their production and their use are known from the prior art . they are produced in particular by reacting glucose or oligosaccharides with primary alcohols containing 8 to 18 carbon atoms . so far as the glycoside unit is concerned , both monoglycosides in which a cyclic sugar unit is attached to the fatty alcohol by a glycoside bond and oligomeric glycosides with a degree of oligomerization of preferably up to about 8 are suitable . the degree of oligomerization is a statistical mean value on which the homolog distribution typical of such technical products is based . typical examples of suitable partial glycerides are hydroxystearic acid monoglyceride , hydroxystearic acid diglyceride , isostearic acid monoglyceride , isostearic acid diglyceride , oleic acid monoglyceride , oleic acid diglyceride , ricinoleic acid monoglyceride , ricinoleic acid diglyceride , linoleic acid monoglyceride , linoleic acid diglyceride , linolenic acid monoglyceride , linolenic acid diglyceride , erucic acid monoglyceride , erucic acid diglyceride , tartaric acid monoglyceride , tartaric acid diglyceride , citric acid monoglyceride , citric acid diglyceride , malic acid monoglyceride , malic acid diglyceride and technical mixtures thereof which may still contain small quantities of triglyceride from the production process . addition products of 1 to 30 and preferably 5 to 10 mol ethylene oxide onto the partial glycerides mentioned are also suitable . suitable sorbitan esters are sorbitan monoisostearate , sorbitan sesquiisostearate , sorbitan diisostearate , sorbitan triisostearate , sorbitan monooleate , sorbitan sesquioleate , sorbitan dioleate , sorbitan trioleate , sorbitan monoerucate , sorbitan sesquierucate , sorbitan dierucate , sorbitan trierucate , sorbitan monoricinoleate , sorbitan sesquiricinoleate , sorbitan diricinoleate , sorbitan triricinoleate , sorbitan monohydroxystearate , sorbitan sesquihydroxystearate , sorbitan dihydroxystearate , sorbitan trihydroxystearate , sorbitan monotartrate , sorbitan sesquitartrate , sorbitan ditartrate , sorbitan tritartrate , sorbitan monocitrate , sorbitan sesquicitrate , sorbitan dicitrate , sorbitan tricitrate , sorbitan monomaleate , sorbitan sesquimaleate , sorbitan dimaleate , sorbitan trimaleate and technical mixtures thereof . addition products of 1 to 30 and preferably 5 to 10 mol ethylene oxide onto the sorbitan esters mentioned are also suitable . typical examples of suitable polyglycerol esters are polyglyceryl - 2 dipolyhydroxystearate ( dehymuls ® pgph ), polyglycerin - 3 - diisostearate ( lameform ® tgi ), polyglyceryl - 4 isostearate ( isolan ® gi 34 ), polyglyceryl - 3 oleate , diisostearoyl polyglyceryl - 3 diisostearate ( isolan ® pdi ), polyglyceryl - 3 methylglucose distearate ( tego care ® 450 ), polyglyceryl - 3 beeswax ( cera bellina ®), polyglyceryl - 4 caprate ( polyglycerol caprate t2010 / 90 ), polyglyceryl - 3 cetyl ether ( chimexane ® nl ), polyglyceryl - 3 distearate ( cremophor ® gs 32 ) and polyglyceryl polyricinoleate ( admul ® wol 1403 ), polyglyceryl dimerate isostearate and mixtures thereof . examples of other suitable polyolesters are the mono -, di - and triesters of trimethylol propane or pentaerythritol with lauric acid , cocofatty acid , tallow fatty acid , palmitic acid , stearic acid , oleic acid , behenic acid and the like optionally reacted with 1 to 30 mol ethylene oxide . typical anionic emulsifiers are aliphatic c 12 - 22 fatty acids , such as palmitic acid , stearic acid or behenic acid for example , and c 12 - 22 dicarboxylic acids , such as azelaic acid or sebacic acid for example . other suitable emulsifiers are zwitterionic surfactants . zwitterionic surfactants are surface - active compounds which contain at least one quaternary ammonium group and at least one carboxylate and one sulfonate group in the molecule . particularly suitable zwitterionic surfactants are the so - called betaines , such as the n - alkyl - n , n - dimethyl ammonium glycinates , for example cocoalkyl dimethyl ammonium glycinate , n - acylaminopropyl - n , n - dimethyl ammonium glycinates , for example cocoacylaminopropyl dimethyl ammonium glycinate , and 2 - alkyl - 3 - carboxymethyl - 3 - hydroxyethyl imidazolines containing 8 to 18 carbon atoms in the alkyl or acyl group and cocoacylaminoethyl hydroxyethyl carboxymethyl glycinate . the fatty acid amide derivative known under the ctfa name of cocamidopropyl betaine is particularly preferred . ampholytic surfactants are also suitable emulsifiers . ampholytic surfactants are surface - active compounds which , in addition to a c 8 / 18 alkyl or acyl group , contain at least one free amino group and at least one — cooh or — so 3 h group in the molecule and which are capable of forming inner salts . examples of suitable ampholytic surfactants are n - alkyl glycines , n - alkyl propionic acids , n - alkylaminobutyric acids , n - alkyliminodipropionic acids , n - hydroxyethyl - n - alkylamidopropyl glycines , n - alkyl taurines , n - alkyl sarcosines , 2 - alkylaminopropionic acids and alkylaminoacetic acids containing around 8 to 18 carbon atoms in the alkyl group . particularly preferred ampholytic surfactants are n - coco - alkylaminopropionate , cocoacylaminoethyl aminopropionate and c 12 / 18 acyl sarcosine . finally , other suitable emulsifiers are cationic surfactants , those of the esterquat type , preferably methyl - quaternized difatty acid triethanolamine ester salts , being particularly preferred . typical examples of fats are glycerides , i . e . solid or liquid , vegetable or animal products which consist essentially of mixed glycerol esters of higher fatty acids . suitable waxes are inter alia natural waxes such as , for example , candelilla wax , carnauba wax , japan wax , espartograss wax , cork wax , guaruma wax , rice oil wax , sugar cane wax , ouricury wax , montan wax , beeswax , shellac wax , spermaceti , lanolin ( wool wax ), uropygial fat , ceresine , ozocerite ( earth wax ), petrolatum , paraffin waxes and microwaxes ; chemically modified waxes ( hard waxes ) such as , for example , montan ester waxes , sasol waxes , hydrogenated jojoba waxes and synthetic waxes such as , for example , polyalkylene waxes and polyethylene glycol waxes . besides the fats , other suitable additives are fat - like substances , such as lecithins and phospholipids . lecithins are known among experts as glycerophospholipids which are formed from fatty acids , glycerol , phosphoric acid and choline by esterification . accordingly , lecithins are also frequently referred to by experts as phosphatidyl cholines ( pcs ). examples of natural lecithins are the kephalins which are also known as phosphatidic acids and which are derivatives of 1 , 2 - diacyl - sn - glycerol - 3 - phosphoric acids . by contrast , phospholipids are generally understood to be mono - and preferably diesters of phosphoric acid with glycerol ( glycerophosphates ) which are normally classed as fats . sphingosines and sphingolipids are also suitable . suitable pearlizing waxes are , for example , alkylene glycol esters , especially ethylene glycol distearate ; fatty acid alkanolamides , especially cocofatty acid diethanolamide ; partial glycerides , especially stearic acid monoglyceride ; esters of polybasic , optionally hydroxysubstituted carboxylic acids with fatty alcohols containing 6 to 22 carbon atoms , especially long - chain esters of tartaric acid ; fatty compounds , such as for example fatty alcohols , fatty ketones , fatty aldehydes , fatty ethers and fatty carbonates which contain in all at least 24 carbon atoms , especially laurone and distearylether ; fatty acids , such as stearic acid , hydroxystearic acid or behenic acid , ring opening products of olefin epoxides containing 12 to 22 carbon atoms with fatty alcohols containing 12 to 22 carbon atoms and / or polyols containing 2 to 15 carbon atoms and 2 to 10 hydroxyl groups and mixtures thereof . the consistency factors mainly used are fatty alcohols or hydroxyfatty alcohols containing 12 to 22 and preferably 16 to 18 carbon atoms and also partial glycerides , fatty acids or hydroxyfatty acids . a combination of these substances with alkyl oligoglucosides and / or fatty acid n - methyl glucamides of the same chain length and / or polyglycerol poly - 12 - hydroxystearates is preferably used . suitable thickeners are , for example , aerosil ® types ( hydrophilic silicas ), polysaccharides , more especially xanthan gum , guar - guar , agar - agar , alginates and tyloses , carboxymethyl cellulose and hydroxyethyl and hydroxypropyl cellulose , also relatively high molecular weight polyethylene glycol monoesters and diesters of fatty acids , polyacrylates ( for example carbopols ® and pemulen types [ goodrich ]; synthalens ® [ sigma ]; keltrol types [ kelco ]; sepigel types [ seppic ]; salcare types [ allied colloids ]), polyacrylamides , polymers , polyvinyl alcohol and polyvinyl pyrrolidone . other consistency factors which have proved to be particularly effective are bentonites , for example bentone ® gel vs - 5pc ( rheox ) which is a mixture of cyclopentasiloxane , disteardimonium hectorite and propylene carbonate . other suitable consistency factors are surfactants such as , for example , ethoxylated fatty acid glycerides , esters of fatty acids with polyols , for example pentaerythritol or trimethylol propane , narrow - range fatty alcohol ethoxylates or alkyl oligoglucosides and electrolytes , such as sodium chloride and ammonium chloride . superfatting agents may be selected from such substances as , for example , lanolin and lecithin and also polyethoxylated or acylated lanolin and lecithin derivatives , polyol fatty acid esters , monoglycerides and fatty acid alkanolamides , the fatty acid alkanolamides also serving as foam stabilizers . metal salts of fatty acids such as , for example , magnesium , aluminium and / or zinc stearate or ricinoleate may be used as stabilizers . suitable cationic polymers are , for example , cationic cellulose derivatives such as , for example , the quaternized hydroxyethyl cellulose obtainable from amerchol under the name of polymer jr 400 ®, cationic starch , copolymers of diallyl ammonium salts and acrylamides , quaternized vinyl pyrrolidone / vinyl imidazole polymers such as , for example , luviquat ® ( basf ), condensation products of polyglycols and amines , quaternized collagen polypeptides such as , for example , lauryldimonium hydroxypropyl hydrolyzed collagen ( lamequat ® l , grünau ), quaternized wheat polypeptides , polyethyleneimine , cationic silicone polymers such as , for example , amodimethicone , copolymers of adipic acid and dimethylamino - hydroxypropyl diethylenetriamine ( cartaretine ®, sandoz ), copolymers of acrylic acid with dimethyl diallyl ammonium chloride ( merquat ® 550 , chemviron ), polyaminopolyamides as described , for example , in fr 2252840 a and crosslinked water - soluble polymers thereof , cationic chitin derivatives such as , for example , quaternized chitosan , optionally in micro - crystalline distribution , condensation products of dihaloalkyls , for example dibromobutane , with bis - dialkylamines , for example bis - dimethylamino - 1 , 3 - propane , cationic guar gum such as , for example , jaguar ® cbs , jaguar ® c - 17 , jaguar ® c - 16 of celanese , quaternized ammonium salt polymers such as , for example , mirapol ® a - 15 , mirapol ® ad - 1 , mirapol ® az - 1 of miranol . suitable anionic , zwitterionic , amphoteric and nonionic polymers are , for example , vinyl acetate / crotonic acid copolymers , vinyl pyrrolidone / vinyl acrylate copolymers , vinyl acetate / butyl maleate / isobornyl acrylate copolymers , methyl vinylether / maleic anhydride copolymers and esters thereof , uncrosslinked and polyol - crosslinked polyacrylic acids , acrylamido - propyl trimethylammonium chloride / acrylate copolymers , octylacryl - amide / methyl methacrylate / tert .- butylaminoethyl methacrylate / 2 - hydroxy - propyl methacrylate copolymers , polyvinyl pyrrolidone , vinyl pyrrolidone / vinyl acetate copolymers , vinyl pyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymers and optionally derivatized cellulose ethers and silicones . other suitable polymers and thickeners can be found in cosm . toil ., 108 , 95 ( 1993 ). uv protection factors in the context of the invention are , for example , organic substances ( light filters ) which are liquid or crystalline at room temperature and which are capable of absorbing ultraviolet radiation and of releasing the energy absorbed in the form of longer - wave radiation , for example heat . uv - b filters can be oil - soluble or water - soluble . the following are examples of oil - soluble substances : 3 - benzylidene camphor or 3 - benzylidene norcamphor and derivatives thereof , for example 3 -( 4 - methylbenzylidene )- camphor as described in ep 0693471 b1 ; 4 - aminobenzoic acid derivatives , preferably 4 -( dimethylamino )- benzoic acid - 2 - ethylhexyl ester , 4 -( dimethylamino )- benzoic acid - 2 - octyl ester and 4 -( dimethylamino )- benzoic acid amyl ester ; esters of cinnamic acid , preferably 4 - methoxycinnamic acid - 2 - ethylhexyl ester , 4 - methoxycinnamic acid propyl ester , 4 - methoxycinnamic acid isoamyl ester , 2 - cyano - 3 , 3 - phenylcinnamic acid - 2 - ethylhexyl ester ( octocrylene ); esters of salicylic acid , preferably salicylic acid - 2 - ethylhexyl ester , salicylic acid - 4 - isopropylbenzyl ester , salicylic acid homomenthyl ester ; triazine derivatives such as , for example , 2 , 4 , 6 - trianilino -( p - carbo - 2 ′- ethyl - 1 ′- hexyloxy )- 1 , 3 , 5 - triazine and octyl triazone as described in ep 0818450 a1 or dioctyl butamido triazone ( uvasorb ® heb ); 2 - phenylbenzimidazole - 5 - sulfonic acid and alkali metal , alkaline earth metal , ammonium , alkylammonium , alkanolammonium and glucammonium salts thereof ; sulfonic acid derivatives of 3 - benzylidene camphor such as , for example , 4 -( 2 - oxo - 3 - bornylidenemethyl )- benzene sulfonic acid and 2 - methyl - 5 -( 2 - oxo - 3 - bornylidene )- sulfonic acid and salts thereof . typical uv - a filters are , in particular , derivatives of benzoyl methane such as , for example , 1 -( 4 ′- tert . butylphenyl )- 3 -( 4 ′- methoxyphenyl )- propane - 1 , 3 - dione , 4 - tert . butyl - 4 ′- methoxydibenzoyl methane ( parsol 1789 ) or 1 - phenyl - 3 -( 4 ′- isopropylphenyl )- propane - 1 , 3 - dione and the enamine compounds described in de 19712033 a1 ( basf ). the uv - a and uv - b filters may of course also be used in the form of mixtures . particularly favorable combinations consist of the derivatives of benzoyl methane , for example 4 - tert . butyl - 4 ′- methoxydibenzoylmethane ( parsol ® 1789 ) and 2 - cyano - 3 , 3 - phenylcinnamic acid - 2 - ethyl hexyl ester ( octocrylene ) in combination with esters of cinnamic acid , preferably 4 - methoxycinnamic acid - 2 - ethyl hexyl ester and / or 4 - methoxycinnamic acid propyl ester and / or 4 - methoxycinnamic acid isoamyl ester . combinations such as these are advantageously combined with water - soluble filters such as , for example , 2 - phenylbenzimidazole - 5 - sulfonic acid and alkali metal , alkaline earth metal , ammonium , alkylammonium , alkanolammonium and glucammonium salts thereof . besides the soluble substances mentioned , insoluble light - blocking pigments , i . e . finely dispersed metal oxides or salts , may also be used for this purpose . examples of suitable metal oxides are , in particular , zinc oxide and titanium dioxide and also oxides of iron , zirconium oxide , silicon , manganese , aluminium and cerium and mixtures thereof . silicates ( talcum ), barium sulfate and zinc stearate may be used as salts . the oxides and salts are used in the form of the pigments for skin - care and skin - protecting emulsions and decorative cosmetics . the particles should have a mean diameter of less than 100 nm , preferably between 5 and 50 nm and more preferably between 15 and 30 nm . they may be spherical in shape although ellipsoidal particles or other non - spherical particles may also be used . the pigments may also be surface - treated , i . e . hydrophilicized or hydrophobicized . typical examples are coated titanium dioxides , for example titandioxid t 805 ( degussa ) and eusolex ®) t2000 ( merck ). suitable hydrophobic coating materials are , above all , silicones and , among these , especially trialkoxyoctylsilanes or simethicones . so - called micro - or nanopigments are preferably used in sun protection products . micronized zinc oxide is preferably used . other suitable uv filters can be found in p . finkel &# 39 ; s review in söfw - journal 122 , 543 ( 1996 ) and in parf . kosm . 3 , 11 ( 1999 ). besides the two groups of primary sun protection factors mentioned above , secondary sun protection factors of the antioxidant type may also be used . secondary sun protection factors of the antioxidant type interrupt the photochemical reaction chain which is initiated when uv rays penetrate into the skin . typical examples are amino acids ( for example glycine , histidine , tyrosine , tryptophane ) and derivatives thereof , imidazoles ( for example urocanic acid ) and derivatives thereof , peptides , such as d , l - carnosine , d - carnosine , l - carnosine and derivatives thereof ( for example anserine ), carotinoids , carotenes ( for example α - carotene , β - carotene , lycopene ) and derivatives thereof , chlorogenic acid and derivatives thereof , liponic acid and derivatives thereof ( for example dihydroliponic acid ), aurothioglucose , propylthiouracil and other thiols ( for example thioredoxine , glutathione , cysteine , cystine , cystamine and glycosyl , n - acetyl , methyl , ethyl , propyl , amyl , butyl and lauryl , palmitoyl , oleyl , γ - linoleyl , cholesteryl and glyceryl esters thereof ) and their salts , dilaurylthiodipropionate , distearylthiodipropionate , thiodipropionic acid and derivatives thereof ( esters , ethers , peptides , lipids , nucleotides , nucleosides and salts ) and sulfoximine compounds ( for example butionine sulfoximines , homocysteine sulfoximine , butionine sulfones , penta -, hexa - and hepta - thionine sulfoximine ) in very small compatible dosages ( for example pmole to μmole / kg ), also ( metal ) chelators ( for example α - hydroxyfatty acids , palmitic acid , phytic acid , lactoferrine ), α - hydroxy acids ( for example citric acid , lactic acid , malic acid ), humic acid , bile acid , bile extracts , bilirubin , biliverdin , edta , egta and derivatives thereof , unsaturated fatty acids and derivatives thereof ( for example γ - linolenic acid , linoleic acid , oleic acid ), folic acid and derivatives thereof , ubiquinone and ubiquinol and derivatives thereof , vitamin c and derivatives thereof ( for example ascorbyl palmitate , mg ascorbyl phosphate , ascorbyl acetate ), tocopherols and derivatives ( for example vitamin e acetate ), vitamin a and derivatives ( vitamin a palmitate ) and coniferyl benzoate of benzoin resin , rutinic acid and derivatives thereof , α - glycosyl rutin , ferulic acid , furfurylidene glucitol , carnosine , butyl hydroxytoluene , butyl hydroxyanisole , nordihydroguaiac resin acid , nordihydroguaiaretic acid , trihydroxybutyrophenone , uric acid and derivatives thereof , mannose and derivatives thereof , superoxid - dismutase , zinc and derivatives thereof ( for example zno , znso 4 ), selenium and derivatives thereof ( for example selenium methionine ), stilbenes and derivatives thereof ( for example stilbene oxide , trans - stilbene oxide ) and derivatives of these active substances suitable for the purposes of the invention ( salts , esters , ethers , sugars , nucleotides , nucleosides , peptides and lipids ). in the context of the invention , biogenic agents are , for example , tocopherol , tocopherol acetate , tocopherol palmitate , ascorbic acid , ( deoxy ) ribonucleic acid and fragmentation products thereof , β - glucans , retinol , bisabolol , allantoin , phytantriol , panthenol , aha acids , amino acids , ceramides , pseudoceramides , essential oils , plant extracts , for example prune extract , bambara nut extract , and vitamin complexes . cosmetic deodorants counteract , mask or eliminate body odors . body odors are formed through the action of skin bacteria on apocrine perspiration which results in the formation of unpleasant - smelling degradation products . accordingly , deodorants contain active principles which act as germ inhibitors , enzyme inhibitors , odor absorbers or odor maskers . basically , suitable germ inhibitors are any substances which act against gram - positive bacteria such as , for example , 4 - hydroxybenzoic acid and salts and esters thereof , n -( 4 - chlorophenyl )- n ′-( 3 , 4 - dichlorophenyl )- urea , 2 , 4 , 4 ′- trichloro - 2 ′- hydroxydiphenylether ( triclosan ), 4 - chloro - 3 , 5 - dimethylphenol , 2 , 2 ′- methylene - bis -( 6 - bromo - 4 - chlorophenol ), 3 - methyl - 4 -( 1 - methylethyl )- phenol , 2 - benzyl - 4 - chlorophenol , 3 -( 4 - chlorophenoxy )- propane - 1 , 2 - diol , 3 - iodo - 2 - propinyl butyl carbamate , chlorhexidine , 3 , 4 , 4 ′- trichlorocarbanilide ( ttc ), antibacterial perfumes , thymol , thyme oil , eugenol , clove oil , menthol , mint oil , farnesol , phenoxyethanol , glycerol monocaprate , glycerol monocaprylate , glycerol monolaurate ( gml ), diglycerol monocaprate ( dmc ), salicylic acid - n - alkylamides such as , for example , salicylic acid - n - octyl amide or salicylic acid - n - decyl amide . suitable enzyme inhibitors are , for example , esterase inhibitors . esterase inhibitors are preferably trialkyl citrates , such as trimethyl citrate , tripropyl citrate , triisopropyl citrate , tributyl citrate and , in particular , triethyl citrate ( hydagen ® cat ). esterase inhibitors inhibit enzyme activity and thus reduce odor formation . other esterase inhibitors are sterol sulfates or phosphates such as , for example , lanosterol , cholesterol , campesterol , stigmasterol and sitosterol sulfate or phosphate , dicarboxylic acids and esters thereof , for example glutaric acid , glutaric acid monoethyl ester , glutaric acid diethyl ester , adipic acid , adipic acid monoethyl ester , adipic acid diethyl ester , malonic acid and malonic acid diethyl ester , hydroxycarboxylic acids and esters thereof , for example citric acid , malic acid , tartaric acid or tartaric acid diethyl ester , and zinc glycinate . suitable odor absorbers are substances which are capable of absorbing and largely retaining the odor - forming compounds . they reduce the partial pressure of the individual components and thus also reduce the rate at which they spread . an important requirement in this regard is that perfumes must remain unimpaired . odor absorbers are not active against bacteria . they contain , for example , a complex zinc salt of ricinoleic acid or special perfumes of largely neutral odor known to the expert as “ fixateurs ” such as , for example , extracts of ladanum or styrax or certain abietic acid derivatives as their principal component . odor maskers are perfumes or perfume oils which , besides their odor - masking function , impart their particular perfume note to the deodorants . suitable perfume oils are , for example , mixtures of natural and synthetic fragrances . natural fragrances include the extracts of blooms , stems and leaves , fruits , fruit peel , roots , woods , herbs and grasses , needles and branches , resins and balsams . animal raw materials , for example civet and beaver , may also be used . typical synthetic perfume compounds are products of the ester , ether , aldehyde , ketone , alcohol and hydrocarbon type . examples of perfume compounds of the ester type are benzyl acetate , p - tert . butyl cyclohexylacetate , linalyl acetate , phenyl ethyl acetate , linalyl benzoate , benzyl formate , allyl cyclohexyl propionate , styrallyl propionate and benzyl salicylate . ethers include , for example , benzyl ethyl ether while aldehydes include , for example , the linear alkanals containing 8 to 18 carbon atoms , citral , citronellal , citronellyloxyacetaldehyde , cyclamen aldehyde , hydroxycitronellal , lilial and bourgeonal . examples of suitable ketones are the ionones and methyl cedryl ketone . suitable alcohols are anethol , citronellol , eugenol , isoeugenol , geraniol , linalool , phenylethyl alcohol and terpineol . the hydrocarbons mainly include the terpenes and balsams . however , it is preferred to use mixtures of different perfume compounds which , together , produce an agreeable fragrance . other suitable perfume oils are essential oils of relatively low volatility which are mostly used as aroma components . examples are sage oil , camomile oil , clove oil , lemon balm oil , mint oil , cinnamon leaf oil , lime - blossom oil , juniper berry oil , vetiver oil , olibanum oil , galbanum oil , ladanum oil and lavendin oil . the following are preferably used either individually or in the form of mixtures : bergamot oil , dihydromyrcenol , lilial , lyral , citronellol , phenylethyl alcohol , α - hexylcinnamaldehyde , geraniol , benzyl acetone , cyclamen aldehyde , linalool , boisambrene forte , ambroxan , indole , hedione , sandelice , citrus oil , mandarin oil , orange oil , allylamyl glycolate , cyclovertal , lavendin oil , clary oil , β - damascone , geranium oil bourbon , cyclohexyl salicylate , vertofix coeur , iso - e - super , fixolide np , evernyl , iraldein gamma , phenylacetic acid , geranyl acetate , benzyl acetate , rose oxide , romillat , irotyl and floramat . antiperspirants reduce perspiration and thus counteract underarm wetness and body odor by influencing the activity of the eccrine sweat glands . aqueous or water - free antiperspirant formulations typically contain the following ingredients : auxiliaries in the form of , for example , thickeners or complexing agents and / or non - aqueous solvents such as , for example , ethanol , propylene glycol and / or glycerol . suitable astringent active principles of antiperspirants are , above all , salts of aluminium , zirconium or zinc . suitable antihydrotic agents of this type are , for example , aluminium chloride , aluminium chlorohydrate , aluminium dichlorohydrate , aluminium sesquichlorohydrate and complex compounds thereof , for example with 1 , 2 - propylene glycol , aluminium hydroxyallantoinate , aluminium chloride tartrate , aluminium zirconium trichlorohydrate , aluminium zirconium tetrachlorohydrate , aluminium zirconium pentachlorohydrate and complex compounds thereof , for example with amino acids , such as glycine . oil - soluble and water - soluble auxiliaries typically encountered in antiperspirants may also be present in relatively small amounts . oil - soluble auxiliaries such as these include , for example , typical water - soluble additives are , for example , preservatives , water - soluble perfumes , ph adjusters , for example buffer mixtures , water - soluble thickeners , for example water - soluble natural or synthetic polymers such as , for example , xanthan gum , hydroxyethyl cellulose , polyvinyl pyrrolidone or high molecular weight polyethylene oxides . standard film formers are , for example , chitosan , microcrystalline chitosan , quaternized chitosan , polyvinyl pyrrolidone , vinyl pyrrolidone / vinyl acetate copolymers , polymers of the acrylic acid series , quaternary cellulose derivatives , collagen , hyaluronic acid and salts thereof and similar compounds . suitable swelling agents for aqueous phases are montmorillonites , clay minerals , pemulen and alkyl - modified carbopol types ( goodrich ). other suitable polymers and swelling agents can be found in r . lochhead &# 39 ; s review in cosm . toil . 108 , 95 ( 1993 ). a suitable self - tanning agent is dihydroxyacetone . suitable tyrosine inhibitors which prevent the formation of melanin and are used in depigmenting agents are , for example , arbutin , ferulic acid , koji acid , coumaric acid and ascorbic acid ( vitamin c ). in addition , hydrotropes , for example ethanol , isopropyl alcohol or polyols , may be used to improve flow behavior . suitable polyols preferably contain 2 to 15 carbon atoms and at least two hydroxyl groups . the polyols may contain other functional groups , more especially amino groups , or may be modified with nitrogen . typical examples are alkylene glycols such as , for example , ethylene glycol , diethylene glycol , propylene glycol , butylene glycol , hexylene glycol and polyethylene glycols with an average molecular weight of 100 to 1000 dalton ; technical oligoglycerol mixtures with a degree of self - condensation of 1 . 5 to 10 such as , for example , technical diglycerol mixtures with a diglycerol content of 40 to 50 % by weight ; methylol compounds such as , in particular , trimethylol ethane , trimethylol propane , trimethylol butane , pentaerythritol and dipentaerythritol ; lower alkyl glucosides , particularly those containing 1 to 8 carbon atoms in the alkyl group , for example methyl and butyl glucoside ; sugar alcohols containing 5 to 12 carbon atoms , for example sorbitol or mannitol , sugars containing 5 to 12 carbon atoms , for example glucose or sucrose ; suitable preservatives are , for example , phenoxyethanol , formaldehyde solution , parabens , pentanediol or sorbic acid and the silver complexes known under the name of surfacine ® and the other classes of compounds listed in appendix 6 , parts a and b of the kosmetikverordnung (“ cosmetics directive ”). suitable perfume oils are mixtures of natural and synthetic perfumes . natural perfumes include the extracts of blossoms ( lily , lavender , rose , jasmine , neroli , ylang - ylang ), stems and leaves ( geranium , patchouli , petitgrain ), fruits ( anise , coriander , caraway , juniper ), fruit peel ( bergamot , lemon , orange ), roots ( nutmeg , angelica , celery , cardamom , costus , iris , calmus ), woods ( pinewood , sandalwood , guaiac wood , cedarwood , rosewood ), herbs and grasses ( tarragon , lemon grass , sage , thyme ), needles and branches ( spruce , fir , pine , dwarf pine ), resins and balsams ( galbanum , elemi , benzoin , myrrh , olibanum , opoponax ). animal raw materials , for example civet and beaver , may also be used . typical synthetic perfume compounds are products of the ester , ether , aldehyde , ketone , alcohol and hydrocarbon type . examples of perfume compounds of the ester type are benzyl acetate , phenoxyethyl isobutyrate , p - tert . butyl cyclohexylacetate , linalyl acetate , dimethyl benzyl carbinyl acetate , phenyl ethyl acetate , linalyl benzoate , benzyl formate , ethylmethyl phenyl glycinate , allyl cyclohexyl propionate , styrallyl propionate and benzyl salicylate . ethers include , for example , benzyl ethyl ether while aldehydes include , for example , the linear alkanals containing 8 to 18 carbon atoms , citral , citronellal , citronellyloxyacetaldehyde , cyclamen aldehyde , hydroxy - citronellal , lilial and bourgeonal . examples of suitable ketones are the ionones , α - isomethylionone and methyl cedryl ketone . suitable alcohols are anethol , citronellol , eugenol , isoeugenol , geraniol , linalool , phenylethyl alcohol and terpineol . the hydrocarbons mainly include the terpenes and balsams . however , it is preferred to use mixtures of different perfume compounds which , together , produce an agreeable perfume . other suitable perfume oils are essential oils of relatively low volatility which are mostly used as aroma components . examples are sage oil , camomile oil , clove oil , melissa oil , mint oil , cinnamon leaf oil , lime - blossom oil , juniper berry oil , vetiver oil , olibanum oil , galbanum oil , ladanum oil and lavendin oil . the following are preferably used either individually or in the form of mixtures : bergamot oil , dihydromyrcenol , lilial , lyral , citronellol , phenylethyl alcohol , α - hexylcinnamaldehyde , geraniol , benzyl acetone , cyclamen aldehyde , linalool , boisambrene forte , ambroxan , indole , hedione , sandelice , citrus oil , mandarin oil , orange oil , allylamyl glycolate , cyclovertal , lavendin oil , clary oil , β - damascone , geranium oil bourbon , cyclohexyl salicylate , vertofix coeur , iso - e - super , fixolide np , evernyl , iraldein gamma , phenylacetic acid , geranyl acetate , benzyl acetate , rose oxide , romillat , irotyl and floramat . suitable aromas are , for example , peppermint oil , spearmint oil , aniseed oil , japanese anise oil , caraway oil , eucalyptus oil , fennel oil , citrus oil , wintergreen oil , clove oil , menthol and the like . suitable dyes are any of the substances suitable and approved for cosmetic purposes as listed , for example , in the publication “ kosmetische färbemittel ” of the farbstoffkommission der deutschen forschungs - gemeinschaft , verlag chemie , weinheim , 1984 , pages 81 to 106 . examples include cochineal red a ( c . i . 16255 ), patent blue v ( c . i . 42051 ), indigotin ( c . i . 73015 ), chlorophyllin ( c . i . 75810 ), quinoline yellow ( c . i . 47005 ), titanium dioxide ( c . i . 77891 ), indanthrene blue rs ( c . i . 69800 ) and madder lake ( c . i . 58000 ). luminol may also be present as a luminescent dye . these dyes are normally used in concentrations of 0 . 001 to 0 . 1 % by weight , based on the mixture as a whole . the total percentage content of auxiliaries and additives may be from 1 to 50 % by weight and is preferably from 5 to 40 % by weight , based on the particular preparations . the preparations may be produced by standard hot or cold processes and are preferably produced by the phase inversion temperature method . various emulsions containing silicone oils and active substances were tested for their stability . the fatty acid amidoamines used were all methyl - quaternized condensation products of cocofatty acid which were present as methosulfates and which only differed in their amide components , namely : qfaaa1 : ethylenediamine qfaaa2 : diethylenetriamine qfaaa3 : aminoethyl ethanolamine qfaaa4 : n , n - dimethyl aminopropylamine the results of the stability tests are set out in table 1 where (+++)= no change , (++)= slight clouding , (+)= slight separations , (−)= distinct separations and (−−)= complete separation . examples 1 to 11 correspond to the invention , example c1 is intended for comparison . [ 0140 ] table 2 examples of cosmetic preparations ( water , preservative to 100 % by weight ) composition ( inci ) 1 2 3 4 5 6 dehyquart ® c 1006 2 . 0 2 . 0 2 . 0 2 . 0 4 . 0 4 . 0 coco fatty acid n , n dimethylamino ethyl amide , methyl quaternized , methosulfate eumulgin ® b2 0 . 8 0 . 8 — 0 . 8 — 1 . 0 ceteareth - 20 eumulgin ® vl 75 — — 0 . 8 — 0 . 8 — lauryl glucoside ( and ) polyglyceryl - 2 polyhydroxystearate ( and ) glycerin lanette ® o 2 . 5 2 . 5 2 . 5 2 . 5 3 . 0 2 . 5 cetearyl alcohol cutina ® gms 0 . 5 0 . 5 0 . 5 0 . 5 0 . 5 1 . 0 glyceryl stearate cetiol ® he 1 . 0 — — — — — peg - 7 glyceryl cocoate cetiol ® pgl — 1 . 0 — — 1 . 0 — hexyldecanol ( and ) hexyldecyl laurate cetiol ® v — — — 1 . 0 — — decyl oleate eutanol ® g — — 1 . 0 — — 1 . 0 octyldodecanol nutrilan ® keratin w — — — 2 . 0 — — hydrolyzed keratin generol ® 122 n — — — — 1 . 0 1 . 0 soja sterol hydagen ® cmf 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 chitosan copherol ® 1250 — — 0 . 1 0 . 1 — — tocopherol acetate | US-47656003-A |
this invention relates to uncoated direct compression tablets containing cefadroxil monohydrate as the active ingredient , which are capable of oral administration to human beings by swallowing , chewing or disintegrating in water resulting in a drinkable dispersion . | the compressed tablet is one of the oldest and most popular unit dosage forms for medicinal substances . the tablet as a dosage form can be traced to well over 1 , 000 years ago when a procedure for molding solid forms containing medicinal ingredients was recorded . as a result of the introduction of new carriers and compression vehicles , tablets are replacing many forms of pills , powders and capsules . accordingly , tablets presently represent the largest production volume of all pharmaceuticals . the reasons for the widespread use of tablets are apparent , since tablets facilitate : ( 1 ) administration of medication in an accurate dose ; ( 2 ) fast and accurate dispensing with less chance of error and contamination ; ( 3 ) ease of administration ; ( 4 ) administration in a form in which the time and area of contact between the active ingredient and the taste buds are reduced , thus obviating the physiological problems associated with the oral administration of drugs that possess a bitter taste and , in the case of coated tablets , with drugs that possess a disagreeable odor ; ( 5 ) release of drugs at specific locations in the gastrointestinal tract to prevent degradation of drugs sensitive to the low ph environment in the stomach , prevent release of drugs that irritate the gastric mucosa in the stomach , and facilitate local action or preferential absorption at specific sites in the tract ; ( 6 ) enhanced stability by effecting a marked reduction in the surface of the drug exposed to the environment ; ( 7 ) rapid production ; and ( 8 ) economy and ease in storage , packaging and shipping . there are currently three basic methods for tableting . they are the wet granulation method , the dry granulation method and the direct compression ( dc ) method . the direct compression method is by far the desired method from the standpoint of processing time and requirements of equipment and materials . however , only a very limited number of pharmaceutical substances possess enough cohesive strength and flowability to allow direct compression without previous granulation . certain crystalline materials , such as potassium bromide and potassium chloride can be can be compressed without preliminary treatment . also , drugs such as aspirin and phenolphthaline can be directly compressed after blending with suitable tableting excipients . it has been estimated that about 20 percent of the materials used for tableting in the pharmaceutical field may be compressed directly . in order to use this method to a greater extent , many more materials are modified either by treating the material in some special way during early stages of preparation , or by adding a direct compression vehicle , i . e ., a dry binder or excipient material which will mix with the active ingredient to provide a flowable powder and form an easily compressible carrier . exemplary united states patents relating to directly compressible tablets include u . s . pat . no . 3 , 584 , 114 to cavalli , et al ., u . s . pat . no . 3 , 725 , 556 to hanssen , et al ., u . s . pat . no . 3 , 873 , 694 to kanig , u . s . pat . no . 4 , 072 , 535 to short , and u . s . pat . no . 4 , 439 , 453 to vogel . there are currently several available binders or excipients which can be used as direct compression vehicles . they include spray - dried lactose ; anhydrous lactose : microcrystalline cellulose ; dibasic calcium phosphate , unmilled ; spray - congealed mannitol ; ungelatinized starch ( e . g ., corn starch ), and partially or fully pregelatinized starch . the final tablet of the invention herein will preferably contain about 1 gram of cefadroxil monohydrate active in an approximate 2 gram tablet . thus , cefadroxil monohydrate accounts for about 50 % of the total tablet weight , although this weight % can be greater up to about 70 - 80 %. the tablet should also contain one or more binding agents or vehicles to promote the direct compression of granular materials into a tablet . preferably , from about 10 - 12 weight % of a microcrystalline cellulose / guar gum mixture containing about 13 parts by weight of guar gum with 87 parts of microcrystalline cellulose . additionally , about 4 - 19 weight % of dibasic calcium phosphate is used . the tablet should also contain one or more disintegrating agents or substances that , in the presence of water or biological fluids ( e . g . mouth saliva or stomach gastric fluids ), promote the release of the active ingredient and the disintegration of the tablet . preferably , about 9 . 5 - 29 weight % of a cross - linked polyvinylpyrrolidone and about 9 - 21 weight % of mannitol or maltitol is used . the tablet should also contain one or more glidant materials which are used to improve the flow of the powder blend and to minimize tablet weight variation . preferably , about 2 . 5 - 10 weight % of colloidal silicon dioxide is used . additionally , and optionally , other substances commonly used in pharmaceutical formulations can be included such as lubricants ( e . g . magnesium stearate ) to facilitate ejection of the finished tablet from the dies after compression and to prevent tablets from sticking to the punch faces ; flavor enhancers or sweetners ( e . g . aspartame , sodium saccharine , strawberry aroma , raspberry aroma , etc . ); and dyes or colorants . generally , the individual ingredients for the final tablet are first milled , if necessary , to obtain a particle size so that they pass through an 80 mesh u . s . sieve screen ( i . e . smaller than 180 μm ). however , the dibasic calcium phosphate and colloidal silicon dioxide need not be specially milled to any particular size . also , the cefadroxil monohydrate particle size is preferably such that at least 85 % pass through a 120 mesh u . s . sieve screen and at least 50 % pass through a 200 mesh u . s . sieve screen . although the foregoing invention has been described in some detail for illustration only , it will be readily apparent to one skilled in the art that changes and modifications may be made without departing from the scope of the invention herein . the following preparation illustrates a particularly preferred embodiment of the invention . an uncoated direct compression tablet having the following composition was prepared by the procedure described below : ______________________________________ ( a ) cefadroxil monohydrate 1000 mg . ( b ) a mixture containing 174 mg . 200 mg . microcrystalline cellulose and 26 mg . guar gum ( avicel ce ® , fmccorporation , newark , delaware , usa )( c ) anhydrous dibasic calcium phosphate 200 mg . ( encompress ® , mendell , a penwest co ., usa )( d ) cross - linked polyvinylpyrrolidone 200 mg . ( crospovidone ® nf , gaf corporation , usa )( particle size & lt ; 75 μm )( f ) mannitol ( particle size & lt ; 180 μm ) 350 mg . ( f ) colloidal silicon dioxide 50 mg . ( aerosil ® , ludeco co ., belgium )( particle size & lt ; 180 μm )( g ) magnesium stearate ( particle size & lt ; 125 μm ) 27 mg . ( h ) aspartame ® ( particle size & lt ; 180 μm ) 4 . 5 mg . ( i ) saccharine ( particle size & lt ; 180 μm ) 4 . 5 mg . ( j ) strawberry aroma ( particle size & lt ; 180 μm ) 30 mg . ( k ) raspberry aroma ( particle size & lt ; 180 μm ) 30 mg . total weight 2096 mg . ______________________________________ twenty tablets having the composition and particle size characteristics as described above were made by first weighing out the necessary amounts of each ingredient . ingredient a ( i . e . cefadroxil monohydrate ) is first passed through a granulating machine ( e . g . fitzmill u6 , made by the fitzpatrick co ., elmhurst , ill ., usa ) so that 98 % of the particles pass through a 120 mesh screen and 70 % pass through a 200 mesh screen ( u . s . sieve ). the fitzmill machine used a screw feeder operating at 55 rpm and cutters operating at 4600 rpm . ingredients a - e were then mixed and blended in a suitable blending machine ( e . g . tubula type taz , made by w . a . bachofen , basel , switzerland ) for 10 minutes . the remaining ingredients f - k are added and the entire mixture is blended an additional 3 - 4 minutes . the resulting blend is then compressed into about 20 tablets , each having the weight and composition as set forth above , using a suitable tableting machine ( e . g . erweka type eko , frankfurt , germany ). the resulting tablets are generally flat , elliptical in shape with scoring lines on the top and bottom , having a length of 23 . 8 mm , a height of 9 . 883 mm , a width of 13 mm , and density of 1 . 2 mg / mm 3 . the tablets are swallowable , chewable with a pleasant mouth taste and disintegrate in water in less than 2 minutes to form a pleasant tasting drinkable dispersion . | US-4288898-A |
a clogging shoe tap device having a first plate for attachment to a shoe , and a second plate pivotally attached to the first plate along a transverse line of attachment , the second plate also having a transverse balance axis , wherein the transverse line of attachment is offset from the transverse balance axis , causing the tapping edge to hang downwardly when in the rest position . | referring first to fig1 the invention is shown in top view . a top plate 10 is adapted for affixing to the bottom of a shoe by means of fasteners passing through the holes 12 - 15 , and anchoring the top plate against the bottom of the shoe . the top plate 10 has upwardly curving tabs 21 - 24 arranged around the perimeter of the plate , and positioned so as to at least partially embed tabs 21 - 24 into a shoe sole portion when the top plate 10 is fastened to the shoe . these tabs provide a means for properly securing the top plate against the shoe bottom , and for preventing any lateral movement of the top plate relative to the shoe . the top plate 10 also has a front tab 25 which is upwardly curved for at least partially wrapping around the forward edge of the shoe , for preventing the plate from catching against an external object , such as a floor irregularity . a bottom plate 20 is attached to plate 10 by two fasteners 31 and 32 , preferably rivets which have been loosely fastened between the two plates . the rivets 31 and 32 are fastened through holes aligned along the dotted line 50 , which is offset from the center of balance line 40 . there preferably is sufficient space between the two plates 10 and 20 to permit separation of the plates while still attached via the rivets , so that the plate 20 , which is mounted below the plate 10 in the operational position , pivots downwardly at its end having a front tab 40 . this spacing occurs because of the offset of the pivot line 50 rearward from the center of balance line 40 . fig2 a shows a rear view of the assembled plates 10 and 20 , and fig2 b shows a front view of the plates . the front tab 40 of the plate 20 preferably curves upwardly about the front tab 25 of plate 10 , making contact with the tab 25 when the plate 20 is pivoted into a striking position . this contact also prevents any excessive rearward shear force against the rivets 31 and 32 . the plate 20 has a transverse radius of curvature so that the initial and primary contact with a floor is made along the curved portion of the plate , which prevents catching the plate against any projecting floor object . fig4 shows a bottom view of the assembled plates 10 and 20 , illustration how the plate 20 is shaped about its perimeter to provide access from below to the holes 12 - 15 , so that fasteners such as nails can be affixed through the holes and into a shoe without disassembling the plates 10 and 20 . each of the holes 12 - 15 is preferably positioned inwardly adjacent one of said tabs 21 - 24 . fig3 shows the plates in a relative operational position , with the front tab portion 40 of plate 20 being spaced away from the front tab portion 25 of plate 10 , by pivoting on the rivets 31 and 32 . the amount of space between the two plates is determined by the relative fit of the rivets in the plates , and by the rear edge of plate 20 contacting plate 10 . at the time the rivets are applied to fasten the plates , they are attached sufficiently loosely to allow for the amount of space shown in fig3 . the rivets can be applied according to any known process which achieves the desired spacing . rivet tools are available which permit adjustment of the crimping distance along the rivet . in operation , the plates 10 and 20 , assembled as shown in the figures are preferably nailed to the bottom toe surface of a dancing shoe . a similar pair of assembled plates are affixed proximate the bottom heel surface of the dancing shoe . of course , the heel plates are shaped and sized to conform with the shape of the shoe heel area , and the toe plates are shaped and sized to conform with the shape of the shoe toe area . when attached , the front tab portion of plate 20 will drop away from contact with the corresponding tab of the plate 10 , until the wearer brings the taps into contact with a floor while executing a dance step . each time contact with the floor is made , a pleasing tap sound is made which can be used to provide a rhythm beat to match the dance step . the foregoing description of a preferred embodiment of the invention is intended to be illustrative and not limiting . the true scope of the invention is to be understood and limited by the claims herein , variations in particular details of the invention being entirely possible within the overall scope of the invention as claimed . | US-26280102-A |
a sagittal approximator for clamping engagement with an open back hook for urging a spinal rod into seating engagement with said hook . the sagittal approximator includes an integral fixed handle and jaw . a shiftable handle is pivotally connected to the fixed handle . a shiftable jaw is pivotally connected to the fixed handle adjacent the fixed jaw . the pivotal handle and jaw are pivotally interconnected such that as the pivotal handle is shifted , the pivotal jaw shifts accordingly . the fixed handle includes a threaded channel and longitudinal guide rib . a spinal rod engagement head is slidably carried by the fixed handle and jaw and includes a spinal rod seat which with contact with the spinal rod produces a balanced seating load on the rod . a threaded pusher rod is carried by the channel which when rotated longitudinally shifts the head relative to the fixed handle . | the preferred embodiments herein disclosed are not intended to be exhaustive or to limit the invention to the precise forms disclosed . rather , they are chosen and described so that others skilled in the art may utilize its teachings . referring now to the drawings , sagittal approximator 10 includes a fixed handle 12 having an integral fixed upper jaw 14 . a generally 0 - shaped channel 16 is formed in the upper surface of handle 12 . channel 16 extends from end 18 of handle 12 toward jaw 14 and terminates abruptly forming an abutment 20 . channel 16 in the preferred embodiment is partially threaded as shown . a t - shaped guide 22 extends along the top surface of handle 12 from abutment 20 toward jaw part 14 and terminates in a sloped end spaced from the jaw end 24 . a pair of spaced legs 26 extend downwardly from the underside of fixed handle 12 adjacent end 18 . each leg 26 includes a bore formed therethrough with one of the bores including threads . a leaf spring 28 is connected to the underside of fixed handle 12 by a fastener 29 . the free end 27 of spring 28 extends between legs 26 . a rack 30 is shiftably connected to legs 26 by a fastener 31 and includes a generally squared end 34 . square end 34 of rack 30 in combination with leaf spring 28 imparts a positive snap feel to rack 30 when pivoted toward the position of fig4 . rack 30 may be collapsed to lie adjacent the underside of handle 12 as shown in fig1 and 2 . rack 30 includes a plurality of teeth 32 . a flange 35 extends downwardly from the underside of handle 12 and includes a bore 36 formed therethrough ( see fig4 ). a pair of spaced legs 38 extend downwardly from the underside of handle 12 as illustrated and each include a through bore 40 therethrough in alignment with one another . legs 38 are longitudinally spaced from flange 35 . one of the bores formed in one leg 38 includes threads for accommodating a fastener 42 . fixed jaw 14 includes a transverse abutment 44 extending downwardly from the jaw and a tooth 46 adjacent end 24 of the jaw 14 . a lower handle 48 is provided and includes a pair of spaced legs 50 each including a bore 52 therethrough for accommodating a fastening device . one of the bores 52 include threads . each leg includes a second bore 54 adjacent the end of the leg with one of the bores 54 including threads . the opposite end of handle 48 includes a single tooth 56 inset relative the handle end 49 for engagement with the teeth 32 of rack 30 . a fastener 58 is threadably accommodated by bores 52 of legs 50 and extends through bore 36 of flange 35 to pivotally connect handle 48 to fixed handle 12 . a lower jaw 60 is pivotally connected to fixed handle 12 at legs 38 by a fastener 42 extending through bore 68 of the lower jaw 60 and bores 40 of legs 38 . lower jaw 60 includes an upwardly extending transverse abutment 62 and a tooth 64 . jaw 60 is connected to handle 12 such that its tooth 64 is aligned with tooth 46 of fixed jaw 14 and its abutment 62 is aligned with abutment 44 of jaw 14 when the jaws are substantially parallel ( see fig4 ). a slotted bore 70 is formed through jaw 60 near end 61 . a fastener 71 extends through bores 54 of handle legs 50 and slotted bore 70 of jaw 60 to pivotally connect pivotable handle 48 to pivotal jaw 60 . due to the pivotal connection of lower handle 48 and of lower jaw 60 to fixed handle 12 , as well as their pivotal interconnection by fastener 71 three pivot points are established about fasteners 58 , 42 and 71 respectively . the use of three pivot points provide a tool wherein the top jaw 14 and handle 12 are stationary and the lower jaw 60 pivots about fastener 42 responsive to pivotal movement of handle 48 . as the handle 48 and jaw 60 pivot , fastener 71 slides within slotted bore 70 of jaw 60 . an introducer rod or pusher rod 72 is threadably accommodated by channel 16 and includes a threaded portion 74 and bulbous end 76 . a thumb wheel 73 is connected to rod 72 adjacent threaded portion 74 . a portion of the shaft of rod 72 along with the bulbous end 76 extends outwardly from channel 16 toward jaw 14 . bulbous end 76 of rod 72 is laterally aligned with t - shaped guide 22 being spaced parallel and above the guide as shown . as rod 72 is rotated within channel 16 the rod is longitudinally shifted along the channel by the threaded engagement between the rod and channel . a spinal rod engaging head 80 is provided and includes a body 82 having a t - shaped channel 83 formed in the bottom of the head ( see fig5 ). a slot 84 having a bulbed end is formed in the upper surface of head 80 and extends rearwardly as shown . head 80 further includes a transverse body part 85 . a leg 86 extends downwardly from each end of part 85 as illustrated . each leg includes a recessed spinal rod seat 88 . in use , a head 80 is connected to sagittal approximator 10 such that t - shaped guide 22 slides within channel 83 of the head . end 76 of rod 72 is seated within slot 84 . the bulbed end of push rod 72 permits rotation of the rod relative to head 80 but prevents the head from shifting longitudinally relative to the push rod 72 . thumb wheel 78 is turned by the surgeon in one direction to draw rod 72 and head 80 rearwardly or turned in the opposite direction to shift the rod and head forwardly . abutment 20 defines the fully rearward position of head 80 . the surgeon seats tooth 46 of fixed jaw 14 into alignment bore of the body of the spinal hook 2 shown in broken lines in fig1 . end 49 of handle 48 is drawn toward fixed handle 12 to pivot jaw 60 toward fixed jaw 14 until tooth 64 of the pivotal jaw seats within a second alignment bore of the body of the hook . slight manipulation may be required to seat the jaw teeth properly . once the teeth are seated , the surgeon squeezes handle 48 to further draw end 49 toward handle 12 to clamp the hook between the jaws . if desirable , rack 30 may be extended prior to seating of the teeth within the hook , such that as end 49 of handle 48 is pivoted toward handle 12 , tooth 56 engages with the rack teeth to temporarily fix handle 48 relative to handle 12 when sufficient clamping pressure is exerted on the hook by the jaws . when the jaws 14 and 60 are clamped to the hook 2 , as described , a spinal rod or section of a spinal rod 3 used in the procedure is positioned between the jaws . fig1 illustrates the positioning of spinal rod 3 relative to jaws 14 and 60 wherein spinal rod 3 is illustrated in broken lines only . the head 80 is positioned such that spinal rod 3 is between the hook 2 and head 80 ( see fig1 ). to seat spinal rod 3 within the open back hook 2 , the user rotates thumb wheel 73 to shift pusher rod 72 longitudinally along handle 12 toward jaw 14 . rod 72 slides head 80 along t - shaped guide 22 . as head 80 is slid toward hook 2 by pusher rod 72 , legs 86 of the head contact spinal rod 3 at seats 88 of the legs to urge the spinal rod toward the hook . continued rotation of thumb wheel 73 pushes the head and spinal rod toward the hook . when the spinal rod reaches the hook , additional rotation of the thumb wheel forces the spinal rod through the opening in the hook 2 and into seating arrangement with the hook . since a leg 86 extends downwardly on each side of the jaw the spinal rod is engaged on each side of hook 2 , and thus the legs 86 of head 80 straddle the hook . the load on the spinal rod is balanced or centered relative to the hook 2 to cause an even seating of the spinal rod and prevent a moment arm from developing on the spinal rod . an alternative embodiment of the spinal rod contacting head is illustrated in fig6 - 8 . spinal rod contacting head 90 includes a body 92 having a t - shaped channel 94 and a bulbous slot 96 similar to head 80 . a pair of legs 98 extend at a downward angle from body 92 and are integral with an interconnecting end wall 100 . a protrusion 101 extends longitudinally from wall 100 and includes an arcuate seat 102 for engaging the spinal rod . as illustrated in fig6 and 7 when head 90 is connected to sagittal approximator 10 previously described , end wall 100 and protrusion 101 are positioned between jaws 14 and 60 . in use , protrusion 101 contacts a spinal rod and seats the spinal rod into the hook as the thumb wheel 78 is rotated . protrusion 101 is centrally aligned with the jaws which aligns the force on the rod with the center of the body of the hook to balance the load on the spinal rod to evenly seat the spinal rod within the hook . the choice of which head 80 or 90 to be used during the procedure is primarily one of surgeon &# 39 ; s preference . however , it may be especially useful to use head 90 when an insufficient length of rod extends from one end of the hook as may be commonly experienced near either the end of the patient &# 39 ; s spine . the heads 80 or 90 may be conveniently interchangeably connected to the sagittal approximator instrument . it should be understood that the invention is not to be limited to the precise forms disclosed but may be modified within the scope of the appended claims . | US-62347090-A |
an automatic locking landing net yoke includes a channeled ramp feature such that , when the handle is drawn through the yoke and the yoke slides over a spring button , the ramp forces or cams the button downwardly and into the handle . toward the lowermost portion of the ramp is a hole such that , as the hole in the yoke slides over the spring button , the force of the button extends it upwardly through the hole . the spring button is never pushed completely into the handle because the backside of the yoke hole prevents the yoke from being extended to the point that the yoke slides off the handle . the yoke is also configured such that the yoke allows use with hoop and handle shapes of various configurations and is molded of a material that does not create any oxidation or corrosion between the handle and yoke , thus providing smooth operation between the two elements . | referring now to the drawings in detail wherein like numbers represent like elements throughout , fig1 and 2 illustrate two similar perspective views of a landing net assembly , generally identified 10 , that uses the preferred embodiment of a yoke 50 constructed in accordance with the present invention . more specifically , fig1 illustrates the landing net assembly 10 in its “ stored ” or “ net - retracted ” position whereas fig2 illustrates the assembly 10 in its “ active ” or “ net - extended ” position . fig1 and 2 each include an enlarged inset view of that area of interest relative to the automatic locking yoke 50 as well . as shown , the landing net assembly 10 includes a handle 20 and a hoop 40 . in their most basic relational functionality , the hoop 40 and the handle 20 are slidably movable relative to one another by virtue of the use of the yoke 50 of the present invention . referring again to fig1 and 2 , it will be seen that the handle 20 comprises a longitudinally - extending tubular shaft portion 22 having a distal portion 24 and a proximal portion 26 . although shown in tubular configuration , it is to be understood that the handle 20 could also be constructed of a solid piece of material without deviating from the scope of the present invention . the proximal shaft portion 26 may be covered by a handle grip 27 which reduces the likelihood of slippage of the handle 20 when the handle 20 is being used as intended . the distal shaft portion 24 includes a round - headed spring button 28 . the spring button 28 is secured to an inner surface 25 of the shaft interior 23 such that the spring button 28 extends through a hole 25 defined within the handle 20 . see fig3 a through 3c . the spring button 28 is biased outwardly of the handle 20 , but is depressible into the handle 20 , but not all the way in . as shown in fig4 a , the handle 20 is configured , in one embodiment , in a unique cross - sectional tubular configuration that includes a substantially rounded and semi - circular bottom contour 32 , a pair of opposing , tangentially and upwardly extending flat side walls 33 , a pair of opposing and rounded shoulder portions 34 , and a pair of slightly upwardly extending flat upper walls 35 , the upper walls 35 connecting at a slightly curved peak portion 36 . the bottom contour 32 , the side walls 33 , the shoulder portions 34 , the upper walls 35 and the peak portion 36 all forming a longitudinally - extending handle surface continuum . in another embodiment , as shown in fig4 b , the tubular handle 20 is formed in a more traditional and generally rounded cross - sectional 38 configuration . this feature and the significance of these alternate configurations will be discussed in more detail later in this detailed description . the hoop 40 of the landing net assembly 10 includes a continuously - arcuate net support portion 42 having a first end 43 and a second end 44 . attached to the net support portion 42 is a fish - retaining net 46 . the net 46 can be made of a flexible plastic material , corded nylon , or any other material without deviating from the scope of the invention . it is not a limitation of the present invention . it is also to be understood that the shape of the net support portion 42 could assume any shape without deviating from the scope of the present invention . in other words , the shape of the net support portion 42 , the length of its perimeter , the material that it is made from , etc . are not limitations of the present invention . the hoop 40 should , however , be of sufficient strength and rigidity to allow the net 46 to be properly supported when the net 46 contains a fish in it . it is possible , however , that the cross - sectional shape of the net support portion 42 , and particularly that of its ends 43 , 44 may assume different shapes , including a generally hexagonal shape as shown in fig4 a and a generally circular shape 43 a , 44 a as shown in fig4 b . this feature will also be discussed in more detail later in this detailed description . the yoke 50 of the present invention includes a generally symmetrical yoke body 52 having a centrally - disposed handle cavity 54 and a pair of opposing and identically — configured hoop cavities 56 disposed in lateral yoke portions 51 to either side of the handle cavity 54 . see fig4 a and 4b . in both of those figures , it will be seen that the handle cavity 54 is configured in a unique cross - sectional configuration that substantially matches that of the first - described embodiment of the cross - sectional shape of the handle 20 . that is , it includes a substantially rounded and semi - circular bottom contour 72 , a pair of opposing , tangentially and upwardly extending flat side walls 73 , a pair of opposing and rounded shoulder portions 74 , and a pair of slightly upwardly extending flat upper walls 75 , the upper walls 75 connecting into an opening 63 . the bottom contour 72 , the side walls 73 , the shoulder portions 74 , and the upper walls 75 , all forming a longitudinally - extending handle - receiving surface continuum . note also that the handle cavity 54 includes a number of handle supporting stubs 59 that extent slightly inwardly of the cavity 54 . the yoke 50 also includes a front face 55 and an upper yoke body portion 60 that includes a yoke ramp 62 . the yoke ramp 62 includes a yoke ramp opening 63 , opposed interior sidewalls 64 , and an interior ramp surface 65 , the ramp surface 65 tapering downwardly from the front face 55 of the yoke body 52 . disposed toward the bottommost portion 66 of the ramp surface 65 is a yoke button hole 67 , the yoke button hole 67 being configured to receive the rounded spring button 28 within it . see fig3 c . the yoke button hole 67 is also uniquely configured to have a back surface 68 and a front surface 69 , the front surface having a point 71 that coincides with the lowest point of travel of the uppermost portion 29 of the spring button 28 . to aid in manual depression of the spring button 28 to release the button 28 from the hole 67 , the hole 67 is surrounded by a circumferential indent 77 that roughly matches the curvature of a user &# 39 ; s thumb . in the preferred embodiment , the yoke ramp opening 63 includes rounded side edges 61 , the purpose of which is to guide the spring button into the opening 63 . the yoke 50 of the preferred embodiment is made of a polymer material , such as polypropylene . this material provides a yoke 50 that is lightweight , durable and not susceptible to corrosion . in application , the hoop 40 is pre - attached to the yoke 50 such that the ends 43 , 44 of the net support portion 42 are inserted into the hoop cavities 56 . the ends 43 , 44 are secured by fasteners 85 inserted into apertures ( not shown ) that are defined within each of the lateral yoke portions 51 . as shown in fig4 a and 4b it will be noted that the cross - sectional shape of the hoop ends 43 , 44 may be hexagonal or circular , the cross - sectional shape of the hoop cavities 56 each being generally hexagonal with longitudinally - extending stubs 58 being disposed at the approximate center of each of the sides 57 of the hexagonal shaped cavity 56 and also extending slightly inwardly of the cavity 56 . the handle 20 is also slidably pre - attached to the yoke 50 by insertion into and through the handle cavity 54 . this is accomplished by manually depressing the spring button 28 below the surface 34 of the handle 20 . the landing net assembly 10 is transported in its stored position as shown in fig1 or readied for use in its active position as shown in fig2 . to move the handle 20 from its position as shown in fig1 to its position as shown in fig2 in the situation where the cross - sectional shape of the handle shaft 22 is as shown in fig4 a , and as previously described , the user needs only to pull the handle 20 rearwardly through the yoke 50 . in this configuration , the user need not worry about rotation of the yoke 50 about the handle 20 since such is not possible . as the user pulls the handle 20 through the yoke 50 , the spring button 28 , which is biased to extend fully outwardly of the handle 20 , is guided into the yoke ramp opening 63 . see fig3 a . as this movement continues , the uppermost portion 29 of the spring button 28 engages the interior ramp surface 65 of the yoke 50 and slides along it , urging the spring button 28 further downwardly . see fig3 b . as the uppermost portion 29 of the spring button 28 passes beneath the lowermost point 71 of the front surface 69 of the yoke button hole 67 , the spring button 28 is pushed inwardly of the handle 20 to its greatest extent . as the spring button 28 passes this point 71 , the spring button “ pops up ” and into the yoke button hole 67 , the back surface 68 of the hole 67 limiting the rearward movement of the button 28 . see fig3 c . in this position , the landing net assembly 10 can be used for its intended purpose . to return the assembly to its stored position , the user inserts his or her thumb into the circumferential indent 77 of the yoke button hole 67 at the same time pushing the spring button 28 inwardly of the yoke 50 and urging the handle 20 forwardly . upon clearance of the lowermost point 71 of the front surface 69 of the yoke hole 67 , the spring button will move forwardly and along the surface 65 of the yoke ramp 62 , eventually exiting the yoke ramp opening 63 and returning the assembly to its position as shown in fig1 . in the case where the handle cross - sectioned shape is generally circular , as shown in fig4 b , the operation of the assembly 10 is similar . the exception is that , given the ability of the circular cross - sectioned handle 20 to rotate within the handle cavity 54 of the yoke 50 , the user must manually align the spring button 28 with the yoke ramp opening 63 . the rounded edges 61 of this opening 63 aid the user in this step . absent this alignment , it is impossible for the spring button 28 to be automatically depressed in any other rotational position which would otherwise risk complete disconnection of the yoke 50 from the handle 20 . once aligned properly , the movement of the handle 20 relative to the yoke 50 , and the movement of the spring button 28 within the yoke ramp 62 , are the same as previously described as is the release of the handle 20 therefrom . based upon the foregoing , it will be seen that there has been provided a new and useful automatic landing net yoke whereby the handle can be slid into a fixed position without manually activating the spring button , thus making the net easier and quicker to use ; whereby the yoke does not allow the spring button to miss the hole , thus making the net more reliable in its use ; whereby the yoke geometry allows multiple shapes of hoops and handles to be used , thus making the yoke design much more valuable due to manufacturability ; whereby the yoke of such design is manufactured of a material that does not allow corrosion or oxidation between the yoke and the handle ; and whereby a yoke is provided that is lightweight , strong , and no more expensive to produce than currently available parts are , thus making the yoke useful and affordable . | US-9887705-A |
a device and method for enterally hydrating a patient , such as a paralyzed or limited upper body mobility patient with a functional gastrointestinal system who is nonetheless incapable or not fully capable of drinking unassisted . here fluids are provided by a suspended semi - flexible container with graduation markings to allow for convenient estimation of fluid use , an upper open and closeable cap to allow the container to be refilled , and a lower fluid conducting tube that terminates in a mouthpiece , which contains a fluid valve formed from at least one slit in an elastic material . patient mouth force on the valve causes the slit to enlarge , thus enabling fluid to flow into the patient . | fig1 shows a flow chart of the hydration decision tree and hydration options generally used for patient hydration management . at present , if a patient is able to drink fluids without outside assistance ( 100 ), then absent other reasons to give the patient an iv , the patient will normally obtain most fluids by simply drinking out of a cup ( 102 ), with the water or other beverage refreshed by a pitcher or other bottle as needed . a fair number of patients , particularly patients in clinical settings such as hospitals , rehabilitation facilities , hospices and the like are unable to drink unassisted however ( 104 ). some of these patients may be so severely sick ( i . e . major gastrointestinal issues , in intensive care , need iv administration for high dose chemotherapy , and the like ( 106 ) that they must be hydrated by iv ( 108 ). there is also an intermediate range of patients ( 110 ) that have adequately functioning gastrointestinal systems ( here adequate means capable of absorbing sufficient fluid to adequately hydrate the patient ) who have other problems that prevent them from adequately self hydrating . they may be too weak , suffer from paralysis or other loss of upper body mobility ( here simply having both arms in casts might be sufficient ), or other problem that prevents them from self administering fluids . at present , prior inventions in the area notwithstanding , the solution is to generally throw a lot of resources at the problem by designating a nurse , nurse assistant , or family member to stand by and administer fluids ( 112 ). this is both costly , and can create gaps where the patient is awake but uncomfortable due to thirst . by contrast , through use of the invention &# 39 ; s device and methods , compliance with the prescribed therapeutic hydration regimen becomes both logistically similar and more reliable . whenever possible , clinicians attempt to step the patient down to normal hydration methods as quickly as possible . sometimes patents can be stepped down from iv administration ( 108 ) directly to self administration with a cup ( 102 ) directly . at other times , patients will initially start with assisted administration with , for example a cup ( 112 ) and step down to self administration with a cup ( 102 ) when ready . at still other times , a patient may need to step down twice — once from iv administration ( 108 ) assisted cup administration ( 112 ), and then again to the normal self cup administration ( 102 ). the invention is based in part on the insight that there remains room for improvement at the assisted cup administration stage ( 112 ). fig2 shows an overview of the patient enteral hydration device ( 200 ). in particular , in one embodiment , the invention may be a both a device and a method of enterally hydrating a patient , such as a patient in need of assisted enteral fluid administration ( 112 ). here , the device and method will often work by providing a substantially transparent fluid container ( often plastic ) ( 202 ) which will usually have several soft deformable sides ( such the flexible soft and deformable sides of an iv bag ), but which in some embodiments may also have at least one substantially non - deformable side . in other embodiments all sides may be flexible and deformable . the top side of this fluid container may be at least in part be substantially rigid , often with a one - piece rigid or semi - rigid press - clamp cap ( 204 ) configured to either open to admit fluids into the container , or to securely snap shut . the back side of the fluid container will often be mounted on ( or by itself ) a back support ( 214 ), optionally ( 218 ). this back support , which optionally will be substantially flat , will generally extend above the level of the cap , and will often have a fenestrated opening ( e . g . a hole in the back support material 216 ) that is also above the level of the cap ( 204 ). the hole or fenestration in the back support ( 216 ) will usually also extend above the cap , and this hole will usually be disposed to enable the container to be suspended from an iv pole or other support structure ; the lower portion of the fluid container will generally have a lower opening with either a tube adapter ( 203 ) connected to the distal opening of a hollow tube , or alternatively a directly connected hollow tube ( 204 ). this hollow tube ( 204 ) will be made of a material ( often plastic as well ) selected for transporting fluids for human consumption , and will generally be long enough to deliver fluid from the fluid container ( while suspended near the patient ) to the patient &# 39 ; s mouth . at the patient &# 39 ; s mouth end , the hollow tube will have a mouthpiece ( 206 ) attached to the proximal opening of the hollow tube ( 204 ). as will be discussed in more detail in fig6 a and 6b , this mouthpiece ( 206 ) that connects to the tube ( often via a coupling region ( 612 )) will generally be configured with at least a fluid valve ( 602 ) comprising at least one narrow slit ( 604 ) in an elastic and deformable surrounding material ( 606 ). in some embodiments , this fluid valve may be further encased in an outer covering or shell ( 608 ), ( 610 ) as well . in the absence of patient mouth generated force ( e . g . sucking , biting ), this deformable material ( 606 ) will hold the slit ( 604 ) shut , thus preventing fluid flow . however in the presence of patient mouth generated force ( e . g . sucking , biting ), said deformable material ( 606 ) deforms thus causing the slit ( 604 ) to enlarge and permitting fluid flow from the container into the patient &# 39 ; s mouth . here , the materials and methods of fawcett ( u . s . pat . no . 5 , 085 , 349 ) may be used , and these materials and methods are incorporated herein by reference . other methods ( previously discussed ) may also be used . to use the device / method , the container will first be filled with fluid ( e . g . water ) by opening the press - clamp cap ( 204 ), filling the fluid container with fluid , and closing the press - clamp cap . alternatively before , after , or during this step , the container will be mounted on a support structure ( e . g . iv pole ) by placing some support member through the fenestrated opening ( 216 ). this is shown in more detail in fig7 . after this , the tube and mouthpiece can be provided to the patient ( e . g . clipped to a convenient location where the patient can easily access ) and as needed , the patient can be instructed on what sort of mouth force is best to use the device . a variety of different types of container designs may be used . in general , containers that have a semi - rigid or rigid back ( 214 ), optionally ( 218 ) have some advantages in that they provide some structure and support to the container even when it is empty , thus making for more accurate fluid measurements as well as increased ease of handling . at the same time , although all sides of the container may be rigid in some embodiments , often it is useful to have the front of the container ( e . g . the side with graduations ( 212 )). as well as the container sides connecting to the optionally semi - rigid or rigid back , be flexible so that they deform outward in response to fluid , and deform inward in response to loss of fluid . this as the container is drained of fluid , the cap ( 204 ) can maintain a tight seal , while at the same time a vacuum will not form inside the container ( because the container walls will move inward as fluid is depleted ), making it uniformly easy for the patient to obtain the fluid , as the fluid levels drop , without any admixture of air or outside contaminants . in some embodiments , it may be useful to further have a thumb controlled tubing clamp ( 208 ) or other secondary fluid shutoff configured to provide an independent shut - off for stopping fluid flow along the hollow tube ( 204 ). additionally , in some embodiments , it may also be useful to have a clip ( 210 ) attached to either the tube or the mouthpiece and configured to at least temporarily fix the mouthpiece to a location near the patient &# 39 ; s mouth . in some embodiments , it may be useful to have the top of the container where the cap is made , at least in part , from a relatively rigid material so that the cap has a complementary port to clip on to that will maintain its rigidity and fluid tightness between both full and empty states . usually it is also useful to make some of the sides of the container , and preferably all of the sides of the container out of a transparent material so that the level of fluid in the container can be easily determined by sight . fig3 a shows a close up of one embodiment of the devices &# 39 ; snap - on cap assembly ( 204 ), here showing one cap design ( 300 ). this cap has a flanged edge ( 302 ) to provide a good hand grip for opening and closing , an inner ring to snap onto the cap &# 39 ; s complementary edge ( 304 ), a thin hinged region ( 306 ) and a plastic ring ( 308 ) to keep the cap adhered to the cap &# 39 ; s complementary edge . fig3 b shows a close up of an alternate embodiment of the cap ( 310 ) where the hinged region is appreciably wider ( 312 ). fig4 a shows a close up of the complementary edge ( 400 ) of the device &# 39 ; s snap - on cap . this will usually be made of rigid or semi - rigid material so as to create a good fluid barrier . this complementary edge may optionally have one or more grooves or detents ( 402 ), ( 404 ) designed to match up and interlock with corresponding grooves or detents in the cap . fig4 b shows a cross sectional view of the snap - on cap ( 204 ), ( 310 ) in the shut position . as previously discussed , the back side of the fluid container may be either mounted on , or directly comprise a substantially flat back support ( 214 ) with a fenestrated opening ( 216 ) extending above the cap ( 204 ). this fenestrated opening may be configured to allow the fluid container to be suspended from an iv pole or other support structure , as is shown in fig7 . fig5 shows a closer view of the device &# 39 ; s fluid reservoir and fenestrated opening . as previously discussed , the fluid container ( 500 ) will often have a lower opening with either a tube adapter connected to the distal opening of a hollow tube ( 203 ), or a directly connected hollow tube . this hollow tube , previously shown in fig2 as ( 204 ), will generally have sufficient length to deliver fluid from the fluid container ( 500 ) while the container is suspended near said patient , and deliver this tube to the mouthpiece ( 206 ). fig6 a shows an overall view of the device &# 39 ; s mouthpiece , and fig6 b shows a close up view of the device &# 39 ; s valve . as previously discussed , this mouthpiece ( 206 ) that connects to the tube ( often via a coupling region ( 612 )) will generally be configured with at least a fluid valve ( 602 ) comprising at least one narrow slit ( 604 ) in an elastic and deformable surrounding material ( 606 ). in some embodiments , this fluid valve may be further encased in an outer covering or shell ( 608 ), ( 610 ) as well . in the absence of patient mouth generated force ( e . g . sucking , biting ), this deformable material ( 606 ) will hold the slit ( 604 ) shut , thus preventing fluid flow . however in the presence of patient mouth generated force ( e . g . sucking , biting ), said deformable material ( 606 ) deforms thus causing the slit ( 604 ) to enlarge and permitting fluid flow from the container into the patient &# 39 ; s mouth . here , the materials and methods of fawcett ( u . s . pat . no . 5 , 085 , 349 ) may be used , and these materials and methods are incorporated herein by reference . other methods ( previously discussed ) may also be used . thus in this particular embodiment , in the absence of patient mouth generated force , the deformable material ( 606 ) holds the slit ( 604 ) shut , thus preventing fluid flow to the mouth of said patient . however when the patient wants fluid , and communicates this by sucking on the mouthpiece or biting on the mouthpiece , this deformable material deforms thus causing the slit to enlarge and permitting fluid flow to the patent &# 39 ; s mouth . fig7 shows an example of the device in use hydrating a patient ( 700 ). in this example , the container ( 500 ) is hanging from an iv pole ( 702 ) support ( 704 ) by way of opening ( 216 ). the mouthpiece ( 206 ) in this example is clipped to the patient &# 39 ; s blanket ( 706 ) in a region near the patient &# 39 ; s mouth by a clip ( 210 ). fig8 shows a flow chart of the hydration decision tree and hydration options generally used for patient hydration management , when using the invention . here the considerations are generally similar to those previously described in fig1 , however now with the use of the invention , what was formerly a very labor intensive assisted enteral fluid administration step ( 112 ) now is greatly labor reduced because the invention &# 39 ; s device and methods are now used in ( 812 ). indeed , the invention reduces the amount of effort required for the patient to self administer fluids to the point where some patients may wish to continue using it even after they regain the ability to use a cup . here , the invention &# 39 ; s use on a non - obligatory basis ( i . e . use by patients capable of self enteral administration ) can be as policy and costs dictate . for example the invention &# 39 ; s device and methods could be useful in pediatric or geriatric wards where patients can drink with a cup , but may be unacceptably messy while doing so . thus the invention can reduce clutter and traffic around the patient , help prevent fluid spills , and allow for fluid intake by ambulatory patients . the device will most commonly be made from one or more plastics . here the plastics will often be selected from the group of transparent polymers generally recognized as suitable for fluid storage and transport in a medical setting . this can include polyethylene , polypropylene , polyvinyl chloride ( pvc ), polyolefin , thermoplastic elastomers , and the like . fig9 shows an alternate embodiment of the invention &# 39 ; s fluid container . in this embodiment , the entire body of container ( 900 ) is made from a flexible and deformable material . the cap ( 902 ) is smaller and circular . there are also separate fill line ( 904 ) and graduation ( e . g . volume ) markers ( 906 ). the back may optionally be made from a non - deformable material . | US-201213347274-A |
the present invention relates to a medical device for intradermal or subcutaneous treatment of a patient , comprising : a piercing element to penetrate a skin portion of the patient ; an illumination arrangement to illuminate the piercing element and / or to illuminate the skin portion prior and / or during a treatment process , wherein the illumination arrangement is further adapted to visually indicate a predefined treatment sequence of the treatment process . | the sketch of fig1 schematically illustrates a typical application scenario when using a pen - type injector 10 for injecting a dose of a medicament . the drug delivery device 10 comprises a dose button 14 at a proximal end which is to be depressed by a thumb of a user . the drug delivery device 10 comprises a cartridge holder 15 at a distal portion which is further equipped with a replaceable injection needle 12 . typically , the injection needle 12 is provided on a needle hub to be screwed onto a distal interface of the cartridge holder 15 . as further depicted in fig1 , the cartridge holder 15 is equipped with an illumination arrangement 24 which is adapted to generate two different cones of light 16 , 18 . whereas the rather focused inner cone of light 18 is intended to illuminate a site of needle puncture 22 on the skin of the patient , the outer cone of light 16 concentrically arranged relative to the inner cone of light 18 is adapted to provide ambient illumination of the surrounding area 20 of the particular skin portion 22 to become subject to medical treatment . a rather similar device 40 is illustrated in fig3 but there , instead of an illumination arrangement 24 concentrically enclosing the injection needle 12 , a single light source 44 is provided at a distal end face of a cartridge holder 15 . as shown in fig3 , the light source 44 is preferably designed as led or as a laser adapted to emit a rather focused light beam 46 to a target area 48 on the skin of the patient . here , the target area 48 marks the site of needle puncture . fig2 is further illustrative of a lancing device 30 having a piercing needle 34 adapted to puncture or to pierce the skin tissue of the patient , e . g . for the purpose of a blood glucose measurement . the lancing device 30 is equipped with an illumination arrangement 24 similar to the one already described with respect to fig1 . the illumination arrangement 24 is adapted to generate two different cones of light 16 , 18 , which may be activated sequentially or simultaneously and may feature equal , similar or different spectral compositions and light intensities . furthermore , a control button 32 to be depressed by a thumb of a user &# 39 ; s hand is illustrated . if , for instance , the control button 32 is depressed by the user , the entire device 30 will be switched on to support a medical treatment process . depression of said button 32 may be detected by the control element 36 , which , depending on a predefined schedule may activate or deactivate the cones of light 16 , 18 , either for a predefined time interval and / or until a stop signal is received by the control element 36 . the flowchart according to fig4 illustrates an example on how the illumination arrangement 24 , 44 can be correlated with the overall handling of e . g . a drug delivery device 10 , 40 . in a first step 100 , the device is activated . for instance a semi - or fully - automated device is switched on . also , such activation 100 of the device 10 , 30 , 40 may be automatically sensed , e . g . by removing a protective cap . in a subsequent step 102 , a dose to be injected by means of the drug delivery device 10 , 40 is set , e . g . by actuation of a respective dose setting element 14 of the device 10 . the dose setting , in particular the termination of a dose setting procedure may also be automatically detected by a control element 36 , for example by detection of a button press of an “ arm ” button . in response to said detection , the illumination arrangement 24 , 44 may be switched on in step 104 . activation of the illumination arrangement 24 , 44 may lead to a sequential or simultaneous generation of the cones of light 16 , 18 . in a subsequent step 106 the dose previously set is injected into the skin portion 22 , 48 by making use of the illumination provided by the illumination arrangement 24 , 44 . in a subsequent step 108 , termination or end of the injection process is detected . with a semi - automated drug delivery device 10 , 40 , the end of an injection procedure can be detected by a substantial decrease of the thrust exerted by the thumb of a user . hence , when the force level acting on a piston of a cartridge arranged inside a drug delivery device 10 , 40 drops below a predefined threshold , a clear indication of the end of an injection process is generally given . with respect to the illumination arrangement and its control , the end of an injection process may trigger a delay or a dwell period . hence , in the following step 110 , the illumination is kept on for a predefined period of time , which is in the range of a few seconds , e . g . around 5 to 10 seconds . thereafter , in step 112 , the illumination is automatically switched off , thereby indicating to the user the end of the dwell period . in this way , the illumination arrangement 24 is indicative to the user that the predefined dwell period has elapsed and that the injection needle 12 can now be removed from the skin portion 22 . fig5 is further illustrative of an alternative way on how to operate the illumination arrangement . in a first step 200 , the medical device is activated . but here , already prior to a setting of a dose in step 204 , the illumination arrangement 24 , 44 is switched on in the first step 202 . accordingly , the illumination arrangement 24 , 44 may be particularly adapted to illuminate a scale or a comparable display of the medical device 10 , 30 , 40 in order to enable and / or to facilitate the procedure of dose setting , even in dark or dim environments . in the proceeding step 204 , the dose to be dispensed by the device 10 , 40 is set and at the end of the dose setting , prior to a dose injecting to be conducted as step 208 , the illumination arrangement is switched into a different illumination mode in step 206 . the illumination mode to be activated in step 206 is particularly intended and adapted to accompany the injection process conducted in step 208 . the illumination mode activated in steps 202 and 206 may differ with respect to spectral composition , spatial light distribution , light intensity and / or with respect to a sequence of on - off cycles . during the injection process 208 the illumination is sustained . after completion of the actual injection process 208 , the control of the illumination arrangement is adapted to provide a delay in step 210 during which the illumination is kept in an activated state before in a final step 212 , e . g . after elapsing of a predefined dwell period , the illumination is finally switched off . the described steps are only exemplary of two of a plurality of modes the device can be operated . in general , the device may comprise various sensors , e . g . to automatically detected various steps of the treatment process to be executed by the device . hence , the device may be equipped with pressure and / or position sensor , in order to track and to monitor a dose setting and / or dispensing action conducted by the user . depending on the signals to be generated by such sensors , the illumination can be modified , e . g switched on and / or off appropriately without any further user interaction . | US-201214130457-A |
a system is disclosed for delivering a beneficial agent at a substantially constant rate over time . the system comprises a wall formed of a microporous polymer , or a wall formed in part of a microporous polymer with the remaining part of the wall formed of a semipermeable polymer . the wall in surrounds a compartment comprising a flexible partition that separates the compartment into a first space containing the beneficial agent and a second space containing a swellable polymer . the wall in surrounds a compartment comprising a flexible partition that separates the compartment into a first space in contact with the microporous wall and containing the beneficial agent , and a second space in contact with the semipermeable polymer containing an osmotically effective solute , or a swellable polymer . in operation , agent is delivered from the system by fluid diffusing through the microporous wall into the second space causing the polymer to swell , or by fluid being imbibed through the semipermeable wall into the second space causing the solute to dissolve and form a solution , or causing the polymer to swell , wherein in or , the second space expands against the partition urging it to move into the first space and maintain the agent in a saturated state at the microporous wall , with the agent diffusing from the first space through fluid filled micropaths in the wall from the system at a substantially zero order rate over a prolonged period of time . | in accordance with the practice of the invention , it has now been found that diffusion delivery system 10 can be manufactured with microporous wall 12 , formed from microporous polymers that are commercially available , or they can be made by art known methods . the microporous materials can be made , and then manufactured into a system , by etched nuclear tracking , by cooling a solution of a flowable polymer below its freezing point whereby solvent evaporates from the solution in the form of crystals dispersed in the polymer , and then curing the polymer followed by removing the solvent crystals , by cold or hot stretching of a polymer at low or high temperatures until pores are formed , by leaching from a polymer a soluble pore forming component by use of an appropriate solvent , by ion exchange reactions consisting of exchanging a large space occupying ion with a smaller ion , by polyelectrolytic processes , and by dissolving or leaching a pore former from the wall of a system in operation in the environment of use . processes for preparing microporous materials are described in synthetic polymer membranes , by r . e . kesting , chapters 4 and 5 , 1971 published by mcgraw hill , inc ; chemical reviews , ultrafiltration , vol . 18 , pages 373 to 455 , 1934 ; polymer eng . and sci ., vol . 11 , no . 4 , pages 284 to 288 , 1971 ; j . appl . poly . sci ., vol . 15 , pages 811 to 829 , 1971 ; and in u . s . pat . nos . 3 , 565 , 259 ; 3 , 615 , 024 ; 3 , 751 , 536 ; 3 , 801 , 692 ; 3 , 852 , 224 ; and 3 , 849 , 528 . materials useful for making the microporous wall 12 include polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups recur in the polymer chain , microporous materials prepared by the phosgenation of a dihydroxyl aromatic such as a bisphenol a , microporous poly ( vinylchloride ), microporous polyamides such as polyhexamethylene adipamide , microporous modacrylic copolymers including those formed from poly ( vinylchloride ) 60 % and acrylonitrite , microporous styrene - acrylic copolymers , porous polysulfones characterized by diphenylene sulfone groups in a linear chain thereof , halogenated poly ( vinylidene ), polychloroethers , acetal polymers , polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol , poly ( alkylenesulfides ), phenolic polyesters , microporous poly ( saccharides ), microporous poly ( saccharides ) having substituted anhydroglucose units exhibiting a decrease permeability to the passage of water and biological fluids , asymmetric porous polymers , cross - linked microporous olefin polymers , hydrophobic or hydrophilic microporous homopolymers , copolymers having a reduced bulk density , and materials described in u . s . pat . nos . 3 , 595 , 752 ; 3 , 643 , 178 ; 3 , 654 , 066 ; 3 , 709 , 774 ; 3 , 718 , 532 ; 3 , 803 , 061 ; 3 , 852 , 224 ; 3 , 852 , 388 ; and 3 , 853 , 601 , in british pat . no . 1 , 126 , 849 , and in chem . abst ., vol . 71 427f , 22573f , 1969 . the pore - formers useful for forming microporous wall 12 in the environment of use include solids and pore - forming liquids . in the latter expression , the term for this invention generically embraces semi - solids and viscous fluids . the pore - formers can be inorganic or organic and the wall forming polymer usually contains from 5 to 95 % by weight . the term pore - former for both solids and liquids include substances that can be dissolved , extracted or leached from the microporous precursor wall by fluid present in the environment of use to form operable , open - celled type microporous walls . additionally , the pore - formers suitable for the invention include pore - formers that can be dissolved , leached , or extracted without causing physical or chemical changes in the polymer . the pore - forming solids have a size of about 100 angstroms to 200 microns , and they include alkali metal salts such as lithium carbonate , sodium chloride , sodium bromide , sodium carbonate , potassium chloride , potassium sulfate , potassium phosphate , sodium benzoate , sodium acetate , sodium citrate , potassium nitrite , and the like . the alkaline earth metal salts such as calcium phosphate , calcium nitrate , calcium chloride , and the like . the transition metal salts such as ferric chloride , ferrous sulfate , zinc sulfate , cupric chloride , manganese fluoride , manganese fluorosilicate , and the like . organic compounds such as polysaccharides including pentoses , hexoses , disaccharides , sugars , sucrose , glucose , fructose , manitol , mannose , galactose , aldohexose , altrose , talose , sorbitol , and the like , carboxy - polymethylene , carbowax ® compounds , polysorbate , and the like . the pore - formers are non - toxic and on their removal from the wall , channels or paths are formed through wall 12 , that fill with fluid . the paths become a means , or diffusional path for diffusion of agent , or drug from the system . the pores extend from inside wall 12 to the outise of wall 12 for effective release of agent or drug to the exterior of system 10 . additional micropores materials for forming wall 12 include microporous poly ( urethanes ), cross - linked , chain - extended microporous poly ( urethanes ), microporous poly ( urethanes ) in u . s . pat . no . 3 , 524 , 753 , micorporous poly ( imides ), microporous poly ( benzimidazoles ), regenerated microporous proteins , semi - solid cross - linked microporous poly ( vinylpyrrolidone ), microporous materials prepared by diffusion of multivalent cations into polyelectrolyte sols as in u . s . pat . no . 3 , 565 , 259 , anisotropic permeable microporous materials of ionically associated polyelectrolytes , microporous polymers formed by the coprecipitation of a polycation and a polyanion as described in u . s . pat . nos . 3 , 276 , 589 ; 3 , 541 , 006 ; 3 , 541 , 055 ; and 3 , 546 , 142 , microporous derivatives of poly ( styrene ) such as microporous poly ( sodium styrene - sulfonate ) and microporous poly ( vinyl benzyltrimethyl - ammonium chloride ), the microporous materials disclosed in u . s . pat . no . 3 , 615 , 024 and u . s . pat . nos . 3 , 646 , 178 and 3 , 852 , 224 . the selective permeable polymers used for partition 14 and wall 12a , when a semipermeable polymer is used for their manufacture in system 10 , include , polymers permeable to fluid present in system 10 and the environment , while remaining impermeable to solutes , agents and drugs . typical materials include semipermeable polymers , also known to the art as osmosis membranes . the semipermeable polymers include cellulose acrylate , cellulose diacylate , cellulose triacylate , cellulose ethers and cellulose esters . typical semipermeable polymers include cellulose acetate , cellulose acetate ethyl carbamate , and the like . other semipermeable polymers include polyurethane , and selectively permeable polymers formed by the coprecipitation of a polyanion and a polycation , and semipermeable ion exchange polymers . generally , semipermeable polymers useful for forming partition 14 , or wall 12a , will have a fluid permeability of 10 - 5 to 10 - 1 ( cc mil / cm 2 hr atm ) expressed per atmosphere of hydrostatic or osmotic pressure difference across 14 or 12a at the temperature of use . exemplary polymers suitable for partition 14 , when it is impermeable to fluid agents and solutes include , plasticized polyvinyl chloride , styrene - butadiene block copolymer , polyester - polyethers , ethylene - propylene copolymer , segmented block polyurethane , chlorinated polyethylene , ethylene vinylchloride copolymer , and the like . the partition in both designs , can contain a plasticizer to increase its flexibility during use . exemplary plasticizers suitable for adding to partition 14 to impart flexibility and stretchability include cyclic and acyclic plasticizers . typical plasticizers are those selected from the group consisting of phthalates , phosphates , citrates , adipates , tartrates , sebacates , succinates , glycolates , glycerolates , benzoates , myristates , sulfonamides , halogenated phenyls , glycols , diols , and polyols . exemplary plasticizers further include dialkyl phthalates , dicycloalkyl phthalates , diaryl phthalates and mixed alkyl - aryl phthaltes as represented by dimethyl phthalate , dipropyl phthalate , di ( 2 - ethylhexyl )- phthalate , di - isopropyl phthalate , diamyl phthalate and dicapryl phthalate ; alkyl and aryl phosphates such as tributyl phosphate , trioctyl phosphate , tricresyl phosphate , trioctyl phosphate , tricresyl phosphate and triphenyl phosphate ; tricresyl phosphate , trioctyl phosphate , tricresyl phosphate and triphenyl phosphate ; alkyl and aryl phosphates such as tributyl phosphate , trioctyl phosphate , tricresyl phosphate , trioctyl phosphate , tricresyl phosphate and triphenyl phosphate ; alkyl citrate and citrates esters such as tributyl citrate , triethyl citrate , and acetyl triethyl citrate ; alkyl adipates such as dioctyl adipate , diethyl adipate and di ( 2 - methoxyethyl )- adipate ; dialkyl tartrates such as diethyl tartrates and dibutyl tartrate ; alkyl sebacates such as diethyl sebacate , dipropyl sebacate and dinonyl sebacate ; alkyl succinates such as diethyl succinate and dibutyl succinate ; alkyl glycolates , alkyl glycerolates , glycol esters and glycerol esters such as glycerol diacetate , glycerol triacetate , glycerol monolactate diacetate , methyl phythayl ethyl glycolate , butyl phthalyl butyl glycolate , ethylene glycol diacetate , triethylene glycol dibutyrate and triethylene glycol dipropionate . other plasticizers include camphor , n - ethyl -( o - and p - toluene ) sulfonamide , chlorinated biphenyl , benzophenone , n - cyclohexyl - ptoluene sulfonamide , substituted epoxides , poly ( alkylene glycols ), poly ( alkylene diols ), esters of alkylene glycols , and the like . suitable plasticizers can be selected for blending with partition 14 forming materials by selecting plasticizers that have a high degree of solvent power for the materials , are compatible with the materials over both the processing and use temperature ranges , exhibit permanence as seen by a strong tendency to remain in the plasticized partition and imparts flexibility to the partition . procedures for selecting a plasticizer having the described characteristics are disclosed in the encyclopedia of polymer science and technology , vol . 10 , pages 228 to 306 , 1979 , published by john wiley & amp ; sons , inc ., new york . also , a detailed description pertaining to the measurement of plasticizer properties , including solvent parameters and compatibility , the hildebrand solubility parameter , the flory - huggins interaction parameter , and the cohesive - energy density , ced , parameter is disclosed in plasticization and plasticizer processes , advances in chemistry series 48 , chapter 1 , pages 1 to 26 , 1965 , published by the american chemical society , washington , d . c . the amount of plasticizer added generally is an amount sufficient to produce the desired film and it will vary according to the plasticizer and the materials . usually about 0 . 001 part up to 25 parts , or higher , of the plasticizer can be used for 100 parts partition forming material with a presently preferred range of 0 . 1 part to 15 parts of plasticizer , or mixtures thereof for 100 parts of partition forming materials . the swellable polymer that can be used as driving member 18 for expanding and enlarging space 16 , and for pushing partition 14 , as in fig2 a and 2b , into agent space 15 , or for swelling and expanding while correspondingly decreasing the agent containing space , are generally lightly cross - linked hydrophilic polymers . these polymers , on swelling , reduce the amount of space available for agent 17 , and this continual decrease in space acts to substantially maintain agent 17 in a substantially saturated phase . the formulation and maintenance at the agent microporous wall boundary layer in system 10 , at substantially the same rate and amount throughout the release period , produces for system 10 , a prolonged zero order rate . representative polymers are those that swell in the presence of fluid to a high degree without dissolution , are lightly cross - linked , usually exhibiting a 5 to 50 fold volume increase . exemplary polymers are cross - linked hydrogels including poly ( hydroxyalkylmethacrylates ), poly ( acrylamide ), poly ( methacrylamide ), poly ( n - vinyl - 2 - pyrrolidone ), anionic and cationic hydrogels , polyelectrolyte complexes , a water - insoluble , water - swellable copolymer produced by forming a dispersion of finely divided copolymers of maleic anhydride with styrene , ethylene , propylene , butylene or isobutylene cross - linked with from about 0 . 001 to about 0 . 5 moles of a polyunsaturated cross - linking agent per mole of maleic anhydride in the copolymer as disclosed in u . s . pat . no . 3 , 989 , 586 , the water - swellable polymers of n - vinyl lactams as disclosed in u . s . pat . no . 3 , 992 , 562 , semi - solid cross - linked poly ( vinyl pyrrolidone ), diester cross - linked polyglucan hydrogels as described in u . s . pat . no . 4 , 002 , 173 , the anionic hydrogels of heterocyclic n - vinyl monomers as disclosed in u . s . pat . no . 4 , 036 , 788 , the ionogenic hydrophillic gels as described in j . biomedical mater . res ., vol . 7 , pages 123 to 126 , 1973 , and the like . the osmotically effective compound that can be used in space 16 , when partition 14 is formed of a polymer selected from the group consisting of a semipermeable and impermeable polymer , and when wall 12a is made of a semipermeable polymer include organic and inorganic compounds or solutes that exhibit an osmotic pressure gradient across semipermeable wall 12a against fluid in the environment , or across a semipermeable partition 14 against fluid in agent space 15 . osmotically effective compounds useful for this purpose include magnesium sulfate , magnesium chloride , sodium chloride , lithium chloride , potassium sulfate , sodium carbonate , potassium acid phosphate , mannitol , urea , sucrose , and the like . the osmotically effective compounds are also known as osmagents and they are disclosed in u . s . pat . nos . 3 , 854 , 770 and 4 , 077 , 407 . these patents are assigned to the alza corporation of palo alto , calif . the expressions &# 34 ; active agent &# 34 ; and &# 34 ; beneficial agent &# 34 ; as used herein broadly include any compound , composition of matter , or mixture thereof , that can be delivered from system 10 to produce a beneficial and useful result . the active agents include air purifiers , algicides , antioxidants , biocides , catalysts , chemical reactants , cosmetics , contraceptives , drugs , disinfectants , food supplements , fermentation agents , fertility inhibitors , fertility promoters , fungicides , germicides , herbicides , insecticides , micro - organism attenuators , pheremones , pro - drugs , plant growth inhibitors , pesticides , preservatives , rodenticides , sex sterilants , slimicides , vitamins and other agents that benefit the environment of use and mankind . representative of drugs that can be delivered by system 10 include transquilizers such as reserpine , thropropazate , perphenazine and chloropromazine ; psychic energizers such as amitriplyline , imipramine and methylphenidate ; analgesics - antipyretics such as aspirin , phenacetin and salicylamide indomethacin , and diclofenac ; anti - inflammatories such as hydrocortisone , dexamethazone , prednisolone , and phenylbutazone ; decongestants such as phenylephrine and pseudoephedrine ; antibiotics such as erythromycin , tetracycline , minocyline , etc ., cardiovascular drugs such as quinidine ; and other agents . representative of drugs that can be dispensed in the vagina from a system sized , shaped and adapted for easy insertion and comfortable retention in the vagina include allantorn , aminoacridine hydrochloride , benzocaine , benzalkonium chloride , candicidin , dienestrol ., dibucaine , ephedrine sulfate , furazoldione , gentain violet , hydrocortisone , methylbenzethium chloride , phenylmercuric acetate , providone - iodine , sulfanilamide , sulfisoxazole , tetracaine , undecylenate , and the like . see techniques of medication , by eric w . martin , pages 106 to 107 , 1969 , published by j . b . lippincott company , philadelphia . representative of drugs that can be dispensed in the ano - rectal environment from a system shaped , sized and adapted for easy insertion and comfortable retention therein include acetarsol , adrenaline with benzocaine , aminophylline , aminophylline with phenobarbitol sodium , ampicillin , aspirin , astroscopolamine , belladonna , benzocaine , bisacodyl , bismuth subgallate , cafferine , ergotamine tartrate , chloralhydrate , chlorpromazine , cinchocaine , cyclomethycaine sulfate , dimenhydrinate , hydrocottisone , ichthammol , isoprenaline , metronidazole , morphine , oxymorphine hydrodiamine , thiethylperzaine meleate , and the like . see martindale the extra pharmacopolia , edited by ainley wade , general index , page 2056 , 1977 , published by the pharmaceutical press , london ; and , national drug code directory , 1972 , published by public health service , u . s . department of health , education and welfare , washington , d . c . the drug present in system 10 can be in various forms , such as uncharged molecules , molecular complexes , pro - drug , pharmacological acceptable salts such as hydrochlorides , hydrobromides , sulfate , laurylate , palmitate , phosphate , nitrate , borate , acetate , maleate , tartrate , oleates , and salicylate . for acidic drugs , salts of metals , amines , or organic cations , for example , quaternary ammonium salts can be used . derivatives of drugs such as esters , ethers and amides , which have solubility characteristics suitable for use herein can be used . the agent or drug can be in the compartment as a suspension , dispersion , paste , cream , particle , granule , emulsion , solution , powder , and the like . the amount of agent in system 10 is preferably initially in excess of the amount that can be dissolved in fluid that enters the agent housing space . under this physical state , when agent 17 is in excess , system 10 will diffusingly operate to give a substantially constant rate of release over time , then member 18 activates and the combined action of member 18 and system 10 operating as a unit system producing a substantially constant rate of release over a prolonged period of time . the length of time agent is released can also be varied by having different amounts of agent in system 10 to form saturated solutions containing saturated concentrations of agent for delivery from the system 10 . generaly , system 10 can house from 0 . 01 ng to 7 g or more , with individual devices containing for example 25 ng , 1 mg 100 mg , 250 mg , 500 mg , 1 . 5 g ., 5 g , 7 . 5 g , 7 . 5 g , 10 g , and the like . the systems of the invention are manufactured by standard techniques . for example , in one embodiment a swellable polymer or a compressed amount of an osmotic solute are independently coated on one surface with a partition forming polymer , and then a compressed amount of agent , having a shape that corresponds to the shape of the polymer or solute . next , a microporus wall forming the system can be applied by molding , spraying or dipping the system intermediate into a wall forming material to completely surround the intemediate and yield the system . in another embodiment , a microporous wall can be partly cast in a preshaped mold to the desired dimension defining the wall that surrounds an internal space , the space partly filled with a mass of agent , followed by a layer of a partition and then a mass of a driving force . the remainder of the wall abutting the driving force , is formed from a microporus or semipermeable polymer for closing the device . walls forming the system also can be joined by various joining techniques , such as high frequency electronic sealing that provides clean edges and firmly formed walls . another , and presently preferred technique that can be used is the air suspension procedure . air suspension preocedures are described in u . s . pat . no . 2 , 799 , 241 ; in j . am . pharm . assoc ., vol 49 , pages 82 to 84 , 1960 . other wall forming techniques include pan coating , in which the materials are deposited by successive tumbling and spraying of the polymer solution on the agent and the driving member tumbling in a rotating pan . other standard manufacturing procedures are described in modern plastic enclyclopedia , vol . 46 , pages 62 to 70 , 1069 ; and in pharmaceutical sciences , by remington , 14th ed ., pages 1626 to 1678 , 1970 , published by mack publishing company , easton , pa . exemplary solvents suitable for manufacturing the wall , or the partition include inert inorganic and organic solvents that do not adversely harm the wall forming materials , the partition forming materials , and the final device . the solvents broadly include members selected from the group consisting of aqueous solvents , and organic solvents , such as alcohols , ketones , esters , ethers , aliphatic hydrocarbons , halogenated solvents , cycloapliphatics , aromatics , heterocyclic solvents and mixtures thereof . typical solvents include acetone , diacetone , alcohol , methanol , ethanol , isopropyl alcohol , butyl alcohol , methyl acetate , ethyl acetate , isopropyl acetate , n - butyl acetate , methyl isobutyl ketone , methyl ether , ethylene glycol monoethyl acetate , methylene dichloride , ethylene dichloride , propylene dichloride , carbon tetrachloride , nitroethane , itropropane , tetrachloroethane , ethyl ether , isopropyl either , cyclohexane clyclo - octane , benzene , toluene , naphtha , 1 , 4 - dioxane , tetrahydrofuran , diglyme , water , and mixtures thereof such as acetone and water , acetone and methanol , acetone and ethyl alcohol , methylene dichloride and methanol , and ethylene dichloride and emethanol . the following examples are merely illustrative of the present invention that produces devices that keep their physical and chemical integrity during their delivery history , and they should not be considered as limiting the scope of the invention in any way , as this example and other equivalents thereof will become more apparent to those versed in the art in the light of the present disclosure , the drawings , and the accompanying claims . first , 125 mg of the osmotic solute sodium chloride is compressed to a preselected shape and coated on one of its surface with a partition forming compostion comprising 70 % cellulose acetate having an acetyl content of 32 % mixed with 30 % polyethylene glycol having a molecular weight of 400 dissolved in methylene chloride methanol , 80 : 20 , wt : wt , until an expandable partition is formed on the solute . next , 235 mg of dry antiarrhythmic and antifirbrillatory p - amino - n ( 2 - diethylamineothyl )- benzamide hydrochloride having a molecular weight of 271 . 19 is compressed into a shape that corresponds to the shape of the solute , and placed onto the available surface of the partition . next the device intermediate comprising of the solute , partition and drug is surrounded with a microporous wall . the microporous wall is formed form a compostion consisting of 65 g of cellulose acetate having an acetyl content of 32 %, 41 g of the pore - former sorlitol , 11 . 7 g of polyethylene glycol 400 , and a wall forming solvent consisting 1900 ml of acetone and 375 ml of water . the wall is formed by air tumbling until a 7 mil thick microporous wall is formed on the system to produce a system manufactured as an oral device . a therapeutic system is manufactured in the form of an oral device for delivering procainamide hydrochloride to the gastrointestinal tract or a warm - blooded animal as follows : first , 200 mg of lightly cross - linked , water swellable , water insoluble polyvinyl alcohol is coated on one surface with a layer of partition forming composition consisting of 70 % cellulose acetate having an acetyl content of 32 % mixed with 30 % polyethylene glycol having a molecular weight of 400 and dissolved in methylene chloride : methanol , 80 : 20 , wt : wt , until a semipermeable partition is formed . next , 235 mg of procainamide hydrochloride having a molecular weight of 271 . 79 is pressed onto the partition in the form of a solid mass having a shape corresponding to the shape of the polyvinyl alcohol . then the just - formed drug - polymer composite device intermediate is surrounded on all surfaces , except the surface of the polymer distant from the partition , with a wall of microporous polymeric polypropylene having a void volume of 0 . 565 to 0 . 075 cm 3 / gm , a density of 0 . 60 to 0 . 85 gm / cm 3 , and a pore size of 150 to 5000 angstroms , as disclosed in u . s . pat . no . 3 , 426 , 754 . finally , the exposed surface of the polyvinyl alcohol polymer is coated with a wall of cellulose acetate having an acetyl content of 38 . 3 % to yield the device . the device of example 1 , is manufactured in this example , except that in this example , the partition is formed of highly plasticized poly ( monochloroethylene ). the procedures of example 1 and 2 are repeated with all conditions as previously described , except the agent in the agent space is selected from the group consisting of hypnotics , sedatives , psychic energizers , tranquilizers , anticonvulsants , muscle relaxants , antiparkinson , analgesics , anti - inflammatory , anesthetic , muscle contractants , anti - microbiols , antimalarials , hormones , sympathomimetic , duiretics , hypoglcmics and nutritional agents . a device for orally administering a useful drug is made as follows : first , 500 mg of dry , quinidine is pressed in a manesty tableting machine to a stoke &# 39 ; s hardness of about 8 kg . then , 350 mg of lightly cross - linked poly ( hydroxyalkyl methacrylate ), having a shape corresponding to the shape of the drug , is pressed firmly onto one surface of the drug , to yield the device intermediate . next , a microporous wall of poly ( vinyl chloride ) with continous diffusional paths is prepared by leaching a sheet of polymer consisting on the poly ( vinyl chloride ) containing the pore forming agent poly ( p - dimethylamino styrene ). the wall is formed by casting in a solvent of cyclohexane and the solvent evaporated . then , an aqueous acidic solution of hydrochloric acid is used to leach the pore formers and yield the microporous wall . the leaching is carried out at room temperature followed by washing with distilled water to remove the acid . the device intermediate is surrounded with the wall to yield the device . the novel systems of this invention uses an expandable member for the obtainment of precise diffusional release rates and enhanced delivery of agent to environments of use while simultaneously maintaining the integrity and character of the systems . and , while there has been described and pointed out features of the invention as applied to presently preferred embodiments , those skilled in the art will appreciate that various modifications , changes , additions and omissions in the device illustrated and described that can be made without departing from the spirit of the invention . | US-26804681-A |
a stentless aortic bioprosthesis having patent , non - ligated coronary artery segments extending therefrom , and methods for surgical replacement of aortic and / or non - aortic heart valves with such stentless aortic bioprosthesis . the presence of the patent , non - ligated coronary segments facilitates end to end anastomosis of the patient &# 39 ; s native coronary arteries and / or existing coronary artery bypass grafts to the coronary segments of the bioprosthesis even when such native coronary arteries are too short to reach the wall of the aortic segment of the bioprosthesis . the presence of such patent , non - ligated coronary segments also eliminates the need for removal of a &# 34 ; button &# 34 ; or segment of the native aorta in connection with the native coronary artery segments prior to implantation of the bioprosthesis , and is thus advantageous for patients whose ascending aorta is diseased or otherwise compromised . | turning now to fig1 - 4 of the drawings , there is seen a stentless aortic bioprosthesis 10 in accordance with this invention . this aortic bioprosthesis 10 is formed of a preserved segment of mammalian aorta 12 having an inflow rim or inflow end ie , an outflow rim or outflow end oe and the donor animal &# 39 ; s aortic valve leaflets 20 positioned therewithin . segments of the donor animal &# 39 ; s right and left main coronary arteries 14a , 14b extend from the aortic segment 12 , and such coronary artery segments 14a , 14b have open , patent lumens extending therethrough . the aortic bioprosthesis 10 of the present invention is preferably of porcine origin . after the tissue of which the bioprosthesis is formed has been harvested from the donor animal , the coronary artery segments 14a , 14b are trimmed to a desired length , such as 1 - 6 mm and preferably as long as possible ( i . e ., up to the first coronary bifurcation present on each main coronary artery of the donor animal ). thereafter internal or external support members are inserted or attached to the coronary segments 14a , 14b to maintain patency of the coronary segment lumens 15a , 15b during subsequent tanning . examples of internal supports which may be used to maintain such patency of the coronary segment lumens 15a , 15b are mandrel members 16 which are sized and configured to be inserted into the lumens 15a , 15b of the coronary artery segments 14a , 14b , as shown in fig1 . such mandrel members 16 may comprise solid members of generally cylindrical configuration , or may comprise segments of tubular members as specifically shown in the drawings , such tubular members having bores 17 extending longitudinally therethrough . the presence of such bores 17 in the tubular mandrel members 16 can be used as passageways for pins or support members which are used to hold or suspend the bioprosthesis 10 during the tanning process . in instances where internal mandrel members 16 are used to maintain patency of the coronary lumens 15a , 15b , ligatures 18 may be tied about the coronary artery segments 14a , 14b following insertion of the mandrel members 16 therein , to frictionally retain the mandrel members 16 within the coronary artery segments 14a , 14b . in the preferred embodiment shown in the drawings the mandrel members 16 are formed of silicone tubing , but they may be formed of other materials such as polyurethane , polyester , polytetrafluoroethylene ( ptfe ), polyethylene , stainless steel , titanium or a metal alloy . the bioprosthesis 10 having the mandrel members 16 inserted in its coronary segments 14a , 14b is then exposed to a chemical agent ( i . e ., a fixative agent or tanning agent ) which will form chemical cross linkages between connective tissue protein molecules present in the tissue of the bioprosthesis 10 . the chemical tanning agents which are useable for this purpose , formaldehyde , dialdehyde starch , hexamethylene diisocyanate and certain polyepoxy compound ( s ), as well as combinations of these agents . the presently preferred embodiment , shown in the drawings , is by immersion in a solution of 0 . 625 % hepes buffered glutaraldehyde at pressures of less than approximately 10 mmhg , as described in detail in copending u . s . patent application ser . no . 08 / 997 , 766 , filed dec . 24 , 1997 entitled system , apparatus and method for chemical fixation of stentless cardiac valvular bioprostheses , which is hereby expressly incorporated by reference . after the tanning process is complete , the bioprosthesis 10 is removed from the tanning solution and the internal or external support members ( e . g ., mandrel members 16 ) are removed . as specifically shown in fig4 in applications wherein internal support members such as the mandrel members 16 have been secured by ligatures 18 , such ligatures 18 will typically be removed prior to extraction of the mandrel members 16 . thereafter , if necessary , any distal portions 19 of coronary artery segments 14a , 14b of length l 2 located beneath or distal to the ligatures 18 may be cut away and discarded , so as to leave remaining coronary segments 14a , 14b of length l 1 and of substantially normal anatomical configuration attached to the bioprosthesis 10 . in this regard , it is desirapossihat such ligatures 18 be placed as distal as possible , so as to maximize the length l 1 of the coronary artery segments 14a , 14b which remain after the distal coronary segments 19 have been cut away and discarded . preferably , the length l 1 of the coronary artery segments remaining after final trimming will be at least 2 mm and typically in the range of 2 - 6 mm , while the length l 2 of the discarded distal coronary segments 19 is preferably less than 5 mm . after the internal or external support members ( e . g ., mandrels 16 ) have been removed and the coronary artery segments 14a , 14b have undergone final trimming ( if necessary ), the bioprosthesis 10 is sterilized by a suitable technique , such as immersion in a biocompatible sterilization solution . the bioprosthesis is then measured to determine its outside diameter , usually rounded off to the nearest millimeter . for commercial applications , bioprostheses 10 which have outside diameters which would round off to an odd number of millimeters ( e . g ., 15 , 17 , 19 , 21 , 23 , 25 , 27 and 29 mm ) may be rejected . after the bioprosthesis 10 has been sized , it is subjected to a second trimming step in which substantially all of the myocardial tissue is shaved away , leaving a thin cartilage rim adjacent to the right coronary septal shelf for reinforcement . the left and right coronary artery segments 14a , 14b are allowed to remain . all trimming is conducted with the goal of leaving an intact aortic wall segment above the protruding coronary segments 14a , 14b , such intact aortic wall segment being of sufficient width to a ) maintain proper alignment of the commissure , b ) prevent distortion of the bioprosthesis 10 during suturing , and / or c ) permit replacement of a supracoronary segment of the patient &# 39 ; s ascending aorta ( e . g ., a &# 34 ; total root replacement &# 34 ;) if so desired . finally , the inflow end ie of the bioprosthesis 10 is trimmed on the same plane as the cusps of the valve leaflets 20 , usually leaving an intact segment of about 3 to 4 mm in width as measured from the hinge of the leaflet . all of the fatty tissue in the aorta is trimmed away . as shown in fig3 a and 3b , the resulting aortic segment contains three valve leaflets 20 , each of which is affixed to the aortic segment at a juncture . the inner edges 25 of the valve leaflets 20 meet when the leaflets 20 are in their closed positions , as shown in the drawings . also , the leaflets 20 form commissures at their junctions with the aortic wall , and the leaflets are joined to the aortic segment 12 along a leaflet junctures 29 . the wall of the aortic segment 12 adjacent junctures 29 forms the sinus of valsalva ( not shown ). the leaflet 20 closest to the right coronary artery segment 14a , is positioned somewhat asymmetrically with respect to the other two leaflets 20 . a fabric covering 28 may optionally be disposed about the inflow end ie of the bioprosthesis 10 and / or upon a portion of one side of the bioprosthesis 10 which corresponds to the right coronary septal shelf , as shown in fig1 . this fabric covering 28 enhances the strength of the bioprosthesis 10 which is sutured to the native aortic annulus , and thus serves to deter the sutures from tearing through the tissue of the bioprosthesis 10 . this fabric covering 28 may be formed of a thin , biocompatible material which is strong enough to hold sutures . for example , such fabric covering 28 may be formed of woven polyester having a thickness of 0 . 008 inch &# 34 ; and a weight of 72 grams per square meter . the fabric used for the covering 28 is preferably cut on the diagonal to assure a snug fit around curved surfaces . the fabric is then sewn to the bioprosthesis 10 by hand , using a nonabsorbable , biocompatible thread . mid - cusp markings 32 , such as stitches formed of thread of a color which contrasts with the body of the bioprosthesis 10 , may be formed on the fabric covering 28 along the inflow rim , preferably at the mid - cusp point of each leaflet 20 , to aid the surgeon in aligning the bioprosthesis 10 with the patient &# 39 ; s natural aorta . for instance , if the cloth is white , the markings 32 may be stitches of navy blue thread , and the like . an exemplary light green marking thread is polyester ptfe - coated thread of 6 . 0 size , having a denier of 110 - 130 . additional commissure markings 33 may also be formed on the fabric covering and / or inflow end of the bioprosthesis 10 at the locations of the valvular commissures to aid the surgeon in aligning the bioprosthesis with the patient &# 39 ; s native anatomical structures . these optional commissure markings 33 may be formed in the same manner as described hereabove with respect to the mid - cusp markings 32 , but will preferably of a color which is different from the mid - cusp markings 32 so as to permit the surgeon to easily distinguish between the mid - cusp markings 32 and commissure markings 33 . a valve retainer fixture 34 may be attached to the outflow end oe of the bioprosthesis , as shown , to facilitate the attachment of an elongate handle thereto . such valve retainer fixture 34 may be of the type described in u . s . pat . no . 5 , 336 , 258 ( quintero et al .). alternatively , in lieu of the use of such valve retainer fixture 34 , the bioprosthesis may be mounted within a cage - like holding apparatus of the type described in copending u . s . patent application ser . no . 08 / 723 , 420 , entitled bioprosthetic heart valve implantation device . b . methods of implanting the preferred aortic bioprosthesis having coronary protuberances the currently used methods for surgical implantation of the bioprosthesis 10 of the present invention typically require that the patient be placed under general anesthesia and on cardiopulmonary bypass . an incision is made in the patient &# 39 ; s chest wall ( e . g ., a median sternotomy ) and the heart is exposed . the malfunctioning endogenous valve ( typically the aortic valve but possibly another cardiac valve such as the pulmonary valve located between the right ventricle and the pulmonary artery ) is then removed and the bioprosthesis 10 ( or a portion thereof ) is sutured into place to act as a prosthetic replacement for the previously - removed endogenous valve . the bioprosthesis 10 shown in fig1 - 4 will typically be implanted at the aortic position to replace the endogenous aortic heart valve . however , in some instances the bioprosthesis 10 may also be utilized to replace another heart valve such as a malfunctioning pulmonary valve located between the right ventricle and pulmonary artery . when used to replace a heart valve other than the aortic valve , the lumens 15a , 15b of the coronary segments 14a , 14b will typically be closed off by suitable closure means such as ligation , embolization , or placement of a purse string suture . in the mini - root and sub - coronary techniques previously known in the art , a bioprosthesis 10 of appropriate size is selected and is either a ) trimmed along marker thread 30 or at some other location selected by the surgeon to separate the aortic root portion of the bioprosthesis 10 ( i . e ., the base of the aortic segment 12 having the leaflets 20 disposed therein ) from the remainder of its aortic segment 12 and coronary segments 14a , 14b or b ) the lumens 15 of the coronary segments 14a , 14b are closed by ligation , placement of a purse string suture thereabout , embolization of other suitable means to prevent blood from subsequently leaking out of the lumens 15 of those coronary segments 14a , 14b . thereafter the bioprosthesis 10 may be implanted at the aortic location to replace the patient &# 39 ; s endogenous aortic valve , without attachment of coronary arteries or other vessels or grafts to the coronary segments 14a , 14b . in other applications , the entire bioprosthesis 10 , including the entire aortic segment 12 and coronary artery segments 14a , 14b may be implanted at the aortic location , in accordance with the procedure shown in fig5 a - 5c . in this procedure , the patient &# 39 ; s right coronary artery rca and left coronary artery lca are transected at locations which are spaced distances away from the wall of the patient &# 39 ; s ascending aorta ao and a segment of the patient &# 39 ; s ascending aorta ao is removed and the native aortic valve leaflets are surgically excised and removed . a bioprosthesis 10 of correct size is selected , and a handle ( not shown ) is attached to the handle connection fixture . the handle ( not shown ) is then used to position the bioprosthesis 10 such that its inflow end ie is in juxtaposition to the aortic annulus , and a proximal anastomosis pa is formed to secure the inflow end ie of the bioprosthesis 10 to the native aortic annulus . thereafter , the native right coronary artery rca is trimmed to length , if necessary , and a right coronary anastomosis car is formed between the transected end of the right coronary artery rca and the distal end of the right coronary segment 14a of the bioprosthesis 10 . the native left coronary artery lca is then trimmed to length , if necessary , and a left coronary anastomosis cal is formed between the transected end of the left coronary artery lca and the distal end of the left coronary segment 14b of the bioprosthesis 10 . the patient &# 39 ; s coronary arterial vasculature is thereby connected to the aortic segment 12 of the bioprosthesis 10 such that a portion of the arterial blood which subsequently flow is into the aortic segment 12 of the bioprosthesis 10 will flow into the right and left main coronary arteries rca , lca to perfuse the patient &# 39 ; s myocardium in accordance with normal hemodynamics . in patients where coronary artery bypass graft ( s ) are present , one of more openings may be made in the aortic segment 12 of the bioprosthesis , and the ends of the bypass graft ( s ) may be sutured to such openings in accordance with well known surgical technique . finally , the outflow end ol the handle ( not shown ) and valve retainer fixture 34 are disconnected and removed , and to end approximation with the outflow end of the bioprosthesis 10 . a distal anastomosis da is then formed therebetween , as shown in fig5 c . thereafter , the patient may be removed from cardiopulmonary bypass and the chest incision may be closed . the invention has been described hereabove with reference to certain presently preferred embodiments only , and no attempt has been made to exhaustively describe all possible embodiments of the invention . for example , with respect to the method for implantation of the bioprosthesis 10 , it may be possible to accomplish implantation of the bioprosthesis by a minimal access ( e . g . &# 34 ; keyhole &# 34 ;) technique without the need for forming large incisions in the patient &# 39 ; s chest wall , but rather by forming a plurality of small minimal access incisions -- and using a thoracoscopic technique to perform the implantation surgery . accordingly , it is intended that the above - described preferred embodiments as well as all possible other embodiments of the invention be included within the scope of the following claims . | US-99831897-A |
a drive mechanism suitable for use in drug delivery devices is disclosed . the drive mechanism may be used with injector - type drug delivery devices , such as those permitting a user to set the delivery dose . the drive mechanism may include a housing , a dose dial sleeve , and a drive sleeve . a clutch is configured to permit rotation of the drive sleeve and the dose dial sleeve with respect to the housing when the dose dial sleeve and drive sleeve are coupled through the clutch . conversely , when the dose dial sleeve and drive sleeve are in a de - coupled state , rotation of the dose dial sleeve with respect to the housing is permitted and rotation of the drive sleeve with respect to the housing is prevented . in the de - coupled state , axial movement of the drive sleeve transfers force in a longitudinal direction for actuation of a drug delivery device . | according to a first aspect of the present invention , a drive mechanism for use in a drug delivery device is provided comprising : a dose dial sleeve having a helical thread engaged with the helical thread of the said housing ; a drive sleeve releasibly connected to the said dose dial sleeve ; and a clutch means located between the dose dial sleeve and the drive sleeve ; a ) when the dose dial sleeve and the drive sleeve are coupled , the dose dial sleeve and the drive sleeve are allowed to rotate with respect to the housing ; and b ) when the dose dial sleeve and the drive sleeve are de - coupled , rotation of the dose dial sleeve with respect to the housing is allowed , whilst rotation of the drive sleeve with respect to the housing is not allowed , whereby axial movement of the drive sleeve is allowed so that a force is transferred in the longitudinal direction to the proximal end of the drug delivery device . in a preferred embodiment of the drive mechanism of instant invention the said drive mechanism further comprises a piston rod adapted to operate through the housing and transfer the said force in the said longitudinal direction to the proximal end of the drug delivery device . in another preferred embodiment of the drive mechanism of instant invention the said dose dial sleeve further comprises a helical thread , which has the same lead as the lead of the helical thread of the said drive sleeve . in a more specific embodiment of instant invention , the drive mechanism further comprises a nut , which is rotatable with respect to the drive sleeve and axially displaceable but not rotatable with respect to the housing . the term “ drug delivery device ” according to instant invention shall mean a single - dose or multi - dose , disposable or re - useable device designed to dispense a selected dose of a medicinal product , preferably multiple selected doses , e . g . insulin , growth hormones , low molecular weight heparins , and their analogues and / or derivatives etc . said device may be of any shape , e . g . compact or pen - type . dose delivery may be provided through a mechanical ( optionally manual ) or electrical drive mechanism or stored energy drive mechanism , such as a spring , etc . dose selection may be provided through a manual mechanism or electronic mechanism . additionally , said device may contain components designed to monitor physiological properties such as blood glucose levels , etc . furthermore , the said device may comprise a needle or may be needle - free . in particular , the term “ drug delivery device ” shall mean a disposable multi - dose pen - type device having mechanical and manual dose delivery and dose selection mechanisms , which is designed for regular use by persons without formal medical training such as patients . preferably , the drug delivery device is of the injector - type . the term “ housing ” according to instant invention shall preferably mean any exterior housing (“ main housing ”, “ body ”, “ shell ”) or interior housing (“ insert ”, “ inner body ”) having a helical thread . the housing may be designed to enable the safe , correct , and comfortable handling of the drug delivery device or any of its mechanism . usually , it is designed to house , fix , protect , guide , and / or engage with any of the inner components of the drug delivery device ( e . g ., the drive mechanism , cartridge , plunger , piston rod ) by limiting the exposure to contaminants , such as liquid , dust , dirt etc . in general , the housing may be unitary or a multipart component of tubular or non - tubular shape . usually , the exterior housing serves to house a cartridge from which a number of doses of a medicinal product may by dispensed . in a more specific embodiment of instant invention , the exterior housing is provided with a plurality of maximum dose stops adapted to be abutted by a radial stop provided on the dose dial sleeve . preferably , at least one of the maximum dose stops comprises a radial stop located between a helical thread and spline means provided at a second end of the housing . alternatively , at least one of the maximum dose stops comprises a part of a raised window portion provided at a second end of the housing . the term “ engaged ” according to instant invention shall particularly mean the interlocking of two or more components of the drive mechanism / drug delivery device , e . g . a spline , thread , or meshed teeth connection , preferably the interlocking of helical threads of components (“ threadedly engaged ”). the term “ helical thread ” according to instant invention shall preferably mean a full or part thread , e . g ., a cylindrical spiral rib / groove , located on the internal and / or external surface of a component of the drug delivery device , having an essentially triangular or square or rounded section designed to allow continuous free rotational and / or axial movement between components . optionally , a thread may be further designed to prevent rotational or axial movement of certain components in one direction . the term “ dose dial sleeve ” according to instant invention shall mean an essentially tubular component of essentially circular cross - section having either : a ) both an internal and external thread , or b ) an internal thread , or c ) an external thread . preferably , the dose dial sleeve according to instant invention comprises a helical thread having a lead , which is similar to , preferably the same as the lead of the helical thread of the drive sleeve . in yet another preferred embodiment the dose dial sleeve is designed to indicate a selected dose of a dispensable product . this may be achieved by use of markings , symbols , numerals , etc ., e . g . printed on the external surface of the dose dial sleeve or an odometer , or the like . in a more specific embodiment of instant invention , the dose dial sleeve is provided with a plurality of radially extending members adapted to abut a corresponding plurality of radial stops provided at a second end of the housing . the term “ lead ” according to instant invention shall preferably mean the axial distance a nut would advance in one complete revolution ; preferably “ lead ” shall mean the axial distance through which a component having a helical thread , i . e . dose dial sleeve , drive sleeve , piston rod , etc ., of the drive mechanism travels during one rotation . therefore lead is a function of the pitch of the thread of the relevant component . the term “ pitch ” according to instant invention shall preferably mean the distance between consecutive contours on a helical thread , measured parallel to the axis of the helical thread . the term “ drive sleeve ” according to instant invention shall mean any essentially tubular component of essentially circular cross - section and which is further releasibly connected to the dose dial sleeve . in a preferred embodiment the drive sleeve is further engaged with the piston rod . in a more particular embodiment of instant invention , the drive sleeve is provided at a first end with first and second flanges with an intermediate helical thread between the first and second flanges , having a nut disposed between the first and second flanges and keyed to the housing by spline means . optionally , a first radial stop may be provided on a second face of the nut and a second radial stop may be provided on a first face of the second flange . the term “ releasibly connected ” according to instant invention shall preferably mean that two components of instant mechanism or device are reversibly joined to each other , which allows coupling and decoupling , e . g . by means of a clutch . the term “ piston rod ” according to instant invention shall mean a component adapted to operate through / within the housing , designed to translate axial movement through / within the drug delivery device , preferably from the drive sleeve to the piston , for the purpose of discharging / dispensing an injectable product . said piston rod may be flexible or not . it may be a simple rod , a lead - screw , a rack and pinion system , a worm gear system , or the like . the “ piston rod ” shall further mean a component having a circular or non - circular cross - section . it may be made of any suitable material known by a person skilled in the art . in a preferred embodiment , the piston rod comprises at least one , more preferably two , external and / or internal helical threads . in another preferred embodiment of the piston rod according to instant invention , a first helical thread is located at a first end and a second helical thread is located at a second end of the said piston rod , whereby the said threads may have the same or , preferably , opposite dispositions . in another preferred embodiment the piston rod of instant invention comprises threads having the same leads at the first and the second end . in yet another preferred embodiment of instant invention the lead of the first helical thread of the piston rod shall be greater than the lead of the second helical thread . more preferred , the ratio of the leads of the helical threads of the said first and the second helical threads is 1 : 1 , 01 to 1 : 20 , even more preferred 1 : 1 , 1 to 1 : 10 . preferably , one of the said threads is designed to engage with the drive sleeve . alternatively , in another preferred embodiment of the piston rod of instant invention , the piston rod is designed to have attached , optionally by means of a journal bearing , a toothed gear , and wherein said toothed gear is designed to mesh with the threads of the drive sleeve and the teeth of a toothed rack , whereby said toothed rack is fixed to the housing . the term “ first end ” according to instant invention shall mean the proximal end . the proximal end of the device or a component of the device shall mean the end , which is closest to the dispensing end of the device . the term “ second end ” according to instant invention shall mean the distal end . the distal end of the device or a component of the device shall mean the end , which is furthest away from the dispensing end of the device . the term “ clutch means ” according to instant invention shall mean any means , which releasibly connects the dose dial sleeve and the drive sleeve and which is designed to allow rotation of the dose dial sleeve and the drive sleeve with respect to the housing when the dose dial sleeve and the drive sleeve are coupled and , when both are de - coupled , allows rotation of the dose dial sleeve with respect to the housing , but does not allow rotation of the drive sleeve with respect to the housing and allows axial movement of the drive sleeve . preferably , the clutch means releasibly connects the drive sleeve to the housing . accordingly , the term clutch means is any clutch engaging for the purpose of reversibly locking two components in rotation , e . g ., by use of axial forces to engage a set of face teeth ( saw teeth , dog teeth , crown teeth ) or any other suitable frictional faces . in a more specific embodiment of instant invention , a second end of the clutch means is provided with a plurality of dog teeth adapted to engage with a second end of the dose dial sleeve . in an alternative embodiment , the clutch means of instant invention is a locking spring , operable , e . g ., by means of a dose dial button , between a first , relaxed position , in which the dose dial sleeve is locked with respect to rotation with the drive sleeve and a second , deformed position , in which the dose dial sleeve is locked with respect to rotation with the housing . in still another embodiment of instant invention , the drive mechanism further comprises a clicker means , optionally disposed between the clutch means and spline means provided on the housing . optionally , the clicker means comprises a sleeve provided at a first end with a helically extending arm , a free end of the arm having a toothed member , and at a second end with a plurality of circumferentially directed saw teeth adapted to engage a corresponding plurality of circumferentially saw teeth provided on the clutch means . alternatively , the clicker means comprises a sleeve provided at a first end with at least one helically extending arm and at least one spring member , a free end of the arm having a toothed member , and at a second end with a plurality of circumferentially directed saw teeth adapted to engage a corresponding plurality of circumferentially directed saw teeth provided on the clutch means . in still another embodiment of the drive mechanism of the invention , the drive mechanism is provided with a first stop means , preferably in the form of an external flange on the dose dial sleeve , adapted to engage limiting means associated with the housing , preferably in the form of an internal flange in the housing , to limit the maximum dose which can be dialed . in yet another embodiment of the drive mechanism of the invention , the drive mechanism is further provided with a second stop means , preferably in the form of an external flange on the drive sleeve , adapted to engage limiting means , preferably in the form of a limiting nut keyed to the housing and mounted for rotation on an external threaded section of the drive sleeve , to provide an end of life stop . a second aspect of instant invention provides an assembly for use in a drug delivery device comprising the drive mechanism according to instant invention . a third aspect of the present invention provides a drug delivery device comprising the drive mechanism or the assembly according to instant invention . a fourth aspect of the present invention provides a method of assembling a drug delivery device comprising the step of providing a drive mechanism or an assembly according to instant invention . a fifth aspect of instant invention is the use of a drug delivery device according to instant invention for dispensing a medicinal product preferably dispensing a pharmaceutical formulation ( e . g . solution , suspension etc .) comprising an active compound selected from the group consisting of insulin , growth hormone , low molecular weight heparin , their analogues and their derivatives . without any limitation , the instant invention will be explained in greater detail below in connection with a preferred embodiment and with reference to the drawings in which : fig1 shows a sectional view of a first embodiment of the drug delivery device in accordance with the present invention in a first , cartridge full , position ; fig2 shows a sectional view of the drug delivery device of fig1 in a second , maximum first dose dialed , position ; fig3 shows a sectional view of the drug delivery device of fig1 in a third , maximum first dose dispensed , position ; fig4 shows a sectional view of the drug delivery device of fig1 in a fourth , final dose dialed , position ; fig5 shows a sectional view of the drug delivery device of fig1 in a fifth , final dose dispensed , position ; fig6 shows a cut - away view of a first detail of the drug delivery device of fig1 ; fig7 shows a partially cut - away view of a second detail of the drug delivery device of fig1 ; fig8 shows a partially cut - away view of a third detail of the drug delivery device of fig1 ; fig9 shows the relative movement of parts of the drug delivery device shown in fig1 during dialing up of a dose ; fig1 shows the relative movement of parts of the drug delivery device shown in fig1 during dialing down of a dose ; fig1 shows the relative movement of parts of the drug delivery device shown in fig1 during dispensing of a dose ; fig1 shows a partially cut - away view of the drug delivery device of fig1 in the second , maximum first dose dialed , position ; fig1 shows a partially cut - away view of the drug delivery device of fig1 in the fourth , final dose dialed , position ; fig1 shows a partially cut - away view of the drug delivery device of fig1 in one of the first , third or fifth positions ; fig1 shows a cut - away view of a first part of a main housing of the drug delivery device of fig1 ; and fig1 shows a cut - away view of a second part of the main housing of the drug delivery device of fig1 ; fig1 shows a sectional view of a second embodiment of the drive mechanism according to instant invention in a first , cartridge full , position . fig1 shows a sectional side view of a third embodiment of the drug delivery device in accordance with the present invention in a first , cartridge full , position ; fig1 shows a sectional side view of the drug delivery device of fig1 in a second , maximum first dose dialed , position ; fig2 shows a sectional side view of the drug delivery device of fig1 in a third , maximum first dose dispensed , position ; fig2 shows a sectional side view of the drug delivery device of fig1 in a fourth , final dose dialed , position ; fig2 shows a sectional side view of the drug delivery device of fig1 in a fifth , final dose dispensed , position ; fig2 shows a fragment of the drug delivery device of fig1 in a larger scale and fig2 shows a further fragment of the drug delivery device of fig1 in a larger scale . referring first to fig1 to 5 , there is shown a drug delivery device in accordance with the present invention in a number of positions . the drug delivery device comprises a housing having a first cartridge retaining part 2 , and second main ( exterior ) housing part 4 . a first end of the cartridge retaining means 2 and a second end of the main housing 4 are secured together by retaining features 6 . in the illustrated embodiment , the cartridge retaining means 2 is secured within the second end of the main housing 4 . a cartridge 8 from which a number of doses of a medicinal product may be dispensed is provided in the cartridge retaining part 2 . a piston 10 is retained in a first end of the cartridge 8 . a removable cap 12 is releasably retained over a second end of the cartridge retaining part 2 . in use the removable cap 12 can be replaced by a user with a suitable needle unit ( not shown ). a replacable cap 14 is used to cover the cartridge retaining part 2 extending from the main housing 4 . preferably , the outer dimensions of the replaceable cap 14 are similar or identical to the outer dimensions of the main housing 4 to provide the impression of a unitary whole when the replaceable cap 14 is in position covering the cartridge retaining part 2 . in the illustrated embodiment , an insert 16 is provided at a first end of the main housing 4 . the insert 16 is secured against rotational or longitudinal motion . the insert 16 is provided with a threaded circular opening 18 extending therethrough . alternatively , the insert may be formed integrally with the main housing 4 having the form of a radially inwardly directed flange having an internal thread . a first thread 19 extends from a first end of a piston rod 20 . the piston rod 20 is of generally circular section . the first end of the piston rod 20 extends through the threaded opening 18 in the insert 16 . a pressure foot 22 is located at the first end of the piston rod 20 . the pressure foot 22 is disposed to abut a second end of the cartridge piston 10 . a second thread 24 extends from a second end of the piston rod 20 . in the illustrated embodiment the second thread 24 comprises a series of part threads rather than a complete thread . the illustrated embodiment is easier to manufacture and helps to reduce the overall force required for a user to actuate the device when dispensing the medicinal product . the first thread 19 and the second thread 24 are oppositely disposed . the second end of the piston rod 20 is provided with a receiving recess 26 . a drive sleeve 30 extends about the piston rod 20 . the drive sleeve 30 is generally cylindrical . the drive sleeve 30 is provided at a first end with a first radially extending flange 32 . a second radially extending flange 34 is provided spaced a distance along the drive sleeve 30 from the first flange 32 . an intermediate thread 36 is provided on an outer part of the drive sleeve 30 extending between the first flange 32 and the second flange 34 . a helical groove ( thread ) 38 extends along the internal surface of the drive sleeve 30 . the second thread 24 of the piston rod 20 is adapted to work within the helical groove 38 . a first end of the first flange 32 is adapted to conform to a second side of the insert 16 . a nut 40 is located between the drive sleeve 30 and the main housing 2 , disposed between the first flange 32 and the second flange 34 . in the illustrated embodiment the nut 40 is a half - nut . this assists in the assembly of the device . the nut 40 has an internal thread matching the intermediate thread 36 . the outer surface of the nut 40 and an internal surface of the main housing 4 are keyed together by splines 42 ( fig1 , 11 , 15 and 16 ) to prevent relative rotation between the nut 40 and the main housing 4 , while allowing relative longitudinal movement therebetween . a shoulder 37 is formed between a second end of the drive sleeve 30 and an extension 38 provided at the second end of the drive sleeve 30 . the extension 38 has reduced inner and outer diameters in comparison to the remainder of the drive sleeve 30 . a second end of the extension 38 is provided with a radially outwardly directed flange 39 . a clicker 50 and a clutch 60 are disposed about the drive sleeve 30 , between the drive sleeve 30 and a dose dial sleeve 70 ( described below ). the clicker 50 is located adjacent the second flange 34 of the drive sleeve 30 . the clicker 50 is generally cylindrical and is provided at a first end with a flexible helically extending arm 52 ( fig6 ). a free end of the arm 52 is provided with a radially directed toothed member 54 . a second end of the clicker 50 is provided with a series of circumferentially directed saw teeth 56 ( fig7 ). each saw tooth comprises a longitudinally directed surface and an inclined surface . in an alternative embodiment ( not shown ) the clicker further includes at least one spring member . the at least one spring member assists in the resetting of the clutch 60 following dispense . the clutch 60 is located adjacent the second end of the drive sleeve 30 . the clutch 60 is generally cylindrical and is provided at a first end with a series of circumferentially directed saw teeth 66 ( fig7 ). each saw tooth comprises a longitudinally directed surface and an inclined surface . towards the second end 64 of the clutch 60 there is located a radially inwardly directed flange 62 . the flange 62 of the clutch 60 is disposed between the shoulder 37 of the drive sleeve 30 and the radially outwardly directed flange 39 of the extension 38 . the second end of the clutch 60 is provided with a plurality of dog teeth 65 ( fig8 ). the clutch 60 is keyed to the drive sleeve 30 by way of splines ( not shown ) to prevent relative rotation between the clutch 60 and the drive sleeve 30 . in the illustrated embodiment , the clicker 50 and the clutch 60 each extend approximately half the length of the drive sleeve 30 . however , it will be understood that other arrangements regarding the relative lengths of these parts are possible . the clicker 50 and the clutch 60 are engaged as shown in fig7 . a dose dial sleeve 70 is provided outside of the clicker 50 and clutch 60 and radially inward of the main housing 4 . a helical groove 74 is provided about an outer surface of the dose dial sleeve 70 . the main housing 4 is provided with a window 44 through which a part of the outer surface of the dose dial sleeve may be seen . the main housing 4 is further provided with a helical rib ( thread ) 46 , adapted to be seated in the helical groove ( thread ) 74 on the outer surface of the dose dial sleeve 70 . the helical rib 46 extends for a single sweep of the inner surface of the main housing 4 . a first stop 100 is provided between the splines 42 and the helical rib 46 ( fig1 ). a second stop 102 , disposed at an angle of 180 ° to the first stop 100 is formed by a frame surrounding the window 44 in the main housing 4 ( fig1 ). conveniently , a visual indication of the dose that may be dialed , for example reference numerals ( not shown ), is provided on the outer surface of the dose dial sleeve 70 . the window 44 conveniently only allows to be viewed a visual indication of the dose currently dialed . a second end of the dose dial sleeve 70 is provided with an inwardly directed flange in the form of a number of radially extending members 75 . a dose dial grip 76 is disposed about an outer surface of the second end of the dose dial sleeve 70 . an outer diameter of the dose dial grip 76 preferably corresponds to the outer diameter of the main housing 4 . the dose dial grip 76 is secured to the dose dial sleeve 70 to prevent relative movement therebetween . the dose dial grip 76 is provided with a central opening 78 . an annular recess 80 located in the second end of the dose dial grip 76 extends around the opening 78 . a button 82 of generally ‘ t ’ section is provided at a second end of the device . a stem 84 of the button 82 may extend through the opening 78 in the dose dial grip 76 , through the inner diameter of the extension 38 of the drive sleeve 30 and into the receiving recess 26 of the piston rod 20 . the stem 84 is retained for limited axial movement in the drive sleeve 30 and against rotation with respect thereto . a head 85 of the button 82 is generally circular . a skirt 86 depends from a periphery of the head 85 . the skirt 86 is adapted to be seated in the annular recess 80 of the dose dial grip 76 . operation of the drug delivery device in accordance with the present invention will now be described . in fig9 and 11 arrows a , b , c , d , e , f and g represent the respective movements of the button 82 , the dose dial grip 76 , the dose dial sleeve 70 , the drive sleeve 30 , the clutch 60 , the clicker 50 and the nut 40 . to dial a dose ( fig9 ) a user rotates the dose dial grip 76 ( arrow b ). with the clicker 50 and clutch 60 engaged , the drive sleeve 30 , the clicker 50 , the clutch 60 and the dose dial sleeve 70 rotate with the dose dial grip 76 . audible and tactile feedback of the dose being dialed is provided by the clicker 50 and the clutch 60 . torque is transmitted through the saw teeth 56 , 66 between the clicker 50 and the clutch 60 . the flexible arm 52 deforms and drags the toothed member 54 over the splines 42 to produce a click . preferably , the splines 42 are disposed such that each click corresponds to a conventional unit dose , or the like . the helical groove 74 on the dose dial sleeve 70 and the helical groove 38 in the drive sleeve 30 have the same lead . this allows the dose dial sleeve 70 ( arrow c ) to extend from the main housing 4 and the drive sleeve 30 ( arrow d ) to climb - the piston rod 20 at the same rate . at the limit of travel , a radial stop 104 ( fig1 ) on the dose dial sleeve 70 engages either the first stop 100 or the second stop 102 provided on the main housing 4 to prevent further movement . rotation of the piston rod 20 is prevented due to the opposing directions of the overhauled and driven threads on the piston rod 20 . the nut 40 , keyed to the main housing 4 , is advanced along the intermediate thread 36 by the rotation of the drive sleeve 30 ( arrow d ). when the final dose dispensed position ( fig4 and 13 ) is reached , a radial stop 106 formed on a second surface of the nut 40 abuts a radial stop 108 on a first surface of the second flange 34 of the drive sleeve 30 , preventing both the nut 40 and the drive sleeve 30 from rotating further . in an alternative embodiment ( not shown ) a first surface of the nut 40 is provided with a radial stop for abutment with a radial stop provided on a second surface of the first flange 32 . this aids location of the nut 40 at the cartridge full position during assembly of the drug delivery device . should a user inadvertently dial beyond the desired dosage , the drug delivery device allows the dosage to be dialed down without dispense of medicinal product from the cartridge ( fig1 ). the dose dial grip 76 is counter rotated ( arrow b ). this causes the system to act in reverse . the flexible arm 52 preventing the clicker 50 from rotating . the torque transmitted through the clutch 60 causes the saw teeth 56 , 66 to ride over one another to create the clicks corresponding to dialed dose reduction . preferably the saw teeth 56 , 66 are so disposed that the circumferential extent of each saw tooth corresponds to a unit dose . when the desired dose has been dialed , the user may then dispense this dose by depressing the button 82 ( fig1 ). this displaces the clutch 60 axially with respect to the dose dial sleeve 70 causing the dog teeth 65 to disengage . however the clutch 60 remains keyed in rotation to the drive sleeve 30 . the dose dial sleeve 70 and associated dose dial grip 76 are now free to rotate ( guided by the helical rib 46 located in helical groove 74 ). the axial movement deforms the flexible arm 52 of the clicker 50 to ensure the saw teeth 56 , 66 cannot be overhauled during dispense . this prevents the drive sleeve 30 from rotating with respect to the main housing 4 though it is still free to move axially with respect thereto . this deformation is subsequently used to urge the clicker 50 , and the clutch 60 , back along the drive sleeve 30 to restore the connection between the clutch 60 and the dose dial sleeve 70 when pressure is removed from the button 82 . the longitudinal axial movement of the drive sleeve 30 causes the piston rod 20 to rotate though the opening 18 in the insert 16 , thereby to advance the piston 10 in the cartridge 8 . once the dialed dose has been dispensed , the dose dial sleeve 70 is prevented from further rotation by contact of a plurality of members 110 ( fig1 ) extending from the dose dial grip 76 with a corresponding plurality of stops 112 formed in the main housing 4 ( fig1 and 16 ). in the illustrated embodiment , the members 110 extend axially from the dose dial grip 76 and have an inclined end surface . the zero dose position is determined by the abutment of one of the axially extending edges of the members 110 with a corresponding stop 112 . in another embodiment of the invention ( fig1 ) there is seen a drive mechanism comprising a second main housing 4 ′ having a first end and a second end . a cartridge , containing medicinal product , can be mounted to the first end of the second main housing 4 ′ and retained by any suitable means . the cartridge and its retaining means are not shown in the illustrated embodiment . the cartridge may contain a number of doses of a medicinal product and also typically contains a displaceable piston . displacement of the piston causes the medicinal product to be expelled from the cartridge via a needle ( also not shown ). in the illustrated embodiment , an insert 16 ′ is provided within the main housing 4 ′. the insert 16 ′ is secured against rotational and axial motion with respect to the second main housing 4 ′. the insert 16 ′ is provided with a threaded circular opening extending therethrough . alternatively , the insert may be formed integrally with the second main housing 4 ′. an internal housing 154 is also provided within the second main housing 4 ′. the internal housing 154 is secured against rotational and axial motion with respect to the second main housing 4 ′. the internal housing 154 is provided with a circular opening extending through its length in which a series of longitudinally directed splines are formed . a helical thread 150 extends along the outer cylindrical surface of the internal housing 154 . alternatively , the internal housing may be formed integrally with the second main housing 4 ′ and / or with the insert 16 ′. a first thread 19 ′ extends from a first end of a piston rod 20 ′. the piston rod 20 ′ is of generally circular section . the first end of the piston rod 20 ′ extends through the threaded opening in the insert 16 ′ and the first thread 19 ′ of the piston rod 20 ′ is engaged with the thread of the insert 16 ′. a pressure foot 22 ′ is located at the first end of the piston rod 20 ′. the pressure foot 22 ′ is disposed to abut a cartridge piston ( not shown ). a second thread 24 ′ extends from a second end of the piston rod 20 ′. the first thread 19 ′ and the second thread 24 ′ are oppositely disposed a drive sleeve 30 ′ extends about the piston rod 20 ′. the drive sleeve 30 ′ is generally cylindrical . the drive sleeve 30 ′ is provided at a first end with a first radially extending flange 32 ′. a second radially extending flange 34 ′ is provided , spaced a distance along the drive sleeve 30 ′ from the first flange 32 ′. an external helical thread ( not shown ) is provided on the outer part of the drive sleeve 30 ′ extending between the first flange 32 ′ and the second flange 34 ′. an internal helical thread extends along the internal surface of the drive sleeve 30 ′. the second thread 24 ′ of the piston rod 20 ′ is engaged with the internal helical thread of the drive sleeve 30 ′. a nut 40 ′ is located between the drive sleeve 30 ′ and the internal housing 154 , disposed between the first flange 32 ′ and the second flange 34 ′ of the drive sleeve 30 ′. the nut 40 ′ can be either a ‘ half - nut ’ or a ‘ full - nut ’. the nut 40 ′ has an internal thread that is engaged with the external helical thread of the drive sleeve 30 ′. the outer surface of the nut 40 ′ and an internal surface of the internal housing 154 are keyed together by means of longitudinally directed splines to prevent relative rotation between the nut 40 ′ and the internal housing 154 , while allowing relative longitudinal movement therebetween . a clicker 50 ′ and a clutch 60 ′ are disposed about the drive sleeve 30 ′, between the drive sleeve 30 ′ and the internal housing 154 . the clicker 50 ′ is located adjacent the second flange 34 ′ of the drive sleeve 30 ′. the clicker 50 ′ includes at least one spring member ( not shown ). the clicker 50 ′ also includes a set of teeth ( not shown ) having a triangular profile disposed towards the second end of the drive mechanism . when compressed , the at least one spring member of the clicker 50 ′ applies an axial force between the flange 34 ′ of the drive sleeve 30 ′ and the clutch 60 ′. the outer surface of the clicker 50 ′ and an internal surface of the internal housing 154 are keyed together by means of longitudinally directed splines to prevent relative rotation between the clicker 50 ′ and the internal housing 154 , while allowing relative longitudinal movement therebetween . the clutch 60 ′ is located adjacent the second end of the drive sleeve 30 ′. the clutch 60 ′ is generally cylindrical and is provided at its &# 39 ; first end with a plurality of teeth of triangular profile disposed about the circumference ( not shown ), that act upon the teeth of the clicker 50 ′. towards the second end of the clutch 60 ′ there is located a shoulder 158 . the shoulder 158 of the clutch 60 ′ is disposed between the internal housing 154 and a radially inwardly directed flange of the dose dial grip 76 ′ ( described below ). the shoulder 158 of the clutch 60 ′ is provided with a plurality of dog teeth ( not shown ) extending in the direction of the second end of the drive mechanism . the clutch 60 ′ is keyed to the drive sleeve 30 ′ by way of splines ( not shown ) to prevent relative rotation between the clutch 60 ′ and the drive sleeve 30 ′. a dose dial sleeve 70 ′ is provided outside of the internal housing 154 and radially inward from the second main housing 4 ′. a helical thread is provided on an inner surface of the dose dial sleeve 70 ′. the helical thread of the dose dial sleeve 70 ′ is engaged with the helical thread 150 of the internal housing 154 . the second main housing 4 ′ is provided with a window ( not shown ) through which part of the outer surface of the dose dial sleeve 70 ′ may be viewed . conveniently , a visual indication of the dose that may be dialed , for example reference numerals ( not shown ), is provided on the outer surface of the dose dial sleeve 70 ′. conveniently , the window of the second main housing 4 ′ allows only the dose that is currently dialed to be viewed . a dose dial grip 76 ′ is located towards the second end of the drive mechanism . the dose dial grip 76 ′ is secured against rotational and axial motion within respect to the dose dial sleeve 70 ′. the dose dial grip 76 ′ is provided with a radially inwardly directed flange 160 . the radially inwardly directed flange 160 of the dose dial grip 76 ′ is provided with a plurality of dog teeth ( not shown ) extending in the direction of the first end of the drive mechanism to abut the dog teeth of the clutch 60 ′. coupling and decoupling of the dog teeth of the dose dial grip 76 ′ with the dog teeth of the clutch 60 ′ provides a releasable clutch between the dose dial grip 76 ′ and the clutch 60 ′. a button 82 ′ of generally ‘ t ’ shaped cross - section is provided at a second end of the drive mechanism . a cylindrical feature of the button 82 ′ extends towards the first end of the drive mechanism , through an opening in the dose dial grip 76 ′ and into a recess in the drive sleeve 30 ′. the cylindrical feature of the button 82 ′ is retained for limited axial movement in the drive sleeve 30 ′ and against rotation with respect thereto . the cylindrical feature of the button 82 ′ has lugs extending radially ( not shown ) that abut the second surface of the shoulder 158 of the clutch 60 ′. the second end of the button 82 ′ is generally circular and has a cylindrical skirt about its &# 39 ; periphery that descends towards the first end of the drive mechanism . the skirt of the button 82 ′ is located radially inward from the dose dial grip 76 ′. operation of the drive mechanism in accordance with the present invention will now be described . to dial a dose , a user rotates the dose dial grip 76 ′. the spring member of the clicker 50 ′ applies an axial force to the clutch 60 ′ in the direction of the second end of the drive mechanism . the force exerted by the spring member of the clicker 50 ′ couples the dog teeth of the clutch 60 ′ to the dog teeth of the dose dial grip 76 ′ for rotation . as the dose dial grip 76 ′ is rotated , the associated dose dial sleeve 70 ′, the drive sleeve 30 ′ and the clutch 60 ′ all rotate in unison . audible and tactile feedback of the dose being dialed is provided by the clicker 50 ′ and the clutch 60 ′. as the clutch 60 ′ is rotated , torque is transmitted from the teeth at the first end of the clutch 60 ′ and the teeth of the clicker 50 ′. the clicker 50 ′ cannot rotate with respect to the internal housing 154 , so the at least one spring member of the clicker 50 ′ deforms allowing the teeth of the clutch 60 ′ to jump over the teeth of the clicker 50 ′ producing an audible and tactile ‘ click ’. preferably , the teeth of the clicker 50 ′ and the teeth of the clutch 60 ′ are disposed such that each ‘ click ’ corresponds to a conventional unit of the medicinal product , or the like . the helical thread of the dose dial sleeve 70 ′ and the internal helical thread of the drive sleeve 30 ′ have the same lead . this allows the dose dial sleeve 70 ′ to advance along the thread 150 of the internal housing 154 at the same rate as the drive sleeve 30 ′ advances along the second thread 24 ′ of the piston rod 20 ′. rotation of the piston rod 20 ′ is prevented due to the opposing direction of the first thread 19 ′ and the second thread 24 ′ of the piston rod 20 ′. the first thread 19 ′ of the piston rod 20 ′ is engaged with the thread of the insert 16 ′ and so the piston rod 20 ′ does not move with respect to the second main housing 4 ′ while a dose is dialed . the nut 40 ′, keyed to the internal housing 154 , is advanced along the external thread of the drive sleeve 30 ′ by the rotation of the drive sleeve 30 ′. when a user has dialed a quantity of medicinal product that is equivalent to the deliverable volume of the cartridge , the nut 40 ′ reaches a position where it abuts the second flange 34 ′ of the drive sleeve 30 ′. a radial stop formed on the second surface of the nut 40 ′ contacts a radial stop on the first surface of the second flange 34 ′ of the drive sleeve 30 ′, preventing both the nut 40 ′ and the drive sleeve 30 ′ from being rotated further . should a user inadvertently dial a quantity greater than the desired dosage , the drive mechanism allows the dosage to be corrected without dispense of medicinal product from the cartridge . the dose dial grip 76 ′ is counter - rotated . this causes the system to act in reverse . the torque transmitted through the clutch 60 ′ causes the teeth at the first end of the clutch 60 ′ to ride over the teeth of the clicker 50 ′ to create the clicks corresponding to the dialed dose reduction . when the desired dose has been dialed , the user may then dispense this dose by depressing the button 82 ′ in the direction of the first end of the drive mechanism . the lugs of the button 82 ′ apply pressure to the second surface of the shoulder 158 of the clutch 60 ′, displacing the clutch 60 ′ axially with respect to the dose dial grip 76 ′. this causes the dog teeth on the shoulder 158 of the clutch 60 ′ to disengage from the dog teeth of the dose dial grip 76 ′. however , the clutch 60 ′ remains keyed in rotation to the drive sleeve 30 ′. the dose dial grip 76 ′ and associated dose dial sleeve 70 ′ are now free to rotate ( guided by the helical thread 150 of the internal housing 154 ). the axial movement of the clutch 60 ′ deforms the spring member of the clicker 50 ′ and couples the teeth at the first end of the clutch 60 ′ to the teeth of the clicker 50 ′ preventing relative rotation therebetween . this prevents the drive sleeve 30 ′ from rotating with respect to the internal housing 154 , though it is still free to move axially with respect thereto . pressure applied to the button 82 ′ thus causes the dose dial grip 76 ′ and the associated dose dial sleeve 70 ′ to rotate into the second main housing 4 ′. under this pressure the clutch 60 ′, the clicker 50 ′ and the drive sleeve 30 ′ are moved axially in the direction of the first end of the drive mechanism , but they do not rotate . the axial movement of the drive sleeve 30 ′ causes the piston rod 20 ′ to rotate though the threaded opening in the insert 16 ′, thereby to advance the pressure foot 22 ′. this applies force to the piston , causing the medicinal product to be expelled from the cartridge . the selected dose is delivered when the dose dial grip 76 ′ returns to a position where it abuts the second main housing 4 ′. when pressure is removed from the button 82 ′, the deformation of the spring member of the clicker 50 ′ is used to urge the clutch 60 ′ back along the drive sleeve 30 ′ to re - couple the dog teeth on the shoulder 158 of the clutch 60 ′ with the dog teeth on the dose dial grip 76 ′. the drive mechanism is thus reset in preparation to dial a subsequent dose . referring to fig1 to 22 there may be seen a drug delivery device in accordance with the present invention . the drug delivery device comprises a two - part housing 2 ″ within which are located a cartridge 4 ″ containing a medicinal product , means for setting or selecting the dose of medicinal product to be expelled and means for expelling the selected dose of medicinal product . the housing 2 ″ is generally cylindrical in shape and houses a rack 6 ″ to be described in more detail below . the cartridge 4 ″ is located within a first part 8 ″ of the housing 2 ″. the dose setting means and the means for expelling the selected dose of medicinal product are retained , that is held , within a second part 10 ″ of the housing 2 ″. the first part 8 ″ of the housing 2 ″ and the second part 10 ″ of the housing 2 ″ may be secured together by any suitable means . the cartridge 4 ″ may be secured in position in the first part 8 ″ of the housing 2 ″ by any suitable means . a needle unit may be secured to a first end of the cartridge 4 ″. a temporary covering 12 ″ is shown in this position in the figures . the cartridge 4 ″ further comprises a displaceable piston 14 ″. advancing the piston 10 ″ towards the first end of the cartridge 4 ″ causes the medicinal product to be expelled from the cartridge 4 ″ through the needle unit . a cap 16 ″ is provided to cover the needle unit when the drug delivery device is not in use . the cap 16 ″ may be releasably secured to the housing 2 ″ by any suitable means . the dose setting means and the means for expelling the selected dose of medicinal product will now be described in more detail . the rack 6 ″ is located within a drive sleeve 18 ″ located within the housing 2 ″ and is fixed both axially and rotationally with respect to the housing 2 ″ by any suitable means . the drive sleeve 18 ″ comprises an internally threaded portion 20 ″, which extends along substantially the entire internal surface of the sleeve . an internal toothed gear 22 ″ is located within the drive sleeve 18 ″ and has helical teeth which match the pitch of the internal thread of the drive sleeve 18 ″. the internal thread of the drive sleeve 18 ″ is a multistart thread with a lead which is the same as the lead of the helical thread of the dose dial sleeve , which will be described later . the drive sleeve 18 ″ terminates in an externally threaded section 24 ″ which extends from an end of the sleeve as far as an external circumferential flange 26 ″ which projects from the drive sleeve 18 ″. a limiting nut 28 ″ is mounted for rotation on the externally threaded section 24 ″ of the sleeve 14 ″. the limiting nut 28 ″ is keyed to the housing 2 ″ by means of a plurality of longitudinally extending splines 30 ″ which extend along the internal surface of the first portion 8 ″ of the housing 2 ″. in the illustrated embodiment , the limiting nut 28 ″ is shown as a half - nut , but a full nut could be used . a piston rod 32 ″ is provided extending along the length of the rack 6 ″ and through a hole in the end of the rack 6 ″. the piston rod 32 ″ is generally elongate and is provided with a pressure foot 34 ″. in use the pressure foot 34 ″ is disposed to abut the cartridge piston 14 ″. the toothed gear 22 ″ is mounted on the end of the piston rod 32 ″ remote from the pressure foot 34 ″ in a journal bearing ( not shown ). a dose dial sleeve 36 ″ of generally cylindrical form comprises a first section 38 ″ of first diameter and a second section 40 ″ of larger second diameter . the first section is located within the housing 2 ″. the second section 40 ″ of the dose dial sleeve 36 ″ is preferably of the same outer diameter as the housing 2 ″. the second part 10 ″ of the housing 2 ″ comprises an external sleeve portion 42 ″ surrounding a coaxial internal sleeve portion 44 ″. the external sleeve portion 42 ″ is closed to the internal sleeve portion 44 ″ at a circular internal flange portion 46 ″. the first section 38 ″ of the dose dial sleeve 36 ″ is located within the second part 10 ″ of the housing 2 ″, between the external sleeve portion 42 ″ and the internal sleeve portion 44 ″. an inner surface of the first section 38 ″ and the outer surface of the internal sleeve portion 44 ″ are provided with interengaging features to provide a helical thread 48 ″ between the internal sleeve portion 44 ″ of the second part 10 ″ of the housing 2 ″ and the dose dial sleeve 36 ″. this helical thread 48 ″ has the same lead as the internal thread of the drive sleeve 18 ″, as noted above . within the helical track , a helical rib provided on the inner surface of the dose dial sleeve 36 ″ may run . this enables the dose dial sleeve 36 ″ to rotate about and along the housing 2 ″. the second section 40 ″ of the dose dial sleeve 36 ″ is provided with an end wall 50 ″ adjacent its free end , which defines a central receiving area 52 ″ between the end wall 50 ″ and the free end of the dose dial sleeve 36 ″. a through hole 54 ″ is provided in the end wall 50 ″. a dose button 56 ″ of generally ‘ t ’, shaped configuration is provided , the head 58 ″ of which is retained within the receiving area 52 ″ and the stem 60 ″ of which is sized to pass through the through hole 54 ″. the stem 60 ″ of the button 56 ″ is provided with a plurality of fingers 62 ″ that are deformable to pass through the through hole 54 ″ of the end wall 50 ″ only in the direction away from the free end of the dose dial sleeve 36 ″. the drive sleeve 18 ″ is closed at its end remote from the externally threaded section 24 ″ by an apertured end wall 64 ″ from which a plurality of engagement features 66 ″ project . external to the drive sleeve 18 ″. a substantially u - shaped locking spring 68 ″ comprising first and second legs 70 ″, 72 ″ joined by a link portion 74 ″ is provided for longitudinal mounting on the exterior of the drive sleeve 18 ″. the link portion 74 ″ is of a length which is substantially equal to the external diameter of the drive sleeve 18 ″. each of the legs 70 ″, 72 ″ of the locking spring 68 ″ terminates in a latch portion 76 ″, the function of which will be described later . when the device is assembled , the locking spring 68 ″ urges the dose button 56 ″ axially away from the piston rod 32 ″ and drive sleeve 18 ″, towards the inside of the end wall 50 ″ of the dose dial sleeve 36 ″. in this position , the dose button 56 ″ is locked with respect to rotation with the dose dial sleeve 36 ″. the dose button 56 ″ is also permanently locked with respect to rotation with the drive sleeve 18 ″. an outer surface of the first section of the dose dial sleeve 36 ″ is provided with graphics 82 ″. the graphics are typically a sequence of reference numerals . the housing 2 ″ is provided with an aperture or window 84 ″ through which a portion of the graphics , representing a dosage value selected by the user , may be viewed . the graphics 82 ″ may be applied to the dose dial sleeve 36 ″ by any suitable means . the graphics 82 ″ may be printed directly on the dose dial sleeve 36 ″ or may be provided in the form of a printed label encircling the dose dial sleeve 36 ″. alternatively the graphics may take the form of a marked sleeve clipped to the dose dial sleeve 36 ″. the graphics may be marked in any suitable manner , for example by laser marking . the external circumferential flange 26 ″ which projects from the drive sleeve 18 ″ is provided with a pair of diametrically opposed through apertures 78 ″ sized to receive the corresponding latch portions 76 ″ of the locking spring 68 ″. a clicker projection 80 ″ from the outer edge of the flange 26 ″ is associated with each through aperture 78 ″. in fig1 , the drug delivery device is provided with a filled cartridge 4 ″. to operate the drug delivery device a user must first select a dose . to set a dose the dose dial sleeve 36 ″ is rotated with respect to the housing 2 ″ until the desired dose value is visible through the window 84 ″. the drive sleeve 18 ″ is linked to the dose dial sleeve 36 ″ and spirals out at the same rate during dialling . during the dialling of a dose , the locking spring 68 is straight and urges the dose button 56 ″ axially away from the piston rod 32 ″ and drive sleeve 18 ″, towards the inside of the end wall 50 ″ of the dose dial sleeve 36 ″, thereby providing a clutch mechanism . the drive sleeve 18 ″ therefore rotates over the toothed gear 22 ″ that is located inside it . the . relative rotation between the drive sleeve 18 ″ and the housing 2 ″ causes an audible confirmation of the dose being dialed by engagement of the two clicker projections 80 ″ with the splines 30 ″ which extend along the internal surface of the first portion 8 ″ of the housing 2 ″. the limiting nut 28 ″ climbs up the drive sleeve 18 ″ in proportion to the dose dialed . the position of the limiting nut 28 ″, which only moves along the external thread of the drive sleeve 18 ″ when there is relative rotation between the drive sleeve 18 ″ and the housing 2 ″, corresponds to the amount of medicinal product remaining in the cartridge 4 ″. once a desired dose has been set ( as shown for example in fig1 ), to deliver the dose the user depresses the dose button 56 ″ to urge the button 56 ″ against the locking spring 68 ″. as the dose button 56 ″ pushes down on the spring 68 ″, the clutch between the dose button 56 ″ and the dose dial sleeve 36 ″ is disengaged . the axial force applied from the dose button 56 ″ onto the dose dial sleeve 36 ″ causes the dose dial sleeve 36 ″ to spin into the housing 2 ″ on the helical thread between the dose dial sleeve 36 ″ and the housing 2 ″. the locking spring 68 ″ deforms and the legs of the spring move axially down the drive sleeve 18 ″. the latch portions 76 ″ of the locking spring 68 ″ engage in the through apertures 78 ″ on the external flange 26 ″ which projects from the drive sleeve 18 ″ and maintain engagement between the clicker projections 80 ″ of the flange 26 ″ with the grooves between the splines 30 ″, locking the drive sleeve to the housing 2 ″ and preventing the drive sleeve 18 ″ from rotation relative to the housing 2 ″ during dispensing of the dose . the drive sleeve 18 ″ is thus prevented from spinning and moves axially in , causing the toothed gear 22 ″ to rotate against the fixed rack 6 ″. the toothed gear 22 ″, together with the piston rod 32 ″ on which it is mounted , move along the rack 6 ″ a distance corresponding to one half of the distance by which the drive sleeve 18 ″ moves axially , creating a 2 : 1 mechanical advantage . this has the two - fold benefit of allowing the display on the dose dial sleeve 36 ″ to be larger for a given amount of travel of the piston 14 ″ within the cartridge 4 ″, that is for a given amount of medicament to be dispensed and secondly of halving the force required to dispense the dose . the piston rod 32 ″ is driven through the drive sleeve 18 ″ towards the first end of the drug delivery device , thereby to advance the cartridge piston 14 ″ and expel the desired dose of medicinal product . the piston rod 32 ″ continues to advance until the drive sleeve 18 ″ and dose dial sleeve 36 ″ have returned to their initial positions ( fig2 ). it can be seen that the dose selecting means and the dose expelling means extend beyond a second end of the housing 2 ″ as the dose is selected and are returned within the housing 2 ″ as the selected dose is expelled . further dosages may be delivered as required . fig2 shows an example of a subsequently selected dosage . as noted above , the position of the limiting nut 28 ″ along the external thread of the drive sleeve 18 ″ corresponds to the amount of medicinal product remaining in the cartridge 4 ″, such that when the nut 28 ″ reaches the external flange 26 ″ and can rotate no further this corresponds to no medicinal product remaining in the cartridge 4 ″. it will be seen that if a user seeks to select a quantity of medical product greater than that remaining in the cartridge 4 ″, this cannot be done since when the nut 28 ″ stops rotating against the drive sleeve 18 ″, the drive sleeve 18 ″ and the housing 2 ″ will become locked together preventing rotation of the drive sleeve 18 ″ and hence the dose dial sleeve 36 ″. this prevents the setting of a larger dose than the amount of medical product remaining within the cartridge 4 ″. fig2 shows a drug delivery device according to the present invention in which the entire medicinal product within the cartridge 4 ″ has been expelled . the illustrated embodiment of the device according to the invention further comprises a maximum dosage dial end stop . when the dose dial sleeve 36 ″ is dialed fully out , the external flange 26 ″ on the drive sleeve 18 ″ engages the internal flange 46 ″ in the housing 2 ″. it will be seen that if the user tries to dial beyond the maximum dosage , this cannot be done . when the drive sleeve 18 ″ stops rotating against the housing 2 ″, the dose dial sleeve is also prevented from rotating . the reaction between the external flange 44 ″ and the internal flange 86 ″ indicates to the user that the maximum dose has been dialed . | US-52059806-A |
