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a cardiac rhythm management device is described in which the rate controlling parameter of a rate adaptive pacemaker is the heart &# 39 ; s total active time . the active time is evaluated using the intraventricular impedance technique , the active time being the length of the interval between the onset of contraction and the point where a line passing through two points on the fast filling segment of the impedance wave form reaches the impedance level corresponding to the end - diastole impedance of the preceding beat . the approach results in a upper rate limit corresponding to the maximum heart rate that does not compromise circulatory function , e . g ., result in a decrease in cardiac output , or an increase in cardiac workload without an associated increase in cardiac output . the application also teaches the use of the heart &# 39 ; s total active time as an indication of hemodynamic instability for triggering a defibrillation .

referring first to fig1 there is shown at 10 a representation of a heart in which an endocardial lead 12 has been implanted within the right ventricle thereof . the lead 12 includes a plurality of electrodes including a tip electrode 14 , generally disposed in the right apex of the heart and a first sensing electrode 16 disposed proximally of the tip electrode either in the right ventricle , the right atrium , or in the superior vena cava . the lead 12 connects to an implantable cardiac stimulator , such as a pacemaker or a aicd 18 having a metal housing or can 20 , at least a portion of which is in ohmic contact with the patient &# 39 ; s body tissue . assuming the device to be a pacemaker , the lead 12 plugs into a connector block 22 formed from an insulating material but including a spot electrode 24 thereon . the pacemaker 18 can thus be said to incorporate a dual indifferent electrode as more particularly described in the hauck et al . u . s . pat . no . 5 , 036 , 849 , assigned to applicant &# 39 ; s assignee . the teachings of the hauck et al . patent are hereby incorporated by reference . referring next to fig2 it can be seen that there is contained within the metal can or housing 20 of the device 18 , an oscillator 26 which is operatively coupled between the exposed electrode surface 21 of the can 20 and the distal tip electrode 14 on the lead 12 . those skilled in the art will appreciate that there is contained within the lead body 12 , elongated , flexible conductors for electrically coupling the electrodes 14 and 16 to the circuitry contained within the can 20 . a sense amplifier , filter and demodulator circuit 26 has a first input connected to the spot electrode 24 and a second input connected to the sensing electrode 16 on the lead body 12 when a voltage of a predetermined frequency in the range of from 1 khz . to 20 khz . is applied between the tip electrode 14 and the electrode 21 of the can 20 , as the heart beats , the alternating current signal from oscillator 26 will be modulated due to the impedance changes resulting from the influx and out - flow of blood from that chamber . that modulated signal is developed between the electrodes 16 and 24 with the amplifier / demodulator / filter circuit 26 being used to create on output line 28 a signal which corresponds to the modulating envelope and is the instantaneous impedance versus time signal . the z vs . t signal is then applied to an analog - to - digital converter 30 which may , in practice , be an on - board portion of the integrated circuit comprising the microprocessor 32 . for ease of representation , however , the a / d converter 30 is shown as a separate component and it operates in a well - known fashion to convert the analog signal z vs . t on line 28 to a digital representation thereof . with reference to fig3 it is also envisioned that two leads including atrial lead 33 and ventricular lead 35 may be used , each with a tip electrode 37 and 39 and a ring electrode 41 and 43 . by coupling a constant current source 45 across the two tip electrodes 37 and 39 and sensing the signal between the two ring electrodes 41 and 43 , a signal proportional to the impedance of the blood volume in these two chambers can be derived and used to compute the heart &# 39 ; s active time in a manner hereinafter described . the microprocessor 32 has its data input &# 34 ; d &# 34 ; connected to receive the digital output from the a / d converter 30 , via i / o module 33 . a system bus 34 contains the necessary data , address and control lines for supporting a rom memory 36 and a ram memory 38 and i / o interface module 33 . stored in the rom 36 is a program of instructions executable by the microprocessor 32 as well as various fixed constants which may be required . the ram 38 provides temporary storage for intermediate calculations and the like . the i / o interface 33 allows the bidirectional flow of digital data and commands between the microprocessor and the a / d converter 30 as well as the stimulating pulse generator 42 . the output from the pulse generator 42 is applied through the lead 12 to the tip electrode 14 , via a conductor 44 , which extends through the lead body 12 from the device 18 to the tip electrode 14 . as will be explained in greater detail below , the microprocessor 32 is programmed to compute from the impedance versus time ( z vs . t ) signal developed at the output of the amplifier / demodulator / filter circuit 26 the heart &# 39 ; s active time and then develops a control signal for the pulse generator 42 , causing it to emit stimulating pulses at a rate which is proportional to the computed active time . referring to fig4 numeral 46 refers to a typical ecg wave form showing the qrs complex 48 , the t - wave 50 , and the p - wave 52 . in temporal alignment with the ecg wave form 46 is an impedance versus time wave form 54 . this impedance waveform , stored in ram 38 , is approximately the average of the waveforms produced by the previous sixteen beats . to minimize the size of ram required , an exponential averaging technique is used . to clarify how this average is calculated , an explanation of how one of its points is calculated may be helpful . for instance , consider as an example an impedance point located t ms after the pacing spike or sensed r wave . first , time , t , is set equal to zero at every ventricular pacing spike or sensed ventricular event . the new average impedance ( z avg . sub . ( n ) ( t )) valve is then calculated at t ms from the ventricular pacing spike or sensed ventricular event as , ## equ1 ## where n represents the beat number and z the raw digitized impedance at t ms . this averaging technique is called ensemble averaging . the ensemble averaged impedance is , in this way , free from any change asynchronous with the heart activity ( like respiration , motion , etc .). it can be seen that the impedance is at a minimum at point 56 just prior to the onset of ventricular contraction . the impedance reaches a maximum at point 58 corresponding to end - systole when the blood volume contained within the heart is at a minimum . at that point , the heart begins to refill and the impedance again begins to decrease , initially at a fast rate , such as between points 60 and 62 , and then at a more gentle or slower rate reflected by the decreasing slope of the impedance waveform segment 64 . the time interval labeled total active time corresponds to the total time that will elapse from the ventricular pacing pulse or ventricular sensed r - wave ( numeral 48 in fig4 ) to the end of the filling phase , provided that the ventricles are refilled at the fast - filling rate reflected by the slope of the line 66 . this parameter value can be estimated by measuring the fast - filling phase rate and calculating the total time needed for the heart to fill to the volume it contained at end - diastole in the previous beat . the end points of the fast - filling phase can be defined , for example , as the end - systolic resistance less 5 percent and less 30 percent of the stroke resistance . these are the points labeled 95 percent and 70 percent , respectively . the microprocessor then computes the time between the ventricular pacing pulse or the ventricular sensed r - wave at point 56 and the intersection between the linear regression line 66 passing through the 95 percent and 70 percent points 60 and 62 and the end - diastolic resistance value associated with the preceding beat , i . e ., intersection point 68 . this line can also be found using a digital filter ( fir or iir ) to look for the maximum slope during the diastolic portion of the impedance waveform . this slope and the time of the maximum can be used to obtain the least square errors line . other approaches will be obvious to those skilled in the art . to maintain hemodynamic stability , pacing must be inhibited during the patient &# 39 ; s active time . this should be apparent in that if not enough time is provided for the ventricular chambers to fill , assuming the maximum filling rate , cardiac output will necessarily drop . in accordance with the present invention , the heart rate controller , i . e ., microprocessor 32 and pulse generator 42 , operates to urge the heart rate towards a minimum rate by utilizing the hemodynamic feedback attendant in the use of active time as the rate controlling parameter . this can be understood by appreciating that active time provides a continuously varying measure of the minimum time needed for the heart to refill . it is responsive to changes in venous return as well as to changes in sympathetic and parasympathetic tone . active time causes a rate increment to be added to the existing maximum heart rate on each beat that will maintain hemodynamic stability , i . e ., a constant or increasing cardiac output . by preventing pacing rates faster than that maximum , it has been found that at does not decrease with rate , except during exercise or increased mental stress . thus , the positive feedback loop tending to drive heart rates higher is disabled . the equation to calculate the escape rate from the computed total active time may be expressed as follows : ## equ2 ## where q = at - at min . if q & lt ; 0 set q = 0 . at is measured in milliseconds and hr in beats per minute . the parameter g is calculated as : ## equ3 ## where at avg is the long term average of the active time and is used to establish the relationship between the lower rate limit with the average value of at . the next beat period ( t = 1 / hr ) is calculated using a 16 beat exponential moving average of the at calculated using equation 1 above . if the time interval between the current and next subsequent beat is within plus or minus 20 percent of the current moving average ( t avg ), the moving average is updated . if the new period is outside the range , t avg is changed only 5 %. the actual rate will be determined by hr avg = 1 / t avg . in this fashion , hr avg is constrained to be between the programmable minimum and maximum heart rates established for the microprocessor - based cardiac stimulator . it is seen then that the maximum hemodynamically stable heart rate ( mhsr ) is calculated on a beat - by - beat basis as ## equ4 ## where at is measured in milliseconds and used to control the rate at which cardiac stimulating pulses may be produced by the pulse generator 42 of fig2 or 3 . the present invention is the first to use the total active time , including electrical depolarization , mechanical contraction , relaxation and fast - filling phase , as the hemodynamic sensor that evaluates the stability of the cardiovascular system . the millerhagen et al . application ser . no . 07 / 651 , 318 , filed feb . 5 , 1991 , and assigned to applicant &# 39 ; s assignee , discloses a cardiac stimulating system having a hemodynamically determined upper rate limit . one sensor is employed to adjust the pacing rate as a function of demand while another sensor , determines whether a further rate increase will compromise the heart &# 39 ; s hemodynamic performance and , if so , will limit the rate increase accordingly . it should be recognized that the computed total at can be used as the &# 34 ; governor &# 34 ; for the maximum pacing rate , i . e ., to inhibit a further rate increase if to do so would compromise hemodynamic performance . this invention has been described herein in considerable detail in order to comply with the patent statutes and to provide those skilled in the art with the information needed to apply the novel principles and to construct and use such specialized components as are required . however , it is to be understood that the invention can be carried out by specifically different equipment and devices , and that various modifications , both as to the equipment details and operating procedures , can be accomplished without departing from the scope of the invention itself .

US-80662691-A

this invention relates generally to a body pillow and support system . due to the need for additional support , pregnant women often encounter difficulty sleeping . the support pregnant women typically need is not just for their head , but for their abdomen , back and / or legs . many pregnant women find themselves hot or cold as well as hot on one part of their body and cold on a different part of their body . all of these conditions are usually met by the pregnant woman finding several pillows and stuffing those same pillows all around her when she is trying to get some rest . this invention also is useful for a diverse group of people who need soft support to rest or recuperate and is not limited to women who are pregnant .

as depicted in fig1 , a preferred embodiment of the current invention provides a full body pillow 10 including a removable or permanently fixed pillow cover 50 . pillow 10 and cover 50 have the general configuration of a question mark . fig1 depicts a view of a front side 60 of pillow 10 . the unique configuration of pillow 10 provides support for both the front and the back of the user &# 39 ; s body . the support is provided by the combination of several elements that include a lower segment 12 of the question mark shape , inner and outer contours 14 , 16 located respectively on the inner and outer perimeters 18 , 20 of lower segment 12 , inner and outer radii 24 , 26 of a generally c - shaped circle segment 28 , and the optional but preferred terminal segment 30 ( or upper end ). the circle segment 28 includes a terminal end 28 a and a nonterminal end 28 b , the terminal segment 30 extending from the terminal end . the lower segment 12 has a terminal end ( or lower end ) 12 a and a nonterminal end 12 b . as shown in fig1 , lower segment 12 and circle segment 28 are joined by transitional segment 34 joining the nonterminal end 12 b of the lower segment to the nonterminal end 28 b of the circle segment . thus , the lower segment 12 and the transitional segment 34 form an elongate body 68 extending from the nonterminal end 28 b of the circle segment 28 . pillow 10 is capable of being manipulated or configured into different shapes . when used as a body pillow , the generally question mark configuration provides support to the head and neck regardless of whether the user is facing segments 12 and 34 of pillow 10 or facing away from segments 12 and 34 . depending upon which way the person is facing , the opposite side of the body is also supported by either the circle segment 28 or segments 12 and 34 . inner contour 14 is designed to be a functional protrusion along inner perimeter 18 . outer contour 16 is designed to be a functional protrusion along outer perimeter 20 . inner contour 14 is formed by sewing a protruding variation in the seam ( not shown ) of inner perimeter 18 seam wherein the smooth nature of inner perimeter 18 is changed to force a portion of pillow 10 to form inner contour 14 . techniques for forming inner contour 14 are well known to those skilled in the art . inner contour 14 functions as a support device to the user of pillow 10 in most of the configurations for use described herein . the main function of inner contour 14 is for inner contour 14 to be positioned under part of the body of the user to provide support . this action forces the body to rotate the opposite direction from inner contour 14 while providing support to the particular body part of the user . in the preferred embodiment , a pregnant woman would have her abdominal area supported by inner contour 14 which lifts and supports the abdominal area thereby reducing pressure on other parts of her body such as her back . inner contour 14 may be located on lower segment 12 , transitional segment 34 or may extend over portions of both segments 12 and 34 . in the preferred embodiment , inner contour 14 is located on segment 12 near transitional segment 34 . outer contour 16 is formed similarly to inner contour 14 except that outer contour 16 is placed lower on lower segment 12 along outer perimeter 20 . preferably , outer contour 16 is on the lower one - third of lower segment 12 . outer contour 16 provides similar support to the body as inner contour 14 . however , outer contour 16 optionally functions as an attachment point for tab ( s ) 36 when forming large circle 44 . in general , a person facing segments 12 and 34 will place their lower arm under pillow 10 . when used in this manner , terminal segment 30 pushes into the upper back of the user providing back support while segments 12 , 28 and 34 provide front torso and head support . additionally , inner contour 14 located on inner perimeter 18 of pillow 10 typically extends through the abdominal region of the user . thus , inner perimeter 18 tucks under the abdomen providing gentle support reducing fatigue and undue strain . lower segment 12 is available to be tucked between the user &# 39 ; s legs or knees providing additional support for the individual and permitting air circulation between the legs . with reference to fig3 , terminal segment 30 preferably carries at least one strap or tab 36 . preferably , tab 36 is incorporated into cover 50 . tab 36 has a length sufficient to permit wrapping around lower segment 12 , transitional segment 34 or the opposite side of circular segment 28 , preferably forming a loop that is slidable along the length of the lower segment 12 , transitional segment 34 or the opposite side of circular segment 28 . thus , tab 36 secures terminal segment 30 to the main body of pillow 10 to form the desired circle 44 . more preferably , terminal segment 30 carries at least two tabs 36 which are stored within a pouch 40 . preferably , pouch 40 is incorporated into cover 50 in the area corresponding to terminal segment 30 . fig3 depicts the un - stowed position of pouch 40 and tab ( s ) 36 . as such , when pouch 40 is pulled open it flips to front side 60 of pillow 10 and collapses into a state wherein a seam 42 is smooth against cover 50 . fig2 depicts pouch 40 with tab ( s ) 36 ( not shown in fig2 ) in the stowed configuration on a backside 62 of pillow 10 . in the preferred embodiment , tabs 36 ( not shown in fig2 ) are prepared from the same material as cover 50 . to improve the comfort of pillow 10 ; tab ( s ) 36 optionally include a suitable batting material 70 thereby providing a thin layer of padding and firmness . further , tabs ( s ) 36 carry connectors such as , but not limited to , hook and loop connectors , fabric ties , zippers , buttons and / or snaps suitable for securing tab ( s ) 36 around or to segments 12 , 34 or the opposite side of segment 28 . one skilled in the art will recognize that various arrangements may be provided to secure tab ( s ) 36 to one another or pillow 10 in a manner that will produce the desired configurations detailed herein . tab ( s ) 36 provide the user of pillow 10 with the ability to configure pillow 10 in a multitude of useful positions tailored to the user &# 39 ; s individual needs . for example , in one configuration the user lies upon the part of the pillow where tab ( s ) 36 are secured about segments 12 , 34 or the opposite of segment 28 . in this arrangement , the user &# 39 ; s lower arm passes through the resulting circle 44 and rests under pillow 10 . further , in this configuration , circular segment 28 combined with terminal segment 30 force the person &# 39 ; s upper body to roll towards segments 12 , 34 and the opposite side of segment 28 resulting in increased support of the abdomen while providing support to the upper back of the person . this configuration also forces inner contour 14 to be pulled into the person &# 39 ; s abdomen thereby providing support to the abdomen by adding a slight opposing pressure or force function from inner contour 14 and the combination of segments 12 , 34 and the opposite side of segment 28 to the person &# 39 ; s abdomen , greatly increasing the overall support and comfort of the person using the invention . the resulting pressure or force function provided by inner contour 14 is one of the distinct benefits of pillow 10 . positioning of tab ( s ) 36 dictates the amount of pressure or force . placing tab ( s ) 36 at a higher location on segment 34 or on the opposite side of segment 28 reduces pressure brought to bear on the user &# 39 ; s abdomen . the inverse is also true in that the lower the placement of tab ( s ) 36 on segment 12 or 34 , the greater the pressure brought to bear on the abdomen of the user . the same effect can be created by not attaching tab ( s ) 36 around the pillow . this configuration places less of the pillow structure under the person using pillow 10 thereby increasing the pressure of the top portion on their upper body . both configurations utilize segment 12 to provide support to the legs . as discussed above , use of tab ( s ) 36 about segments 12 , 34 and the opposite side of segment 28 forms circle 44 . note : for the purposes of this disclosure , the preferred embodiment utilizes two tabs 36 and is described herein with reference to two tabs 36 . however , the current invention will also perform satisfactorily with a single tab 36 which must have a length sufficient to wrap around and attach to itself . alternatively , single tab 36 may attach directly to pillow 10 . adjustment of the size of circle 44 is provided by securing tabs 36 at various locations along segments 12 , 34 and the opposite side of segment 28 . thus , placing tabs 36 high on segment 34 or the opposite side of circular segment 28 , as shown in fig3 , produces a tight , small circle 44 . this configuration allows more flexibility in lower segment 12 of the pillow . when tab ( s ) 36 are placed midway on segment 12 close to inner contour 14 a moderately sized or medium circle 44 is formed . due to the improved abdominal support and increased comfort provided by a medium size circle 44 most users will likely place tab ( s ) 36 near inner contour 14 . the medium circle 44 configuration reduces the flexibility of lower segment 12 and increases the force applied by lower segment 12 of pillow 10 to the user &# 39 ; s abdomen . when tab ( s ) 36 are placed low on lower segment 12 of pillow 10 a wide or large circle 44 configuration is formed . tab ( s ) 36 are typically placed below outer contour 16 to obtain this variant . large circle 44 configuration places the user &# 39 ; s abdomen inside of circle 44 with their head and shoulders . this variant allows the person to rest with nearly complete support all around the upper body while pulling lower segment 12 of the pillow in tightly to the abdomen . fig5 depicts a person using pillow 10 to support their head , neck , abdomen and legs . in this configuration , inner contour 14 provides abdominal support while her legs are supported by lower segment 12 . using this particular configuration or similar variants , a person may alleviate the problem encountered by the pillow putting too much pressure on the person &# 39 ; s ear . a person desiring reduced pressure on their ear employs pillow 10 as seen in fig5 . as depicted the head does not rest completely upon circular segment 28 . rather the person simply places the upper most part of their head on the middle of circle segment 28 thereby allowing their ear to be suspended in the well area of circle 44 thereby avoiding pressure from pillow 10 and circle segment 28 . when used in this fashion , pillow 10 and circle segment 28 roll up around the edges to provide greater support for the neck area . pillow 10 of the current invention may also be used in alternative configurations . for example , fig6 shows a person using pillow 10 inverted with circle 44 and segments 28 and 30 placed between their legs to provide support and ventilation . in this configuration , lower segment 12 is pulled into the body either by use of tab ( s ) 36 or by the person wrapping their arms around lower segment 12 . when circle 44 , with or without tab ( s ) 36 , is between the person &# 39 ; s legs , it creates an air pocket . when properly positioned , tab ( s ) 36 reduce the size of circle 44 thereby providing the user with improved abdominal area support resulting from tab ( s ) 36 increasing pressure upon the abdomen . alternatively , repositioning tab ( s ) 36 as seen in fig7 increases the size of circle 44 , thereby providing greater ventilation for the person around and in between their legs due to a greater capacity for air to circulate . the configuration depicted in fig7 , supports a user &# 39 ; s legs while allowing air circulation around the legs thereby alleviating a common problem experienced by pregnant women . thus , fig6 and 7 demonstrate that altering the location of tab ( s ) 36 provides the ability to adjust the size of circle 44 and the amount of air circulation in and around the legs of the user . it is a long - standing problem for the mother to be able to rest comfortably while nursing her new infant . this invention has solved that problem by facilitating numerous configurations where both the mother and infant are positioned in a restive state that is also secure enough to keep the infant from rolling away or being accidentally crushed by the mother . in the preferred embodiment using tab ( s ) 36 , the mother lies on pillow 10 facing lower segment 12 . she is then able to rest the infant on inner perimeter 18 of lower segment 12 such that the infant naturally rolls toward her and is able to nurse . alternatively , the mother lies on pillow 10 with her back to lower segment 12 and the infant is cradled within circle 44 . the invention may further be used as a nursing aid or provide support for someone in a sitting or reclining position . as seen in fig8 , 9 and 10 , a mother or person desiring support can place circle 44 behind their back with or without tab ( s ) 36 connected and lean up against a solid surface such as a wall or bed headboard . fig8 shows the invention in a configuration where circle 44 is placed parallel against flat , vertical surface 100 and lower segment 12 is bent at the juncture formed when tab ( s ) 36 are connected to form circle 44 . in this configuration lower segment 12 extends perpendicular to flat , vertical surface 100 . the configuration of pillow 10 in fig8 is identical to fig9 except there is not a person in fig8 . as seen in the configuration of fig9 , lower segment 12 may be placed along side the body as an arm rest or , as seen in fig1 lower segment 12 may be pulled across the lap of the user to provide a support area for nursing . the configuration of lower segment 12 in an arm rest configuration results in reducing pressure on the elbow , forearm and wrist thereby providing comfort to those suffering carpal tunnel syndrome or any other wrist or hand injury requiring elevation . when lower segment 12 is pulled across the lap it may also be used for any lap related activity such as reading , writing , computer use or other activity requiring support . in this configuration the user has the option of putting circle 44 partly behind them anywhere along their back , neck or head while lower segment 12 lies beside them or across their lap , depending upon whether the desire is for lower back , middle back or neck support . in alternative configuration ( not shown ) a mother will place lower segment 12 behind her back while leaning up against a solid surface by wrapping circle segment 28 and terminal segment 30 around her waist . use of pillow 10 in this manner allows the mother to create a place were the infant is naturally cradled in her lap at an appropriate height for nursing . advantageously when used in this manner , pillow 10 will roll the infant toward the mother . additionally , lower segment 12 supports the mother &# 39 ; s back . proper positioning of pillow 10 will also support the mother &# 39 ; s upper back , neck and head . in the configurations found in fig8 , 9 and 10 , individuals using pillow 10 are able to obtain support for their back in the reclining or supine positions . individuals suffering the effects of osteoporosis , acid reflux disease , respiratory ailments or other maladies whereby there is a need to rest in a sitting or reclining position , reducing back pain or easily pained back bone structures , will be able to use pillow 10 as previously described to obtain supportive relief . circle 44 provides a well wherein the spine of the user has less pressure applied against it thereby increasing the overall comfort and support seen by the user . support is varied for users by increasing or decreasing the size of circle 44 by moving tab ( s ) 36 . pillow 10 may also be used to provide support for a person following an injury or surgery in the groin or buttocks area . often these individuals cannot sit directly on a solid surface even if it were padded . however , when pillow 10 is configured with a tight or small circle 44 the user may sit on pillow 10 surface without placing pressure on the sensitive areas . still further , pillow 10 may be used to reduce pressure on the lower back while supporting the legs . in this configuration , the user places their buttocks next to pillow 10 with their legs across lower segment 12 and their feet touching the floor on the other side of lower segment 12 . in this position the user &# 39 ; s knees are bent . alternatively , a person can use a similar approach to support the entire length of a leg by having lower segment 12 traverse the entire leg . this configuration still relieves pressure on the lower back and it reduces the pressure on the legs . this alternate configuration also provides elevation for the user &# 39 ; s legs . yet another configuration allows the user person to lie down with circle 44 under their legs functioning similar to when lower segment 12 is perpendicular to the legs . in still yet another configuration the person may sit in small circle 44 with lower segment 12 providing support to their legs when it is stretched out in the direction the person is facing . due to frequent usage pillow 10 will eventually require cleaning . thus in a preferred embodiment , pillow cover 50 is removable to permit laundering . one embodiment providing an easily removable cover 50 is shown in fig2 . in this embodiment pillow cover 50 is put on and removed by opening and closing flap 54 on backside 62 of the pillow 10 . because the use of pillow 10 is for restful purposes it is important that flap 54 have a soft , durable seam 56 sewn around outer edge 58 . placement of flap 54 is shown to be high on lower segment 12 which facilitates removal and replacement of pillow cover 50 in a manner easily understood by the user of the product . preferably , flap 54 bisects lower segment 12 from inner perimeter 18 seam to outer perimeter 20 seam with seam 56 overlapping pillow cover 50 by at least the width of the seam . in the preferred embodiment seam 56 overlaps pillow cover 50 by at least two inches . however , any flap structure or flap - like structure facilitating removal of pillow cover 50 is contemplated as part of this invention and is known to those skilled in the art . alternatively , pillow cover 50 may be removably secured as part of pillow 10 in lieu of flap 54 by any conventional device such as , but not limited to , a hook and loop connection or a zipper connection placed along inner perimeter 18 seam or outer perimeter 20 seam . additionally , flap 54 may be replaced with or may include a hook and loop connection or a zipper connection . further , flap 54 or one of the alternative connections may be located at any convenient location on pillow 10 . although the current invention is directed towards women who are pregnant , the distinct shape of the invention and its versatility make it an ideal candidate for any user requiring support along their torso in order to achieve restful sleep . overweight and obese people may see the same benefits as pregnant women . people with back problems may use it to lie on or to support their legs as they lay down flattening their back . additionally individuals with severe respiratory problems frequently sleep sitting up or in a steeply vertical position would be able to employ this invention to provide comfort . it is envisioned there will be a variety of sizes of this invention to include sizes appropriate for children , small adults , medium adults and large adults . thus , the present invention is well adapted to carry out the objects and attain the ends and advantages mentioned as well as those inherent therein . while preferred embodiments of the present invention have been illustrated for the purpose of the present disclosure , changes in the arrangement and construction of parts and the performance of steps can be made by those skilled in the art , which changes are encompassed within the scope and spirit of the present invention as defined by the appended claims .