the present invention comprises a set of instruments and a method for their use in preparing a knee joint to receive knee implants . the inventive instruments and method are generally suitable for knee joint surgery . furthermore , they include features that make them suitable for performing minimally invasive knee surgery . | the present invention relates to methods and corresponding instruments for performing minimally invasive total knee arthroplasty . by way of example and not by limitation , depicted in fig1 is a knee 10 having a lateral side 12 . the knee 10 is flexed to about 90 degrees and marks are made on the skin over select areas . specifically , marks 14 are made over gerdy &# 39 ; s tubercle , marks 16 are made over the tibial tuberosity , and marks 18 are made over the lateral border of the patella . an incision , marked by a dashed line 20 , is made beginning at the mid - portion of the patella and just lateral to the patellar border and extending along the lateral parapatellar region distally to the tibial tuberosity . the incision passes between the tibial tuberosity and gerdy &# 39 ; s tubercle . the lateral retinaculum is divided in line with the skin incision . the lateral edge of the distal incision is now elevated from the bone at the tibia until gerdy &# 39 ; s tubercle is encountered . at this point gerdy &# 39 ; s tubercle is elevated , such as with a curved ½ - inch osteotome , leaving approximately 2 mm of bone thickness to the illiotibial band insertion at gerdy &# 39 ; s tubercle . subperiosteal dissection is then continued laterally along the proximal tibia to the posterior lateral corner . a retractor is put in place which extends around the posterolateral corner to a point midway between the posterior cruciate ligament and the posterolateral corner . the anterior half of the lateral meniscus is excised , and a portion of the fat pad is also excised to give full visualization of the lateral compartment . the tissue just proximal to the tibial tuberosity is subperiosteally dissected from the tibial tuberosity to the joint line . subperiosteal dissection is then carried out medially , elevating the capsule and soft tissue from the joint line to a point approximately 8 mm distal to the joint . this is elevated around the anteromedial corner , and a retractor is put in place containing the patella tendon and the anteromedial capsule . as depicted in fig2 the exposure now reveals a lateral compartment 22 , both anteriorly and laterally , wherein the distal end of a femur 4 , proximal end of a tibia 6 , and a joint line 8 formed therebetween are exposed . optionally , the lateral epicondyle can now be osteotomized . a curved ⅜ - inch osteotome is utilized to elevate the base of the lateral epicondyle beginning anteriorly and extending distally to the edge of the articular surface and then elevating it as a greenstick fracture by leaving the final attachment at the posterior border of the epicondyle . this is elevated sharply , and the attached tendons are retracted posterolaterally to expose the lateral joint and allow for opening with varus stress to expose the posterior horn of the lateral meniscus and the posterior cruciate ligament . this optional osteotomy is utilized to give exposure and access to the posterior cruciate to protect this structure when the tibial cut is made from lateral to medial . once the lateral compartment 22 is formed , the tibial plateau of the tibia 6 is resected along a cut plane 5 that is substantially parallel to the joint line 8 . in one embodiment , as depicted in fig3 the proper orientation of the cut plane is determined by initially mounting a tibial template 24 on the anteriolateral side of the proximal end of the tibia 6 . the tibial template 24 comprises a base 26 having a front face 28 and an opposing back face 30 . at least two spaced apart passageways 32 extend between the front 28 and back 30 faces . a placement arm 34 having a flat end 35 projecting outwardly from the front face 28 is spaced a predetermined distance from the passageways 32 . a support arm 37 also projects from the front face 28 at the same distance from the placement arm and the passageways 32 . the support arm and passageways are selectively adjustable along the height of the front face 28 to vary their spacing from the support arm 37 . the support arm 37 thus indicates the location on the bone that fasteners will penetrate when inserted through the passageways 32 . finally , an alignment assembly 38 is mounted on the back face 30 of the base 26 . the alignment assembly 38 includes a bracket 36 that is rotatable relative to the base 26 about an axis that is substantially parallel with the longitudinal axis of the placement arm 34 . an elongated rod 39 projects from the bracket 36 at an orientation substantially normal to the long axis of the placement arm 34 . the flat end 35 of the placement arm 34 is rested on the lower posterior side of the lateral facet of the superior articular surface of the tibia 6 . the medial - lateral tilt ( or varus - valgus angle ) of the cut plane for resection of the tibial plateau is set by positioning the rod 39 in parallel alignment with the mechanical axis of the tibia 6 . in one embodiment , this is accomplished by using line - of - sight to position the rod 39 in parallel alignment with the tibial ridge of the tibia 6 , as shown in fig4 . the anterior - posterior tilt ( or posterior slope ) for the cut plane is set by orienting the flat end 35 of the placement arm 34 , which is rigidly mounted to the base 26 , in alignment with the plane of the joint line 8 . in one embodiment this is accomplished through feel and line - of - sight , as shown in fig5 . alternatively , by using relative degree markings formed between the bracket 36 and base 26 of the tibial template 24 , the base 26 and the placement arm 34 can be set at a predetermined angle relative to the rod 39 which , as discussed above , is disposed in parallel alignment with the mechanical axis of the tibia 6 . the angle can be set in a range between about 3 ° to about 7 ° which is the statistical norm for the posterior slope of the joint line 8 . alternatively , the angle can be measured by using conventional instruments to measure the change in height between the anterior and posterior side of the superior articular surface . once the tibial template 24 is properly oriented , fasteners 40 ( see fig6 ), such as pins , nails , screws , and the like , are drilled , hammered or otherwise passed through the passageways 32 and into the proximal end of the tibia 6 distal of the cut plane . tibial template 24 is then removed over the fasteners 40 so that the fasteners 40 remain in place . the fasteners thus establish a datum for referencing the varus - valgus angle and posterior slope of the proximal tibial cut that records , or preserves , this position information after the template is removed . as depicted in fig6 a tibial guide 44 is then mounted on the fasteners 40 . specifically , the tibial guide 44 comprises a body 46 having a front face 48 and an opposing back face 50 with passageways 52 extending therebetween . the passageways 52 of the tibial guide 44 have substantially the same size and spacing as the passageways 32 of the tibial template 24 . however , extra passageways 52 can be provided to allow for vertical fine tuning of the tibial guide 44 . a bounded guide slot 54 also extends between the front 48 and back 50 faces . the tibial guide 44 is advanced so that the fasteners 40 are received within corresponding passageways 52 . a threaded nut 56 or other form of retaining structure is then mounted on the exposed proximal end of each fastener 40 so as to tightly secure the tibial guide 44 to the tibia 6 . as a result of the predetermined positioning of the fasteners 40 , the guide slot 54 defines a cut plane at a predetermined location approximately 10 mm distal of the top of the tibial plateau . a stylus 57 can be inserted through the guide slot 54 to visualize where the cut will be made to permit further adjustment if desired . if adjustment is necessary , the tibial guide 44 can be pulled off of the fasteners 40 and repositioned on a different set of passageways 52 . an oscillating saw blade is then passed through the guide slot 54 and used to cut through the proximal end of the tibia 6 along the cut plane from lateral to medial . this cut is completed anteriorly and medially sacrificing the anterior cruciate ligament , but not posteriorly . prior to removal of the tibial plateau , the bone is resected around the posterior cruciate ligament . in one embodiment , a ½ - inch curved osteotome is inserted from the lateral side of the joint with the knee in varus to protect the bone block containing the tibial insertion of the posterior cruciate ligament . a large osteotome is then inserted into the cut and used to elevate the cut proximal tibial bone . the cut bone is put in traction by gripping it with a pair of forceps . the soft tissues are then removed from the periphery allowing extraction of the cut bone . in an alternative embodiment , conventional arthroscopic procedures can be used to drill or otherwise resect the bone bounding the posterior cruciate ligament prior to initial cutting of the incision 20 . arthroscopic procedures can also be used to remove the meniscus and any soft tissue attachments to the proximal tibia that restrict the removal of the cut proximal tibia from the lateral side . it is appreciated that there are a number of alternative methods and instruments that can be used in association with resection of the tibial plateau . for example , the tibial template 24 and tibial guide 44 can be combined into a single guide system that does not require changing parts over fasteners 40 . fig7 shows an illustrative embodiment of such a guide system 55 . the guide system 55 comprises a base 58 through which passageways 45 and a guide slot 47 are formed . an elongated rod 49 projects from the base either rigidly or hingedly . a placement arm 51 is mounted on a bracket 59 having a flange 60 projecting therefrom . during initial attachment , the flange 60 is inserted into the guide slot 47 so that the base 58 can be properly oriented using substantially the same procedure as discussed above with regard to the tibial template 24 . once the base 58 is oriented , fasteners 53 are passed through the passageways 45 to secure the base 58 to the tibia 6 . as depicted in fig8 and 9 , the placement arm 51 is then removed from the base 58 so that a blade 62 can be inserted into guide slot 47 . alternatively , it is also appreciated that base 58 can be formed with a large exposed top surface which functions as a guide without the need for a bounded guide slot . various instruments such as drills , oscillating chisels , oscillating saws , and other conventional bone cutting instruments can be used to remove the tibial plateau . with the tibial plateau removed , the femur 4 and tibia can be moved together to allow more movement in the joint and give more room to access the femur . in this position , a cutting guide is mounted on the lateral side of the distal end of the femur 4 to facilitate selective resection thereof . the cutting guide , however , must be appropriately positioned so that each of the cuts , as discussed below , has a desired orientation . as depicted in fig1 , the femur 4 has associated therewith both an anatomic axis 64 , which extends centrally along the femoral shaft , and a mechanical axis 66 . the mechanical axis 66 defines the axis through which vertical load is carried by the femur 4 . the mechanical axis 66 extends from the center of the femoral head 68 to the center of the distal end of the femur 4 at an angle approximately 6 ° from the anatomic axis 64 . the cuts on the distal end of femur 4 are made relative to the mechanical axis 66 . as such , a reference to the mechanical axis 66 is first ascertained . by way of example , in one embodiment an incision is made through the skin of the patient in the parapatella region such that the incision is in alignment with the anatomic axis 64 . as depicted in fig1 , a guide wire 74 is passed through the incision and drilled into the distal end of femur 4 so as to extend into the medullary canal along at least a portion of the length of the anatomic axis 64 . in one embodiment , the alignment of guide wire 74 with the anatomic axis 64 is established by using fluoroscopic observation simultaneously with drilling of the guide wire 74 . alternatively , a larger guide wire can be inserted into the medullary cannel and aligned with the anatomic axis 64 through sight and feel . as depicted in fig1 , the guide wire , or intramedullary rod , 74 includes a main portion 76 and an extension portion 78 . the main portion 76 includes a distal end 80 and an opposing proximal end 82 . the proximal end 82 terminates at a threaded tip 84 which freely projects from the distal end of the femur 4 . during placement , the extension portion 78 is threaded onto the main portion 76 . a drill handpiece is then mounted to extension portion 78 for drilling the guide wire 74 into the femur . once the guide wire 74 is inserted , extension portion 78 is temporarily removed . in this position , the knee and soft tissue are manipulated so that the proximal end 82 of the main portion 76 or the guide wire 74 is shifted from the incision formed in the parapatella region to the lateral compartment 22 . the extension portion 78 is then reattached to the main portion 76 . as an alternative to making an incision in the parapatella region , the knee joint and soft tissue can initially be manipulated so that the guide wire 74 is drilled directly into the distal end of the femur 4 through the lateral compartment 22 . in this embodiment , it is not necessary that the guide wire 74 be comprised of two portions . as depicted in fig1 , a positioning guide 90 is slidably attached to the guide wire 74 . the positioning guide 90 comprises a substantially u - shaped body 92 having a top side 94 and a bottom side 96 each extending between a first end 98 and an opposing second end 100 . elongated slots 102 extend between the opposing sides 94 , 96 at the first end 98 , second end 100 , and a central portion 104 of the body 92 . a first guide stake 106 and a second guide stake 108 are slidably mounted on the ends 98 , 100 of the body 92 . each guide stake 106 , 108 has a pointed distal end 110 . the guide stakes 106 , 108 are disposed in coaxial alignment with their distal ends 110 facing oppositely . a knob 112 is associated with each guide stake 106 , 108 . each knob 112 is threaded through a portion of the body 92 to selectively bear against its corresponding guide stake 106 , 108 to enable selective fixed attachment of the guide stakes 106 , 108 to the body 92 . a guide border 114 , is positioned on the top side 94 of the body 92 . the guide border 114 comprises an arched plate 116 having a first post 118 projecting upwardly from a first end 120 of the plate 116 and a second post 122 projecting upwardly from a second end 124 of the plate 116 . a plurality of radially spaced apart grooves 128 are recessed along the side of each post 118 , 122 . knobs 126 extend through the slots 102 at the first end 98 and central portion 104 of the body 92 and engage the posts 118 , 122 so as to selectively secure the guide border 114 to the body 92 . the knobs 126 can be loosened to allow the guide border 114 to slide in an arc along the body 92 to change the angle of the guide wire 74 relative to the guide stakes 106 , 108 . the knobs 126 can be tightened to fix the guide border in place . depending on the operating parameters , the knobs 126 can be removed and the guide border 114 shifted to the second end 100 of the body 92 . a retainer 130 is mounted to the second post 122 . the retainer 130 comprises a collar 132 that encircles the second post 122 and a sleeve 134 that encircles the guide wire 74 . a set screw 136 is threaded through the collar 132 so as to bear against the second post 122 within a select groove 128 . by loosening set screw 136 , the retainer 130 can be selectively raised or lowered along the second post 122 . when the set screw 136 is tightened , the engagement between the set screw 136 and corresponding groove 128 prevents rotation of the retainer 130 about the second post 122 and raising or lowering of the retainer 130 along the second post 122 . a pilot 140 is selectively mounted to the first post 118 . the pilot 140 comprises a collar 142 that encircles the first post 118 and a pin guide 144 that projects outwardly from a side of the pilot 140 . a pair of spaced apart channels 150 extend through the pin guide 144 in parallel alignment . a slot 152 is recessed into one end of the pin guide 144 between the channels 150 . an elongated stylus 154 is selectively mounted within slot 152 and projects from it . a plurality of ports 146 extend through the collar 142 so as to communicate with the first post 118 . a set screw 148 is threaded into a select port 146 so as to bear against the first post 118 within a corresponding groove 128 . each port 146 is positioned at a unique predetermined radial position on the collar 142 such that by positioning the set screw 148 in a specific port 146 , the pin guide 144 , and thus the channels 150 therein , rotates to a predefined angle . in the embodiment depicted , nine ports 146 are provided each having a one degree variance . for example , if the set screw 148 is fixed in the number one port , the channels 150 are oriented at a one degree offset from perpendicular to the guide wire 74 . when the set screw 148 is in the number nine port , the channels 150 are oriented at a nine degree offset from perpendicular to the guide wire 74 . during operation , the proximal end of the guide wire 74 is slid within the sleeve 134 of the retainer 130 so that the opposing ends 98 , 100 of the positioning guide 90 are positioned laterally and medially of the knee 10 , respectively . a small stab wound is made over the medial epicondyle and the guide stakes 106 , 108 are advanced so as to bear against the lateral epicondyle and medial epicondyle , respectively . to enable placement of the stakes 106 , 108 over the respective epicondyles , it may be necessary to loosen the set screw 136 and slide the retainer 130 along the second post 122 . it may also be necessary to loosen the knobs 126 and slide the plate 116 along the arc defined by the u - shaped body 92 thereby changing the angle of the guide wire 74 relative to the guide stakes 106 , 108 . once the stakes 106 , 108 are appropriately positioned , the knobs 112 , 126 and set screw 136 are tightened so that the stakes 106 , 108 and retainer 130 are locked in place . in this position , the guide wire 74 is still disposed in alignment with the anatomic axis of the femur 4 and the guide stakes 106 , 108 lie along the epicondylar axis . the epicondylar axis will be used to establish the external rotation for subsequent femoral cuts and implant placement . the pilot 140 is set at an angle corresponding to the angle between the mechanical axis and the anatomic axis of the femur either before or after attachment of the positioning guide 90 to the guide wire 74 . in one embodiment , this angle is determined in a preoperative procedure by use of standing x - ray . alternatively , the angle can be set to approximately 6 ° which is a statistical norm . again , the desired angle is set by inserting the set screw 148 into a corresponding port 146 on the first post 118 so that the set screw 148 is received within a corresponding groove 128 . this effectively sets the varus - valgus angle for subsequent bone cuts and implant placement . finally , the pilot 140 is also set at a desired anterior - posterior position along the length of the first post 118 . this is set by raising or lowering the pilot 140 along the first post 118 until the free end 155 of the stylus 154 contacts the surface of the lateral anterior femoral ridge . this determination is made by sight and feel . once the pilot 140 is at the proper orientation , it is secured in place by tightening the set screw 148 . this effectively sets the anterior - posterior position for subsequent bone cuts and implant placement . once the positioning guide 90 is locked in place , alignment pins 160 are passed through the channels 150 of the pilot 140 and drilled , hammered or otherwise advanced into the lateral side of the femur 4 . as depicted in fig1 , each alignment pin 160 has a proximal segment 162 and an intermediate segment 164 having a diameter smaller than the diameter of the proximal segment 162 . as such , a proximal annular shoulder 166 is formed between the proximal segment 162 and the intermediate segment 164 . a narrow breakaway segment 168 , a threaded segment 170 , and a distal segment 172 terminating at a sharpened tip 174 extend distally of the intermediate segment 164 . the threaded segment 170 is smaller in diameter than the distal segment 172 thereby forming a distal annular shoulder 173 between the distal segment 172 and the threaded segment 170 . the alignment pins 160 are advanced until the shoulders 166 contact the pilot 140 , thereby precluding further advancement and placing the two pins at the same depth relative to the pin guide 144 . in this position , as shown in fig1 , the distal tips of the alignment pins 160 are disposed adjacent to the guide wire 74 . once the alignment pins 160 are placed , the positioning guide 90 is loosened and removed from the knee 10 . the positioning guide 90 is separated from the implanted pins 160 by fracturing each pin 160 at the breakaway segment 168 . the guide wire 74 is also removed from the femur 4 . the two alignment pins 160 now act as datums and record by their placement the desired varus - valgus angle , external rotation angle , and anterior - posterior position as determined during the placement of positioning guide 90 . as depicted in fig1 , a template 180 is mounted on the alignment pins 160 . the template 180 comprises a substantially u - shaped body 182 having an exposed perimeter edge 190 comprised of a plurality of flat planar surfaces . specifically , the perimeter edge 190 comprises an anterior surface 192 , an opposing posterior surface 194 , a distal surface 196 , a first chamfered surface 198 extending between the anterior 192 and distal 196 surfaces , and a second chamfered surface 200 extending between the posterior 194 and distal 196 surfaces . in alternative embodiments , it is appreciated that the body 182 need not be u - shaped but can be any substantially square or any other desired configuration that contains the desired surfaces on perimeter edge 190 . body 182 further includes a front face 184 , a back face 186 , and a plurality of spaced passageways 188 extending between them . in one embodiment at least two passageways 188 are disposed adjacent to each surface of the perimeter edge 190 , although a single passageway 188 can be associated with more than one surface . an elongated slot 191 and one or more anchoring ports 202 also extend between the front 184 and back 186 faces . as depicted in fig1 , the template 180 is mounted on the alignment pins 160 by passing slot 191 over the pins 160 and then threading nuts 204 onto the exposed threaded segments 170 of each pin 160 . the nuts 204 bias the template 180 against the distal annular shoulder 173 of each pin 160 so as to secure the template 180 in place and oriented in the varus - valgus and posterior slope alignment pre - set by the pins . in this position , the template 180 is mounted on the lateral side of the femur 4 with the surfaces 192 , 194 , 196 , 198 , 200 of the perimeter edge 190 denoting cut planes for the femur 4 . by measuring the distance between each surface of perimeter edge 190 of the template 180 and corresponding outer surfaces of the femur 4 , a template 180 of an appropriate size is selected so that the cuts on the femur 4 are made at the desired thickness . by loosening the nuts 204 , the template 180 can be slid on the pins to adjust the proximal - distal position for subsequent bone cuts and implant placement . once an appropriately sized template 180 is chosen , positioned , and secured on the alignment pins 160 , additional pins , anchors , screws or other types of fastens are anchored into the femur 4 through the anchoring ports 202 , thereby further securing template 180 to the femur 4 . a modular cut guide 210 is selectively mounted on the front face 184 of the template 180 . the cut guide 210 has a bounded guide slot 212 and a pair of spaced apart passageways 214 extending through it . the cut guide 210 is configured such that its passageways 214 can be selectively aligned with each pair of passageways 188 associated with each perimeter edge surface of the template 180 . screws can be passed through the cut guide passageways 214 and threaded into the template passageways 188 to secure the cut guide 210 to the template 180 . alternatively , any form of fastener such as screws , nails , pins and the like can be passed through both the cut guide 210 and the template 180 and secured within the femur 4 , thereby also securing the cut guide 210 to the template 180 . by securing the cut guide 210 , a bottom surface 211 of the guide slot 212 is disposed in the same plane as the corresponding surface of the perimeter edge 190 of the template 180 . a saw , drill , chisel or the like is then passed through the guide slot 212 so as to resect the distal end of the femur 4 along the cut plane defined by the guide slot 212 and the corresponding surface of the perimeter edge 190 of the template 180 . once a cut is completed , the cut guide 210 is moved into alignment with the next perimeter edge surface of the template 180 and another cut is made . as such , each cut is made individually beginning anteriorly and extending distally and posteriorly . it is appreciated that the cuts can be formed on the femur 4 using a number of different techniques and apparatus . for example , instead of the cut guide 210 having the bounded slot 212 , a cut guide can be provided which simply provides an enlarged exposed support surface that is disposed in the same plane as the perimeter edge surfaces of the template 180 . the cutting instrument , which can comprise any form of drill , blade , chisel or the like is then supported on the support surface while facilitating the cuts . in like manner , a separate cut guide can be eliminated and simply replaced with a thicker template which also functions as the cut guide . likewise , the template need not have a cut guiding surface on its perimeter . the cut guide slot alone can guide the cut . fig1 - 21 depict an alternative illustrative embodiment of a template and modular cut guide assembly for use with the alignment pins 160 set in the femur . referring to fig1 the template 300 comprises a distal cut guide body 302 having opposing first 304 and second 306 side walls , opposing first 308 and second 310 end walls , and opposing top 312 and bottom 314 faces . an axial through bore 316 extends through the cut guide body 302 from the first end wall 308 to the second end wall 310 . a slide lock knob 318 has a threaded shaft ( not shown ) threaded into a bore in the bottom face 314 in communication with the axial through bore 316 . an implement lock knob 320 has a threaded shaft ( not shown ) threaded into a bore in the top face 312 in communication with the axial through bore 316 . a pair of pin receiving bores 322 extends through the cut guide body 302 transverse to the axial bore 316 . the pin receiving bores 322 are offset from the axial bore 316 so that pins may pass through them without interfering with the axial bore 316 . the length of each pin receiving bore 322 is extended by a pin sleeve 324 projecting from each side 304 , 306 of the cut guide body 302 . a slide 330 comprises a cylindrical body 332 having an axial through bore 334 extending from a first end 336 to a second end 338 . an annular flange 340 extends radially from the second end 338 and has a diameter larger than the axial through bore of the cut guide body 302 . an elongated slot 342 extends through one side of the slide body 332 in communication with the through bore 334 . the slide 330 is slidably received in the through bore 316 of the cut guide body 302 . slide lock knob 318 can be threaded further into the cut guide body 302 to bear against the slide 330 and lock it in a desired axial position along the through bore 316 axis . the flange 340 will bottom on the second end wall 310 to prevent the slide 330 from sliding completely through the cut guide body 302 . the shaft of the implement lock knob 320 aligns with the slot 342 when the slide is inserted into the cut guide body 302 . an implement 350 includes a working end 352 , a support arm 354 , and a mounting shaft 356 . the base of the arm 354 is larger than the mounting shaft 356 diameter such that a shoulder 358 is formed at the junction of the shaft 356 and arm 354 . the shaft 356 is generally cylindrical with a flat 360 formed along one side . the mounting shaft 356 is slidably received in the axial through bore 334 of the slide 330 . the shoulder 358 will bottom on the second end 338 of the slide such that the working end 352 is located at a predetermined distance from the second end 338 . the implement lock knob 320 can be threaded further into the cut guide body 302 and through the slot 342 in the slide 330 to bear against the slide flat 360 and lock the shaft in a desired axial position along the slide through bore 334 axis . a selection of implements 350 is provided offering different working ends 352 . each implement in the selection has a mounting shaft for engaging the slide 330 through bore 334 and shoulder for bottoming on the second end 338 to position its working end at a predetermined distance from the second end 338 of the slide . fig1 - 21 depict a progression of implements mounted on the cut guide body for preparing the distal femur . a distal cut stylus 370 has a flat working end 372 defining a reference surface 374 . the working end 372 connects via a support arm 376 to a shaft ( not shown ) forming a shoulder as described in reference to fig1 . the reference surface 374 lies at a known distance and orientation relative to the shaft and shoulder . in the illustrative embodiment , the reference surface 374 lies in a plane generally perpendicular to the shaft at a predetermined distance from the shoulder . the reference surface 374 projects away from the shaft axis toward the femoral bone to position the reference surface 374 in the incision adjacent to the bone . a distal femoral cut guide 380 has a cut guide working end 382 for guiding a cutter to cut the distal femur . in the illustrative embodiment , the working end 382 comprises a saw slot 384 for maintaining a saw blade in a desired cutting plane . the working end 382 connects via a support arm 386 to a shaft ( not shown ) forming a shoulder as previously described . the saw slot 384 lies at a known distance and orientation relative to the shaft and shoulder . in the illustrative embodiment , the saw slot lies in a plane generally perpendicular to the shaft at a predetermined distance from the shoulder . the working end 382 projects away from the shaft axis toward the femur to position the saw slot in the incision adjacent to the bone . an anterior femoral cut guide 390 has a cut guide working end 392 for guiding a cutter to make the anterior and anterior chamfer cuts on the distal femur . in the illustrative embodiment , the working end 392 comprises an anterior cut saw slot 394 and an anterior chamfer cut saw slot 396 . the working end 392 connects via a support arm 398 to a shaft ( not shown ) forming a shoulder as previously described . the saw slots 394 , 396 lie at known distances and orientations relative to the shaft and shoulder . the working end 392 projects away from the shaft axis toward the femur to position the saw slots in the incision adjacent to the bone . a posterior femoral cut guide 400 has a cut guide working end 402 for guiding a cutter to make the posterior and posterior chamfer cuts on the distal femur . in the illustrative embodiment , the working end 402 comprises a posterior cut saw slot 404 and a posterior chamfer cut saw slot 406 . the working end 402 connects via a support arm 408 to a shaft ( not shown ) forming a shoulder as previously described . the saw slots 404 , 406 lie at known distances and orientations relative to the shaft and shoulder . the working end 402 projects away from the shaft axis toward the femur to position the saw slots in the incision adjacent to the bone . in use , alignment pins 160 are placed in the femur as described above to establish desired varus - valgus angle , external rotation angle , and anterior - posterior position . the pin receiving bores 322 of the cut guide body 302 are slid over the alignment pins 160 until one or both of the pin sleeves 324 bottoms on the femoral bone . a nut can be threaded onto each of the alignment pins 160 to secure the cut guide body in place . the distal cut stylus 370 is then inserted into the slide 330 until its shoulder bottoms on the second end 338 of the slide 330 . the slide 330 is translated axially within the cut guide body 302 through bore 316 until the reference surface 374 contacts the lateral distal condyle . with the distal cut stylus 370 bottomed in the slide 330 the slide lock knob 318 is rotated to lock the slide 330 . this fixes the proximal - distal position of all of the femoral cuts since each cut guide is referenced to the end 338 of the slide 330 . now the varus - valgus angle , external rotation angle , anterior - posterior position , and proximal - distal position of each cut are now fixed since the cut guides are keyed to the slide 330 , which is locked to the cut guide body , which is in turned fixed in position by the alignment pins through the pin receiving bores 322 . the distal cut stylus 370 is removed from the slide 330 . the distal cut guide 380 is slid into the slide 330 until it bottoms and is locked in place by tightening the implement lock knob 320 . a saw blade is directed through the saw slot 384 to resect the distal femur . the anterior 390 and posterior 400 femoral cut guides are used similarly to make the anterior , anterior chamfer , posterior and posterior chamfer cuts . the anterior 390 and posterior 400 femoral cut guides can be provided in a range of sizes to prepare different sizes of femurs to receive appropriately sized implants . in an alternative embodiment , templates can be mounted on the lateral side of the femur 4 without the use of the positioning guide 90 . fig2 depicts a set guide 270 having an exposed perimeter surface 272 . the perimeter surface 272 has a configuration substantially complementary to the perimeter contour of the distal end of the femur 4 taken from a lateral view . a pair of spaced apart passageways 274 extends through the set guide 270 . in one embodiment , the set guide 270 is comprised of a material that is semitransparent to fluoroscopic rays . as depicted in fig2 and 23 , the set guide 270 is disposed adjacent the lateral compartment 22 so that the perimeter surface 272 of the set guide 270 is aligned with the perimeter contour of the distal end of the femur 4 taken from a lateral view . in one embodiment , this alignment is assisted by the use of real - time fluoroscopic rays 276 passing through the set guide 270 and the femur 4 . once the set guide 270 is aligned with the distal end of the femur 4 , fasteners 278 are passed through each of the passageways 274 and into the femur 4 . in one embodiment , the fasteners 278 can comprise the alignment pins 160 . once the fasteners 278 are placed , the set guide 270 is removed . the template is then mounted on the fasteners 278 in the same way that the template is mounted on the alignment pins 160 . the cutting process is then completed in the same way as previously discussed with regard to the template . once the cuts are made and the bone fragments are removed through the lateral compartment 22 , the template , the cut guide 210 and all related pins and fasteners are removed from the femur 4 . the distal end of the femur 4 is moved laterally to expose the femur through the lateral incision 20 . conventional cuts are then made on the posterior side of the patella to accommodate a prosthetic patellar articular surface . all of the prosthetic components can then be fixed in place through the lateral incision . closure is obtained by leaving the retinaculum open on the lateral side adjacent to the patella and closing only the retinaculum beginning at the proximal and lateral patella and extending distally to the tibial tuberosity . gerdy &# 39 ; s tubercle does not have to be reattached , because this has been partially excised in the excision of the proximal tibia , and the iliotibial band is continuous with the aponeurosis over the perineal musculature . it will reattach itself and secure anterolateral stability . the above described minimally invasive process for total knee arthroplasty is described with reference to forming incision 20 and thus compartment 22 on lateral side 12 of knee 10 . it is appreciated that the same methods and instruments can be used to perform the minimally invasive procedure on the medial side of knee 10 . the described embodiments are to be considered in all respects only as illustrative and not restrictive . the present invention may be embodied in other specific forms without departing from the spirit and scope of the appended claims . | US-35640403-A |
the present invention provides a chewable composition containing granules of water - soluble dietary fiber . the chewable composition has highly agreeable organolpetic properties and is consumable without the need of an ingestion aid . | the chewable composition of the present invention contains compression molded granules of water - soluble dietary fibers . the granules of the chewable composition have a size distribution profile that results in pleasing organoleptic properties , unlike other chewable fiber supplements that can be hard to chew or give viscid texture when masticated . dietary fibers suitable for the present chewable composition are water - soluble fibers , although minor amounts of water - insoluble fibers can be added . the chewable fiber composition contains between 30 wt % and 90 wt %, desirably between 35 wt % and 75 wt %, more desirably at least 40 wt % and 60 wt %, most desirably between 45 wt % and 55 wt %, of water - soluble fiber . particularly suitable water - soluble dietary fibers for the present invention are water - soluble fibers that impart a relatively small increase in viscosity when dissolved in water . it has been found that a low viscosity increasing water - soluble fiber avoids undesirable organoleptic properties , such as gelling in the mouth when masticated . particularly suitable dietary fibers , when dissolved in water at room temperature , form a 10 wt % solution that has less than 100 cp at room temperature , preferably less than 50 cp , and more preferably less than 25 cp . suitable dietary fibers include guar gum , inulin , and fructooligosaccharide , arabinogalactan and mixtures thereof . more specifically , suitable guar gum fiber is partially hydrolyzed guar gum , and suitable inulin and fructoologosaccharide are low molecular weight having a degree of polymerization less than 60 , preferably less than 30 . particularly desirable inulin has an average degree of polymerization less than 20 monomeric fructose units , and fructooligosaccharide has an average degree of polymerization less than 8 fructose units . of these suitable water - soluble fibers , especially desired is partially hydrolyzed guar gum dietary fiber . partially hydrolyzed guar gum dietary fiber is commercially available from novartis consumer health under the trademark benefiber ®. the guar gum fiber is produced by partially hydrolyzing guar gum to reduce its average molecular weight to around one tenth of unmodified guar gum . the partially hydrolyzed guar gum fiber does not significantly increase the viscosity of water or other aqueous liquid even when the daily recommended amount of the dietary fiber is dissolved in a readily consumable amount of liquid . preferred partially hydrolyzed guar gum is purified guar gum prepared by controlled enzymatic hydrolysis of guar gum . prior to hydrolysis , the molecular weight of guar gum is approximately 200 , 000 , and after hydrolysis , it is 15 , 000 to 35 , 000 , preferably 20 , 000 to 30 , 000 . the chewable composition of the present invention is produced by using a wet granulation process . in general , a conventional wet granulation process forms granules by wetting a powder material with an aqueous composition of a granulating agent to cause the powder to agglomerate to form wet agglomerated granules . unlike the conventional granulating process , which supplies a large volume of the liquid granulating agent to from a large cohesive , deformable , plastic mass that is later divided into small granules , the present wet granulation process supplies a limited amount of the liquid granulating agent , which is supplied as a fine spray , to form small granules . a preferred granulation process uses a high shear granulator , e . g ., oattersin - kelly liquids / solids granulator , tk fielder mixer / granulator , collette high shear mixer / granulator or lodige mixer / granulator , and supplies a fine spray of the liquid granulating agent , e . g ., water . the granulator prepares a dry mixture of dietary fiber and other dry ingredients , if needed , such as a binder , e . g ., lactose , sucrose , maltodextrin , starch , polyethylene glycol , gums , hypromellose , methylcellulose or microcrystalline cellulose . the binder can be supplied as a powder form mixed with the dry mixture or dissolved in the liquid granulating agent . the powder mixture is then agglomerated by supplying a fine spray of the liquid granulating agent while applying high shear to the mixture of the dietary fiber composition ingredients . desirably , the fine spray of the liquid granulating agent is applied the powder mixture with a fully aspirated fan - type flat nozzle , e . g ., nozzle number 9508 , and the moisture content of the produced wet granules is between 8 wt % and 17 wt %, preferably between 10 wt % and 15 wt %, based on the total weight of the wet granule . the wet agglomerated granules are collected from the granulator and dried using , e . g ., a fluid bed dryer until the moisture content of the granules are between 0 . 05 wt % and 4 wt %, preferably between 0 . 75 wt % and 3 . 5 wt %, and more preferably between 0 . 1 wt % and 3 wt %. any suitable temperature that does not cause thermal decomposition of the ingredients can be used to dry the granules . in accordance with the present invention , the dried granules are collected and screened using a mesh screen to separate small granules from large granules . a suitable screen size for the initially screening step is between about 500 μm ( 35 mesh ) and about 710 μm ( 25 mesh ). a particularly suitable screen size is about 600 μm ( 30 mesh ). the fine granules that pass through the screen are collected , and the large granules left on the screen are separately collected and milled using a conventional milling machine , e . g ., fitzmill , which is equipped with a screen of about 710 μm ( 25 mesh ) to about 1000 μm ( 18 mesh ), desirably about 850 μm ( 20 mesh ). once the milling process is completed , the initially screened granules and the milled granules are combined and mixed with other ingredients that are conventionally used to produce chewable products , e . g ., tablets , to form a granule mixture using a mixer , e . g ., tumble mixer or v - blender . other ingredients suitable for the chewable composition include fillers , binders , excipients , sweeteners , flavorants , lubricants and the like , as further discussed below . the granule mixture is then compression molded to form the chewable composition using , e . g ., a conventional compression tablet molding press , e . g ., courtoy rotary press , kilian tablet press , manesty rotary press , fette rotary press or korsch rotary press . a desired tablet press is a rotary tablet press that compresses the granule mixture to a tablet of a hardness of 10 - 20 kp , preferably 12 - 15 kp , as measured by a tablet hardness tester , e . g ., vk 200 vankel tablet hardness tester . as discussed above , in addition to the main fiber ingredient , the chewable composition may contain other ingredients . ingredients that facilitate the manufacture , improve the aesthetics and improve the organoleptic properties of the chewable composition can be added . these ingredients include stabilizer , colorants and fillers . other materials that can also be added include fillers , e . g ., compressible sugars , dextrose , sorbitol and mannitol ; compression aids , e . g ., microcrystalline cellulose and starch ; binders , e . g ., lactose , sucrose , maltodextrin , starch , polyethylene glycol , gums , hypromellose , methylcellulose or microcrystalline cellulose ; lubricants , e . g ., stearates ; flavorants ; natural sweeteners ; and artificial sweetener . flavoring agents well - known in the food and confection art may be added to the chewable fiber compositions . these flavoring agents may be chosen from synthetic flavor oils and / or those derived from natural fruits , plants , leaves , flowers and so forth , and combinations thereof . suitable flavors are artificial , natural or synthetic fruit flavors , such as citrus oil including lemon , orange , grape , lime and grapefruit ; and fruit essences including apple , apricot , strawberry , cherry , pineapple and so forth . also useful are flavor oils , such as spearmint oil , cinnamon oil , oil of wintergreen ( methylsalicylate ) and peppermint oils . the chewable composition desirably contains at least one sweetening agent . the sweetening agent may be selected from a wide range of materials , including water - soluble sweetening agents , water - soluble artificial sweeteners , dipeptide based sweeteners and mixtures thereof . additionally suitable ingredients are lubricants and release agents , such as magnesium stearate , stearic acid and polyethylene glycol . in accordance with the present invention , the granules forming the chewable composition have a size distribution , which provides desirable organoleptic properties . it has been found that having very small granules and very large granules adversely effect the organoleptic properties of the chewable composition . if the particle size of the fiber granules forming the tablet is too large , it is perceived as gritty or sandy , whereas if it is too fine , the tablet is perceived as dry or dusty and gummy . desirably , the chewable composition contains less than 10 wt %, based on the total weight of the chewable composition , preferably less than 7 . 5 wt %, more preferably less than 5 wt %, most preferably less than 4 wt %, of granules having particle size larger than 850 μm ( 20 mesh ), and less than 35 wt %, preferably less than 30 wt %, more preferably less than 25 wt %, most preferably less than 20 wt %, of granules having a particle size smaller than 75 μm ( 200 mesh ). although the present invention is illustrated mostly with a chewable tablet , the chewable composition can be in any chewable form , e . g ., a bar or wafer . the present invention is further illustrated by reference to the following example . the example is intended to illustrate desired embodiments and is not intended to limit the scope of the invention . dry blend 133 kg of guar gum fiber , which is available from novartis consumer health under the trademark benefiber ®, 25 kg of confectioner &# 39 ; s sugar , available from imperial sugar co , georgia , and 25 kg of maltodextrin , maltrin ® m100 in a fielder high shear granulator . add 28 l of purified water over 18 minutes using a fully aspirated fan - type nozzle 9508 , which provides a fine spray of water , to form agglomerate granules . the granules are dried using a fitzpatrick fluid bed dryer at 70 ° c . until the moisture content of the granules is less than 3 wt %. the dried granules are screened using a 30 mesh ( u . s . standard ) screen collecting the screened granules to a container . the large granules retained on the screen are conveyed to a fitzpatrick mill , which is equipped with a 20 mesh screen and run at medium speed . the milled granules are collected in a container . the granule size distribution of the two granules batches are tested , and the combined granules have less than 4 wt % of granules having a particle size larger than 20 mesh and less than 19 wt % of granules having a particle size smaller than 200 mesh . in a 2 ft 3 v - blender , a premix is prepared by loading , after passing through a 20 mesh screen , 0 . 2 kg of fd & amp ; c yellow # 6 , 2 kg of orange durarome , which is available from firmenich , 1 . 4 kg of orange cream flavor sd - 1002 , which is available from ottens manufacturing co ., pa , 2 . 7 kg of citric acid anhydrous granules , which is available from a . e . staley , ill ., 0 . 5 kg of micronized sucralose , which is available from splenda , inc . the premix is blended for 10 minutes and set aside . in a 20 ft 3 v - blender , the two granules and the premix prepared above are loaded . additionally , 58 kg of soritol ( neosorb p60 ), which is available from roquette corp , il , and 19 . 6 kg of dextrates are added , and the mixture is blended for about 10 minutes . into the mixture , 2 . 2 kg of magnesium stearate , which is screened with a 30 mesh screen , is added and blended for 5 minutes . using a rotary tablet machine having a 0 . 81 inch round flat punch and applying 40 - 60 kilonewtons of force , compressed tablets are formed . the molded tablets have highly - pleasing organoleptic texture when masticated , unlike tablets prepared with fiber granules having higher percentage of smaller and / or larger granules than specified above . tablets produced from a granule batch that has more than 10 wt % of granules having a size larger than 850 μm have gritty organoleptic texture , and tablets produced from a granule batch that has more than 35 wt % of granules having a size smaller than 75 μm have dusty or dry , as well as gummy organoleptic texture . | US-5748005-A |
an endoscopic instrument for ligating multiple lesions within a hollow body organ . a flexible endoscope 10 is provided with channels 16 - 21 for accomodating means for illumination , viewing and application of suction and is also provided with a hollow tubular member 101 affixed to the insertion end of the endoscope . a plurality of cords 103 are laid over the tube 101 to extend longitudinally thereon and be folded over the distal end of the tube . the cords 103 are connected to one another at a common point by a connector 106 inside the tube 101 . a plurality of elastic rings 50 are mounted on the tube 101 in stretched condition and overlaying the cords 103 . the segment of each cord 103 between each pair of adjacent rings 50 is in slack condition and of a length which equals or exceeds the distance of the tube &# 39 ; s distal end to the furthest ring of the pair . by a trip cord 105 threaded through a working channel 19 of the endoscope and connected to the cords 103 , a pull can be exerted thereon to simultaneously retract the cords 103 and dislodge each of the rings in controlled stepped sequence in a procedure wherein only one elastic ring at a time moves over the tube in the process of its dislodgement to ligate a lesion which has been suctioned part way into the tube 101 . | referring more particularly to the drawings , there is shown in fig1 a flexible endoscopic instrument 10 of a length which permits access to the deeper regions of a hollow body organ , such as the alimentary tract . the instrument 10 comprises a conventional endoscope with an operating controls section 11 of rigid construction and a flexible section 12 which extends therefrom and is of a length sufficient to reach the deeper regions of the alimentary tract . the distal end of the flexible section 12 is the insertion end 13 of the endoscope and the viewing end 14 of the endoscope is at the end of the rigid operating controls section 11 remote from the end thereof which connects to the flexible section 12 . the endoscope is provided with passages 16 - 21 which extend longitudinally therein from its insertion end 13 to exit ports near the viewing end 14 of the endoscope . the passages comprise an illumination channel 16 through which is inserted a fiber optic cable for the transmission of light from a light source , a viewing channel 17 which is also provided with a fiber optic cable for viewing purposes , and a channel through which objects may be passed or suction applied 18 . the illumination channel and suction channel exit laterally through a lateral extension 22 of the side wall of the endoscope at a location on the operating controls section 11 near the viewing end 14 . at their exit location , the fiber optic cable from channel 16 and the channel 18 are connectable through an umbilical cable 23 to a control device ( not shown ) which is adaptable for supplying illumination to the transmission optic cable and for connecting the channel 18 to an appropriate means for applying a suction therethrough . the fiber optic viewing channel 17 extends to the viewing end 14 of the endoscope which may be provided with a viewing lens and an adapter for mounting a camera thereon , if desired . the endoscope is also provided with a working channel 19 which extends through the endoscope from its insertion end 11 to an exit in the lateral extension 22 . the working channel 19 includes a branch 19a which extends through an angularly extending protuberance 24 to a second exit near the viewing end of the endoscope . additional channels 20 and 21 , shown in fig2 may be utilized for delivering pressurized air or a jet stream of water for cleaning the lens . in the embodiment of the invention shown in fig1 through 6 , the insertion end of the endoscope is fitted with an assembly of coaxially arranged tubes 25 , 26 , the outer tube 26 of which is secured in coaxial relation thereto preferably by a tubular adapter 27 which provides a friction fit as shown in fig3 although other fastening means such as a threaded connection might be suitably employed . the tube 26 is preferably of transparent plastic material for enhancing the illumination and field of vision from the insertion end of the endoscope , although other inert material might also be suitable including stainless steel . the tube 26 is provided at its attaching end with an external frusto - conical bevel surface 28 to facilitate the placement of the tubular adapter 27 thereover . the adapter 27 is preferably of a flexible material such as plastic and is provided with an internal diameter which allows it to be sleeved tightly over the tube 26 . for further enhancing the connection , the adapter 27 is provided with an internal annular flange 31 which is adapted to seat in an accommodating annular groove 32 formed externally about the surface of the tube 26 , thereby locking the adapter 27 to the tube 26 . at its other end , the inner wall of the adapter 27 is formed with a succession of outwardly diverging frusto - conical grooved surfaces 34 which provide teeth - like edges for enhancing its grip on the endoscope when sleeved over the end thereof . in addition , it is provided with an internal annular latching flange 36 which is adapted to seat in a latching groove 37 formed about the exterior of the endoscope . the inner wall of outer tube 26 is formed with a helical groove 40 which extends from its distal end for the greater part of its length . near its attaching end , the inner wall of outer tube 26 is formed with an internal annular flange 41 . the inner tubular member 25 has a forward end 42 and a rearward end 43 and comprises a first elongate section 44 and an adjoining shorter section 45 of circular cylinder configuration and larger radial dimensions . the tubular member 25 has an external annular shoulder 46 formed at the junction of the elongate tubular section 44 with the larger diameter section 45 . the tubular member 25 is also provided an internal annular radial shoulder 47 , which is formed at the junction of the bore of section 45 with the smaller bore of the elongate section 44 . the elongate section 44 has a radial cross section in the configuration of a segmented circle and an external cylindrical surface characterized by an elongate planar surface section 48 which extends from the forward end 42 of the tubular member 25 to the radial shoulder 46 . the inner tubular member 25 serves as a carrier for a plurality of elastic ligating rings 50 which are placed in stretched condition about the elongate section 44 and mounted thereon in side - by - side relation to one another and in sleeved relation to the section 44 . the elastic rings 50 are typically of rubber material or an inert non - toxic plastic composition . the tubular member 25 is also provided with a circular planetary gear 52 which is seated in the bore of the circular section 45 in the coaxial relation therewith . the gear 52 may be fabricated as an integral part of the tubular member 25 or it could be separately formed and bonded to the radial shoulder 47 and the inner cylindrical wall of circular section 45 by an appropriate adhesive although other fastening means could also be used . an opening 49 is also provided in the radial shoulder 47 to insure full communication of the interiors of the tubular members 25 and 26 with the suction channel 18 . when completely assembled as shown in fig3 the gear teeth of planetary gear 52 are in meshing engagement with a drive gear 53 which is mounted by a connecting adapter 54 on the end of a flexible steel cable 55 , preferably a single wire , which is inserted through the working channel 19 of the endoscope . the cable 55 extends through the working channel section 19a where it is fitted with a rotary control means such as a knob 56 for manually effecting axial rotation of the cable 55 . the adapter 54 comprises a shaft 57 enlarged at one end which is provided with a socket 58 characterized by a socket cavity of rectangular transverse cross section which receives the squared end of the cable 55 . at its other end , the shaft 57 is journalled for rotation on a transverse support 60 fitted internally of tube 25 . the shaft 57 is also fitted with a drive gear 53 which is fixed on the shaft 57 in coaxial relation thereto by a press fit or any suitable bonding means . also sleeved about the shaft 57 is a plastic spacer 59 which is in abutting engagement with the drive gear 53 and one end of the socket 58 . also shown in fig3 a retaining ring 61 is also fitted into the end of the inner tubular member 25 in coaxial relation therewith and in abutting engagement with both the rearward end of the tubular member 25 and the planetary gear 52 . the retaining ring 61 is provided in its outer surface with a circumferential groove 62 which receives the annular flange 41 of the tubular member 25 and latches the retaining ring 61 in position . in assembly of the instrument 10 the elastic ligating rings 50 must be placed onto the inner tubular member 25 before it is inserted in the outer tubular member 26 . this is also done before the tubular members 25 , 26 are fitted onto the endoscope . the elastic ligating rings 50 , when in the relaxed state are of a diameter less than that of the insertion end of the endoscope , which for representative endoscopes , is in the range of approximately 9 mm . to 13 mm . the rings 50 are placed in stretched condition onto the elongate section 44 of the tubular member 25 in side - by - side relation to one another and in sleeved relation to the section 44 . the tubular member 25 is then inserted with an axially twisting motion through the attaching end of the outer tubular member 26 whereby each elastic ring , except for the portion thereof which rests atop the planar surface of the inner tubular member 25 , is placed in a coil of the helical groove 40 in spaced relation to the adjacent elastic ring in the next adjacent coil of the helical groove . the tubular assembly , comprising tubular member 25 and 26 with tubular adapter 27 secured to the member 26 , is then sleeved onto the insertion end of the endoscope such that the planetary gear 52 and drive gear 53 are in meshed driving engagement with one another and the attaching end of the tubular member 26 abuts the insertion end of the endoscope . when treating a patient , the endoscopic instrument of the invention is first inserted into the affected organ , such as the alimentary tract , to place the insertion end of the endoscope in the vicinity of lesions in the alimentary tract . in some instances , however , it may be preferred that insertion of the instrument be preceded by the insertion of an endoscopic overtube ( not shown ) into the alimentary tract and the instrument then be inserted through the overtube . in either case , the instrument is then oriented for sighting of a target lesion , such as lesion 77 shown in fig7 and the instrument advanced under the control of a human operator until the distal end of the tubular member 25 contacts the lesion area and is placed in surrounding relation to the target lesion . a suction force is then applied through the suction channel 18 to completely draw the lesion tissue into the inner tubular member 25 as shown in fig7 . the operator then manually initiates axial rotation of the cable 55 and the inner tubular member 25 in the spirally forward direction of the helical groove 40 whereby the elastic rings 50 are driven along the surface of the tubular member 25 by the walls of the helical groove 40 until one of the elastic rings is dislodged from the instrument and placed in ligating relation about the base of the target lesion as shown in fig8 . the end of the instrument 10 is then withdrawn from around the lesion tissue , as shown in fig9 . it is to be appreciated that by continuing the axial rotation of the tubular member 25 , more of the elastic rings can be dislodged from the instrument . accordingly , the endoscopic instrument of the invention permits the successive ligation of multiple lesions during a single insertion of the instrument . with patients who are not bleeding , the ligation treatment is started at the most distal point in the alimentary tract and then continued proximally so that elastic bands which are placed about lesion tissue are not disturbed by movement of the instrument . the instrument therefore facilitates the treatment of multiple lesions and alleviates the need for repeated removal and reinsertion of the instrument and reloading of an elastic ring for treating each lesion . in some instances , particularly where vision is obscured , the instrument operator may have difficulty in ascertaining the precise amount of rotation of the flexible cable 55 that is necessary for dislodging one and only one elastic ring 50 when ligating a single target lesion . in this respect , a modified form of the invention , which enables the axial rotation of the cable 55 in steps of precise amounts , is represented by the endoscopic instrument 70 as shown in schematic form in fig1 . the instrument 70 is identical in all respects to the instrument 10 except for the means of imparting axial rotation to the flexible cable 55 and identical components are identically numbered . in lieu of a knob 56 which enables the manual rotation of the cable 55 , the instrument 70 is provided with automatic means represented by a stepping motor 72 and a controller 74 for rotation of the cable 55 in precisely controlled amounts . the controller 74 and motor 72 are connected to receive power from an electrical power source 76 . a foot pedal trigger switch 75 is used by the operator to energize the stepping motor 72 for a precise time interval during which time the flexible cable 55 is axially rotated by an amount which moves the elastic rings a precise distance along the tubular member 25 such that the most distal elastic ring 50 is forced off the end of the tubular member 25 and the remaining rings 50 are retained thereon . in effect , the precise time interval of motor operation moves the elastic rings a distance which corresponds to the distance between adjacent coils of the helical groove 40 . it is to be appreciated therefore that the endoscopic instrument 70 provides the operator with means for precisely controlling when an elastic ring 50 is dislodged from the instrument and for insuring that only one elastic ring is dislodged when ligating a target lesion . it is therefore possible for the operator to dislodge additional elastic rings in sequence and at times controlled by the operator so that multiple lesions can be ligated during a single insertion of the instrument . a further embodiment of the invention represented by the endoscopic instrument 80 is disclosed in fig1 through 15 . the endoscopic instrument 80 differs from the instruments 10 and 70 in the nature and operation of the tubular assembly which is affixed to the insertion end of the endoscope , but is otherwise identical thereto . as shown in fig1 , a rigid tube 81 is fixed in coaxial relation to the insertion end of the endoscope , preferably by a sleeve adapter 82 . a tubular textile member 83 of an inelastic material , such as the commercial product kevlar or other inelastic flexible material , is mounted onto the rigid tube 81 such that the member 83 is folded over the distal end of the tube 81 with a first portion 83a thereof being sleeved over the tube 81 and a second portion 83b thereof disposed internally of the tube 81 and substantially coaxial thereto . as shown in fig1 , a plurality of elastic ligating rings 50a are placed in stretched condition in encircling relation about the portion 83a of the tubular member 83 . the textile material of portion 83a is provided with an external surface having a plurality of annular ridges 84 in the encircling relation thereto and preferably arranged in pairs which define a plurality of uniformly spaced annular recesses or grooves 85 , each of which is adapted to receive an elastic ring 50a therein . the elastic rings 50a are therefore maintained in uniform side - by - side spacing on the tubular portion 83a . the end of the second portion 83b of the textile tubular member 83 is fitted with a rigid annular ring clamping assembly 86 to which the textile fabric of the tubular member 83 is attached . the clamping assembly 86 comprises an outer retaining ring 86a and an inner clamping ring 86b which is of a smaller external diameter than the internal diameter of the outer ring 86a and is insertable therein from the distal end of the tube 81 to clamp the portion 83b of the textile tubular member 83 therebetween . preferably , the inner wall of the outer ring 86a is formed with an annular coaxial groove 87 and the outer wall of the inner ring 86b is formed with an annular ridge 88 of conforming configuration and location such as to serve in retaining the textile member 83 therebetween . the outer ring 86a is also provided with at least three centering protuberances 90 which are in uniform angular spacing and serve to maintain the ring 86a in coaxial relation to the tube 81 and in a tight friction fit therein . as best seen in fig1 , the adapter 82 is sleeved over an annular bevel surface 89 on the attaching end of the tube 81 and is provided with an internal annular flange 91 which latches in an annular groove 92 formed about the external surface of the rigid tube 81 . at its other end , the adapter is designed for a press fit connection with the insertion end of the endoscope as provided for the adapter 27 in the embodiment of fig1 or could be provided with threads , if desired . a flexible cable 55a , similar to the cable 55 shown in the embodiment of fig1 and similarly threaded through the working channel of the endoscope is attached to an internal flange 93 on the inner wall of the clamping ring 86b . as best seen in fig1 and 12 , one end of the cable 55a is placed in an axial blind bore formed inwardly from one end of a sleeve member 94 which is swaged in engagement therewith . the sleeve member 94 which is externally threaded at its other end , is inserted through an opening in the flange 93 and secured by a nut 95 on its threaded end . it is thus to be seen that by a pull on the cable 55a to the right as shown in fig1 , the portion 83b of textile tubular member 83 which is interior of the rigid tube 81 is increased and the portion 83a which is exterior of the tube 81 is decreased . the relative movement of the flexible tube 83 with respect to the rigid tube 81 is illustrated by arrows in fig1 which show the textile tubular member 83 sliding over the distal end of the tube 81 . as this movement increases , the most distal of the elastic ligating rings 50a passes over the distal end of the tube 81 and is discharged therefrom . when the assembly of tubes 81 , 83 are placed in surrounding relation to a target lesion , and lesion tissue is drawn into the tube 83 by suction in a manner as previously described , it is to be appreciated that ligation of a lesion as shown in fig9 can be readily achieved . it is important that only a single ligating ring 50a be discharged from the instrument 80 for treating each lesion and the movement of the cable 50a must be determined accordingly . after treating one lesion , the instrument can be reoriented in surrounding relation to another lesion and the procedure repeated . accordingly , multiple lesions can be ligated during a single insertion of the instrument . for most applications , the instrument should be provided with at least six elastic rings 50a . in fig1 , the cable 55a is shown attached to a reel 96 whereby an indexed rotation thereof is designed to move the cable 55a a predetermined distance to cause the discharge of only a single ligating ring 50a . obviously , the movement could be controlled manually or other techniques employed for controlling a precise axial movement of the cable 55a . a variation in the arrangement of ridges 84 on the external surface of the textile tubular member 83 is shown in fig1 . in this modified form of the member 83 , only a single ridge 84 is used for aligning the elastic rings 50a in uniform spacing on the member 83 . the rings 50a are installed whereby each is in abutting engagement with the side of a ridge 84 which faces toward the distal end of the tubular assembly so as to prevent their being moved or disturbed as the instrument is inserted into a body organ . it is to be noted that in the embodiment of the invention disclosed in fig1 through 15 , the force required to pull the sleeve member 83 over the distal end of the tube 81 increases proportionately with the number of elastic rings , such that a strong and sturdy construction must be used for the parts mounted on the insertion end of the endoscope and the component parts for imparting sliding movement between the sleeve 83 and the tube 81 and for a precise amount of sliding to ensure that only one ring is dislodged at a time . the force to dislodge the first ring , which must be strong enough to pull the sleeve and all the elastic rings towards the distal end of the tube , is considerably greater than the force required to dislodge the last remaining elastic ring from the tube . a third embodiment of the invention represented by the endoscopic instrument 100 disclosed in fig1 through 19 requires a pulling force to dislodge an elastic ring which is comparable to that required for dislodging the last ring of the sleeve version disclosed in fig1 through 15 . as best seen in fig1 , a transparent rigid tube 101 is fitted to the insertion end of the endoscope 100 by an adapter section 102 which provides a friction fit with the insertion end of the endoscope . the endoscope 100 is provided with a plurality of flexible and substantially elastic cords 103 , each of which is folded over the distal end of the tube 101 and includes a first portion which is laid over the exterior surface of the tube and a second portion which is disposed internally of the tube . the ends of the cords 103 inside the tube are fastened to one end of a flexible line 105 as by tying thereto or the use of an adapter connector 106 . from its connection with cords 103 , the flexible line 105 is threaded through the working channel 19 of the endoscope and exits near the rearward end of the endoscope such that the exiting end portion of the line 105 may be fitted with a handle . as best seen in fig1 , the cords 103 are disposed in preferably uniform angular spacing about the longitudinal axis 107 of the tube 101 . a plurality of elastic ligating rings 50 are each placed in stretched condition in sleeved relationship about the tube 101 and in overlying relation to the plurality of cords 103 to thereby hold the cords against the tube 101 . it is to be noted in fig1 , 18 and 20 that the rings 50 are spaced from one another in the longitudinal direction of the tubular member at successsingly greater distances from the distal end 108 . each cord 103 is also provided with a series of longitudinally spaced knots 109 against each of which an elastic ring 50 is placed on the forward side of the knot . a means for imparting sliding motion between said cords and the tubular member is provided by the flexible line element 105 by which because of its connection to the ends of the cords 103 within the tubular member 101 , a pulling force may be exerted at its outer end to cause sliding movement between the cords and the tubular member so as to dislodge each of the elastic rings in desirably controlled sequence . when the pull is applied , a knot 109 acts as a shoulder which precludes relative movement between the elastic ring and the cord until the ring is dislodged at the distal end of the tubular member . as is best shown in fig1 , each cord 103 includes a segment of cord between each pair of adjacent elastic rings which is in slack condition and of a length which is equal to the distance between said pair plus the distance from the distal end of the tube 101 to the ring of the pair which is nearest the distal end 108 . it will therefore be seen that when the cords are pulled a distance which moves the forward ring of the pair to the distal end of the tube and off the tube , the slack length of cord suffices to preclude any movement of the remaining elastic rings . it is therefore to be noted that the required pulling force to dislodge a ring is that which is necessary to move a single ring and the required force does not increase as additional rings are dislodged . after the cords 103 and elastic rings 50 have been loaded on the rigid tube 101 and positioned thereon as shown in fig1 and 18 , it may be a desirable option to place a flexible sleeve of plastic or a textile materal to fit loosely over the cords 103 and the tube 101 . such a sleeve , when attached at one end to the flexible section 12 of the endoscope and extending over the cords 103 and elastic rings 50 to approximately the distal end of the tube 101 , would serve to protect against &# 34 ; snagging &# 34 ; of the slack segments or loop of cords between the rings when the endoscope is in use or prepared for use . it is to be understood that the foregoing descriptions of a preferred embodiment of the invention has been presented for purposes of illustration and explanation and are not intended to limit the invention to the precise forms disclosed . for example , a motor control could be provided for controlling the movement of the cable 55a in precise steps . also , the number of elastic ligating rings 50 or 50a could be greater or less than those illustrated herein . in some instances the rings 50a can be aligned on the textile tubular member 83 without ridges 84 . it is to be appreciated therefore , that various material and structural changes may be made by those skilled in the art without departing from the spirit of the invention . | US-26038094-A |
a system for managing the food intake of a person comprises means for collecting information about food consumed by the subject , and means for providing feedback to the subject regarding the food consumed . it further comprises a sensor for obtaining a signal related to the person and monitoring means for generating the information by performing a pattern recognition of the obtained signal for detecting whether the person is consuming food . the sensor comprises a camera and the pattern recognition comprises image processing . the image processing comprises the detection of a mouth and of a hand and of food . the system further comprises means for causing an audio / video - rendering device to deliver the feedback . the camera is attached to the rendering device . the system further comprises means for identifying available rendering devices arranged for being caused to deliver feedback . | fig1 shows a schematic diagram of an embodiment of the present invention . it shows a microprocessor 51 , a memory 52 , receiving means 54 , and transmitting means 53 . the microprocessor 51 performs instructions stored in the memory 52 . it communicates with a sensor device 57 , such as a camera , and with a modality 56 capable of presenting a multimedia presentation , such as for example a television , using the receiving means 54 and transmitting means 53 . advantageously , the receiving means 54 and transmitting means 53 are implemented using at least one communication standard such as usb , firewire , ethernet , or the wlan standard ieee 802 . 11 . using such communication standards allows the system to work with many different modalities 56 , including different brands of television and different types of cameras . advantageously , the communication means 53 / 54 also include video and audio communication means such as scart or coax . the communication means 53 / 54 can also communicate eating patterns to a separate unit 55 , for example a dedicated device , or a personal computer running suitable software . such a device or personal computer may be used to display graphical or textual reports of the progress made in reducing the undesirable eating behavior . the memory 52 is used to store instructions for making the processor 51 perform the inventive method . the memory 52 is also used to store the data needed for creating the reports of the progress made in reducing the undesirable eating behavior . fig2 shows a schematic diagram of an embodiment of the present invention . the method is started in step 1 when the subject has started a primary sedentary activity , such as watching a movie or reading a book , or for example a standing activity . in step 2 , data from the monitoring devices are collected . the data can include images from a camera . the data can also include a signal from a motion sensor or for example accelerometer data collected by an accelerometer attached to for example the subject &# 39 ; s wrist , or signals from two accelerometers , one attached to each wrist . in step 3 , the data are analyzed for features correlated with a limited moving pattern . a limited moving pattern can indicate that the subject is watching a multimedia presentation . a limited moving pattern can also indicate that the subject is picking up food from a nearby table and consuming the food . if a limited moving pattern is found in step 4 , the next step is to detect the presence of , possibly unhealthy , food in step 5 . unhealthy drinks such as beer or soda with sugar are also detected . many different means can be used to detect the presence of food . for example , image processing of camera images may be used to detect the food itself or the packaging of the food . alternatively , the packaging of the food may comprise detection means , such as a bar code or an rfid chip , allowing easy detection of the food on the table . in another embodiment , the food may be detected at the time it is retrieved from the cupboard or from the refrigerator , or the packaging may be arranged to transmit a signal that is received by the receiving means 54 when a package is opened by the user . alternatively , a more accurate analysis of the limited moving pattern may be used . if an accelerometer is attached to the wrist , the accelerometer patterns correlated with picking up food from the table and bringing the food into the mouth are detected and distinguished from random movements not related to eating and drinking . preferably , multiple types of analysis are combined to achieve the greatest degree of reliability . if both a limited moving pattern and unhealthy food are detected ( steps 4 and 5 ), the system can provide feedback to the user about the undesired behavior in step 7 . for example , the system can provide the feedback immediately upon detecting the undesired behavior , or it can provide the feedback only when the undesired behavior continues for a predetermined period . the preferred timing and the type of feedback depends on several factors , including the condition of the subject , his or her preferred diet , and his or her motivation to stop the undesired behavior . for example , if the subject is very obese and has a high degree of motivation to stop the undesired behavior , it is preferable to provide the feedback immediately upon detection of undesired behavior . if the subject is not motivated to stop snacking completely , but only wants to avoid eating continuously the whole evening , it is preferable to provide the feedback only after the undesired behavior has been detected for predetermined time duration . the system may also use the memory 52 to store the cumulative time the subject has been eating during a day , so that the system will only provide feedback when a predetermined daily limit has been exceeded . preferably , the feedback is presented in a way that has the greatest motivating effect on the long term . this is realized by feedback that is not irritating for the user . for example , a tone , a text message , or a voice message can be used . advantageously , animated feedback can be used . the animation can involve a multi - media puppet . the animated puppet becomes gradually thicker indicating to the user that the snacking behavior will lead to weight gain . for multiple users involved in the sedentary activity , multiple puppets can appear on the screen animated with different images , or even personalized with the faces of the different users . the system can mirror the eating and activity habits of the individuals in the group by proper animation of the multiple puppets . more multimedia tools can be utilized such as speech , ring tones and text prompts . feedback can also be presented , for example , related to collected food intake information during a predefined period of time . for example , an animated puppet can be rendered that gradually collects animated foods representing foods consumed during the predefined period on an animated table . confronting the users with a visual picture of total quantities and types of nutrients consumed has a profound effect over their awareness and is a step towards changing eating habits . the puppet can replace the unhealthy nutrients , for example food with a relatively high amount of saturated fat , salt and / or sugar , by healthy nutrients like fruits and vegetables , thereby educating the user about healthy meal decisions . advantageously , a tool kit comprising for example fruit and / or vegetable shaped objects of which , for example , the size , shape , or color can be controlled , is used to make the objects reflect the user &# 39 ; s compliance to a healthy food intake pattern . the objects can be animated objects or real touchable objects comprising , for example , plastic material or textile . for example , if the user has an unhealthy food intake pattern the objects will be small and wrinkled , and if the user has a healthy food intake pattern , the objects will be large , and their shape and color will represent fruits or vegetables in good condition to be eaten . other object shapes such as flower - shaped objects can also be used in a similar fashion . if a limited moving pattern has been recognized in step 4 , but no unhealthy food or drinks have been detected in step 5 , and the limited moving pattern continues to be recognized for a predetermined time duration , the system proceeds to step 6 , in which the subject is provided feedback about the need to engage in physical activity . this feedback may be provided in a way similar as in step 7 . for example , an animated puppet can be shown from time to time that performs exercises to give some examples to the sedentary user of ways to achieve a sufficient level of activity . in case the users are children , for example detected automatically by detecting a children &# 39 ; s tv program or a children &# 39 ; s tv channel , the puppet can act as a kid &# 39 ; s watcher that prompts the children to move from the sedentary activity to an active play after a children &# 39 ; s tv program has finished . in step 8 , the system checks whether the subject is still performing the primary activity , and if so , the system continues at step 2 . alternatively , the system can continue monitoring the moving patterns of the subject independently of the primary activity . in another embodiment , if a limited moving pattern is not detected in step 4 , the system checks whether a non - moving pattern is detected in step 10 , and if so , a timer is set in step 11 . the non - moving pattern is associated with inactivity of the user for a period of time . detecting this pattern is indicative for a user fallen asleep or a user with deteriorating health conditions . correspondingly , the system can react by adapting the multimedia presentation or generating an alarm as follows . in step 12 it is checked if a non - moving pattern has been detected for longer than a predetermined period x , and if so , in step 13 the multimedia presentation is stopped by switching off the video source and / or the display , and control is taken of the audio source . alternatively , the multimedia presentation is adapted to a sleeping condition of the subject , for example by lowering the volume or switching off or lowering a light source . in step 14 it is checked if the non - moving pattern is detected for a longer predetermined period x + y . in that case , in step 15 the audio source is used to produce a sound , for example a ring tone , in order to wake up the subject . alternatively , another signal may be produced such as executing a multimedia presentation , increasing the volume , or turning on the light . other ways to wake up the subject are obvious to the person skilled in the art . moreover , the system may be arranged to produce a wake - up signal only at predetermined times , for example only at the time the subject should go to bed at night , or for example only at the time the subject should wake up in the morning . if the subject wakes up , this is detected , for example , as a limited moving pattern in step 16 , and the method continues from step 2 . if a limited moving pattern is still not detected in step 16 after producing the ring tone , a warning message can be produced in step 17 in the form of , for example , a louder sound , an sms , a voice mail message , or by causing any predetermined device to produce an alarm , such that another subject is warned about the condition of the first , monitored , subject . a preferred embodiment is shown in fig3 . the available feedback modalities are discovered in step 101 , for example through at least one upnp / dlna standardized “ discovery ” mechanism . in step 102 , currently active modalities are identified , for example using at least one upnp / dlna standardized “ control ” mechanism to query the status of a modality , and optionally using content analysis techniques to detect which modalities are most perceptible by the user . in step 103 , a number of modalities are selected to be used for generating the feedback message . the selection criteria can include the capabilities of individual modalities , such as video and / or audio generation , and the presence of the possibility to cause the modality to reproduce the feedback message . in step 104 , a feedback - option is selected from a list of possible feedback - options , preferably sorted according to appropriateness , and the feedback - message is digitally enhanced to best match the primary activity , for example , the sound level is increased or the timing of the feedback is adapted such that it coincides with a period of low noise of the primary activity . finally , in step 105 , the feedback is added to the selected modality for example using overlay techniques in combination with an already active modality , or for example using a previously inactive modality . such overlay techniques are known to the skilled artisan . the feedback can be provided by replacing the image associated with the multimedia presentation with an image associated with the feedback , or by overlaying the image associated with the feedback on top of the image associated with the multimedia presentation . the feedback can be provided in the form of a text message . it can also be provided by means of a multimedia presentation such as for example an animated and / or pre - recorded video message or an audio message . a sensor capable of detecting a non - moving pattern of the subject and generating data relating to the detected non - moving pattern , and means for causing a modality arranged for executing a multimedia presentation to adapt the multimedia presentation in dependence on the data relating to the detected non - moving pattern . this aspect of the invention allows the invention to be used as a safety mechanism . a non - moving pattern can be related to for example a sleeping condition or a deteriorating health condition . in case of sleeping , it is appropriate to adapt the multimedia presentation to the sleeping condition , for example by reducing the volume . in case the modality also controls a light source , the system may for example be arranged to switch off the light after detecting a non - moving pattern . according to another aspect of the invention , the means for causing the modality to adapt the multimedia presentation comprises means to stop the multimedia presentation . in case of a sleeping condition or a deteriorating health condition , it may be helpful to stop the multimedia presentation . according to another aspect of the invention , it further comprises means for generating a sound in dependence on the data relating to the detected non - moving pattern . in case of a sleeping condition , it may be helpful to generate an alarm to wake up the subject . in case of a deteriorating health condition , it may be helpful to generate an alarm to let one or more other people know about the condition of the subject . according to another aspect of the invention , it further comprises means for causing a device to generate an audible signal or a visible signal in dependence on the data relating to the detected non - moving pattern . for example , in case of a deteriorating health condition , it may be helpful to generate a signal using a device in the vicinity of one or more other people , to let the other people know about the condition of the subject . for example , the device can be in the same room as the subject , but advantageously it also works with the device in another room or further away , for example more than a kilometer away , from the subject . it will be appreciated that the invention also extends to computer programs , particularly computer programs on or in a carrier , adapted for putting the invention into practice . the program may be in the form of source code , object code , a code intermediate source and object code such as partially compiled form , or in any other form suitable for use in the implementation of the method according to the invention . the carrier may be any entity or device capable of carrying the program . for example , the carrier may include a storage medium , such as a rom , for example a cd rom or a semiconductor rom , or a magnetic recording medium , for example a floppy disc or hard disk . further the carrier may be a transmissible carrier such as an electrical or optical signal , which may be conveyed via electrical or optical cable or by radio or other means . when the program is embodied in such a signal , the carrier may be constituted by such cable or other device or means . alternatively , the carrier may be an integrated circuit in which the program is embedded , the integrated circuit being adapted for performing , or for use in the performance of , the relevant method . it should be noted that the above - mentioned embodiments illustrate rather than limit the invention , and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims . in the claims , any reference signs placed between parentheses shall not be construed as limiting the claim . use of the verb “ comprise ” and its conjugations does not exclude the presence of elements or steps other than those stated in a claim . the article “ a ” or “ an ” preceding an element does not exclude the presence of a plurality of such elements . the invention may be implemented by means of hardware comprising several distinct elements , and by means of a suitably programmed computer . in the device claim enumerating several means , several of these means may be embodied by one and the same item of hardware . the mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage . | US-9712406-A |
a specific clinical protocol for use toward therapy of defective , diseased and damaged neurons in the mammalian brain , of particular usefulness for treatment of neurodegenerative conditions such as parkinson &# 39 ; s disease and alzheimer &# 39 ; s disease . the protocol is practiced by directly delivering a definite concentration of recombinant neurotrophin , into a targeted region of the brain using an expression vector . the neurotrophin is delivered to , or within close proximity of , identified defective , diseased or damaged brain cells . the method stimulates growth of targeted neurons , and reversal of functional deficits associated with the neurodegenerative disease being treated . | i . target tissues for treatment of neurodegenerative disorders according to the invention the invention identifies and defines the required parameters of a method for successful regeneration of neurons in the brain with neurotrophins , especially the neurons whose loss is associated with neurodegenerative conditions with impairment of cognition such as ad . the first method parameter defined by the invention is selection of a suitable target tissue . a region of the brain is selected for its retained responsiveness to neurotrophic factors . in humans , cns neurons which retain responsiveness to neurotrophic factors into adulthood include the cholinergic basal forebrain neurons , dopaminergic neurons of the substantia nigra , the entorhinal cortical neurons , the thalamic neurons , the locus coeruleus neurons , the spinal sensory neurons and the spinal motor neurons . in normal subjects , neurotrophins prevent sympathetic and sensory neuronal death during development and prevents cholinergic neuronal degeneration in adult rats and primates ( tuszynski , et al ., gene therapy , 3 : 305 - 314 ( 1996 )). the resulting loss of functioning neurons in this region of the basal forebrain is believed to be causatively linked to the cognitive decline experienced by subjects suffering from neurodegenerative conditions such as ad . similarly , loss of functionality in dopaminergic neurons of the substantia nigra is causatively associated with the onset of pd . treatment of the targeted region of the brain with vector composition at upwards of 10 separate in vivo gene vector delivery sites is desirable . importantly , specific gene delivery sites are selected so as to cluster in an area of neuronal loss . such areas may be identified clinically using a number of known techniques , including magnetic resonance imaging ( mri ) and biopsy . in humans , non - invasive , in vivo imaging methods such as mri will be preferred . once areas of neuronal loss are identified , delivery sites are selected for stereotaxic distribution so each unit dosage of ngf is delivered into the brain at , or within 500 μm from , a targeted cell , and no more than about 10 mm from another delivery site . materials useful in the methods of the invention include in vivo compatible recombinant expression vectors , packaging cell lines , helper cell lines , synthetic in vivo gene therapy vectors , regulatable gene expression systems , encapsulation materials , pharmaceutically acceptable carriers and polynucleotides coding for nervous system growth factors of interest . known nervous system growth factors include nerve growth factor ( ngf ), brain - derived neurotrophic factor ( bdnf ), neurotrophin - 3 ( nt - 3 ), neurotrophin - 4 / 5 ( nt - 4 / 5 ), neurotrophin - 6 ( nt - 6 ), ciliary neurotrophic factor ( cntf ), glial cell line - derived neurotrophic factor ( gdnf ), the fibroblast growth factor family ( fgf &# 39 ; s 1 - 15 ), leukemia inhibitory factor ( lif ), certain members of the insulin - like growth factor family ( e . g ., igf - 1 ), the neurturins , persephin , the bone morphogenic proteins ( bmps ), the immunophilins , the transforming growth factor ( tgf ) family of growth factors , the neuregulins , epidermal growth factor ( egf ), platelet - derived growth factor ( pdgf ), and others . ngf and nt - 3 in particular have been tested with promising results in clinical trials and animal studies ( see , e . g ., hefti and weiner , ann neurol ., 20 : 275 - 281 ( 1986 ); tuszynki and gage , ann . neurol ., 30 : 625 - 636 ( 1991 ); tuszynski , et al ., gene therapy , 3 : 305 - 314 ( 1996 ) and blesch and tuszynski , clin . neurosci ., 3 : 268 - 274 ( 1996 )). of the known nervous system growth factors , ngf and nt - 3 ( for treatment of the ch4 region , as in ad ) are preferred for use in the invention . human neurotrophins are preferred for use in therapy of human disease according to the invention due to their relatively low immunogenicity as compared to allogenic growth factors . however , other nervous system growth factors are known which may also be suitable for use in the invention with adequate testing of the kind described herein . coding polynucleotides for a number of human neurotrophins are known , as are coding sequences for neurotrophins of other mammalian species ( e . g ., mouse , in which the coding sequence for ngf is highly homologous to the human coding sequence ). for example , the coding sequence for hngf is reported in genbank at e03015 ( kazuo , et al ., japanese patent application no . jp19911175976 - a ); for gdnf is reported in genbank at l190262 and l19063 ; genomic hngf ( with putative amino acid sequence ) is reported in genbank at hsbngf ( ullrich , nature , 303 : 821 - 825 ( 1983 )); the hngf mrna sequence is reported in genbank at hsbngfac ( borsani , et al ., nucleic acids res ., 18 : 4020 ( 1990 ); and the genomic nucleotide sequence of hnt3 is reported in genbank at e07844 ( asae , et al ., jp patent application no . 1993189770 - a4 ). these references are incorporated herein to illustrate knowledge in the art concerning nucleotide and amino acid sequences for use in synthesis of neurotrophins . the strategy for transferring genes into target cells in vivo includes the following basic steps : ( 1 ) selection of an appropriate transgene or transgenes whose expression is correlated with cns disease or dysfunction ; ( 2 ) selection and development of suitable and efficient vectors for gene transfer ; ( 3 ) demonstration that in vivo transduction of target cells and transgene expression occurs stably and efficiently ; ( 4 ) demonstration that the in vivo gene therapy procedure causes no serious deleterious effects ; and ( 5 ) demonstration of a desired phenotypic effect in the host animal . although other vectors may be used , preferred vectors for use in the methods of the present invention are viral and non - viral vectors . the vector selected should meet the following criteria : 1 ) the vector must be able to infect targeted cells and thus viral vectors having an appropriate host range must be selected ; 2 ) the transferred gene should be capable of persisting and being expressed in a cell for an extended period of time ( without causing cell death ) for stable maintenance and expression in the cell ; and 3 ) the vector should do little , if any , damage to target cells . because adult mammalian brain cells are non - dividing , the recombinant expression vector chosen must be able to transfect and be expressed in non - dividing cells . at present , vectors known to have this capability include dna viruses such as adenoviruses , adeno - associated virus ( aav ), and certain rna viruses such as hiv - based lentiviruses , feline immunodeficiency virus ( fiv ) and equine immunodeficiency virus ( eiv . other vectors with this capability include herpes simplex virus ( hsv ). however , some of these viruses ( e . g ., aav and hsv ) can produce toxicity and / or immunogenicity . recently , an hiv - based lentiviral vector system has recently been developed which , like other retroviruses , can insert a transgene into the nucleus of host cells ( enhancing the stability of expression ) but , unlike other retroviruses , can make the insertion into the nucleus of non - dividing cells . lentiviral vectors have been shown to stably transfect brain cells after direct injection , and stably express a foreign transgene without detectable pathogenesis from viral proteins ( see , naldini , et al ., science , 272 : 263 - 267 ( 1996 ), the disclosure of which is incorporated by reference ). following the teachings of the researchers who first constructed the hiv - 1 retroviral vector , those of ordinary skill in the art will be able to construct lentiviral vectors suitable for use in the methods of the invention ( for more general reference concerning retrovirus construction , see , e . g ., kriegler , gene transfer and expression , a laboratory manual , w . freeman co . ( ny 1990 ) and murray , e j , ed ., methods in molecular biology , vol . 7 , humana press ( nj 1991 )). construction of vectors for recombinant expression of nervous system growth factors for use in the invention may be accomplished using conventional techniques which do not require detailed explanation to one of ordinary skill in the art . specifics for construction of an hiv - 1 lentiviral vector are set forth in example i . for further review , those of ordinary skill may wish to consult maniatis et al ., in molecular cloning : a laboratory manual , cold spring harbor laboratory , ( ny 1982 ). briefly , construction of recombinant expression vectors employs standard ligation techniques . for analysis to confirm correct sequences in vectors constructed , the ligation mixtures may be used to transform a host cell and successful transformants selected by antibiotic resistance where appropriate . vectors from the transformants are prepared , analyzed by restriction and / or sequenced by , for example , the method of messing , et al ., ( nucleic acids res ., 9 : 309 , 1981 ), the method of maxam , et al ., ( methods in enzymology , 65 : 499 , 1980 ), or other suitable methods which will be known to those skilled in the art . size separation of cleaved fragments is performed using conventional gel electrophoresis as described , for example , by maniatis , et al ., ( molecular cloning , pp . 133 - 134 , 1982 ). expression of a gene is controlled at the transcription , translation or post - translation levels . transcription initiation is an early and critical event in gene expression . this depends on the promoter and enhancer sequences and is influenced by specific cellular factors that interact with these sequences . the transcriptional unit of many prokaryotic genes consists of the promoter and in some cases enhancer or regulator elements ( banerji et al ., cell 27 : 299 ( 1981 ); corden et al ., science 209 : 1406 ( 1980 ); and breathnach and chambon , ann . rev . biochem . 50 : 349 ( 1981 )). for retroviruses , control elements involved in the replication of the retroviral genome reside in the long terminal repeat ( ltr ) ( weiss et al ., eds ., the molecular biology of tumor viruses : rna tumor viruses , cold spring harbor laboratory , ( ny 1982 )). moloney murine leukemia virus ( mlv ) and rous sarcoma virus ( rsv ) ltrs contain promoter and enhancer sequences ( jolly et al ., nucleic acids res . 11 : 1855 ( 1983 ); capecchi et al ., in : enhancer and eukaryotic gene expression , gulzman and shenk , eds ., pp . 101 - 102 , cold spring harbor laboratories ( ny 1991 ). other potent promoters include those derived from cytomegalovirus ( cmv ) and other wild - type viral promoters . promoter and enhancer regions of a number of non - viral promoters have also been described ( schmidt et al ., nature 314 : 285 ( 1985 ); rossi and de crombrugghe , proc . natl . acad . sci . usa 84 : 5590 - 5594 ( 1987 )). methods for maintaining and increasing expression of transgenes in quiescent cells include the use of promoters including collagen type i ( 1 and 2 ) ( prockop and kivirikko , n . eng . j . med . 311 : 376 ( 1984 ); smith and niles , biochem . 19 : 1820 ( 1980 ); de wet et al ., j . biol . chem ., 258 : 14385 ( 1983 )), sv40 and ltr promoters . in addition to using viral and non - viral promoters to drive transgene expression , an enhancer sequence may be used to increase the level of transgene expression . enhancers can increase the transcriptional activity not only of their native gene but also of some foreign genes ( armelor , proc . natl . acad . sci . usa 70 : 2702 ( 1973 )). for example , in the present invention collagen enhancer sequences are used with the collagen promoter 2 ( i ) to increase transgene expression . in addition , the enhancer element found in sv40 viruses may be used to increase transgene expression . this enhancer sequence consists of a 72 base pair repeat as described by gruss et al ., proc . natl . acad . sci . usa 78 : 943 ( 1981 ); benoist and chambon , nature 290 : 304 ( 1981 ), and fromm and berg , j . mol . appl . genetics , 1 : 457 ( 1982 ), all of which are incorporated by reference herein . this repeat sequence can increase the transcription of many different viral and cellular genes when it is present in series with various promoters ( moreau et al ., nucleic acids res . 9 : 6047 ( 1981 ). transgene expression may also be increased for long term stable expression using cytokines to modulate promoter activity . several cytokines have been reported to modulate the expression of transgene from collagen 2 ( i ) and ltr promoters ( chua et al ., connective tissue res ., 25 : 161 - 170 ( 1990 ); elias et al ., annals n . y . acad . sci ., 580 : 233 - 244 ( 1990 )); seliger et al ., j . immunol . 141 : 2138 - 2144 ( 1988 ) and seliger et al ., j . virology 62 : 619 - 621 ( 1988 )). for example , transforming growth factor ( tgf ), interleukin ( il )- 1 , and interferon ( inf ) down regulate the expression of transgenes driven by various promoters such as ltr . tumor necrosis factor ( tnf ) and tgf1 up regulate , and may be used to control , expression of transgenes driven by a promoter . other cytokines that may prove useful include basic fibroblast growth factor ( bfgf ) and epidermal growth factor ( egf ). collagen promoter with the collagen enhancer sequence ( coll ( e )) can also be used to increase transgene expression by suppressing further any immune response to the vector which may be generated in a treated brain notwithstanding its immune - protected status . in addition , anti - inflammatory agents including steroids , for example dexamethasone , may be administered to the treated host immediately after vector composition delivery and continued , preferably , until any cytokine - mediated inflammatory response subsides . an immunosuppression agent such as cyclosporin may also be administered to reduce the production of interferons , which downregulates ltr promoter and coll ( e ) promoter - enhancer , and reduces transgene expression . to form a neurotrophic composition for use in the invention , neurotrophin encoding expression vectors ( including , without limitation , viral and non - viral vectors ) may be placed into a pharmaceutically acceptable suspension , solution or emulsion . suitable mediums include saline and liposomal preparations . more specifically , pharmaceutically acceptable carriers may include sterile aqueous of non - aqueous solutions , suspensions , and emulsions . examples of non - aqueous solvents are propylene glycol , polyethylene glycol , vegetable oils such as olive oil , and injectable organic esters such as ethyl oleate . aqueous carriers include water , alcoholic / aqueous solutions , emulsions or suspensions , including saline and buffered media . parenteral vehicles include sodium chloride solution , ringer &# 39 ; s dextrose , dextrose and sodium chloride , lactated ringer &# 39 ; s or fixed oils . intravenous vehicles include fluid and nutrient replenishers , electrolyte replenishers ( such as those based on ringer &# 39 ; s dextrose ), and the like . preservatives and other additives may also be present such as , for example , antimicrobials , antioxidants , chelating agents , and inert gases and the like . further , a composition of neurotrophin transgenes may be lyophilized using means well known in the art , for subsequent reconstitution and use according to the invention . a colloidal dispersion system may also be used for targeted gene delivery . colloidal dispersion systems include macromolecule complexes , nanocapsules , microspheres , beads , and lipid - based systems including oil - in - water emulsions , micelles , mixed micelles , and liposomes . liposomes are artificial membrane vesicles which are useful as delivery vehicles in vitro and in vivo . it has been shown that large unilamellar vesicles ( luv ), which range in size from 0 . 2 - 4 . 0 μm can encapsulate a substantial percentage of an aqueous buffer containing large macro molecules . rna , dna and intact virions can be encapsulated within the aqueous interior and be delivered to cells in a biologically active form ( fraley , et al ., trends biochem . sci ., 6 : 77 , 1981 ). in addition to mammalian cells , liposomes have been used for delivery of operatively encoding transgenes in plant , yeast and bacterial cells . in order for a liposome to be an efficient gene transfer vehicle , the following characteristics should be present : ( 1 ) encapsulation of the genes encoding the antisense polynucleotides at high efficiency while not compromising their biological activity ; ( 2 ) preferential and substantial binding to a target cell in comparison to non - target cells ; ( 3 ) delivery of the aqueous contents of the vesicle to the target cell cytoplasm at high efficiency ; and ( 4 ) accurate and effective expression of genetic information ( mannino , et al ., biotechniques , 6 : 682 , 1988 ). the composition of the liposome is usually a combination of phospholipids , particularly high - phase - transition - temperature phospholipids , usually in combination with steroids , especially cholesterol . other phospholipids or other lipids may also be used . the physical characteristics of liposomes depend on ph , ionic strength , and the presence of divalent cations . examples of lipids useful in liposome production include phosphatidyl compounds , such as phosphatidylglycerol , phosphatidylcholine , phosphatidylserine , phosphatidylethanolamine , sphingolipids , cerebrosides , and gangliosides . particularly useful are diacylphosphatidylglycerols , where the lipid moiety contains from 14 - 18 carbon atoms , particularly from 16 - 18 carbon atoms , and is saturated . illustrative phospholipids include egg phosphatidylcholine , dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine . the targeting of liposomes can be classified based on anatomical and mechanistic factors . anatomical classification is based on the level of selectivity , for example , organ - specific , cell - specific , and organelle - specific . mechanistic targeting can be distinguished based upon whether it is passive or active . passive targeting utilizes the natural tendency of liposomes to distribute to cells of the reticulo - endothelial system ( res ) in organs which contain sinusoidal capillaries . active targeting , on the other hand , involves alteration of the liposome by coupling the liposome to a specific ligand such as a monoclonal antibody , sugar , glycolipid , or protein , or by changing the composition or size of the liposome in order to achieve targeting to organs and cell types other than the naturally occurring sites of localization . the surface of the targeted gene delivery system may be modified in a variety of ways . in the case of a liposomal targeted delivery system , lipid groups can be incorporated into the lipid bilayer of the liposome in order to maintain the targeting ligand in stable association with the liposomal bilayer . various linking groups can be used for joining the lipid chains to the targeting ligand . following the protocol defined by the invention , direct delivery of a neurotrophic composition may be achieved by means familiar to those of skill in the art , including microinjection through a surgical incision ( see , e . g ., capecchi , cell , 22 : 479 - 488 ( 1980 )); electropotation ( see , e . g ., andreason and evans , biotechniques , 6 : 650 - 660 ( 1988 )); infusion , chemical complexation with a targeting molecule or co - precipitant ( e . g ., liposome , calcium ), and microparticle bombardment of the target tissue ( tang , et al ., nature , 356 : 152 - 154 ( 1992 )). as used in this disclosure , “ unit dosage ” refers generally to the concentration of neurotrophin / ml of neurotrophic composition . for viral vectors , the neurotrophin concentration is defined by the number of viral particles / ml of neurotrophic composition . optimally , for delivery of neurotrophin using a viral expression vector , each unit dosage of neurotrophin will comprise 2 . 5 to 25 μl of a neurotrophic composition , wherein the composition includes a viral expression vector in a pharmaceutically acceptable fluid and provides from 10 10 up to 10 15 expressing viral particles per ml of neurotrophic composition . the neurotrophic composition is delivered to each delivery cell site in the target tissue by microinjection , infusion , scrape loading , electroporation or other means suitable to directly deliver the composition directly into the delivery site tissue through a surgical sincision . the delivery is accomplished slowly , such as over a period of about 5 - 10 minutes ( depending on the total volume of neurotrophic composition to be delivered ). those of skill in the art will appreciate that the direct delivery method employed by the invention obviates a limiting risk factor associated with in vivo gene therapy ; to wit , the potential for transfection of non - targeted cells with the vector carrying the ngf encoding transgene . in the invention , delivery is direct and the delivery sites are chosen so diffusion of secreted ngf takes place over a controlled and predetermined region of the brain to optimize contact with targeted neurons , while minimizing contact with non - targeted cells . startlingly , in primates , viral vectors with an operable neurotrophin encoding transgene have been shown to express human neurotrophin after delivery to the brain and to the cns for up to 12 months ( example viii ). as such , the invention provides a chronically available source for neurotrophin in the brain . in non - human primate subjects , the process of aging simulates the neurological changes in the brain experienced in aging humans ( example ii ). an non - aged animal model that models parkinson &# 39 ; s disease with a high degree of integrity is 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 - tetrahydropyridine ( mptp ) treated monkeys ( see , e . g ., kordower , et al ., exp . neurology , 160 : 1 - 16 ( 1999 ). such treatment results in extensive degeneration of dopaminergic neurons in the substantia nigra , with concomitant behavioral modification and motor deficits ( example v ). data demonstrating the use and efficacy of the method of the invention in aged non - human primates is provided in examples iii and iv ; and , in mptp treated animals , in examples v and vi . the absence of lentiviral immunogenicity in treated animals is confirmed in example vii . clinical evaluation and monitoring of treatment can be performed using the in vivo imaging techniques described above as well as through biopsy and histological analysis of treated tissue . in the latter respect , neuronal numbers can be quantified in a tissue sample with respect to , for example , th immunoreactivity , anti - neurotrophin antibody ( for immunoassay of secreted neurotrophin ) or ngf - receptor ( p75 ), and choline acetyltransferase ( chat ) for labeling of neurons . a sample protocol for in vitro histological analysis of treated and control tissue samples is described in the example ii . the invention having been fully described , examples illustrating its practice are set forth below . these examples should not , however , be considered to limit the scope of the invention , which is defined by the appended claims . those of ordinary skill in the art will appreciate that while the examples illustrate an ex vivo application of the invention , the results achieved will be accessible through in vivo delivery of the nervous system growth factor encoding transgenes described , as taught herein , with in vivo gene delivery sites and direct delivery means substituted for the grafting sites and grafting methods discussed in the examples . in the examples , the abbreviation “ min .” refers to minutes , “ hrs ” and “ h ” refer to hours , and measurement units ( such as “ ml ”) are referred to by standard abbreviations . all printed materials cited are incorporated herein by reference . the cdna coding for a nuclear - localized β - galactosidase ( lacz ) and the human gdnf containing a kozak consensus sequence ( a 636 - bp fragment : position 1 to 151 and 1 to 485 ; genbank accession numbers l19062 and l19063 ) were cloned in the sin - w - pgk transfer vector ( r . zufferey , et al ., j . virol . 73 , 2886 ( 1999 ), incorporated herein by reference ). the packaging construct and vesicular stomatis virus g protein ( vsv - g ) envelope used in this study were the pcmvdr8 . 92 , prsv - rev , and the pmd . 6 plasmids described previously ( see , r . zufferey , d . nagy , r . j . mandel , l . naldini , d . trono , nature biotechnol . 15 , 871 ( 1997 ); a . f . hottinger , m . azzouz , n . déglon , p . gebischer , a . d . zurn , j . neurosci . 20 , 5587 ( 2000 ), incorporated herein by reference ). the viral particles were produced in 293t cells as previously described . the titers ( 3 to 5 × 108 tu / ml ) of the concentrated lacz - expressing viruses ( 200 , 000 and 250 , 000 ng p24 / ml in experiment 1 and 450 , 000 ng p24 / ml in experiment 2 ) were determined on 293t cells . the gdnf - expressing viral stocks were normalized for viral particles content using p24 antigen measurement . transgene expression and anterograde transport of gdnf expression product within the aged primate brain non - lesioned aged monkeys that model pd like neurodegeneration ( 17 ) display a slow progressive loss of dopamine within the striatum and tyrosine hydroxylase ( th ) within the substantia nigra without frank cellular degeneration . eight aged ( approximately 25 years old ) female rhesus monkeys received injections of lentiviral vectors encoding galactosidase ( lenti - gal ; n = 4 ) or gdnf ( lenti - gdnf ; n = 4 ) targeted for the striatum and substantia nigra and were killed 3 months later . under mri guidance , each monkey received six stereotaxic injections of lenti - gal or lenti - gdnf bilaterally into the caudate nucleus , putamen , and substantia nigra . injections were made into the head of the caudate nucleus ( 10 μl ), body of the caudate nucleus ( 5 μl ), anterior putamen ( 10 μl ), commissural putamen ( 10 μl ), postcommissural putamen ( 5 μl ), and substantia nigra ( 5 μl ). injections were made through a 10 - μl hamilton syringe connected to a pump at a rate of 0 . 5 μl / min . during the injection , the needle was raised 1 to 2 mm to better disperse the lentivirus through the intended target . the needle was left in place for an additional 3 min to allow the injectate to diffuse from the needle tip . the left side was injected 6 weeks before the right . during the first surgical session , there was a technical failure with the virus aggregating in the needle , which prevented its injection into the brain . this was confirmed at postmortem examination using gdnf - immunohistochemistry and gal histochemistry . thus , the left side served as an additional control for the right side . postmortem , all gdnf injections were localized to the caudate nucleus , putamen , and supranigral regions , as revealed by standard staining procedures . all aged monkeys receiving lenti - gdnf displayed robust gdnf immunoreactivity within the right striatum ( fig1 a ) and substantia nigra ( fig1 c ). in contrast , no monkeys receiving lenti - gal displayed specific gdnf immunoreactivity in the right striatum ( fig1 b ). rather , these monkeys displayed robust expression of gal similar to that reported previously . in lenti - gdnf - treated animals , gdnf immunoreactivity within the striatum was extremely dense and distributed throughout the neuropil ( fig1 ). when the primary antibody concentration was decreased to one - tenth of the standard , the intense striatal neuropil staining was diminished , and gdnf - immunoreactive perikarya were easily seen . numerous gdnf - immunoreactive perikarya were also seen within the substantia nigra of lenti - gdnf - injected monkeys . within the striatum and substantia nigra , niss1 - stained sections revealed normal striatal cytoarchitecture without significant cytotoxicity . macrophages were occasionally observed within the needle tracts . gliosis was similar across treatment groups and was principally confined to the regions immediately surrounding the needle tracts . lenti - gdnf injections resulted in marked anterograde transport of the trophic factor . intense gdnf immunoreactivity was observed within fibers of the globus pallidus ( fig1 d ) and substantia nigra pars reticulata ( fig1 e ) after striatal injections . gdnf - containing fibers emanating from putaminal injection sites were seen coursing medially toward and into the globus pallidus ( fig1 d ). these staining patterns were clearly distinct from the injection site and respected the boundaries of the striatal target structures . in contrast , anterograde transport of gal was not observed in lenti - gal monkeys . this suggests that secreted gdnf , and not the virus per se , was anterogradely transported . aged monkeys underwent fluorodopa ( fd ) positron emission tomography ( pet ) before surgery and again just before being killed . before treatment , all monkeys displayed symmetrical fd uptake in the caudate and putamen bilaterally ( ratio : 1 . 02 ± 0 . 02 ) ( fig2 a and 2b , left ). similarly , there was symmetrical ( 4 % difference ) fd uptake in all lenti - gal - treated monkeys after lentivirus injections ( fig2 a , right ). in contrast , fd uptake was significantly asymmetrical ( 27 %) in lenti - gdnf - treated monkeys with greater uptake on the side of the gdnf expression ( p & lt ; 0 . 007 ; fig2 b , right ). with respect to absolute values , lenti - gal animals displayed a trend toward reduced fd uptake after treatment relative to baseline levels ( p = 0 . 06 ). qualitatively , three of four lenti - gdnf - treated monkeys displayed clear increases in fd uptake on the treated side . within the striatum , lentiviral delivery of gdnf increased a number of markers of dopaminergic function . optical density measurements were performed to assess the relative intensity of th staining within the caudate nucleus and putamen ( fig3 a and b ). on the left side where there was no lenti - gdnf expression , the intensity of th immunoreactivity within the caudate nucleus and putamen was similar between groups ( fig3 a and b ). in contrast , significant increases in optical density measures of th immunoreactivity were seen in the right striatum of lenti - gdnf - infused monkeys ( fig3 a ) relative to lenti - gal - treated animals ( fig3 b ) or the contralateral side ( fig3 a ). in this regard , there was a 44 . 1 % and a 38 . 9 % increase in optical density measures of th immunoreactivity within the caudate nucleus and putamen , respectively ( fig4 d ). at the time of death , tissue punches were taken throughout the caudate nucleus and putamen of all monkeys . relative to lenti - gal - treated animals , measurement of dopamine ( da ) and homovanillic acid ( hva ) revealed significant increases in the right caudate nucleus ( 140 % da , p & lt ; 0 . 001 ; 207 % hva , p & lt ; 0 . 001 ) and putamen ( 47 . 2 % da , p & lt ; 0 . 05 ; 128 % hva , p & lt ; 0 . 01 ) in lenti - gdnf - treated aged monkeys ( fig4 e and f ). lentiviral delivery of gdnf to aged monkeys resulted in an increase in the number of th - immunoreactive neurons within the substantia nigra ( fig3 c and d ). regardless of the extent of gdnf immunoreactivity within the midbrain , the organization of th - immunoreactive neurons was similar in all animals , and these neurons were not observed in ectopic locations within this locus . stereological counts revealed an 85 % increase in the number of th - immunoreactive nigral neurons on the side receiving lentivirally delivered gdnf ( fig4 a ) relative to lenti - gal - treated animals . on the side ( left ) that did not display gdnf immunoreactivity , lenti - gdnf - treated animals contained 76 , 929 ± 4918 th - immunoreactive neurons . this is similar to what was seen in lenti - gal - infused animals ( 68 , 543 ± 5519 ). whereas lenti - gal - infused monkeys contained 63 , 738 ± 6094 th - immunoreactive nigral neurons in the right side , lenti - gdnf - treated monkeys contained 118 , 170 ± 8631 th - immunoreactive nigral neurons in this hemisphere ( p & lt ; 0 . 001 ). a similar pattern was seen when the volume of th - immunoreactive substantia nigra neurons was quantified ( fig4 b ). th - immunoreactive neurons from lenti - gal - and lenti - gdnf - treated monkeys were similar in size in the left nigra where there was no gdnf expression ( 11 , 147 . 5 ± 351 μm3 and 11 , 458 . 7 ± 379 μm3 , respectively ). in contrast , a 35 % increase in neuronal volume was seen on the gdnf - rich right side in lenti - gdnf - injected aged monkeys ( lenti - gal 10 , 707 . 5 ± 333 μm3 ; lenti - gdnf 16 , 653 . 7 ± 1240 μm3 ; p & lt ; 0 . 001 ). although stereological counts of th mrna - containing neurons were not performed , there was an obvious increase in the number of th mrna - containing neurons within the right substantia nigra in lenti - gdnf - treated monkeys ( fig3 e ) compared with lenti - gal - containing animals ( fig3 f ). with regard to the relative levels of th mrna expression within individual nigral neurons , the pattern of results was similar to that observed with th - immunoreactive neuronal number and volume ( fig4 c ). on the left side , the optical density of th mrna within nigral neurons was similar between lenti - gal - and lenti - gdnf - treated monkeys ( 78 . 28 ± 2 . 78 and 80 . 58 ± 2 . 5 , respectively ). in contrast , there was a significant ( 21 . 5 %) increase in the optical density for th mrna in lenti - gdnf - treated monkeys ( 98 . 3 ± 1 . 5 ) relative to lenti - gal - treated monkeys ( 77 . 2 ± 2 . 3 ) on the right side ( p & lt ; 0 . 01 ). for a second model of neurodegenerative changes similar to those occurring in pd , young adult monkeys received unilateral intracarotid injections of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 - tetrahydropyridine ( mptp ) to induce extensive nigrostriatal degeneration , resulting in a behavioral syndrome characterized by robust motor deficits . in the second experiment , 20 young adult rhesus were initially trained 3 days per week until asymptotic performance was achieved on a hand - reach task in which the time to pick up food treats out of recessed wells was measured ( 16 , 24 ). each experimental day , monkeys received 10 trials per hand . once per week , monkeys were also evaluated on a modified parkinsonian clinical rating scale ( crs ). all monkeys then received an injection of 3 mg mptp - hcl into the right carotid artery , initiating a parkinsonian state . one week later , monkeys were evaluated on the crs . only monkeys displaying severe hemiparkinsonism with the classic crooked arm posture and dragging leg on the left side continued in the study ( n = 10 ). monkeys with this behavioral phenotype generally display the most severe lesions neuroanatomically and do not display spontaneous recovery behaviorally . on the basis of crs scores , monkeys were matched into two groups of five monkeys , which received on that day lenti - gal or lenti - gdnf treatment . using magnetic resonance imaging ( mri ) guidance , all monkeys were given lentivirus injections into the caudate nucleus ( n = 2 ), putamen ( n = 3 ), and substantia nigra ( n = 1 ) on the right side using the same injection parameters as in experiment 1 . one week later , monkeys began retesting on the hand - reach task three times per week for 3 weeks per month . for statistical analyses , the times for an individual week were combined into a single score . during the weeks of hand - reach testing , monkeys were also scored once per week on the crs . individuals blinded to the experimental treatment performed all behavioral assessments . before mptp treatment , all young adult monkeys scored 0 on the crs . after mptp , but before lentivirus injection , monkeys in the lenti - gdnf and lenti - gal groups averaged 10 . 4 ± 0 . 07 and 10 . 6 ± 0 . 6 , respectively , on the crs ( p & gt ; 0 . 05 ). after lentivirus treatment , significant differences in crs scores were seen between the two groups ( kolmogorov - smirnov test , p & lt ; 0 . 0001 ; fig5 a ). crs scores of monkeys receiving lenti - gal did not change over the 3 - month period after treatment . in contrast , crs scores of monkeys receiving lenti - gdnf significantly diminished during the 3 - month period after treatment . scores began to decrease in the first month after lenti - gdnf treatment . however , statistically significant differences between lenti - gdnf and lenti - gal were only discerned at posttreatment observations 6 , 7 , 8 , and 9 ( kolmogorov - smirnov test , p & lt ; 0 . 04 for each comparison ). lenti - gdnf - treated animals also improved performance on the operant hand - reach task . under the conditions before mptp administration , animals in both groups performed this task with similar speed ( fig5 b ). for the “ unaffected ” right hand , no differences in motor function were discerned for either group relative to performance before mptp administration or to each other ( p & gt ; 0 . 05 ). in contrast , performance with the left hand was significantly improved in lenti - gdnf - treated animals relative to controls ( p & lt ; 0 . 05 ). after mptp , all lenti - gal - treated animals were severely impaired , with monkeys often not performing at all , or requiring more than the maximally allowed 30 s . in contrast , three of the four lenti - gdnf monkeys performed the task with the left hand at near - normal levels , whereas one lenti - gdnf - treated monkey was impaired and performed this task in a manner similar to the lenti - gal - treated animals . between groups , significant differences in performance were discerned on posttreatment tests 4 , 6 , 7 , 8 , and 9 ( p & lt ; 0 . 05 for each comparison ). all monkeys underwent fd pet scans . qualitatively , all lenti - gal - treated monkeys displayed pronounced fd uptake in the left striatum and a comprehensive loss of fd uptake on the right side ( fig2 c ). in contrast , two of four lenti - gdnf - treated animals displayed robust and symmetrical fd uptake on both sides ( fig2 d ). the remaining two lenti - gdnf monkeys displayed reduced fd uptake on the right side , but with ki values 50 to 100 % greater than lenti - gal controls ( fig2 ). quantitatively , no differences in fd uptake were observed between groups within the left striatum ( p & gt ; 0 . 05 ). in contrast , there was a significant (& gt ; 300 %) increase in fd uptake in lenti - gdnf - treated animals in the right striatum relative to lenti - gal - treated animals ( p & lt ; 0 . 05 ). when the right striatum was subdivided , significant increases in fd uptake were only seen within the putamen of lenti - gdnf - treated animals ( p & lt ; 0 . 05 ). after death , a strong gdnf - immunoreactive signal was seen in the caudate nucleus , putamen , and substantia nigra of all lenti - gdnf - treated , but none of the lenti - gal - treated animals . the intensity and distribution of gdnf immunoreactivity was indistinguishable from what was observed in aged monkeys ( see fig1 ). all lenti - gal - treated monkeys displayed a comprehensive loss of th immunoreactivity within the striatum on the side ipsilateral to the mptp injection ( fig6 a ). in contrast , all lenti - gdnf - treated monkeys displayed enhanced striatal th immunoreactivity relative to gal controls ( fig6 b ). there was variability in the degree of striatal th immunoreactivity in lenti - gdnf - treated animals and that variability was associated with the degree of functional recovery seen on the hand - reach task . two lenti - gdnf - treated monkeys displayed dense th immunoreactivity throughout the rostrocaudal extent of the striatum ( fig6 b ). in these monkeys , the intensity of the th immunoreactivity was greater than that observed on the intact side . these two animals displayed the best functional recovery . a third lenti - gdnf - treated monkey also displayed robust functional recovery on the hand - reach task . however , the enhanced striatal th immunoreactivity in this animal was limited to the post - commissural putamen . the fourth lenti - gdnf - treated monkey did not recover on the hand - reach task . although putaminal th immunoreactivity in this animal was still greater than controls , the degree of innervation was sparse and restricted to the medial post - commissural putamen . lenti - gdnf treatment enhanced the expression of th - immunoreactive fibers throughout the nigrostriatal pathway . unlike what was observed in aged monkeys , however , some th - immunoreactive fibers in the striatum displayed a morphology characteristic of both degenerating and regenerating fibers . large , thickened fibers could be seen coursing in an irregular fashion in these animals . rostrally , these fibers appeared disorganized at times , with a more normal organization seen more caudally . th - immunoreactive sprouting was also seen in the globus pallidus ( fig6 g and h ), substantia innominata ( fig6 a and b ), and lateral septum . these novel staining patterns were not immunoreactive for dopamine - hydroxylase confirming the dopaminergic phenotype of this response . quantitatively , lenti - gal - treated monkeys displayed significant decreases in the optical density of th - immunoreactive fibers within the right caudate nucleus ( 71 . 5 %; p & lt ; 0 . 006 ; fig7 d ) and putamen ( 74 . 3 % p & lt ; 0 . 0007 ; fig7 d ) relative to the intact side . when analyzed as a group , th optical density in the right caudate nucleus and putamen of lenti - gdnf - treated monkeys was significantly greater than that seen in lenti - gal - treated monkeys ( p & lt ; 0 . 001 for both ) and was similar to that seen on the intact side of these animals ( p & gt ; 0 . 05 for both ). all lenti - gal - treated monkeys displayed a dramatic loss of th - immunoreactive neurons within the substantia nigra on the side ipsilateral to the mptp injection ( fig7 a ). in contrast , the nigra from all four of the lenti - gdnf - treated displayed complete neuroprotection ( fig7 a ), regardless of the degree of functional recovery . in lenti - gal - treated monkeys , intracarotid injections of mptp resulted in an 89 % decrease in the number ( fig7 a ), and an 81 . 6 % decrease in the density , of th - immunoreactive nigral neurons on the side ipsilateral to the toxin injection ( p & lt ; 0 . 001 ). in contrast , lenti - gdnf - treated monkeys displayed 32 % more th - immunoreactive nigral neurons ( p & lt ; 0 . 001 ) and an 11 % increase in th - immunoreactive neuronal density ( p & lt ; 0 . 05 ) relative to the intact side . in lenti - gal - treated animals , mptp significantly reduced ( 32 %) the volume of residual th - immunoreactive nigral neurons on the lesion side relative to the intact side ( p & lt ; 0 . 001 ; fig7 b ). the volume of th - immunoreactive neurons in lenti - gdnf - treated animals was significantly larger ( 44 . 3 %) on the lesioned side relative to the intact side ( p & lt ; 0 . 001 ). finally , the optical density of th mrna was quantified bilaterally in all animals ( fig7 c ). in lenti - gal - treated animals , there was a significant decrease ( 24 . 0 %) in the relative optical density of th mrna within residual neurons on the mptp - lesioned side relative to the intact side ( p & lt ; 0 . 03 ). in contrast , lenti - gdnf - treated animals displayed a significant increase ( 41 . 7 %) in relative optical density of th mrna relative to the intact side or lenti - gal - treated animals ( p & lt ; 0 . 001 ). sections from all monkeys were stained for cd45 , cd3 , and cd8 markers to assess the immune response after lentiviral vector injection . these antibodies are markers for activated microglia , t cells , and leukocytes including lymphocytes , monocytes , granulocytes , eosinophils , and thymocytes . staining for these immune markers was weak , and often absent , in these animals . mild staining for cd45 and cd8 was seen in two animals . some cd45 - immunoreactive cells displayed a microglial morphology . other monkeys displayed virtually no immunoreactivity even in sections containing needle tracts . two additional intact young adult rhesus monkeys received lenti - gdnf injections into the right caudate and putamen and the left substantia nigra using the same injection protocol utilized in example vi . these animals were killed 8 months later and were evaluated by immunohistochemistry and enzyme - linked immunosorbent assay ( elisa ) for long - term gene expression . robust gdnf immunoreactivity was seen in the right caudate , right putamen , and left ventral midbrain in both animals . in the right substantia nigra , many gdnf - immunoreactive neurons were seen . this labeling represents retrograde transport of gdnf after injections of lenti - gdnf into the right striatum . further , dense gdnf - immunoreactive fiber staining , representing anterograde transport of the trophic factor , was seen within the right substantia nigra pars reticulata . tissue punches taken at the time of death revealed significant levels of gdnf produced by striatal cells 8 months after lenti - gdnf injections . on the side without a striatal injection , 0 . 130 ± 0 . 062 and 0 . 131 ± 0 . 060 ng / mg protein of gdnf were seen in the caudate nucleus and putamen , respectively . significantly higher gdnf levels were observed within the caudate nucleus ( 2 . 25 ± 0 . 312 ng / mg protein ; p & lt ; 0 . 001 ) and putamen ( 3 . 5 ± 0 . 582 ng / mg protein ; p & lt ; 0 . 001 ) on the lenti - gdnf - injected side . | US-3295201-A |
this invention relates to a method of treating certain disorders by administering a compound of the formula 1 or a pharmaceutically acceptable salt thereof , wherein : r 1 is hydrogen , straight or branched alkyl of from 1 to 6 carbon atoms or phenyl ; and r 2 is straight or branched alkyl of from 4 to 8 carbon atoms , straight or branched alkenyl of from 2 to 8 carbon atoms , cycloalkyl of from 3 to 7 carbon atoms , alkoxy of from 1 to 6 carbon atoms , - alkylcycloalkyl , - alkylalkoxy , - alkyl oh , - alkylphenyl , - alkylphenoxy , or - substituted phenyl . the invention also relates to a method of treating the above disorders by administering the compound - 3 - aminomethyl - 5 - methyl - octanoic acid . | compounds of the formula 1 can be prepared as described below and in u . s . patent application ser . nos . 10 / 009 , 938 , filed dec . 10 , 2001 , and 10 / 324 , 929 , filed dec . 20 , 2002 . in the schemes and discussion that follow , r 1 and r 2 are defined as above . the following examples are illustrative of the instant invention ; they are not intended to limit the scope . to a stirred suspension of pyridinium dichromate ( 112 . 17 g , 298 . 1 mmol ) in dichloromethane 500 ml was added 3 - methyl - 1 - pentanol 10 ( 15 g , 146 . 79 mmol ). after stirring for 2 . 5 hours , ether 400 ml was added , and stirring was continued for another 5 minutes . the filtrate from the mixture was concentrated to a small volume and applied to a column of florisil . the compound was eluted with petroleum ether , and further chromatographed on silica gel column using 10 % ether in petroleum ether as eluent gave 11 ( 6 . 5 g , 44 %). 1 h - nmr ( cdcl 3 ) δ 9 . 72 , ( d , — c h o ), 2 . 38 ( dd , 1h , — c h 2 cho ), 2 . 19 ( dd , 1h , — c h 2 cho ), 1 . 95 ( m , 1h , c 2 h 5 ( ch 3 ) c h ch 2 —), 1 . 4 - 1 . 0 ( m ), 0 . 9 - 0 . 8 ( m ). sodium hydride ( 60 % dispersion , 2 . 4 g , 65 mmol ) was washed with hexane and suspended in dimethoxyethane 60 ml . while cooling in ice water bath triethyl phosphonoacetate was slowly added , calcd . 5 minutes . the reaction was stirred for 15 minutes at 0 ° c . and a solution of 3 - methyl - 1 - pentanal 11 ( 6 . 5 g , 65 mmol ) in methoxyethane 20 ml was added . after refluxing overnight , it was concentrated , water and hexane were added , the organic phase was separated , and the aqueous portion discarded . the solution was washed twice with brine and dried on magnesium sulfate . the solvent was evaporated to give 12 ( 6 . 75 g , 61 %). 1 h - nmr ( cdcl 3 ) δ 6 . 89 ( m , 1h , — ch 2 c h : chcooet ), 5 . 77 ( d , 1h , — ch 2 ch : c h cooet ), 4 . 16 ( q , 2h , — cooc h 2 ch 3 ), 2 . 15 and 1 . 98 ( 1h each and a multiplet , — c h 2 ch : chcooet ), 1 . 48 ( m , 1h , c 2 h 5 ( ch 3 ) c h ch 2 ), 1 . 30 - 1 . 10 ( m ), and 0 . 83 . ethyl 5 - methyl - 2 - heptanoate 12 ( 6 . 75 g , 39 . 70 mmol ), dbu ( 6 . 0 g , 39 . 7 mmol ), nitromethane ( 21 . 97 g , 359 . 9 mmol ) in acetonitrile 80 ml was stirred at room temperature under nitrogen atmosphere overnight . the mixture was concentrated to an oil . a solution of the oil in ether was washed with 1n hcl , brine and dried . it was evaporated to give a light oil which was chromatographed on silica gel , eluting with 5 % to 10 % ether in pet . ether to give 13 ( 3 . 6 g , 42 %). 1 h - nmr ( cdcl 3 ) δ 4 . 49 - 4 . 39 ( m ), 4 . 12 - 4 . 07 ( m ), 3 . 61 ( m ), 2 . 36 ( m ), 1 . 36 - 1 . 18 ( m ), 0 . 86 - 0 . 79 . ethyl 5 - methyl - 3 - nitromethylheptanoate 13 ( 3 . 6 g ) was hydrogenated in ethanol in the presence of 20 % pd / c and evaporated to give 14 . six normal hydrochloric acid 30 ml was added and refluxed overnight . the solvent was evaporated at reduced pressure , and the residue was azeotroped with toluene . aqueous solution of the residue was applied to dowex 50wx 8 - 100 ion exchange resin that had been washed to neutral ph with hplc grade water . the column was eluted with water until eluent was neutral ph , and then with 0 . 5n . nh 4 oh solution to give factions containing 3 - aminomethyl - 5 - methylheptanoic acid . the fractions were combined and further chromatographed on a c 18 column . the compound was eluted with 40 % water in methanol and crystallized from methanol - ether to give example 1630 mg . 1 h - nmr ( cd 3 od ) δ 2 . 83 ( m , 1h ), 2 . 75 ( m , 1h ), 2 . 35 ( m , 1h ), 2 . 15 ( m , 1h ), 1 . 95 ( 1h , bs ), 1 . 38 ( 1h , m ), 1 . 3 - 1 . 15 ( m , 2h ), 1 . 14 - 0 . 95 ( m , 2h ). 0 . 80 ( m , 2ch 3 ). ms found molecular ion at ( m + 1 ) 174 and other ions at 156 , 139 , and 102 . anal . calcd . for c 9 h 19 no 2 : c , 62 . 39 ; h , 11 . 05 ; n , 8 . 08 . found c , 62 . 00 ; h , 10 . 83 ; n , 7 . 98 . 3 - aminomethyl - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 5 - methyl - octanoic acid ; 3 - aminomethyl - 5 - methyl - nonanoic acid ; 3 - aminomethyl - 5 - methyl - decanoic acid ; 3 - aminomethyl - 5 - methyl - undecanoic acid ; 3 - aminomethyl - 5 - methyl - dodecanoic acid ; 3 - aminomethyl - 5 - methyl - tridecanoic acid ; 3 - aminomethyl - 5 - cyclopropyl - hexanoic acid ; 3 - aminomethyl - 5 - cyclobutyl - hexanoic acid ; 3 - aminomethyl - 5 - trifluoromethyl - hexanoic acid ; 3 - aminomethyl - 5 -( 2 - chlorophenyl )- hexanoic acid ; 3 - aminomethyl - 5 -( 3 - chlorophenyl )- hexanoic acid ; 3 - aminomethyl - 5 -( 4 - chlorophenyl )- hexanoic acid ; 3 - aminomethyl - 5 -( 2 - methoxyphenyl )- hexanoic acid ; 3 - aminomethyl - 5 -( 3 - methoxyphenyl )- hexanoic acid ; 3 - aminomethyl - 5 -( 4 - methoxyphenyl )- hexanoic acid ; and 3 - aminomethyl - 5 -( phenylmethyl )- hexanoic acid . a ) ( r )-(−)- 4 - phenyl - 2 - oxazolidinone , ( ch 3 ) 3 ccocl , et 3 n , licl , thf , − 20 to 23 ° c . ; c ) nahmds , brch 2 co 2 tbu , thf , − 78 ° c . to − 40 ° c . ; e ) bh 3 sme 2 , thf , 0 to 25 ° c . ; h ) raney nickel , meoh , h 2 ; i ) 3m hcl , reflux , ion exchange resin ( dowex 50wx8 , strongly acidic ). trimethylacetyl chloride ( 7 . 8 g , 0 . 065 mol ) was added to acid 14 ( 6 . 9 g , 0 . 06 mol ) and triethylamine ( 18 g , 0 . 187 mol ) in thf ( 200 ml ) at − 20 ° c . after 1 hour , lithium chloride ( 2 . 35 g , 0 . 55 mol ) and ( r )-(−)- 4 - phenyl - 2 - oxazolidinone ( 8 . 15 g , 0 . 05 mol ) were added and the thick suspension warmed to room temperature . after 20 hours , the suspension was filtered and the filtrate concentrated . the resultant solid was recrystallized from hexane / ethyl acetate ( 5 : 1 ) to give the oxazolidinone 16 as a white solid ( 8 . 83 g , 68 %). 1 h nmr ( cdcl 3 ) δ 7 . 35 ( m , 5h ), 7 . 18 ( dd , 1h , j = 15 . 4 and 1 . 2 hz ), 7 . 02 ( dd , 1h , j = 15 . 4 and 6 . 8 hz ), 5 . 45 ( dd , 1h , j = 8 . 8 and 3 . 9 hz ), 4 . 68 ( t , 1h , j = 8 . 8 hz ), 4 . 22 ( dd , 1h , j = 8 . 8 and 3 . 9 hz ), 2 . 50 ( m , 1h ), 1 . 04 ( d , 1h , j = 1 . 4 hz ), 1 . 02 ( d , 1h , j = 1 . 4 hz ). ms , m / z ( relative intensity ): 260 [ m + h , 100 %]. to copper ( i ) bromide - dimethyl sulphide complex in thf ( 45 ml ) at − 20 ° c . was added methylmagnesium chloride ( as a 3 m solution in thf ). after 20 minutes , the oxazolidinone 16 ( 3 . 69 g , 0 . 014 mol ) in thf ( 20 ml ) was added dropwise over 10 minutes . after 2 . 5 hours , the reaction was quenched through the addition of a saturated aqueous solution of ammonium chloride . the resultant two layers were separated and the aqueous phase extracted with ether . the combined organic phases were washed with 1 m hydrochloric acid , then with 5 % aqueous ammonium hydroxide . the organic phases were dried ( mgso 4 ) and concentrated to give the oxazolidinone 17 as a white solid ( 3 . 39 g , 88 %). 1 h nmr ( cdcl 3 ) δ 7 . 30 ( m , 1h ), 5 . 40 ( dd , 1h , j = 8 . 8 and 3 . 7 hz ), 4 . 63 ( t , 1h , j = 8 . 8 hz ), 4 . 21 ( dd , 1h , j = 8 . 8 and 3 . 7 hz ), 2 . 85 ( dd , 1h , j = 16 . 1 and 5 . 6 hz ), 2 . 8 ( dd , 1h , j = 16 . 1 and 8 . 5 hz ), 1 . 90 ( m , 1h ), 1 . 56 ( m , 2h ), 0 . 83 ( d , 3h , j = 6 . 8 hz ), 0 . 78 ( d , 3h , j = 6 . 8 hz ), 0 . 75 ( d , 3h , j = 6 . 8 hz ). ms , m / z ( relative intensity ): 276 [ m + h , 100 %]. sodium bis ( trimethylsilyl ) amide ( 14 . 4 ml , 0 . 014 mol of a 1 m solution in thf ) was added to a solution of the oxazolidinone 17 ( 3 . 37 g , 0 . 012 mol ) in thf ( 35 ml ) at − 78 ° c . after 35 minutes , tert - butyl bromoacetate ( 3 . 5 g , 0 . 018 mol ) was added and the solution immediately warmed to − 40 ° c . after 3 hours , the reaction was quenched through the addition of a saturated aqueous solution of ammonium chloride . the resultant two layers were separated and the aqueous phase extracted with ether . the combined organic phases were dried ( mgso 4 ) and concentrated . flash chromatography ( 9 : 1 to 5 : 1 hexane / ethyl acetate gradient ) gave the ester 18 ( 3 . 81 g , 82 %) as a white solid . 1 h nmr ( cdcl 3 ) δ 7 . 35 ( m , 5h ), 5 . 37 ( dd , 1h , j = 8 . 4 and 3 . 1 hz ), 4 . 67 ( t , 1h , j = 8 . 7 hz ), 4 . 41 ( dt , 1h , j = 12 . 0 and 3 . 5 hz ), 4 . 25 ( dd , 1h , j = 8 . 68 and 3 . 1 hz ), 2 . 65 ( dd , 1h , j = 16 . 9 and 12 . 0 hz ), 2 . 25 ( dd , 1h , j = 16 . 9 and 3 . 5 hz ), 1 . 6 ( m , 1h ), 1 . 45 ( m , 1h ), 1 . 23 ( s , 9h ), 1 . 02 ( d , 1h , j = 6 . 5 hz ), 0 . 93 ( d , 1h , j = 6 . 7 hz ), 0 . 80 ( d , 1h , j = 7 . 0 hz ). ms , m / z ( relative intensity ): 429 [ m − h + ch 3 cn , 100 %], 388 [ m − h , 20 %]. to the oxazolidinone 18 ( 3 . 62 g , 9 . 3 mmol ) in thf ( 54 ml )/ water ( 15 ml ) was added a premixed solution of lithium hydroxide ( 20 ml of a 0 . 8 m aqueous solution , 0 . 016 mol )/ h 2 o 2 ( 5 . 76 ml of a 30 % aqueous solution ). after 7 hours , the solution was diluted with water and sodium bisulfite added (˜ 10 g ). after stirring for a further 0 . 5 hours , the two layers were separated and the aqueous phase extracted with ether . the aqueous phase was then rendered acidic ( ph 2 ) with 1 m hydrochloric acid and extracted with ether . the combined organic phases were dried ( mgso 4 ) and concentrated . flash chromatography ( 5 : 1 hexane / ethyl acetate ) gave the acid 19 ( 2 . 1 g , 95 %) as a colorless oil . 1 h nmr ( cdcl 3 ) δ 3 . 0 ( m , 1h ), 2 . 55 ( dd , 1h , j = 16 . 6 and 11 . 2 hz ), 2 . 27 ( dd , 1h , j = 16 . 6 and 3 . 4 hz ), 1 . 70 ( m , 1h ), 1 . 53 ( m , 1h ), 1 . 45 ( m , 1h ), 1 . 43 ( s , 9h ), 0 . 95 ( d , 1h , j = 6 . 8 hz ), 0 . 90 ( d , 1h , j = 6 . 6 hz ), 0 . 83 ( d , 1h , j = 6 . 8 hz ). ms , m / z ( relative intensity ): 243 [ m − h , 100 %]. borane - methyl sulfide complex ( 16 ml , 0 . 032 mol of a 2 m solution in thf ) was added to a stirred solution of the acid 19 ( 1 . 96 g , 8 mmol ) in thf ( 20 ml ) at 0 ° c . after 20 hours , methanol was added until effervescence ceased and the solution concentrated . flash chromatography ( 5 : 1 hexane / ethyl acetate gradient ) gave the alcohol 20 ( 1 . 29 g , 70 %) as a colorless oil . 1 h nmr ( cdcl 3 ) δ 3 . 62 ( m , 1h ), 2 . 32 ( m , 1h ), 2 . 14 ( m , 1h ), 1 . 6 ( m , 1h ), 1 . 45 ( s , 9h ), 1 . 35 ( m , 1h ), 0 . 93 ( d , 1h , j = 6 . 8 hz ), 0 . 86 ( d , 1h , j = 6 . 8 hz ), 0 . 77 ( d , 1h , j = 6 . 9 hz ). ms , m / z ( relative intensity ): 175 [ m - tbu , 100 %]. p - toluenesulfonyl chloride ( 847 mg , 4 . 4 mmol ) was added to a stirred solution of the alcohol 6 ( 850 mg , 3 . 7 mmol ), dmap ( 10 mg , 0 . 08 mmol ) and triethylamine ( 1 . 23 ml , 8 . 88 mmol ) in ch 2 cl 2 ( 20 ml ) at 0 ° c . and the solution warmed to room temperature . after 15 hours , the solution was washed with 1n hydrochloric acid then with brine . the combined organic phases were dried ( mgso 4 ) and concentrated . flash chromatography ( 100 to 92 % hexane / ethyl acetate gradient ) gave the tosylate 7 ( 1 . 22 g , 86 %) as a thick gum . 1 h nmr ( cdcl 3 ) δ 7 . 80 ( d , 2h , j = 8 . 2 hz ), 7 . 25 ( d , 2h , j = 8 . 2 hz ), 3 . 92 ( m , 1h ), 2 . 38 ( s , 3h ), 2 . 20 ( m , 2h ), 1 . 95 ( m , 1h ), 1 . 40 ( m , 1h ), 1 . 32 ( s , 9h ), 1 . 27 ( m , 1h ), 0 . 78 ( d , 1h , j = 6 . 6 hz ), 0 . 73 ( d , 1h , j = 6 . 6 hz ), 0 . 63 ( d , 1h , j = 7 . 1 hz ). ms , m / z ( relative intensity ): 311 [ 85 %], 198 [ 100 %], 157 [ 95 %]. a solution of the tosylate 21 ( 1 . 19 g , 3 . 1 mmol ) and sodium azide ( 402 mg , 6 . 2 mmol ) in dmso ( 15 ml ) was warmed to 60 ° c . for 2 . 5 hours . water ( 100 ml ) was added and the solution extracted with ether . the combined organic phases were dried ( mgso 4 ) and concentrated . flash chromatography ( 9 : 1 hexane / ethyl acetate ) gave the azide 22 ( 628 mg , 80 %) as a colorless oil . 1 h nmr ( cdcl 3 ) δ 3 . 4 ( dd , 1h , j = 12 . 21 and 6 . 11 hz ), 3 . 3 ( dd , 1h , j = 21 . 11 and 6 . 59 hz ), 2 . 30 ( dd , 1h , j = 15 . 14 and 3 . 66 hz ), 2 . 25 ( m , 1h ), 2 . 05 ( dd , 1h , j = 15 . 14 and 9 . 04 hz ), 1 . 55 ( m , 1h ), 1 . 45 ( s , 9h ), 1 . 35 ( m , 1h ), 0 . 95 ( d , 1h , j = 6 . 59 hz ), 0 . 90 ( d , 1h , j = 6 . 83 hz ), 0 . 80 ( d , 1h , j = 7 . 08 hz ). ms ( m / z ): ( relative intensity ): 228 [ m − n 2 , 35 %], 172 [ m − n 2 - tbu , 100 %]. the azide 8 ( 640 mg , 2 . 5 mmol ) and raney nickel ( 1 g ) in methanol ( 50 ml ) were shaken under an atmosphere of hydrogen for 4 hours . the solution was filtered and the filtrate concentrated to give a mixture of the amine 23 and lactam 24 which was used without further purification in the next step . a solution of the amine 23 and lactam 24 ( 500 mg ) in 3 m hydrochloric acid were heated to reflux for 9 hours , then stirred at room temperature for 15 hours . the solution was concentrated and the resultant solid subjected to a sequential purification which involved ion exchange chromatography ( dowex 50wx8 , strongly acidic ), oxalate salt formation then further purification by ion exchange chromatography ( dowex 50wx8 , strongly acidic ) to give the example 2 ( 343 mg ) as a white solid . 1 h nmr ( d 2 o ) δ 2 . 87 ( m , 2h ), 2 . 22 ( dd , 1h , j = 15 . 4 and 3 . 4 hz ), 2 . 12 ( m , 1h ), 1 . 93 ( dd , 1h , j = 15 . 4 and 9 . 5 hz ), 1 . 38 ( m , 1h ), 1 . 12 ( m , 1h ), 0 . 77 ( d , 1h , j = 6 . 6 hz ), 0 . 74 ( d , 1h , j = 6 . 6 hz ), 0 . 70 ( d , 1h , j = 6 . 8 hz ). ms , m / z ( relative intensity ): 174 [ m + h , 100 %]. 3 - aminomethyl - 4 , 5 - dimethyl - hexanoic acid ; ( 3r , 4s )- 3 - aminomethyl - 4 , 5 - dimethyl - hexanoic acid mp ; ( 3s , 4s )- 3 - aminomethyl - 4 , 5 - dimethyl - hexanoic acid ; ( 3r , 4r )- 3 - aminomethyl - 4 , 5 - dimethyl - hexanoic acid mp ; 3 - aminomethyl - 4 - isopropyl - hexanoic acid ; 3 - aminomethyl - 4 - isopropyl - heptanoic acid ; 3 - aminomethyl - 4 - isopropyl - octanoic acid ; 3 - aminomethyl - 4 - isopropyl - nonanoic acid ; 3 - aminomethyl - 4 - isopropyl - decanoic acid ; and 3 - aminomethyl - 4 - phenyl - 5 - methyl - hexanoic acid . a compound of structure 30 could be prepared from a compound of structure 29 by treatment with an aqueous acid such as hydrochloric acid and alike at a temperature between room temperature and reflux . as an alternative , a compound of structure 30 can be prepared from a compound of structure 32 by treatment with trifluoroacetic acid in a solvent such as ch 2 cl 2 or etoac and alike . compound 32 could be prepared by base mediate hydrolysis of a boc protected lactam such as compound 31 which itself could be prepared from a compound of structure 29 by treatment with di - tert - butyl dicarbonate in a solvent such as thf and alike . the treatment of the boc - lactam 31 with aqueous sodium hydroxide for example would give rise to the acid 32 . a compound of structure 29 could be prepared from compound of structure 28 ( n = 0 ) by treatment with sodium or lithium metal in ammonia . preferably , the reaction is carried out with sodium metal in ammonia . alternatively , a compound of structure 29 could be prepared from compound of structure 28 ( n = 1 or 2 ) by treatment with ceric ammonium nitrate in a mixture of acetonitrile and water . other methods known in the literature for the removal of substituted alkoxy benzyl groups from nitrogen are described in green , protective groups in organic synthesis , wiley , 2 ed , 1991 and could be utilized . a compound of structure 28 could be prepared from a compound of structure 27 ( where lg is a suitable leaving group such as a halide or an alkyl sulphonate , preferably an iodide would be used ) by carbon - carbon bond forming reactions known in the art . several methods exist in the literature for the coupling of organohalides or organoalkyl sulphonates with organometallic reagents in the presence of various metal salts as summarized in comprehensive organic synthesis , volume 3 : 413 which could be utilized . for example , a compound of structure 28 could be prepared from a compound of structure 27 ( where lg is iodide ) by treatment with a suitable secondary halide ( chloride or iodide ) in the presence of magnesium metal , iodine and copper bromide dimethylsulphide in a solvent such as tetrahydrofuran and alike . alternatively the method according to el marini , synthesis , 1992 : 1104 could be used . hence , a compound of structure 28 could be prepared from a compound of structure 27 ( where lg is iodide ) by treatment with suitable methyl - substituted secondary halide such as an iodide in the presence of magnesium , iodine and lithium tetrachlorocuprate in a solvent such as tetrahydrofuran and alike . a compound of structure 27 incorporates a suitable leaving group , which would undergo nucleophilic substitution with suitable nucleophile . examples of such leaving groups include halides such as chloride , bromide , or iodide , and sulphonic esters such as mesylate , tosylate , triflate , nosylate , and alike . a compound of structure 27 ( where lg = iodide ) could be prepared from a compound of structure 26 through treatment with iodine , triphenylphosphine , and imidazole in a solvent such as toluene and alike . a compound of structure 26 could be prepared from compound of structure 25 by treatment with a metal borohydride , such as sodium borohydride in a solvent such as tetrahydrofuran or dme and alike . compound 25 could be prepared in a similar fashion to the procedures of zoretic et al , j . org . chem ., 1980 ; 45 : 810 - 814 or nielsen et al j . med . chem ., 1990 ; 33 : 71 - 77 using an appropriate benzylamine , such as but not limited to benzylamine , 4 - methoxybenzylamine or 2 , 4 - dimethoxybenzylamine . as an alternative approach , a compound of structure 26 could be treated with sodium metal and ammonia to give 4 - hydroxymethyl - pyrrolidinone which could be iodinated affording 4 - iodomethyl - pyrrolidinone . 4 - iodomethyl - pyrrolidinone could then be coupled with organometallic reagents according to the above procedures avoiding protection of the lactam nitrogen as below . analogous to the above methods a lactam of structure 33 ( see nielsen et . al ., j . med . chem ., 1990 ; 33 : 71 - 77 for general method of preparation ) could be employed thus establishing fixed stereochemistry at c3 of the final amino acids . 3 - aminomethyl - 5 - methyl - 6 - phenyl - hexanoic acid ; 3 - aminomethyl - 6 -( 4 - chloro - phenyl )- 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 -( 3 - chloro - phenyl )- 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 -( 2 - chloro - phenyl )- 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 -( 4 - fluoro - phenyl )- 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 -( 3 - fluoro - phenyl )- 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 -( 2 - fluoro - phenyl )- 5 - methyl - hexanoic acid ; 3 - aminomethyl - 5 - methyl - 7 - phenyl - heptanoic acid ; 3 - aminomethyl - 7 -( 4 - chloro - phenyl )- 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 -( 3 - chloro - phenyl )- 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 -( 2 - chloro - phenyl )- 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 -( 4 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 -( 3 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 -( 2 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 6 - cyclopropyl - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 - cyclobutyl - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 - cyclopentyl - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 - cyclohexyl - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 7 - cyclopropyl - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 - cyclobutyl - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 - cyclopentyl - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 - cyclohexyl - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 8 - cyclopropyl - 5 - methyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 8 - cyclobutyl - 5 - methyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 8 - cyclopentyl - 5 - methyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 8 - cyclohexyl - 5 - methyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - nonanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - decanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - undecanoic acid ; ( 3s )- 3 - aminomethyl - 5 , 7 - dimethyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 5 , 8 - dimethyl - nonanoic acid ; ( 3s )- 3 - aminomethyl - 5 , 9 - dimethyl - decanoic acid ; ( 3s )- 3 - aminomethyl - 5 , 6 - dimethyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 , 6 , 6 - trimethyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - cyclopropyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 - fluoro - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 7 - fluoro - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 8 - fluoro - 5 - methyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 7 , 7 , 7 - trifluoro - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 8 , 8 , 8 - trifluoro - 5 - methyl - octanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - hept - 6 - enoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - oct - 7 - enoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - non - 8 - enoic acid ; ( e )-( 3s )- 3 - aminomethyl - 5 - methyl - oct - 6 - enoic acid ; ( z )-( 3s )- 3 - aminomethyl - 5 - methyl - oct - 6 - enoic acid ; ( e )-( 3s )- 3 - aminomethyl - 5 - methyl - non - 6 - enoic acid ; ( z )-( 3s )- 3 - aminomethyl - 5 - methyl - non - 6 - enoic acid ; ( e )-( 3s )- 3 - aminomethyl - 5 - methyl - non - 7 - enoic acid ; ( z )-( 3s )- 3 - aminomethyl - 5 - methyl - non - 7 - enoic acid ; ( e )-( 3s )- 3 - aminomethyl - 5 - methyl - dec - 7 - enoic acid ; ( z )-( 3s )- 3 - aminomethyl - 5 - methyl - dec - 7 - enoic acid ; 3 - aminomethyl - 6 - cyclopropyl - 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 - cyclobutyl - 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 - cyclopentyl - 5 - methyl - hexanoic acid ; 3 - aminomethyl - 6 - cyclohexyl - 5 - methyl - hexanoic acid ; 3 - aminomethyl - 7 - cyclopropyl - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 - cyclobutyl - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 - cyclopentyl - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 7 - cyclohexyl - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 8 - cyclopropyl - 5 - methyl - octanoic acid ; 3 - aminomethyl - 8 - cyclobutyl - 5 - methyl - octanoic acid ; 3 - aminomethyl - 8 - cyclopentyl - 5 - methyl - octanoic acid ; 3 - aminomethyl - 8 - cyclohexyl - 5 - methyl - octanoic acid ; 3 - aminomethyl - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 5 - methyl - octanoic acid ; 3 - aminomethyl - 5 - methyl - nonanoic acid ; 3 - aminomethyl - 5 - methyl - decanoic acid ; 3 - aminomethyl - 5 - methyl - undecanoic acid ; 3 - aminomethyl - 5 , 7 - dimethyl - octanoic acid ; 3 - aminomethyl - 5 , 8 - dimethyl - nonanoic acid ; 3 - aminomethyl - 5 , 9 - dimethyl - decanoic acid ; 3 - aminomethyl - 5 , 6 - dimethyl - heptanoic acid ; 3 - aminomethyl - 5 , 6 , 6 - trimethyl - heptanoic acid ; 3 - aminomethyl - 5 - cyclopropyl - hexanoic acid ; 3 - aminomethyl - 6 - fluoro - 5 - methyl - hexanoic acid ; 3 - aminomethyl - 7 - fluoro - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 8 - fluoro - 5 - methyl - octanoic acid ; 3 - aminomethyl - 7 , 7 , 7 - trifluoro - 5 - methyl - heptanoic acid ; 3 - aminomethyl - 8 , 8 , 8 - trifluoro - 5 - methyl - octanoic acid ; 3 - aminomethyl - 5 - methyl - hept - 6 - enoic acid ; 3 - aminomethyl - 5 - methyl - oct - 7 - enoic acid ; 3 - aminomethyl - 5 - methyl - non - 8 - enoic acid ; ( e )- 3 - aminomethyl - 5 - methyl - oct - 6 - enoic acid ; ( z )- 3 - aminomethyl - 5 - methyl - oct - 6 - enoic acid ; ( e )- 3 - aminomethyl - 5 - methyl - non - 6 - enoic acid ; ( z )- 3 - aminomethyl - 5 - methyl - non - 6 - enoic acid ; ( e )- 3 - aminomethyl - 5 - methyl - non - 7 - enoic acid ; ( z )- 3 - aminomethyl - 5 - methyl - non - 7 - enoic acid ; ( e )- 3 - aminomethyl - 5 - methyl - dec - 7 - enoic acid ; and ( z )- 3 - aminomethyl - 5 - methyl - dec - 7 - enoic acid . a compound of structure 40 could be prepared from compound of structure 39 through treatment with diethylaminosulphur trifluoride in a solvent such as methylene chloride at a temperature between − 78 ° c . and room temperature . other methods for the fluorination of alcohols are known and could be utilized as exemplified in wilkinson , chem . rev . 1992 ; 92 : 505 - 519 . compounds of structure 40 can be converted to the requisite γ - amino acid as described in method 3 above . a compound of structure 39 could be prepared from compound of structure 38 through treatment with osmium tetroxide and sodium periodate in a solvent such as thf and water and reduction of the resultant intermediate with sodium borohydride in a solvent such as ethanol . compounds of structures 38 and 34 could be prepared from compound of structure 33 according to the principles described in method 3 . an alternative procedure for the synthesis of alcohol 39 ( n = 0 ) involves the treatment of a compound of structure 36 with a metal borohydride , such as sodium borohydride in a solvent such as tetrahydrofuran or dme and alike to give a compound of structure 37 , the fluorination of which could be achieved in a similar manner to the preparation of a compound of structure 40 . a compound of structure 36 could be prepared from compound of structure 35 through treatment with sodium or lithium chloride in aqueous dmso at a temperature between room temperature and reflux . preferably the reaction is carried out using sodium chloride in aqueous dmso at reflux . a compound of structure 35 could be prepared from compound of structure 34 through treatment with a suitable methyl malonic acid diester , such as dimethyl methylmalonate and alike with sodium hydride in a solvent such as dmso or thf and alike . preferably the reaction is carried out by adding nah to a solution of dimethyl methylmalonate in dmso followed by the addition of the lactam 34 ( where lg is preferably iodide or as defined in method 3 ) pre - dissolved in dmso . compounds 39 and 37 can be converted to the free amino acids bearing a hydroxyl group by the methods described above . a compound of structure 41 could be prepared from compound of structure 39 through treatment with a suitable alkyl iodide ( or alkyl sulphonate ), such as methyl iodide and alike , and a base such as n - butyl lithium or sodium hydride and alike , in a solvent such as dmso or thf and alike . preferably the reaction is carried out by adding nah to a solution of the alcohol in dmso followed by the addition of the alkyl iodide and heating of the reaction mixture at a temperature between room temperature and reflux . the conversion of compounds of structure 41 to the γ - amino acids has been described above . alternatively , compounds of structure 41 could be derived from compounds of structure 42 ( where lg = iodide , bromide or an sulphonic acid ester , as exampled in method 3 ) by treatment of an appropriate alkoxy anion in a solvent such as dmso or thf and alike . a compound of structure 42 would also serve as a substrate for carbon - carbon bond forming procedures as outlined in method 3 . ( 3s )- 3 - aminomethyl - 7 - hydroxy - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 - methoxy - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 - ethoxy - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 - propoxy - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 - fluoromethoxy - 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 2 - fluoro - ethoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 -( 3 , 3 , 3 - trifluoro - propoxy )- heptanoic acid ; ( 3s )- 3 - aminomethyl - 6 - hydroxy - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 - methoxy - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 - ethoxy - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 6 - propoxy - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 - fluoromethoxy - 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 2 - fluoro - ethoxy )- 5 - methyl - hexanoic acid ; and ( 3s )- 3 - aminomethyl - 5 - methyl - 6 -( 3 , 3 , 3 - trifluoro - propoxy )- hexanoic acid . compounds of structure 53 could be prepared from a compound of structure 45 as shown above and by the general procedures described in hoekstra et . al ., organic process research and development , 1997 ; 1 : 26 - 38 . compounds of structure 45 can be prepared from compounds of structure 44 by treatment with a solution of chromium trioxide in water / sulfuric acid . alternative methods of cleaving the olefin in 44 could be utilized as detailed in hudlicky , oxidations in organic chemistry , acs monograph 186 , acs 1990 : 77 . compounds of structure 44 ( where r 2 = alkyl , branched alkyl , cycloalkyl , alkyl - cycloalkyl ) could be prepared from ( s )- citronellyl bromide by carbon - carbon bond forming reactions known in the art and as described in method 3 . the substitution of the halide in ( s )- citronellyl bromide with alkoxy anions could also be used to provide compounds of structure 44 where r = alkoxy or phenoxy ethers ( and appropriate substitutions thereof as according to formula 1 ). alternatively ( s )- citronellol could be utilized to afford compounds of structure 44 by treatment of ( s )- citronellol with a base such as sodium hydride , and treatment of the resultant alkoxide with an appropriate alkyl halide to afford ethers . in another method ( s )- citronellyl bromide ( or an appropriate sulphonic ester such as , but not limited to , methanesulfonic acid ( s )- 3 , 7 - dimethyl - oct - 6 - enyl ester ) could be reduced with an appropriate metal borohydride or with an aluminum hydride species , such as lah , to provide ( r )- 2 , 6 - dimethyl - oct - 2 - ene . to one skilled in the art it will be appreciated that rational choice of either r - or s - citronellol or r - or s - citronellyl bromide would give rise to the requisite isomer at c5 of the final amino acid . ( 3s , 5s )- 3 - aminomethyl - 7 - methoxy - 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 - propoxy - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 - isopropoxy - 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 - tert - butoxy - 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 - fluoromethoxy - 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 2 - fluoro - ethoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 -( 3 , 3 , 3 - trifluoro - propoxy )- heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 - benzyloxy - 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 - phenoxy - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 4 - chloro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 3 - chloro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 2 - chloro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 4 - fluoro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 3 - fluoro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 2 - fluoro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 4 - methoxy - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 3 - methoxy - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 -( 2 - methoxy - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 -( 4 - trifluoromethyl - phenoxy )- heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 -( 3 - trifluoromethyl - phenoxy )- heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 -( 2 - trifluoromethyl - phenoxy )- heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 -( 4 - nitro - phenoxy )- heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 -( 3 - nitro - phenoxy )- heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 7 -( 2 - nitro - phenoxy )- heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 - cyclopropyl - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 - cyclobutyl - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 - cyclopentyl - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 - cyclohexyl - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 - cyclopropyl - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 - cyclobutyl - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 - cyclopentyl - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 - cyclohexyl - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - nonanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - decanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - undecanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 , 9 - dimethyl - decanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 - fluoro - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 - fluoro - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 , 8 , 8 - trifluoro - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - 7 - phenyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 4 - chloro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 3 - chloro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 2 - chloro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 4 - methoxy - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 3 - methoxy - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 2 - methoxy - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 4 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 3 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 2 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; and 10 ( 3s , 5r )- 3 - aminomethyl - 5 , 10 - dimethyl - undecanoic acid . a compound of structure 58 can be prepared from a compound of structure 57 by treatment with borontrifluoride diethyletherate and triethylsilane in a solvent such as ch 2 cl 2 . alternatively the method described in meyers , j . org . chem ., 1993 ; 58 : 36 - 42 , could be utilized thus treating a compound of structure 57 with sodium cyanoborohydride in a solvent such as thf / methanol with 3 % hcl in methanol . a compound of structure 57 can be prepared from a compound of structure 56 by treatment with dimethylamine in a solvent such as dmf and alike according to the procedure of koot , tetrahedron lett ., 1992 ; 33 : 7969 - 7972 . a compound of structure 56 can be prepared from a compound of structure 54 by treatment of a suitable primary halide 55 ( iodide , bromide , or chloride ) under standard transmetallation conditions with tbuli and treatment of the resultant organometallic reagent with suitable copper salt , such as but not limited to , copper bromide or copper iodide . the resultant organo - cuprate is added to lactam ( see koot et al , j . org . chem ., 1992 ; 57 : 1059 - 1061 for the preparation of the chiral lactam 54 ) in a solvent such as thf and alike . the procedure of koot , tetrahedron lett ., 1992 ; 33 : 7969 - 7972 exemplifies this method . to one skilled in the art it will be appreciated that rational choice of either r - or s - primary halides 55 would give rise to the requisite isomer at c5 of the final amino acid . ( 3s , 5s )- 3 - aminomethyl - 5 - methoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - ethoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - propoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - isopropoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - tert - butoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - fluoromethoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 2 - fluoro - ethoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 3 , 3 , 3 - trifluoro - propoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - phenoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 4 - chloro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 3 - chloro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 2 - chloro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 4 - fluoro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 3 - fluoro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 2 - fluoro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 4 - methoxy - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 3 - methoxy - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 2 - methoxy - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 4 - nitro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 3 - nitro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 -( 2 - nitro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 6 - propoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 - isopropoxy - 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 - tert - butoxy - 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 - fluoromethoxy - 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 2 - fluoro - ethoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 6 -( 3 , 3 , 3 - trifluoro - propoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 6 - phenoxy - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 4 - chloro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 3 - chloro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 2 - chloro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 4 - fluoro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 3 - fluoro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 2 - fluoro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 4 - methoxy - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 3 - methoxy - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 2 - methoxy - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl 6 -( 4 - trifluoromethyl - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl 6 -( 3 - trifluoromethyl - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl 6 -( 2 - trifluoromethyl - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl 6 -( 4 - nitro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl 6 -( 3 - nitro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl 6 -( 2 - nitro - phenoxy )- hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 - benzyloxy - 5 - methyl - hexanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 6 - cyclopropyl - 5 - methyl - hexanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 6 - cyclobutyl - 5 - methyl - hexanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 6 - cyclopentyl - 5 - methyl - hexanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 6 - cyclohexyl - 5 - methyl - hexanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - nonanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - decanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - undecanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - dodecanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 , 7 - dimethyl - octanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 , 9 - dimethyl - decanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 , 10 - dimethyl - undecanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 , 6 - dimethyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 , 6 , 6 - trimethyl - heptanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - cyclopropyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 - fluoro - 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 - fluoro - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 - fluoro - 5 - methyl - octanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 7 , 7 , 7 - trifluoro - 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 8 , 8 , 8 - trifluoro - 5 - methyl - octanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - 6 - phenyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 4 - chloro - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 3 - chloro - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 2 - chloro - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 4 - methoxy - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 3 - methoxy - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 2 - methoxy - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 3 - fluoro - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5s )- 3 - aminomethyl - 6 -( 2 - fluoro - phenyl )- 5 - methyl - hexanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - 7 - phenyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 4 - chloro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 3 - chloro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 2 - chloro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 4 - methoxy - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 3 - methoxy - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 2 - methoxy - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 4 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 3 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; ( 3s , 5r )- 3 - aminomethyl - 7 -( 2 - fluoro - phenyl )- 5 - methyl - heptanoic acid ; 5 ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - hept - 6 - enoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - oct - 7 - enoic acid ; ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - non - 8 - enoic acid ; ( e )-( 3s , 5s )- 3 - aminomethyl - 5 - methyl - oct - 6 - enoic acid ; ( z )-( 3s , 5s )- 3 - aminomethyl - 5 - methyl - oct - 6 - enoic acid ; ( z )-( 3s , 5s )- 3 - aminomethyl - 5 - methyl - non - 6 - enoic acid ; ( e )-( 3s , 5s )- 3 - aminomethyl - 5 - methyl - non - 6 - enoic acid ; ( e )-( 3s , 5r )- 3 - aminomethyl - 5 - methyl - non - 7 - enoic acid ; ( z )-( 3s , 5r )- 3 - aminomethyl - 5 - methyl - non - 7 - enoic acid ; ( z )-( 3s , 5r )- 3 - aminomethyl - 5 - methyl - dec - 7 - enoic acid ; and ( e )-( 3s , 5r )- 3 - aminomethyl - 5 - methyl - undec - 7 - enoic acid . a compound of structure 60 can be prepared from a compound of structure 59 through treatment with an appropriately substituted phenol ( including phenol itself ) under conditions described by mitsunobu , synthesis , 1981 : 1 . a compound of structure 59 could be prepared from compound of structure 39 by treatment with sodium or lithium metal and alike in ammonia . preferably , the reaction is carried out with sodium metal in ammonia . the direct hydrolysis of compound 60 would give rise to the desired amino acid or the approach via hydrolysis of the boc protected lactam could be utilized . ( 3s )- 3 - aminomethyl - 5 - methyl - 7 - phenoxy - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 4 - chloro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 3 - chloro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 2 - chloro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 4 - fluoro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 3 - fluoro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 2 - fluoro - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 4 - methoxy - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 3 - methoxy - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 7 -( 2 - methoxy - phenoxy )- 5 - methyl - heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 -( 4 - trifluoromethyl - phenoxy )- heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 -( 3 - trifluoromethyl - phenoxy )- heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 -( 2 - trifluoromethyl - phenoxy )- heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 -( 4 - nitro - phenoxy )- heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 -( 3 - nitro - phenoxy )- heptanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 7 -( 2 - nitro - phenoxy )- heptanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 3 - chloro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 2 - chloro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 4 - fluoro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 3 - fluoro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 2 - fluoro - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 4 - methoxy - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 3 - methoxy - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 6 -( 2 - methoxy - phenoxy )- 5 - methyl - hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl 6 -( 4 - trifluoromethyl - phenoxy )- hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl 6 -( 3 - trifluoromethyl - phenoxy )- hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl 6 -( 2 - trifluoromethyl - phenoxy )- hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl 6 -( 4 - nitro - phenoxy )- hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl 6 -( 3 - nitro - phenoxy )- hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl 6 -( 2 - nitro - phenoxy )- hexanoic acid ; ( 3s )- 3 - aminomethyl - 5 - methyl - 6 - phenoxy - hexanoic acid ; and ( 3s )- 3 - aminomethyl - 6 -( 4 - chloro - phenoxy )- 5 - methyl - hexanoic acid . a compound of structure 64 could be prepared from compound of structure 63 by treatment of 63 with hydrogen at 50 psi in the presence of a catalyst such as such as raney nickel in the presence of a base such as triethyl amine in an organic solvent for example methanol . the resulting product is then treated with an aqueous acid such as 6n hcl at a temperature between room temperature and reflux . the resulting mixture could be subjected to ion exchange chromatography to isolate the product 64 . a compound of structure 63 can be prepared from a compound of structure 62b by treatment with an appropriate base , such as but not limited too sodium hydride , n - butyl lithium and alike , and an alkylating reagent such as t - butylbromoacetate or benzylbromoacetate in a solvent such as dmso or thf an alike . preferably , the reaction is carried out by treating a solution of a compound of structure 62b in thf with sodium hydride and alkylation of the resultant anion with t - butylbromoaceate . a compound of structure 62b can be prepared from a compound of structure 62a by treatment with sodium chloride in a solvent such as aqueous dmso at a temperature between 50 ° c . and reflux . a compound of structure 62a can be prepared from a compound of structure 61 by treatment with an appropriate alkylmetalhalide such as an alkyllithium reagent or an organomagnesium halide in a solvent such as thf or ether in the presence of a copper salt , such as but not limited to copper iodide , copper bromide dimethylsulphide . alternatively , the reaction may be carried out by the treatment of the nitrile in a solvent such as ether at , or below , room temperature with an alkylmagenisum chloride . a compound such as 61 can be prepared according to known literature procedures between the condensation of isobutylaldheyde and methylcyanoacetate . doubly branched 3 - substituted gaba analogs 72 can be prepared in two steps from the azide 71 through hydrogenation of the azide 71 in the presence of a noble metal catalyst such as 5 % palladium on carbon and hydrolysis of the resulting lactam with a strong acid such as 6 n hcl at reflux . the final product 72 can then be isolated using ion exchange chromatography . compound 71 can be prepared in two steps by treatment of a lactone such as 70 with hbr in a solvent such as ethanol at a temperature such as 0 ° c . and reacting the resulting bromide with sodium azide in a solvent such as dimethyl sulfoxide at a temperature between 10 ° c . and 80 ° c . lactone 70 can be prepared in two steps by oxidation of a compound such as 69 with an oxidant such as sodium periodate in the presence of a catalytic amount of ruthenium trichloride in a solvent such as acetonitrile at a temperature between 0 ° c . and 100 ° c . and treatment of the resulting compound with potassium carbonate in methanol followed at a temperature between 25 ° c . and 70 ° c . and then treatment with an acid such as p - toluene sulfonic acid in a solvent such as thf at reflux or an aqueous acid such as hcl in water at ambient temperature . a compound such as 69 can be prepared by a by reduction of a compound such as 68 with a hydride reducing agent such as lithium aluminum hydride in a solvent such as ether or thf and reaction of the resulting alcohol with an acylating agent such as acetic anhydride in the presence of a base such as triethyl amine or pyridine or the like . compounds of structure 68 can be prepared by reaction of a compound such as 67 with hydrogen at approximately 50 psi in the presence of a noble metal catalyst such as 5 % palladium on carbon in a solvent such as ethanol . a compound of the formula 67 can be prepared by reaction of a compound of structure 66 with a solution of ethanol saturated with hydrogen bromide gas . a compound such as 66 can be prepared from a compound such as 65 by treatment of a compound such as one with a strong base such as lithium diisopropyl amine in a solvent such as thf at a temperature such as − 78 ° c . and reaction of the resulting anion with a compound such as benzyl bromide or benzyl iodide . compounds of the structure 66 ( r ═ h or lower alkyl ) can be prepared in optical form from methods known in the literature ( davies , j . org . chem ., 1999 ; 64 ( 23 ): 8501 - 8508 ; koch j . org . chem ., 1993 ; 58 ( 10 ): 2725 - 37 ; afonso , tetrahedron , 1993 ; 49 ( 20 ): 4283 - 92 ; bertus , tetrahedron , asymmetry 1999 ; 10 ( 7 ): 1369 - 1380 ; yamamoto , j . am . chem . soc ., 1992 ; 114 ( 20 ): 7652 - 60 ). sodium borohydride ( 8 . 0 g , 0 . 211 mol ) was added to a solution of methyl - 1 - benzyl - 5 - oxo - 3 - pyrrolidnecarboxylate 73 ( see zoretic et al , j . org . chem ., 1980 ; 45 : 810 - 814 for general method of synthesis ) ( 32 . 0 g , 0 . 137 mol ) in 1 , 2 - dimethoxyethane ( 600 ml ) and refluxed for 19 hours . the reaction was cooled to room temperature and 200 ml of water was added . the reaction was quenched with 1 m citric acid and concentrated under reduced pressure . the residue was extracted with dichloromethane , dried over magnesium sulfate , and evaporated to dryness to give 17 . 47 g , 62 % of the alcohol 74 as clear oil . 1 h nmr ( cdcl 3 ) δ 7 . 30 ( m , 5m ), 4 . 38 ( d , 1h , j = 14 . 7 ), 4 . 46 ( d , 1h , j = 14 . 7 ), 3 . 56 ( m , 2h ), 3 . 36 ( m , 1h ), 3 . 10 ( m , 1h ), 2 . 52 ( m , 2h ), 2 . 26 ( m , 1h ). ms , m / z ( relative intensity ): 207 [ m + 2h , 66 %]. ir ( kbr ) 3345 , 2946 , 2866 , 1651 , 1445 , 1025 , 737 , and 698 cm − 1 . to alcohol lactam 74 ( 11 . 18 g , 0 . 056 mol ) in 210 ml toluene was added in turn , triphenylphosphine ( 20 . 0 g , 0 . 076 mol ), imidazole ( 10 . 8 g , 0 . 159 mol ), and iodine ( 19 . 0 g , 0 . 075 mol ). after stirring the suspension for 1 . 5 hours , the supernatant was poured into another flask . the sticky yellow residue was washed twice with ether and the solutions were combined . the solvent was evaporated and the residue was chromatographed on silica , eluting with 1 : 1 acetone / hexane to give 7 . 92 g , 46 % of the iodolactam 75 as yellow oil . 1 h nmr ( cdcl 3 ) δ 7 . 25 ( m , 5h ), 4 . 38 ( d , 1h , j = 14 . 6 ), 4 . 46 ( d , 1h , j = 14 . 6 ), 3 . 38 ( dd , 1h , j = 7 . 8 and 2 . 2 ), 3 . 20 ( dd , 1h , j = 5 . 6 and 4 . 4 ), 3 . 12 ( dd , 1h , j = 7 . 3 and 2 . 4 ), 2 . 96 ( dd , 1h , j = 5 . 8 and 4 . 4 ), 2 . 60 ( m , 2h ), 2 . 22 ( dd , 1h , j = 10 . 5 and 9 . 7 ). ms , m / z ( relative intensity ): 224 [ m − h - bn , 94 %], 317 [ m + 2h , 64 %]. ip 3027 , 2917 , 1688 , 1438 , 1267 , and 701 cm − 1 . to a suspension of magnesium turnings ( 0 . 50 g , 0 . 021 mol ) in 15 ml of dry thf under nitrogen , was added an iodine crystal and 2 - bromopentane ( 2 . 88 g , 0 . 019 mol ). after an exothermic reaction which was periodically cooled in an ice bath , the reaction was stirred at room temperature for 2 hours . eight milliliters of li 2 cucl 4 ( made from 84 mg licl and 134 mg cucl 2 in 10 ml of dry thf ) was added at 0 ° c . followed by dropwise addition of 1 - benzyl - 4 - iodomethyl - pyrrolidine - 2 - one 75 in 15 ml dry thf , and the resulting suspension was let stir at 0 ° c . for 3 hours . stirring was continued at room temperature for 1 hour before quenching with a saturated solution of ammonium chloride . water was added to dissolve the precipitate formed , and the solution was then extracted with ether and dried over magnesium sulfate . the solvent was evaporated under vacuum and the residue chromatographed on silica eluting with 1 : 1 acetone / hexane to give 1 . 13 g , 69 % of the 1 - benzyl - 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 76 . 1 h nmr ( cdcl 3 ) δ 7 . 30 ( m , 5h ), 4 . 44 ( m , 2h ), 3 . 32 ( m , 1h ), 2 . 86 ( m , 1h ), 2 . 56 ( m , 1h ), 2 . 40 ( m , 1h ), 2 . 10 ( m , 1h ), 1 . 30 ( m , 6h ), 1 . 10 ( m , 1h ), 0 . 90 ( m , 6h ). ms , m / z ( relative intensity ): 261 [ m + 2h , 100 %], 301 [ m − h + ch 3 cn , 82 %], 260 [ m + h , 72 %]. a 250 ml 3 - neck flask equipped with a dry ice condenser was chilled to − 78 ° c . ammonia ( 80 ml ) was condensed into the flask and 1 - benzyl - 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 76 ( 1 . 67 g , 0 . 006 mol ) in 15 ml thf was added . freshly cut sodium beads were added until a deep blue color persisted . the cooling bath was removed and the reaction stirred at reflux (− 33 ° c .) for 1 hour . the reaction was quenched with ammonium chloride and the excess ammonia was allowed to evaporate . the resulting residue was diluted with water , extracted with dichloromethane , and dried over magnesium sulfate . evaporation of the solvent followed by chromatography on silica eluting with 1 : 1 acetone / hexane gave 0 . 94 g , 86 % of the 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 77 . 1 h nmr ( cdcl 3 ) δ 6 . 25 ( br , 1h ), 3 . 44 ( m , 1h ), 2 . 95 ( m , 1h ), 2 . 54 ( m , 1h ), 2 . 40 ( m , 1h ), 1 . 98 ( m , 1h ), 1 . 30 ( m , 6h ), 0 . 80 ( m , 6h ). ms , m / z ( relative intensity ): 212 [ m + 2h + ch 3 cn , 100 %], 171 [ m + 2h , 72 %], 170 [ m + 1h , 65 %]. the 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 77 ( 0 . 94 g , 0 . 007 mol ) was dissolved in 70 ml of 6n hcl and refluxed for 20 hours . the solution was evaporated under vacuum and an aqueous solution of the residue was applied to dowex 50wx 8 - 100 ( strongly acidic ) ion exchange resin that had been washed with hplc grade water . the column was eluted , first with water until the eluent was at constant ph , and then with 5 % ammonium hydroxide solution . the ammonium hydroxide fractions were evaporated and azeotroped with toluene . the white solid was washed with acetone filtered and dried in a vacuum oven for 24 hours to give the amino acid 0 . 61 g , 59 %. 1 h nmr ( cd 3 od ) δ 3 . 00 ( m , 1h ), 2 . 85 ( m , 1h ), 2 . 48 ( m , 1h ), 2 . 30 ( m , 1h ), 2 . 14 ( brm , 1h ), 1 . 60 ( brm , 1h ), 1 . 38 ( m , 4h ), 1 . 18 ( m , 2h ), 0 . 60 ( m , 6h ). ms , m / z ( relative intensity ): 188 [ m + h , 100 %]. to 4 - methoxybenzylamine ( 42 g , 0 . 306 mol ) in methanol ( 40 ml ) at 0 ° c . was added the dimethyl itaconate ( 48 g , 0 . 306 mol ) in methanol ( 13 ml ). the solution was stirred at room temperature for 4 days . 1n hcl was added to the solution followed by ether . the two layers were separated and the aqueous phase extracted with ether . the combined organic phases were dried ( mgso 4 ). upon filtration of the drying agent the desired material 79 precipitated from solution that was collected and dried under vacuum . 23 . 26 g , 29 %. ms , m / z ( relative intensity ): 264 [ m + h , 100 %]. anal . calcd for c 14 h 17 n 1 o 4 : c , 63 . 87 ; h , 6 . 51 ; n , 5 . 32 . found : c , 63 . 96 ; h , 6 . 55 ; n , 5 . 29 . nabh 4 ( 15 g , 0 . 081 mol ) was added in portions to ester 79 in ethanol ( 600 ml ) at room temperature . after 4 . 5 hours water (˜ 200 ml ) was carefully added to the reaction and the solution stirred at room temperature overnight . the resultant solid was removed by filtration and the filtrate concentrated to give alcohol 80 as an oil . 15 . 33 g , 81 %. ms , m / z ( relative intensity ): 235 [ m + h , 100 %]. to alcohol 80 ( 12 . 9 g , 0 . 055 mol ) in phme was added triphenylphosphine ( 20 g , 0 . 077 mol ), imidazole ( 10 . 8 g , 0 . 16 mol ), and iodine ( 19 g , 0 . 075 mol ). the suspension was stirred at room temperature 5 hours . a saturated aqueous solution of sodium thiosulphate was added and the two layers separated . the aqueous phase was extracted with ether and the combined organic phases washed with brine , dried ( mgso 4 ) and concentrated . flash chromatography ( 6 : 1 to 4 : 1 toluene / acetone ) of the residue gave iodide 81 as an oil . 11 . 9 g , 63 %. ms , m / z ( relative intensity ): 346 [ m + h , 100 %]. a procedure similar to the preparation of 1 - benzyl - 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 76 was utilized to give 4 -( 2 , 4 - dimethyl - pentyl )- 1 -( 4 - methoxy - benzyl )- pyrrolidin - 2 - one as an oil . 1 . 22 g , 29 %. ms , m / z ( relative intensity ): 304 [ m + h , 100 %]. to the lactam ( 1 . 17 g , 3 . 86 mmol ) in mecn ( 20 ml ) at 0 ° c . was added ceric ammonium nitrate ( 4 . 2 g , 7 . 7 mmol ) in h 2 o ( 10 ml ). after 50 minutes a further portion of ceric ammonium nitrate ( 2 . 1 g , 3 . 86 mmol ) was added , and after 1 hour the mixture was absorbed onto silica and flash chromatographed to give an oil . ms , m / z ( relative intensity ): 183 [ m + h , 100 %]. a procedure similar to the preparation of 3 - aminomethyl - 5 - methyl - octanoic acid ( example 3 ) was utilized to give the amino acid as a solid . ms , m / z ( relative intensity ): 202 [ m + h , 100 %]. to the ester 33 ( 49 g , 0 . 198 mol ) in etoh ( 600 ml ) was added sodium borohydride ( 22 g , 0 . 595 mol ). after 7 hours , 1 m citric acid was carefully added and , after effervescence had ceased , water was added to fully quench the reaction . the ethanol was removed under reduced pressure and ethyl acetate added . the resultant two layers were separated , the aqueous phase was extracted with etoac , and the combined organic phases dried ( mgso 4 ) and concentrated to give a heavy oil . ms , m / z ( relative intensity ): [ m + h , 100 %]. a procedure similar to the iodination of compound 80 was utilized giving iodide 85 as an oil . 35 . 2 g , 56 %. anal . calcd for c 13 h 16 i 1 n 1 o 1 : c , 47 . 43 ; h , 4 . 90 ; n , 4 . 25 . found : c , 47 . 41 ; h , 4 . 83 ; n , 4 . 17 . a procedure similar to the preparation of 1 - benzyl - 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 76 was utilized to give 2 . 71 g , 81 . 0 % of 86 as an oil . ms , m / z ( relative intensity ): 274 [ m + 1h , 100 %], 315 [ m + h + ch 3 cn , 65 %]. a procedure similar to the preparation of 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 77 was used to give 1 . 14 g , 72 . 8 % of 87 as an oil . ms , m / z ( relative intensity ): 170 [ m + 1h , 10 %], 211 [ m + 1h + ch 3 cn , 90 %]. a procedure similar to the preparation of 3 - aminomethyl - 5 - methyl - octanoic acid ( example 3 ) was used to give the amino acid ( example 5 ) 0 . 88 g , 74 . 3 %. 1 h nmr ( cd 3 od ) δ 2 . 95 ( m , 1h ), 2 . 80 ( m , 1h ), 2 . 40 ( m , 1h ), 2 . 25 ( m , 1h ), 2 . 05 ( brm , 1h ), 1 . 50 ( brm , 1h ), 1 . 30 ( m , 4h ), 1 . 10 ( m , 2h ), 0 . 90 ( m , 6h ). ms , m / z ( relative intensity ): 188 [ m + 1h , 100 %], 186 [ m − 1h , 100 %], 229 [ m + 1h + ch 3 cn , 30 %]. a procedure similar to the preparation of 1 - benzyl - 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 76 was followed giving the adduct 88 as an oil . 6 g , 74 %. ms , m / z ( relative intensity ): 272 [ m + h , 100 %]. oso 4 ( 2 ml of a 4 % wt solution in t - buoh ) was added to the alkene 88 ( 5 . 8 g , 0 . 021 mol ) in thf / h 2 o ( 3 : 1 , 100 ml ). after 1 hour , sodium periodate ( 11 . 4 g , 0 . 053 mol ) was added . after 2 hours , the suspension was filtered and the solids washed with dichloromethane . the filtrate was concentrated and the residue azeotroped with toluene . the residue was dissolved in ethanol and sodium borohydride ( 2 . 5 g ) added . the suspension was stirred at room temperature overnight . 1n citric acid was added and the mixture diluted with ether . the resultant two layers were separated and the aqueous phase was extracted with ether and the combined organic dried ( mgso 4 ) and concentrated . flash chromatography ( 1 : 1 hexane / etoac ) of the residue gave an oil . 4 . 2 g , 73 %. ms , m / z ( relative intensity ): 276 [ m + h , 100 %]. to alcohol 89 ( 2 g , 7 . 66 mmol ) in dmso ( 60 ml ) at room temperature was added nah ( 368 mg , 60 % in oil ). after 30 minutes the methyl iodide ( 1 . 08 g , 7 . 66 mmol ) was added and the solution stirred at room temperature overnight , upon which the reaction was diluted with water ( 500 ml ). the solution was extracted with ether , and the combined organic extracts were dried ( mgso 4 ) and concentrated . flash chromatography ( 90 % to 50 % hexane / acetone ) of the residue gave the product 90 as an oil ( 1 . 1 g , 52 %). ms m / z 290 ( m + h , 100 %). a procedure similar to the synthesis of 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 77 was utilized giving lactam 91 as an oil . ms m / z 186 ( m + h , 100 %). a procedure similar to the synthesis of example 3 was followed . the resultant amino acid isolated from ion - exchange chromatography was recrystallized from methanol / ethyl acetate to give the example 6 as a white solid . ms m / z 204 ( m + h , 100 %). anal . calcd for c 10 h 21 n 1 o 3 : c , 59 . 09 ; h , 10 . 41 ; n , 6 . 89 . found : c , 58 . 71 ; h , 10 . 21 ; n , 6 . 67 . to dimethyl methylmalonate ( 1 . 06 g , 7 . 29 mmol ) in dmso ( 7 ml ) at room temperature was added nah ( 291 mg of a 60 % dispersion in oil ). after the effervescence had ceased the lactam 85 ( 2 g , 7 . 29 mol ) in dmso ( 5 ml ) was added . after 1 hour water was added and the aqueous solution extracted with ether . the combined organic extracts were dried ( mgso 4 ) and concentrated . flash chromatography ( 1 : 1 hexane / acetone ) of the residue gave the product as an oil ( 1 . 7 g , 81 %). ms m / z 348 ( m + h , 100 %). the ester 92 ( 483 mg , 1 . 4 mmol ), nacl ( 104 mg , 1 . 8 mmol ), water ( 105 μl ) and dmso ( 5 ml ) were heated to reflux for 2 hours . the solution was cooled to room temperature water was added and the aqueous solution extracted with ether . the combined organic extracts were dried ( mgso 4 ) and concentrated . flash chromatography ( 80 % to 66 % hexane / acetone ) of the residue gave the product as an oil ( 160 mg , 40 %). ms m / z 290 ( m + h , 100 %). to the ester 93 ( 4 . 82 g , 0 . 017 mol ) in etoh ( 100 ml ) was added nabh 4 ( 3 . 7 g , 0 . 10 mol ) and the mixture heated to reflux for 2 . 5 hours . the solution was cooled to 0 ° c . and 1 m citric acid carefully added followed by water . the solution was concentrated to half volume added and extracted with ether . the combined organic extracts were dried ( mgso 4 ) and concentrated . flash chromatography ( 1 : 1 hexane / acetone ) of the residue gave the product as an oil ( 2 . 6 g , 59 %). ms m / z 262 ( m + h , 100 %). to dast ( 1 g , 6 . 2 mmol ) in ch 2 cl 2 ( 20 ml ) at − 78 ° c . was added the alcohol 37 in ch 2 cl 2 ( 10 ml ). after 1 hour at − 78 ° c . the solution was warmed to room temperature . after 7 hours the solution was carefully quenched with a saturated aqueous solution of sodium bicarbonate and the two layers separated . the organic phase was dried ( mgso 4 ) and concentrated . flash chromatography ( 90 % to 66 % hexane / acetone ) of the residue gave the product as an oil ( 600 mg , 37 %). ms m / z 264 ( m + h , 100 %). a procedure similar to the preparation of 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 77 was utilized affording the lactam as an oil ( 242 mg , 68 %). ms m / z 159 ( m , 100 %). a procedure similar to the synthesis of example 3 was followed . the resultant amino acid isolated from ion - exchange chromatography was recrystallized from methanol / ethyl acetate to give example 7 as a white solid . ms m . 177 ( m , 100 %). anal . calcd for c 8 h 16 f 1 n 1 o 2 : 0 . 02h 2 o : c , 54 . 11 ; h , 9 . 10 ; n , 7 . 89 . found : c , 53 . 75 ; h , 9 . 24 ; n , 7 . 72 . a procedure similar to the synthesis of ( s )- 4 -( 4 - methoxy - 2 - methyl - butyl )- 1 -(( s )- 1 - phenyl - ethyl )- pyrrolidin - 2 - one 90 was utilized giving ether 96 as an oil ( 90 mg , 37 %). ms m / z 276 ( m + h , 100 %). a procedure similar to the synthesis of 4 -( 2 - methyl - pentyl )- pyrrolidin - 2 - one 77 was utilized giving 97 as an oil ( 760 mg , 93 %). ms m / z 171 ( m + h , 100 %). a procedure similar to the synthesis of example 3 was followed . the resultant amino acid isolated from ion - exchange chromatography was recrystallized from methanol / ethyl acetate to give example 8 as a white solid . ms m / z 190 ( m + h , 100 %). anal . calcd for c 9 h 19 n 1 o 3 : c , 57 . 12 ; h , 10 . 12 ; n , 7 . 40 . found : c , 57 . 04 ; h , 10 . 37 ; n , 7 . 30 . a second batch precipitated from the mother liquors ( 1 : 5 ratio of c5 isomers by 1 h nmr ). ms m / z 190 ( m + h , 100 %). to ( s )- citronellyl bromide ( 50 g , 0 . 228 mol ) in thf ( 800 ml ) at 0 ° c . was added licl ( 4 . 3 g ) followed by cucl 2 ( 6 . 8 g ). after 30 minutes methylmagnesium chloride ( 152 ml of a 3 m solution in thf , aldrich ) was added and the solution warmed to room temperature . after 10 hours the solution was cooled to 0 ° c . and a saturated aqueous solution of ammonium chloride carefully added . the resultant two layers were separated and the aqueous phase extracted with ether . the combined organic phases were dried ( mgso 4 ) and concentrated to give an oil . 32 . 6 g ; 93 %. used without further purification . 13 c nmr ( 100 mhz ; cdcl 3 ) 131 . 13 , 125 . 28 , 39 . 50 , 37 . 35 , 32 . 35 , 25 . 92 , 25 . 77 , 20 . 31 , 19 . 74 , 17 . 81 , 14 . 60 . to alkene 98 ( 20 g , 0 . 13 mol ) in acetone ( 433 ml ) was added a solution of cro 3 ( 39 g , 0 . 39 mol ) in h 2 so 4 ( 33 ml )/ h 2 o ( 146 ml ) over 50 minutes . after 6 hours a further amount of cro 3 ( 26 g , 0 . 26 mol ) in h 2 so 4 ( 22 ml )/ h 2 o ( 100 ml ) was added . after 12 hours the solution was diluted with brine and the solution extracted with ether . the combined organic phases were dried ( mgso 4 ) and concentrated . flash chromatography ( gradient of 6 : 1 to 2 : 1 hexane / etoac ) gave the product 99 as an oil . 12 . 1 g ; 65 %. ms , m / z ( relative intensity ): 143 [ m − h , 100 %]. to the acid 99 ( 19 g , 0 . 132 mol ) and triethylamine ( 49 . 9 g , 0 . 494 mol ) in thf ( 500 ml ) at 0 ° c . was added trimethylacetylchloride ( 20 g , 0 . 17 mol ). after 1 hour licl ( 7 . 1 g , 0 . 17 mol ) was added followed by the oxazolidinone ( 30 g , 0 . 17 mol ). the mixture was warmed to room temperature and after 16 hours the filtrate was removed by filtration and the solution concentrated under reduced pressure . flash chromatography ( 7 : 1 hexane / etoac ) gave the product 100 as an oil . 31 . 5 g ; 79 %. [ α ] d = 5 . 5 ( c 1 in chcl 3 ). ms , m / z ( relative intensity ): 304 [ m + h , 100 %]. to oxazolidinone 100 ( 12 . 1 g , 0 . 04 mol ) in thf ( 200 ml ) at − 50 ° c . was added nahmds ( 48 ml of a 1 m solution in thf ). after 30 t - butylbromoaceate ( 15 . 6 g , 0 . 08 mol ) was added . the solution was stirred for 4 hours at − 50 ° c . and then warmed to room temperature . after 16 hours a saturated aqueous solution of ammonium chloride was added and the two layers separated . the aqueous phase was extracted with ether and the combined organic phases dried ( mgso 4 ) and concentrated . flash chromatography ( 9 : 1 hexane / etoac ) gave the product 101 as a white solid 12 g ; 72 %. [ α ] d = 30 . 2 ( c 1 in chcl 3 ). 13 c nmr ( 100 mhz ; cdcl 3 ) 176 . 47 , 171 . 24 , 152 . 72 , 133 . 63 , 128 . 87 , 125 . 86 , 80 . 85 , 78 . 88 , 55 . 34 , 39 . 98 , 38 . 77 , 38 . 15 , 37 . 58 , 30 . 60 , 28 . 23 , 20 . 38 , 20 . 13 , 14 . 50 , 14 . 28 . to ester 101 ( 10 . 8 g , 0 . 025 mol ) in h 2 o ( 73 ml ) and thf ( 244 ml ) at 0 ° c . was added a premixed solution of lioh ( 51 . 2 ml of a 0 . 8 m solution ) and h 2 o 2 ( 14 . 6 ml of a 30 % solution ). after 4 hours a further 12 . 8 ml lioh ( 0 . 8 m solution ) and 3 . 65 ml of h 2 o 2 ( 30 % solution ) was added . after 30 minutes sodium bisulfite ( 7 g ), sodium sulfite ( 13 g ), and water ( 60 ml ) was added followed by hexane ( 100 ml ) and ether ( 100 ml ). the two layers were separated and the aqueous layer extracted with ether . the combined organic phases were concentrated to an oil that was dissolved in heptane ( 300 ml ). the resultant solid was filtered off and the filtrate dried ( mgso 4 ) and concentrated to afford an oil ( 6 g , 93 %) which was used without further purification . ms , m / z ( relative intensity ): 257 [ m + h , 100 %]. to acid 102 ( 3 . 68 g , 0 . 014 mol ) in thf ( 100 ml ) at 0 ° c . was added bh 3 . me 2 ( 36 ml of a 2 m solution in thf , aldrich ) upon which the solution was warmed to room temperature . after 15 hours ice was carefully added ( in order to control the effervescence ) to the solution followed by brine . the solution was extracted with ether and the combined organic phases dried ( mgso 4 ) and concentrated under reduced pressure . flash chromatography ( 4 : 1 hexane / etoac ) gave alcohol 103 as an oil ( 2 . 0 g , 59 %). 13 c nmr ( 100 mhz ; cdcl 3 ) 173 . 56 , 80 . 85 , 65 . 91 , 39 . 74 , 39 . 20 , 38 . 90 , 35 . 65 , 29 . 99 , 28 . 31 , 20 . 18 , 19 . 99 , 14 . 56 . to alcohol 103 ( 1 . 98 g , 8 . 1 mmol ) in ch 2 cl 2 ( 40 ml ) at room temperature was added triethylamine ( 2 . 4 g , 0 . 024 mol ), dmap ( 20 mg ) and tosyl chloride ( 2 . 3 g , 0 . 012 mol ). after 14 hours 1n hcl was added and the two layers separated . the aqueous phase was extracted with ether and the combined organic phases dried ( mgso 4 ) and concentrated . flash chromatography ( 95 % hexane / etoac ) gave tosylate 104 as an oil ( 2 . 94 g , 91 %). 13 c nmr ( 100 mhz ; cdcl 3 ) 171 . 60 , 144 . 92 , 133 . 07 , 130 . 02 , 128 . 12 , 80 . 80 , 72 . 15 , 39 . 73 , 38 . 09 , 37 . 89 , 32 . 67 , 29 . 71 , 28 . 22 , 21 . 83 , 20 . 10 , 19 . 54 , 14 . 49 . tosylate 104 ( 2 . 92 g , 7 . 3 mmol ) and sodium azide ( 1 . 43 g , 0 . 02 mol ) were warmed to ˜ 50 ° c . in dmso ( 30 ml ). after 2 hours the solution was cooled to room temperature and diluted with water . the solution was extracted with ether and the combined organic phases dried ( mgso 4 ) and concentrated to give an oil 1 . 54 g , 79 %. further purification by flash chromatography ( 95 % hexane / etoac ) gave an oil . [ α ] d =− 8 . 3 ( c 1 in chcl 3 ). 13 c nmr ( 100 mhz ; cdcl 3 ) 172 . 01 , 80 . 73 , 54 . 89 , 39 . 73 , 39 . 46 , 39 . 00 , 33 . 40 , 29 . 85 , 28 . 30 , 20 . 15 , 19 . 82 , 14 . 52 . azide 105 was treated with 5 % pd / c and shaken under an atmosphere of hydrogen for 20 hours where upon a further 200 mg of 5 % pd / c added . after 6 hours the filtrate was concentrated to afford an oil which by 1 h nmr was found to be a mixture of primary amine 106 and lactam 107 ( 1 . 75 g ) which was used without further purification . the mixture of the amine 106 and the lactam 107 ( 1 . 74 g ) was treated with 3n hcl ( 40 ml ) and the solution warmed to 50 ° c . for 4 hours then cooled to room temperature . after 12 hours the solution was concentrated and the residue recrystallized from ethyl acetate to give the amino acid as a white solid 605 mg . ms , m / z ( relative intensity ): 188 [ m + h , 100 %]. anal . calcd for c 10 h 21 n1o 2 : h 1 cl 1 c , 53 . 68 ; h , 9 . 91 ; n , 6 . 26 . found : c , 53 . 83 ; h , 10 . 12 ; n , 6 . 07 . to s -(−)- citronellol ( 42 . 8 g , 0 . 274 mol ) and triethylamine ( 91 ml , 0 . 657 mol ) in ch 2 cl 2 ( 800 ml ) at 0 ° c . was added methanesulphonyl chloride ( 26 ml , 0 . 329 mol ) in ch 2 cl 2 ( 200 ml ). after 2 hours at 0 ° c . the solution was washed with 1n hcl then brine . the organic phase was dried ( mgso 4 ) and concentrated to afford an oil ( 60 . 5 g , 94 %) which was used without further purification . 1 h nmr ( 400 mhz ; cdcl 3 ) 5 . 05 ( 1h , m ), 4 . 2 ( 2h , m ), 2 . 95 ( 3h , s ), 1 . 98 ( 2h , m ), 1 . 75 ( 1h , m ), 1 . 6 ( 3h , s ), 1 . 5 ( 4h , m ), 1 . 35 ( 2h , m ), 1 . 2 ( 1h , m ), 0 . 91 ( 3h , d , j = 6 . 5 hz ). to alkene 108 ( 60 g , 0 . 256 mol ) in thf ( 1 l ) at 0 ° c . was added lithium aluminum hydride ( 3 . 8 g , 0 . 128 mol ). after 7 hours , a further 3 . 8 g of lithium aluminum hydride was added and the solution warmed to room temperature . after 18 hours , a further 3 . 8 g of lithium aluminum hydride was added . after a further 21 hours , the reaction was carefully quenched with 1n citric acid and the solution diluted further with brine . the resultant two phases were separated and the organic phase was dried ( mgso 4 ) and concentrated to afford an oil which was used without further purification . ms , m / z ( relative intensity ): 139 [ m − h , 100 %]. a procedure similar to the synthesis of ( r )- 4 - methyl - heptanoic acid 99 was utilized giving the acid as an oil ( 9 . 3 g , 56 %). ms , m / z ( relative intensity ): 129 [ m − h , 100 %]. a procedure similar to the synthesis of ( 4r , 5s )- 4 - methyl - 3 -(( r )- 4 - methyl - heptanoyl )- 5 - phenyl - oxazolidin - 2 - one 100 was utilized giving oxazolidinone 111 as an oil ( 35 . 7 g , 95 %). ms , m / z ( relative intensity ): 290 [ m + h , 100 %]. a procedure similar to the preparation of ( 3s , 5r )- 5 - methyl - 3 -(( 4r , 5s )- 4 - methyl - 2 - oxo - 5 - phenyl - oxazolidine - 3 - carbonyl )- octanoic acid tert - butyl ester 101 was followed giving 112 as an oil ( 7 . 48 g ; 31 %). to ester 112 ( 7 . 26 g , 0 . 018 mol ) in h 2 o ( 53 ml ) and thf ( 176 ml ) at 0 ° c . was added a premixed solution of lioh ( 37 ml of a 0 . 8 m solution ) and h 2 o 2 ( 10 . 57 ml of a 30 % solution ) and the solution warmed to room temperature . after 2 hours sodium bisulfite ( 7 g ), sodium sulfite ( 13 g ), and water ( 60 ml ) was added and the two layers were separated and the aqueous layer extracted with ether . the combined organic phases were concentrated to an oil that was dissolved in heptane ( 200 ml ). the resultant solid was filtered off and the filtrate dried ( mgso 4 ) and concentrated to afford an oil ( 4 . 4 g ) that was used without further purification . a procedure similar to the preparation of ( 3s , 5r )- 3 - hydroxymethyl - 5 - methyl - octanoic acid tert - butyl ester 103 was utilized giving alcohol 114 as an oil ( 2 . 68 g , 69 %). ms , m / z ( relative intensity ): 216 [ 89 %], 174 [ m —( ch 3 ) 3 c , 100 %]. to 114 alcohol ( 2 . 53 g , 0 . 011 mmol ) in ch 2 cl 2 ( 140 ml ) at 0 ° c . was added pyridine ( 2 . 6 g , 0 . 033 mol ), dmap ( 100 mg ), and tosyl chloride ( 3 . 15 g , 0 . 016 mol ) and the solution warmed to room temperature for 3 . 5 hours whereupon more dmap and tscl ( 3 . 15 g ) were added . after 14 hours 1n hcl was added and the two layers separated . the organic phase was washed with brine then or dried ( mgso 4 ) and concentrated . flash chromatography ( 95 % to 86 % hexane / etoac ) gave tosylate 115 as an oil ( 1 . 53 g , 36 %). 13 c nmr ( 100 mhz ; cdcl 3 ) 130 . 03 , 128 . 12 , 72 . 18 , 37 . 89 , 37 . 71 , 32 . 67 , 31 . 49 , 29 . 88 , 28 . 22 , 21 . 83 , 19 . 07 , 11 . 37 . a procedure similar to the preparation of ( 3s , 5r )- 3 - azidomethyl - 5 - methyl - octanoic acid tert - butyl ester 105 was utilized giving an oil 0 . 956 g , 97 %. ms , m / z ( relative intensity ): 228 [ m − n 2 , 80 %]. azide 116 ( 689 mg ) was treated with 20 % pd / c ( 90 mg ) in thf ( 20 ml ) and shaken under an atmosphere of hydrogen for 36 hours . the catalyst was removed by filtration and the resultant oil used without further purification . the mixture of amine 117 and lactam 118 was treated with 6n hcl and the solution warmed to 50 ° c . for 17 hours then cooled to room temperature and concentrated . the resultant oil was subjected to ion - exchange chromatography ( dowex , strongly acidic resin ) using 5 % ammonium hydroxide to give a cream solid which was recrystallized from methanol / ethyl acetate to give ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - heptanoic acid , example 10 . ms , m / z ( relative intensity ): 174 [ m + h , 100 %]. anal . calcd for c 19 h 19 n 1 o 2 . c , 62 . 39 ; h , 11 . 05 ; n , 8 . 08 . found : c , 62 . 23 ; h , 11 . 33 ; n , 7 . 89 . cucl 2 ( 5 . 36 g , 39 . 7 mmol ) and licl ( 3 . 36 , 80 . 0 mmol ) were stirred together in dry thf ( 40 ml ) for 15 minutes . the resulting solution was added to methylmagnesium chloride , 3 . 0 m in thf ( 168 ml ) at 0 ° c . under nitrogen atmosphere and stirred at that temperature for 15 minutes . to the reaction suspension was added slowly ( r )-(−)- citronellyl bromide ( 55 . 16 g , 251 . 8 mmol ) in thf ( 100 ml ), and stirred at 0 ° c . for 2 . 5 hours . it was warmed to room temperature and stirring was continued for an additional 1 hour . the mixture was cooled to 0 ° c . and quenched with saturated ammonium chloride solution . the suspension was then extracted into ether , washed with water , and dried over mgso 4 . the solution was concentrated under reduced pressure to afford 36 . 3 g ; 94 % of ( s )- 2 , 6 - dimethyl - non - 2 - ene as an oil . ms , m / z ( relative intensity ): 153 [ m − 1h , 100 %], 194 [ m − 1h + ch 3 cn , 45 %]. to the ( s )- 2 , 6 - dimethyl - non - 2 - ene 119 ( 39 . 0 g , 253 . 2 mmol ) in acetone ( 1 l ) at 0 ° c . was added jones reagent ( 2 . 7 m , 600 ml ) dropwise over 1 . 5 hours and let stir at room temperature for 18 hours . the reaction mixture was poured into a saturated solution of na 2 so 4 and extracted into ether . it was washed with brine and concentrated in vacuo . the oily residue was dissolved in methanol ( 70 ml ) and 1 m naoh ( 700 ml ) and then stirred for 30 minutes . the aqueous solution was washed with ch 2 cl 2 , acidified with 10 % hcl and extracted into ch 2 cl 2 . the solution was dried over mgso 4 and concentrated to dryness to give 24 . 22 g ; 66 % of ( s )- 4 - methyl - heptanoic acid as an oil . ms , m / z ( relative intensity ): 143 [ m − 1h , 100 %]. a procedure similar to the preparation of ( 4r , 5s )- 4 - methyl - 3 -(( r )- 4 - methyl - heptanoyl )- 5 - phenyl - oxazolidin - 2 - one 100 was utilized giving ( 4r , 5s )- 4 - methyl - 3 -(( s )- 4 - methyl - heptanoyl )- 5 - phenyl - oxazolidin - 2 - one 121 6 . 2 g ; 80 . 0 %, as an oil . ms , m / z ( relative intensity ): 304 [ m + 1h , 90 %], 355 [ m + 1h + ch 3 cn , 60 %]. n - buli , 1 . 6 m in hexane ( 18 . 0 ml , 30 . 1 mmol ) was added dropwise to a solution of diisopropylamine ( 4 . 6 ml , 32 . 6 mmol ) in dry thf ( 50 ml ) under nitrogen at − 5 ° c . keeping the temperature below 0 ° c . during addition . the mixture was let stir at − 5 ° c . for 20 minutes and then cooled to − 78 ° c . 121 ( 7 . 6 g , 25 . 1 mmol ) in dry thf ( 12 ml ) was added to the lda solution and stirred at − 78 ° c . for 30 minutes . t - butylbromo acetate ( 4 . 8 ml , 32 . 6 mmol ) as added to the reaction and stirring at − 78 ° c . was continued for 2 hours . it was let warm to room temperature before stirring for an additional 18 hours . the reaction was quenched with a saturated solution nah 2 po 4 , extracted into ethylacetate , and dried over mgso 4 . the solution was concentrated to give a solid residue which was dissolved in hot hexane . the hexane solution was allowed to cool to room temperature before cooling further in an ice bath . the resulting precipitate was collected and allowed to air dry to give 122 as a fluffy white solid . 4 . 3 g ; 41 %. ms , m / z ( relative intensity ): 362 [ m − c ( ch 3 ) 3 + 1h , 100 %], 418 [ m + 1h , 20 %]. to the ester 122 in a mixture of thf ( 203 . 0 ml ) and water ( 61 . 0 ml ) at 0 ° c . was added a premixed solution of 30 % h 2 o 2 ( 12 . 2 ml ) and lioh ( 0 . 8 m , 42 . 7 ml ). the resulting solution was stirred at 0 ° c . for 4 hours . to the reaction was added sodium bisulfite ( 7 g ), sodium sulfite ( 13 g ), and water ( 60 ml ). a 1 : 1 mixture of ether / hexane ( 200 ml ) was then added and the organic phase was separated . the aqueous phase was extracted with ether and the combined organic extract was dried over mgso 4 and concentrated in vacuo . the residue was dissolved in heptane and let stir for 5 minutes . the resulting precipitate was filtered and the filtrate was concentrated to dryness to give as an oil . a procedure similar to the preparation of ( 3s , 5r )- 3 - hydroxymethyl - 5 - methyl - octanoic acid tert - butyl ester 103 was followed giving 123 as an oil . 4 . 0 g ; 76 . 0 %. ms , m / z ( relative intensity ): 230 [ m − c ( ch 3 ) 3 + 1h + ch 3 cn , 100 %], 189 [ m − c ( ch 3 ) 3 + 1h , 70 %]. a procedure similar to the preparation of ( 3s , 5r )- 5 - methyl - 3 -( toluene - 4 - sulfonyloxymethyl )- octanoic acid tert - butyl ester 104 was followed giving 6 . 9 g of 124 . ms , m / z ( relative intensity ): 343 [ m − c ( ch 3 ) 3 + 1h , 70 %], 384 [ m − c ( ch 3 ) 3 + 1h + ch 3 cn , 100 %]. a procedure similar to the preparation of ( 3s , 5r )- 3 - azidomethyl - 5 - methyl - octanoic acid tert - butyl ester 105 was followed giving 2 . 9 g ; 66 % of 125 as an oil . ms , m / z ( relative intensity ): 212 [ m − c ( ch 3 ) 3 - 1 h , 45 %]. a mixture of 125 ( 2 . 8 g , 10 . 4 mmol ) and 10 % pd / c ( 1 . 0 g ) in methanol ( 50 . 0 ml ) was hydrogenated at 41 psi for 96 hours . the solution was filtered to give 1 . 7 g of crude 126 which was used in the next step without further purification . ms , m / z ( relative intensity ): 244 [ m + 1h , 100 %], 285 [ m + 1h + ch 3 cn , 25 %]. a procedure similar to the preparation of example 10 ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - heptanoic acid was followed giving example 11 . 380 mg ; 29 . 0 %. 1 h nmr ( cd 3 od ) δ 2 . 90 ( dd , j = 3 . 9 , 8 . 8 hz , 1h ), 2 . 80 ( dd , j = 7 . 6 , 5 . 1 hz , 1h ), 2 . 40 ( dd , j = 3 . 2 , 12 . 51 hz , 1h ), 2 . 20 ( dd , j = 8 . 8 , 6 . 8 hz , 1h ), 2 . 05 ( m , 1h ), 1 . 55 ( m , 1h ), 1 . 30 ( m , 3h ), 1 . 10 ( m , 2h ), 0 . 85 ( m , 6h ); ms , m / z ( relative intensity ): 187 [ m + 1h , 100 %], 211 [ m + 1h + ch 3 cn , 30 %]. ( r )-(−)- citronellyl bromide ( 49 . 1 g , 224 . 2 mmol ) was dropwise added to a solution of lah 1 . 0 m in thf ( 336 ml , 336 mmol ) at 0 ° c . over a 45 - minute period . stirring was continued for an additional 4 hours at 0 ° c . the reaction was slowly quenched with a saturated solution of ammonium chloride followed by the addition of ether ( 100 ml ). the resulting white slurry was filtered and the filtrate was dried over mgso 4 . the solution was concentrated under reduced pressure to afford 26 . 2 g ; 83 % of 127 as an oil . ms , m / z ( relative intensity ): 180 [ m − 1h + ch 3 cn , 100 %], 139 [ m − 1h , 90 %]. a procedure similar to that used to prepare compound 120 was used giving 15 . 9 g of 128 as an oil . ms , m / z ( relative intensity ): 129 [ m − 1h , 100 %], 170 [ m − 1h + ch 3 cn , 70 %]. a procedure similar to that used to prepare ( 4r , 5s )- 4 - methyl - 3 -(( s )- 4 - methyl - heptanoyl )- 5 - phenyl - oxazolidin - 2 - one 121 was used giving 35 . 0 g of crude ( 4r , 5s )- 4 - methyl - 3 -(( s )- 4 - methyl - hexanoyl )- 5 - phenyl - oxazolidin - 2 - one 129 as an oil . it was used in the next step without further purification . ms , m / z ( relative intensity ): 290 [ m + 1h , 100 %], 331 [ m + 1h + ch 3 cn , 20 %]. a procedure similar to that used to prepare ( 3s , 5s )- 5 - methyl - 3 -(( 4r , 5s )- 4 - methyl - 2 - oxo - 5 - phenyl - oxazolidine - 3 - carbonyl )- octanoic acid tert - butyl ester 122 was used to give 4 . 6 . 0 g , 25 . 4 % of 130 as a white solid . ms , m / z ( relative intensity ): 348 [ m − c ( ch 3 ) 3 + 1h , 100 %], 443 [ m − 1h + ch 3 cn , 100 %], 402 [ m − 1h , 55 %], 404 [ m + 1h , 45 %]. a procedure similar to that used to prepare ( 3s , 5s )- 3 - hydroxymethyl - 5 - methyl - octanoic acid tert - butyl ester 123 was giving 1 . 2 g , 52 . 1 % of 131 as an oil . ms , m / z ( relative intensity ): 175 [ m − c ( ch 3 ) 3 + 1h , 100 %], 173 [ m − c ( ch 3 ) 3 - 1 h , 100 %], 216 [ m − c ( ch 3 ) 3 + 1h + ch 3 cn , 95 %]. a procedure similar to the preparation of ( 3s , 5r )- 5 - methyl - 3 -( toluene - 4 - sulfonyloxymethyl )- octanoic acid tert - butyl ester 104 was followed giving 2 . 1 g of 132 as an oil . the product was used in the next step without further purification . ms , m / z ( relative intensity ): 329 [ m − c ( ch 3 ) 3 + 1h , 85 %], 370 [ m − c ( ch 3 ) 3 + 1h + ch 3 cn , 65 %]. a procedure similar to the preparation of ( 3s , 5r )- 3 - azidomethyl - 5 - methyl - octanoic acid tert - butyl ester 105 was followed giving 0 . 76 g , 54 . 0 % of 133 as an oil . ms , m / z ( relative intensity ): 198 [ m − c ( ch 3 ) 3 - 1 h , 100 %] a procedure similar to that used for ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - octanoic acid tert - butyl ester 126 was used giving 0 . 62 g of 134 as an oil . the product was used in the next step without further purification . ms , m / z ( relative intensity ): 230 [ m + 1h , 100 %], 271 [ m + 1h + ch 3 cn , 45 %]. a procedure similar to that used for example 11 was used giving ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - heptanoic acid ( 0 . 3 g , 65 . 1 %) as a white solid . 1 h nmr ( cd 3 od ) δ 2 . 80 - 3 . 00 ( m , 2h ), 2 . 40 ( m , 1h ), 2 . 20 ( dd , j = 8 . 2 , 7 . 1 hz , 1h ), 2 . 05 ( m , 1h ), 1 . 30 - 1 . 50 ( m , 3h ), 1 . 00 - 1 . 20 ( m , 2h ), 0 . 9 ( m , 6h ); ms , m / z ( relative intensity ): 187 [ m + 1h , 100 %], 211 [ m + 1h + ch 3 cn , 30 %]. ms , m / z ( relative intensity ): 174 [ m + 1h , 100 %], 172 [ m − 1h , 100 %], 215 [ m + 1h + ch 3 cn , 20 %]. lithium chloride ( 0 . 39 g , 9 . 12 mmol ) and copper ( i ) chloride ( 0 . 61 g , 4 . 56 mmol ) were combined in 45 ml thf at ambient temperature and stirred 15 minutes , then cooled to 0 ° c . at which time ethylmagnesium bromide ( 1 m solution in thf , 45 ml , 45 mmol ) was added . ( s )- citronellyl bromide ( 5 . 0 g , 22 . 8 mmol ) was added dropwise and the solution was allowed to warm slowly to ambient temperature with stirring overnight . the reaction was quenched by cautious addition of sat . nh 4 cl ( aq ), and stirred with et 2 o and sat . nh 4 cl ( aq ) for 30 minutes . the phases were separated and the organic phase dried ( mgso 4 ) and concentrated . the crude product was used without purification . to a solution of alkene 135 ( 3 . 8 g , 22 . 8 mmol ) in 50 ml acetone at 0 ° c . was added jones &# 39 ; reagent ( 2 . 7 m in h 2 so 4 ( aq ), 40 ml , 108 mmol ) and the solution was allowed to warm slowly to ambient temperature with stirring overnight . the mixture was partitioned between et 2 o and h 2 o , the phases were separated , and the organic phase washed with brine , dried ( mgso 4 ), and concentrated . the residue was purified by flash chromatography ( 8 : 1 hexanes : etoac ) to afford 2 . 14 g ( 59 %) of acid 136 as a colorless oil : lrms : m / z 156 . 9 ( m +); 1 h nmr ( cdcl 3 ): δ 2 . 33 ( m , 2h ), 1 . 66 ( m , 1h ), 1 . 43 ( m , 2h ), 1 . 23 ( m , 5h ), 1 . 10 ( m , 1h ), 0 . 86 ( m , 6h ). jones &# 39 ; reagent was prepared as a 2 . 7m solution by combining 26 . 7 g cro 3 , 23 ml h 2 so 4 , and diluting to 100 ml with h 2 o . to acid 136 ( 2 . 14 g , 13 . 5 mmol ) in 25 ml ch 2 cl 2 at 0 ° c . was added 3 drops dmf , followed by oxalyl chloride ( 1 . 42 ml , 16 . 2 mmol ) resulting in vigorous gas evolution . the solution was warmed directly to ambient temperature , stirred 30 minutes , and concentrated . meanwhile , to a solution of the oxazolidinone ( 2 . 64 g , 14 . 9 mmol ) in 40 ml thf at − 78 ° c . was added n - butyllithium ( 1 . 6 m soln in hexanes , 9 . 3 ml , 14 . 9 mmol ) dropwise . the mixture was stirred for 10 minutes at which time the acid chloride in 10 ml thf was added dropwise . the reaction was stirred 30 minutes at − 78 ° c ., then warmed directly to ambient temperature and quenched with sat . nh 4 cl . the mixture was partitioned between et 2 o and sat . nh 4 cl ( aq ), the phases were separated , and the organic phase dried ( mgso 4 ), and concentrated to furnish 3 . 2 g of oxazolidinone 137 as a colorless oil . lrms : m / z 318 . 2 ( m +); 1 h nmr ( cdcl 3 ): δ 7 . 34 ( m , 5h ), 5 . 64 ( d , j = 7 . 3 hz , 1h ), 4 . 73 ( quint , j = 6 . 8 hz , 1h ), 2 . 96 ( m , 1h ), 2 . 86 ( m , 1h ), 1 . 66 ( m , 1h ), 1 . 47 ( m , 2h ), 1 . 26 ( m , 5h ), 1 . 13 ( m , 1h ), 0 . 88 ( m , 9h ). the crude product was used without purification . to a solution of diisopropylamine ( 1 . 8 ml , 12 . 6 mmol ) in 30 ml thf at − 78 ° c . was added n - butyllithium ( 1 . 6 m soln in hexanes , 7 . 6 ml , 12 . 1 mmol ), and the mixture stirred 10 minutes at which time oxazolidinone 137 ( 3 . 2 g , 10 . 1 mmol ) in 10 ml thf was added dropwise . the solution was stirred for 30 minutes , t - butyl bromoacetate ( 1 . 8 ml , 12 . 1 mmol ) was added quickly dropwise at − 50 ° c ., and the mixture was allowed to warm slowly to 10 ° c . over 3 hours . the mixture was partitioned between et 2 o and sat . nh 4 cl ( aq ), the phases were separated , and the organic phase dried ( mgso 4 ), and concentrated . the residue was purified by flash chromatography ( 16 : 1 to 8 : 1 hexanes : etoac ) to provide 2 . 65 g ( 61 %) of ester 138 as a colorless crystalline solid , mp = 84 - 86 ° c . [ α ] d 23 + 17 . 1 ( c = 1 . 00 , chcl 3 ); 1 h nmr ( cdcl 3 ): δ 7 . 34 ( m , 5h ), 5 . 62 ( d , j = 7 . 3 hz , 1h ), 4 . 73 ( quint , j = 6 . 8 hz , 1h ), 4 . 29 ( m , 1h ), 2 . 67 ( dd , j = 9 . 8 , 16 . 4 hz , 1h ), 2 . 40 ( dd , j = 5 . 1 , 16 . 4 hz , 1h ), 1 . 69 ( m , 1h ), 1 . 38 ( s , 9h ), 1 . 28 ( m , 7h ), 1 . 08 ( m , 1h ), 0 . 88 ( m , 9h ); 13 c nmr ( cdcl 3 ) δ 176 . 45 , 171 . 22 , 152 . 71 , 133 . 64 , 128 . 86 , 125 . 86 , 80 . 83 , 78 . 87 , 55 . 33 , 40 . 02 , 38 . 21 , 37 . 59 , 36 . 31 , 30 . 86 , 29 . 29 , 28 . 22 , 23 . 14 , 20 . 41 , 14 . 36 , 14 . 26 . anal . calcd for c 25 h 37 no 5 : c , 69 . 58 ; h , 8 . 64 ; n , 3 . 25 . found : c , 69 . 37 ; h , 8 . 68 ; n , 3 . 05 . to a solution of ester 138 ( 2 . 65 g , 6 . 14 mmol ) in 20 ml thf at 0 ° c . was added a precooled ( 0 ° c .) solution of lioh monohydrate ( 1 . 0 g , 23 . 8 mmol ) and hydrogen peroxide ( 30 wt % aqueous soln , 5 . 0 ml ) in 10 ml h 2 o . the mixture was stirred vigorously for 90 minutes , then warmed to ambient temperature and stirred 90 minutes . the reaction was quenched at 0 ° c . by addition of 100 ml 10 % nahso 3 ( aq ), then extracted with et 2 o . the phases were separated , and the organic phase washed with brine , dried ( mgso 4 ), and concentrated . the crude acid 139 was used without purification . to a solution of the crude acid 139 ( 6 . 14 mmol ) in 30 ml thf at 0 ° c . was added borane - dimethyl sulfide complex ( 2 . 0 m soln in the , 4 . 6 ml , 9 . 2 mmol ), and the mixture was allowed to warm slowly to ambient temperature overnight . additional bh 3 - dms was added until the acid was completely consumed ( ca . 5 ml ). the reaction was quenched by addition of meoh , then partitioned between et 2 o and sat . nahco 3 ( aq ). the phases were separated , and the organic phase washed with brine , dried ( mgso 4 ), and concentrated to provide alcohol 140 . lrms : m / z 226 . 1 ; 1 hnmr ( cdcl 3 ): δ 3 . 63 ( dd , j = 11 . 0 , 4 . 2 hz , 1h ), 3 . 42 ( dd , j = 11 . 0 , 6 . 8 hz , 1h ), 2 . 30 ( dd , j = 14 . 9 , 7 . 6 hz , 1h ), 2 . 20 ( dd , j = 14 . 9 , 5 . 6 hz , 1h ), 2 . 03 ( m , 2h ), 1 . 42 ( s , 9h ), 1 . 24 ( m , 6h ), 1 . 02 ( m , 2h ), 0 . 85 ( m , 6h ). the crude product was used without purification . to alcohol 140 ( 6 . 14 mmol ) in 30 ml ch 2 cl 2 at 0 ° c . was added dmap ( 0 . 1 g ), p - toluenesulfonyl chloride ( 1 . 37 g , 7 . 2 mmol ), and then triethylamine ( 1 . 8 ml , 13 mmol ) was added quickly dropwise . the mixture was warmed immediately to ambient temperature following addition and stirred overnight , and did not proceed to completion . the mixture was partitioned between et 2 o and 1n hcl ( aq ), the phases were separated , and the organic phase washed with sat . nahco 3 ( aq ), dried ( mgso 4 ), and concentrated to provide tosylate 141 . the is product was used without further purification . a procedure similar to the preparation of ( 3s , 5r )- 3 - azidomethyl - 5 - methyl - octanoic acid tert - butyl ester 105 was followed giving azide 142 as a colorless oil . lrms : m / z 200 . 1 ; 11h nmr ( cdcl 3 ): δ 3 . 31 ( dd , j = 12 . 2 , 4 . 2 hz , 1h ), 3 . 19 ( dd , j = 12 . 2 , 5 . 9 hz , 1h ), 2 . 22 ( m , 1h ), 2 . 10 ( m , 1h ), 1 . 39 ( s , 9h ), 1 . 21 ( m , 8h ), 1 . 00 ( m , 2h ), 0 . 81 ( m , 6h ). the azide 142 ( 1 . 0 g ) was hydrogenated in the presence of 20 % pd / c , etoh , at 45 psi of h 2 for 15 hours to provide the crude amino ester 143 which was concentrated and used without purification . to the amino ester 143 was added 6 ml 6n hcl ( aq ) and the mixture was heated to reflux 90 minutes , cooled , and concentrated . recrystallization from etoac : hexanes provided 0 . 38 g ( 45 % from azide ) of ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - nonanoic acid hydrochloride as a colorless crystalline solid ( hcl salt ), and a second crop of 82 mg ( 10 % from azide ) was also obtained . mp = 146 - 156 ° c . lrms : m / z 200 . 1 ( m +); 1 h nmr ( cdcl 3 ): δ 2 . 87 ( dd , j = 13 . 2 , 5 . 4 hz , 1h ), 2 . 79 ( dd , j = 13 . 2 , 7 . 3 hz , 1h ), 2 . 29 ( d , j = 6 . 8 hz , 2h ), 2 . 08 ( m , 1h ), 1 . 31 ( m , 1h ), 1 . 09 ( m , 7h0 , 0 . 92 ( m , 1h ), 0 . 68 ( m , 6h ). anal . calcd for c 11 h 24 no 2 c1 : c , 55 . 57 ; h , 10 . 17 ; n , 5 . 89 . found : c , 55 . 69 ; h , 10 . 10 ; n , 5 . 86 . the ( s )- acid 145 was prepared from ( r )- citronellyl bromide according to the procedure outlined above for ( r )- 4 - methyl - octanoic acid 136 . the yield was comparable and the 1 h nmr spectrum was identical to that of the ( r )- acid enantiomer . lrms : m / z 158 . 9 ( m + 1 ). oxazolidinone 146 was prepared from acid 145 as described above for ( 4r , 5s )- 4 - methyl - 3 -(( r )- 4 - methyl - octanoyl )- 5 - phenyl - oxazolidin - 2 - one 137 . lrms : m / z 290 . 1 ( m − 27 ); 1 h nmr ( cdcl 3 ): δ 7 . 38 ( m , 3h ), 7 . 28 ( m , 2h ), 5 . 64 ( d , j = 7 . 1 hz , 1h ), 4 . 74 ( quint , j = 6 . 8 hz , 1h ), 2 . 92 ( m , 2h ), 1 . 71 ( m , 1h ), 1 . 42 ( m , 7h ), 1 . 18 ( m , 1h ), 0 . 88 ( m , 9h ). t - butyl ester 147 was prepared from oxazolidinone 146 as described above for compound 138 . lrms : m / z 348 . 1 ( m - 83 ). alcohol 149 was prepared from the t - butyl ester 147 as described above for ( 3s , 5r )- 3 - hydroxymethyl - 5 - methyl - nonanoic acid tert - butyl ester 140 . lrms : m / z 156 . 9 ( m − 100 ); 1 h nmr ( cdcl 3 ): δ 3 . 60 ( dd , j = 11 . 0 , 4 . 6 hz , 1h ), 3 . 45 ( dd , j = 11 . 0 , 6 . 8 hz , 1h ), 2 . 24 ( m , 2h ), 2 . 04 ( m , 2h ), 1 . 42 ( s , 9h ), 1 . 17 - 1 . 38 ( m , 7h ), 1 . 11 ( m , 1h ), 0 . 84 ( m , 6h ). ( 3s , 5s )- 3 - aminomethyl - 5 - methyl - nonanoic acid was obtained from 149 as described above for ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - nonanoic acid hydrochloride . the crude hcl salt thus obtained was purified by ion exchange chromatography on dowex 50wx8 50 - 100 mesh , h - form resin , using 10 % nh 4 oh as eluant to provide the free base . the waxy solid was washed twice with et 2 o and dried to furnish an amorphous white solid , mp 144 - 146 ° c . lrms : m / z 172 . 0 ( m − 28 ); 1 h nmr ( cdcl 3 ): δ 2 . 76 ( d , j = 5 . 9 hz , 2h ), 2 . 14 ( m , 1h ), 1 . 96 ( m , 2h ), 1 . 25 ( m , 1h ), 1 . 12 ( m , 6h ), 0 . 96 ( m , 2h ), 0 . 66 ( m , 6h ). a procedure similar to the preparation of ( s )- 2 , 6 - dimethyl - non - 2 - ene 119 was used giving 153 as a colorless oil ( 20 . 16 g , 98 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 5 . 10 - 5 . 06 ( m , 1h ), 2 . 10 - 1 . 89 ( m , 2h ), 1 . 66 ( s , 3h ), 1 . 58 ( s , 3h ), 1 . 34 - 1 . 23 ( m , 4h ), 1 . 15 - 1 . 06 ( m , 2h ), 0 . 88 - 0 . 81 ( m , 11h ). ( r )- 2 , 6 - dimethylundec - 2 - ene 153 ( 10 . 03 g , 55 . 03 mmol ) was dissolved in acetone ( 270 ml ) and cooled to 0 ° c . jones reagent ( cro 3 / h 2 so 4 ) ( 2 . 7 m , 120 ml ) was added dropwise , and the reaction allowed to warm to room temperature over 18 hours . the reaction was poured on to water / na 2 so 4 ( 200 ml ), and the aqueous layer extracted with ethyl acetate ( 4 × 100 ml ). the combined organics were dried over mgso 4 , filtered and rotovapped to give an oil . the crude oil was dissolved in ch 2 cl 2 ( 400 ml ) and cooled to − 78 ° c . ozone was bubbled into reaction until blue to remove traces of the impurity ( 6e )( 3s )- 3 , 7 - dimethylocta - 1 , 6 - diene . dimethylsulfide ( 5 ml ) was added , and the reaction stirred at room temperature for 2 hours . the solvent was removed , and the crude material chromatographed on silica eluting with 20 % etoac / hex to give oil . the oil was dissolved in ether ( 100 ml ) and extracted with 10 % naoh ( 2 × 25 ml ). the aqueous layers were combined and extracted with ether ( 50 ml ). the aqueous layer was cooled to 0 ° c . and acidified with hcl . the acidic layer was extracted with etoac ( 3 × 100 ml ), and the combined extracts dried over mgso 4 , filtered and rotovapped to give 154 as an oil ( 6 . 86 g , 54 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 2 . 40 - 2 . 25 ( m , 4h ), 1 . 70 - 1 . 62 ( m , 2h ), 1 . 47 - 1 . 11 ( m , 8h ), 0 . 87 - 0 . 84 ( m , 6h ); [ α ] d =− 11 . 4 ( c1 in chcl 3 ). compound 154 ( 6 . 504 g , 37 . 76 mmol ) was dissolved in thf ( 95 ml ) and cooled to 0 ° c . triethylamine ( 19 . 74 ml , 141 . 6 mmol ) was added dropwise , followed by dropwise addition of trimethylacetyl chloride ( 6 . 98 ml , 56 . 64 mmol ). the thick white suspension was stirred at 0 ° c . for 90 minutes . licl ( 1 . 86 g , 41 . 54 mmol ), ( 4r )- 4 - methyl - 5 - phenyl - 1 , 3 - oxazolidin - 2 - one ( 6 . 824 g , 38 . 51 mmol ), and thf ( 70 ml ) were added , and the reaction warmed to room temperature overnight . the solvent was evaporated . the solids were taken up in etoac , filtered off , and washed generously with etoac . the filtrate was washed with water ( 2 × 50 ml ), and brine . the organics were dried over mgso 4 , filtered , and rotovapped . the crude material was chromatographed on silica eluting with 10 % etoac / hexanes to give 155 as an oil ( 10 . 974 g , 88 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 44 - 7 . 35 ( m , 3h ), 7 . 31 - 7 . 26 ( m , 2h ), 5 . 66 ( d , j = 7 . 33 hz , 1h ), 4 . 76 ( quin , j = 7 . 03 hz , 1h ), 3 . 04 - 2 . 96 ( m , 1h ), 2 . 93 - 2 . 86 ( m , 1h ), 1 . 74 - 1 . 66 ( m , 1h ), 1 . 52 - 1 . 47 ( m , 1h ), 1 . 46 - 1 . 36 ( m , 2h ), 1 . 27 - 1 . 16 ( m , 2h ), 0 . 92 - 0 . 87 ( m , 8h ); [ α ] d =+ 34 . 1 ( c1 in chcl 3 ). a procedure similar to the preparation of ( 3s , 5s )- 5 - methyl - 3 -(( 4r , 5s )- 4 - methyl - 2 - oxo - 5 - phenyl - oxazolidine - 3 - carbonyl )- octanoic acid tert - butyl ester 122 was followed giving ( 3s , 5r )- 5 - methyl - 3 -(( 4r , 5s )- 4 - methyl - 2 - oxo - 5 - phenyl - oxazolidine - 3 - carbonyl )- decanoic acid tert - butyl ester 156 as an oil ( 0 . 668 g , 90 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 41 - 7 . 28 ( m , 5h ), 5 . 63 ( d , j = 7 . 33 hz , 1h ), 4 . 74 ( quin , j = 6 . 84 hz , 1h ), 4 . 33 - 4 . 26 ( m , 1h ), 2 . 68 ( dd , j = 16 . 4 , 9 . 77 hz , 1h ), 2 . 41 ( dd , j = 16 . 6 , 4 . 88 hz , 1h ), 1 . 68 ( quin , j = 6 . 6 hz , 1h ), 1 . 50 - 1 . 32 ( m , 10h ), 1 . 28 - 1 . 21 ( m , 1h ), 1 . 15 - 1 . 08 ( m , 1h ), 0 . 90 - 0 . 86 ( m , 9h ); ms ( apci ) m / z 348 ( m + − 97 , 100 %); [ α ] d =+ 18 . 8 ( c1 in chcl 3 ). compound 156 ( 5 . 608 b , 12 . 59 mmol ) was dissolved in thf / h 2 o ( 60 ml / 14 ml ) and cooled to 0 ° c . lioh ( 1n , 18 . 89 ml ) and h 2 o 2 ( 35 %, 4 . 45 ml , 50 . 4 mmol ) were combined , and then added to the reaction dropwise keeping t & lt ; 5 ° c . the reaction was stirred at 0 ° c . for 4 hours , and quenched with na 2 so 3 ( 6 . 3 g ) and nahso 3 ( 3 . 4 g ) in 50 ml h 2 o added dropwise . the reaction was stirred for 15 minutes , and the layers separated . the aqueous layer was extracted with etoac ( 3 × 100 ml ), and the combined extracts dried over mgso 4 , filtered , and rotovapped to give an oil . the crude material was dissolved in etoac ( 10 ml ) and added dropwise to heptane ( 250 ml ). the suspension was stirred for 20 minutes , and the solids filtered and washed with heptane . the filtrate was washed with 60 ° c . h 2 o ( 100 ml ), dried over mgso 4 , filtered , and rotovapped to give 157 as an oil ( 3 . 52 g ). the material was used directly in the next step . compound 157 ( 3 . 52 g , 12 . 3 mmol ) was dissolved in anhydrous thf ( 123 ml ) and cooled to 0 ° c . borane dimethylsulfide complex ( 10 m , 3 . 69 ml ) was added dropwise , and the reaction then warmed to room temperature and stirred for 1 hour . the reaction was cooled to 0 ° c ., and quenched with meoh ( 20 ml ) added dropwise . the reaction was stirred for 18 hours , and the solvent rotovapped off . the crude material was chromatographed on silica eluting with 20 % etoac / hexanes to give 158 ( 2 . 28 g , 68 %) as an oil . 1 h nmr ( 400 mhz , cdcl 3 ) δ 3 . 65 - 3 . 59 ( m , 1h ), 3 . 43 ( dd , j = 11 . 1 , 6 . 96 hz , 1h ), 2 . 31 ( dd , j = 14 . 9 , 7 . 57 hz , 1h ), 2 . 21 ( dd , j = 15 . 1 , 5 . 62 hz , 1h ), 2 . 06 - 2 . 02 ( m , 1h ), 1 . 43 ( s , 9h ), 1 . 40 - 1 . 25 ( m , 4h ), 1 . 07 - 1 . 13 ( m , 1h ), 1 . 03 - 0 . 96 ( m , 1h ), 0 . 86 - 0 . 84 ( m , 6h ); ms ( apci ) m / z 216 ( m + − 56 , 100 %). compound 158 ( 2 . 27 g , 8 . 33 mmol ) was dissolved in ch 2 cl 2 ( 30 ml ) and cooled to 0 ° c . tosyl chloride ( 1 . 91 g , 10 . 0 mmol ) and catalytic dmap were added , followed by dropwise addition of triethylamine ( 2 . 55 ml , 18 . 33 mmol ). the reaction was then stirred at 0 ° c . for 18 hours . the solvent was rotovapped off ( removed under reduced pressure ), and the crude material washed with etoac and filtered . the solids were washed with etoac , and the filtrate washed with 0 . 5n hcl ( 20 ml ), brine ( 30 ml ), dried over mgso 4 , filtered and rotovapped . the oil was chromatographed on silica eluting with a 5 % etoac / hexanes gradient to 10 % etoac / hexanes to give 159 ( 3 . 399 g , 96 %) as an oil . 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 75 ( d , j = 8 . 30 hz , 2h ), 7 . 31 ( d , j = 8 . 30 hz , 2h ), 3 . 99 ( dd , j = 9 . 65 , 3 . 54 hz , 1h ), 3 . 89 ( dd , j = 9 . 52 , 5 . 37 hz , 1h ), 2 . 42 ( s , 3h ), 2 . 28 ( dd , j = 14 . 7 , 6 . 23 hz , 1h ), 2 . 19 - 2 . 14 ( m , 1h ), 2 . 10 ( dd , j = 14 . 9 , 6 . 35 hz , 1h ), 1 . 38 ( s , 9h ), 1 . 31 - 1 . 17 ( m , 3h ), 1 . 08 - 0 . 81 ( m , 2h ), 0 . 79 - 0 . 76 ( m , 6h ); [ α ] d =− 10 . 1 ( c1 in chcl 3 ). compound 159 ( 3 . 01 g , 7 . 05 mmol ), sodium azide ( 1 . 26 g , 19 . 40 mmol ) and dmso ( 12 ml ) were combined and heated to 60 ° c . for 3 hours . etoac ( 100 ml ) was added to the reaction and filtered . the solids were washed with etoac ( 20 ml ), and the filtrated evaporated . the crude material was chromatographed on silica eluting with 5 % etoac / hexanes to give 160 as an oil ( 1 . 86 g , 89 %). a solution of compound 160 ( 1 . 86 g , 6 . 25 mmol ) in thf ( 50 ml ) was shaken over 5 % pd / c under hydrogen and pressure for 8 hours with three purges of hydrogen . the catalyst was filtered off and the filtrate evaporated . the crude material was chromatographed on silica eluting with methanol to give 161 as an oil ( 1 . 21 g , 71 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 2 . 70 ( dd , j = 12 . 9 , 4 . 40 hz , 1h ), 2 . 54 ( dd , j = 12 . 7 , 6 . 59 hz , 1h ), 2 . 26 ( dd , j = 14 . 5 , 6 . 96 , 1h ), 2 . 12 ( dd , j = 14 . 5 , 6 . 47 hz , 1h ), 1 . 91 ( m , 1h ), 1 . 91 ( m , 1h ), 1 . 43 ( s , 12h ), 1 . 39 - 1 . 25 ( m , 4h ), 1 . 14 - 1 . 07 ( m , 1h ), 1 . 03 - 0 . 97 ( m , 1h ), 0 . 86 - 0 . 82 ( m , 6h ). compound 161 ( 1 . 20 g , 4 . 44 mmol ) was heated to 50 ° c . in 3n hcl ( 30 ml ) for 4 hours . the solvent was evaporated , and the oil washed with toluene , and evaporated . the crude material was passed through an ion exchange column ( dowex 50wx8 - 100 , strongly acidic ) eluting with water , then 0 . 5n nh 4 oh . isolate ( 3s , 5r )- 3 - aminomethyl - 5 - methyl - decanoic acid as a white solid ( 0 . 725 g , 75 %): mp = 174 - 175 ° c . ; 1 h nmr ( 400 mhz , cdcl 3 ) δ2 . 83 ( dd , j = 12 . 69 , 4 . 88 hz , 1h ), 2 . 70 ( dd , j = 13 . 1 , 7 . 45 hz , 1h ), 2 . 08 ( d , j = 6 . 59 hz , 2h ), 1 . 98 ( m , 1h ), 1 . 28 - 1 . 20 ( m , 1h ), 1 . 19 - 1 . 09 ( m , 2h ), 0 . 99 - 0 . 91 ( m , 2h ), 0 . 66 ( m , 6h ); ms ( apci ) m / z 215 ( m + , 10 %), 174 ( m + − 41 , 100 %); [ α ] d =− 5 . 7 ( c1 . 025 in h 2 o ). npropylmagnesium chloride / ether solution ( 2 . 0 m , 228 ml ) was cooled to − 20 ° c . under a n 2 atmosphere . licl ( 3 . 87 g , 91 . 25 mmol ), cucl 2 ( 6 . 13 g , 45 . 63 mmol ), and distilled thf ( 456 ml ) were combined and stirred for 30 minutes . the li 2 cucl 4 solution was added via cannula to the grignard reagent , and the resulting solution stirred for 30 minutes at − 20 ° c . r -(−)- citronellyl bromide ( 50 g , 228 . 1 mmol ) was dissolved in thf ( 60 ml ) and added dropwise to the grignard solution . the reaction was stirred at 0 ° c . for 1 hour . the reaction was cooled to − 40 ° c . and quenched with nh 4 cl ( sat &# 39 ; d , 200 ml ) added dropwise . the layers were separated and the aqueous layer extracted with ether ( 3 × 100 ml ). the combined organics were dried over mgso 4 , filtered , and rotovapped to give an oil . the crude material was chromatographed on silica eluting with hexanes to give 162 as a colorless oil ( 9 . 15 g , 22 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 5 . 10 - 5 . 06 ( m , 1h ), 2 . 10 - 1 . 89 ( m , 2h ), 1 . 66 ( s , 3h ), 1 . 58 ( s , 3h ), 1 . 34 - 1 . 23 ( m , 4h ), 1 . 15 - 1 . 06 ( m , 2h ), 0 . 88 - 0 . 81 ( m , 11h ). compound 162 ( 7 . 97 g , 43 . 7 mmol ) was dissolved in acetone ( 214 ml ) and cooled to 0 ° c . jones reagent ( cro 3 / h 2 so 4 ) ( 2 . 7 m , 95 ml ) was added dropwise , and the reaction allowed to warm to room temperature over 18 hours . the reaction was poured on to water / na 2 so 4 ( 200 ml ), and the aqueous layer extracted with ethyl acetate ( 4 × 100 ml ). the combined organics were dried over mgso 4 , filtered , and rotovapped to give an oil . the crude oil was chromatographed on silica eluting with hexanes to give 163 as an oil ( 5 . 56 g , 74 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 2 . 40 - 2 . 25 ( m , 4h ), 1 . 70 - 1 . 62 ( m , 2h ), 1 . 47 - 1 . 11 ( m , 8h ), 0 . 87 - 0 . 84 ( m , 6h ); ms apci m / z 170 . 9 ( m − 1 , 100 %). a procedure similar to that used to prepare compound 155 was used except that ( s )- 4 - methylnonanoic acid 163 ( 5 . 56 g , 32 . 27 mmol ) was used as a reactant to give 164 as an oil ( 10 . 70 g 100 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 42 - 7 . 34 ( m , 3h ), 7 . 28 ( d , j = 6 . 59 hz , 2h ), 5 . 64 ( d , j = 7 . 33 hz , 1h ), 4 . 74 ( quin , j = 6 . 78 hz , 1h ), 2 . 94 - 2 . 85 ( m , 2h ), 1 . 73 - 1 . 67 ( m , 1h ), 1 . 47 - 1 . 43 ( m , 1h ), 1 . 39 - 1 . 22 ( m , 7h ), 0 . 90 - 0 . 84 ( m , 8h ). a procedure similar to that used to prepare compound 156 was used to give 165 as a solid ( 4 . 25 g , 61 %). ms ( apci ) m / z 446 ( m + + 1 , 10 %), 390 ( m + − 55 , 100 %, - tbu ). a procedure similar to that used for compound 157 was used except that ester 165 ( 8 . 42 g , 18 . 89 mmol ) was used as a reactant to give 166 as an oil ( 5 . 81 g ). the material was used directly in the next step . ms ( apci ) m / z 285 ( m − 1 , 100 %). a procedure similar to that used to prepare compound 158 was used except that ( s )- 2 -(( s )- 2 - methyl - heptyl )- succinic acid 4 - tert - butyl ester 166 ( 5 . 78 g , 20 . 18 mmol ) was used as a reactant to give 167 as an oil ( 4 . 18 g , 76 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 3 . 64 - 3 . 58 ( m , 1h ), 3 . 84 - 3 . 42 ( m , 1h ), 2 . 28 - 2 . 20 ( m , 1h ), 2 . 09 - 2 . 02 ( m , 1h ), 1 . 43 ( s , 9h ), 1 . 26 - 1 . 18 ( m , 8h ), 1 . 11 - 1 . 04 ( m , 2h ), 0 . 87 - 0 . 83 ( m , 6h ); ms ( apci ) m / z 217 ( m + − 55 , 50 %, - tbu ). a procedure similar to that used to prepare compound 159 was used except that ( 3s , 5s )- 3 - hydroxymethyl - 5 - methyl - decanoic acid tert - butyl ester 167 ( 4 . 164 g , 15 . 29 mmol ) was used as a reactant to give 168 as an oil ( 4 . 17 g , 64 %). 1 h nmr ( 400 mhz , cdcl 3 ) δ 7 . 75 ( d , j = 8 . 30 hz , 2h ), 7 . 31 ( d , j = 8 . 30 hz , 2h ), 3 . 97 ( dd , j = 9 . 52 , 4 . 15 hz , 1h ), 3 . 90 ( dd , j = 9 . 52 , 5 . 13 hz , 1h ), 2 . 42 ( s , 3h ), 2 . 28 , 2 . 19 - 2 . 13 ( m , 2h ), 1 . 37 ( s , 9h ), 1 . 27 - 1 . 01 ( m , 1h ), 0 . 85 ( t , j = 7 . 08 hz , 3h ), 0 . 76 ( d , j = 6 . 35 hz , 3h ). a procedure similar to that used to prepare compound 160 was used except ( 3s , 5s )- 5 - methyl - 3 -( toluene - 4 - sulfonyloxymethyl )- decanoic acid tert - butyl ester 168 ( 4 . 155 g , 9 . 74 mmol ) was used as a reactant to give 169 as an oil ( 2 . 77 g , 96 %). ms ( apci ) m / z 270 ( m + − 27 , 30 %, — n 2 ), 214 ( m + − 87 , 100 %, - tbu , — n 2 ). a procedure similar to that used to prepare compound 161 was used except that ( 3s , 5s )- 3 - azidomethyl - 5 - methyl - decanoic acid tert - butyl ester 169 ( 2 . 50 g , 8 . 405 mmol ) was used as a reactant to give 170 as an oil ( 1 . 648 g , 72 %). ms ( apci ) m / z 272 ( m + + 1 , 100 %). a procedure similar to that used for example 15 was used except tert - butyl ( 3s , 5s )- 3 -( aminomethyl )- 5 - methyldecanoate 170 ( 1 . 6 g , 6 . 00 mmol ) was used as a reactant to give example 16 as a white solid ( 72 %). ms ( apci ) m / z 272 ( m + + 1 , 100 %). mp = 174 - 175 ° c . ; 1 h nmr ( 400 mhz , cd 3 od ) δ 2 . 91 ( dd , j = 12 . 9 , 3 . 91 hz , 1h ), 2 . 83 ( dd , j = 12 . 7 , 7 . 57 hz , 1h ), 2 . 43 ( dd , j = 15 . 6 , 3 . 17 hz , 1h ), 2 . 19 ( dd , j = 15 . 6 , 8 . 80 hz , 1h ), 2 . 08 - 2 . 04 ( m , 1h ), 1 . 53 ( m , 1h ), 1 . 38 - 1 . 27 ( m , 7h ), 1 . 78 - 1 . 03 ( m , 2h ), 0 . 90 - 0 . 86 ( m , 6h ), 0 . 66 ( m , 6h ); ms ( apci ) m / z 216 ( m + + 1 , 100 %), 214 ( m − 1 , 100 %); [ α ] d =+ 21 . 4 ( c1 in meoh ). large scale procedure for the synthesis of acetic acid ( s )- 2 - benzyl - 3 - methyl - butyl ester 173 from 171 a of n - butyl lithium ( 10 m in hexane , 100 ml , 1000 mmol , 3 . 9 equiv .) was added to a solution of diisopropylamine ( 108 . 9 g , 150 . 9 ml , 1 . 076 mol , 4 . 20 equiv .) in thf ( 600 ml ), at − 78 ° c . the resulting solution was stirred for 10 minutes and warmed to 0 ° c ., and hold at the temperature for 10 minutes . borane - ammonia complex ( 31 . 65 g , 1 . 025 mmol , and 4 . 0 equiv ) was added in one portion , and the suspension was stirred at 0 ° c . for 15 minutes , and at 23 ° c . for 15 minutes , and then cooled to 0 ° c . a solution of amide 171 ( 86 g , 256 . 41 mmol , 1 equiv .) in thf was added to the cold hydride via a cannula over 3 minutes . the reaction was stirred at 23 ° c . for overnight , then cooled to 0 ° c . excess hydride was quenched by the slow addition of 3n hcl ( 700 ml ). the reaction mixture was diluted with more aqueous hcl ( 3n , 200 ml ), and brine and then extracted with ether ( 4 × 15 ml ). the ether solution was concentrated to a small volume , and 200 ml 2n naoh was added , and stirred at 23 ° c . for 2 . 5 hours . more ether was added and the layers were separated . the aqueous layer was saturated with salt and extracted with ether ( 3 × 200 ml ). the combined organic was washed with brine and dried on sodium sulfate . the residue was flash chromatographed ( pet . ether - 25 % ether - tea ) to give alcohol 172 , 50 g . nmr ( cdcl 3 ) δ 7 . 35 - 7 . 16 ( m , 5h , c 6 h 5 ), 3 . 55 ( app . t , 2h , — ch 2 oh ), 2 . 71 ( dd , 1h , arch 2 ch —), 2 . 52 ( dd , 1h , arch 2 ch ), 1 . 87 ( m , 1h , chch ( me ), 1 . 67 ( m , 1h , ch ( me ) 2 ), 0 . 98 ( d , 3h , ch 3 ) and 0 . 96 ( d , 3h , ch 3 ). a sample 3 . 3 g was saved for characterization and the rest was immediately acetylated ( triethylamine 50 ml , dmap 4 . 6 g , acetic acid anhydride 32 ml ) overnight at room temperature . work up followed by chromatography on silica gel eluted with pet ether and then 10 % ether in pet ether gave 62 g of 173 . nmr ( cdcl 3 ) δ 7 . 30 - 7 . 14 ( m , 5h , c 6 h 5 ), 3 . 98 ( m , 2h , — ch 2 oac ), 2 . 71 ( dd , 1h , arch 2 ch —), 2 . 51 ( dd , 1h , arch 2 ch ), 1 . 99 ( s , 3h , ch 3 c ═ o ), 1 . 82 ( m , 1h , chch ( me ) and ch ( me ) 2 ), 0 . 97 ( d , 3h , ch 3 ) and 0 . 95 ( d , 3h , ch 3 ). acetate 173 ( 15 g , 68 . 18 mmol ) was dissolved in ch 3 cn ( 150 ml ), carbon tetrachloride ( 150 ml ) and hplc grade water ( 300 ml ) and stirred . sodium periodate ( 262 . 50 g , 1220 mmol ) was added followed by ruthenium chloride ( 650 mg , 3 . 136 mmol ). after overnight stirring it was diluted with ether and water , and filtered through a pad of celite . the organic portion was separated and the aqueous phase was further extracted with ether . after drying on magnesium sulfate the solvent was evaporated . potassium carbonate ( 42 g ) was added to the residue and refluxed overnight in methanol ( 250 ml ) and cooled to room temperature . after evaporation , water was added to dissolve the solid , and conc . hcl was added to bring the ph to 2 . chloroform was added and extracted overnight . the organic phase was separated , and aqueous was further extracted with chloroform . the combined organic extracts were dried , evaporated , and the product was purified on a silica gel column and the compound was eluted with 20 % ether in methylene chloride . fractions were monitored by tlc , and spots were detected with i 2 / ki solution . fractions were combined to give 4 . 6 g of lactone 175 . nmr ( cdcl 3 ) δ 4 . 38 ( dd , 1h , ch a h b o ), 3 . 93 ( app . t , 1h , ch a h b o ), 2 . 54 ( dd , 1h , ch c h d c ═ o ), 2 . 23 ( m , 2h , chch ( me ) and ch c h d c ═ o ), 1 . 60 ( m , 1h , ch ( me ) 2 ), 0 . 92 ( d , 3h , ch 3 ) and 0 . 85 ( d , 3h , ch 3 ). lithium bis ( trimethylsilyl ) amide ( 1 . 0 m solution in thf , 92 ml , 92 mmol ) was added in 3 - 5 minutes to a solution of ( s )- β -( 2 - propyl )- γ - butyrolactone 175 ( 11 . 68 g , 91 . 25 mmol ) in dry thf 100 ml at − 78 ° c . under argon atmosphere . it was stirred for 1 h and a solution of benzyl iodide ( 21 . 87 g , 100 . 37 mmol ) in dry thf was added rapidly . stirring was continued for 1 . 5 hours and quenched at − 78 ° c . by the addition of a solution of brine followed by ethyl acetate . the organic phase was separated and the aqueous was further extracted with ether . chromatography on silica gel first eluted with 5 % methylene chloride in pet ether , and finally with 10 % ether in pet ether gave desired compound 11 . 6 g , 58 %. nmr ( cdcl 3 ) δ 7 . 19 ( m , 5h , c 6 h 5 ), 4 . 02 ( app . t , 1h , ch a h b o ), 3 . 87 ( dd , 1h , ch a h b o ), 2 . 98 ( d , 2h , arch 2 ), 2 . 57 ( q , 1h , bnchc ═ o ), 2 . 05 ( m , 1h , chch ( me ) 2 , 1 . 55 ( m , 1h , ch ( me ) 2 ), 0 . 81 ( d , 3h , ch 3 ) and 0 . 72 ( d , 3h , ch 3 ). lactone 176 ( 6 . 5 g , 29 . 8 mmol ) was dissolved in abs . ethanol ( 80 ml ) and cooled in ice bath . anhydrous hbr was bubbled through the solution for 1 hour and stirred at room temperature overnight while maintaining reaction under dry atmosphere . it was poured onto ice cooled mixture of pet ether and brine . the organic phase was separated , and the aqueous was further extracted with pet ether . the combined organic solution was washed repeatedly with cold water and dried . solvent was removed in vacuo to give crude compound 7 . 0 g . nmr ( cdcl 3 ) δ 7 . 27 ( m , 5h , c 6 h 5 ), 4 . 02 ( m , 2h , ch 3 ch 2 o ), 3 . 70 ( dd , 1h , ch a h b br ), 3 . 55 ( dd , 1h , ch a h b br ), 2 . 97 ( m , 2h , arch 2 ), 2 . 83 ( q , 1h , bnchc ═ o ), 2 . 11 ( m , 1h , chch ( me ) 2 , 1 . 97 ( m , 1h , ch ( me ) 2 ), 1 . 10 ( t , 3h , ch 3 ch 2 o ), 0 . 96 ( d , 3h , ch 3 ) and 0 . 93 ( d , 3h , ch 3 ). bromoester 177 ( 7 . 25 g , about 80 % pure ), in ethanol ( 100 ml ) containing triethylamine ( 3 . 2 ml ) was hydrogenated overnight in the presence of 20 % pd / c ( 1 . 0 g ). it was filtered through a pad of celite , and the cake was washed with ethanol . solvent was evaporated , and the residue was taken up in ether , whereupon solid ( et 3 n . hcl ) separated . the solid was removed by filtration . the filtrate was concentrated , and the procedure was repeated to eliminate all hydrochloride salt . product was chromatographed on a silica gel column which was eluted with pet ether to give the desired debrominated compound 3 . 35 g . nmr ( cdcl 3 ) δ 7 . 21 ( m , 5h , c 6 h 5 ), 3 . 95 ( m , 2h , ch 3 ch 2 o ), 2 . 85 ( m , 2h , arch 2 ), 2 . 64 ( q , 1h , bnchc ═ o ), 1 . 85 ( m , 1h , chch ( me ) 2 , 1 . 62 ( m , 1h , ch ( me ) 2 ), 1 . 05 ( t , 3h , ch 3 ch 2 o ), 0 . 95 ( d , 3h , ch 3 ) 0 . 84 ( d , 3h , ch 3 ) and 0 . 82 ( d , 3h , ch 3 ). ms gave 290 ( m + ch 3 cn ), 249 ( m + 1 ), and others at 203 . further elution with ether gave lactone ( 2 . 25 g ) that was carried over from previous step . ethyl ester 178 ( 3 . 20 g , 12 . 85 mmol ) was dissolved in anhydrous ether and cooled in ice bath under inert atmosphere . lithium aluminum hydride ( 500 mg , 13 . 15 mmol ) was added , and the suspension was stirred at room temperature overnight . excess lah was destroyed by careful addition of ethyl acetate while the reaction was stirred in ice bath . saturated sodium sulfate was added cautiously to coagulate the alumina that separated at room temperature as white precipitate . the reaction mixture was diluted with methylene chloride , and anhydrous sodium sulfate was added to dry the mixture . after filtration the solution was concentrated to give an oil 3 . 0 g . the material ( 3 . 0 g ) was dissolved in dichloromethane ( 30 ml ) and triethylamine ( 2 . 5 ml ), dmap ( 200 mg ), and acetic anhydride ( 1 . 5 ml ) were added . it was stirred at room temperature for 3 hours , and diluted with ether . the ether solution was washed with waster , 1n hcl , saturated sodium bicarbonate , brine and dried . the solution was concentrated in vacuo to give the acetoxy compound 179 3 . 16 g . nmr ( cdcl 3 ) δ 7 . 19 ( m , 5h , c 6 h 5 ), 4 . 03 ( m , 2h , ch 3 ch 2 o ), 2 . 69 ( m , 2h , arch 2 ), 2 . 09 ( m , 1h , bnchch 2 o ), 2 . 02 ( s , 3h , ch 3 c ═ o ), 1 . 68 ( m , 1h , ch 3 chch ( me ) 2 , 1 . 23 ( m , 1h , ch ( me ) 2 ), 0 . 87 ( d , 3h , ch 3 ), 0 . 84 ( d , 3h , ch 3 ) and 0 . 81 ( d , 3h , ch 3 ). to a solution of aromatic compound 179 ( 5 . 0 g , 20 . 16 mmol ) in hplc grade acetonitrile ( 60 ml ), carbon tetrachloride ( 60 ml ), and water ( 120 ml ) was added sodium periodate ( 86 . 24 g , 403 . 32 mmol , 20 equiv . ), followed by rucl 3 ( 414 mg , 10 mol %/ 0 ). the mixture was stirred vigorously overnight at room temperature , and diluted with methylene chloride ( 400 ml ). the mixture was filtered through a pad of celite to remove the solid precipitate . the organic portion was separated , and the aqueous was further extracted with methylene chloride . after the combined organic portions concentrated , the residue was dissolved in ether and applied to a column of florisil . the compound was eluted with 3 % methanol in ether , evaporated to a paste that was dissolved in methanol ( 100 ml ). potassium carbonate ( 8 . 0 g ) was added , and the mixture was refluxed for 6 hours . the solvent was evaporated , and the solid residue was dissolved in water . the ph was adjusted to 2 by the careful addition of concentrated hcl while being cooled in ice water bath and stirred . chloroform ( 200 ml ) was added to the solution and stirred as such overnight at room temperature . the organic phase was separated , and the aqueous portion was further extracted with chloroform . after drying , the solvent was evaporated to give the lactone 180 5 . 0 g . nmr ( cdcl 3 ) δ 4 . 36 ( app . t , 1h , ch a h b o ), 3 . 85 ( app . t , 1h , ch a h b o ), 2 . 46 ( m , 2h , ch c h d c ═ o ), 2 . 13 ( m , 2h , chch 2 c ═ o ), 1 . 60 ( m , 1h , ch ( me ) 2 ), 1 . 35 ( m , 1h , ch 3 chch ( me ) 2 ), 0 . 86 ( d , 3h , ch 3 ) and 0 . 72 ( t , 3h , ch 3 ). lactone 180 ( 5 . 0 g ) was dissolved in absolute ethanol ( 25 ml ) and flushed with argon . while being cooled in ice water bath , anhydrous hbr gas was bubbled through the mixture for 45 minutes and allowed to stand at room temperature overnight . the mixture was poured into ice - salt water and hexane . the organic phase was separated , and the aqueous was further extracted with hexane . the combined organic extract was dried and evaporated . flash chromatography with 10 % ether in pet ether on a silica gel column gave the bromoester 181 3 . 54 g . nmr ( cdcl 3 ) δ 4 . 14 ( q , 2h , ch 3 h 2 o ), 3 . 60 ( dd , 1h , ch a h b br ), 3 . 41 ( dd , 1h , ch c h b br ), 2 . 54 ( dd , 1h , ch a h b c ═ o ), 2 . 44 ( dd , 1h , ch a h b c ═ o ), 2 . 22 ( m , 1h , o ═ cch 2 chch 2 br ), 1 . 67 ( m , 1h , chch 3 ch ( me ) 2 , 1 . 37 ( m , 1h , ch ( me ) 2 ), 1 . 26 ( t , 3h , ch 3 ch 2 o ), 0 . 94 ( d , 3h , chch 3 ch ( me ) 2 , 0 . 81 ( d , 3h , (( ch 3 ) 2 ) chch 3 ch ) and 0 . 79 ( d , 3h , (( ch 3 ) 2 ) chch 3 ch ). bromoester 181 ( 3 . 54 g , 13 . 34 mmol ), sodium azide ( 1 . 04 g , 16 . 13 mmol ) in anhydrous dmf ( 8 . 0 ml ) was stirred at room temperature overnight . water ( 16 ml ) and hexane were added , the organic portion was separated , and the aqueous portion was further extracted with hexane . it was dried and evaporated to give azido ester 3 . 0 g . nmr ( cdcl 3 ) δ 4 . 14 ( q , 2h , ch 3 h 2 o ), 3 . 48 ( dd , 1h , ch a h b n 3 ), 3 . 21 ( dd , 1h , ch c h b n 3 ), 2 . 34 ( m 2h , ch a h b c ═ o ), 2 . 20 ( m , 1h , o ═ cch 2 chch 2 n 3 ), 1 . 60 ( m , 1h , chch 3 ch ( me ) 2 . compound was submitted for hydrogenation ( hpl , 66480 × 100 ). the hydrogenated crude was dissolved in 6n hcl and refluxed overnight . the solvent was evaporated in vacuo the residue was azeotroped with toluene . the crude was further purified by loading onto an ion exchange column chromatography ( dowex 50wb × 8 - 100 ), washed to neutral eluent with hplc grade water followed by elution of compound with 0 . 5n nh 4 oh solution . crystallization of product from methanol gave 720 mg . nmr ( cd 3 od ) δ 3 . 04 ( dd , 1h , ch a h b nh 2 ), 2 . 82 ( dd , 1h , ch c h b nh 2 ), 2 . 52 ( dd , 1h , ch a h b c ═ o ), 2 . 40 ( dd , 1h , ch a h b c ═ o ), 2 . 07 ( m , 1h , o ═ cch 2 chch 2 nh 2 ), 1 . 67 ( m , 1h , chch 3 ch ( me ) 2 , 1 . 35 ( m , 1h , ch ( me ) 2 ), 0 . 97 ( d , 3h , chch 3 ch ( me ) 2 , 0 . 88 ( d , 3h , (( ch 3 ) 2 ) chch 3 ch ) and 0 . 83 ( d , 3h , (( ch 3 ) 2 ) chch 3 ch ). [ α ] d − 5 . 3 ( c , meoh , 1 . 9 mg / ml ). anal . calcd for c 9 h 19 no 2 : c , 62 . 39 ; h , 11 . 05 ; n , 8 . 08 . found c , 62 . 01 ; h , 11 . 35 ; n , 7 . 88 . ms showed ions at 215 ( m + ch 3 cn ), 197 ( m + na + ), 174 ( m + h + ). analysis of derivative by reverse phase hplc , hypersil bds c 18 5 micron and mobile phase 50 / 50 ch 3 cn - water containing 0 . 1 % tfa gave 99 . 93 % purity at retention time of 8 . 21 minutes . a solution of isobutyraldehyde ( 30 . 0 g , 416 mmol ), methyl - cyano - acetate ( 20 . 6 g , 208 mmol ), ammonium hydroxide ( 3 . 2 g , 41 . 6 mmol ) and acetic acid ( 5 . 0 g , 83 . 2 mmol ) in 500 ml of toluene is warmed to reflux under a dean - stark trap for 12 hours . the mixture is cooled to room temperature and extracted with saturated nahso 3 ( 3 × 100 ml ), saturated nahco 3 ( 3 × 100 ml ), and 100 ml of brine . the organic layer is dried over na 2 so 4 , and the solvent is evaporated . the remaining oil is distilled under high vacuum ( 0 . 5 mm hg , b . p .= 115 - 120 ° c .) to give 28 . 8 g of 2 - cyano - 4 - methyl - 2 - pentenoic acid methyl ester 61 as an oil ( 90 % yield ). a 2 . 0 m solution of propyl magnesium chloride in et 2 o ( 9 . 8 ml , 19 . 6 mmol ) is added to a solution of 2 - cyano - 4 - methyl - 2 - pentenoic acid ( 3 . 0 g , 19 . 6 mmol ) in 50 ml of thf which is cooled in an ipa / dry ice bath to − 40 ° c . under argon . the solution is stirred for 4 hours , and the reaction is quenched by addition of 50 ml of saturated kh 2 po 4 . the thf is evaporated , and the remaining oil is chromatographed under medium pressure over silica gel with 50 % ch 2 cl 2 / hexane . yield 1 . 9 g ( 50 %) of 2 - cyano - 3 - isopropyl - hexanoic acid methyl ester as an oil . a solution of 2 - cyano - 3 - isopropyl - hexanoic acid methyl ester ( 1 . 9 g , 9 . 6 mmol ) in 10 ml of thf is added to a slurry of nah ( washed with hexane , 0 . 23 g , 9 . 6 mmol ) in 20 ml of thf which is cooled in an ice water bath under argon . the solution is stirred for 10 minutes , and t - butyl bromoacetate ( 2 . 1 g , 10 . 6 mmol ) is added . the solution is warmed to room temperature . after 12 hours , the reaction is quenched by addition of 50 ml of saturated kh 2 po 4 and the thf is evaporated . the organic products are extracted into et 2 o ( 3 × 50 ml ), and the combined organic layers are dried over mgso 4 . the solvent is evaporated , and the remaining oil is chromographed under medium pressure over silica gel in 25 % hexane / ch 2 cl 2 . yield of 2 - cyano - 2 -( 1 - isopropyl - butyl )- succinic acid 4 - tert - butyl ester 1 - methyl ester = 1 . 3 g ( 42 %) as an oil . a mixture of 2 - cyano - 2 -( 1 - isopropyl - butyl )- succinic acid 4 - tert - butyl ester 1 - methyl ester ( 1 . 3 g , 4 . 2 mmol ), nacl ( 0 . 25 g , 4 . 2 mmol ), and h 2 o ( 0 . 15 g , 8 . 3 mmol ) in 25 ml of dmso is warmed to 130 ° c . for 12 hours . the mixture is cooled to room temperature and diluted with 100 ml of brine . the organic products are extracted into et 2 o ( 3 × 50 ml ). the organic layers are combined and washed with 50 ml of h 2 o and 50 ml of brine . drying over na 2 so 4 and evaporation of the solvent gives 0 . 8 g ( 75 % yield ) of 3 - cyano - 4 - isopropyl - heptanoic acid t - butyl ester as an oil . 3 - cyano - 4 - isopropyl - heptanoic acid t - butyl ester ( 0 . 8 g , 3 . 2 mmol ) is reduced under 50 psi of h 2 in meoh containing tea and ra ni . when the theoretical amount of h 2 is taken up , the catalyst is removed by filtration , and the solvent is evaporated to give 0 . 6 g ( 100 % yield ) of 4 -( 1 - isopropyl - butyl )- 2 - pyrrolidone as an oil . 4 -( 1 - isopropyl - butyl )- 2 - pyrrolidone ( 0 . 6 g , 2 . 3 mmol ) is warmed to reflux in 50 ml of 6 . 0 m hcl for 12 hours . the solution is cooled to room temperature and filtered through celite . the filtrate is evaporated , and the solid remaining is recrystallized from meoh / etoac . yield 0 . 035 g ( 6 % yield ) of 3 - aminomethyl - 4 - isopropyl - heptanoic acid as an hcl salt , mp 160 - 170 ° c . 1 h nmr ( cd 3 od ) δ 0 . 9 ( m , 9h ), 1 . 30 ( m , 5h ), 1 . 78 ( m , 1h ), 2 . 30 ( m , 2h ), 2 . 45 ( m , 1h ), 2 . 95 ( m , 2h ). ms ( apci , ch 3 cn , h 2 o ) 201 ( m + , 100 %). prepared according to the procedure of example 18 . yield = 0 . 13 g ( 15 %) of 3 - aminomethyl - 4 - isopropyl - octanoic acid . mp = 160 - 170 ° c . 1 h nmr ( cd 3 od ) δ 0 . 9 ( m , 9h ), 1 . 30 ( m , 7h ), 1 . 78 ( m , 1h ), 2 . 30 ( m , 1h ), 2 . 45 ( m , 2h ), 2 . 95 ( m , 2h ). ms ( apci , ch 3 cn , h 2 o ) 198 ( m − 17 , 100 %), 216 ( m + , 50 %). prepared according to the procedure of example 18 . yield = 0 . 11 g ( 42 %) of 3 - aminomethyl - 4 - isopropyl - hexanoic acid . mp = 170 - 180 ° c . 1 h nmr ( cd 3 od ) δ 0 . 9 ( m , 9h ), 1 . 18 ( m , 1h ), 1 . 39 ( m , 3h ), 1 . 78 ( m , 1h ), 2 . 30 ( m , 1h ), 2 . 45 ( m , 1h ), 2 . 95 ( m , 2h ). ms ( apci , ch 3 cn , h 2 o ) 188 ( m + , 100 %). ( s )-(−)- citronellal 187 ( 2 . 0 ml , 11 . 03 mmol ) was stirred at 40 ° c . in dry tetrahydrofuran ( 30 ml ) with methyl triphenylphosphoranylidene acetate ( 3 . 69 g , 11 . 03 mmol ). after 8 hours the mixture was cooled to room temperature and stirred overnight . the solvent was removed in vacuo and the residue stirred with n - pentane ( 50 ml ). after 1 hour the solid was removed by filtration and the solvent removed in vacuo to give an oil which was purified by flash chromatography ( silica , ethyl acetate : heptane 1 : 9 ) to give 2 . 05 g ( 88 %) of 188 as a clear oil . 1 h nmr ( 400 mhz ) ( cdcl 3 ) δ 0 . 90 ( 3h , d , j = 6 hz ); 1 . 12 - 1 . 40 ( 2h , m ); 1 . 60 ( 3h , s ); 1 . 62 ( 1h , m ); 1 . 68 ( 3h , s ); 2 . 01 ( 3h , m ); 2 . 21 ( 1h , m ); 3 . 73 ( 3h , s ); 5 . 08 ( 1h , m ); 5 . 82 ( 1h , d , j = 16 hz ); 6 . 94 ( 1h , m ). ms ( ci + ) ( m / z ): 211 ( mh + , 75 %), 179 ( 78 %), 151 ( 100 %). ir ( thin film ) ( cm − 1 ) ν : 1271 , 1436 , 1728 , 2917 . the ester 188 ( 2 . 02 g , 9 . 6 mmol ) was dissolved in nitromethane ( 25 ml ) with 1 , 8 - diazabicyclo [ 5 , 4 , 0 ] undec - 7 - ene ( 1 . 44 ml , 9 . 6 mmol ) and stirred at room temperature . after 23 hours the mixture was diluted with diethyl ether ( 150 ml ) and washed with water ( 50 ml ) and then 2n hcl ( 50 ml ). the organic phase was collected , dried ( mgso 4 ), and the solvent removed in vacuo . the residue was purified by flash chromatography ( silica , ethyl acetate : heptane 3 : 7 ) to give 2 . 26 g ( 87 %) of 189 as a clear oil . note that this and all subsequent compounds are equimolar mixtures of 2 diastereoisomers . 1 h nmr ( 400 mhz ) ( cdcl 3 ) δ 0 . 90 ( 2 × 3h , each d , j = 6 hz ); 1 . 09 - 1 . 58 ( 10h , m ); 1 . 602 ( 6h , s ); 1 . 685 ( 6h , s ); 1 . 94 ( 4h , m ); 2 . 42 ( 4h , m ); 2 . 66 ( 2h , m ); 3 . 70 ( 6h , s ); 4 . 42 ( 4h , m ); 5 . 07 ( 2h , m ). ms ( ci + ) ( m / z ): 272 ( mh + , 90 %), 240 ( 100 %), 151 ( 100 %). ir ( thin film ) ( cm − 1 ) v : 1554 , 1739 , 2918 . the nitro ester 189 ( 2 . 09 g , 7 . 7 mmol ) was dissolved in methanol ( 75 ml ) and shaken over raney nickel ( catalytic , prewashed with water and then methanol ) under an atmosphere of hydrogen gas ( 39 psi ) at 35 ° c . after 17 hours the mixture was filtered through celite . the solvent was removed in vacuo to give an oil . 1 h nmr showed there had been partial reduction of the double bond so this was carried on without further purification . a sample of this partial reduced product ( 440 mg , 2 . 1 mmol ) was dissolved in methanol ( 40 ml ) and shaken over 5 % pd — c under an atmosphere of hydrogen gas . after 18 hours the catalyst was removed by filtration through celite to obtain 442 mg ( 99 % from partial reduced material ) as a clear oil which did not need purification . note that this and all subsequent compounds are equimolar mixtures of 2 diastereoisomers . 1 h nmr ( 400 mhz ) ( cdcl 3 ) δ : 0 . 88 ( 18h , m ); 1 . 04 - 1 . 58 ( 20h , m ); 1 . 96 ( 2h , m ); 2 . 40 ( 2h , m ); 2 . 58 ( 2h , m ); 2 . 98 ( 2h , m ); ( 3 . 45 ( 2h , m ), 5 . 82 ( 2h , br s ). ms ( ci + ) ( m / z ): 212 ( mh + , 100 %). the lactam 191 ( 428 mg , 2 . 0 mmol ) was heated to reflux in 6n hcl ( 20 ml ). after 5 hours the mixture was cooled to room temperature and washed with dichloromethane ( 2 × 10 ml ). the aqueous phase was collected and the solvent removed in vacuo . the residue was dissolved in water ( 10 ml ) and freeze - dried to give 382 mg ( 71 %) of example 34 as a white solid . note that this compound is an equimolar mixture of 2 diastereoisomers . 1 h nmr ( 400 mhz ) ( d 6 - dmso ) δ 0 . 82 ( 18h , m ); 0 . 95 - 1 . 55 ( 20h , m ); 2 . 05 - 2 . 45 ( 6h , m ); 2 . 75 ( 4h , m ); 7 . 98 ( 6h , br s ). ms ( ci + ) ( m / z ): 230 ([ mh - hcl ] + , 90 %), 212 ( 100 %). to one skilled in the art , the use of ( r )-(+)- citronellal would afford compounds of opposite c5 - stereochemistry to example 21 . the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms . thus , the compounds of the present invention can be administered by injection , that is , intravenously , intramuscularly , intracutaneously , subcutaneously , intraduodenally , or intraperitoneally . also , the compounds of the present invention can be administered by inhalation , for example , intranasally . additionally , the compounds of the present invention can be administered transdermally . it will be obvious to those skilled in the art that the following dosage forms may comprise as the active component , either a compound of formula 1 or a corresponding pharmaceutically acceptable salt of a compound of formula 1 . for preparing pharmaceutical compositions from the compounds of the present invention , pharmaceutically acceptable carriers can be either solid or liquid . solid form preparations include powders , tablets , pills , capsules , cachets , suppositories , and dispersible granules . a solid carrier can be one or more substances which may also act as diluents , flavoring agents , binders , preservatives , tablet disintegrating agents , or an encapsulating material . in powders , the carrier is a finely divided solid which is in a mixture with the finely divided active component . in tablets , the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired . the powders and tablets preferably contain from five or ten to about seventy percent of the active compound . suitable carriers are magnesium carbonate , magnesium stearate , talc , sugar , lactose , pectin , dextrin , starch , gelatin , tragacanth , methylcellulose , sodium carboxymethylcellulose , a low melting wax , cocoa butter , and the like . the term “ preparation ” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component , with or without other carriers , is surrounded by a carrier , which is thus in association with it : similarly , cachets and lozenges are included . tablets , powders , capsules , pills , cachets , and lozenges can be used as solid dosage forms suitable for oral administration . for preparing suppositories , a low melting wax , such as a mixture of fatty acid glycerides or cocoa butter , is first melted , and the active component is dispersed homogeneously therein , as by stirring . the molten homogenous mixture is then poured into convenient sized molds , allowed to cool , and thereby to solidify . liquid form preparations include solutions , suspensions , and emulsions , for example , water or water propylene glycol solutions . for parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution . aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants , flavors , stabilizing and thickening agents as desired . aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material , such as natural or synthetic gums , resins , methylcellulose , sodium carboxymethylcellulose , and other well - known suspending agents . also included are solid form preparations which are intended to be converted , shortly before use , to liquid form preparations for oral administration . such liquid forms include solutions , suspensions , and emulsions . these preparations may contain , in addition to the active component , colorants , flavors , stabilizers , buffers , artificial and natural sweeteners , dispersants , thickeners , solubilizing agents , and the like . the pharmaceutical preparation is preferably in unit dosage form . in such form the preparation is subdivided into unit doses containing appropriate quantities of the active component . the unit dosage form can be a packaged preparation , the package containing discrete quantities of preparation , such as packeted tablets , capsules , and powders in vials or ampoules . also , the unit dosage form can be a capsule , tablet , cachet , or lozenge itself , or it can be the appropriate number of any of these in packaged form . the quantity of active component in a unit dose preparation may be varied or adjusted from 0 . 1 mg to 1 g according to the particular application and the potency of the active component . in medical use the drug may be administered three times daily as , for example , capsules of 100 or 300 mg . the composition can , if desired , also contain other compatible therapeutic agents . in therapeutic use , the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0 . 01 mg to about 100 mg / kg daily . a daily dose range of about 0 . 01 mg to about 100 mg / kg is preferred . the dosages , however , may be varied depending upon the requirements of the patient , the severity of the condition being treated , and the compound being employed . determination of the proper dosage for a particular situation is within the skill of the art . generally , treatment is initiated with smaller dosages which are less than the optimum dose of the compound . thereafter , the dosage is increased by small increments until the optimum effect under the circumstances is reached . for convenience , the total daily dosage may be divided and administered in portions during the day , if desired . illustrative examples of compounds made in accordance with the present invention are tested as described in example 22 . rat model of footpad tactile allodynia from prior injection of acid into the gastrocnemius muscle patients with fibromyalgia syndrome ( fms ) typically demonstrate widespread , chronic musculoskeletal pain , which is often accompanied by tactile allodynia ( pain in response to a relatively light tactile stimulus that is normally not painful ). a rat model of persistent mechanical allodynia has been developed that is consistent with the muscle tenderness found in these patients . multiple injections of acidified saline into the gastrocnemius muscle in rats produce a long - lasting allodynia ( conveniently measured at the footpad ) that is thought to be centrally mediated ( sluka k ., et al ., unilateral intramuscular injections of acidic saline produce a bilateral , long - lasting hyperalgesia , muscle nerve , 2001 ; 24 : 37 - 46 ; sluka k ., et al ., chronic muscle pain induced by repeated acid injection is reversed by spinally administered mu - and delta -, but not kappa - opioid receptor agonists , j . pharmacol . exp . ther ., 2002 ; 302 : 1146 - 50 ). this model was utilized to evaluate a compound of the invention for its ability to inhibit allodynia . allodynia is induced as described by sluka , et al ., supra , with minor modifications . on day 0 , male sprague - dawley rats (˜ 200 g body weight ) in their dark cycle are placed in suspended wire - bottom cages and allowed to acclimate for 0 . 5 hours . the baseline paw withdrawal threshold is determined on the right hind paw by von frey monofilament hairs ( bending forces of 2 . 0 , 3 . 6 , 5 . 5 , 8 . 5 , 15 . 1 , and 28 . 8 g ) using the dixon up - down method ( dixon w ., efficient analysis of experimental observations , ann . rev . pharmacol . toxicol . 1980 ; 20 : 441 - 62 ). von frey hairs are applied to the plantar surface for up to 6 seconds , and a flinching of the paw during that time frame is considered a positive response . after assessment , the right gastrocnemius muscle is shaved , swabbed with alcohol , and injected with 0 . 1 ml of 0 . 9 % nacl solution acidified to ph 4 with hcl . the injection is repeated on day 5 . animals are manipulated with a dynamic plantar aesthesiometer ( ugo basile , comerio - varese , italy ) on days 6 , 7 , and 8 to facilitate induction of the allodynia . to screen the rats for the development of allodynia , the 15 . 1 g von frey hair is applied to the ipsilateral paw on day 11 . positive responders from that test are included in the compound evaluation study . on day 12 ( the day of peak allodynia ), animals are assigned into treatment groups , and then their ipsilateral paw withdrawal thresholds are determined to establish the allodynia ( reduction in paw withdrawal threshold ) compared to baseline values . rats are then orally dosed with 10 ml / kg vehicle ( 0 . 5 % hydroxypropyl - methylcellulose / 0 . 2 % tween 80 ) or an indicated dose of a compound of the invention . paw withdrawal thresholds are reassessed by von frey hairs in blinded fashion 2 hours after dosing for the dose - response study , and 2 , 5 , 8 , and 24 hours after dosing in the time course experiment . the inhibition of allodynia is determined for each animal by dividing the increase in paw withdrawal threshold after treatment by the difference between baseline and pretreatment paw withdrawal values . this fraction is then converted to percent inhibition by multiplying by 100 . in this manner , one or more compounds described above is evaluated for its ability to dose - dependently attenuate allodynia , and minimum effective doses of are determined ). to determine the time course of inhibition , allodynia is monitored at various time points after a minimum effective dose of a compound of the invention . in this manner , it is evaluated whether administration of one or more compounds described above reduces tactile allodynia to the footpad caused by prior injection of acidic saline . the time period for sustained efficacy is also determined . the results allow evaluation of a compound of the invention for treating the allodynia associated with fibromyalgia syndrome . | US-42650109-A |
systems and methods of supplementing blood flow from the heart of a patient involving superficial , non - invasive procedures . in one general method , a first conduit is directed into the left side of the heart , a second conduit is directed into a superficial vessel and a pump is connected between the first and second conduits . the pump is implanted superficially in the patient and a power supply is connected to the pump . blood is then suctioned from the left side of the patient &# 39 ; s heart through the first conduit into the pump and expelled from the pump into the second conduit and the superficial vessel . a transcutaneous power supply is disclosed in one aspect and includes an external portion with a connection and alignment feature to assure reliable transmission of power . | fig1 illustrates a patient 10 having a heart 12 , shown in longitudinal cross section , coupled with a supplemental assist device or system 14 . system 14 comprises a pump 16 which may be implanted in a small pocket made subcutaneously over the patient &# 39 ; s chest , such as in the subclavicular region as shown in the drawing . this is a similar implantation procedure to conventional pacemakers . pump 1 6 is coupled with a control 17 and a suitable electric power supply 18 . pump 16 and control 17 may be constructed in various manners known in the art , for example , as a centrifugal pump or a screw type pump . some more specific types of pumps are disclosed in u . s . pat . nos . 5 , 344 , 443 ; 5 , 941 , 813 ; and 5 , 947 , 892 . pump 16 may reside directly within one of the cannulas or conduits of system 14 . power supply 18 may be an implanted power supply or a power supply partially or wholly external to the patient . one particularly desirable power system comprises a transcutaneous power supply using a power coil which is periodically charged from outside the body to continuously operate pump 16 . this system is discussed further below . pump 16 is coupled with an inflow catheter 20 which extends through the heart , such as through the right atrium and septum , and into the left atrium 22 . blood is withdrawn from the left atrium 22 by pump 16 and discharged into catheter or conduit 24 which is connected for fluid communication with an artery in the shoulder region , such as axillary artery 26 . as further illustrated in fig1 and 1a , power supply 18 most preferably comprises a first coil or power supply portion 19 implanted within the body of patient 10 , such as in the lower abdominal region , and a second coil or power supply portion 21 positioned outside the patient &# 39 ; s body . second coil 21 may be in the form of a pack carried on a belt 23 worn by patient 10 . in accordance with another inventive aspect , second coil 21 includes a first alignment element 25 and a second alignment element 27 is carried by an adhesive pad 29 affixed to the skin of patient 10 . as further shown in fig1 a power lead 31 is connected between first coil 19 and pump 16 for supplying electrical power to operate pump 16 . periodically , electrical power is transferred between second coil 21 and first coil 19 such that first coil 19 can deliver stored electrical power to pump 16 . as one example , such a system may take the form of the one disclosed in u . s . pat . no . 5 , 704 , 891 , the disclosure of which is fully incorporated herein by reference . such systems may allow second coil 21 to be removed from the patient for a period of time , such as during physical activity . fig2 illustrates an alternative heart assist pump system 14 ′ comprising a pump 16 and respective inflow and outflow catheters or conduits 20 , 24 as in the embodiment shown in fig1 . in this embodiment , like reference numerals refer to like elements with the first embodiment . in this embodiment , however , catheter 20 is installed through the axillary vein 21 and is directed into the heart 12 through the right atrium and septum and again into the left atrium 22 . conduit or catheter 24 is again coupled for fluid communication with the axillary artery 26 as in the embodiment of fig1 . in both embodiments , blood is withdrawn from the right atrium through conduit 20 and discharged into a suitable artery , such as the axillary artery 26 . as another alternative shown in fig2 pump 16 may instead be coupled between left atrium 22 and an artery in the patient &# 39 ; s lower body , such as a femoral artery 30 . fig3 illustrates another alternative heart assist device system 32 in which like reference numerals indicate like elements with fig1 and 2 . in this embodiment , system 32 again includes conduits or catheters 20 , 24 for respectively providing inflow and outflow of blood . this embodiment counteracts the potential obstruction created by conduit or catheter 20 in the axillary vein 21 by providing a separate set of conduits 34 , 36 . specifically , in this embodiment a first pump 38 withdraws blood from the left atrium 22 through catheter or conduit 20 and discharges this blood through catheter or conduit 24 into axillary artery 26 . a second pump 40 , which may be superimposed on pump 38 in a pancake fashion as shown , withdraws blood from axillary vein 21 through conduit 36 and discharges this blood into conduit or catheter 34 to the right side of heart 12 . this allows blood from the patient &# 39 ; s arm to bypass the obstruction created by catheter or conduit 20 and therefore prevent any potential swelling problems of the patient &# 39 ; s arm . it will be appreciated that the pumps associated with this invention may take many different forms including , but not limited to compact centrifugal pumps and peristaltic pumps . fig4 illustrates another alternative solution to the obstruction problem referred to above . in this embodiment , pump 16 includes a conduit or catheter 24 which again provides outflow of blood to axillary artery 26 . however , in this embodiment the inflow catheter or conduit 42 is connected to both the left side of the heart ( not shown ) through a catheter segment or branch 42 a and also fluidly coupled to an opposite side of the axillary vein 21 , for example , through a second catheter portion or branch 42 b . this second catheter branch 42 b may comprise an orifice in branch 42 a . here , the intention is to mix the blue blood or nonoxygenated blood returning from the patient &# 39 ; s arm through axillary vein 21 and catheter branch 42 b with the red blood or oxygenated blood being withdrawn from the left side of the patient &# 39 ; s heart ( not shown ). up to 25 % of the venous blood or nonoxygenated blood may be mixed with the red blood before desaturation occurs . in this embodiment , the mixture of blood travels through conduit or catheter 42 and into pump 16 before being discharged through conduit or catheter 24 into axillary artery 26 . fig5 illustrates a system similar to the system shown in fig1 with like reference numerals indicating like elements between the two embodiments . power supply 18 may be the transcutaneous power supply illustrated in fig1 or another transcutaneous system , fully implanted power supply system , or fully external power supply system . the only other difference between these two embodiments , as illustrated in fig5 is the provision of a return conduit 50 coupled with system 14 ′. return conduit 50 may lead to various locations of the system to provide a cleansing or rinsing function . for example , as there may be pumps 16 which include stagnant interior portions susceptible to accumulating blood clots , return conduit 50 is provided between an output 52 of pump 16 and an input 54 coupled with a suction side of pump 16 for returning a small portion of the blood output to the pump and , more particularly , to any portion or portions of the interior of pump which may be susceptible to stagnation and blood clot formation . different pump configurations will have different areas of potential stagnation and these areas may be determined by those of ordinary skill in the art depending on the particular internal pump configuration . it is anticipated that return conduit 50 will preferably be sized and coupled with pump 16 such that only 5 - 10 % of the blood output will be returned to pump 16 for this rinsing or cleaning function of any stagnant internal pump area . as necessitated by the particular pump system , additional return outputs may be provided depending on the number of system areas necessitating this function . one other example for the use of a return conduit in system 14 ′ would be to lead a return conduit into the left atrium 22 to rinse an outside or inside end portion of conduit or catheter 20 to prevent clogging at this location . while the present invention has been illustrated by a description of preferred embodiments and while these embodiments have been described in some detail , it is not the intention of the applicant to restrict or in any way limit the scope of the appended claims to such detail . additional advantages and modifications will readily appear to those skilled in the art . the various features and concepts of the invention may be used alone or in numerous combinations depending on the needs and preferences of the user . as one example , one or more conduits may be integrated into a single conduit structure having multiple flow paths . this has been a description of the present invention , along with the preferred methods of practicing the present invention as currently known . however , the invention itself should only be defined by the appended claims , wherein | US-55756200-A |
a quiz game content producing method enables a quiz creator to make , register , and publicize a quiz game set so that other people are able to use the quiz game set in the unit of the quiz game set which comprises one or more quiz steps and game progression material . the present invention also relates to a system and a method for providing a quiz game for a quiz participant who is connected to a quiz channel by enabling a quiz operator to use a publicized quiz game set . in addition , the present invention relates to a system and a method for providing a quiz game using a bidirectional quiz step . the present invention enables a quiz creator to : compose each quiz step by using a unique creative technique in the arrangement of quiz questions or the progression schedule of a quiz game according to selections or difficulties of the overall quiz questions ; and develop quiz game content of a quiz game set unit which includes the quiz step . the creation of a quiz game set can be activated by accumulating points or providing a prize for a quiz creator and a quiz operator in a process in which the quiz creator creates the quiz game set and the quiz operator provides a quiz game for quiz participants . the present invention is able to provide a quiz solving game based on the quiz game set by enabling anyone to easily open a quiz channel and invite acquaintances as quiz participants . | hereinafter , embodiments of the present invention will be described in detail with reference to accompanying drawings . in the drawings , parts irrelevant to the description are omitted for a clear explanation of the present invention , and the same reference numeral is applied to the same parts throughout the specification . throughout the specification , when a part is described as including an element , it should be interpreted that other elements may be further included rather than being excluded unless mentioned otherwise . in addition , a term such as a “˜ unit ”, a “˜ module ”, etc . described in the specification refers to a unit that processes at least one function or operation , and may be implemented in a hardware form or a software form , or a combination of the hardware form and the software form . in the whole specification , the quiz means a question for requesting the submission of the answer at the online quiz participant and scoring the answer of the quiz participant . in the whole specification , a “ quiz game set ” is the form of contents data configured to progress the quiz game of one set . the quiz game set includes at least one quiz step and quiz progression information . the game progress data for automatically progressing the quiz game includes a reflecting method of the score result and the answer closing condition of the quiz step etc . the game progress data further includes the guide material about the quiz game set , the delay time or data transfer schedule materials of each progress step , the beginning and closing notice materials of the quiz game , the delay time of the quiz step etc . if the quiz channel is prepared , it provides the quiz game of one unit by using at least one quiz game set . in the whole specification , a “ quiz step ” is the form of the quiz data including at least one quiz or survey and the best answer or the best answer condition . or , it means the procedure of the quiz game progress of receiving the answer from the plural quiz participants connected in real time according to the fixed answer closing condition to be scored and reflecting the score results to the participants . moreover , the quiz step can further include a hint , a presenting data , a question help , a solving message , a description etc . the presenting data included and presented in the quiz question may be any type of a presenting word , a presenting drawing , a presenting sound etc . in the whole specification , a “ quiz channel ” is a virtual operation space of the quiz game arbitrarily opened and operated in the quiz operating server according to the request of the quiz operator . the quiz channel is opened in the quiz operating server and the quiz operator and quiz participant enter the quiz channel to be participated in the quiz game by using the quiz terminal . the quiz channel is subdivided into a private quiz channel capable of entering through only the invitation of the quiz participant , a disclosure quiz channel capable of participating anyone , and an exposure quiz channel of showing the list on the quiz terminal . in the whole specification , a “ quiz operator ” is a person of opening the quiz channel in the quiz operating server by using the quiz terminal , inviting the quiz participant to the quiz channel , and providing the quiz game to the quiz participants based on the quiz game set . in the whole specification , a “ quiz participant ” is a person of connecting to the quiz operating server by using the quiz terminal , entering the specific quiz channel , participating in the quiz game provided from the quiz channel . in the whole specification , a “ quiz producer ” is a person of producing the specific quiz game set or the quiz step . the quiz producer may be the quiz owner , since the quiz producer involves in the producing of the quiz and exercises the possessing right of the quiz . in the whole specification , an “ individual event ” means the form of the quiz game in which the quiz participants of participating in the unit quiz channel compete through the quiz solving while managing the individual score administration . in the whole specification , a “ team event ” means the form of the quiz game in which the quiz participants of participating in the unit quiz channel constitute several teams while managing the team score . in the whole specification , a “ quiz history information ” means the overall record according to the production and the application of the quiz . the quiz history information includes a quiz use information on the quiz game set or the quiz step used by the quiz operator in the providing of the quiz game , the quiz reference information referred by the quiz producer when the quiz producer prepares the quiz game set and quiz step , and a quiz satisfaction or quiz users &# 39 ; comments as an evaluation result about the quiz of the quiz operator or the quiz participant . in the whole specification , a “ quoted information ” means the information quoted on the existing quiz game set or the quiz step when the quiz producer prepares the new quiz game set and quiz step . it may be any one of the quoted number thereof , the quoted quiz operator , the quoted and generated quiz game set , and the satisfaction or users &# 39 ; comments . in the whole specification , a “ giveaway ” means the cost about the activity of the quiz producer , the quiz operator , and the quiz participant . it may be any one of a cash , a gift certificate , a goods , a point , a cyber money , a discount ticket , a free ticket , and a securities . the quiz game set as one unit capable of operating the quiz game of one set by means of participation the simultaneously participating in the quiz channel includes at least one quiz step and the game progress data . the game progress data includes a best answer , an answer closing condition , a scoring method , and a reflecting method of the score result etc . the game progress data can further include a presenting data , a hint , a guide data , a solving data etc . used in each quiz step . the quiz step is comprised of the quiz query , divided into a survey type and a definite answer type according to the format of the construction thereof , and classified into objective and subjective type according to the answer form thereof . the objective quiz step can further include the example sentence . the survey type quiz step further includes a survey query . the game progress data can be established as the base value so as to be commonly applied to all quiz steps included in the quiz game set or separately designated in each quiz step . that is , the analysis method about the answer , the answer closing condition , or the reflecting method of the score result can be equally designated in all the quiz steps and the values of the items can be separately designated in only the specific quiz step . the game progress data of the quiz game set or the quiz step includes a time data necessary for the delay in the procedure of the game , or any data on the transmission schedule of various data . the data having the quiz game set includes at least any one data format of the text , the sound , the image , the moving picture etc . the best answer may be a correct answer inputted as a data of a determined format or a condition format of determining the correct answer in future according to the answer analysis of the specific quiz participant . the quiz step further includes an example answer , a hint data , a presenting data , a guide data etc . the hint , the presenting data , the guide data etc . can set up according to the time or the receipt section of the answer . the quiz step can further include the survey for determining the best answer about the survey quiz . the quiz step can further include an explanation data for helping the understanding about the quiz answer and a quiz guide message for guiding the quiz progress . each of element information of the quiz step described in the above can include the schedule information on the fixed time zone or the receipt section of the answer transmitted to the participation terminal . the receipt section of the answer means the section in which the answer goes on . it can be established as the answer completion of the participant of the specific number , the answer completion condition of the participant of the specific ratio , or the repeating condition of the answer completion . the game progress data of the quiz game set includes the establishment for providing the progress message and the analysis information before and after the quiz step . moreover , it includes the information of the quiz producer of the quiz game set , the category classification code , the searching key word , the game introduction guideline , and the game over guide etc . the game progress data of the quiz game set of the sponsor quiz or the quiz step having the sponsor quiz further includes the information of the background image , the quiz question , the image , the sponsor related phrases , and the sound etc . the quiz game set can further include the set values on the method of analyzing the data or the scoring information received from the quiz terminals on the survey or the quiz question included in each quiz step about the specific quiz step or the entire quiz step and the method of notifying the quiz participant or the quiz operator . the quiz operating server includes a quiz channel module for transmitting the quiz question to the quiz terminals simultaneously connected , receiving the answers to be automatically scored , managing the scoring contents by user , and determining the ranking thereof . the quiz channel module allows the participants to solve the questions of each quiz step in real time in a state that at least two participants are connected thereto . the quiz channel module automatically progresses all the quiz steps designated by the quiz operator . the embodiment 1 relates to a system and a method for preparing the quiz channel in the quiz server by means of quiz operator using the quiz terminal and providing the quiz game to the plurality of the quiz participants using the quiz terminal according to the operating command of the quiz operator . fig1 briefly shows the configuration of the real time quiz operation system of becoming a background of the embodiment 1 . the quiz terminal 100 of using by means of the quiz operator or the quiz participant in the embodiment includes a quiz terminal hardware such as a smart tv , a tablet pc , a laptop personal computer , a pc etc . and a software thereof prepared in the hardware to be executed . it is preferred that the quiz terminal 100 is configured to easily create the quiz channel by anybody to be operated and participate in the quiz game , which is operated by the others . in the embodiment 1 , the quiz operating server 200 serves to allow the access of the plurality of the quiz terminals , transmit the quiz to the connected quiz terminal or receive the answer from the quiz terminal , and transmit an automatic scoring , an automatic score accumulating , a ranking result , a ranking change or an analysis material associated with these so as to operate the quiz game . preferably , the quiz operating server 200 is configured to be capable of always connecting through the quiz terminal by using the communication means including the internet etc . it is preferred that the quiz operating server 200 is developed in the form of the software set up in the hardware of the pc etc . also , the quiz operating server is developed in the form of the software installed in the smart phone , the smart tv , the tablet pc etc . also , it is possible to organize a single system or multiple systems . fig2 is a block diagram of the quiz operating server for providing a quiz solving service of various quiz game sets through a real - time synchronization for the plural quiz participants . the quiz operating server 200 includes a log - in module 220 . the log - in module 220 including a log - in maintenance unit and a member management unit serves to register a user id and a password so as to use them through the log - in . the member registers as the quiz operator , the quiz participant , or the quiz producer and it activates therein through the log - in . also , the log - in module supports the log - in of the quiz participant as a guest qualification . the member management unit serves to manage a basic information and a history information of the member . the basic information includes a telephone number , an id , and a password and a personal information . the personal information includes the information about the private details , the history information relating to the quiz game , the history information related to the quiz game participation , the quiz usage record , the quiz quoting information , and the quiz copyright information etc . the quiz operating server 200 includes a search module 270 for searching and inquiring the quiz recorded in the quiz db 240 . where the search request is received from the quiz terminal 100 , the search module 270 serves to transmit the search result searched through the search method including the category classification search and the keyword search etc . to the quiz terminal 100 . the quiz operating server 200 further includes a quiz storage module 250 . the quiz storage module 250 includes a quiz storage unit for managing the information including the quiz game set , the quiz step etc . and a quiz history management unit for managing a usage record of the quiz game set and the quiz step . the quiz storage module 250 serves to record and manage the use information of the quiz step and quiz game set and the quiz participant , and the ranking information of the participant etc . the quiz storage module 250 records the participation point of the quiz participant from the participation times , the quiz score , and the ranking result . also , whenever the participants use the set quiz game set and the quiz step produced by the quiz producer , the quiz storage module 250 serves to store the use information such as the usage count , the participant number , the participating degree of the participant , and the quiz satisfaction etc . the quiz storage module 250 serves to register or delete the quiz game set according to the request of the quiz producer . also , the quiz storage module 250 sets up a disclosure or a nondisclosure etc . on the set quiz game set produced by the quiz producer , and stores or manages the quoting information or the quoted information of the quiz game set during the registration of the quiz game set registration . the quiz operating server 200 includes a quiz channel module 260 . the quiz channel module 260 provides the quiz game to the quiz participants at the same time , where the plural quiz participants are connected thereto . that is , the quiz channel module 260 serves to perform the quiz step of transmitting the queries to the quiz terminal 100 through the communication module and receiving the answer from the quiz terminal for the designated time limit to be scored . one quiz step includes at least one quiz query . also , one quiz step further includes a question query . in case of the objective question , it has a data format further including an example answer data . the quiz channel module 260 includes the plural quiz channels , which are virtual spaces so as to support the plural quiz games at the same time . at this time , it has identifiers for each quiz , so that the quiz terminal sets up the specific quiz channel according to the request of the quiz terminal and it distinguishes only the quiz terminal corresponding to the specific quiz channel so as to provide the quiz game . the quiz channel module 260 serves to generate or delete the quiz channel according to the request of the quiz terminal . the quiz channel module 260 servers to manage the information about the quiz channel and transmit the related information to the quiz terminal . the related information includes the information related to the exposure quiz channel and the information on the disclosure quiz channel capable of participating by anyone . moreover , where it has the invite of the private quiz channel per the quiz terminal , the related information includes the information corresponding to this . the quiz operating server 200 further includes a communication module 230 for the log - in of the quiz terminal of the user or the connection maintenance thereof . the communication module 230 serves to allow the access of the quiz terminal through the network by using a protocol corresponding to the quiz terminal and transmit and receive the data with the quiz terminal . the quiz storage module 250 serves to store the information of the quiz game set designed for the progress of the quiz solving service of one unit or the information of the quiz step capable of selectively adding and using in the quiz solving . the information of the quiz game set and the quiz step includes a name , an identification code , a title , a theme , a keyword for classification , a classified identification table etc . also , the information of the quiz game set and the quiz step includes the producer , the disclosure condition , and the help etc . the disclosure condition includes a free of charge disclosure information , a chargeable disclosure information , a sponsor disclosure information , a nondisclosure information . the disclosure condition can include a copyright indication condition or any condition of notifying a specific guideline . the chargeable disclosure information may be a toll payment condition or a point and cyber money payment condition . the sponsor disclosure information may be the type for providing the giveaway to the quiz operator and the quiz participant on condition that the disclosed quiz game set or the quiz step is used . the quiz storage module 250 serves to create the quiz game set or the quiz step for the user to be stored . also , it allows the quiz producer to privately use the set quiz game set or the quiz step produced by oneself . the quiz history management unit of the quiz storage module 250 records and manages an individual quiz history information on the quiz game set or the quiz step . the quiz history information includes a quiz usage information of using the quiz game by the quiz operator , a quiz reference information referred by the quiz producer when the quiz producer prepares the quiz game set and the quiz step , a quiz copyright information associated with the quiz producer , a quiz satisfaction or quiz users &# 39 ; comments as an evaluation result about the quiz of the quiz operator or the quiz participant . here , the quiz reference information and the quiz use information separately classify into the quiz quoting information . preferably , the quiz storage module 250 manages the quiz quoting information so as to induce the lively development and registration of the quiz game set of the quiz producer and reflects to the design for inducement plan including the point supply and the offer of premium etc . the quiz search module 270 provides the systematic searching function and the keyword searching function so as to allow the quiz operator to easily find the quiz game set and the quiz step stored in the quiz db 240 . where the quiz operator requests the quiz search through the quiz terminal 10 , the quiz search module 270 transmits the search result data on the quiz step and the searched quiz game set to the quiz terminal 100 . the quiz terminal 100 outputs the received search result data to the output module 160 . the search result data includes the name , the identification code , the delimiter , the title , the quiz query language , the disclosure condition , the quoting related materials etc . capable of identifying the searched quiz game set or quiz step . fig3 is a flowchart illustrating an automatic quiz game progressing of a quiz channel module of one embodiment according to the present invention . the quiz channel module 260 creates newly the quiz channel or initializes and prepares the existing quiz channel in response to the request of the quiz terminal 100 ( s 101 ). the quiz channel module sets up the identification code and quiz progression environment of the quiz channel . it sets up the quiz progression environment including the background image , the quiz game title , the background music , the giveaway , and the other announcement etc ., so that all quiz operators participate in the quiz game mood in the same mood . the quiz channel module 260 prepares for the quiz game set for the quiz game operation with the request of the quiz operator ( s 102 ) and prepares an individual event or a team event according the configuration mode of the quiz game set so as to operate the team - based quiz game ( s 103 ). in case of the team - based quiz game , the teams are organized according to the team organization mode established by the quiz operator . the team organization mode may be an automatic classification mode based on the personal information , a mode selected by the quiz participant , a mode directly designated by the quiz operator . in the mode using the personal information , the teams can be divided according to the blood type or can be automatically divided into the residential zone sort or the sex etc . also , it can be divided into the odd number team and the even number team etc . in terms of the entrance order . moreover , the teams can be organized by the family or the husband and wife . if each team is established , it can set up a head among the team members . or , the parts among the other quiz participants organize the teams respectively and invite other quiz participants so as to organize new team under the agreement of the quiz participants . the quiz channel module 260 allows the participants to be participated by using the identification code capable of identifying each quiz channel . the quiz operator transmits the text message including the link capable of immediately connecting in response to the invitation or it invites the quiz participant by means of the e - mail , the text transfer , or other web notice etc ( s 101 ). the quiz channel module 260 transmits the beginning message to the quiz channel participants if it is included in the quiz game set ( s 104 ). the quiz channel module automatically progresses each quiz step of the prepared quiz game set based on the game progress data ( s 101 ). the quiz channel module 260 transmits the quiz step beginning message in the quiz step progress to the quiz terminal 100 ( s 110 ). thereafter , the query information is transmitted at the appointed time ( s 111 ). the query information includes the quiz query or the question query . in case of the objective query , the example answer can be further included . or , the query information can further include the presenting data and the answer closing time etc . the quiz channel module 260 starts the answer receipt from the quiz terminal 100 ( s 112 ). the quiz channel module 260 transmits the progress information of the specific quiz step to the quiz terminal . the progress information of the quiz step may be any one of the total number of the quiz step , the present quiz step number , the number of the remaining quiz step , the total number of the present participant , the present condition of the answer completion , and the participant present condition of the major rank , the average score , the residual answer stop time , the scoring method , and the reflection method of the score result . the quiz channel module 260 transmits the data related to a presentation word of the quiz step , the hint , the process guide etc . to the participation terminal before the deadline of the answer receipt ( s 113 ). if it satisfies the answer closing condition of the quiz step , the quiz channel module 260 ends the answer receipt ( s 114 ). the answer closing condition may be designated as any one of a first mode of checking the progress of the designated answer closing hour , a second mode of checking the answer input completion from the participants corresponding to the predefined number or rate , and a third mode of checking the progress of the designated time after the answer of the first answerer . however , it can be applied to various modes . after the answer input of the quiz step is finished , the quiz channel module 260 stores the analysis materials of analyzing the answer situation through the mode designated to the quiz step ( s 116 ) or the quiz channel module 260 transmits the analysis materials to the quiz terminal of each quiz participant or the quiz operator ( s 117 ). the analysis materials includes the kind of many answers , the number of input persons , the kind of the answer according to the age , the sex , the blood type , the residence etc . of the quiz participant , and the deviation thereof etc . after the answer receipt is finished , the quiz channel module 260 scores the received answers according to the scoring method of the quiz step ( s 115 ). where the correct answer is determined in advance , the answer can be marked as the correct answer or the wrong answer by comparing them with each other . also , where the best answer is a format of a condition , it analogizes the best answer by analyzing the survey of the quiz participants or the quiz host or the answers of the quiz to be graded . for example , in case of the quiz step including the survey “ what is your favorite night rituals ?” and the quiz query “ what is likely to be the second choice of food ?” in the survey , it gives the marks as an answering / non - answering etc . in the survey and it admits the correct answer to only the person of inputting the second most selected food by analyzing the result on the survey in the quiz query . there is an index of coincidence as another type in the condition format . in case of the index of coincidence , it can admit the correct answer when it inputs the same answer as the specific quiz participant or the answer of the selected person is recognized as correct answer . for example , where the husband and wife are participated as one team in the quiz , the question “ the first date place ?” corresponds to this format . also , the quiz format including a quiz query “ what are the words to evoke from this picture ?” is included this format while presenting multiple images in order . the best answer of the condition format includes a mode designated as the correlation between the answers of the quiz participants . for example , in case of the quiz step using continuous paper - rock - scissors games , when the specific quiz participant selects the scissor , it admits the correct answer to only the participants of inputting the scissor or the rock . the quiz channel module 260 reflects the score results of the individual participant or the team according to the reflecting method of the score result of the quiz step ( s 118 ). the method of reflecting the score result on the individual participant or the team may be any one method of adding a certain score , reducing a certain score , initializing the existing score , failing the specific team or the individuals , and relieving the specific team or the individuals . also , it can give the score to the individual or the team according to the determined scoring method on correct answer / incorrect answer / non - inputting . where it fails to find the correct answer of the quiz step , the certain points are reduced or it is initialized as 0 point to be eliminated . moreover , even in case of inputting the correct answer , it establishes the answer input time , the answer receipt time , the answer receipt rank etc ., so that the scores thereof can be differently set up . if there is no designated materials in the scoring method of the quiz step , the answer input closing condition of the quiz step , and the reflecting method of the score result of the quiz step etc ., it can basically applied according to the data established in the quiz game set . the quiz channel module 260 goes over to the next quiz step when it has the residual quiz step ( s 119 ). when the quiz solving of all quiz steps included in the quiz game set is completed , the quiz channel module 260 notifies the final ranking and the present condition of the score ( s 120 ). it stores the quiz solving related information and terminates the quiz game service . the quiz solving related information includes the usage record on the quiz game set or the specific quiz step , the quiz producer of the quiz game set and the quiz step , the quiz operator , and the usage record of the quiz participant , and the point data . if the quiz channel module receives the control signal of the quiz progression from the quiz operator , it controls the automatic progress method according to the control signal . the control signal includes the temporary pause of the quiz progress , the change of configuration value about the progressing , the omission of the quiz progress step , the addition of the quiz progress step , and the deletion of the quiz progress step . as described in fig3 , in the embodiment 1 , it gives the scores in each quiz step , determines the scores of the team or the individual , and determines the midterm ranking according to this . however , after the query transmission and the answer receipt are progressed over the plural quiz steps , it is possible to score each quiz step in a lump and reflect the score result on the participants to decide the ranking again . moreover , instead of giving the score , the drop - out concept can be introduced . the drop - out can be applied to the quiz participants or the quiz team , when it fails to answer the question or the aggregate score is less than the certain score . in order to smoothly solve the quiz in the repeated quiz step progress by the quiz participant , it designates a proper delay time . however , it is preferred that the delay time included in the game progress data of the quiz game set is used . fig4 illustrates a classification table for the classification search of the embodiment 1 . the classification table of the tree form subdivides into a large classification — a middle classification — small classification — detailed classification , so that it can search the quiz game set or the quiz step included in the range thereof . the quiz search module 270 includes a classification search and a keyword search . the quiz search module arranges the search data or designates the given range value by using the satisfaction of the quiz participant or the quiz operator , the periodical usage count , the whole usage count , and the usage count of the specific quiz participant section etc . so as to raise the efficiency of the search . the specific quiz participant section can be classified according to the age groups such as twenty or thirty , the sex , or the residential zone etc . moreover , it can be classified according to the mix of the multiple standards such as the worker in his 20s . fig5 is a block diagram of the quiz terminal 100 of the embodiment 1 . the quiz terminal 100 includes a personal information module 110 for managing an individual information , a quiz operating module 120 for connecting to the quiz operating server , opening the quiz channel , preparing for the quiz game set and providing the quiz game ; a quiz edit module 130 for preparing the quiz game set including the plural quiz questions and the quiz solving e progress information ; a communication module 140 for connecting with the quiz operating server so as to transmit and receive the data ; an input module 150 for inputting the answer from the user ; an output module 160 for outputting the data to the user ; and the quiz solving module 170 for displaying the received quiz data thereon , waiting for the input of the quiz answer sheet or determining the transmittance on the inputted quiz answer sheet . here , the quiz terminal 100 is shown as one terminal system for convenience . however , it is possible to organize the plural terminal system having the branched functions . the quiz terminal 100 transmits the personal information of the quiz participant to the quiz operating server so as to register the user or maintain the log - in of the user and provide the means for participating in the specific quiz channel to the quiz participant . in order to participate in the open quiz channel , the quiz terminal indicates the information including the title of the open quiz channel , the quiz operator , and the giveaway etc . received from the quiz operating server . if the quiz participant selects the specific open quiz channel , an entrance notification data is transmitted to the quiz channel . where the quiz participant inputs the identification code of the specific open quiz channel , the entrance notification data is transmitted to the quiz channel corresponding to the corresponding identification code . in case of the private quiz channel of meeting with the invitation , the list is selected or the link is clicked , so that the entrance notification data is transmitted to the corresponded private quiz channel . when the quiz terminal user successfully enters in the quiz channel , he becomes the quiz participant . at this time , the quiz terminal receives the data of constituting the quiz progress background of the quiz channel so as to establish the quiz progress background of the quiz channel . where the data of constituting the quiz progress background is the moving picture or the acoustic data , the moving picture or the acoustic data is indicated according to the desired value such as the time and the repetition thereof etc . the output module 160 of the quiz terminal 100 outputs the quiz progress related data received from the quiz operating server . that is , in order to progress the quiz step , it outputs the query information , receives the subjective answer from the user or displays the example answers for inputting the selecting answer among them . the input module 150 receives the answer from the quiz participant . here , if the answer closing time is indicated on the query information , the answer can be inputted until the answer closing time . also , if it receives the analysis information or the ranking information from the server , the corresponding contents is outputted as any data such as the table , the voice , and the graph etc . the quiz operating module 120 is provided with a quiz operating tool for controlling a temporary suspension of the quiz progress , an omission or an addition of the specific quiz step , and a change of the setting value of ongoing quiz step which is progressing etc . in the quiz solving service of each quiz step based on the quiz game set . the setting value of each quiz step includes the best answer , the reflection method of the score result , the answer closing condition , and the answer deadline hour etc . when the quiz operator inputs the specific command through the input module 150 , the quiz operating module 200 requests the quiz channel or transmits the command of progressing the quiz game through the quiz channel based on the specific command . the quiz operating module 120 serves to output the information associated with the quiz game received from the quiz operating server for the quiz operator . the information associated with the quiz game includes the present participation number , the analyzed result of the survey query , the ranking information etc . the quiz operating module 120 transmits the message inputted individually by the quiz operator and the guide message to quiz participants through the quiz channel . it is preferred that the quiz terminal 100 displays the progress information of the quiz step . the progress information of the quiz step includes any one of the number of the total quiz steps , the number of the present quiz step , the number of the remaining quiz steps , the number of total participants , the present condition of the answer completion , the participants of the major rank , the average score , the closing time of the remaining answer , the scoring method , and the reflecting method of the score result . if the quiz participant selects or inputs the answer about the question by using the quiz terminal , the quiz terminal transmits the answer input time , the symbol corresponding to the selected answer , and the answer data to the quiz server . the quiz terminal 100 includes the quiz operating module 120 . the quiz operating module 120 requests the preparation of the preparation of the quiz channel to the quiz operating server 200 or transmits the command about the quiz game operation in the quiz channel to the quiz operating server 200 according to the command of the quiz operator . the quiz operating module 120 serves to progress automatically or manually each quiz step according to the command of the quiz operator . the quiz operating module includes an ui for supporting the key word input for the search of the quiz and the category search service . the quiz operating module 120 transmits the identification code for identifying the quiz channel included in the e - mail or the message to the quiz terminal of the quiz participant so as to invite the participant . the quiz terminal 100 includes an answer input module . the answer input module serves to express the example answer on the objective question , allow the participant to input and select the answer through the touch , the click , the voice , the moving picture or the message input etc ., and allow the participant to input the answer through the mouse , the keypad , the keyboard , or the motion etc . on the subjective question . the answer input module indicates the sequence number of the quiz steps or the remaining time limit , plays the audio data established by the quiz operator , or displays the screen through the moving picture , the image , and the text etc . the chargeable disclosure quiz is a quiz game set or a quiz step of paying the price for the chargeable condition . the quiz operator uses the chargeable disclosure by means of a mode of using the designated chargeable disclosure quiz after the payment of a certain amount or the promise of payment . the cost according to the use of the chargeable disclosure quiz is any one of a first method of using points purchased or accumulated by the quiz operator in advance for the usage of the chargeable disclosure quiz , a second method of directly purchasing through the electronic commerce , a third method of settling the amount of money on the use of the chargeable disclosure quiz after the use thereof for the specified period , and a fourth method of paying the cost on the right to use the chargeable disclosure quiz of the specified range for the specified period . the giveaway according to the use of the chargeable disclosure quiz can be provided to the quiz producer . when the disclosure condition is determined in the chargeable disclosure quiz , it can set up the limit of the maximum number available or the limit of the number of simultaneous quiz participant . the sponsor quiz is a quiz game set or a quiz step using a format including a payment condition of providing to a user subject by means of a sponsor subject in the use of the quiz solving . the use subject may be the quiz operator or the quiz participant . when the quiz operator organizes the quiz game set , the sponsor quiz is included therein , so that the quiz questions can be solved by the quiz participant . in case of the quiz game set , it reuses the quiz game set so as to progress the quiz solving . in the sponsor quiz , the giveaway paid according to the use thereof is charged in advance . whenever the sponsor quiz is used , the sponsor giveaway is provided according to the accumulation of the quotation number . if the sponsor giveaway is exhausted , the quiz operator can no longer use it . the sponsor giveaway may be any one of the goods , the cash , the point , the cyber money , the gift certificate , the discount ticket , the free ticket , and the application ticket . in the sponsor quiz , it can restrict the usage thereof or the supply of the giveaway according to the number of simultaneous quiz participant , and the number of the answerer , and the number of the correct answerer . the quiz terminal includes the quiz edit module 130 for preparing the quiz game set or the quiz step . the quiz edit module 130 includes the input means for inputting the query of the quiz , the example sentence , the answer limiting condition , and the best answer etc . the quiz edit module 130 receives the data necessary for the construction of at least one quiz step based on the quiz question and the game progress data for progressing the game on the quiz game set so as to constitute the quiz game set data used in the quiz game of one set . the game progress data may be the schedule according to the game progress of the quiz step and the data such as the text , the voice , and the video information etc . sent to the quiz terminal . the game progress data may be additional materials such as the hint , the presented word , the help , the example answer , the correct answer comment , the background music , and the background image etc . the game progress data can further include the team organization condition . the team organization condition may be any one of the number of team , the number limit of the member , and the team organization mode . the team organization mode includes the quiz game history information and the personal information of the quiz participant such as the entrance order of the quiz channel , the number of the participation , the average score ratio , the accumulation rank etc . moreover , the information condition of dividing the team includes the relation condition between the persons such as the family , the husband and wife , and the friend etc . the quiz edit module 130 serves to edit a new quiz game set by linking with the quiz search module 270 of the quiz operating server 200 , so that the quiz producer quotes the existing quiz game set and quiz step , thereby editing the new quiz game set . the quiz edit module requests the search of the quiz game set and the quiz step stored in the quiz db 240 according to the quiz producer and receives the data of the quiz step and quiz game set . also , the quiz edit module edits the data including the quiz step and prepares the new quiz game set . if the quiz producer completes the preparing of the quiz game set , the quiz game set data is transmitted to the quiz operating server 200 . the quiz game set data includes the quoting information about the original quiz game set . the quiz operating server 200 of receiving the quiz game set data serves to record it in the quiz db 240 . at this time , the quiz storage module 250 additionally records the quoted information about the original quiz game set with reference to the quoting information about the original quiz game set . if the quiz operator or the quiz participant inputs the quiz satisfaction or quiz users &# 39 ; comments on the quiz game set or each quiz step to the quiz terminal , the quiz terminal transmits the correspond data in the quiz operating server 200 . the quiz storage module 250 of the quiz operating server 200 records the information on the quiz satisfaction or quiz users &# 39 ; comments in the quiz db 240 . the quiz edit module 130 allows the quiz step included in the quiz game set to be configured to include the information related to at least one quiz question , the best answer , the answer closing condition , the scoring method , and the reflecting method of the score result etc . also , in the quiz step , it includes the data of the survey , the example answer , the hint , the presenting data , the progressing message , the correct answer explanation , the comment , the description etc . the quiz step and the quiz game set include the data of the text , the image , the sound , and the voice etc . and the quiz edit module 130 serves to support the construction of the quiz step by using such various data . in the quiz step included in the quiz game set , preferably , it is individually divided into the reflecting method of the score result , the schedule , and the answer closing condition etc . however , they are commonly designate in the quiz game set so as to be commonly applied to the quiz step included in the quiz game set . fig7 is a schematic diagram illustrating an ui for the quiz edit module 130 . in fig7 , the text - centered inquiry data , the presenting data , the hint , the example answer , the best answer , and the best answer condition etc . are inputted . also , it is additional possible to input the voice , the image , and the moving picture . as shown in the screen of fig7 , the quiz edit module 130 can set up the detailed data on each quiz step . although it is not illustrated in the drawing , it is preferred that the quiz edit module 130 separately provides the setting step of the progress data of the quiz game set . the game progress data of the quiz game set can further include the data such as the progress sequence of the quiz step , the delay time per the quiz step , the beginning guidance , the end guidance etc . the quiz edit module 130 transmits the data established as the quiz game set and quiz step to the quiz storage module of the quiz operating server to be recorded and the persons can openly establish it according to the demand of the quiz producer . fig8 is a flow chart illustrating an automatic solution about the bidirectional quiz step in that the best answer is designated as a condition form . the best answer of the condition form includes a survey quiz step , the conformity type quiz step , the relational quiz step etc . it automatically gives marks from the answers of the quiz operator or the quiz participant . for example , in the quiz step including the survey “ the most you want something to eat in a get - together today ?” and the question “ the food in second in a get - together today ?”, the answer is not sealed . that is , since the answer is determined through the analysis of the survey result , it can automatically give marks through the clear statement of the best answer condition . there is the conformity type quiz step as another quiz step for automatic scoring of the best answer condition . the conformity type quiz step is a mode of recognizing as a correct answer only when the answer is in accord with the answer of the specific person . for example , there are a first mode of adopting as the answerer only when the quiz participant inputs the same answer as that selected or inputted by the quiz operator and a second mode of recognizing as a correct answer only when the answer of the team member is in accord with the answer of the team leader in case of including the plural teams . for example , in the quiz solving in which the husband and wife constitute one team , where it asks the first place of date , it recognize as a correct answer only when the answers of the husband and wife are in accord with each other . there is a relational quiz step as further another quiz step for automatic scoring of the best answer condition . the relational quiz step is mode of determining the best answer by means of the relation with the answer of the specific quiz participant . the paper - rock - scissors game can be given as an example . that is , the specific quiz participants select one of rock , paper , and scissors in each quiz step and it compares with the answer presented by the specific quiz participant or the quiz operator , so that it determines the best answer on the winner or the loser etc . the answer closing condition designates as to when it finishes the answer . in the quiz solving service presented as the embodiment of the present invention , where many persons are participated at the same time , it is configured to add the answer closing condition so as to prevent the progress speed of the quiz operation from being slowed owing to the poor answer of the participant . the answer closing condition includes the condition of passing the answer deadline , the condition of presenting the answer by means of the whole answerers , and the condition of providing the answer over the number of the designated answers or the fixed rate thereof . also , it can mix various conditions . in the scoring method , it can choose any one of a mode of adding the designated score by sorting correct answer / incorrect answer / non - answering etc . in the specific quiz step and a mode of adding and subtracting the score by discriminating the correct answerer and the incorrect answer etc . also , it can provide the score according to the answer input time , and the order of answer arrival or the answer arrival time . when one question and the example answer are used in the plural quiz steps , it can share the quiz question or the example answer in the quiz step . the quiz edit module 130 serves to organize the quiz synchronized and solved by participants stage by stage and establish the time necessary for the progressing per these steps . also , the message , which is delivered to the participants is set up at regular time so as to constitute one quiz game set . referring to fig8 , the process of the bidirectional quiz is automatically executed . in the survey type bidirectional quiz step included in the quiz game set necessary for progressing the quiz game , the quiz channel module 260 of the quiz operating server serves to transmit the survey ( s 201 ) and the query ( s 202 ). here , the order of the survey and the query may be reversed or the survey and the query may be transmitted together . then , the survey answer ( s 203 ) and the query answer ( s 204 ) are received from the quiz terminal . at this time , the order of the survey answer and the query answer may be reversed . the quiz channel module 260 determines the best answer from the result of the survey answer using the best answer condition ( s 205 ) and progresses the scoring ( s 206 ) on this and the reflection ( s 207 ) of the score result and then , sums up the ranking ( s 208 ). in this process , the quiz help or the hint of the quiz step etc . can be provided during the receiving of the answer . however , when the answer receipt is finished , the quiz channel module 260 stops the hint remained in the corresponding quiz step . fig9 is a flowchart illustrating a constitution method of the quiz game set using the recording function of the quiz terminal . in the constitution mode of the quiz game set using the recording function of the quiz terminal according to fig9 , in a state that only the quiz question of each quiz step is inputted , the method for adding the additional data on the quiz progress is presented . it can be altogether commonly applied to the embodiments 1 and 2 . it prepares the quiz game set including the plural quiz steps , manually progresses the quiz solving after the execution of the timer , measures the time of each progress step , and records the automatic execution unit of the quiz game set to complete the quiz solving schedule of the quiz game set . the quiz game set constituted through the record is established as the final quiz game set by means of the adjustment of the quiz game set edit module . the quiz edit module 130 prepares the quiz game set for additional editing ( s 301 ). it starts the timer according to the recording ( s 302 ). the quiz edit module 130 receives the beginning message of the quiz game set from the quiz producer ( s 303 ). subsequently , it receives the beginning message of each quiz step included in the quiz game set ( s 304 ). the query of the quiz step is outputted ( s 305 ) and the hint and presenting data ( s 306 ) are input . until the answer closing time is ended , the hint and the presented word are continuously received in each step ( s 306 ). here , each time information is accumulated and each time information is changed into the relative time information . if the answer closing time is not designated , the separate answer closing time is inputted to be designated . after the answer closing time is designated , it receives the best answer or the best answer condition ( s 308 ). also , it receives the items on the reflection of the score result and the decision of rank , so that the schedule and the input of the progress information of the quiz step are terminated and it continues the next quiz step . if all the quiz steps are terminated , it receives the decision mode of rank ( s 311 ) and the closing message ( s 312 ). then , it altogether stores the timer and the received records ( s 313 ) to be ended . the quiz edit module 130 serves to transmit the quiz game set constituted by the above method to the quiz operating server or the quiz storage server . the quiz operating server or the quiz storage server stores the quiz game set in the quiz db . here , each quiz step includes the quiz queries prepared in advance so as to complete the quiz game set having each quiz step or the quiz queries of each quiz step can be directly inputted in the recording process . in the embodiments of the present invention , as though the function of the quiz operating server is different from that of the quiz terminal for the convenience of the explanation thereof , the major function of the quiz operating sever is integrated with the quiz terminal , so that the personal terminal can be utilized as the quiz operating server and the quiz terminal at the same time . the embodiment 2 relates to a method and a system of providing the bidirectional quiz solving service in that the software corresponding to the opening of the quiz channel and the quiz channel module , which is the major function of the quiz operating server , is installed in the terminal of the smart phone , the tablet pc , the laptop personal computer , the pc etc ., so that it is utilized as the quiz terminal , thereby the quiz terminals of other quiz participants can be communicated with the quiz operating terminal through the network means . fig1 is a schematic diagram illustrating the embodiment 2 . as shown , the quiz channel module 260 of the quiz operating server is added to the quiz application terminal 300 and the quiz application terminal 300 serves to provide the quiz game to the quiz terminal 100 through the network . in the embodiment 2 , it is preferred that the separate quiz storage server for performing a major function of storing and searching the quiz is provided . at this time , the quiz storage server is connected to the quiz operating terminal through the network means . the quiz storage server serves to perform the quiz search and the transmit function about quiz game set and quiz step according to the request of the quiz operating terminal . the quiz operating terminal serves to receive the quiz game set or the quiz step from the quiz storage server ( not shown ) and provide the quiz game to the quiz terminals . the embodiment 2 is different from the embodiment 1 in terms of the format of incorporating the quiz channel module for providing the quiz game of the quiz operating server to the smart terminal including the smart phone , the cellular phone , the tablet pc etc . since the configuration principle and driving mode thereof are similar with each other , the separate description is omitted here . although the invention has been described according to the preferred embodiment mentioned above , the invention can be variously changed and modified without deviating from the essential point and scope of the invention . accordingly , the accompanying claims include such change and modification belonging to the essential point of the invention . | US-201414768695-A |