US-51116006-A

this invention relates to the treatment of tobacco and tobacco smoke with chelating agents to reduce the concentration of pb - 210 and po - 210 . chelating formulations such as the tetrasodium salt of ethylenediaminetetraacetic acid in aqueous solution with a wetting agent are sprayed onto the tobacco during growth and / or the chelating formulations are used to soak or wash the tobacco after harvest but before curing the tobacco . pb - 210 , po - 210 and other metals are removed from tobacco smoke by applying chelating agents to the surface of the tobacco and / or the filter material .

in the treatment of tobacco , the chelating agent is used in aqueous solution with or without wetting agents . the chelating formulation can be applied to the leaves of the plant during growth or after harvest but before curing . treatment may involve spraying the leaves or soaking the leaves with or without mechanical agitation . in addition to reducing the pb - 210 and po - 210 content of the tobacco , the aforementioned treatment will have the added benefit of reducing the concentration of other metals such as cadmium , zinc , nickel , copper , thorium , uranium and non radioactive lead that are found in tobacco and tobacco smoke . within three hours after harvesting , tobacco leaves were immersed and gently agitated in an aqueous solution of 1 % na 4 edta and a wetting agent for one minute . the wetting agent used was 0 . 5 ml . of a 10 % aqueous solution of dioctyl sodium sulfosccinate per liter of chelating solution . the leaves were then rinsed for one minute in water and hung in bunches to dry and cure . a separate set of leaves , harvested at the same time , was hung in similar bunches to cure . both sets of leaves were left hanging indoors for two weeks . there was no apparent difference in appearance , smell and texture of the treated and untreated leaves . the treated and untreated leaves were then shredded and separately placed in 500 ml . plastic bottles . the pb - 210 concentration was measured by gamma spectroscopy using a high purity germanium detector . the pb - 210 concentration for the untreated leaves was measured at 1 . 2 pci / g and the pb - 210 concentration for the treated leaves was measured at 0 . 2 pci / g , indicating that approximately 80 % of the pb - 210 had been removed . washing tobacco leaves with water alone had no effect in reducing the pb - 210 concentration . increasing the concentration of chelating agent and / or the time the leaves are washed with the chelating formulation will result in more complete removal of the pb - 210 and the po - 210 . cured tobacco leaves were soaked with gentle agitation in an aqueous solution of 1 % na 4 edta and a wetting agent for one minute and then rinsed for one minute in water using the same wetting agent as in example 1 . before treatment , the tobacco was measured at 1 . 4 pci / g pb - 210 and after treatment the pb - 210 was measured at 0 . 8 pci / g . it is estimated that about 40 % of the pb - 210 was removed . treating the tobacco with water ( soaking and rinsing ) had no effect in reducing the pb - 210 content . although the po - 210 was not measured in these experiments , it is expected that the chelating agents will be as effective in removing the po - 210 as they are for pb - 210 . in addition , pb - 210 is the precursor for po - 210 so that once the pb - 210 is removed , po - 210 cannot be formed on the tobacco or in the human body from the decay of pb - 210 . tobacco is often aged for years prior to use . since po - 210 has a half life of 138 days , most of the unsupported po - 210 would decay away during storage . although it has been previously demonstrated that chelating agents can be effective in removing the pb - 210 and po - 210 from cured tobacco , we believe there are advantages in treating tobacco during growth or shortly after harvest before the tobacco is cured . most of the pb - 210 and po - 210 that is on the tobacco is trapped on the surface of the leaf by a sticky substance on the tricomes of the tobacco . if treated with chelating agents before curing , the pb - 210 and po - 210 are quite easily removed . after curing , the sticky exudates harden into resinous material with most of the pb - 210 and po - 210 held within the hardened resin . to remove the pb - 210 and po - 210 from cured tobacco using chelating agents requires higher concentrations of chelating agent and longer contact time than is needed in the treatment of tobacco before curing as is demonstrated in examples 1 and 2 above . in addition , treatment of tobacco before curing may have less effect on the removal of constituents that make smoking organoleptically acceptable . a chelating agent or a combination of chelating agents can also be applied to the tobacco and / or filter material to reduce the pb - 210 and po - 210 in the smoke and combustion products passing through the tobacco and / or the filter material . when a chelating agent or a combination of chelating agents have been applied to tobacco , the volatilized and particle borne pb - 210 and po - 210 produced by the burning tobacco will react with chelating agents on the surface of the unburned tobacco removing pb - 210 and po - 210 from the smoke and combustion products being drawn through the unburned tobacco . similarly , chelating agents applied to the surface of or incorporated into the filter material used in filtering tobacco smoke and combustion products will remove pb - 210 and po - 210 in the smoke and combustion productions passing through the filter material . the literature ( polonium - 210 : removal from smoke by resin filters by erich w . bretthauer and stuart c . black , science , 156 ( 3780 ) pp . 1375 - 1376 , 1967 ) indicates that the use of cation and anion exchange resins in the filters of cigarettes removed some of the po - 210 from the tobacco smoke passing through the filter . the resins used apparently have sulfate and trimethylamine functional groups to react with the po - 210 . we believe chelating agents such as na 4 edta applied to the surface of the tobacco and / or filter material or otherwise incorporated into the filter will be more effective in removing pb - 210 and po - 210 from the smoke . applying a chelating agent to the surface of the tobacco and / or filter or otherwise incorporating the chelating agent into the filter may facilitate advantages in production over the process described by bretthauer and black . in addition to pb - 210 and po - 210 , tobacco smoke contains significant concentrations of other radioactive and non - radioactive metals that may be toxic when inhaled . metals in tobacco smoke with the highest concentrations are zinc , lead , cadium and copper . the process described in the application to reduce the concentration of pb - 210 and po - 210 in tobacco smoke will also reduce the concentration of the other metals in the tobacco smoke .

US-63913003-A

an improved apparatus for processing sea cucumbers having stages for orienting / aligning , cutting , splitting , flattening , eviscerating and cleaning the sea cucumber , and for collecting the eviscerated innards . a method for the automated splitting and evisceration of sea cucumbers using the apparatus of the present disclosure . a flattening plate and trough during the orienting / aligning step relax the sea cucumber and discourage its defence mechanisms . a wedge shaped flattening plate splits and flattens the sea cucumber immediately after the incision . pronged discs maintain positioning of the sea cucumber during an aggressive wash and brush cleaning cycle , which may be repeated . optionally , a vacuum may suction off a portion of the innards prior to cleaning .

one or more examples of the sea cucumber processing machine and the related methods of use will now be explained in greater detail with reference to the accompanying figures . in one aspect , as shown in fig1 , the sea cucumber processing apparatus is a complete machine 27 having a lower feed guide 12 , a housing 28 , and an output chute 4 . a sea cucumber is placed , either by a user or from an orienting device , longitudinally in the lower feed guide 12 from where the sea cucumber would be pulled into the machine for processing . in the example shown , the machine &# 39 ; s lower assembly 1 supports a sea cucumber carcass through the operational steps of cutting , splitting , flattening , cleaning and outputting the meat for possible packaging or further processing . the machine 27 may comprise a viscera collection tray 3 to collect and process waste water and sea cucumber viscera for other purposes . fig2 , 4 , 5 , 6 , 7 , 8 and 9 each show different view of the same example machine or parts thereof from different angles and exposure . in fig2 the housing has been removed , and the machine lower assembly 1 is shown connected to the machine upper assembly 2 . also shown are the viscera collection tray 3 and output chute 4 . in fig3 , the machine upper assembly 2 is opened for cleaning from back hinge 29 and held open by forward struts 30 . fig4 shows only the machine lower assembly 1 , in which a stand 31 supports a transport assembly 32 comprising front belt guide plate 11 , rear belt guide plate 10 , lower feed guide 12 , belt tensioner assembly 13 , optional rear restriction disc assembly 14 , optional front restriction disc assembly 15 , drive roller assembly 16 , and a plurality of spiked belts , 5 , 6 , 7 , 8 and 9 . the spikes on the middle belt 7 grip a sea cucumber to pull it into the machine for processing , and the spikes on the other belts grip the sea cucumber skin as the sea cucumber is progressively cut , split and flattened in the machine . together , the spiked belts , 5 , 6 , 7 , 8 and 9 , form a conveyor belt , and the gaps between the spiked belts can be referred to as conveyor belt spacings or simply spacings . as shown in fig5 , as the drive roller assembly 16 turns , the spiked belts 5 , 6 , 7 , 8 and 9 , move at a common speed about the tensioning assembly 13 . optional rear restriction disc assembly 14 and front restriction disc assembly 15 have restriction discs with radial prongs protruding above the conveyor belt spacings to provide additional connection to the sea cucumber to prevent the sea cucumber from moving faster than the belts during the cleaning stages — discussed further below . fig6 shows the machine upper assembly 2 , with upper feed guide assembly 18 , for positioning above the lower feed guide assembly 1 so as to form a narrowing input channel . as the sea cucumber is pulled by the belt into the machine , the upper feed guide assembly 18 and lower feed guide assembly 12 center the sea cucumber as it is directed into the machine . the front water spray manifold 19 , rear water spray manifold 20 and rear flattening plate 17 are also shown . in the side view of fig7 , the blade 25 is sized and positioned to cut the upper skin , muscle and wall of the sea cucumber without cutting the lower wall . in the example shown ( as more particularly shown in fig1 ( a ) and 10 ( b ) ), the blade 25 is positioned within slots / guides of the forward point of the wedge 33 and the front flattening plate assembly 23 . the forward point of the wedge 33 spreads the incision formed by the blade , and resists the natural tendency of the sea cucumber flesh to roll inward upon itself when cut , and splits the cut sea cucumber outward and flattens it for further processing . the front flattening plate assembly 23 maintains the sea cucumber in a flat position and prevents the inward roll . in the example shown , the belt 7 , then belts 6 , 7 , 8 and finally all belts 5 , 6 , 7 , 8 and 9 , pull the cut and split sea cucumber past the wedge portion of the front flattening plate assembly 23 , and under the wide portion of the front flattening plate assembly 23 . other belt configurations or designs are possible , including a single belt ( in which can the restriction discs could be mounted between the brushes . the configuration in the example permits the optional rear restriction disc assembly 14 and front restriction disc assembly 15 to be used as shown . the evisceration stage of sea cucumber processing presents a number of design challenges related to the tendency of the sea cucumber to roll and slip . in the example shown , the evisceration stage of the machine addresses these design challenges and includes some features for additional robustness . at a basis level , the sea cucumber is pulled by the belts as it is pressed between the belts and the upper flattening plate . as it is pulled past the trailing edge 35 of the front flattening plate 23 a front roller brush 22 scrubs the visceral material from the exposed meat of the sea cucumber , and then the sea cucumber is pressed by the intermediate plate 26 ( alternatively referred to as the first post - cleaning flattening plate ) without sufficient gap to permit the sea cucumber meat to roll upward between the brush and the plates . additionally , the water jets of the front water spray manifold 19 spray water onto the bristles 34 of the brushes 21 and 22 , as they pass between the gap formed by the brush roller 22 and the trailing edge 35 of the front plate 23 . as shown in fig8 , in order to further prevent the brushes and water from accelerating the sea cucumber forward without cleaning , the prongs 36 on the front restriction disc assembly 15 prevent the sea cucumber from moving substantially faster than the belts 5 , 6 , 7 , 8 and 9 . the rear restriction disc assembly 14 provides the function in respect of the rear brushes and water . the water and visceral material falls into water and viscera collection tray 3 ( shown in fig3 ), where it can be strained for collection of the viscera and the water safely collected for treatment . optionally , a vacuum attachment may be positioned above the front flattening plate 23 to pull the viscera upward through opening 38 in the front flattening plate as the sea cucumber is pulled along by the belts 5 , 6 , 7 , 8 and 9 . the bulk of the viscera is detached from the inner wall of the sea cucumber and transported by vacuum to a collection vessel . the remaining viscera may then be removed by the brushes 21 and 22 , and spray nozzles 19 and 20 . viscera removed by vacuum is more whole than viscera removed by brushing and can be of higher quality . optionally , in the example of fig7 , the flattening plate after the front brush assembly is the centre flattening plate 26 , and it is followed by a second stage of cleaning by rear brush assembly 21 , rear water spray manifold 20 , rear restriction disc assembly 14 ( as shown in fig8 ), and the belts 5 , 6 , 7 , 8 and 9 before further flattening by the rear flattening plate assembly 17 . the second stage cleaning happens in an analogous fashion to the first stage . although it is within the scope of the invention for the brushes and water to point in the other direction and using the driving restriction discs to provide additional forward force , the system functions more smoothly with all parts encouraging motion through the machine . a common water and viscera collection tray 3 ( of fig3 ), can be used to collect the viscera and the water from both the first and second stages of cleaning . finally , the belts 5 , 6 , 7 , 8 and 9 pull the split and cleaned sea cucumber to a discharge area for further processing . in the example shown , the discharge area is a chute , but it could also be towards a skin removal stage , skin cleaning stage , cooker , drying , freezer or other processing machinery which adapted to receive sea cucumber which has been cleaned , split and flattened . fig1 through 16 show the live sea cucumber 37 as it enters the machine ( fig1 ( a ) and ( b ) ), is guided into the cutting blade ( fig1 ( a ) and ( b ) ), is cut and progressively flattened by the front flattening plate ( fig1 ( a ) and ( b ) and 13 ( a ) and ( b ) ). the cut , split and flattened sea cucumber 37 passes through the machine beneath the flattening plates to an optional viscera suction mechanism ( fig1 ( a ) and ( b ) ), or simply goes to the cleaning stage of the spray nozzles and brushes ( fig1 ( a ) and ( b ) ), and the fully processed sea cucumber ejected from the machine by the belts ( fig1 ( a ) and ( b ) ). the advantages of the method of processing the sea cucumber using the device disclosed herein can be described in one or more of the following steps or stages in reference to the figures : i . aligning — fig1 ( a ) and 10 ( b ) : the sea cucumber 37 is aligned and elongated by an input channel formed where an upper feed guide 18 forms a channel with a lower feed guide 12 to align the sea cucumber 37 ; ii . cutting — fig1 ( a ), 11 ( b ), 12 ( a ) and 12 ( b ) : the sea cucumber 37 is cut by a blade 25 positioned vertically over the centre of the lower feed guide 12 , and the incision goes from skin surface , through an upper lateral wall to viscera without cutting a bottom lateral wall , from mouth to anus of the sea cucumber , as the conveyor belt 7 pulls the sea cucumber 37 ; iii . splitting — fig1 ( a ), 11 ( b ), 12 ( a ) and 12 ( b ) : the sea cucumber 37 is split by a forward flattening plate 23 having a wedge shaped leading edge 33 disposed about a trailing edge of the blade 25 , which splits the sea cucumber 37 along the cut as the conveyor belt 5 , 6 , 7 , 8 and 9 pulls the sea cucumber under a bottom side of the forward flattening plate 23 ; iv . flattening — fig1 ( a ) and 13 ( b ) : the sea cucumber 37 is now flattened between forward flattening plate 23 and the opposite side of processing channel on which the convey belts belt 5 , 6 , 7 , 8 and 9 pull the sea cucumber for additional processing . v . optional evisceration — fig1 ( a ) and 14 ( b ) : the sea cucumber 37 may be eviscerated in a manner to preserve high quality viscera material for future processing by a vacuum nozzle and hole 38 in the front flattening plate 23 which permit removal of some viscera by suction during flattening . vi . cleaning — fig1 ( a ) and 15 ( b ) : two stages of cleaning are shown . a first cleaning stage , where at a front gap between a trailing edge 35 of the front flattening plate 23 and a leading edge of a central flattening plate 26 , a rotating front brush 22 scrubs viscera from the inner wall of the sea cucumber 37 and a front water spray manifold 19 sprays water on the front brush 22 where the front brush 22 contacts the sea cucumber 37 while restraining prongs 36 on a front restriction disc 15 ( see fig8 ) which protrude above the conveyor belt 5 , 6 , 7 , 8 and 9 to attach under the sea cucumber 37 to resist acceleration of the sea cucumber 37 by the front brush 22 , as the conveyor 5 , 6 , 7 , 8 and 9 pulls the sea cucumber 37 towards a second cleaning stage , where at a rear gap between a trailing edge of the central flattening plate 26 and a leading edge of a rear flattening plate 17 , a rotating rear brush 21 scrubs the inner wall of the sea cucumber and a rear water spray manifold 20 sprays water on the rear brush 21 where the rear brush 21 contacts the sea cucumber 37 while restraining prongs 36 on a rear restriction disc 14 ( see fig8 ) which protrude above the conveyor belt 5 , 6 , 7 , 8 and 9 to attach under the sea cucumber 37 to resist acceleration of the sea cucumber by the rear brush 21 . vii . output — fig1 ( a ) and 16 ( b ) show the sea cucumber 37 : exiting the apparatus past the rear flattening plate 17 . the foregoing examples and advantages are merely exemplary and are not to be construed as limiting the present inventions . the present teaching can be readily applied to other types of apparatuses and machines , or use thereof . also , the descriptions of the examples of the present inventions are intended to be illustrative , and not to limit the scope of the claims , and many alternatives , modifications , and variations will be apparent to those skilled in the art . in particular , the individual structural elements claimed as being may be practiced alone and not in combination with other stages of the machine and remain independently inventive .