a hanger specifically designed for holding and suspending lightweight clothing , particularly delicate fabrics , has a rigid , elongated body terminating at each end in a pair of arms , one on top and one on the bottom of the body forming article receiving slots opening toward the center of the hanger . a third arm creates a downwardly opening slot at the end of the body . the arms are designed to permit limited flexing for seating and removing articles from the slots . the flexing occurs as a hinging action at the point of attachment to the body and at this point the arms are reinforced . the upper of the slots may have a pocket portion for positively securing garment straps and the like and also a finger member spaced from the inner end of the upper arm to form an upwardly opening entry to the slot or it may have a spring - like finger in the pocket which clamps a garment inserted into the pocket area . the downwardly opening end slots may have an upwardly extending finger to clamp a garment against the finger forming the outer side of the slot . | the numeral 10 refers to a hanger having an elongated body 11 and an upstanding hook 12 . the hook is centered midway between the ends of the body 11 and preferably is integral with the body . preferably , the body and the hook and all structure which is integral with both is molded of a suitable plastic as a single , integral unit . suitable plastics for this purpose include polyethylene and polypropylene . as best seen in fig5 to obtain maximum strength with minimum material , the body 11 is shaped as an i - beam with upper and lower flanges 14 and 15 connected by a vertical web 16 . the hook 12 is provided with a panel 17 for attachment of a size indicator . this type of panel and the size indicator system used with such panel is described in u . s . pat . no . 4 , 450 , 639 , entitled hanger with size indicator panel , issued may 29 , 1984 , to everett l . duester . the opposite ends of the body 11 are identical and each is designed to provide multiple means for engaging and supporting garments . since the ends are identical , the description of one end will be considered to apply equally to the opposite end of the body . referring now specifically to fig2 it will be seen that the body terminates in a vertical web portion 19 from the top of which an arm 20 extends outwardly and downwardly to an outwardly curved end portion 21 . the arm 20 forms a garment receiving slot or channel 22 which is open at its lower end . the shape of the arm 20 is such that the mouth or open end of the slot 22 is narrower than the upper or inner end 23 , thus , providing a garment clamping zone . in addition , the surface of the body facing into the slot 22 is provided with a plurality of spaced projections or protrusions 24 which serve as grips for garments inserted into the slot 22 and pressed against the protrusions by the arm 20 . the protrusions are smoothly rounded so that they will not cut or snag the delicate fabrics of the garments with which the hanger is designed to be used . it will be seen from fig2 that the web 16 of the body is reinforced adjacent the slot 22 by a front to back extending flange 25 . this flange is reinforced by a portion of the web which is integral with the outer face of the flange , forming an arm of t - shaped cross section . it will also be noted from both fig2 and 4 that that portion of the flange which extends around the closed end of the slot 22 is thickened to improve its structural characteristics and to provide additional resistance to flexing . this structure is particularly important in providing the portion connecting the arm to the body itself with both the resilient but relatively stiff characteristics necessary to create an effective garment grip and also to provide the necessary resistance to fatigue resulting from the frequent flexing . this latter is a serious problem with molded plastic products which require a part of the body of the molded product to be repeatedly flexed , particularly when the area in which the bending is to occur cannot be molded of a plastic which is particularly suited to flexing because of the need for relatively high resistance to flexing . also , the thickened flange is reinforced by the outwardly extending web which provides substantial support and resistance to the joint as well as durability and strength . the vertical portion 19 of the end of the body 11 from which the arm 20 extends has an inwardly extending portion forming an upper arm 30 . the upper arm 30 , like the outer arm 20 , has a cross flange 31 at its inner face which is an extension of the upper flange 14 . the flange 31 extends around and defines the slot 32 formed between the upper arm 30 and the upper face of the body 11 . again , the flange 31 , where it passes around the blind end or outer end of the slot 32 is increased in thickness to provide the same type of resistance to flexing as is provided for the arm 20 and also serving the same purpose . like the slot 22 , the slot 32 is narrowed adjacent its open end and in the narrow portion is provided with a plurality of protrusions 34 identical to the protrusions 24 . outwardly , from the protrusions 34 and adjacent the blind end of the slot 32 , the slot is deepened to form a pocket 35 which is recessed downwardly into the body 11 . at the entrance to the pocket , the upper flange 14 of the body is extended outwardly a short distance into the pocket 35 to provide a tongue 36 overlying a recess 37 . spaced inwardly a short distance from the upwardly turned inner end of the upper arm 30 , a finger 38 extends upwardly and outwardly at an angle from the upper flange 14 of the body 11 . the outer end of the finger extends over a recess 39 between it and the upper flange 11 . the outer end of the finger 38 in cooperation with the inner end of the upper arm 30 defines a restricted upwardly opening entrance 32a to the slot 32 . this particular arrangement is effective in positively preventing unintentional release of garments secured by having a strap or the like seated in the slot from becoming detached from the hanger . this is in addition to the fact that the tongue 36 is also an effective restraint against accidental garment release . also , extending from the end of the arm 11 is a lower finger 40 defining a slot 41 between it and the lower flange 15 of the body . the slot 41 , for all practical purposes , is identical to the slot 22 , except that it extends horizontally and its blind end is toward the outer end of the body 11 . it also has a plurality of protrusions 42 narrowing the entrance to the slot as well as the thickened portion of the flange in the hinge area where the arm joins the body . both of the fingers 30 and 40 are stiffened and reinforced by the rib - like extensions of the web 16 extending outwardly from the slots 32 and 41 , respectively . by providing the three different slots , two or which extend lengthwise of the beam and one vertically , the hanger is equipped to handle a wide variety of garments . because the hinge areas where the arms join the body 11 are thickened and reinforced , the fatigue failure which has been experienced in hangers of this construction in the past has been eliminated . further , the stiffness of the hinge is increased and , therefore , the hangers are successful in effectively gripping garments manufactured of materials which provide surfaces having low friction surface characteristics , thus , materially reducing the chance that a garment will be unintentionally released . the construction of the upper arm with the upwardly opening entrance to the slot is particularly desirable as a means of securing the support of garments which are of a fabric having a slick or low friction surface or may be of a nature such that they cause the hanger to tilt about its center hook creating a tendency to allow at least one side of the garment to be released from the pocket in which it is mounted . this will positively not occur in the case of this construction because the garment has to move upwardly , rather than simply laterally , to escape the confines of the pockets 35 . with the reinforced construction of the arms 20 , 30 and 40 , the garment clamping and holding effectiveness of the hanger is materially increased . fig7 - 10 illustrate modifications of the hanger construction described above . in each case , the arms forming the slots remain the same cross - sectional design as the corresponding arms shown in fig3 and 4 . in each of the modified constructions , the tongue 36a has been lengthened to prevent the garment from entering the lower portion of the pocket 35 . also , protrusions or projections 34a have been added to the upper surface of the tongue 36a adjacent its free end and a projection 34b has been added to the lower surface of the flange 31 . as illustrated in fig7 and 8 , the projections 34a and b are offset from each other lengthwise of the tongue but in the construction illustrated in fig9 they are vertically aligned . when they are offset , as in fig7 and 8 , they can be and preferably do vertically overlap . in the construction illustrated in fig7 additional projections 42a have been added to the walls of the slot 41 . in the construction illustrated in fig8 the slot 41a has been modified to be similar to the pocket 35 and a tongue 60 similar to the tongue 36a is added . the tongues 36a and 60 are resilient and , by reason of their length , act in the manner of a leaf spring . thus , they cause the projections 34a and b to grip the garments , further anchoring them against unintended release . since the garments have not been passed around a projection into a recess having a partially closed entrance , removal of the garments is facilitated because they do not have to be lifted and passed around the guard or tongue as is the case with the construction illustrated in fig2 . at the same time , construction provides a positive guard against accidental release . fig1 - 13 illustrate another modification of the hanger &# 39 ; s construction . in this construction , the body 11a is similar in cross section to the body 11 and is supported at its center by a hook l2a . the hook l2a is the same as hook 12 except it is illustrated as modified by elimination of the panel 17 . the body 11a , like the body 11 , has an i - beam type of cross section , such as illustrated in fig5 . however , its ends 70 are vertically enlarged . this enlargement makes it possible to provide end clamps having greater vertical depth and , thus , more frictional contact with a garment . this also provides the hanger with the ability to handle a wider range of garment constructions , particularly those having wide waistbands . as is best seen in fig1 , at each end of the body , the arm 71 extends downwardly . the arm is spaced outwardly from the end wall 72 of the body to form a generally vertical slot - like pocket 73 , open at the bottom and closed at the top . the lower end of the arm 71 is curved outwardly to provide a guide when garments are being mounted on the hanger . the lower edge of the body extends partially across the lower end of the pocket 73 providing a nexus 78 which supports an upwardly extending finger 74 , the upper end of which is adjacent to but detached from the closed end of the pocket 73 . the finger 74 divides the pocket into a relatively narrow garment receiving channel 75 between the finger 74 and the arm 71 and a wider chamber 76 between the arm 71 and the end wall 72 of the hanger body . the chamber 76 provides a space into which the finger can be deflected by a garment inserted into the channel 75 . the finger 74 is as wide as the flange 76 which extends around the pocket 73 ( fig1 ). preferably , the pocket 73 is wider at the top than at the bottom to provide the upper end of the finger adequate deflection room . the thickness of the finger is such as to resist deflection but not so great that it will not deflect before the necessary tension applied by the garment will cause injury to the garment or make use of the hanger difficult . the vertical member 77 of the arm which forms the lower horizontal clamp 81 extends under the nexus 78 supporting the finger 74 and provides strength and support for the base of the arm where it is joined to the end of the hanger body . also , the laterally outer end of this flange extends into the entrance of the channel 75 providing a smoothly rounded projection 79 serving as a positive restriction . this serves the dual purpose of assuring the application of positive clamping pressure against the garment to hold it in the channel 75 and provide a ledge to seat under any hem or similar band at the top of the garment to further support it . also , by so extending around the nexus supporting the finger , it further stiffens and strengthens it . horizontally extending garment clamps are provided on both the top and the bottom of the hanger adjacent the pocket 73 . these clamps are identical except for the fact that the lower pocket 80a is inverted with respect to the upper pocket 80 . the upper pocket 80 is formed by an arm 82 which extends inwardly along the top of the hanger body forming an article receiving slot 83 between it and the top of the hanger body . access to the slot is through the opening 84 between the hanger body and the curved end of the arm 82 . the pocket widens vertically and is divided by a tongue 85 which extends in cantilever fashion almost the entire length of the pocket . the outer end of the tongue 85 is spaced from the end wall of the pocket and above the bottom of the pocket whereby the tongue has space to deflect under pressure from a garment inserted in the slot 83 . within the slot , the top of the tongue 85 forming the bottom of the slot 83 has a plurality of upwardly extending protrusions arranged in two groups . the first protrusion 86 adjacent the entrance to the slot is wedge shaped having an elongated , inclined surface facing the entrance to the slot to facilitate the introduction of garments into the slot . four additional protrusions 87 and 87a , arranged in pairs , are provided . the protrusions 87a are spaced further apart than the protrusions 87 creating a gap above which a protrusion 88 extending downwardly from arm 82 is provided to form an article grip . the slot formed by the lower arm 81 has the same pattern of protrusions . the protrusions 87 , 87a and 88 have the same construction as the protrusions 34a and b illustrated in fig1 . the fact that the arms 71 , 81 and 82 are all t - shaped in cross section is important . this construction not only provides the arms with the degree of resistance to deflection necessary to effectively grip and hold the garments it also strengthens the joinder of the arms to the hanger body . this is important in eliminating breakage of this type of arm construction which has been experienced in the use of hangers which have this type of garment grip . fig1 and 15 illustrate a further refinement of the invention . the only changes introduced into that illustrated in fig1 - 13 relate to the tongue or finger in the vertical end pocket and the tongue or fingers in the upper and lower pockets . in this construction , the finger 74a is reinforced by a central rib 94 which extends from the base of the finger or its nexus to the body a major portion of the finger &# 39 ; s length . the height of the rib from the surface of the finger tapers with the height being greatest at the base of the finger and gradually tapering to nothing toward the finger &# 39 ; s free end . the finger 74a is also provided with an enlarged head 95 at its free end which extends into the deflection chamber . the head 95 acts as a stop to limit deflection , thus , if necessary , requiring the clothes situated in the garment channel to deflect the intermediate portion of the finger , if additional space is required . this provides a very positive grip on the garments . the tongues or fingers 85a in the pockets 80 and 80a are constructed the same way and function in the same manner . having described the preferred embodiments of our invention and certain modifications thereof , it will be understood that additional embodiments can be made without departing from the principles thereof . such embodiments are to be considered as included in the hereinafter appended claims , unless these claims by their language , expressly state otherwise . | US-27027188-A |
a spill - resistant pharmaceutical formulation for oral administration from a squeezable container comprises a pharmaceutical agent in a suitable vehicle comprising a liquid base and a thickening agent , the formulation consisting of mutually compatible components and having the following proper ties : a viscosity within the range of about 7500 to about 12 , 500 cps using a brookfield viscometer with a ‘ c ’ spindle with helipath movement at a spindle speed of 20 rpm and 20 - 25 ° c ., a viscometric yield value of a semi - solid , a spill - resistant consistency permitting the composition to be squeezed by light manual pressure through a channel , to spread in a spoon bowl sufficiently quickly for accurate measurement , and to remain in the spoon bowl without spilling on spoon inversion , tilting at 90 degrees , and vibration , homogeneity such that the components do not separate under conditions of use , and a storage stability such that the foregoing properties are retained for at least two years shelf life . a method for producing a formulation for a spill - resistant pharmaceutical composition comprises combining a per - unit dose effective amount of a pharmaceutical agent with suitable vehicle components comprising a liquid base and a thickening agent and testing the formulation for acceptance criteria . | in describing preferred embodiments of the present invention illustrated in the drawings , specific terminology is employed for the sake of clarity . however , the invention is not intended to be limited to e specific terminology so selected , and it is to be understood that each specific element include all technical equivalents which operate in a similar manner to accomplish a similar purpose . oral drug delivery systems are typically either liquid or solid dosage forms . the invention provides a new system combining a squeezable container and a semisolid oral dosage formulation . there has been longstanding need for such a system , and there is nothing like it available . this system include a formulation that has certain physico - chemical and rheological characteristics : such a formulation is ( a ) semisolid , ( b ) spill - resistant , ( c ) easy to administer and measure , ( d ) storage stable , ( e ) comprised of compatible components , and ( f ) has viscosity within a specific range . the meaning of these terms is apparent to one experienced with drug formulation , and as defined herein . viscosity is measured using a brookfield viscometer with a ‘ c ’ spindle with helipath movement at 20 rpm and 20 - 25 ° c ., or equivalent . viscosity decreases slightly with increasing temperature . it has been noted that viscosity measured at 10 rpm may be significantly higher ( 50 - 100 %) than measured at 20 rpm ; however for some of the formulations , it is impossible to measure the viscosity accurately at , the slower spindle speed . it was therefore determined that the 20 rpm spindle speed gave a better reflection of the important rheologic properties of the inventive formulations . semi - solid character is used to indicate a formulation that has a viscometric yield value determined as a relative value , e . g . using the shutting off motion of a brookfield viscometer with dial gauge . ease of administration is intended to mean ( a ) extrudability under light manual pressure from a squeezable container or a proxy ( e . g . a syringe with a 5 mm orifice ), and ( b ) spreadability in a spoon bowl measured by extruding the formulation into a spoon bowl and determining whether the material spreads to the edges of the spoon bowl . spill resistance is meant as something different than non - spill characteristics . a spill - resistant formulation according to the invention begins to spill from a spoon bowl during test periods of vibrations , inversion , and tilting , but slowly enough to conform with practical time limits between dispensing and ingesting , and quickly enough to enable the product to be readily consumed from a spoon bowl . mutual compatibility of the components means that they do not separate in preparation and storage for the equivalent of two years at room temperature ( as indicated by three - months accelerated stability testing at 40 ° centigrade and 75 % relative humidity ). storage stability means that the materials do not lose their desirable properties during storage for the same period . preferred compositions do not exhibit a drop in viscosity of more than 50 % or an increase in viscosity of more than 100 % during that period . only certain formulations may be prepared to have the physico - chemical and rheological characteristics described herein rendering them suitable for the drug delivery system of the application . other formulations lack the critical characteristics and are therefore distinct . they are semi - solid , in that they have a viscometric yield value determined as a relative value , e . g using the shutting off motion of a brookfield viscometer with dial gauge . they are easy to administer — they were easily squeezed from a tube into a teaspoon with light manual pressure such as could be applied by an elderly or infirm person ; they tended to level themselves in the spoon by spreading to the edge of the spoon to allow accurate measurement of a teaspoon dose ; they did not spill quickly when the spoon was shaken , tipped , or inverted ; and they had a consistency making them readily removed orally from the spoon ( when a subject inserted the spoon into his mouth , closed his lips , and removed the spoon ). they are spill - resistant — this characteristic was quantified in experiments emulating the behavior of elderly , infirm , and young people , in which full teaspoon samples of the formulations were shaken , tilted , and inverted . they are storage - stable for an extended period , without any evidence of separation , hardening , or softening ; they retain their preferred viscosity range . the components are mutually compatible in that they do not interfere with the bioactivity of the pharmaceutical agent or physical properties of the vehicle , and the components do not separate and retain their properties . the formulations are suitable for a squeezable container such as a tube , and for extrusion into a receptacle such as a spoon bowl . the receptacle is sized to hold a unit dose , to hold it conveniently without spilling , and to be comfortable and provide a good fit into the mouth between the lips for oral administration . the oval sectional shape of a typical teaspoon bowl as evolved over history satisfies these criteria and is a suitable receptacle , although other shapes can work as well . these properties complement the characteristics of a simple preferably tamper - resistant and childproof dispensing system for a storage stable , semi - solid , spill - resistant oral systemic pharmaceutical that is easy to administer and measure . to compare the drug delivery system of the invention to other technologies , experiments were conducted with the goal of identifying and quantifying the relevant physico - chemical characteristics of formulations according to the invention . these were compared to characteristics of other formulas that are commercially available or disclosed in the prior art . the results indicate that the properties of the pharmaceutical compositions herein have surprising advantages and critical characteristics necessary for a non - spill drug delivery system and that the other tested products are unsatisfactory for this system . test samples ( examples 21 to 31 ): laboratory scale ( 100 g - 500 g ) batches of pharmaceutical formulations were prepared essentially according to the methods and compositions described in examples 2 - 4 , 7 , 9 , 11 - 13 , 15 - 16 , and 18 of the earlier ross application , u . s . ser . no . 08 / 114 , 315 . these compositions were tested for the new acceptance criteria set forth herein . these formulations have liquid bases in a concentration of from about 45 % to about 97 %, and thickeners in range of 1 % for carbomer , 2 - 3 % for cellulose derivative , or 45 % for polyethylene glycol ( peg ). peg with a molecular weight less than 800 is a solid and works as a thickener and over 800 is a liquid . thus , in s . n . 21 , about 18 % of the formulation is peg 3350 ( a liquid ) and about 55 . 5 % is peg 400 ( a thickener ). reference samples ( serial nos . 32 - 37 ): the following commercially available formulations were obtained ( serial nos . 32 - 34 ). these were selected as examples of thick viscous liquid reparations suitable for pharmaceutical use . ( manufactured by ciba , canada ), containing phenylpropanolamine hydrochloride , chlorpheniramine maleate , antifoam a , corn syrup , ethyl cellullose , flavoring , methyl and propyl paraben , polyethylene glycol , polysorbate 80 , starch , vegatable oil , xantham gum , and water . ( manufactured by warner lambert co ., canada ), containing mineral oil , glycerin , phenolphthalein , agar , sodium cyclamate , and water . also several noncommercial pharmaceutical formulations disclosed in prior patents were also prepared ser . nos . 35 - 37 ) to determine whether the characteristics of the formulations ( such as viscosity , semisolid character , non - spillability , ease of administration , storage stability ) would be suitable for the drug delivery system of the invention . the formulations were as described in e patents , except the materials were prepared as placebos ( without the active ingredient ). the characteristics of the formulations should not be expected to be significantly different with the active ingredient . as to tachon et al . ( nos . 36 - 37 ), the two formulations selected were closest to those in the examples herein in that they lacked xanthan gum and other extraneous ingredients . sterling patent ( gorman et al ., u . s . pat . no . 5 . 288 , 479 ), example , placebo nestec patent ( tachon et al ., u . s . pat . no . 5 , 300 , 302 , example 24 , placebo nestec patent ( tachon et al ., u . s . pat . no . 5 , 300 , 302 , example 31 , placebo viscosity : to measure viscosity , a brookfield viscometer was used with a ‘ c ’ spindle with helipath movement at 20 rpm and 20 ° c . further details are given in table 1 . semi - solid character : if a material is a semisolid then it has a measurable yield value . yield value was measured as a relative value for all the samples utilizing the shutting off motion of the brookfield viscometer ( with dial gauge ). semisolid products in gel or other semi - solid form have a significant yield value ; thick liquids or suspensions do not . the character of the material can be confirmed by visual and tactile observation . ease of administration : ease of administration is reflected both ( a ) in extrudability and ( b ) spreadability . extrudability was measured by loading 8 ml of the product into a syringe having an orifice of about 5 mm or less , then pressing the product out through the orifice . extrudability is the ease of extruding a product from a squeezable container through a small orifice onto a spoon . a product that is difficult to extrude under these conditions is unsuitable for administration from a squeezable container . extrudability also reflects the ease of ingesting the formulation when the spoon is placed in the mouth and the tongue is used to remove the product cleanly from the spoon . spreadability ( leveling ) was measured by observing the behavior of the product over 5 minutes to determine whether the material remains as a heap or tends to spread to the edges of the spoon . spreadability is also important to the ability to measure and administer a predetermined dose ( typically one teaspoon ) of a formulation . spill resistance — vibration : three components of spill resistance measured : vibrations , inversion , and tilting . as to vibration , a lab shaker with minor modification was used to demonstrate , quantitatively , the extent of non - spillability of the claimed products when shaken in the spoon . the lab shaker was modified to exhibit controlled horizontal motion of the spoon ( s ) attached . see fig5 a . spill resistance — inversion : a custom - made platform was prepared to show the comparative spilling of the product from a spoon , when inverted ( turned upside down ). spill resistance — tilting : measurements were made to determine the time at which the products tend to come off the spoon . the method used was to clamp spoons at a 90 ° angle and monitor the product sliding off the spoon . see fig5 b . the data generated on the above samples is presented in tables 1 and 2 . the data emphasizes the important properties and advantages of a semi - solid drug delivery system . table 1 presents the physico - chemical characteristics of the test samples and reference samples . table 2 presents the spill resistance data . * viscosity measurements done by brookfield viscometer , model bvii , using ‘ c ’ spindle at 20 rpm and 20 deg c . except in nos . 8 & amp ; 17 , where the ‘ c ’ spindle could not be used due to instrument error . the viscosity results shown above are extrapolated from measurements using ‘ d ’ spindle . ** ease of administration is demonstrated through the extrudability of the product from tube onto spoon and then measurability / spreadibility of the product in the spoon , as discussed in the text . grades ‘+’ to ‘+++’ indicate the products have acceptable extrudability / measurability , whereas product marked ‘++++’ behave like a thick # liquid which has a tendency to spill off the spoon on overfilling . products marked ‘−’ indicate the products do not extrude as uniform gel and also do not have spreading characteristics . ( a ) the test samples ( s . n . 21 - 31 ) all had a viscosity when made within the range of 13 , 500 - 45 , 000 at 20 degrees c and 20 rpm . reference sample s . n . 32 , 33 , and 36 all had very low viscosity , below 3500 cps . ( b ) the test samples all had semisolid characteristics . reference samples s . n . 32 - 34 and 36 did not . viscosity was independent of yield value ( semi - solid character ) so that a product with the same viscosity can be distinguished as a liquid or semi - solid . ( c ) the test samples all rated “+” to “+++” for ease of administration ( extrudability spreadability ). the samples of s . n . 21 - 31 have a semi - solid gel - like consistency which can be squeezed out of a tube to the spoon . however , they are thick and the leveling is somewhat slow . this represents an intermediate level of ease of administration and measurability of dosage by spoon - leveling indication . reference samples s . n . 35 and 36 lacked ease of administration . ease of administration was also observed to be a characteristic somewhat independent of the other measured characteristics . for example , it may be difficult to administer a unit dose of a thick liquid because the liquid will dribble from the container instead of extrude as a cohesive mass . the results of table 2 are summarized as follows : the ross test samples all had non - spill characteristics . reference samples s . n . 32 - 36 lacked non - spill characteristics and lacked spill resistance . the characteristics were observed to be largely independent of those reported in table 1 . in particular , for the test samples , the spill start time on vibration was 15 minutes or more , the spills time on inversion was half a minute or more , and the spill start time on tilting at 90 degrees was at least about 30 seconds . the only prior art reference sample that matched this non - spill characteristic was s . n . 37 , but it was too stiff for ease of administration ( see above ). a ) by vibration : the ross examples are non - spilling for as much as 15 - 60 minutes at a shaking speed of 1 . 5 ″ amplitude w / 28 per sec . frequency . in contrast , the marketed products like corsym ( thick suspension ), agarol laxative liquid ( gel like product ), and natural honey tend to spill - off the spoon in less than one to about 30 minutes . b ) by inversion and tilting : many of the ross test non - spill base products do not spill off the spoon when inverted upside down for as long as 20 minutes , whereas most of the other prior art samples spill off immediately . it was also observed that the test products do not leave residual co tent of the drug product on the spoon , and are not likely to do so when ingested by mouth . this be correlated to the assurance of full dosage administration . in contrast , the thick liquids do not come off cleanly . as to s . n . 35 ( gorman et al . ), the preparation when completed as per the process mentioned in patent does not form a uniform gel . instead , water starts separating out on storage within few hours . this renders the product not suitable for uniform dosage when the active component will be incorporated , nor is it physically stable . also , the spill resistance qualities are not met , with special reference to vibration and invertibility . this is different than the qualities covered for the non - spill formulations of the invention . as to tachon et . al ., s . n . 36 turned out to be a thick liquid and not a semisolid gel , and it lacked spill - resistance as claimed here . s . n . 37 on the other hand yielded a very stiff consistency product which is not easily squeezable from a tube / dispenser and is also non - spreading . thus this product is inconsistent , and is not easy to administer or measure as to dose . conclusion : non - spill formulations according to the ross invention and the prior art products exhibit particular rheological properties which may be measured as a proxy for administration to dexterity - impaired patients . the test methods described herein are a useful way to determine whether a formulation is suitable for use as a spill - resistant formulation according to the invention , as a non - spill formulation or otherwise . examples 21 - 31 are very thick , and examples 32 - 37 leave other properties that make them unsuitable as a drug delivery system for children and geriatric and motor - disordered patients . these patients find it difficult to keep the hands steady and hence are likely to spill the drug product from the spoon before ingesting . in formulations according to the ross application , the non - spill base and pharmaceutical formulations offer an absence of spilling despite invertibility . in these experiments , spill resistant formulations were prepared containing dextromethorphan hydrobromide ( dm ), guafenesin ( gu ), acetaminophen ( ac ), or pseudoephedrine hydrochloride ( pe ), in a cellulose - based gel and in a carbomer gel according to the invention . the formulations are given in table 3 . each of these formulations had suitable characteristics of viscosity , spill - resistance , and ease of administration . they were semi - solids . they were freer - flowing gels than the compositions of ross . they all had ph between about 6 and about 7 . examples 42 - 45 were essentially free from sodium except for small quantities of sodium hydroxide used to adjust the ph . in addition , the formulations were subjected to stability testing for several months at room temperature and accelerated stability conditions with elevated temperature and elevated humidity ( 40 degrees c , 75 % relative humidity ). in all cases , the formulations were homogeneous at the outset and after stability testing . viscosity remained suitably constant . table 3 gives the viscosity data for stored formulation after storage for 3 months at elevated temperature ( 40 degrees c ) and 75 % humidity . an additional unexpected advantage of example 44 was that the carbopol had a very effective taste - masking effect , making the formulation palatable despite the bitterness of acetaminophen . this feature permits the avoidance of other taste - masking agents . as can be seen from table 4 , the inventive formulations are semi - solids , unlike the liquid formulations of the prior art . the inventive formulations have very high spreadability , at least as high as honey . they do not spill from a spoon immediately on tilting or inversion , as do the liquids , but they do come off within several seconds , much faster than the non - spill formulations of ross . in addition , the formulations were tested at high frequency vibration similar to the tremors of parkinsonian patients . at amplitudes of 1 to 2 inches , and frequency of 120 - 240 per minute ( 4 / sec ), the inventive formulations do not spill . this spill - resistance is better than honey at room temperature . each reference cited herein is incorporated by reference in its entirety as if specifically incorporated by reference . the embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention . nothing in this specification should be considered as limiting the scope of the present invention . modifications and variations of the above - described embodiments of the invention are possible without departing from the invention , as appreciated by those skilled in the art in light of the above teachings . it is therefore to be understood that , within the scope of the claims and their equivalents , the invention may be practiced otherwise than as specifically described . | US-54892700-A |
polymorph 1 of 4 -- 1h - benzidimazole - 2 - yl ]- 1 - piperidinyl ] ethyl ]- αα - dimethyl - benzenoacetic acid of formula is described , procedures for its preparation , pharmaceutical formulae containing polymorph 1 and the use of polymorph 1 to treat allergic reactions and pathological processes mediated by histamine in mammals such as man . | we have found that bilastin can exist in three clearly different polymorphic forms called polmorph 1 , polymorph 2 and polymorph 3 . the procedure described in u . s . pat . no . 5 , 877 , 187 generates a mixture of polymorphs 2 and 3 . we have discovered experimental conditions and specific solvents to produce clearly different polymorphic forms of bilastin . the crystalline polymorph 1 of pure bilastin is prepared according to the procedures of this invention . the polymorphic forms 1 and 2 are stable . polymorph 3 is not very stable and is difficult to obtain in the pure form . both polymorph 2 and polymorph 3 are converted into polymorph 1 for the purposes of this invention . polymorph 1 of bilastin has a melting point of 200 . 3 ° c . polymorph 2 has a melting point of 205 . 2 ° c . polymorph 3 has a melting point of 197 . 0 ° c . the crystalline polymorphic form 1 of bilastin is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands , expressed in reciprocal centimetres : 3430 ( s )*; 3057 ( w )*; 2970 ( s ); 2929 ( s ); 2883 ( m )*; 2857 ( m ); 2797 ( w ); 1667 ( m ); 1614 ( m ); 1567 ( w ); 1509 ( s ); 1481 ( m ); 1459 ( vs )*; 1431 ( m ); 1378 ( w ); 1346 ( m ); 1326 ( m ); 1288 ( w ); 1254 ( m ); 1199 ( w ); 1157 ( w ); 1121 ( vs ); 1045 ( w ); 1020 ( w ); 1010 ( w ); 991 ( w ); 973 ( w ); 945 ( w ); 829 ( w ); 742 ( s ); 723 ( w ); 630 ( w ), * where ( w )= weak intensity , ( m )= medium intensity , ( s )= strong intensity , ( vs )= very strong intensity . fig1 represents the infrared spectrum of the crystalline polymorph 1 of the bilastin in a potassium bromide tablet recorded in a fourier perkin elmer spectrum one transformer spectrophotometer . the crystalline polymorphic form 2 of bilastin is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands , expressed in reciprocal centimetres : 3429 ( s )*; 3053 ( w )*; 2970 ( s )*; 2932 ( s ); 2868 ( s ); 2804 ( w ); 1699 ( m ); 1614 ( m )*; 1567 ( m ); 1508 ( s ); 1461 ( vs )*; 1381 ( m ); 1351 ( s ); 1331 ( m ); 1255 ( m ); 1201 ( w ); 1156 ( m ); 1121 ( vs ); 1048 ( w ); 995 ( w ); 823 ( w ); 767 ( w ); 744 ( s ); 724 ( d ); 630 ( w ), * where ( w )= weak intensity , ( m )= medium intensity , ( s )= strong intensity , ( vs )= very strong intensity . fig2 represents the infrared spectrum of the crystalline polymorph 2 of bilastin in a potassium bromide tablet recorded in a fourier perkin elmer spectrum one transformer spectrophotometer . the crystalline polymorphic form 3 of bilastin is also characterised by its infrared absorption spectrum in potassium bromide that has the following characteristic absorption bands , expressed in reciprocal centimetres : 3430 ( s )*; 3053 ( w )*; 2970 ( s ); 2932 ( s ); 2868 ( s ); 2804 ( w ); 1921 ( w ); 1708 ( m )*; 1614 ( m ); 1568 ( m ); 1508 ( s ); 1461 ( vs )*; 1380 ( m ); 1351 ( m ); 1330 ( m ); 1271 ( m ); 1255 ( m ), 1201 ( w ); 1156 ( m ); 1121 ( vs ); 1048 ( w ); 995 ( w ); 823 ( m ); 767 ( w ); 744 ( s ); 724 ( w ); 630 ( w ), * where ( w )= weak intensity , ( m )= medium intensity , ( s )= strong intensity , ( vs )= very strong intensity . fig3 represents the infrared spectrum of the crystalline polymorph 3 of the bilastin in a potassium bromide tablet recorded in a fourier perkin elmer spectrum one transformer spectrophotometer . we have discovered that , in selected experimental conditions , the mixture of the polymorphic forms 2 and 3 , obtained according to u . s . pat . no . 5 , 877 , 187 , is surprisingly transformed into polymorph 1 . we have also discovered that polymorph 1 of bilastin is very stable and is not transformed into any of the other polymorphs 2 and 3 . similarly , in the same experimental conditions , the pure polymorphic form 2 of bilastin is surprisingly transformed into the pure polymorphic form 1 . polymorphic form 3 , which is the most unstable , undergoes the same transformation in the same conditions . polymorph 1 of bilastin is a very stable polymorph at room temperature and is , therefore , very useful as an active ingredient of a pharmaceutical preparation . polymorph 1 is also stable when stored at , temperatures above room temperature . the polymorphic crystalline form 1 of bilastin is characterised by the following data of its x - ray crystallographic analysis as a monocrystal , with crystal parameters of approximately the following values : crystallograph system monoclinical spatial group p2 ( 1 )/ c crystal size 0 . 56 × 0 . 45 × 0 . 24 mm cell dimension a = 23 . 38 ( 5 ) a angstrom α = 90 ° b = 8 . 829 ( 17 ) a β = 90 ° c = 12 . 59 ( 2 ) a γ = 90 ° volume 2600 a 3 z , calculated density 4 , 1 . 184 mg / m 3 during the development of polymorph 1 of bilastin for pharmaceutical preparations , elaborated according to correct manufacturing procedures , we have discovered that crystallization of bilastin ( prepared according to the description given in u . s . pat . no . 5 , 877 , 187 ) of short chained alcohols , preferably isopropylic alcohol and n - butanol and its mixtures , leads to generation of the pure polymorphic form 1 of bilastin with a high yield . crystallisation of acetone , dimethylsulphoxide , dimethylformamide , acetonitrile and tetrahydrofurane or its mixtures also lead to generation of polymorph 1 , although with lower yields . it is , therefore , preferable to use the former solvents . the infrared spectrum of polymorph 1 of bilastin in potassium bromide is characterised by the following bands , absent from polymorphs 2 and 3 : fig1 shows the complete infrared spectrum of polymorph 1 of bilastin in potassium bromide , recorded with a fourier perkin elmer spectrum one transformer spectrophotometer . pharmaceutical preparations of this invention can contain , as well as an effective quantity of polymorph 1 of bilastin as an active ingredient as an antiallergic or antihistaminic agent , several pharmaceutically acceptable excipients that can be solid or liquid . the solid pharmaceutical preparations include powders , tablets , dispersible granules , capsules , stamps and suppositories . a solid excipient can be one of several substances that act as diluents , aromatising agents , agglutinants or disintegrating agents and an encapsulation material . the powders and tablets preferentially contain from approximately 5 to approximately 20 per cent of the active ingredient . appropriate solid excipients are magnesium carbonate , magnesium stearate , talc , sugar , lactose , pectin , dextrin , starch , gelatin , tragacanth , methylcellulose , sodium carboxymethylcellulose , waxes with low melting point , cocoa butter and similar products . the term “ preparations ” includes the formulation of the active ingredient with an excipient for encapsulation to produce a capsule in which the active ingredient ( with or without other excipients ) is surrounded with the excipient by an encapsulation material . tablets , powders , stamps and capsules can be used as suitable forms for oral administration . the active ingredient can also be incorporated into a chewing gum that can contain sweeteners , flavorings and colorings as appropriate . to prepare suppositories , a compound with a low melting point , such as a mixture of fatty acid glycerides or cocoa butter , is melted and the active ingredient is mixed well and homogeneously dispersed in the mixture . the homogeneous melted mixture is placed in the appropriate moulds and left to cool until it solidifies . liquid preparations include suspensions , lotions and emulsions . an example of these corresponds to aqueous suspensions that can be made by mixing the finely divided active ingredient in water with suspension agents . aqueous solutions can be prepared by placing the active ingredient in water and adding suitable coloring agents , aromas , stabilising agents , sweeteners , solubilising and thickening agents as appropriate . also , topical preparations are considered for nasal , ophthalmic and dermal use . appropriate formulae for nasal administration can correspond to solutions or suspensions . ophthalmic formulae can be lotions , suspensions or ointments . dermal preparations can be lotions , suspensions , ointments and creams . ointments usually contain lipophylic excipients such as mineral oil or vaseline . solutions for ophthalmic use can contain sodium chloride , acid and / or base to adjust the ph , and purified water and preservatives . similarly , a compound is being contemplated for transdermic use , consisting of a therapeutically effective amount of active ingredient incorporated into an excipient that corresponds to a liquid , a gel , a solid matrix or an adhesive patch sensitive to pressure , to be released via a transdermic administration system . the effective antiallergic or antihistaminic amount of polymorph 1 of bilastin for topical administration varies between 0 . 1 and 5 % of the total weight of the pharmaceutical compound . the preferred amount ranges from 0 . 1 to 2 % of the total weight of the pharmaceutical compound . the effective antiallergic or antihistaminic amount of polymorph 1 of bilastin for oral administration varies from 1 to 50 mg / day , with preferably an amount corresponding to approximately 2 to 20 mg / day in a single or fractionated doses . polymorph 1 of bilastin has antihistaminic properties that have been demonstrated in experimental pharmacological models , such as preventing histamine - induced lethality in the guinea - pig and antagonism against cutaneous capillary permeability induced by histamine in the rat . the following examples illustrate but do not limit the scope of the present invention . dissolve bilastin ( see the u . s . pat . no . 3 , 877 , 187 ) in isopropylic alcohol heated to reflux for approximately 15 - 20 minutes under nitrogen while stirring . cool the solution to 50 ° c . over 6 hours and stop stirring . let the solution cool to room temperature and stir again for three hours , filter and wash with cold isopropylic alcohol . dry the solid residue in a vacuum cabinet at 35 - 40 ° c . to constant weight . heat a suspension of bilastin ( see u . s . pat . no . 5 , 877 , 187 ) in n - butanol and reflux for 3 hours under nitrogen while stirring . leave the solution to cool while stirring , filter off the solid residue and dry it in a vacuum chamber at 35 - 40 ° c . to constant weight . treat a mixture of polymorphs 2 and 3 of bilastin for several hours with hot acetone . let the mixture cool to room temperature and filter off the solid residue . dry it to constant weight . dissolve polymorph 3 of bilastin in isopropylic alcohol heated to reflux and stir for approximately 15 - 20 minutes under nitrogen . let the solution reach room temperature constantly stirring , filtering and washing with cold isopropanol . dry the solid in a vacuum chamber at 35 - 40 ° c . to constant weight . dissolve polymorph 2 of bilastin in n - butanol heated to reflux while stirring for approximately 3 hours . let the solution reach room temperature while stirring , filtering and draining . dry the solid in a vacuum chamber at 35 - 40 ° c . to constant weight . | US-51182205-A |
a cardiac pacemaker for implanting in a patient includes a device for applying stimulating pulses to the heart of the patient at a rate determined by a pacing parameter ; a plurality of devices for detecting a corresponding plurality of physiological parameters which are respectively associated with physical exertion of the patient and producing a corresponding plurality of output signals representative of the corresponding physiological parameters ; a circuitry device receiving the first output signals for varying the pacing parameter as a function of the first output signal , an external programming device in communication with the circuitry device ; a linking element in communication with the external programming devices which selectably links the circuitry device with a selectable one of the plurality of device for detecting ; and the external programming device causing the linking element to select a given one of the plurality of detecting device for linking with the circuitry device . | in the exemplary embodiment described below of a cardiac pacemaker according to the invention , various components serving to perform signal processing and described as matrix - organized memories or memories containing characteristic fields are used multiply in similar configurations , so that for understanding the invention it will suffice to describe these basic components generally in terms of their function . in the descriptions of the functional cooperation of the apparatus as a whole that are given below in conjunction with the block circuit diagrams , it will accordingly not be necessary to describe the function of these components in detail . in fig1 first , the basic design of a cardiac pacemaker is shown , with means for processing at least one input measured variable for physiological variation , preferably of the heart rate . on the input side , accordingly , at least one measured value pickup is provided for a measured variable that can be picked up inside or outside the body ; this variable can be utilized for physiological control of the pacing rate or -- in the case of a demand pacemaker -- of the basic heartbeat interval . these variables are of the type that differ from signals electrically derivable in the heart , and they serve only to prevent pacing in competition with spontaneous ventricular actions or to synchronize the pacing pulses , and they relate only to a current heart action . correspondingly , all the pacing variables can be varied in accordance with the &# 34 ; physiological &# 34 ; input variables for which a relationship for a pacing behavior can be found that is valid over a plurality of heartbeats . these input variables , in turn , are all variables that are relevant to pacing and that are not related to merely one specific cardiac action but rather pertain in general to the pacing behavior . among them are also the parameters that in pacemakers are &# 34 ; programmable &# 34 ;, as well as others to be discovered in future , which improve the pacing behavior -- measured in terms of the intended functional capacity of the heart . corresponding measured value pickups are known in principle , in the form of temperature - dependent variable resistors for measuring the blood temperature , measuring electrodes for ascertaining impedance cardiographic ( electroplethysmographic ) data , photoelectric measured value pickups for ascertaining the blood oxygen saturation by means of a beam of light or light gate , chemical sensors for ascertaining the ph value , or pressure or sound pickups for measured values that have a relationship to mechanical contractions . in particular , the measured variables picked up in the heart itself , and which form a standard for the chamber filling , and thus are already linked with a variable characterizing the cardiac output -- and hence the functional capacity of the heart -- can advantageously be utilized for varying the pacing parameters ( in particular , the heart rate ). additional physiological measured values can also be obtained from the electrical voltage potentials picked up from the heart , however , such as the q - t interval , which can also be used to control the heart rate . in the ensuing description these variables will be called &# 34 ; physiological measured or input variables &# 34 ;. a pacemaker that processes a plurality of input signals can accordingly be called a &# 34 ; multi - physiological pacemaker &# 34 ;. the analog output signals of the measured value pickups are each supplied to an analog / digital converter connected to their output side , which converts the input signals into corresponding signals that are processable with the digital memory means or signal processors described . the processing of the data words , each forming a measured value , is effected by means of a microprocessor and its peripheral modules for data storage and data processing . in the exemplary embodiment shown in fig1 the physical ( i . e ., hardware ) structure of the pacemaker system described below is shown . this is a microprocessor system 110 , which is capable of bidirectional communication with an external control unit 125 , as a programming unit , by means of telemetry . the implantable unit contains a conventional multiprogrammable system 111 , which enters into interaction with the ventricle and / or atrium via one or two electrodes . as an interface with the rest of the pacemaker system , a parameter memory 112 is provided , which at the same time serves as a buffer for data exchange with the conventional pacemaker system . contained in the parameter memory are , first , those data that are prespecified to the pacemaker 111 as operating parameters or in other words control variables . these variables form the values of a one - or two - chamber pacemaker that are adjustable by external programming , and the operating mode ( from voo through ddd ) is likewise programmable . also contained in the memory 112 are operating parameters of the kind that are picked up in the patient &# 39 ; s body by further measured value pickups and are derived from &# 34 ; physiological &# 34 ; input variables . in the case of the q - t intervals , however , they can also be derived via the pacing electrodes themselves . while the pacemaker system 111 itself thus contains those circuits that prevent competition of pacing events with spontaneous pulses , the microprocessor system encompassing this block serves to define further control variables , preferably the basic rate , and in this sense to expand the system 111 . this has the advantage that for using the system 110 in the conventional manner , no additional skills are required beyond those necessary in the use of known multiprogrammable pacemakers . the pacemaker 111 is capable of operating even without &# 34 ; physiological &# 34 ; picked - up measured variables , the basic pacing rate being predetermined by external programming as in conventional pacemakers . depending on the technological realization , the necessary signal and data processing for the operation of the pacemaker portion 111 can also be performed by the cpu 113 of the microprocessor . associated with the cpu 113 are a random - access memory or ram 114 and a read - only memory or rom 115 as well as an input / output unit 116 , by means of which the data traffic with the peripheral components 111 and 125 is carried out . it should be noted that with the system shown , signal processing is done in the manner described below , and the memories and data linkages described below are generated by suitable programming , that is , by software , and are already present in the ram or rom memory areas . the system is perceived by the user as if it were an apparatus having the described physical structure , which can also be realized by hardware provisions . to avoid having to describe the chronological sequence in the processing of programs in typical data processing structures , which is dictated by the solely serial processing performed by the cpu in a microprocessor system , the description here will be made as if the various memories were generated separately as hardware and were connected to the control and data transmission lines that represent the flow of data in the block diagrams . connected to the input / output unit 116 is both the parameter memory 112 and various measured value pickups 117 , 118 , 119 , 120 , which via digital / analog converters 121 - 124 deliver the picked - up signals to the unit 116 . the signal pickups were mentioned at the outset above and are disposed in or on the patient &# 39 ; s body -- in particular on the pacing electrode or on the housing of the pacemaker itself . the signal processing done by the cpu is serial , and the individual components of the structure to be described below are optionally included in the data exchange in accordance with appropriate interrupt commands , so that the signal processing -- adapted to the temporal commands of the signals -- is performed in a clocked , quasi - simultaneous manner . by means of the control unit 150 , a data transfer from and to the implanted unit is effected via a telemetry component 151 , which communicates with the corresponding telemetry component 125 . the control unit has its own cpu 152 , which exchanges data with its own ram memories 153 or rom memories 154 . an input / output unit 155 is also provided , to which the telemetry unit 151 and a video interface 156 are connected . the video interface is connected to a monitor 157 , which in accordance with the program present in the external unit 150 makes it possible to call up data from the implantable system and vary these data . it is particularly significant that the entire operation by the user and the means for graphic display are present in the external unit , including data relating to the general structure of the implantable system . by graphic display of the data obtained and of the findings necessary for programming the internal system , a comfortable mode of operation is provided which provides the operator with information on the operating state of the implantable system at all times . programming is done by means of a light wand 158 , with which data can be selected by contact with the screen . correspondingly , a pressure - sensitive screen can be used , in which the selection of information is possible by touching the surface of the screen . in accordance with the known techniques of graphic image processing , a selection of screen pages ( corresponding to &# 34 ; paging through &# 34 ; a card file ), and both during operation and in evaluating the data ascertained during operation , presentation is preferably done in graphic display using internationally understood symbols . the individual function regions of the implantable system can be dialed separately , and a search tree structure leads from those parameter ranges that pertain to the basic functioning of the pacemaker to more - subtle linkages , and this structure is attainable with various access codes to a depth assigned to a particular user . by means of a printer 159 , a protocol can be printed out for documentation purposes . the external form of the components 110 and 150 is also shown in fig1 showing that the implantable part has the dimensions of a standard pacemaker 160 , while the external communication part 161 has not only an antenna part 162 that can be placed on the head of the patient but also a graphic display surface 163 . the ensuing description relates to details of the component 116 and especially to the linkage of the &# 34 ; physiological &# 34 ; input variables of the measured value pickups 117 - 120 as well as to the data linking and the control thereof . in fig2 the matrix - like memory structure of a characteristic field provided for controlling the system is shown , and the memory locations of the matrix can be addressed by column and line address signals , and the numerical value present at the addressed memory location can be read in or out . each characteristic field is addressable by means of a common address characteristic , so that on the one hand a simplified addressing is possible in normal operation , but on the other hand a new configuration of the processing and a self - contained reading out or a changing of the contents of one characteristic field can readily be done in connection with the external communication unit . while in normal operation a linkage of the address inputs and data inputs or outputs is done in accordance with a predetermined linking plan , where in preceding characteristic field memories , data read out by addressing serve to address successive characteristic field memories , these data can also contain information which relate to the linkage of the data with successive characteristic fields themselves , either in terms of the direction of the linkage or in terms of the operations to be performed ( logical or mathematical ) in the linkage . the corresponding data contents differ from one another in additional attributes , which can be distinguished in suitable subsequent data discriminators ( not shown ). during the external communication , by means of the common address characteristic of each characteristic field memory , direct access to the contents of the particular total memory region is possible for reading data in and out or changing data . the characteristic field data for the data processing preferably have access addresses , which can be called up similarly to those of auxiliary memories , and which contain solely linkage , selection or other auxiliary information such as data sets that can be read out from the communication unit with graphic data or specifications for the particular pacemaker type . this direct access is represented in fig2 and 3 in the lower part of each of the drawings by the control and access plane 306 . accordingly , a data field may be not only a module of the signal processing , in the sense of linking input and output signals but may also be a memory , the information in which form for determining the sequence in terms of combining together input and output data of various characteristic field modules . the memory unit shown in fig2 need not -- as shown -- in this form embody a physical or hardware - type unit in the memory region of the system . the pertinent structure can also be generated purely by software . the memory unit of fig2 -- which here is also synonymously called the &# 34 ; characteristic field memory &# 34 ; or &# 34 ; memory matrix &# 34 ;-- forms a part of a &# 34 ; cell &# 34 ; shown in fig3 as a signal processing module , in which the memory unit is also surrounded by auxiliary components , which are favorably provided in a modular structure in each characteristic field and which are linked along with them in the network formation , so that only the inputs and outputs of this cell appear as interfaces . modules not needed in a particular application are each rendered inactive by the loading of appropriate control parameters in the auxiliary memory ( as will be described hereinafter ). the combining of the signals of various measured value pickups is effected in a block 301 , taking into account the weighting signal assigned to each signal of each measured value pickup . the block 301 also at the same time forms a switch component , which via the access plane 306 selects various signals as input ( that is , address ) signals and depending on the &# 34 ; switch position &# 34 ; ( influenced via the selection information of the control plane 306 ) links various signals by means of the following characteristic field for the variable addressing of the output of signals from the following characteristic field memory 302 , in the form of digitized amplitude data . the selected input signals each form partial address signals , which taken as a whole encompass the memory range of the following characteristic field . by means of linking data to be supplied separately to the block 301 , the input data can not only be switched but also ( individually or in common ) subjected to logical or mathematical operations ; that is , data can be selected , shifted or in some other way &# 34 ; processed &# 34 ;. in particular , operating ranges or operating characteristic curves can be selected in this way , and the selection data , which characterize authorized address regions , are stored in a suitable characteristic field . with parallel addressing of the memories containing the signal data and the selection data , and linking via block 301 , the selection data ( for example by means of an and linkage called up via the control plane 306 ) characterize only signal data that have a data value deviating from &# 34 ; zero &# 34 ; as authorized addresses . the selectable address range can thus be restricted or affected in some other way arbitrarily . preferably , a limited number of linkage operations that are to be used often are held in reserve for this purpose such that they can be called up directly via the control plane . input variables can also be subjected to more - complex operations by means of a correspondingly programmed characteristic field memory , which authorizes any evaluation of input signals by means of a corresponding specification of output signal values as data values in the pertinent memory locations addressed by combination of the input signals . on the other hand , input signals can also be subjected exclusively to illogical linkage in the block 301 , with the following characteristic field either being &# 34 ; bridged &# 34 ; in terms of data processing by a corresponding control signal ( not shown ), or it is rendered ineffective by the pertinent characteristic field by storing the addresses in the memory locations , so that the input signals appear directly once again at the output of block 302 . the control plane 306 itself can -- as also shown hereinafter , referring to fig3 and 4a -- be reached by output signals of the characteristic field memory 302 , so that as a function of signals contained in characteristic fields , the signal linkage can be influenced via the blocks 301 . a data set contained in a corresponding memory 302 accordingly includes not only an instruction as to whether it is signal , selection , or linkage or other auxiliary information , but also in the case of selection information the designations of the pertinent characteristic field cells that form the output and input for the signal to be processed . in the case of linkage information , the agreed - upon designation of a logical or mathematical operation is also included . additionally , as a function of data addressed in characteristic fields , a plurality of data linkages can also be affected in the overall structure of the system . these are stored in fact by means of linkage memories -- as will be described hereinafter . if such a linkage memory is called up , by means of a signal contained in a memory location , the system structure changes more or less fundamentally . in this manner , the cardiac pacemaker described is &# 34 ; self - teaching &# 34 ; in such a manner that the configuration of the processing can be predominantly automatically adapted in terms of the measured value selection in processing to the input signals found and to their changes . such changes are in particular the following : the shutoff of malfunctioning measured value pickups , and in this connection in particular the transition from operation determined by a plurality of physiological measured value pickups to the mode of operation that is influenced by one such pickup , or by no such pickups . while two measured value pickups for the same variable can often be operated in differential operation , a single remaining pickup can often -- given a suitably increased error probability -- contribute effectively to control as well . together with the data signals , evaluation numbers are also carried in the processing , which in an evaluated combination contain a conclusion as to the value of an input signal in terms of its expected reliability . the evaluated combination is preferably performed with standardized input signals . it links input signals containing identical information to form one combined output signal , which is done in accordance with mathematical laws for the formation of mean values of measured values having weighting . this mean value formation can be effected either by digital processing , via calculation in accordance with a relationship expressed in a formula , or by means of a table storable in memory in the form of the characteristic field memory . to ascertain the weight of the pertinent input signal , additional evaluation of the pertinent signal in terms of inherent faults are expressed by unexpected fluctuations or superimposed amplitudes . the corresponding malfunction recognition circuits correspond to circuits such as those already used for the elimination of faulty input signals in medical electronics . accordingly , digitized data of various types are supplied to the component groups 301 . in detail , the data of one input plane each are combined following a linkage that can be predetermined via the external programming access plane 306 . the input signals serve to address the lines of the characteristic field memory 302 , and the data g 1 - g 3 serve to address the lines , while the data 1 - 3 relate to the data contents -- that is , the data to be written into the individual addressed memory locations . via the external control ( access or programming ) plane , the type of linkage in the memory 301 can be predetermined , and various mathematical linkages ( summation , multiplication ) or logical linkages can be selected , so that the data can be added , multiplied or otherwise transferred in accordance with a logical condition ; the logical conditions may comprise not only and , and / or or other known linkages performable by logical gates , including &# 34 ; greater than &# 34 ;, &# 34 ; less than &# 34 ; or &# 34 ; equal to &# 34 ; relationships . it can also be predetermined that while satisfying the predetermined condition a particular fixed logical value will be output . the component group 301 accordingly allows the processing of signals with either a fixed logical level or with a variable level in digital representation . the number of planes of the component element 301 increases accordingly if the characteristic field memory 302 is embodied multidimensionally , as indicated by the perspective layering in fig3 . for each dimension , an additional addressing plane is required . the illustration in fig3 is accordingly more symbolic in form . any other suitable embodiment of the actual memories is also possible . following the circuit 302 is a programmable signal processing component group 303 , which enables a time - dependent linear processing of the signal value , while in the component group 302 a non - linear , tabulatable relationship between the input and output variable is present in the form of a characteristic graph . the two component groups 302 and 303 are to be influenced by external programming means via the control plane 306 , and preferably the coefficients of a linear differential equation determining the chronological transfer behavior ( in a similarly matrix - like arrangement corresponding to the other data component groups ) are preferably capable of being fed into the component group 303 . the chronological processing is done by means of the internal microprocessor in accordance with such systems that by digitally adjustable parameters enable the digital simulation of linear physical systems . by the separation of non - linear and linear system components of the signal processing , a simple system structure is obtained with simple adaptability , and the system is uncomplicatably adjustable externally . the signal processing portion 303 may also effect a signal delay in such a manner that by means of a certain parameter , a predetermined signal delay is predetermined ( by the designation of the corresponding number of clock signals of a system clock ), and thereupon the output signals appear delayed at the output , as compared with the input , only by the indicated number of clock signals , the delay being in accordance with the set number in the manner of a digital delay line ( shift register ). the representations shown in block 303 provide examples of a possible transfer behavior , which is described by the characteristic values of the pertinent linear differential equations . the component groups 304 and 305 generate an identification for the reliability of the signal emitted by the component 300 , which is supplied to the input of the following corresponding component , so that in each state a standard for the reliability is provided , which can be taken into account in the ensuing combination . faulty signals can be eliminated in this manner , so that in the ensuing processing , access is made instead to other , error - free signals . thus it can be ascertained whether the pertinent input is associated with faulty signals . an indication of this occurs if with meassured values which are inherently subject to a slow change ( blood temperature , etc . ), signals arrive for processing that have an abruptly changing character . furthermore , one criterion is that in the comparison of two or more signals which under certain conditions exhibit an identical course of change , deviations from this identical course occur . an important fact for processing with the pacemaker described is that in the form of an additional datum of at least one bit , an identification relating to the reliability of the corresponding measured value -- or in accordance with the time - dependent processing in a component 303 -- is added to the digital input signals , for a linkage of measured values . in the simple case for error recognition , the weighting apparatus 304 includes a mean value former and a comparator , to which the input signal from the component group 301 is supplied directly and the output signal of the error recognition is also supplied , and if the input signal deviates beyond a predetermined amount , the output signal of the weighting apparatus 304 indicates that the input signals possibly have only a reduced reliability , so that the weighting in the evaluation is to be decreased accordingly . the signal g combines the weighting signals of previous stages , which stages have already performed respective corresponding evaluations . in the component group 305 , the signal g is added to the output signal of the stage 304 , and the evaluated combination is made available to the stage 300 as an output signal . the component groups 304 and 305 can likewise be switched via the control plane 306 , as well as in accordance with signal data and by means of external programming . the &# 34 ; cells &# 34 ; containing characteristic fields may contain variant kinds of information . for example , they form read - only memories even without linkage of their data contents with other cells , and they are addressable by means of physiological measured values or output signals of other characteristic value memories . in this manner regions that are run through by the ( address - forming ) input signals can be particularly identified for subsequent stages or for external communication with graphic representation . authorized operating ranges or emphasized ranges , or logical linkages on the other hand , can be predetermined . if the memory contents , as output signals , are not intended for subsequent memory cells for addressing or as data signals , such characteristic fields can also serve merely for the information of the user or for controlling the communication system , in order to emphasize particular operating ranges for the external communication in the graphics used there . in fig4 the arrangement of the above - described component groups in a matrix - like structure is shown , in a manner that is the basis for the addressing of the individual component groups in the context of their linkage in a linkage memory 406 . for the association of the selection , they can also be presented correspondingly graphically . a function group addressable by means of line and column numbers includes the function elements , of a cell selectable as such by addressing , comprising a summing portion 402 , characteristic field 403 , linear time element 404 and weighting unit 405 ( corresponding to the illustration in fig3 ). these function groups are repeated in an arbitrary line and column grid , and by means of two memory ranges organized in matrix fashion on the one hand for each functional component group in terms of its inputs , the &# 34 ; map square &# 34 ; of that particular component group the output signals of which are supplied to this component group can be input . since the summing unit 402 has a plurality of inputs , a plurality of columns and address identifications can be provided for each component group . additionally , the output signal data can be associated with the following cells , as described above . in the outermost column on the right of the memory 406 receiving the linkage information , for example , the input variables of the pacemaker system are each assigned to one memory element of one line , so that by means of the corresponding input it can be determined whether the output signals of which component group should form the pertinent parameters . the first memory 406 contains the signal linkages valid in normal operation -- in a manner programmable by the external communication portion . in a second memory 407 organized in matrix fashion , the system structure for an alternative operating state , such as can be called up by the signal data themselves via the control plane 306 ( 409 ), is shown -- once again in column and line association . in fig4 a , it is shown how by linking two characteristic field cells 410 and 411 ( corresponding to the cells 401 in fig4 ) and one counter cell 414 , a histogram memory is formed , can , which upon later being read out provides information as to behavior of the pacemaker system . the cell 410 here forms a ( programmable ) reference field , in the memory locations of which , which are addressable by means of output signals of preceding cells or by input signals , values are stored that serve as reference variables in comparison operations . in a counter matrix 411 , counter states are stored in the individual memory locations , which once again are organized in matrix fashion , the counter states representing the appearance of particular events -- in the normal case , the exceeding of or failure to attain the corresponding reference value contained in the cell 410 . the memory cells 410 and 411 are addressed in parallel for this purpose . the input signal which is to be compared with the values stored in the reference cell 410 is supplied to a comparator 413 , which compares it with the particularly addressed signal in the reference cell 410 in accordance with an externally predeterminable condition . if the condition is met , then by the single occurrence of this state ( controlled by a clock signal ), the value present in the addressed position after the output of the counting memory is raised by one and read in again . in this manner , a characteristic field to be read out later is produced , which in the graphic representation indicates the frequency with which predetermined operating values are attained . the possibility of varying the operating behavior of the pacemaker taking into account the frequency with which predetermined operating values are adhered to as well is also provided . to this end , preferably the contents of the counter characteristic field 411 of fig4 a is supplied to a block 300 shown in fig3 as an input variable , and the operating behavior is varied in accordance with corresponding logical decisions by means of a corresponding characteristic field . to this end , the characteristic field matrix addressed on the basis of the counter state ( behavior in the past ) is followed by a further characteristic field memory for the call up of different characteristic fields , which vary existing linkages ( linkage memory 406 in fig4 or affect the parameter memory ( 112 in fig1 ) or correspondingly switch over or replace characteristic fields serving as read - only memories . to this end , it is favorable if the parameter memory 112 which influences the conventional behavior of the pacemaker is likewise designed in accordance with the characteristic fields that monitor the physiological control . in this manner , it is also possible to program the conventional portion in accordance with the processing of the physiological parameters . &# 34 ; physiological &# 34 ; measured variables , which are ascertained in the conventional portion of the pacemaker , such as the q - t interval or a spontaneous frequency occurring at particular states of exertion , can thus be transferred into the remaining system via the parameter memory 112 as an interface . this interface is also suitable for the transfer in ascertaining physiological variables via the electrodes or other measured value pickups provided in the conventional region of the pacemaker . via a corresponding control of the control plane 306 , a switching element which as a function of the output signal of block 411 emits a signal to the control plane , which signal influences a linkage matrix 406 which in turn again triggers the block 301 ( in fig3 ), can be connected to the output side of the block 411 ( or any other component group ). in this way , as a function of the previous behavior -- optionally also to be averaged over predetermined time segments -- the future behavior can be influenced . characteristic fields can be switched over , or in other words exchanged , evaluated differently or changed in their linkage with preceding and subsequent characteristic fields . how these changes should be made is stored in the characteristic fields involved which store the linkages . the system is thus likewise &# 34 ; self - teaching &# 34 ;, and a change in the configuration is not done until there is a certain frequency of events . a standard for the change of the system behavior is faults of a predetermined frequency or intensity , or the non - occurrence of predetermined operating states , which from the standpoint of therapy necessitate a certain pacemaker configuration , so that the pacing can always be done in the simplest kind of operation -- and the one easiest for the physician to monitor . thus the physician is also capable of using the memory for monitoring success of the programming he has performed . now that the basic component groups have been described , the cooperation of these component groups will be described in further detail referring to the block circuit diagram of fig5 . particularly important for the operation of the system is the fact that the signal variables are linked in accordance with their physical or physiological significance . in accordance with a calibration table ( characteristic field ) connected to the output of the relevant measured value pickup a conversion into a variable adapted to the current performance deficit of the heart is now effected in a further processing cell . a differentiating component is assigned to the blood temperature , since a rise in temperature always takes place with a delay as compared with the current exertion level . an increase in exertion beyond a predetermined value is limited in time ( the contents of the counter matrix 411 in fig4 a is raised by means of a system clock serving as a time clock ). when a predetermined duration of time is exceeded , the emitted exertion variable is lowered by means of a corresponding switchover of the pertinent characteristic field via the control plane , until the temperature again attains a lower output value . in this manner , in a fever condition a permanent increase in the heart rate is avoided . the physiological variables picked up in the body are each linked on corresponding &# 34 ; linkage planes &# 34 ; with the further identical signals , so that a physically correct further processing takes place . between two linkage stages ( if necessary ), an adaptation of the temporal and amplitude behavior of the signal to be processed and linked is performed , so that the pertinent signal is adapted at the particular linkage location with a further physiological variable , which is of significance in controlling cardiac activity . the advantage is thus obtained that the system can operate parallel to the signals taking their course in the body and calling up a variation of the cardiac activity and parallel to the endogeneous regulation processes , and in the various linkage stages the particular pertinent physiological signals are likewise ascertained at the pertinent stage by additional measured value pickups and are usable either as monitoring signals or are incorporated in accordance with their value into the further signal processing . a separate characteristic field memory is provided for the &# 34 ; calibration &# 34 ; of each of the measured value pickups . a further factor is that signals which on the one hand are standard for the performance required and on the other hand are jointly characterizing for the cardiac output itself , as well as variables that are only briefly available ( monitoring measurement of physical exertion by means of an ergometer for the sake of calibrating measured value pickups ) are likewise fed in in a system - correct manner and enable a conclusion to be made as to the processing capability of the preceding stages , or permit correct setting of the corresponding processing parameters ( components 302 and 303 ). furthermore , by feedback of a variable that enables drawing a conclusion as to the cardiac performance capability , the signal processing can also be influenced . this feedback is done in such a manner that the physiological measured values in the processing are combined and converted in such a manner that they form a standard for the instantaneous requirement of the cardiac output . a criterion for the actual cardiac output derived from the heart is utilized as a comparison criterion , this cardiac output being taken into consideration as feedback in the selection of the pacing rate in the context of the table . in a preferred embodiment , the table establishing the pacing parameters is updated based on the cardiac output actually established with the pacing using the pertinent parameters . in the case of input addresses that require a particular cardiac performance , the particular pacing parameter , or signal values that lead to the necessary pacing parameters , are entered . for the linkage of signals in the form of digital characteristic field , the following basic principles -- depending on the applications mentioned -- arise : 1 . pure control functions are formed by simple linkage of input measured variables of address variables and by the pacing parameters as stored values . 2 . regulation functions are realized in a corresponding manner , with measured input variables being converted by corresponding characteristic fields into a variable that is representative for the physical exertion , in accordance with the required cardiac output . this variable addresses the characteristic field together with a variable representative of the current stroke volume , and the then necessary heart rate can be read out of the individual memory locations . in particular , instead of the various absolute values , the particular deviation from a predetermined set - point value is usable as a signal value , and the ensuing processing then likewise relates to the corresponding deviations . in the case of measured variables which follow the actual physical reference value with a temporal delay , a compensation is preferably provided where the pertinent measured variable is present in the most unadulterated possible form . the temporal delay in the rise in temperature of the blood during physical exertion is compensated for by differentiating component ( 303 in fig3 ), so that the rate change begins more quickly . 3 . the calibration of a measured variable dependent in particular on exertion is effected by providing that in the calibration period , the value expected ( and optionally ascertained be a different measuring method ) is respectively written into the memory location addressed by the current measured variable . in particular , to this end the exertion ascertained externally by means of an ergometer is written into a memory to be addressed by means of the measured variable or variables characterizing the exertion , in each case in form of a value . this value in turn , during the subsequent operating state , addresses the corresponding rate in a characteristic field , and this rate is selected such that ( in particular in the case of combined addressing with a measured value representative of the current stroke volume ) the product of the stroke volume and the rate , as the cardiac output , corresponds to and is followed up with the ascertained current exertion variable . 4 . the error control is ascertained by comparison of two ( or more ) variables . the pertinent characteristic field effects a shutoff of one or all values , in the case of deviations that are greater than a predetermined extent . in the addressing of memory locations , correspondingly , with three comparison signals the particular signal that deviates substantially from two others can be excluded from further processing . to do this , a characteristic field is needed which is addressed by address signals in which all three address components are combined . three different signals acting as shutoff commands are contained in the various memories addressed by the unauthorized signal combinations , and in the event of a deviating signal preclude this signal from further processing , and in the case of two deviations preclude all three signals from further processing . furthermore , ( optionally in accordance with further signals ), expectation values can be predetermined , which permit further processing of the input signals ( by logical association in a corresponding characteristic field memory ) only whenever the input signal is within a predetermined expectation interval . 5 . in the control plane , a selected operating characteristic curve is predeterminable ( for example by external communication ), in such a manner that in an additional characteristic field ( addressable by only one input variable ) the value is firmly associated as memory contents with the other variable . this can be done for example by means of a calibration process ( as indicated above ). the second characteristic field is then merely &# 34 ; one - dimensional &# 34 ;. in a perspective ( graphic ) representation of a two - dimensional characteristic field , the points on the operating characteristic curve can also be represented such that they are graphically emphasized , by superimposing the one - dimensional characteristic field . with one operating field , a corresponding region of input signals in a characteristic field is declared allowable , by means of corresponding memory contents and subsequent logical linkages , and delivered for further processing . in fig5 a pacemaker system as it is presented to the attending physician on the screen of its control unit is shown in block form , at the same time it represents the basis for the functional description of a pacemaker system of a kind that can also be generated in a conventional manner -- for instance by means of hardware . fig5 shows the implantable portion , and the pertinent arrangement is naturally not restricted to implantable systems but is also applicable to external pacemakers correspondingly . the block 501 shown in dashed lines characterizes the regions of the human body located outside the heart , from which physiological measured variables are derived that pertain to the function of the pacemaker , while the heart 502 enters into interaction with the system via the pacing electrodes and measured value pickups emplaced in the heart . a conventional pacemaker 503 is capable of functioning autonomously and is optionally multiprogrammable via a programming unit 504 . ( in a system shown according to fig1 which represents the real linkages , the programming is done by means of the unitary control unit by means of the parameter memory 112 .) in the system presented graphically to the physician as shown in fig5 the programming is done with a block 504 , which can be called up on the control unit in the form of a page and contains the conventionally programmable parameters in the usual designations . selectively , different types of pacemakers can be implemented completely here . the translation of the real parameters set in the implantable system into a conventional system is done in the external control portion , and a selector switch is provided which permits different kinds of implantations . the blocks outlined in solid lines are component groups according to fig4 which contain the function elements of fig2 and 3 and are logically connected in the manner shown by means of the linkage matrix indicated in fig4 . the exemplary embodiment according to fig5 shows exemplary types of linkages in a preferred embodiment , the operating mode of which will be described in further detail hereinafter . it is apparent that the output signals of various analog measured value pickups 505 - 509 in the block diagram are linkable in different groups in the course of the signal processing . previously , a conversion of the analog input variables was done by means of analog / digital converters 510 - 514 . the output variables of the converters are supplied respectively to evaluation component groups 515 - 519 , in which an individual , or in other words programmable , adaptation takes place . this adaptation , by corresponding programming of the characteristic field shown previously , includes the elimination of non - linearities of the measured value pickups , enables the programming in of time - dependent changes of the transfer characteristic and of weighting factors . thus the transfer behavior of a measured value pickup can be changed by means of the characteristic field programming . while the measured value pickups 506 ascertain the partial pressure orv of oxygen in the right ventricle or the respiration rate , the measured value pickup 507 serves to ascertain the blood temperature tb , preferably in the vena cava . while the partial pressure of oxygen or the respiration rate is a good standard for the instantaneous oxygen deficit -- presuming a suitable calibration of the corresponding characteristic field -- the blood temperature has an integrating character and rises or falls only after a certain time delay . in order in the component 520 following and identical to the blocks 516 , 517 , which component 520 links the output variables of the preceding blocks with pre - programmed weighting ( with an exertion variable obtained as an agreeing reference base ), inside the component 517 the time constant is provided by corresponding programming with a differentiating characteristic , so that preferably the differential changes of the blood temperature as a standard for a state of activity or repose are linked with the output variable of the block 516 . the superposition can be done either by weighted sum formation , linearly , or by means of a characteristic field , and in the case of a two dimensional characteristic field one input variable each addresses one coordinate axis . the linkage in the component 520 is also dependent on sensors 521 - 523 emitting a number of digital output signals , which sensors -- as described above referring to fig2 -- effect switchovers of the characteristic field present in the block 520 . thus a mercury switch 521 , which is implanted along with the pacemaker housing , recognizes the instantaneous position of the patient ( lying down , standing up ) and thereby furnishes an additional possibility for evaluating the exertion of the patient . a digital activity sensor 522 furthermore recognizes , by the appearance of accelerations and decelerations beyond a predetermined threshold value , whether the patient at the time is generally at rest or in motion and switches the characteristic field located in block 520 over accordingly . the control of the measured value processing is affected by means of a common system clock , to assure synchronism . a digitally operating error recognition means ascertains whether an exertion variable at the time can just then not be ascertained . for instance , if the respiration rate is picked up by means of a microphone , then by means of an additional microphone present in the error recognition unit 523 , loud noises originating in coughing by the patient or the like are recognized and utilized for blanking out the measured values of the pickup 506 , which could be done by switchover of the corresponding characteristic field , or also by reducing the weighting factor by connection with the block 516 . an additional measured value pickup 505 forms a recognition for the activity of the patient with an analog output signal . in accordance with the component 522 , the acceleration and delays are ascertained in terms of amplitude and frequency and processed further via the component groups 510 and 515 . while in the component group 520 the exertion variables ascertained in the circulatory system were combined , the block 524 serves to unite the output variable of the block 520 with a signal resignating the actual physical activity . the output signal of the block 524 thus indicates the cardiac output ( hzv ) requirement . the output signals of the blocks 515 and 520 are to some extent redundant and can be put in relation to one another in the subsequent characteristic field in order to increase the reliability . of particular significance is an additional transfer component 525 , which is included in the telemetry system of fig1 . via this component group , external exertion data ascertained by means of an ergometer can be fed into the block 524 , and by means of external programming both the output variable of block 515 and that of block 520 can be set in relation to the instantaneous load . by insertion of the current exertion data into the memory locations of the characteristic field in block 525 , which locations are addressed by the means of the output signals of block 515 or 520 , the other signals characterizing the hzv requirement can be monitored or calibrated , so that the reliability of the system can be increased or a regulation brought about . by the transfer and calibration of the exertion signal available outside the body with the corresponding intracorporeally obtained signal , a possibility for calibration or a linkage for regulation can be obtained . two further measured value pickups 508 and 509 ascertain signals which likewise relate to the cardiac output . in the illustration in fig5 the measured value pickup 508 for the stroke volume represents ( via the systolic intervals as a pressure pickup or microphone or by means of impedance cardiography or a combination of the two methods ) a standard for the volume adaptation of the heart as a reaction to a predetermined physical exertion . the further measured value pickup 509 for the q - t interval ascertains a standard for the current rate requirement from the signals picked up in the heart at the pacing pulses , likewise by means of a corresponding characteristic field . following a corresponding analog / digital conversion in conversion blocks 513 and 514 and an optional non - linear distortion of the transfer behavior are blocks 518 and 519 containing characteristic field groups , the combination of the variables determining the rate takes place in a block 526 . the linkage of the variables characterizing an hzv requirement is effected in block 527 , and depending on the programming of block 527 various linkages can be selected : the output variables of blocks 524 and 526 can be superimposed on one another and control the heart rate directly ( as the basic rate of the demand pacemaker 503 ). this control can be performed taking into account the instantaneous stroke volume isv ( arrow from block 518 to 527 ), so that all the variables that have an influence on the heart rate are processed in combined form , and a favorable cardiac output for the instantaneous rate [ sic ; word missing ] based on the ascertained variables is established . the additional evaluation of the stroke volume in block 527 can be done with a different weighting than that fed into block 526 as a trend for the rate to be adhered to , so that in particular , regulation fluctuations can be avoided here . if a great number of variables that must be ascertained in a stable fashion are present , then optionally the stroke volume can be left out entirely from the processing in block 526 . the same applies to the variable q t . in a corresponding manner , the pacemaker can also be used in regulated operation , where only the linkage in component 527 needs to be converted . to this end , the hzv requirement in the characteristic field of block 527 is calibrated with the product of the stroke volume and the instantaneous rate , the rate being raised or lowered until the product of the stroke volume and the stroke rate corresponds to the cardiac output predetermined by the block 524 . it is apparent that by means of different linkages , various control or regulating mechanisms can be realized , and in particular within the characteristic field the rate can be varied incrementally by means of a search strategy in such a manner that the largest possible cardiac output is attained . an additional error recognition means 528 shuts off the signals picked up in the heart if faults are ascertained there , and the error criteria correspond to those that in demand pacemakers prevent control of the pacemaker by the heart . an arrow from the output of block 527 and pointing toward the parameter memory 504 indicates that the programmed parameters of the pacemaker undergo variation . among these is in particular an expansion of the programmed time variables , such as refractory or blanking times with decreasing frequency . this relationship can be related generally to the time control of the pacemaker . the programmable variation in block 504 is effected preferably by means of a characteristic field stored in memory there , the memory of which , containing the programmed operating values of the pacemaker , is addressed by means of a variable derived from the frequency . the pacemaker 503 is in particular a single - chamber pacemaker for ventricular stimulation , because in this way it is unnecessary to place an additional electrode in the atrium . the measured value pickup for further physiological variables are disposed in the pacemaker housing or in the ventricle electrode , so that the implantation technique does not differ from the conventional pacemaker , or is even simplified as compared with av pacemakers . fig5 a shows how by means of the external communication unit the individual characteristic fields 532 - 534 are addressed in the corresponding cells -- as described above -- and data located there are read out or new data are read in . the addressing is effected independently of the other operation of the cardiac pacemaker 535 , which is determined by non - physiological data , and during the programming of the physiological portion this control is rendered inactive ( fixed - value signal ). the basic pacing rate and the other physiologically determined operating parameters are fixed during the programming to a value corresponding to the resting state of the patient . as a special feature it is also provided that by means of the configuration data ( characteristic field 534 ) contained in the pacemaker , which data define the data linkage of the characteristic fields , a graphic representation is called up , which corresponds to this configuration . the individual characteristic fields are represented as blocks on a screen or lcd screen and can be called for programming by dialing with a light wand or by means of pressure in the case of a touch sensitive display . the particular characteristic field called up , or the corresponding component , then appears enlarged on the screen , so that the data fields marked with a cursor can be changed . to facilitate programming , arbitrary individual structures of the linkage diagram can be called up and varied using the so - called &# 34 ; windows &# 34 ; technique . here not only data sets but also , depending on the access authorization of the communication portion , configurations of the processing ( input and output linkages ) can be changed as well , so that the system is extremely flexible and can be tailored to an individual patient in accordance with the empirical values obtained . for calling up the graphic representation of the screen configuration , either the data of the configuration characteristic field are used for direct addressing of a corresponding memory region , or a corresponding block circuit diagram is synthesized based on the pertinent linkage information , using cad techniques . it is particularly advantageous here that the communication system shown can be incorporated in a standard type of data processing system ( pc or the like ), and the communication interface with the pacemaker is provided by an additional assembled circuit board that can be inserted into the pc , which is furnished along with the associated software that contains the above - mentioned functions in programmed fashion , so that the communication portion in an existing pc entails only slight additional cost . nevertheless -- depending on the existing expansion of the pc -- a very great processing capacity is available , which enables the simultaneous call - up and representation of even complex illustrations , and the operator guidance provides the user with instructions and warnings for the configuration programming of the system . via a printer , a protocol relating to the programming process is prepared , which documents the set operating state of the pacemaker . the programmed data inputs for the configuration can simultaneously be stored in a central memory , so that the operating parameters of the particular pacemaker can preferably also be called up via external data communication options and in emergency cases be available to any physician . the programming portion is designed in particular as a communication terminal , so that complex software that also relates to operator guidance and to the configuration of the pacemaker is centrally stored in memory and transferred to the particular communication terminal . in this way it is assured that in programming , the latest software is used , so that further development -- taking into consideration the particular hardware situation -- can be done even after the implantation . experience with a particular pacemaker type in a great number of patients with corresponding clinical pictures thus contributed subsequently to optional further development or improvement of the already implanted system . the illustration shown on the screen of the communication unit for instance corresponds to a block diagram such as that shown in fig5 . the characteristic fields shown in fig6 a - 6c provide examples for relationships , stored in memories having a matrix organization , between variables such as are used in the abovedescribed pacemaker concept . the representation is preferably done in a three - axis coordinate system , so that a perspective graphic illustration in the external control unit can be provided . if only two coordinate axes are used , then the illustration will be in two dimensions . an additional illustration option is provided by superimposing two characteristic fields in one diagram . to standardize the triggering , the characteristic fields selected here are based on three - axis systems , because the associated memory is then designed as a two - dimensional matrix , so that the corresponding numerical values are likewise capable of being illustrated in two dimensions , that is , on the screen , and thus are variable either by means of graphic entries made with a light wand or by numerical input with cursor addressing . in the characteristic field shown in fig6 a , the numerical values k1 and k2 can be two different input variables , which are linked , or they may be one measured variable and one parameter -- for example , the current heart rate or the blood temperature . thus a non - linear characteristic curve of a measured value pickup with temperature correction can be performed . by superimposing two characteristic fields , a calibration in which the two characteristic fields are matched spatially with one another can be realized , or a regulation of a predetermined strategy , which for instance comprises making the volume between two superimposed characteristic fields , or the dependent variable is sought by means of incremental variation of an independent variable a relative or absolute maximum . in the last - mentioned case , the independent variable represents a measured value , wherein the dependent variables are varied in accordance with the strategy and the variation is monitored in accordance with a differential criterion . in a further embodiment , one of the axes is the time axis , so that by means of the characteristic fields heart events in the past are stored in memory by means of the characteristic fields and are transferrable out of the heart to the control unit with the same graphic illustration means that also pertain to the rest of the pacemaker system . correspondingly , the time - dependent behavior of the pacemaker can be illustrated in the control portion , by graphic means , as a function of heart events , as is known in conventional pacemakers from the representation of the pacing rate as a function of the followup frequency of spontaneous heart actions . while in the control functions the characteristic fields are thus firmly programmed , in the regulation they serve as memories for the variable values , which are used as a basis for the regulating criterion ; the regulating operation makes the status of the system graphically clear to the attending physician by means of graphic representation of the current field of the most recently run - through values . by corresponding programming , the system is switchable -- as described -- at any time between an open - loop control system and a closed - loop control system . this switchover can be done automatically as a function of preceding signals , if a corresponding characteristic field association is provided . in fig6 b , in a further characteristic field , the cardiac output is shown as a function of the heart rate and in [ sic ] the stroke volume . this characteristic field has particular significance for the controlling of the pacemaker , because the cardiac output is a standard for the performance capacity of the heart , especially since the variation of the heart rate by itself is not a sufficient criterion , if the attainable stroke volume is left out of consideration . the characteristic field shown in fig6 b shows the purely mathematical relationship that is attained by calculation , where two different load curves l1 and l2 are plotted on the precondition that a constant physical load must be countered , in the control of the pacemaker , with a likewise corresponding cardiac output . the stroke volume is variably shown between the minimum and maximum physiologically allowable values , and the same is true for the heart rate . for the pacemaker , however , only the heart rate can be influenced , while the stroke volume is established automatically is accordance with the existing adaptability of the heart . that is , it furnishes on the one hand , as a product with the heart rate , a standard for the current performance of the heart , while on the other hand a decrease or increase -- with respect to a constant heart rate -- is a criterion that the intracorporeal regulating system desires an increase or decrease in the cardiac output , as long as this adaptability is still present in the particular patient . to enable better evaluation on the part of the physician as to what consequence the individual open - or closed - loop control variables and optionally a correspondingly selected operating characteristic curve have for the control , the illustration of fig6 c is provided . here , in a further characteristic field , the dependency of the stroke volume on the heart rate and on exertion is shown ; the axial direction has been selected in accordance with that in the characteristic field of fig6 b , to enable simpler comparison . it is demonstrated here that the stroke volume , in the case of restricted adaptability of the heart rate -- as shown here -- is limited toward higher values , and toward higher frequency values the stroke volume decreases , because the chamber filling decreases , in particular in the ischemic heart . by superimposition of the values of the corresponding diagrams , the operating range of the pacemaker is to be defined , and in the case of automatic adjustment by characteristic field superimposition , the point of departure is that the external exertion variable must not be allowed to deviate by more than a predetermined amount from the cardiac output , if the performance capacity of the heart is to be adequate to exertion over the long term . the solid line in the illustration shows that an overly great increase in the heart rate ( characteristic curve with slight upward slope with respect to the axis hr ) leads to a drop in the cardiac output and is therefore not favorable in the case shown . contrarily , the plotted course of a characteristic curve is favorable , in the event that the exertion of the particular patient must continue to be limited because of the restricted volumetric adaptation of the heart . if the characteristic field of fig6 c extends to higher rates hr , contrarily -- as shown in dashed lines -- then the operating characteristic curve can be selected flatter toward higher heart rates [ and ] a region without reduction of the stroke volume is attainable , in which the cardiac output is correspondingly increased . if there are times of spontaneous activity of the heart , then the operating characteristic curve of fig6 c is ascertained by ergometric exertion of the patient during spontaneous actions , and in the pacing instance is used accordingly , using the stroke volume as a control variable . in the case where there is additional knowledge of measurement variables which -- as described -- enable [ sic ; word missing ] the requirement of the cardiac output on the basis of current physiological exertion data of the heart , a further possibility for control exists , wherein in this case the working points resulting on the basis of the stroke volume that is established as shown in diagram 6c and the working points resulting on the basis of the required cardiac output as shown in fig6 b are superimposed , and an average is taken based on the weighted data ; however , an allowable rate range can be predetermined , which results from the comparison of the diagrams of fig6 b and 6c , under the aforementioned conditions that the cardiac output and the exertion in the characteristic field should not deviate substantially from one another . the characteristic field according to fig6 c is in particular laid out such that rate ranges in which increasing load [ sic ; word missing ] a reduction of the stroke volume ( with respect to the corresponding stroke volume at a higher rate ), are to be circumvented , because in such a case a higher rate value leads to a better cardiac performance . these relationships , however , are readily apparent in the characteristic field representation , and the attending physician can make optimal arrangements by using the control unit having the possibility for a graphic display . an additional favorable application of the characteristic fields shown here is in the graphic monitoring of adaptation of the programmable time constants . here measured variables that are associated with time constants -- for instance thermal regulation of the circulation , taking the blood value into account -- are [ sic ; no remaining verb in sentence ]. in this case , with an external abruptly increasing exertion , the rise in the blood temperature is monitored by comparative measurement and chronologically displayed , and the &# 34 ; programmable time constant &# 34 ; contained in the corresponding processing component group is now varied in such a way that the theoretical course resulting therefrom is adapted as much as possible to the actual time behavior , and in the three - axis perspective characteristic field display the variation of one parameter can be taken into account as additional independent variables . in fig6 with the aid of the diagram known from the foregoing drawing figures , the linkage of the control of the heart rate by means of a plurality of input signals in shown in accordance with an exclusive or linkage . the illustration is at the same time an example of a system configuration in which the signal processing method is dependent on a signal event itself . the heart rate is influenced first in a manner linked to the stroke volume , as described above . in the case of the arrow shown in the diagram , however , it is presumed that the variation of the stroke volume in the particular patient ( or a corresponding variable ) is usable only to a limited extent for controlling the heart rate . in the case of the rate r 1 , it is assumed that there is an intrusion i , resulting in a rise of the exertion b in the peripheral region of the useful field , without the rate r 1 reducing the stroke volume to a value adequate for this exertion . in the case of a heart rate influenced solely by the stroke volume , the rate would attain a maximum value r 0 , and upon an increase in the exertion would decrease again , because the stroke volume undergoes an intrusion toward the frequency r 1 , and decreases from r 0 on , which in turn leads to another rate reduction . thus in this case r 0 represents the upper rate limitation of the pacemaker . in order in this case as well to offer the patient a physiologically correct control , a further load - related parameter of the pacemaker ( for example , the blood temperature ) is additionally utilized for control . the blood temperature picked up is converted in a corresponding characteristic field into the associated exertion level b , which is linked by means of an or relationship with the output signal of the characteristic field which contains the rate programmed in accordance with a variable correlated with the stroke volume , so that the control of the heart rate is taken over by the blood temperature , if upon attaining a certain temperature level an associated heart rate is not attained . in the graphic display presented to the physician for monitoring , the exertion level as a function of the temperature is represented by a horizontal surface , which shifts by level . if the level exceeds an exertion value that is greater than a corresponding exertion that is adequately covered by the cardiac output resulting at the heart rate stroke volume , then the temperature sensor takes over the task of &# 34 ; guidance &# 34 ;, in that the heart rate is now influenced such that the cardiac output is adapted to the direction . this corresponds to a switchover of the outputs of the characteristic fields in the manner of an or linkage . the variable linked to the stroke volume now serves with the product of the heart rate for ascertaining the actual cardiac output , and the heart rate is raised enough that the attainable cardiac output is again equivalent to the exertion . this is the case at the rate r 2 . the control shown by means of superimposition of two physiological parameters results in a relatively rapid runthrough of the rate range from r 0 to to r 2 in the patient with increasing exertion , so that at all times an adequate cardiac output for the exertion is made available . referring to the diagram shown in fig6 e , an exemplary embodiment will be explained , in which the switchover to various physiological parameters for the sake of controlling the heart rate is done not as a function of a picked up parameter , but rather as a function of the heart rate . in the physiological course represented in the diagram shown , a variable characteristic of the stroke volume no longer varies beyond a certain heart rate , even though at higher rates a stroke volume adaptation still takes place . this can for instance happen if the signal pep ( presphygmic period ) is also used for the rate control , while lvet ( systolic discharge time ) is initially not taken into account , but does increase further with increasing exertion . in this case , a control exclusively as a function of pep would means that the physiological regulation would become effective up to a certain heart rate range . above this value , an exertion adaptation takes place only by means of a physiological stroke volume adaptation , which in the case of peak exertions can lead to an unsatisfactory adaptation behavior . a changed programming of the characteristic curve ( fl ) in the operating range that is available does not produce any change here , because with a lower rise in the heart rate as the pep increases , only the stroke volume adaptation based on lvep is utilized to a greater extent already at lower rates . in this case ( as described for the diagram shown earlier ), use is made of the fact that by means of an additional performance - related physiological parameter ascertained in the body of the patient , the heart rate is additionally raised upon exertion whenever the product of the stroke volume and the heart rate is no longer adequate for the physical exertion . to this end , however , a measured variable must then be picked up which is correlated exactly with the current stroke volume , while the characteristic variable pep picked up here furnishes information for only a portion of the stroke volume adaptation . in that case , a characteristic field is used which as a function of the current heart rate effects a switchover to the control by means of another parameter . the signals pep and lvep here form signals picked up by means of acoustic receivers in the heart chamber , these signals being representative for the stroke volume . above a predetermined heart rate hr , the heart rate is thus controlled by the blood temperature , so that an additional heart rate increase with increasing exertion is possible , which permits a further heart rate increase . in this case , by means of a suitable programmed characteristic field which as data contains a linkage instruction for different characteristic fields in programmed form and to this end assures that above a predetermined rate level the blood temperature , at a value that corresponds to a major physical exertion , contributes to the further rate increase , so that the cardiac output is adapted to the actual exertion , and the additional adaptation capability of the stroke volume ( which with control by pep does not need to be ascertained ) also forms an additional reserve at higher rates . the blood temperature , for instance as a differential value , will generate an additional programmable relative variation of the heart rate , so that no consideration need be taken of measurement deviations inherent in the absolute values . ( an additional measurement of the absolute stroke volume is possible , for example , by electroplethysmographic measurement .) a control of this kind has the advantage that brief adaptations of the stroke volume do not lead to excessive jumps in the rate , yet nevertheless an additional adaptation of the cardiac performance to exertion is possible in the case of a long - lasting major physical exertion ( the blood temperature rises in a delayed manner ). in the case of regulation with the cardiac output as the reference variable , where the current stroke volume is used together with an exertion variable as an address for the rate data in the characteristic field , a corresponding rate increase takes place once again , and lvet or some other stroke - volume - dependent measured variable ( preferably impedance cardiography ) should be used , in order to attain the stroke volume adaptation in the range of greater exertion as well . it will be understood that in accordance with signal levels , in the manner described , other signal linkages ( open -/ closed - loop control ) are also variable . the foregoing description shows that the linkages in terms of measurement technology by means of programming of the system on the one hand exactly determine the technical function of the system and make it into an automatic control or regulation system -- but on the other hand , the attending physician can monitor the functioning of the system at any time and intervene as needed by monitoring the memory instructions . the invention is not restricted in its scope to the example described above . instead , a great many variants are conceivable , which make use of the provisions described even with fundamentally different kinds of embodiments . in particular , the invention is not restricted to realization using discrete logical component groups , but instead can advantageously also be realized with programmed logic -- in particular including the use of a microprocessor . | US-2667887-A |
the present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound represented by the general formula i ; wherein x , y , z , d and r 3 are as defined in the specification . | the present invention relates to the use of 8 - azaprostaglandin analogs as ocular hypotensives . the compounds used in accordance with the present invention are encompassed by the following structural formula i : the preferred group of the compounds of the present invention includes compounds that have the following structural formula ii . in the above formulae , the substituents and symbols are as hereinabove defined . preferably d represents a covalent bond or is ch 2 ; more preferably d is ch 2 . preferably r is h or c 1 - c 5 lower alkyl . preferably r 3 is selected from the group consisting of phenyl and monosubstituted derivatives thereof , e . g . chloro and trifluoromethyl phenyl . preferably x is co 2 r and more preferably r is selected from the group consisting of h and ethyl . the above compounds of the present invention may be prepared by methods that are known in the art or according to the working examples below . the compounds , below , are especially preferred representative , of the compounds of the present invention . pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention , or a pharmaceutically acceptable acid addition salt thereof , as an active ingredient , with conventional ophthalmically acceptable pharmaceutical excipients , and by preparation of unit dosage forms suitable for topical ocular use . the therapeutically efficient amount typically is between about 0 . 0001 and about 5 % ( w / v ), preferably about 0 . 001 to about 1 . 0 % ( w / v ) in liquid formulations . for ophthalmic application , preferably solutions are prepared using a physiological saline solution as a major vehicle . the ph of such ophthalmic solutions should preferably be maintained between 6 . 5 and 7 . 2 with an appropriate buffer system . the formulations may also contain conventional , pharmaceutically acceptable preservatives , stabilizers and surfactants . preferred preservatives that may be used in the pharmaceutical compositions of the present invention include , but are not limited to , benzalkonium chloride , chlorobutanol , thimerosal , phenylmercuric acetate and phenylmercuric nitrate . a preferred surfactant is , for example , tween 80 . likewise , various preferred vehicles may be used in the ophthalmic preparations of the present invention . these vehicles include , but are not limited to , polyvinyl alcohol , povidone , hydroxypropyl methyl cellulose , poloxamers , carboxymethyl cellulose , hydroxyethyl cellulose and purified water . tonicity adjustors may be added as needed or convenient . they include , but are not limited to , salts , particularly sodium chloride , potassium chloride , mannitol and glycerin , or any other suitable ophthalmically acceptable tonicity adjustor . various buffers and means for adjusting ph may be used so long as the resulting preparation is ophthalmically acceptable . accordingly , buffers include acetate buffers , citrate buffers , phosphate buffers and borate buffers . acids or bases may be used to adjust the ph of these formulations as needed . in a similar vein , an ophthalmically acceptable antioxidant for use in the present invention includes , but is not limited to , sodium metabisulfite , sodium thiosulfate , acetylcysteine , butylated hydroxyanisole and butylated hydroxytoluene . other excipient components which may be included in the ophthalmic preparations are chelating agents . the preferred chelating agent is edentate disodium , although other chelating agents may also be used in place or in conjunction with it . ingredient amount (% w / v ) active ingredient about 0 . 001 - 5 preservative 0 - 0 . 10 vehicle 0 - 40 tonicity adjustor 1 - 10 buffer 0 . 01 - 10 ph adjustor q . s . ph 4 . 5 - 7 . 5 antioxidant as needed surfactant as needed purified water as needed to make 100 % the actual dose of the active compounds of the present invention depends on the specific compound , and on the condition to be treated ; the selection of the appropriate dose is well within the knowledge of the skilled artisan . the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application , such as in containers equipped with a dropper , to facilitate the application to the eye . containers suitable for dropwise application are usually made of suitable inert , non - toxic plastic material , and generally contain between about 0 . 5 and about 15 ml solution . the compounds of examples 1 through 8a are made according to the methods disclosed in examples 1 and 2 of published pct patent application wo 01 / 46140 , which is hereby incorporated by reference herein . the compounds of examples 9 through 12a are made by methods analogous to the methods used to make the compounds of examples 1 through 8 , with [ 3 -( phenyl )- 2 - oxo - propyl ]- phosphonic acid dimethyl ester replacing [ 3 -( 3 - chloro - phenyl )- 2 - oxo - propyl ]- phosphonic acid dimethyl ester . these compounds are tested for in vitro activity as described below and the results given in the tables . [ 0088 ] table 2 8 - azaprostaglandin analogs - radioligand binding data example # structure hfp hep 1 hep 2 hep 3d hep 4 htp hip 3a na 300 2a na 300 1a & gt ; 10 4 0 . 4 2 na 1000 1 5800 12 4a na & gt ; 10 4 12a na & gt ; 10 4 11a na 300 12 na 8900 11 na 1500 9 na 18 10a na 600 9a na 9 10 8a na & gt ; 10 4 6a na 200 8 na & gt ; 10 4 7a & gt ; 10 4 500 5a na 5 7 na 2200 6 na 1200 5 na 17 human recombinant ep 1 , ep 2 , ep 3 , ep 4 , fp , tp , ip and dp receptors : stable transfectants . plasmids encoding the human ep 1 , ep 2 , ep 3 , ep 4 , fp , tp , ip and dp receptors were prepared by cloning the respective coding sequences into the eukaryotic expression vector pcep4 ( invitrogen ). the pcep4 vector contains an epstein barr virus ( ebv ) origin of replication , which permits episomal replication in primate cell lines expressing ebv nuclear antigen ( ebna - 1 ). it also contains a hygromycin resistance gene that is used for eukaryotic selection . the cells employed for stable transfection were human embryonic kidney cells ( hek - 293 ) that were transfected with and express the ebna - 1 protein . these hek - 293 - ebna cells ( invitrogen ) were grown in medium containing geneticin ( g418 ) to maintain expression of the ebna - 1 protein . hek - 293 cells were grown in dmem with 10 % fetal bovine serum ( fbs ), 250 μg ml − 1 g418 ( life technologies ) and 200 μg ml − 1 gentamicin or penicillin / streptomycin . selection of stable transfectants was achieved with 200 μg ml − 1 hygromycin , the optimal concentration being determined by previous hygromycin kill curve studies . for transfection , the cells were grown to 50 - 60 % confluency on 10 cm plates . the plasmid pcep4 incorporating cdna inserts for the respective human prostanoid receptor ( 20 μg ) was added to 500 μl of 250 mm cacl 2 . hepes buffered saline × 2 ( 2 × hbs , 280 mm nacl , 20 mm hepes acid , 1 . 5 mm na 2 hpo 4 , ph 7 . 05 - 7 . 12 ) was then added dropwise to a total of 500 μl , with continuous vortexing at room temperature . after 30 min , 9 ml dmem were added to the mixture . the dna / dmem / calcium phosphate mixture was then added to the cells , which had been previously rinsed with 10 ml pbs . the cells were then incubated for 5 hr at 37 ° c . in humidified 95 % air / 5 % co 2 . the calcium phosphate solution was then removed and the cells were treated with 10 % glycerol in dmem for 2 min . the glycerol solution was then replaced by dmem with 10 % fbs . the cells were incubated overnight and the medium was replaced by dmem / 10 % fbs containing 250 μg ml − 1 g418 and penicillin / streptomycin . the following day hygromycin b was added to a final concentration of 200 μg ml − 1 . ten days after transfection , hygromycin b resistant clones were individually selected and transferred to a separate well on a 24 well plate . at confluence each clone was transferred to one well of a 6 well plate , and then expanded in a 10 cm dish . cells were maintained under continuous hygromycin selection until use . radioligand binding studies on plasma membrane fractions prepared for cells stably transfected with the cat or human receptor were performed as follows . cells washed with tme buffer were scraped from the bottom of the flasks and homogenized for 30 sec using a brinkman pt 10 / 35 polytron . tme buffer was added as necessary to achieve a 40 ml volume in the centrifuge tubes . tme is comprised of 50 mm tris base , 10 mm mgcl 2 , 1 mm edta ; ph 7 . 4 is achieved by adding 1 n hcl . the cell homogenate was centrifuged at 19 , 000 rpm for 20 - 25 min at 4 ° c . using a beckman ti - 60 or ti - 70 rotor . the pellet was then resuspended in tme buffer to provide a final protein concentration of 1 mg / ml , as determined by bio - rad assay . radioligand binding assays were performed in a 100 μl or 200 μl volume . the binding of [ 3 h ]( n ) pge 2 ( specific activity 165 ci / mmol ) was determined in duplicate and in at least 3 separate experiments . incubations were for 60 min at 25 ° c . and were terminated by the addition of 4 ml of ice - cold 50 mm tris - hcl followed by rapid filtration through whatman gf / b filters and three additional 4 ml washes in a cell harvester ( brandel ). competition studies were performed using a final concentration of 2 . 5 or 5 nm [ 3 h ]( n ) pge 2 and non - specific binding was determined with 10 − 5 m unlabelled pge 2 . for radioligand binding on the transient transfectants , plasma membrane fraction preparation was as follows . cos - 7 cells were washed with tme buffer , scraped from the bottom of the flasks , and homogenized for 30 sec using a brinkman pt 10 / 35 polytron . tme buffer was added to achieve a final 40 ml volume in the centrifuge tubes . the composition of tme is 100 mm tris base , 20 mm mgcl 2 , 2m edta ; 10n hcl is added to achieve a ph of 7 . 4 . the cell homogenate was centrifuged at 19000 rpm for 20 min at 4 ° c . using a beckman ti - 60 rotor . the resultant pellet was resuspended in tme buffer to give a final 1 mg / ml protein concentration , as determined by biorad assay . radioligand binding assays were performed in a 200 μl volume . the binding of [ 3 h ] pge 2 ( specific activity 165 ci or mmol − 1 ) at ep 3d , receptors and [ 3 h ]- sq29548 ( specific activity 41 . 5 ci mmol − 1 ) at tp receptors were determined in duplicate in at least three separate experiments . radiolabeled pge 2 was purchased from amersham , radiolabeled sq29548 was purchased from new england nuclear . incubations were for 60 min at 25 ° c . and were terminated by the addition of 4 ml of ice - cold 50 mm tris - hcl , followed by rapid filtration through whatman gf / b filters and three additional 4 ml washes in a cell harvester ( brandel ). competition studies were performed using a final concentration of 2 . 5 or 5 nm [ 3 h ]- pge 2 , or 10 nm [ 3 h ]- sq 29548 and non - specific binding determined with 10 μm of the respective unlabeled prostanoid . for all radioligand binding studies , the criteria for inclusion were & gt ; 50 % specific binding and between 500 and 1000 displaceable counts or better . the effects of the compounds of this invention on intraocular pressure may be measured as follows . the compounds are prepared at the desired concentrations in a vehicle comprising 0 . 1 % polysorbate 80 and 10 mm tris base . dogs are treated by administering 25 μl to the ocular surface , the contralateral eye receives vehicle as a control . intraocular pressure is measured by applanation pneumatonometry . dog intraocular pressure is measured immediately before drug administration and at 6 hours thereafter . the compounds of this invention are useful in lowering elevated intraocular pressure in mammals , e . g . humans . the foregoing description details specific methods and compositions that can be employed to practice the present invention , and represents the best mode contemplated . however , it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner , and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions . similarly , different pharmaceutical compositions may be prepared and used with substantially the same result . thus , however detailed the foregoing may appear in text , it should not be construed as limiting the overall scope hereof , rather , the ambit of the present invention is to be governed only by the lawful construction of the appended claims . | US-41103603-A |
a rolling collection tool allows for retrieval of ground objects including pine cones by a user while standing erect . a method for construction of the device is provided in which a plurality of wires are formed into a generally oval shaped chamber and covered in a flexible covering in sets of two or more wires . the chamber is connected to a bail and handle and rolls to pick up and store objects in the chamber until emptied . the objects enter the chamber as the device rolls by temporary separation of the covered wires for the object , and the device retains the objects by resilient return movement of the covered wires to their original position . the flexible covering on the wires rotates around sets of the wires as the device retrieves objects . | referring now to the drawings , a gathering device 2 and the process of manufacturing such device is shown . the device is constructed in a way that the device is effective for gathering fragile objects such as pine cones from the ground . as shown in fig1 , the completed device 2 includes a basket 4 comprised of a plurality of wires 10 that are combined in small sets of preferably two wires and sheathed in plastic tubes 12 . in operation , the device rolls along the ground causing the wires to separate upon encountering a pine cone or object until the object enters the basket and the resilient wires 10 return to their normal position causing the object to be entrapped within the basket . during operation the tubes 12 roll about the wires to prevent damage to the objects entering the basket ; further , the tubes hold sets of the wires together to permit larger openings between the wires upon encountering an object both in terms of the spacing between the sets of wires and the propensity for the wires to separate more easily for swallowing the objects . once the basket is filled , the objects are emptied by separating the wires to form a gap and dispense the objects from the basket to some other container or location . the method for the manufacture of the device is taught by first referring to fig1 in which the first of several steps is shown . the device is constructed in several steps as will be described herein . in a first step a plurality of wires 10 of substantially equal length are provided and these wires are grouped together . once expanded , the wires form a chamber of the basket portion of the device . the wires , generally comprised of steel , are gathered in parallel arrangement with an open ended circular configuration . the circle of wires is wrapped around an inner sleeve blank 14 on one end of the inside of the wires , whereby the wires form a cylinder shape about the inner sleeve blank for further processing . the wires 10 should be flexible and resilient for the purpose of retrieving objects from the ground by separation of the wires through contact with an object ; suitable wires have been used for nut harvesting devices comprised of 0 . 041 gauge music wire . the wires are cut longer than on a prior nut gathering device to provide increased capacity and flexibility found uniquely suitable for gathering pine cones . whereas , the additional length of the wires would cause the device to be less effective in gathering smaller and firmer objects such as nuts , the wires on the present device have been found effective for pine cones . a preferred length of raw wire for manufacture of the device is 23 to 25 inches in length . in preparation for the next step of manufacture , the wires may be held and supported on the inner sleeve blank 14 by a rubber band 16 or other retention device . with the inner sleeve blank wrapped within the wires on one end , insert a first inner sleeve 18 that is shorter and smaller circumference than the inner sleeve blank within the opposing end of the wires as shown in fig1 . slide the first inner sleeve within the wires to where it rests on top of or abutting the edge of the inner sleeve blank within the wire structure . at this point in construction , leave the first inner sleeve in abutting relation for inner sleeve blank for further processing . while the first inner sleeve 18 and the inner sleeve blank 14 remain within the wrapped wires 10 , insert a first outside sleeve 20 over the opposing ends of the wires and , then , slide the first outside sleeve downwards or toward the first inner sleeve until the first outside sleeve will not slide any further down by hand or without additional force as in fig2 . sliding the first outside sleeve over the wires begins the process of locking the wires into place between the first outside sleeve and the first inner sleeve . with the first outside sleeve 20 positioned over the wires 10 , slide a washer 22 over the outside of the wires on the end opposing the first inner sleeve 18 in accordance with the illustration in fig3 . slide the washer downward or toward the first outside sleeve until the waster touches the first outside sleeve or abuts against it . next , remove the inner sleeve blank 14 using a knife or similar means inserted through the wires and by pressing downward on the inner sleeve blank to slide it out from within the wires as shown in fig4 . in fig4 , after removing the inner sleeve blank 14 , slide the first inner sleeve 18 down to a position that is flush with the ends of the wires 10 at a first end of the device . use a knife or like to move the first inner sleeve into position as needed . flush the ends of the wires against a flat surface to ensure an even alignment of the wires and the first inner sleeve . after putting the first inner sleeve into position at the first end of the wires , push the first outside sleeve 20 and the washer 22 downward or toward the first inner sleeve until both the first outer sleeve and washer fit tight together and can no longer be moved downward by hand over the wires . reinsert the inner sleeve blank above the washer for support of the wires during the construction process . use a rubber band 16 or retention device to hold the wires and the inner sleeve blank together in place . fig5 shows the alignment of the wires 10 on the first end of the device 2 . check the alignment and position of the wires about the first inner sleeve 18 and the inner sleeve blank 14 . ensure that all of the wires are both straight and level before locking the first outside sleeve 20 over the first inner sleeve by forcing the first outside sleeve over the wires and the first inner sleeve . to lock the wires 10 into place , firmly tap the washer 22 downward or toward the first inside sleeve 18 as shown in fig6 . during the tapping process , the peripherally arranged wires are pressed between the sleeves 18 and 20 , and the wires will be compressed between the sleeves and impinged upon between the outer sleeve 20 and the inner sleeve 18 . this same process of compressing the peripherally arranged wires between the inner and outer sleeves is repeated on the opposing second end of the wires . the inner and outside sleeves should be properly sized circumference to allow for a tight fit between the sleeves for the wires to be securely held . the ends of the wires may be positioned against a flat surface during forceful tapping of the outside sleeve over the inner sleeve and compression of the wires to keep the ends of the wires flush and provide a support against the force of tapping the washer . the washer pushes the outside sleeve over the smaller circumference inside sleeve . thereby , the first outside sleeve locks the wires in place between the first outside sleeve and first inner sleeve through compression of the wires between the two sleeves . once the washer 22 and first outside sleeve 20 have been forced into position over the first inner sleeve 18 , the wires 10 will be flush on the end and tightly held within the sleeves similar to the illustration of fig7 . the friction between the wires and the sleeves will hold the wires and also cause the plurality of wires to separate slightly in the center . a dye 24 is used to further expand and separate the wires and form the chamber defined by the basket 4 in subsequent steps . before proceeding to form the wires and lock the opposing second end of the wires , remove the inside sleeve blank 14 that was inserted before the process of locking the first outside sleeve 20 and first inner sleeve 18 . the inner sleeve blank will be easy to remove by hand , as the wires 10 are spread on the end opposing the locked sleeves . any retention device 16 or rubber band used on the wires during the prior steps of assembly can be removed to facilitate removal of the inside sleeve blank from the wires . the spread of the wires prepares the assembly for insertion of a small dye 24 that is illustrated in fig8 inside the wires as shown in fig9 . to bend the wires on the first end , insert the small dye 24 into the open spread end of the wires 10 and move the dye downward into the secured end of the wires by hand as represented in fig9 . the circular dye in fig8 will be used to bend the wires outward at an angle , which helps to form the chamber of the basket 4 for pine cone retrieval and storage with the device . referring further to fig9 , the dye 24 is positioned by hand into the wires 10 as far as possible , and the dye is aligned into a position with the circumference of the dye contacting the inside surface of the wires within the chamber . this positions the dye for being pressed further downward or toward the locked first end of the wires where the first inner sleeve 18 and first outside sleeve 20 is positioned . an unlocked end of the wires that are situated at the opposite end of the wires opposing the locked end will naturally spread apart with the dye inserted . with the dye inserted into this position , a retention device 26 may be placed around the unlocked second end of the wires as in fig9 to hold the wires closer together temporarily while pressing the dye toward the locked end . pressing the dye will naturally cause the wires to expand if not retained by some means . retaining the wires will provide a safe environment for pressing the wires , whereby the unlocked ends of the wires are not able to stab a person . also shown in fig9 , the wires 10 are pressed by sliding the locked end of the assembly over the shaft of a press 28 , the process begins by slightly pressing the wires to open the chamber and cause the dye 24 to slide further downward toward the locked end of the wires at the first inner sleeve 18 and first outside sleeve 20 . the dye is then fully pressed into engagement with the first inner sleeve or so far toward the first inner sleeve as desirable , so as to deform and bend the wires to the extent specified for the final design and shape of the chamber to be formed . pressing the dye toward the first inner sleeve , therefore , permanently deforms the wires and causes the wires to spring outward from the first locked end . the dye is then removed and the wires retain the deformed shape causing the wires to spring outward on the unlocked second end of the wires as shown in fig1 . spreading the wires 10 prepares them for insertion of a rotatable covering or tubes 12 over sets of one or more of the wires . a retention device , such as a rubber band , may be used for safety to keep the wires closer together and less hazardous for accidental injury . once the wires are prepared , a plurality of rotatable coverings or tubes 12 are placed over individual or groupings of wires as shown in fig1 . the coverings slide over the wires from the unlocked end and slide toward the locked end , thereby exposing the unlocked ends of the wires for further processing in manufacture of the device . in the preferred embodiment shown , the majority of the wires are paired in sets of two , and a covering is placed over each pair to provide a rotatable sheathing over the wires . some individual wires may be stranded and can be covered individually by such covering if more precision is not required for the quality and application . the covering comprises flexible plastic tubing that is cut into tubes 12 ; the tubing is commonly used as a conduit for electrical wiring . the flexible tubing is flexible enough for the chamber to spread apart as the wires 10 spring into position and form an ovoid chamber having an area for collecting a multitude of pine cones or other objects . the flexible tubing is also durable enough for long lasting use in collecting objects such as pine cones while rolling the device on the ground . a typical flexible tubing section or tube 12 is shown in fig1 and comprises conduit tubing or like tubing material as discussed above . nylon provides both a flexible and durable material for the tubing ; thus , nylon is a suitable material for the tubing . for a preferred size pine cone retrieval device 2 , the wires 10 are manufactured to a specification desirable for use of 18 inch tubing sections . thus , each tube is cut to a length of 18 inches prior to insertion onto the wires . in one embodiment , as the tubing is installed over the wires , a piece of tubing may be inserted over every two naked wires in series until all of the wires are covered in sets of two by a section of tubing . referring to fig1 , once all of the wires are covered by tubing , the wires are brought closer together at the center of the length thereof and retained in close proximity by a retention device such as a rubber band 30 for work on the unlocked end of the wires . the process for locking the wires on the opposing end is very similar to the process for locking the first end . first as illustrated in fig1 , a second washer 32 like that on the first end of the wires is placed over the loose end of the wires by sliding the wires 10 through the aperture of the washer such that the wires are situated on the inside of the washer and run through with loose ends of the wires extending beyond the washer . next , as depicted in the assembly of fig1 and fig1 , a second outside sleeve 36 is then inserted over the loose ends of the wires that extend beyond the washer . the second outside sleeve slides over the wires 10 and then abuts the second washer 32 . then , in accordance with fig1 , the partially assembled device is then placed over a rod 38 , whereby the rod is positioned on the inside of the chamber created by the wires . an end of the rod has a dye formed for pressing a second inner sleeve 34 into position inside of the wires and the second outside sleeve . thus , the second inner sleeve is positioned onto the dye end of the rod , and the dye end of the rod is position into alignment with the unlocked end &# 39 ; s outside sleeve and wires . the opposing end of the rod 38 is situated through the locked end within the chamber as shown in fig1 for operation of the press 28 . the second inner sleeve 34 is pressed down or into the second outside sleeve 36 on the unlocked second end of the wires to lock the wires 10 on the second end into place between the second outside sleeve and the second inner sleeve . the press may be operated by tapping the second inner sleeve into the second outer sleeve or by using a press machine . the enlarged portion of fig1 shows the second end of the wires of the device showing the wires locked in place between the second inside sleeve and second outside sleeve ; thereby , the wires on both ends of the chamber formed by the wires are then locked into place . the second end of the wires 10 is locked and prepared for removal of the press . the rod 38 used for the press 28 may then be pulled out and removed from the device , and the second end of the wires of the device is then ready for a dye to be inserted inside the chamber for expansion of the wires on the second end . care is used not to injure the tubes 12 on the wires and the dye is pressed on the second end to expand the wires . the chamber is pressed causing the chamber to further enlarge into a generally oval shaped configuration . the wires are formed on each end to bend the wires slightly and form the basket 4 defined by the chamber . next , the inner wall of the chamber is pressed causing deformations in the wires near the first and second ends of the chamber . the deformations are equally spaced from the washers 22 and 32 near each end of the wires of chamber . the deformations allow the plurality of wires 10 to bend toward a vertical orientation near the washers , such that the final structure of the chamber will appear as shown in fig1 with the plurality of wires formed into a generally oval chamber having generally flattened ends . the device 2 is formed to include a basket 4 for retrieval of pine cones 40 as shown in fig1 . the device includes a means for attaching the device to a bail 42 and a handle 44 that are used during hand operated use of the device . in particular , after the deformations are pressed into the wires 10 , bolts 46 are inserted through the inner sleeves 18 , 34 , and the heads 48 of the bolts bear against the outer and inner sleeves shown in fig1 . rubber washers are disposed on the bolts 46 and against the inside of the ends of the chamber . metal washers are disposed on the bolts against the rubber washers , such that both the metal washers and rubber washers are inner washers 50 within the chamber . hex nuts 52 are threaded on the ends of bolts , whereby the nuts are tightened on the bolts 46 . as the hex nuts are tightened on the bolts , the ends of the wires are clamped tightly between the inner washers 50 and the outer washers 22 , 32 , thereby deforming the wires further and thus causing the ends of the chamber to flatten and bowing the center portion of the chamber into a larger generally oval shaped configuration forming the basket 4 . a small cavity 54 shown in fig1 is drilled into the head 48 of each bolt 46 on both ends of the device 2 for receiving the bail 42 . a handle 44 is attached to bail as shown in fig1 by means of a wing nut 56 welded to said bail . the handle may be constructed of wood , plastic , fiberglass or suitable material depending on the qualities desired including cost and durability . a threaded bolt inserted through the wing nut tightens into a threaded receptacle of the handle . thereby , the bail retains the basket 4 and allows the basket to roll as the device 2 is operated by the handle 44 to retrieve pine cones 40 as depicted in fig1 . | US-201213631823-A |