US-201615287295-A

a device for sharpening ski edges and the like which is useful in sharpening both the side and bottom edges of skis is disclosed . the device is operable easily by an individual , is portable and allows a bevel to be sharpened into the edge where desired quickly and easily .

now referring to the drawings in greater detail , a motorized ski sharpening device is presented for sharpening the bottom and side edges of a ski or the like . fig1 is a perspective view of an edge guide 20 utilized by the sharpening device of the invention having a flat portion 22 . its width 24 is designed to be at least about half the width of a ski or at least wide enough to form a stable platform against a ski base when in position . in one embodiment , width 24 of flat portion 22 is about two to three inches . the length 25 is sufficient to stably run the length of the ski and provides aperture 27 for accommodating the grinding stone 41 ( shown in fig3 ). also , runner portion 29 is formed at about ninety degrees to flat portion 22 and runs along the length of a ski edge to be sharpened . motor mount 31 is designed as a means to hold a motor at a desired position or at a desired angle for beveling . in this embodiment , motor mounting holes 32 are designed to receive a pair of mounting bolts from a hand held motor 34 . fig2 is a front elevation view of edge guide 20 showing flat portion 22 and motor mounting plate 31 . in this view , the runner portion 29 on both sides of grinding stone aperture 27 is clearly seen . motor mounting holes 32 are also clearly seen . fig3 is again a perspective view of edge guide 20 . this time motor 34 is shown mounted to motor mounting plate 31 via bolts 36 ( only one of which is seen ) into motor mounting holes 32 . shown on motor 34 is variable speed switch 38 for adjusting the speed of spindle 40 to a desired speed . in one embodiment , motor 34 can drive the spindle apparatus from zero to about 25 , 000 to 35 , 000 rpm however more or less rotation is acceptable , as desired . at the end of spindle 40 is the solid columnar grinding stone 41 . in one embodiment , stone 41 is an aluminum oxide grinding stone . other embodiments are contemplated but in all cases must be a solid grinding material , either artificial or natural , for grinding as opposed to , for example , a grinding stone sandpaper on a mounting wheel that has grinding material on the surface of the circumference only such as in french patent 2 , 516 , 064 . fig4 is a pictorial view of the solid columnar grinding stone 41 . from this perspective , spindle 40 can be seen mounted in collet 44 . collet 44 is internally threaded to tighten around spindle 40 . in one embodiment , spindle 40 is threaded opposite to the direction of spin of motor 34 . for example , where motor 34 rotates spindle 40 in a counter clockwise direction as viewed from the end of collet 44 , collet 44 would have a right hand thread . the advantage of this arrangement will be explained later . also shown in this view is compression spring 45 is mounted on spindle 40 . spring 45 allows a height adjustment of solid columnar grinding stone 41 when spindle 40 is not completely tightened in collet 44 . after proper desired height is reached , collet 44 can be tightened in any manner desired . in this embodiment , the surface of grinding stone bottom 47 is flat and is used in the device of the invention to shape and grind the bottom edge of a ski . in this embodiment , the surface is flat but in other embodiments where a bevel is needed on the bottom edge , other shapes are contemplated for the bottom 47 . also seen is the circumferential edge 48 of columnar grinding stone 41 . the circumferential edge 48 is used to grind and sharpen a ski side edge when edge guide 20 is properly placed on a ski . fig5 is a side view showing a cross section of the edge guide 20 with the motor 34 and grinding stone 41 attached . the device is resting in this view on a ski bottom edge 53 shown also in cross section . ski 51 has a bottom edge 53 and side edge 54 as depicted . motor mounting plate 31 is shown as an upright with flat portion 22 shown horizontally resting on ski 51 . angle “ a ” is shown in this embodiment as ninety degrees . when spindle 40 is mounted parallel to motor mounting plate 31 and bottom surface 47 perpendicular to the spindle 40 grinding stone 41 will put a zero degree bevel on the bottom edge 53 of ski 51 . adjusting of angle “ a ” will create a different bevel angle on bottom edge 53 as desired . normally this is between about zero degrees and five degrees bevel angle . fig6 depicts a view of an alternate embodiment of the mounting plate 31 arrangement . in the previous fig5 the motor mounting angle of the mounting plate 31 is fixed at angle “ a ” meaning that the bevel angle is predetermined and fixed . while the angle “ a ” can be made to different angles , once made , the angle “ a ” of the edge guide 20 will not change . in the embodiment depicted in fig6 angle wedge 56 is placed between motor 34 and motor mounting plate 31 . wedge 56 can be fixed but in one embodiment can be removable and interchanged with wedges of different angles thus allowing for changing of the final bevel angle on the bottom edge 53 of a ski . fig7 is a side view of another embodiment of the invention for adjusting the bevel angle of ski bottom edge 53 . in this view , the grinding stone bottom 47 has a bevel angle “ b ”. this angle is imparted to the ski edge 53 as a bevel when the grinding stone 41 is mounted as previously described in fig5 . fig8 is a perspective view of the device of the invention in use on a ski , sharpening the bottom edge 53 of a ski 51 . in use , motor 34 is mounted to edge guide 20 . spindle 40 of grinding stone 41 is placed loosely in collet 44 . edge guide 20 is then placed on a ski bottom aligned with the runner portion tight against side edge with the bottom of grinding stone 41 flat against bottom edge 53 . the user then pushes grinding stone spindle up further into collet 44 . motor 34 is started at about 25 , 000 to 35 , 000 rpm and edge guide 20 is moved up back and forth on the edge of ski 51 . in one embodiment , this loose spindle will be tightened at the proper height due to the counter clockwise rotating of motor collet 44 and the right hand tightening nut of collet 44 . the device is run back and forth on the ski edge until the desired level of sharpness or bevel is achieved . fig9 is a perspective view of the device of the invention in use on a ski , sharpening a side edge 54 of ski 51 . in order to use the device , motor 34 is mounted on edge guide 20 as above . spindle 40 is tightened in collet 44 at a height such that grinding stone circumferential edge 48 rests against ski 51 side edge 54 when edge guide 20 is positioned as shown . the flat portion 22 is again against the ski bottom . in this embodiment , the circumferential edge 48 is against ski side edge 54 , which means that runner portion 29 does not fit flat against the ski side edge 54 . instead , runner edge corner 59 and circumferential edge 48 is held against ski side edge 54 and moved back and forth on the ski side edge 54 until the desired level of sharpness is achieved . it is clear that substitution of grinding stones , spindles , motors , desired angles and the like are well within the skill in the art in view of the disclosure herein . nothing in the embodiments or drawings herein is designed to be limiting .

US-24433902-A

a multiple fluid pulse dispenser comprising a plurality of interconnected fluid reservoirs defined by mating , oppositely directed concavities at least one of which mating concavity is formed from an invertable , preferrably permanently deformable blister . the reservoirs are in fluid communication with an outlet through which the contents of the reservoirs may be dispensed . a preferred embodiment permits fluid to flow through a reservoir after it has been discharged to allow random activation of the individual reservoirs .

a manually operated multiple fluid pulse dispenser according to this invention is shown generally as 1 in fig1 and 2 . the dispenser 1 comprises a base member 2 provided with a multiplicity of depressions 3 formed in the base . overlying base member 3 is a cover sheet 4 provided with a multiplicity of raised blisters 5 , which are located above the corresponding depressions 3 to provide therebetween a reservoir for a predetermined fluid volume . the cover 4 and base 2 are bonded to each other substantially across their contacting faces by adhesive or solvent bonding or any other suitable means to provide a fluid tight seal which retains the fluid contents of the reservoir and permits discharge only through passageways 6 specifically provided for that function . passageways 6 comprise channels in base 2 which , in cooperation with cover 4 , provide a fluid flow path between the various reservoirs and a common outlet 7 to which may be attached a needle 8 or any other suitable cannula for conveying the fluid to a distant location . alternatively , in certain embodiments outlet 7 can merely be left open or provided with a burstable seal for example . the opposite end of the passageway 6 is provided with a puncturable self - sealing septum or plug 9 through which the reservoirs and the passageways can be filled . it is preferable , in order to permit operation of the device in any sequence , to have the channel forming passageway 6 extend both between depressions 3 and along the bottom surface thereof . this will permit fluid to flow through a reservoir to the common outlet after the contents of a reservoir have been discharged by manual pressure on blister 5 to cause it to invert and conform substantially to the shape of the depression 3 as is shown at 5a in fig1 and 2 . cover 5 is made from any of a wide variety of materials known to the art for use in blister packaging which are impermeable to the fluid contained within the device and sufficiently flexible to be deformed from their convex initial configuration to the concave final configuration shown at 5a without breaking , while being of sufficient stiffness to resist returning to their original configuration after the pressure of operation is removed . suitable materials include polyvinyl chloride , polyolefin and polyester resins all as is known to be blister packing art . typical blister films are approximately 10 mil in thickness . in the embodiment shown in fig1 and 2 , all of the recesses 3 other than than those shown in the far right of fig1 are provided with grooves in their lower surfaces to permit the flow of fluid after blister 5 is depressed . as is noted above , this is done to permit random access to the contents of the individual reservoirs . obviously , if a predetermined serial sequence is intended , this feature can be omitted . it should be noted however , that if such a feature is omitted , the possibility of inadvertent , out of sequence , operation still exists . thus the depression of an intermediate reservoir could have the effect of reversing a previously inverted blister which would then merely fill one of the previously used reservoirs rather than eject a fluid pulse . for this reason it is preferred that passageway means providing flow through used reservoirs be provided even if serial , rather than random , actuation is intended . it is desired to keep the volume of these passageways as small as possible in order to minimize the amount of active material which will remain unused in the device after its blisters have all been actuated . while the grooves in the surfaces of the recesses 3 are a simple and convenient manner of providing for fluid passageways , the invention is not limited thereto and as an alternative , the blister 5 could be sized such that when it is inverted it is not in complete contact with the interior surface 3 leaving a small gap through which fluid flow can occur . alternatively , the groove can be formed in the interior surface of the blister 5 rather than in the base 2 and and this invention is not limited to the specific means by which the passageways 6 are formed . as shown in fig1 and 2 , the bottom surface of base 2 is curved slightly so that it may be comfortably attached to the arm or thigh of a patient and secured in place by tape or other suitable fastening means . the needle shown is adapted to be introduced slightly under the skin , however it is readily apparent that the device need not be configured for mounting on the body nor the outlet connected to a needle . any suitable tubing or other means for delivering the contents to any desired site can be employed . dispensers may also be connected in series by inserting the needle 8 of one dispenser into the septum 9 of another dispenser for example . it should be apparent that the shape of the dispenser as well as the pattern of the orientation of the blisters can be varied to adapt the device for any particular contemplated use . referring now to fig3 and 5 , alternative blister patterns are disclosed . in fig3 the blisters 5 and depressions 3 are arranged in a circular pattern on passageways 6 which extend radially outward , like spokes on a wheel , from a common centrally located outlet 7 . in the embodiment of fig5 the blisters 5 , depressions 3 and the interconnecting passageway 6 are arranged in a spiral pattern . in fig3 septums 9 are provided for the outermost reservoirs on each spoke to facilitate filling . in fig5 only one septum 9 need be provided . fig3 and 4 show a pulse dosage form according to this invention mounted on a infusion pump which is adapted to deliver a constant flow rate of a biologically active fluid to the body of a patient . by combining the pulse dosage form of this invention with such a pump it is possible to provide a dosage regime for those drugs which require a predetermined constant basal flow rate and pulse increases to adjust for changing conditions experienced by the user . such a regime is common in the treatment of diabetes in which a predetermined basal insulin flow rate is required which is supplemented by additional pulses after meals , for example . the particular structure of the pump with which the multiple pulse dosage form of this invention is used is not part of this invention ; however , for illustrative purposes , the pump is shown in conjunction with a pump of the type disclosed and claimed in co - pending , co - assigned patent application of eckenhoff , et al . for body mounted pump housing and pump assembly employing the same , ser . no . 452 , 523 filed dec . 23 , 1982 . as shown in fig3 and 4 a pump assembly 20 is mounted on the body 21 of a subject by an adhesive overlay 22 ( omitted for clarity in fig3 ) with the outlet 23 of the pump connected to a hollow needle 24 which is introduced under the skin of the patient . an inlet passageway 25 is blocked with a resealable septum 26 for filling pump . as shown in fig4 outlet 7 of the pulse dosage form 10 is provided with a hollow needle 28 which punctures releasable septum 27 extending through the top wall of pump housing 20 . the dosage form 10 is provided with spaced depressions 3 to define between blisters 5 and depressions 3 a multiplicity of reservoirs . needle 28 is in fluid communication with the displacement chamber 29 of the pump containing the drug to be dispensed such that when one of the blisters 5 is depressed such as 5a a fluid pulse equal in volume to that contained in that reservoir is impressed upon the tonic flow rate and discharged into the subject through needle 24 . a protective cap 40 preferably made of a rigid transparent material is provided over the dosage form to prevent inadvertent actuation . in the embodiments shown in fig1 - 5 , the base of the device having the depressions in its surface is shown as a relatively rigid structure compared to the deformable cover sheet containing the permanently reversible blisters . it should , however , be readily apparent that the two members between which the volume for each pulse reservoir is defined can be in sheet form . thus as shown in fig6 dosage form 30 comprises first and second members 31 and 32 formed from the typical sheet material used in blister packaging ; each being provided with a multiplicity of opposing blisters 33 which are shown in their used position as 33a . members 31 and 32 are bonded together by adhesive or fusion or other suitable means at substantially all of their surfaces except at the blisters and in the area of the intercommunicating grooves 34 which are provided in the surface of one or both of the members to permit the operation of the device in random sequence rather than in a predetermined fixed sequence . as discussed above , the pulse generator of this invention can be used to deliver various substances into an environment of use such as algacides or nutients for an aquarium , fertilizers in a natural or hydroponic gardening , nutrients for growing microorganisms , antiseptics for urinary bags and antibiotics , chemotherapeutic or nutritional agents to iv lines ; as some representative non - limiting examples . in those uses , the device would simply be connected to or placed within the environment of use and periodically actuated either directly or through a flexible wall as would be the case with a urinary or i . v . bag . the pulse dosage forms disclosed herein can either be provided to the pharmacist in empty form and thereafter filled by the pharmacist with any particular drug formulation that is desired simply by insertion of a filling hypodermic needle through the septum and filling the device until a continuous flow of fluid is observed leaving the outlet . bubbles may be readily removed by tipping the device and visual observation through the transparent cover sheet will verify that bubbles are in fact absent with the device being tipped as necessary to prevent any air from being trapped . alternatively the devices can be prefilled at a factory and provided to the pharmacist with an appropriate seal over outlet 7 . this invention has been described with respect to specific embodiments thereof and it should not be construed as being limited thereto . various modifications and substitutions may be made by workers skilled in the art without departing from the scope of this invention which is limited only by the following claims wherein :

US-45252282-A

a high - frequency application device for vascular use , in particular for application of high - frequency energy to the renal arterial wall , including : a catheter with a lumen passing through it in the longitudinal direction ; a self - expanding stent - like support guided in the lumen ; and an hf applicator arranged on the support for delivering hf energy to bodily tissue , wherein the hf applicator , as a multipole arrangement , has a plurality of hf contact elements distributed axially and peripherally over the support , which are insulated from the support and are connectable to an hf source for simultaneous or sequential delivery of hf energy to different positions of the bodily tissue .

as can be seen from fig1 , a high - frequency application device for vascular use has a catheter 1 formed as an elongate tube with an outer shaft 2 and an inner shaft 3 arranged therein . an annular lumen 4 is formed between these shafts and passes through the catheter 1 in the longitudinal direction . a support 6 that is stent - like at least at the distal end 5 is arranged in this lumen 4 and is to be actuated at its proximal end 7 by a schematically indicated actuation mimic 8 in a manner that is yet to be described in greater detail . at the distal end 5 of the support 6 , an hf applicator denoted on the whole by 9 is provided , for example to apply hf energy for complete or partial transection or traumatization of sympathetic nerves at the renal artery for lasting therapy of chronic hypertension . this hf energy is not generally used to completely transect or destroy the nerve physiologically , but to make it incapable of function as a result of processes induced by the hf energy . fig1 shows a purely schematic illustration of an hf source 10 for supplying energy to the hf applicator 9 , said hf source being connected to the hf applicator 9 via a suitable line 11 . a first embodiment for the hf applicator 9 is illustrated in fig2 and 3 . the support 6 is formed in this case in the manner of a slotted tube stent , which forms a type of net structure from main meander struts 12 and longitudinal bridge struts 13 . hf contact elements 14 are distributed over the support 6 at various meander points of the main meander struts 12 and are each connectable as an electrode to the hf source 10 for the delivery of hf energy at different positions of the bodily tissue . with use of the high - frequency application device , the catheter 1 is advanced via its distal end 5 to the corresponding position within the body , together with the support 6 retracted into its lumen 4 , as indicated in fig1 . once in this position , the outer shaft of the catheter 1 is withdrawn , so that the self - expanding support 6 expands when it exits from the lumen 4 , as shown in fig3 . the hf contact elements 14 are each formed in this case by a contact zone 15 , freed from surrounding material of the support 6 by corresponding cutouts , at a connecting web 16 carrying said contact zone for mechanical connection thereof to the support 6 . as can be seen in fig3 , the contact zones 15 of the hf contact elements 14 are displaced radially outwardly as a result of the expansion of the support 6 , such that a reliable contact between the contact zones 15 and the bodily tissue , for example of the renal artery , surrounding the hf applicator 9 is ensured . in this state , the contact zones 15 can then be supplied by the hf source 10 with corresponding hf energy , and corresponding ablations can be carried out at the contact points for therapeutic purposes . fig4 illustrates an alternative embodiment for the support 6 , which in this case is designed in the manner of a stent graft . this again has main meander struts 12 , which are interconnected in the longitudinal direction by a flexible woven fabric 17 however . similarly to the embodiment according to fig2 and 3 , hf contact elements 14 again sit on the main meander struts 12 . in the embodiment shown in fig5 , the support 6 is formed of a plurality of self - expanding annular segments 18 , 19 , 20 , which are each fastened on the inner shaft 3 of the catheter 1 via sleeves 21 . similarly to the embodiments according to fig2 and 4 , each annular segment again has main meander struts 12 with hf contact elements 14 fitted thereon . the main meander struts 12 are in this case connected to the sleeves 21 via longitudinal coupling struts 22 . as can be seen clearly on the basis of fig5 , the annular segments 18 , 19 , 20 are folded together in an umbrella - like manner when the inner shaft 3 is retracted into the outer shaft 2 of the catheter 1 , whereby the stent - like annular segment structure contracts . inversely , the annular segments 18 , 19 , 20 expand when the outer shaft 2 is withdrawn over the inner shaft 3 , whereby the hf contact elements 14 again contact the inner wall of the vessel . different embodiments of the hf contact elements 14 are to be explained on the basis of fig6 to 10 . fig6 thus shows an hf contact element 14 , of which the contact zone 15 is formed as a closed therapeutic contact surface 23 having a flat , paddle - like form . this is decoupled galvanically from the connecting webs 16 , and thus from the rest of the support 6 , in a suitable manner , for example by a thin plastics coating 24 . the variant illustrated in fig7 and 8 shows an hf contact element 14 having a contact zone 15 , which forms an annular mechanical holder 25 in the form of an aperture 26 . an hf electrode head 27 is housed in this aperture 26 as a therapeutic contact surface 23 , which is insulated galvanically in the aperture 26 via a suitable ring insulator 28 . the electrode head 27 itself is supplied with hf energy via the above - mentioned lines 11 , as also shown in fig8 . in the embodiment illustrated in fig9 , the hf electrode head 27 likewise sits in a galvanically decoupled manner via the ring insulator 27 in the aperture 26 of the mechanical holder 25 , which is formed by the contact zone 15 , but a printed circuit board 29 is in this case provided beneath the contact zone 15 , the hf electrode head 27 being assembled on said printed circuit board and being connected accordingly to the hf source 10 via strip conductors ( not illustrated in greater detail ). in the embodiment according to fig1 , the hf electrode head 27 is likewise assembled on a printed circuit board 29 , wherein this sits on the mechanical holder 25 however , such that the aperture 26 can be omitted . the hf electrode head 27 is again supplied with energy via strip conductors on the printed circuit board 29 . with the hf electrode heads 27 shown in fig7 to 10 , a temperature sensor 30 is integrated and is used to measure the temperature in the direct vicinity of the ablation location . the application of hf energy to the bodily tissue can thus be controlled in a particularly reliable manner . fig1 , 12 and 13 show a support 6 based on a slotted tube design with lattice struts 31 arranged in a diamond - shaped manner , wherein annular surfaces 32 are formed as contact zones 15 at different points of this structure and are connected to the structure of the support 6 via meandering connecting webs 16 . as is clear from fig1 and 13 , the meandering connecting webs 16 compensate for the expansion movement of the lattice struts 31 and ensure that the annular surfaces 32 remain far outwards in the radial direction and protrude radially beyond the contour of the support 6 . a further example of a support design with main meander struts 12 , curved longitudinal bridge struts 13 and a contact zone 15 , designed as an annular surface 32 , of the hf contact elements 14 is shown in fig1 and 15 . the contact zones 15 are in this case connected to the main meander struts 12 via a single , narrow connecting web 16 . as can be seen from fig1 , the annular surfaces 32 , which , in the contracted position , are embedded into the structure between two curved bridge struts 13 , slide outwardly beyond the bridge struts 13 during the expansion process , whereby the contact with the surrounding tissue is again ensured . the basic designs of the support 6 shown in fig1 to 13 and 14 and 15 are known in principle as a “ closed - cell ” slotted tube design ( closed cell design ), apart from the additions provided in accordance with the invention . lastly , an individual segment having main meander struts 12 and longitudinally extending bridge struts 13 is illustrated in fig1 , wherein a contact zone 15 formed as an annular surface 32 is again connected between two meander curves to the main meander struts 12 via a connecting web 16 . it will be apparent to those skilled in the art that numerous modifications and variations of the described examples and embodiments are possible in light of the above teaching . the disclosed examples and embodiments are presented for purposes of illustration only . other alternate embodiments may include some or all of the features disclosed herein . therefore , it is the intent to cover all such modifications and alternate embodiments as may come within the true scope of this invention .