a method and apparatus of aligning calibration projection data with object projection data to improve calibration corrections of the object projection data . in a first implementation , the method interpolates and upsamples both the calibration and object data , then shifts the upsampled calibration data to match a sub - view angular offset of the object data , and then performs calibration corrections before down - sampling the corrected object data . in a second implementation , the method continuously scans an object space — with the object absent in the object space — to obtain calibration data and object data both having the same sub - view angular offset . in a third implementation , the method obtains multiple scans having different sub - view angular offsets , organizes the scans into bins according to their respective sub - view angular offsets , and chooses the appropriate sub - view angular offsets bin for calibration corrections of the object data . | embodiments described herein relate generally to calibrating and correcting projection data , and more specifically to matching the offset angle of the object projection data with the offset angle of calibration data , and then performing corrections to the object projection data using the calibration data . according to one embodiment , there is provided an apparatus comprising processing circuitry configured to obtain object projection data and calibration projection data , wherein the object projection data represents an intensity of x - rays transmitted through an image object and detected by x - ray detectors , the object projection data being measured at a plurality of projection angles relative to the image object , and the calibration projection data represents an intensity of x - rays transmitted through a predetermined calibration object and detected by x - ray detectors , the object projection data being measured at a plurality of projection angles relative to the calibration object . the processing circuitry is also configured to align the projection angles of the calibration projection data to have a sub - view angular offset matching the sub - view angular offset of the object projection data . moreover , the processing circuitry is configured to correct the object projection data using the calibration projection data . the embodiment of the apparatus also includes a gantry having an aperture with an object space in the aperture , where the object space is an intersection between the aperture and a projection plane of the x - rays from the x - ray source . the gantry also has a rotational component provided around the object space that is rotatably connected to a stationary component of the gantry . moreover , the gantry has an x - ray source fixedly connected to the rotation component and radiating x - rays into the object space . according to another embodiment is provided a method that includes obtaining object projection data and calibration projection data . the object projection data represents an intensity of x - rays transmitted through an image object and detected by x - ray detectors , the object projection data being measured at a plurality of projection angles relative to the image object . the calibration projection data represents an intensity of x - rays transmitted through a predetermined calibration object and detected by x - ray detectors , the object projection data being measured at a plurality of projection angles relative to the calibration object . the method also includes aligning the projection angles of the calibration projection data to have a sub - view angular offset matching the sub - view angular offset of the object projection data . moreover , the method includes correcting the object projection data using the calibration projection data . referring now to the drawings , wherein like reference numerals designate identical or corresponding parts throughout the several views , fig1 b shows source and detector portions of a computed tomography ( ct ) scanner having both energy - integrating detectors arranged in a third - generation geometry and photon - counting detectors arranged in a fourth - generation geometry . illustrated in fig1 b is an implementation for placing the photon - counting detectors ( pcds ) in a predetermined fourth - generation geometry in combination with a detector unit 103 in a predetermined third - generation geometry in a ct scanner system . the diagram illustrates relative positions among an object obj to be scanned resting on a table 116 , an x - ray source 112 , a collimator / filter 114 , an x - ray detector 103 , and photon - counting detectors pcd 1 through pcdn . the pcds have a front surface , oriented towards the object obj and a back surface oriented away from the object obj . x - rays traveling through the object obj are either detected by the pcds ( at the front surface ) or pass through the spaces between the sparsely arranged pcds and are detected by the tightly packed energy integrating detectors in the x - ray detector 103 . in one implementation , the x - ray source 112 , the collimator / filter 114 , and the x - ray detector 103 are fixedly connected to a rotational component 110 that is rotatably connected to a gantry , and the pcds are fixedly connected to a circular component 120 that is fixedly connected to the gantry . the gantry houses many pieces of the ct scanner . in one implementation , the x - ray source 112 , the collimator / filter 114 , the x - ray detector 103 are each fixedly connected to a first circular component 110 that is a rotational component rotatably connected to the gantry , and the pcds are fixedly connected to a second circular component 120 that is fixedly connected to the gantry . the gantry of the ct scanner also includes an open aperture 115 enabling the object obj to be placed in a projection plane of the x - rays from the x - ray source . the “ projection plane ” is a volume wherein x - rays pass from the x - ray source 112 to the detectors including the pcds and the detector unit 103 . the “ object space ” is the intersection of the projection plane and the open aperture 115 of the gantry . the “ image space ” includes the union of projection planes corresponding to all projection angles of the x - ray source 112 as the x - ray source 112 rotates around the aperture of the gantry . a scan is performed when an object obj occupies the object space and the x - ray source is rotated through a series of projection angles with the ct scanner acquiring projection data of the x - ray transmission / attenuation through the object obj at each projection angle . a scan of the “ object projection data ” is performed when an image object occupies the object space . a scan of the “ calibration projection data ” is performed when a calibration object occupies the object space . calibration objects include air or a known phantom . calibration projection data is used to correct measurement artifacts in the object projection data , and the corrected object projection data is used to reconstruct an image of the image object . in general , the photon - counting detectors pcd 1 through pcdn each output a photon count for each of a predetermined number of energy bins . in addition to the photon - counting detectors pcd 1 through pcdn arranged in the fourth - generation geometry , the implementation shown in fig1 b includes a detector unit 103 having energy - integrating detectors arranged in a conventional third - generation geometry . the detector elements in the detector unit 103 can be more densely placed along the detector unit surface than the photon - counting detectors . in one implementation , the x - ray source 112 and collimator 114 are fixedly placed on a predetermined first circular component 110 in a gantry and diametrically opposed to the detector unit 103 that is also fixedly placed to the circular component 110 . in one implementation , the photon - counting detectors are sparsely placed around the object obj in a predetermined geometry such as a circle . for example , the photon - counting detectors pcd 1 through pcdn are fixedly placed on a predetermined second circular component 120 in a gantry . in one implementation , the photon - counting detectors pcd 1 through pcdn are fixedly placed on the circular component 120 at predetermined equidistant positions . in an alternative implementation , the photon - counting detectors pcd 1 through pcdn are fixedly placed on the circular component 120 at predetermined non - equidistant positions . the circular component 120 remains stationary with respect to the object obj and does not rotate during the data acquisition . both the x - ray source 112 , collimator 114 ( e . g ., a bow tie filter ), and the detector unit 103 rotate around the object obj while the photon - counting detectors pcd 1 through pcdn are stationary with respect to the object obj . in one implementation , the x - ray source 112 and collimator 114 are mounted on a first rotating portion 110 such as an annular frame mounted in the gantry so that the x - ray source 112 projects x - ray radiation with a predetermined source fan beam angle θ a towards the object obj while the x - ray source 112 rotates around the object obj outside the sparsely placed photon - counting detectors pcd 1 through pcdn . furthermore , an additional detector unit 103 is mounted on the first rotating portion 110 in the third - generation geometry . the rotating portion 110 mounts the detector unit 103 at a diametrically opposed position from the x - ray source 112 across the object obj and rotates outside the stationary circular component 120 , on which the photon - counting detectors pcd 1 through pcdn are fixed in a predetermined sparse arrangement . in one implementation , the back surface of each pcd is provided a protective rear cover to shield the pcds from irradiation from behind as the x - ray source 112 travels outside the first circular path of the sparsely placed photon - counting detectors . in one implementation , the x - ray source 112 optionally travels a helical path relative to the object obj , wherein the table 116 moves the object obj linearly in a predetermined direction perpendicular to the rotational plane of the rotating portion 110 as the rotating portion 110 rotates the x - ray source 112 and detector unit 103 in the rotational plane . the motion of the rotating portion 110 around the object obj is controlled by a motion control system . the motion control system can be integrated with a data acquisition system or can separately provide one - way information regarding the angular position of the rotating portion 110 and the linear position of the table 116 . the motion control system can include position encoders and feedback to control the position of the rotating portion 110 and the table 116 . the motion control system can be an open - loop system , a closed - loop system , or a combination of an open - loop system and a closed - loop system . the motion control system can use linear and rotary encoders to provide feedback related to the position of the rotating portion 110 and the position of the table 116 . the motion control system can use actuators to drive the motion of the rotating portion 110 and the motion of the table 116 . these positioners and actuators can include : stepper motors , dc motors , worm drives , belt drives , and other actuators known in the art . in one implementation , a measurement scan is performed by detecting , at the pcds and detector unit 103 , the intensity of x - ray radiation that has propagated from the x - ray source 112 and through the object obj before falling incident on the detectors . the x - rays are detected and recorded as the position of the x - ray source 112 is rotated through a series of angles φ = φ 1 , φ 2 , . . . , φ nφ . due to backlash and hysteresis in the actuators , among other factors , the repeatability of the angular position φ between scans is imperfect . angular variations between calibration scans and measurement scans can result in residual measurement artifacts persisting in the calibration - corrected projection data , and those residual measurement artifacts degrade the image quality for images reconstructed from the corrected projection data . the calibration scans can correct or cancel out many types of measurement artifacts . for example , the absorption values of the calibration scans can be subtracted pixel - by - pixel and frame - by - frame from the absorption values of the object scan . among these measurement artifacts are the shadowing effect , which results from the back surfaces of pcds immediately in front of the x - ray source . as the x - ray source position changes , different portions of the object obj will be shadowed by these pcds . if a calibration is used to correct for these shadow regions , a reconstructed image can still be obtained for the entire object obj because all shadowed portions of the object obj corresponding to one projection angle will be illuminated at other projection angles . however , if there is an offset between the projection angles of the calibration and the object projection data , then the calibration correction ( e . g ., subtraction ) will be imperfect , resulting in residual measurement artifacts ( e . g ., an offset in the calibration and object projection data shadow regions ). fig2 shows a reconstructed image from object data that has been corrected using calibration data . the object data is taken under identical conditions to the calibration data ( i . e ., only air is in the object space ); therefore , if the calibration correction were perfect the fig2 would show a uniform background of no attenuation . however , because the sub - view angular offset is different between the object data and the calibration data , the calibration correction is imperfect giving rise to the structure shown in fig2 corresponding to attenuation and shadowing by the pcds . the calibration scans , which are used to measure and correct measurement and detector artifacts , are usually acquired to mimic the real patient scan scenario , including the scan parameters as well as the phantom choices . in some applications , it is important to assure the repeatability of the projection angles of the calibration scan relative to the object / patient scan . for example , in a third - and fourth - generation photon - counting ct scanner , as shown in fig1 b and fig6 , the pcd ring blocks the x - rays , causing shadows on the detectors . methods have been proposed to use air or phantom scans to measure the attenuation and beam hardening caused by the pcd . in these calibration scans , it is important to ensure the accuracy and repeatability of the projection angles of the calibration scans . a small sub - angle misalignment ( i . e ., offset ) would cause residual artifacts in the reconstruction , as shown in the fig2 . to mitigate these artifacts , several novel methods are proposed herein to ensure the angular repeatability of the scans . these methods can be used for pcd shadow correction , as well as other calibration tasks that require high view angle accuracy and repeatability . by accurately accounting and correcting for the relative offset angle between calibration and object projection data , the image quality of a reconstructed image can be improved . fig3 shows a first method 300 to match the offset angle between the actual projection angles of calibration and object data . the term sub - angle refers to deviations from nominal / intended projection angle recorded by the data acquisition system and the motion control system of the ct scanner . the sub - angles nδ are intervals between the measurement angles φ = φ 1 , φ 2 , . . . , φ nφ , such that δ =( φ i - 1 − φ i )/ n . thus , the region surrounding each measurement angle φ i , is further subdivided into sub - angles φ i ± nδ , n = 0 , 1 , . . . ( n − 1 )/ 2 . each projection data scan will include a sub - view angular offset ( i . e ., the actual offset angle will fall into one of the bins defined by the sub - angles ), where each projection angle φ i is offset from its nominal value by an offset angle n ′ δ . this offset angle results from imperfections in the motion control system ( e . g ., backlash in the gears or servo motor ). a single sub - view angular offset is assigned to each scan , and the sub - view angular offset is the average angular offset for all of the projections angles in a given scan . different scans will generally have different sub - view angular offsets , where scans are different if the rotation of the x - ray source 112 is stopped and started between scans . where a scan begins with a given sub - view angular offset , generally , that sub - view angular offset continues to be the offset angle throughout the entire scan . stopping and starting the rotation between scans will generally result in different sub - view angular offsets between scans . thus , calibration projection data and object projection data that are obtained in separate scans will generally not have identical sub - view angular offsets . the effectiveness of the calibration correction is limited by how well the sub - view angular offsets match between the calibration data and the object data — a better match resulting in the calibration data better canceling out measurement artifacts ( e . g ., shadowing by the pcds ) in the object data . therefore , shifting the sub - view angular offset of the calibration data to match the object data improves the calibration correction and improves the reconstructed image quality . fig3 shows a method 300 that is a first embodiment of a method for matching the sub - view angular offsets between the calibration data and the object data . the method 300 is divided into two parts : a pre - acquisition calibration part and an object data acquisition part . the pre - acquisition calibration part of method 300 begins with step 310 in which a calibration scan is performed . the calibration scan includes measuring x - ray projection data at a series of projection angles , wherein the object obj is a calibration object ( e . g ., either air or a predetermined phantom ). after step 310 , the pre - acquisition calibration part of method 300 proceeds to step 312 , wherein the sinogram of the calibration data is interpolated and upsampled by a factor n , wherein the interpolation and upsampling is in the time / angle dimension , as shown in fig1 a . the object data acquisition part of method 300 begins with step 320 by performing an object scan . like the calibration scan 310 , the object scan measures x - ray projection data at a series of projection angles , except in step 320 the scan object obj is an image object ( e . g ., a medical patient ) rather than a calibration object . the second step 322 of method 300 is interpolating and upsampling the sinogram of the object data by a factor n , wherein the interpolation and upsampling of the object data is also in the time / angle dimension . following step 322 , upsampled calibration data and upsampled object data are each used in step 324 , and the sub - view angular offset of the upsampled calibration data is adjusted to match the upsampled object data . in one implementation , the sub - view angular offset of the upsampled calibration data is adjusted by shifting the calibration data sinogram along the time / angle dimension , and the shifted calibration sinogram is compared to the object sinogram . this adjustment of the sub - view angular offset is repeated through numerous iterations to find the best match between the offset angles of the calibration and object data , wherein the “ goodness ” of the match is determined by a matching function . in one implementation , this iterative search for the best match is an exhaustive search . in one implementation , this iterative search for the best match is a global optimum search method . in one implementation , this iterative search for the best match is a local optimum search method . the matching function determines the similarity between the upsampled sinogram of the object data and the shifted - upsampled sinogram of the calibration data . in the sinograms the measurement artifacts appear as sine waves having different phases in the object and calibration data . the matching function detects a phase match between the object and calibration sinograms by outputting an extreme value ( either a minimum value for a difference measure or a maximum value for an inner product measure ). in one implementation , the matching function will provide a distance measure between the object and calibration data ( e . g ., taking the difference between the object data and the shifted calibration data , and then taking the mean square or a weighted mean square of the difference ). in another implementation , the matching function will provide an overlap integral of the object and calibration data ( e . g ., the inner product between the object data and the shifted calibration data ). for the difference measure , a minimum indicates a good match ; while , for an inner - product - based match function , a maximum indicates a good match . as seen in fig1 a , near the vertical center line of the sinogram , there is significant overlap between sine waves from the object obj , which is near the center of rotation , and measurement artifact sine waves for objects located far from the center of rotation ( e . g ., pcds ). this overlap can be an obstacle for determining the matching offset angle . for example , saturation effects ( e . g ., beam hardening ) create cross - coupling between superimposed sine waves , making it difficult to determine the phase of the sine wave in the region of overlap . on method to overcome this ambiguity is to use regions of no overlap between sine waves , which is possible when using markers located outside the object space to obtain the matching sub - view angular offset . often a ct scanner will include a marker outside the object space but still within the image space . this marker is a constant absorber that is clearly distinguishable in both the calibration data and in the object data . the marker can be a reference . any easily identifiable / distinguishable measurement artifact can be used as a marker , e . g ., the pcds would be ideal markers . the “ object space ” is the intersection of the x - ray projection plane and the open aperture 115 of the gantry 640 , as shown in fig1 b and fig6 . the “ image space ” includes the union of all projection planes corresponding to projection angles of the x - ray source 112 as the x - ray source 112 rotates around the aperture of the gantry 640 . a marker that is outside the object space ( e . g ., the pcds shown in fig1 b ) is advantageous because the sine wave corresponding to the marker has a greater amplitude than sine waves corresponding to objects in the image space . thus , near its peak and its trough the sine wave of the marker will not overlap with sine waves from the object space . by calculating the matching function in the sinogram regions corresponding to the peaks and troughs of these larger sine waves corresponding to markers outside the object space ( i . e ., the left - and right - hand regions in the sinogram shown in fig1 a ), the deleterious effects of nonlinear superposition of sine waves can be avoided . having matched the sub - view angular offset of the upsampled calibration data to the object data , the method 300 proceeds to step 326 , wherein measurement artifacts are corrected using the phase - corrected - upsampled calibration data . in one implementation , the correction of the object data includes taking the difference between the upsampled object data and the phase - corrected - upsampled calibration data . in one implementation , the correction of the object data includes flagging as unreliable data values of the object data , when the corresponding data values of the phase - corrected - upsampled calibration data exhibit attenuation values above a predetermined threshold ( e . g ., not using data values for reconstruction when the data values correspond to shadowed detector regions ). following step 326 , method 300 proceeds to step 328 , wherein the corrected object data is downsampled by a factor of n , in order to return the corrected object data to the original dimensions of the acquired object data . in an alternative implementation , the order of the measurement - artifact correction step and the downsampling step are reversed . thus , in this alternative implementation , step 326 includes downsampling the phase - corrected - upsampled calibration data by a factor of n , and then the object data is corrected using the phase - corrected calibration data . upsampling before comparing the calibration data to the object data enables finer matching between these two sets of data in order to more exactly determine the sub - view angular offset between the upsampled calibration data and the object data . downsampling converts the final object data to a resolution matching the original object scan . fig4 shows a second embodiment of a method for matching the sub - view angular offsets between the calibration data and the object data . the method 400 is divided into two parts : a pre - acquisition calibration part and a patient data acquisitions part . the pre - acquisition calibration part of method 400 includes three steps : step 410 , step 412 , and step 414 . step 410 includes acquiring multiple ( k ) calibration scans , where each scan includes a complete scan rotation of the ct scanner and the rotation is not continuous between scans ( i . e ., the rotation is stopped and then started between scans to obtain a unique offset angle for each scan ). in one implementation , step 410 includes performing calibration scans to obtain the calibration data . in an alternative implementation , the calibration scans are performed prior to step 410 and the calibration data is stored in a computer readable medium . in this alternative implementation , step 410 includes obtaining the calibration data from the computer readable medium . following step 410 , step 412 checks the angular offset of each scan . this can be performed by comparing the k calibration scans using the matching function of step 324 to determine the relative offset angles , and assigning the offset angle of one of the calibrations as the zero offset angle . following step 412 , method 400 proceeds to step 414 where the k calibration scans are each assigned to a sub - view angular offset bin ( i . e ., nδ , n = 0 , 1 , . . . ( n − 1 )/ 2 ) according to their angular offset relative to the zero offset angle ( e . g ., the zero offset scan is assigned to the bin n = 0 ). the object data acquisition part of method 400 includes three steps : step 420 , step 422 , and step 424 . step 420 includes acquiring an image object scan . the image object ( e . g ., a medical patient ) is located in the object space of the gantry , and the x - ray source is scanned through series of projection angles , measuring the x - ray transmission through the object at each angle . following step 420 , method 400 proceeds to step 422 in which the object scan is compared to each bin of the calibration scans . in one implementation , a bin average is calculated for each sub - view angular offset bin . the bin average is the average over all calibration scans in a given bin . the comparison between object data and the calibration data uses a matching function to determine the similarity between the object and calibration data . as in step 324 of method 300 , in one implementation , the matching function includes a distance measure between the object and calibration data ( e . g ., taking the difference between the object data and the shifted calibration data , and then taking the mean - square or a weighted mean - square of the difference ). in another implementation , the matching function includes an overlap integral of the object and calibration data ( e . g ., the inner product between the object data and the shifted calibration data ). the best match between object data and sub - view angular offset bin is given by the matching function having the optimal value ( i . e ., a minimum value for a difference measure matching function and a maximum value for an inner product matching function ). having determined the optimal sub - view angular offset bin , in step 424 the object data is corrected using the calibration data from the sub - view angular offset bin . this correction step is performed similarly to the correction step 326 in method 300 , except unlike step 326 , there is no downsampling in step 424 . fig5 shows a continuous scan method of calibration correction . because differences in the offset angle between calibration and object data result from stopping and starting the rotation between scans , method 500 uses a continuous scan for both calibration and object data so that the offset angle is the same . this can be achieved by arranging the object obj on the table 116 outside of the projection plane and object space . then after taking a calibration scan with the object obj absent from the object space , translating the table 116 to move the object obj into the object space while the rotation component 110 is continuously rotating . in order to limit the radiation dosage to a patient , the x - ray source can be prevented from radiating into the object space during this table translation time . with the object obj in the object space , the x - ray source radiating into the object space , and the rotation component 110 still continuously rotating , the object data is acquired by recording the x - ray transmissions incident on the detectors . for method 500 , the order of the calibration scan and the object scan can be switched provided that the rotation is continuous through both scans . method 500 can be subdivided into 6 steps , as illustrated in fig5 . the first step 510 is a scout scan to determine the range of the scan . next , in step 512 , the object is moved out of the object space . this can be achieved by translating the table after the scout scan , such that the object obj on the table is no longer in the object space . next , the gantry rotation is started in step 514 and the rotation will run continuously until after the object scan is finished in step 518 . also , in step 514 the calibration scan is acquired with the gantry rotation running continuously and the object obj absent from the object space . in step 516 , the rotation of the gantry is maintained as the object obj is repositioned in the object space . in order to limit the radiation dosage to a patient , the x - ray source can be prevented from radiating into the object space during step 516 . following step 516 , the object scan is performed in step 518 with the gantry rotation running continuously and the object obj present in the object space . finally , in step 520 , similar to steps 326 and 424 of methods 300 and 400 respectively , the object data is corrected using the calibration data . after the object scan data has been corrected using the aligned calibration data , a ct image can be reconstructed from this projection data using any known ct reconstruction method . for example , the ct reconstruction method can be performed using filtered back projection , iterative image reconstruction methods , or stochastic image reconstruction methods . further , the ct reconstruction method can be any back - projection method ( e . g ., filtered back - projection ), any iterative reconstruction method ( e . g ., the algebraic reconstruction technique ( art ) method and the total variation minimization regularization methods ), any fourier - transform - based method ( e . g ., the direct fourier method ), or a statistical method ( e . g ., the maximum - likelihood expectation - maximization algorithm based methods ). furthermore , if a full scan is not performed , then a short - scan ct reconstruction method can be used , such as the dreike - boyd parallel rebinning algorithms , complementary rebinning algorithms , applying suitable weighting function such as the parker weights to the sinogram , the katsevich &# 39 ; s method , and the feldkamp method . one of ordinary skill will recognize that many methods of ct reconstruction are possible depending on the type of detectors , source , scan , object , and desired image . fig6 shows a computed tomography ( ct ) scanner having both energy - integrating detectors arranged in a third - generation geometry and pcds arranged in a fourth - generation geometry . illustrated in fig6 is an implementation for placing the pcds in a predetermined fourth - generation geometry in combination with a detector unit 103 in a predetermined third - generation geometry in a ct scanner system . the diagram illustrates relative positions among the x - ray source 112 , the collimator / filter 114 , the x - ray detector 103 , and the photon - counting detectors pcd 1 through pcdn . also shown in fig6 is circuitry and hardware for acquiring , storing , processing , and distributing x - ray projection data . the circuitry and hardware include : a processor 670 , a network controller 680 , a memory 678 , and a data acquisition system 676 . in one alternative implementation , the ct scanner includes pcds but does not include the energy - integrating detector unit 103 . as the x - ray source 112 and the detector unit 103 rotate around circular paths 610 and 630 respectively , the photon - counting detectors pcds and the detector unit 103 respectively detect the transmitted x - ray radiation during data acquisition . the photon - counting detectors pcd 1 through pcdn intermittently detect the x - ray radiation that has been transmitted and individually output a count value representing a number of photons , for each of the predetermined energy bins . on the other hand , the detector elements in the detector unit 103 continuously detect the x - ray radiation that has been transmitted and output the detected signals as the detector unit 103 rotates . in one implementation , the detector unit 103 has densely placed energy - integrating detectors in predetermined channel and segment directions on the detector unit surface . in one implementation , the x - ray source 112 , the pcds and the detector unit 103 collectively form three predetermined circular paths that differ in radius . at least one x - ray source 112 rotates along a first circular path 610 while the photon - counting detectors are sparsely placed along a second circular path 620 . further , the detector unit 103 travels along a third circular path 630 . the above exemplary embodiment illustrates that the third circular path is the smallest and inside the first and second circular paths . although not illustrated , an alternative embodiment optionally changes the relative relation of the first and second circular paths so that the second circular path for the x - ray source 112 is smaller and inside the second circular path 620 of the sparsely placed photon - counting detectors pcd 1 through pcdn . the third circular path 630 is always larger and outside of the second circular path 620 in order that the detector unit 103 does not shadow the pcds from the x - ray source 112 . furthermore , in another alternative embodiment , the x - ray source 112 also optionally travels on the same third circular path as the detector unit 103 , as illustrated in fig1 b . there are other alternative embodiments for placing the photon - counting detectors in a predetermined fourth - generation geometry in combination with the detector unit in a predetermined third - generation geometry in the ct scanner . several alternative embodiments of the x - ray ct scanner as described in u . s . patent publication no . 2013 - 0291097 , herein incorporated by reference in its entirety . in one implementation , the x - ray source 112 is optionally a single energy source . in another implementation , the x - ray source 112 is configured to perform a kv - switching function for emitting x - ray radiation at a predetermined high - level energy and at a predetermined low - level energy . in still another alternative embodiment , the x - ray source 112 is a single source emitting a broad spectrum of x - ray energies . in still another embodiment , the x - ray source 112 includes multiple x - ray emitters with each emitter being spatially and spectrally distinct . the detector unit 103 can use energy integrating detectors such as scintillation elements with photo - multiplier tubes or avalanche photo - diodes to detect the resultant scintillation photons from scintillation events resulting from the x - ray radiation interacting with the scintillator elements . the scintillator elements can be crystalline ( e . g ., nai ( tl ), csi ( tl ), csi ( na ), csi ( pure ), csf , ki ( tl ), lii ( eu ), baf 2 , caf 2 ( eu ), zns ( ag ), cawo 4 , cdwo 4 , yag ( ce ), y 3 al 5 o 12 ( ce ), gso , lso , lacl 3 ( ce ), labr 3 ( ce ), lyso , bgo , lacl 3 ( ce ), labr 3 ( ce ), c 14 h 10 , c 14 h 12 , and c 10 h 8 ), an organic liquid ( e . g ., an organic solvent with a fluor such as p - terphenyl ( c 18 h 14 ), pbd ( c 20 h 14 n 2 o ), butyl pbd ( c 24 h 22 n 2 o ), or ppo ( c 15 h 11 no )), a plastic ( e . g ., a flour suspended in a solid polymer matrix ), or other know scintillator . the pcds can use a direct x - ray radiation detectors based on semiconductors , such as cadmium telluride ( cdte ), cadmium zinc telluride ( czt ), silicon ( si ), mercuric iodide ( hgi 2 ), and gallium arsenide ( gaas ). semiconductor based direct x - ray detectors generally have much faster time response than indirect detectors , such as scintillator detectors . the fast time response of direct detectors enables them to resolve individual x - ray detection events . however , at the high x - ray fluxes typical in clinical x - ray applications some pile - up of detection events will occur . the energy of a detected x - ray is proportional to the signal generated by the direct detector , and the detection events can be organized into energy bins yielding spectrally resolved x - ray data for spectral ct . the ct scanner also includes a data channel that routes projection measurement results from the photon - counting detectors and the detector unit 103 to a data acquisition system 676 , a processor 670 , memory 678 , network controller 680 . the data acquisition system 676 controls the acquisition , digitization , and routing of projection data from the detectors . the data acquisition system 676 also includes radiography control circuitry to control the rotation of the annular rotating frames 610 and 630 . in one implementation data acquisition system 676 will also control the movement of the bed 116 , the operation of the x - ray source 112 , and the operation of the x - ray detectors 103 . the data acquisition system 676 can be a centralized system or alternatively it can be a distributed system . in an implementation , the data acquisition system 676 is integrated with the processor 670 . the processor 670 performs functions including reconstructing images from the projection data , pre - reconstruction processing of the projection data , and post - reconstruction processing of the image data . the processor 670 also performs the functions and methods ( i . e ., those methods shown in fig3 , fig4 , and fig5 ) of matching the offset angle of calibration data to the offset angle of object data . the pre - reconstruction processing of the projection data can include correcting for detector calibrations , detector nonlinearities , polar effects , noise balancing , and material decomposition . post - reconstruction processing can include filtering and smoothing the image , volume rendering processing , and image difference processing as needed . the image reconstruction process can be performed using filtered back projection , iterative image reconstruction methods , or stochastic image reconstruction methods . both the processor 670 and the data acquisition system 676 can make use of the memory 676 to store , e . g ., projection data , reconstructed images , calibration data and parameters , and computer programs . the processor 670 can include a cpu that can be implemented as discrete logic gates , as an application specific integrated circuit ( asic ), a field programmable gate array ( fpga ) or other complex programmable logic device ( cpld ). an fpga or cpld implementation may be coded in vhdl , verilog , or any other hardware description language and the code may be stored in an electronic memory directly within the fpga or cpld , or as a separate electronic memory . further , the memory may be non - volatile , such as rom , eprom , eeprom or flash memory . the memory can also be volatile , such as static or dynamic ram , and a processor , such as a microcontroller or microprocessor , may be provided to manage the electronic memory as well as the interaction between the fpga or cpld and the memory . alternatively , the cpu in the reconstruction processor may execute a computer program including a set of computer - readable instructions that perform the functions described herein , the program being stored in any of the above - described non - transitory electronic memories and / or a hard disk drive , cd , dvd , flash drive or any other known storage media . further , the computer - readable instructions may be provided as a utility application , background daemon , or component of an operating system , or combination thereof , executing in conjunction with a processor , such as a xenon processor from intel of america or an opteron processor from amd of america and an operating system , such as microsoft vista , unix , solaris , linux , apple , mac - os and other operating systems known to those skilled in the art . further , cpu can be implemented as multiple processors cooperatively working in parallel to perform the instructions . in one implementation , the reconstructed images can be displayed on a display . the display can be an lcd display , crt display , plasma display , oled , led or any other display known in the art . the memory 678 can be a hard disk drive , cd - rom drive , dvd drive , flash drive , ram , rom or any other electronic storage known in the art . the network controller 680 , such as an intel ethernet pro network interface card from intel corporation of america , can interface between the various parts of the ct scanner . additionally , the network controller 680 can also interface with an external network . as can be appreciated , the external network can be a public network , such as the internet , or a private network such as an lan or wan network , or any combination thereof and can also include pstn or isdn sub - networks . the external network can also be wired , such as an ethernet network , or can be wireless such as a cellular network including edge , 3g and 4g wireless cellular systems . the wireless network can also be wifi , bluetooth , or any other wireless form of communication that is known . while certain implementations have been described , these implementations have been presented by way of example only , and are not intended to limit the teachings of this disclosure . indeed , the novel methods , apparatuses and systems described herein may be embodied in a variety of other forms ; furthermore , various omissions , substitutions and changes in the form of the methods , apparatuses and systems described herein may be made without departing from the spirit of this disclosure . | US-201514622372-A |
a detachable cutting tool capture for a cutting block provides a guide surface to convert an open surface block into a slotted block for plying a surgical cutting tool along the surfaces of the guide during a surgical procedure such as a bone resection with a blade . a magnetized catch provides a convenient device for securing the capture and the block together . a triangular cam on the detachable capture in conjunction with a “ v ” groove in a magnetized lever of the catch permits a pin of the catch to be selectively retracted from or extended into an aperture of the block when the lever is rotated so that when the pin extends , it serves to secure the combined apparatus for cutting . mating surfaces of the block and capture provide additional structure for supporting the capture with the block to secure them from relative movement . | the invention generally involves a detachable or modular capture apparatus that attaches to an open - face cutting block and provides a slot for guiding a cutting tool such as an oscillating saw blade to make a bone cut . the device preferably converts the open - face cutting block to a slotted block , thus giving a user the option to use either . with particular reference to fig1 through 11 , in a preferred embodiment of the detachable capture 2 , the device consists of a main housing 4 and a locking mechanism or catch 6 . the preferred embodiment of the catch 6 includes a locking lever 8 , locking pin 10 , and integrated magnet 12 that can bias the catch 6 in a locked or unlocked position . to prevent the catch 6 from disassembling from the main housing 4 , the locking pin 10 of the catch 6 preferably consists of two coaxial cylindrical portions . the first cylindrical portion 16 has a larger diameter than the second cylindrical portion 18 to form a shoulder 20 . the main housing 4 also includes a corresponding counter - bored hole 22 . the counter - bored hole 22 and the locking pin 10 are closely dimensioned to allow translation of the pin 10 along the axis of the counter - bored hole 22 . the close dimensioning also permits rotation of the pin 10 in the counter - bored hole 22 . however , the pin shoulder 20 prohibits disassembly in one direction as a result of the corresponding diameters of the counter - bored hole 22 . the lever 8 also impedes removal of the pin 10 from the main housing 4 of the detachable capture 2 when the lever 8 , which is larger than the counter - bored hole 22 , is fixed to the pin 10 . for convenience , the pin 10 is press fit with the lever 8 . in this regard , the lever 8 has an upper lever surface 24 and a lower lever surface 26 , which may be parallel to each other . a locking pin hole 28 , preferably perpendicular to the upper surface 24 , optionally extends from the upper surface to the lower surface 26 . the locking pin hole 28 is dimensioned to accept the second cylindrical portion 18 of locking pin 10 by press fitting . as a result , depending on the length of the pin 10 , the locking lever 8 may be employed as a handle to extend or retract the locking pin 10 through the counter - bored hole 22 of the main housing 4 , but due to the impediments of the lever 8 and the pin shoulder 20 , the catch 6 remains movable or traversable but also a component of the main housing 4 . thus , the length of the locking pin 10 is chosen such that when it is housed in the counter - bored hole 22 and placed perpendicularly through a lower surface of main housing 4 , it extends through the entire thickness of main housing 4 and into the lever 8 . with regard to the magnetization of the catch 6 , for preference a magnet 12 is housed in a magnet aperture 30 . the magnet aperture 30 may be machined adjacent and parallel to locking pin hole 28 of locking lever 8 . the magnet aperture 30 is counter - bored , extending from upper surface 24 of locking lever 8 to a depth that is less than the overall thickness of locking lever 8 leaving a thin wall to allow the magnet to be in close proximity to the main housing 4 . a cylindrical cap 32 is pressed fitted into the counter - bore magnet aperture 30 to preferably hermetically seal the magnet . thus , the locking lever 8 may be made of non - magnetic material , such as titanium , or type 304 stainless steel . beneficially , a recessed or inwardly projecting “ v ” groove 34 is machined on lower surface 26 of locking lever 8 . this inward projection is reciprocally configured and dimensioned to couple with a matching cam 36 on a surface of main housing 4 of the detachable capture 2 giving them a profile with the same shape . in the preferred embodiment , the cam 36 includes an outwardly projecting triangular section 38 . the locking lever 8 , also includes a non - reciprocal portion not matching the cam 36 . the locking lever 8 , when positioned over the cam 36 so that the “ v ” groove 34 and triangular section 38 of the cam 36 match , will magnetically attach with the lower lever surface 26 of the locking lever 8 to upper main surface 40 of the main housing 4 , extending the pin 10 outward from an opposing surface of the main housing . in this position , the triangular section 38 is received in the “ v ” groove of the lever . this secured position of the catch 6 is best viewed in the illustrations in fig7 , 8 and 10 . when a non - reciprocal portion of the locking lever 8 is rotated to a position over the projection of the cam 36 , the lower lever surface 26 gradually departs from upper main surface 40 of the main housing 4 , rising on the cam 36 , and thereby retracts the locking pin 10 into the main housing 4 at the opposing surface of the main housing 4 . this unsecured position of the catch 6 is best illustrated in fig1 through 6 and 11 through 14 . the main housing 4 includes an upper main surface 40 and a lower main surface 42 , which , is adjacent and parallel to upper main surface 40 . the lower main surface 42 may serve as part of a slotted guide or guide envelope for a cutting tool when coupled to a cutting block mated for the detachable capture 2 . the upper main surface 40 is formed of a magnetic material such that it will be attracted by the magnet 12 of the magnetized catch 6 . extending from the central region of lower main surface 42 is a raised pad 44 of constant thickness forming a step with lower main surface 42 . the raised pad 44 is chosen to be a preferred slot thickness for the cutting envelope formed when the detachable capture is coupled to the cutting block because the raised pad 44 will serve to separate the opposing surfaces of the formed cutting envelope . optionally , the raised pad 44 may include a beveled end 45 to facilitate coupling of the capture 2 with a cutting block as the cutting block is positioned onto the cutting block . adjacent to lower main surface 42 is a tab 46 with a rectangular configuration . tab 46 contains an upper tab surface 48 and a lower tab surface 50 to form a thickness and is connected to the main housing by a bridged portion 52 . upper tab surface 48 and lower tab surface 50 of tab 46 are parallel with lower main surface 42 of main housing 4 . tab 46 is bisected by a tab slot 54 , which extends from upper tab surface 48 to lower tab surface 50 of tab 46 . as will be described in more detail herein , together the surfaces of the tab 46 , the surface of the raised pad 44 , and the catch 6 in conjunction with mating or corresponding features of a cutting block 56 , serve as a means for securing the detachable capture 2 with a cutting block to form a cutting envelope . in this regard , the mating features of a preferred cutting block 56 that can be magnetically secured in a coupled position with the detachable capture 2 are illustrated in fig1 - 15 . the cutting block 56 , which includes an open face guide 58 against which a cutting tool may ply , consists of a plate 60 having an upper plate surface 62 and a lower plate surface 64 which is adjacent and parallel with upper plate surface 62 and a central rib 66 , which is preferably perpendicular to upper plate surface 62 . as illustrated in the preferred embodiment , the upper plate surface 62 may serve as an open face guide 58 . the cutting block 56 also includes a pin aperture 68 sized and positioned to receive the locking pin 10 of the catch 6 . the surfaces of the plate 60 , the rib 66 , and pin aperture 68 serve as the mating features of the block for securing the capture and the block . in an alternative embodiment of the capture , the catch 6 ( with or without the magnet 12 ) may include a locking spring 13 to bias or further bias the pin 10 . in such an embodiment , the spring may be configured with the pin 10 or lever 8 to bias the catch 6 with an elastic force to remain in the locked position when the detachable capture 2 and cutting block 56 are coupled . an example of the embodiment with a spring is illustrated in fig1 to 18 . as illustrated in fig1 , locking spring 13 is installed around the first cylindrical portion 18 of the locking pin 10 . although other implementations are possible , in this example the locking spring 13 provides an elastic compression force between shoulder 20 of the locking pin 10 and the pin aperture of the main housing 4 to bias the locking pin 10 to extend from the main housing 4 into the pin aperture 68 of the cutting block 56 . thus , when the lever 8 of the catch 6 is lifted from the upper main surface 40 of the main housing 4 or rotated to its unlocked position on the peak of the cam 36 as illustrated in fig1 and 18 an elastic force is compressed into the spring providing a bias for its return to the locked position . as such , it will tend to return to the locked position unless the lever 8 is positioned on the peak of the cam 36 , out of the “ v ” grove 34 of the lever 6 . in operation , the main housing 4 may be engaged with the cutting block 56 such that raised pad 44 and upper tab surface 48 of tab 46 straddle the plate . thus , the raised pad 44 contacts the upper plate surface 62 and the upper tab surface 48 contacts the lower plate surface 64 . similarly , tab 46 straddles the central rib 66 when the rib 66 resides in the tab slot 54 . finally , the locking lever 8 may be rotated so that the “ v ” groove 34 of the lever is positioned over the triangular section 38 of the cam 36 . in this position , lever 8 may be lowered to magnetically attach to the upper main surface 40 of the main housing when the triangular section 38 enters the “ v ” groove 34 . consequently , the locking pin 10 traverses to extend out of the main housing through the raised pad 44 to extend into and couple with the pin aperture 68 , thereby securing the cutting block 56 and the detachable capture in a coupled position . when so assembled , movement of the main housing 4 with respect to the cutting block in the x - y directions illustrated in fig1 or 12 is limited only by the clearance that exists between mating surfaces . thus , when the rib 66 is inserted in the tab slot 54 , the opposing surfaces of the tab slot 54 and rib 66 impede movement of the detachable capture 2 with respect to the cutting block 56 in any direction along the imaginary x axis illustrated by the x axis of fig1 or 12 . similarly , when the upper tab surface 48 of the tab 46 and the surface of the raised pad 44 straddle the plate , the opposing surfaces of the tab 46 , raised pad 44 and plate 60 , impede movement of the capture 2 with respect to the block 56 in any direction along the imaginary y axis of fig1 or 12 . the x and y axes and the directions discussed above with respect to each are generally perpendicular to each other . finally , the insertion of the locking pin 10 into the pin aperture 68 prevents or impedes movement of the detachable capture 2 with respect to cutting block 56 in any direction along the imaginary z axis illustrated in fig1 . optionally , a surface of the bridge portion 52 and a side 53 of the plate ( see in fig1 ) may mate so as to impede relative movement of the cutting block 56 and the detachable capture along a direction of the imaginary z axis . with such contact between the side 53 of the plate 60 and the bridge portion 52 , a stop is provided to simplify alignment of the locking pin 10 with the pin aperture 68 for insertion . generally , the z axis and the directions of movement described above with respect to it are perpendicular to the x and y axes of fig1 or 12 . in this magnetically and / or elastically biased secured or locked position , the lower lever surface 26 of the locking lever 8 is in full contact with the upper main surface 40 of main housing 4 . with such contact , the locking lever 8 remains biased to the locked position by the magnetic force of magnet 12 and / or the elastic force of the locking spring 13 . the cutting block 56 and main housing 4 when assembled are dimensioned such that a guide slot 70 is formed for guiding a cutting tool , ( e . g ., a saw blade ) by the upper plate surface 62 and the lower main surface 42 . this guide slot 70 is illustrated in fig1 . cutting block 56 may optionally include multiple plates which may be converted by a single detachable capture 2 simply by re - attaching the capture 2 in a different position with respect to different plates to create different envelopes or slotted guides . in the preferred embodiment , the block also includes an integrated guide slot 72 . when the capture is not assembled with the block , the upper plate surface 62 may be utilized as an open face cutting guide . of course , for a resection procedure on bone as previously described , the block would also include a fixing device 74 to temporarily fix the block to the bone for the surgical cutting procedure . to remove the capture 2 , the locking lever 8 is turned 90 degrees . when it rotates about the axis of counter - bored hole 22 in main housing 4 , the camming action of the “ v ” groove and triangular cam results in the entire locking lever 8 being forced away from upper main surface 40 , thus retracting the locking pin 10 into the main housing 4 which disengages it from the pin aperture 68 on cutting block 56 . conveniently , the magnet 12 of the lever 8 holds the lever 8 at the peak of the cam 36 in an unlocked or unsecured position by a magnetic force to impede the lever 8 from unintentionally returning to the locked position of the cam 36 . with such a design for a detachable capture , cleaning is made easier . for example , by virtue of the readily removable nature of the capture , complete open access to the guide surfaces of the slotted guide is permitted . thus , such a design is easier to clean than an integral capture , retractable or otherwise . moreover , in a cutting block as illustrated in fig1 - 15 , where the capture may be installed in multiple positions on multiple open face guides of the cutting block , a single capture may be reused , cutting down on the number of parts which need to be cleaned . the locking features and method of attachment allows the capture to be rapidly and easily secured to the cutting block with minimal risk of disassociation during use . the magnet provides a positive locking implementation . in conjunction with the cam and mating surfaces , the locking feature provides an ergonomic , self - aligning locking mechanism . moreover , with the preferred design , the capture can be made very small since the locking mechanism itself is very small and is centralized with respect to the width of the capture . a smaller capture allows the cutting block to also be made smaller . this is a benefit since the current trend is to make minimally invasive incisions thus requiring smaller instruments . adding to the smaller size theme is the use of a magnet to bias the locking lever in the locked position . this results in a very low profile locking lever , a benefit compared to the use of springs which require more room . although the invention herein has been described with reference to a particular preferred embodiment , it is to be understood that this embodiment is merely illustrative of the principles and applications of the present invention . it is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims . for example , one skilled in the art will recognize that the mating surfaces associated with the rib 66 and tab slot 54 can be optional since the pin 10 , when residing in a pin aperture 68 that closely corresponds with the surfaces of the pin 10 , can limit relative movement between the capture 2 and the cutting block 56 along two perpendicular axes ( e . g ., axes z and x ) being generally perpendicular to a remaining axis ( e . g ., the y axis ). relative movement with respect to this remaining axis would still be limited by the mating surfaces of the plate 60 , the raised pad 44 and the upper tab surface 48 of the tab 46 . other modifications will also be apparent . throughout the description and claims of this specification , forms of the word “ comprise ” including all variations of the word , such as “ comprising ” and “ comprises ”, are not intended to exclude other additives , components , integers or steps , etc . | US-50426409-A |
a multiple use , light weight , cost - effective , indoor and all - weather outdoor construction toy for stimulating children &# 39 ; s imaginations and encouraging physical activity comprises a basic modular unit with open ended cup - like coupling - means on its perimeter for male to female coupling and decoupling to other couple - able units , is described . the coupling - means may be molded as an integral part forming one seamless basic unit . the open bottom end of the coupling means provides for coupling , the open top end prevents the buildup of snow inside the coupling unit . coupling can be achieved via coupling - means on basic units to each other or through the use of accessory independent coupler - units . the basic unit of the modular toy may be in the form of a saucer , disc , an oval , or in a rectilinear - shape for use as a sled , skiing device , a flotation device , or as fort building modules . additional accessory parts include skis and inner - tubes , for example . | referring now , with more particularity , to the drawings , it should be noted that the disclosed invention is disposed to embodiments in various sizes , shapes , and forms . therefore , the embodiments described herein are provided with the understanding that the present disclosure is intended as illustrative and is not intended to limit the invention to the embodiments described herein . the present invention is a toy that provides a range of play choices . the fundamental structure on which all variations are based is what we refer to as the basic unit . in one favored embodiment , illustrated herein , a basic unit comprises a disc - shaped saucer that is available in a smaller size to support one child or in a larger size to support several . it is to be understood that the shape and the size of the basic unit may vary , as desired , and that the invention does not reside in either the shape or the size of the units of the present invention . however , the there are some features upon which the invention relies . in order to provide for the maximum amount of stability each basic unit should be either round or have a shape of a regular polygon . all of the vertices of a regular polygon lie on a common circle ( the circumscribed circle ) which is what is referred to as the perimeter of the basic units as described herein . these shapes all share the fact that either all points on the circumference ( the perimeter ) of the basic unit or all of the vertices of the perimeter of the basic unit are equidistant from the center point of the basic unit , which is turn provides the seating position of greatest stability for the user on the unit . additionally , each unit is made to have a depressed center to provide for a comfortable and secure seating area . by itself , the disc - like device may be used as a sled for gliding on surfaces one equates with winter - like weather . the toy , however , is designed to be much more than a simple saucer or sled . for example , it may also be used in conjunction with a floatation device , such as an inner - tube for use either in winter on the snow or in summer on the water , which will be described in more detail below . as such , the fundamental basic unit of the toy may be fully enjoyed by itself . each fundamental basic toy unit however is provided with coupling means that extend out away from the perimeter of the basic unit so that , when desired , each basic unit may be coupled to other basic units to provide the user with a wide variety of toys . additionally , the invention includes accessory pieces that further expand the ways the toy may be used . one such accessory is a set of skis where each ski is provided with one or more coupling means that are couple - able with the coupling means on a basic unit . the resulting ski - sled could be used either in winter on the snow or in summer on the water . furthermore , each of the basic units may be coupled to one or two other basic units to provide for a multi - ski - vehicle toy . moreover , the basic units may be coupled , either directly , or indirectly using one of a variety of coupling units , to other basic units to provide for a walled or domed forts . turning now to the drawings , fig1 a , a top plan view , illustrates basic unit 10 of the modular construction toy of this invention . in this exemplary illustration , basic unit 10 is presented as a saucer - like disc form having a circumferential perimeter . as mentioned , it is to be appreciated that a modular construction toy basic unit according to the principles of the present invention may assume a variety of shapes , as long as the shapes may be described as polygonal to provide maximum stability for a user on the basic unit , has a depressed central seating area , and is available in a variety of sizes . fig1 a , a planar view , and fig1 b , a perspective view , illustrate coupling means 12 disposed about and extending out and away from the perimeter of body 14 of basic unit 10 . coupling means 12 in the example illustrated are male to female couplers providing for coupling and decoupling of the basic unit to like coupling - means of at least one other unit , such as another basic unit or other types of units which will be discussed below . body 14 comprises an upper sitting surface 16 and bottom surface 18 . the embodiment chosen for illustration presents body 14 in the form of a circular disc , which is but one of many possible styles for the basic unit . the convex disc shape of upper sitting surface 16 provides for a depressed comfortable and secure seat for one or more users . in the example illustrated , the basic unit has a round shape , meaning that all points on the perimeter ( the circumference ) of the body are equidistance from the center . the centering of a user in a centrally located depressed seating area provides for the user to be in a maximum stable position . fig1 c , a cross - sectional view , of the basic unit , illustrates clearly that in this embodiment coupling means 12 are molded as an integral part of the basic unit . fig1 a and fig1 b illustrate eight coupling means positioned proximate to , but extending , out away from the perimeter of the saucer shaped disc . having the coupling means extending out and away from the perimeter of the body of the unit provides for the modular construction toy basic unit 10 to be linked directly to other like modular construction toy basic units ( see fig4 a ). it is to be understood that the number of coupling means is not confined to eight coupling means ; any number desired will be effective . in the examples illustrated , the coupling means are presented as female / male coupling cups 12 . in this embodiment , coupling cups 12 are shown as cups with both their top and bottom ends open . the bottom ends of the coupling means 12 are open to receive other coupling means for coupling purposes . the top ends of coupling means 12 are open to avoid the coupling cups from becoming packed with snow when the toy is used in the snow . fig2 a , a top plan view , and fig2 b , a partial perspective view , illustrate one embodiment of a coupler - unit according to the principles of this invention . central coupler body 24 of coupler - unit 20 is illustrated having a triangular polygonal perimeter with coupling - means 12 affixed proximate to but extending our and away from said perimeter , wherein coupling - means 12 provide for male or female coupling and decoupling of said coupler - unit to like coupling - means on at least one other unit provided with coupling means . fig2 c a side plan view of the coupler coupling means , illustrates coupling - means 12 molded as an integral part of coupler - unit 20 forming one seamless coupler - unit . as are the coupling means discussed above , the bottom ends of the coupling means 12 of coupler - unit 20 are open to receive other coupling means for coupling purposes . the top ends of coupling means 12 are open to avoid the coupling cups from becoming packed with snow when the toy is used in the snow . fig3 a , a top plan view , illustrates another embodiment of a coupler - unit according to the principles of this invention . right - angled coupler body frame 34 of coupler - unit 30 has coupling - means 12 a affixed at and defining each apex , where coupling - means 12 a provides for male or female coupling and decoupling of said coupler - unit to the cup - like coupling - means found on other coupling units and on the basic units . unlike the cup - like coupling means described previously , the height of coupling - means 12 a is limited to the height of coupler frame 34 . looking down into coupling - means 12 a in the top plan view of fig3 a , gives the impression that the coupling - means are open holes because , as can be seen in the side view presented in fig3 b the circumference of coupling - means 12 a increases with depth , whereas in fig3 c , which is a bottom plan view of the coupler coupling unit , both the bottom circumference line and the top circumference line are seen . as are the coupling means discussed above , the bottom ends of the coupling means 12 a of coupler - unit 30 are open to receive other coupling means for coupling purposes . incised into each of the two arms of coupler unit defining the right angle is a threaded aperture 36 . the use for these apertures will become apparent in the discussion of fig1 . fig4 a , a top plan view , illustrates three basic units 10 each coupled to coupler - unit 20 via coupling means 12 forming a multi - person sled . fig4 b , a side plan view , provides an enlarged view of two cup - like coupling - means 12 to illustrate how simple it is to couple and to decouple coupling - means . no tools or special skills are required for coupling . one cup - like coupling means is simply placed under or over another cup - like coupling means to couple . to decouple one cup - like coupling means is simply lifted up from or down away from the cup - like coupling means to which it is coupled . although , fig4 a illustrates three basic units 10 coupled via coupler - unit 20 the three basic units 10 could just as easily and rapidly be coupled to each other without the use of coupler - unit 20 . fig5 a , a top plan view , illustrates basic unit 10 snugly situated on an inner - tube 55 providing tube - disc 50 for use in the water or on the snow or ice . fig5 b , a top plan view , illustrates four basic units 10 each situated on an inner - tube 55 and each coupled directly via coupling means 12 to basic unit 10 not situated on an inner - tube forming a multi - person device for use in the snow or water . fig6 a , a partial perspective view , illustrates a top side 62 s of short ski 64 s having only one coupling - means 12 . fig6 b , a partial perspective , illustrates a top side 62 of full length ski 64 having coupling - means 12 on each of its two ends . fig6 c , a plan view , illustrates bottom side 63 s of a short ski 64 s having only one coupling - means 12 . fig6 d , a plan view , illustrates bottom side 63 of full length ski 64 having a coupling - means on each of its two ends . fig6 e , a top plan view , illustrates basic unit 10 coupled to an accompanying set of couple - able skis and including a set of two full length skis 64 and one short ski 64 s providing for ski - disc 60 that can be used to ski on snow or ice or for water skiing . for indoor and all - season outdoor play , various numbers of basic units 10 may be coupled together to form structures , such as play forts of varying complexity . fig7 , a perspective view , illustrates six basic units coupled to each other forming vertically - walled structure 70 . fig8 , a perspective view , illustrates nine basic units coupled to each other to form domed fort 80 . fig9 , a perspective view , illustrates thirteen basic units coupled to each other to form more complicated domed fort 90 . each of the structures illustrated in fig7 - 9 are constructed by coupling the coupling means 12 of each basic unit directly to the coupling means of neighboring basic units . the ease by which the coupling and decoupling is accomplished and the light weight of the each of the modules means that even young children are able to build a fort of their imagination . fig1 a , a side plan view , and fig1 b , a perspective view , illustrate rotatable , turntable - like sitting device 100 , another accessory part of the indoor and all season outdoor coupleable / decoupleable modular construction toy of the present invention . rotatable sitting device 100 comprises rotable seating platform 105 rotably attached to shaft 107 that is in turn rotably connected to top cover part 109 a rotably positioned over bottom support part 109 b of base part 109 . rotatable sitting device 100 is a sit - on - able variation of a turntable . there are a number of known ways to construct turntables in the art and any of these would work within the principle of the present invention . the uses for rotatable sitting device 100 are limited only by the user &# 39 ; s imagination . one contemplated use is described below . fig1 , which is , in part , a cutaway longitudinal view of the fort illustrated in fig8 with the front central basic unit removed to provide a view of the inside of the fort , also illustrates rotable sitting device 100 positioned within the fort to construct helicopter - like toy 110 . rotable sitting device 100 comprises base 109 a , connecting shaft 107 , and rotable seat 105 . fig1 a , a side plan view , illustrates multi - use device 111 comprising multi - use part 122 that functions as part of an oar , paddle , propeller , or support , for example , and multi - use shaft part 119 . in the embodiment illustrated , there are also accessory parts long rod - like shaft 119 and rear tire axel 145 that , in this instance , are connected to each other , for example , by screwing their reciprocally receiving threaded ends together or alternatively , if desired to be manufactured without threaded parts , by friction fitting the parts to each other . there are many ways to connect such shafts known to those of ordinary skill in the art and , thus , need not be discussed in any further detail here . one end of the two section rod - like shaft is then connected to rotatable sitting device 100 using , for example , receiving threaded aperture 103 . the opposite end of the elongated , the two section rotable shaft is connected to rotable connecting part 115 to which propeller - like blades 122 are also connected . to make the propeller - like blades 122 spin , a child , for example , may simply sit on rotable seating part 105 of rotatable sitting device 100 and use his or her feet to rotate the seat , which turns the two section shaft , which turns part 115 , which turns the propellers . fig1 , a side plan view illustrates airplane - like toy 120 constructed using the fort shown in fig9 . several of the front basic units of the fort are removed to provide a view of the airplane propeller driving structure constructed within the interior of the fort . to make the airplane propeller driving structure , the inside surface of a first rear tire 142 is positioned against the inside surface of the first right angle defining arm of coupler - unit 30 , as is illustrated in fig3 a , 3 b , and 3 c , so that the threaded receiving aperture 142 c of first rear tire 142 is aligned with threaded receiving aperture 36 of the first right angle defining arm of coupler - unit 30 , then the inside surface of a second rear tire 142 is positioned against the inside surface of the second right angle defining arm of coupler - unit 30 so that the threaded receiving aperture 142 c of second rear tire 142 is aligned with threaded receiving aperture 36 of the second right angle defining arm of coupler - unit 30 . next , a first end of rear tire axel 145 is rotably connected to rotable sitting means 100 while the second end of rear tire axel 145 is screwed into threaded receiving aperture 36 of first right angle defining arm of coupler - unit 30 and then into threaded receiving aperture 142 c of rear tire 142 . similarly , screwed into threaded receiving aperture 36 on the second right angle defining arm of coupler - unit 30 , is a first end of rod - like shaft 119 . connected to the second end of shaft 119 is rotable connecting part 115 for connecting propeller - like blades 122 . fig1 , a top plan view , illustrates a first , second , and third tube - disc 50 coupled to each other and to coupleable sled 135 to form steerable multiple coupled tube - discs sled 130 . in particular , steerable multiple coupled tube - discs sled 130 comprises a first tube - disc 50 coupled via two coupler - means 12 of first coupler - unit 20 to second tube - disc 50 which is coupled via two coupler - means 12 of second coupler - unit 20 to third tube - disc 50 . coupleable , steerable sled 135 is coupled to second tube - disc 50 via coupleable sled attachment means 139 . coupleable sled attachment means 139 comprises washer 139 a , threaded bolt 139 b , and nut 139 c ( illustrated in fig1 a ). coupleable steerable sled 135 comprises coupleable accessory seat 136 coupled to first and second full length skies 64 with coupling - means , as described above . the steering of tube - discs sled 130 is accomplished using coupleable steering bar 133 that is coupled to the sled , in this embodiment by screwing steering bar mechanism 133 onto threaded coupleable sled attachment means 139 . a first end of steering bar 133 is adapted to fit into aperture 12 d of the coupling - means 12 of first coupler - unit 20 that is not being used to couple the first and second tube - discs 50 while a second end of steering bar mechanism 133 is adapted to fit into aperture 12 e of the coupling - means 12 of second coupler - unit 20 that is not being used to couple the second and third tube - discs 50 so that moving an end of the steering bar in a desired direction directs the movement the tube - disc functionally attached to that end of the steering bar to move in the desired direction . optional coupleable backrest 137 may be coupled to coupleable accessory seat 136 providing for a more comfortable ride . fig1 a , a side plan view , fig1 b , a perspective view , and fig1 c , a top plan view , illustrate yet still another way the accessory parts of the coupleable construction toy of the present invention may be used for creative construction . in this embodiment , the accessory parts provide for the construction of coupleable tricycle 140 . fig1 d provides a plan view of the individual accessory parts that are used to make coupleable tricycle 140 . in particular , coupleable tricycle 140 comprises coupleable accessory seat 136 adapted for rotably receiving rear axel 145 onto which is mounted the pair of rear wheels 142 . fig1 d illustrates the individual parts used in the construction of the coupleable tricycle , such as threaded axel receiving aperture 142 c located on the inside side 142 b of rear wheel 142 opposite outside side 142 a . optional backrest 137 may be coupled onto the sitting surface of accessory seat 136 by inserting coupleable stems 136 c into coupleable accepting apertures 136 b . the upwardly directed portion 136 a of accessory seat 136 supports steering fork 146 of conventional construction to be functionally engaged with steering bar mechanism 133 . front wheel 143 is of conventional construction in that it includes an axle ( not shown ) that extends outwardly from both planar wheel cover faces 174 of the extent of the wheel through steering fork 146 to be then bent into a pair of oppositely disposed crank arms 148 that in turn support pedals 144 . front wheel 143 is constructed to function as a tricycle front wheel and as a water cycle wheel ( which will be discussed below ), therefore the wheel construction includes a right side planar face 174 wheel cover and a left side planar face wheel cover each having opening or aperture 170 in the center . aperture 170 serves to receive the axle and also serves as an inlet for water when used as part of the water cycle . instead of ordinary spokes , front wheel 143 has “ water wheel blades ” 172 that are constructed and function just as the blades or paddles do on a conventional water wheel , however , the only function “ water wheel blades ” 172 serve coupleable tricycle 140 is to provide support to the wheel and to the tricycle . yet still another imaginative construction that can be constructed using the accessory parts already described with the addition of one other part is water disc - cycle 150 , as illustrated in fig1 . the buoyancy of water disc - cycle 150 is , in part , maintained by a first 55 a , second 55 b , and third inner - tube ( third inner - tube is hidden from view behind first inner tube 55 a ). water disc - cycle 150 comprises accessory seat 136 . upwardly directed portion 136 a of accessory seat 136 supports steering fork 146 for functional engagement with steering bar mechanism 133 . front wheel 143 is of conventional construction in that it includes an axle ( not shown ) that extends outwardly from both planar wheel cover faces 174 of the extent of the wheel through steering fork 146 to be then bent into a pair of oppositely disposed crank arms 148 that in turn support pedals 144 . front wheel 143 is constructed to function as a water cycle wheel in addition to a tricycle wheel therefore the construction includes a right side planar face cover 174 and a left side planar face wheel cover 174 ( mirror image cannot see in illustration ) having an aperture in the center . the aperture serves to hold the axle and as an inlet for water when used as part of the water cycle . instead of spokes , front wheel 143 has “ water wheel blades ” 172 ( see fig1 b and 14 c ) that are constructed and function just as the blades or paddles do on a water wheel . peddling pedals 144 in a conventional peddling manner turns water wheel 143 which causes water disc - cycle 150 to be propelled through the water . opening 170 allows water to be drawn in adding to the amount of water present to turn the wheel . attached to upwardly directed portion 136 a of accessory seat 136 via rod shaped connector means 132 a is rotable shaft 107 that is in turn connected to seating part 105 that is hooked over the second inner - tube to hold the second inner - tube securely to the cycle . basic disc 10 provides for a sun roof for the user who sits on accessory seat 136 . basic disc 10 is supported in its sun roof position by three long , rod - like shafts , of which only 119 a and 119 b can be seen in the figure . fig1 a illustrates the construction used to support seat 136 , to secure first and third inner - tube to seat 136 , and to support sun - roof basic unit 10 . each end of rear tire axel , which is used as the support for seat 136 is connected to a paddle part 122 via connector attachment means 132 . in particular , the male threaded ends of 145 and 122 and secured into the female threaded accepting part of 132 b forming not only a support for seat 136 , but providing the curved blades 122 that rests on first inner tube 55 and on not seen third inner tube . moreover , the threaded ends of parts 132 a are now in position to be connected to the complementary threaded ends of shaft 119 a ( as a mirror image , and thus not shown , first end of the third shaft is supported by a second propeller - like curved blade that rests on third inner tube ) which positions shaft 119 a to be inserted through the coupling - means 12 to be screwed into the axel accepting aperture 142 c ( as illustrated in fig1 d ) of rear wheel 142 which is situated on top of basic unit 10 to hold basic unit 10 securely in its place as a sun umbrella . again , in mirror imagine and thus not shown , there is an identical support on the other side of the device . first shaft 119 a also serves to keep first inner tube 55 a fixed to water disc - cycle 150 . a second support for basic disc 10 sun roof is provided by second shaft 119 b where first end of second shaft 119 b is supported in coupling connector aperture 132 b that is fixed about rod shaped connector means 132 a while second end of second shaft 119 b is positioned through the apertures of a second coupling cup 12 to provide support for basic disc 10 . securely tucked in between and supported by second shaft 119 b and first inner tube 55 a is second inner tube 55 b , which is also kept securely related to the cycle by rotable shaft 107 that is connected to seating part 105 . only the rearward half of second inner tube 55 b is shown so as not to obscure the relationship between second inner tube 55 b and the cycle parts . hidden from view in this figure , is third inner tube that is a mirror image of first inner tube 55 a which also provides support for the opposite side of basic disc 10 . fig1 a is a top plan view and fig1 b is a side plan view illustrating yet another style coupler - unit of this invention . coupler - unit 160 serves as a bi - coupler having first coupler 12 on a first end of body part 165 and second coupler 12 on a second end of body part 165 . coupler - unit 160 also serves as a means for making snow or ice cube - like toys . body part 165 of coupler - unit 160 is provided with a plurality of casting impressions 166 that can be filled with snow or water . in the example illustrated in fig1 a the impressions are of a penguin , but they can be of anything desired . once the snow or water sets or freezes in the cast to form a set of molded impression toys , the molded toys are removed from the casts . the toys can be used in a multitude of ways . one way is for children to throw the toys down a snowy hill to see who can retrieve the largest number of toys as they slide down the hill on their coupleable sled , for example . the toys may be used to play catch , for juggling , or to throw through coupler openings , to give just a few more examples . the toys of this invention are designed to allow and encourage children to use their imaginations . the foregoing description , for purposes of explanation , uses specific and defined nomenclature to provide a thorough understanding of the invention . however , it will be apparent to one skilled in the art that the specific details are not required in order to practice the invention . thus , the foregoing description of the specific embodiment is presented for purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise form disclosed . those skilled in the art will recognize that many changes may be made to the features , embodiments , and methods of making the embodiments of the invention described herein without departing from the spirit and scope of the invention . furthermore , the present invention is not limited to the described methods , embodiments , features or combinations of features but include all the variation , methods , modifications , and combinations of features within the scope of the appended claims . the invention is limited only by the claims . | US-77923510-A |
a solid formulation of clopidogrel bisulfate and its preparation method are disclosed . the formulation comprises clopidogrel bisulfate as active ingredient , colloidal silicon dioxide as anti - adherent / coating and the carriers selected from diluent , binder , glidant , disintegrant and / or lubricant . | the invention is further illustrated by the following examples but not be restricted by them . the colloidal silicon dioxide used in the examples are manufactured by evonik degussa co ., ltd . its trade name is aerosil 200 ® pharma . the method used in this invention to indicate s sticking is : the following table contains results of sticking when clopidogrel bisulfate raw material is premixed with different ratios colloidal silicon dioxide based on tablet weight , for clopidogrel bisulfate tablets prepared according to the formula and technology from international publication wo2008059298 : from the table , according to the method of determining sticking on the punch and / or die , when there is no colloidal silicon dioxide , the tablet was sticking on punch and / or die ; when colloidal silicon dioxide is only as glidant in the tablet , the tablet shows slight sticking on punch and / or die ; when colloidal silicon dioxide is premixed with raw material as anti - adherent / coating agent , even if the content is only half of the content of glidant in each tablet , the sticking decreased ; the sticking also decreased as the same amount of glidant was used at the same time . when the content of glidant was not changed , the sticking has been solved completely by increasing the content of colloidal silicon dioxide as anti - adherent / coating agent . it is known that colloidal silicon dioxide as anti - adherent / coating agent was premixed with raw material to make it uniformly dispersed on the surface of drug material particles . even if the quantity of colloidal silicon dioxide is only 0 . 75 mg / tablet , the sticking also decreased on the punch and / or die . the example applied the formulation of international publication wo2008059298 , the sticking has not been improved during the process of compression . it is shown in the above table that premixing colloidal silicon dioxide with microcrystalline cellulose as diluent and adhesive according to international publication wo2008059298 method of preparing tablets , the sticking has not been improved during the process of compression . the tablets prepared according to the present invention formulation and technology are better than the above tablets in solving sticking on punch and / or die . so the tablet quality is better . the reason is that , the function of colloidal silicon dioxide is completely different with different manufacturing technology and it is also different affect on the tablet quality although using the same colloidal silicon dioxide . 97 . 88 g clopidogrel bisulfate was mixed with 60 . 0 g lactose , 40 . 00 g microsrystalline cellulose . adding the 10 % prepared hydroxypropyl cellulose solution and granulation . the granules were dried and screening . blending with 26 . 00 g microcrystalline cellulose , 6 . 00 g crospovidone , 17 . 00 g of hydrogenated vegetable oil and sodium lauryl sulphate and compression . the tablet weight is 250 mg with diameter 9 mm . 97 . 88 g clopidogrel bisulfate was mixed with 60 . 00 g lactose , 40 g of microcrystalline cellulose . adding the 10 % prepared hydroxypropyl cellulose solution and granulation . the granules were dried and blended with aerosil ( 1 . 5 g , the weight equivalent to 0 . 6 % of tablet weight ), microcrystalline cellulose 26 . 00 g , crospovidone 6 . 00 g , 17 . 00 g hydrogenated vegetable oil and sodium lauryl sulphate . then compression with tablet weight 250 mg and diameter 9 mm . 97 . 88 g clopidogrel bisulfate was premixed with aerosil , ( 0 . 75 g , equivalent to 0 . 3 % of tablet weight ), then mixed with lactose 60 . 00 g , microcrystalline cellulose 40 . 00 g . adding the 10 % prepared hydroxypropyl cellulose solution to and granulation . the granules were dried and blended with microcrystalline cellulose 26 . 00 g , crospovidone 6 . 00 g , 17 . 00 g hydrogenated vegetable oil and sodium lauryl sulphate . then compression with tablet weight 250 mg with diameter 9 mm . 97 . 88 g clopidogrel bisulfate was premixed with aerosil ( 0 . 75 g , equivalent to 0 . 3 % of tablet weight ), then mixed with lactose 60 . 00 g , microcrystalline cellulose 40 . 00 g . adding the 10 % prepared hydroxypropyl cellulose solution and granulation . the granules were dried and blended with aerosil ( 0 . 75 g , equivalent to 0 . 3 % of tablet weight ), microcrystalline cellulose 26 . 00 g , crospovidone 6 . 00 g , 17 . 00 g hydrogenated vegetable oil and sodium lauryl sulphate . then compression with tablet weight 250 mg with diameter 9 mm . 97 . 88 g clopidogrel bisulfate was premixed with aerosil ( 2 . 50 g , equivalent to 1 . 0 % of tablet weight ), then mixed with lactose 60 . 00 g , microcrystalline cellulose 40 . 00 g . adding the 10 % prepared hydroxypropyl cellulose solution and granulation . the granules were dried and blended with aerosil ( 0 . 75 g , equivalent to 0 . 3 % of tablet weight ), microcrystalline cellulose 26 . 00 g , crospovidone 6 . 00 g , 17 . 00 g of hydrogenated vegetable oil and sodium lauryl sulphate . then compression with tablet weight 250 mg with diameter 9 mm and coated . 97 . 88 g clopidogrel bisulfate was premixed with aerosil ( 5 . 00 g , equivalent to 2 . 0 % of tablet weight ), then mixed with lactose 60 . 00 g , microcrystalline cellulose 40 . 00 g . adding the 10 % prepared hydroxypropyl cellulose solution and granulation . the granules were dried and blended with aerosil ( 0 . 75 g , equivalent to 0 . 3 % of tablet weight ), microcrystalline cellulose 26 . 00 g , crospovidone 6 . 00 g , 17 . 00 g of hydrogenated vegetable oil and sodium lauryl sulphate . then compression with tablet weight 250 mg with diameter 9 mm . according to the formula and technology of international publication wo2008059298 , premixing the aerosil ( 5 . 00 g , equivalent to 1 . 56 % of tablet weight ) with microcrystalline cellulose 50 g and passed through 0 . 5 mm sieve . this mixture is further blended with clopidogrel bisulfate 97 . 9 g , 144 . 2 g microcrystalline cellulose , 12 gl - hpc , 12 g hydrogenated vegetable oil . blending speed is 20 rpm and blending time is 20 minutes . then compression with tablet weight 320 mg with diameter 10 mm . according to the preparation described in example 1 , clopidogrel bisulfate tablet without aerosil shows sticking on the punch soon after starting compression . according to the preparation described in example 2 , clopidogrel bisulfate tablet with aerosil ( weight equivalent to 0 . 6 % of tablet weight ) still shows sticking on punch after 10 minutes of compression . according to the preparation described in example 3 , clopidogrel bisulfate premixing with aerosil ( weight equivalent to 0 . 3 % of tablet weight ), the tablet sticking decreases during compression . according to the preparation described in example 4 , clopidogrel bisulfate premixing with aerosil ( weight equivalent to 0 . 3 % of tablet weight ) and the same quantity of aerosil in the external phase , the sticking decreased during compressing similar to example 3 . according to the preparation described in example 5 and example 6 , clopidogrel bisulfate premixed with aerosil ( weight equivalent to 1 . 0 % - 2 . 0 % of tablet weight ) and external phase aerosil ( weight equivalent to 0 . 3 % of tablet weight ), the tablets showed no sticking on punch . according to the preparation described in example 7 , aerosil premixed with microcrystalline cellulose at the ratio of 1 : 10 and sieved , the quantity of aerosil is equivalent to 1 . 56 % of tablet weight , then mixed with clopidogrel bisulfate raw materials and other excipients . the tablet is sticking on punch during compression . | US-201213567676-A |
a high performance coil over - core guide wire . the guide wire incorporates a nickel - titanium core with a stainless steel coil to provide a wire with improved kink resistance and good pushability . | the following detailed description should be read with reference to the drawings in which like elements in different drawing are numbered identically . the drawings , which are not necessarily to scale , depict selected embodiments and are not intended to limit the scope of the invention . examples of constructions , materials , dimensions , and manufacturing processes are provided for selected elements . all other elements employ that which is known to those skilled in the field of the invention . those skilled in the art will recognize that many of the examples provided have suitable alternatives that may also be used . fig1 shows a first embodiment of the guide wire 10 . core 20 may be 50 - 450 cm in length and 0 . 008 - 0 . 038 inches in diameter depending on the medical application . the distal portion 25 of core 20 may be tapered to provide flexibility to guide wire 10 . preferably the tapered distal portion 25 is formed by grinding 5 - 20 cm of core 20 . the tapered distal portion 25 may be ground into a conical shape with a circular cross - section or stamped such that it has a rectangular cross - section . core 20 may be formed of a super - elastic material such as the alloys of nickel and titanium , commonly known as nitinol . while nitinol is the most common super - elastic material , any of a variety of other super - elastic materials may be used for core 20 . other alloys by chemical name include ; cualni , cusn , cuzn , inti , nial , fept , mncu , and femnsi . a detailed discussion of super - elastic alloys and their processing is presented in u . s . pat . no . 4 , 925 , 445 to sakamoto and is herein incorporated by reference . in addition to super - elastic materials , linear - elastic materials may be used . linear - elastic materials are describe in u . s . pat . no . 5 , 238 , 004 to sahatjian which is also incorporated by reference . in general , linear - elastic materials are composed of the same alloys above . however , different material processing strategies are used to provide a wire which has many of the important characteristics of a super - elastic material without some of the difficulties related to machining , specifically grinding . as such , core 20 may preferably be formed of a linear - elastic alloy of nickel - titanium . surrounding core 20 is coil 30 . coil over core wires are well known in the art and are described in detail in u . s . pat . no . 5 , 147 , 317 to shank which is incorporated by reference . coil 30 may be made of a variety of metallic materials including super - elastic or linear - elastic materials such as nitinol , radio - opaque materials such as gold or tungsten , precipitation hardenable alloys such as the non - ferrous cobalt - based alloys mp35n or elgiloy ™ and the ferrous alloys such as k91 from sanvic corp . and ph455 from carpenter , or more conventional stainless steel alloys such as 304 . preferably coil 30 may be 0 . 001 - 0 . 015 inches in diameter , and made of 304 stainless steel . coil 30 is wrapped around substantially the entire length of core 20 . preferably , coil 30 is not wrapped around the tapered distal portion 25 of core 20 . coil 30 may be formed of flat ribbon ranging in dimensions 0 . 001 - 0 . 003 inches in thickness by 0 . 005 to 0 . 015 inches in width . coil 30 is wrapped in a helical fashion about core 20 by conventional winding techniques . the pitch of adjacent turns of coil 30 may be tightly wrapped so that each turn touches the succeeding turn or the pitch may be set such that coil 30 is wrapped about core 20 in an open fashion shown at 35 . preferably , the pitch coil 30 is such that the coils are tightly wrapped over most of the proximal portion of core 20 with the pitch of each turn changing such that coil 30 has an open wrap shown at 35 near the distal end of core 20 . varying the pitch of coil 30 allows guide wire 10 to have a more flexible distal segment . alternatively , coil 30 may be formed of cross - wound multifilar or multifilar single coil wire . multifilar cross - wound coils are described in u . s . pat . no . 4 , 932 , 419 to de toledo which is herein incorporated by reference . a cross - wound multifilar coil consists essentially of a first inner coil of multiple coil wires wound in a first helical direction and a second outer coil of multiple coil wires disposed about the first coil and wound in a second opposite helical direction . coil over core wires tend to wind up and store energy when torqued rather than transmitting the torque . multifilar coils provides less wind up and therefore lessen the potential for the distal tip of the wire to whip while the proximal end is being turned . bonding core 20 to coil 30 also improves the torque transmission of guide wire 10 . coil 30 may be bonded to core 20 along the length of core 20 or in discrete sections . bonding may be achieved in a variety of ways including using adhesives , brazing , is welding , crimping , and swaging . welding may be done through any of the techniques known in the art including spot welding using laser or resistance welding or ball welding using laser or plasma welding . soldering may be done through any of the techniques known in the art and must include the step of preparing the surface of the nitinol core 20 by plating or etching . preferably the coil 30 will be bonded to the core 20 by laser spot welding thereby removing the need for preparing the surface of the core 20 . laser spot welding is also advantageous because it may be done through coatings . an alternative method of bonding the coil 30 to the core 20 is to provide a stainless steel hypotube ( not shown ) with an inner diameter dimensioned to closely fit about core 20 . the stainless steel hypotube may then be crimped onto core 20 and the coil 30 wound about the hypotube . the hypotube then provides a surface which is much easier to bound to a stainless steel coil 30 using conventional methods . metal a foils or other materials may also be used as an intermediate which facilitates bonding between the coil 30 and the core 20 . yet another bonding method utilizes the polymer jacket 40 of the distal tip . the polymer may be applied in a manner that allows the polymer to flow between the coil and core . the polymer will provide a high integrity bond which will help to prevent the polymer jacket from separating from the coil 30 and bond the coil to core 20 . in addition to the these improvements , the polymer coating will make a better transition from the core 20 to the distal portion 25 . a tip bonded in this manor provides a further improvement by producing coloration differences between the coil wire and polymer . these differences act as stripes for the detection of guidewire advance in endoscopy application . the distal portion 25 of core wire 20 may further include a polymer tip 40 . polymer tip 40 serves several functions . polymer tip 40 improves the flexibility of the distal portion 25 of core wire 20 . choice of polymers for polymer tip 40 will vary the flexibility of the distal portion 25 of core wire 20 . for example , polymers with a low durometer or hardness will make a very flexible or floppy tip . conversely , polymers with a high durometer will make a wire tip which is stiffer . polymer tip 40 also provides a more atraumatic tip for guide wire 10 . an atraumatic tip is better suited for passing through fragile body passages . finally , polymer tip 40 may act as a binder for radio - opaque materials . loading polymers with radio - opaque materials is well known in the art for producing a bright image under fluoroscopy and thereby allowing the user of guide wire 10 a better understanding of where the distal portion 25 of guide wire 10 is located within a patient &# 39 ; s body . suitable medical grade radio - opaque materials include tungsten , platinum , and iridium . suitable polymeric materials for polymer tip 40 include urethanes , elastomeric nylons such as pebax , silicones , and co - polymers . polymer tip 40 may be a single polymer , multiple layers , or a blend of polymers . coating ( not shown ) may also be done to the wire proximal to polymer tip 40 . hydrophobic coatings such as fluoropolymers provide a dry lubricity which improves guide wire handling and device exchanges . a second lubricious polymer ( not shown ) may coat distal portion 25 of guide wire 10 or the entire wire 10 . lubricious coatings improve steerability and improve lesion crossing capability . suitable lubricious polymers are well known in the art and may include hydrophilic polymers . guide wire 10 may further include a colored coating . colored guide wires are described in detail in u . s . pat . no . 5 , 739 , 779 to rowland which is herein incorporated by reference . in general , colored coatings may improve the visibility of the guide wire when it is being used in an endoscopic procedure . striping may also be done . striping allows the physician to gauge wire movement and position . striping may be achieved by spray coating different colors on the wire 10 . another way to stripe the wire 10 is to coat the wires of coil 30 prior to winding . fig2 depicts a second embodiment of the high performance coil wire where like elements are similarly numbered . all design advantages , materials of construction , and methods of manufacture are similar to those described above unless explicitly modified below . guide wire 10 is comprised of a solid core 20 surrounded by a coil 30 . the distal portion 25 of core 20 may be tapered as described above or preferably is not tapered . similar to the embodiment of fig1 the distal portion 35 of coil 30 changes pitch to provide a softer less traumatic tip . guide wire 10 further includes a rounded tip 37 . tip 37 may be polymeric or a metal tip welded to the distal portion 35 of coil 30 . unlike common spring tipped guide wires , guide wire 10 does not have a safety ribbon connecting core 20 to tip 37 . instead guide wire 10 may include a polymer 40 which may be flowed into the space between coils 35 and the space between the distal portion 25 and tip 37 . suitable polymers are described above where choice of polymer may control the flexibility of the tip . polymer 40 may also be loaded with radio - opaque materials . finally , guide wire 10 may be coated as described above and may also include various colors or stripes . the distal portion of guide wire 10 is thereby provided with a very floppy tip which uses polymer 40 as a safety ribbon instead of a metallic safety ribbon . guide wire 10 is provided with the advantage that core 20 does not need to be ground . while the specification describes the preferred designs , materials , methods of manufacture and methods of use , those skilled in the art will appreciate the scope and spirit of the invention with reference to the following claims . | US-7894698-A |
what is provided is a fixation system that offers a strong and stable construct for maximum fusion augmentation and yet is versatile enough for any patient and is easy to use . disclosed is a connection assembly for connecting a spinal implant , the assembly comprising : a body , the body including a body opening for receiving at least a portion of a first connector ; a swivel having first and second ends and being operatively connected to the body , the first end including a swivel opening for receiving at least a portion of a second connector ; a locking plate having an arm at least partially extending into the body opening ; a locking unit operatively connected to the body and contacting the second end of the swivel ; and whereby activation of the locking unit causes the arm to engage the first connector and swivel opening to engage the second connector thereby preventing relative rotation between the first and second connectors . | detailed descriptions of one or more preferred embodiments are provided herein . it is to be understood , however , that the present invention may be embodied in various forms . therefore , specific details disclosed herein are not to be interpreted as limiting , but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in any appropriate system , structure or manner . fig5 - 7 illustrate the process of fusing two vertebrae 800 , 810 using a plurality of clamps 10 a , 10 b , 10 c , and 10 d of the construction shown in fig1 - 4 . all clamps 10 can be of substantially identical construction ( however , clamps 10 a , 10 b are shown as mirror images of clamps 10 c , 10 d to have both rods 80 a , 80 b set between the clamps ). the operation of clamp 10 a will be described in specific detail . in each case , for an effective fusion , vertebra 800 is held in contact with vertebra 810 . in its simplest form , clamp 10 a can be mechanically connected to vertebra 810 and a second clamp 10 b can be mechanically connected to vertebra 800 . this mechanical connection can be achieved by means of screws 20 or other fasteners which are compatible with vertebrae and the human body and installed by a driver 24 . clamp 10 a and 10 b can be mechanically connected to each other by rod 80 a . on the opposite side of vertebrae 800 , 810 a second set of clamps 10 c , 10 d and rod 80 b can be used to mechanically connect vertebrae 800 , 810 . these two clamps can be placed over screws 20 c , 20 d as schematically indicated by arrows 28 , 27 . a driver 24 can be used to mechanically lock each clamp through tightening of the clamp &# 39 ; s set screw by turning in the direction of arrow 26 . the two rods 80 a , 80 b can be mechanically connected to each other for additional support . over a period of time , after being mechanically connected , the bone in vertebrae 800 , 810 will grow or fuse together thus completing the fusion . fig1 and 2 are exploded views of a preferred clamp 10 ( showing two examples of the clamp 10 a , 10 b ). although constructed similar to each other the individual components of clamp 10 a and clamp 10 b will be differentiated by the addition of an “ a ” or a “ b .” clamp 10 can be used to mechanically connect bone screws 20 with rods 80 . clamp 10 can comprise body 130 , locking plate 120 , rod disc 110 , and swivel 100 . set screw 150 and retainer 140 can be used to lock in place swivel 100 , rod clamp 110 , and locking plate 120 ( which can be assembled in the direction of arrow 815 as shown in fig1 ). alternatively , set screw 150 can be used by itself without retainer 140 . screw 20 can be connected to body 130 through bore 540 . rod 80 can be connected to body 130 through opening 210 . the mechanics of the connections with rod 80 and screw 20 will be described below . during installation each clamp 10 preferably is adjustable in various directions with respect to rod 80 and screw 20 ( as schematically indicated by fig3 ). fig3 shows clamp 10 having screw 20 and rod 80 mounted . because of variations when inserting screw 20 in a specific vertebra , clamp 10 is provided with various adjustment options related to screw 10 . for screw 20 the two principal adjustment options are indicated by arrows 840 , 850 . the longitudinal axis of screw 20 is shown parallel to arrow 840 . rod 80 is shown being parallel to arrow 820 . when clamp 10 is not tightened body 130 can slide relative to screw 20 in both directions indicated by arrow 840 . also when clamp 10 is not locked , body 130 can rotate relative to screw 20 in both directions indicated by arrow 850 . for rod 80 the three principal adjustment options are indicated be arrows 820 , 860 , 870 . when clamp 10 is not locked , rod 80 can slide relative to body 130 in both directions indicated by arrow 820 . additionally , when not locked , rod 80 can rotate relative to body 130 in both directions indicated by arrow 870 and both directions indicated by arrow 860 . the above described possible relative movements between rod 80 and body 130 along with the relative movements between body 130 and screw 20 provide adjustability between rod 80 and screw 20 . the relative movement between rod 80 and screw 20 facilitates fixation of two or more clamp 10 members regardless ofthe relative positions ( angular , height , location ) of respective screws 20 . for example , as shown in fig5 - 7 , clamps 10 a , 10 b can be connected to rod 80 a even where screws 20 a , 20 b are not parallel to each other and are not at the same relative height . fig4 is a top view of a portion of clamp 10 showing rod 80 inserted into opening 210 of swivel 100 and swivel 100 inserted into rod disc 110 . rod 80 can sit in recess 310 . fig3 is a perspective view of clamp 10 showing bone screw 20 inserted into bore 540 of body 130 with locking plate 120 lying on top of body 130 . fig3 and 4 illustrate how arm 440 of locking plate 120 enters opening 530 of body 130 to engage bone screw 20 . also shown is tapped bore 510 wherein set screw 150 enters to lock clamp 10 . below the individual components of clamp 10 ( including body 130 , locking plate 120 , rod disc 110 , and swivel 100 ) will be described in specific detail . swivel 100 can comprise base 240 , shaft 230 , mid portion 220 , and head 200 . base 240 can be circular and include beveled or angled edge 250 and bottom 260 . beveled or angled edge 250 can be used as the contact point of set screw 150 ( when set screw 150 is tightened in the direction of arrow 890 , swivel 100 is pulled in the direction of arrow 880 thereby locking clamp 10 — see fig3 ). the top of head 200 can have a rectangular cross section with rounded edges . shaft 230 can include a circular cross section which is smaller than base 240 . mid portion 220 can include a circular cross section which is larger than shaft 230 . head 200 can include opening 210 , face 270 , and a plurality of edges 272 , 274 . rod disc 110 can include top 300 and bottom 340 . on bottom 340 can include a plurality of teeth 350 . recess 310 can be included on top 300 . first bore 320 can pass from top 300 to bottom . second bore 330 can be included which starts at the top but stops before hitting the bottom . first bore 320 can be circular . second bore 330 is preferably a non - circular shape to restrict relative rotation between rod disc 110 and swivel 100 ( head 200 of swivel 100 can seat in second bore 330 ). second bore 300 can operatively connect with head 200 of swivel 100 . rod 80 can seat in recess 310 when at least partially inserted in opening 210 . when clamp 10 is locked , rod 80 can be frictionally engaged between opening 210 and recess 310 . also when clamp 10 is locked , plurality of teeth 350 of rod disc 110 can be engaged with plurality of teeth 420 of locking plate 120 thereby preventing relative rotation between rod disc 110 and locking plate 120 . in a preferred embodiment seventy two teeth are used , but the number can vary based on size and strength considerations . using sixty teeth 420 provide positioning approximately every six degrees while seventy two teeth 420 provide positioning approximately every five degrees . locking plate 120 can include arm 440 and bore 410 . arm 440 can include cup 450 which includes plurality of ribs 452 . plurality of ribs 452 can be used to prevent relative rotation between bone screw 20 and arm 440 ( and also body 130 ). when arm 440 of locking plate 120 enters opening 530 of body 130 , relative rotation between locking plate 120 and body 130 is restricted . body 130 can include transverse bore 500 for insertion of base 240 of swivel 100 . longitudinal bore 540 can be included for receiving screw 20 . longitudinal bore 540 can include plurality of ribs 570 . plurality of ribs 452 can be used to prevent relative rotation between bone screw 20 and body 130 . plurality of ribs 452 can be placed on only a radial portion of longitudinal bore 540 ( and not around the complete radius of bore 540 ). recessed area 520 can be included to receive locking plate 120 . opening 530 can be included to receive arm 440 of locking plate 120 . body 130 can include threads 550 in tapped bore 510 . at the base of tapped bore 510 can be included bore 590 and edge 560 . fig1 a shows an enlarged perspective view of retainer 140 . retainer 140 can include top 600 , shaft 610 , first edge 620 , second edge 630 , curved surface 640 , and bottom 650 . shaft 610 can be inserted in bore 590 of body 130 ( see fig1 , and 4 ). retainer 140 can be used to provide support for set screw 150 , when set screw 150 is contacting base 240 of swivel 100 . shaft 610 of retainer 140 can be press fit into bore 590 as a means for retaining swivel 100 in body 130 when set screw 150 is not tightened . when press fit into body 130 , first edge 620 of retainer 140 can operatively engage beveled edge 250 of swivel 100 thereby preventing swivel 100 from being removed complete from bore 500 of body 130 . retainer 140 can be used to prevent the various pieces of clamp 10 from coming apart during use and possibly being lost in a patient . however , swivel 100 preferably has enough play that swivel 100 along with rod disc 110 can rotate relative to locking plate 120 and body 130 . alternatively , retainer 140 can be connected to body 130 in various ways , such as welding , adhesives , along with other conventionally available connection methods . set screw 150 can include top 700 , angled tip 715 , threads 720 , and star socket 710 . set screw 150 can be threaded into tapped bore 510 of body 130 . other means of tightening set screw 150 besides star socket 710 can be used , such as a phillips head ; flat head ; bolt head , allen wrench head . screw 20 can include shank 30 and course threaded portion 40 . for tightening screw 20 can also include star socket 70 . other means of tightening screw 20 besides star socket 70 can be used , such as a phillips head ; flat head ; bolt head , allen wrench head . rod 80 can be a shaft and include a circular cross section . the locking mechanism of clamp 10 will now be described . clamp 10 can comprise body 130 , locking plate 120 , rod disc 110 , and swivel 100 . set screw 150 can be used to lock in place swivel 100 , rod clamp 110 , and locking plate 120 . rod 80 can be connected to body 130 through opening 210 of swivel 100 . bone screw 20 can be connected to body 130 through bore 540 . before set screw 150 is tightened ( locking clamp 10 ) both rod 80 and bone screw 20 can be adjusted in all directions as described in the discussion of fig3 . however , after set screw 150 is used to lock clamp 10 , both rod 80 and screw 20 will be held firmly in place . to assemble clamp 10 , base 240 of swivel is placed through first bore 320 of rod disc 110 , through bore 410 of locking plate 120 , and then through bore 500 of body 130 . arm 440 of locking plate 120 enters opening 530 of body 130 , thereby preventing relative rotation between body 130 and locking plate 120 . plurality of teeth 420 of locking plate 120 are facing plurality of teeth 350 of rod disc 110 , however , when clamp 10 is not locked these two sets of teeth do not engage each other and rod disc 110 can rotate relative to locking plate 120 . when locked these two sets of teeth engage each other preventing relative rotation . part of head 200 of swivel 100 sits in second bore 330 of rod disc 110 and head 200 will rotate with rod disc 110 . recess 310 of rod disc 110 preferably is aligned with opening 210 of swivel 100 . such alignment will allow rod 80 to at least be partially inserted in opening 210 and rest in recess 310 . recess 310 preferably confirms with the shape of rod 80 . rod 80 can be at least partially inserted into opening 210 of swivel 100 . bone screw can be inserted at least partially into bore 540 of body 130 . when clamp 10 is not locked , rod 80 can slide relative to opening 210 ( and therefore relative to clamp 10 ). also when not locked rod 80 can rotate relative to clamp 10 because swivel 100 and rod disc 110 can rotate relative to body 130 . when not locked screw 20 can slide relative to body 130 ( and therefore relative to clamp 10 ). also when not locked screw 20 can rotate inside of bore 540 of body 130 . to lock clamp 10 , set screw 150 can be threaded into tapped bore 510 . tip 715 of set screw 150 will contact base 240 of swivel 100 causing swivel 100 to be pulled further into bore 500 of body 130 . pulling swivel 100 into body 130 causes plurality of teeth 420 of locking plate 120 to engage plurality of teeth 350 of rod disc 110 thereby preventing relative rotation between rod disc 110 and locking plate 120 . because locking plate 120 is restricted from rotating relative to body 130 ( via arm 440 of locking plate 120 being at least partially inserted in opening 530 of body 130 ) rod disc 110 will also be restricted from so rotating . head 200 of swivel 100 at least partially seating in second bore 330 of rod disc 110 also prevents relative rotation of swivel 100 in relation to body 130 . swivel 100 being pulled inside of body 130 also causes rod 80 to be frictionally engaged between bore 210 of swivel 100 and recess 310 of rod disc 110 . in effect rod 80 is squeezed between rod disc 110 and bore 210 . when frictionally engaged rod 80 is restricted from moving relative to body 130 in all manners ( e . g ., sliding or rotating ). swivel 100 being pulled further into bore 500 of body 130 causes bore 210 to pull on rod 80 , rod 80 then pushes on rod disc 110 , rod disc 100 then pushes on locking plate 120 , arm 440 of locking plate 120 then pushes through opening 530 on screw 20 . screw 20 is thereby frictionally engaged between arm 440 of locking plate 120 and bore 540 of body 130 . when frictionally engaged screw 20 is restricted from moving relative to body 130 in all manners ( e . g ., sliding or rotating ). in such manner both rod 80 and screw 20 can be securely held in clamp 10 . a single version clamp 10 has been disclosed . preferably , both left and right hand versions of clamp 10 will be used on the left and right hand sides of a fusion . persons of ordinary skill in the art will understand the mechanics of making left and right hand versions of clamp 10 . fig6 and 7 show left and right hand versions of clamps 10 . clamps 10 a and 10 b are left hand versions and clamps 10 c and 10 d are right hand versions . left and right hand versions are used to have a symmetry between positioning of screws 20 and heads 100 of swivels 100 . if only a single version of clamp 10 was used the clamps 10 used on the left hand side would appear to be offset from the clamps used on the right hand side . an alternative method of allowing a single clamp 10 to be used as both a left and right hand version is to have tapped bore 510 extend completely through body 130 . to switch from the left to right hand version in this alternative embodiment , set screw 150 is switched from entering tapped bore 510 on opposite sides . list for reference numerals ( part no .) ( description ) 10 clamp 20 screw 24 driver 26 arrow 27 arrow 28 arrow 30 shank 32 ribs 40 coarse thread 50 fine thread 60 mid portion 70 star socket 80 rod 100 swivel 110 rod disc 120 locking plate 130 body 140 retainer 150 set screw 200 head 210 opening 220 mid - portion 230 shaft 240 base 250 beveled edge 260 bottom 270 face 272 edge 274 edge 300 top 310 recess 320 first bore 330 second bore 340 bottom 350 plurality of teeth 400 top 410 bore 420 plurality of teeth 430 edge portion 440 arm 450 cup 452 plurality of ribs 453 angle 454 angle 460 bottom 500 bore 510 tapped bore 520 recessed area 530 opening 540 bore 550 threads 560 edge 570 plurality of ribs 580 angle 590 bore 600 top 610 shaft 620 first edge 630 second edge 640 curved surface 650 bottom 700 top 710 star socket 715 tip 718 point 720 threads 800 vertebra 810 vertebra 815 arrow 820 arrow 830 arrow 840 arrow 850 arrow 860 arrow 870 arrow 880 arrow 890 arrow all measurements disclosed herein are at standard temperature and pressure , at sea level on earth , unless indicated otherwise . all materials used or intended to be used in a human being are biocompatible , unless indicated otherwise . the components of the clamp 10 are preferably constructed from titanium grade 6al - 4veli which is a standard medical grade of titanium . the type and heat treatment of material can be determined by those of ordinary skill in the art based on the stress and forces encountered by the individual components . however , other materials can be used which are compatible with the body . for example surgical steel can be used along with polymers of sufficient strength . it will be understood that each of the elements described above , or two or more together may also find a useful application in other types of methods differing from the type described above . without further analysis , the foregoing will so fully reveal the gist of the present invention that others can , by applying current knowledge , readily adapt it for various applications without omitting features that , from the standpoint of prior art , fairly constitute essential characteristics of the generic or specific aspects of this invention set forth in the appended claims . the foregoing embodiments are presented by way of example only ; the scope of the present invention is to be limited only by the following claims . | US-35097206-A |
a concussive injury micronutrient formulation is provided and the formulation comprises vitamin a , vitamin e , natural mixed carotenoids , vitamin c , vitamin d , coenzyme q10 , alpha lipoic acid , n - acetyl cysteine , acetyl l - camitine , vitamin b , folic acid , calcium , magnesium , selenium , chromium , biotin , zinc , and omega - 3 fatty acids . the formulation is to be taken orally by humans and taken twice a day . | as required , detailed embodiments of the present invention are disclosed herein ; however , it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various forms . the figures are not necessarily to scale , some features may be exaggerated to show details of particular components . therefore , specific structural and functional details disclosed herein are not to be interpreted as limiting , but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention . the specific example below will enable the invention to be better understood . however , they are given merely by way of guidance and do not imply any limitation . traumatic brain injury ( tbi ) occurs when sudden trauma causes damage to the brain . tbi can occur with or without penetrating head injury . tbi without penetrating head injury is known as a concussive brain injury that may be expressed as a mild , moderate or severe form . a concussion occurs when the brain is violently rocked back and forth within the skull following a blow to the head or neck , such as observed in vehicular accidents and contact sports like football , or when the victim is in close proximity to a concussive blast pressure wave , such as in industrial or combat - related circumstances . because there is no penetration of the skull , concussive brain injury may be difficult to identify after the inciting event . therefore prevention strategies and standardized treatment guidelines remain elusive . this patent exploits an understanding of the mechanisms of cellular damage , the biological events that impact long - term neurologic outcomes , and the application of antioxidant science to develop a rational strategy for reducing the progression of tbi . both experimental and human studies suggest that increased levels of oxidative stress from excessive production of free radicals ( 1 - 5 ), products of uncontrolled acute and chronic inflammation ( 6 - 12 ) and release of a neurotoxic substance , glutamate , in the brain are involved in the progression of damage following concussive injury , and contribute to the initiation and progression of brain damage . these observations are supported by the fact that individual antioxidants ( known to neutralize free radicals , reduce inflammation , and prevent the release and toxicity of glutamate ), have reduced damage when administered either before or soon after concussion ( 2 , 4 , 13 , 14 ). the expression of oncogene proteins , c - myc and c - fos , is elevated in rat brains after concussion ( 15 , 16 ), and cortical expression of nuclear factor kappa b ( nf - kappa b ) is elevated in human contused brain ( 17 ). the fact that antioxidants and their derivatives reduce expression of c - myc oncogene ( 18 ) and activation of nf - kappa b ( 19 ), further suggests their value in reducing brain damage following concussive injury . this application presents the scientific rationale and evidence that a specific formulation of multiple micronutrients , including dietary and endogenous antioxidants and glutathione - elevating agents , may prevent and improve standard therapy for tbi , and defines the composition , dosage , and dose schedule that most effectively impacts the acute - and long - term management of concussive brain injury . annually , about 1 . 4 million people in the u . s . suffer from tbi , of which 1 . 1 million are treated and released from an emergency department , 235 , 000 are hospitalized , and 50 , 000 die ( 20 ). among children ages 0 to 14 years , concussive brain injuries cause 2685 deaths , 37 , 000 hospitalizations and 435 , 000 emergency room visits each year . the cdc injury center has estimated that about 3 . 8 million sports - and recreation - related concussions occur annually in the u . s . in total , at least 5 . 3 million americans who suffered from a tbi have long - term or life - long need for assistance to perform the routine activities of daily living . the cost per year per person with mild tbi is about $ 32 , 000 ; with moderate to severe tbi , it is from about $ 268 , 000 to more than $ 408 , 000 . in 2000 , the direct medical costs and indirect costs such as lost productivity because of concussive brain injury were estimated to be $ 60 billion in the u . s . ( 21 ). in the military , this is becoming a serious issue as about 30 % of all soldiers with combat - related injuries seen at walter reed army medical center from 2003 to 2005 sustained a concussive blast . by 2011 , about 320 , 000 soldiers who served in iraq and afghanistan suffered a tbi . symptoms of concussive injury can be mild , moderate or severe , depending upon the extent of damage to the brain . individuals with a mild tbi may remain conscious or may become unconscious for a few second or minutes , and may exhibit headache , confusion , lightheadedness , dizziness , blurred vision , tinnitus ( ringing in the ears ), fatigue , alterations in sleeping patterns , mood changes , trouble with memory , concentration , and thinking . individuals with a moderate or severe tbi can suffer additional symptoms including a headache that gets worse or remains persistent , repeated vomiting or nausea , convulsions or seizures , an inability to awaken from sleep , dilation of one or both pupils of the eyes , slurred speech , weakness or numbness in the extremities , loss of coordination , and increased confusion , restlessness or agitation . this impact on long - term quality of life may affect individuals with tbi for extended periods of time . despite evolutionary changes in protective equipment , concussive injuries remain a major health risk for those who engage in potentially violent sports ( 22 , 23 ) or hazardous occupations , including military combat . cerebral concussion is a type of tbi that is normally produced by acceleration and deceleration of the head . it can also happen during the rapid displacement and rotation of the cranium after peak head acceleration and momentum transfer by helmet impacts ( 24 ). it is characterized by a sudden brief impairment of consciousness , paralysis of reflex activity and loss of memory . sport - related concussions have been classified into simple and complex concussions ( recommendation of the second international conference on concussion in sport , 2005 ). athletes who are slow to recover ( i . e ., greater than 10 days ) are classified having complex concussions . brain deformation may occur after the primary head acceleration ( 24 ). damage to the mid brain correlated with memory and cognitive problems after concussion . the major depression commonly observed after concussion contributes to impairment of memory , processing speed , verbal memory and executive function ( 25 - 27 ). an early onset of dementia may be initiated by repetitive cerebral concussions in professional football players ( 28 , 29 ). balance disorders are also considered one of the major health problems associated with the tbi ( 29 , 30 ). current efforts on reducing the impact of concussion have focused on the development of physical protection . indeed , the introduction of newer football helmets appears to lower the risk of concussion by about 10 - 20 % ( 30 ). extensive evaluation of the relationship between post - traumatic stress disorder ( ptsd ) and concussive brain injury has been demonstrated in two recent epidemiologic studies in u . s . soldiers returning from iraq and afghanistan ( 31 , 32 ). among 2525 soldiers , 4 . 9 % reported injury with loss of consciousness , 10 . 3 % reported injuries with altered mental status , and 17 . 2 % reported other injuries during deployment . among those who reported loss of consciousness , the incidence of ptsd was about 43 . 9 %. among those reporting altered mental status , it was 27 . 3 %, and among those reported other injuries , it was 16 . 2 %. in contrast , among those soldiers reporting no injury in combat , the incidence of ptsd was only 9 . 1 %. this patent describes a novel biological protection strategy to reduce the acute and long - term impact of concussion and would be complimentary to existing physical protection . the development of this strategy is based on the biochemical events that initiate damage and that contribute to the progression of damage following concussion . both animal and human studies show that tbi causes a significant loss of cortical tissue at the site of injury ( primary damage ). this is followed by secondary damage involving increased oxidative damage , mitochondrial dysfunction , release of predominantly pro - inflammatory cytokines and toxic levels of glutamate leading to cognitive impairment and neurological dysfunction . therefore , attenuation of these biochemical events may help to reduce the onset and progression of damage . increased oxidative stress due to production of excessive amounts of free radicals derived from oxygen and nitrogen occur after concussions ( 33 - 36 ). the extent of oxidative damage appeared to be directly proportion to the severity of tbi ( 37 ). in rats , there appears to be a close relationship between the degree of oxidative stress and severity of brain damage following concussive brain injury as evidenced by the high levels of malondialdehyde ( lipid peroxidation marker of oxidative damage ) and low levels of ascorbate ( antioxidant vitamin ) ( 38 ). tbi induced peroxynitrite - mediated oxidative damage to mitochondrial function that precedes neuronal loss in the brain . the oxidation of nitric oxide ( no ) forms peroxynitrite . animal studies show that tbi increased no production that impairs mitochondrial function by inhibiting cytochrome oxidase ( 39 ). cytochrome oxidase is a key enzyme needed to generate energy . thus , the energy level in tissue decreased after concussive injury and this may interfere with repair processes . tbi also increased inducible nitric oxide synthase ( inos ) activity that contributes to neurological deficits by generating excessive amounts of no ( 40 ). in a rat model of traumatic injury ( unilateral moderate cortical contusion ), increased oxidative damage occur as early as 3 hours following tbi that adversely affects synaptic function and neuronal plasticity , and thereby , enhances cognitive dysfunction ( 41 ). in another model of tbi ( fluid percussion brain injury in rat ), it was observed that levels of oxidative stress increased in the cortex of the brain when measured one and three months following injury . human studies also confirm the role of oxidative stress in the progression of tbi . f2 - isoprostane is a marker of lipid peroxidation , whereas neuron - specific enolase ( nse ) is considered a marker of neuronal damage . the levels of f2 - isoprostane and nse increased in the cerebral spinal fluid ( csf ) following concussive brain injury in children and infants ( 42 ). the levels of the antioxidants ascorbate and glutathione decreased in the csf of children and infants following tbi ( 43 ). it has also been reported that the levels of beta - amyloid fragment ( a beta - 42 ) increased in the csf of patients after severe concussive brain injury ( 44 ). this peptide has been implicated in causing neuronal damage in patients with alzheimer &# 39 ; s disease ( 45 - 48 ). increased oxidative stress contributes to the mitochondrial dysfunction that plays a central role in causing cognitive impairment and eventually cell death following tbi ( 49 , 50 ). in a rat model , several mitochondrial proteins involved in bioenergetics were oxidized following injury causing mitochondrial dysfunction ( 51 ). in another rat model , it was found that the activity of the mitochondrial enzymes decreased , while acid - base balance was disrupted and levels of oxidative stress increased in the blood following concussions . these changes contribute to the severity of brain injury . generally , oxidative stress - induced mitochondrial dysfunction is observed one to three hours after tbi , suggesting the importance of early intervention to reduce the oxidative stress ( 52 ). there is a direct link between energy metabolism and n - acetylaspartate . in a human clinical study involving 14 patients ( 6 patients with diffuse brain injury and 8 with focal brain lesions ), it was observed that reduction in the brain levels of n - acetylaspartate in the absence of ischemic insult reflected mitochondrial dysfunction ( 53 ). following tbi , brain cells generate excessive amounts of pro - inflammatory cytokines , prostaglandins , reactive oxygen species , complement proteins and adhesion molecules that are highly toxic to neurons ( 54 - 58 ). evidence of inflammation is also found by the infiltration and accumulation of polymorphonuclear leukocytes . pro - inflammatory cytokines increased the expression of the enzyme inducible nitric oxide synthase ( inos ) producing excessive amounts of no that can become oxidized to form peroxynitrite and contributes to the pathogenesis of concussive brain injury ( 59 - 61 ). an inhibitor of inos provided neuroprotection against damage produced by peroxynitrite ( 62 ). the pro - inflammatory cytokine interleukin - 6 ( il - 6 ) is elevated in patients with acute tbi , and a significant relationship exists between the severity of tbi and the il - 6 level ( 63 ). in a clinical study involving 75 patients with moderate to severe concussions , the role of cytokines and lipids relative to 30 - day mortality was evaluated . the results showed that the levels of cytokines ( il - 6 and il - 8 ) increased and lipid decreased in all patients , especially non - survivors , compared to those in the healthy control group ( 64 ). in addition , severe tbi in infants and children ( n = 36 ) increased the levels of pro - inflammatory cytokines ( il - 1beta , il - 6 and il - 12p70 ) and anti - inflammatory cytokines ( il - 10 ) and chemokines ( il - 8 and mip - 1alpha ) compared to controls . in animal models , the levels of inflammation markers such as inos and cyclooxygenase 2 activity , and markers of oxidative stress ( loss of glutathione and oxidized : reduced glutathione ratio , 3 - nitrotyrosine , and 4 - hydroxynonenal ) increased after concussions ( 65 ). motor performance and spatial memory acquisition were improved in genetically protected mice compared to control mice after subjecting them to a brain impact model of tbi ( 66 ). the role of pro - inflammatory cytokines in the progression of damage following concussive injury is further supported by the fact that inhibitors of these cytokines improved neuronal loss and cognitive dysfunction . the excitatory amino acids ( glutamate and aspartate ) play a significant role in the progression of injury following concussions ( 67 ). excessive amounts of glutamate in the extracellular space may cause swelling , edema and eventually cell death . in a clinical study involving 80 patients with severe head injury , it was observed that the levels of excitatory amino acids increased and enhanced neuronal damage ( 68 ). in patients with focal and diffuse brain injury , the levels of glutamate were elevated in both cerebrospinal fluid and extracellular space ( 69 ). in another clinical study , it was found that patients who died of their head injury had higher levels of dialysate glutamate and aspartate compared to those who recovered ( 67 ). it was also observed that the levels of adenosine and glutamate were elevated in the ventricular csf in 27 children with severe tbi compared to 21 children without concussive brain injury ( 70 ). the involvement of glutamate in the progression of damage following concussion is further suggested by the fact that administration of antagonists to glutamate release improved motor function and cognitive dysfunction in animal models of tbi ( 71 , 72 ). since increased oxidative stress , chronic inflammation and glutamate release are involved in the development and progression of neurological deficits , and since antioxidants are known to reduce these factors , a novel biological protection strategy of daily supplementation with appropriate types of multiple micronutrients including dietary and endogenous antioxidants can be expected to reduce the risk of neurological dysfunction . resveratrol , a phenolic antioxidant , administered immediately after tbi reduced oxidative damage and lesion volume in rats ( 73 , 74 ). edaravone , an fda approved drug , reduced oxidative damage by neutralizing free radicals after concussive injury in humans ( 75 ). superoxide dismutase improved tbi - induced mitochondrial dysfunction in mice ( 76 ). treatment with alpha - lipoic acid reduced markers of pro - inflammatory cytokines and oxidative stress , and improved histological changes in the brain , preserved blood - brain - barrier permeability and reduced edema following tbi in animals ( 77 ). administration of n - acetylcysteine provided neuroprotection in animal models following concussion by reducing markers of pro - inflammatory cytokines and adhesion molecules ( 78 ). melatonin , a pineal hormone exhibiting antioxidant activity , protected against tbi - induced damage ( 79 ). dietary supplementation with vitamin e or curcumin protected the brain against damage after concussive injury by reducing the biochemical changes involved in synaptic plasticity and cognitive function ( 14 , 80 , 81 ). vitamin e also inhibited the release and toxicity of glutamate ( 82 , 83 ). dietary supplementation of omega - 3 fatty acids in an animal model protected against tbi - induced reduced synaptic plasticity and cognitive impairment ( 84 ). in addition to the data relative to oxidative damage , there is substantial evidence that dietary and endogenous antioxidants and antioxidants derived from herbs and fruits and vegetables inhibit inflammation ( 85 - 97 ). increased pro - inflammatory stimuli and oxidative stress cause brain tissue to release excessive amounts of glutamate after tbi , which contributes to loss of neurons ( 98 ). release of glutamate was blocked by vitamin e ( 98 ). both vitamin e ( 83 ) and coenzyme q10 ( 82 ) also protect against glutamate - induced neurotoxicity in cell culture models . while laboratory studies in animal models show that supplementation with a single micronutrient such as an antioxidant may protect the brain against tbi - induced biochemical and structural damage , similar clinical studies have produced inconsistent results . it is well established that the internal oxidative environment in these populations is high , and that an individual antioxidant when oxidized acts as a pro - oxidant . therefore , administration of a single antioxidant under high risk conditions may produce pro - oxidant rather than antioxidant effects . because increased levels of oxidative stress and chronic inflammation , as well as enhanced release of glutamate follow tbi , oral supplementation with appropriate multiple micronutrients including dietary and endogenous antioxidants as an adjunct to standard therapy can be expected to reduce the risk of late adverse effects on brain function . in addition , when administered in a concussion - prone environment , but before the event occurs , they may prevent or reduce the level of initial damage . for the purpose of uniqueness in this patent application , specific comprehensive combinations of antioxidants and glutathione - elevating agents is mandatory because their mechanisms of action and distribution at cellular and organ levels differ , their cellular and organ environments ( oxygenation , aqueous and lipid components ) differ , and their affinity for various types of free radicals differs . for example , beta - carotene ( bc ) is more effective in quenching oxygen radicals than most other antioxidants ( 99 ). bc can perform certain biological functions that cannot be produced by its metabolite vitamin a , and vice versa ( 100 , 101 ). it has been reported that bc treatment enhances the expression of the connexin gene which codes for a gap junction protein in mammalian fibroblasts in culture , whereas vitamin a treatment does not produce such an effect ( 101 ). vitamin a can induce differentiation in certain normal and cancer cells , whereas bc and other carotenoids do not ( 102 , 103 ). thus , bc and vitamin a have , in part , different biological functions . the gradient of oxygen pressure varies within cells . some antioxidants , such as vitamin e , are more effective as quenchers of free radicals in reduced oxygen pressure , whereas bc and vitamin a are more effective in higher atmospheric pressures ( 104 ). vitamin c is necessary to protect cellular components in aqueous environments , whereas carotenoids and vitamins a and e protect cellular components in lipid environments . vitamin c also plays an important role in maintaining cellular levels of vitamin e by recycling vitamin e radical ( oxidized ) to the reduced ( antioxidant ) form ( 105 ). also , oxidative dna damage produced by high levels of vitamin c could be protected by vitamin e . oxidized forms of vitamin c and vitamin e can also act as radicals ; therefore excessive amounts of any one of these forms , when used as a single agent , could be harmful over a long period of time . the form of vitamin e used is also important in any clinical trial . it has been established that d - alpha - tocopheryl succinate ( alpha - ts ) is the most effective form of vitamin both in vitro and in vivo ( 106 , 107 ). this form of vitamin e is more soluble than alpha - tocopherol and enters cells more readily , and , therefore , is expected to cross the blood - brain barrier more efficiently in tbi . glutathione is one of the body &# 39 ; s most important antioxidants . however , oral supplementation of this substance failed to significantly increase plasma levels of glutathione in human subjects ( 108 ) suggesting that this tripeptide is completely hydrolyzed in the gastrointestinal tract . n - acetylcysteine and alpha - lipoic acid increase the cellular levels of glutathione by different mechanisms and can be effectively combined in a multiple micronutrient preparation . selenium is a co - factor of glutathione peroxidase that also increases the intracellular level of glutathione . in addition , r - alpha - lipoic acid and acetyl - l - carnitine together promoted mitochondrial biogenesis whereas no effect was observed when these antioxidants were used individually ( 109 ). other endogenous antioxidants , such as coenzyme q 10 , also have potential value in prevention and adjunctive treatment of tbi . since mitochondrial dysfunction occurs in patients with concussive injury and since coenzyme q 10 is needed for the generation of atp by mitochondria , this antioxidant is essential to improve the mitochondrial function . ubiquinol ( coenzyme q 10 ) scavenges peroxy radicals faster than alpha - tocopherol ( 110 ) and like vitamin c , can regenerate vitamin e in a redox cycle ( 111 ). coenzyme q 10 administration has also been shown to improve clinical symptoms in patients with mitochondrial encephalomyopathies ( 112 ). antioxidant micronutrients can reduce the risk of neurological dysfunction in other conditions such as alzheimer &# 39 ; s and parkinson &# 39 ; s disease , and this neuroprotective value is directly relevant to concussive brain injury and the common late adverse effects . beta - amyloid fragments that are associated with neurodegeneration in alzheimer &# 39 ; s disease mediate their action by free radicals ( 113 ). this is supported by the fact that vitamin e protects neuronal cells in culture against beta - amyloid - induced toxicity ( 114 ). vitamin e at a dose of 2 , 000 iu per day can produce beneficial effects in patients with alzheimer &# 39 ; s disease ( 115 ). patients consuming antioxidants also showed reduced risk of vascular dementia and slower decline of cognitive function in cases of dementia and alzheimer &# 39 ; s disease ( 116 ). prostaglandin e2 , a product of inflammatory reactions , is very toxic to mature neurons , and a mixture of antioxidants reduces this toxicity ( 117 ). furthermore , glutathione deficiency has been consistently found in autopsied brain samples from patients with neurological conditions such as alzheimer &# 39 ; s disease ( 118 ) and parkinson disease ( 119 , 120 ), again demonstrating the relevance of employing micronutrients that increase glutathione for tbi . the formulations for concussive brain injury can be placed in the following forms capsules , pills , beverages , powders , chewables ( e . g . gummies ), dissolvables ( e . g oral wafers and disks ), solids ( e . g . bars ), functional foods ( e . g . yogurts and creams ), sprays , inhaled aerosols , suspensions , liposomes , extended release technologies , and other absorbable forms such as skin patches and injectables . these comprehensive formulations are intended for individuals who have already suffered initial or repeated tbi from contact sports , accidents , dangerous occupational environments or military combat , or for those who may likely suffer such an event because of exposure to these high risk circumstances . the cognitive dysfunction and other neurological abnormalities may be noted soon after concussions or may not be evident until several years later . a formulation for “ youth ”, for example ages 9 - 13 years , is provided in a bottled form ( two capsules taken twice per day ), liquid form ( one packet dissolved in liquid twice per day ), beverage bottle ( 8 - 12 ounces ) or bar form ( one bar consumed twice per day ) and is recommended ( but not required ) to be taken year round by young athletes . one serving of the daily consumption ( two servings per day ) is comprised of : vitamin a ( retinyl palmitate , fish oil , or natural mixed carotenoids ) 1500 iu , vitamin e ( both d - alpha - tocopherol 50 iu and d - alpha tocopheryl succinate 50 iu , vegetable products , natural tocopheryl , or wheat germ products ), vitamin c ( calcium ascorbate , citrus , rose , or berry products ) 250 mg , vitamin b - 5 ( pantothenic acid , d - calcium pantothenate , pantothenate , yeast sources , rice bran , or liver sources ) 5 mg , a formulation for “ adults ”, for examples ages 14 years and older , is provided in a bottled form ( three capsules plus one fatty acid gel - cap taken twice per day ), liquid form ( one packet dissolved in liquid twice per day ), beverage bottle ( 8 - 32 ounces ), or bar form ( one bar consumed twice per day ) and is recommended ( but not required ) to be taken year round by those engaging in contact sports , working in hazardous occupations , or those in the active military . vitamin a ( retinyl palmitate , fish oil , or natural mixed carotenoids ) 3000 iu , vitamin e ( both d - alpha - tocopherol 100 iu and d - alpha tocopheryl succinate 300 iu , vegetable products , natural tocopheryl , or wheat germ products ), vitamin c ( calcium ascorbate , citrus , rose , or berry products ) 1000 mg , pantothenic acid ( d - calcium pantothenate , yeast , rice bran , or liver sources ) 10 mg , a “ booster ” formulation , for ages 14 years and older , is provided in a package form ( one capsule plus one fatty acid gel - cap ), liquid form ( one packet dissolved in liquid ), beverage bottle ( 2 - 8 ounces ) or bar form ( one bar ) and is intended to be taken once as a separate “ neuroprotective ” package one to two hours prior to engaging in potentially violent contact sports , undertaking an occupationally - related hazardous activity where the risk of concussive injury is increased , or , for active military personnel , entering a combat or hazardous duty zone . vitamin e ( d - alpha tocopheryl succinate , vegetable products , natural tocopheryl , or wheat germ products ) 50 iu , vitamin c ( calcium ascorbate , citrus , rose , or berry products ) 200 mg , a “ protection ” formulation , ages 8 years older , is provided in a package form ( one capsule plus one fatty acid gel - cap taken twice per day ), liquid form ( one packet dissolved in liquid twice per day ), or bar form ( one bar consumed twice per day ) and is intended to be taken for the total number of days as directed by health care professional for those who have sustained a concussive brain injury . vitamin e ( d - alpha tocopheryl succinate , vegetable products , natural tocopheryl , or wheat germ products ) 50 iu , vitamin c ( calcium ascorbate , citrus , rose , or berry products ) 100 mg , doses in the above examples are recommended but can be flexible . doses for example formulations 1 , 2 , & amp ; 4 should be taken at least once per day . example formulations are target doses , but doses may vary within above ranges . the micronutrient supplements should be taken orally and divided into two doses , half in the morning and the other half in the evening preferably with meals . this is because the biological half - lives of micronutrients ( water - soluble and fat - soluble ) are highly variable which can create marked fluctuations in tissue levels , differences in gene profile expression and cellular stress . this is also important to maintain relatively consistent levels of micronutrients in the brain . no iron , copper or manganese would be included because these trace minerals are known to interact with vitamin c to produce free radicals . these minerals are also absorbed more readily from the intestinal tract in the presence of antioxidants , and this could result in potentially harmful increased body stores of unbound minerals . increased iron stores have been linked to a higher risk of several chronic diseases ( 121 ). prospective , randomized , double - blind , placebo - controlled trial in 34 u . s . marine corps 1 st tank volunteers subjected to cold , high altitude and exertion stress at the mountain warfare training center , 29 palms , calif . ( 122 ). the study group consumed the pmc formulation and the control group received a placebo supplement for duration of the 12 week training course . serial urine samples were taken from all participants and analyzed before and after supplementation for sensitive markers of oxidative damage ( 8 - hydroxyguanosine ). safety was assessed by field reports of adverse reactions . in the placebo group , 42 % of subjects had low levels of the biological marker before supplementation , and the remaining 58 % exhibited high levels of oxidative damage reflecting the extreme conditions . after consuming the placebo , only 25 % of the subjects still had low levels of oxidative damage and 75 % had high levels , demonstrating 17 % deterioration in oxidative status . conversely , in the antioxidant treated group , 30 % of the subjects had low levels of 8 - hydroxyguanosine before supplementation and 70 % exhibited high levels of the marker . after receiving the pmc formulation , 71 % of the subjects showed low oxidative damage levels and only the remaining 29 % had high levels , demonstrating 41 % improvement in oxidative status ( table ). this documented that the formulation not only prevented more oxidative stress from occurring during extreme exercise but , in fact , reduced the oxidative damage that was already present . this significant recovery in the treatment group showed a highly desirable impact during military training and translates directly to the exertion and stress experienced in elite or recreational sports , and hazardous occupations . in addition , the changes in plasma levels of antioxidant micronutrients were also documented . the placebo group showed no difference in the levels of alpha - tocopherol ( vitamin e ) in the blood , before ( 4 . 8 ug · ml ) or after ( 4 . 6 ug / ml ) supplementation . however , the average value almost doubled ( 4 . 1 ug / ml to 7 . 6 ug / ml ) in the antioxidant treated group , documenting that the pmc formulation is absorbed well even in the face of extreme conditions and intense exercise . there were no reported or observed adverse effects from consuming the formulation . the 8 - hydroxuguanosine level ( μg / mg creatine ) up to 2 . 0 was considered low value ( low oxidative damage ) and 2 . 1 to 3 . 0 as high value ( high oxidative damage ).). the number of subjects with high oxidative damage increased after placebo consumption . however , the number of subjects with high oxidative damage decreased after antioxidant treatment . n refers to the number of subjects in each group . prospective , randomized , double - blind clinical trial in 42 u . s . marine corps personnel suffering tbi from moderate concussive brain injury ( blasts ) after returning from war in iraq ( 123 ). all patients had received their injury 3 - 20 weeks prior to study entry . the control group received standard rehabilitation ( steroids , physical therapy , vestibular rehabilitation and supportive care ) for 12 weeks . the study group received standard care plus the formulation ( two capsules by mouth twice per day ) for the same time period . all patients were evaluated by the same outcome measures that included the sensory organization test ( sot ) by computerized dynamic posturography ( cdp ), dynamic gait index ( dgi ), the activities balance confidence ( abc ) scale , dizziness handicap index ( dhi ), vestibular disorders activities of daily living ( vadl ) score , and the balance scoring system ( bess ) test . the therapist who performed and graded the testing was blinded as to whether or not the patient was in the control group or receiving antioxidant therapy . the pre - trial test scores did not differ significantly between the two groups on any of the tests . the study group receiving the micronutrient formulation demonstrated more rapid and complete recovery than did the control group even though the formulation was not consumed until well after the concussions were suffered . postural stability , dynamic gait index , and dizziness handicap scores were already significantly different after only 4 weeks , and this improvement grew in significance by the end of 12 weeks . the sot score by cdp was 78 for the antioxidant group as compared to 63 for the control group ( p & lt ; 0 . 05 ). the improvement noted in the micronutrient group on the other tests also trended to a greater degree than that of the control group . questionnaires were also administered regarding energy levels , exercise , and overall cognitive issues by an investigator who did not know to which group the patient belonged . the study group demonstrated a significant increase in energy level , exercise tolerance and cognitive ability at every weekly time point . there were no adverse effects from the pmc formulation . this was a laboratory study of parkinson &# 39 ; s disease in a validated rodent model ( 124 ). the agent , mptp ( 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 - tetrahydropyridine ), is a contaminant in certain recreational drugs and can induce parkinson &# 39 ; s disease in humans . this substance can also be administered intraperitoneally in rats and induces severe parkinsonian symptoms allowing this model to be used to understand the mechanisms of the disease . the pmc formulation was fed to the study group prior to administration of mptp and provided a significant degree of neuroprotection compared to the control group . the supplemented rodents demonstrated an 86 % reduction in the development of parkinson &# 39 ; s disease compared to the rats that received only standard diets . this was a laboratory study of concussive blast overpressure in a validated rodent model ( 125 ). the study formulation was administered orally to rats for 7 days before exposure to a whole - body concussive blast dose of 150 kilopascals . this is generally a lethal overpressure dose in rodents , and represents a potentially concussion - producing blast in humans , both of which would cause a significant rise in markers of severe inflammation in the bloodstream . the supplementation demonstrated a dramatic protective effect in that it completely prevented the rise of inducible nitric oxide synthase , a critical enzymatic marker of the inflammatory cascade in the blood of the animals . in addition , the supplementation did not adversely affect certain enzymatic markers of oxidative damage such as hemeoxygenase - 1 and superoxide dismutase . the formulations in this application support tissue repair and recovery during exertion and extreme conditions as related to oxidative damage and inflammation . the validating studies , now published in the peer - reviewed clinical medical literature ( 126 ), show beneficial impact on concussive events , both preventatively before an event occurs , and supportively after an event is suffered . in addition to the risk of tbi , high intensity activity in sports , occupational or military environments is also associated with enormous production of excess free radicals and results in measurable oxidative damage to the body &# 39 ; s cells and tissues . this type of effort also causes significant inflammatory responses in the body and is known to suppress normal immune function . specific formulations based on biochemical mechanisms in concussive brain injury and exploiting the known antioxidant science have been developed to addresses the risks from this spectrum of violent activity . numerous modifications and variations of the present invention are possible in light of the above teachings . it is therefore to be understood that within the scope of the attendant claims attached hereto , this invention may be practiced otherwise than as specifically disclosed herein . | US-201414775987-A |
a method for treating depression is disclosed . by allowing patients suffering from depression to hear jinyangjo - jangdan of sanjo , the method can be useful in replacing medicinal treatment since the method has an excellent therapeutic effect with a level similar to that when a drug is administered even without administering any drugs , by promoting the activities of monoamine compounds such as serotonin and a brain - derived neurotrophic factor in the brains of patients suffering from depression . | the present invention will now be described more specifically with reference to the following embodiments . it is to be noted that the following descriptions of preferred embodiments of this invention are presented herein for purpose of illustration and description only ; they are not intended to be exhaustive or to be limited to the precise form disclosed . in some embodiments of the present invention , the method for the present invention includes a step of allowing patients suffering from depression to hear jinyangjo - jangdan ( a very slow rhythm ) of sanjo ( a style of traditional korean music ). sanjo is a style of instrumental solo within traditional korean music . sanjo includes at least four rhythms including jinyangjo , jungmori , jungjungmori , and jajinmori , and a melody is composed in one of three tonal systems including gyemyeonjo ( mi , sol , la , do , and re ; tonic : la ), pyeongjo ( re , mi , sol , la , and do ; tonic : sol ) and ujo ( sol , la , do , re , and mi ; tonic : do ). jinyangjo - jangdan is the slowest rhythm among the sanjo rhythms , and the period of jinyangjo - jangdan is twenty - four quarter notes , and these 24 beats are divided into four parts in sextuple time . the present inventors have found that expression of serotonin and dopamine in the brains of patients suffering from depression is promoted , and expression of a brain - derived neurotrophic factor ( bdnf ) is also promoted when the patients suffering from depression are allowed to hear jinyangjo - jangdan of sanjo . also , they have confirmed that phosphorylation of erk in the brains of the patients suffering from depression is promoted , expression of er - β is also promoted , and expression of blood inflammatory cytokines is inhibited . as a result , the present inventors have found that jinyangjo - jangdan of daegeum sanjo has an effect of treating depression . jinyangjo - jangdan is the slowest rhythm among the jangdan of pansori and sanjo , and is used in sad and lyrical passages . it is similar to a minor chord in western music in that it expresses heartbreaking grief and mourning . the effect of treating depression is considered to be derived from the fact that the jinyangjo - jangdan provides a catharsis by means of such sad and mourning rhythms . sanjo is classified into gayageum sanjo , geomungo sanjo , daegeum sanjo , piri sanjo , haegeum sanjo , ajaeng sanjo , and danso sanjo according to the musical instrument played by a musician . the sanjo according to one exemplary embodiment of the present invention may include gayageum sanjo , geomungo sanjo , daegeum sanjo , piri sanjo , haegeum sanjo , ajaeng sanjo , danso sanjo , etc ., and preferably daegeum sanjo . this is because the sounds of the daegeum are interpreted as sighs ( grievous sounds ). daegeum ( a traditional korean transverse flute , korean bamboo flute ) has one blowing hole , six finger holes , and an extra hole covered with a thin membrane called ‘ cheong ’ ( located between the blowing hole and finger holes ). cheong is a white resonant membrane cut from a reed and makes this instrument produce a distinctive refined , calm sound . sanjo is traditional music which is re - created and changed into a new form of music by adding its own melodies to traditional tunes or changing the melodies . therefore , various schools of sanjo have been formed and handed down . specific examples of the daegeum sanjo existing in korea include eight schools of sanjo played by beak - cheon kang , dong - jin kim , jong - gi park , yong - seon seo , saeng - gang lee , jang - hyeon won , beom - soo han , and ju - hwan han . in the case of the sanjo according to one exemplary embodiment of the present invention , the daegeum sanjo is not limited to a certain school , and may belong to any of the exemplified schools of sanjo . the present inventors have found that jinyangjo - jangdan of daegeum sanjo played by jang - hyeon won has a therapeutic effect when the patients suffering from depression are allowed to hear the jinyangjo - jangdan of daegeum sanjo played by jang - hyeon won . however , the other schools of sanjo are essentially identical to the daegeum sanjo played by jang - hyeon won in that various schools of sanjo have common modes ( i . e ., ujo , pyeongjo , and gyemyeonjo ) to form sanjo , and the jangdan also include jinyangjo , jungmori , jungjungmori , and jajinmori . therefore , the other schools of sanjo are also considered to have an effect of treating depression like the daegeum sanjo played by jang - hyeon won . the term “ patient ” refers to an animal , preferably a mammal , and most preferably a human , who is the object of treatment , observation or experiment . the mammal may be selected from the group consisting of mice , rats , hamsters , gerbils , rabbits , guinea pigs , dogs , cats , sheep , goats , cows , horses , giraffes , platypuses , primates , such as monkeys , chimpanzees , and apes . in some embodiments , the subject is a human . bdnf , erk , er - β , blood inflammatory cytokines may be independently derived from the patient . in this case , these proteins may have amino acid sequences known in the related art . blood inflammatory cytokines may be at least one protein selected from the group consisting of tnf - α , il - 1β , il - 6 . a time when the patients suffering from depression are allowed to hear jinyangjo - jangdan of sanjo is not particularly limited , and may be properly selected according to a treatment purpose , a condition of a patient , a background , etc . for example , the patients may be allowed to hear the jinyangjo - jangdan of sanjo for 5 minutes to 60 minutes a day , for example , 5 minutes to 60 minutes , 10 minutes to 60 minutes , 20 minutes to 60 minutes , and 30 minutes to 60 minutes a day . in an aspect of improvement of depression , the patients may preferably be allowed to hear the jinyangjo - jangdan of sanjo for 30 minutes or more a day . such music treatment may be performed for a period of time of one day or several years , for example , one day to a year , one day to 6 months , 10 days to 6 months , 15 days to 60 days , 21 days to 180 days , 21 days to 365 days , according to the conditions of a patient . preferably , the music treatment may be performed for a period of time of 3 weeks or more . male icr mice ( 3 weeks old ) weighing 10 - 12 g were purchased from the dae - han experimental animal center ( daejeon , republic of korea ), and subsequently maintained at the college of korean medicine , kyung hee university . animals were housed 5 - 10 % in as laminar air - flow room maintained at a temperature of 22 ± 1 ° c . and a relative humidity of 55 ± 10 % under a 12 : 12 l / d cycle light ( on at 7 : 00 h ) throughout the study . food and water were provided ad libitum . all manipulations were carried out between 9 : 00 and 16 : 00 h and no animal was used more than once . the study protocol was approved beforehand by the institutional animal care use committee of kyung hee university ( khuasp ( se )- 10 - 032 ). icr mice were divided into five groups according to fst results : the untreated control group ( without jds music ), the fluoxetine group ( the positive control ), and jds music 10 min , 20 min , or 30 min groups . background sound levels in the special isolation booth constructed on the non - treated control and fluoxetine groups were 10 ˜ 40 db and in the three music treatment groups was 70 db . mice were exposed to jds music daily for 3 weeks . all experiments were carried out in a quite environment other sounds . in this study , jds of the jang - hyun won genre was used , and was played by prof hyung - min kim , who is a disciple of won . the music was recorded and copied using a mp3 player to ensure precisely the same music was played for mice in all treatment groups . after measuring immobility times , 10 mice were allocated to each of the five study groups in an immobility time - matched manner . fluoxetine was dissolved in distilled water ( d . w ). fluoxetine ( 10 mg / kg , a classical antidepressant ) was orally administered to mice once daily for 3 weeks using an atraumatic feeding needle . the fst was performed as the end of the 3 weeks administration period . during the 6 min fst , immobility times were measured as described by porsolt et al . ( 1977 ). the fst apparatus consisted of two plexiglas cylinders ( height : 25 cm , diameter : 10 cm ) placed side by side in a makrolon cage filled with water at 23 - 25 ° c . two mice were tested simultaneously for 6 min period inside the vertical plexiglas cylinders ; a nontransparent screen was placed between the two cylinders to prevent mice from seeing each other during the test . total duration of immobility , during the 4 min period from 2 to 6 min was recorded . a mouse was considered immobile when it ceased struggling and remained floating motionless on the water , making only movements necessary to keep its head above water . 5 - ht levels in brain were measured a 5 - hydroxytryptamine assay kit ( mybiosource , san diego , calif ., usa ), and levels of da in brain were measured using the da elisa kit ( genway biotech inc ., san diego , calif ., usa ). immediately after the fst , mice were sacrificed , brains were rapidly removed , and frozen in liquid nitrogen . samples were dissected and homogenized in ice - cold buffer supplemented with 0 . 2 mm dtt , 0 . 5 mm sodium vanadate , and protease inhibitors . nacl was then added to a final concentration of 0 . 45 m , and homogenates were centrifuged at 15 , 000 × g for 30 min . supernatants were collected and stored at − 70 ° c . samples were subjected to western blot analysis for erk , phosphorylated - erk ( p erk ), bdnf , and gapdh . supernatant samples obtained as described above were heated at 95 ° c . for 5min and briefly cooled on ice . after centrifugation , 50 μg aliquots were resolved by 12 % sds - polyacrylamide gel electrophoresis . proteins were then transferred to nitrocellulose membranes , which were blocked for 2 h with phosphate - buffered saline ( pbs ) containing tween - 20 ( pbst ) containing 6 % bovine serum albumin . membranes were incubated overnight at 4 ° c . with primary antibodies diluted 1 : 500 with pbst , and washed nine times for 10 min with pbst . for protein detection , blots were incubated with secondary antibodies conjugated peroxidase ( 1 : 5000 ) for 2 h . finally , protein bands were visualized using an enhanced chemiluminescence kit ( ge healthcare , piscataway , n . j ., usa ) according to the manufacturer &# 39 ; s instructions . cytokine levels in serum were measured by elisa . the elisa was performed by coating 96 - well plates with 1 μg / well of capture antibodies for il - 1β , il - 6 , and tnf - α . before the subsequent steps in the assay , the coated plates were washed twice with pbst . all reagents and coated wells used in this assay were incubated for 2 h at room temperature . the standard curve was generated from known concentrations of cytokine , as provided by the manufacturer . after exposure to the medium , the assay plates were exposed sequentially to each of the biotin - conjugated secondary antibodies , and avidin - peroxidase , and 2 ′- azino - bis ( 3 - ethylbenzithiazoline - 6 - sulfonic acid ) substrate solution containing 30 % h2o2 . the plates were read 405 nm . appropriate specificity controls were included , and all samples were run according to the total protein . the protein was estimated using the bicinchoninic acid method . quantitative real time - pcr was performed using a sybr green master mix and mrna levels were analyzed using an abi stepone rt - pcr system ( applied biosystems , foster city , calif ., usa ). primer sequences for the reference gene ( gapdh ) and genes of interest were as follows : gapdh ( 5 ′ ggc aaa ttc aac ggc aca 3 ′ ( seq id no : 1 ) ; 5 ′ gtt agt ggg gtc tcg ctc ctg 3 ′ ( seq id no : 2 )); and er - β ( 5 ′ gac tgt aga acg gtg tca tca a 3 ′ ( seq id no : 3 ); 5 ′ cct gtg agg tag gaa tgc gaa c 3 ′ ( seq id no : 4 )). the quantitative pcr amplification protocol was as follows : 2 min at 50 ° c . and 10 min 95 ° c ., followed by 40 cycles of 15 s at 95 ° c . and 1 min at 60 ° c ., with data collection during the last 30 s . results are presented as means ± sems . the independent t - test and anova with tukey &# 39 ; s post hoc test were used to determine statistical significance . spss statistical software ( spss inc ., chicago , ill ., usa ) was used throughout , and statistical significance was accepted for p values & lt ; 0 . 05 . immobility times were determined 1 h after fluoxetine or jds music treatment ( 10 , 20 , and 30 min ). mean baseline immobility times ( 0 day ) were similar in all five study groups { fluoxetine group ( 94 . 2 ± 23 . 9 s ), jds music groups ( 95 . 6 ± 21 . 9 s for 10 min , 96 . 2 ± 13 . 4 s for 20 min , and 94 . 0 ± 8 . 4 s for 30 min ), and untreated control group ( 96 . 0 ± 24 . 1 s )}. however , after the 3 - week treatment period mean immobility times in the fluoxetine ( 60 . 4 ± 14 . 3 s ) and jds music groups ( 112 . 4 ± 10 . 9 s for 10 min , 111 . 6 ± 9 . 8 s , for 20 min , and 111 . 0 ± 15 . 1 s for 30 min ) were significantly lower than in the untreated control group ( 199 . 3 ± 11 . 8 s ) ( fig1 a , p & lt ; 0 . 05 ). selective serotonin reuptake inhibitors have an antidepressant effect by blocking serotonin reuptake at brain synapses . da is also involved in the pathophysiology and treatment of depression and research studies on da have led to the developments of a new class of antidepressants . thus , we analyzed 5 - ht and da levels mouse brains after fst . we found 5 - ht and da levels were significantly lower in untreated control group than in non - fst tested normal control ( fig1 b and c , p & lt ; 0 . 05 ). however , 5 - ht and da levels in the jds music and fluoxetine groups were significantly higher than in the untreated control group ( fig1 b and c , p & lt ; 0 . 05 ). bdnf is a regulator of memory and synaptic plasticity and induces neurogenesis in the brain . as shown in fig2 a and b , jds music and fluoxetine significantly increased bdnf levels as compared with the untreated control group . the erk pathway is a key pathway downstream of bdnf and plays an important role in the actions of antidepressants . therefore , we examined whether the erk pathway was involved in the antidepressant effect of jds music . as shown in fig2 c and d , mice exposed to jds music showed significant increases in perk ( p & lt ; 0 . 05 ), whereas total erk protein levels were not altered . similarly , fluoxetine also significantly elevated perk levels ( fig2 c and d , p & lt ; 0 . 05 ). we next investigated whether the estradiol pathway was associated with the antidepressant effect of jds music . quantitative real time - pcr showed that jds music significantly increased the expression of er - β mrna ( fig3 , p & lt ; 0 . 05 ). the severity of depression has been showed to be associated with inflammatory cytokine levels . thus , we analyzed serum protein levels of tnf - α , il - 1β , and il - 6 by elisa . jds music ( 10 and 30 min ) significantly reduced serum tnf - α and il - 6 levels versus untreated controls ( fig4 a and b , p & lt ; 0 . 05 ). however , serum il - 1β levels were only significantly reduced in the jds music 30 min group ( fig4 c , p & lt ; 0 . 05 ). in the present invention , jds music increased the brain expressions of bdnf and er - β and reduced the levels of inflammatory cytokines , which suggests the antidepressant effect of jds is associated with activation of bdnf pathways . in conclusion , this results show jds music exhibits antidepressant - like effects as determined by the fst , and that these effects appear to be related to modulations of serotonergic system and bdnf signaling pathway in brain . | US-201514681912-A |
display hardware for lock sets which is adapted to display a variety of lock sets enabling a viewer to visually and manually demonstrate the various features and components of each lock set is disclosed . the hardware comprises a lock assembly fixedly secured in a mounting block with generally flat sides and apertures receiving the lock assembly , the lock assembly being disposed through the apertures in flat sides of the block to display the lock assembly in a mounted condition . the block for displaying the lock assembly is coupled to and extends outwardly from a suitable shelf . the shelf has at least one generally elongated horizontal member which is arranged and configured so as to be adapted to receive , store and display packaged lock sets corresponding to the lock sets displayed on the mounting block coupled to the shelf . the display hardware enables one to quickly and easily determine the particular lock set on the shelf , and to demonstrate the specific features associated with that lock set and the manner in which the lock set operates . | referring first to fig1 there is shown , as the presently preferred embodiment , the first embodiment of the present invention . lock assembly 10 is disposed through a suitable opening in a portion of the mounting means 20 . the lock assembly 10 and the mounting means 20 are arranged and configured such that a complete demonstration of the locking and unlocking action of the lock assembly may be viewed , for example , by a purchaser . the mounting means 20 for displaying the lock assembly is shown as vertically coupled to , and extending outwardly from the shelf 24 . the shelf 24 may be of a general rack type construction such as is known in the art having at least one horizontal member 25 capable of receiving and displaying the packaged lock sets to be stored thereon . in the first embodiment of the present invention the means for displaying the lock includes an angular shaped block 21 . the shape and size of the block 21 can vary depending on the nature of the lock and the desired appearance of the block . a typical lock assembly 10 is shown as circumferentially disposed in the block 21 . the lock assembly 10 includes an associated key 12 , a handle actuator 18 and outside rosettes 41 and 14 &# 39 ;. the outside rosettes 14 and 14 &# 39 ; are generally mounted on the door to cover the opening in the door for receiving the lock mechanism . on one side of the block 21 is the handle 18 and on the other side is the key actuated mechanism and key 12 . by rotation of the key 12 and / or the handle 18 , the latch bolt 17 located in the latch plate 16 extends and retracts . thus , when the purchaser desires to see the specific action of a specific lock assembly , for example , typical lock assembly 10 , he need only rotate handle 18 and / or the associated key 12 to see the type of action and movement of the latch bolt 17 and other features . this provides the customer with a working knowledge of the operation and various features associated with this specific lock assembly . further , the appearance , general relationship of the various components , their mode of construction , and their method of assembly , is more apparent than when viewed in a package . of course , other types and kinds of lock assemblies , handle means , and latch bolts may be disposed in the mounting means 20 and are within the scope of the invention . referring again to fig1 the angular block 21 is shown as having two flat sides 21a and 21b respectively with the lock assembly 10 disposed through an opening in these flat sides and mounted in the same fashion as the lock would be on a door in actual use . in the presently preferred embodiment , the flat sides 21a and 21b have a generally trapezoidal shape , with one of the parallel edges of the trapezoid being the edge along which the block 21 is coupled to the shelf 24 and the other parallel edge contains the latch plate 16 . the trapezoidal shape provides a desirable configuration for the imprinting various reference and model numerals and other customer information on the surface t of the block which can be seen by the customer . the block 21 is coupled to the shelf 24 such that it extends outwardly from the shelf and is mounted so as to be in a generally vertical position with respect to the horizontal member 25 . any conventional means for coupling the block 21 to the shelf 24 may be utilized . for example , screws , rivets , bolts , glue are all within the scope of the present invention . in the presently preferred embodiment , however , the block 21 is coupled to a vertical mounting strip 22 of a generally rectangular shape . the vertical mounting strip 22 is disposed to the front of the horizontal member 25 of the shelf 24 . in the presently preferred embodiment , the rack type shelf 24 is constructed of a plurality of metal strut sections 26 generally shown in fig1 . by way of example , the shelf can be about 151 / 2 inches wide , 14 inches deep and from 4 to 8 inches high . the size of the shelf is dependent on the size and quantity of the lock packages to be stored thereon . the strut sections 26 are joined together in a conventional manner towards the back of the shelf 24 by means of back support member 28 and toward the front of the shelf 24 by means of front support member 30 . the sides of the shelf are defined by shaped metal strut sections 32 and 32a respectively . in the presently preferred embodiment , this rack type shelf 24 is adapted so as to be readily portable , basically complete , and may be selectively coupled to what is generally referred to in the art as a &# 34 ; peg board .&# 34 ; peg boards usually come in sheets and are usually attached to a mounting wall . the peg board has a plurality of holes disposed therethrough which allow various curved metal members to become selectively disposed in the holes such that the members may be easily coupled and uncoupled from the board . now referring to fig2 the block 21 and the mounting means 20 are shown as coupled together by means of screws 36 and 36a . screws 36 and 36a represent the presently preferred embodiment of coupling the block 21 to the shelf 24 , but other means described above are within the scope of the invention . referring now to fig3 a number of the hereinbefore described shelves and associated mounting for the lock assemblies means have been disposed on a peg board 42 as is typically done in a hardware store and the like to form display 40 . packages of the lock sets , represented generally by numeral 43 , have been arranged in the various shelves so as to correspond to the specific lock assemblies disposed in the mounting means . as can be readily seen in this figure , a purchaser , upon passing the display , can readily , accurately , and conveniently determine all of the necessary features of a specific lock assembly and easily and accurately select the corresponding lock from the specific shelf . in another embodiment of the present invention , the vertical mounting strip 22 and the means for displaying the lock assembly 20 are color coded ( i . e ., the same color ) enabling even easier selections of the specific lock desired and preventing most mistakes associated with selecting locks from a display . by the term &# 34 ; color coding &# 34 ; it is meant that the mounting means 20 and the vertical mounting strip 22 are colored in such a manner as to indicate the specific lock located generally behind the lock assembly disposed in the mounting means 20 . the specific color coding also includes the use of various printed material which enables the purchaser to readily distinguish among associated locks . for example , on the top row of a typical display , all of the locks having a &# 34 ; dead bolt &# 34 ; may be disposed . the word &# 34 ; dead bolt &# 34 ; would appear on each of the mounting means 20 and on the vertical mounting strip 22 . but to distinguish among all the dead bolts , for each different dead bolt , a different color would be used ; the color used on the mounting means 20 and the vertical mounting strip 22 would correspond to a color on that specific box , containing the specific lock assembly disposed in the mounting means 20 fig1 and 3 also show that the block 21 is generally disposed in the middle of the front of each separate shelf 24 . this also helps prevent mistaken purchases as the shelf and the corresponding lock set are easily associated . in addition because the shelf 24 is readily portable and basically complete , the shelf 24 or a series of shelves may be disposed and / or where desired with relative ease . referring now to fig4 a second embodiment of the present invention is shown . in this embodiment , the horizontal support member or shelf 50 is a generally solid member extending outwardly from a mounting wall , with a plurality of mounting holes 51 disposed therethrough . the mounting means 20 is coupled to the horizontal member 50 by means of an angular bracket 48 and screws 44 and 44a , 46 and 46a respectively . in fig4 a an enlarged view of the angular bracket 48 is demonstrated . the angular bracket 48 is adjustable on the horizontal member 50 and on the mounting means 20 because of slots 52 located on the horizontal section of the bracket and slots 54 located on the vertical section of bracket . these slots enable some movement for adjustment of the bracket with respect to the horizontal member 50 as well as some movement for adjustment of mounting means 20 with respect to the horizontal member 50 . moreover , the bracket 48 enables the mounting means 20 to be easily coupled to shelves which already have a plurality of holes disposed on the horizontal member as is often the case on commercially available display shelves . in the second embodiment of the present invention , horizontal member 50 , with a plurality of holes h therethrough , is utilized . these holes h are spaced apart at various distances on the shelf to provide a plurality of mounting positions . by providing slots 52 on the bracket 48 , the bracket may be coupled to the horizontal member in various positions . thus , the mounting means 20 may be positioned where desired on the horizontal member 50 so as to insure a secure and conveniently located mounting . it should be noted that in the first embodiment the shelf 24 is free standing , and forms a readily portable unit which is easy to relocate and is comprised of the shelf 24 and the means 20 for mounting and displaying the lock unit 10 . in the second embodiment , such over - all portability of the display shelf is not present . however , by means of the angular bracket 48 , any present shelf may be readily adapted to the mounting means 20 without the need of any type of specific mounting wall or hooks . also , the mounting means 20 can be moved from one shelf to another , if desired . in fig5 packages of the packaged lock sets , generally represented by the numeral 52 , are shown on the horizontal shelf means 50 . by placing the packaged lock set 62 behind the corresponding assembly 10 and mounting means 20 , consumers are able to quickly see the features of each lock assembly shown in the display 56 and to select the proper packaged lock set . there has been described herein a new and novel display hardware for lock sets which provides for relative ease in displaying a number of different lock sets , and which enables the purchaser to accurately and easily determine the appearance and other features associated with the various lock sets and to aid in the selection of the correct lock set without opening packages . although this invention has been disclosed and described with reference to particular embodiments , the principles are susceptible of other applications which will be apparent to persons skilled in the art . this invention , therefore , is not intended to be limited to the particular embodiments herein disclosed . | US-54953675-A |
this invention is a golf putter head alignment system . the putter can be of most styles used having a shaft and an alignment bar on the putter head which are brightly colored , such as white , to contrast in aligning the shaft and putter head to the intended putting line . the shaft can be attached in any position on the head and the putter head may be configured to suit the preferred putter style of a player . the putter head is colored a darker color to that of the shaft and alignment bar to increase the contrast of the alignment system and create an appearance to the player that the alignment bar is an extension of the shaft . aligning the shaft and the white portion of the putter will easily aligns the putter on the intended line and allow for correction in the event of misalignment due to improper putting form . | referring now to the drawings and , more particularly to fig1 and 2 , there is shown an isometric and front view of the shaft and head alignment putter 10 configured for easy putter alignment . generally , the alignment putter 10 contains a grip section 12 , a shaft section 13 , and a club head 14 . grip section 12 generally comprises a grip 12 a wrapped or formed around the upper portion of shaft section 13 as to provide comfortable grip of putter 10 by a player . grip 12 a is envisioned to be any suitable material conventional in the art , such as tape , leather , rubber , or synthetic rubber materials which are extremely durable and provide for the enhanced grip needed in controlling putter 10 . some new synthetic materials , offer additional benefits of superior vibration dampening and long - lasting tackiness to provide for enhanced grip for a golfer in controlling putter 10 . for golfers who play in wet or humid conditions ( or have wet hands due to sweat ), grip 12 a may be or include a cord weave which provides additional traction to prevent a player &# 39 ; s hands from slipping . another option is a grip made with a unique - feeling thermo - plastic material which offers a much softer , tacky feel . shaft section 13 is comprised of a narrow shaft 15 affixed between grip section 12 and club head 14 . best seen in fig1 and 3 , shaft 15 generally is directly connected to club head 14 , wherein the shaft meets the club head 14 at a substantially perpendicular angle . when desired the shaft 15 may be generally angled relative to the position of club head 14 as to allow for club head 14 to lie parallel to the ground while being comfortably held away from a player . as can be seen in fig1 and 11 , shaft 15 may also be affixed to club head 14 by an intermediary shaft junction rod 16 which changes the angle of shaft section 13 to impart the necessary change in direction to place club head 14 in a flat parallel oriented position to the ground while being held away from a player . shaft section 13 is envisioned to be composed of steel , graphite , carbon fiber , or composite materials to give the shaft section 13 adequately desired stiffness to keep grip section 14 , shaft section 13 , and club head 14 in linear alignment throughout a player &# 39 ; s swing . furthermore , shaft section 13 is further envisioned to be of a suitable desired length and weight to facilitate the comfortable use by players of varying heights and skill levels . referring now to fig3 - 7 , club head 14 generally comprises a heel 17 affixed to shaft section 13 and a projecting toe 18 connected to heel 17 by bridge 49 , wherein club head 14 further includes a rear face 20 and a blade face 21 . an alignment bar 22 is provided between heel 17 and toe 18 along bridge 19 . as can be seen in fig7 , alignment bar 22 is positioned upon club head 14 as to lie in linear alignment with shaft section 13 as viewed above . positioning of alignment bar 22 as such creates a visual alignment cue for a player , wherein shaft section 13 and alignment bar 22 create a straight line along the shaft line α of shaft section 13 when putter 10 is in a properly aligned position for contacting ball b . in the event that a player allows club head 13 to shift out of alignment , alignment bar 22 will shift out of linear alignment with shaft line α and present the player with a view of the straight line of shaft 15 changing direction at the club head 13 . it is advantageous to have alignment bar 22 running along and over heel 17 , toe 18 , and bridge 19 of club head 14 . in traditional putter design , the club head is left exposed to the view of the player wherein the player may attempt to watch the contact between the club head and the target golf ball which , in many cases , cause the player to misalign the golf club due to improper form . after several misaligned contacts with golf balls , a player may become anxious and overcorrect , thus causing additional misaligned contacts and adding to the anxiety of the player . having alignment bar 22 running along and over heel 17 , toe 18 , and bridge 19 , blade face 21 is obstructed from view from above , thus no longer visible to a player . with the blade face 21 obstructed by alignment bar 22 the golfer will not actually see the contact when stroking a ball , thus removing that anxiety , and encouraging a smoother stroke . elevated portions 23 , 24 at heel 17 and toe 18 are provided to raise blade face 21 a sufficient height to adequately contact ball b to impart momentum upon ball b . a visual marker 25 may further be place upon bridge 19 as to provide a target area for contracting ball b on blade face 21 during a swing . generally , marker 25 is intended to be place within the center of mass region of club head 14 which is commonly referred to as the “ sweet spot ” of putter 10 . striking of ball b at the center of mass of club head 14 is preferable as the weight of putter 10 behind blade face 21 will impart an equal balanced force upon ball b and transfer momentum upon ball b in a straight line . it is envisioned that marker 25 may be placed upon flat foot 27 , as seen in fig6 , or on bridge 19 , as seen in fig8 , as to be clearly visible to a player . marker 25 may be of any suitable shape , conventional in the art to aid in the targeting of contacting club head 14 with ball b . though depicted in fig6 as a crescent pointer design wherein the radius of the crescent portion of marker 25 matches the outer radius of the ball b for pinpoint accuracy , the marker 25 may be of any targeting marker design conventional in the art . it is advantageous that alignment bar 22 , shaft 15 , and rod 16 be of the same color , preferably a color which is distinct from that of grip section 12 and the remainder of club head 14 . use of a dynamically distinct color with alignment bar 22 , shaft 15 , and rod 16 will create an apparent differentiation of colors allow a player to better perceive the linear alignment of alignment bar 22 , shaft 15 , and rod 16 during a swing . alignment bar 22 , shaft 15 , and rod 16 may further be sized with similar width dimensions w . with substantially the same width w the relation of the shaft 15 and rod 16 with an identical looking alignment bar 22 will give the impression that the alignment bar 22 is an extension of shaft section 13 . as best seen in fig8 and 9 , putter 10 may be configured as a blade style putter with a cavity 26 in bridge 19 between elevated portions 23 , 24 at heel 17 and toe 18 , respectively . cavity 26 may be inset upon club head 14 as to create a flat foot 27 , as seen in fig3 , or , as can be seen in fig8 and 9 , may be left to create a blade type club head 14 without a flat foot 27 . further , as best seen in fig1 and 11 , putter 10 may be further configured as a mallet style putter formed with the flat foot 27 extended back from bridge 19 . in such blade and mallet style embodiments , marker 25 may be set upon the bridge 19 or flat foot 27 , respectively , to allow for adequate targeting of a swing for contact with ball b . as can be seen in fig1 , a wing style option of club head 14 may be created by narrowing bridge 19 to at or near the width w of alignment bar 22 , wherein toe 18 and heel 17 are left thick to maintain the balanced weight of club head 14 . in each of the putter &# 39 ; s 10 embodiments , club head 14 is envisioned to be composed of steel , graphite , carbon fiber , or composite materials such as that of shaft section 13 , wherein the weight of putter 10 would be evenly balanced throughout . though , it should be understood that club head 14 may be composed of whichever material suitable to those skilled in the art including , but not limited to , manganese bronze , beryllium copper , or carbon steel . having thus described exemplary embodiments of the present invention , it should be noted by those skilled in the an that the within disclosures are exemplary only , and that various other alternatives , adaptations , and modifications may be made within the scope of the present invention , such as the creation of a milled style putter milled from a single block of metal , an insert type putter running cavity 26 completely through bridge 19 and inserting a desired hard or soft insert material , an onset putter having blade face 21 in front of the meeting point of the shaft section 13 and club head 14 thus placing the face closer to a golf hole , an offset putter having blade face 21 behind the meeting point of the shaft section 13 and club head 14 thus placing the face farther than the shaft section 13 to a golf hole , a toe weighted putter 10 having shaft section 13 meet club head 14 at the toe , and center shafted putters having the shaft section 13 meet club head 14 on bridge 19 . accordingly , the present invention is not limited to the specific embodiments as illustrated herein , but is limited only by the following claims . | US-201615216869-A |
a cone hair care brush is provided which enables multiple curls of varying diameters within each lock of hair . also , the cone hairbrush allows for a root lifter to achieve more body to the overall look of the hair by applying the smallest end of the cone brushhead invention to the scalp while lifting and blow drying the hair simultaneously . the cone brushhead may include ventilation holes that would allow the hair to blow dry much faster . | with general reference to the drawings a cone brush head for styling hair is identified at reference numeral 10 and includes a rigid body 12 ideally molded from plastic and metal material . fig1 - 4 illustrate one embodiment of the cone brush head 10 of the present invention . with initial reference to fig1 is a front view of a person with a view of the cone brush head ( as viewed by the viewer ). brush 10 of the present invention is illustrated to generally include a main body 12 having a handle portion 14 and a head portion 16 . fig2 a illustrate an embodiment of the cone brush head 10 of the present invention . fig2 b illustrates a top end view at the vertex of the cone brush head 10 . fig2 c illustrates an exploded view of the top end of the cone brush head 10 with and without a portion of the bristles 30 to better define the details of the invention 10 . fig3 a illustrates an exploded side view of the present invention 10 showing only the inside portion . fig3 b illustrates the metal hollow cavity 16 excluding the bristles 30 . fig4 illustrates an additional exploded side view of the brush head embodiment 10 that includes the metal material 16 in a flat form . the main body 12 is ideally made of plastic and metal material . the handle portion 14 is generally cylindrical in shape . a distal end 22 of the handle portion 14 includes an aperture 20 so that the brush 10 can be hung from a peg . the head portion 16 of the brush 10 is specifically cone in shape and made of thin metal material with a cone shaped hollow cavity 16 along its length and has defined thereon a number of holes 17 . these holes include circular holes 17 that allow the air from the hot - air brush to pass through the cone brush head 10 , thereby aiding in the drying and shaping of the hair . with particular reference to fig2 c , fig3 a and fig4 the bristled element 30 of the brush 10 of the present invention is constructed in a conventional manner to include a pair of metal wires 40 . the wires 40 are twisted one to the other in an elongated fashion and capture a plurality of bristles 30 protruding through the round air vents 17 of the cone brush head 10 portion . a retainer cap 18 , preferably made of plastic material , is located at the vertex top end view of the cone brush head 10 . fig5 a - 6 illustrate an alternate embodiment of the cone brush head 200 of the present invention . fig5 a illustrates a frontal view of hair brush 200 . fig5 b illustrates a top view of hair brush 200 . fig5 c illustrates an additional top view with a small exploded view of hair brush 200 . fig6 illustrates an exploded frontal view of hair brush 200 . as shown in fig5 a , hair brush 200 includes a handle 214 , a cone brush head 216 , and bristles 230 . in the embodiment shown in fig5 a , the cone brush head 200 is hollow and has a defined number of holes 217 that aide in the drying process . the difference between hair brush 10 and hair brush 200 is that the materials used in hair brush 10 contain metal and plastic while hair brush 200 is made of plastic material . also , in hair brush 10 the bristles 30 protrude through the air vent holes 17 of the cone brush head while the bristles 230 of hair brush 200 are attached to the surface and radiate outward of hair brush 200 . fig7 a - 8 illustrate still another alternate embodiment of the cone brush head 300 of the present invention . fig7 a illustrate a frontal view of the hair brush 300 . fig7 b illustrate a top end view of the brush head 300 . fig7 c illustrate an additional top end view with a small exploded view of hair brush 300 . fig8 a illustrate an exploded frontal view of hair brush 300 . as shown in fig7 a , hair brush 300 includes a handle 314 , a cone brush head 316 , and bristles 330 . in the embodiment shown in fig7 a , the cone brush head 300 is hollow and has a defined number of holes 317 that aide in the drying process . in the embodiment shown in fig8 b , one difference between hair brush 200 and hair brush 300 is the root lifting tip 319 which is a continuation of bristles 330 located at the vertex top end of hair brush 300 . due to the unique shape of the cone brush head , different portions of hair are wrapped around a single area of the diameter and the resulting curls will vary , depending upon the diameter portion of the cone brush head onto which each part of hair is wound . for example , various curl sizes can be achieved by the use of this one present invention by simply wrapping the hair around a smaller or larger diameter of the cone brush head . the hair can start out having a small diameter , then progress to a larger diameter , then again to a larger diameter . thus , the use of the cone brush head provides the advantage of producing a helical curl with a continuum of differing diameters . also , the cone brush head provides an unexpected advantage of a root lifter due to the small size diameter located at the vertex of the brush head . root lifting can be achieved by selecting a portion of damp hair at the roots touching the scalp and partially drying the hair before wrapping it around the diameter of choice , then blow drying the hair for rapid curl results . conventional hot - air brushes are unable to provide the advantages and / or hair styling shapes and techniques obtained by using the cone brush head of the present invention . this is the result of the hair being wrapped around a cylindrical curler having a single diameter . also there would be a need for multiple hairbrushes to produce similar curl diameters that this one present invention provides . additionally , the unique shape of the cone brush head allows the hairbrush of the present invention to be used in a manner which can not be duplicated using conventional , cylindrical hairbrushes . for example , the cone brush head can provide small to large size curls with a single lock of hair that achieves a unique spiral curl technique in one setting . while several preferred embodiments of this invention have been described in the specification and illustrated in the drawings with reference to a preferred embodiment , it is to be understood that this invention is not limited to these precise embodiments and that it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope or spirit of the invention as defined in the appended claims . | US-18940702-A |
buccal aerosol sprays or capsules using polar and non - polar solvents have now been developed which provide alprazolam for rapid absorption through the oral mucosa , resulting in fast onset of effect . the buccal polar compositions of the invention comprise formulation i : aqueous polar solvent , alprazolam , and optional flavoring agent ; formulation ii : aqueous polar solvent , alprazolam , optionally flavoring agent , and propellant ; formulation iii : non - polar solvent , alprazolam , and optional flavoring agent ; formulation iv : non - polar solvent , alprazolam , optional flavoring agent , and propellant ; formulation v : a mixture of a polar solvent and a non - polar solvent , alprazolam , and optional flavoring agent ; formulation vi : a mixture of a polar solvent and a non - polar solvent , alprazolam , optional flavoring agent , and propellant . | the preferred active compounds of the present invention are in an ionized , salt form or as the free base of the pharmaceutically acceptable salts thereof ( provided , for the aerosol or pump spray compositions , they are soluble in the spray solvent ). these compounds are soluble in the non - polar solvents of the invention at useful concentrations or can be prepared as pastes at useful concentrations . these concentrations may be less than the standard accepted dose for these compounds since there is enhanced absorption of the compounds through the oral mucosa . this aspect of the invention is especially important when there is a large ( 40 - 99 . 99 %) first pass effect . as propellants for the non polar sprays , propane , n - butane , iso - butane , n - pentane , iso - pentane , and neo - pentane , and mixtures thereof may be used . n - butane and iso - butane , as single gases , are the preferred propellants . it is permissible for the propellant to have a water content of no more than 0 . 2 %, typically 0 . 1 - 0 . 2 %. all percentages herein are by weight unless otherwise indicated . it is also preferable that the propellant be synthetically produced to minimize the presence of contaminants which are harmful to the active compounds . these contaminants include oxidizing agents , reducing agents , lewis acids or bases , and water . the concentration of each of these should be less than 0 . 1 %, except that water may be as high as 0 . 2 %. suitable non - polar solvents for the capsules and the non - polar sprays include ( c 2 - c 24 ) fatty acid ( c 2 - c 6 ) esters , c 7 - c 18 hydrocarbon , c 2 - c 6 alkanoyl esters , and the triglycerides of the corresponding acids . when the capsule fill is a paste , other liquid components may be used instead of the above low molecular weight solvents . these include soya oil , corn oil , other vegetable oils . as solvents for the polar capsules or sprays there may be used low molecular weight polyethyleneglycols ( peg ) of 400 - 1000 mw ( preferably 400 - 600 ), low molecular weight ( c 2 - c 8 ) mono and polyols and alcohols of c 7 - c 18 linear or branch chain hydrocarbons , glycerin may also be present and water may also be used in the sprays , but only in limited amount in the capsules . it is expected that some glycerin and water used to make the gelatin shell will migrate from the shell to the fill during the curing of the shell . likewise , there may be some migration of components from the fill to the shell during curing and even throughout the shelf - life of the capsule . therefore , the values given herein are for the compositions as prepared , it being within the scope of the invention that minor variations will occur . the preferred flavoring agents are synthetic or natural oil of peppermint , oil of spearmint , citrus oil , fruit flavors , sweeteners ( sugars , aspartame , saccharin , etc . ), and combinations thereof . the compositions may further include a taste mask . the term “ taste mask ” as used herein means an agent that can hide or minimize an undesirable flavor such as a bitter or sour flavor . a representative taste masks is a combination of vanillin , ethyl vanillin , maltol , iso - amyl acetate , ethyl oxyhydrate , anisic aldehyde , and propylene glycol ( commercially available as “ pfc 9885 bitter mask ” from pharmaceutical flavor clinic of camden , n . j .). a taste mask in combination with a flavoring agent is particularly advantageous when the active compound is an alkaloid since alkaloids often have a bitter taste . the active substances include the active compounds selected from the group consisting of cyclosporine , sermorelin , octreotide acetate , calcitonin - salmon , insulin lispro , sumatriptan succinate , clozepine , cyclobenzaprine , dexfenfluramine hydrochloride , glyburide , zidovudine , erythromycin , ciprofloxacin , ondansetron hydrochloride , dimenhydrinate , cimetidine hydrochloride , famotidine , phenytoin sodium , phenytoin , carboprost thromethamine , carboprost , diphenhydramine hydrochloride , isoproterenol hydrochloride , terbutaline sulfate , terbutaline , theophylline , albuterol sulfate and neutraceuticals , that is to say nutrients with pharmacological action such as but not limited to carnitine , valerian , echinacea , and the like . in another embodiment , the active compound is a p - fox ( fatty acid oxidation ) inhibitor , acetylcholinesterase inhibitor , nerve impulse inhibitor , anti - cholinergic , anti - convulsant , anti - psychotic , anxiolytic agent , dopamine metabolism inhibitor , agent to treat post stroke sequelae , neuroprotectant , agent to treat alzheimer &# 39 ; s disease , neurotransmitter , neurotransmitter agonist , sedative , agent for treating attention deficit disorder , agent for treating narcolepsy , central adregenic antagonist , anti - depression agent , agent for treating parkinson &# 39 ; s disease , benzodiazepine antagonist , stimulant , neurotransmitter antagonist , tranquilizer , or a mixture thereof . in one embodiment the active compound is a p - fox inhibitor . a suitable p - fox inhibitor for use in the buccal sprays of the invention includes , but is not limited to , ranolazine . in one embodiment the active compound is an acetylcholinesterase inhibitor . suitable acetylcholinesterase inhibitors for use in the buccal sprays of the invention include , but are not limited to , galantamine , neostigmine , physostigmine , and edrophonium . in one embodiment the active compound is a nerve impulse inhibitor . suitable nerve impulse inhibitors for use in the buccal sprays of the invention include , but are not limited to , levobupivacaine , lidocaine , prilocaine , mepivacaine , propofol , rapacuronium bromide , ropivacaine , tubocurarine , atracurium , doxaurium , mivacurium , pancuronium , vercuronium , pipecuronium , and rocuronium . in one embodiment the active compound is an anti - cholinergic . suitable anti - cholinergics for use in the buccal sprays of the invention include , but are not limited to , amantadine , ipratropium , oxitropium , and dicycloverine . in one embodiment the active compound is an anti - convulsant . suitable anti - convulsants for use in the buccal sprays of the invention include , but are not limited to , acetazolamide , carbamazepine , clonazepam , diazepam , divalproex ( valproic acid ), ethosuximide , lamotrignine acid , levetriacetam , oxcarbazepine , phenobarbital , phenytoin , pregabalin , primidone , remacemide , trimethadione , topiramate , vigabatrin , and zonisamide . in one embodiment the active compound is an anti - psychotic . suitable anti - psychotics for use in the buccal sprays of the invention include , but are not limited to , amisulpride , aripiprazole bifemelane , bromperidol , clozapine , chlorpromazine , haloperidol , iloperidone loperidone , olanzapine , quetiapine , fluphenazine , fumarate , risperidone , thiothixene , thioridazine , sulpride , and ziprasidone , in one embodiment the active compound is an anxiolytic agent . suitable anxiolytic agents for use in the buccal sprays of the invention include , but are not limited to , amitryptiline , atracurium , buspirone , chlorzoxazone , clorazepate , cisatracurium , cyclobenzaprine , eperisone , esopiclone , hydroxyzine , mirtazapine , mivacurium , pagoclone , sulperide , zaleplon , and zopiclone . in one embodiment the active compound is a dopamine metabolism inhibitor . suitable dopamine metabolism inhibitors for use in the buccal sprays of the invention include , but are not limited to , entacapone , lazebemide , selegiline , and tolcapone . in one embodiment the active compound is an agent to treat post stroke sequelae . suitable agents to treat post stroke sequelae for use in the buccal sprays of the invention include , but are not limited to , glatiramer , interferon beta 1a , interferon beta 1b , estradiol , and progesterone . in one embodiment the active compound is a neuroprotectant . suitable neuroprotectants for use in the buccal sprays of the invention include , but are not limited to , donepezil , memanine , nimodipine , riluzole , rivastigmine , tacrine , tak147 , and xaliproden . in one embodiment the active compound is an agent to treat alzheimer &# 39 ; s disease . suitable agents to treat alzheimer &# 39 ; s disease for use in the buccal sprays of the invention include , but are not limited to , carbidopa , levodopa , tacrine , donezepil , rivastigmine , and galantamine . in one embodiment the active compound is a neurotransmitter . suitable neurotransmitters for use in the buccal sprays of the invention include , but are not limited to , acetylcholine , serotonin , 5 - hydroxytryptamine ( 5 - ht ), gaba , glutamate , aspartate , glycine , histamine , epinephrine , norpinephrine , dopamine , adenosine , atp , and nitric oxide . in one embodiment the active compound is a neurotransmitter agonist . suitable neurotransmitter agonists for use in the buccal sprays of the invention include , but are not limited to , almotriptan , aniracetam , atomoxetine , benserazide , bromocriptine , bupropion , cabergoline , citalopram , clomipramine , desipramine , diazepam , dihydroergotamine , doxepin duloxetine , eletriptan , escitalopram , fluvoxamine , gabapentin , imipramine , moclobemide , naratriptan , nefazodone , nefiracetam acamprosate , nicergoline , nortryptiline , paroxetine , pergolide , pramipexole , rizatriptan , ropinirole , sertraline , sibutramine , sumatriptan , tiagabine , trazodone , venlafaxine , and zolmitriptan . in one embodiment the active compound is a sedative . suitable sedatives for use in the buccal sprays of the invention include , but are not limited to , dexmedetomidine , eszopiclone , indiplon , zolpidem , and zaleplon . in one embodiment the active compound is an agent for treating attention deficit disorder . suitable agents for treating attention deficit disorder for use in the buccal sprays of the invention include , but are not limited to , amphetamine , dextroamphetamine , methylphenidate , and pemoline . in one embodiment the active compound is an agent for treating narcolepsy . suitable agents for treating narcolepsy for use in the buccal sprays of the invention include , but are not limited to , modafinil and mazindol . in one embodiment the active compound is a central adregenic antagonists . a suitable central adregenic antagonists for use in the buccal sprays of the invention includes , but is not limited to , mesoridazine . in one embodiment the active compound is an anti - depression agent . suitable anti - depression agents for use in the buccal sprays of the invention include , but are not limited to , amitriptyline , amoxapine , bupropion , clomipramine , clomipramine , clorgyline , desipramine , doxepin , fluoxetine , imipramine , isocarboxazid , maprotiline , mirtazapine , nefazodone , nortriptyline , paroxetine , phenelzine , protriptyline , sertraline , tranylcypromine , trazodone , and venlafaxine . in one embodiment the active compound is an agent for treating parkinson &# 39 ; s disease . suitable agents for treating parkinson &# 39 ; s disease for use in the buccal sprays of the invention include , but are not limited to , amantadine , bromocriptine , carvidopa , levodopa , pergolide , and selegiline . in one embodiment the active compound is a benzodiazepine antagonist . a suitable benzodiazepine antagonist for use in the buccal sprays of the invention includes , but is not limited to , flumazenil . in one embodiment the active compound is a neurotransmitter antagonist . a suitable neurotransmitter antagonist for use in the buccal sprays of the invention includes , but is not limited , to deramciclane . in one embodiment the active compound is a stimulant . suitable stimulants for use in the buccal sprays of the invention include , but are not limited to , amphetamine , dextroamphetamine , dinoprostone , methylphenidate , methylphenidate , modafinil , and pemoline . in one embodiment the active compound is a tranquilizer . a suitable tranquilizer for use in the buccal sprays of the invention includes , but is not limited to , mesoridazine . in one embodiment , the active compound is alprazolam or a pharmaceutically acceptable salt thereof . typically , when the active compound is alprazolam or a pharmaceutically acceptable salt thereof the buccal spray composition contains form about 0 . 01 to 20 weight / weight ( w / w ) percent alprazolam or a pharmaceutically acceptable salt thereof , preferably , about 0 . 1 to 15 w / w percent , and more preferably about 0 . 2 to 10 w / w percent alprazolam or a pharmaceutically acceptable salt thereof . the invention further relates to a method of treating anxiety in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising alprazolam or a pharmaceutically acceptable salt thereof . the invention further relates to a method of treating panic disorder in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising alprazolam or a pharmaceutically acceptable salt thereof . the invention further relates to a method of inducing sleep in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising alprazolam or a pharmaceutically acceptable salt thereof . the invention further relates to a method of treating the symptoms of premenstrual syndrome in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising alprazolam or a pharmaceutically acceptable salt thereof . the invention further relates to a method of treating chemotherapy induced emesis in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising alprazolam or a pharmaceutically acceptable salt thereof . the invention further relates to a method of treating irritable - bowel syndrome in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising alprazolam or a pharmaceutically acceptable salt thereof . the formulations of the present invention comprise an active compound or a pharmaceutically acceptable salt thereof . the term “ pharmaceutically acceptable salts ” refers to salts prepared from pharmaceutically acceptable non - toxic acids or bases including organic and inorganic acids or bases . when an active compound of the present invention is acidic , salts may be prepared from pharmaceutically acceptable non - toxic bases . salts derived from all stable forms of inorganic bases include aluminum , ammonium , calcium , copper , iron , lithium , magnesium , manganese , potassium , sodium , zinc , etc . particularly preferred are the ammonium , calcium , magnesium , potassium , and sodium salts . salts derived from pharmaceutically acceptable organic non - toxic bases include salts of primary , secondary , and tertiary amines , substituted amines including naturally occurring substituted amines , cyclic amines and basic ion - exchange resins such as arginine , betaine , caffeine , choline , n , n dibenzylethylenediamine , diethylamine , 2 - diethylaminoethanol , 2 - dimethyl - aminoethanol , ethanolamine , ethylenediamine , n - ethylmorpholine , n - ethylpiperidine , glucamine , glucosamine , histidine , isopropylamine , lysine , methyl - glucosamine , morpholine , piperazine , piperidine , polyamine resins , procaine , purine , theobromine , triethylamine , trimethylamine , tripropylamine , etc . when an active compound of the present invention is basic , salts may be prepared from pharmaceutically acceptable non - toxic acids . such acids include acetic , benzenesulfonic , benzoic , camphorsulfonic , citric , ethane - sulfonic , fumaric , gluconic , glutamic , hydrobromic , hydrochloric , isethionic , lactic , maleic , mandelic , methanesulfonic , mucic , nitric , pamoic , pantothenic , phosphoric , succinic , sulfuric , tartaric , p - toluenesulfonic , etc . particularly preferred are citric , hydrobromic , maleic , phosphoric , sulfuric , and tartaric acids . in the discussion of methods of treatment herein , reference to the active compounds is meant to also include the pharmaceutically acceptable salts thereof . while certain formulations are set forth herein , the actual amounts to be administered to the mammal or man in need of same are to be determined by the treating physician . the invention is further defined by reference to the following examples , which are intended to be illustrative and not limiting . the following are examples of certain classes . all values unless otherwise specified are in weight percent . most amounts preferred amount preferred amount cyclosporine 5 - 50 10 - 35 15 - 25 water 5 - 20 7 . 5 - 50 9 . 5 - 12 ethanol 5 - 60 7 . 5 - 50 10 - 20 polyethylene glycol 20 - 60 30 - 45 35 - 40 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount cyclosporine 1 - 50 3 - 40 5 - 30 migylol 20 25 30 - 40 polyoxyethylated 20 25 30 - 40 castor oil butane 25 - 80 30 - 70 33 - 50 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount cyclosporine 1 - 35 5 - 25 10 - 20 olive oil 25 - 60 35 - 55 30 - 45 polyoxyethylated 25 - 60 35 - 55 30 - 45 oleic glycerides flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount cyclosporine 5 - 50 10 - 35 15 - 25 polyethylene 20 - 60 30 - 45 35 - 40 glycol glycerin 5 - 30 7 . 5 - 25 10 - 20 propylene glycol 5 - 30 7 . 5 - 25 10 - 20 flavors 0 . 1 - 10 1 - 8 3 - 6 amounts preferred amount most preferred sermorelin ( as the . 01 - 5 . 1 - 3 . 2 - 1 . 0 acetate ) mannitol 1 - 25 5 - 20 10 - 15 monobasic sodium 0 . 1 - 5 1 - 31 . 5 - 2 . 5 phosphate , dibasic sodium 0 . 01 - 5 . 05 - 3 0 . 1 - 0 . 5 phosphate water ethanol 5 - 30 7 . 5 - 25 9 . 5 - 15 polyethylene glycol 20 - 60 30 - 45 35 - 40 propylene glycol 5 - 25 10 - 20 12 - 17 flavors 0 . 1 - 5 1 - 4 2 - 3 most amounts preferred amount preferred amount octreotide acetate 0 . 001 - 0 . 5 0 . 005 - 0 . 250 0 . 01 - 0 . 10 acetic acid 1 - 10 2 - 8 4 - 6 sodium acetate 1 - 10 2 - 8 4 - 6 sodium chloride 3 - 30 . 5 - 25 15 - 20 flavors 0 . 1 - 5 0 . 5 -. 4 2 - 3 ethanol 5 - 30 7 . 5 - 20 9 . 5 - 15 water 15 - 95 35 - 90 65 - 85 flavors 0 . 1 - 5 1 - 4 2 - 3 most amounts preferred amount preferred amount calcitonin - salmon 0 . 001 - 5 0 . 005 - 2 01 - 1 . 5 ethanol 2 - 15 3 - 10 7 - 9 . 5 water 30 - 95 50 - 90 60 - 80 polyethylene 2 - 15 3 - 10 7 - 9 . 5 glycol sodium chloride 2 . 5 - 20 5 - 15 10 - 12 . 5 flavors 0 . 1 - 5 1 - 4 2 - 3 most amounts preferred amount preferred amount insulin 20 - 60 4 - 55 5 - 50 glycerin 0 . 1 - 10 0 . 25 - 5 0 . 1 - 1 . 5 dibasic sodium 1 - 15 2 . 5 - 10 4 - 8 phosphate m - cresol , 1 - 25 5 - 25 7 . 5 - 12 . 5 zinc oxide 0 . 01 - 0 . 25 . 05 - 0 . 15 0 . 075 - 0 . 10 m - cresol 0 . 1 - 1 0 . 2 - 0 . 8 0 . 4 - 0 . 6 phenol trace amounts trace amounts trace amounts ethanol 5 - 20 7 . 5 - 15 9 - 12 water 30 - 90 40 - 80 50 - 75 propylene glycol 5 - 20 7 . 5 - 15 9 - 12 flavors 0 . 1 - 5 0 . 5 - 3 0 . 75 - 2 cns active amines and their salts : including but not limited to tricyclic amines , gaba analogues , thiazides , phenothiazine derivatives , serotonin antagonists and serotonin reuptake inhibitors most amounts preferred amount preferred amount sumatriptan succinate 0 . 5 - 30 1 - 20 10 - 15 ethanol 5 - 60 7 . 5 - 50 10 - 20 propylene glycol 5 - 30 7 . 5 - 20 10 - 15 polyethylene glycol 0 - 60 30 - 45 35 - 40 water 5 - 30 7 . 5 - 20 10 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 most amounts preferred amount preferred amount sumatriptan succinate 0 . 01 - 5 0 . 05 - 3 . 5 0 . 075 - 1 . 75 polyethylene glycol 25 - 70 30 - 60 35 - 50 glycerin 25 - 70 30 - 60 35 - 50 flavors 0 . 1 - 10 1 - 8 3 - 6 most preferred amounts preferred amount amount clozepine 0 . 5 - 30 1 - 20 10 - 15 ethanol 5 - 60 7 . 5 - 50 10 - 20 propylene glycol 5 - 30 7 . 5 - 20 10 - 15 polyethylene glycol 0 - 60 30 - 45 35 - 40 water 5 - 30 7 . 5 - 20 10 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount clozepine 0 . 5 - 30 1 - 20 10 - 15 migylol 20 - 85 25 - 70 30 - 40 butanol 5 - 80 30 - 75 60 - 70 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount clozepine 0 . 5 - 30 1 - 20 10 - 15 migylol 70 - 99 . 5 80 - 99 85 - 90 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount cyclobenzaprine 0 . 5 - 30 1 - 20 10 - 15 ( base ) migylol 20 - 85 25 - 70 30 - 40 iso - butane 15 - 80 30 - 75 60 - 70 flavors 0 . 1 - 5 1 - 4 2 - 3 most preferred amounts preferred amount amount dexfenfluramine hcl 5 - 30 7 . 5 - 20 10 - 15 ethanol 5 - 60 7 . 5 - 50 10 - 20 propylene glycol 5 - 30 7 . 5 - 20 10 - 15 polyethylene glycol 0 - 60 30 - 45 35 - 40 water 5 - 30 7 . 5 - 20 10 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 most amounts preferred amount preferred amount glyburide 0 . 25 - 25 0 . 5 - 20 0 . 75 - 15 ethanol 5 - 60 − 7 . 5 - 50 10 - 20 propylene glycol 5 - 30 7 . 5 - 20 10 - 15 polyethylene glycol 0 - 60 30 - 45 35 - 40 water 2 . 5 - 30 5 - 20 6 - 15 flavors 0 . 1 - 5 1 - 4 2 - 3 most amounts preferred amount preferred amount glyburide 0 . 01 - 10 0 . 025 - 7 . 5 0 . 1 - 4 olive oil 30 - 60 35 - 55 30 - 50 polyoxyethylated oleic 30 - 60 35 - 55 30 - 50 glycerides flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount zidovudine 10 - 50 15 - 40 25 - 35 soya oil 20 - 85 25 - 70 30 - 40 butane 15 - 80 30 - 75 60 - 70 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount erythromycin 25 - 65 30 - 50 35 - 45 polyoxyethylene 5 - 70 30 - 60 45 - 55 glycol glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 flavors 1 - 10 2 - 8 3 - 6 amounts preferred amount most preferred amount ciprofloxacin 25 - 65 35 - 55 40 - 50 hydrochloride glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 polyethylene 120 - 75 30 - 65 40 - 60 glycol flavors 1 - 10 2 - 8 3 - 6 preferred most preferred amounts amount amount zidovudine 10 - 50 15 - 40 25 - 35 water 30 - 80 40 - 75 45 - 70 ethanol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 polyethylene glycol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 flavors 0 . 1 - 5 1 - 4 2 - 3 preferred most amounts amount preferred amount ondansetron hydrochloride 1 - 25 2 - 20 2 . 5 - 15 citric acid monohydrate 1 - 10 2 - 8 2 . 5 - 5 sodium citrate dihydrate 0 . 5 - 5 1 - 4 1 . 25 - 2 . 5 water 1 - 90 5 - 85 10 - 75 ethanol 5 - 30 7 . 5 - 20 9 . 5 - 15 propylene glycol 5 - 30 7 . 5 - 20 9 . 5 - 15 polyethylene glycol 5 - 30 7 . 5 - 20 9 . 5 - 15 flavors 1 - 10 3 - 8 5 - 7 . 5 preferred amounts amount most preferred amount dimenhydrinate 0 . 5 - 30 2 - 25 3 - 15 glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 polyethylene glycol 45 - 95 50 - 90 55 - 85 flavors 1 - 10 2 - 8 3 - 6 preferred amounts amount most preferred amount dimenhydrinate 3 - 50 4 - 40 5 - 35 water 5 - 90 10 - 80 15 - 75 ethanol 1 - 80 3 - 50 5 - 10 polyethylene glycol 1 - 80 3 - 50 5 - 15 sorbitol 0 . 1 - 5 0 . 2 - 40 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 preferred amounts amount most preferred amount cimetidine hcl 10 - 60 15 - 55 25 - 50 glycerin 5 - 20 7 . 5 - 15 10 - 12 . 5 polyethylene glycol 20 - 90 25 - 85 30 - 75 flavors 1 - 10 2 - 8 3 - 6 preferred amounts amount most preferred amount famotidine 1 - 35 5 - 30 7 - 20 water 2 . 5 - 25 3 - 20 5 - 10 l - aspartic acid 0 . 1 - 20 1 - 15 5 - 10 polyethylene glycol 20 - 97 30 - 95 50 - 85 flavors 0 . 1 - 10 1 - 7 . 5 2 - 5 amounts preferred amount most preferred amount famotidine 1 - 35 5 - 30 7 - 20 soya oil 10 - 50 15 - 40 15 - 20 butanel 5 - 80 30 - 75 45 - 70 polyoxyethylated 10 - 50 15 - 40 15 - 20 oleic glycerides flavors 0 . 1 - 5 1 - 4 2 - 3 preferred amounts amount most preferred amount phenytoin sodium 10 - 60 15 - 55 20 - 40 water 2 . 5 - 25 3 - 20 5 - 10 ethanol 5 - 30 7 . 5 - 20 9 . 5 - 15 propylene glycol 5 - 30 7 . 5 - 20 9 . 5 - 15 polyethylene glycol 5 - 30 7 . 5 - 20 9 . 5 - 15 flavors 1 - 10 3 - 8 5 - 7 . 5 preferred most preferred amounts amount amount phenytoin 5 - 45 10 - 40 15 - 35 migylol 10 - 50 15 - 40 15 - 20 butane 15 - 80 30 - 75 60 - 70 polyoxyethylated 10 - 50 15 - 40 15 - 20 oleic glycerides flavors 0 . 1 - 10 1 - 8 5 - 7 . 5 preferred most amounts amount preferred amount carboprost thromethamine 0 . 05 - 5 0 . 1 - 3 0 . 25 - 2 . 5 water 50 - 95 60 - 80 65 - 75 ethanol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 polyethylene glycol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 sodium chloride 1 - 20 3 - 15 4 - 8 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount carboprost 0 . 05 - 5 0 . 1 - 3 0 . 25 - 2 . 5 migylol 25 - 50 30 - 45 35 - 40 butane 5 - 60 10 - 50 20 - 35 polyoxyethylated 25 - 50 30 - 45 35 - 40 oleic glycerides flavors 0 . 1 - 10 1 - 8 5 - 7 . 5 amounts preferred amount most preferred amount carnitine 6 - 80 30 - 70 45 - 65 fumarate soya oil 7 . 5 - 50 10 - 40 12 . 5 - 35 soya lecithin 0 . 001 - 1 . 0 0 . 005 - 0 . 5 . 01 - 0 . 1 soya fats 7 . 5 - 50 10 - 40 12 . 5 - 35 flavors 1 - 10 2 - 8 3 - 6 preferred amounts amount most preferred amount valerian extract 0 . 1 - 10 0 . 2 - 7 0 . 25 - 5 water 50 - 95 60 - 80 65 - 75 ethanol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 polyethylene glycol 5 - 20 7 . 5 - 15 9 . 5 - 12 . 5 flavors 1 - 10 2 - 8 3 - 6 preferred amounts amount most preferred amount echinacea extract 30 - 85 40 - 75 45 - 55 soya oil 7 . 5 - 50 10 - 40 12 . 5 - 35 soya lecithin 0 . 001 - 1 . 0 0 . 005 - 0 . 5 . 01 - 0 . 1 soya fats 7 . 5 - 50 10 - 40 12 . 5 - 35 flavors 1 - 10 2 - 8 3 - 6 preferred amounts amount most preferred amount magnesium oxide 15 - 40 20 - 35 25 - 30 chromium picolinate 0 . 01 - 1 . 0 0 . 02 - 0 . 5 . 025 - 0 . 75 folic acid . 025 - 3 . 0 0 . 05 - 2 . 0 0 . 25 - 0 . 5 vitamin b - 12 0 . 01 - 1 . 0 0 . 02 - 0 . 5 . 025 - 0 . 75 vitamin e 15 - 40 20 - 35 25 - 30 soya oil 10 - 40 12 . 5 - 35 15 - 20 soya lecithin 0 . 1 - 5 0 . 2 - 4 0 . 5 - 1 . 5 soya fat 10 - 40 15 - 35 17 . 5 - 20 preferred amounts amount most preferred amount diphenhydramine 3 - 50 . 4 - 40 5 - 35 hcl water 5 - 90 10 - 80 50 - 75 ethanol 1 - 80 3 - 50 5 - 10 polyethylene glycol 1 - 80 3 - 50 5 - 15 sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 preferred most amounts amount preferred amount isoproterenol hydrochloride 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 water 5 - 90 10 - 80 50 - 75 ethanol 1 - 80 3 - 50 5 - 10 polyethylene glycol 1 - 80 3 - 50 5 - 15 sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 preferred amounts amount most preferred amount terbutaline sulfate 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 water 5 - 90 10 - 80 50 - 75 ethanol 1 - 10 2 - 8 2 . 5 - 5 sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 preferred most preferred amounts amount amount terbutaline 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 migylol 25 - 50 30 - 45 35 - 40 isobutane 5 - 60 10 - 50 20 - 35 polyoxyethylated 25 - 50 30 - 45 35 - 40 oleic glycerides flavors 0 . 1 - 10 1 - 8 5 - 7 . 5 preferred amounts amount most preferred amount theophylline 5 - 50 10 - 40 15 - 30 polyethylene glycol 20 - 60 25 - 50 30 - 40 glycerin 25 - 50 35 - 45 30 - 40 propylene glycol 25 - 50 35 - 45 30 - 40 flavors 0 . 1 - 5 1 - 4 2 - 3 amounts preferred amount most preferred amount albuterol sulfate 0 . 1 - 10 0 . 2 - 7 . 5 0 . 5 - 6 water 5 - 90 10 - 80 50 - 75 ethanol 1 - 10 2 - 8 2 . 5 - 5 sorbitol 0 . 1 - 5 0 . 2 - 4 0 . 4 - 1 . 0 aspartame 0 . 01 - 0 . 5 0 . 02 - 0 . 4 0 . 04 - 0 . 1 flavors 0 . 1 - 5 1 - 4 2 - 3 preferred most - preferred amount amount amount glyburide 0 . 1 - 25 % 0 . 5 - 15 % 0 . 6 - 10 % ethanol 40 - 99 % 60 - 97 % 70 - 97 % water 0 . 01 - 5 % 0 . 1 - 4 % 0 . 2 - 2 % flavors 0 . 05 - 10 % 0 . 1 - 5 % 0 . 1 - 2 . 5 % propellant 2 - 10 % 3 - 5 % 3 - 4 % preferred most - preferred amount amount amount prostaglandin e 1 0 . 01 - 10 % 0 . 1 - 5 % 0 . 2 - 3 % ethanol 10 - 90 % 20 - 75 % 25 - 50 % propylene glycol 1 - 90 % 5 - 80 % 10 - 75 % water 0 . 01 - 5 % 0 . 1 - 4 % 0 . 2 - 2 % flavors 0 . 05 - 10 % 0 . 1 - 5 % 0 . 1 - 2 . 5 % propellant 2 - 10 % 3 - 5 % 3 - 4 % preferred most - preferred amount amount amount promethazine 1 - 25 % 3 - 15 % 5 - 12 % ethanol 10 - 90 % 20 - 75 % 25 - 50 % propylene glycol 1 - 90 % 5 - 80 % 10 - 75 % water 0 . 01 - 5 % 0 . 1 - 4 % 0 . 2 - 2 % flavors 0 . 05 - 10 % 0 . 1 - 5 % 0 . 1 - 2 . 5 % propellant 2 - 10 % 3 - 5 % 3 - 4 % preferred most - preferred amount amount amount meclizine 1 - 25 % 3 - 15 % 5 - 12 % ethanol 1 - 15 % 2 - 10 % 3 - 6 propylene glycol 20 - 98 % 5 - 90 % 10 - 85 % water 0 . 01 - 5 % 0 . 1 - 4 % 0 . 2 - 2 % flavors 0 . 05 - 10 % 0 . 1 - 5 % 0 . 1 - 2 . 5 % propellant 2 - 10 % 3 - 5 % 3 - 4 % a . a propellant free alprazolam formulation in a polar solvent has the following formula : component percent ( w / w ) alprazolam 1 . 03 bitter mask 0 . 1 oleic acid 0 . 1 alpha - tocopherol acetate ( vitamin e ) 2 ethanol qs to 100 b . a propellant free alprazolam formulation in a non - polar solvent can be made according to the following formula : component percent ( w / w ) alprazolam 1 bitter mask 0 . 1 alpha - tocopherol acetate ( vitamin e ) 2 liquid paraffin qs to 100 c . a propellant free alprazolam formulation in a mixture of a polar solvent and a non - polar solvent has the following formula : component percent ( w / w ) alprazolam 1 migyol 810 20 polysorpate ( span ) 1 lemon oil 0 . 1 ethanol qs to 100 d . an alprazolam formulation in a polar solvent with a propellant can be made according to the following formula : component percent ( w / w ) alprazolam 1 bitter mask 0 . 2 ethanol 60 butane qs to 100 e . an alprazolam formulation in a non - polar solvent with a propellant can be made according to the following formula : component percent ( w / w ) alprazolam 1 lemon oil 0 . 2 miglyol 20 butane qs to 100 f . an alprazolam formulation in a mixture of a polar solvent and a non - polar solvent with a propellant can be made according to the following formula : component percent ( w / w ) alprazolam 1 miglyol 810 20 polysorpate ( span ) 1 lemon oil 0 . 1 ethanol 20 butane qs to 100 | US-67172003-A |
a simple , efficient , and rugged dairy parlor entry gate which is especially useful for identifying animals , minimizing the need for lead animals to back up as the gates swing open , and provides for indexing the animals into proper position . the entry gate preferably includes a pair of opposed stanchions defining therebetween a passageway , at least one and preferably a pair of gate members , and mounting structure for swingably carrying the gate members and mounting them in offset relationship . an antenna may be provided in each of the gate members so that the interrogation field generated thereby swings with the gate member . the gate also preferably includes a motive member for swinging the gate members between an open position allowing the passage of animals therebetween and a closed position which both inhibits the passage of animals into the parlor and indexes the last animal into a proper position . | referring now to the drawing , a dairy parlor entry gate 10 in accordance with the present invention is shown in fig1 and broadly includes a first stanchion 12 and a second stanchion 14 defining therebetween a passageway 16 , a first , upstream gate member 18 , a second , downstream gate member 20 , portal 22 , and motive member 24 . the portal 22 and first and second stanchions 12 and 14 overlie a floor 26 presenting a pathway p along which animals move before entering a milking parlor 28 , shown in fig2 - 5 . it may be appreciated that while the invention hereof is especially useful for dairy cows in conjunction with a milking parlor 28 , it is not intended to be limited to dairy cows but may be useful in handling beef cattle , goats , sheep , pigs or any other animal when controlled entry to of one or a number of animals to an area is desired . the present invention is shown as used in conjunction with a milking parlor for dairy cows , but could be used with pens , corrals , or any other area where restricted entry of animals is desired . as shown in fig4 passageway 16 is sized to receive a cow 30 for movement along a path 32 . the passageway 16 is preferably sized for a single animal , and has a width w , defined as the distance between stanchions 12 and 14 , of about 36 inches in the case of a passageway 16 sized for dairy cows . the cows 30 are retained in the passageway 30 when the gate members 18 and 20 are transverse to the path 32 and thus closed , as shown in fig3 . the stanchions 12 and 14 may include upright posts 34 and lead - in rails 36 , which direct the cows &# 39 ; movement along pathway 32 from an upstream end 38 of the passageway 16 to a downstream end 40 . preferably , each cow 30 entering the passageway 16 has a collar 42 from which a transponder tag 44 is suspended , although it will be understood by those skilled in the art that transponders can also be attached as an ear tag or injected as a bolus . the dairy parlor entry gate is shown in use with a parallel style milking facility wherein the floor 26 is elevated relative to an operators &# 39 ; pit 46 which typically separates two such floors 26 and provides access to the operator for attaching the milking machines to the teats of the cows on each of the floors separated by the pit 46 . to direct the cows into the passageway 16 and prevent undesired movement of the animals into the pit 46 , diversion panel 50 proximate the pit 46 side and first stanchion 12 and diversion panel 52 proximate the exit lane side and second stanchion 14 are provided . thus , cows 30 may be crowded into single file strings entering the passageway 16 and through the portal 22 into the milking parlor 28 . gate member 18 is located for swinging about an axis located on the pit 46 side of the passageway 16 and thus proximate the tail end of the animal in the parlor 28 , while gate member 20 is located for swinging about an axis located on the exit lane side of the passageway and thus more proximate the head end of the cow 30 turned normal to the path 32 while in a milking position in the parlor 28 . each gate member 18 , 20 includes a number of like components which are numbered similarly in the drawing , with the suffix &# 34 ; a &# 34 ; applying to the components of first , upstream gate member 18 and the suffix &# 34 ; b &# 34 ; referring to the components of the second , downstream gate member 20 . each of the gate members 18 , 20 thus include an upper axle bar 54 which carries a drive mount pipe 56 . a d - shaped main tube 58 includes an axis leg 59 which extends downwardly from the upper axle bar to a curve upon which a bracket 60 is mounted . the bracket is provided of stainless steel or the like with an axle foot 62 extending downwardly to receive thereon a swivel isolator 64 of ultra high molecular weight polyethylene ( uhmwpe ) or other suitable electrically non - conductive material . the swivel isolator 64 of each gate member is received in a socket 66 which is embedded in or otherwise anchored into the floor 26 . the main tube 58 also includes an upper arm 68 , an outboard leg 70 and a lower leg 72 . a column 67 intersects and is welded or otherwise secured to upper arm 68 , with strut 74 welded or otherwise secured to and extending upwardly from lower leg 72 in alignment with column 67 . crossbrace 76 connects column 67 to upper axle bar 54 and provides additional rigidity to the gate member . with the exception of the swivel isolator 64 , the aforementioned components of the gate members are preferably provided of tubular metal such as steel , aluminum or more preferably stainless steel . in addition , the second , downstream gate member 20 is designed so that the portion radially distanced from the swing axis comes proximate to the butt end of last cow 30 in the milking parlor 28 . to assist in moving the cow 30 into a proper , indexed position , an indexing extension 78 is vertically centered on the outboard leg 70b as shown in fig1 and 5 and includes an upper bend 80 welded at its upper end to outboard leg 70b and a lower bend 82 welded at its lower end to outboard leg 70b . the various components , including upper bend 80 and lower bend 82 are joined but prevented from coming into contact by couplers 84 , which may be tubular to present an access 86 therethrough in the case of couplers 84 &# 39 ; or solid as in the case of couplers 84 &# 34 ;. each of the couplers include an enlarged waist 88 which separates insert sections 90 and 92 sized to be received within the tubular components . the couplers 84 are preferably provided of uhmwpe or other synthetic resin materials . the drive mount pipes 56 are domed at the top and present a pair of apertures each receiving a rubber grommet 94 . the downstream end of the stanchions 12 , 14 further include respective side fences 96 and 98 to prevent the escape of cows 30 from adjacent the gate members 18 and 20 when the gate members are closed . the side fences 96 , 98 each include a plurality of respective vertically spaced curved bars 100 , 102 which are connected to a post 32 of the stanchions , the posts 32 of each of the stanchions 12 , 14 in turn being connected by an overhead arch 104 at both the upstream end and adjacent where the curved bars 100 and 102 are respectively connected to the downstream post 34 . a stop 106 provided with a rubber or synthetic resin bumper 108 is secured by welding or the like to one of the curved bars 100 and one of the curved bars 102 to prevent the gate members 18 and 20 from swinging too widely apart and thereby engaging the curved bars 100 and 102 . such overswinging has several disadvantages , including creating an undesired loop reducing the magnetic field , moving the gate members further away from the transponders as the cows move along the path 32 , and overstressing the mounts and motive member 24 , thereby lessening the mechanical efficiency . portal 22 includes an upright support 109 and a suspended archway 110 . the archway 110 is unitary and presents an upright strut 112 anchored to the floor 26 and a crossbar 114 which is welded to the support 108 . a first gate pivot mount 116 extends upstream from crossbar 114 and includes bearing fist 118 for pivotally receiving therein the drive mount pipe 56a of first upstream gate member 18 . for dairy cow applications , the first pivot mount 116 positions the axis of rotation of the first gate 18 centered in bearing fist 118 about 14 to 15 inches upstream from the centerline of the crossbar 114 . a stop bar 120 is connected to the crossbar 114 and oriented substantially parallel to the first pivot mount 116 , the stop bar 120 presenting a bumper 108 thereon for engaging the column 67a of the first gate member 18 when the latter swings to a closed position across the path 32 . a second gate pivot mount 122 extends a relatively short distance upstream from crossbar 114 and includes a bearing fist 124 thereon for pivotally receiving the gate mount pipe 56b of second downstream gate member 20 therein and defining a pivot or swing axis for the gate member 20 . for example , in a typical dairy cow application , the second pivot mount 122 positions the pivot axis of the second gate member 20 and thus the center of the bearing fist 124 only about 3 to 4 inches upstream from the crossbar 114 , thus providing an upstream separation and offset relationship between the first gate member 18 and the second gate member 20 . a second stop bar 126 is connected to the crossbar 114 and positioned closer to the centerline of the passageway 16 than the second pivot mount 122 , the second stop bar 126 also presenting a bumper 108 thereon for engaging the second gate member 20 when the latter swings into a closed , cow indexing position as shown in fig3 . the gate members 18 and 20 are preferably simultaneously actuated by motive member 24 to swing between the closed position shown in fig3 and the open position shown in fig4 . the motive member 24 is shown as including a double acting hydraulic cylinder 128 , but it is understood that motors , screw and follower devices , or other devices for extending and retracting could also be used . as shown in fig3 and 4 , one end of the hydraulic cylinder is pivotally connected to a link 130 in turn directly connected to a lug 132 on the first gate pivot mount 116 . a reciprocating shaft 134 extends from the other end of the cylinder 128 , the remote end of the shaft being pivotally connected to a drive mount tab 136 carried on drive mount pipe 56b of second gate member 20 . the drive mount pipes 56a and 56b of the respective first and second gate members 18 and 20 are further interconnected to permit simultaneous movement of the first gate member 18 with the second gate member 20 . a connecting rod 138 is coupled to a crank arm 140 of the drive mount pipe 56b of second gate member 20 and pivotally coupled to link tab 142 of drive mount pipe 56a of first gate member 18 . the crank arm 140 and the drive mount tab 136 are in fixed angular orientation to one another , both being welded or otherwise secured to the drive mount pipe 56b , whereby retraction of the shaft 134 into the cylinder causes the drive mount tab 136 to swing toward the cylinder 128 and pull second gate member 20 to the closed position shown in fig3 . as the drive mount tab 136 swings in a counterclockwise direction as viewed in fig3 and 4 , the crank arm 140 is also caused to swing in a counterclockwise direction , thereby pulling on connecting rod 138 and turning link tab 142 in a clockwise direction to close first upstream gate member 18 . first upstream gate member 18 receives therein an antenna 144 and second downstream gate member 20 receives therein an antenna 146 . each antenna 144 and 146 is in the form of an antenna wire 148 with a conduit 150 of copper or the like and a synthetic resin insulating sheath 152 to protect the wire and prevent short circuits with the gate members or other metallic components . fig5 illustrates the routing of the antenna wire 148 through couplers 84 &# 39 ; and the upper axle bar 54 and main tube 58 of each gate member 18 , 20 wherein the antennas are respectively received within the gate member and swing therewith . the antenna 144 within the first upstream gate 18 produces a first magnetic field 154 which is roughly elliptical presenting two foci , as is the second magnetic field 156 generated by antenna 146 within the second downstream gate 20 . as a result of their offset relationship along the path 32 , the fields 154 , 156 have respective predominant influences , with the first magnetic field 154 predominating upstream and closer to the pit 46 , while the second magnetic field predominates downstream and toward the exitway side of the gate 10 . to properly generate the first and second magnetic fields 154 , 156 diagrammatically illustrated in fig4 an axle wire 158 of one gate member is connected to the d - bar wire 160 of the other gate member , with the remaining axle wire 158 and the remaining d - bar wire 160 being routed for connection to an electronic board within a suitable controller , illustrated diagrammatically in fig5 by reference character 162 . to provide a substantial balance between the fields 154 , 156 , the wires should be of substantially equal length . a suitable controller for use in this application is the alpro ™ automation system controller available from alfa laval agri inc . of kansas city , mo . the milking parlor 28 illustrated in drawing fig2 through 4 is arranged in parallel milking stalls available as the alfa laval / blue diamond parallel stalls from alfa laval agri inc . of kansas city , mo . it may be appreciated that the present invention may also be used with other types of stalls or pens , including herringbone , tandem , and rotary milking parlors , as desired . such parallel parlors include pivotally mounted gang - type headstalls 164 for holding ( as in fig2 ) or releasing ( as shown in dashed lines in fig3 ) a plurality of cows 30 at a time . in order to realign the cows 30 with their heads toward the headstalls 164 and their butts toward the pit 46 , turnstyles 166 are provided which include dividers 168 which pivot about a vertical axis as each successive cow 30 in a string enters the parlor 28 , proceeds to the furthest available stall , and is indexed into a parallel , milking position shown in fig3 . upright support 109 is connected or positioned adjacent to an exit fence 170 which , together with diversion panel 52 , keeps cows 30 not in passageway 16 away from the gate members 18 , 20 to avoid miscounts and misidentification of cows 30 which are part of the entering string . in use , cows 30 are kept in a holding area prior to milking and then crowded toward the entry gate 10 by the dairyman . the stanchions 12 and 14 are sized so that only one cow may pass along the path 32 at a time . when other cows are already in the parlor 28 beyond the portal 22 and being milked , then the gate members 18 and 20 are in a closed position across the path 32 to prevent movement of any cows therepast . this condition remains in a parallel or herringbone parlor until all of the cows in the parlor 28 are finished milking , while in a tandem or rotary parlor , the cows may be admitted individually or in groups as desired by the operator . the already milked cows then leave the parlor 28 in groups as the headstalls 164 lift to permit exit , the cows in fig3 normally turning left along an exitway 172 and being kept away from the gate 10 by exit fence 170 to prevent unwanted interrogation of their transponders 44 . after the operator has reset the controller and reoriented the turnstyles 166 to the position shown in fig4 a new string of cows is ready to enter . because of crowding , the lead cow 30 normally has her nose close to the downstream gate member 20 , as shown in solid lines in fig3 . the operator typically pushes a button generating a direct signal to swing the gate members 18 and 20 to the open position shown in fig4 although this may be accomplished as a part of a sequence when the operator signals the headstalls to lower and the milking controllers to reset for the new string of cows . when the operator generates a signal to open the gate members 18 , 20 , the hydraulic cylinder 128 extends the reciprocating shaft 134 and thereby causes the drive mount tab 136 to swing the downstream gate member 20 open . at the same time , the crank arm 140 pushes on connecting rod 138 to move link tab 142 in a clockwise direction and swing the upstream gate member 18 open . because of the staggered upstream and downstream relationship of the gate members , the lead cow &# 39 ; s nose may already be past the first , upstream gate member 18 when the gate members 18 , 20 begin to swing open , so that to avoid the swinging gate members she need only shift her head away ( to the right in fig3 ) from the downstream gate member 20 and lift her head over the indexing extension 78 to avoid the gate members without the need to back up against the other cows crowded against her butt . as the gates members swing open the antennae 144 and 146 are energized and the magnetic fields 154 and 156 are generated . as a result , the transponder 44 is interrogated and its signal received by the antennae and routed to the controller to identify the cow 30 as a particular animal in the herd . the cow 30 moves along the path 32 through the portal and into the milking parlor 28 and , as the lead cow in the string , moves to the stall furthest away from the portal 22 and turns into a milking position as is conventional . as illustrated in fig4 the magnetic fields 154 and 156 generated by the respective gate members 18 and 20 are offset in an upstream to downstream orientation . the overlap area 174 of the fields is advantageously small and oriented at a diagonal to the path 32 . in this manner , cows 30 moving along the pathway 32 are more likely to be identified than in conventional parlors because even if they move along the centerline of the passageway , they will pass into successive areas of predominance of one field or another and thereby achieve a good interrogation and receipt of the transponder &# 39 ; s signal by at least one of the antennae . after the last cow 30 in the string passes through the portal , she is turned to the left into the &# 34 ; last cow &# 34 ; position 176 shown in fig3 . when the last cow in the string is recorded by the controller 162 , the gate members 18 and 20 swing on their pivot axes which extend from the center of their respective bearing fist downward to their respective swivel isolators and sockets . the gate members 18 and 20 swing to the closed position as shown in fig3 . as the downstream gate member 20 closes , its indexing extension 78 may engage the butt or side of the cow 30 in the last cow position 176 to move her into proper alignment in the stall so that a line passing from her nose to her tail is substantially perpendicular to the path 32 along which she initially entered through the portal 22 . this positions her butt against the buttplate on the pit 46 side of the stall to contain urine and feces and to position her udder proximate the milking machine . for this reason , the downstream gate member 20 should be positioned with its pivot axis on the other side of the passageway 16 from the pit 46 . it may be appreciated that as the gate members 18 and 20 close , the magnetic fields generated by the antenna within the gate members are also shifted toward the passageway 16 . this advantageously swings the downstream gate member 20 and its antenna , which are closest to the transponder 44 worn around the cow &# 39 ; s neck , a greater distance away from the transponder 44 . thus , when the cow 30 in the last cow position 176 is finished milking and the controller 162 is reset , there is less likelihood of interference or miscount by that cow &# 39 ; s transponder 44 . the use of the stops and bumpers keeps the gate members 18 and 20 in proper orientation for moving the animals therethrough and optimizing the interrogation configuration . in addition , they help electrically and magnetically isolate the gate members from the remainder of the gate 10 and parlor components to avoid diffusion of the field and degradation of the interrogation results . from the foregoing description of the preferred embodiment , those skilled in the art will appreciate that various modifications may be provided without departing from the invention limited only by the following claims . | US-78682897-A |
one embodiment is a machine comprising a sequential wavefront scanner , a variable aperture , a position sensing device and a controller . the controller is coupled to the variable aperture and sequential wavefront scanning device and configured to coordinate the operation of the variable aperture and the sequential wavefront scanning device . | reference will now be made in detail to various embodiments of the invention . examples of these embodiments are illustrated in the accompanying drawings . while the invention will be described in conjunction with these embodiments , it will be understood that it is not intended to limit the invention to any embodiment . on the contrary , it is intended to cover alternatives , modifications , and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims . in the following description , numerous specific details are set forth in order to provide a thorough understanding of the various embodiments . however , the present invention may be practiced without some or all of these specific details . in other instances , well known process operations have not been described in detail in order not to unnecessarily obscure the present invention . fig1 shows the sequential wavefront sensor that was disclosed in a pending patent application entitled “ sequential wavefront sensor ” ( application ser . no . 11 / 335 , 980 ). it comprises a light beam scanning module 130 , an aperture 118 , a sub - wavefront focusing lens 120 , a detector with more than one photosensitive area 122 and a processor for calculating the sequentially obtained centroids of the sub - wavefronts to determine the aberration of the input wavefront . in particular , the sub - wavefront focusing lens 120 and the detector 122 are fixed in space and the input beam is scanned by the light beam scanning module 130 to sequentially project different portions of the input wavefront or a replica of the wavefront to the sub - wavefront focusing lens 120 and the detector 122 . in this pending patent application , it has also been mentioned that the size of the sub - wavefront being sampled can be varied by controlling the size of the aperture 118 . with further improvement , such a wavefront sensor can be made more adaptive to provide a number of additional advantages to a number of applications . we will now discuss the advantages that one can further obtain by turning the sequential wavefront sensor into an adaptive one . note that since the sampling of each sub - wavefront is sequential , they are separated in time and consequently , there is no longer the concern of a cross talk between neighboring sub - wavefronts as would happen for the simultaneous parallel sensing format when the tilting of a sub - wavefront is significant . although in the parallel case , larger lenslet grid size can reduce cross talk , it will reduce the spatial resolution as well . in the adaptive sequential case , the aperture size for a sub - wavefront to be sampled by the adaptive sequential wavefront sensor can be made either large to achieve a desired high light sensitivity , adequate resolution and sub - wavefront averaging effect or as small as the diffraction limit allows , to substantially increase the spatial resolution as needed . the small aperture and hence high spatial resolution is especially beneficial for precision measurement of certain high order aberrations which , in the case of a human eye , are more predominant when the iris is widely open or in older patients . on the other hand , the larger aperture will allow more averaging effect for higher order aberrations and faster data processing in exchange for the lower spatial resolution . in the case of a human eye , the aperture can be opened more for the central regions of the eye . furthermore , for an adaptive sequential wavefront sensor , the photodetector used is typically a quadrant detector or in general a light spot position sensing device having a number of light sensing areas with parallel output ports . such a detector brings two more advantages . the first one is its high speed and the second one is its larger dynamic range for light detection . for the adaptive sequential wavefront sensor , there are at least a number of electronic switching techniques to sequentially sample different sub - wavefronts . for example , if the light intensity or optical power from the light source is not a limitation , the light source that generates the wavefront to be sensed can be turned on continuously with a relatively high output power and an electronic shutter can be implemented for the quadrant detector . in this case , the wavefront scanning module can perform the scanning operation continuously . by turning the electronic shutter of the quadrant detector on and off for a desired pulse duration and repetition rate , a multiple number of sub - wavefronts can be sampled . on the other hand , if there is a limit to the amount of light that can be used in terms of peak power , or optical energy , or average optical power as for the case of human eye aberration measurement , the light source used to create the wavefront can be pulsed or operated in burst mode at high speed in synchronization with the quadrant detector while the wavefront scanning module can be operated continuously . since the light source and the quadrant detector both are much faster than a ccd , which will be limited by its frame rate , the only possible limitation to the sampling speed of an adaptive sequential wavefront sensor may come from the wavefront scanning module . if the wavefront scanning module is operated in a stepped fashion , it may be relatively slow . however , if it is operated in continuous mode , it can be fast enough for many applications . at present , mems based scanning mirrors or galvanometer scanners can operate at several khz , while a typical ccd camera has a frame rate of only several tens of frames per second . high frame rate ccd or cmos cameras are available but this would mean increased noise , and also a much higher price . in general , the sequential wavefront sensor can operate orders of magnitude faster than a typical parallel type wavefront sensor , not to mention the use of any electro - optical beam scanning device that can provide even higher beam scanning speed . as for the dynamic range , a typical ccd only has 8 to 12 bits of data range and hence its dynamic range is limited to only 256 to 4096 . a quadrant detector has four parallel channels with each channel capable of detecting signals with a dynamic range many orders of magnitude larger than a ccd . by selecting a proper optical power from the light source , this substantially improved dynamic range can lead to much higher resolution / precision for aberration measurement , enabling high precision sensing of tiny difference for each aberration mode . the above - mentioned advantages can be exploited for a number of applications . in one embodiment , as shown in fig2 , the operation of the wavefront scanning module 230 , the variable aperture 218 , and the quadrant detector 222 , is coordinated . electrical wires are connected to the three devices and their synchronization is monitored and controlled by the electronic control and detection system 232 . by synchronizing the operation of these devices , the wavefront sampling speed , the spatial resolution , and the sampling pattern can all be controlled . in particular , for the measurement of a certain order of wavefront aberration , the number , size and scan pattern of the sub - wavefronts to be sampled can be optimized , which can result in a substantial reduction in the time required and the amount of data processed to calculate the magnitude of that particular order of wavefront aberration , in a manner similar to narrow band filtering or lock - in detection of an electronic signal . in the example of an eye , lower order aberrations are predominant when the iris opening is small while higher order aberrations contribute more to the drop in optical performance when the iris is wide open . therefore a dynamic adaptive sub - wavefront sampling approach can be adopted , in which the sub - wavefront aperture size for the central portion of the input wavefront can be made larger by opening the variable aperture more and the sub - wavefront aperture size for the outer portion of the input wavefront can be made smaller by reducing the size of the aperture opening . the density of the sampling points could also be increased for the outer portion by sampling at higher data rates . since in most cases the input wavefront is circular , a polar coordinate based scanning will be advantageous . the scanning pattern can be in the form of a number of annular rings or a spiral or a number of radial spikes or others . various scanning patterns can be programmed into the electronic control and detection system 232 . note that in terms of system configuration , the variable aperture 218 does not need to be arranged in the front of the sub - wavefront focusing lens 220 and it can be arranged behind it or anywhere before the detector 222 as long as it can serve the purpose of controlling the size of the sub - wavefront being sampled and projected to the detector 222 . meanwhile it should also be understood that the word “ coordination ” should be interpreted in a broader sense to include the case in which the opening of the aperture remains unchanged . fig3 a , fig3 b , and fig3 c show some other embodiments in which the adaptive sequential wavefront sensor is used for measuring the wavefront from an eye . a narrow beam from a light source 334 a 334 b , 334 c is directed to the eye retina through a beam directing element 336 a 336 b , 336 c such as a mirror or a beam splitter . the wavefront from the eye is relayed by an objective lens 304 a , 304 b , 304 c into a wavefront sensor as described in fig2 . here several variations in the optical layout are illustrated and discussed . in fig3 a , the light beam is projected from a point between the patient &# 39 ; s eye and the objective lens 304 a of the wavefront sensor . a focusing mechanism 337 a is placed in the front of the light source 334 a . based on the pre - calibration data , real time measurement of wavefront error and eye accommodation , the focusing mechanism 337 a can be used to maintain the focus of a narrow light beam onto the retina , resulting in a minimization of the measurement errors . in the variation as shown in fig3 b , a focusing mechanism 305 b is added to the objective lens 304 b of the wavefront sensor , which can be used to calibrate the wavefront sensor to a known reference and can be operated independently from the focusing mechanism 337 b being used for the input light beam . the focusing mechanism 337 b functions in the same fashion as 337 a in fig3 a . in the optical arrangement illustrated in fig3 c , the objective lens 304 c and the focusing lens 305 c are shared by the projected narrow light beam and reflected wavefront from the eye . the focusing lens 305 c not only is used to remove the defocus term from the wavefront sensor measurement , but also is used to maintain the focus of the projected light beam on the patient &# 39 ; s retina . an infrared ( ir ) camera 384 a 384 b , 384 c can be combined with an ir imaging lens 382 a , 382 b , 382 c and a beam splitter 386 a , 386 b 386 c to monitor the position of the fovea . the same ir camera module can also be used for the alignment and registration of the eye . owing to the fact that the amount of light sent to an eye needs to be limited as required for safety reasons , the light source 334 ( such as a superluminescent diode or sld ) is preferably operated in pulse and / or burst mode , and its operation in terms of the pulse turn - on time , duration and peak optical power or optical energy , is also coordinated or synchronized with the operation of the wavefront scanning module 330 , the variable aperture 318 , and the quadrant detector 322 under the control of the same electronic control and detection system 332 . in other words , the light source will only be turned on for a short duration when the wavefront is scanned to the desired position , when the variable aperture is opened to the desired size , and when the detector is instructed to pick up the signal . as mentioned before , a key advantage associated with the coordination of the variability of the aperture 318 with the wavefront scanning module 330 , the light source 334 and the detector 322 , is the capability to change the spatial resolution as well as the dynamic range of wavefront sensing in a synchronized way . for the case of a real eye , the higher order aberrations are more predominant in the outer or peripheral portion of the optical aperture . the varying sub - aperture and the larger dynamic range of the adaptive sequential wavefront sensor can be explored to cater for such demands . in particular , as the wavefront sensing sub - aperture is moved to the outer or peripheral region , the light source can be operated at a higher peak power and the size of the variable aperture opening can be reduced . this operation will provide a higher precision in terms of both spatial resolution and signal magnitude resolution because by increasing the light source power , the signal to noise ratio is also increased . one challenge associated with a wavefront sensor for eye aberration measurement is that the safety requirement will put a limit to the amount of optical energy or peak power that can be delivered to the eye . a consequence of this limitation is that the signal to noise ratio of the detected wavefront signal may also be limited , which will translate to a limited light intensity resolution or detection limit the use of a quadrant detector instead of a ccd or cmos sensor will enable one to achieve a higher signal to noise ratio . in this respect , in addition to the inherently lower noise equivalent power of a quadrant detector as compared to a ccd or cmos detector array , the use of a simple photo detector allows more sophisticated small signal detection schemes to be employed . those proven techniques can significantly increase the light sensitivity for the wavefront sensor which often has very poor signal - to - noise input . one example of the detection scheme is to have the light source modulated or operated in a burst mode to create a stream of light pulses , in which each pulse is then modulated by a carrier or modulation frequency at higher frequency . accordingly , lock - in detection or synchronized detection can be utilized in the electronic circuitry to detect the intended light signal while suppressing the noise from the background . as an example , each photodiode channel of the four quadrant of the quad - detector can be arranged in an lc oscillation tank circuit that has a corresponding oscillation frequency the same as that used for modulating the light pulses . the circuitry can boost up the level of electronic signal even before the pre - amplifier stage . alternatively , the electronic signal from each quadrant can be sampled at a frequency ten or more times higher than the modulation frequency , converted to a digital signal and then digitally filtered to achieve lock - in detection . once converted to a digital signal , other digital signal extraction algorithms such as kalman filtering can also be employed . it should be understood that in addition to a normal eye , the eye examination for wavefront error or aberration can also be done pre and post refractive correction procedures . for example , the cornea might have undergone a refractive surgery such as lasik ( laser - assisted stromal in - situ keratomileusis ), there might be an intraocular lens ( iol ) already implanted in the eye or the eye might be wearing a contact lens or an ordinary spectacle lens . the presently disclosed adaptive sequential wavefront sensor potentially can be applied for characterizing the performance of these refractive correction procedures pre , intra and post the operation . for example , in lasik , the high speed adaptive sequential wavefront sensor can be used to provide monitoring of the wavefront correction as the corneal ablation is being done . in intraocular lens ( iol ) implantation , the high speed adaptive sequential wavefront sensor can be used to indicate if the implanted iol is positioned correctly in real time . in particular , for a multi - focal lens , be it in the form of a contact or an intraocular lens , the sub - wavefronts from different zones of the multi - focal lens will have different light focusing powers , and accordingly , the adaptive sequential wavefront sensor can be operated to sample the different zones with a correspondingly appropriate scanning pattern as well as a desired spatial resolution . often , the optical surface of a multi - focal contact lens or a multi - focal intraocular lens is generally divided into a number of annular rings with each ring having a different focusing power . generally , as the zone gets further away from the center and closer to the outer peripheral region , the width of the annular ring gets narrower . the variability of the presently disclosed adaptive sequential wavefront sensor is extremely suitable for sensing the different focusing powers of the different zones . the sub - wavefront aperture can be opened more for the central zone , and as the zone to be sensed moves to the outer regions , the sub - wavefront aperture opening can be reduced to a gradually smaller size to cater for the change in the width of each following zone &# 39 ; s annular ring . fig4 shows another embodiment in which a micro display based internal fixation / visual acuity projector module is added to the system of fig3 a , fig3 b or fig3 c to enable additional functions that the adaptive sequential wavefront sensor can advantageously provide . the internal fixation module include a micro display target 444 which can also act as a visual acuity target projector , a focusing mechanism 446 ( which can be constructed with an axially movable lens ), and a beam splitter 448 that optically links the eye to the internal fixation / visual acuity projector module 442 for the eye &# 39 ; s focusing on the micro display target . the focusing mechanism 437 is independently operated from the focusing mechanism 446 used for the input light beam . based on the pre - calibration and real time measurement of wavefront error and eye accommodation , the focusing mechanism 437 is used to maintain the focus of a narrow light beam onto the retina , resulting in a minimization of the measurement errors . a typical application of such a system , as shown in fig4 , is in auto - refraction measurement of eye . traditional auto - refractors are unable to do wavefront measurement , too slow to measure the dynamics of eye accommodation and they need additional subjective trial - and - error lens testing for prescription on a separate phoroptor . the adaptive sequential wavefront sensor can be turned into an auto - refractor / wavefront sensor by operating the micro display target 444 as a programmable visual acuity projector . the focusing mechanism 446 can be operated to induce a change in the accommodation of the eye being examined and also to fog the eye . as the eye changes its accommodation , the instantaneous refractive errors and / or wavefront aberrations of the eye along a full accommodation range can be measured in real time . such a measurement can thus provide information on the dynamics of accommodation , including the accommodation range or amplitude , the response speed of the eye &# 39 ; s accommodation , and the associated instantaneous refractive errors or wavefront aberrations , the stabilized or dwelled refractive error , as well as higher order aberrations . one particular benefit that the adaptive sequential wavefront sensor can provide is the higher precision in determining the refractive errors . i . e . the sphero - cylinder errors , of the eye as wavefront measurement will be more accurate than a standard autorefraction measurement . it is understood that the narrow light beam , as shown in fig4 , is projected from the point between the eye and beam splitter 448 . in a practical application , various arrangements can also be implemented to achieve the same intended result . examples have been provided in the configurations illustrated in fig3 b and fig3 c . the input light beam can also be projected into the fixation / target module first , going through or not through the focusing mechanism 446 , and then into the eye through beam splitter 448 . it should be understood that other standard functions that are generally implemented for a standard auto - refractor can also be added to the system as shown in fig4 to match the functionality . for example , near infrared illumination can be combined with a near infrared ccd camera together with some imaging lenses and dichroic mirror ( s ) to display a live image of the front portion of the eye such as the iris for an initial coarse alignment of the eye with respect to the auto - refractor / wavefront sensor . such alignment system can provide tracking information for the orientation of the cornea , which , when combined with the location of iris , can be used as fiducial markers for the registration of optical reference plane . a near infrared light based automatic eye alignment mechanism can also be implemented as for a standard auto - refractor . in addition , as mentioned in fig3 a , 3 b and 3 c , an infrared ( ir ) camera 484 can be combined with an ir imaging lens 482 and a beam splitter 486 to monitor the position of the fovea . the same ir camera module can also be used for the alignment and registration of the eye . furthermore , it can also be used to make sure that the patient is looking at the fixation light 444 . fig5 shows another embodiment in which a wavefront compensation module is added to the adaptive sequential wavefront sensor to enable additional functions . the wavefront compensation module can be made from a deformable minor 552 . the real time adaptive sequential wavefront sensor can sense the overall input wavefront 502 and drive the deformable mirror 552 so that the aberrated wavefront 554 from the eye 538 can be fully or partially compensated by the wavefront compensation module 550 . one particular application of the configuration as shown in fig5 is an integrated objective - subjective autorefractor . in such a case , the sub - wavefronts to be sampled can be selected around an annular ring of the input wavefront to the wavefront sensor , which will efficiently reveal the refractive errors as has been elaborated in the pending application entitled “ sequential wavefront sensor ” ( application ser . no . 11 / 335 , 980 ). at the same time , the micro display can be operated to fixate the eye to the desired distance and also programmed to display a visual acuity chart . meanwhile , the wavefront compensation module can be activated to fully or partially compensate for the refractive error of the eye based on the measured wavefront errors . the patient can be asked to read the visual acuity display to confirm that a desired visual acuity ( for example 20 / 20 ) has been reached with the activated wavefront compensation . if not , the compensation can be fined tuned until the desired visual acuity is achieved . if only sphero - cylindrical error correction is desired instead of both low and high order corrections , the wavefront compensation module can be activated to only provide partial sphero - cylindrical compensations . in this particular case , instead of using a high cost deformable minor , an axially movable lens can be combined with a cylindrical aberration compensator , which can consist of two rotatable cylindrical lenses , to replace the deformable mirror to achieve the sphero - cylindrical compensations . the refractive correction that the wavefront compensation module provides does not need to exactly match the measured sphero - cylindrical aberrations and can be fine tuned around these measured values to also partially compensation the measured higher order aberrations so that the overall correction is optimized in spite of the fact that the correction is only in terms of sphero - cylindrical . again , the patient can be asked in real time to read the visual acuity display to confirm that a desired visual acuity ( such as 20 / 20 ) has been achieved with the activated sphero - cylindrical wavefront compensation and that he / she is comfortable with the correction . the focusing mechanism 546 is used to introduce accommodation changes in a patient &# 39 ; s eye to simulate the near side and far side vision conditions . the change in wavefront errors can be used to provide separate correction for near side and far side vision . during the process , the range or amplitude of accommodation and dynamics of accommodation , the difference in corrections obtained based on objective and subjective autorefraction are recorded for future study . the wavefront compensation , combined with the residual wavefront error measurement from the wavefront sensor , can be used to generate prescription for other vision correction means , including contact lens , lasik procedure , iol replacement , etc . such a new digital platform as an all - in - one instrument for lens prescription has a number of advantages when compared with use of a standard autorefractor and a standard phoroptor . in addition to the fact that the new platform has both functions integrated into one instrument , the wavefront measurement can calculate both low and high order aberrations leading to higher precision lens prescription than a standard autorefractor ; the integrated system is more compact with a smaller footprint compared with today &# 39 ; s multiple instruments ; the overall time taken to complete a lens prescription for a clinician will be drastically shortened ; the micro display based programmable and focus - adjustable fixation target / visual acuity projector will enable real time detection for the amplitude and dynamics of eye accommodation as well as simultaneous objective and subjective refraction . the focusing mechanism 537 is independently operated from the focusing mechanism 546 . based on the pre - calibration and real time measurement of wavefront error and eye accommodation , the focusing mechanism 537 can be used to maintain the focus of narrow light beam onto the retina , resulting in a minimization of the measurement errors . it is understood that the narrow input light beam , as shown in fig5 , is projected from the point between the eye and wavefront compensation module 550 . in a practical application , various arrangements can also be implemented to achieve the same intended result . examples are provided in the configurations illustrated in fig3 b and fig3 c . the light beam can also be projected into the fixation / target module first , going through or not through the focusing mechanism 546 , and then into the eye through beam splitter 548 . the introduction of a focusing lens next to objective lens 504 , in the same arrangement as illustrated in fig3 b , fig3 c , enables compensation for the defocus term in the wavefront sensor which a deformable mirror often cannot do . one important application of the adaptive sequential wavefront sensor is to provide the prescription for a cornea laser ablation profile , the prescription for an intra ocular lens ( iol ) be it phakic or non - phakic , and the prescription for a contact lens . however , in order to generate accurate prescriptions , the cornea surface profile must also be measured and with its measurement registered against reference of the wavefront measurement . traditionally , wavefront measurement and corneal topography measurement are performed using two separate instruments . as a result , the alignment or registration between the two measured data maps becomes a main issue . the cylindrical aberration introduced by a misalignment could be mistakenly considered as an inherent cylindrical wavefront error , resulting in wrong prescription . these problems can be solved by integrating the two instruments into one . fig6 shows an embodiment in which the adaptive sequential wavefront sensor based autorefractor , which is illustrated in detailed in fig5 , is combined with a corneal topographing device . the corneal topography module 660 can include a placido disc 662 , which is a series of illuminated concentric circles that are reflected off the cornea , a beam splitter 664 , a lens 666 and an imaging camera 668 . since the concentric circles from the placido disc 662 are imaged onto the imaging camera 668 through the reflection by the corneal surface and the refraction by lens 666 , as is well known to those skilled in the art , as the corneal surface is not perfect optical reflective element , the imaging camera captured circles will be distorted and the distortion will reveal the surface profile of the cornea under examination . the integrated system shown in fig6 has a number of advantages . the wavefront map and corneal topographic map are captured and generated simultaneously , or in a time sequential fashion but with such short separation so that the status of the eye is kept the same . in addition to the automatic alignment or registration between the captured topographic map of the cornea and the measured wavefront aberration map , the system is also more compact than two separate instruments . a single internal fixation target or visual acuity projector 644 can be used for both measurements and this will ensure the same eye accommodation and iris dilation for both measurements . the measured corneal topographic map , when correlated with the position and other characteristics of the iris , including surface texture , could provide a unique and repeatable registration reference coordinate if the patient &# 39 ; s eye is also fixated with the calibrated internal fixation light . this unique registration , when recorded with the patient &# 39 ; s medical data can provide a reliable reference for future measurements , and reduce the inter - operative measurement errors associated with variations in reference points . with the corneal surface profile map registered with the wavefront map , the use of the high speed adaptive sequential wavefront sensor will enable real time monitoring of the dynamics of eye lens accommodation by subtracting the contribution of cornea from the wavefront map for the whole ocular system , and the effect of iris dilation . the wavefront compensation module 650 can be activated to compensate for the eye aberration along with the change in the accommodation , and meanwhile a subjective confirmation of the refractive correction can also be obtained by projecting visual acuity target to the patient . when a desired eye accommodation is selected , the patient can be asked to confirm if a desired visual acuity is reached , once a final fine - tuned wavefront compensation that leads to a desired visual acuity has been reached , it can then be considered a preferred overall refractive prescription for the patient . for the prescription for an intra ocular lens , the refractive focusing power of the cornea alone obtained through corneal topography measurement can be subtracted from the overall focusing power of the eye obtained from the wavefront measurement . for a contact lens , the corneal topography measurement will help in determining the profile of the posterior surface for the contact lens and the front surface profile of the contact lens can then be figured out with the help of the wavefront measurement . for lasik , the corneal topography measurement can be combined with the wavefront measurement to give a prescription on the corneal ablation profile . since the wavefront sensor is operated in high speed , the topographer and the wavefront sensor can be operated sequentially to reduce interference between the two measurements . alternatively , parallel measurements can be done by using light sources of different optical wavelengths , and with a dichroic beam splitter to combine the two optical paths . it should be understood that the corneal topographer shown in fig6 is only for illustrative purpose . other types of corneal topographer can also be used . for example , scanning optical slit based corneal topographer can also be used and in this apparatus , an additional advantage is added because the corneal thickness can also be mapped . because the refractive power of the crystal lens of the eye alone can be calculated by subtracting the optical power of the cornea that can be obtained through the corneal topography and thickness measurement , from the overall focusing power of the eye that can be obtained through the wavefront measurement . other types of corneal topographers including those based on optical interferometry can also be used . although the interferometry based corneal topographers may cost more , an advantage is their high precision in the measurement of the corneal surface profiles which may include both the anterior and the posterior surface and hence the corneal thickness map . the interferometric approach may also reveal more details of the optical characteristics of ocular system ; and this information will be valuable for intra ocular lens prescription and implantation . it is understood that the measured range and dynamics of accommodation , combined with the wavefront errors at various accommodation status for the ocular lens can provide much more accurate prescription for intra ocular lens replacement , in which the accommodation is adjustable by the patient once it is implanted . the same measurement , with registered reference , can be performed after the replacement operation , to confirm performance of the artificial lens , or to provide accurate prescription if additional fine tuning of the optical performance is required . in addition to corneal topography , corneal thickness , and wavefront measurements , for precision intraocular lens ( iol ) prescription and implantation , measurements of the biometry of the anterior chamber of the eye as well as the eye length are also preferred . fig7 shows another embodiment in which an optical coherence tomography ( oct ) module 770 is integrated with the adaptive sequential wavefront sensor based autorefractor / aberrometer . since an oct module can provide relatively accurate measurement of many parameters of the eye , including the corneal surface profile , eye length and the anterior chamber biometry of the eye , the corneal topography module can be complemented or replaced by the oct module . the oct module is preferably a spectral domain oct based as it has a higher speed and also a high sensitivity than a time domain based system . for example , the oct module can be constructed using a tunable laser 771 , a circulator 772 , a 2 ′ 2 optical fiber coupler 773 , a narrow beam collimator 774 to collimate the light from a fiber end , a two dimensional mems beam scanning minor 775 , a lens 776 to direct and focus the transversely scanned sample beam to the desired location of the eye , a dichroic minor 777 , a reference path reflection mirror 778 , and a pair of detectors 779 for achieving balanced detection . the near infrared wavelength used for oct can be different from that used for the adaptive sequential wavefront sensor . the oct module can be dedicated for the measurement of the anterior part of the eye . it can also be used for measuring the eye length by introducing a step change in the reference path length when the oct beam is scanned to the center of the eye . note that although we have placed the oct module before the wavefront compensation module because the oct module is intended for measuring the anterior part of the eye , however , this should not limit the possibility of arranging the oct module after the wavefront compensation module if the oct module is to be used for measuring the retina of the eye , in which case , the wavefront compensation will result in a high transverse resolution of the oct beam spot to the focus on the retina to provide super - resolution for the oct image . as for the case of corneal topographer integration , in the oct integration case , a single internal fixation target or visual acuity projector 744 can be used for both oct and wavefront measurements and this will ensure the same eye accommodation and iris dilation for both measurements . with the oct generated map registered with the wavefront map , the use of the high speed adaptive sequential wavefront sensor will enable real time monitoring of the dynamics of eye accommodation and iris dilation . the wavefront compensation module 750 can again be activated to compensate for the eye aberration along with the change in the accommodation , and meanwhile a subjective confirmation of the refractive correction can also be obtained . when a desired eye accommodation is selected , the patient can be asked to confirm if a desired visual acuity is reached , once a final fine - tuned wavefront compensation that leads to a desired visual acuity has been reached , it can then be considered a preferred overall refractive correction for the patient . for the prescription for an intra ocular lens , the refractive focusing power of the cornea as well as other anterior chamber biometric parameters obtained through oct measurement can be combined with the preferred overall refractive correction obtained from the wavefront measurement . the display of the information in real time related to the position and optical performance of the ocular after the implantation can help physician in making fine adjustment to the position of implant or the optical power / prescription of the implant to achieve the best performance . for a contact lens , the oct measurement will help in determining the profile of posterior surface for the contact lens and the anterior surface profile of the contact lens can then be figured out with the help of the wavefront measurement . for lasik , the oct measurement can be combined with the wavefront measurement to give a prescription on the corneal ablation profile . it must be noted that although in the illustrated embodiments , we have been adding modules to explain the additional functions that can be combined with the adaptive sequential wavefront sensor , however , these illustration should not limited the various possibilities of combining different module ( s ) with the adaptive sequential wavefront sensor . for example , the wavefront compensation module can be combined with the adaptive sequential wavefront sensor and a simple internal fixation target instead of a micro display based target can be used to accommodate the eye . alternatively , the corneal topographer can be combined with the adaptive sequential wavefront sensor without the wavefront compensation module . similarly , the oct module can be combined with the adaptive sequential wavefront sensor without the wavefront compensation module . the adaptive sequential wavefront sensor can also be combined with all the modules include the oct module , the corneal topography module , the wavefront compensation module and the internal fixation / visual acuity projection module . there exist other possible combinations . it should be re - emphasized that the presently disclosed high speed adaptive sequential wavefront sensor can be used for many applications . in addition to real time monitoring of the wavefront from an eye as the eye changes its accommodation and iris dilation , it can also be used for prescription of eyeglass lenses , contact lenses , intra ocular lenses and lasik ablation profiles . these applications may require additional measurement of the eye and hence the presently disclosed adaptive sequential wavefront sensor can be integrated or combined with other instruments to accomplish the task . furthermore , other benefits that the adaptive sequential wavefront sensor can provide , including the variability of the sub - wavefront aperture , the larger dynamic range , the synchronized operation of the various changeable elements , the adaptive sequential wavefront sensor can also be applied for many other applications , especially those that do not have a limitation on the optical power used , including astronomy , outer space imaging , optical lens or system characterization , optical alignment , and also military applications . it should be understood that the description of the preferred embodiments of the invention are only for illustration purpose . those skilled in the art may recognize other equivalent embodiments to those described herein ; which equivalents are intended to be encompassed by the claims attached hereto . | US-201113048806-A |
a surgical instrument holder , adapted to be received and retained by an operating room table clamping apparatus is disclosed . the inventive holder is particularly suited for adjustably mounting and stabilizing a laparoscope , endoscope or similar instrument which has an elongated shaft . the holder comprises a clamping assembly mounted at one end of the holder for holding the shaft of the instrument . the clamping assembly includes a pair of movable jaws adapted for being closed about the shaft of the instrument . means carried by another end of the holder for cooperating with the operating room table clamping apparatus are provided . | referring now in detail to the drawings wherein like parts are designated by like reference numerals throughout , there is illustrated in fig1 - 4 the first embodiment of the surgical instrument holder of the present invention , designated generally by reference numeral 10 . referring now to fig1 holder 10 generally comprises an arm 14 and clamp assembly 16 . the clamp assembly 16 is shown holding a typical laparoscope 18 which has been introduced into a patient &# 39 ; s abdomen via a trocar cannula 20 . holder 10 may similarly be used to grip the cannula portion of the trocar 20 or any other instrument introduced through the trocar such as probes , grasping forceps , and the like . arm 14 of holder 10 is removably attached to the iron intern ® operating room table clamping apparatus 26 described in the meir et al patent . the iron intern ® comprises a plurality of elongated members 28 pivotably connected by means of joints 29 , a socket 30 for receiving arm 14 and a threaded adjustment knob 31 to retain arm 14 therein . with reference to fig2 and 3 , clamp assembly 16 comprises a pair of movable jaws 36 , 38 . each jaw has three openings or holes formed therein . a lower pair of spaced holes 32 , 33 are provided in jaw 36 through which a pair of axially aligned guide rods 37 , 39 are passed . the guide rods 37 , 39 are fixedly mounted in holes 32 &# 39 ;, 33 &# 39 ; in the upper jaw 38 so as to be slidably received in the corresponding lower holes 32 , 33 . aligned holes 34 , 35 are also provided in jaws 36 , 38 . a threaded shaft or bolt 40 is positioned in the holes 34 , 35 to permit activation of the holder . aligned hole 35 in jaw 38 has a smooth bore whereas aligned hole 34 in jaw 36 is threaded to engage the threaded portion of bolt 40 . a t - handle 42 is mounted to bolt 40 and secured thereto by pin 43 to rotate bolt 40 thereby causing jaws 36 , 38 to open and close with respect to each other . a coil spring 41 is disposed about bolt 40 intermediate jaws 36 , 38 so as to bias the jaws for ease in opening the holder and removing the instrument . a boss 44 is provided on the end of shaft 40 opposite t - handle 42 limits the extent to which jaws 36 , 38 may be opened to at least about 13 mm or more so as to accommodate instruments having differing diameters . boss 44 also prevents the components of the holder from inadvertently being disconnected . with reference to fig4 a and 4b , the inner face of each jaw is preferably provided with a longitudinal notch 50 , 52 for receiving and gripping the laparoscope or other instrument . the notches readily receive a surgical instrument having a diameter of between 2 . 5 and 12 mm . notches 50 , 52 extend parallel to the longitudinal axis of the laparoscope 18 to also provide a more even distribution of force about the circumference of the instrument to lessen the deformation and bending thereof . longitudinal notches 50 , 52 are formed of a pair of inclined surfaces 60 , 62 directed inwardly towards each other such that the angle there - between is approximately 90 °. it is also preferable that inclined surfaces 60 be significantly longer than inclined surfaces 62 . with reference to fig4 a , when an instrument of suitable diameter is inserted into the device , guide rods 37 , 39 function to further stabalize the instrument as shown . allowing instrument 18 to abut guide rods 37 , 39 creates five separate points of contact between the instrument and the device thereby lessening the liklihood of deformation . in addition to the longitudinal notch , other notch configurations can be utilized , such as , a curved indentation having a hemispherical cross - section . irrespective of the notch shape , the surface is smooth so as not to mar the instrument being secured . another feature of the first embodiment of the present invention is that the longitudinal notches 50 , 52 are spaced a sufficient distance from holes 32 , 33 and 34 , 35 , such that , when the instrument 18 is held by the jaws it will avoid touching the spring 41 . it has been found that the operability of some sensitive medical instruments has been interfered with when the spring is permitted to contact the instrument . the second embodiment of the present invention , illustrated in fig5 a , 5b and 6 , is designed to grip the head portion 82 of a disposable trocar , such as that commercially sold under the trademark surgiport ®, and described in u . s . pat . no . 4 , 654 , 030 to moll et al or others sold by the ethicon corporation . disposable trocars have cannulae 84 constructed of radioluscent plastic which will easily collapse and bend from the clamping force . it is therefore desirable to support the trocar by gripping the rigid , rectangular trocar head 82 . thus , jaws 70 , 72 are provided with planar surfaces 71 , 73 which are roughened on the respective confrontilg faces of jaws 70 , 72 to securely grip the rectangular trocar head 82 . it is necessary to provide rough surfaces only on the portion of the confronting face of jaws 70 , 72 which is in contact with the instrument . since the trocar head 82 is about 12 . 5 to 27 mm wide , a larger bolt 74 is provided to permit a wide opening of the jaws 72 , 74 to receive head 82 . naturally , the length of the bolt 74 can be varied depending on the width or thickness of the instrument being secured . to prevent the holder of the second embodiment from being inadvertently applied to a laparoscope , metal trocar cannula , or other fragile instrument , bolt 74 is comprised of a threaded portion 75 and an unthreaded portion 77 such that further tightening is prevented when jaw 70 abuts the unthreaded portion 77 ( fig5 a ). threaded portion 75 is of a length such that jaws 70 , 72 are prevented from closing closer than 12 . 5 mm which effectively prevents application of the second embodiment on laparoscopes and the like -- which rarely have diameters exceeding 12 mm -- so as to prevent damage to the expensive instrument . this contrasts with the first embodiment which utlizes a constant diameter rod thereby allowing the jaws to be closed fully or partially , depending on the nature of the use . alternatively , and with reference to fig5 b guide rods 76 of the second embodiment may include an expanded portion 78 having a diameter larger than that of the adjacent portion which passes through the holes 80 , such that further tightening is prevented when the jaw 70 abuts the expanded portion 78 . in use , the operating room table clamping apparatus 26 , preferably the iron intern ® device disclosed in the meir et al patent , is mounted to the operating room table . arm 14 of instrument holder 10 is inserted into socket 30 of the iron intern ® and is locked therein by tightening handle 31 . as more completely described by meir et al , the subject matter of which is incorporated herein by reference , the plurality of interconnecting hinges and ball joints provided with table stand 28 ( not completely shown ) allows a full range of movement of holder 10 . holder 10 is positioned such that the jaws are adjacent the laparoscope 18 which has been inserted into the abdomen of the patient . the jaws are opened , laparoscope 18 or trocar cannula 20 is passed therebetween and the jaws are tightened accordingly . it is a particular feature of the present invention that holder 10 need not be positioned on the laparoscope or other instrument prior to the instrument being inserted into the body of the patient thereby allowing the instrument to be positioned with ease prior to applying mechanical fixation . the second embodiment of the present invention is used substantially the same as the first embodiment except that jaws 70 , 72 are made to pass over trocar head 82 . although certain presently preferred embodiments of the invention have been described herein , it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiment may be made without departing from the spirit and scope of the invention . accordingly , it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law . | US-74870591-A |
a method of processing toothbrushes includes supplying a plurality of toothbrushes with tufts of bristles attached to heads of the toothbrushes . similar portions of each of the toothbrushes differ in color from each other . a color of the portion of each of the toothbrushes is determined . the toothbrushes are reorganized according to the determined color . | beginning with fig2 - 4 , the elements 10 , 12 , 14 and 16 are substantially the same as described with respect to fig1 . however , a color sorter 17 has been added to the system . a supply of toothbrushes exit stapling / finishing machine 12 single file and are moved by a conveyer belt 14 in the direction of an arrow 18 . a mechanical stop stops a lead toothbrush adjacent a removal element 20 . an optical sensor detects the presence of a toothbrush at the mechanical stop and signals removal element 20 to remove the toothbrush from conveyor 14 . the removal element will be discussed in more detail below . a color sensor then determines a color of a portion of the removed toothbrush , for example the rubber overmolded portion of the handle . once the color is determined , removal element 20 moves the removed toothbrush over one of five buffer conveyors 22 a - e ( 22 a being the lowest conveyor in fig2 ). for example , if the color of the rubber is determined to be red , removal element 22 is moved over conveyor 22 a . the removal element then deposits the toothbrush onto conveyor 22 a . the other buffer conveyors 22 b - e are designated to respectively hold toothbrushes having different colors . for example , conveyor 22 b would hold toothbrushes with yellow rubber portions , conveyor 22 c would hold toothbrushes with green rubber portions , and so on . the number of conveyor buffers used are set to match the number of different colored toothbrush portions being produced by stapling / finishing machine 12 . each toothbrush produced by stapling / finishing machine 12 is placed by a color sort into one of buffers 22 a - e . once a toothbrush is placed on one of conveyors 22 a - e , an optical sensor detects this event and signals for that conveyor to be actuated to move the toothbrush in the direction of arrow 18 . another optical sensor detects that the toothbrush has been moved below a return element 24 and signals for the conveyor to be turned off . this parks the toothbrush below the return element and frees up the space below the removal element for the next toothbrush to be placed on that conveyor buffer . return element 24 is similar to removal element 20 except that it takes toothbrushes one at a time out of buffers 22 a - e and places them back onto conveyor 14 downstream from the mechanical stop mentioned above . the removal element is instructed to remove toothbrushes from buffers 22 a - e in a designated sequence in order to feed toothbrushes to tray loader 16 in a desired color sequence . removal element 20 and return element 24 have substantially the same parts . these parts will be described in terms of return element 24 . a pick - up head in the form of a pneumatically operated gripper 26 is attached to a pneumatic vertical actuator 27 . the gripper has jaws which can move towards each other or away from each other in the direction of a double - headed arrow 28 to respectively grab or release a toothbrush . portions of side walls 29 of conveyor belt 14 are removed so that gripper 26 can grip a toothbrush . vertical actuator 27 moves the pick - up head up or down in the direction of a double - headed arrow 30 to move a grasped toothbrush away from one of buffers 22 a - e and towards conveyor belt 14 . a linear actuator controlled by a servo drive 32 moves vertical actuator 27 , and thus gripper 26 back and forth in the direction of a double - headed arrow 34 . in this way , toothbrushes can be moved between conveyor belt 14 and buffer conveyors 22 a - e . the following example will assist in understanding this embodiment of the invention . assume r = red , b = blue , g = green , y = yellow and p = purple . a sequence of toothbrushes coming out of stapling / finishing machine 12 might be in the order rrbgprypyypgbbg . after color sorter 17 reorganizes the toothbrushes , they would continue onto tray loader 16 in the order rgpybrgpybrgpyb . this would provide a perfect color mix of toothbrushes of course , any designated color sequence can be obtained with this system , such as rrbbggyypp . it may happen that , for example , five red toothbrushes come into the color sorter in a row . in this case , four of the five toothbrushes would get buffered on their designated buffer conveyor . these extra brushes get stored to the left in fig2 on their conveyor . when return element 24 later needs a red toothbrush and none is available under removal element 24 , the red conveyor is run in the reverse direction ( i . e . opposite to arrow 18 ) to move one of the buffered red brushes under return element 24 . this buffering system can be described as a last in first out ( lifo ) system . each conveyor buffer 22 a - e can store up to 10 brushes . in the unlikely event that the capacity for a specific buffer conveyor is exceeded , the extra brushes will fall off the left end of the conveyor into a tote . these extra brushes are either manually reintroduced to their conveyor at a later time when there is room , or are manually introduced to tray sorter 16 . a programmable logic controller ( plc ) receives input from the optical sensors for determining toothbrush position and from the color sensor for determining the color of a portion of each toothbrush . the plc directs operation of conveyor 14 , buffer conveyors 22 a - e , removal element 20 and return element 24 . turning to fig5 , a portion of a color sorter 36 is shown which has only four buffer conveyors 38 a - d . toothbrushes 40 are shown on the conveyors . a toothbrush 42 has just been placed on conveyor 38 b by the removal element . conveyor 38 b would now be actuated to move the two toothbrushes on this conveyor to the left until toothbrush 42 is located where a toothbrush 44 is currently located in fig5 . this effectively moves toothbrush 42 from a removal zone 46 to a return zone 48 , thus freeing up the entire removal zone for receipt of a toothbrush of any of four colors from the removal element . now assume return element returned a toothbrush 50 from buffer conveyor 38 a to conveyor 14 . buffer conveyor 38 a would now be operated to move a toothbrush 52 to the right and park toothbrush 52 in return zone 48 . this demonstrates that this is a lifo system . the invention has been described with reference to a preferred embodiment . however , it will be appreciated that variations and modifications can be effected by a person of ordinary skill in the art without departing from the scope of the invention . | US-90167604-A |
a method and device to support blood circulation during ventilation of the lungs which include controlling the application of the respiratory gases to occur at a particular point in time in the heart activity , and applying a uniform pressure to resist expansion of the thorax cavity to increase pressure on the heart during the heart &# 39 ; s systole . the device which applies a respiratory gas and the uniform pressure includes a control device which senses the heart &# 39 ; s activity to determine the desired point in time of the heart cycle . | the principles of the present invention are particularly useful in a respirator generally indicated at 1 in the figure . the respirator 1 receives respiratory gas on a line 2 , which is connected to an external gas source 40 . instead of the single gas line 2 , a plurality of such lines for various components of the gas can be provided . the respiratory gas is supplied to the patient 6 through a valve arrangement 3 as well as a tracheal cannula 4 connected thereto and the tracheal cannula 4 terminates tightly in the trachea 5 of the patient 6 . a cuff 7 can , for example , be provided for the termination of the trachea cannula 4 in the trachea 5 . an eduction or ejection valve 8 is also connected to the tracheal cannula 4 . the valve arrangement 3 , which produces a metered feed of respiratory gas received in the line 2 from the pressurized source 40 can , for example , be of a known type such as disclosed in the international patent application no . pct / se82 / 00063 . ( w082 / 03014 ). however , it is also possible to utilize an open cannula for spontaneous breathing . the open cannula has a thin additional cannula for the feed of the respiratory gas instead of a tracheal cannula terminating in the trachea and the eduction or ejection valve 8 . the emptying of the lungs then occurs directly over the open cannula . further , it is also possible to insert a thin cannula directly into the trachea in a surgical manner . the expiration then occurs over the natural breathing organs . in the two latter instances , a hfppv respiration method ( a high frequency positive pressure ventilation ) is then advantageously employed . the respirator 1 also includes a valve 9 which receives gas from an additional pressurized source 50 on a line 10 . compressed air is usually employed in the simplest case as the pressurized gas from the source 50 . a line 11 leads from the valve 9 to a plurality of closed chambers 12 consisting of flexible material . the closed chambers 12 are disposed around the chest and / or partially around the abdomen of the patient 6 . a hollow body 13 consisting of a rigid material which is matched to the shape of the thorax is situated around these chambers . a fluid can also be utilized for filling the chambers instead of pressurized gas . the eduction valve or ventilation valve 14 is again connected to the line 11 to enable exhaust or venting these chambers . the ventilator or respirator 1 further contains an amplifier 15 to which the signals of a sensor are supplied . in the embodiment which is illustrated , two ecg electrodes 36 and 37 are applied to the patient &# 39 ; s body and register the electrical heart signals and act as the sensor . these heart signals are processed by the amplifier and then applied to a detector 16 which detects the high electrical heart voltage during the systole and emit a pulse to an electronic circuit 17 or , respectively , a circuit 18 . the circuits 17 and 18 each contain means for setting a selectable delay of the pulse coming from the detector 16 . the valve arrangement 3 as well as the valves 8 , 9 and 14 are driven by pulse - shaping circuits 19 , 20 and 21 , respectively . the pulse - shaping circuits 19 - 21 can , for example , by one - shot multivibrators with different pulse widths . in addition , the pulse - shaping circuits should contain means for setting the pulse width . as illustrated , the output of the electronic circuit 17 goes to the pulse - shaper 20 whose output goes to both the pulse - shaper 21 and also to the valve 9 . from the pulse - shaper 21 , pulses go to the eduction valve 8 and also to the exhaust or eduction valve 14 . in a similar manner , the signal from the detector 16 is applied to the electronic circuit 18 , which has the time delay , and the output of the circuit 18 goes to the pulse - shaper 19 , which applies a pulse to the valve arrangement 3 . the schematic illustration of the figure also shows that the lungs 25 and 26 of the patient surround a large part of the heart of which the left ventricle 27 is shown . pressure on the heart will occur due to the expansion of the lungs 25 and 26 . under normal conditions , however , this pressure increase is slight since the volume of the thorax easily enlarges particularly due to the outwardly directed movement of the thorax wall 28 and partially due to the downward directing movement of the diaphragm 29 into the abdomen cavity . according to the invention , the thorax and the upper part of the abdomen are surrounded by a hollow body 13 which consists of a shapable envelope consisting of rigid material . this envelope is positioned around the body so that a certain expansion of the respiratory organs , i . e ., the lungs and the chest and / or the abdomen , is possible without the envelope significantly impeding this expansion . when due to the application of the respiratory gas , this expansion has reached a certain amplitude , further expansion is prevented by the envelope as a result of which an increased pressure will occur inside the envelope and thus inside the thorax and around the heart . the function of the respirator ventilator 1 and thus of the method utilizing the respirator is described in greater detail hereinbelow . the electrical activity of the heart at the beginning of the systole is registered by the electrodes 36 and 37 and initiates the feed of respiratory gas through the valve arrangement 3 . the psychological delay between the electrical heart signal for the systole ( the qrs complex ) and the mechanical contraction of the heart is exploited in order to fill the lungs in one breath through the fast action of the valve arrangement 3 . however , it is also possible to set a delay in the electrical circuits 17 and 18 so that the feed of the respiratory gas will occur during the systole that is related to the next following heartbeat . at the same time as the feed of the respiratory gas or nearly simultaneously therewith , the elastic chamber 12 is filled with pressurized gas through the valve 9 and the line 11 . the amount of gas supplied can also be regulated . an excess pressure will occur when the lungs expand because of the flow of the respiratory gas and this excess pressure is then amplified by the movement when the outwardly directed movement of the thorax wall 28 and / or downwardly directed movement of the diaphragm 29 , respectively , is partially arrested by the hollow body 13 and by the filled chambers 12 . this excess pressure is propagated through the cardiac wall so that the pressure on the blood enclosed in the heart will rise . by the correct setting of the electrical circuits such as 17 , 18 , 19 , 20 and 21 , the pressure increase on the heart will occur chronologically and synchronously with the pumping of the blood from the left ventricle into the large systemic aorta of the body . the blood in the systemic aorta 30 will then proceed to the important organs such as through additional artery 31 to the brain . the various delay times and pulse durations are set according to the following principle . the amount of respiratory gas supplied to the patient at each respiration is defined by means of setting the valve arrangement 3 and / or the pressure in the line 2 so that the ventilation of the lungs suffices for a good gas exchange . the hollow body 13 is applied around the patient so that it adapts to the external contour of the body without exerting high pressure on the body at the beginning of each respiration cycle . the supply of air to the closed chambers 12 is likewise controlled so that the movement of the walls of the thorax and the diaphragm 29 during the feeding of the respiratory gas are restricted to such a degree that a suitable intensification of the pressure around the heart is generated during its pumping process . the thorax itself is not compressed by the flexible chambers 12 to such a degree that the force thereby exerted produces an inwardly directed movement on the thorax wall 28 . the flexible chambers 12 only fill out the cavity between the body surface and the hollow body 13 . the flexible chambers 12 serve to limit the outwardly directed movement of the body surface in a definable and controllable manner . moreover , they also serve to balance out certain inequities of the pressure on the body surface that could , for example , be produced by a rigid hollow body . the pressure on the lungs 25 and 26 which occurs due to the supplying of the respiratory gas is composed of the pressure required for the expansion of the lungs and of the thorax walls and of the pressure arising in the thorax due to the hollow body 13 and the pressure chambers 12 . the pressure gradient across the lung structure , however , does not exceed the gradient that occurs given a standard high - frequency ventilation in which experience has shown to be harmless . any kind of deforming force that could damage the thorax wall is prevented by the pressure equalization of the air - filled , flexible chambers 12 . an injurious effect on the blood circulation due to an impeded refilling of the heart ventricle is avoided in that every form of undesirable pressure on the thorax and in the thorax is prevented during the relaxation phase of the heart because the flexible chambers 12 are emptied through the exhaust valve 14 at the end of the systole . the lungs empty at the same time through the valve 8 . the electrical coupling according to the sample illustrated embodiment is as follows : the output signal of the detector 16 proceeds over the two delay circuits 17 and 18 , respectively , to the pulse - shaping circuits 19 and 20 , respectively . the pulse - shaping circuit 19 determines the chronological duration during which the respiratory gas is supplied to the patient through the valve arrangement 3 and also determines the point in time to which this feed is to begin . correspondingly , the circuit 20 determines when and how long the valve 9 should be opened . the point in time for opening the valves 14 and 8 , respectively , is determined through a further circuit 21 . at the same time it is presumed here that the valves 8 and 14 , respectively , are closed when the arrangement 3 or , respectively , the valve 9 is opened . the described sample embodiment is only of an explanatory nature . the support of the blood circulation strived for with the invention is also assured when the respirator is modified within the framework of the invention . for example , the sensors instead of being ecg electrodes could be connected to a heart pacemaker or a device which generates pulse to control the heart &# 39 ; s activity . to provide a dead space or variable volume for receiving co 2 exhaled from the lungs , the tube or cannula 4 may have an excess portion such as a loop 4a . although various minor modifications may be suggested by those versed in the art , it should be understood that we wish to embody within the scope of the patent granted hereon , all such modifications as reasonably and properly come within the scope of our contribution to the art . | US-3849487-A |
the invention provides an oral prosthesis in the form of a dental plate wh fits against the inside of a user &# 39 ; s teeth . the plate when fitted projects from the teeth toward the user &# 39 ; s tongue . the extent of the projection , and the thickness of the plate , is selected to displace the tongue in a predetermined manner . | as illustrated in fig1 to 3 , an oral prosthesis for a lower jaw is shown in the form of a plate ( 1 ), having a shaped outer edge ( 2 ), formed to be located against the inner surface of a set of teeth ( 3 ) of a lower jaw ( fig1 ). the plate is thus generally &# 34 ; u &# 34 ;- shaped and its inner surface ( 4 ) projects away from the inside surface of the teeth into the cavity of the lower jaw . the extent of this projection over the gums and slightly under the tongue , as well as the thickness of the plate in various positions around the extent thereof , is selected according to experience and knowledge of anatomy . clips ( 5 ) assist in securing the plate in position . as illustrated in fig4 and 5 , a plate ( 10 ) can also be formed to be located in use against the inner surface of a set of teeth ( 4 ) of an upper jaw ( fig4 ). the plate locates against the molars on either side of the jaw and extends across the palate . the plate does not locate against the front teeth and permits the tip of the tongue to contact the front of the palate , so as not to interfere with speech . this in turn allows the plate to be worn in the day time as well as at night which makes the plate effective for 24 hours a day . the position of the tongue can be adjusted by the presence of the plate , and thus the position of the jaws can be altered by moving the tongue . the jaw position may be altered to relax jaw muscles , and this can relieve associated and referred pain . the plate is made , generally speaking , in accordance with well known techniques for forming and producing dental prostheses . the position of any thickening or extent need not be uniform around the periphery of the operative position , and the plate will often require final adjustment to the thickness and / or the extent of projection into the mouth cavity , to achieve optimal results . normally , when a person is relaxed , the tip of the tongue rests lightly against the front of the palate just behind the upper teeth . the remainder of the tongue does not touch the palate and there is a space between the tongue and the palate furthest back . the position of tongue influences the position of the lower jaw , which in turn impacts on the amount of tension in the muscles at the side of the head which are responsible for controlling the posture of the lower jaw . in patients with headaches of muscular origin , the muscles at the side of the head contract as a response to stress and tension , and the lower jaw is consequently displaced from its proper rest position . as the lower jaw is elevated , the tongue is in turn elevated and the resting space between the tongue and palate is reduced . by inducing the tongue to assume its proper rest position , relaxation of the muscles which caused the headaches is achieved . the prosthesis of the invention for an upper jaw is thus contoured to fit the resting space between the tongue and the palate exactly so that the tongue is encouraged to resume its natural rest position . this is achieved by ensuring that the patient &# 39 ; s tongue does not touch the prosthesis during speech . conveniently , the patient is made to speak with the prosthesis in the mouth and then the prosthesis is ground away until there is no contact between the tongue and the prosthesis during speech . once this is achieved , the prosthesis is the correct shape . if the prosthesis is even slightly too thick , the tongue is displaced to a position lower than its normal rest position and the prosthesis will not work . it is thus important that the prosthesis for use in the upper jaw does not cover the front of the palate as this is where the tongue would normally rest in the relaxed position . if this area were to be covered , the tongue would be depressed below its normal rest position causing the muscles at the side of the head to lengthen beyond the ideal resting length . experience has shown that when this occurs , the muscles remain painful and the headaches do not improve . on the contrary , this can often lead to headaches being aggravated . these embodiments of the invention are further exemplified in the clinical histories given below . patient a was examined and complained of &# 34 ; deep , dull , unbearable pain &# 34 ; behind the eyes , in the frontal region , and over the temples , occipital regions and neck . the pain occurred with a frequency of 3 - 4 times a week , and lasted between 2 and 24 hours . the patient first experienced these symptoms at the age of 25 years and was 55 years old at the time of examination . the pain was made worse by stress and certain foodstuffs . clinical examination and diagnostic tests revealed the cause of his pain to originate in a trigger area in the antero - superior fibers of the temporalis muscles , and was most probably related to stress . the object of treatment with an embodiment of the invention , was to encourage relaxation of the temporalis muscles . the prosthesis was molded and prepared , and fitted . it initially caused a slurring of the patient &# 39 ; s speech , particularly when pronouncing the letter &# 34 ; s &# 34 ;. the anterior portion of the plate in the midline was trimmed down until it no longer caused any speech impediment . this is necessary , and clinical experience has shown that if the plate is too thick it can cause an intensification of symptoms . some three weeks later , the patient was completely symptom free . the patient complained of severe and chronic headaches which started in 1988 , but which intensified two years ago following an attack of encephalitis . the headaches occurred every 6 to 7 days , and were made worse by loud noises , &# 34 ; episodes of sinusitis &# 34 ; and by hormonal changes occurring during menstruation . however , a radiologist &# 39 ; s report showed the sinuses to be clear . it has been found that patients frequently mistakenly believe their headaches are caused by sinusitis , because of the distribution of their pain over the frontal and maxillary sinuses . with proper diagnostic procedures , the pain can often be found to originate from the muscles of mastication . the origin of the patient &# 39 ; s pain on clinical examination and diagnostic testing was found to be the anterior fibers of the masseter muscles and the digastric muscles . to cause relaxation in the muscles , the mandible has to be repostured not only lower , but also slightly forward . a prosthesis was prepared to act as a shim between the lower teeth and longual mandibular gingival surface on the one hand , and the sensitive ventral surface of the tongue on the other . the action was designed to separate the lower jaws slightly from the tongue , and as the tongue cannot position itself higher in the mouth because of its relationship to the palate , the net result is designed to cause the mandible to reposition itself slightly lower . the positioning of the anterior portion of the plate between the anterior part of the ventrum of the tongue and the anterior teeth , caused the mandible to be postured slightly forward , relieving tension in the digastric muscles . sixteen days after fitting , there was a follow up consultation during which the plate was thickened by some 2 mm with good results . the patient estimates a reduction in symptoms of some 80 %. the final shape of the prosthesis has to be determined by clinical examination and trial and error . the exact degree of relaxation and movement of the jaw has to be established during follow up consultations , and with reference to symptomatic response . it is considered that the invention provides a simple oral prosthesis for altering jaw posture . if necessary clips can be provided to retain the plate in position , and these clips will be positioned between suitable gaps in the teeth so as not to affect the teeth themselves . unlike the commonly used appliance called a &# 34 ; bite plate &# 34 ;, which is specifically designed to change the patient &# 39 ; s occlusion when worn , the prosthesis of the inventor is designed not to affect the occlusion at all , but rather to change the posture of the tongue . the prosthesis of the invention , therefore , does not interfere with a person &# 39 ; s bite , is comfortable to use , and can be worn during eating and speaking . | US-87049697-A |
a yieldable baseball base construction with improved mounting assembly for baseball , softball , and other ball games . the mounting assembly includes cooperating male and female members ; two guiding rods fixed in a base frame carry the male member . springs mounted on the guiding rods allow the male member to deflect relative to the female member which is anchored in the ground | before explaining the present invention in detail , it is to be understood that the invention is not limited in its application to the details of construction and arrangement of parts illustrated in the accompanying drawings , since the invention is capable of other embodiments and of being practiced or carried out in various ways . also , it is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation . referring now to the drawings wherein the same numerals refer to like and corresponding parts in the two views , the preferred embodiment of the invention is portrayed in fig1 and 2 and comprises a base or sack generally designated as 1 . the base 1 is generally square in shape and has a covering 10 filled with relatively thick soft resilient material 12 . the resilient material may be foam rubber , vinyl , urethane or other like material . the covering is tied or secured to the frame 16 of the base by strips 14 which are secured by screws 15 , but may be secured by rivets or other means . the covering material is determined by league rules ; usually , it is a hard type of material , for example , canvas , nylon , rubber , etc . when the rules require shoes with rubber spikes then canvas may be used for the covering material . if shoes with metal spikes are required , then a strong nylon or rubber covering is preferred . the size of a bag depends on the official rules for the size of the base . most of the bags are 15 &# 34 ; square and about 3 &# 34 ; thick . the bases are positioned in such a way that springs 20 face a runner . when the runner tags a base , he hits or strikes its edge . as a result of the strike the springs 20 are compressed , displacing the base 1 about 2 &# 34 ;- 23 / 4 &# 34 ; from its normal or rest position . it will be appreciated that when such pressure is removed the base will promptly return to its original position . the frame 16 is a recessed square plate to define a recessed or sunken main plate 18 surrounded by normally vertically extending walls 22 on all four sides which each terminate in an edge flange 24 normally extending from the edge of wall 22 remote from the main plate 18 and extending parallel with main plate 18 . a pair of guide rods 26 ar fixed to opposite walls 22 by welding or otherwise and extend parallel to one another in a spaced relationship and parallel to and spaced from main plate 18 . a male anchor member 28 suitably provided with holes is slidingly carried on the guide rods 26 . male anchor member 28 consists of a t shaped bar square in cross section with the top cross element 30 of member 28 provided with the holes and carried by the guide rods 26 . a guide pin 56 is welded to end of element 30 and projects parallel to and in between the two guide rods 26 . the pin 56 is telescopically received in a sleeve 58 welded to main plate 18 and to wall 22 . the vertical depending leg element 32 of member 28 cooperates with a female anchor member 36 consisting of a square cross section tube 38 open at the top to receive the leg element 32 in a sliding , nonrotatable manner and two crossed plates 40 welded together and to the bottom of tube 38 . both tube 38 and depending element 32 are non - circular in cross section to resist lateral movements . springs 20 are mounted on the guide rods 26 and bear against the top cross element 30 at one end and a wall 22 at their other ends and bias the cross element 30 relative to the frame 16 . the frame 16 is fitted with a protective core member 44 consisting of a circular cross section firm resilient core 46 covered by a cloth 48 or like material . the core member is sized to fit against the outside of walls 22 and be supported by the edge flanges 24 . the filling or padding 12 completely fills the interior space of the base projecting outwardly of frame 16 and is held in place by covering 10 . the edge flanges 24 are provided with a series of tapped holes . securing strips 14 of the same length as the edge flanges are provided with matching holes . the edges of the covering 10 are drawn around the base and brought between strips 14 and edge flanges 24 where they are secured or sandwiched by means of screws 15 which firmly secure the strips 14 to the edge flanges 24 with the edges of covering 10 caught between them . as shown in fig2 the female anchor member 36 is set in concrete 50 in the ground 52 with the open top of tube 38 at or near ground level . the base is set into position by inserting the vertical leg element 32 into the tube 38 with spring 20 lying on the side of the base facing the runner . when a runner strikes the base 1 as indicated by the arrow 54 , the base 1 will deflect to the right as seen in fig2 to the position shown in dotted lines . this deflection compresses springs 20 which restores the base to the solid line position when pressure is taken off the base . although a single embodiment of the invention has been disclosed and described herein , it is obvious that many changes may be made in the size , shape , arrangements and detail of the various elements of the invention without departing from the scope of the novel concepts of the present invention . | US-4335287-A |
method and apparatus for thermal ablation or coagulation of biological tissue using a scanning laser beam with real - time video monitoring and monitoring of therapeutic treatment parameters , such as temperature prior to or during treatment . in a preferred embodiment , a unique reflective optical delivery system is employed in conjunction with temperature control of the treatment area , and possibly , cryogenic treatment of the treatment area , to eliminate or reduce the need for anesthetics . all therapeutic parameters can be displayed on a video monitor , which is attached to a laser scanner . the reflective optics of the laser scanner can provide precise single - layer vaporization by the laser without thermal injury to the underlying tissue , and the video monitor allows a surgeon to monitor all therapeutic parameters both before and during a treatment procedure . the video monitor also can provide a three - dimensional view of the treatment area . this also can be videotaped for documentation purposes . | referring now to the drawings , where like or similar elements are designated with identical reference numerals throughout the several views , and referring in particular to fig1 a laser beam deliver apparatus 10 in accordance with a first embodiment of the present invention may comprise a housing 12 sized for manipulation by a human hand ( not shown ). the housing 12 may be formed as a unitary element , or the housing 12 may comprise a main body section 13 and distal sleeve section 15 . the housing 12 preferably further includes a connector 14 for coupling to , or engaging , a beam carrier element , such as an optical waveguide or fiber optic cable ( not shown ), and the housing 12 may have mounted therein a ccd imager 16 , an associated focusing lens 17 , a beam splitter 18 , and first and second mirrors 20 and 22 . the beam splitter 18 functions to deliver a beam provided by the beam carrier element ( not shown ) to a target 24 and to deliver light reflected from the target 24 ( i . e ., an image of the target 24 ) to the ccd imager 16 . the first mirror 20 may comprise a convex mirror , and the second mirror 22 may comprise a concave mirror such that the mirrors 20 and 22 function to focus the beam delivered by the beam carrier element ( not shown ) upon the target 24 . in a presently preferred embodiment , the ccd imager 16 may comprise a portion of a video - monitoring system , such as the endoview system produced by urohealth surgical division . that system includes an lcd monitor 26 that is coupled electronically to the ccd imager 16 and may be mounted within the housing 12 of the beam delivery apparatus 10 . the beam splitter 18 may be purchased from balzers thin films , inc ., of golden , colo . the treatment beam ( not shown ) delivered by the beam carrier element ( not shown ) can be a co2 laser beam , or any other laser beam , including , for example , argon , ktp , nd : yag , erbium , etc . if the treatment beam is invisible , for example , if the treatment beam has a frequency falling within the infrared spectrum , then a guiding beam can be employed , and the guiding beam can be red , green , orange , yellow , blue or any other color available in the market . mirrors 20 and 22 preferably comprise a portion of a scanning system ( not shown ) and preferably can be manipulated or rotated , as described in u . s . pat . no . 4 , 923 , 263 , issued to johnson , which is hereby incorporated by reference . those skilled in the art will appreciate that by changing the input parameters provided at a control unit ( not shown ) of the beam deliver apparatus 10 , it is possible to create a variety of different treatment patterns , at the discretion of the laser operator or surgeon . such patterns also can be pre - programmed prior to surgery and displayed at the operating site , and several exemplary scanning patterns are illustrated in fig7 a - g . the scanning mechanism employed by this novel apparatus can contain two optical elements , such as those contained in the accuscan laser scanner produced by reliant technologies , foster city , calif . that scanner can combine simultaneously a variety of different lasers for ablation ( co2 , erbium , or holmium lasers ) and coagulation ( nd : yag , argon , ktp ) and at the same time can scan and focus such laser beams . the scanning mechanism also could be implemented using a swiftlase or silktouch scanner produced by sharplan laser industries , allendale , n . j . such systems , however , can be used with only one specific treatment laser beam that is selected by the operator or surgeon prior to surgery , because they utilize a focusing lens of specific transparent material for transmission of a specific beam . turning now also to fig2 in a presently preferred embodiment , the beam delivery apparatus 10 may further comprise a cryogenic fluid delivery apparatus 30 that is carried by , or formed within , the sleeve portion 15 of the housing 12 . the cryogenic fluid delivery apparatus 30 preferably has a special configuration at the treatment site , which allows cooling gas to concentrate at a specific point or , alternatively , to concentrate within a variety of different areas having different shapes and sizes . further , in a preferred form , the cryogenic fluid delivery apparatus 30 can be switched easily from one fluid delivery configuration to another . as shown in fig2 the beam delivery apparatus 10 also may include a light channel 36 for illuminating a target 24 . the light channel 36 can be connected to a conventional light source 32 , such as one produced by wolf inc ., rosemont , ill ., via a suitable fiberoptic cable 34 . the configuration and use of light channels of the type described herein are well known in the art . turning now also to fig3 the sleeve portion 15 of the housing 12 may further include a distal extension 40 with a holding hook or flange 42 that is used for ensuring proper positioning of an area of tissue to be treated . in embodiments , such as that shown in fig3 the distal extension 40 may extend laterally from a center line ( not shown ) of the sleeve 15 and may have mounted therein a reflector or mirror 44 for directing the treatment beam toward the tissue to be treated . the sleeve 15 may take the form of a standard otoscope cannula , and may be identical in design to those produced by heine usa ltd . when configured in this manner , the beam delivery apparatus 10 will allow physicians to treat numerous conditions including , for example , otitis media in children and adults . in such embodiments , the distal portion of the sleeve 15 can be used not only to protect surrounding tissues from thermal damage , but also to guide the treatment beam to a desired area . turning now also to fig4 a laser beam delivery apparatus 10 in accordance with the present invention may further include a thermodetector 50 that is coupled to the video monitor 26 via a microprocessor 52 . the thermodetector 50 is available , for example , from exergen corporation , newton , mass ., and is preferably located on a front end of the sleeve 15 of the beam delivery apparatus 10 . the thermodetector 50 may be configured for physical contact with biological tissue at or near the target area 24 , or the thermodetector 50 can be configured for indirect , non - contact monitoring of the tissue at or near the target 24 . use of the thermodetector 50 and related circuitry allows for indications of tissue temperatures at the target 24 to be displayed on the video monitor 26 . this enables real - time verification of tissue temperatures and conditions during treatment regimens , and when used in conjunction with a cryogenic fluid delivery system 30 ( described with reference to fig2 ), will enable physicians to control tissue temperatures during a procedure to prevent or reduce overheating of , and thermal damage to , surrounding and underlying treatment surfaces . this also may allow physicians to forgo the use of anesthetics when performing numerous procedures . this temperature control capability may be very important , because an apparatus 10 in accordance with the present invention may , as described above , include a cryogenic fluid delivery system 30 that comprises a plurality of angular elements ( not shown ) to provide a variety of patterns for cryogenic treatment of biological tissues . use of the cryogenic fluid delivery system 30 may allow physicians to perform procedures without the use of anesthetic , because in such procedures the physician can use a cooling gas to lower the temperature of a target area 24 before treatment , and the physician can monitor the temperature of the target area 24 during treatment to ensure that the target area temperature stays within a selected range that is tolerable to the patient . those skilled in the art will appreciate that , when using an apparatus 10 in accordance with various embodiments of the present invention , it is possible to view a target area 24 in either two or three dimensions . moreover , those skilled in the art will appreciate that by modifying the monitor 26 and utilizing 3 - d view eyeglasses , such as crystaleyes , produced by stereographics , san rafael , calif ., or virtual i - glasses produced by virtual i - o , inc ., it is possible to provide a physician with both planar and three - dimensional views of a target area 24 , and that under such conditions the physician should have increased control of the penetration depth used within a given procedure . this , of course , enables the physician to deliver a three - dimensional treatment regiment to a target location 24 , if that is desired . accordingly it is a primary object of the present invention to provide a method and apparatus for treating biological tissue surfaces with lasers and real - time video monitoring . moreover , laser systems in accordance with various embodiments of the present invention can provide a physician ( or other device operator ) with significant information during a treatment regimen . this information may include , for example , all relevant device parameters , such as laser type , the laser power or energy setting , total time of laser during treatment , the number of pulses provided to a target area within prescribed time limits and over the course of an entire procedure ; the temperature of tissue within and surrounding a target area prior to and during treatment ; the temperature tissue following cryogenic treatment ; and the like . thus , devices in accordance with various aspects of the present invention will provide physicians , and other relevant personnel , with improved information about , and significantly increased control over , a given therapy regimen . devices of the type described and claimed herein can be used to treat numerous conditions , including otitis media , which accounts in the u . s . for approximately 30 , 000 , 000 patient visits per year among children and adults . it will be clear to one skilled in the art , that the above embodiments may be altered in many ways without departing from the scope of the invention . for example , many various laser scanning mechanisms can be used , many different video monitoring systems can be employed , many biological and non - biological surfaces can be treated , many different laser sources ( continuous wave or pulse ) can be used , and many different medical conditions can be treated . accordingly , those skilled in the art will appreciate that the invention is not to be limited to the particular forms or methods disclosed herein , but rather , is to cover all modifications , equivalents , and alternatives falling within the spirit and scope of the appended claims . | US-21863902-A |
a bowling pin storage bin assembly for use as part of a bowling pin delivery system of a pinspotter apparatus , as well as a method of manufacturing such bin . the storage bin is molded as a one - piece article having a plurality of cavities or pockets for storing bowling pins in an essentially horizontal plane above a pin spotter and for delivering the pins to a plurality of pin cups or a pin spotter for spotting on a pin deck . | fig2 illustrates a storage bin 13 for a bowling pin spotting apparatus according to a first embodiment of the invention . the bin 13 is mounted to a frame that includes channels 14 , 15 made of light tubular steel , for example . the bin 13 is to be used in conjunction with a shuttle assembly for retaining pins in . and releasing pins from , the ten cavities 16 a - 16 j of the bin to the spotting / respotting table , such as the shuttle linkage assembly disclosed in u . s . pat . no . 5 , 439 , 418 , the disclosure of which is hereby incorporated by reference thereto for this purpose . in fact , the bin 13 could be substituted for the pin storage device 2 of u . s . pat . no . 5 , 439 , 418 in a bowling pin spotting apparatus . as can be seen , the bin 13 is not formed as a hollow structure in the manner of the bin of the aforementioned u . s . pat . no . 5 , 439 , 418 and u . s . design pat . no . 366 , 510 . in fact , because bin 13 is not hollow , it could not be made by means of a rotational mold . instead , bin 13 is made by thermoforming . in addition , in a particular embodiment of the invention , the bin made from a high - density polyethylene ( hdpe ), rather than from the lope ldpe disclosed in u . s . pat . no . 5 , 439 , 418 , processed into sheets for manufacture by thermoforming . during a period of investigation and impact testing , it has been determined that , rather than using a ldpe and relying upon a rotomolding process to make a one - piece plastic bin , as disclosed by u . s . pat . no . 5 , 439 , 418 , a different material and a different manufacturing process could be implemented to advance the technology currently used in bowling pinspotting apparatuses . more specifically , it was determined that the bin 13 could be made from a high - density polyethylene ( hdpe ), processed into sheets , such as by extrusion , and used in a thermoforming process . it should be recognized that other materials are also contemplated by the present invention such as , for example , other plastics including other polyethylene type of materials , and even more specifically , thermoplastic olefin ( tpo ), and more particularly hdpe manufactured by primex plastic corporation . the hdpe or other materials contemplated by the invention provide high impact for the bowling pinspotting apparatus . hereinafter , the present invention is discussed mainly with reference to hdpe ; although the other high impact materials discussed herein work equally well with the invention . thermoforming has a special cross - linking property that rotomolding , which relies upon the heating and melting of a polymer powder , does not . specifically , cross - linking is introduced into the hdpe material when the material is extruded and rolled into sheet form , for subsequent use in thermoforming , which causes the long polymer molecule chains to bind together at various intersections along their lengths . interweaving and cross - linking of the polymer chains yield a plastic material that is very strong , flexible and , most importantly for the particular subject matter of the invention , increased impact resistance . in a particular embodiment , the extruded sheet used in manufacturing the bin 13 has a thickness of 5 / 16 inch , although that particular thickness is not intended to limit the invention . thermoforming is a method of manufacturing plastic parts by preheating a flat sheet of plastic , such as an aforementioned extruded sheet of hdpe , the edges of which are damped in a frame , then bringing the sheet into contact with a single - surface temperature - controlled mold whose shape it takes . the mold can be typically made of cast or machined aluminum , due to the relatively high coefficient of thermal conductivity of aluminum , which allows for consistent cooling cycle times through a production run , although other materials can be used , particularly if low volume productions are contemplated . once cooled , the formed sheet is removed from the mold and trimmed as necessary . thermoforming broadly relates to any process of forming a sheet of plastic , typically a thermoplastic sheet , which comprises heating the sheet until it become pliable and forcing it onto or into a surface mold . tooling used in thermoforming is referred to as either male or female . if a male mold is used , the sheet is forced onto the mold ; if a female mold is used , the sheet is forced into the mold . typically , the forcing of the sheet into or onto the surface mold is accomplished with a vacuum , although air pressure and direct mechanical force can be used , including combinations of such forces . the thermoforming process used to produce bin 13 of fig2 is made using a male mold ( not shown ). that is , the heated sheet of extruded plastic ( such as hdpe ) is draped over the projecting surfaces of the male mold , such as projections shaped for the purpose of forming the oblong cavities 16 a - 16 j of the bin 13 . the details of the surfaces of the bin 13 of fig2 , including the relatively complex shapes of the cavities , are largely based upon the assembled geometries of the metal bin 1 of fig1 . for example , as shown in fig3 , the pin guiding surfaces 17 of the bin 13 of the first embodiment of the invention are designed to replicate , in form and function , the pin guides 3 of the prior bin 1 . similarly , the end surfaces 18 of the bin 13 of the first embodiment of the invention are designed to replicate , in form and function , the pin butt guides 9 of the prior bin 1 . further , the top surfaces 19 of the bin 13 of the first embodiment of the invention are designed to replicate the top surfaces of the spacers 6 of the prior bin 1 . in addition , the shoulders 20 of the bin 13 of the first embodiment of the invention are designed to replicate the pin assembly brackets 4 of the prior bin 1 . other similarities can also be observed . as with the bin of u . s . pat . no . 5 , 439 , 418 , each of the cavities 16 a - 16 j of bin 13 defines a minimum cross sectional area , i . e ., an opening having the general shape of a bowling pin taken along its longitudinal axis but having a width slightly larger than the width of a conventional bowling pin . as shown , for example , in fig3 , each of the cavities 16 a - 16 j includes a shoulder 20 at its forward portion , i . e ., the portion which corresponds to the head of a bowling pin . each of the cavities 16 a - 16 j is also shorter than the length of a conventional bowling pin and the cavities are constructed and arranged to bias the base of a bowling pin in a forward direction so that the head of the pin rests on the shoulder 20 in the forward part of a cavity 16 and the base of the pin is supported from below by movable support members of the shuttle assembly ( not shown ) when the pins are stored in the bin 13 in a first supported , or stored , position . when pins are to be released from the bin 13 , by means of the reciprocation of the support members of the shuttle assembly from beneath the pins , the pins pivot downward base - first through their respective cavities as opposite surfaces 17 ( see fig3 ) of the cavities support and guide the upper portion of the base of each pin in their pivoting and downward release from their respective cavities . the geometry of the bin 13 of the first embodiment of the invention differs from that of u . s . pat . no . 5 , 439 , 418 and u . s . design pat . no . 366 , 510 . a first difference relates to the geometry of the cavities 16 a - 16 j . in us &# 39 ; 418 and usd &# 39 ; 510 , the cavities are relatively widely scalloped along their interior surfaces from the upper surface of the bin down to the through opening of each cavity . this geometry has been found to allow the pins to bounce around as they are delivered by the distributor , rather than to settle into the various cavities 16 a - 16 j relatively quickly . by contrast , as can be seen in fig2 and 3 , the interior surfaces of the cavities are more steeply inclined , which allow the pins to bounce around less and to become more firmly engaged in the respective cavities as the pins are delivered by the distributor . for example , the interior surfaces of the cavities in the area of the head of the pin and the base of the pin provide for a closer fit between the cavities and the pins . in addition , the geometry of the bins of us &# 39 ; 418 and usd &# 39 ; 510 includes a relatively flat upper surface surrounding the pin cavities , whereas the bin of the invention includes a number of functional projections “ p ” extend upwardly from the area surrounding the cavities , which also facilitate the settling of the distributed pins within the various cavities . the utilization of the process of thermoforming for the manufacture of a bowling pin storage bin , particularly with its unique geometry , has been found to present challenging issues to be overcome , such as potential part defects such as webbing , surface blemishes , thin material areas at key impact areas , and warping . as recognized by those skilled in the art of thermoforming , as a heated pliable sheet of plastic brought down to be formed over the male cavity , or vice versa , the top surface of the part is controlled by the mold . that is , the area of the mold that contacts the plastic first tends to be the thickest , while the remainder of the plastic sheet is drawn and thins as the sheet is brought further down upon the mold . using a thermoforming technique , sometimes referred to as drape forming , using a male mold , seemed logical because of the complexity of the pocket geometry , i . e ., the complex shapes of the cavities 16 a - 16 j . but , while the top surface is controlled by the mold and tends to be the thickest , with this technique the top surface forms the bottom of the bin and the top of the bin , which is used for mounting the bin , is created by the uncontrolled surface . another challenge that is confronted when thermoforming a bin of the invention is that of forming key edges of internal cup shapes . with thermoforming as the plastic sheet is moved onto or into the irregularities of the mold , such as forming the plastic sheet around corners , there is a tendency for the plastic to form relatively large radii which , when compared to the prior art sheet metal bin , such as that shown in fig1 , can considerably change the ability of the shapes thus formed to function in the manner intended . the result can disadvantageously affect the ability of the bin to consistently catch and hold the incoming pins . also , because the bin must function as a two - layer pin storage unit , the ability to catch and hold a second layer of pins can be exacerbated by the aforementioned tendency to form large radii in the internal geometry of the pin cavities . still further , because of unique application of thermoforming techniques to the manufacture of a bowling pin storage bin , which is a large part , which includes ten relatively complex and deep pockets , one is challenged to ensure that the horizontal stiffness of the finished product is adequate . this consideration is of importance , for example , particularly when considering the use to which the bin is put , such as , e . g ., if a person were to support their weight by leaning out over the bin to grab an orphaned pin . in addition , unlike prior art sheet metal bins , which can be relatively precisely and firmly mounted to the supporting frame , a plastic bin produces additional challenges . for example , rubber grommets can be used at least fastening locating to allow the bin to expand and contract thermally with temperature change , to help soften impact noise , and to silence any rattle of large free floating washers , e . g ., used to retain the bin at locations where shoulder screws are used . inherent in thermoforming hdpe , or other plastic , is the inability to accurately trim and machine the mounting holes . because of this , mounting holes can be replaced with slots to ease any hole alignment issues . fig4 illustrates a second embodiment of a storage bin according to the invention . in addition to variations in the geometry of the bin of this embodiment , compared to that of fig2 , this embodiment is preferably formed using female tooling in the thermoforming process . in contrast to utilizing male tooling , i . e ., a male cavity or mold , the heated pliable polymer sheet is bought into engagement with the mold to assume the shapes of the recesses therein . fig4 a and 4 b schematically illustrate two stages of a thermoforming process using a female mold and relying upon a vacuum assist in positioning the polymer sheet . in fig4 a , after the application of suitable heating , schematically shown as radiating from above , to render the extruded sheet pliable , while clamped in a frame , the extruded sheet is brought to engage the female mold . as can be seen in fig4 a , the top surfaces of the mold are the first surfaces to come into engagement with the sheet . as the vacuum continues to be applied through the mold , shown in fig4 b , atmospheric pressure pushes the pliable sheet into the recess of the female mold , stretching the sheet to lie against the inner surfaces of the mold . after cooling and removal of the clamped frame , fig4 c shows the part that has been formed . fig4 c schematically illustrates the tendency of those areas of the sheet which are the last to engage the mold are the thinnest , i . e ., the areas which had been stretched during the application of vacuum to the pliable sheet . the thickest areas of the part are those which first engaged the mold , particularly the top of the part . returning to the second embodiment of the storage bin of the invention , fig5 illustrates , in perspective view , a longitudinal cross section of the bin . because the bin of fig5 is produced with a thermoforming process like that of fig4 a , 4 b , the top surfaces 21 of the bin are those that are “ uncontrolled ,” i . e ., surfaces that had not been in direct engagement with surfaces of the mold , whereas the undersurfaces 22 of the bin are those that are “ controlled ,” i . e ., surfaces that are formed by being in direct engagement with the surfaces of the mold . in addition , unlike the bin of the first embodiment shown in fig2 , the uppermost areas 23 of the bin are those which , during manufacture according to a process like that of fig4 a , 4 b , are areas of the pliable sheet that had engaged the surfaces of the female mold first and , therefore , they are the thicker areas of the bin , whereas the bottom areas of the bin of fig5 are those that had engaged surfaces of the female mold later in the process and , therefore , they are the thinner areas , but for which impact resistance is not as much of a factor . although the surfaces of the bottom areas include those which are contacted by the distributed pins , the impact forces are typically not as significant as those that are absorbed the surfaces of the uppermost areas 23 . fig6 shows top views of localized portions of the 10 - pin areas of the first embodiment ( portion 1 ) and the second embodiment ( portion 11 ) of the storage bins according to the invention . because the bins are essentially symmetrical on either side of a vertical longitudinal median plane through the one and five pins , the portions of the bins shown in fig6 also are representative of the 7 - pin areas . the rear wall 25 of the embodiment i is a double drafted backstop wall at 12 degrees to the vertical . although the pins that are delivered to the bin by the distributor rebound within , the pockets for the seven and ten pins , following initial impact with the bin , fall and settle within the pockets , this somewhat flat , angled backstop can occasionally cause pins to rebound up and out rather than down and in . the double drafted backstop wall 26 of the embodiment ii creates a more horizontal impact surface . fig6 also shows that the pin receptacle geometry of the pockets of embodiment ii includes more vertical internal shoulders 27 to catch and hold the pins on rebound compared to those of embodiment i , such as the more angled surfaces such as surfaces 27 ′ of embodiment ii . further , the pockets of embodiment ii are more “ pin - shaped ” than those of embodiment i . that is , particularly for the pockets for the 7 - pin and the 10 - pin , the outside walls 28 for engagement with the body of a pin more closely follow the contour of pin , compared to the outside walls 29 of the pockets of embodiment i . still further , the embodiment ii includes a scalloped entrance edge 30 , shown in both fig5 and 6 , which facilitate entry of the pins particularly into the pockets for the seven and ten pins . in addition , a terraced section 31 , again particularly for the pockets for the seven and ten pins , help to trap and hold the second layer pin . that is , as mentioned above , the bins of both embodiment i and embodiment ii ( fig2 and 4 , respectively ), are constructed and arranged to hold two layers of pins , i . e ., second pin lying upon a first pin , so that the bin can readily supply a pin to the pin table below the bin when needed . fig7 illustrates the bins of the first and second embodiments , with particular reference to structures facilitating horizontal stiffness . structural shapes of embodiment ii include those that aid in longitudinal support of the bin , which also facilitate the thermoforming process . for example , the somewhat abrupt backstop bosses 32 of embodiment i are not a feature of embodiment ii , the pockets of embodiment ii instead having a smoother perimeter that particularly improves the catch and hold of second layer pins . in addition , the side edges 33 of the bin of embodiment ii are vertically flanged , whereas those of the bin of embodiment i are not . also for the purpose of increasing stiffness , the storage bin of embodiment ii includes deep and integrated ribs 34 extending generally longitudinally toward the front edge of the bin , whereas the ribs 35 of the bin of embodiment i are shallow . fig8 illustrates a support frame 36 for the storage bins of the first and second embodiments of the invention . the frame can be seen , at least in part , in fig2 and 4 , in combination with the bins of the first and second embodiments , respectively . both bins are mounted to a c - channel sections 37 , 38 at the front and rear edges , such sections being made from steel , for example , or other suitable material . extending between the c - channel sections for the purpose of aiding in the support of the center section of the bins are generally longitudinally extending tubular members 39 , shaped to fit the contours of the underside of the bins , in conjunction with attached vertical plates 40 . like the c - channel sections , the tubes 39 and plates 40 can be made from steel or other material . in addition , shapes other than those particularly illustrated for the members 39 and 40 could alternatively be utilized . as shown in fig8 , and in combination with the bin of the second embodiment in fig4 , the brackets 41 , made of steel or other suitable material , are attached to the flanges 42 at the pockets for the seven and ten pins , which flanges also support the shuttle . the combination of attachments shown in fig8 , and in fig4 , helps to reinforce both the shuttle and the bin , particularly for adequately supporting the bin if one were to put his / her weight on one of the flanges to prevent the twisting of the rear channel . the increased stiffness of the edges of the second embodiment also increase such reinforcement . fig9 illustrates respective portions of the storage bins of the first and second embodiments of the invention , with exploded showings of the mounting hardware . for each bin , only one assembly of hardware components is shown in detail , it being understood that the bins are mounted in a plurality of locations along its periphery , for example . the storage bin of the first embodiment i includes a shoulder screw 43 ( ¼ × ⅜ inch , # 10 thread , e . g . ), to extend through a slot 46 , a fender washer 44 ( ¼ in . id , 1 in . od , e . g . ), a grommet 45 ( ¼ in . id , 7 / 16 in . hole , ⅝ in . od , e . g . ), and a flex lock nut ( 3 / 16 in ., not shown ). the storage bin of the second embodiment ii includes a cap screw 43 ( ¼ × 1 inch , e . g . ), to extend through a hole 51 , a fender washer 48 ( ¼ in . id , 1 in . od , e . g . ), a grommet 49 ( ⅜ in . id , 718 in . hole , 1 1 / 16 in . od , e . g . ), and a flex lock nut ( ¼ in ., not shown ). grommet diameters play a large role in the extent to which a hdpe bin can expand and contract before damage is done to the bin or to the fasteners holding it . the embodiment i uses a radial grommet 45 having a radial modulus of 3 / 32 inch . the embodiment ii uses a grommet 49 with a radial modulus of ¼ inch , allowing 25 % more movement in all directions . the grommet 49 is mounted in a hole 51 rather than a slot ( 46 , e . g .) for the purpose of ensuring proper function of the grommet in all physical situations that would be encountered during use . fig1 illustrates the storage bin of the second embodiment ii with indexing and time stamp features . during the thermoforming manufacturing process described above , after the part which is to become a bin according to the invention is removed from its mold , the part must be removed from its clamping frame , trimmed and routed to create the particular details necessary , such as the openings at the underside of the bin . such trimming and routing is typically automated and , therefore , the part must be precisely positioned . fig1 illustrates a conical feature 52 to constrain the part in the x and y directions , as well as a v - groove feature 53 to rotationally constrain the part , throughout the trimming and routing process . in addition , adjacent the conical feature , an in - mold time stamp can be formed on a control surface of the part . the storage bin assembly of the invention , manufactured and constructed as described above , improves upon prior metal bins and the known bin made by a rotomolding process , providing significant stiffness and impact resistance , not suffering from premature material fatigue , and which can withstand a significant number of impacts with bowling pins , such as at least 1 , 000 , 000 cycles of a pin spotting apparatus the invention is not limited to the particulars of the embodiments described hereinabove as examples , but encompasses any equivalent embodiment . for example , although sheets of a high molecular weight polyethylene ( hmwpe ) can be used for the storage bins of both the first and second embodiments , the invention encompasses the manufacture from other polymers . in addition , the polymer sheets used for the storage bins of both the first and second embodiments can be formed from 5 / 16 inch extruded sheets ( hmwpe , e . g .). although other thicknesses are also contemplated . in this regard , because of the stiffening described above in connection with the storage bin of the second embodiment , the invention encompasses the manufacture of bins of the second embodiment from ¼ inch thick sheets , which results in savings of material and related processing time , thereby lowering the cost of manufacture . | US-76660407-A |