US-201314076884-A

a device for the in situ clearing of blockages in a tube includes a controller and a clearing member . the controller can have a housing and an actuator for generating repetitive motion . the clearing member can be releasably coupled to the controller and suitable for insertion in the tube . the tube can be at least partially disposed within a living being . the controller can be located external to the living being . the clearing member can have a first end releasably coupled to the actuator , at least one flexible section which permits axial displacement of the clearing member , and a second end suitable for repetitively engaging and disrupting the blockage . the flexible section permits the clearing member to repetitively engage and disrupt the blockage within one of a straight and a curved portion of the artificial tube .

the preferred embodiments of this present invention are illustrated in fig1 - 29e with the numerals referring to like and corresponding parts . the present inventions are portable devices , as well as methods for such devices , for effectively removing , moving or breaking up a clog from the internal portions of an artificial tube or catheter , enteral tube , and preferably a feeding tube , including pediatric feeding tubes . the action of removing clogs and clearing artificial tubes can also be referred to as a “ maintenance action ”. as will be discussed in detail later , there are basically two types of tube clearers ( tc ) disclosed herein , both of which are mechanical tube clearers . the first type of tube clearer tci includes several embodiments that generate reciprocating motion of a clearing member for removing , moving or otherwise breaking up a clog in the artificial tube . this tube clearer tci is preferred for use in nastrogastic ( ng ) feeding tubes , although it should be understood that tci is not limited for only clearing ng feeding tubes . fig1 - 17b , 29 , 29 b , 29 c , 29 d and 29 e are directed to tci . the second type of tube clearer tc 2 involves the generation of rotational motion of a clearing member for removing , moving or otherwise breaking up a clog . this tube clearer tc 2 is preferred for use in percutaneous endoscopic gastric ( peg ) feeding tubes , although it should be understood that tc 2 is not limited for only dealing peg feeding tubes . fig5 a , 5 d , 18 a - 28 , and 29 a - 29 d are directed to tc 2 . both types of tube clearers tci and tc 2 are unique to feeding tube clearing and overcome major obstacles in critical and long - term care medicine by clearing clogged feeding tubes quickly and efficiently . as will be discussed in detail later , the tube clearer tci and tc 2 can remove a clog much faster ( e . g ., in less than 6 minutes ) and at a much greater success rate than other currently - available clearing methodologies / devices , while at the same time , resulting in cleaner tube walls . existing methodologies / devices simply do not work at all , do not clear the clogs properly , or they take a considerable time to do so . in both tube clearers tci and tc 2 , an activation unit or controller remains external to the artificial tube and therefore the patient . the activation unit or controller delivers energy to a clearing stem ( also referred to as a “ clearing member ”) which is inserted into the artificial tube and whereby the clearing stem destroys the clog ( e . g ., clogs of food and / or ground medication , etc .) and cleans the tube walls . as a result , the activation units in these clearers tci and tc 2 are reusable devices and the clearing stems are disposable . the clearing stems of tci and tc 2 operate in narrow tube diameters , through several radial curves sufficient to reach , e . g ., the bowel . thus , the tube clearers tci and tc 2 clear safely and with greater efficiency for ng -, peg -, gj - and nj - tubes . both tube clearers tci and tc2 require no complicated set up , e . g ., no tuning is required . reciprocating tube clearer tci as shown in fig1 , the tube clearer tci comprises an activation unit ( also referred to as the “ control box ” or “ controller ”) 1 which remains external to the artificial tube 39 ( see fig4 ) being cleared , and therefore is also external to the patient ( not shown ). the activation unit 1 delivers energy to a clearing stem 26 which clears as it moves through the tube inner lumen 41 of the indwelling artificial tube 39 , destroying the clog 40 and clearing the walls of the artificial tube 39 , viz ., the tube inner lumen 41 walls . where feeding tubes are being cleared by the tube clearer tci , the tube clearer tci breaks up clogs of food and ground medication in a short time ( e . g ., less than 6 minutes ). the reusable control box 1 includes a motor which drives ( actuates ) the disposable clearing stem 26 . the control box 1 is positioned and releasably secured onto a table , tray , or nursing cart 38 , such as shown in fig1 . alternatively , the control box 1 can be positioned on a pole cart 38 a ( see fig1 a ), or bed rail or any other type of support that is adjacent , or which can be moved adjacent to the patient or living being . as shown most clearly by way of example in fig3 a , the clearing stem 26 comprises a wire 28 running concentrically through a sheath 30 . the wire 28 protrudes from the end of the sheath 30 and is actuated while the sheath 30 remains stationary and is secured to a non - moving portion of the control box 1 . the motion at the wire tip 29 clears the occlusion or clog 40 . as shown in fig2 - 2b , the control box 1 comprises a motor 14 , drive electronics 10 , electrical connectors , wiring , and clearing stem connectors . the control box 1 is preferably constructed of polymer , although metallic , rubber , or a combination of all three materials may be used . the preferred polymer is flame - retardant abs plastic , although other polymers such as polyurethane , polypropylene , and nylon , but not limited to such , may be used for , among other things , their lightweight composition and structural integrity . metals such as aluminum , titanium , steel , brass in sheet or machined form may also be used , especially where certain motor technologies ( e . g ., amplified piezoelectric actuators ( apas )) are used ; to maintain efficiency of apas , the non - moving portion of them needs to be effectively clamped or else too much deflection on the side that should be clamped will greatly reduce the apas &# 39 ; efficiency ; a metal control box provides sufficient rigidity to properly clamp . the control box 1 has a releasable securing mechanism such as rubber feet , mechanically actuated suction cup , screws , rubber stops , or magnetic feet , etc . that facilitates its use on a table or nursing cart . as such , the control box 1 remains portable but is stationary during use . the motor 14 drives a motor shaft 15 that generates the reciprocating motion . it should be understood that fig2 b depicts the preferred control box 1 because it comprises a novel clearing stem - control box interface , as will be discussed in detail later with regard to fig1 b - 16c . fig2 b also depicts , by way of example only , the use of a counter balance mechanism 14 a to counteract vibration caused by the reciprocation of an actuating motor 14 , as will also be discussed later . in another embodiment , the electronic circuit and componentry for example power indicator 3 , fault indicator 4 , enable switch 72 can be incorporated into a membrane switch such as xymox technologies , inc . model no . 54894 . the clearing stem 26 comprises a sheath 30 which is fed into the clogged artificial tube . the preferred sheath material is polytetrafluoroethylene ( ptfe ) although other tube materials may also be used such as , but not limited to , nylon , polyvinyl chloride ( pvc ), polyurethane , polyethylene , polypropylene , fluoropolymer , viton , hytrel . as mentioned previously , within the sheath 30 is a wire 28 , which is attached to the motor 14 . the motor 14 supplies reciprocating ( also referred to as “ oscillating ”) motion to the wire 28 , causing the wire 28 and its wire tip 29 to reciprocate back and forth . as can be seen most clearly in fig3 - 3a , the wire 28 protrudes beyond the end of the sheath 30 , and into the clog 40 ( fig4 ) which causes the disruption of the clog 40 . the length of the wire protrusion 28 a beyond the end of the sheath 30 strongly impacts the effectiveness of the clearing . in addition , the roundness of the wire tip 29 strongly impacts the ease of insertion of the clearing stem 26 into the artificial tube 39 . the clearing stem 26 may comprise a length of 60 cm to 250 cm , but preferably 180 - 220 cm , and most preferably , 203 cm . in addition , the wire 28 may comprise a flexible wire most preferably stainless steel twisted wire , but could also be helical wrapped wire or a flexible stainless steel wire encased in a polymer wrapping , such as shrink wrap . the wire 28 protrudes from the end of the sheath a distance of 0 to 13 cm , but preferably 1 to 5 cm and most preferably 2 . 54 cm . the clearing stem 26 releasably secures to the control box 1 via a luer clearing stem connector 6 . it should be noted that that , alternatively , the wire 28 may be hollow to enable other features such as irrigation or aspiration of the artificial lumen , as will be discussed later . fig3 - 3a depict the clearing stem 26 which uses a magnetic - based and luer lock connection to the control box motor 14 , a stem stiffener 31 at a proximal end of the clearing stem 26 , the amount that the wire tip 29 extends beyond the sheath 30 ( referred to as the “ protrusion ” or “ wire protrusion ”) 28 a , a wire stop 27 , and tube depth - control collar 22 . in particular , the proximal end of the clearing stem 26 comprises a clearing stem magnet 33 and a luer clearing stem fitting 32 ( fig3 - 3a ). the control box 1 includes a luer clearing stem connector 6 ( fig2 - 2a ) along with a motor magnetic coupler 13 which itself includes an internal magnet 12 in the coupler bore . to releasably secure the clearing stem 26 to the control box 1 , the clearing stem magnet 33 is passed through the luer clearing stem connector 6 , through a diaphragm 9 and into the motor magnetic coupler 13 where the clearing stem magnet 33 and magnet 12 come into contact to form the magnetic coupling . the luer clearing stem fitting 32 and luer clearing stem connector 6 are then engaged to form the luer lock configuration . advantages to this magnetic connector include : the omission of threads ( which can suffer from stripping ), the avoidance of any special tools to facilitate connection , reduced occurrence of bio - contamination , and the avoidance of having to disassemble any portion of the control box 1 in order to switch clearing stems 26 . the design of the mechanical components and the strength of the two magnets 33 / 12 are critical to avoid detaching the clearing stem 26 when the motor 14 is reciprocating . by way of example only , the magnets 12 / 33 may comprise rare earth magnets ( e . g ., neodymium ) for holding the clearing stem wire 28 to the motor shaft 15 . the appropriately - sized magnets may provide from 0 . 5 to 3 . 0 lbs of holding force . the sheath is held fast to the control box 1 by the luer lock connector / receptacle combination . it should be understood that clamping of the sheath 30 needs to have a certain force to secure the sheath 30 , but not crush the sheath 30 . the stiffness of the sheath 30 must be adequate to preserve the inner diameter cross section during operation . this is necessary to ensure the wire 28 is not pinched by the operator and its motion impeded . the wire 28 must also be flexible enough to navigate a small radius of curvature , such as 2 . 54 cm radius , while maintaining operation , as can be seen in fig4 . in particular , fig4 depicts a clog 40 blocking the tube inner lumen 41 of an artificial tube 39 and wherein the clearing stem 26 navigates a tight radius of curvature , r , and clears the clog 40 which is located past the radius of curvature r . the magnets 33 / 12 may be cylindrical in shape and the magnet 12 within the motor magnetic coupler 13 is recessed within the motor magnetic coupler 13 that fits over the motor shaft 15 . the magnet recess 12 a keeps the magnet from sliding along its surface plane and becoming detached while it is reciprocating . a sensor ( magnetic or contact , not shown ) may also be implemented to illuminate an indicator 75 a ( e . g ., an led , see fig2 a and 17a ) on the control box 1 to confirm that the magnetic connection is securely made . this feature also alerts the user if the connection becomes broken during use . in an alternate embodiment , the magnet 33 ( or 12 ) may only be located on one of the mating pieces , and a disc or cylinder of magnetic material , be located on the other . it should be understood that this magnetic luer lock coupling is by way of example only . it is within the broadest scope of the invention to include other types of releasably securable connector mechanisms , such as , but not limited to , threaded couplings . as mentioned previously , the control box 1 includes a diaphragm 9 which seals the control box 1 from contamination from the outside . as can be seen most clearly in fig2 - 2a , the diaphragm 9 permits magnetic attachment of the clearing stem 26 so that the magnets 33 / 12 can make contact while at the same time sealing the box 1 such that no debris , biological or other , enters the control box 1 . fig1 a is an enlarged partial view showing the sealing diaphragm 9 that does not interfere with motor shaft 15 motion . the diaphragm 9 prevents , among other things , the ingress of liquids into the control box 1 . the diaphragm 9 may also be located externally or on the boundary of the control box 1 so that it can be cleaned more easily . as also mentioned previously , the preferred control box 1 is that shown in fig2 b wherein a preferred novel clearing stem - control box interface is used . in particular , fig1 b - 16c depict the drive side of the control box 1 which includes a sheath attachment bracket 83 , an alternate diaphragm 9 a , a diaphragm sealing ring 84 ( see also fig2 b ), the motor ( e . g ., voice coil motor , vcm ) shaft 15 along with an alternate motor magnetic coupler 13 a ( e . g ., a magnetic coupler for a vcm ). as can be seen from fig1 b , the alternate diaphragm 9 a contains no holes or apertures through which the clearing stem 26 passes . the diaphragm sealing ring 84 secures the compliant alternate diaphragm 9 a in place . to facilitate coupling the clearing stem 26 to this control box , as can be seen most clearly in fig1 c , the proximal end of the clearing stem 26 comprises an alternate clearing stem fitting 32 a and an alternate clearing stem magnet 33 a positioned within an alternate clearing stem magnetic fitting 33 b . in order to couple the clearing stem 26 to the control box motor 14 , the alternate clearing stem magnet fitting 33 b is brought into close proximity with the alternate diaphragm 9 a such that the two magnets 12 and 33 a are magnetically coupled and abutting through the alternate diaphragm 9 a . thus , there is no breach of the seal of the control box 1 because the alternate diaphragm 9 a remains closed . simultaneously , the alternate clearing stem fitting 32 a is secured in the sheath attachment bracket 83 . as a result , reciprocation of the motor shaft 15 can occur without passing through any aperture or opening in the alternate diaphragm 9 a . fig1 and ia depict a drive - end view of the clearing stem 26 coupled to the control box 1 . as can be appreciated from fig3 a , the wire stop 27 limits the amount of travel of the wire 28 to the right ( i . e ., towards the motor 14 ) during operation . in an alternate embodiment , as shown in fig3 c and 3d , the wire stop 27 has been removed and instead an alternate wire stop 27 a is used closer to the proximal end of the clearing stem 26 . this alternate wire stop 27 a comprises a stretchable / pliant ( e . g ., silicon ) tube whose ends are bonded to the alternate clearing stem fitting 32 a on one side and to the alternate clearing stem magnet fitting 33 b on its other side . this alternate wire stop 27 a supports the wire 28 that passes through it . during operation , the alternate wire stop 27 a compresses and expands accordingly without interfering with wire 28 oscillation / travel . this alternate wire stop 27 a is preferred because it is located externally of the artificial tube 39 and thereby avoids having a stop at the working end of the wire 28 that could interfere with operation . thus , the alternate wire stop 27 a serves to keep the wire 28 from sliding out of the sheath 30 . as shown in fig3 a , the wire tip 29 of the wire is rounded to allow the wire 28 to break up a clog 40 ( fig4 ), and to resist penetrating an organ ( e . g ., stomach or other tissue / organ , etc .) should the wire tip 29 ever make its way close to an organ . the wire protrusion 28 a may also be given added flexibility by design compared to that of the rest of the wire 28 , to further reduce the risk of the clearing stem wire tip 29 having enough force to penetrate an organ ( e . g ., the stomach ) and / or to increase displacement at the wire tip 29 and facilitate clearing of the clog 40 . as mentioned previously , the length of the wire protrusion 28 a beyond the end of the sheath 28 and the roundness of the wire tip 29 strongly impact the ease of insertion into an artificial tube . ideally , the wire tip 29 radius is 0 . 5 to 2 . 0 times the overall wire 28 diameter . the stiffness of the sheath 30 comprises a balance between being stiff enough to prevent the operator from clamping down on the wire 28 and stopping wire 28 motion versus being flexible enough to enter an artificial ( e . g ., feeding ) tube 39 and to navigate curves in the tube inner lumen 41 of the artificial tube 39 . another safety feature of the present invention tci is that the force generated at the end of the wire tip 29 is less than 5 % of the force generated at the motor 14 and therefore , this force reduction provides a safety feature of avoiding puncturing an organ accidentally but yet providing sufficient force to break up the clog 40 and helping to clear the walls of the tube . as mentioned previously , a stem stiffener 31 ( fig3 - 3a ) is provided at the proximal end of the clearing stem 26 which prevents the operator from over - bending the clearing stem 26 and thereby stopping the reciprocation . the stem stiffener 31 may be constructed of the same material ( of a larger diameter than the wire 28 or sheath 30 ), may be integrated into the sheath 30 via custom extrusion , or may be constructed of a different material , such as any polymer or metal . to prevent the “ over - insertion ” of the clearing stem 26 , a tube depth - control collar 22 ( fig3 - 3a and 9 a - 9 c ) is provided . the tube depth - control collar 22 comprises a tube depth - control collar body 24 which includes an internal spring 25 . a tube depth - control collar push button 23 is provided to lock or unlock the tube depth - control collar 22 . in particular , as shown most clearly in fig9 a , the depth control collar push button 23 has a central passageway of push button 23 a and the tube depth - control collar body 24 has a central passageway of collar body 24 a . a spring 25 acts to misalign these two passageways 23 a / 24 a . thus , to re - position the tube depth - control collar 22 along the length of the sheath 30 ( not shown ), the depth control collar push button 23 is depressed which momentarily relieves any clamping force on the sheath 30 and the tube depth - control collar 22 can then be moved . when the operator wishes to lock the tube depth - control collar 22 in position , he / she releases the tube depth - control collar push button 23 which results in the sheath 30 being clamped between an upper portion of collar body 24 b of the tube depth - control collar body 24 and a lower portion 23 b of the tube depth - control collar push button 23 . the force applied by the depth - control collar to the sheath 30 needs to be compressive enough to hold the tube depth - control collar body 24 in place against the sheath 30 , but not to clamp the sheath 30 onto wire 28 . sheath length markings 30 a ( fig3 b ) and integer markings 30 b ( fig3 b ) are provided to facilitate positioning the tube depth - control collar 22 along the length of the sheath 30 depending on the length of the artificial tube 39 being cleared . the markings 30 a / integers 30 b are in ascending or descending order from the distal end 30 c of the sheath 30 to the proximal end 30 d . along with the stiffness of the sheath 30 , the spring constant of the spring 25 comprises a balance between the force necessary to maintain the tube depth - control collar body 24 in place on the sheath 30 while avoiding the tube depth - control collar body 24 from clamping down on the wire 28 and stopping wire 28 motion . it should be understood that it is within the broadest scope of the present invention to include fixed tube depth - control collars 22 a , such as that shown in fig3 c , 3 d and 9 d . in particular , a plurality of clearing stems 26 may be provided , each having a fixed tube depth - control collar 22 a fixed at a predetermined length ( e . g ., 35 inches , 44 inches , etc .) along the sheath 30 . fig9 d shows the fixed tube depth - control collar 22 a abutting the proximal end of the feeding tube ft thereby preventing the sheath 30 from entering any further within the feeding tube ft . using this embodiment , the operator selects one clearing stem 26 , from a plurality of clearing stems 26 , having a particular fixed tube depth - control collar 22 a and clearing stem 26 length that is appropriate for the particular feeding tube ft that contains a clog that is to be cleared . to facilitate clearing , a brush may be included on the wire tip 29 or on the distal end of the sheath 30 . for example , fig6 depicts a wire tip brush 35 on the end of the wire 28 whereas fig7 and 8 depict respective brushes with sheath tip brush 36 and forward swept sheath tip brush 37 on the end of the sheath 30 . therefore , as the wire protrusion 28 a reciprocates , the wire tip brush 35 cleans the tube walls or when the sheath 30 is inserted into the artificial tube 39 , the insertion motion causes the brush 36 or 37 to clean the tube walls , as well as facilitate the movement of the dislodged blockage and / or its pieces . in particular , the small brush ( e . g ., polyester , foam , or twisted in wire ) on the distal end of sheath ( 36 or 37 ) or wire ( 35 ) provides more thorough clearing of tube walls . with particular regard to brush 36 or 37 , mounted on the distal end of the sheath 30 , the brush 36 or 37 is non - moving in this embodiment , which helps to clear excess particles from tube walls after the wire protrusion 28 a has cleared the clog 40 and as the sheath 30 is retracted and moved out of the artificial tube 39 . the advantage of the brush 36 or 37 on the sheath 30 is that the brush 36 or 37 does not impede the wire 28 motion at all . it should be noted that the forward swept sheath tip brush 37 on the distal end of the sheath 30 shown in fig8 includes bristles that are swept in the distal direction . this makes clearing effective as the forward swept sheath tip brush 37 is inserted into the tube , but also allows for a smoother retraction because the sweep - direction of the bristles reduces the resistance of the forward swept sheath tip brush 37 when the operator is removing the clearing stem 26 from the artificial tube 39 . this reduced resistance minimizes the chance of dislodging the artificial tube 39 from the patient when the clearing stem 26 is removed . other configurations of the clearing stem 26 include a range of wire tip 29 designs . for example , a sphere ( e . g ., metal or plastic ) anywhere along the length of the wire protrusion 28 a may be included , such as the ball tip 34 e in fig5 d . if the sphere is included at the wire tip 29 , this helps prevent the inadvertent insertion into an organ ( e . g ., stomach ) wall , and also prevents the inadvertent retraction of the wire protrusion 28 a into the sheath 30 during use , setup or clearing illustrated in fig5 d . another alternative end may comprise a plastic end wherein a plastic tip is fused or ultrasonically welded to the wire tip 29 and which may comprise the shape of a point , helix , or radius , etc ., illustrated in fig5 a . in addition , these alternative tips may further comprise ridges or a pattern designed to sweep broken debris away from the clog 40 site . fig5 a depicts the distal end of the wire 28 with a plastic wire tip 34 . an alternative tip design may include a spring guide wire design possibly exemplified by lake region medical paragon pre - coat guide wires . another alternative tip could be flexible such as a tecoflex ® tip which causes the tip to slide across contacted tissue rather than puncturing tissue , thus providing an additional safety feature . fig5 b depicts another alternative end which may comprise a small spring mechanism which provides increased displacement and protection against an over - insertion puncture . in particular , a plastic or metal alternate tubing tip 34 a is positioned over the distal end of the wire 28 . the rear end of the alternate tubing tip 34 a is secured to one end of a tip compression spring tcs that is slid onto the wire 28 . a fixed member 34 b is secured to the wire 28 and to the other end of the tip compression spring tcs . thus , the alternate tubing tip 34 a acts as a further protection against accidental contact with soft tissue , since the alternate tubing tip 34 a can only be retracted when it encounters a solid object , e . g ., a clog , and whereby the wire tip 29 is then exposed to the solid object . once the clog is cleared , the alternate tubing tip 34 a springs back in position ahead of the wire tip 29 to shield it from contact with bodily tissue or organs . moreover , the wire tip 29 may also comprise a small gripping mechanism wherein the wire tip 29 contains a small cable - actuated gripping mechanism to dislodge clogs 40 or retrieve samples of clog material . in particular , fig5 c depicts gripping / chopping mechanism 34 c that are hinged or pivoted at pivot point 34 d . by actuating a control member ( not shown , e . g ., a cable , rod , electromechanical motor , piezoelectric motor etc . ), the gripping / chopping mechanism 34 c can be closed around a clog specimen or used to tear away the clog material to dislodge clogs or retrieve a sample of the clog material . an alternative design to the wire 28 is the provision of a flexible portion of wire 28 located between the end of the sheath 30 and the wire tip 29 . thus , the wire protrusion 28 a may comprise a material that is more flexible than the remaining part of the wire 28 that couples to the motor shaft 15 . as mentioned previously , the motor 14 drives the wire 28 , creating linear displacement . the back and forth displacement of the wire 28 allows it to break up and clear clogs 40 in artificial tubes ( e . g ., enteral feeding tubes and especially ng feeding tubes ), while simultaneously cleaning debris from the tube walls . the wire tip 29 of the wire 28 has a linear displacement , preferably , in the range of 0 . 25 to 25 mm , more preferably 2 - 10 mm from the distal end of the sheath 30 . the frequency of operation of the motor shaft 15 preferably varies from 10 to 100 hz but more preferably in the 15 - 40 hz range . the motor 14 has a range of displacement preferably from 1 - 40 mm and more preferably in the range of 10 - 30 mm . the motor blocking force ( i . e ., the maximum force output ) has a preferable range of 2 - 25n and more preferably 6 - 14n . the reciprocating motion of the clearing stem 26 of the present invention tci can be achieved using a variety of motor technologies , such as , but not limited to , voice coil motors ( vcms ) as illustrated for the motor 14 ( fig2 - 2b , 10 - 10 a and 15 ), dc motors 49 ( fig1 , 11 a - 11 c ), piezoelectric transducers , including amplified piezoelectric actuator motors 59 ( apa , such as those disclosed in u . s . pat . no . 6 , 465 , 936 ( knowles , et . al ), whose entire disclosure is incorporated by reference herein ) ( fig1 - 12a ), piezoelectric actuators , active polymer compound actuators , solenoid motors 55 ( fig1 - 13a ), pneumatic motors 42 ( fig1 - 14a ), magnetorestrictive transducers , electrorestrictive transducers , etc . as shown in fig2 - 2a , 10 - 10 a , and 15 the motor 14 may comprise a voice coil motor ( vcm ) having a vcm body 16 mounted within end bearings 18 , a displaceable motor shaft 15 , dampers or spring 19 , and magnets 20 mounted to the motor shaft 15 , with pole pieces 21 a , 21 b and 21 c ( fig2 a , 10 a and 15 ) located at the ends and within the center of the magnets 20 . coil windings 17 are wound around the vcm body 16 and thus do not interfere with vcm motor shaft 15 displacement . motor mounts 7 and motor mount dampers 8 secure the motor 14 within the control box 1 while avoiding direct coupling against the bottom surface of the control box 1 . a motor printed circuit board ( pcb ) 11 distributes the current commands from the electronics 10 to the coil windings 17 through wires 53 . when an electric current is applied through the coil windings 17 , a magnetic field , due to ampere &# 39 ; s law , is produced inside the coil windings . the non - uniform magnetic field at the ends exerts a force on the permanent magnets 20 . alternating the current alternates the direction of the magnetic field gradients and results in a reciprocating motion of the motor shaft 15 with respect to the vcm body 16 . the magnitude of the force is determined by the magnetic flux density , which is proportional to the number of turns per length of the coil , current magnitude , cross - sectional area of the coil , as well as the strength of the permanent magnets 20 . the springs 19 absorb the energy associated with abrupt changes in the direction of the inertial force of the magnets 20 and vcm body 16 when actuated , resulting in a lowering of vibration and increasing the tube clearer tci usability and efficiency . by way of example only , the spring constant of the springs 19 can range from 0 . 5 - 5 lb / in , and more preferably 1 . 5 - 2 . 5 lb / in . a soft stop ss may be installed at the free end of the vcm motor shaft 15 because the shaft tends to drift off center during use . a further variation of the use of a plurality of magnets is to arrange the plurality of magnets into two “ driving members ” disposed between the pole pieces 21 a - 21 c , mentioned previously . pole pieces 21 a - 21 c are typically ferromagnetic and are preferably stainless steel . as shown most clearly in fig1 , the south poles of the first magnetic driving member 20 n and the south poles of the second magnetic driving member 20 s are fixedly secured to the opposing faces of the pole piece 2 ib in order to provide a zone of maximum magnetic flux density which extends radially outwardly from the central portion of the pole piece 21 b , similar to the configuration disclosed in u . s . pat . no . 4 , 363 , 980 ( peterson ) whose entire disclosure is incorporated by reference herein . alternatively , each magnetic driving member 20 n and 20 s may be replaced with a single elongated permanent magnet , rather than using a plurality of magnet elements as shown in fig1 . in either case , the driving members 20 n and 20 s have opposite pole directions . it is within the broadest scope of the present invention that the relative positions of the coil windings 17 and the magnets 20 are reversed ( not shown ), i . e ., the coil windings 17 are wound directly around the motor shaft 15 and the magnets 20 are positioned around the vcm body 16 and thus do not interfere with the motor shaft &# 39 ; s 15 reciprocation . alternatively , a dual coil motor or actuator ( also not shown ) is also within the broadest scope of the present invention . in particular , instead of using magnets 20 , two coil windings are used wherein one coil is wound directly around the motor shaft 15 and a second or outer coil is wound around the first or inner coil but without interfering with shaft displacement . each coil is supplied with respective alternating current sources which generate respective electromagnetic fields that also generate a reciprocating motion of the motor shaft 15 . the inner coil may conduct direct current dc while the outer coil conducts alternating current ac . alternatively , the inner coil may conduct alternating current ac while the outer coil conducts direct current dc , or both the inner coil and the outer coil may conduct alternating current ac . moreover , to reduce vibration caused by the oscillating motion of the motor shaft 15 , a secondary vcm or counter balance mechanism 14 a of similar size ( also referred to as a “ countermass ” or “ counterbalance ”) may be included and driven at an opposite phase ( e . g ., 180 ° phase lag ) for cancelling vibration caused by the motor 14 . see fig2 b . thus , when the tube clearer tci is operated such that the first vcm is activated to cause the motor shaft 15 to move , a first momentum vector is produced . the second vcm is operated such that it creates a second momentum vector equal in magnitude but opposite in direction to the first momentum vector , such that the net sum of the first and second momentum vectors is minimized and preferably equal to zero . in particular , to maximize vibration reduction , the moving parts ( shaft , magnets , pole pieces , attachments , etc .) of the counter balance mechanism 14 a should have a moving mass and velocity ( frequency and displacement ) equal to that of the moving parts of the actuating motor 14 . this is based on the principle of conservation of momentum . the sine waves that actuate both vcms must have a 180 degree phase lag between them . this causes their forces to be opposite and ( ideally ) equal , cancelling each other out . as such , operation of the tube clearer tci does not cause “ chatter ” and therefore there is no irritation to the operator or patient . the motor may also comprise dc or dc brushless motor 49 for creating reciprocating displacement via a scotch yoke sy or similar mechanism . fig1 depicts the control box 1 using a dc motor 49 and scotch yoke sy as the actuating mechanism . no signal generating electronics are needed for this application since the dc motor 49 is simply turned on to cause a rotating crank cr to drive the scotch yoke slider 50 and the scotch yoke shaft 52 in reciprocating motion . the adapter 51 transmits the scotch yoke sy motion to the scotch yoke shaft 52 . fig1 a - 11c show three still frames as an example of scotch yoke sy motion . fig1 a and fig1 b show scotch yoke forward displacement direction 50 a and fig1 c shows scotch yoke rearward displacement direction 50 b are moving in a reciprocating motion . an amplified piezoelectric actuator ( apa ) 60 creates reciprocating displacement in the lower range , preferably ( 0 . 1 to 2 . 0 mm ), anchored to the control box 1 . one or more apa motors 59 can be used in series , as this increases displacement . fig1 - 12a depict the control box 1 with an apa as the actuating mechanism . in particular , the apa actuator 60 is mounted to the control box via an actuator mount 61 which is indirectly coupled to the control box 1 bottom via motor mount damper 8 . an actuator shaft 62 conveys the reciprocating motion , from apa actuator 60 expansion and contraction , to the clearing stem ( not shown ) via the magnetic coupling discussed earlier for the other embodiments . a langevin transducer 77 can be used for the motor 14 . as shown in fig1 b , the langevin transducer comprises a plurality of piezoelectric elements 78 are arranged to cause a horn 81 to vibrate to form the reciprocating motion . the horn 81 is secured to an actuator mount 61 using a pre - stress bolt 79 . the langevin transducer 77 includes a tail mass 80 for bolt - clamping the langevin transducer 77 to the actuator mount 61 . the forward end of the horn 81 is tapered such that a distal end of the horn passes through the control box alternate diaphragm 9 a . a clearing stem attachment 82 is provided to receive / mate with the clearing stem 26 as discussed previously . a power source ( not shown ) that provides the proper activation energy is coupled through the power plug 5 and via electronic control wires 53 . it should be noted that activation of the langevin transducer 77 creates reciprocating motion with the introduction of several overtones ( viz ., first - fourth overtones ), shown in fig1 c . as part of the design of the present invention , the lateral displacement caused by these overtones is kept to a minimum . in particular , the piezoelectric elements 78 ( e . g ., a plurality of piezoelectric ceramic discs ) are held in compression between the tail mass 80 and horn 81 ; and the pre - stress bolt 79 passing from a proximal end of the tail mass 80 and threading into the horn 81 . vibratory motion is caused by the activation of the piezoelectric elements 78 upon being exposed to an alternating electric field such as from an ac electrical current applied to electrical contacts ( not shown ) formed on opposing sides of each of the piezoelectric elements 78 . the vibratory motion is translated as a standing harmonic wave spanning longitudinally across the horn 81 and to the clearing stem ( not shown ). therefore , when operated at ultrasonic frequencies , the langevin transducer 77 translates the ultrasonic energy as a reciprocating vibration to the clearing stem 26 , and produces a standing wave within the flexible member . the horn 81 and tail mass 80 are made of a metal such as titanium , stainless steel or , preferably , aluminum . the pre - stress bolt 79 is generally of stainless steel , but not limited thereto . the solenoid motor 55 shown in fig1 - 13a mounted in the control box 1 operates in a very similar manner as does the motor 14 , discussed previously . a return spring 58 is required with the solenoid 56 since it has one - way actuation . in particular , the electronics 10 are configured to pulse the solenoid 56 such that during the pulse , the solenoid shaft 57 is driven to the left in fig1 - 13a and when the pulse is terminated , the return spring 58 restores the solenoid shaft 57 to the right . this action is repeated at the frequencies discussed previously . fig1 - 14a depict a pneumatic motor 42 for creating the reciprocating motion . in particular , the pneumatic motor shaft 44 is driven by the pneumatic motor 42 which receives pneumatic pulses from a pneumatic pulse generator ( not shown ) via an air supply inlet 54 on the control box 1 and through internal tubing 47 . the pneumatic motor 42 is positioned within a pneumatic motor housing 43 which includes a pneumatic motor diaphragm 46 for distributing the pneumatic pulse evenly to the pneumatic motor shaft 44 , thereby maintaining its alignment , while at the same time providing a tightly - sealed motor configuration . the pneumatic pulse causes the pneumatic motor shaft 44 to be driven to the left while compressing a return spring 58 . once the pneumatic pulse is terminated , the return spring 58 restores the pneumatic motor shaft 44 to the right . this action is repeated at the frequencies discussed previously . fig1 a provides a block diagram of the electronic system 63 contained within the electronics 10 . a microprocessor ( e . g ., msp430f2618tpmr ) controls the power electronics 73 to the motor 14 . although not shown , a power supply ( e . g ., an autodyne ul medically - approved power supply amp6301 - 08 ) converts the 120 vac from the wall outlet to 24 vdc . a microprocessor power unit mpu 69 ( e . g ., a voltage regulator circuit , such as the lm317 / lm337 ) reduces the incoming ( e . g ., + 24 vdc ) power 67 to a lower power ( e . g ., + 3 . 3 vdc indicated by 70 ) for use by the microprocessor 71 . the microprocessor 71 controls the motor 14 via power electronics 73 , as well as all of the associated indicators , such as led indicators 3 , 4 , 75 and 75 a . the power electronics 73 convert the microprocessor 71 commands into a power signal to motor 76 ( 24v p - p ac ) using internal inverters to activate the motor 14 . an enable switch 72 is provided to permit the clearing stem to be continuously reciprocated for a predetermined period of time ( e . g ., 4 - 20 minutes ), which avoids running the device tci for too long but provides sufficient time to effect clearing the clog . a control box power switch 2 is coupled to the microprocessor power unit ( mpu ) 69 via a fuse 66 . a power indicator ( e . g ., led ) 3 is provided on the control box 1 . when the control box 1 is externally powered , e . g ., from 120 vdc , 60 hz wall power , a power - cord ( not shown ) is supplied with the control box 1 , and which includes an ac / dc converter . it should be understood that this does not limit the operation of the present invention to wall power in any manner and that the control box 1 can be operated off any type of power source , including battery power . the electronic system 63 may also include a displacement sensor ds ( e . g ., an lvdt ( e . g ., macro sensors cd 375 - 500 ) or force sensor / load cell ( e . g ., futek lpm 200 ); or eddy current sensor ( e . g ., micro - epsilon eddy ncdt 3010 ), etc .) for accomplishing closed loop motor control as well as detecting changes in the clearing process . for example , the sensor ds forms a closed loop with microprocessor 71 for maintaining the motor shaft 15 in a centered position , which maintains the motor 14 where the force is the greatest and provides optimum control . alternatively , the sensor ds may comprise a displacement / force feedback sensor or even an optical displacement sensor ( e . g ., variohm eurosensor ). the ds sensor output may also be used for self - centering of the wire 28 during operation . as part of the closed loop control , it may be advantageous to also change any dc offset to alter the force profile at the wire tip 29 and to provide more power to one side . in addition , an impedance sensor / current sensor is may be included for detecting the change in voltage / current of the motor 14 and communicating with the microprocessor 71 for determining the status of the clearing process , such as initial contact with blockage , passage therethrough , etc . this status can be conveyed through a display or clearing status indicator 75 ( e . g ., leds , 7 - segment displays , audible indicators , etc .) or a series of differently - colored leds 75 ( e . g ., from green to yellow to red ). alternatively , where the displacement sensor ds comprises a displacement / force feedback sensor , this sensor &# 39 ; s output can be used to detect when the clog 40 is contacted and when it is penetrated . as mentioned earlier , in order to indicate that the clearing stem magnet 33 and the control box magnet 12 are coupled properly , a magnetic / conductive sensor to determine if a solid clearing stem connection has been made which can then be provided to an indicator 75 a . by way of example only , a magnetic sensor could be implemented to determine safe connectivity between magnets in operation , such as a honeywell magnetometer , hmr2300 . these magnetometers measure both magnetic field intensity and direction using their anisotropic magneto - resistive sensors . the ability to acquire this information can be utilized by the microprocessor 71 to ensure the magnet polarities are correct , and that the magnets field intensity is at a safe level ( e . g ., they have not been de - magnetized ). similarly , an anti - tamper circuit may also be included in the electronic system 63 which interrupts operation if the control box 1 is attempted to be opened . a corresponding tamper sensor may also be provided that causes the indicator 75 a on the control box 1 to indicate if someone has opened , or attempted opening the lid of the control box 1 . furthermore , control box screws can be configured to disable operation of the control box 1 , if they are attempted to be removed during activation . the microprocessor 71 can be programmed to drive the electronic system 63 at the needed voltage and frequency , converting 120v 60 hz wall power to needed parameters to drive the motor 14 at , for example 15 - 40 hz ( e . g ., 25 hz ). in particular , several fault conditions are programmed into the microprocessor 71 for which it interrupts device tci operation : v input & lt ; 20 vdc ; v input & gt ; 25 vdc ; overtemperature condition pertaining to the amplifier ic ; short circuit condition pertaining to the amplifier ic ; should any of these fault conditions occur , the microprocessor 71 activates a fault indicator 4 . also , as discussed earlier , the enable switch 72 permits the operator to initiate the reciprocating motion without the need to hold any trigger . the enable switch 72 permits the control box 1 to maintain the reciprocating motion for a predetermined period of time ( e . g ., 4 - 20 minutes ) before the reciprocating motion is terminated . fig1 b provides a flow diagram of the microprocessor 71 operation : at step power up 85 , the microprocessor 71 is powered up following activation of the power switch 2 by the operator . the microprocessor 71 then conducts a one second step initialization 86 . once the initialization 86 is completed the microprocessor 71 activates the power indicator 3 ( e . g ., typically a green light ( gl ) or indication ). at this point , device tci remains in a disabled state until the enable switch 72 is activated by the operator ; “ enable button pressed ” step 89 of the flow diagram represents activation of the enable switch 72 resulting in the enabled state 88 of the device where the clearing stem 26 is being reciprocated as described previously . the microprocessor 71 then maintains operation of this reciprocation for the predetermined period ( e . g ., 4 - 20 minutes ) shown as time interval 93 in the flow diagram . at the end of the predetermined period , the microprocessor 71 terminates the reciprocating movement of the clearing stem 26 and returns to step disabled 87 . in addition , upon activation of the enable switch 72 by the operator , the microprocessor 71 monitors the device tci for the faults described above , indicated by the paths - fault detected 90 of the flow diagram . if a fault 91 is detected by the microprocessor 71 , the microprocessor 71 terminates clearing stem reciprocation and activates the fault indicator 4 ( e . g ., typically a yellow light ( yl ) or indication ). the microprocessor 71 then shuts down ( step power cycle 92 ) the device tci . operation of the present invention tube clearer tci is as follows : if wall power is being used , the connector end of the power cord ( not shown ) is inserted into power plug 5 ( fig2 - 2a ) on the control box 1 and the other end of the power cord is coupled to a power supply which is coupled to a standard 120v rms / 60 hz three - prong outlet . the control box 1 is turned on using the power switch 2 which turns on the power indicator 3 which verifies that the control box 1 is operating properly . a new clearing stem 26 is removed from its packaging ( but not discarded since the contaminated clearing stem 26 will be placed in the packaging and then discarded ). if a plurality of clearing stems 26 are provided with tube depth - control collars fixed at different positions , the operator needs to select the clearing stem which has the appropriate fixed collar position ; if , the tube depth - control collar is adjustable , the operator needs to position the collar appropriately along the clearing stem . the following discussion of the operation is based upon the control box shown in fig2 - 2a , it being understood that this is by way of example only . the wire end of the wire 28 comprising the clearing stem magnet 33 is gently pulled out from within the sheath 30 and then the clearing stem magnet 33 is inserted into the bore of the luer clearing stem connector 6 until the operator feels the pull of the clearing stem magnet 33 to the other magnet 12 and / or hears the magnets connect . the sheath 30 is then pushed until the luer clearing stem fitting 32 is flush with the luer clearing stem connector 6 on the control box 1 . the luer clearing stem fitting 32 is then twisted onto the luer clearing stem connector 6 . next , the distal end wire tip 29 of the clearing member 26 is inserted a few inches into the artificial tube . the enable switch 72 is pressed to activate the reciprocating motion . while holding the artificial tube 39 in one hand , the clearing stem 26 is held in the other hand while the clearing stem 26 is advanced into the artificial tube . when the clog is initially encountered , the clearing status indicator 75 changes to alert to the initial contact , and the operator begins to apply a slight force to the clearing stem 26 . facilitating clog clearance can be achieved by the operator moving the clearing stem 26 back and forth slightly to clear the clog . these steps are repeated until the clog has cleared , in which case , the clearing status indicator 75 showing that the clog has been cleared activates . if the clog is cleared before the predetermined period ( e . g ., 4 - 20 minutes ) is reached , the operator can depress the enable switch 72 again to stop the reciprocating movement and then depress the power switch 2 to shut off power to the device tci . the clearing stem 26 can then be removed from the artificial tube ( e . g ., feeding tube ft ) and then the working end of the clearing stem 26 can be inserted into the packaging . the artificial tube should be flushed with water to verify that the clog has been cleared ; if not , the working end of the clearing stem 26 should be removed from the packaging and the clearing procedure repeated . if the clog is verified as being cleared , the clearing stem 26 is disengaged from the control box 1 in accordance with the version of the control box 1 being used . for example , if the preferred control box 1 ( e . g ., fig1 c ) is being used , the alternate clearing stem fitting 32 a is disengaged from the sheath attachment bracket 83 and the alternate clearing stem magnet 33 a is pulled away from the alternate diaphragm 9 a ; alternatively , where the luer fitting version of the control box 1 ( e . g ., fig1 a ) is used , the operator twists the luer clearing stem fitting 32 and removes the clearing stem magnet 33 end of the clearing stem 26 from the control box 1 . in either situation , the clearing stem 26 is placed back in the packaging and this is discarded in a suitable biohazard container . fig2 provides a partial isometric end view of a working end 401 of the wire 28 of the clearing stem 26 which utilizes a sheath with channels 30 e that includes ports 402 which can be used for irrigation and / or aspiration . these ports 402 form the end of conduits in the sheath with channels 30 e whose other ends are coupled to an aspiration source ( not shown , e . g ., a vacuum source , etc .) and / or an irrigation source ( also not shown , e . g ., a saline solution source , or other liquid source ). during clog break - up , broken pieces of the clog can be aspirated out of the artificial tube using the sheath with channels 30 e and where irrigating the clog vicinity is required , the sheath with channels 30 e can be used to deliver such liquids . when aspirating and irrigating simultaneously , aspiration flow should equal irrigation flow rate . the appropriate flow rates are preferably 1 - 15 ml / min . another alternate clearing stem configuration is replacing the wire 28 with a hollow lumen or wire 403 to allow aspiration or irrigation down the hollow lumen or wire 403 to achieve the same purposes discussed with regard to fig2 . this alternative configuration is shown in fig2 b . thus , the sheath ports 402 and the hollow lumen or wire 403 may cooperate in different configurations to achieve irrigation / aspiration alternatively or simultaneously . by way of example , the sheath ports 402 can be irrigating while the hollow lumen or wire 403 is suctioning , or vice versa . alternatively , all of the ports 402 and the hollow lumen or wire 403 can be operating as irrigators or aspiration . another alternate clearing stem configuration is to use the indwelling artificial tube 39 effectively as the sheath , as illustrated in fig2 c . in this case , a wire 28 or hollow lumen or wire 403 is inserted directly into an artificial tube 39 without the sheath 30 . the motor 14 drives the wire 28 or hollow lumen or wire 403 with motion as described previously , to disrupt the clog 40 . although not shown , the tube depth - control collar 22 may also be secured at the desired length to prevent over - insertion of the wire 28 or hollow lumen or wire 403 , with the collar 22 impacting the end of open proximal end of the artificial tube 39 during operation . alternatively , the wire 28 or hollow lumen or wire 403 may include the fixed tube depth - control collar 22 a to also limit over - insertion . using this configuration , the hollow lumen or wire 403 can achieve irrigation or suction alternatively . an advantage of this configuration is that elimination of the sheath can allow access to narrower lumens . the phrase “ completely exposed ” when used with the device tci means a device tci that does not use a sheath . another alternate clearing stem configuration is a very narrow hollow lumen or wire 403 compared to the sheath 30 such that the areal differential between the hollow lumen or wire 403 and sheath 30 allows for aspiration / irrigation as illustrated in fig2 d . another alternate clearing stem configuration is the sheath 30 has two ports . one is quite small and is possibly used for a very narrow hollow lumen or wire 403 and the port 402 is used for aspiration / irrigation as illustrated in fig2 e . as with tci , tube clearer tc 2 is a mechanical tube clearer but instead of generating reciprocating motion , tube clearer tc 2 generates rotating motion to achieve artificial tube clearing , preferably for peg feeding tubes . fig1 a depicts the tube clearer tc 2 which comprises a reusable handset 115 ( which remains outside the artificial tube and the patient ) having a motor 108 ( e . g ., a dc motor ) that drives ( rotates ) a disposable or limited - reuse clearing member 114 . the handset 115 is held by the operator &# 39 ; s hand 136 during the clearing procedure . it should be noted that , alternatively , clearing member 114 may also be hollow for irrigation or aspiration , or other features . the tube clearer tc 2 ( fig1 ) comprises a clearing member 114 that includes a magnetic connector 103 at one end which attaches to a torque limiter 105 of the handset 115 . attached at the distal end of the clearing member 114 is a narrow flexible rod , preferably a polymer piece of tubing with a clearing brush 101 located on its distal end . the clearing member 114 can be solid or hollow . in the solid embodiment , the distal end of the clearing member 114 is attached to the clearing brush 101 and the proximal end of the clearing member 114 is attached to a magnetic connector 103 . in the hollow embodiment , the wire holding the clearing brush 101 may extend the central length of the clearing member 114 to the magnetic connector 103 . the clearing member 114 is flexible in order to conform to various radius of curvatures r . it is rotated by the motor 108 within the handset 115 . the rotary motion of the clearing brush 101 clears the clog , occlusion , or debris from the tube ( not shown ). the clearing member 114 comprises a polymer tube with a clearing brush 101 inset at its distal end . the preferred polymer materials are nylon and polyurethane , although other materials may be used , such as polytetrafluoroethylene ( ptfe ), polyvinyl chloride ( pvc ), polyethylene , polypropylene , and fluoropolymer . the length of the clearing member 114 is equal to the length of the feeding tube +/− one inch , depending on application . fig2 shows the layout of the clearing member 114 . at the proximal end of the clearing member 114 is a polymer magnetic connector 103 which includes a clearing member magnet adapter 104 in its inner bore and which sits flush to the proximal end of the clearing member 114 . to attach the clearing member 114 to the handset , as shown in fig1 , the magnetic connector 103 is inserted into a receiving bore 105 a within the torque limiter 105 of the handset 115 . disposed within the bore end is a magnetic element 105 b and wherein when the magnetic connector 103 is inserted into the receiving bore 105 a , the clearing member magnet adapter 104 and magnetic element 105 b contact . to facilitate a tight connection , the magnetic connector 103 comprises a hexagonal - shape , or other non - round shape , that fits into a correspondingly - shaped receiving bore 105 a . dc motor 108 output is conveyed to the clearing member stem 102 through a gear train 107 and gear train output shaft 106 . the clearing brush 101 at the distal end has several unique features . it could be a twisted - in - wire type clearing brush 101 with a negative taper nt , as shown in fig2 . by way of example only , the clearing brush 101 may comprise a twisted - in wire type ; alternatively , the brush 101 may comprise a helical - wound wire or other type brush design . “ negative taper ” implies that the dealing brush 101 bristles are wider in diameter at the distal end than at the proximal end of the clearing brush 101 . there are several reasons for this configuration in the clearing member &# 39 ; s 114 design . most conventional brushes have a taper smaller at the distal end and larger at the proximal end . however , for this application it would require over - insertion to clear the full bore of the end of the artificial tube ( e . g ., feeding tube ) 119 . the negative taper nt also allows the helix - type wound clearing brush 101 to be extended rearward , as shown by the path of freed clog particles arrow 120 in fig2 . when rotating ( indicated by the rotation of brush arrow 121 ), this clearing brush 101 design forces wicking of the loosened clog debris away from the clog 122 also in the direction of the path of freed clog particles arrow 120 . this is important for fast , effective clearing . if the clog 122 was not removed from the clog site , it could be compacted further , making the clog 122 even more difficult to remove . the negative taper nt also allows for contact with the tube walls ( in order to clean them ), but only in a limited area . having contact only in a limited area reduces the amount of drag on the artificial tube 119 and the torque transmitted to it and thus this minimizes any chance of dislodging the artificial tube 119 from within the patient when the clearing member 114 is removed from the artificial tube 119 . the shape of the ( distal ) tip of the clearing brush 101 is also important for this application . unlike many standard twisted - in - wire brushes , which are cut at the ends after twisting , the tc 2 clearing brush 101 could possibly be wound with a rounded tip — the wire bends 180 degrees . this bend prevents any sharp end from coming into contact with the stomach , intestine , or other organs / tissues if over - inserted past the end of the artificial tube 119 . thus , the clearing brush 101 transfers minimal torque due to its unique geometry , but its helical design is also able to remove loosened debris from the clog 122 . in another embodiment , the brush tip 101 a ( fig1 ) radius of the clearing brush 101 can be modified , e . g ., rounded to allow the clearing brush 101 to break up a clog , but to not penetrate an organ ( e . g ., stomach or other tissue / organ , etc .) should the brush tip 101 a ever make its way close to an organ . the clearing brush 101 may also be retracted from the distal end of the clearing member to decrease the chance of the clearing brush 101 catching in stomach or other tissue . in another embodiment , the brush tip 101 a can be modified by the addition of a flexible tip such as a tecoflex ® tip . in another embodiment , brush tip 101 a can be modified by the addition of ball tip 34 e as illustrated in fig5 d . preferably , the handset 115 is shaped like a pistol , with contours to fit the user &# 39 ; s fingers comfortably while he / she is using it , as shown by the operator &# 39 ; s hand 136 ( fig1 a ). an index finger trigger 109 controls operation . the trigger 109 is a momentary power switch that only provides power when being pressed . the handset 115 is composed of three parts , one battery cover and two halves which are fastened together by screws or built - in snap fit connectors to form a handset housing 113 . it also contains an isolated battery compartment 112 to facilitate battery 111 changes without exposing any components to contaminants that could cause device failure or reduce reliability . a control circuit 110 ( fig1 ) conveys power to the dc motor 108 . in this embodiment the handset contains an isolated compartment in which a common battery size is used . for example , the handset 115 can be designed to accommodate any battery size such as 9v , aa , aaa , or a specialty size and a plurality of batteries where required . alternatively , the handset 115 may comprise a rechargeable battery such that there is no need to remove any batteries . a charger ( not shown ) may accompany the handset 115 such that the rechargeable battery can be inductively charged and this configuration has advantages over the battery operated setup , including : no panels are removable on the handset 115 which eliminates the possibility of contamination ; and also reduces cost and disposal of batteries . the inductive charger may comprise a base unit , rechargeable battery , and circuitry . the base unit may comprise an enclosure with a slot or depression or cradle into which the handset 115 is positioned . the base unit plugs into a standard 120v outlet . a coil in the base unit transmits a magnetic field to a coil in the handset 115 , and a charging circuit would transform the signal to the correct voltage and route it to the rechargeable battery located in the handset 115 . the motor 108 of the tube clearer tc 2 is preferably a dc motor or a brushless dc motor and gear combination . the gear mechanism may be a precision gear head , such as one utilizing a planetary gear train 116 or a compound gear train 118 utilizing two or more standalone gears . motor and gear output speed ranges from 600 rpm to 1800 rpm , more preferably 740 to 1140 rpm . the torque limiter 105 is also preferred in this embodiment . the maximum output torque can preferably range from 20 mnm to 40 mnm with a more preferable torque of 24 to 34 mnm . a voltage of less than or equal to 9 volts dc is preferred to drive the motor 108 , such that standard commercially - available batteries can be used . fig2 shows a dc motor 108 with a planetary gear train 116 whereas fig2 shows a dc motor 108 with a compound gear train 118 configuration that is coupled to the motor output shaft 117 . thus , torque , speed and geometry of the clearing stem define the optimal operation of the device tc 2 . alternatively , the motor 118 itself may have a torque output of preferably 20 mnm to 40 mnm , with a more preferable torque of 24 to 34 mnm , in which case the torque limiter 105 would not be necessary . in another embodiment , a dc or brushless dc motor 108 and gear combination is used in combination with a torque limiter 105 . the torque limiter 105 is attached in - line with the motor output shaft 117 and allows slippage once the maximum output torque is reached . in another embodiment , a dc or brushless dc motor 108 and gear combination is used in combination with a hammering device , similar to that found in hammer drills ( u . s . pat . no . 5 , 653 , 294 ( thurler , et al .) and whose entire disclosure is incorporated by reference herein ). this device creates an oscillatory motion along with the rotary motion to clear the clog . in another embodiment , the dc or brushless dc motor in all examples above is replaced with a piezoelectric motor with similar specifications . as with tci , tube clearer tc 2 comprises a tube depth - control collar 133 , as shown in fig2 . this depth - control collar permits one - handed operation using no special tools . the tube depth - control collar 133 mounts along the rod portion of the clearing member 114 . the tube depth - control collar 133 is formed to be well - balanced and lightweight so as to not cause unwanted harmonics in the clearing member 114 during rotation . the tube depth - control collar 133 comprises a lightweight , circular tube depth - control collar housing 129 which includes a displaceable tube depth - control collar push button 130 that acts against a preloaded spring 132 bias and which locks against the clearing member 114 which passes through the opening for clearing member 131 . fig1 a depicts the tube depth - control collar 133 on the clearing member 114 . in a preferred embodiment of the handset 115 , the torque applied to the clearing member 114 is limited by controlling the voltage and current applied to the dc motor and ultimately to the gears . these voltage and current limits are established by testing and determining the minimum angle of twist that are unacceptable when the clearing brush 101 is in a locked condition within tubes under test . an alternative method involves the use of a dc motor with a torque limiter 105 as depicted in fig1 and 25 . the torque limiter 105 is a two - piece patterned disc , preloaded by a preload spring 125 . the spring force controls torque at which disc slippage occurs . in particular , the torque limiter 105 comprises an input coupler 123 , a torque limiter output shaft 135 , a preload collar 134 and a torque limiter profile 124 . the input coupler 123 couples to the gear train 107 and the torque limiter output shaft 135 couples the clearing member 114 . as can be appreciated , when a certain applied torque is exceeded , the torque limiter 105 is designed to slip at the interface or torque limiter profile 124 to disengage and thereby prevent the clearing member 114 from exceeding the torque limit . the tube clearer tc 2 must control harmonics so that the clearing member 114 does not become uncontrollable and cause injury / damage . during device activation , the tube clearer tc 2 rotates the clearing member 114 with a displacement diameter that is preferably from 0 mm to 40 mm and a more preferred diameter of 25 . 4 mm or less . fig2 shows multi - nodal harmonics ( i . e ., node points 126 ) occurring in the clearing member 114 while spinning and also depicts the maximum desired displacement 127 a . this is preferred as its shape limits the displacement by geometry . the distance between the first two nodal points 126 is indicated by distance between nodal points 128 , and as can be seen in fig2 , this distance decreases for subsequent nodal points 126 . the maximum desired displacement 127 a of the clearing stem is preferred to be kept to 25 . 4 mm or less . in contrast , fig2 depicts a commercially - available rotary tool 115 a ( e . g ., a hand - held drill ) rotating the clearing member 114 , showing the undesirable profile of rotating stem 129 a ( and its undesirable corresponding maximum radial displacement 127 b ) of the clearing stem motion because there is only one nodal point at the proximal end of the clearing member 114 . this type of deformation is not preferred because it is more likely to be unstable . fig2 depicts a block diagram of the electronics of the device tc 2 . in particular , a dc motor 108 provides the rotational motion to the clearing stem 114 . the motor 108 receives its input voltage 140 from a voltage regulator 137 which in turn receives power 139 from a power source or battery 111 ( e . g ., 9v battery , a rechargeable battery , etc .) when the trigger 109 is activated by the operator . a power indicator 138 ( see fig1 a also ), driven by the voltage regulator , is also provided . fig2 a provides a partial isometric end view of the device tc 2 showing the clearing brush 101 coupled to the clearing member stem 102 which utilizes a sheath with channels 30 e that includes ports 402 which can be used for irrigation and / or aspiration . these ports 402 form the end of conduits in the sheath with channels 30 e whose other ends are coupled to an aspiration source ( not shown , e . g ., a vacuum source , etc .) and / or an irrigation source ( also not shown , e . g ., a saline solution source , or other liquid source ). during clog break - up , broken pieces of the clog can be aspirated out of the artificial tube using the sheath with channels 30 e and where irrigating the clog vicinity is required , the sheath with channels 30 e can be used to deliver such liquids . when aspirating and irrigating simultaneously , aspiration flow should equal irrigation flow rate . the appropriate flow rates are preferably between 1 - 15 ml / min . the clearing brush 101 can also be placed back along the clearing member stem 102 away from the distal end of the clearing member 114 to decrease the potential for the clearing brush 101 grabbing or interacting with the stomach or other organ or tissue . alternatively , the various configurations shown in fig2 and 29 b - 29 e can also be used with the device tc 2 . the phrase “ completely exposed ” when used with the device tc 2 means a device tc 2 that does not use a sheath . fig1 b - 18c depict an alternative voice coil motor tube clear device tc 2 . instead of using a “ pistol - style ” housing , the device tc 2 of fig1 b - 18c comprise an elongated hand grip 301 . in addition , unlike the rotational motion of the tc 2 device shown in fig1 a , the alternative voice coil motor tube clear device 300 generates reciprocating motion ( as discussed previously with regard to the tci devices ). in particular , within the hand grip 301 is positioned a voice coil motor 305 that , when energized , causes the clearing stem 303 to reciprocate . the tip of the clearing stem 303 includes a clearing brush 304 . as shown most clearly in fig1 b , a clearing stem adapter 302 is provided on an end of the hand grip 301 for securing the clearing stem 303 to the voice coil motor 305 in the hand grip 301 . a power indicator 138 is also provided to indicate when power is being provided to the clearing stem 303 for reciprocating motion . a power switch / trigger 109 a is provided so that the user can manually control the activation of the device , similar to the pistol - style embodiment . it should be noted that , alternatively , clearing stem 303 may also be hollow for irrigation or aspiration , or other features and may have similar configurations as shown in fig2 - 29e . it should be further understood that the preferred embodiments of the present invention are for the in - situ clearing of artificial lumens in a living being , but that these embodiments can be used for clearing lumens located outside of the living being , as well as for clearing other types of lumens not associated with living beings . now that exemplary embodiments of the present invention have been shown and described in detail , various modifications and improvements thereon will become readily apparent to those skilled in the art . accordingly , the spirit and scope of the present invention is to be construed broadly and limited only by the appended claims , and not by the foregoing specification . while the invention has been described in detail and with reference to specific examples thereof , it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof .

US-201213571104-A

an apparatus for measuring a lacrimal punctum and a canaliculus is provided . the apparatus comprises a handle and a tip disposed at one end of the handle , said tip having a gauge portion of size and shape to allow measurement of the lacrimal punctum and the canaliculus . the apparatus may further comprise a dilator portion disposed between the gauge portion and handle .

the eye contains round or slightly ovoid openings approximately 0 . 3 mm in size ( lacrimal punctum or punctal opening ) and surrounded by connective tissue ( sphincter ) about 1 mm in depth . each of the punctal openings leads into a vertical portion of the respective canaliculus , which is about 2 . 5 to 3 . 5 mm in length , before turning horizontally for about 8 mm to join its other canaliculus at the entrance of a lacrimal sac . referring to fig1 there is shown a representation of an apparatus 1 according to the present invention for sizing and dilating a lacrimal punctum 6 . apparatus 1 comprises a handle 4 and a tip 5 . the tip 5 has a dilator portion 3 and a gauge portion 2 . the gauge portion 2 is of cylindrical shape , has a diameter ranging from about 0 . 1 - 1 . 0 mm ( preferably from about 0 . 4 mm to about 0 . 9 mm ) and is of 0 . 5 mm to about 2 mm in length ( preferably about 2 mm ). tapered tip 11 located at the end of the gauge portion 2 facilitates the insertion of the gauge into the lacrimal punctum . the dilator portion 3 has a diameter that is about 0 . 1 mm larger than the diameter of the gauge portion 2 . this graduated system provides for actual measurement of the lacrimal punctum 6 and canaliculus 8 ( e . g ., the vertical portion of the canaliculus ) with the gauge 2 followed by insertion of the dilator 3 to provide a controlled dilation of the punctal dilation prior to insertion of a punctum plug . as previously described , in the treatment of keratoconjunctvitis sicca prevention of the drainage of lacrimal fluid from the eye may be achieved by blocking the lacrimal punctum 6 . fig2 and 4 depict a method for proper measurement of the lacrimal punctum and canaliculus , and dilation of the punctum , prior to insertion of a punctum plug . referring to fig2 which depicts proper insertion of the gauge portion 2 , e . g ., it is inserted into the lacrimal punctum 6 until the sphincter 7 seats flush around the gauge portion 2 providing a snug fit . in the preferred embodiment a series of gauge portion 2 of the tip 5 ranging from 0 . 4 to 0 . 9 mm are used to measure the lacrimal punctum 6 and canaliculus 8 . by inserting the gauge portion 2 of the tip 5 into the lacrimal punctum 6 and canaliculus 8 in a graduated fashion from the smallest gauge to the largest gauge , a snug fit can be : observed and measured . the gauge size that provides the snug fit is then used to determine the correct size punctum plug to use . when performing the measurement step , it is important to observe the seating of the gauge portion 2 without advancing the tip 5 farther into the canaliculus 8 , as doing so may cause premature or over - dilation of the sphincter . referring to fig3 which depicts insertion of the tip into the lacrimal punctum 6 . when the gauge portion 2 of the tip 5 appears to enter the sphincter 7 with little or no resistance , the gauge is too small and the next largest size gauge should be used . it is recommended that the next gauge tested be about 0 . 1 mm larger than the previous gauge used . alternatively , if the gauge portion 2 offers substantial resistance when entering the lacrimal punctum 6 , it is to large . the next smallest gauge should be tested . continue insertion of the gauge portion 2 incrementally with the next gauge until the gauge portion 2 of the tip 5 fits snugly . referring to fig4 which depicts controlled punctal dilation , the dilator portion 3 of the tip 5 may be inserted in the lacrimal punctum 6 . insertion of the dilator 3 results in a controlled dilation of the sphincter 7 . once sphincter dilation is observed remove the tip 5 . insert a punctum plug into the lacrimal punctum following insertion instructions for the specific punctum plug used . insertion of the punctum plug is done as quickly as possible to ensure dilation of the sphincter . in describing the invention , reference has been made to a preferred embodiment and illustrative advantages of the invention . those skilled in the art , however , may recognize additions , deletions , modifications , substitutions and other changes which will fall within the purview of the subject invention and claims .

US-1539801-A

a self - contained breathing device for use in fighting fires comprising a hood for covering a wearer &# 39 ; s head , a membrane for sealing the hood to create a breathing chamber inside the hood , and a source of oxygen disposed inside the hood . the source of oxygen is connected to the user by a conduit inside of the hood , and another conduit directs user - exhaled carbon dioxide to the source of oxygen . the breathing device includes a visual indicator inside of the hood that reacts to the presence of a gas within the hood and provides visual feedback to the user based on a quantity of the gas present in the hood .

the protective breathing equipment , or pbe , of the present invention is generally shown in fig1 and 2 . a hood 20 is sized to fit over a human head 15 , and includes a membrane 25 that the head 15 is slipped into and forms a seal to prevent gases or smoke from entering the breathing chamber 30 . behind the user &# 39 ; s head 15 is an oxygen generating system 40 described in more detail below . an oronasal mouthpiece 45 allows oxygen to enter through a one - way inhalation valve 55 , while carbon dioxide expelled from the user is routed back to the oxygen generating system 40 via an exhalation duct 50 . oxygen is produced in a chemical reaction and is communicated from the oxygen generating system 40 through an inhalation duct 60 to the mouthpiece 45 or the breathing chamber 30 generally . during operation , the user exhales into the oronasal mouthpiece 45 . the exhaled breath travels through the exhalation duct 50 and enters a canister 62 containing ko 2 ( potassium superoxide ). the exhaled carbon dioxide and water vapor are absorbed and replacement oxygen is released according to the reaction below : the regenerated oxygen gas passes through the inhalation duct 60 and enters the main compartment , or breathing chamber 30 , of the hood 20 . the interior hood volume above the neck seal membrane 25 serves as the breathing chamber 30 . when the user inhales , the one - way inhalation valve 55 allows the regenerated gas to enter the oronasal mouthpiece 45 and thus travel to the respiratory tract of the user . the breathing cycle will continue until the ko 2 canister 62 is exhausted . according to the present invention , an indicator would be visible from inside the mask 20 that will provide a status of the oxygen and / or carbon dioxide levels within the pbe as the device is operating . technology that evaluates the oxygen levels and carbon dioxide levels are known in the art . for example , oxygen indicators can be found in u . s . pat . nos . 6 , 325 , 974 and 4 , 504 , 522 , as well as u . s patent publication no . 2005 / 037512 . for carbon dioxide indicators , see u . s . pat . nos . 6 , 338 , 822 and 5 , 326 , 531 , and u . s . patent publication no . 2003 / 045608a . a gas sensitive ink or film may be adhered to the inside of a crew member pbe within the visible periphery of the user . in a preferred embodiment , there are two indicators inside the pbe . the first indicator detects the presence of oxygen (+ 30 %), and rapidly changes color when a threshold value is reached or surpassed . the second indicator detects the presence of carbon dioxide (& gt ; 4 %) and also quickly turns from one color to another . alternatively , the indicators can have words change color on the strips ( i . e . “ oxygen ” or “ remove hood ”). the indicators thus provide the user with an immediate method to determine the oxygen and / or carbon dioxide levels without removing the apparatus . fig3 and 4 illustrate examples of visual indicators that can be used with the present invention . for use on an aircraft , the pbe of the present invention is preferably vacuum sealed and stored at designated locations within the aircraft . the pbe can quickly be donned in the event of a cabin fire by air crew in order to combat the fire . the present invention is particularly well suited to protect the user from the hazards associated with toxic smoke , fire and hypoxia . the hood 20 has a visor 180 to protect the user &# 39 ; s eyes and provides a means for continued breathing with a self - contained oxygen generating system 40 . in a preferred embodiment , the system has a minimum of 15 minutes of operational life and is disposed of after use . the pbe hood operation is described in more detail below . during the donning sequence , the user actuates a chlorate starter candle 70 by pulling the adjustment straps 90 in the direction indicated by arrows 95 , thereby securing the oronasal mouthpiece 45 against the user &# 39 ; s face . the chemical reaction of the starter candle 70 is shown below : the small chlorate candle 70 ( starter candle ) produces about 8 liters of oxygen by the chemical decomposition of sodium chlorate . this candle 70 is mounted to the bottom of the ko 2 canister 62 . the starter candle 70 is preferably actuated by pulling a release pin 75 that is deployed automatically by a lanyard 80 when the user adjusts the straps 90 that tension the oronasal mouthpiece against the user &# 39 ; s face . the gas of the starter candle 70 discharges into the ko 2 canister 62 on the side where exhaled breath enters the canister from the exhalation duct 50 . some of the oxygen from the starter candle 70 provides an initial fill of the exhalation duct , while the bulk of this oxygen travels through the ko 2 canister 62 and fills the main compartment 30 of the hood 20 . one of the challenges in current technology is lack of any indication regarding the remaining useful duration of the pbe after it has been activated . in addition , the operational duration is dependent upon workload performed by the user , which is dependent on the breathing rate . if the pbe is used to the point of its limit , then the ensuing collapse of the hood 20 can be uncomfortable at a minimum and frightening in a panic situation . the invention described herein allows the user to first know that the device is working as expected , and subsequently alert the user so she or he can retire to a safe zone to remove the device once gas levels become problematic . in addition , the new version of the faa crewmember pbe ( tso - c116a ) requires “ failure of the unit to operate or to cease operation must be apparent to the user . this must be accomplished with aural and / or visual warning that also must activate at gas supply exhaustion .” this device would meet the “ exhausted of gas supply ” requirements of tso - c116a . intelligent , smart , or diagnostic inks respond to their environment by exhibiting a change in , for example , color or luminescence intensity . specific environmental parameters can be monitored , such as temperature , humidity , oxygen concentration , and carbon dioxide concentration . the basic operating principle is that the compound used changes color in the presence and proportion of oxygen via the reduction oxidation ( redox ) mechanism . the range of materials used to do this is quite extensive , but only one specific type below is described for brevity . the indicator may comprise an ink having a catalyzed thin film ( nano particles ) of a transition metal oxide , but alternatively may be formed by four more common constituents : an aqueous dispersion of a semiconductor ( tio 2 ), a sacrificial electron donor ( triethanolamine ), an aqueous solutions of a redox indicator dye ( methylene blue ), and an encapsulating polymer ( hydroxyethylcellulose ). the tio 2 particles create electron - hole pairs when exposed to uv light . the electrons reduce the dye , causing it to be bleached , and the holes oxidize the triethanolamine . polymer encapsulation allows the dye to be spin - coated onto plastic , metal , paper , or other surfaces . in one preferred embodiment , a solvent - based , irreversible oxygen indicator ink is used , comprising semiconductor photocatalyst nanoparticles , a solvent - soluble redox dye , mild reducing agent and polymer . the ink loses its color rapidly (& lt ; 30 s ) upon exposure to the uva light and remains colorless in an low oxygen concentration atmosphere , returning to its original color ( blue ) upon exposure to the appropriate concentration of oxygen . in the latter step , the rate of color recovery is proportional to the level of oxygen concentration . the film is reversible and can be returned to its white / clear color by uv activation . as part of the present invention , the ink or film is designed to be an indicator that is adhered to the inside of a crew member pbe . in a preferred embodiment , there will be two indicators inside the pbe , one for oxygen 105 and one for carbon dioxide 110 . instead of the indicators just being a colored strip , it is possible to have text or a scale / spectrum color change on the strips . for example , the “ text ” shows the operation mode , and could even outline the scale for co 2 and the scale for o 2 ( see fig4 a , b ). the scale would be produced as the levels change ( i . e . more or less of the scale becomes colored ). in this way , the wearer can tell something about the consumption of oxygen capacity . the benefit is that this invention provides the user with an immediate and continuous way to determine the status of the oxygen supply . it also allows the pbe user to wear the unit longer if needed because the oxygen generation of the assembly is continuously monitored . it further provides an immediate indication of an improperly fitted or damaged hood ( leakage ). the exhaustion of the ko 2 canister 62 results in a loss of active oxygen generation capability , coupled with a rapid increase in internal temperature and release of moisture from the ko 2 canister . previously , the loss of oxygen generating capability resulted in a gradual reduction of the interior volume of the hood 20 . the hood 20 would need to collapse around the wearer &# 39 ; s head 15 ; and as a result inhalation would become increasingly difficult , indicating that the hood 20 should be removed . the rapid rise in temperature inside the hood reinforced this indication . the present invention alleviates the subjective nature of determining the depletion of the oxygen generation chemicals because the user would have a visual indication of the amount of o 2 and co 2 within the hood 20 . this , in turn , will allow users to retire into a safe zone to remove the hood . the present invention has been described in a general manner , but the foregoing description and included drawings are not intended to be limiting in any manner . one of ordinary skill in the art would envision many modifications and substitutions to the embodiments described herein , and the invention is intended to incorporate all such modifications and substitutions . therefore , the scope of the invention is properly evaluated by the words of the claims appended hereto , and not strictly to any described embodiment or embodiment depicted in the drawings .