embodiments of this invention include methods for increasing the amount of the enzyme tyrosine hydroxylase in the central nervous system of mammals in need of an increase in th . methods include the use of the tripeptide , gly - pro - glu to increase th in the cns . gpe can increase the amount of th and / or decrease the loss of th in conditions characterized by a loss of dopamine , such as parkinson &# 39 ; s disease and cns injury . gpe may act to increase the expression of th or by inhibiting a decrease in th expression within the cns or by inhibiting the loss of th - containing neurons within the cns . by increasing the amounts of th in the cns , gpe can increase the amount of the neurotransmitter , dopamine , in areas of the cns responsible for adverse symptoms of neural injury or disease . | as indicated above , the present invention is broadly based upon the applicants surprising finding that gpe and its analogs are capable of increasing the amount of th within the cns . this increase , which is through upregulating th expression or through preventing the loss or degradation of th , is achieved through increasing the effective concentration or amount of gpe or the analog in the cns of a patient . the effective increase in the amount of th in turn effects an increase in the production of dopamine within the cns . it is presently preferred by the applicants that gpe itself be used to increase the amount of th / dopamine . most conveniently , this is effected through the direct administration of gpe to the patient . however , while this is presently preferred , there is no intention on the part of the applicants to exclude administration of other forms of gpe . by way of example , the effective amount of gpe in the cns can be increased by administration of a prodrug form of gpe which comprises gpe and a carrier , gpe and the carrier being joined by a linkage which is susceptible to cleavage or digestion within the patient . any suitable linkage can be employed which will be cleaved or digested to release gpe following administration . another option is for gpe levels to be increased through an implant which is or includes a cell line which is capable of expressing gpe in an active form within the cns of the patient . gpe can be directly administered as part of a medicament or pharmaceutical preparation . this can involve combination of gpe with any pharmaceutically appropriate carrier , adjuvant or excipient . the selection of the carrier , adjuvant or excipient will of course usually be dependent upon the route of administration to be employed . the administration route can vary widely . an advantage of gpe is that it can be administered peripherally . this means that it need not be administered directly to the cns of the patient in order to have effect in the cns . any peripheral route of administration known in the art can be employed . these can include parenteral routes with injection into the peripheral circulation being a suitable example . however , alternative administration routes selected from oral , rectal , nasal , subcutaneous , inhalation , intraperitonial or intramuscular can be employed . two of the most convenient administration routes will be by subcutaneous injection ( eg . dissolved in 0 . 9 % sodium chloride ) or orally ( in a capsule ). it will also be appreciated that it may on occasion be desirable to directly administer gpe to the cns of the patient . again , this can be achieved by any appropriate direct administration route . examples include administration by lateral cerebro - ventricular injection or through a surgically inserted shunt into the lateral cerebro - ventricle of the brain of the patient . the calculation of the effective amount of gpe or its analogs to be administered will be routine to those persons skilled in this art . needless to say , the final amount to be administered will be dependent upon the route of administration and upon the nature of the neurological disorder or condition which is to be treated . a suitable dose range may for example be between about 0 . 04 mg to 1000 mg of gpe and / or analog per 100 g of body weight where the dose is administered centrally . for inclusion in a medicament , gpe and its analogs can be obtained from a suitable commercial source . alternatively , gpe and its analogs can be directly synthesised by conventional methods such as the stepwise solid phase synthesis method of merryfield et al . ( j . amer . chem . soc . 85 2149 - 2156 ( 1963 )) alternatively , synthesis can involve the use of commercially available peptide synthesisers such as the applied biosystems model 430a . the present invention will now be illustrated with reference to the following nonlimiting examples . this experiment was blind with respect to the treatment ( with gpe or the vehicle ) and with respect to the counting of neurons expressing th ( between sections from animals treated with gpe or vehicle ). the objective of this experiment was to determine the effects of administering gpe on the expression of tyrosine hydroxylase ( th ) in the presence or absence of cns injury . the experiment involved treating the rats with a control vehicle or gpe 2 hours after a chemically induced lesion in the substantia nigra region of the brain . specifically , 9 pairs of adult male wistar rats ( 280 - 320 g ) were prepared under 3 % halothane / o 2 anaesthesia . the oxygen free radical producing neurotoxin 6 - hydroxydopamine ( 6 - ohda ) which produces degeneration of dopamine neurones ( 8 μg / 2 μl ) was injected into the median forebrain bundle using a 30 gauge needle ( coordinates : anterior - posterior + 4 . 7 mm , right + 1 . 6 mm , vertical − 8 . 5 mm ). a guide cannula was placed on the dura 7 . 5 mm anterior from stereotaxic zero and 1 . 5 mm from the midline on the right . the rats were left to recover at room temperature . 2 hours after the administration of 6 - ohda the rats were treated , via the guide cannula , with 3μg gpe or vehicle alone ( 15μl injected with a pump rate of 2 μl / minute , 0 . 1m acetate buffer [ ph6 ], diluted 10 times in 0 . 1 bovine serum albumin in 0 . 1m phosphate buffered saline [ pbs ][ ph7 . 31 ]). the rats were sacrificed using pentobarbital 14 days after 6 - ohda induced injury . brains were perfused with normal saline and 4 % paraformaldehyde and fixed in perfusion fixative overnight . the brains were paraffin embedded using a standard processing schedule . sections ( 8 μm ) were cut through the substantia nigra using a microtome . immunoreactivity for th was established with sections mounted on chrome alum coated slides . briefly , the sections were dewaxed , rehydrated and washed in 0 . 1m pbs . the sections were pre - treated with 1 % h 2 o 2 in 50 % methanol for 20 minutes and then washed in 0 . 1m pbs ( 5 minutes × 3 ). the antibodies were diluted in 1 % goat serum . the sections were then incubated with rabbit ( rb ) anti - th ( 1 : 500 ) antibodies ( the primary antibodies ) for 2 days . the sections were washed using 0 . 1m pbs ( 5 minutes × 3 ) and then incubated with goat anti - rabbit biotinylated secondary antibodies ( 1 : 200 ) at room temperature overnight . the sections were washed in 0 . 1m pbs ( 5 minutes × 3 ) and then incubated in ( extravidin tm sigma 1 : 200 ) for 3 hours and followed by h 2 o 2 ( 0 . 01 %) in 3 , 3 - diaminobenzidine tetrahydrochloride ( dab , 0 . 05 %) reaction . the sections were then dehydrated and coverslipped . the neurons in the pars compacta region of the snc at 3 levels in both hemispheres which showed specific immunoreactivities corresponding to th were counted using a light microscope . the total counts of neurons were compared between the gpe and the vehicle treated group . data were analysed with paired t - test and presented as mean ± sem . the results are presented in fig1 . fig1 shows that the number of th immunopositive dopaminergic neurons increased with gpe on the lesioned ( right ) side of the brain . this indicates that the administration of gpe is effective in upregulating th expression . example 2 was performed using a second set of rats ( 9 pairs ), using the same experimental parameters except that only the immunopositive neurons at 2 levels of the snc were counted . the results are shown in fig2 , and again demonstrated upregulation of th expression . these experiments were approved by the university of auckland animal ethics committee and all efforts were made to minimise the suffering incurred and the numbers of animals used . a paired experimental design was used and the experimenter was blinded to the treatment groups . eighteen male wistar rats ( 50 - 60 days old , 280 - 310 g ) were used for this study . 6 - hydroxy dopamine ( 6 - ohda ) was prepared as 8 μg in a base of 2 μl 0 . 9 % saline containing 1 % ascorbic acid . it was administered into the right medial forebrain bundle ( mfb ) using coordinates of ap + 4 . 7 mm , r 1 . 6 mm , v − 8 mm under anaesthesia of 3 % halothane . 6 - ohda was injected into the right mfb using a hamilton syringe ( 100 μl with a 30g needle ) controlled by a microdialysis infusion pump at an infusion rate of 0 . 2 μl / minute . the infusion needle was then slowly withdrawn 5 minutes after the infusion . the surgery and procedures for the intracerebroventricular administration have been described by guan et al ( 1993 ), journal of cerebral blood flow and metab , 13 , 609 - 616 . briefly , a guide cannula ( 21g , 6 mm ) was fixed on the top of the dura with coordinates of ap + 7 . 5 mm , r 1 . 5 mm immediately after the injection of 6 - ohda . either gpe ( 3 μg / 15 μl ) or its vehicle were infused into the right lateral ventricle 2 hours later at an infusion rate of 2 μl / minute . rats were then housed in a holding room with food and water ad libitum for the next 2 weeks . the rats were then deeply anaesthetized with an overdose of pentobarbital and transcardially perfused with normal saline followed by 10 % buffered formalin . the brains were removed from the skull and kept in the same fixative for the next 48 hours . a standard paraffin tissue preparation was used to process the tissue so that it could be used for immunohistochemistry . coronal sections ( 8 μm ) were cut using a microtome , and the sections were mounted on chrome alum coated microscopy slides and air - dried . snc sections used for immunohistochemical staining were deparaffinized , rehydrated and washed in pbs ( 0 . 1m ). the sections were then pretreated with 1 % h 2 o 2 for 20 minutes , washed with 0 . 1m pbs ( 3 × 5 minutes ) and incubated with rabbit polyclonal antisera raised against tyrosine hydroxylase ( protos biotech , usa ) diluted 1 : 500 with 1 % goat serum for 48 hours at 4 ° c . the sections were washed in pbs ( 3 × 5 minutes ) and incubated with donkey anti - rabbit biotinylated secondary antibody ( 1 : 200 , amersham , life science ) overnight at room temperature . the sections were washed , incubated in streptavidin - biotinylated horseradish peroxidase ( 1 : 200 , amersham , life science ) for 3 hours , washed again in pbs and then reacted in 0 . 05 % 3 , 3 - diaminobenzidine tetrahydrochloride ( dab ) and 0 . 01 % h 2 o 2 to produce a brown reaction product . the sections were dehydrated in a graded alcohol series , cleared in xylene and coverslipped with mounting medium . the number of th positive neurons on both sides of the snc were counted using light microscopic examination ( 20 × magnification ) at three representative levels ( ap + 4 . 2 , + 3 . 8 mm and 3 . 4 mm ) ( paxinos , et al ( 1982 ), new york : academic press ). the average density from the background was also measured . the analyst was blinded to the treatment and control groups . the difference in average density between the background and th immunostaining was calculated and used for data analysis . right / left ( r / l ) ratios of both the number of th immunopositive neurons and the average density of th immunostaining from each level was compared between the two treatment groups using one way anova . data are presented as mean ± sem . fig3 shows that th immunoreactivity was restored with gpe on the lesioned ( right ) side of the brain . this effect was more pronounced in caudal levels ( 16 ± 11 . 2 to 99 . 6 ± 27 %) compared with the rostral level ( fig3 ). this indicates that the administration of gpe is effective and selective in upregulating th expression . gpe treatment restored the density of th immunostaining in both the cytoplasm and processes of neurons ( fig4 ). gpe also showed 99 . 6 ± 27 . 0 % restoration in th immunoreactivity with only 60 ± 13 . 0 % neuronal survival in the most caudal level analysed of the snc . the above example shows the effect of gpe administration on th expression in the snc . gpe was particularly effective in upregulating th expression in the most caudal region of snc analysed . gpe upregulated th expression in the cytoplasm of both the neuronal cell body and neuronal processes . gpe prevented the loss of th immunopositive neurons in the snc compared to the control group . gpe provided protection for the dopaminergic neurons against the neurotoxin 6 - ohda . these experiments were approved by the university of auckland animal ethics committee and all efforts were made to minimise the suffering incurred and the numbers of animals used . adult male wistar rats ( 200 - 220 g ) were anaesthetized with 75 mg / kg nembutal and positioned in a stereotaxic apparatus . unilateral transection of the medial forebrain bundle which contains the ascending nigral dopaminergic projection fibers was made 1 . 3 mm rostral to the rostral tip of the snc using a retractable wire knife ( david kopf instruments , tujunga , calif .). the knife was lowered into the brain using the following coordinates from the atlas of paxinos and watson ( 1986 ), sydney : academic press : 3 . 3 mm posterior to bregma , 2 . 4 mm lateral from midline , and 8 . 5 mm ventral from skull , the blade was extended 2 . 0 mm toward midline , raised 2 . 5 mm dorsally , retracted and extended again , and then returned 2 . 5 mm ventrally . the wire blade was retracted and the knife withdrawn . next , a 22 - gauge metal guide cannula was permanently fixed into place supranigrally at 5 . 0 mm posterior to bregma , 2 . 0 mm lateral to midline , and 6 . 8 mm ventral to skull . a second set of intact unlesioned rats were cannulated supranigrally at the same coordinates . animals received daily supranigral injections of trophic factors via a hamilton syringe attached to a 28 - gauge cannula 1 μl of either gpe ( 0 . 3 μg / μl ), or 1 μg of the control vehicle pbs with 0 . 1 % bovine serum albumin ( bsa ) beginning immediately after lesioning and extending for two weeks post - lesioning . gpe was diluted in phosphate buffered saline ( pbs ) containing 0 . 1 % bsa ( ph 7 . 4 ). after two weeks of treatment , animals were perfused under deep anaesthesia with pbs ( ph 7 . 4 ) followed by 4 % paraformaldehyde in phosphate buffer ( ph 7 . 4 ). brains were post - fixed for 24 hours at 4 ° c . in the same fixative then transferred sequentially to 10 % and 30 % sucrose in pb for 2 - 5 days until sunken . floating 30 μm coronal nigral sections were stained by avidin - biotin - peroxidase immunocytochemistry . rabbit anti - rat tyrosine hydroxylase ( th ) polyclonal antibody ( te101 , eugene tech international , new jersey , usa ) was diluted 1 : 100 in pbs containing 0 . 2 % triton x - 100 , 3 % goat serum , and 0 . 02 % sodium azide . sections were first incubated for 1 hour at room temperature in primary antibody vehicle . incubation with the primary antibody was for 3 - 4 days at 40 ° c . biotinylated anti - rabbit igg ( vector laboratories ) secondary antibody was diluted at 4 μl / ml in pbs containing 0 . 1 % triton x - 100 and normal rabbit serum . sections were incubated for 2 hours at room temperature , followed by an avidin - biotin - peroxidase cocktail ( vector laboratories ) incubation for 1 hour at room temperature . peroxidase was visualized with 1 mg / ml 3 , 3 ′- diaminobenzidine in 0 . 03 % h 2 o 2 for 5 minutes . controls were conducted by replacing the primary antibody with pre - immune igg or by omitting the primary and / or secondary antibody from the procedure . sections were mounted on gelatin - coated slides , dehydrated in serial ethanol , cleared in xylene and coverslipped with mounting media . immunopositive cells were counted in the central snc counts were made ventral and lateral to the lemniscus medialis , including both the pars compacta and pars reticulata , but excluding the ventral tegmental area in the ventromedial midbrain and the retrorubral field in the caudolateral midbrain . a cell was counted if it had an intact cell body and soma membrane . counts were taken on both the contralateral and ipsilateral sides from 2 - 3 animals per treatment . the number of cells was represented by the mean number of immunopositive cells within the described field on each side of the brain . to reveal percent survival , percent changes were calculated by dividing the ipsilateral value by contralateral value . the percent cell survival of th immunopositive neurons increased with gpe treatment on the lesioned side of the brain ( fig5 ). this indicates gpe is effective in upregulating th expression . the above examples show the effect of gpe administration on th expression in the pars compacta region of the snc . the experimental results demonstrate the ability of gpe to increase the amount of th in the cns through a direct increase in enzyme expression . in turn , the increased expression of th leads to an increase in th - mediated dopamine production . these findings make gpe and its analogs applicable in treating a number of neurological disorders or conditions , either therapeutically or prophylactically . indeed , it will be apparent to those persons skilled in the art that gpe and its analogs can be employed at any time where a patient would benefit from an increase in the expression of th / dopamine within the cns . neurological disorders or conditions which would benefit from this include , but are not limited to parkinson &# 39 ; s disease . it will be appreciated that although the present invention is described above with reference to certain specific embodiments , the description provided is exemplary only and that the invention is not limited thereto . | US-60657403-A |
a collapsible fluid containment bag for irrigating and cleaning wounds on extremities having semi - rigid support members and an elevated lower support member attached to the bottom of the proximal end of the containment bag creating a gradient for allowing irrigation fluids and biological tissue to drain to the distal end of the bag for removal . the containment bag is collapsible , making it a convenient size for storage , transport , and disposal . | referring now to fig1 - 7 , the present invention is a fluid containment device 10 illustrated in the figures and including the following components , namely , bag body 12 , having a lower section 14 and an upper section 16 . the fluid containment device 10 includes bottom 18 and continuous wall 20 . the fluid containment device 10 can be made from one - piece clear plastic , such as polyvinylchloride , or can be manufactured from multiple pieces , including a separate floor , sidewalls , and top . the bottom and sidewalls define a proximal opening 22 in which a patient &# 39 ; s limb may be inserted for care and treatment at proximal end 23 . distal portion 24 defines an area where tubing , hosing , or other means enter bag body 12 for removal of irrigation fluids and biological tissue from drainage area 25 . the shape of the fluid containment device 10 is maintained with flexible , semi - rigid supports 26 , which support the bag body and fluid containment device so that the patient &# 39 ; s limb may be inserted therein . the flexible support members define containment space 28 , which can receive the patient &# 39 ; s limb for irrigation , wound treatment , debridement , or subsequent surgical procedures . semi - rigid flexible structural support member 26 may engage fluid containment device 10 in any practical or conventional manner . however , it is preferred that the walls 20 and the lower section 14 and the upper section 16 of bag body 12 contain a double - wall sleeve 27 defining an opening for insertion of the flexible support member 26 . the two - sided sleeve comprises an outside wall 30 comprising the bag body 12 and wall 20 . it also comprises a lower side 32 defining open space 34 for insertion of the semi - rigid flexible support member 26 as illustrated in fig4 . the structural support member has a rounded shape approximately a semicircle when operatively associated with continuous wall 20 and bottom 18 . the semi - rigid flexible support member 26 is made from suitable material for providing flexibility for opening the containment device 10 from a collapsed position 72 and an open position for supporting containment device 10 creating containment space 28 . the structural support member 26 also must be sufficiently flexible to be compressed into a collapsed position 72 for storage in a container or package 74 . further , the material utilized in manufacturing the structural support member 26 must be an approved material that can withstand sterilization treatment of the containment device 10 prior to use . many conventional materials , including various plastics may be utilized , however , polypropylene is preferred . in addition , fluid containment device 10 may contain access ports 36 wherein one or more may be placed on the upper section of the bag body or in any other convenient location . the access ports 36 provide access to the body for the care provider and can be resealed . zippers are illustrated . however , any conventional closure means is acceptable . fluid is drained or withdrawn from the bag body 12 by tube 38 , which may have one or more extension tubes . the tubes enter the bag through port 40 at distal end 24 . one tube 42 may enter the bag for collection of fluids that may drain through that area of the bag . indeed , one or more perforated tubes 44 descending into the bag , preferably to the proximal end 23 or opening 22 for collection of fluids , may be utilized . it is preferred to have perforations 46 in the tubes for collecting fluids and tissue as they drain toward tube 42 and drain 48 . drain 48 includes a funnel device 50 having a set diameter 52 connected to hose 54 . the large diameter 52 of the funnel and large diameter 56 of hose 54 allows for the insertion of tube 42 or perforated tube 44 therein , creating a double - walled tube 58 . a vacuum pump ( not shown ) can be attached to double - walled tube 58 to remove liquid and biological tissue through perforated tube 44 . further , drain 48 may capture liquids and tissue as they collect in the bottom 18 of distal portion 24 of bag body 12 . the funnel shaped device 50 assists in the collection of liquids and tissue . when vacuum is applied , it assists in the removal of liquids and tissue through hose 54 also , which is surrounding perforated tube 44 , as well as through perforated tube 44 . an especially useful feature of the present invention is lower support 60 , which is attached to bottom 18 in the lower section 14 of the fluid containment device 10 for elevating the limb of the patient at the proximal end 23 of the device . support 60 runs the width of bottom 18 . by elevating the limb , a gradient is created allowing gravity to assist the flow of irrigation fluids and tissue to the port 40 for removal from the bag . to assist in the removal of irrigation fluids and tissue from the bag , the tube 36 and perforated tubes 44 may be subjected to vacuum pressure . lower support 60 may be made from any lightweight , sturdy material , for example , polystyrene , that is fitted within sleeve 62 and the floor 18 of the fluid containment device 10 as shown in fig5 . sleeve 62 has outer wall 64 defining open space 66 wherein lower support member 60 is inserted . lower support 60 also provides comfort to the patient by providing support to the limb . any suitable means for closing the device at its proximal end to secure the device to the patient &# 39 ; s limb may be utilized . it is preferable , however , to use hook and loop fastening means 29 for convenience . referring to fig1 , fluid containment device 10 is shown in a collapsed or folded position 72 . in position 72 , the device may be stored for transportation . fig7 shows a container or package 74 that has a flat bottom 76 and rounded surface wall 78 that matches the contour of the folded fluid containment device 10 . more specifically , wall 78 matches the contour of the folded structural support members 26 . the package 74 provides convenient , sterile and secure storage of fluid containment device 10 for transport . the folded position 72 of the containment device provides less space for transportation of sterile devices . in addition , package 74 may be used to transport a contaminated fluid containment device 10 with irrigation fluid and tissue for disposal . the combination of the containment device 10 and storage package 74 provides a convenient solution for proper handling and disposal of contaminated irrigation fluid and biological tissue . fig2 illustrates a top view of the fluid containment device 10 with a patient &# 39 ; s leg inserted therein to illustrate perforated tubes 44 extending from the distal end of the bag body 12 to the proximal end 23 for the collection of fluids and other materials . drain 48 is shown for collecting fluid at the distal portion 24 in bottom 18 of the bag because of the gradient created by the use of lower support 60 ( not shown ) at the proximal end 23 of the fluid containment device . fig6 illustrates a shorter version 11 of containment device 10 with two semi - rigid support members 26 . it should be apparent to those skilled in the art that various modifications and adaptation of the structure described above are possible without departing from the spirit of the invention , the scope of which is defined in the appended claims . | US-68450907-A |
a corneal surgical apparatus for incising a cornea of a patient &# 39 ; s eye in a layered form includes : a suction ring unit , having a circular opening , that is to be vacuum - fixed onto a peripheral part of the cornea ; a rotatable shaft ; an eccentric pin projecting from a distal end of the shaft , the eccentric pin being located at a position offset from a rotational central axis of the shaft ; and a cutting unit movable in an incising direction above the suction ring unit . the cutting unit including : cornea applanating means that applanates the cornea within the opening into a substantially flat form ; a blade that incises the cornea ; a first oscillation transmitting member having a part with which the eccentric pin is engaged ; a second oscillation transmitting member having a part with which a part of the first oscillation transmitting member is engaged ; and a holder that holds the first and second oscillation transmitting members to be movable in a lateral direction which is perpendicular to the rotational central axis of the shaft . movement of the second oscillation transmitting member in the lateral direction causes the blade to be moved in the same direction . | hereinafter an embodiment of the invention will be explained with reference to the drawings . fig1 is a cross - sectional view of a corneal surgical apparatus according to a first embodiment and a schematic diagram of a control system . reference numeral 1 denotes a main body of the apparatus , and numeral 1 a denotes a grip portion to be held by an operator during a surgery . a suction unit 3 for fixation to the patient &# 39 ; s eye , and a cutting unit 2 having a blade 20 for incising the cornea , to be moved rectilinearly above the suction unit 3 are provided on the front side ( left side in the figure ) of the main body 1 . a feed motor 11 for rectilinearly moving the cutting unit 2 in the incising direction is fixed in the main body 1 , with a feed screw 13 having a threaded portion corresponding in length to the rectilinear movement of the cutting unit 2 , attached to the rotation shaft of the motor 11 . an oscillating motor 12 for imparting lateral oscillation to the blade , and a connecting member 17 to be connected with the cutting unit 2 at its tip portion are fixed to an attaching member 14 to be screwed into the threaded portion of the screw 13 . a rotation shaft 15 mounted on the rotation shaft of the motor 12 is held by the connecting member 17 rotatably . an eccentric pin 16 is embedded on the tip of the shaft 15 at a position offset from the rotation center ( rotation central axis ), projecting therefrom . the cutting unit 2 moves forward or backward with the motor 12 and the connecting member 17 mounted on the attaching member 14 according to the forward or reverse rotation of the motor 11 . next , the configuration of the cutting unit 2 and the suction unit 3 will be explained with reference to fig2 and 4 . fig2 is an enlarged explanatory diagram of the cutting unit 2 and the suction unit 3 of the apparatus according to the first embodiment . fig3 is a cross - sectional view taken on the line a - a of fig2 and fig4 is a cross - sectional view taken on the line b - b of fig2 . the cutting unit 2 comprises the blade 20 , a blade holder 21 a , a holder block 21 b , a first oscillation transmitting member 22 , and a second oscillation transmitting member 23 . a rotation hole in which the shaft 15 is inserted is provided in the holder block 21 b so that the tip portion of the connecting member 17 is fixed thereto . a metal blade having a blade edge of stainless steel , or steel , or an ore blade having a blade edge of diamond or sapphire is used as the blade 20 . the blade 20 is held between the blade holder 21 a and the holder block 21 b laterally oscillatably with an appropriate angle with respect to the horizontal plane . a shallow recess 210 a is formed at a portion , where the blade 20 is to be placed , at the blade holder 21 a side . the lateral width of the recess 210 a is provided larger than the oscillation width of the lateral oscillation of the blade 20 . the first transmitting member 22 is held laterally movably in an oscillating space 210 c formed in the holder block 21 b . further , a vertical groove 22 a to be engaged with the pin 16 is formed in the first transmitting member 22 . when the shaft 15 is rotated by the rotation drive of the motor 12 , a lateral force is applied to the first transmitting member 22 according to the circumferential movement of the pin 16 engaged with the vertical groove 22 a . accordingly , the first transmitting member 22 oscillates laterally . the second transmitting member 23 is held laterally movably in an oscillating space 210 b formed in the holder block 21 b . further , a vertical groove 23 a to be engaged with a pin part 22 b provided below the first transmitting member 22 is formed in the second transmitting member 23 . when the first transmitting member 22 is oscillated laterally by the rotation of the shaft 15 ( circumferential movement of the pin 16 ), the lateral oscillation provides a lateral force to the second transmitting member 23 via the pin part 22 b and the vertical groove 23 a . accordingly , the second transmitting member 23 oscillates laterally , and further , the blade 20 fixed to the second transmitting member 23 oscillates laterally as well . the movement of the first transmitting member 22 , the second transmitting member 23 , and the blade 20 will be explained with reference to fig5 a and 5b . the first transmitting member 22 moves reciprocally in the lateral direction ( x direction ) ( this will be referred to as a first lateral oscillation ) as well as moves reciprocally in the vertical direction ( y direction ) ( this will be referred to as a first vertical oscillation ) according to the circumferential movement of the pin 16 according to the rotation of the shaft 15 ( according to split of the force generated by the circumferential movement of the pin 16 into the pushing force for pushing the side surface of the vertical groove 22 a and the friction force functioning in the vertical direction on the side surface of the vertical groove 22 a ) as shown in fig5 a . the dashed line d 1 in the figure denotes the locus of the movement of the point p , which is the center of the pin part 22 b . the second transmitting member 23 moves reciprocally in the lateral direction ( x direction ) ( this will be referred to as a second lateral oscillation ) as well as slightly moves reciprocally in the vertical direction ( y direction ) ( this will be referred to as a second vertical oscillation ) according to the movement of the pin part 22 b of the first transmitting member 22 as shown in fig5 b . the dashed line d 2 in the figure denotes the locus of the movement of the point q , which is the center of the blade 20 . the displacement amount in the lateral direction according to the first vertical oscillation is based on the distance of the gap between the first transmitting member 22 and the holder block 21 b . in contrast , the displacement amount in the vertical direction according to the second vertical oscillation is much smaller than that of the first vertical oscillation because the circumferential movement of the pin 16 is converted to the first lateral oscillation already , thereby generating the second lateral oscillation ( the displacement amount in the lateral direction of the first lateral oscillation and the second lateral oscillation is same , and it corresponds to the eccentric amount of the pin 16 ). moreover , the displacement amount difference in the vertical direction according to the second vertical oscillation derived from the gap at the time of generating the first lateral oscillation and the gap at the time of generating the second vertical oscillation is small because the displacement amount itself is extremely small . as mentioned above , the locus d 2 has a smaller displacement amount in the vertical direction compared with the locus d 1 . that is , the second transmitting member 23 has a smaller displacement amount in the vertical oscillation at the time of the lateral oscillation with respect to the first transmitting member 22 . accordingly , the “ rampage ” can be restrained at the time of the lateral oscillation . furthermore , as shown in fig6 according to the conventional apparatus configuration , the position of a blade 400 in the up and down direction is limited due to the radius ( diameter ) of a rotation shaft 401 , the circumferential movement of an eccentric pin 402 , and the displacement amount in the vertical direction ( vertical groove 403 ). in contrast , according to an apparatus of the invention , since the position of the blade 20 in the up and down direction is limited onto to the displacement amount in the vertical direction ( vertical groove 23 a ), and further , the displacement amount in the vertical direction is smaller than the conventional configuration , the point of action for transmitting the lateral oscillation to the second transmitting member 23 can be provided adjacent to the blade 20 , to which the load is applied . therefore , the second transmitting member 23 can be made smaller than the conventional transmitting member 404 ( see fig7 ). accordingly , the rotation torque applied on the blade 20 is smaller than the conventional configuration , and thus the blade 20 can efficiently be oscillated laterally so that the “ rampage ” can be smaller . in fig2 a cornea applanating part 24 is fixed to the holder block 21 b by an attaching member 24 a so as to be provided on the front side ( left side in the figure ) of the blade 20 . the cornea applanating part 24 moves according to the movement of the cutting unit 2 for applanating the cornea of the patient &# 39 ; s eye flatly preceding incision with the blade 20 . since the blade 20 incises the cornea thus applanated flatly by the applanating part 24 , a flap of a uniform layer is formed . the distance between the edge of the blade 20 attached to the blade holder 21 a and the lower surface of the applanating part 24 is about 150 μm so that the cornea can be incised with this thickness in a layered form . the suction unit 3 comprises a fixing member 30 , a suction ring 31 , and a suction pipe 32 . the suction ring 31 is fixed to the main body 1 by the fixing member 30 . the suction ring 31 having a substantially cylindrical shape with a u - shaped cross - section , comprises a circular recess 31 a to be contacted with the patient &# 39 ; s eye and an opening 31 b concentric with the recess 31 a . when the suction ring 31 is set on the patient &# 39 ; s eye for surgery , the cornea of the patient &# 39 ; s eye projects upward from the opening 31 b so that the lower end portion of the suction ring 31 and the opening end portion of the opening 31 b are contacted so as to provide a space s for suction . the suction pipe 32 is embedded in the suction ring 31 , and connected with a vacuum tube ( not illustrated ) elongating to a pump 41 . a suction path 32 a provided inside the suction pipe 32 communicates with the recess 31 a . according to suction and discharge of the air in the space s by the pump 41 via the suction path 32 a , the suction ring 31 is vacuum - fixed to the patient &# 39 ; s eye . in this fixation , as the operator holds the grip portion 1 a , positioning of the opening 31 b can be facilitated , and the apparatus can be held stably . in addition , a pipe for pressure detection ( not illustrated ) is embedded in the suction ring 31 at a position facing to the suction pipe 32 . the pipe for pressure detection is connected with a pressure detector 33 via a tube ( not illustrated ). the pressure detector 33 detects the air pressure in the space s sucked by the pump 41 via the pipe for pressure detection . a control unit 40 controls the operation of the motor 11 , the motor 12 , and the pump 41 based on the air pressure detected by the pressure detector 33 . hereinafter the operation of the apparatus with the above - mentioned configuration will be described . while confirming the state of inclination of the suction ring 31 ( main body 1 ) and the position of the pupillary center based on a mark applied on the cornea of the patient &# 39 ; s eye with an instrument such as a marker , the operator positions the center of the opening 31 b with respect to the pupillary center and disposes the suction ring 31 on the patient &# 39 ; s eye . after installation of the suction ring 31 , the operator operates the pump 41 so as to suck the air in the space s between the suction ring 31 and the patient &# 39 ; s eye while keeping the position and the posture of the main body 1 for thereby reducing the air pressure ( to the negative pressure ). when the air pressure in the space s is reduced to a certain value ( when it reaches a sufficiently negative pressure ), the operation of the pump 41 is controlled by the control unit 40 so as to maintain the air pressure . accordingly , the suction ring 31 is vacuum - fixed onto the patient &# 39 ; s eye . after completion of the fixation of the apparatus , the operator operates a foot switch 42 for rotation drive of the motor 11 and the motor 12 . the control unit 40 controls for rotation drive of the motor 11 and the motor 12 . the control unit 40 controls the drive of the motor 12 by the input of a drive command signal by the foot switch 42 so as to oscillate the blade 20 laterally by a fixed or variable oscillation frequency . further , the control unit 40 controls the rotation of the motor 11 according to a fixed or variable feeding speed so as to rectilinearly move the cutting section 2 in the hinge direction . at the time , the shaft 15 slides in the advancing direction integrally with the cutting unit 2 while making a rotational motion for imparting lateral oscillation to the blade 20 . after being converted to the lateral oscillation of the first transmitting member 22 , the rotational motion of the shaft 15 is converted to the lateral oscillation of the second transmitting member so as to provide the rectilinear oscillation to the blade 20 , and thus the “ rampage ” caused by the vertical oscillation can be restrained so as to form a good flap stably . when the edge of the blade 20 has incised the cornea with the hinge portion left so as to complete the flap formation , the motor 11 is rotated reversely so as to return the cutting unit 2 to its initial position . at the time , the rotation of the motor 12 is stopped according to the independent control of the motors so that the blade 20 can be taken out from the flap while avoiding the unnecessary oscillation of the blade 20 . accordingly , the possibility of cut off of the thus formed flap can be reduced . after the return of the cutting unit 2 to the initial position , air is introduced into the space s so as to release the suction for removing the apparatus ( suction ring 31 ). subsequently , the corneal stroma is ablated for the refractive correction amount , and then the flap is returned to its original position so as to finish the surgery . although the first transmitting member 22 comprising the vertical groove 22 a to be engaged with the pin 16 and the pin part 22 b , and the second transmitting member 23 comprising the vertical groove 23 a to be engaged with the pin part 22 b of the first transmitting member 22 ( in this case , the blade 20 is fixed to the second transmitting member 23 ) are used in this embodiment for converting the rotation of the shaft 15 ( circumferential movement of the pin 16 ) to the lateral oscillation of the blade 20 , it is also possible to further provide a pin part similar to the pin part 22 b in the second transmitting member and a third oscillation transmitting member comprising a vertical groove to be engaged with the pin part of the second transmitting member . in this case , the blade is fixed to the third transmitting member . that is , although the rotation of the rotation shaft is converted to the lateral oscillation of the blade by the conversion by twice , but the conversion needs to be at least twice and can be increased to three times or four times . another embodiment of the invention will be explained with reference to the drawings . fig8 is a cross - sectional view of an apparatus according to the second embodiment and a schematic diagram of a control system . fig9 is an enlarged cross - sectional view of a cutting unit 2 and a suction unit 3 . fig1 is a cross - sectional view taken on the line c - c of fig9 . the same numerals are applied to the same components as in the first embodiment . the cutting unit 2 comprises the blade 20 , the blade holder 21 a , the holder block 21 b , a bearing part 21 c , a rock ( swing ) transmitting member 25 , and a lateral oscillation transmitting member 26 . a rotation hole in which the shaft 15 is inserted is provided in the blade holder 21 a so that the tip portion of the connected member 17 is fixed thereto . the rock transmitting member 25 is pivoted by the holder block 21 b and the bearing part 21 c rotatably ( rockably ) with two upper and lower rotation shaft parts 25 c as the rotation central axes in the oscillation space 210 c formed in the holder block 21 b ( that is , the rock transmitting member 25 is pivoted rockably in the lateral direction , centering the axial line l elongating in the vertical direction ). further , a vertical groove 25 a to be engaged with the pin 16 is formed in the rock transmitting member 25 . when the shaft 15 is rotated according to the rotation drive of the motor 12 , a force in the lateral direction is applied on the rock transmitting member 25 by the circumferential movement of the pin 16 engaged with the vertical groove 25 a . accordingly the rock transmitting member 25 is rocked . the lateral oscillation transmitting member 26 is held movably in the lateral direction in the oscillation space 210 b formed in the holder block 21 b . a pin receiving part 26 a to be engaged with the a pin part 25 b provided at a lower portion of the rock transmitting member 25 is formed in the lateral oscillation transmitting member 26 . when the rock transmitting member 25 is rocked in the lateral direction with the shaft parts 25 c as the rotation center by the rotation of the shaft 15 ( circumferential movement of the pin 16 ), a force in the lateral direction is applied on the lateral oscillation transmitting member 26 via the pin part 25 b and the pin receiving part 26 a according to the rock . accordingly , the lateral oscillation transmitting member 26 oscillates laterally , and further , the blade 20 fixed to the oscillation transmitting member 26 oscillates laterally as well . the movement of the pin 16 , the rock transmitting member 25 , the lateral oscillation transmitting member 26 , and the blade 20 will be explained with reference to fig1 . when the shaft 15 is rotated by the motor 12 , the projecting portion of the pin 16 provided eccentrically in the shaft 15 moves circumferentially , centering the rotation central axis of the shaft 15 . the force generated by the circumferential movement of the pin 16 can be split in the vertical and lateral directions , that is , the force in the vertical direction functioning on the side surface of the vertical groove 25 a in the up and down direction as the friction force , and the force in the lateral direction pushing the side surface of the vertical groove 25 a in the lateral direction as the pushing force . according to the force applied on the side surface of the vertical groove 25 a , the rock transmitting member 25 rocks with the shaft parts 25 c as the rotation center . since the shaft parts 25 c are held sufficiently by the holder block 21 b and the bearing part 21 c with respect to the force in the vertical direction generated by the pin 16 , the “ rampage ” in the vertical direction an be restrained so that the rotational motion of the shaft 15 can be converted efficiently to the rock of the rock transmitting member 25 . according to the rock of the rock transmitting member 25 in the lateral direction , the pin part 25 b formed in the lower portion thereof is rocked in the lateral direction with substantially no displacement in the vertical direction . since the pin part 25 b rocking in the lateral direction applies a force on the side surface of the pin receiving part 26 a , the lateral oscillation transmitting member 26 oscillates in the lateral direction with the oscillation space 210 b as the guide . at the time , by providing a substantially spherical tip end shape to the pin part 25 b , a force can be applied efficiently to the pin receiving part 26 a so that the lateral oscillation can be provided smoothly . since the blade 20 is fixed to the lateral oscillation transmitting member 26 , it oscillates according to the lateral oscillation of the lateral oscillation transmitting member 26 . according to the configuration , after being converted to the rock with the shaft parts 25 c of the rock transmitting member 25 as the rotation center , the rotational motion of the shaft 15 applies rectilinear oscillation to the blade 20 in the lateral direction . since the force according to the circumferential movement of the pin 16 in the vertical direction is supported by the shaft parts 25 c , the “ rampage ” by the vertical oscillation can be restrained so that a good flap can be formed stably . moreover , since the sliding portion is only in the peripheral part of the shaft parts 25 c , worn out of the oscillating portion can be restrained so as to prolong the life cycle of the parts . the pin 16 can be attached to the shaft 15 , elongating parallel in the rotation central axis direction of the shaft 15 ( as in the conventional apparatus shown in fig1 a ), but the pin 16 is provided tilting with respect to the rotation central axis direction of the shaft 15 in this embodiment . that is , the pin 16 is provided eccentrically , elongating passing through the intersection of the axial line l passing through the rotation center of the rock of the rock transmitting member 25 and the rotation central axis of the shaft 15 . according to the configuration , since the rocking angle of the pin 16 in the lateral direction and the rocking angle of the rock transmitting member 25 in the lateral direction coincide , the contacting property of the pin 16 engaged with the vertical groove 25 a is improved and thus the rotational motion can be converted smoothly and efficiently to the lateral rock . moreover , the shape of the vertical groove 25 a and the tip end portion shape of the pin 16 to be engaged therewith can be a simple shape ( linear shape ) so that the production of components can be facilitated . furthermore , although the rock of the pin part 25 b is converted to the linear lateral oscillation of the lateral oscillation transmitting member 26 in this embodiment , it is also possible to fix the pin part 25 b and the lateral oscillation transmitting member 26 , rock the lateral oscillation transmitting member 25 , and have arc - like oscillation of the blade 20 . moreover , as shown in fig1 , the rock transmitting member 25 can be eliminated . furthermore , the rock transmitting member 25 needs to rock with oscillation with a lateral direction component for oscillating the blade 20 in the lateral direction , and therefor , the axial line l to be the center of the rock should be provided at a position offset from the rotation central axis of the shaft 15 . for the efficient conversion of the rotation of the shaft 15 into the oscillation of the lateral direction component , it is preferable that the axial line l to be the center of the rock is in the same plane as the rotation central axis of the shaft 15 , and further , it is preferable that the axial line l as the rocking center is disposed in the plane in the vertical direction passing through the rotation central axis of the shaft 15 with respect to the lateral direction for oscillating the blade 20 , and the rock transmitting member 25 is rocked with the axial line l as the center . the conversion efficiency of the oscillation in the lateral direction can be most efficient by providing the axial line l orthogonal to the rotation central axis of the shaft 15 as in this embodiment . moreover , the vertical groove 25 a formed in the rock transmitting member 25 can be provided at the grip portion 1 a side with respect tot he rotation center of the shaft parts 25 c . furthermore , by changing the distance of the vertical groove 25 a and the distance of the pin 25 b from the rotation center of the shaft parts 25 c , respectively , the width of the lateral oscillation of the blade 20 with respect to the eccentric amount of the pin 16 can be adjusted freely ( it is also possible to enlarge the oscillation width with a small eccentric amount ). moreover , although explanation has been given with the motor 12 for rotating the shaft 15 in this embodiment , an air turbine can be used as well . furthermore , as the mechanism for feeding the blade , a mechanism for incising the cornea by rotational movement of the blade as disclosed in jp - a - 11 - 19115 and jp - a - 11 - 99167 filed by the present inventor can be adopted as well . as heretofore explained according to the invention , a good flap can be formed by preventing the “ rampage ” of the blade . moreover , the lateral oscillation of the blade can be generated efficiently , the cost rise according to the high accuracy of the mechanism can be restrained , and the durability of the mechanism is improved so as to prolong the life cycle . | US-75356801-A |
an assembly for implanting ocular implants into a mammalian eye is provided . the assembly generally includes a cannula having a curved distal end , an injector mechanism coupled to the cannula for linearly moving one or more implant segments in the cannula toward the curved distal end , and a rotator mechanism for rotating the cannula about a longitudinal axis thereof . | an exemplary embodiment of the invention is shown in the figures and is described below . the assembly , or device 10 , of the invention , shown generally in fig1 , can be configured as a single use device , made of simple molded components . the device 10 may be in the form of a self - contained , single use , handpiece , easily manipulable by an operator , e . g . physician , without need for batteries or motor . turning as well briefly to fig2 , device 10 is structured to be capable of injecting multiple implant segments into the eye 30 , for example , the posterior segment of the eye , with sufficient separation such that the implant segments 20 that are injected first are not disturbed by the injection of subsequent segments . contact between an implant and fragile structures of the eye , such as the retina , can be controlled or avoided . in other words , the device 10 allows an implant to be delivered in the form of multiple particles or segments , into an eye 30 , for example , in a spaced apart manner and , advantageously , using a single insertion of a needle 40 . advantageously , after positioning the needle or cannula distal tip 88 in a desired target region of the eye 30 , an operator of the device need not reposition the device in order to deliver multiple , separate implant segments 20 . further , delivery of subsequent segments 20 does not disturb or disrupt the position of prior delivered segments 20 . generally , this may be achieved by providing cannula 40 , ( also interchangeably referred to herein as a needle 40 ) which has a slightly curved distal end 88 , and providing a mechanism for rotating the cannula 40 , for example , in a stepwise manner , after each segment 20 is delivered into the eye 30 . see briefly , for example , fig6 b . the rotator mechanism is structured to rotate the cannula 40 in a stepwise manner such that a distal tip 88 of the cannula 40 becomes offset , for example , rotationally offset , relative to a position of the distal tip prior to each rotation step . more specifically , assembly 10 can be used to introduce ocular implants 20 , for example , polymeric drug delivery systems , through a cannula , for example , a 22 g , 23 g , 24 g , 25 g , 26 g , 27 g , 28 g or finer needle 40 , into the eye 30 . in one aspect of the invention , the cannula or needle 40 has a curvature radius of between about r 20 to about r 80 . the distal tip of the cannula may be offset by between about 0 . 1 mm to about 1 . 0 mm . in a certain embodiment , the cannula has a curvature of about r 50 and the cannula distal tip is offset by 0 . 3 mm . in one embodiment , the assembly 10 comprises a 0 . 51 mm diameter needle ( 25 g ) 40 which produces a leak - free wound with simple needle insertion technique . the needle 40 has a tip offset by about 0 . 30 mm . using this needle 40 with device 10 , four implant segments 20 can be delivered to the eye in a spaced apart relationship , without need to withdraw or reposition the device between delivery of segments 20 , as shown in fig2 . more specifically , in one aspect of the invention , a single dose of drug to be delivered is delivered in the form of one or more of plurality of ocular implants , for example , one , two , three , four , five , six or more implant segments 20 , into a target region of an eye , for example , a target region of the vitreous . the total implant , comprising the one or more implant segments 20 , to be implanted in an eye in a single procedure may be an implant having a total implant length of between about 10 and about 40 mm , for example , between about 20 and about 30 mm . in one embodiment the total implant length is about 24 mm and comprises 4 segments each of about 6 mm in length . it will be appreciated that the assembly 10 can be modified within the scope of the invention to accommodate other implant variants , for example , longer or shorter implants comprising fewer or greater numbers of implant segments . in one embodiment , the implants 20 are intravitreal implants , such as solid , bioresorbable , or biodegradable , polymeric drug delivery systems ( dds ) and / or other intraocular implants , such as , for example , those disclosed in u . s . pat . nos . 6 , 369 , 116 ; 6 , 726 , 918 ; 7 , 033 , 605 ; 8 , 043 , 628 ; 7 , 846 , 468 ; 8 , 034 , 366 ; and 7 , 625 , 582 , the entire disclosure of each of these patents being incorporated herein by this specific reference . the implant segments 20 may be housed within needle / cannula 40 prior to device actuation . the implant segments 20 may be injected at a controlled speed such that the distance they are injected into the eye is repeatable . the injection speed is unaffected by the force with which the user operates an actuation mechanism , for example , an activation trigger , button or switch . although any suitable mechanism can be employed to accomplish the aims of the present invention , such mechanisms being considered within the scope of the invention , an exemplary mechanism is described hereinafter . turning now to fig3 - 5 , the present device 10 may include a drive rod assembly 12 housed within a rear drive assembly 14 . the drive rod assembly 12 functions as a linear drive mechanism to force a plunger rod forward to cause ejection of implants . the drive rod assembly 12 may comprise a drive rod 42 , a drive rod outer 44 , a seal 46 and a plunger 48 , fixed together and axially slidable within a rear body part 52 of the rear drive assembly 14 , and otherwise relatively fixed thereto . the plunger 48 passes into the end of the needle / cannula 40 secured to distal end of the device 10 to cause ejection of implant segments 20 into the eye . the device 10 may be actuated by the user pressing a release button 62 , which drives the plunger 48 to push the implant segments 20 along the needle by means of a compression spring 64 . the compression spring 64 is used to provide energy to drive the injection mechanism . the compression spring 64 may be stored in a compressed state in the device 10 , and impinges on the rear body 52 and drive rod 42 . damping may be used to control the speed at which the drive rod 42 moves under the compression spring action . the damping function may be achieved in any suitable manner . for example , in one embodiment , an enclosed air cavity is formed in the rear body 52 . as the drive rod 42 moves forward , the volume of the air cavity then increases . a small hole in the rear body may be provided to allow air to be drawn into the cavity restricting the mechanism &# 39 ; s speed . the hole size and compression spring characteristics may be structured such that the full travel of the drive rod assembly occurs in approximately 1 . 5 seconds . the release button 62 , retained by a release button retainer 71 , and functions as a catch to stop the drive rod assembly 12 from being pushed forward by the compression spring 64 prior to actuation . features , for example , catch faces , on either side of the release button 62 engage with features on the drive rod outer 44 . when the user presses on the release button 62 , the release button 62 pivots and the catch faces move out of engagement . the catch faces and pivot position are such that the compression spring is compressed slightly as the release button 62 is pivoted resulting in a release button actuation force felt by the user . the release button 62 is prevented from pivoting when a cap 72 is on , for example , by a suitable feature , for example , a tab feature on the cap 72 . this prevents the device 10 from being inadvertently actuated , for example when the device 10 is being transported in its packaging . a helix sleeve 76 is housed in drive rod outer 44 and can be rotated about a cylindrical axis of the device 10 . two tangs of a torsion spring 78 are located on the helix sleeve 76 and drive rod outer 44 such that the torsion spring 78 applies a restoring torque as the helix sleeve 76 is rotated . a needle hub rear 82 is provided which fixes to needle 40 . the needle hub rear 82 may include features , for example , a pair of stepped rib features 84 , positioned such that they impinge on the helical surface of ribs on helix sleeve 76 causing the helix sleeve 76 to rotate as the helix sleeve 76 and drive rod outer 44 move forward . this relative rotation causes the torsion spring 78 and helix sleeve 76 to apply a torque between the drive rod outer 44 and the needle hub rear 82 . the needle 40 secured to needle hub 80 , and needle hub rear 82 may be fixed together and can be rotated about the cylindrical axis of the parts and are fixed in the axial direction . in addition to the features on the helix sleeve 76 as previously described , the pair of stepped rib features 84 on the needle hub rear 82 may be provided to be acted on by a pair of cooperating peg features on the drive rod outer 44 . the peg features , or other structure may be provided to act as a stop to prevent the needle hub rear 82 from rotating under the torque applied by the torsion spring 78 and helix sleeve 76 . in the shown embodiment , the needle 40 is rotated in increments of 90 degrees between each ejection of an implant segment . for example , when the peg features pass trailing corners on the stepped ribs 84 , the needle components are rotated 90 ° under to action of the torsion spring 78 , stopping when the peg features come into contact again with the stepped rib 84 . the 90 ° rotation occurs in a fraction of the time it takes the linearly driven parts of the mechanism to be driven between steps and therefore the needle has an intermittent 90 ° step rotation . in one aspect of the invention , the rotator mechanism is configured to rotate the cannula in the stepwise manner to complete a 360 degree rotation cycle . this may facilitate removal of the cannula from the eye at the end of treatment . turning briefly to fig2 , 6 a and 6 b , the implant segments 20 may be kept in the device 10 prior to being ejected from the tip 88 of needle 40 . this may be achieved by any number of ways , for example , having a hole 90 through the sidewall of the needle 40 which allows a flexible finger feature on the needle hub to form a stop within the needle 40 . before the device 10 is actuated , there is sufficient space between the needle hub stop finger feature and plunger for a 4 - dose segment stack . the doses push past the flexible finger feature when they are pushed by the plunger when the device is actuated . when the cap 72 is on the device 10 , for example in storage , a rib feature on the cap may prevent the finger feature from flexing such that that the dose segments are more securely held in the needle 40 . means to confirm the correct number of dose segments are loaded into the device , both in manufacturing and immediately prior to use by the user , may be provided . this may be achieved by having the same number of holes 94 in the needle 40 as segment placed such that a segment will be visible through each hole 94 if the correct number of segments is present in the device . after use and when the needle has been withdrawn from the patient &# 39 ; s eye , the plunger 48 will be visible projecting from the tip of the needle 40 . this allows the user to confirm that all of the segments have been ejected from the device . it is possible to use the device to inject fewer segments than the 4 shown in fig2 , simply by inserting fewer implants into the device in manufacturing . note however that , in this case , the position of the segments in the needle may not be well controlled in the needle and the visibility of the segments would not give reliable indication of the presence correct number of segments . to avoid this issue , a backstop part may be included on the 2 and 3 segment variant device assemblies . the backstop part is fixed to the needle and has a flexible finger feature with passes through a hole in the sidewall of the needle . there is sufficient space between the backstop and needle hub finger features for the 2 or 3 dose segment stack . the flexible finger of the backstop does not allow the dose segments to move past it towards the plunger but allows the plunger past to eject the segments when the device is actuated . turning back now to fig1 and 2 , in the embodiment shown , a front body 90 on the distal portion of the device 10 may be transparent such that the drive rod outer 44 moves into view through the front body at the end of the linear stroke when the device is actuated . suitable means , for example , an embossed line on the transparent front body , may be provided to provide a more accurate indication that the device has ejected all of the dose segments . while this invention has been described with respect to various specific examples and embodiments , it is to be understood that the invention is not limited thereto and that it can be variously practiced within the scope of the invention . | US-201213718991-A |
a personal hygiene storage unit , particularly that functions both as a hanging storage / dispensing unit and as a personal hygiene travel pack includes : a hollow body with a bottom , upwardly projecting walls and an open top ; a top connected to the bottom and having closing mechanism to fix the top in a closed position ; and , a pair of opposing elongated hanging hooks connected to at least one of the main housing , the back hatch top and the front hatch top , for attachment to a toilet paper roll rod and hinges for folding the hooks to create a compact travel pack and positioned for ergonomically beneficial tilting for access when under a roll of toilet paper . | referring now in detail to the drawings wherein like reference numerals designate corresponding parts throughout the several views , various embodiments of the present invention are shown . fig1 illustrates an oblique back view of one preferred embodiment present invention personal hygiene storage unit 100 . it includes a hollowed body main housing that has a bottom 3 , with an open top , upwardly projecting walls that include a front wall , a back wall and side walls , with rounded corners , as shown . storage unit 100 has a top cover 5 hingedly connected via hinge 35 to the back of bottom 3 . at the front 7 of top cover 5 is latch 11 to fix top cover 5 to bottom 3 of the main housing in a closed position that may be reopened for subsequent use . in this embodiment hinge 35 is a living hinge . top cover 5 may repeatedly be opened and closed for storing and accessing personal hygiene items , such as wet wipes , bandages , medicine , tampons , feminine napkins and the like . the exact closing latch and positioning is not a critical feature and may be located in any workable configuration . in this case , the top cover 5 has the male component and the bottom 3 has the female component and is a recessed receiver , but the opposite arrangement would function as well . referring now to fig1 and 2 collectively , when the top cover 5 and the bottom 3 of the present invention storage unit 100 are closed , there is an imaginary side - to - side centerline . behind this centerline , on bottom 3 , are two receiver straps 23 and 37 for receiving elongated hanging hooks 13 and 15 , as shown . hook 15 has a proximal end 41 with spring latches 27 and 33 that snap into the main housing bottom 3 receiving strap 23 . hook 13 has a proximal end as well , that snaps into the main housing bottom receiving strap 37 . both hooks 15 and 13 have living hinges 25 and 29 , respectively , so as to be foldable for compact transport . because the hooks 13 and 15 are located behind the side - by - side centerline , an intentional feature in preferred embodiments , the unit 100 will tilt downwardly forward when hung , due to the offset center of gravity , and will create both clearance and content gravity feed . fig3 represents a side view of an elongated hanging hook 15 of the present invention personal hygiene storage unit 100 shown in fig1 and 2 . proximal end 41 has spring latches 27 and 33 to lock hook 15 into its receiving orifice ( strap 23 ) described above . living hinge 25 is a thin region that permits the hooks to be folded . distal end 17 is curved to hook over a rod such as a toilet paper roll rod or a closet rod . fig4 shows a side view of the present invention storage hygiene unit 100 of fig1 and 2 hanging from a toilet paper roll rod of toilet paper roll 45 , supported by rod bracket 47 , attached to wall 43 . also illustrated is female latch component 9 , hidden in prior views . in this hanging , tilted , closed configuration , unit 100 is conveniently located for access and use , yet not interfering with the use of the toilet paper . fig5 shows the present invention personal hygiene storage unit 100 of fig4 but opened to provide personal hygiene products for use , e . g ., wet wipes 51 . fig6 shows an alternative embodiment of a preferred present invention personal hygiene storage unit 200 . it includes a hollowed body main housing that has a bottom 203 with an open top , upwardly projecting walls that include a front wall , a back wall and side walls and rounded corners ; bottom permanent latch component 209 ( permanent meaning not readily reopenable ); a main top 205 ; main top front 207 with permanent latch component 211 . in this embodiment , there are two hanging hooks ( one hidden ) represented by hanging hook 215 . hook 215 has a proximal end 241 with spring latches 227 and 233 that snap into the main housing bottom 203 receiving orifice , i . e ., strap 223 . hook 215 has living hinge 225 , as does the hidden hook , so as to be foldable for compact transport . thus , the elongated hanging hooks , such as hook 215 , are each made from the assemblage of two separate pieces , and are inserted into the receiving orifices . they have curved distal ends , such distal end 219 for hooking onto a rod , such as toilet paper rod 245 . unit 200 has a main top 205 with a separate hinged top dispensing cover 249 and latch 253 , with the main top 205 having a large dispensing office for dispensing moist wipes 251 . the dispensing cover 249 may be closed and latch 253 engaged with catch 255 to cover and seal the moist wipes 251 for subsequent use . as to storage and hanging , this unit 200 may be used in the same manner as unit 100 described in more detail above . ( the non - invention components shown in fig4 and 5 are repeated and identically numbered and need not be individually repeated .) fig7 shows an alternative embodiment of a preferred present invention personal hygiene storage unit 300 . it includes a hollowed body main housing that has a bottom 303 with an open top , upwardly projecting walls that include a front wall , a back wall and side walls and rounded corners ; bottom permanent latch component 309 ( permanent meaning not readily reopenable ); a main top 305 ; main top front 07 with permanent latch component 11 . in this embodiment , there are two hanging hooks ( one hidden ) represented by hanging hook 315 . hook 315 has a proximal end 323 that is integrally formed with the main housing bottom 303 , as shown . hook 315 has living hinge 325 , as does the hidden hook , so as to be foldable for compact transport . the elongated hanging hooks , such as hook 315 , are each made as part of the overall structure in a single mold and the entire structure is “ unistructurally ” formed . the hooks have curved distal ends , such distal end 319 for hooking onto a rod , such as toilet paper rod 345 . unit 300 has a main top 305 with a dispensing orifice 349 and latch 253 , for dispensing wipes 351 . the dispensing cover 249 may be closed and latch 253 may be engaged with catch 255 to cover and seal the moist wipes 251 in the container for subsequent use . as to storage and hanging , this unit 300 may be used in the same manner as unit 100 described in more detail above . ( the non - invention components shown in fig4 and 5 are repeated and identically numbered and need not be individually repeated .) fig8 shows the present invention personal moist wipe storage unit 400 of a type that is a hybrid of those shown in fig6 and fig7 , combining both a dispensing main top with a dispensing orifice therein , and a top cover ( overcap ), and being in generally circular rather than rectangular shape . unit 400 includes a hollowed body main housing that has a bottom 403 in a generally circular shape . the main housing 403 may include an open top and upwardly projecting walls that include a front wall 407 , a back wall 405 and side walls 409 and 411 , and a bottom ( not shown ). a main top 417 is permanently attached to main housing 403 ( permanent meaning not readily reopenable ). main top 417 has a dispensing orifice 419 ( such as a criss - cross cut out ) for dispensing wipes 450 , as well as an overcap , namely , top cover 421 with latch 425 , connected to the bottom ( or top , as desired ) via living hinge 423 . as to storage and hanging , this unit 400 may be used in the same manner as the units described in more detail above . in the alternative , fig8 may be a cap for an existing product container of wipes wherein it fits over the existing product container , to provide both a closeable top and a hanger capability for hanging from a rack or rod . in this version , main housing 403 is an outer portion of a lid , with main top 417 integrally formed therewith to form the lid top . the components - dispensing orifice 419 , cover 421 , etc ., in reality , however , a tapered shaft with an increasing or decreasing internal cross section allows for easier mold release during manufacturing . this creates a new problem in that the piston in the parent case is shown to be of a constant diameter . the present invention addresses this problem by adding a flexible seal over an expandable piston . function the same as described immediately above . its walls would be short and it would be without a bottom to fit directly onto an existing product container of wipes . although particular embodiments of the invention have been described in detail herein with reference to the accompanying drawings , it is to be understood that the invention is not limited to those particular embodiments , and that various changes and modifications may be effected therein by one skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims . | US-201113199393-A |
a unit is provided to facilitate carrying with one hand a plurality of handle bearing articles , such as suitcases , for example . the handle of one of the articles is encircled by the strap portion of the unit , and a handle portion at the ends of the strap portion is grasped in one hand together with the handle of another of the articles , to carry them . one embodiment has latching handle portions at opposite ends of the strap portion , and another embodiment has latching means at opposite ends of the strap portion , and an associated handle . | for the purposes of promoting an understanding of the principles of the invention , reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe the same . it will nevertheless be understood that no limitation of the scope of the invention is thereby intended , such alterations and further modifications in the illustrated device , and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates . referring in particular to fig1 through 3 , there is shown one embodiment of a gripping apparatus for carrying a plurality of articles according to the present invention . gripping apparatus 10 includes loop portions 11 and 22 and intermediate portion 23 . part of loop portion 22 is thicker than the other portions of gripping apparatus 10 , as best shown in fig2 the loop portion 22 includes slot 24 within this thicker portion ( fig2 ). as best shown in fig3 intermediate portion 23 comprises thin - walled areas 14 , 15 and 16 , which are separated by transvere ribs such as 26 . extending along the edges of intermediate portion 23 , from the attachment points of loop portions 11 and 22 and intermediate portion 23 , are thick side boundaries such as 17 and 18 . gaps 27 and 28 are left between the boundaries extending from the opposite loop portions . gripping apparatus 10 is an integral unit of flexible plastic material , and gaps 27 and 28 facilitate the bending of gripping apparatus 10 into the carrying position described hereinafter . thin walled area 16 and thick plastic boundaries 17 and 18 are shown in cross section in fig4 . as shown in fig5 and 6 , gripping apparatus 10 is in its carrying position . the areas 12 and 13 , defined by loop portions 11 and 22 respectively , are adjacent in this position , and the intermediate portion 22 encircles attache case handle 19 . loop portion 11 is received within slot 24 of loop portion 22 and the two portions are thus mated , becoming handle portions and serving as a handle 25 . in order to carry the cases as shown in fig6 loop portions 11 and 22 are grasped simultaneously by extending the fingers through areas 12 and 13 , and the handle 30 of the large suitcase is placed immediately thereunder and likewise grasped in the hand , and the combination is lifted and carried . upon arrival at a destination , the cases are set down and the handles 25 and 30 are released . however , due to the length of the unit from handle 19 to handle 25 ( approximately 7 inches ), handle 25 will rest conveniently on top of the large case , while both rest on the floor , ready to again be picked up and carried . upon arrival at the final destination , loop portion 11 may be easily removed from slot 24 in loop portion 22 , and gripping apparatus 10 removed from its position encircling handle 19 . a . 14 inches e . 3 / 4 inchesb . 4 - 3 / 4 inches f . 4 - 3 / 8 inchesc . 3 - 3 / 4 inches g . 3 / 16 inchesd . 3 - 1 / 4 inches referring now to the embodiment of fig7 - 10 , there is a loop portion 31 which serves as a handle , and a strap portion 32 which adjoins the loop portion at 33 . a lug 34 is provided near the end of the strap opposite the handle . as shown in fig8 the lug includes a tongue 36 and the tongue spacer and mount 37 , these cooperating with the strap to form a slot 38 . a notch 39 is provided in the strap at the handle opening 41 and has sloped edges 42 which cooperate with the sloped edges 43 of the lug when the unit is folded to the condition shown in fig1 - 14 to align the two ends and edges of the strap portion . there are two edges 44 indented with respect to edges 46 - 47 of the unit to fit within the handle of the luggage to be carried by the unit . in order to facilitate inserting the lugged , handle - less end of the unit through a luggage handle , a pair of grooves 48 is provided as shown in fig7 and 10 . these are slightly inboard of the indented edges 44 and extend to the lugged end of the strap portion . they facilitate folding of wing portions 49 of the strap in the direction of the projection of the lug as shown by the dotted lines 49a in fig1 to facilitate passing this end of the strap through a luggage handle , such as handle 51 of the case 50 in fig1 . the resilience of the plastic material of the strap will cause it to return to the solid line position of fig1 when the manual force is removed . in the use of the unit of fig7 - 10 , after passing the lugged end through the handle of the case as just described , the lugged end is pulled up to the position shown in fig1 - 14 and the lug is hooked over the top edge 51 of the notch 39 . when the lug 34 has been hooked over the edge 51 , the end 52 of the lug becomes disposed in face - to - face relation with the end 53 of a shield cam 54 . at this time , the upper edge portion 51 of the strap is in the slot 38 to securely prevent separation of the lugged end of the strap from the handle and in the direction of the arrow 56 in fig1 . at the same time , the wing portions 49 have their upper edges 57 in abutting relationship with the shoulders 58 under the handle portion to prevent separation of the lugged portion in the direction of the arrow 59 in fig1 . the shield cam 54 shields the end 52 of the lug 34 from grazing blows so that they cannot strike the end of the lug and dislodge it in the direction of the arrow 59 . further consideration of this matter will reveal that during closure of the unit , as the lug is pushed down over the edge 51 , the wing portions deflect to the position shown by the dotted lines 49b in fig1 , in order to clear the shoulders 58 and then snap into a position under the shoulders 58 as shown in fig1 and 12 . referring further to fig8 , and 12 through 14 , it can be seen that point - to - point bight portion 61 of the handle has an inclined lower rear face 62 which is curved from end to end as is the top of the bight portion . the upward slant of the face 62 aids in fitting together this handle and the luggage handle to be carried in the same hand with it as shown in fig1 , where luggage handle 30 is carried conveniently with its bight portion immediately under the bight portion of the handle of this invention . also , the curvature of the bight portion 61 as shown in fig9 , and 15 enables a pointto - point type of contact with the bight portion of the luggage handle 26 as shown at 63 - 64 in fig1 . therefore , even if the bight portion of the luggage handle is somewhat curved as shown , there is a stable mating of the two handles in the hand of the person carrying them . by way of example , preferred dimensions for the embodiment of fig7 - 15 are as follows : j . 11 - 1 / 4 inches r . 2 inchesk . 4 - 3 / 4 inches s . 3 / 4 inchesl . 2 - 1 / 8 inches u . 2 - 1 / 2 inchesm . 3 - 1 / 4 inches v . 1 / 2 inchn . 3 / 4 inches w . 1 / 8 incho . 1 / 2 inches x . 1 / 8 inch ( or less ) p . 2 - 1 / 2 inches y . 3 / 8 inchq . 2 - 1 / 2 inches z . 3 - 1 / 8 inches in fig9 and 12 through 15 , a surface 66 generated by revolution of a line about an axis about 18 inches away , for example , is provided on the rear of the handle , adjacent and above surface 62 which is generated in the same way . this surface 66 facilitates gripping handles together side by side instead of the illustrated one above the other relationship shown in fig1 and 15 . it serves to both reduce the overall horizontal thickness of the two handles squeezed together , and enhances the stability by providing the arcuate shape and two point contact much as shown at 63 - 64 in fig1 . | US-50815174-A |
the disclosure relates to sunscreen compositions having a synergistic combination of ultraviolet light filtering agents that provide a high sun protection factor . compositions according to the disclosure have high spf values without requiring high overall amounts of uv filtering agents , and without requiring the use of oxybenzone . furthermore , the disclosure relates to methods of using the described compositions for protecting keratinous substances such as skin and hair from uv radiation . | the present disclosure also relates to a sunscreen composition having the following combination of uv filters : octocrylene , avobenzone , octyslate , and homosalate , and optionally oxybenzone ; wherein the ratio of each filter relative to avobenzone is as follows : typically , the sunscreen compositions are free of oxybenzone , or have less than 0 . 025 , 0 . 05 , 0 . 10 , 0 . 50 or 1 . 00 wt . % oxybenzone . in particular the ratio of each filter relative to avobenzone is about : 2 . 0 : 1 . 0 : 0 . 0 : 1 . 7 : 3 . 0 ( octocrylene : avobenzone : oxybenzone : octyslate : homosalate ). in one embodiment the uv filters are present in the following percentages by weight relative to the entire weight of the sunscreen composition : from 1 , 2 , 3 , 4 , or 5 to 5 , 6 , 7 , 8 , 9 or 10 wt . % octocrylene from 1 , 2 , or 3 to 3 , 4 , or 5 wt . % avobenzone ; from 1 , 2 , 3 , 4 , or 5 to 5 wt . % octisalate ; and from 1 , 2 , 4 , 6 , 8 , or 10 to 10 , 12 , 14 , 15 wt . % homosalate . in another embodiment the uv filters are present in the following percentages by weight relative to the entire weight of the sunscreen composition : about 5 . 9 wt . % octocrylene ; about 3 . 0 wt . % avobenzone ; about 4 . 9 wt . % octysalate ; and about 8 . 8 wt . % homosalate . the present disclosure makes it possible to achieve the described spfs in sunscreen compositions without the use of boosters , or essentially without the use of boosters , e . g ., sorbeth - 2 - hexaoleate . although boosters may be included in the sunscreen compositions of the instant disclosure , they are not required . the present disclosure is also directed to methods of protecting a keratinous substrate from ultraviolet radiation and to methods of absorbing ultraviolet light . such methods encompass applying a sunscreen composition to a keratinous substrate and subjecting the keratinous substrate to ultraviolet radiation . where the following terms are used in this specification , they are used as defined below . the terms “ comprising ,” “ having ,” and “ including ” are used in their open , non - limiting sense . the terms “ a ” and “ the ” are understood to encompass the plural as well as the singular . as used herein , the expression “ at least one ” means one or more and thus includes individual components as well as mixtures / combinations . “ cosmetically acceptable ” means that the item in question is compatible with any keratinous substrate . for example , “ cosmetically acceptable carrier ” means a carrier that is compatible with any keratinous substrate . a “ physiologically acceptable medium ” means a medium which is not toxic and can be applied to the skin , lips , hair , scalp , lashes , brows , nails or any other cutaneous region of the body . the composition of the instant disclosure may especially constitute a cosmetic or dermatological composition . the phrase “ essentially without ” refers to less than or equal to 0 . 5 , 0 . 1 , 0 . 05 or 0 . 01 wt . %. the phrase “ stable emulsion ” refers to a composition that does not undergo phase separation up to a temperature of 45 c .°. examples of oils / emollients that may be included in the sunscreen compositions include : hydrocarbon - based oils of plant origin , such as liquid triglycerides of fatty acids containing from 4 to 10 carbon atoms , for instance heptanoic or octanoic acid triglycerides , or alternatively , for example , sunflower oil , corn oil , soybean oil , marrow oil , grapeseed oil , sesameseed oil , hazelnut oil , apricot oil , macadamia oil , arara oil , coriander oil , castor oil , avocado oil , caprylic / capric acid triglycerides , for instance those sold by the company stearineries dubois or those sold under the names miglyol 810 , 812 and 818 by the company dynamit nobel , jojoba oil , shea butter oil and caprylyl glycol ; synthetic esters and ethers , especially of fatty acids , for instance purcellin oil , 2 - octyldodecyl stearate , 2 - octyldodecyl erucate , isostearyl isostearate ; hydroxylated esters , for instance isostearyl lactate , octyl hydroxystearate , octyldodecyl hydroxystearate , diisostearyl malate or triisocetyl citrate ; fatty alcohol heptanoates , octanoates or decanoates ; polyol esters , for instance propylene glycol dioctanoate , neopentyl glycol diheptanoate and diethylene glycol diisononanoate ; and pentaerythritol esters , for instance pentaerythrityl tetraisostearate , or isopropyl lauroyl sarcosinate , sold especially under the trade name eldew sl 205 by the company ajinomoto ; linear or branched hydrocarbons , of mineral or synthetic origin , such as volatile or non - volatile liquid paraffins , and derivatives thereof , petroleum jelly , polydecenes , isohexadecane , isododecane , hydrogenated polyisobutene such as parleam oil , or the mixture of n - undecane ( c 11 ) and of n - tridecane ( c 13 ) sold under the reference cetiol ut by the company cognis ; fluoro oils that are partially hydrocarbon - based and / or silicone - based , for instance those described in document jp - a - 2 295 912 ; silicone oils , for instance volatile or non - volatile polymethylsiloxanes ( pdms ) with a linear or cyclic silicone chain , which are liquid or pasty at room temperature , in particular volatile silicone oils , especially cyclopolydimethylsiloxanes ( cyclomethicones ) such as cyclohexadimethylsiloxane and cyclopentadimethylsiloxane ; polydimethylsiloxanes comprising alkyl , alkoxy or phenyl groups , which are pendent or at the end of a silicone chain , these groups containing from 2 to 24 carbon atoms ; phenyl silicones , for instance phenyl trimethicones , phenyl dimethicones , phenyltrimethylsiloxydiphenylsiloxanes , diphenyl dimethicones , diphenylmethyldiphenyltrisiloxanes or 2 - phenylethyl trimethylsiloxy silicates , and polymethylphenylsiloxanes ; mixtures thereof . additional examples include benzoic acid esters of c 9 - c 15 alcohols , isononyl iso - nonanoate , c 12 - c 15 alkyl benzoate , or any combinations thereof . specific examples of oils / emollients include cocoglyceride , cyclomethicone , dimethicone , dicapryl maleate , caprylic / capric triglyceride , isopropyl myristate , octyl stearate , isostearyl linoleate , lanolin oil , coconut oil , cocoa butter , olive oil , avocado oil , aloe extracts , jojoba oil , castor oil , fatty acid , oleic acid , stearic acid , fatty alcohol , cetyl alcohol , hexadecyl alcohol , diisopropyl adipate , hydroxybenzoate esters , benzoic acid esters of c 9 - c 15 alcohols , isononyl iso - nonanoate , alkanes , mineral oil , silicone , dimethyl polysiloxane , ether , polyoxypropylene butyl ether , polyoxypropylene cetyl ether , c 12 - c 15 alkyl benzoate , aryl alkyl benzoate , isopropyl lauroyl sarcosinate , and any combinations thereof . examples of hydrophilic organic solvents that may be included in the sunscreen compositions include : monohydric c 1 - c 8 alcohols such as ethanol , propanol , butanol , isopropanol , isobutanol ; polyethylene glycols from 6 to 80 ethylene oxides such as propylene glycol , isoprene glycol , butylene glycol , glycerol , sorbitol ; mono or di - alkyl isosorbides such as dimethyl isosorbide ; examples of amphiphilic organic solvents include : polypropylene glycol ( ppg ) like propylene glycol alkyl ester or alkyl ether of ppg like ppg - 23 oleyl ether and ppg - 36 oleate . the total amount of oils / emollient present in the compositions is typically about 0 . 1 , 0 . 5 , 1 . 0 , or 2 . 5 wt . % to about 5 . 0 , 7 . 5 , 10 . 0 , 15 . 0 , 20 . 0 , or 30 wt . % of the total weight of the composition . film - formers are often incorporated into sunscreen compositions to ensure even coverage of the uv filters and can be used to render the composition water resistant . the film former is typically a hydrophobic material that imparts film forming and / or waterproofing characteristics . one such agent is polyethylene , which is available from new phase technologies as performalene ® 400 , a polyethylene having a molecular weight of 400 . another suitable film former is polyethylene 2000 ( molecular weight of 2000 ), which is available from new phase technologies as performalene ®. yet , another suitable film former is synthetic wax , also available from new phase technologies as performa ® v - 825 . other typical film - formers include acrylates / acrylamide copolymer , acrylates copolymer , acrylates / c 12 - c 22 alkylmethacrylate copolymer , polyethylene , waxes , vp / dimethiconylacrylate / polycarbamylpolyglycol ester , butylated pvp , pvp / hexadecene copolymer , octadecene / ma copolymer , pvp / eicosene copolymer , tricontanyl pvp , brassica campestris / aleuritis fordi oil copolymer , decamethyl cyclopentasiloxane ( and ) trimethylsiloxysilicate , and mixtures thereof . in some cases , the film former is acrylates / c 12 - c 22 alkylmethacrylate copolymer sold under the tradename allianz opt ® by isp . many of the common film - forming polymers included in sunscreen compositions are not soluble in ethanol ( such as pvp / eicosene copolymer ). a common film - former employed in ethanol based sunscreen products is dermacryl lt or dermacryl 79 marketed by akzo nobel ( inci name : acrylates / octylacrylamide copolymner ). dermacryl lt ( cas number : 80570 - 62 - 3 ) is a hydrophobic , high molecular weight carboxylated acrylic copolymer . it functions as a film - former in a broad range of cosmetic formulations , imparting waterproofing , increased occlusivity and decreased rub - off of actives . the total amount of film - formers present in the compositions is typically in an amount of about 0 . 1 , 0 . 5 , 1 . 0 , or 5 wt . % to about 5 , 10 , 20 , or 25 wt . %, based on the total weight of the composition . the sunscreen compositions typically include at least one emulsifier such as an amphoteric , anionic , cationic or nonionic emulsifier , used alone or as a mixture , and optionally a co - emulsifier . the emulsifiers are chosen in an appropriate manner according to the emulsion to be obtained ( w / o or o / w ). the emulsifier and the co - emulsifier are generally present in the composition in a proportion ranging from 0 . 3 wt . % to 30 m . % and preferably from 0 . 5 wt . % to 20 wt . % by relative to the total weight of the composition . for w / o emulsions , examples of emulsifiers that may be mentioned include dimethicone copolyols , such as the mixture of cyclomethicone and dimethicone copolyol sold under the trade name dc 5225 c by the company dow corning , and alkyl dimethicone copolyols such as the lauryl dimethicone copolyol sold under the name dow corning 5200 formulation aid by the company dow corning , and the cetyl dimethicone copolyol sold under the name abil em 90 ™ by the company goldschmidt . a crosslinked elastomeric solid organopolysiloxane comprising at least one oxyalkylene group , such as those obtained according to the procedure of examples 3 , 4 and 8 of u . s . pat . no . 5 , 412 , 004 and of the examples of u . s . pat . no . 5 , 811 , 487 , especially the product of example 3 ( synthesis example ) of u . s . pat . no . 5 , 412 , 004 , such as the product sold under the reference ksg 21 by the company shin - etsu , may also be used as surfactants for w / o emulsions . for o / w emulsions , examples of emulsifiers that may be mentioned include nonionic emulsifiers such as oxyalkylenated ( more particularly polyoxyethylenated ) fatty acid esters of glycerol ; oxyalkylenated fatty acid esters of sorbitan ; oxyalkylenated ( oxyethylenated and / or oxypropylenated ) fatty acid esters ; oxyalkylenated ( oxyethylenated and / or oxypropylenated ) fatty alcohol ethers ; sugar esters such as sucrose stearate ; and mixtures thereof . the fatty acid esters of a sugar that can be used as nonionic amphiphilic lipids can be chosen in particular from the group comprising esters or mixtures of esters of a c 8 - c 22 fatty acid and of sucrose , of maltose , of glucose or of fructose , and esters or mixtures of esters of a c 14 - c 22 fatty acid and of methylglucose . the c 8 - c 22 or c 14 - c 22 fatty acids forming the fatty unit of the esters that can be used in the emulsion comprise a saturated or unsaturated linear alkyl chain having , respectively , from 8 to 22 or from 14 to 22 carbon atoms . the fatty unit of the esters can be chosen in particular from stearates , behenates , arachidonates , palmitates , myristates , laurates , caprates and mixtures thereof . by way of example of esters or of mixtures of esters of a fatty acid and of sucrose , of maltose , of glucose or of fructose , mention may be made of sucrose monostearte , sucrose distearate , sucrose tristearate and mixtures thereof , such as the products sold by the company croda under the name crodesta f50 , f70 , f110 and f160 having , respectively , an hlb ( hydrophilic lipophilic balance ) of 5 , 7 , 11 and 16 ; and , by way of example of esters or of mixtures of esters of a fatty acid and of methylglucose , mention may be made of the disearate of methylglucose and of polyglycerol - 3 , sold by the company goldschmidt under the name tego - care 450 . mention may also be made of glucose monoesters or maltose monoesters , such as methyl o - hexadecanoyl - 6 - d - glucoside and o - hexadecanoyl - 6 - d - maltoside . the fatty alcohol ethers of a sugar that can be used as nonionic amphiphilic lipids can be chosen in particular form the group comprising ethers or mixtures of ethers of a c 8 - c 22 fatty alcohol and of glucose , of maltose , of sucrose or of fructose , and ethers or mixtures of ethers of a c 14 - c 22 fatty alcohol and of methylglucose . they are in particular alkylpolyglucosides . the c 8 - c 22 or c 14 - c 22 fatty alcohols forming the fatty unit of the ethers that can be used in the emulsion of the present disclosure comprise a saturated or unsaturated linear alkyl chain having , respectively , from 8 to 22 or from 14 to 22 carbon atoms . the fatty unit of the ethers can be chosen in particular from decyl , cetyl , behenyl , arachidyl , stearyl , palmityl , myristyl , lauryl , capryl and hexadecanoyl units , and mixtures thereof such as cetearyl . by way of example of fatty alcohol ethers of a sugar , mention may be made of alkylpolyglucosides , such as decylglucoside and laurylglucoside sold , for example , by the company henkel under the respective names plantaren 2000 and plantaren 1200 , cetostearylglucoside , optionally as a mixture with cetostearyl alcohol , sold , for example , under the name montanov 68 by the company seppic , under the name tego - care cg90 by the company goldschmidt and under the name emulgade ke3302 by the company henkel , and also arachidylglucoside , for example in the form of the mixture of arachidyl and behenyl alcohols and of arachidylglucoside sold under the name montanov 202 by the company seppic . use is more particularly made , as nonionic amphiphilic lipid of this type , of sucrose monostearate , sucrose distearate , sucrose tristearate and mixtures thereof , the distearate of methylglucose and of polyglycerol - 3 , and alkylpolyglucosides . the glycerol fatty esters that can be used as nonionic amphiphilic lipids can be chosen in particular from the group comprising the esters formed from at least one acid comprising a saturated linear alkyl chain having from 16 to 22 carbon atoms , and from 1 to 10 glycerol units . use may be made of one or more of these glycerol fatty esters in the emulsion of the instant disclosure . these esters may be chosen in particular from stearates , behenates , arachidates , palmitates and mixtures thereof . stearates and palmitates are preferably used . by way of example of a surfactant that can be used in the emulsion of the instant disclosure , mention may be made of decaglycerol monostearate , distearate , tristearate and pentastearate ( 10 glycerol units ) ( ctfa names : polyglyceryl - 10 stearate , polyglyceryl - 10 distearate , polyglyceryl - 10 tristearate , polyglyceryl - 10 pentastearate ), such as the products sold under the respective names nikkol decaglyn 1 - s , 2 - s , 3 - s and 5 - s by the company nikko , and diglyceryl monostearate ( ctfa name : polyglyceryl - 2 stearate ) such as the product sold by the company nikko under the name nikkol dgms . the sorbitan fatty esters that can be used as nonionic amphiphilic lipids chosen in particular from the group comprising esters of a c 16 - c 22 fatty acid and of sorbitan and oxyethylenated esters of a c 16 - c 22 fatty acid and of sorbitan . they are formed from at least one fatty acid comprising at least one saturated linear alkyl chain , having , respectively , from 16 to 22 carbon atoms , and from sorbitol or from ethoxylated sorbitol . the oxyethylenated esters generally comprise from 1 to 100 ethylene oxide units , and preferably from 2 to 40 ethylene oxide ( eo ) units . these esters can be chosen in particular from stearates , behenates , arachidates , palmitates and mixtures thereof . stearates and palmitates are preferably used . by way of example of sorbitan fatty ester and of an oxyethylenated sorbitan fatty ester , mention may be made of sorbitan monostearate ( ctfa name : sorbitan stearate ) sold by the company ici under the name span 60 , sorbitan monopalmitate ( ctfa name : sorbitan palmitate ) sold by the company ici under the name span 40 , or sorbitan 20 eo tristearate ( ctfa name : polysorbate 65 ) sold by the company ici under the name tween 65 . the ethoxylated fatty ethers are typically ethers made up of 1 to 100 ethylene oxide units and of at least one fatty alcohol chain having from 16 to 22 carbon atoms . the fatty chain of the ethers can be chosen in particular from behenyl , arachidyl , stearyl and cetyl units , and mixtures thereof , such as cetearyl . by way of example of ethoxylated fatty ethers , mention may be made of ethers of behenyl alcohol comprising 5 , 10 , 20 and 30 ethylene oxide units ( ctfa names : beheneth - 5 , beheneth - 10 , beheneth - 20 and beheneth - 30 ), such as the products sold under the names nikkol bbs , bb10 , bb20 and bb30 by the company nikko , and the ether of stearyl alcohol comprising 2 ethylene oxide units ( ctfa name : steareth - 2 ), such as the product sold under the name brij 72 by the company ici . the ethoxylated fatty esters that can be used as nonionic amphiphilic lipids are esters made up of 1 to 100 ethylene oxide units and of at least one fatty acid chain comprising from 16 to 22 carbon atoms . the fatty chain of the esters can be chosen in particular from stearate , behenate , arachidate and palmitate units , and mixtures thereof . by way of example of ethoxylated fatty esters , mention may be made of the ester of stearic acid comprising 40 ethylene oxide units , such as the product sold under the name myrj 52 ( ctfa name : peg - 40 stearate ) by the company ici , and the ester of behenic acid comprising 8 ethylene oxide units ( ctfa name : peg - 8 behenate ), such as the product sold under the name compritol hd5 ato by the company gattefosse . the block copolymers of ethylene oxide and of propylene oxide that can be used as nonionic amphiphilic can be chosen in particular from poloxamers and in particular from poloxamer 231 , such as the product sold by the company ici under the name pluronic l81 of formula ( v ) with x = z = 6 , y = 39 ( hlb 2 ); poloxamer 282 , such as the product sold by the company ici under the name pluronic l92 of formula ( v ) with x = z = 10 , y = 47 ( hlb 6 ); and poloxamer 124 , such as the product sold by the company ici under the name pluronic l44 of formula ( v ) with x = z = 11 , y = 21 ( hlb 16 ). as nonionic amphiphilic lipids , mention may also be made of the mixtures of nonionic surfactants described in document ep - a - 705593 , incorporated herein for reference . suitable hydrophobically - modified emulsifiers include , for example , inulin lauryl carbamate , commercially available from beneo orafti under the tradename inutec sp1 . the total amount of emulsifier present in the compositions is typically in an amount of about 0 . 1 , 0 . 2 , or 0 . 5 wt . % to about 4 . 0 , 5 . 0 , 6 . 0 , or 7 . 5 wt . %, based on the total weight of the composition . examples of suitable hydrophilic gelling agents include carboxyvinyl polymers such as the carbopol products ( carbomers ) and the pemulen products ( acrylate / c10 - c30 - alkylacrylate copolymer ); polyacrylamides , for instance the crosslinked copolymers sold under the names sepigel 305 ( ctfa name : polyacrylamide / c13 - 14 isoparaffin / laureth 7 ) or simulgel 600 ( ctfa name : acrylamide / sodium acryloyldimethyltaurate copolymerfisohexadecane / polysorbate 80 ) by the company seppic ; 2 - acrylamido - 2 - methylpropanesulfonic acid polymers and copolymers , which are optionally crosslinked and / or neutralized , for instance the poly ( 2 - acrylamido - 2 - methylpropanesulfonic acid ) sold by the company hoechst under the trade name “ hostacerin amps ” ( ctfa name : ammonium polyacryldimethyltauramide ); cellulose - based derivatives such as hydroxyethylcellulose ; polysaccharides and especially gums such as xanthan gum ; and mixtures thereof . lipophilic gelling agents ( thickeners ) that may be mentioned include modified clays such as hectorite and its derivatives , for instance the products sold under the name bentone . in some instances , the gelling agent is ammonium acryloyldimethyltaurate / steareth - 25 methacrylate crosspolymer , commercially available from clariant under the tradename aristoflex hms . the gelling agent is typically used in an amount of about 0 . 05 to about 1 . 5 % by weight , from about 0 . 08 to about 1 . 0 % by weight , or about 0 . 1 to about 0 . 5 % by weight , based on the total weight of the composition . the sunscreen compositions can include additional sunscreen filters such as , for example , mineral uv filters . examples of mineral uv filters include pigments and nanopigments ( mean size of the primary particles is generally is from 5 nm to 100 nm or from 10 nm to 50 nm ) of treated or untreated metal oxides such as , for example , nanopigments of titanium oxide ( amorphous or crystallized in rutile and / or anatase form ), of iron oxide , of zinc oxide , of zirconium oxide or of cerium oxide . the treated nanopigments are pigments that have undergone one or more surface treatments of chemical , electronic , mechanochemical and / or mechanical nature with compounds as described , for example , in cosmetics & amp ; toiletries , february 1990 , vol . 105 , pp . 53 - 64 , such as amino acids , beeswax , fatty acids , fatty alcohols , anionic surfactants , lecithins , sodium , potassium , zinc , iron or aluminium salts of fatty acids , metal ( titanium or aluminium ) alkoxides , polyethylene , silicones , proteins ( collagen or elastin ), alkanolamines , silicon oxides , metal oxides , sodium hexametaphosphate , alumina or glycerol . the treated nanopigments may more particularly be titanium oxides treated with : silica and alumina , such as the products “ microtitanium dioxide mt 500 sa ” and “ microtitanium dioxide mt 100 sa ” from the company tayca , and the products “ tioveil fin ”, “ tioveil op ”, “ tioveil motg ” and “ tioveil ipm ” from the company tioxide ; alumina and aluminium stearate , such as the product “ microtitanium dioxide mt 100 t ” from the company tayca ; alumina and aluminium laurate , such as the product “ microtitanium dioxide mt 100 s ” from the company tayca ; iron oxides and iron stearate , such as the product “ microtitanium dioxide mt 100 f ” from the company tayca ; silica , alumina and silicone , such as the products “ microtitanium dioxide mt 100 sas ”, “ microtitanium dioxide mt 600 sas ” and “ microtitanium dioxide mt 500 sas ” from the company tayca ; sodium hexametaphosphate , such as the product “ microtitanium dioxide mt 150 w ” from the company tayca ; octyltrimethoxysilane , such as the product “ 1 - 805 ” from the company degussa ; alumina and stearic acid , such as the product “ uvt - m160 ” from the company kemira ; alumina and glycerol , such as the product “ uvt - m212 ” from the company kemira ; alumina and silicone , such as the product “ uvt - m262 ” from the company kemira . other titanium oxide nanopigments treated with a silicone are tio 2 treated with octyltrimethylsilane and for which the mean size of the elementary particles is between 25 and 40 nm , such as the product sold under the trade name “ 1805 ” by the company degussa silices , tio 2 treated with a polydimethylsiloxane and for which the mean size of the elementary particles is 21 nm , such as the product sold under the trade name “ 70250 cardre uf tio2si3 ” by the company cardre , anatase / rutile tio 2 treated with a polydimethylhydrogenosiloxane and for which the mean size of the elementary particles is 25 nm , such as the product sold under the trade name “ microtitanium dioxide usp grade hydrophobic ” by the company color techniques . uncoated titanium oxide nanopigments are sold , for example , by the company tayca under the trade names “ microtitanium dioxide mt 500 b ” or “ microtitanium dioxide mt 600 b ”, by the company degussa under the name “ p 25 ”, by the company wackher under the name “ oxyde de titane transparent pw ”, by the company myoshi kasei under the name “ uftr ”, by the company tomen under the name “ its ” and by the company tioxide under the name “ tioveil aq ”. those sold under the name “ z - cote ” by the company sunsmart ; those sold under the name “ nanox ” by the company elementis ; and those sold under the name “ nanogard wcd 2025 ” by the company nanophase technologies . those sold under the name “ zinc oxide cs - 5 ” by the company toshibi ( zno coated with polymethylhydrogenosiloxane ); those sold under the name “ nanogard zinc oxide fn ” by the company nanophase technologies ( as a 40 % dispersion in finsolv tn , c 12 - c 15 alkyl benzoate ); those sold under the name “ daitopersion zn - 30 ” and “ daitopersion zn - 50 ” by the company daito ( dispersions in cyclopolymethylsiloxane / oxyethylenated polydimethylsiloxane , containing 30 % or 50 % of nanozinc oxides coated with silica and polymethylhydrogenosiloxane ); those sold under the name “ nfd ultrafine zno ” by the company daikin ( zno coated with perfluoroalkyl phosphate and copolymer based on pertluoroalkylethyl as a dispersion in cyclopentasiloxane ); those sold under the name “ spd - z1 ” by the company shin - etsu ( zno coated with silicone - grafted acrylic polymer , dispersed in cyclodimethylsiloxane ); those sold under the name “ escalol z100 ” by the company isp ( alumina - treated zno dispersed in an ethylhexyl methoxycinnamate / pvp - hexadecene / methicone copolymer mixture ); those sold under the name “ fuji zno - sms - 10 ” by the company fuji pigment ( zno coated with silica and polymethylsilsesquioxane ); and those sold under the name “ nanox gel tn ” by the company elementis ( zno dispersed at a concentration of 55 % in c 12 - c 15 alkyl benzoate with hydroxystearic acid polycondensate ). the uncoated cerium oxide nanopigments are sold under the name “ colloidal cerium oxide ” by the company rhone - poulenc . the uncoated iron oxide nanopigments are sold , for example , by the company arnaud under the names “ nanogard wcd 2002 ( fe 45b )”, “ nanogard iron fe 45 bl aq ”, “ nanogard fe 45r aq ” and “ nanogard wcd 2006 ( fe 45r )” or by the company mitsubishi under the name “ ty - 220 ”. the coated iron oxide nanopigments are sold , for example , by the company arnaud under the names “ nanogard wcd 2008 ( fe 45b fn )”, “ nanogard wcd 2009 ( fe 45b 556 )”, “ nanogard fe 45 bl 345 ” and “ nanogard fe 45 bl ” or by the company basf under the name “ transparent iron oxide ”. mixtures of metal oxides may also be used , especially of titanium dioxide and of cerium dioxide , including the silica - coated equal - weight mixture of titanium dioxide and of cerium dioxide , sold by the company ikeda under the name “ sunveil a ”, and also the alumina , silica and silicone - coated mixture of titanium dioxide and of zinc dioxide , such as the product “ m 261 ” sold by the company kemira , or the alumina , silica and glycerol - coated mixture of titanium dioxide and of zinc dioxide , such as the product “ m 211 ” sold by the company kemira . the compositions according to the instant disclosure may be prepared according to techniques that are well known to those skilled in the art , in particular those intended for the preparation of emulsions of oil - in - water or water - in - oil type . they may be in particular in the form of a simple or complex emulsion ( o / w , w / o , o / w / o or w / o / w emulsion ) such as a cream or a milk , in the form of a gel or a cream - gel , or in the form of a lotion . the instant disclosure will be better understood from the examples that follow , all of which are intended for illustrative purposes only and are not meant to limit the scope of the instant disclosure in any way . samples comprising different amounts of uv filters were prepared by dissolving the uv filters in ethanol and solvent as illustrated in the table below . each sample was applied to a ppma plate with a draw down bar to control the thickness and the homogeneity of the film . the in vitro spf was measured using a labsphere 2000 . each measurement was made 6 times ( 6 times on each plate ) on 3 plates for each composition . the amount of uv filters included in each sample and the resulting spf is reported in the table below . | US-201113304202-A |
cone beam breast ct is a three - dimensional breast imaging modality with high soft tissue contrast , high spatial resolution and no tissue overlap . cbbct - based computer aided diagnosis technology is a clinically useful tool for breast cancer detection and diagnosis that will help radiologists to make more efficient and accurate decisions . the cbbct - cad is able to : 1 ) use 3d algorithms for image artifact correction , mass and calcification detection and characterization , duct imaging and segmentation , vessel imaging and segmentation , and breast density measurement , 2 ) present composite information of the breast including mass and calcifications , duct structure , vascular structure and breast density to the radiologists to aid them in determining the probability of malignancy of a breast lesion . | a preferred embodiment will be set forth in detail with reference to the drawings , in which like reference numerals refer to like elements or steps throughout . the first step is skin removal . although the skin in cbbct images has higher intensity than the fatty stroma , its intensity is only slightly higher than that of the glandular tissue . a simple thresholding cannot segment the skin from other tissue . based on the fact that the skin is on the outermost layer of the whole breast , a morphological process is proposed to remove the skin from the breast in cbbct images . 1 . a histogram thresholding method is applied to the whole cbbct image volume to separate the image into three distinct parts which have significant different intensities : air , fat and tissues ( including skin and glands ). 2 . based on the fact that the skin is between the inner breast and the air , a morphological 3d erosion operation is applied to erode the tissue between air and fat . 3 . when the erosion kernel reaches the fat area in the inner breast , the erosion stops . 4 . in case the glandular tissue is connected to the skin in cbbct images , during the erosion , a global ratio of fat area vs . total edge area is recorded along the edge of the breast . when the ratio reaches 80 % ( or another suitably chosen value ), the skin removal process stops . glandular tissue segmentation will now be explained . the fuzzy c - means ( fcm ) algorithm is widely used for image segmentation . it is also used for breast density assessment in both mammography and breast mri . in cbbct images , due to the high soft tissue contrast , fcm is also an effective algorithm to segment glandular tissue from fat . the fcm is taught in james c . bezdek , “ pattern recognition with fuzzy objective function algorithms ”, kluwer academic publishers , norwell , mass ., 1981 . in the fuzzy c - means clustering algorithm , an objective function is defined as : where x i is the data vector to be clustered , c j is the center vector of the jth cluster , u ij is the degree of the vector x i in the jth cluster , m is the fuzziness exponent , n is the number of total data vectors , and c is the number of total clusters . ∥*∥ is a distance function measuring the similarity between any data vector and cluster center . the fuzzy c - means clustering algorithm iteratively optimizes the objective function j m by updating u ij and c j with the algorithm stops when max ij {| u ij ( k + 1 ) − u ij k |}& lt ; ε , where ε is the termination parameter between 0 and 1 . the cluster number c is set to 3 . each cluster represents air , fat , and glands . bias areas include low density glandular tissue with attenuation ( as measured in hounsfeld units , or hu ) close to the fat and non - uniform areas caused by imaging artifacts . to achieve better accuracy of tissue segmentation , the bias areas need to be handled . in addition to the clusters for air , fat and glands , an extra cluster is used for bias areas . to further assign voxels in a bias area into the three clusters . the following process is used : 1 . a local contrast process is applied to the cbbct images after skin removal . the local contrast is based on the following equation : here , f ( x , y , z ) is the hu of a voxel at a position ( x , y , z ), and r is a local cube with size n × n × n . by this process , the non - uniform artifact is reduced . 2 . voxels in the bias area are extracted to go through a second clustering using the images from step 1 . the cluster number here is set to 3 . the cluster with the highest center value is considered to be glands , and the rest of clusters are considered to be fat . 3 . combine the clustering results from first clustering and second clustering to yield a final result of air , fat and gland segmentation . after the cbbct images are segmented into skin , fat and glands , the percentage of each tissue with respect to the whole breast volume can be calculated . from the cbbct clinical database , 5 patient data sets were selected for a preliminary experiment . each patient data set had its mammography records reviewed by a radiologist , and its breast density category was assigned based on the mammograms . the computer aided breast density evaluation was applied to the cbbct images of each patient . fig1 shows the mammograms and the cbbct slices of 4 cases used in this study , corresponding to the 4 bi - rads breast density categories . more specifically , that figure shows four clinical cases with mlo mammogram images and cbbct slice images . top row : mammography images ; bottom row : corresponding cbbct slices . left column : birads - 1 ( fatty ) breast ; middle left column : birads - 2 ( scattered ) breast ; middle right column : birads - 3 ( hetero dense ) breast ; right column : birads - 4 ( extreme dense ) breast . the cbbct breast density auto - evaluation process is applied to each of the clinical cases . fig2 shows the skin removal results , and fig3 shows the auto - segmentation results . more specifically , fig2 shows a ) original cbbct image , b ) cbbct image with skin removed , and c ) skin image . fig3 shows a ) original cbbct image with skin removed , b ) fat tissue area , and c ) glandular tissue area . based on the segmented image , the percentages of skin , fat , and glands could be acquired . table i lists the density measurement and compares it with the bi - rads category of each case . breast density changes over time . an increase in breast density is associated with greater risk of breast cancer , regardless of the original breast density measurement . accurate measurement over time is important for active surveillance of the breast density change . the breast density auto - evaluation provides accurate volumetric measurement to detect the changes of density ; hence timely cancer risk assessment can be possible . table i above gives the comparison result between cbbct breast density measurement and the mammography based bi - rads category . as can be seen from the table , there are obvious disagreements between those two systems , especially within breasts with higher density categories in bi - rads . measuring breast density with two - dimensional mammograms and true three - dimensional cbbct images can yield different results for the same breast . a new breast density measurement system may be defined based on cbbct images . the preferred embodiment is not limited to measuring breast density . mass detection and calcification detection will now be disclosed . the algorithm is taught in xiaohua zhang , ruola ning and dong yang , “ three dimensional breast masses auto detection in cone beam breast ct ,” proc . spie 2009 ; 7260 : 726027 . abnormal density and structural distortion are radiographic signs for radiologists to detect masses . in 3d cbbct images , breast masses are observed as congregated volumetric regions which have a denser structure than the surrounding normal tissues . malignant masses have irregular or spiculated margins , while benign masses usually have smooth margins . the high contrast of cbbct images reveals the density difference between tissues . a 3d mass detection algorithm takes advantage of high contrast resolution and the 3d characteristic of the cbbct images . in cbbct , high contrast resolution reveals the contrast changes of tissue components across voxels . the 3d detection algorithm is able to measure these changes and uses the difference between masses and normal tissues for suspicious region detection . according to the preliminary study on 14 pathology - proven masses , after image calibration , the average contrast between masses and their surrounding tissues ranged from 10 to 80 hu . other characteristics , such as the gradient congregation of the mass , were also used to distinguish mass from normal tissue . in the preliminary studies , a 3d weighted average algorithm was applied , followed by a 3d iris filtering to cbbct volume images to highlight the congregate tissue volume . the highlighted areas are selected as candidates of breast masses . in the preliminary result , 12 of the 14 masses were correctly detected . after the mass regions are detected , the corresponding measurements of each region are calculated . the measurements include density , size , volume and shape descriptors . the marked results and corresponding measurements will be provided as output results . fig4 shows the results of preliminary studies on mass detection . images ( a ) and ( c ) show pathology - proven masses . images ( b ) and ( d ) show the results of automatic mass detection . calcification detection will now be disclosed . the algorithm is taught in xiaohua zhang , ruola ning and jiangkun liu , “ computer aided breast calcification auto - detection in cone beam breast ct ,” proc . spie 2010 ; 7624 : 76242m . in cbbct images , calcifications have high contrast to the surrounding tissues and high hu variations both inside the calcification area and at the edges . the contrast between calcification and background material is from − 200 hu to − 800 hu , and the hu standard deviation can be more than 200 hu . a calcification auto - detection scheme has been developed to locate the calcifications within cbbct images . a 3d local thresholding process and a histogram thresholding process are first applied to the cbbct images to select all voxels with relatively high hu value and hu variation with respect to the neighborhood voxels . to further reduce false positives , six features are extracted from each remaining connected voxel object . the features are fed into an artificial neural network ( ann ) which is trained with known calcification features . the ann output values are used as criteria to differentiate calcification objects from false positive objects . a preliminary study achieves sensitivity of 95 % with average 10 false positives calcifications per case . fig5 illustrates one example of cbbct calcification auto - detection , in which image ( a ) indicates known calcifications and image ( b ) indicates eth results of the calcification algorithm . after the detection , measurements of the calcifications will be provided , including cluster size , number of calcifications in clusters and shape descriptors . breast ducts and blood vessels can be segmented . segmenting algorithms are known in the art , e . g ., for segmenting colons . a suitable algorithm is taught in d chen , r fahmi , a a farag , r l falk , g w dryden , “ accurate and fast 3d colon segmentation in ct colonography ,” proc . of isbi 2009 ; 490 - 493 . such segmentation can be used for active surveillance of duct carcinoma in situ ( dics ) and abnormal vasculature relating to tumors . artifact correction will now be disclosed . a suitable method is taught in ning r : apparatus and method for x - ray scatter reduction and correction for fan beam and cone beam volume ct . u . s . pat . no . 6 , 618466 issued on sep . 9 , 2003 and pct / us03 / 04871 . scattering is one of the major problems that are associated with cbbct because the large - area flat - panel detector in a cbbct system receives scattered x - rays as well as primary x - rays . at 49 kvp , the scatter - to - primary ratio can be as high as 0 . 5 for an average - sized breast . scattering produces inaccurate ct numbers , reduces tissue contrast and causes cupping artifact in the reconstructed cbbct images . given the roughly symmetric geometry of a breast and the slowly varying nature of scattered radiation , the scattered radiation is estimated based on the breast shape in a projection image , and the projection image is corrected by subtracting the scattered radiation . as the shape and position and breast shadow are different across different projection images , such a correction is performed for all projections . the axial and longitude uniformity can be improved to 20 hu and 40 hu respectively . motion artifacts are associated with patient movement and breathing during the scan , appearing as blurs in the reconstruction images . usually , the moment of motion can be identified by examining projection images . the data before or after this moment can be considered as motion - free data which can be used for reconstruction with half scan algorithms . a suitable algorithm is taught in dong yang , ruola ning , yong yu , david conover and xianghua lu , “ implementation and evaluation of the half - scan scheme based on cbct ( cone - beam ct ) system ” proc . spie 5368 , 542 ( 2004 ). this method can efficiently remove motion artifacts . a system on which the preferred or another embodiment can be implemented is set forth in u . s . pat . no . 6 , 480 , 565 , whose disclosure is hereby incorporated by reference in its entirety into the present disclosure . fig2 a of that patent , which is reproduced herein as fig6 , shows an exemplary device . in the scanner 200 , the patient p rests on an ergonomically formed table 202 so that the breast b to be scanned descends through a hole 204 in the table 202 into a safety cover 205 . below the table 202 , a gantry 206 supports a detector 208 and an x - ray tube 210 , one on either side of the safety cover 205 . the gantry is turned by a motor 212 to be rotatable around an axis a passing through the safety cover 205 , so that as the x - ray tube travels along an orbit o , the breast b remains in the path of a cone beam c emitted by the x - ray tube 210 . the gantry is also movable by a motor 214 to go up and down along a vertical path v . alternatively , the table 202 can be moved up and down along a vertical path v . the detector 208 can be moved toward and away from the axis a by a motor 216 to change the magnification factor if necessary . in some embodiments , a piston 218 may be used to push the nipple toward the chest wall to reduce z - direction coverage by a couple of centimeters , although usually , the breast does not have to be re - shaped . a contrast injector 220 can be provided for contrast enhanced tomographic imaging , angiogenesis studies and some other dynamic contrast studies . various contrast injection media , such as iodine , are known in the art . it is not always necessary to inject a contrast medium into the patient . the cbbct - cad software / hardware includes the modules shown in fig7 : image artifact correction modules : the image artifact correction modules are executed either before or after the cbbct reconstruction . as shown , the modules include pre - correction 704 and post - correction 708 . the pre - correction is performed on the projections acquired from the cbbct scan . a suitable method is taught in ning r : apparatus and method for x - ray scatter reduction and correction for fan beam and cone beam volume ct . u . s . pat . no . 6 , 618 , 466 issued on sep . 9 , 2003 and pct / us03 / 04871 . the post - correction is performed on the isotropic 3d images from the cbbct reconstruction . detection and segmentation modules : the four detection and segmentation modules are interconnected . those modules are density assessment 710 , duct segment detection 712 , calcification detection 714 , and mass detection 716 . the density assessment algorithm has been described above . a suitable calcification detection algorithm is taught in xiaohua zhang , ruola ning and jiangkun liu , “ computer aided breast calcification auto - detection in cone beam breast ct ,” proc . spie 2010 ; 7624 : 76242m . a suitable mass detection algorithm is taught in xiaohua zhang , ruola ning and dong yang , “ three dimensional breast masses auto detection in cone beam breast ct ,” proc . spie 2009 ; 7260 : 726027 . the users are able to choose one or multiple modules for better diagnostic assistance . each of the modules is designed to run on both the cpu and the gpu to reduce the processing time . the output results of each module can be superimposed so that radiologists can combine different information to make an accurate decision . the task manager 718 is the main interface of the cad system between the users and the cad modules . system connections , data send / receive configurations and task scheduling / queuing are defined through the task manager . the task manager organizes all applicable cases and dispatches the tasks to the detection and segmentation modules based on the specific requirements for each case . the task manager also plans all possible resources in the system and assigns the resource to the appropriate modules . data access interface 720 : this is a dicom interface to pacs / image archive system 722 for image data retrieve / store and the radiologists &# 39 ; feedback , annotation or report , for further processing . multiple dicom outputs , including dicom printers , structured reporting , dicom 6000 overlay , secondary image capture and rtss are supported . fig8 shows the hardware structure of the cbbct cad system , based on the system of the above - cited &# 39 ; 565 patent or any other suitable system . three major hardware components will be included in the cad system : cad server 802 : the cad server provides the interface for all clients and external pacs 722 or image archive systems 804 , as well as dicom printers 806 . it is equipped with highly configured parts to provide fast and reliable services . the cad server accepts the schedules from pre - configured tasks or the user inputs , read data from the pacs / archive system , dispatches the computation tasks to the cad workstations , receives the result from the workstations and writes the cad reports back to the pacs / archive system or prints the reports . cad workstation 808 : the major functional modules of the cad system are running on the high performance workstation . it provides fast and reliable computation to satisfy the practical requirements . the workstation is attached to the server by hi - speed connection . multiple workstations can be installed and connected in each system to perform the tasks parallelly to provide enough computation capability . thin client 810 : the thin client gives users easy access to the system . it can be browser - based application or stand - alone gui application . it communicates with the cad server within the intranet or over the internet to provide the services from anywhere with internet connection . the users setup the configurations and schedule tasks on the cad server through the intuitive gui provided by the thin client . with the parallel processing capability of the hardware and software design , the total processing time of the cbbct - cad system is expected to be within 5 minutes . while a preferred embodiment has been set forth in detail above , those skilled in the art who have reviewed the present disclosure will readily appreciate that other embodiments can be realized within the scope of the invention . for example , recitations of specific hardware and of numerical values are illustrative rather than limiting . in addition , the disclosed cone beam ct image - based cad method and system can be used for other cone beam ct imaging applications , such as angiography imaging and lung imaging . therefore , the present invention should be construed as limited only by the appended claims . | US-201213985517-A |
an asexually reproduced cultivar of perennial zoysiagrass that possess a unique combination of characteristics including purple anthers and white stigmas , an absence of leaf blade hairs , high turf quality and density , good shade tolerance , salinity tolerance , resistance to rhizoctonia blight and zoysiagrass mite , moderate resistance to tropical sod webworm and hunting billbug , susceptibility to fall army worm and tawny mole cricket and a distinct dna fingerprint . | ‘ royal ’ was characterized in greenhouse and field conditions and is a unique variety of zoysiagrass . seeds collected from open pollinated maternal clones of the zoysiagrass germplasm nursery were planted , developed into plugs , and established in small field turf plots . ‘ royal ’ demonstrated superior biotic and phenotypic characteristics and , thus , propagated by cuttings of stolons and rhizomes by rooting them in soil and expanding the rooted material to provide planting stock . the planting stock was observed for performance characteristics and for comparison of morphological characters after propagation . the inventive variety has been propagated by sod , plugs , sprigs and stolons . seed reproduction with self - fertility is not common in the zoysia spp . no seedling establishment from ‘ royal ’ has been observed in either greenhouse or field studies . ‘ royal ’ is distinguished from other varieties of zoysiagrass by a combination of characteristics including shade tolerance , salinity tolerance , turf quality , resistance to zoysiagrass mite and rhizoctonia blight ( brown patch ) and moderate resistance to tropical sod webworm and hunting billbug . ‘ royal ’ is closest in phenotypic appearance to the zoysiagrass variety ‘ emerald ’ ( unpatented ). ‘ royal ’ generally demonstrates fair - to - good winter hardiness . further , the inventive variety grows at an intermediate to rapid rate , and exhibits an intermediate water use requirement . ‘ royal ’ produces little thatch with an optimum mowing height of 1 to 5 mm . ‘ royal ’ generally grows to cover a plot area within 10 - 12 months of establishment from 7 mm × 10 mm plugs planted on 30 mm centers . ‘ royal ’ spreads by both rhizome and stolon growth . the stolons have a mean internode length of 23 . 6 mm between the fourth and fifth nodes , with a mean internode width of 1 . 21 mm and node diameter of 1 . 53 mm ( table 1 ) ( reinert et al ., 2002a ). stolons of ‘ royal ’ root adventitiously at the nodes . the internode stolon color of ‘ royal ’ exposed to full sun is 5r 3 / 2 ; color notations of plant tissues were based on the munsell color charts for plant tissues , munsell color , baltimore , md ., 1977 . one of ordinary skill in the art recognizes that color notations are affected by light quality , photoperiod , and general growth of the plant . measured in full - sun under field conditions in august , 2000 , the genetic , adaxial leaf color of ‘ royal ’ is 2 . 5g 4 / 4 to 2 . 5g 5 / 2 as compared to ‘ el toro ’ ( u . s . plant pat no . 5 , 845 ), which has a leaf color of 2 . 5 g 5 / 2 , and ‘ meyer ’ ( unpatented ), which has a color of 2 . 5 g 4 / 2 ( munsell , 1977 ). the ligule of ‘ royal ’ is a row of silky hairs , achieving approximately 1 mm in maximum length . the ligule is illustrated in fig1 . leaf blades of ‘ royal ’ are rolled in the bud , and are flat and stiff . measurements of the third youngest leaf included a width of 1 . 36 mm and a length of 8 . 2 mm ( table 2 ) ( reinert et al ., 2002a ), which is significantly narrower and shorter than ‘ meyer ’, ‘ crowne ’ and ‘ el toro ’ varieties . the abaxial / adaxial leaf surfaces lack hairs . leaf blades are illustrated in fig1 . measured under greenhouse conditions at dallas , tex ., january 1996 , the flag leaf of ‘ royal ’ has a mean length of 5 . 24 mm . ‘ royal ’ has purple anthers and white colored stigmas , undistinguishable in shade of color . the inflorescence is a terminal spike - like raceme , with spikelets on short pedicels ( see fig2 ). ‘ royal ’ has a mean culm length of 6 . 7 cm , and an inflorescence length of 22 . 9 mm with a mean of 27 . 6 florets per raceme . the raceme is longer than ‘ diamond ’ and more similar in length to ‘ crowne ’. ‘ royal ’ was entered in the national turfgrass evaluation program , national zoysiagrass test - 1991 ( ntep - 1991 ) and was evaluated alongside 23 other zoysiagrass genotypes at 22 different geographic locations covering 17 states in the united states . the evaluation period lasted 4 years ( 1992 - 1995 ). in the ntep - 1991 test for the years 1992 - 1995 , ‘ royal ’ ranked ninth for the last two years and ninth overall in quality among the zoysiagrass genotypes tested ( table 3 ) ( morris , 1995b ). further , ‘ royal ’ had the best density rating among the entries over the 4 - yr evaluation period ( table 4 ) ( morris , 1993 ; morris , 1994a ; morris , 1994b ; and morris 1995a ). the turf performance index ( tpi ) is based on the number of times an entry occurred in the top statistical group , ranked ‘ royal ’ in the top grouping 25 times as compared to ‘ cavalier ’ ( 24 top groupings ), ‘ emerald ’ ( 23 top groupings ) and ‘ diamond ’ ( 22 top groupings ). in contrast , the commercial standard varieties , ‘ meyer ’ and ‘ el toro ’, ranked in the top statistical grouping only 13 and 11 times , respectively . in studies in griffin , ga ., ‘ royal ’ was ranked among the densest turfs having good genetic color ( carrow , 1991 ; carrow , 1992 ). in the ntep - 1991 evaluation , ‘ royal ’ exhibited good shade tolerance as compared to the other zoysiagrasses . each genotype was planted and evaluated in a shaded site ( ca . 90 %) under live - oak trees ( quercus virginiana mill .) in dallas , tex ., on september 1992 ( table 5 ) ( yamamato and engelke , 1996 ). turf performance characteristics evaluated at the shaded site included ; turf quality , turf cover , green cover , color , density and texture . turf cover was evaluated as a percentage of plot area covered with turf , and the tpi was used to evaluate overall turf quality . in general , the varieties took nearly 9 months to spread and cover at least 50 % of the plot area . thereafter , the ‘ royal ’, ‘ crowne ’, ‘ emerald ’, ‘ zorro ’ and ‘ diamond ’ varieties increased turf cover to greater than 80 %. ‘ royal ’ ranked fifth behind ‘ diamond ’, ‘ zorro ’ and ‘ crowne ’ among the 25 entries in the trial . the inventive variety exhibits excellent salt tolerance . under greenhouse conditions in hydroponics tanks , the salinity was gradually increased from zero to 400 mm nacl . ‘ royal ’ sustained a 33 . 6 % leaf - firing injury , which was similar to ‘ el toro ’, ‘ emerald ’ and ‘ cavalier ’ and significantly less than ‘ meyer ’, which sustained 54 . 3 % damage ( marcum et al ., 1998 ). ‘ royal ’ is resistant to rhizoctonia blight and zoysiagrass mite and moderately resistant to tropical sod webworm and hunting billbug . rhizoctonia blight ( brown patch ) is caused by the fungal pathogen rhizoctonia solani kühn . ‘ meyer ’ and ‘ royal ’ ( 10 . 8 and 15 . 8 % disease infection , respectively ) were among the most resistant to the fungus over a 7 - day evaluation period when 24 zoysiagrass genotypes were inoculated under ideal disease conditions with the fungal pathogen in a growth chamber at dallas , tex . ( table 7 ) ( metz et al ., 1994 ). ‘ royal ’ is resistant to the zoysiagrass mite eriophyes zoysiae baker , kono and o &# 39 ; neill as compared to ‘ meyer ’, ‘ belair ’ ( unpatented ) and many other zoysiagrass genotypes which are very susceptible to the mite ( table 8 ) ( reinert et al ., 1993 ). this mite has been identified in maryland , florida , texas and other zones of extensive use of zoysiagrass . under heavy infestation pressure in greenhouse conditions , a mean of 0 . 2 infested leaves per 5 × 5 cm plant was observed in the inventive variety . in comparison , ‘ diamond ’, ‘ cavalier ’, ‘ belair ’ and ‘ meyer ’ each exhibited greater than 9 . 4 infested leaves per plant . the inventive variety is susceptible to fall armyworm ( spodoptera frugiperda j . e . smith ) larvae ( reinert and engelke , unpublished data ) and tawny mole cricket ( scapteriscus vicinus scudder ) ( braman et al ., 1994 ). ‘ royal ’ is moderately resistant to feeding by tropical sod webworm ( herpetogramma phaeopteralis guenée ) larvae . the visual rating was 4 . 6 for the inventive variety as compared to the 1 . 4 visual rating of ‘ meyer ’ ( table 9 ) ( reinert and engelke , 2001 ). the visual rating is determined on a scale of 1 - 9 , with 1 = near complete defoliation . larvae that developed on ‘ royal ’ weighed 15 . 1 mg after 15 days of feeding , which was larger than the 7 . 2 mg larvae that developed on the most resistant ‘ cavalier ’, and one - half the size of larvae that developed on ‘ meyer ’ ( 36 . 4 mg ) ( table 10 ). additionally , larvae on ‘ royal ’ required 4 . 4 days longer to develop to adult emergence . ‘ royal ’ is moderately resistant to the hunting billbug ( sphenophorus venatus vestitus ( chittenden )) in a cage study with eight other zoysiagrasses in dallas , tex . ( table 11 ) ( reinert et al ., 2002b ). compared to ‘ meyer ’ and ‘ palisades ’, which exhibited 44 . 4 and 45 . 5 % leaf - firing damage of the plant canopy , respectively , ‘ royal ’ expressed 20 . 95 % leaf - firing damage . evaluation of whole plant growth potential ( dry weight ) indicated that ‘ royal ’ sustained a 53 . 46 % reduction as compared to a 70 . 2 %, a 73 . 9 % and a 73 . 9 % reduction for ‘ el toro ’, ‘ meyer ’ and ‘ palisades ’, respectively . the lower the reduction the greater expression of natural plant resistance . molecular markers have been used widely and successfully for genotyping varieties and species . amplified fragment length polymorphism ( aflp ) is one such highly informative marker assay to generate fingerprints of simple and complex species and cultivars . the fingerprints generated for the identification of the cultivar ‘ royal ’ as compared to cultivars ‘ emerald ’, ‘ meyer ’, ‘ diamond ’ and ‘ crowne ’ used sixty aflp primer combinations . of which , the primer combinations that provided the greatest separation included p - aga / m - caa , p - aga / m - cca , p - aga / m - cgt and p - aga / m - ctc . the latter primer combination , p - aga / m - cct , allowed amplification of signature bands at 320 , 300 , 300 , 320 and 240 base pair lengths ( fig3 ). these signature bands are useful to identify and differentiate ‘ royal ’ cultivar from other varieties tested . 1 to determine statistical differences among entries , subtract one entry &# 39 ; s mean from another entry &# 39 ; s mean . statistical differences occur when this value is larger than the corresponding lsd value ( p = 0 . 05 ). 1 turf performance index is the number of times an entry was rated in the top statistical group maximum number of observations = 49 . 2 leaf - firing was considered as an above ground symptom expression of the root feeding damage by billbug larvae . plants were ranked on a scale of 1 - 9 , 1 = severe leaf firing , 9 = no leaf firing . the % damage = [( check − treatment ) / check ] × 100 . 3 % reduction for cultivar = [( amount in check ) − ( amount in treatment ) / check ] × 100 . 4 means in a column not followed by the same letter are significantly different by lsd test ( p & lt ; 0 . 05 ). as one of ordinary skill in the art will readily appreciate from the disclosure of the present composition of matter may be utilized according to the present invention . accordingly , the appended claim is intended to include within its scope such compositions . braman , s . k ., a . f . pendley , r . n . carrow and m . c . engelke . 1994 . potential resistance in zoysiagrasses to the tawny mole crickets ( orthoptera : gryllotalpidae ) fl entomol . 77 ( 3 ): 301 - 305 . carrow , r . n . 1991 . zoysiagrass performance , water use , and rooting as affected by traffic and nitrogen . usga annu . rep ., univ . of ga ., griffin , ga . 5p . 1 table . carrow , r . n . 1992 . zoysiagrass performance , water use , and rooting as affected by traffic and nitrogen . usga annu . rep ., univ . of ga , griffin , ga . 18 p . 11 tables . marcum , k . b ., s . j . anderson and m . c . engelke . 1998 . salt gland ion secretion : a salinity tolerance mechanism among five zoysiagrass species . crop . sci . 38 : 806 - 810 . metz , s . p ., p . f . colbaugh and m . c . engelke . 1994a . rhizoctonia blight on inoculated zoysiagrasses . aps bct test data 9 : 158 . morris , k . 1993 . national zoysiagrass test — 1991 , progress report 1992 . nat . turfgrass eval . prog . usda - ars , beltsville , md . ntep no . 93 - 4 : 32 p . morris , k . 1994a . national zoysiagrass test — 1991 , progress report 1993 . nat . turfgrass eval . prog . usda - ars , beltsville , md . ntep no . 94 - 5 : 54 p . morris , k . 1994b . national zoysiagrass test — 1991 , progress report 1994 . nat . turfgrass eval . prog . usda - ars , beltsville , md . ntep no . 95 - 8 : 66 p . morris , k . 1995a . national zoysiagrass test — 1991 , progress report 1995 . nat . turfgrass eval . prog . usda - ars , beltsville , md . ntep no . 96 - 6 : 54 p . morris , k . 1995b . national zoysiagrass test — 1991 , final report 1992 - 95 . nat . turfgrass eval . prog . usda - ars , beltsville , md . ntep no . 96 - 15 : 101 p . munsell color service . 1977 . munsell soil and plant tissue chart . gretagmacbeth , new windsor , n . y . reinert , j . a . and m . c . engelke . 2001 . resistance in zoysiagrass , zoysia spp ., to the tropical sod webworm , herpetogramma phaeopteralis guenee . int . turfgrass soc . res . j . 9 : 798 - 801 . reinert , j . a ., m . c . engelke , j . e . mccoy , d . l . hays , d . genovesi and j . j . heitholt . 2002a . growth characteristics of nine zoysia cultivars . ( unpublished manuscript ). reinert , j . a ., m . c . engelke , j . e . mccoy , d . l . hays and j . j . heitholt . 2002b . resistance in zoysiagrass ( zoysia matrella ) to the hunting billbug ( sphenophorus venatus vestitus ). ( unpublished manuscript ). reinert , j . a ., m . c . engelke , and s . j . morton . 1993 . zoysiagrass resistance to the zoysiagrass mite , eriophyes zoysiae ( acari : eriopyidae ). int . turfgrass soc . res . j . 7 : 349 - 352 . white , r . h ., m . c . engelke , s . j . morton and b . a . ruemmele . 1993 . irrigation water requirement of zoysiagrass . int . turfgrass soc . res . j . 7 : 587 - 593 . yamamoto , i . and m . c . engelke . 1996 . 1996 update of zoysiagrass performance under 90 % shade conditions . tx turfgrass res .- 1996 . consolidated prog . rep . turf - 96 - 11 : 65 - 72 . | US-19360702-V |
the intervertebral disc is avascular . with aging , calcified layers occlude the cartilaginous endplates , blocking the diffusion of nutrients and oxygen into the avascular disc . under anaerobic condition , excessive production of lactic acid irritates nerves and further hinders transport of sodium sulfate essential for biosynthesis of the water retaining and load sustaining sulfated glycosaminoglycans . as the result of acid irritation and load shifting to facet joints , pain ensues . through the pedicle , calcified endplate is punctured by a well - supported and elastically curved needle , injecting antacid to neutralize the lactic acid and enhance transport of sodium sulfate into the shielded discs between ilia . disc filler or nutrients can also be injected through the curved needle into the degenerated disc . | fig5 shows rigid needle 220 with a syringe 276 puncturing or entering the pedicle 278 adjacent to a degenerated disc 100 . pedicle puncturing may require the guidance of fluoroscopy , ultrasound , mri or other . in addition , trocar puncturing and / or pedicle drilling is preferred prior to rigid needle 220 puncturing . radiopaque or echogenic coating on the rigid needle 220 and curved needle 101 enhances visual detection and ascertains device position within the vertebral body 159 during endplate 105 puncturing . fig6 shows insertion of the rigid needle 220 and elastically curved needle 101 into the pedicle 278 and partially into the vertebral body 159 . the distal end of the rigid needle 220 is used to support the convex side of the deployed elastically curved needle 101 during calcified endplate 105 puncturing into the disc 100 , as shown in fig7 . fig8 shows a top view of the endplate 105 punctured by the supported elastically curved needle 101 . buffering agent 288 or filler 289 from syringe 276 is injected into the disc 100 through the elastically curved needle 100 , as shown in fig9 . the curved needle 101 is then retrieved and resiliently straightened within the rigid needle 220 , as shown in fig1 . the assembly of rigid needle 220 , curved needle 101 and syringe 276 can be rotated 180 ° to puncture the inferior endplate 105 and inject buffering agent 288 or filler 289 into the inferior degenerated disc 100 . multiple factors prevent successful endplate puncture . for pedicle 278 entry and disc injection , the minimum length of the elastically curved needle 101 within the rigid needle 220 is about 10 cm , the proper length is about 15 cm . since the curved needle 101 is elastic , it is likely to twist within the rigid needle 220 , allowing directional shift at the tip of the needle 101 during contact with the calcified endplate 105 . a lengthy curved needle 101 intensifies the twisting problem . the tip of the needle 101 is deflected by the endplate 105 and fails to puncture through the endplate 105 , as shown in fig1 . a cross - sectional view of the curved needle 101 twisting within the rigid needle 220 is depicted in fig1 . to prevent twisting between the curved needle 101 and rigid needle / sleeve 220 , the cross sections of both needles are made non - round . fig1 shows elliptical cross - sections in both curved needle 101 and sleeve 220 . an elliptical cross - sectional view of the curved needle 101 within the rigid needle 220 is depicted in fig1 to ensure success of endplate 105 puncture . prior art , de 44 40 346 a1 by andres melzer filed on nov . 14 , 1994 and fr 2 586 183 - a1 by olivier troisier filed on aug . 19 , 1985 , is not designed for puncturing hard surfaces , such as the calcified endplate 105 . in prior art , distal tips of the rigid needles 220 are at the concave sides of their unsupported elastically curved needles 101 , as shown in fig1 . during calcified endplate 105 puncture using the prior art , bending or drooping of the unsupported curved needle 101 is likely , resulting in failure to puncture the endplate 105 . in this invention , the sharpened tip of the rigid needle 220 beneath the convex side of the curved needle 101 provides support to reduce bending or drooping during endplate 105 puncturing , as shown in fig1 . to further support the curved needle 101 for injection into the degenerated disc 100 , an extended distal end of the rigid needle 220 lengthens the support beneath the convex side of the curved needle 101 during endplate 105 puncturing , as depicted in fig1 . a window 270 near the distal end of a rigid sleeve 220 with an elliptical cross - section is shown in fig1 . the distal portion of the window 270 is slanted or sloped , conforming to the outer wall of the curved needle 101 . fig1 shows the sharp tip of the elastically curved needle 101 located on the concave side of the curvature to avoid scraping or snagging on the distal portion of the window 270 during deployment of needle 101 . the window 270 with the distal slanted configuration is made to saddle and secure the elastically curved needle 101 from deflecting during endplate 105 puncturing , as shown in fig2 . fig2 shows a rigid needle 220 with securing or supporting window 270 for the elastically curved needle 101 . as back pain patients age , calcified endplates 105 harden further . additional shape memory devices may be essential to support puncturing of the hardened calcified endplate 105 for injection into the degenerated disc 100 . fig2 depicts the elastically curved needle 101 housed within a curved shape memory extension 271 with a curved distal end . fig2 shows resilient straightening of both the shape memory extension 271 and curved needle 101 within the rigid sleeve 220 . fig2 shows support at the convex side of the curved needle 101 by the extension 271 , enabling needle 101 puncture into the calcified endplate 105 . the curvature and inner wall of the curved shape memory extension 271 complement , support and shape - conform to the curvature and outer wall of the curved needle 101 . since the curved shape memory extension 271 supports only the base or convex side of the needle 101 , the size of the punctured hole at the endplate 105 remains small to minimize loss of hydrostatic pressure or content of the disc 100 . fig2 shows a sharpened , tubular shape memory extension 271 for penetrating the cancellous bone within the vertebral body 159 and supporting endplate 105 puncturing . the elastically curved needle 101 can be made with non - uniform outer diameter , thinner at the distal end as shown in fig2 . the thin and sharp distal end of the curved needle 101 is used for puncturing a small opening at the calcified endplate 105 . the thickened body of the curved needle 101 provides strength and support during endplate 105 puncture with crucial support at the base of the curvature near the rigid needle 220 . the lumen 268 of the rigid needle 220 may have a bevel 102 and a double - sided ramp 272 , as shown in fig2 . the bevel 102 at the distal end of the lumen 268 minimizes friction against the concave side of the curved needle 101 during deployment and retrieval . the double - sided ramp 272 is protruded at the side opposite to the bevel 102 with the distal side in continuation with the sharp tip or extended end of the rigid needle 220 . the proximal side of the ramp 272 or protrusion can be shaped to conform to and support the convex side of the curved needle 101 during endplate 105 puncturing . the ramp 272 can be made with epoxy , solder or other hardened material , then shaped by machining . the ramp 272 can also be created during a molten process to seal the lumen 268 at the distal end . the sealed end is then cut , the ramp 272 and bevel 102 are shaped , and the lumen 268 is re - opened by machining . after injecting buffering agent 288 or disc filler 289 from the syringe 276 into the degenerated disc 100 , leakage into the vertebral body 159 is likely following needle 101 withdrawal . a shape conforming endplate plug 292 is positioned to slide over the curved needle 101 , abutting a shape memory extension 271 , as shown in fig2 . the plug 292 has a tapered outer wall , thin at the distal end and thick at the proximal end for sealing . after injection of buffering agent 288 or filler 289 , the shape memory extension 271 is advanced to push the plug 292 into the puncture hole at the endplate 105 , as shown in fig2 . while the curved needle 101 is slightly withdrawn from the endplate 105 , the shape memory extension 271 is further advanced , pushing the plug 292 further into the endplate 105 and collapsing the inner lumen 374 of the soft or shape conforming plug 292 , as shown in fig2 , to seal the buffering agent 288 or filler 289 within the degenerated disc 100 . the plug 292 can be made with biocompatible material , such as collagen , hyaluronate , alginate , polyethylene glycol , polyurethane , silicon or other . the plug 292 can also swell from hydration to occlude the puncture hole at the endplate 105 and seal the lumen 374 of the plug 292 . studies indicated that lumbar pain correlates well with high lactate levels and low ph . antacid , buffering agent or base 288 can be injected from the syringe 276 through the curved needle 101 to neutralize the lactic acid within the degenerative disc 100 , minimize acid irritation and alleviate back pain , as depicted in fig9 . the antacid , buffering agent or base 288 can be aluminum carbonate , aluminum hydroxide , aluminum oxide , aluminum phosphate , calcium carbonate , calcium hydroxide , calcium phosphate , hydrotalcite , magnesium carbonate , magnesium glycinate , magnesium hydroxide , magnesium oxide , magnesium trisilicate , sodium bicarbonate , sodium carbonate , sodium phosphate or other . sulfate is an essential ingredient for biosynthesizing the sulfated glycosaminoglycans , responsible for retaining water within the intervertebral disc 100 . transport of sulfate into the disc 100 is hindered by the acidic ph . after injection of antacid 288 , the normalized ph enhances transport of sodium sulfate into the disc 100 to promote biosynthesis of sulfated glycosaminoglycans necessary for retaining additional water , capable of sustaining compressive loads upon the disc 100 . as a result , excessive loading and strain on the facet joints 129 are minimized and pain is alleviated . in addition , collagen within the annulus 378 of the disc 100 is sensitive to acid hydrolysis . acidic ph accelerates decomposition and hydrolysis of the degenerating disc 100 . injection of antacid 288 normalizes ph to preserve peptide bonds in collagen and proteoglycans in disc 100 . back pain from spinal instability initiated by disc 100 degeneration is very common . similar to repairing and re - inflating a flat tire of a car , filling and fortifying the degenerated disc 100 minimize instability , lift compressive loads from the facet joints 129 and alleviate back pain . through minimally invasive punctures using a rigid needle 220 through the pedicle 278 and curved needle 101 through the calcified endplate 105 , disc filler 289 is infused from the syringe 276 to fortify and support the degenerated disc 100 . methacrylic acid or methyl - methacrylic acid , with molecular structure shown in fig3 , is a monomer , which can be polymerized into bone cement , poly - methyl - methacrylate ( pmma ) as shown in fig3 . methacrylic acid , methyl - methacrylic acid can be used as disc fillers 289 to repair , inflate and stabilize degenerated disc 100 with the polymerized pmma . polymerization of methyl - methacrylic acids into pmma is promoted by a base or radical generator . two syringes 276 connect to the proximal end of a static mixer 375 , the distal end of the mixer 375 connects to the elastically curved needle 101 , as shown in fig5 . methyl - methacrylic acid as a filler 289 is filled in one syringe 276 , while the base or radical generator is filled as the second filler 376 in another syringe 276 . the filler 289 and second filler 376 are injected simultaneously into the static mixer 375 , infusing the polymerizing methyl - methacrylic acids into the degenerated disc 100 . as a result , the viscosity of both fillers 289 and 376 increases , preventing leakage through herniated disc 100 or the endplate 105 punctured hole . polyethylene glycol ( peg ) in fig3 can be a biocompatible filler 289 , capable of retaining water as the sulfated glycosaminoglycans in the nucleus pulposus 128 . methoxy peg in fig3 , methoxy peg amine in fig3 , di - amine peg in fig3 , methoxy sulfhydro peg in fig3 , and di - sulfhydro peg in fig3 can be used as fillers 289 and crosslinking derivatives of peg . the peg can also be activated for crosslinking reactions with n - hydroxysuccinimide , maleimide , thioester , acrylate and vinyl sulfone with molecular structure of methoxy - peg - n - hydroxysuccinimide in fig3 , peg - propionate - n - hydroxysuccinimide in fig3 , peg - butanoate - n - hydroxysuccinimide in fig4 , peg - succinimidyl - n - hydroxysuccinimide in fig4 , methoxy - peg - maleimide in fig4 , peg - thioester in fig4 , maleimide - peg - n - hydroxysuccinimide in fig4 , maleimide - peg - maleimide in fig4 , methoxy - peg - di - maleimide in fig4 , acrylate - peg - n - hydroxysuccinimide in fig4 and vinyl sulfone - peg - n - hydroxysuccinimide in fig4 . di - n - hydroxysuccinimide - peg as a filler 289 is loaded in a syringe 276 , and di - sulfhydro - peg as the second filler 376 in ph 5 . 5 - 8 . 0 solution is loaded in another syringe 276 . both fillers 289 and 376 are mixed within the static mixer 375 and injected through the curved needle 101 into the degenerated disc 100 . the chemical reaction is shown in fig4 . the rate of crosslinking reaction is ph sensitive , where high ph promotes rapid crosslinking to prevent leakage from herniated disc 100 or the punctured hole at the endplate 105 . as a result , the spinal segment is stabilized and the heavy load on facet joint 129 is partially lifted to alleviate back pain . similarly , maleimide - peg - n - hydroxysuccinimide can be a filler 289 in a syringe 276 , while di - sulfhydro - peg can be the second filler 376 for mixing into a polymerizing peg to fortify the degenerated disc 100 from within , through the minimally invasive needle puncturing procedure . the chemical reaction is shown in fig5 . di - maleimide - peg and di - sulfhydro - peg can be another filler 289 and the second filler 376 with chemical reaction shown in fig5 . di - sulfhydro - peg is usually more biocompatible than di - amine - peg . however , the disc 100 is avascular with little immuno exposure . as a disc filler 289 or 376 , the di - sulfhydro - peg can probably be interchangeable with di - amine - peg . the chemical reaction of di - thioester - peg with di - amine - peg and di - sulfhydro - peg is shown in fig5 . vinyl - sulfone - peg as one of the function groups can be used to crosslink with di - amine - peg as shown in fig5 to form peg polymeric filler 289 within the degenerated disc 100 to stabilize the painful segmental instability . other filler 289 , such as polyurethane , collagen , hyaluronate , silanolate or calcium / barium crosslinked alginate , can also be used . since nutrient permeability through the calcified endplate 105 diminishes with age , injection of nutrients 288 can significantly increase biosynthesis of chondroitin sulfate and keratan sulfate to retain additional water and regain swelling pressure of the degenerative disc 100 . unlike the traditional needle used in prior art ( klein r g , eek b c , o &# 39 ; neill c w , elin c ., mooney v ., derby rr : biochemical injection treatment for discogenic low back pain : a pilot study , spine j ., may - june 3 ( 3 ), 220 - 226 , 2003 ), the elastically curved needle 101 can inject nutrients into the centers of l4 - 5 , l5 - s1 problematic discs even though they are shielded between the ilia . nutrients in the syringe 276 through the curved needle 101 can be chondroitin sulfate , keratan sulfate , glucose , glucuronate , galactose , glucosamine , n - acetyl - 6 - sulfate - d - galactosamine , n - acetyl - 6 - sulfate - d - glucosamine , proline , glycine , amino acids , thiamine , riboflavin , niacin , niacinamide , pantothenate , pyridoxine , cyanocobalamin , biotin , folate , ascorbate , alpha - tocopheryl , magnesium , selenium , copper , manganese , chromium , molybdenum , vanadium , zinc , silicon , silicone , silicic acid , silanolate , silane , boron , boric acid , sodium sulfate or other . by injecting nutrients , production of sulfated glycosaminoglycans may significantly increase to restore swelling pressure . restoration of swelling pressure within the nucleus pulposus 128 reinstates the tensile stresses within the collagen fibers of the annulus 378 , thus reducing the inner bulging and shear stresses between the layers of annulus 378 . similar to a re - inflated tire , disc 100 bulging is reduced and nerve impingement is minimized . the load on the facet joints 129 is also reduced to ease pain , the motion segment is stabilized , and disc 100 space narrowing may cease . the progression of spinal stenosis is halted and / or reversed to ease pain . a growth factor can also be injected through the elastically curved needle 101 , puncturing through the calcified endplate 105 into the disc 100 to promote disc regeneration . injection of the growth factor , antacid 288 , filler 289 or nutrients through the pedicle 278 using the well supported elastically curved needle 101 minimizes risks and optimizes success of endplate puncture . the rigid needle 101 can be made with stainless steel or other metal or alloy . the elastically curved needle 101 and shape memory extension 271 can be formed with nickel - titanium alloy . the needle 101 , rigid needle 220 and shape memory extension 271 can be coated with lubricant , tissue sealant , analgesic , antibiotic , radiopaque , magnetic and / or echogenic agents . it is to be understood that the present invention is by no means limited to the particular constructions disclosed herein and / or shown in the drawings , but also includes any other modification , changes or equivalents within the scope of the claims . many features have been listed with particular configurations , curvatures , options , and embodiments . any one or more of the features described may be added to or combined with any of the other embodiments or other standard devices to create alternate combinations and embodiments . the elastically curved needle 101 can be called the elastic needle 101 or the resilient needle 101 . some figures show the rigid needle 220 being blunt as a rigid tube 220 . the rigid needle 220 or needle 101 can be generally described in the claims as a sheath with a lumen . injection of the antacid 288 can also be done with a straight or traditional needle , especially for l3 - 4 level and above . the vertebral body 159 can be called a vertebra . it should be clear to one skilled in the art that the current embodiments , materials , constructions , methods , tissues or incision sites are not the only uses for which the invention may be used . different materials , constructions , methods , coating or designs for the injection device can be substituted and used . nothing in the preceding description should be taken to limit the scope of the present invention . the full scope of the invention is to be determined by the appended claims . | US-41844606-A |
this invention relates to an improvement in the method of treating hair in which water wet hair is wrapped around rollers , a mercaptan - containing solution is applied to the hair on the rollers , and the mercaptan - wetted hair is thereafter neutralized with an oxidizing agent . this improvement comprises wetting the hair prior to wrapping it with an aqueous solution of a prewrap agent selected from the group consisting of alkali metal and ammonium sulfites and alkali metal and ammonium bisulfites . these prewrap agents are present at about 0 . 1 to about 1 . 0 molar , at a ph of about 6 . 5 to about 7 . 5 and cleave no more than about 5 percent of the hair disulfide bonds before the mercaptan - containing solution is applied . | we have found that aqueous solutions containing prewrap agents such as sulfite and bisulfite salts are particularly mild to the user &# 39 ; s hands when used in place of waving lotion in a prewrap solution , and that such solutions provide waved hair having a tighter curl than if water alone is used as a prewrap solution . the sulfite and bisulfite salts which are preferred as prewrap agents in our invention are the alkali metal and ammonium salts . these include sodium sulfite heptahydrate , potassium sulfite dihydrate , ammonium sulfite monohydrate and the like as well as sodium , potassium and ammonium bisulfites and the like . ammonium bisulfite is particularly preferred . the concentrations of these preferred prewrap agents in the aqueous prewrap solution can range from about 0 . 1 molar to about 1 . 0 molar . the preferred range is about 0 . 2 molar to about 0 . 3 molar . at a given ph , the amount of disulfide bond cleavage is dependent at least upon the concentration of sulfite or bisulfite prewrap agents , the duration of contact of these prewrap agents with the hair and the temperature at which these reagents are used to treat the hair . high concentrations , long contact times and elevated temperatures are factors which promote increased disulfide bond cleavage . therefore , these factors may be altered or played against each other to produce a desired amount of disulfide bond rupture . in practicing the method of our invention , the preferred concentration of sulfite or bisulfite , placed on the hair without external heating , allows the user a leisurely pace for applying the waving lotion so that the lotion is applied before too many disulfide bonds are broken by the prewrap agents . although sulfite and bisulfite salts are known in the art for use in waving hair , the methods of such use as taught in the art and as practiced herein are different . in waving , at least about 15 percent , and preferably about 20 to about 30 percent of the disulfide bonds are broken by the waving lotion , using virgin , european hair as the standard . as practiced in our prewrap method , no more than about 5 percent of the disulfide bonds in virgin , european hair are broken by the sulfite or bisulfite salts of the prewrap solution . while these salts may be used to practice our invention at a concentration of about 1 molar , as is frequently practiced in the waving art , the user must work quickly at such concentrations to avoid breaking too many disulfide bonds to thereby avoid forming too many bunte salt groups [ protein -- sso 3 --] which remain in the hair after waving . problems associated with excessive residual bunte salt groups are discussed hereinbelow . by using the preferred concentration of about 0 . 2 molar to about 0 . 3 molar , the user need not rush as such concentrations will not cleave the minimal 15 percent disulfide bonds needed for waving within normal working times . another difference between the bisulfite waving art and that of our invention is that the sulfhydryl groups ( protein -- sh ) and the bunte salt groups [ protein -- sso 3 --] formed in either method by the action of bisulfite or sulfite ions with the disulfide bonds of the hair protein are reformed into disulfide bonds in the conventional waving processes with the aid of a fixing step carried out at a ph of about 8 to about 10 , while in our invention , no such fixing step is used and the hair protein disulfide bonds are reformed by the oxidizing neutralizer which is used in conjunction with the mercaptan - containing waving lotion . if sufficient amounts of bunte salt groups are present to allow waving to occur , i . e ., greater than about 15 percent , oxidative neutralization as practiced herein leaves the hair harsh to the touch , brittle when dry and spongy when wet . however , as practiced by our method , fewer than about 5 percent bunte salt groups are formed prior to application of the waving lotions , and , there is little tendency toward harsh feeling , brittle hair after oxidative neutralization . u . s . pat . no . 3 , 644 , 084 to hsiung and wolfram discloses a method for reforming hair disulfide bonds broken by sulfitolysis . in their method , the hair disulfide bonds are cleaved by use of a sulfite type reagent and the bonds are reformed by a sulfur - containing reagent ( including a mercaptan ) present at about 0 . 02 to 0 . 3 molar . in our method , only a small amount of the disulfide bonds ( less than about 5 percent ) are cleaved by sulfite reagents , while the great majority of bonds are broken by the mercaptan - containing reagent present , as in commercial waving lotion , at about 0 . 5 to about 2 . 5 molar . the hsiung and wolfram method includes a step , not found in our method , in which sulfite reagent is rinsed from the hair prior to application of the sulfur - containing reagent . essentially , the hsiung and wolfram method starts with a strong sulfite treatment ( to cleave more than 15 percent of the disulfide bonds ) and follows it with a weak mercaptan treatment ( to reform the already cleaved disulfide bonds ). in contrast , the instant invention starts with a weak sulfite treatment ( to cleave fewer than about 5 percent of the disulfide bonds ) and follows it with a strong mercaptan treatment ( to cleave the remaining bonds necessary to provide a good wave ). the hsiung and wolfram patent also discloses an analytical method for determining the amounts of bunte salt groups and protein -- sh groups in the hair as well as the residual amounts of these groups after reformation of the disulfide bonds . the first step of this analytical method is hereby incorporated by reference for determining the amount of disulfide bond cleavage caused by the prewrap solution of our invention . the ratio of disulfide bond cleavage to total disulfide present , as found by the mnp method , times 100 percent yields the percent disulfide bond rupture as discussed herein . additionally , in bisulfite waving , the usual practice is to treat the hair , wound on rods or rollers , with waving lotion , cover the hair with a plastic turban for 10 to 20 minutes , rinse , treat the hair with fixing lotion , followed by another rinse and then the neutralization step . in our method , the moistened hair is simply treated with our prewrap formulation to achieve limited disulfide cleavage , wound on rollers and then treated with a mercaptan containing waving lotion . the preferred ph of the prewrap solutions of our invention is about 6 . 5 to about 7 . 5 . more preferred is a ph of about 6 . 9 to about 7 . 0 . this preferred ph range is also the ph range at which many commercial waving lotions , including the acid waving lotions are supplied and thus , there is little if any problem of ph incompatibility between the prewrap solution and the waving lotion . the prewrap solutions of our invention also have a minimal buffering capacity so that if a buffered waving lotion of a higher ph is used , the ph of the prewrap solution does not greatly affect that of the waving lotion . because of the bisulfite - sulfite equilibrium , the bisulfite ion predominates in solution at ph values less than about 7 . 2 . to use the prewrap solutions of our invention , the hair to be waved is usually first dampened . this usual dampening is often the result of a prior shampoo treatment although such a shampooing is not necessary to practice this invention . after such a dampening or shampoo treatment , the hair is preferably towelled dry so that it is not dripping wet . an aqueous prewrap solution of this invention is then applied to the hair . the prewrap solution treated hair is then wrapped upon rollers of the desired diameter , and the hair treated with the mercaptan - containing waving lotion and oxidizing neutralizer as is the usual practice in the art . upon drying , the curls obtained are tighter than those obtained when water alone is used as a prewrap liquid . the prewrap solutions used in the practice of this invention are usually formulated to contain emulsifiers , conditioners , swelling agents , preservatives , perfumes , coloring agents and the like . these added materials enhance the effect and appearance of the product and treated hair , but are not necessary for the practice of our invention . the present invention is illustrated by , but not limited to the following examples . a specific ammonium bisulfite containing prewrap lotion was prepared as follows : ______________________________________formulacomponents percent by weight______________________________________ ( 1 ) deionized water 90 . 00 ( 2 ) ammonium bisulfite ( 60 %) 5 . 40 ( 3 ) ammonium sulfate 0 . 50 ( 4 ) ascorbic acid 0 . 10 ( 5 ) ammonium hydroxide to ph 6 . 5 - 6 . 8 approx . 1 . 25 ( 6 ) ceraphyl 65 . sup . 1 0 . 20 ( 7 ) tween 20 . sup . 2 0 . 40 ( 8 ) fragrance 0 . 05 ( 9 ) coloring solutions 0 . 025 ( 10 ) nh . sub . 4 oh to ph 6 . 9 - 7 . 0 --( 11 ) deionized water balance 100 . 00______________________________________ . sup . 1 an amide formed from mink oil fatty acid and 1amino - propyl - 3 , 3 - dimethyl - 3 - hydroxyethylammonium chloride . . sup . 2 polyoxyethylene sorbitan monolaurate . components 3 and 4 were dissolved in component 1 . component 5 was added followed by component 2 . components 6 , 7 and 8 were premixed and added to the above mixture with agitation . the final components , 10 and 11 were added and the entire mixture agitated to ensure homogeneity . glyceryl monothioglycolate is an item of commerce which typically contains about 80 percent by weight glyceryl monothioglycolate , about 1 percent to about 6 percent by weight free thioglycolic acid , with the remainder of the material being free glycerol . portion a is packaged separately from portions b and c . ______________________________________formulacomponents weight percent______________________________________ ( 1 ) deionized water 96 . 05 ( 2 ) borax 1 . 00 ( 3 ) dantoin mdmh . sup . 1 0 . 10 ( 4 ) igepal co 730 . sup . 2 0 . 75 ( 5 ) fragrance 0 . 10 ( 6 ) ammonium hydroxide 28 % app . 2 . 00 100 . 00 solution ph is 9 . 9 - 10 . 1______________________________________ . sup . 1 monomethylol dimethylhydantoin . . sup . 2 nonylphenol condensed with ethylene oxide to about 73 % of the phenol &# 39 ; s weight . components 1 - 5 may all be added together and mixed , component 6 is added last and then mixed in thoroughly . about 29 . 4 gm of portion a are mixed with about 78 . 0 gm of portion b to yield a buffered , acid waving formulation whose ph is about 6 . 9 . ______________________________________formulacomponents weight percent______________________________________1 ) deionized water 92 . 2522 ) fatty acid quaternary ammonium complex . sup . 1 1 . 5003 ) hydrogen peroxide ( 35 % aqueous ) 6 . 2304 ) silicone antifoam agent 0 . 0105 ) phosphoric acid to ph 3 . 5 app . 0 . 008 100 . 000______________________________________ . sup . 1 the fatty acid quaternary ammonium complex is a conditioning agent which serves to improve the combability of the finished waves . components 1 - 4 may all be added together and mixed with component 5 added last and then mixed in thoroughly . models &# 39 ; heads were shampooed and rinsed in a usual fashion and then towelled so that while they were wet , they were not dripping wet . one side of their heads was then wrapped ( while the hair was wet ) on standard waving rollers . the other side of the models &# 39 ; heads was treated with the prewrap formulation of example 1 by pouring the formulation onto the hair , working it into the hair and then wrapping sections of the treated hair onto rollers identical to those used on the water - only treated sides . portions a and b of example 2 were mixed as discussed in example 2 and applied to the rolled hair on both sides of the heads as soon as the wrapping operation was completed ( within about 15 - 45 minutes , depending on the speed of the operator and the hair of the model ). after a suitable time , up to about 30 minutes , depending upon the models &# 39 ; hair type and desired curl tightness , the prewrap solution and waving lotion were rinsed from the hair . portion c of example 2 was added to the rolled hair on both sides of the heads . the neutralizer was then rinsed from the hair , and the hair dried . evaluations for curl tightness for each half - head showed that those half - heads treated with the prewrap formulations of this invention had tighter curls than those treated with water alone . while the invention has been described with respect to its preferred embodiments , it will be understood by those skilled in the art that modifications and variations may be made without departing from the invention as defined in the appended claims . | US-92932678-A |
a poultry watering device for use with a conduit system in a confinement house having at least a portion thereof associated with the actuation of the device by birds marked by a photo - luminescent material such that the birds can drink therefrom in darkness or low light conditions . | referring to fig1 to 6 , it will be appreciated that the invention is intended for use in commercial poultry houses 10 in which a watering system provides water to thousands of birds . typically the house 10 has an external source of water , not shown and a network of conduits 11 supplying water under low pressure throughout the house 10 . the conduits 11 will have a number of drop pipes 12 or extensions which terminate in valved drinking units 13 . such units are shown in u . s . pat . nos . 4 , 185 , 590 ; 4 , 770 , 126 ; 5 , 293 , 836 ; and others . as noted in various instances in the cited patents poultry quickly learn to drink from these valved drinking units by actuating the valve with their beak . however , even though there are thousands of such drinking units in a confinement house , the majority of the poultry confined therein do not drink in darkness . the present invention provides the drinking unit with a photo - luminescent marker which is visible to the poultry in low light or dark conditions . observation in confinement houses in which prototypes of the markers were installed show that poultry generally settled down to roost when the lights go out , but also rise to drink from the marked drinking units even in darkness , then return to the roosting position . accordingly , as shown in fig2 to 6 the drinking units 13 typically include body unit 40 , valve actuating member 50 , metering pin 70 and an internal valve chamber 80 . drinking units 13 are attached to conduit system 11 as described in the prior art . it known to make housing 40 out of abs plastic . housing 40 has a frusto - conical bore 44 located at one end , which provides the outlet for water as is well known . actuating member 50 includes a generally cylindrical pin 52 with an actuator head , not shown , disposed at one end thereof within the housing 40 . as described in u . s . pat . no . 5 , 293 , 836 a drinking disc 60 may be disposed on actuating member 52 in a nipple type drinker as shown in fig2 and may be made from plastic , metal or any suitable material . photo - luminescent pigments are available which are non toxic , water proof , non - radioactive and which can be blended with plastics or ceramics , mixed in paint , and applied to films or tapes . these pigments are activated by exposure to light from incandescent bulbs , fluorescent lighting , sunlight or uv light depending on the type pigment selected and will remain luminescent for up to several hours in darkness . accordingly in fig4 , the plastic body or housing 40 is made with photo - luminescent pigments in the plastic such that the housing 40 glows in the dark . alternatively , for disk watering stations , the disk 60 may be made completely or partially from plastic or ceramic which is impregnated with photo - luminescent pigment such that the poultry can see the disc directly as in fig5 . in drinking units without discs , trigger pin 52 may be painted with luminescent paint which is waterproof and durable as in fig3 . likewise all or part of a metal watering disc 60 may be painted with photo - luminescent paint . although photo - luminescent tape is available and is considered within the scope of the claims for use in each instance in which the component is made from or painted with photo - luminescent material , the durability of such tape in this application has not been evaluated . also encompassed within the scope of the invention is a retrofit adapter 65 made from photo - luminescent material that can be attached to the drinking unit such as depicted in fig6 . the physical construction of such units will be dependant upon the type watering units are in place . flexible tabs may be provided to support a marker , or the marker may comprise a sleeve or snap on rim made from plastic or other suitable photo - luminescent material . other type drinkers which are amenable to use with the present invention . as with fig3 - 5 , selected components may be made from photo - luminescent material or may be painted or coated with such material in a manner that will allow the poultry to see the drinker mechanism in the dark and allow the poultry to actuate the drinker and return to roosting . it is to be understood that the form of the invention shown is a preferred embodiment thereof and that various changes and modifications may be made therein without departing from the spirit of the invention or scope as defined in the following claims . | US-88684904-A |
segmented articulatabte stent of open structure comprised of end - connected struts of first and second lengths making up first and second segments with angular interconnects between adjacent first and second segments . | while this invention may be embodied in many different forms , there are described in detail herein specific preferred embodiments of the invention . this description is an exemplification of the principles of the invention and is not intended to limit the invention to the particular embodiments illustrated . for the sake of consistency , the terms ‘ peak ’ and ‘ trough ’ shall be defined with respect to the proximal and distal ends of the stent . each of the stents has a proximal end 91 and a distal end 93 and a longitudinal axis 95 , as seen in fig1 a . peaks 36 are generally concave relative to the proximal end of the stent and generally convex relative to the distal end of the stent . troughs 40 , on the other hand , are generally convex relative to the proximal end of the stent and generally concave relative to the distal end of the stent . notwithstanding this definition , the term peak is also intended to extend to regions 48 that are generally peak - like which may , nevertheless , contain trough - like regions within the peak - like region as seen in fig1 b . similarly the term trough is also intended to extend to regions 52 that are generally trough - like which may , nevertheless , contain peak - like regions within the trough - like region as seen in fig1 b . corresponding to each peak 36 is an inner diameter peak 38 where the inner diameter of the band - like element reaches its peak . the set of points on a given band - like element which are distal to inner diameter peak 38 is denoted peak region 48 . similarly , corresponding to each trough 40 is an inner diameter trough 42 where the inner diameter of the band - like element reaches its trough . the set of points on a given band - like element which are proximal to inner diameter trough 42 is denoted trough region 52 . for the sake of clarity , unless otherwise indicated , analogous portions of stents will be similarly labeled , using three digit reference numerals to distinguish among the various embodiments shown . also included within this definition of peak regions and trough regions are peak regions which are comprised of multiple peaks as well as trough regions which are comprised of multiple troughs such as those shown schematically in fig1 b . peak 36 is seen to consist of two sub - peaks 36 a , b and trough 40 is similarly seen to consist of two sub - troughs 40 a , b . in the case of peaks containing sub - peak and troughs containing sub - troughs , the peak region 48 includes all of the points along the band - like element between the sub - peaks that make up the peak and similarly , the trough region 52 includes all of the points along the hand - like element between the sub - troughs that make up the trough . the inventive stents may incorporate one or more bands of a chosen wavelength . in some embodiments , the inventive stents include one or more small amplitude , short wavelength bands to provide for flexibility and one or more large amplitude , long wavelength bands to give side branch access or to provide for sections of alternative strengths such as soft and / or stiff sections . turning to the figures , fig2 shows a flat view of a stent configuration and fig3 shows the stent of fig2 in tubular form . that is , the stent is shown for clarity in fig2 in the flat and may be made from a flat pattern 110 ( fig2 ) which is formed into a tubular shape by rolling the pattern so as to bring edges 112 and 114 together ( fig2 ). the edges may then joined as by welding or the like to provide a cylindrical configuration such as that shown generally at 115 in fig3 . a more preferred method of manufacture begins with a thin walled tube which is then laser cut to provide the desired configuration . it may also be chemically etched or edm &# 39 ; d ( electrical discharge machined ) to form an appropriate configuration . the configuration can be seen in these figures to be made up of one or more spaced first band - like elements 120 . first band - like elements have a generally serpentine configuration to provide continuous waves to the first band - like elements . the waves are characterized by a plurality of peaks 124 and troughs 128 taking a generally longitudinal direction along the cylinder such that the waves in first band - like elements 120 open as the stent is expanded from an unexpanded state having a first diameter to an expanded state having a second diameter . the stent further comprises a plurality of spaced second band - like elements 132 having a generally serpentine configuration to provide continuous waves to the second band - like elements . the waves are characterized by a plurality of peaks 136 and troughs 140 taking a generally longitudinal direction along the cylinder such that the waves in the second band - like elements open as the stent is expanded from an unexpanded state having a first diameter to an expanded state having a second diameter . first and second band - like elements are characterized by respective wavelengths and amplitudes with the wavelength and amplitude of the second band - like elements exceeding the wavelength and amplitude of the first band - like elements . adjacent first band - like elements 120 and second band - like elements 132 are interconnected via a plurality of interconnecting elements 144 . the ends of interconnecting element are circumferentially offset from each other . in an embodiment , as shown in fig2 and 3 , first band - like elements 120 and second band - like elements 132 alternate over the length of the stent . optionally , as shown in fig2 and 3 , each end 152 of the stent may terminate in a first band - like element . the invention also , however , contemplates each end terminating in a second band - like element , or further , one end terminating in a first band - like element and the other end terminating in a second band - like element . while a minimum of one connecting element is required to join adjacent band - like elements , two or more interconnecting elements are preferred . in one embodiment , as shown in fig2 and 3 , adjacent first and second band - like elements 120 and 132 are connected with three interconnecting elements 144 . further , in one embodiment , adjacent interconnecting elements 144 extending from peaks 136 on a first band - like element 120 are spaced five peaks apart on the first band - like element while adjacent interconnecting elements 144 extending from troughs 140 on a second band - like element 132 are spaced three troughs apart on the second band - like element . it is a further feature of the present invention that peaks 124 on first band - like elements 120 are circumferentially displaced on the periphery of the stent from troughs 140 on adjacent second band - like elements 132 . it is desirable that peaks and troughs be displaced in the expanded state of the stent to minimize the possibility of pinching or overlap between adjacent band - like elements . although the stent of fig2 is comprised of two different wavelength band - like elements , the invention contemplates stents with a plurality of different wavelength band - like elements . as such , other stents may have three , four or more different wavelength band - like elements . in another embodiment , the inventive stent is comprised of band - like elements of a single wavelength , interconnected by interconnecting elements . turning to fig4 a and 4 b , band - like elements 220 a , b are interconnected by interconnecting elements 244 a , b . adjacent band - like elements 220 a , b are 180 ° out of phase with one another . in the compressed state , the band - like elements consist of a plurality of peaks 236 a , b and troughs 240 a , b . peak region 248 a , b and trough region 252 a , b have been shaded in one instance for illustrative purposes . in the embodiment shown in fig4 a , each interconnecting element 244 a extends between a peak region 248 a and a trough region 252 a . rectilinear interconnecting elements 244 a consist of a first shank 280 a , a second shank 284 a and a link 288 a disposed in - between the first and second shanks 280 a and 284 a . first shank 280 a extends in a longitudinal direction from peak region 248 a and is substantially perpendicular to link 288 a . second shank 284 a extends in a longitudinal direction from trough region 252 a and is perpendicular to link 288 a . in the embodiment shown in fig4 b , the stent differs from the embodiment of fig4 a in that interconnecting element 244 b extending between a peak region 248 b and a trough region 252 b is curvilinear rather than rectilinear . in both fig4 a and 4 b , the interconnecting elements are seen to emanate from the middle of the peak and trough regions . in another embodiment , as shown in fig5 a , the inventive stent is comprised of band - like elements 320 a of a single wavelength , interconnected by interconnecting elements 344 a . adjacent band - like elements 320 a are 180e out of phase with one another . the band - like elements consist of a plurality of peaks 336 a and troughs 340 a . interconnecting elements 344 a extend between a peak region 348 a and a trough region 352 a . the peak regions 348 a and trough regions 352 a from which interconnecting elements 344 a emanate on a given band - like element 320 a are seen to extend longitudinally beyond adjacent peak regions 348 a ′ and trough regions 352 a ′ from which no interconnecting elements extend . the extension is such that at least a portion of peak regions 348 a overlap longitudinally along the stent with at least a portion of trough region 352 a on an adjacent band - like element 320 a ′. of course , the overlap is limited to the longitudinal direction and not to the circumferential direction . in another embodiment , as shown in fig5 b , interconnecting elements 344 b extend between peak region 348 b and a second closest trough region 352 b on an adjacent band - like element . interconnecting elements 344 b are seen to be perpendicular to the longitudinal axis . as in the stent of fig5 a , peak regions 348 b from which interconnecting elements 344 b extend and trough regions 352 b from which interconnecting elements 344 b extend may extend beyond adjacent peak regions 348 b ′ and trough regions 352 b ′ from which no interconnecting elements 344 b emanates . in another embodiment , as shown in fig6 , adjacent band - like elements 420 are in phase with each other . as in previous figs , band - like elements 420 are of a single wavelength , interconnected by interconnecting elements 444 . the band - like elements consist of a plurality of peaks 436 and troughs 440 . interconnecting elements 444 extend at an oblique angle relative to the longitudinal axis of the stent between a peak region 448 and a trough region 452 . as such , ends of interconnecting elements 444 are circumferentially offset relative to each other . the exact angle will , of course , depend on the region from which the interconnecting elements extend , as well as on whether interconnecting elements interconnect nearest peaks and troughs , next nearest peaks and troughs or peaks and troughs that are further separated . in fig5 a , 5 b and 6 , the interconnecting elements are seen to emanate from the sides of the peak and trough regions . although for the embodiments of fig1 - 6 , the interconnecting elements extend from peak regions on band - like elements to trough regions on adjacent band - like elements , the invention further contemplates interconnecting elements extending from a position between a peak region and an adjacent trough region on a band - like element to a position intermediate a trough region and a peak region on an adjacent second band - like element as in fig7 . in the embodiment of fig7 , interconnecting elements are seen to extend from a region between the peak region and the trough region on a band - like element . the stent is formed of adjacent band - like elements 520 which are 180e degrees out of phase with one another . interconnecting elements 544 extend from a region intermediate a peak region 548 and a trough region 552 on a band - like element to a region intermediate a peak region 548 and a trough region 552 on an adjacent band - like element . interconnecting elements 544 consist of a first shank 560 , a second shank 564 , and an intermediate member 568 disposed in - between first and second shanks 560 and 564 . first shank 560 and second shank 564 are substantially perpendicular to intermediate member 568 which extends in the longitudinal direction . although not depicted , the region from which interconnecting elements 544 emanate may be midway between peaks and troughs . the embodiment of fig7 also differs from the embodiments of fig2 - 6 in the orientation of the interconnecting elements . whereas the interconnecting elements in fig2 - 6 are all similarly oriented , in the embodiment of fig7 , the orientation of interconnecting elements alternates between adjacent pairs of adjacent band - like elements . specifically , second shanks 564 ′ of interconnecting elements 544 ′ are seen to be displaced in a clockwise circumferential direction along the stent relative to first shanks 560 ′, and seconds shank 564 ″ of interconnecting elements 544 ″ are seen to be displaced in a counterclockwise circumferential direction along the stent relative to while first shank 560 ″. this feature is also seen in the embodiment of fig8 in which adjacent in - phase band - like elements 620 are interconnected by interconnecting elements 644 . interconnecting elements 644 extend at an oblique angle relative to the longitudinal axis of the stent between a peak region 648 and a trough region 652 . as in fig7 , the orientation of interconnecting elements alternates between adjacent pairs of adjacent band - like elements . specifically , the distal ends of interconnecting elements 644 ′ are seen to be oriented in a counterclockwise circumferential direction along the stent relative to the proximal end of the interconnecting elements while the distal ends of interconnecting elements 644 ″ are seen to be displaced in a clockwise circumferential direction along the stent relative to the proximal ends . although in the embodiments of fig2 - 8 , adjacent bands are connected by five interconnecting elements , additional or fewer interconnecting elements may be used . further , while interconnecting elements are shown spaced three peaks apart and three troughs apart , other separations are contemplated as well . in the embodiment of fig9 , each band - like element 720 is seen to comprise peaks 736 of more than one amplitude and troughs 740 of more than one amplitude . large amplitude peaks 736 a and small amplitude peaks 736 b alternate as do large amplitude troughs 740 a and small amplitude troughs 740 b . as in the previous embodiments , the interconnecting elements are oriented at an oblique angle relative to the longitudinal axis 795 of the stent . more generally , the invention is directed at stents comprising band - like elements whose amplitude varies along the band - like element . in another embodiment of the invention , as shown in fig1 , each band - like element 820 is seen to comprise peaks 836 of more than one amplitude and troughs 840 of more than one amplitude , however , peaks of the same amplitude are grouped together within a band - like element as are troughs of the same amplitude . it is further noted that in the embodiment of fig1 , the location of a group of peaks of given amplitude in a band - like element varies circumferentially along the length of the stent . interconnecting elements 844 connect peaks 836 and troughs 840 in adjacent band - like elements 820 . where several peaks of different amplitudes are present in a band - like element , the invention further contemplates the possibility of interconnecting elements extending from the large peaks 836 a to large troughs 840 a as in fig9 as well as the possibility of interconnecting elements extending from large peaks to small troughs or from small peaks 836 b to large troughs 840 a as in fig1 . further , the interconnecting elements between any two adjacent band - like elements may be of different lengths from one another as seen in fig1 and commence at different longitudinal positions within a band - like element and terminate at different longitudinal positions within a band - like element . interconnecting element 844 a is seen to be longer than interconnecting element 844 b . as in the previous embodiments , the interconnecting elements are oriented at an oblique angle relative to the longitudinal axis 895 of the stent . in the embodiment of fig1 , interconnecting element 844 a is seen to be oriented at a smaller oblique angle relative to the longitudinal axis of the stent than interconnecting element 844 b . as is apparent from fig1 , the invention is also directed to stents comprised of band - like elements whose wavelength varies along a given band - like element . region 898 and region 899 of band - like element are characterized by different wavelengths . it is also noted that in the embodiment of fig1 , all of the troughs 840 a , b in a given band - like element 820 are aligned longitudinally along the stent and differ only in their circumferential position along the stent . it is further noted in the embodiment of fig1 , the stent comprises a first group of interconnecting elements 844 a and a second group of interconnecting elements 844 b . the interconnecting elements of the first group are all parallel to one another and disposed at a different oblique angle relative to the longitudinal axis than the members of the second group which are all parallel to one another . as such , the invention contemplates stents having several different groups of obliquely disposed interconnecting elements where the oblique angle differs from group to group . in another embodiment of the invention , as shown in fig1 , each band - like element 920 is seen to comprise peaks 936 a , b of different amplitudes and troughs 940 of different amplitudes , however , peaks of the same amplitude are grouped together within a band - like element as are troughs of the same amplitude . it is further noted that in the embodiment of fig1 the location of groups of peaks of given amplitude in a band - like element varies circumferentially along the length of the stent . interconnecting elements 944 connect large amplitude peaks 936 a and small amplitude troughs 940 b in adjacent band - like elements 920 . similarly , interconnecting elements 944 also connect small amplitude peaks 936 b and large amplitude troughs 940 a . the invention also contemplates stents similar to that shown in fig1 in which interconnecting elements extend from large peaks 936 a to large troughs 940 a , as in fig9 . similarly , interconnecting elements may extend from small peaks 936 b to small troughs 940 b . further , the interconnecting elements between any two adjacent band - like elements may be of different lengths from one another and disposed at different oblique angles . as is apparent from fig1 , the invention is also directed to stents comprised of band - like elements whose wavelength varies along a given band - like element . region 998 and region 999 of band - like element 920 are characterized by different wavelengths . it is also noted that in the embodiment of fig1 the large amplitude portions 999 of band - like element 920 are symmetrically disposed about the center 1001 of the band - like element as are the small amplitude portions 998 . the center 1001 of the band - like element is defined as a ring that runs along a path that is midway between the large peaks 936 a and large troughs 940 a of the band - like element . this feature may also be seen in the embodiment of fig9 . the invention is also directed to a tubular , flexible , expandable stent having a longitudinal axis , comprising one or more cylindrical shaped first segments . cylindrical shaped first segments 20 as seen in fig1 , have first struts 23 having first 25 and second 27 ends . first segments 20 are defined by a member formed in an undulating pattern of interconnected paired first struts 23 , in which adjacent pairs of first struts 29 ′ and 29 ″ in a given first segment 20 are interconnected at opposite ends 31 ′ and 31 ″, respectively . adjacent segments are interconnected . the stent may be seen more clearly in fig2 - 8 . as shown , the stent of fig3 , in addition to comprising first segments 120 which are defined by an undulating pattern of interconnected paired first struts 123 in which adjacent pairs of first struts 129 ′ and 129 ″ in a given first segment 120 are interconnected at opposite ends 131 ′ and 131 ″, respectively , the stent further comprises one or more cylindrical shaped second segments 132 , each second segment being defined by a member formed in an undulating pattern of interconnected paired second struts 135 and in which adjacent pairs of second struts 137 ′ and 137 ″ in a given second segment 132 are interconnected at opposite ends 139 ′ and 139 ″, respectively . first struts 123 are shorter than second struts 135 . first segments 120 are formed of a number of first struts 123 and second segments 132 formed of a number of second struts 135 , the number of first struts in a first segment exceeding the number of second struts in a second segment . first and second segments 120 and 132 are aligned on a common longitudinal axis 195 to define a generally tubular stent body , shown generally at 115 . first and second segments 120 and 132 alternate along the stent body . adjacent first and second segments 120 and 132 are connected by a plurality of interconnecting elements 144 . each interconnecting element 144 extends from an end 131 ″ of paired first struts on a first segment 120 to an end 139 ″ of paired second struts on an adjacent second segment 132 . the ends of interconnecting elements 144 are circumferentially offset relative to each other . desirably , upon expansion of stent 115 , paired struts 129 ″ and 137 ″ of adjacent segments 120 and 132 are displaced relative to each other about the periphery of the stent body to accommodate longitudinal flexing of the stent within the segments and without interference between adjacent segments . in the embodiments as shown in fig4 a , b , cylindrical shaped segments 220 a , b are formed of interconnected struts 223 a , b having first 225 and second 227 ends . adjacent pairs of struts 229 a , b ′ and 229 a , b ″ in a given segment 220 a , b are interconnected at opposite ends 231 a , b ′ and 231 a , b ″, respectively . adjacent segments are connected by a plurality of interconnecting elements 244 a , b . each interconnecting element 244 a , b extends from an end of paired struts 231 a , b ″ on a segment to an end of paired struts 231 a , b ′ on an adjacent segment . first end 245 a , b and second end 247 a , b of interconnecting elements 244 a , b are seen to be circumferentially displaced along the stent . similar structure , denoted by similar reference numerals may be found in the stents of fig5 a , b , and 6 - 8 . in particular , in the embodiment as shown in fig8 , cylindrical shaped segments 620 are formed of interconnected struts 623 , having first 625 and second 627 ends . segments 620 are defined by a member formed in an undulating pattern of interconnected paired struts 623 in which adjacent pairs of struts 629 ′ and 629 ″ in a given segment 620 are interconnected at opposite ends 631 ′ and 631 ″, respectively . segments 620 are aligned on a common longitudinal axis 695 to define a generally tubular stent body . adjacent segments are connected by a plurality of interconnecting elements 644 ( and 644 ′) having first 645 ( 645 ′) and second 647 ( 647 ′) ends , each interconnecting element 644 ( 644 ′) extending from an end of paired struts 631 ″ on a segment to an end of paired struts 631 ′ on an adjacent segment . first end 645 ( 645 ′) and second end 647 ( 647 ″) are seen to be circumferentially displaced along the stent . additional embodiment of the stents are shown in fig1 - 15 . fig1 and fig1 show a fragmentary flat view of an unexpanded stent configuration and the actual tubular stent ( unexpanded ), respectively . that is , the stent is shown for clarity in fig1 in the flat and may be made from a flat pattern 1110 ( fig1 ) which is formed into a tubular shape by rolling the pattern so as to bring edges 1112 and 1114 together ( fig1 ). the edges may then joined as by welding or the like to provide a configuration such as that shown in fig1 . the configuration can be seen in these figures to be made up of a plurality of adjacent segments generally indicated at 1116 , each of which is formed in an undulating flexible pattern of substantially parallel struts 1118 . pairs of struts are interconnected at alternating end portions 1119 a and 1119 b . as is seen in fig1 , the interconnecting end portions 1119 b of one segment are positioned opposite interconnecting end portions 1119 a of adjacent segments . the end portions as shown are generally elliptical but may be rounded or square or pointed or the like . any configuration of end portions is acceptable so long as it provides an undulating pattern , as shown . when the flat form 1110 is formed into an unexpanded tube as shown in fig1 , the segments are cylindrical but the end portions 1119 of adjacent segments remain in an opposed position relative to each other . a more preferred method of manufacture begins with a thin walled tube which is then laser cut to provide the desired configuration . it may also be chemically etched or edm &# 39 ; d ( electrical discharge machined ) to form an appropriate configuration . interconnecting elements 1120 extend from one end portion 1119 of one segment 1116 to another end portion 1119 of another adjacent segment 1116 but not to an oppositely positioned end portion 1119 of an adjacent segment 1116 . there are at least three struts included between the points on each side of a segment 1116 at which an interconnecting element 1120 contacts an end portion 1119 . this results in the interconnecting elements 1120 extending in an angular direction between segments around the periphery of the tubular stent . interconnecting elements 1120 are preferably of the same length but may vary from one segment to the other . also , the diagonal direction may reverse from one segment to another extending upwardly in one case and downwardly in another , although all connecting elements between any pair of segments are substantially parallel . fig1 , for example shows them extending downwardly , right to left . upwardly would extend up left to right in this configuration . as a result of this angular extension of the interconnecting elements 1120 between adjacent segments and loops , upon expansion of the stent as seen in fig1 , the closest adjacent end portions 1119 between segments 1116 are displaced from each other and are no longer opposite each other so as to minimize the possibility of binding or overlapping between segments , i . e ., pinching . the number of interconnecting elements 1120 may vary depending on circumstances in any particular instance . three per segment are satisfactory for the configuration shown and at least three will be used typically . the alternate design shown in fig1 includes longer struts 1118 a in the two end segments 1116 a than in the intermediate segments 1116 . this allows the end segments ( 1116 a ) to have less compression resistance than the intermediate segments ( 1116 ), providing a more gradual transition from the native vessel to the support structure of the stent . otherwise , the configuration is the same as that shown in fig1 . as indicated in the figures , the invention contemplates a variation of interconnecting element shapes ranging from rectilinear to curvilinear . the invention further contemplates embodiments in which all interconnecting elements are similarly oriented as well as embodiments in which adjacent sets of interconnecting elements extending between adjacent pairs of segments are oppositely oriented ( e . g ., fig7 and 8 ). the invention also contemplates the use of interconnecting elements which extend from a range of positions along the segments , ranging from various positions in the area in which paired struts are interconnected to other positions along the struts . the invention also contemplates the possibility of interconnecting elements extending at an oblique angle relative to the longitudinal axis of the stent and connecting adjacent peaks and troughs on adjacent segments as well as peaks and troughs on adjacent segments which are separated by one or more peaks and / or troughs . the invention also contemplates reversing the orientation of interconnecting elements as shown in fig7 and 8 . finally , there are preferably at least three interconnecting elements joining adjacent first and second segments although fewer or additional interconnecting elements are also contemplated . it is understood that the peaks and troughs of the present invention need not be rounded , as shown in the figures . the peaks and troughs may be bulbous , triangular , square , pointed , or otherwise formed of interconnected straight sections . as already indicated , this invention is applicable to self - expanding configurations , mechanically expandable configurations and to a wide variety of materials , including both metal and plastic and any other material capable of functioning as an expandable stent . for example , the stent may be of metal wire or ribbon such as tantalum , stainless steel or the like . it may be thin - walled . it may be of shape memory alloy such as nitinol or the like , etc . the interconnecting elements may be formed integrally with the band - like elements ( or segments ) or may be bonded thereto via such methods as adhesive bonding , welding or any other known method of bonding . the above examples and disclosure are intended to be illustrative and not exhaustive . these examples and this description will suggest many variations and alternatives to one of ordinary skill in this art . all these alternatives and variations are intended to be included within the scope of the attached claims . those familiar with the art may recognize other equivalents to the specific embodiments described herein which equivalents are also intended to be encompassed by the claims attached hereto . | US-201313866597-A |
a plant , which affords moment - by - moment control of quantities of individual substances to be simultaneously diffused into the environment to provide , for example , control of insect pests . unused active substances are preserved away from light and air . | the present invention affords many advantages such as practicality of use , complete automation of all operations , as well as the possibility of maintaining any unused active substance under ideal conditions for preserving the specific characteristics thereof , away from light and air . these and further advantages are all attained by a plant which exhibits controlled diffusion of vaporizable active substances , containing a diffuser in the form of ribbon or filament of considerable length , joined at the end thereof to create an endless closed - circuit line positioned within the environment the subject of the diffusion along a predetermined path , the diffuser being slidable along the path and movable by traction mechanisms , and being charged with the active substances directly in the field by a charging apparatus positioned along the path of the diffuser and containing distributors able to transfer small quantities of the active substance to be vaporized onto small portions of defined segments of the movable ribbon or filament used as the diffuser , the segments being dedicated to the diffusion of a single substance and being locatable on the ribbon or filament by suitable sensors for optical or other signs printed on the ribbon or filament in other segments dedicated to this purpose , the movement of the diffuser relative to the distributor within the dedicated segment of the ribbon or filament being measurable by a similar method . the quantity of active substance deposited on the diffuser being then adjustable roughly and occasionally by varying the structure of the distributor , and adjustable finely and continuously by regulating the time involved in distributing the active compound on the diffuser and the speed of advancement of the diffuser , there being controlled both the movement of the diffuser ribbon or filament , and the time of operation of the individual distributors in distributing active substance onto the diffuser , by a microprocessor on the basis of predefined time programs having as variables environmental parameters measured by suitable sensors connected to the microprocessor . further characteristics and advantages will be more apparent from the description of a preferred but not exclusive embodiment of a plant for the controlled diffusion of active substances in defence against insects using the technique of sexual disorientation or confusion . fig1 is a schematic plan view showing a possible path of the diffuser ribbon or filament in apple tree cultivation ; fig2 is a schematic view of a possible structure for the apparatus for charging the diffuser ribbon or filament with active substances ; fig3 illustrates a portion of diffuser ribbon or filament with a possible system for locating , by colour bands , the segments dedicated to diffusion ; this arrangement is suitable for the charging apparatus shown in fig2 . fig4 illustrates , enlarged compared with fig2 a distributor element for active substances in the liquid state , in this case pheromone , of the charging apparatus of fig2 ; fig5 and 7 illustrate three possible structures for the end part of the distributor element which lies in proximity to the diffuser ribbon or filament to be charged , this latter being shown as a ribbon or filament in section ; fig8 illustrates a further possible structure of the charging apparatus with jet operation for distributing three different active substances ; fig9 illustrates on the diffuser a possible arrangement of those segments dedicated to location and two possible quantitative levels of active compound charge on the segments dedicated to diffusion ; this arrangement is suitable for the charging apparatus of fig8 . with reference to fig1 d indicates the diffuser consisting of an endless ribbon or filament , the diffuser being supported and guided along the path defined by rollers r and eyelets p mounted on the poles t supporting the plants indicated by a . along the path , in a position comfortable for normal maintenance , there is situated the active substance charging apparatus y inside which , in this case , there is also provided the drive pulley m for driving the ribbon or filament along the path . the arrows indicate the direction of movement of the diffuser along the oath . it is noted that along the diffuser path , which is particularly suitable for applying the sexual confusion or disorientation technique , the most recently charged and hence most active segments of the diffuser are positioned on the outside , and only subsequently are they brought to the inside , a region in which a lesser concentration of active substance is acceptable . in fig2 . e 1 , e 2 , e 3 , e 4 and e 5 indicate five distributors for five different active substances and controlled by microprocessors , d indicates the diffuser ribbon or filament supported by rollers u and driven by the drive pulley m controlled by microprocessors . l indicates an optical reader able to sense color variations printed on the diffuser ( black bars ) and to continuously feed the processor with information on the position of the diffuser ribbon or filament . fig3 illustrates a possible dedicated segment distribution along a diffuser portion ; z , showing 10 black bars , indicates the segment dedicated to providing information on the position of the next segments ; the 10 bars correspond to 10 positions on each of the next five segments . z 2 , z 3 , z 4 , z 5 and z 6 , which are each dedicated to receiving , transporting and diffusing the corresponding different active substance . in fig4 mo indicates a spring , e indicates an electrical winding within which the iron core b visible through the spring turns is free to move , and c indicates a connection of non - ferrous material between the core and the reservoir for the active substance f . the reservoir contains the active substance f which is able to reach the diffuser ribbon d , shown in section , only by the distributor terminal part n making contact with the diffuser ribbon or filament . in the successive fig5 and 7 , f indicates the active substance , i indicates a capillary transport element for liquids , s indicates a ball and h indicates a tube of capillary dimensions , while d again indicates the diffuser shown in section . in fig8 f 1 , f 2 and f 3 indicate three different active compounds , also highlighted by different symbols , contained in the reservoirs of the jet charging apparatus , and g indicates the jet distributor which deposits the active substances on the diffuser d , l is an optical reader . in fig9 z 11 , z 12 and z 13 indicate the segments dedicated to identifying the next segment 1 , 2 and 3 and 4 , 5 and 6 respectively , these being dedicated exclusively and respectively to diffusion of the active compounds f 1 , f 2 and f 3 . the symbols which differentiate the various liquids in the distributor reservoir shown in fig8 and represented on the six dedicated segments of the diffuser in fig9 . represent two possible quantitative charging levels of the three substances onto the diffuser . with regard to plant operation , the drive pulley m transmits motion to the diffuser , and the distributors deposit defined quantities of active substance on the diffuser in relation to their operating time and the speed of travel of the diffuser ribbon or filament . the movement of the diffuser distributes the segments charged with the active substances along the defined path and hence into the environment concerned in the diffusion . said segments diffuse the vaporizable active compound . depending on requirements and the rate of vaporization o , the active substance , the diffuser can either move continuously and the dedicated segments be continuously charged , or be programmed to effect a complete periodic revolution ( for example daily ), and hence in the period considered each dedicated segment will be charged only once . the quantity of compound ( pheromone ) distributed on the surface can hence be readily varied on the basis of the dedicated segment length charged and of the charging frequency . as interference between the different compounds is possible , the diffuser has been divided into segments dedicated to diffusion , i . e . segments proposed for transporting and diffusing a single active compound during the progress of the diffuser revolutions through the path , and segments dedicated to identifying and recognizing the aforesaid diffuser segments and sensing the movements of the diffuser relative to the active substance distributors . in practice the reader , indicated in the figures by l and which can be optical or magnetic , reads the message on the diffuser ribbon or filament and feeds the data to the processor , which on the basis of the information received locates the segment dedicated to the diffusion of a certain substance and causes the distributor to charge it with the said substance , in the case of fig4 by bringing the distributor into contact with the ribbon by the electromagnet e . the dedicated segment length covered by the substance , which in the final analysis defines the quantity of substance diffused , is determined by the processor program and by environmental variables , and is controlled by the optical or magnetic reader or by electronic angular sensors positioned on drive or driven pulleys inserted into the path of the diffuser . in practice , the materials used and the dimensions and the form of the paths and ribbons or filaments used as diffusers , the arrangement of the diffusers and their number , and the number of active substances diffused can be chosen at will according to requirements . the present invention will now be further described by reference to certain examples which are provided solely for purposes of illustration and are not intended to be limitative . controlling the population of cydia molesta and anarsia lineatella on peach trees a field of peach trees ( red haven and nectaross ) of 8 , 000 sq . m surface was monitored by pheromone traps for cydia molesta and anarsia lineatella . at the first capture of cydia molesta males ( in the first decade of april ) a controlled diffusion plant was installed and started up , composed of 1 , 200 meters of the line laid in a closed loop , above the tree crowns and parallel to the rows . in addition to the borders , the path also covered alternate rows of the lot . the passing time of the line ( silicon - coated dacron ) along the loop was of 3 hours ( 400 m / hour ). the daily activation of the plant was automatically programmed , by anticipating it about 3 hours before sunset . the starting pulley , adjusted so as to distribute a dosage of 0 . 8 cc / day of a 50 % pheromone solution , was equipped with 6 distributing elements over a circumference of 90 cm . ( 1 starting point for every 15 cm length of the line ). at the first capture of the males of anarsia lineatella ( mid - may ) the system was modified to achieve the simultaneous diffusion of both types of pheromones ( cydia m . and anarsia l . ), by substituting half of the distributing elements of the cydia molesta pheromone with an equal number of elements of the anarsia l . pheromone . the operation of the plant was modified by doubling the period of activity , so as to cover both the sunset period ( 3 hours ) and the sunrise period ( 3 hours ). from the time of installing the system up to the time of harvesting the peaches , the capturing of the two phytophages was monitored in the traps installed within the test lot ( peach tree field a ) and in a neighboring peach tree field of similar characteristics , treated with specific insecticides ( peach tree field b ). at the time of harvesting the percentage of damage due to cydia molesta and anarsia lineatella in lot a was compared with that on lot b . the results are reported in table 3 . a field of peach trees ( morsiani 51 ) of 7 , 000 sq . m surface was monitored by pheromone traps for cydia molesta and anarsia lineatella . at the first capture of cydia molesta males ( end of april ) a controlled diffusion plant was installed and started up , composed of 1 , 000 meters of line laid in a closed loop , above the tree crowns and parallel to the rows . in addition to the borders , the path also covered alternate rows of the lot . the passing time of the line ( silicon - coated dacron ) along the loop was of 2 . 5 hours ( 400 m / hour ). the daily activation of the plant was automatically programmed , by anticipating it about 3 hours before sunset . the starting pulley , adjusted so as to distribute a dosage of 0 . 7 cc / day of a 50 % pheromone solution , was equipped with 6 distributing elements over a circumference of 90 cm . ( 1 starting point for every 15 cm length of the line ). at the first capture of the males of anarsia lineatella ( mid - may ) the system was modified to achieve the simultaneous diffusion of both types of pheromones ( cydia m . and anarsia l . ), by substituting half of the distributing elements of the cydia molesta pheromone with an equal number of elements of the anarsia l . pheromone . the operation of the plant was modified by doubling the period of activity , so as to cover both the sunset period ( 3 hours ) and the sunrise period ( 3 hours ). from the time of installing the system up to the time of harvesting the peaches , the capturing of the two phytophages was monitored at regular 7 - day intervals in the traps installed within the test lot ( peach tree field a ) and in a neighboring peach tree field of similar characteristics , treated with specific insecticides ( peach tree field b ). the insecticide treatments applied in peach tree field b are reported in table 4 . at the time of harvesting the percentage of damage due to cydia molesta and anarsia lineatella in lot a was compared with that on lot b . the results are reported in table 6 . a field of pear trees ( guyot ) of 10 , 000 sq . m surface was monitored by pheromone traps for cydia pomonella . at the first capture of cydia molesta males ( mid april ) a controlled diffusion plant was installed and started up , composed of 1 . 500 meters of line laid in a closed loop , above the tree crowns and parallel to the rows . in addition to the borders , the path also covered alternate rows of the lot . the passing time of the line ( 0 . 6 mm nylon ) along the loop was of 3 hours ( 500 m / hour ). the daily activation of the plant was automatically programmed , by anticipating it about 3 hours before sunset . the starting pulley , adjusted so as to distribute a dosage of 0 . 5 cc / day of a 25 % pheromone solution , was equipped with 12 distributing elements over a circumference of 90 cm . ( 1 starting point for every 7 . 5 cm length of the line ). from the time of installing the system up to the time of harvesting the pears . the capturing of the phytophage was monitored at regular 7 - day intervals in the traps installed within the test lot ( pear tree field a ) and in a neighboring pear tree field of similar characteristics , treated with specific insecticides ( pear tree field b ). the insecticide treatments applied in pear tree field b are reported in table 7 . at the time of harvesting the percentage of damage due to cydia pomonella in lot a was compared with that on lot b . the results are reported in table 9 . at the first capture of cydia pomonella males ( mid april ) a controlled diffusion plant was installed and started up , composed of 1 , 200 meters of line laid in a closed loop , above the tree crowns and parallel to the rows . in addition to the borders , the path also covered alternate rows of the lot . the passing time of the line ( 0 . 6 mm diameter nylon ) along the loop was of 3 hours ( 400 m / hour ). the daily activation of the plant was automatically programmed , by anticipating it about 3 hours before sunset . the starting pulley , adjusted so as to distribute a dosage of 0 . 4 cc / day of a 25 % pheromone solution , was equipped with 12 distributing elements over a circumference of 90 cm . ( 1 starting point for every 7 . 5 cm length of the line ). from the time of installing the system up to the time of harvesting the pears , the capturing of the phytophages was monitored at regular 7 - day intervals in the traps installed within the test lot ( pear tree field a ) and in a neighboring pear tree field of similar characteristics , treated with specific insecticides ( pear tree field b ). the insecticide treatments applied in pear tree field b are reported in table 10 . at the time of harvesting the percentage of damage due to cydia pomonella in lot a was compared with that on lot b . the results are reported in table 12 . generally , the present invention may be advantageously used in agriculture , generally , without restriction for crops , such as corn soy or wheat , and for fruits and vegetables . for example , the present invention may be used to advantage in the cultivation of fruits , such as , apples , peaches , pears , grapes , citrus or tomatoes , and for vegetables , such as broccoli , lettuce or celery . however , the present invention is particularly useful when used in cultivation of fruit trees , such as apples and pears . having described the present invention , it will now be apparent and are skilled in the art that many changes and modifications may be made to the above - described embodiments without departing from the spirit and the scope of the present invention . obviously , numerous modifications and variations of the present invention are possible in light of the above teachings . it is therefore to be understood that within the scope of the appended claims , the invention may be practiced otherwise than as specifically described herein . | US-36406699-A |
a heart assist device in which an inflatable balloon or chamber is held against an outside surface of a curved arterial vessel by a wrap formed from a flexible sheet - like material . the wrap having a first end portion , a second end portion and an intermediate portion connecting together the first and second end portions . the intermediate portion comprising at least three separate elongate sections arranged in side by side array each connected at each end to a respective one of the end portions of the wrap . the improvement in that the laterally outer ones of the elongate sections are longer than the central one of them . as a result , if the wrap was laid on a planar surface , the central one of the elongate sections would lie substantially in that plane and the laterally outer ones of the elongate sections would , intermediate their ends , project above that plane . | turning firstly to fig1 , there is shown an embodiment of an improved wrap 20 for use with , for example , a heart assist device of the type shown in the actuator pct application . the wrap 20 is formed from an elongate piece of woven polyester , or similar non - absorbable , bio - stable and bio - compatible material . in contrast to the wrap disclosed in the wrap pct application , the wrap 20 , when developed or extended along its longitudinal direction ( as shown ), is not substantially planar but instead includes three dimensional portions which will be described in more detail below . the wrap 20 is generally comprised of five portions namely : a relatively wide suture tab 22 ; a relatively wide domed portion 24 ; a relatively narrow slotted portion 26 ; a relatively wide planar section 28 ; and a pull tab 30 . the planar section 28 also acts as a suture tab as it mates with the tab 22 after encircling the vessel , which will be described in more detail below . the suture tab 22 includes a buckle 32 at its proximal end . the buckle 32 is of the type shown in the applicant &# 39 ; s international pct patent application no . pct / au2004 / 001488 ( wo 2005 / 041781 ), hereafter “ the buckle pct application ”. the buckle 32 receives the pull tab 30 therethrough during the implantation of a heart assist device , as is described in the buckle pct application . the relevant contents of the buckle pct application are incorporated herein by cross reference . when the wrap 20 is laid on a planar surface , the domed surface 24 curves outwardly away from that plane . the domed surface 24 has a generally ovular cross - sectional shape and an inlet / outlet port opening 34 at its apex or geometric centre . the domed surface 24 tapers outwardly away from the opening 34 to the remainder of the wrap 20 . the fluid inlet / outlet tube of an actuator is positioned through the opening 34 prior to implantation of a heart assist device . the domed shape of the surface 24 substantially corresponds to the exterior shape of an inflated balloon / chamber type actuator , when implanted on an arterial vessel . the domed surface 24 also has a curvature to fit the secondary radius of the aorta . the steps included in forming of the domed surface 24 will be described in more detail below . the portion 26 includes a pair of longitudinally extending curved openings or slits 36 a and 36 b , similar to the slits 32 shown in the wrap pct application . the slits 36 a and 36 b divide the portion 26 into three parts or strips , namely : two outer strips 26 a and 26 b , which are between the side of the wrap 20 and each of the slits 36 a and 36 b ; and also a central strip 26 c which is between the slits 36 a and 36 b . the laterally outer strips 26 a and 26 b are longer than the central strip 26 c . when the wrap 20 is laid on a planar surface , the central strip 26 c lies substantially in that plane , whereas the laterally outer strips 26 a and 26 b , being longer , project out of that plane . if the material of the wrap is is relatively stiff the outer strips 26 a and 26 b will curve upwardly out of the plane . if the material is softer and more flexible then the projection out of the plane will be more in the nature of crumpling of the material above the plane . further , the laterally outer edges of the outer strips 26 a and 26 b curve , intermediate their ends , more upwardly out of that plane than the laterally inner edges of the outer strips 26 a and 26 b . it is also to be noted that the longitudinal axes of the strips 26 a and 26 b diverge from one another , and from the central strip 26 c , as they extend from the central portion 26 ( relatively narrow ) to the planar portion 28 and domed portion 24 . the strips 26 a and 26 b are longer than the strips 26 c in the longitudinal direction of the wrap 20 . as a result , when the wrap 20 encircles a curved arterial vessel ( e . g . an ascending aorta ) with the slits 36 a , 36 b positioned against the inner concave surface of the vessel , at a tension lower than would substantially deform the vessel , the strips 26 a , 26 b and 26 c gather together in a manner substantially conforming to the adjacent surface of the vessel without kinking or folding . moreover , the strips 26 a , 26 b and 26 c conform to the adjacent surfaces of the vessel more closely than the equivalent components of the wrap disclosed in the wrap pct application , which all had a corresponding length in the longitudinal direction of the wrap . the different lengths of the strips 26 a , 26 b and 26 c also allows for the maintenance of the same elastic properties at each location normal to the longitudinal axis of the vessel . the manufacture of the outer strips 26 a and 26 b shall be described in more detail below . the pull tab 30 is formed from two layers of the wrap material , as opposed to the one layer that forms the remainder of the wrap 20 , in order to increase its rigidity . this makes the pull tab 30 easier to handle and position by a surgeon during implantation of a heart assist device . the external edges or sides of the portions 24 and 26 include a series of spaced apart slits 38 . the slits 38 result in those parts of the sides of the wrap 20 being more elastic or stretchable than the intermediate central portion of the wrap 20 . as a result , when the wrap is placed around the aorta and tightened to a snug fit , less tension is placed in the sides or edges of the wrap 20 than in the centre . this avoids the depression / kinking , and associated high strain levels , associated with earlier wraps , as is discussed in the wrap pct application . the wrap 20 also includes two small slots 40 and 42 and a large slot 44 . the slots 40 , 42 and 44 are used as location points during the manufacture of the wrap , as will be discussed in more detail below . slot 44 is used for allis clamps or forceps during implant to allow the wrap to be tensioned using standard length surgical instruments . the slots 40 and 42 also provide areas to enable revascularization or improved blood supply under the wrap 20 when implanted . the wrap 20 also includes one , two or three size identification markings , in the form of one or more dots 46 adjacent the pull tab 30 . one dot indicates a ‘ small ’ size wrap . two dots indicate a ‘ medium ’ size wrap . three dots indicate a ‘ large ’ size wrap . the manufacture of the wrap 20 shall now be described with reference to fig2 to 15 . all steps in the manufacture of the wrap 20 are performed in a controlled environment room ( cer ) with all of the operator &# 39 ; s material and tools being cleaned to applicable standards . fig2 shows a stainless steel cutting template 50 adjacent a piece of wrap material 52 . the first stage in the production of the wrap 20 is to iron the wrap material 52 . the ironing is conducted at a linen / dry heat setting . the material 52 in the template &# 39 ; s five central openings 54 a , 54 b 54 c , 54 d ( 2 of ) is then cut and removed in order to form the openings 34 , 40 , 42 and 44 respectively . the material 52 exterior to the wrap template 50 is then cut and removed . the material 52 is cut on its bias , at 45 degrees to the warp / weft of the fabric weave . this allows the warp and weft fibres to change angle relative to one another and therefore increase and decrease longitudinally when force is applied or removed , which improves the ability of the wrap 20 to conform to the aorta . the c shaped cut out 30 c between the tail ends 30 b ensures only a single layer of material is in the suturing region . this single layer also reduces the stiffness of the wrap when conforming to the aorta . with reference to fig3 , the right hand end of the wrap material 52 is folded over itself to align the two openings 54 d that form the large slot 44 in order to form the pull tab 30 . the fold at the distal end of the pull tab 30 is then ironed with tail ends 30 b aligned with the ends of the slits 36 to create a smooth transition between these parts . this folding also provides a portion for attaching the adjacent ends of the strips 26 a and 26 b , as will be described in more detail below , whilst also conveniently permitting the wrap 20 to be produced from a single piece of material . as shown in fig4 , the folded wrap material 52 is then positioned under an adhesive template 56 . the template 56 includes alignment holes 58 and 60 . the alignment hole 58 is aligned with the small slot 40 . the alignment hole 60 is aligned with the size identification markings 46 . the holes 58 , 60 thus provide references to enable the wrap material to be accurately positioned in relation to the template 56 and ensure the correct size template is used . the exposed edge of the wrap material 52 is then traced with adhesive in the three locations indicated by arrows 62 . the template 62 is then removed and the wrap material 52 is folded to the position shown in fig3 and clamped under a load 64 , as shown in fig5 , until the adhesive cures . the load 64 is then removed leaving the wrap material 52 shown in fig6 . fig7 shows the wrap material of fig6 clamped beneath an adhesive template 66 ( with the strips 26 a and 26 b folded out of the way towards the suture tab 22 ). the template 66 is aligned with the wrap material 52 at the three locations indicated by arrows 68 . adhesive is then applied along the exposed edges 70 of the pull tab 30 . as shown in fig8 , the outer strips 26 a and 26 b then have their edges 72 positioned in contact with the adhesive 70 . the edge 72 is attached to the wrap material closer to the pull tab end of the wrap 20 compared to from where it was cut and on a 30 deg angle from it &# 39 ; s original cut edge . this longitudinal repositioning results in the outer strips 26 a and 26 b , intermediate their ends , curving away from the remainder of the wrap 20 when the wrap 20 is positioned on a flat surface . the edge 72 is also attached more outwardly than compared to from where it was cut . this lateral repositioning results in the laterally outer edges of the outer strips 26 a and 26 b , intermediate their ends , curving away more from the remainder of the wrap 20 than the laterally inner edges of the outer strips 26 a and 26 b . in addition , the laterally outer edge of strips 26 a and 26 b when positioned on edge 72 provide a straight section 28 with edges parallel to the central longitudinal axis of the wrap 20 providing suture region adjustable for within a defined range of vessel diameters as shown in fig9 , an additional clamping template 74 is then positioned over the overlapping surfaces 70 and 72 being glued together . as best shown in fig1 , a load 76 ( similar to the load 64 ) is then applied to the clamped surfaces until the adhesive has cured . as shown in fig1 , the wrap material 52 has a substantially triangular section removed at 78 either side of the opening 34 . the edges 80 and 82 either side of the removed section are then overlapped , to form a slot at the edge , and initially held in this position by a suture 84 passing through location 86 and 88 . a similar procedure is performed on the opposite side of the wrap material 52 . this forms the basis for producing the domed surface 24 . as shown in fig1 , the sutured wrap material 52 is then positioned within a mould 90 with an outwardly concave or female recess with an arc on its main axis corresponding in shape an inflated actuator for a heart assist device . the wrap material 52 adjacent the domed surface 24 is then heat shaped by applying a male outwardly convex dome to apply heat consistently across the surface , adding folds in the correct location and heat shaping the remainder . the heat is provided by an iron applied to the mould parts whilst they are clamped together . the ironing is conducted at a linen / dry heat setting for approximately 20 to 30 seconds . the overlapped material and the deformation caused by the moulding and the iron &# 39 ; s heat produces the smooth domed surface 24 . as shown in fig1 , the sutures 84 are then removed and the overlapped parts of the wrap material 52 are separated so that adhesive can be applied where indicated by arrows 92 . as shown in fig1 , the previously overlapped parts of the wrap material 52 are then repositioned in contact with one another and placed over a male mould part 94 . as shown in fig1 , a corresponding female mould part 96 is then used to clamp the overlapping surfaces until the adhesive cures . the use of the wrap 20 in the implantation of a heart assist device is substantially identical to that descried in the buckle pct application . the relevant contents of which are incorporated herein by cross reference . the wrap 20 formed by the above process , will , when implanted encircling the balloon or chamber of a heart assist device and a curved arterial vessel ( eg . the ascending aorta ) at a tension lower than would substantially deform the vessel , will substantially conform to the adjacent exterior surfaces of the balloon , chamber and arterial vessel that are in contact with the wrap . more particularly , the wrap 20 will substantially conform to the exterior surface of the balloon , chamber and arterial vessel substantially without wrinkles or folds , whereby the application of force from actuation of the balloon / chamber will be effectively translated normal to the axis of the vessel at any location along the vessel . although the invention has been described with reference to a preferred embodiment , it will be appreciated that the invention is not limited to this particular embodiment and may be embodied in many other forms . | US-43810507-A |
a single serving scoop and funnel both conveniently measures a correct amount of any liquid , gel , solid , granulated , or any pourable material , and facilitates pouring the measured material into a container . the funnel is moveably attached to a scoop handle , and may be moved between a first position over the scoop , and a second position withdrawn from the scoop . in one embodiment the funnel is hingedly attached to the scoop handle and rotates 180 degrees to latch opposite to the scoop , and may contain projections on each side of a funnel handle allowing single had use . in another embodiment the funnel slides along the handle away from the scoop . | the following description is of the best mode presently contemplated for carrying out the invention . this description is not to be taken in a limiting sense , but is made merely for the purpose of describing one or more preferred embodiments of the invention . the scope of the invention should be determined with reference to the claims . where the term “ generally ” is associated with an element of the invention , it is intended to describe a feature &# 39 ; s appearance to the human eye , and not a precise measurement . for example , when an element is described as generally horizontal , it is intended to describe an element which at least appears to be horizontal to the human eye , and not necessarily horizontal if measured by an instrument . a scoop 14 is shown scooping brewing extract 15 from a container 13 in fig1 and the scoop 14 is shown pouring the brewing extract 15 into an extract holder 13 in fig2 . the extract holder 13 is used in a single serving brewer and must fit into the brewing cavity of the brewer , thus limiting the size of the extract holder 13 . as a result , it is often difficult to pour the brewing extract 15 into the extract holder 13 without spilling some of the brewing extract . a perspective view of single serving scoop and pivoting funnel 10 a , the funnel 12 a pivoted away from the scoop 14 a in a scooping position , according to the present invention , is shown in fig3 a , a perspective view of the single serving scoop and pivoting funnel 10 a with the funnel 12 a partially pivoted towards the scoop 14 a is shown in fig3 b , and a perspective view of the single serving scoop and pivoting funnel 10 a with the funnel 12 a fully pivoted over the scoop 14 a in a pouring position is shown in fig3 c . the combination of the scoop 14 a and funnel 12 a permits scooping and pouring brewing extract 15 ( or any a liquid , gel , solid , granulated , or any pourable material ) into the extract holder 13 without spilling the brewing extract material . the scoop 14 a includes a scoop mouth 24 for scooping the brewing extract 15 from the container 11 , and a scoop handle 26 extending generally horizontally from the scoop 14 a . the funnel 12 a includes a base 18 matched to close against the scoop mouth 24 and a pouring mouth 16 for pouring a measured amount of material . the funnel 12 a and funnel handle 20 rotate around pivot 22 from the position opposite to the scoop 14 a for scooping brewing extract , to a position over the scoop 14 a for pouring the beverage extract into a holder used in a beverage brewer . the pivot 22 is generally centered on the scoop handle 26 and preferably comprises a scoop handle portion 22 a and a funnel handle portion 22 b connected by a pin ( or hinge ) 23 . in either position , the funnel handle 20 may rest against a scoop handle 26 , and the act of grasping the scoop handle 26 holds the funnel 12 a in position . the scoop handle reaches in a handle direction 21 from the scoop 14 a . while the funnel 12 a is shown having the pouring mouth 16 opposite to the base 18 , the pouring mouth may be on the side of the funnel 12 a or any position on the funnel 12 a separated from ( i . e ., not overlapping ) the base 18 . a side view of the single serving scoop and pivoting funnel 10 a with the funnel 12 a residing away from scoop 14 a is shown in fig4 a , and a side view of the single serving scoop and pivoting funnel 10 a with the funnel 12 a fully rotated around the pivot 22 to close against the scoop 14 a is shown in fig4 b . the funnel 12 a may include a tab 29 projecting towards the pivot 22 , and in the fully rotated position of fig4 a , the tab 29 overlaps a scoop handle end 27 of the scoop holding the funnel 12 a , to hold the funnel 12 a in the fully rotated position . the scoop handle 26 has a length l 1 of preferably between three and five inches , and more preferably four inches . the funnel handle 20 has a length l 2 of preferably between 1 . 5 and 2 . 5 inches and more preferably two inches , and the length l 2 is preferably about half the length l 1 , the length l 2 being selected to facilitate the cooperation of the tab 29 with the handle end 27 to hold the pivoting funnel 12 a in the separated position . a perspective view of a single serving scoop and sliding funnel 10 b according to the present invention with sliding funnel 12 b residing over a scoop 14 b is shown in fig5 a and a perspective view of the single serving scoop and sliding funnel 10 b is shown in fig5 b . the funnel 12 b slides on the scoop handle 36 from a first position over the scoop 14 b for pouring brewing extract 15 into the extract holder 13 , to a second position separated from the scoop 14 b for scooping the brewing extract 15 from the container 11 . the scoop handle 36 includes rails 34 engaged by slots 38 ( see fig7 ) in a thumb rest 30 of the funnel 12 b . a stop 32 on the scoop handle 36 lim its the sliding of the sliding funnel 12 b . the sliding funnel 12 b is just past the scoop mouth 24 when the thumb rest 30 touches the stop 32 . a side view of the single serving scoop and sliding funnel 10 b is shown in fig6 a and a side view of the single serving scoop and sliding funnel 10 b with the sliding funnel 12 b residing over the scoop handle 36 is shown in fig6 b . a cross - sectional view of the thumb rest portion 30 of the sliding funnel 12 b and a cooperating portion of the scoop handle taken along line 7 - 7 of fig6 a is shown in fig7 . the slots 38 in the thumb rest engage the channel 34 of the scoop handle 30 to limit the sliding funnel 12 b to sliding motion on the scoop handle 36 . a perspective view of a second scoop and pivoting funnel 10 c in a scooping position , according to the present invention , is shown in fig8 a , a perspective view of the scoop and pivoting funnel 10 c with the funnel 12 a partially pivoted towards the scoop 14 a is shown in fig8 b , and a perspective view of the scoop and pivoting funnel 10 c with the funnel 12 a fully pivoted to reside over to the scoop 14 a in a pouring position is shown in fig8 c . the scoop and pivoting funnel 10 c is similar to the single serving scoop and pivoting funnel 10 a , but includes at least one projection 40 , and preferably two opposing projections 40 extending from each side of the funnel handle 20 , preferably proximal to the hinge 23 ( see fig9 a ). the projections 40 may be flat ( wing like ), cylindrical , spherical , triangular , rectangular , etc ., and a scoop and pivoting funnel with any shaped protrusion extending from the funnel handle is intended to come within the scope of the present invention . the projections 40 extend laterally from the funnel handle 20 , and generally perpendicularly from the funnel handle 20 . the projections 40 permit a user to hold the scoop and pivoting funnel 10 c and flip the funnel 12 a over the scoop 14 a with a finger or thumb of a single hand . such single handed use is important when the user must also hold a container being filled from the scoop and pivoting funnel 10 c . further , a rear portion 26 a of the scoop handle 26 is angled down at a second angle a 2 of preferably between five and fifteen degrees , and preferably ten degrees . the rear portion 26 a is preferably cylindrical with a spherical end or may be contoured to an easier grasp and consistent positioning of the user &# 39 ; s hand . a cross - sectional side view of the scoop and pivoting funnel 10 c taken along line 9 a - 9 a of fig8 a with the funnel 12 a residing opposite to the scoop 14 a is shown in fig9 a , and a cross - sectional side view of the scoop and pivoting funnel 10 c taken along line 9 b - 9 b of fig8 c with the funnel 12 a fully pivoted to reside over the scoop 14 a is shown in fig9 b . an o - ring 42 may reside around an exterior top edge of the scoop 14 a ( or alternatively inside a cooperating surface of the funnel 12 a ) to resist or prevent liquid from escaping between the scoop 14 a and funnel 12 a when the scoop and pivoting funnel 10 c is used to measure liquids . a hinge 23 at the base of a funnel arm 20 engages a generally mid point of the scoop handle 26 , and the funnel 12 a pivots through a first angle a 1 between 120 and 180 degrees , and preferably between 160 and 170 degrees , and most preferably 165 degrees , to a position opposite to the scoop and snaps into place . a cross - sectional view of the funnel handle 20 engaging the scoop handle 26 , taken along line 10 - 10 of fig9 b , is shown in fig1 . the scoop handle 26 includes a slot 26 a , and the funnel handle 20 includes a rib 20 a . when the funnel handle 20 is rotated about the hinge 23 to engage the funnel 12 a with the scoop 14 a , the rib 20 a engages the slot 26 a to align the funnel 12 a with the scoop 14 a . the rib 20 a preferably extends the length of the funnel handle 20 , and the slot 26 a preferably extends the length of the scoop handle 26 . the projections 40 extend laterally generally perpendicular to the funnel handle 20 , a width w beyond the outside edge of the scoop handle 26 . the width w is preferably at least ⅛ inches , and more preferably between ¼ and ¾ inches , and most preferably ½ inches . while the invention herein disclosed has been described by means of specific embodiments and applications thereof , numerous modifications and variations could be made thereto by those skilled in the art without departing from the scope of the invention set forth in the claims . | US-201514820762-A |
a joint prosthesis has a bending hinge , which is formed by a hinge fork and an axle pin , which comprises two axle stubs , which are arranged in an installation position for insertion , in which installation position the axle stubs are retracted in a coupling piece , and in an expanded position after implantation by movement in the axial direction into aligned hinge holes of the hinge fork , wherein the axle pin has two bearing areas at the ends of the axle pin and a joining area lying therebetween , and the axle pin is separated in the joining area along a plane extending in the axial direction , which plane intersects with the jacket of the axle pin at two points . | the endoprosthesis according to an exemplary embodiment of the invention will be explained using a knee joint endoprosthesis . the endoprosthesis of a knee joint substantially comprises two components 1 , 2 , one being in the form of a tibial component 1 and the other being in the form of a femoral component 2 . in the femoral component 2 , a femoral bearing half 21 , which has two condyle - like runners 22 which project in the manner of a fork in relation to the tibial component 1 , adjoins a stem 20 which is inserted into a femur of a patient . said runners are supported on a tibial plateau 12 which is arranged on a tibial bearing half 11 which is fastened to a tibia of the patient by means of a stem 10 . a coupling piece 3 is arranged between said stems , said coupling piece a t - shaped piece 30 as a main body with a receiving eye 33 , which is arranged in its upper region , for an axial pin 4 and with a bearing pin 31 for being received in a bearing bushing in the tibial bearing half 11 . a first bearing ( flexion bearing ) allows a pivoting movement between the components 1 and 2 , that is to say realizes the bending movement between the thigh and the lower leg . this pivoting movement about the axis of the axial pin 4 therefore forms the first axis for the movement of the knee joint prosthesis . the pin 31 is oriented transverse to said first axis by way of its center axis which forms a second axis for the rotary movement with which the femur part 2 rotates about the second axis relative to the tibia component 1 . for this rotary bearing , the pin 31 of the coupling piece 3 projects into the bearing bushing . a bearing insert 32 is arranged between said pin and bearing bushing . the spreadable axial pin 4 is arranged in the receiving eye 33 . said axial pin has a plurality of regions , in each case a bearing region 41 at the two ends and a joining region 40 between said two ends . in fig3 b , said axial pin is illustrated in its installation position in which it is retracted into the receiving eye 33 , and in fig3 c is illustrated in its spread position in which the bearing regions 41 project out of the receiving eye 33 on both sides . said axial pin is passed through an aperture in a separating element 30 in the receiving eye 33 , said aperture having the shape of a flattened oval and preventing rotation of the axial pin 4 . the coupling piece 3 is provided with a flat receiving area 35 on its front side ( on the left - hand side in the illustration in fig3 a ). a pocket 36 is formed in the receiving eye 33 at the upper end of said receiving area , said pocket merging with the receiving area 34 in a flat manner at its base . a retaining opening 35 which is designed in the form of a blind hole is provided in the central region of the receiving area 34 . an impact - protection plate 37 can be mounted on the receiving area 34 and is inserted into the pocket 36 . as a result , the pocket 36 is secured against lifting off from the receiving area 34 by way of its upper edge , specifically also under the action of force from the front ( from the left - hand side in fig3 a ) when the extended stop position of the flexion bearing is reached . the impact - protection plate 37 is protected against movement , in particular in the downward direction , by means of a projection which is formed on the rear face of said impact protection plate and engages in the retaining opening 35 in an interlocking manner . the axial pin 4 has a separating plane 49 , which runs along to form its center axis , in the joining region 40 . said separate plane intersects the casing in the joining region 40 at two diametrically opposite points ( see fig3 a ). the axial pin 4 is thereby divided into two pin stubs 42 , 43 . the two said pin stubs have a projecting half - peg 44 , 45 , which pegs form the cross section of the axial pin 4 in the joining region 40 when combined . furthermore , each of the two pin stubs 42 , 43 has a cavity 46 , 47 in the shape of a half moon . said cavities are shaped to complement the half - pegs 44 , 45 , with the result that each half - peg enters the cavity 46 , 47 when the pin stubs are pushed together ( for the installation position , as illustrated in fig3 b ). in the spread position , the half - pegs 44 , 45 move out of the cavities 46 , 47 , said half - pegs being securely guided by the wide separating plane 49 . owing to this wide guidance in a flat plane , the spreading process does not lead to jamming or to tilting ; the same applies when said half - pins are pushed together in the case of adjustment of the knee joint prosthesis . the design of the pin stubs 42 , 43 is illustrated in detail in fig4 . said pin stubs further have an actuator opening 48 , which is designed to receive a spreading instrument 5 , on their casing . two actuator openings 48 are preferably provided for each pin stub , specifically symmetrically in relation to the separating plane 49 . one is used in each case , specifically depending on the installation position . in the illustrated exemplary embodiment , the pin stubs 42 , 43 are the same shape , that is to say the same element can be used both as pin stub 42 and also as pin stub 43 . in order to spread the pin stubs 42 , 43 , two access slots 38 are formed on the receiving eye 33 . said access slots are oriented on an aligned line with an orientation of their elongate extent in the direction of the center axis of the axial pin 4 . a fastening opening 39 is provided above and centrally between said access slots . a pointed instrument can be inserted through the access slots 38 , said instrument engaging in one of the two actuator openings 48 . the pin stub 42 is removed from the other pin stub , and vice versa , by moving the instrument outward . the spreading instrument used for this purpose is illustrated in greater detail in fig5 and 6 . said spreading instrument comprises a wire clip 50 with two free ends 51 at its front end , said free ends diverging at an angle α . said wire clip forms a three - point loop in its rear region , a sliding sleeve 54 being mounted on said three - point loop . said sliding sleeve has a radially projecting collar 56 , which is provided with a recess 55 , on its side which faces away from the ends 51 . the sliding sleeve 54 can , between its spreading position , as illustrated in fig5 , be moved forward into an inoperative position , as a result of which the free ends 51 are pushed into a position in which they are closer together . a certain adjustment force is required for this purpose , with the result that the sliding sleeve 54 functions as a means for preventing unintentional movement . the recess 55 ensures that the collar 56 does not collide with the wire clip 50 during the movement . said recess also ensures unimpeded straight access to the fastening sleeve 60 . the fastening sleeve 60 is part of a fastening guide 6 which is arranged at the end of the wire clip 50 . the fastening sleeve has an internal thread 62 in its inner opening 61 , a locking screw 63 being screwed into said internal thread . in the inoperative position , the locking screw 63 projects only slightly by way of its tip 64 , specifically to such an extent that it engages in the opening 39 by way of its thread and in this way secures the fastening guide to the coupling piece 3 . during installation , the sliding sleeve 5 is moved backwards for the purpose of spreading the axial pin 4 , as a result of which the free ends 51 , which are inserted into the actuator openings 48 in the pin stubs 42 , 43 through the access slots 38 , are moved away from one another and thereby spread apart the pin stubs 42 , 43 . once said pin stubs have reached their spread position ( see fig3 c and 7 ), the locking screw 63 is turned further , until it enters the separating plane 49 by way of its tip and secures the pin stubs 42 , 43 by clamping and , if there is a corresponding receiving opening 49 ′, even in an interlocking manner . if the locking screw 63 has been turned sufficiently far , it is no longer in engagement with the internal thread 62 . the fastening guide 6 is therefore free , and the spreading instrument 5 can then be removed ( for the first time ). this ensures that the spreading instrument can be removed only when the pin stubs 42 , 43 are spread . in the event of an adjustment , it is necessary to move the pin stubs 42 , 43 out of the spread position ( see fig3 c ) back into the installation position ( see fig3 b ). to this end , a set of adjustment pliers 7 is provided with a handle 70 at the rear end and with receiving fingers 70 on jaws 71 at the front end ( see fig8 ). the dimensions of the receiving fingers are such that said receiving fingers can be inserted through the access slots 38 and engage with the actuator openings 48 . the receiving fingers 72 are preferably arranged in a converging manner . this means that they are oriented so as to point toward one another , specifically through an angle β of approximately 10 degrees . this angle is selected such that the receiving fingers 72 are approximately parallel in the position of the set of adjustment pliers 7 when the pin stubs 42 , 43 have reached their installation position ( see fig3 b ), for the purpose of simpler removal . | US-201214112812-A |
a femoral slideway and femoral slideway / femur - size template combination is employed to create an installed knee prosthesis that creates a reduced amount of stress in the collateral ligaments relative to previous prosthesis . in one embodiment , the reduced stress is achieved by employing a femoral slideway / femur - size template combination which results in installation of a femoral slideway which has a smaller dorsal - ventral dimension than a corresponding dimension of the femur prior to resection . | in fig1 and 2 the femur component 10 , called a femoral slideway , of a knee endoprosthesis is shown . the femoral slideway 10 comprises two convexly curved condyle shells 11 , 12 and a patellar shield 13 , which connects the two condyle shells 11 , 12 rigidly to one another . the condyle shells 11 , 12 and the patellar shield 13 in their interiors define anterior and posterior fitting surfaces 14 , 15 that correspond to a femoral ventral , and dorsal cut , respectively , and are associated with a ventral and a dorsal saw - cut surface produced at the distal end of the femur when the latter was resected for fitting of the femoral slideway . the convex outer shape of the condyle shells 11 , 12 specifies dorsal sliding surfaces 11 a , 12 a in the posterior region , over which the corresponding surfaces of the tibia insert slide when the knee endoprosthesis is flexed . the patellar shield 13 , which is recessed with respect to the convex outer surfaces of the condyle shells 11 , 12 , defines a so - called patellar pit 16 , within which there is supported a patella component 17 of the knee endoprosthesis , which is indicated by a dashed outline in fig2 and does not belong to the femoral slideway 10 . to assist anchoring and central placement of the femoral slideway 10 on the femur , on the inner surface of the femoral slideway two pegs 18 , 19 are formed , the long axis of which is substantially parallel to the posterior fitting surface 15 . these pegs project into holes in the femur , which have been drilled in the appropriate positions with the aid of a corresponding drilling template ( see below ), and this engagement gives the attachment of femoral slideway to bone greater stability than is provided by the fitting surfaces alone . to ensure that the femoral slideway will function optimally as a replacement for destroyed sliding surfaces on the femur , the construction must reflect as accurately as possible the anatomical arrangements and dimensions , but also within the scope of the invention includes a specific modification that will now be explained . one of the relevant dimensions of the femoral slideway is the maximal anterior - posterior or dorsoventral extent of the condyle shells 11 , 12 , a distance labeled “ a ” in fig1 . another relevant dimension is the maximal lateral extent of the femoral slideway , i . e ., the distance between the most lateral point on the lateral condyle shell 11 and the most medial point on the medial condyle shell 12 , which in fig1 is labeled “ c ”. also significant is the distance from the outermost posterior point on the dorsal sliding surfaces 11 a , 12 a of the condyle shells 11 , 12 to the posterior bounding edge of the patellar shield 13 , which in fig1 is labeled “ b ”. a final significant distance is that between the outermost posterior points on the dorsal sliding surfaces 11 a , 12 a and the long axis of the pegs 18 , 19 ( which lie in one and the same coronal plane ), labeled “ d ” in fig2 . in the exemplary embodiment described here , the ratio a : c is 0 . 9 and the ratio b : a is 44 . on grounds of biomechanics and surgical technique , it has proved useful to make the distance “ d ” ( between sliding surface and peg axis ) uniform for all sizes of femoral slideways used in a knee endoprosthesis system . in the present case , this distance is 29 mm . to determine the correct femoral slideway size , a femur - size template 20 shown in fig3 and 4 is used . this comprises a basic part 21 with two flanks 22 and 23 , each of which ends in a contact section 22 a , 23 a that is bent at a right angle and is apposed to the condyles of a femoral bone that is to be fitted with a femoral slideway ( fig1 and 2 ). in the middle of the basic part 21 a measurement tongue 24 , bent at an angle in two places , is mounted so that it can be displaced in a direction perpendicular to the plane in which the contact sections 22 a , 23 a lie . the measurement tongue 24 is marked with a scale 25 , which indicates the maximal anterior - posterior extent of the head of the femur , i . e . the condyles , and thus indicates to the doctor the required size of the implant . in the basic part 21 of the femur - size template 20 two peg - hole bores 26 , 27 are provided , which — in accordance with a supplementary drilling - template function of the femur - size template — assist the positioning of peg - holes in the femur so that they correspond to the pegs 18 , 19 of the femoral slideway 10 , as shown in fig1 . the axes of the peg - hole bores 26 , 27 are separated by a distance “ e ” from the contact surfaces of the contact sections 22 a , 23 a . this distance — along with the distance “ d ” between the sliding surfaces and pegs on the femoral slideway 10 itself ( cf . fig2 )— is an additional relevant dimension in the concrete implementation of a knee endoprosthesis , for the following reason : so that the above - mentioned peg - holes — which serve not only to position the implant but also to position the cutting guides used to produce the various saw cuts on the femur — can be drilled into the bone , drill bushes ( not shown ) are inserted into the peg - hole bores 26 , 27 . it has proved advantageous , in particular from the viewpoint of reducing the load on the collateral ligaments during flexion of the artificial knee joint , to resect more bone dorsally on the femur than will be replaced there by the thickness of the dorsal parts of the condyle shells . for this reason the distance “ e ” is made larger than the corresponding distance “ d ” ( fig2 ). in the preferred embodiment , the relative distance reduction , i . e . the quantity ( e − d )/ d , is about 10 %. the effect thus achieved can be seen in fig5 , where a sketch representing the conventional way of attaching a femoral slideway 10 ′ to a femur f ′, shown in fig5 a , is compared with the representation in fig5 b of the arrangement proposed here . the anterior - posterior extent of the femoral slideway 10 in fig5 b , mounted on a femur f resected further in the dorsal region , is smaller by the amount ( e − d ) than in the conventional implant 10 ′. because the distance “ e ” is permanently specified by the femur - size template , which is used for ail implants regardless of their size , and according to what has been stated above , the distance “ d ” in the embodiment of the femoral slideway is preferably kept constant for all implant sizes , the geometric relations will be slightly different for implants of different sizes . this is acceptable , however , in view of the advantages for manufacture and manipulation that such a system brings . fig6 b shows — in comparison to a conventional femur carriage coating as shown in fig6 a — the appearance in the scanning electron microscope of a cross - section through a two - component titanium - coating construction consisting of a dense base layer g , about 50 μm thick , and an open - pored cover layer d averaging about 250 μm thick , on a cocrmo substrate s . although the thickness and average roughness of the coating according to fig6 b , which is applied by a vacuum plasma process , are comparable to those of the known , sprayed - on coating according to fig6 a , it should be emphasized that the former has a more open - pored structure and a considerably reduced number of interface defects ( indicated in both pictures by vertical arrows ). implementation of the invention is not limited to the exemplary embodiment described above , but can also incorporate modifications , which in particular include departures from the specified dimensions and ratio values . | US-201615044564-A |
the present invention provides a photoreactive reagent that binds specifically to ca 2 + - binding proteins , links to them covalently after photo - activation , and labels them . the novel reagent enables the characterization , purification , inhibition and screening of ca 2 + - binding proteins , as well as the preparation of a new affinity chromatography matrix and a new protein biosensor . the invention also relates to the use of the reagent in inhibiting apoptosis and necrosis and in diagnosing a disorder associated with a defect in the function of a ca 2 + - binding protein , and in the preparation of a medicament for treating such disorders . | this invention provides a new azido - ruthenium , which is photoreactive , and exhibits a specific interaction with ca 2 + - binding proteins . synthesis of three azido - ruthenium compounds were reported [ seok w . k . et al . : j . organomelallic chem . 559 ( 1998 ) 65 - 71 ; siebald h . g . l . et al . : polyhedron 15 ( 1996 ) 4221 - 5 ; vrestal j . et al . : collection czechoslov . chem . commun . 25 ( 1960 ) 2155 - 60 ]. effects of these non - photoreactive reagents on biological activities were not described . another known ruthenium reagents , ruthenium red and ru360 are not photoreactive . the preferred reagent of this invention can be prepared by reacting sodium azide with ruthenium chloride ( iii ) and purifying the product on a chromatographic column , e . g . cation - exchanger or hydrophobic . chromatography purification methods , useful for this purpose comprise , for example , cm - cellulose or sephadex lh - 20 columns . ir spectrum of the novel azido - ruthenium ( azru ) product shows the characteristic absorption of the bound azido group at 2072 cm − 1 . it was surprisingly found that the azido - ruthenium compound of this invention interacts with ca 2 + - binding proteins and inhibits their activity . when photo - activated , by uv - irradiation , the reagent binds covalently to the ca 2 + - binding sites . the effect of the reagent of this invention on activities of various proteins , including channels , receptors and enzymes , were tested , and it was found by us that the interaction is specific for the ca 2 + - binding proteins ( table 1 ). azido - ruthenium according to this invention can be synthesized from radiolabeled reagents , thus enabling labeling of binding sites in ca 2 + - binding proteins . such labeling enables discovering still unknown proteins , explaining still unclear aspects of regulations and signal transduction pathways depending on calcium ions , separating and characterizing the involved peptides and proteins , as well as determining their structure and function . in one embodiment , to identify ca 2 + - binding proteins , proteins labeled by radiolabeled reagents are separated by sds - page , identified by autoradiography , cut from the gel and exposed to cleavage conditions . the degradation products are separated by a second sds - page , and the coomassie stained labeled bands are sequenced to identify the ca 2 + - binding sites . the labeled protein bands can be cut from electrophoresis gels , and subjected to maldi - tof analysis or lc - ms / ms , and the identity of the protein can be determined by a sequence homology search . above mentioned approach can be used , for example , for identifying mitochondrial systems for transporting ca 2 + , like ruthenium red - sensitive uniporter , na + or h + dependent efflux mechanisms , and the rapid mode of uptake transporter . our results show that azido - ruthenium of this invention specifically inhibits the activity of proteins which mediate ca 2 + transport such as the muscle ca 2 + - pump , the mitochondrial uniporter , and the channel protein vdac . an azru compound according to this invention also inhibits the activity of proteins possessing regulatory ca 2 + - binding sites such as the muscle ca 2 + - release channel / ryanodine receptor and calmodulin . in contrast to that , azido - ruthenium has no significant effect on ca 2 + - independent enzymatic reactions . using radioactive azru , ca 2 + - binding proteins can be identified , purified and their functions can be established , e . g ., autoradiography helps to localize suspected proteins . in a preferred embodiment , the radioisotope used for the synthesis of azru is 103 ru . in another preferred embodiment , the azru reagent of this invention is used for separation of ca 2 + - binding proteins by affinity chromatography , wherein the azru reagent is covalently attached to an inert support filled in chromatographic column . the support can be , for example , a porous polymer , such as agarose , cellulose , or dextrane , etc . a protein mixture is loaded into the column , ca 2 + - binding proteins are reversibly retained while other proteins pass . the retained proteins may be released , for example , by a calcium containing buffer . in another embodiment of this invention , azru is coupled to polysaccharides , and is used for construction of unique and novel bio - sensor chips for isolation and identification of ca 2 + - binding proteins . in a preferred embodiment , this invention enables to identify proteins that have affinity for ca 2 + - binding proteins , i . e . proteins that are not necessarily calcium binding themselves , but interact with ca 2 + - binding proteins , forming elements of the signal transduction pathways , often elements that are difficult to detect and identify . in a preferred embodiment of this invention , surface plasmon resonance ( spr ) is used for detecting intermolecular interactions . the chip of this invention can be used , for example , for identifying new ca 2 + - binding proteins , or sites of interaction ; binding affinity and kinetics , as well as epitope map can be also obtained . based on the above findings , the present invention is also directed to a pharmaceutical composition for use in inhibiting calcium dependent proteins involved in various disorders associated with ca 2 + - binding proteins and defects in these proteins . the invention provides a process for preparing an azido - ruthenium compound , having the ratio ru : n 3 of 2 : 1 , that specifically binds to , and inhibits , ca 2 + - binding proteins , comprising the steps of : i ) reacting in dark of sodium azide with ruthenium ( iii ) chloride in the presence of hcl , ii ) applying the reaction mixture of the previous step onto a chromatographic column , e . g . cation - exchanger or hydrophobic , iii ) collecting the fractions which contain the required product , possibly identifying such fractions by measuring absorbance ; and optionally iv ) steps of drying the collected fractions , redissolving them , rechromatographing them , and drying said compound from methanol , eventually crystallizing it . the process of this invention provides an azru product that migrates as a single spot with rf being about 0 . 9 during tlc on cellulose f plates , using 0 . 16 m ammonium formate , ph 8 . 5 and 20 % methanol , said product having an absorbance maximum at about 290 nm , and its absorbance is preferably about from 10 , 000 to 20 , 000 at a concentration of 1 . 0 m in a water solution , usually said absorbance at 290 is about 15 , 000 . thus , this invention provides a novel tool to identify , purify and characterize ca 2 + - binding proteins , and to sequence the ca 2 + - binding sites . in addition , the requirement for ca 2 + in a protein reaction or in the regulation of its activity can be tested . the invention may be useful as a pharmaceutical agent to monitor the involvement of ca 2 + in the activity or regulation of proteins . the invention can be used as well for the detection of defected ca 2 + - binding proteins in certain diseases and disorders . the invention will be further described and illustrated in the following examples . aldolase , alkaline phosphatase , atp , bovine liver catalase , choline oxidase , cm - cellulose , n - decane , glucose 6 - phosphate dehydrogenase , glutamate dehydrogenase , glyceraldehyde 3 - phosphate dehydrogenase , hepes , yeast hexokinase , lactate dehydrogenase , leupeptin , luciferase , mannitol , horseradish peroxidase , pmsf , pyruvate kinase , soybean asolectin , sucrose , tris and triton x - 100 were purchased from sigma ( st . louis , mo ., usa ). [ 45 ca ], [ 103 ru ] and [ 3 h ] ryanodine were purchased from nen ® life science products , inc . ( boston , usa ). unlabelled ryanodine was obtained from calbiochem . sephadex lh - 20 was purchased from amersham biosciences . n - octyl - β - d - glucopyranoside ( β - og ) was obtained from bachem ag ( germany ). lauryl -( dimethyl )- amineoxide ( ldao ) and ruthenium red ( 98 % pure ) were obtained from fluka ( chemie , gmbh ). ruthenium chloride was purchased from aldrich . hydroxyapatite ( bio - gel htp ) was purchased from bio - rad laboratories ( hercules , calif .) and celite from merck . synthetic firefly d - luciferin reagent was purchased from biosynth ag . ru360 was synthesized according to ying [ ying et al . : biochemistry 30 ( 1991 ) 4949 - 52 ]. sarcoplasmic reticulum ( sr ) membranes were prepared from rabbit fast twitch skeletal muscle as described by saito [ saito et al . : j . cell biol . 99 ( 1984 ) 875 - 85 ]. mitochondria were isolated from rat liver as described by us previously [ gincel d . et al . : biochem j . 358 ( 2001 ) 147 - 55 ]. vdac was purified by a method developed in our laboratory , using columns of hydroxyapatite and reactive red agarose [ gincel d . et al . : j . bioenerget . biomembr . 32 ( 2000 ) 571 - 83 ]. calsequestrin was isolated from rabbit skeletal muscle sarcoplasmic reticulum membranes as described by cala s . e . et al . [ j . biol . chem . 258 ( 1983 ) 11932 - 6 ]. calmodulin was isolated from sheep brain as described by gopalakrishna r . et al . [ biochem . biophys . res . commun . 104 ( 2 ) ( 1982 ) 830 - 6 ]. troponin was isolated from rabbit skeletal muscle as described by potter j . d . [ methods in enzymol . 85 ( 1982 ) 241 - 65 ]. protein concentrations were determined by the standard lowry procedure [ lowry o . h . et al : j . biol . chem 193 ( 1951 ) 224 - 265 ] for the determination of [ 3 h ] ryanodine binding , sr membranes were incubated for 20 - 60 min at 37 ° c . in a standard binding solution containing 1m nacl , 20 mm mops ( ph 7 . 4 ), 50 μm free ca 2 + and 20 nm [ 3 h ] ryanodine . unbound ryanodine was separated from protein - bound ryanodine by vacuum filtration of the sample through nitrocellulose filters ( 0 . 45 μm ), followed by two washes with 4 ml ice - cold buffer containing 0 . 2 m nacl , 10 mm mops ( ph 7 . 4 ) and 50 μm cacl 2 . the retained radioactivity in the dried filters was determined by liquid scintillation counting . specific binding of [ 3 h ] ryanodine was defined as the difference between the binding in the presence of 20 nm [ 3 h ] ryanodine and in the presence of 20 μm unlabeled ryanodine . ca 2 + - accumulation in freshly prepared mitochondria ( 0 . 5 mg / ml ) was assayed for 1 to 20 minutes at 30 ° c . in the presence of 225 mm mannitol , 75 mm sucrose , 120 μm cacl 2 ( containing 3 × 10 4 cpm / nmol 45 ca 2 + ), 5 mm hepes / koh ph 7 . 0 , and 5 mm succinate with 0 . 1 mm pi , or 4 mm mgcl 2 with 3 mm atp . the ca 2 + - uptake was terminated by rapid millipore filtration , followed by a wash with 5 ml of 0 . 15 m kcl . the ca 2 + - accumulation in sr was determined as described previously [ shoshan - barmatz v . & amp ; shaineberg a . : biochim . biophys . acta 1065 ( 1991 ) 82 - 8 ]. electron transport from succinate to cytochrome c was described in above cited article [ gincel d . et al . : j . bioenerget . biomembr . 32 ( 2000 ) 571 - 83 ]. reconstitution of purified vdac into planar lipid bilayer ( plb ), single channel current recording , and data analysis were carried out as described in above mentioned publication . all steps were carried out in the dark rucl 3 ( 29 . 8 mg , 0 . 144 mmol ) and nan 3 ( 6 . 24 mg , 0 . 096 mmol ) were dissolved in 1n hcl ( 2 ml ), silted and incubated at 100 ° c . for 3 hrs . the sample was then applied to a sephadex lh - 20 column ( 1 . 5 cm × 44 cm ) pre - equilibrated with water ( fig1 ). free ru 3 + , but not the product , remained bound to the column matrix . the absorbance at 290 was measured and the peak was collected , lyophilized and analyzed by tlc on cellulose f plates using 0 . 16 m ammonium formate , ph 8 . 5 and 20 % methanol as a developer . the product migrated as a single spot with rf = 0 . 9 ( fig2 ). the product is soluble in water , dmf and dmso , less soluble in methanol , and insoluble in ethanol , ether , chloroform , ethyl acetate , n - butanol , and isopropyl alcohol . the purified product of azido - ruthenium has a maximal absorbance at 290 nm , the absorbance of a solution of 1 . 0 m being about 15 , 000 . the spectrum of the product is different from that of the substrates and of ruthenium red ( rur ), a known inhibitor of calcium dependent activity , which is not photoreactive ( fig3 ). infrared spectrum of the product indicates the presence of a specific peak representing a bound azido group ( fig4 ). for further purification , the dried product was dissolved in water and subjected to a second chromatography on sephadex lh - 20 . the elution of radioactive product [ 103 ru ] azru is shown in fig5 . azru was prepared as in example 1 , the product eluting as the second peak ( fig1 ), having the absorption maximum at 290 nm , was dried . the elemental analysis of the compound was carried out by sgs cervac wolff ( france ) and the composition was determined in the department of chemistry of ben gurion university , israel , to provide the empiric formula of the product : ru 2 n 3 cl 5 . 5h 2 o ( h 2 o , hcl ). the effect of azido - ruthenium on ca 2 + - dependent proteins and its photoactivation was demonstrated by the inhibition of the ca 2 + - pump activity involved in muscle relaxation as shown in fig6 . the preparation of sr membranes from skeletal muscle , and the measurement of ca 2 + - accumulation were carried out as described above . the sensitivity of the ca 2 + - pump activity to azido - ruthenium was increased more than two - fold by photoactivation , demonstrating that azido - ruthenium of this invention is a photoreactive compound . fig6 shows that the inhibition is dependent on time of uv irradiation , as well as on the concentration of the reagent . uv irradiation increases the inhibitory effect of the compound on ca 2 + - accumulation by sr membranes , confirming the photoactivation , and suggesting irreversible binding of the reagent to the protein . the effect of azru on mitochondrial process of electron transport from the donor succinate to the acceptor cytochrome c was characterized as described above . the effect of azido - ruthenium on the ca 2 + - uptake , and on the electron transport in mitochondria is shown in fig7 . although said electron transfer involves several dozens electron transfer carriers , this reaction was not affected by azido - ruthenium of this invention . on the other hand , ca 2 + transport , which is carried out by a yet unidentified uniporter protein , was inhibited by azido - ruthenium , demonstrating the specificity of azido - ruthenium of this invention . the effect of azido - ruthenium on the binding of the toxic alkaloid ryanodine to its receptor , known as the ca 2 + - release channel that possesses regulatory ca 2 + - binding sites , was measured as described above . azido - ruthenium of this invention strongly inhibited the binding of ryanodine to sr membranes , as demonstrated in fig8 , in which a comparison is also shown with ru360 . vdac is a channel protein which transports ca 2 + across the mitochondrial outer membrane . it possesses ca 2 + - binding sites [ gincel d . et al . : biochem j . 358 ( 2001 ) 147 - 55 ] and thus is involved in regulation of its own activity . azido - ruthenium inhibited the channel activity of vdac . purified vdac was reconstituted into a planar lipid bilayer as multichannels . the channel activity was measured as the ions passed the current across the bilayer in response to a voltage gradient of 10 mv , as a function of time . in the absence of azru , vdac is stable in a long - lived , fully opened state and remains open for up to 2 hours of recording . however , addition of azru to the same channel induced vdac closure , in a time - dependent manner . ca 2 + , in the presence of 1 m nacl , prevented the inhibitory effect of azru on vdac activity . as has been shown for rur [ gincel d . et al . : biochem j . 358 ( 2001 ) 147 - 55 ], chelation of ca 2 + with egta re - established azru inhibition , suggesting specific interaction of azru with vdac ca 2 + - binding sites . azru also decreased vdac conductance in multi - channel experiments at all voltages tested and stabilized vdac conductance at a constant low level regardless of the voltage gradient applied . similar results have been obtained with rur and ru360 . the specificity of the binding of azru to ca 2 + - binding proteins is demonstrated by testing its effects on the activity of different enzymes . the results , summarized in table 1 , indicate that the activities of ca 2 + - independent proteins such as glutamate dehydrogenase , lactate dehydrogenase , glyceraldehyde 3 - phosphate dehydrogenase , glucose 6 - phosphate dehydrogenase , choline oxidase , catalase , lysozyme , aldolase , alkaline phosphatase , as well as electron transfer in mitochondria involving over two dozen polypeptides , were only slightly inhibited by the reagent ( less than 10 % at 100 μm ). in contrast , the activities of ca 2 + - dependent proteins were strongly inhibited by azido - ruthenium ( up to 90 % at ≦ 20 μm ). the inhibition was observed for various proteins with different activities . such proteins include , for example , proteins which catalyze the transport of ca 2 + across the membrane by distinct mechanisms , all of which involve ca 2 + - binding to the protein , like the ca 2 + - pump that transports ca 2 + at the expense of atp hydrolysis , and the uniporter protein which transports ca 2 + accumulated in the mitochondrial matrix as a result of the membrane potential established by the electron transport chain . another inhibited activity is that of the ryanodine receptor , ca 2 + - release channel , which possesses regulatory ca 2 + - binding sites that control its channel activity and its ability to bind the toxic alkaloid ryanodine . the results also indicate that the activities of mg 2 + - dependent proteins , such as yeast and brain hexokinase , pyruvate kinase , luciferase and ( na + / k + ) atpase , and the zn 2 + - sensitive kcnk0 channel were not affected or were weakly inhibited at high azru concentrations (˜ 30 % at 100 μm ). by using radiolabeled [ 103 ru ] azido - ruthenium , it is possible to identify ca 2 + - binding proteins in a biological sample such as whole cells , isolated mitochondria , er , or other protein containing fractions . uv irradiation of sr or mitochondria in the presence of [ 103 ru ] azru resulted in its covalent binding to several proteins , as revealed by sds - page followed by coomassie staining and autoradiography . as expected for the photoreactive [ 103 ru ] azru , the labeling of the proteins was significantly increased upon uv irradiation , indicating the formation of a stable covalent bond . in skeletal muscle sr incubated with 0 . 5 nmol [ 103 ru ] azru / mg protein ( 0 . 5 μm ) with or without uv irradiation , nine out of about thirty proteins stained by coomassie were labeled with [ 103 ru ] azru . among the labeled proteins are known ca 2 + - binding proteins such as ryr , myosin , ca 2 + - atpase and calsequestrin , but there were also two unidentified proteins of 37 and 25 kda ( fig1 a ). similarly , in an isolated mitochondrial membranal fraction from which soluble proteins were extracted , photoactivated [ 103 ru ] azru labeled seven out of about twenty seven proteins stained by coomassie ( fig1 b ). weak [ 103 ru ] azru labeling of the proteins was observed with no uv irradiation indicating a very stable interaction , which is not surprising when considering the reported labeling of mitochondrial proteins with the non - photoreactive reagent [ 103 ru ] ru360 [ zazueta c . et al . : j . bioenerg . biomembr . 30 ( 1998 ) 489 - 98 ]. the specific reversible interaction between a ca 2 + - binding protein and azido - ruthenium can be exploited in separation of ca 2 + - binding proteins by affinity chromatography ( fig1 ). azido - ruthenium of this invention can be coupled to an inert support such as agarose , polyacrylamide or polystyrene by photoactivation , for example cellulose or sepharose r beads can be used for said covalent attachment . from the proteins applied to the column , only ca 2 + - binding proteins interact with the ruthenium bound in the column , and are retained . the retained proteins can be eluted with a ca 2 + - containing buffer . proteins eluted with ca 2 + represent ca 2 + - binding proteins . the proteins can be sequenced and the sequences can be used for the sequence homology search and identification of the proteins . purification of ca 2 + - binding proteins using afch on azru column azru , 4 . 5 mg , obtained as described in examples 1 and 2 , was incubated with cellulose fibers ( sigma - aldrich ), 1 . 25 g , in the presence of 10 mm carbonate buffer , ph 7 . 5 , irradiated by uv light for 7 times 2 minutes with short intervals between , and left overnight . the unbound azru was removed by washing with said buffer to provide azru - cellulose . the protein preparations were applied to the column , and , after washing with said buffer , eluted from the column with said buffer further containing 2 - 20 mm cacl 2 . rat liver mitochondria , rabbit sarcoplasmic reticulum , rat brain extract , calsequestrin , calmodulin , and troponin were isolated as described above . in order to solubilize the rat liver mitochondrial membrane proteins , mitochondria were treated with 3 % triton x - 100 , 2 % c 12 e 9 or 3 % triton x - 114 . to some of the eluted proteins , either egta ( 2 mm ) or cacl 2 ( 2 mm ) was added , and the samples were subjected to sds - page ( fig1 ). it can be seen that cacl 2 shifts the electrophoretic mobility of the proteins , which was demonstrated for some known ca 2 + - binding proteins [ gregersen h . j . et al . : adv . exp . med . biol . 269 ( 1990 ) 89 - 92 ]. among several dozens of proteins applied to the column , only few proteins were bound to the column and were eluted with cacl 2 . some of the proteins that were eluted from the column with the cacl 2 - containing buffer were identified by maldi - tof analysis and are presented in table 2 . the results clearly indicate the specificity of the azru - cellulose column to ca 2 + - binding proteins . the specific interaction of azru with ca 2 + - binding proteins enables to develop a biosensor chip for real - time monitoring of macromolecular interactions with ca 2 + . it can be an optical biosensor using surface plasmon resonance ( spr ). in principle , the spr - based technique detects mass and has been designed for the study of biomolecular binding and therefore provides an invaluable tool for proteomics studies of the relationship between protein structure and function . the azru - based bio - sensor chip is an optical biosensor that contains azru interacting specifically with ca 2 + - binding proteins . some of the potential applications include : i ) identification of new ca 2 + - binding proteins . by applying protein containing sample to the chip ; only ca 2 + - binding proteins would interact with the reagent bound to the chip . those proteins could be eluted with a ca 2 + - containing buffer . identification of the eluted proteins can be done by the techniques known in the art , such as maldi - tof , lc - ms / ms , interactions with antibodies , etc . the chip requires small amounts of the protein relative to column , and a ca 2 + - eluted protein can be obtained within 10 min . ii ) the second chip type allows identification of proteins interacting with ca 2 + - binding proteins . proteins often function as a part of multi - protein compounds ; identifying the individual proteins and determining their sites of interaction within the compound are essential for defining their mode of action and function . chips containing known ca 2 + - binding proteins can be used for the identification of other proteins specifically interacting with them . one of the challenges , facing life sciences researchers today , is bridging the gap between the knowledge of genomic sequence and its protein products at one side , and the understanding of the protein function and cellular behavior at the other side . this invention can contribute to said bridging . a novel chip containing several dozens of known ca 2 + - binding proteins can be used in searching for their interacting partners . binding affinity and kinetics , binding stoichiometry , binding specificity , and epitope mapping can be obtained by charging the chip with known ca 2 + - binding proteins and studying their interaction with known proteins . alternatively , the protein - charged chip can be used to search for unknown interacting protein . in this case the chip will be exposed to potential protein candidates . to identify the interacting protein , the chip will be exposed to ca 2 + or egta to dissociate said interacting protein from the chip , and the protein will be subjected to analysis by known methods , such as maldi - tof , lc - ms / ms , etc . the invention , in one of its aspects , can provide a tool for fast screening of proteins , for example proteins that are involved in cross - talk within the cell or proteins modified in certain pathological conditions , thus adding another general technique to those provided by genomics and proteomics . cellular ca 2 + signals are crucial in the control of most physiological processes including cell injury and programmed cell death ( apoptosis ). this regulation is mediated through ca 2 + interaction with a number of ca 2 + - dependent enzymes such as phospholipases , proteases , and nucleases . mitochondria and er play pivotal roles in regulating intracellular ca 2 + content and thereby involved in apoptotic cell death . moreover , members of the bcl - 2 family , a group of proteins that plays important roles in apoptosis regulation , appear to differentially regulate intracellular ca 2 + level . the u - 937 human monocytic cell line was grown under an atmosphere of 95 % air and 5 % co2 in rpmi 1640 supplemented with 10 % fetal calf serum ( fcs ), 1 mm l - glutamine , 100 u / ml penicillin , and 100 μg / ml streptomycin . cells were plated at a density of 5 . 4 × 10 4 cells / cm 2 in 24 - well plates and then incubated with or without azru for 18 hr before exposure to 1 . 25 μm staurosporine ( sts ) to induce apoptosis . cell viability was analyzed 5 and 7 hrs after sts addition by staining with 100 μg / ml acridine orange ( acor ) and 100 μg / ml ethidium bromide ( etbr ) in pbs . the cells were then visualized by fluorescence microscopy ( olympus ix51 ) and images were recorded on an olympus dp70 camera , using an swb filter . the effect of azru on apoptotic cell death induced by exposure of u - 937 cells to sts is shown in fig1 . exposure of the cells to sts for 5 or 7 hrs resulted in apoptotic cell death of about 42 % and 76 % of the cells , respectively , whereas only 6 % of the sts non - exposed cells died . azru , added 18 h before exposure to sts , dramatically reduced sts - activated apoptotic cell death by about 75 % and 47 % after 5 and 7 h of exposure to sts , respectively . azru had no effect on the viability of the cells that were not exposed to sts . in fig1 a , u - 937 cells were incubated without ( a , c ) or with azru ( 10 μm ) ( b , d ) for 18 hrs and thereafter were exposed to sts ( 1 . 25 μm ) ( c and d ). after five hours the cells were stained with acridine orange and ethidium bromide . arrows indicate cells in early apoptotic state , represented as degraded nucleus , but with intact cell membrane ( stained by acridine orange ). arrowheads indicate a late apoptotic state , as shown by the presence of a degraded nucleus ( stained by both acridine orange and ethidium bromide ). scale bar , 20 μm . in fig1 b , quantitative analysis of apoptotic cell death in control cells and cells exposed to azru was assessed 5 and 7 hr after their exposure to sts ( 1 . 25 by anova and t - test . p & lt ; 0 . 001 was considered statistically significant (***). data are the means ± sem , n = 3 . in each independent experiment , approximately 200 cells were counted for each treatment . the hexavalent rur and the trivalent ru360 have been employed in various studies as inhibitors of ca 2 + - dependent reactions . as shown here , even with no photoactivation , azru , in contrast to rur and ru360 , was effective in inhibiting the sr ca 2 + - pump ( table 3 ). azru was also more effective than rur or ru360 , with or without photoactivation , in inhibiting the ca 2 + - dependent binding of ryanodine to ryr ( table 3 ). this may open the way to inhibit other ca 2 + - dependent activities that are not sensitive to rur , such as the plasma membrane ca 2 + - atpase . in intact cells , rur was shown to slowly cross the plasma membrane and to protect against cell death induced by various stimuli . azru protected against apoptotic cell death induced by sts ( fig1 ), suggesting that azru is able to enter into the cell . rur was employed to improve mitochondrial production in ischemic reperfused pig myocardium , was employed in the nervous system to follow neuronal death progress and can act as an anti - oxidant in certain conditions . considering the potent activity of azru in rur - insensitive reactions ( see table 3 ), its applications in various biological studies should be explored . ca 2 + accumulation in sr and mitochondria was assayed as described above in the absence and presence of different concentrations of rur ( 0 . 05 - 100 μm ), ru360 ( 0 . 01 - 100 μm ) or azru ( 0 . 1 - 100 μm ). the concentration required for 50 % inhibition ( ic 50 ) was derived from the plot of ca 2 + accumulation activity or ryanodine binding as a function of the reagent concentration . the results are the mean ± sem of 3 to 5 experiments ( table 3 ). while this invention has been described in terms of some specific example , modifications and variations are possible . it is therefore understood that within the scope of the appended claims , the invention may be realized otherwise than as specifically described . | US-58917005-A |
a crawfish trap which includes a pair of frame members , one of which is fitted with a receiving loop and the other carrying a mating hook for engagement with the receiving loop , both of the frame members having a pair of legs and feet extending from the point of attachment of the loop and hook , respectively , to support the trap netting . the open mesh netting is fitted to the frame and covers the bottom and a portion of all four sides formed by the frame members to define a generally truncated pyramid with an opening in the top of the trap immediately below the frame loop and hook to permit entry of the crawfish . the trap is designed to be submerged in a body of water and located by a float and float line attached to the frame members , which float and line also serve to permit the trap to be lifted from the water for collection of the entrapped crawfish . | referring now to fig1 and 2 of the drawing , a conventional crawfish net , generally illustrated by reference numeral 1 , is illustrated with conventional netting 2 on a conventional frame 3 , the latter of which is formed of frame legs 4 . as illustrated in fig1 frame legs 4 can be spread to open conventional netting 2 in order to place conventional crawfish net 1 in functional configuration . this positioning of conventional netting 2 is made possible by frame loops 5 in frame legs 4 , which loops are interlocking , and permit frame legs 4 to be folded as illustrated in fig2 . as illustrated in both fig1 and 2 , conventional netting 2 is fitted on frame legs 4 by net loops 6 , formed in the ends of frame legs 4 . referring now to fig3 and 5 - 8 of the drawings , the crawfish trap of this invention is generally illustrated by reference numeral 8 and includes first frame 9 , formed of first frame legs 10 , and second frame 14 , formed of second frame legs 15 . first frame legs 10 are also provided with first frame feet 11 , and with a common first frame loop 12 , which is shaped to form first frame loop shoulders 13 , closed by weld 30 , as illustrated in fig3 and 7 of the drawings . similarly , second frame legs 15 are fitted with second frame feet 16 and a common second frame hook 17 , the latter of which is shaped and fitted with bend 28 to engage first frame loop 12 as illustrated in fig3 , 7 and 8 . trap netting 19 is provided on the bottom and a portion of the sides of crawfish trap 8 , leaving an opening 18 in the top of the trap to provide access for the crawfish . trap netting 19 is preferably fitted to first frame 9 and second frame 14 while second frame hook 17 is engaged with first frame loop 12 and may be sewn in place , but is preferably not attached to first frame 9 and second frame 14 , to permit easy collapse for storage . as illustrated in fig3 and 4 of the drawings , in a preferred embodiment of the invention crawfish trap 8 is formed generally in the shape of a truncated pyramid and is designed to permit crawfish to enter opening 18 while preventing easy exiting of the crawfish from the trap . first frame feet 11 and second frame feet 16 serve to stretch the corners of trap netting 19 and define the bottom of the trap . a float 26 is attached to either first frame 9 or second frame 14 by means of float line 27 in order to mark the location of the submerged trap and to retrieve it when it is desired to collect the entrapped crawfish . referring now to fig5 , 9 and 10 of the drawings , it will be appreciated that second frame hook 17 can be quickly and easily disengaged from first frame loop 12 to permit crawfish trap 8 to be folded and hung in stored configuration , much in the same manner as a coathanger and coat is hung on a support bar in a closet . this configuration of crawfish trap 8 permits trap netting 19 to hang loosely from first frame legs 10 and second frame legs 15 until such time as it is desired to again use the crawfish trap , when second frame hook 17 is engaged with first frame loop 12 and crawfish trap 8 placed in functional configuration as illustrated in fig3 and 4 of the drawings . the engagement and disengagement of second frame hook 17 from first frame loop 12 is more particularly illustrated in fig5 - 8 of the drawings . in order to initially engage second frame hook 17 with first frame loop 12 , second frame hook 17 is placed in essentially the same plane as first frame loop 12 , as illustrated in fig5 and 6 of the drawings , and the projecting end of second frame hook 17 is subsequently fitted over the end of first frame loop 12 and positioned under first frame loop shoulders 13 , as illustrated in fig7 and 8 of the drawings , to releasably secure first frame 9 to second frame 14 . bend 28 in second frame hook 17 serves to provide a positive lock between second frame hook 17 and first frame loop 12 , and weld 30 , joining first frame loop shoulders 13 , serves to prevent second frame hook 17 from disengaging first frame loop 12 when crawfish trap 8 is being retrieved while loaded with crawfish . alternatively , a band or ring can be fitted on first frame loop shoulders 13 to prevent the shoulders from spreading and second frame hook disengaging under load . in a preferred embodiment of the invention the bait provided in the interior of crawfish trap 8 for attracting crawfish therein is placed in a bait pocket 29 located between a section of bait netting 20 and the bottom segment of trap netting 19 , as illustrated in fig3 and 11 - 14 of the drawings . in this embodiment it is also preferred to secure bait netting 20 to trap netting 19 by means of fasteners , generally illustrated by reference numeral 21 . the bait [ not illustrated ] is preferably placed between bait netting 20 and trap netting 19 in order to minimize loss of bait due to the feeding of crawfish which have entered the trap by means of opening 18 . two preferred techniques for attaching bait netting 20 to trap netting 19 are illustrated in fig1 and 12 and fig1 and 14 , respectfully . referring first to fig1 and 12 of the drawings , in a preferred method of attachment , bait netting 20 is secured to fastener top 22 , which is typically one - half of a loop pile type fastener and is fitted with fastener top loops 23 . fastener bottom 24 is secured to trap netting 19 , fastener bottom 24 being fitted with a cooperating fastener bottom pile 25 , for engagement with fastener top loops 23 . this configuration defines bait pocket 29 and permits a bait material to be placed between bait netting 20 and trap netting 19 within the confines of bait netting fasteners 21 to prevent rapid consumption of the bait by crawfish which have entered the trap . an alternative method for defining bait pocket 29 in crawfish trap 8 is illustrated in fig1 and 14 of the drawing , where fastener top 22 and fastener bottom 24 are fitted together over bait netting 20 and trap netting 19 as illustrated , to define bait pocket 29 . furthermore , as illustrated in fig1 , the mesh size of bait netting 20 and / or trap netting 19 at the point where bait pocket 29 is defined by bait netting fasteners 21 may be of any suitable size depending upon convenience and the size of the crawfish being taken . it will be appreciated from a comparison of the conventional crawfish net illustrated in fig1 and 2 , and the crawfish trap of this invention as illustrated in fig3 and 4 of the drawings , that the latter is far superior to the former in design configuration for entrapment of crawfish . as heretofore described , one of the chief disadvantages in using crawfish nets of the design illustrated in fig1 and 2 is the propensity for crawfish to quickly exit the net area when the net is approached , touched or lifted to retrieve the crawfish . accordingly , the successful use of such a net depends upon rapid insertion of a pole or rod beneath conventional frame loops 5 of the net to quickly force the net upward and out of the water using water pressure to keep the crawfish from swimming out of the net during the retrieval process . experience has shown that if the lifting pole or rod touches conventional frame loops 5 or frame legs 4 prior to the lifting process , that most , if not all of the feeding crawfish will quickly exit the net and immediate retrieval of the net will be to no avail . furthermore , in some instances , merely approaching the net by wading to a point which is sufficiently close to retrieve the net by manipulation of the rod or pole will cause some crawfish to exit the net . furthermore , such nets are not generally equipped with a bait pouch or pocket to contain the bait and minimize consumption by feeding crawfish , which necessitates periodic replenishing of bait . in contrast , referring again to the drawings , the crawfish trap of this invention provides a trap netting 19 which is generally shaped in the form of a truncated pyramid as mounted on first frame 9 and second frame 14 to permit crawfish to crawl up inclined sides and into an opening 18 in trap netting 19 for access to bait which is placed on the bottom of trap netting 19 . as heretofore described , the bait is preferably , although not necessarily , placed within a bait pocket 29 defined by bait netting fasteners 21 , bait netting 20 and trap netting 19 . furthermore , unlike conventional crawfish net 1 which is designed to be placed in a body of water with conventional frame loops 5 and a portion of conventional frame legs 4 projecting from the surface of the water for access by a lifting pole or rod , crawfish trap 8 is designed to be completely submerged in the water body and located by means of a float 26 , which is attached to first frame 9 or second frame 14 by means of a float line 27 , as heretofore described . thus , while conventional crawfish net 1 is limited in use to water bodies of relative shallow depth , crawfish trap 8 is not so limited , and may be used in water of substantially any depth by simply adjusting the length of float line 27 accordingly . retrieval of crawfish trap 8 is thus made possible by grasping float 26 and float line 27 and hoisting crawfish trap 8 from the water , with little liklihood of losing the entrapped crawfish . it has been found that there is very little liklihood that entrapped crawfish will exit opening 18 after having entered crawfish trap 8 , since crawfish have a tendency to move rapidly in a horizontal plane when disturbed , and this tendency leads to movement from the bait area in the bottom center of crawfish trap 8 to the inside perimeter of the trap when crawfish trap 8 is lifted by means of float 26 and float line 27 . furthermore , water pressure flowing from top to bottom through crawfish trap 8 in the lifting process serves to further insure that very few , if any , crawfish exit the trap by means of opening 18 during the lifting process . another advantage of crawfish trap 8 over prior art traps and nets lies in the disengaged storing configuration of the trap . referring now to fig2 and 10 of the drawings , it will be appreciated that when conventional crawfish net 1 is collapsed as illustrated , and several such nets are stacked on top of each other , that net loops 6 of frame legs 4 have a tendency to become entangled in the netting of other nets and cause difficulty in disengaging the nets from each other when it is desired to use them . in contrast , the design of crawfish trap 8 includes formation of first frame feet 11 and second frame feet 16 in the form of loops , the ends of the loops being preferably joined to first frame legs 10 and second frame legs 15 , respectively , by solder , glue of other techniques , to prevent entanglement with trap netting 19 . in a preferred embodiment of the invention first frame 9 and second frame 14 are formed of wire and first frame feet 11 and second frame feet 16 are formed by bending the extended ends of first frame legs 10 and second frame legs 15 in a circle or ellipse with the terminal end of the legs in close proximity to the legs themselves , respectively , to permit soldering or gluing the ends and prevent entanglement of the ends in trap netting 19 . thus , first frame feet 11 and second frame feet 16 serve not only as stretching points to define the shape of the bottom of trap netting 19 but also to prevent entanglement of trap netting 19 when several crawfish traps are collapsed as illustrated in fig9 and 10 , and hung on a rod or pole for storage . as described above , the trap netting 19 of crawfish trap 8 can be formed of substantially any open mesh net material , but is preferably formed of a flexible material such as nylon or cotton to permit the trap to be collapsed as illustrated in fig9 and 10 of the drawings . furthermore , the netting mesh size may be of substantially any convenient size which is larger than the average size of the crawfish to be contained , but is preferably from about one - fourth to about five - eighths of an inch , and most preferably , about one - half inch in size . furthermore , while access opening 18 may be of substantially any shape , it is preferably formed in a square or a rectangle having an area of from about one - eighth to about one - fourth of the bottom area of the trap ; in a most preferred embodiment of the invention , the opening 18 is about one - sixth of the area of the bottom of crawfish trap 8 . referring again to fig4 of the drawings , it will be appreciated that the angle of inclination of first frame 9 and second frame 14 with respect to the horizontal to define the pitch of the sides of crawfish trap 8 can be of substantially any acute angle . however , an angle of pitch of from about 20 ° to about 40 ° is preferred , and in a most preferred embodiment of the invention , the angle of inclination or pitch is about 30 °. similarly , the angle of extension of first frame legs 10 and second frame legs 15 with respect to each other , respectively , can be varied to produce a crawfish trap which is either square or rectangular in shape . however , in a preferred embodiment of the invention the crawfish trap base is square , and the angle of extension between the respective legs is about 90 °. it will be appreciated by those skilled in the art that in another preferred embodiment of the invention first frame 9 and second frame 14 are characterized by first frame legs 10 and second frame legs 15 which are extended and shaped to form first frame feet 11 and second frame feet 16 , and are not joined at first frame feet 11 and second frame feet 16 , respectively . however , it will be appreciated that support members can be provided to span the distance between first frame feet 11 and between second frame feet 6 as desired , in order to provide additional support for first frame 9 and second frame 14 and to further define the bottom of trap netting 19 , should it be desired to use a smaller guage member in the construction of first frame 9 and second frame 14 . in a most preferred embodiment of the invention , first frame 9 and second frame 14 are formed of wire of sufficient stiffness to maintain structural integrity , both when second frame hook 17 is in engagement with first frame loop 12 and when crawfish trap 8 is in disengaged , stored configuration as illustrated in fig9 and 10 of the drawings , without the necessity of utilizing additional supports provided between first frame feet 11 and between second frame feet 16 , respectively . in this regard , it is important that first frame feet 11 and second frame feet 16 be shaped such that the surfaces contacting trap netting 19 are larger than the mesh netting in order to prevent first frame feet 11 and second frame feet 16 from projecting through the netting . | US-84845977-A |
a contact lens , according to the present invention , comprises : a housing having a light - incident part on which a therapeutic beam oscillated from a beam generation part is incident , and a light - emitting part for guiding the therapeutic beam incident from the light - incident part to an eyeball ; a first sensing part arranged between the light - incident part and the light - emitting part so as to sense the reaction occurring in a healing site of the eyeball on which the therapeutic beam is irradiated ; and a second sensing part arranged in a region of the light - emitting part spaced from the first sensing part so as to sense whether contact has been made with the eyeball . | hereinafter , a contact lens and an ophthalmic device having the same according to an embodiment of the present invention will be described in detail with reference to the accompanying drawings . prior to describing the invention , it is to be noted beforehand that different reference numerals are used to designate identical elements between contact lenses according to first and second embodiments of the present invention . also , it should be noted beforehand that a contact lens according to a third embodiment further includes a gaze part , in addition to the elements of the contact lens according to the second embodiment , and the same elements as the second embodiment are denoted by the same reference numerals as the second embodiment . an ophthalmic device according to an embodiment of the present invention is described as including the contact lens according to the third embodiment of the present invention . fig1 illustrates a contact lens being placed in contact with a patient &# 39 ; s eye according to embodiments of the present invention . fig2 is a cross - sectional view of a contact lens according to a first embodiment of the present invention . as illustrated in fig1 and 2 , a contact lens 1 according to the first embodiment of the present invention includes a housing 10 , a lens part 30 , a first detecting part 50 , and a second detecting part 70 . the housing 10 includes a main body 10 , an entrance part 14 , and an exit part 16 . the main body 12 of the housing 10 accommodates the lens part 30 , the first detecting part 50 , and the second detecting part 70 . also , the main body 12 of the housing 10 forms the entrance part 14 and exit part 16 through which a treatment beam enters and exits . the exit part 16 is placed in contact with a patient &# 39 ; s eye . the lens part 30 is accommodated in the main body 12 of the housing 10 and guides a treatment beam entering through the entrance part 14 to the exit part 16 . the lens part 30 consists of a plurality of concave lenses or convex lenses , and serves to collimate the treatment beam entering through the entrance part 14 or change the exit path of the treatment beam . the first detecting part 50 is located between the entrance part 14 and the exit part 16 , inside the main body 12 of the housing 10 . the first detecting part 50 detects a reaction in a treated area of the eye to which a treatment beam is delivered . that is , the first detecting part 50 detects the amount of bubbles generated when a treatment beam is delivered to the eye . in one embodiment of the present invention , an ultrasonic sensor is used as the first detecting part 50 . alternatively , various well - known sensors capable of detecting the amount of bubbles in the eye , generated by the delivery of a treatment beam , as well as the ultrasonic sensor , may be used as the first detecting part 50 . the second detecting part 70 is located in the area of the exit part 16 of the housing 10 , spaced apart from the first detecting part 50 . the second detecting part 70 detects whether there is contact with the eye . in one embodiment of the present invention , a proximity sensor is used as the second detecting part 70 . the ophthalmologist can tell whether the contact lens 1 is placed in contact with the eye , based on a detection signal from the second detecting part 70 . fig3 is a cross - sectional view of a contact lens according to the second embodiment of the present invention . as illustrated in fig3 , a contact lens 3000 according to the second embodiment of the present invention includes a first housing 3100 , a second housing 3300 , a lens part 3500 , a first detecting part 3700 , and a second detecting part 3800 . unlike the contact lens 1 according to the first embodiment of the present invention , the first and second housings 3100 and 3300 of the contact lens 3000 according to the second embodiment of the present invention are detachably held together . the first detecting part 3700 is located in either the first housing 3100 or the second housing 3300 and detects a reaction in a treated area of the eye to which a treatment beam is delivered . preferably , the first detecting part 3700 and the second detecting part 3800 may be located together inside the second housing 3300 , as in the first embodiment of the present invention . the second detecting part 3800 is located inside the second housing 3300 and detects whether there is contact with the eye . a proximity sensor is used as the second detecting part 3800 . as such , the contact lens 3300 according to the second embodiment of the present invention has the advantage that the first housing 3100 and the second housing 3300 may be replaced individually if the first detecting part 3700 or the second detecting part 3800 breaks down , since the first housing 3100 and the second housing 3300 are detachably held together . therefore , repair and maintenance costs of this product may be reduced . fig4 is a cross - sectional view of a contact lens according to the third embodiment of the present invention . as illustrated in fig4 , a contact lens 300 according to the third embodiment of the present invention includes a first housing 3100 , a second housing 3300 , a lens part 3500 , a first detecting part 3700 , a second detecting part 3800 , and a gaze part 3900 . that is , the contact lens 300 according to the third embodiment of the present invention further includes a gaze part 3900 , in addition to the contact lens 3000 according to the second embodiment . the gaze part 3900 is located in an inner region visible to the eye and emits gaze fixation light for the patient to look at that forms a point of gaze . the gaze part 3900 is prepared as a light source that is located inside the contact lens 3000 , close to the eye and that emits light for the patient to look at that is visible to the eye . in particular , the gaze part 3900 emits a wide wavelength band of light for the patient to look at to form a point of gaze visible to the eye . the light for the patient to look at that is emitted by the gaze part 3900 forms a point of gaze at which the eye is looking , thereby preventing the eye from moving when the contact lens 3000 is in contact with the eye . the gaze part 3900 is applicable to the contact lens 1 of the first embodiment of the present invention , as well as to the contact lens 3000 of the second embodiment of the present invention . fig5 is a schematic diagram of an ophthalmic device including the contact lens of fig4 according to an embodiment of the present invention . fig6 is a control block diagram of an ophthalmic device according to the present invention . fig7 is a combined perspective view of a contact lens and a rotation support unit according to the present invention . fig8 is an exploded perspective view of a contact lens and a rotation support unit according to the present invention . as illustrated in fig5 to 8 , an ophthalmic device 100 including the contact lens 3000 according to the third embodiment of the present invention includes a main body 1000 , a beam generator 2000 , the contact lens 3000 , a holder unit 4000 , a connecting unit 5000 , an input part 6000 , a measuring part 7000 , and a control unit 8000 . the main body 1000 constitutes the outer appearance of the ophthalmic device 100 , and includes an eye examination part ( not shown ) such as a microscope that can magnify , with which the patient &# 39 ; s eye can be examined . the beam generator 2000 is equipped within the main body 1000 and generates a treatment beam and emits it to the contact lens 3000 . the beam generator 2000 includes a laser diode in order to generate and emit laser light used as a treatment beam . for example , a q - switched nd : yag laser , etc . may be used as the beam generator 2000 . the contact lens 3000 includes a first housing 3100 , a second housing 3300 , a lens part 3500 , a first detecting part 3700 , a second detecting part 3800 , and a gaze part 3900 . the first and second housings 3100 and 3300 of the contact lens 3000 are detachably held together . the first housing 3100 is held in the holder unit 4000 , and the second housing 3300 is detachably attached to the first housing 3100 held in the holder unit 4000 . the first housing 3100 includes a first housing body 3110 , an entrance part 3130 , hooks 3150 , and connecting pins 3170 . the first housing body 3110 forms the outer appearance of the first housing 3100 , and one side of the first housing body 3110 forms the entrance part 3130 through which a treatment beam generated from the beam generator 3000 enters . the hooks 3150 are provided to detachably hold the first housing 3100 and the second housing 3300 together . while the hooks 3150 are provided on the first housing 3110 in one embodiment of the present invention , they may be switched with hook joints 3350 of the second housing 3300 to be described later and provided on the second housing 3300 . using the hooks 3150 is an example of the method of detachably holding the first housing body 3110 and a second housing body 3310 together , and various well - known joining methods such as pinning or screwing may be used instead of using the hooks 3150 . the connecting pins 3170 is located downward from the first housing body 3110 . the connecting pins 3170 are attached to the holder unit 4000 . more specifically , the connecting pins 3170 are attached to pin joints 4113 of a holder support 4110 to be described later to hold the holder unit 4000 and the first housing 3100 of the contact lens 3000 together . needless to say , the connecting pins 3170 are merely an example , and the holder unit 4000 and the first housing 3100 of the contact lens 3000 may be held together by various well - known joining methods such as hooking or screwing . the second housing 3300 includes the second housing body 3310 , an exit part 3330 , and the hook joints 3350 . the second housing body 3310 guides a treatment beam entering through the entrance part 3130 of the first housing 3100 to the patient &# 39 ; s eye . in this instance , the exit part 3330 needs to be placed in contact with the patient &# 39 ; s eye . the hook joints 3350 are provided on the second housing 3310 in one embodiment of the present invention . more specifically , the hook joints 3350 are provided at points where the first housing body 3110 and the second housing body 3310 are held together . as described above , the hook joints 3350 may be switched with the hooks 3150 of the first housing 3100 , rather than being provided on the second housing body 3310 . for example , if the hooks 3150 of the first housing 3100 are located on the second housing 3300 , the hook joints 3350 of the second housing 3300 are provided on the first housing 3100 . the lens part 3500 is accommodated in the first housing body 3110 and the second housing body 3310 . the lens part 3500 is a combination of convex lenses and concave lenses , and serves to collimate a treatment beam entering through the entrance part 3130 or regulate the exit path of the treatment beam and guide it to the exit part 3330 . the first detecting part 3700 and the second detecting part 3800 are accommodated in the second housing body 3310 in one embodiment of the present invention . an ultrasonic sensor and a proximity sensor are used as the first detecting part 3700 and the second detecting part 3800 , respectively . the first detecting part 3700 is accommodated in the second housing body 3310 , spaced apart from the second detecting part 3700 . the first detecting part 3700 detects a reaction in the treated area of the eye and sends a detection signal to the control unit 8000 . more specifically , the first detecting part 3700 detects the amount of bubbles in the treated area of the eye , generated by the delivery of a treatment beam and sends a detection signal to the control unit 8000 . based on the detection signal from the first detecting part 3700 , the control unit 8000 may control the operation of the beam generator 3000 or of a beam delivery part that is not shown in the present disclosure . the second detecting part 3800 is located in the area of the exit part 3330 of the second housing 3300 . the second detecting part 3800 detects whether the contact lens 3000 is placed in contact with the patient &# 39 ; s eye . a detection signal from the second detecting part 3800 is sent to the control unit 8000 . based on the signal from the second detecting part 3800 , the operation of the beam generator 2000 or of the beam delivery part is controlled . for example , if the contact lens 3000 is deemed to be in contact with the eye , based on the signal from the second detecting part 3800 , a second controller 8300 of the control unit 8000 to be described later controls the operation of the beam generator 2000 so as to deliver a treatment beam to the treated area of the eye . fig9 is a view of a first magnetic polarity of the holder support of the rotation support unit of fig8 . fig1 is a view of a second magnetic polarity of the holder support of the rotation support unit of fig8 . fig1 is an operational view of how the rotation support unit is actuated by the magnetic polarity indicated by the line a - a of fig9 . fig1 is an operational view of how the rotation support unit is actuated by the magnetic polarity indicated by the line b - b of fig9 . the holder unit 4000 is detachably attached to the contact lens 3000 , and rotates the contact lens 3000 relative to the eye . that is , the holder unit 4000 operates in a way that automatically adjusts the position of the contact lens 3000 in response to an input signal from the operator . in one embodiment of the present invention , the holder unit 4000 includes a rotation support unit 4100 , a driving unit 4300 , and a driving detecting part 4500 . the rotation support unit 4100 includes a holder support 4110 , a rotation stage 4130 , and a rotary joint part 4150 . the rotation support unit 4100 supports the contact lens 3000 , and rotates the contact lens 3000 about at least one axis such as an x - axis on which the contact lens 3000 pivots , a y - axis on which the contact lens 3000 tilts , or a z - axis on which the contact lens 3300 swivels . the pivoting , tilting , and swiveling of the rotation support unit 4100 are caused by a driving force from the driving unit 4300 . the holder support 4110 includes a support body 4111 and the pin joints 4113 . the holder support 4110 detachably supports the contact lens 3000 . the holder support 4110 , in response to the operation of the rotation stage 4130 and of the rotary joint part 4150 , causes the contact lens 3000 to pivot , tilt , and swivel . the support body 4111 is formed in the shape of a magnetic disk . the support body 4111 is made from a magnetic material having an n pole and an s pole so that a magnetic force is generated between the support body 4111 and magnetic regions 4311 of a first driver 4310 to be described later . as illustrated in fig9 , the support body 4111 is made of a magnet that is split into four sections about the z - axis , and each pair of two sections facing each other across the center point has the same pole . on the other hand , in another embodiment , the support body 4111 may be a magnet that is split into two horizontally , i . e ., in the direction of the x - axis and has opposite n and s poles , as illustrated in fig1 . regarding the operation of the support body 4111 , the support body 4111 depicted in fig9 , together with the magnetic regions 4311 of the first driver 4310 , will be described with reference to the operational views of fig1 and 12 . the pin joints 4113 are pierced through the surface of the support body 4111 on which the contact lens 3000 is supported . the pin joints 4113 and the connecting pins 3170 of the first housing 3100 are attached together . as such , the first housing 3100 of the contact lens 3000 is detachably attached to the holder support 4110 . as the first housing 3100 is substantially detachably attached to the second housing 3300 , it is deemed that the contact lens 3000 is detachably attached to the holder support 4110 . the pin joints 4113 are merely an example of the present invention , and if hooks , etc . are used in place of the connecting pins 3170 of the first housing 3100 because of a design change , other types may substitute for the pin joints 4113 . the rotation stage 4130 is formed in a way that the holder support 4110 swivels . the rotation stage 4130 is connected to a second driver 4330 of the driving unit 4300 and rotates by the driving force of the second driver 4330 . in this instance , the holder support 4110 and the rotation stage 4130 are connected together by the rotary joint part 4150 , and the rotational force of the rotation stage 4130 is delivered to the holder support 4110 by the rotary joint part 4150 . the rotary joint part 4150 connects the holder support 4110 and the rotation stage 4130 together . in one embodiment of the present invention , the rotary joint part 4150 includes a first rotary joint part 4151 , a second rotary joint part 4153 , and a fastener member 4155 . the rotary joint part 4150 is capable of receiving a rotational force from the rotation stage 4130 and transmitting a rotational driving force that swivels the holder support 4110 . also , a magnetic force generated between the support body 4111 of the holder support 4110 and the magnetic regions 4311 of the first driver 4310 make the rotary joint part 4150 pivot or tilt , thus pivoting or tilting the holder support 4110 . the first rotary joint part 4151 is rotatably attached to the bottom of the holder support 4110 and tilts the holder support 4110 . the first rotary joint part 4151 does not substantially tilt the holder support 4110 in an active way , but instead guides the tilting of the holder support 4110 that rotates by a magnetic force between the s pole of the support body 4111 facing each other across the cross - section of the line b - b of fig9 and the s pole of the magnetic regions of fig1 . the second rotary joint part 4153 connects the first rotary joint part 4151 and the rotation stage 4130 together , and the second rotary joint part 4153 is attached to the first rotary joint part 4151 so that its axis of rotation ( x - axis ) is perpendicular to the axis of rotation of the first rotary joint part 4151 . the second rotary joint part 4153 pivots the holder support 4110 by a driving force from the first driver 4310 . the second rotary joint part 4153 does not substantially pivot the holder support 4110 in an active way , but instead guides the pivoting of the holder support 4110 that rotates by a magnetic force between the n pole of the support body 4111 facing each other across the cross - section of the line a - a of fig9 and the n pole of the magnetic regions 4311 of fig1 . the fastener member 4155 fastens the holder support 4110 and the first rotary joint part 4151 together so as to allow the holder support 4110 to tilt relative to the first rotary joint part 4151 . also , the fastener member 4155 fastens the first rotary joint part 4151 and the second rotary joint part 4153 so as to allow the holder support 4110 to pivot . the driving unit 4300 includes the first driver 4310 and the second driver 4330 . the first driver 4310 generates driving force to make the holder support 4110 pivot or tilt . the first driver 4310 includes the magnetic regions 4311 and a current supply part 4313 . the magnetic regions 4311 are having a pair of n pole and a pair of s pole , each pair facing each other along the x - axis and the y - axis , respectively , and are placed at regular interval in a circumferential direction . the magnetic regions 4311 are located between the holder support 4110 and the rotation stage 4130 , corresponding to the four sections of the holder support 4110 having an n pole and an s pole . in one embodiment of the present invention , the magnetic regions 4311 form a magnetic force repulsive on the n pole or s pole of the holder support 4110 , corresponding to the direction or amount of electric current from the current supply part 4313 , thereby causing the holder support 4110 to pivot or tilt . needless to say , the amount of electric current supplied from the current supply unit 4311 to the magnetic regions 4311 needs to be controlled so as to allow the holder support 4110 to pivot or tilt by adjusting the strength of the magnetic force of opposing magnetic regions . the magnetic regions 4311 of the holder support 4110 may be either permanent magnets or electromagnets . the second driver 4330 transmits driving force to the rotation stage 4130 . preferably , a stepping motor may be used as the second driver 4330 to allow the holder support 4110 to swivel at a certain angle . besides , various well - known driving mechanisms , such as motors , capable of finely adjusting the swivel angle or angular speed of the holder support 4110 may be used as the second driver 4330 . the driving detecting part 4500 is placed on the rotation stage 4130 and detects the adjusted position of the holder support 4110 relative to the operation of the holder support 4110 . that is , the driving detecting part 4500 detects a changed position of the holder support 4110 caused by pivoting , tilting , or swiveling of the holder support 4110 . the driving detecting part 4500 may be implemented as an optical sensor including a light source for emitting light and a light receiving part for detecting emitted light . the driving detecting part 4500 , implemented as an optical sensor including the light source and the light receiving part , may detect the adjusted position of the holder support 4110 based on the amount of light received by the light receiving part . next , the connecting unit 5000 includes a first connecting unit 5000 and a second connecting unit 5000 . the connecting unit 5000 connects the main body 1000 and the holder unit 4000 together . also , the connecting unit 5000 reciprocates the holder unit 4000 along the y - axis and the x - axis . that is , the first connector 5100 of the connecting unit 5000 is connected to the main body 1000 , and reciprocates along the y - axis ( horizontally ) on which the holder support 4110 tilts . the second connector 5200 connects the first connector 5100 and the holder unit 4000 together in a direction transverse to the movement direction of the first connector 5100 , and reciprocates along the z - axis ( vertically ) on which the holder support 4110 swivels . the connecting unit 5000 may further include a connecting unit driver ( not shown ) that delivers driving force to the connecting unit 5000 . the input part 6000 is provided to apply an actuation signal to the holder unit 4000 and the connecting unit 5000 . the input part 6000 may substantially apply an actuation signal to actuate the driving unit 4300 of the holder unit 4000 and an actuation signal to actuate the connecting unit 5000 . preferably , the input part 6000 may be located in an area the operator &# 39 ; s hands can access easily . the measuring part 7000 serves to measure a detection signal sent from the first detecting part 3700 of the contact lens 3000 . for example , the measuring part 7000 measures a detection signal sent in real time from the first detecting part 3700 , that is , information about the amount of bubbles generated in the treated area of the eye . in this way , the measuring part 7000 analyzes a signal sent in real time from the first detecting part 3700 and transmits it to the control unit 8000 . for reference , although the measuring part 7000 is provided to analyze and measure a signal from the first detecting part 3700 in one embodiment of the present invention , the measuring part 7000 may be omitted so long as it has an algorithm by which a detection signal from the first detecting part 3700 is analyzed directly by the control unit 8000 . lastly , the control unit 8000 may control the operation of the holder unit 4000 and of the connecting unit 5000 based on an actuation signal applied from the input part 6000 , and also may control the operation of the beam generator 2000 or of the beam delivery part based on signals from the first detecting part 3700 and second detecting part 3800 . in one embodiment of the present invention , the control unit 8000 includes a first controller 8100 and a second controller 8300 . the first controller 8100 controls the operation of the holder unit 4000 and of the connecting unit 5000 based on an actuation signal from the input part 6000 . the second controller 8300 controls the operation of the beam generator 2000 based on signals from the first detecting part 3700 and second detecting part 3800 . more specifically , as well as controlling the operation of the beam generator 2000 based on a signal from the measuring part 7000 that has measured a detection signal from the first detector 3700 , the second controller 8300 of the present invention applies a control signal based on a detection signal from the second detecting part 3800 in such a way as to actuate the beam generator 2000 if the contact lens 3000 is in contact with the eye , or to stop the operation of the beam generator 2000 ( or to keep the beam generator 2000 stopped ) if the contact lens 3000 is not in contact with the eye . with this construction in mind , the operational process of the ophthalmic device 100 according to the present invention will be described below . prior to the description , it is to be noted that the operational process of the ophthalmic device 100 including the contact lens 3000 according to the third embodiment of the present invention will described . first , the first housing 3100 and second housing 3300 of the contact lens 3000 are held together , and then the contact lens 3000 and the holder support 4110 are held together with the connecting pins 3170 of the first housing 3100 and the pin joints 4113 of the holder support 4110 . alternatively , the first housing 3100 may be attached to the holder support 4110 first , and then the second housing 3300 of the contact lens 3000 may be attached to the first housing 3100 . next , the following first to fourth operational process steps are performed by applying an actuation signal to the input part 6000 so as to place the contact lens 3000 in contact with the patient &# 39 ; s eye . first , the connecting unit 5000 is actuated to bring the contact lens 3000 close to the eye second , if pivoting of the contact lens 3000 is required , the current supply part 4313 of the first driver 4310 applies an electric current to the magnetic regions 4311 so as to generate a magnetic force between the holder support 4110 and the magnetic regions 4311 . third , if tilting of the contact lens 3000 is required , the current supply part 4313 of the first driver 4310 applies an electric current to the magnetic regions 4311 . fourth , if swiveling of the contact lens 3000 is required , the second driver 4330 is actuated to rotate the rotation stage 4130 , thus causing the holder support 4110 to swivel . once the contact lens 3000 is placed in contact with the eye , the gaze part 3900 emits gaze fixation light for the patient to look at to prevent the eye from moving . the above - mentioned first to fourth operational process steps are not sequentially performed , but may be performed selectively by the operator . when the contact lens 3000 is brought close to the patient &# 39 ; s eye by the operation of the holder unit 4000 and of the connecting unit 5000 , the second detecting part 3800 generates a detection signal indicative of whether the contact lens 3000 is in contact with the eye . if the contact lens 3000 is deemed to be in contact with the eye , based on the detection signal from the second detecting part 3800 , the second controller 8300 generates a control signal to actuate the beam generator 2000 . the beam generator 2000 may be actuated automatically or by unlocking a device that applies an input signal to the beam generator 2000 , in response to the control signal from the second controller 8300 . on the contrary , if the contact lens 3000 is deemed to be not in contact with the eye , based on the detection signal from the second detecting part 3800 , the second controller 8300 generates a control signal to not actuate the beam generator 2000 . during the delivery of a treatment beam to the treated area of the eye in response to a control signal from the second controller 8300 , the first detecting part 3700 detects the amount of bubbles in the area to which the treatment beam is delivered . if it is deemed that a preset amount of bubbles is detected , based on a signal from the first detecting part 3700 , the second controller 8300 generates a control signal to stop the operation of the beam generator 2000 . in view of this , the second detecting part capable of detecting whether the contact lens is placed in contact with the eye and the first detecting part capable of detecting a change in the status of the eye caused by the delivery of a treatment beam may be provided inside the contact lens , thus improving the reliability of the product . although the foregoing embodiments of the present invention have been described with reference to the attached drawings , it will be understood by those of ordinary skill in the art to which the present invention pertains that the present invention may be embodied in other specific forms without changing the technical idea or essential features of the present invention . accordingly , it should be understood that the above - described embodiments are exemplary in all aspects and do not limit the scope of the present invention . the scope of the present invention is defined by the appended claims rather than the detailed description as described above , and it will be construed that all changes and modifications derived from the meanings and scope of the following claims and the equivalent concept fall within the scope of the present invention . | US-201414907519-A |
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