US-201213546115-A

a new and distinct nectarine tree variety , prunus persica var . nucipersica ‘ sunectwentyfour ’ is characterized by early ripening , large sized fruit , lower chilling requirements and nearly 100 % over - color .

throughout this specification , color names beginning with a small letter signify that the name of that color , as used in common speech is aptly descriptive . color names beginning with a capital letter designate values based upon the r . h . s . colour chart published by the royal horticultural society , london , england , 1986 . the descriptive matter which follows pertains to 6 year old ‘ sunectwentyfour ’ plants on nemared ( unpatented ) rootstock , grown in the vicinity of wasco , kern county , calif ., and is believed to apply to plants of the variety grown under similar conditions of soil and climate elsewhere . general : ( measurements taken on 6 year old tree unless otherwise noted .). size .— large . normal for most nectarine varieties . reaches a height of approximately 3 meters including normal pruning . spread .— normal for most nectarine varieties . approximately 15 feet with normal vase pruning . vigor .— strong . approximately 1 . 8 to 2 meters of growth in the first growing season . growth .— upright to spreading . productivity .— productive . fruit set is usually two or more times the desired amount for marketable size fruit . thinning is necessary . form .— vase formed . bearer .— regular . fertility .— self - fertile . canopy density .— dense . pruning is necessary to maintain tree vase shape and allow light into canopy . hardiness .— hardy in all fruit growing areas of california . disease resistance / susceptibility .— no specific testing for relative plant disease resistance / susceptibility has been undertaken . under close observation in kern county , calif ., no particular plant / fruit disease resistance / susceptibility has been observed . diameter .— approximately 25 cm . texture .— medium shaggy . trunk color .— outer bark is a combination of light greyed - green 198d and 178a dark greyed - red . trunk color becomes darker with age . size .— diameter ranges from approximately 8 - 10 cm . texture .— smooth on young wood , increasing roughness with tree age . color .— a combination of dark greyed - orange 166a and light greyed - green 198d . lenticels .— present . lenticels numbers .— numerous . lenticels density .— approximately 3 - 5 per cm 2 . lenticels color .— about medium greyed - orange 164c . lenticels size .— medium . lenticels length .— approximately 6 mm . lenticels width .— approximately 2 mm . flowering shoots : ( data taken in june at midpoint of current - season growth .). size .— average diameter approximately 5 mm . color .— topside : about dark greyed - brown 199a to dark green 141b . underside : about dark green 141b . thickness .— medium . internode length .— medium ; approximately 2 cm . midway on flowering shoot . flowering shoot lenticels .— none observed . flowering shoot leaf buds .— shape : obovate . width : approximately 2 mm . length : approximately 3 mm . color : about dark greyed - orange 165a . flowering shoot flower buds .— shape : obovate . width : approximately 2 . 5 mm . length : approximately 4 mm . color : about dark greyed - orange 165a . number of buds per node : usually 2 . presence of anthocyanin coloration .— present , dark red . density of buds .— medium . flower bud distribution .— generally isolated on one year old shoots . ratio of wood ( leaf ) buds to flowering shoots .— ½ on short spurs . size .— medium . average length .— medium ; approximately 162 mm . average width .— medium ; approximately 40 mm . thickness .— medium . color .— upper surface : about dark green 135b , lower surface : about 135c . form .— lanceolate . tip .— acuminate . base .— v - shaped . margin .— crenate . venation .— pinately veined . vein color .— about light green 139d . red mid vein on lower side .— present . surface texture .— smooth on both upper and lower surfaces . leaf blade ( ratio of length to width ).— high ; approximately 5 / 1 ratio . shape in the cross section .— concave . angle at apex .— small . angle at base .— acute . profile .— up folded . leaf blade tip .— curved downwardly . angle of tip .— acute . undulation of margin .— slight . timing of beginning of leaf bud burst .— early . average length .— medium ; approximately 6 mm . average diameter .— approximately 0 . 7 mm . color .— about dark greyed - red 180a when dry . nectaries .— present . shape of nectaries .— reuniform . thickness .— medium , approximately 1 mm . number / leaf bud .— approximately 2 when present . typical length .— medium , approximately 8 mm . color .— about medium yellow - green 151a . persistence .— falls off . form .— reniform . average number .— about 3 - 4 . position .— on both leaf base and petiole , alternate . average size .— medium ; approximately 1 mm long . color .— about dark greyed - red 180a when dry . flower blooming period .— first bloom : approximately first week in february . location of first bloom : toward base of tree . full bloom : approximately first week in february . location of full bloom : midway on tree . time of bloom .— early . duration of bloom .— medium ; approximately 10 days . type .— campanulate ( non - showy ). time of beginning of flowering .— early . diameter of fully opened flower .— medium , approximately 32 mm . flower aroma .— very slight . corolla ( main color on inner side ).— about dark red - purple 63a . length .— medium ; approximately 3 - 4 mm . diameter .— medium ; approximately 2 mm . color .— about medium yellow - green 146b . pubescence .— absent . number .— 5 . arrangement .— free . length .— approximately 15 mm . diameter .— approximately 10 mm . shape .— broadly ovate . width .— medium . apex shape .— rounded . base shape .— narrows at point of attachment . color ( inner and outer surfaces ).— about dark red - purple 63a . surface texture .— smooth . margins .— smooth , undulating . frequency of flowers with double petals .— none . size .— medium approximately 10 mm wide . claw length .— medium . margin waviness .— medium . base angle .— narrow . division of upper margin .— entire . pubescence of inner surface .— absent . pubescence of outer surface .— absent . number .— 5 . length .— approximately 5 mm . diameter .— approximately 4 mm . shape .— ovate . color .— about medium red 54b . surface texture .— smooth to slightly bumpy . margins .— smooth . positioning .— not touching petals or receptacle . pubescence of inner surface .— absent . pubescence of outer surface .— absent . frequency of flowers with double sepals .— none . number .— many , approximately 42 . average length .— approximately 7 mm . filament color .— white . 155a . anther color .— about dark red 53b when drying . flower pollen color .— about dark yellow - orange 17b . position compared to petals .— slightly below . number .— one , occasionally up to 4 . average length .— approximately 17 mm . ovary diameter .— approximately 1 - 1 . 5 mm . pubescence .— none . stigma extension in comparison to anthers .— above . frequency of supplementary pistils .— few . hardiness .— hardy . size .— medium , approximately 4 mm long and 2 . 5 mm wide . length .— medium . shape .— obovate . positioning .— free . pubescence .— few . color .— about dark greyed - orange 165a . general : ( at firm - ripe , on tree managed to obtain maximum size for commercial production near wasco , kern county , calif . description taken near wasco , kern county , calif . on may 14 , 2012 ).). harvest .— date of first pick .— approximately may 10 , 2012 . date of last pick .— approximately may 20 , 2012 . average size .— large . length ( stem end to apex ).— approximately 70 mm . diameter in line with suture plane .— approximately 69 mm . diameter perpendicular to suture plane .— approximately 69 mm . average weight .— approximately 168 gm . shape of pistil end ( excluding mucron tip ): weakly depressed under conditions in bakersfield , calif . shape .— rounded . depth .— medium , approximately 3 mm . breath .— approximately 1 cm . width .— medium . length .— medium , approximately 7 mm . diameter .— approximately 2 mm . color .— about medium greyed - orange 164b . adherence to stone .— strong . thickness .— medium . adherence to flesh .— strong . surface texture .— smooth . pubescence .— absent . bloom .— none . ground color .— about medium yellow - orange 20b . overcolor .— about dark red 44b to dark red 46a . taste .— none . firmness .— firm . reticulation .— absent . roughness .— absent . tenacity .— tenacious to flesh . relative area of over color of skin .— very large . pattern of over color of skin .— solid to slightly blotchy . tendency to crack .— slight , in wet season . ripens .— evenly . texture .— melting . fibers .— moderate . flavor .— bland tart - sweet . brix .— approximately 11 °- 12 °. juice .— moderate . aroma .— slight . color .— about medium yellow 11b . sweetness .— low - medium . anthocyanin color of flesh in central part of flesh .— absent or very weak . anthocyanin color of flesh next to skin .— absent or very weak . anthocyanin color of flesh around stone .— absent or very weak . amygdalin .— wanting . acidity .— medium . eating quality .— fair . carotenoid coloration of flesh .— about medium yellow 11b . stone / flesh ratio .— about 1 / 28 by weight . firmness .— firm . length .— approximately 30 mm . diameter in line with suture plane .— approximately 25 mm . diameter perpendicular to suture plane .— approximately 20 mm . color .— about medium yellow 11b . fruit shipping and keeping quality : good for early - season variety . quality remains good up to 5 weeks at 0 ° c . stone freeness .— clings over entire surface . adherence to flesh .— present . degree of adherence to flesh .— strong . stone size .— size : medium . size compared to fruit : small . length : medium , approximately 30 mm . diameter in line with suture plan ): approximately 25 mm . diameter perpendicular to suture plane : approximately 20 mm . width of stalk end : medium ; approximately 5 mm . angle of stalk end : right angle . hilum : oval . stone form .— viewed from stem end : oval - flattened . viewed from side : oval . viewed from ventral side : oval - flattened . stone shape .— lateral view : oval . base shape : nearly straight . apex shape : pointed . relief of surface .— predominately pits . stone surface .— pitted throughout . stone halves .— nearly symmetric . stone ridges .— continuous . stone outgrowing keel .— well developed . stone tendency to split .— low . anthocyanin coloration .— absent . intensity of brown color .— light . position of maximum diameter .— middle . sides .— equal . pits .— circular - to - elongated . fibers .— retains short fibre - like threads along ridges . ventrical edge .— medium . dorsal edge .— full , deep grooves . kernel .— shape : oval with rounded base and pointed apex . average length : 15 mm . average width : 11 mm . average depth ( perpendicular to suture ): 5 mm . color : about 165b when dried .

US-201213694270-V

a surgical installation tool to insert a vertebral implant into a patient includes an elongated handle and a head attached to one end . the vertebral implant may be attached to the head . the head may include an engagement member that is movable between engaged and released positions . the engagement member may be outwardly biased so that it naturally rests in the released position . the engagement member may be inwardly movable from the released position to the engaged position . a reactive force caused by the inward deflection may supply the attachment force between the installation tool and the vertebral implant . the attachment between the vertebral implant to the installation tool may be maintained while the engagement member is in the engaged position .

the various embodiments disclosed herein are directed to a low profile surgical implant insertion tool . an exemplary embodiment of the insertion tool 10 is illustrated in fig1 . in this particular embodiment , the insertion tool 10 is illustrated holding a hook implant 50 . the hook 50 may be a conventional distraction hook or other hook implant such as that belonging to the cd horizon ® legacy ™ spinal system available from medtronic sofamor danek in memphis , tenn . various types of hooks may be held and positioned using the insertion tool 10 , including for example pedicle hooks , supralaminar hooks , infralaminar hooks , and transverse process hooks . in fig1 , the hook 50 is held by the exemplary insertion tool 10 . in contrast , fig2 shows the hook 50 separated from the insertion tool 10 . the insertion tool 10 includes an elongated bar 12 having a head or retainer 20 disposed at an end of the elongated bar 12 . the insertion tool 10 may be manipulated during surgery by maneuvering the elongated bar 12 to place the hook 50 in a desired position relative to a vertebral member ( not shown ). the retainer 20 is configured to hold the hook 50 in a releasable manner . thus , once the hook 50 is positioned , the insertion tool 10 may be extracted , leaving the hook 50 substantially in the desired position . the retainer 20 is shaped to fill much of the saddle portion 52 of the hook 50 . in the embodiment shown , the saddle portion 52 comprises spaced apart side walls 54 having a substantially u - shaped open channel therebetween . it is between these side walls 54 that a spinal rod 60 of a spinal implant system is inserted . in the illustrated embodiment of a hook 50 , the side walls 54 include a threaded central portion 56 into which a retaining member 70 is inserted to secure the rod 60 within the saddle portion 52 of the hook 50 . the retainer 20 has a generally u - shaped configuration , which permits insertion of the retainer 20 into the saddle portion 52 of the hook 50 . the retainer 20 further comprises a plurality of biasing members 22 . in this embodiment , the biasing members 22 are configured as cantilevered leaf springs and operate as engagement elements that contact the hook 50 . furthermore , in the embodiment shown , the retainer 20 has four biasing members 22 , though a different number may be used . the insertion tool 10 is configured such that , when the retainer 20 is inserted into the saddle 52 of the hook 50 as shown in fig1 , the biasing members 22 frictionally engage inner faces 58 of the side walls 54 on either side of the threaded portion 56 . the biasing force applied by the biasing members 22 against the inner side walls 58 of the hook 50 is sufficient to support the weight of the hook 50 . however , as suggested above , the retainer 20 and the biasing members 22 hold the hook 50 in a releasable manner . thus , the biasing members 22 should not create so large a retaining force that the insertion tool 10 cannot be extracted from the hook 50 as needed . the exemplary insertion tool 10 also includes an enlarged flange 14 adjacent to the retainer 20 . the flange 14 serves to limit the depth to which the hook 50 may be inserted onto the retainer 20 . in addition , the flange 14 permits the application of an insertion force in the direction indicated by the letter f in fig1 . for instance , it may be necessary to apply an insertion force in the direction of arrow f during surgical installation of the hook 50 . however , once the hook 50 is positioned as desired , the arrangement of the retainer 20 and flange 14 allow the insertion tool 10 to be removed in the directions indicated by arrow a or arrow p or some vector combination thereof . these arrows f , a , and p are shown relative to an x - y - z coordinate system . note also that the direction of deflection of the biasing members 22 caused by installation of the hook 50 onto the retainer 20 in one or more embodiments may be substantially aligned with the y - coordinate . fig3 a shows arrows a and p relative to the same x - y - z coordinate system and to the entire insertion tool 10 and hook 50 . notably , the elongated bar 12 is substantially aligned with the direction of removal along arrow p . this direction p is towards the open part of the u - shaped channel in the saddle 52 ( see fig2 ). this direction p is also substantially perpendicular to the rod 60 that lies within the u - shaped channel in saddle 52 . the ability to remove the insertion tool in this direction may help preserve the desire to maintain small surgical incisions and may also prevent interference with vertebrae or other anatomy ( not shown ). furthermore , since the retainer 20 fits substantially within the interior of the saddle 52 , the extent to which the insertion tool 10 is a limiting factor in guiding and placing the hook 50 in a desired position may be minimized . also , the size of the insertion tool 10 in the direction of arrow a may be minimized by adjusting the size of the bend 16 in the elongated bar 12 and the distance between the bend 16 and the distal end at which the hook 50 is attached . as described above and shown in fig2 , the retainer 20 uses friction to grasp the inner surfaces 58 of side walls 54 of the hook 50 . consequently , there is some amount of flexibility in orienting the hook 50 onto the retainer 20 . that is , as fig3 b shows , the hook 50 may be rotated slightly up and down in the x - z plane as indicated by the arrows h relative to the insertion tool 10 . this additional degree of flexibility may further improve approach angles during surgical installation as well as in removing the insertion tool 10 from the hook 50 . the u - shaped configuration of the retainer 20 is more clearly visible in the frontal view shown in fig4 . this particular view is aligned with a longitudinal axis labeled d . the bottom surface 24 is curved to fit within the saddle 52 of hook 50 . in one embodiment , the bottom surface 24 of retainer 20 has a radius of curvature that matches that of the bottom of saddle 52 ( see fig2 ). this same radius of curvature may also correspond to a diameter of rod 60 ( also shown in fig2 ). fig4 also illustrates a small outward bow of the biasing members 22 relative to the width of the bottom surface 24 . the biasing members 22 are resilient and deflect inward , conforming to the size of the saddle 52 of hook 50 ( as shown in fig1 ). the reaction force caused by this inward deflection supplies the friction that holds the hook 50 onto the retainer 20 . fig5 shows a top view of the exemplary retainer 20 , including the biasing members 22 , in relation to the flange 14 and elongated bar 12 . notably , the middle portion 26 between the biasing members 22 extends wider than the biasing members 22 ( also visible in fig3 ). when the retainer 20 is inserted into the saddle 52 of the hook 50 as shown in fig1 , these middle portions 26 fit within the threaded portion 56 of the hook 50 . a close fit between the middle portions 26 of retainer 20 and the threaded portions 56 of hook 50 may contribute to a more robust retention , reducing unwanted motion between the two parts 10 , 50 . a widened middle portion 26 may omitted in cases where the hook 50 or other vertebral implant does not have the threaded portions 56 . fig5 also shows that the retainer 20 is oriented along the longitudinal axis labeled d . the biasing members 22 are positioned in a free state and are spaced apart a first width w 1 in a direction substantially perpendicular to the longitudinal axis d . when the hook 50 is attached as illustrated in fig1 , the biasing members 22 deflect inward towards an engaged state where the biasing members are space apart a second width illustrated by the dimension labeled w 2 . this inward deflection of the biasing members 22 creates the outward retention force that keeps the hook 50 attached to the retainer 20 . note that the length of the retainer in the left to right direction of fig5 remains substantially constant . an alternative embodiment of a retainer 120 is illustrated in fig6 - 9 . fig6 shows an exploded view of components in this particular embodiment . the retainer 120 uses a biasing member 122 to apply a retaining force to a hook 50 . in the embodiment shown , the biasing member 122 is a compression ring . the biasing member 122 fits within a recess 126 formed between retaining walls 128 of a substantially u - shaped retainer body 124 protruding from flange 114 . in one embodiment , this retainer body 124 is sized to fit within the saddle 52 of the hook 50 shown in fig2 . the biasing member 123 is captured within the recess 126 by a substantially cylindrical plug 130 . the plug 130 includes three portions 132 , 134 , 136 defined by different diameters . a flange portion 132 has a diameter that is larger than the inner diameter of the biasing member 122 . the body portion 134 has a diameter that is smaller than the inner diameter of the biasing member 122 . further , a plug portion 136 has a diameter that is sized to fit within a corresponding aperture 138 in the retainer body 124 . the plug portion 136 may be threaded to fit within a corresponding threaded aperture 138 . alternatively , the plug portion 136 may be press fitted into the aperture 138 . in other embodiments , the plug portion 136 may be loosely fit into aperture 138 , but retained using an adhesive compound . as configured , the plug 130 may retain the biasing member 122 as shown in fig7 . the biasing member 122 further comprises a gap 123 that is larger than a corresponding orienting feature 133 in the body portion 134 of the plug 130 . this relationship among these features is more readily visible in fig8 , which shows a top view of the exemplary retainer 120 . the gap 123 in biasing member 122 is aligned with the orienting feature 133 . the gap 123 is wider than the orienting feature 133 as evidenced by the existence of gaps 123 on either side of the orienting feature 133 . also as indicated , the body portion 134 ( see fig6 ) has a diameter that is smaller than the biasing member 122 . this difference in size allows resilient compression of the biasing member 122 in the direction indicated by the arrows labeled c in fig8 , which is substantially perpendicular to the longitudinal axis d . fig8 also shows that the biasing member 122 is marginally wider than the retaining walls 128 of the retainer body 124 . fig9 illustrates that this configuration mates with a corresponding configuration in a hook 50 . specifically , the biasing member 122 in the present embodiment engages the threaded portion 56 of the sidewalls 54 of hook 50 . fig9 also shows that upon inserting the retainer 120 into the hook 50 , the biasing member 122 compresses slightly , creating a reaction force that frictionally engages the hook 50 . the compression of the biasing member 122 is visible in the vicinity of the orienting feature 133 , where the amount of gap 123 on either side of the orienting feature 133 is reduced as compared to fig8 . in yet another embodiment of a retainer 220 illustrated in fig1 and 11 , a biasing member 222 is used to apply a frictional retaining force when compressed in the direction of arrows c . a single biasing member 222 is illustrated though a plurality may be used . however , in contrast with previously described embodiments , the biasing member 222 in this embodiment does not directly contact a hook 50 of the type shown in the various figures . instead , the biasing member 222 imparts a reactive force on complementary plungers 226 disposed within a head 224 and that are configured to fit within the threaded portion 56 of the sidewalls 54 of hook 50 . fig1 shows this same embodiment with the hook 50 attached to the retainer 220 and the plungers 226 compressed as compared to the position shown in fig1 . as with the embodiment of the retainer 20 shown in fig1 - 2 , and 4 - 5 , the retention mechanism created by biasing members 122 and 222 provides some flexibility in attaching a hook 50 . that is , the adjustability represented by the arrows labeled h in fig3 b is equally applicable to these embodiments of the retainer 120 , 220 . accordingly , the hook 50 may be rotated slightly up and down in the x - z plane as indicated by the arrows h relative to the insertion tool 10 . this additional degree of flexibility may further improve approach angles during surgical installation as well as in removing the insertion tool 10 from the hook 50 . in another embodiment of a retainer 320 illustrated in fig1 and 13 , a biasing member 222 similar to that shown in fig1 and 11 is used to apply a frictional retaining force when compressed in the direction of arrow c . a single biasing member 222 is illustrated though a plurality may be used . in contrast with the embodiment shown in fig1 and 11 , the biasing member 222 imparts a reactive force on a single plunger 226 that is disposed within a head 324 and is also configured to fit within the threaded portion 56 of sidewalls 54 of hook 50 . fig1 shows this same embodiment with the hook 50 attached to the retainer 320 and the single plunger 226 compressed as compared to the position shown in fig1 . the present invention may be carried out in other specific ways than those herein set forth without departing from the scope and essential characteristics of the invention . for example , while certain embodiments described above have contemplated engaging a threaded portion 56 on the interior of the sidewall 54 of hook 50 , other hooks may have threaded portions on the exterior of the sidewall 54 or transversely formed through the sidewalls 54 . however , the friction forces applied by the various biasing members 22 , 122 , 222 may be generally applied to the inner surface 58 of the sidewalls 54 , regardless of the positioning or existence of threads . furthermore , while a hook 50 has been used as an exemplary implant that may be placed with the insertion tool 10 , other implant devices may be positioned using the insertion tool . for instance , pedicle screws , clamps for securing a rod to a plate , and other items featuring a rod clamp similar to the illustrated saddle 52 of hook 50 may be inserted and positioned using the insertion tool 10 disclosed herein . the present embodiments are , therefore , to be considered in all respects as illustrative and not restrictive , and all changes coming within the meaning and equivalency range of the appended claims are intended to be embraced therein . spatially relative terms such as “ under ”, “ below ”, “ lower ”, “ over ”, “ upper ”, “ distal ”, “ proximal ”, and the like , are used for ease of description to explain the positioning of one element relative to a second element . further , the terms “ down ”, “ downward ”, “ up ”, “ upward ”, and the like , are used to explain the positioning of the elements as viewed in the figures . these terms are intended to encompass different orientations of the device in addition to different orientations than those depicted in the figures . further , terms such as “ first ”, “ second ”, and the like , are also used to describe various elements , regions , sections , etc and are also not intended to be limiting .

US-31303805-A

a method is provided , including identifying a subject as suffering from pain in a first limb of the subject . in response to the identifying , treatment of the pain in the first limb is facilitated by implanting electrodes in a limb of the subject that is contralateral to the first limb . other embodiments are also described .

reference is now made to fig1 , which is a schematic illustration of an implantable element 10 that includes electrodes 20 for stimulating a subject &# 39 ; s tibial nerve 22 , in accordance with some applications of the present invention . the electrodes are typically implanted in contact with the tibial nerve ( e . g ., by inserting the electrodes into the nerve , and / or by placing a housing 24 in contact with the nerve , the electrodes being disposed inside the housing ). for some applications , the electrodes are implanted within 0 . 5 mm of the tibial nerve , e . g ., within 0 . 3 mm of the tibial nerve . alternatively , the electrodes are implanted at a distance of more than 0 . 5 mm , and / or less than 1 mm from the tibial nerve , e . g ., within 0 . 5 mm to 1 mm from the tibial nerve . the electrodes are typically implanted on or near the tibial nerve , at a position in the vicinity of the subject &# 39 ; s ankle . at this location , the tibial nerve is relatively close to the surface of the skin . thus , in order to implant the electrodes at this location , it is typically not required to penetrate deeply into the subject &# 39 ; s tissue . typically , the electrodes are implanted in order to treat a subject who is identified as suffering from polyneuropathy . typically , electrodes 20 are disposed on a housing 24 , at least a portion of which is flexible ( e . g ., a flexible silicone housing ). the flexibility of the housing maintains contact between electrodes 20 and tibial nerve 22 , even though the region of the subject &# 39 ; s body in the vicinity of the implantation site undergoes significant motion . for some applications , the housing is an elongated silicone housing . two electrodes are disposed inside the housing , there being gaps in the housing to provide contact of the electrodes with the tibial nerve . for some applications , a portion of the housing is not flexible , although most of the housing is flexible . typically , the disposition of electrodes 20 with respect to housing 24 , and / or the shape of the housing is such that the current path of current from the electrodes , away from the tibial nerve is reduced . for example , the electrodes may be disposed on an inner surface of a housing that is placed around the tibial nerve , such that the housing directs the current flow toward the tibial nerve and reduces the current flow away from the tibial nerve . for some applications , the housing is shaped as a cuff . for some applications , coupling elements ( for example , a flexible hook ( e . g ., a silicone hook )), extend from housing 24 and are configured to couple the housing to the nerve , for example , in accordance with the techniques described hereinbelow . alternatively or additionally , staples , a biological adhesive , and / or sutures are applied to the tibial nerve , and / or to tissue in the vicinity of the tibial nerve , in order to couple the housing to the nerve . further alternatively or additionally , a mesh ( e . g ., a dacron mesh ) is disposed on an outer surface of the housing . the mesh causes fibrosis in the vicinity of the housing , thereby stabilizing the housing . for some applications , electrodes 20 are disposed on a flexible coil that is placed around tibial nerve 22 . the flexibility of the coil is typically such that the coil maintains contact between electrodes 20 and tibial nerve 22 , even though the region of the subject &# 39 ; s body in the vicinity of the implantation site undergoes significant motion . for some applications , the coil is placed around the tibial nerve in a minimally - invasive surgical procedure . electrodes 20 are actuated to drive a current into the tibial nerve by an external controller 26 , which is external to the subject &# 39 ; s body . for some applications , as shown in fig1 , the controller is coupled to a sock that is worn by the subject . alternatively , the controller is placed in the vicinity of the electrodes , and outside the subject &# 39 ; s body by alternative means , for example , by strapping external controller 26 to the subject &# 39 ; s ankle , and / or by applying a patch to the subject &# 39 ; s ankle , controller 26 being coupled to the patch . further alternatively , controller 26 is coupled to housing 24 , and is implanted in the vicinity of the tibial nerve . reference is now made to fig2 , which is a block diagram of external controller 26 , in accordance with some applications of the present invention . the external controller typically includes a power supply 29 , a control unit 30 , and a transmitter 32 . in a typical application , the control unit wirelessly transmits a signal to implantable element 10 , via the transmitter . an antenna 34 ( shown in fig1 ) of implantable element 10 receives the signal and relays the signal to the electrodes . the signal drives the electrodes to drive a current into the tibial nerve . the control unit typically comprises at least one power coupling element , a frequency down - converter , and at least one rectifier . for some applications , the control unit is configured to receive a signal , e . g ., a myographic signal , and to actuate the electrodes responsively thereto . the current that is driven into the tibial nerve typically has a frequency of more than 10 hz , e . g ., more than 20 hz , and / or less than 100 hz ( e . g ., 10 - 100 hz , e . g ., 20 - 100 hz , e . g ., 20 - 40 hz ). for example , the frequency may be more than 30 hz , and / or less than 80 hz ( e . g ., 30 - 80 hz ), or more than 40 hz , and / or less than 60 hz ( e . g ., 40 - 60 hz ). the current typically has an amplitude of more than 0 . 2 ma , and / or less than 8 ma ( e . g ., 0 . 2 - 8 ma ). for example , the amplitude may be more than 0 . 5 ma , and / or less than 4 ma ( e . g ., 0 . 5 - 4 ma ). for some applications , for example , if the electrodes cannot be placed in close proximity to the tibial nerve , an amplitude of up to 10 ma is used . for some applications , the location of the posterior tibial nerve is determined in accordance with the following procedure , and implantable element 10 is implanted based on the determined location . the skin of the subject is stimulated ( typically electrically ) at a distal site , e . g ., on the sole of the foot . nerve conduction signals along the tibial nerve that result from the stimulation are detected , in order to determine the location of the tibial nerve . alternatively or additionally , sites in the subject &# 39 ; s ankle are stimulated . in order to localize the tibial nerve , the response of a foot muscle ( e . g ., the abductor hallucis ) of the subject to the stimulation at respective sites is recorded , typically , in accordance with nerve localization techniques that are known in the art . reference is now made to fig3 a - b , which are schematic illustrations of housing 24 having rigid portions 23 and flexible portions 35 thereof . for some applications , as shown , the housing includes a plurality of portions , which are coupled to each other articulatably ( i . e ., in a manner that facilitates movement of the portions with respect to each other ), typically via joints ( as shown ). typically , electronic control components ( e . g ., antenna 34 , and / or another control component for receiving a signal from control unit 26 ) are disposed within a rigid seal ( such as glass or metal ) in one or more rigid portions . the electrodes are disposed on the flexible portions , such that contact between the electrodes and the tibial nerve is maintained due to the flexibility of the portion . for some applications , the flexible portions are made of a polymer and / or silicone . for some applications , the flexibility of the flexible portions is less than the flexibility provided by the joints , which couple the portions to each other . typically , the flexible portions and / or the rigid portions are coupled to the tibial nerve in accordance with the techniques described herein . for some applications , a single rigid portion is disposed at one end of the housing , as shown in fig3 a . alternatively , a single rigid portion is disposed in a central region of the housing , as shown in fig3 b . further alternatively , other combinations of flexible and rigid housing portions are used , as would be obvious to one skilled in the art , having read the specification of the present patent application . electrodes 20 are typically disposed on an inner surface of flexible portions of the housing . alternatively , the electrodes are disposed at other positions on the housing . typically , electrodes 20 are spaced at a distance of 8 - 10 mm from each other . depending on the length of each of the flexible portions , a single electrode , or a plurality of electrodes are disposed on each of the flexible portions . reference is now made to fig4 a , which is a schematic illustration of electrodes 20 on housing 24 being injected into the subject &# 39 ; s ankle to a vicinity of tibial nerve 22 , using an introducer 40 , in accordance with some applications of the present invention . for some applications , at least one electrode 42 is disposed on the distal end of introducer 40 ( as shown ). alternatively , at least one electrode 42 is disposed on the distal end of a dedicated electrode needle , the dedicated electrode needle being extendible from the distal end of introducer 40 . for some applications , electrodes 42 are stimulating electrodes . the electrodes are moved along the subject &# 39 ; s tibial nerve and are used to stimulate the subject &# 39 ; s tibial nerve . an implantation site for housing 24 is selected based upon the subject &# 39 ; s response to the stimulation of the tibial nerve by electrodes 42 , in accordance with the techniques described hereinabove . for some applications , a site of the tibial nerve is chosen as the implantation site , based upon the subject feeling pain relief when the stimulating electrodes stimulate the site . alternatively or additionally , electrodes 42 are sensing electrodes . the sensing electrodes are used to detect the location of the tibial nerve , and / or to determine a suitable implantation site for housing 24 , by detecting action potentials . for example , the electrodes may detect action potentials generated in the tibial nerve in response to the subject &# 39 ; s foot being electrically stimulated , in accordance with the techniques described hereinabove . reference is now made to fig4 b - d , which are schematic illustrations of respective steps of housing 24 being injected to a vicinity of tibial nerve 22 , in accordance with some applications of the present invention . for some applications , flexible coupling elements 50 are coupled to housing 24 and are disposed distally to the housing during injection of the housing into the subject &# 39 ; s body , via introducer 40 . for some applications , the coupling elements function as electrodes 20 . in a first step of the injection procedure , the distal end of introducer 40 is placed in the vicinity of tibial nerve 22 , e . g ., within 0 . 3 mm of the tibial nerve , such as within 0 . 5 mm ( or within more than 0 . 5 mm , and / or less than 1 mm ) of the tibial nerve . fig4 b shows the distal end of the introducer being placed in the vicinity of the tibial nerve . for some applications , the distal end of the introducer is positioned in response to stimulation and or sensing of electrodes 42 , as described with reference to fig4 a . once the distal end of introducer 40 is suitably positioned , a pushing element 44 is used to push housing 24 distally , through introducer 40 . upon emerging from the distal end of the introducer , one or more distal coupling elements 50 curve outwards ( fig4 c ) and anchor themselves to tissue , for example , to tibial nerve 22 ( fig4 c ), or to tissue in the vicinity of the tibial nerve ( e . g ., within 0 . 3 mm of the tibial nerve , such as within 0 . 5 mm ( or within more than 0 . 5 mm , and / or less than 1 mm ) of the nerve ). subsequent to the anchoring of distal coupling element 50 to the tissue , pushing element 44 continues to push housing 24 out of the distal end of introducer 40 . when the proximal end of housing 24 emerges from the distal end of the introducer , proximal coupling element 50 couples the proximal end of the housing to the nerve , as shown in fig4 d . reference is now made to fig4 e , which is a schematic illustration of housing 24 having spiral coupling elements 50 , in accordance with some applications of the present invention . as shown , for some applications , the coupling elements are spirals , which couple housing 24 to the tibial nerve by curving around the tibial nerve . for some applications , the spiral coupling elements function as electrodes 20 . alternatively or additionally , electrodes 20 are disposed on the coupling elements and / or on housing 24 . reference is now made to fig5 a - b , which are cross - sections of housing 24 , shaped to facilitate alignment of the housing with the tibial nerve , in accordance with some applications of the present invention . fig5 a shows the housing during insertion of the housing into the subject &# 39 ; s body , via introducer 40 , and fig5 b shows the housing disposed on tibial nerve 22 . for some applications , a protrusion 58 protrudes from housing 24 . introducer 40 is shaped to define a lumen , a cross - section of which includes a groove that corresponds to the protrusion from the housing , as shown in fig5 a . electrode 20 is coupled to the housing in a rotational position that is fixed with respect to the protrusion from the housing , for example , opposite the protrusion , as shown . thus , during insertion of the housing into the subject &# 39 ; s body and to the vicinity of the tibial nerve , the rotational location of the electrode with respect to the introducer may be controlled . typically , the introducer is oriented such that the electrode is placed in direct contact with the tibial nerve , as shown in fig5 b , or within 0 . 3 mm of the tibial nerve , such as within 0 . 5 mm ( or within more than 0 . 5 mm , and / or less than 1 mm ) of the nerve . further typically , placing the electrode in direct contact with or within this distance of the tibial nerve reduces energy loss from the electrode , for example , relative to if the electrode were placed further from the tibial nerve . in addition , the shape of the injectable housing reduces the current path of current from the electrode , away from the tibial nerve . alternatively to the configuration of the apparatus shown in fig5 a , housing 24 is shaped to define a groove , and the introducer is shaped to define a lumen having a cross - section that includes a protrusion . reference is now made to fig6 a - b , which are schematic illustrations of housing 24 , shaped to facilitate alignment of the housing with tibial nerve 22 , in accordance with some applications of the present invention . fig6 a shows the housing during insertion of the housing into the subject &# 39 ; s body , via introducer 40 , and fig6 b shows the housing disposed on tibial nerve 22 . for some applications , housing 24 has a non - circular cross - section . for example , the cross - section of the housing may be crescent shaped , as shown in fig6 a - b . introducer 40 is shaped to define a lumen 41 having a cross - section that corresponds to the shape of the cross - section of the housing , such that the housing can only be inserted through the lumen in a given rotational orientation . electrode 20 is fixedly coupled to the housing . thus , during insertion of the housing into the subject &# 39 ; s body and to the vicinity of the tibial nerve , the rotational location of the electrode with respect to the introducer may be controlled . typically , the introducer is oriented such that the electrode is placed in direct contact with the tibial nerve , as shown in fig6 b , or within 0 . 3 mm of the tibial nerve , such as within 0 . 5 mm ( or within more than 0 . 5 mm , and / or less than 1 mm ) of the nerve . reference is now made to fig7 a - c , which are schematic illustrations of a housing 24 that undergoes a shape change , in accordance with some applications of the present invention . for some applications , housing 24 is placed on tibial nerve 22 , while the housing has a first shape thereof . for example , fig7 a shows the housing in a first shape thereof inside introducer 40 ( i . e ., during insertion of the housing into the subject &# 39 ; s body ), and 7 b shows the housing , in the first shape thereof , disposed on the tibial nerve . for some applications , while the housing is disposed around the tibial nerve in the first shape thereof , the housing defines an angle alpha around a longitudinal axis 80 of the tibial nerve of less than 180 degrees ( as shown ) or less , e . g ., less than 90 degrees . typically , subsequent to the housing having been placed on or in the vicinity of the tibial nerve , the shape of the housing is changed to a second shape thereof . for example , the housing may comprise nitinol and / or another shape - change material , and the shape of the housing is changed by heating the housing . fig7 c shows the housing disposed around the tibial nerve in the second shape thereof . for some applications , while the housing is disposed around the tibial nerve in the second shape thereof , the housing defines an angle beta around longitudinal axis 80 of the tibial nerve of more than 180 degrees , e . g ., 270 degrees or more . reference is now made to fig8 a - b , which are schematic illustrations of electrodes 20 that are configured to be inserted into the tibial nerve , in accordance with some applications of the present invention . electrodes are disposed on housing 24 , and are generally similar to electrodes 20 described hereinabove . during insertion of the electrodes to the vicinity of tibial nerve 22 , housing 24 is advanced in the direction of arrow 60 , such that even if the electrodes contact the tibial nerve , the electrodes slide past the tibial nerve , as shown in fig8 a . subsequently , the housing is withdrawn in the direction of arrow 62 . this causes electrodes 20 to become inserted into the tibial nerve , as shown in fig8 b . reference is now made to fig9 a - b , which are schematic illustration of electrodes 20 being inserted into tibial nerve 22 , in accordance with some applications of the present invention . for some applications , electrodes 20 are needle electrodes . a spring 70 is disposed inside housing 24 . housing 24 is positioned adjacent to the tibial nerve while the spring is in a constricted configuration , as shown in fig9 a . when the housing is positioned at an implantation location of the housing , spring 70 is allowed to expand . expansion of the spring pushes the needle electrodes into the tibial nerve . for some applications , insertion of electrodes 20 into tibial nerve 22 in accordance with the techniques described with reference to fig8 a - b and / or fig9 a - b , anchors housing 24 to the tibial nerve . alternatively or additionally , other techniques are used for anchoring the housing to the tibial nerve . for some applications , insertion of the electrodes into the tibial nerve maintains contact between the electrodes and the tibial nerve . the inventors of the present application conducted an experiment in which emg stimulating needle electrodes were inserted in close proximity to the tibial nerve of nine patients . in all of the patients , the electrode was placed in proximity to the tibial nerve on one side of the patient , and not in proximity to the tibial nerve of the other side of the patient . all of the patients suffered from a level of pain that was 2 - 9 , based upon the following scale : 0 - 1 : no pain 2 - 3 : mild pain 4 - 5 : discomforting — moderate pain 6 - 7 : distressing — severe pain 8 - 9 : intense — very severe pain 10 : unbearable pain eight of the subjects were suffering from polyneuropathy , or neuropathic pain . one subject did not suffer from neuropathy , and may have been suffering from fibromyalgia . all patients were treated for 30 minute treatment sessions . each treatment session was divided into five cycles of six minutes each , the cycles including five minutes of stimulation and a one minute pause . the patients were stimulated with a stimulating signal having an amplitude of 2 - 8 ma , and a frequency of 50 hz . all eight neuropathy patients , without exception , experienced marked alleviation of the neuropathic pain in the stimulated leg during stimulation . there was no beneficial effect on the patient who was not suffering from neuropathy , but was suffering from pain . in all of the neuropathic patients , the effect lasted after the stimulation ceased . in all of the neuropathic patients , the effect lasted for a total of at least three hours , and in one of the patients the effect lasted for five days . seven of the neuropathic patients had been treated with a wide range of anti - neuropathic pain medications , without significant improvement in their pain . these patients stated that tibial nerve stimulation was the only procedure that substantially improved their symptoms . one of the neuropathic patients had not received any medications , and the stimulation was the first treatment of her neuropathic pain . this patient experienced marked improvement of pain in both sides , although the improvement was more pronounced in the stimulated side . in about half of the neuropathic patients , the beneficial effect of the stimulation ( i . e ., the pain relief ) was bilateral , despite the stimulation having been applied to the tibial nerve of one side only . the inventors hypothesize that this is due to a spinal cord loop . based on the results of the aforementioned experiment , in accordance with some applications , the following treatment is applied to a subject who is identified as suffering from polyneuropathy . implantable element 10 ( shown in fig1 ) is implanted in contact with or in the vicinity of the subject &# 39 ; s tibial nerve , for example , in accordance with the techniques described hereinabove . external controller 26 ( also shown in fig1 ), or an implantable controller that is generally similar to external controller 26 is used to drive the electrodes to drive a current into the tibial nerve for a therapy period . for example , the therapy period may last more than 30 minutes , and / or or less than three hours . alternatively , the therapy period may last more than two minutes , less than 10 minutes , and / or for a different period of time . for some applications , therapy is administered to the subject once a day , several times ( e . g ., more than two , and / or less than eight times ) a week or more , and / or in several therapy periods ( e . g ., more than two , and / or less than eight periods ) over the course of a day . typically , the length and / or frequency of the therapy periods is reduced , in response to the subject &# 39 ; s condition improving . for some applications , therapy periods are applied on demand , based upon the subject feeling pain . for some applications , the apparatus includes a lock - out mechanism to prevent the subject from applying the treatment for more than a maximal safe number of therapy periods over a given time period . during the therapy period the subject wears sock 28 , or uses other means for keeping the external controller in the vicinity of the implantable element . as described above , in about half of the neuropathic patients , the beneficial effect of the stimulation ( i . e ., the pain relief ) was bilateral , despite the stimulation having been applied to the tibial nerve of one side only . based on the results of the aforementioned experiment , in accordance with some applications , it is hypothesized that stimulation of a tibial nerve of a limb contralateral to that in which pain is experienced , may provide pain relief for subjects in whom such stimulation would not be desirable , justifiable , or even possible , in the limb that is ipsilateral to the pain being experienced . that is , in such subjects , pain may be treated by stimulating a contralateral limb . for example , the limb in which pain is being experienced ( i . e ., the ipsilateral limb ) may have been damaged by disease ( e . g ., diabetes ) or trauma , such that the ipsilateral limb is unsuitable to receive implanted apparatus . similarly , in unilateral leg amputees who experience pain in the remaining leg , it may be undesirable to implant apparatus ipsilaterally . in such a case , stimulation may be applied to the contralateral leg ( i . e ., to the stump ). conversely , in unilateral amputees who experience phantom pains associated with the amputated limb , the ipsilateral tibial nerve in the stump may simply be absent or otherwise unavailable to be stimulated . in such a case , stimulation may be applied to the contralateral , remaining , leg . for each of these examples , it may be that little or no pain is experienced in the contralateral limb , and thus it would ordinarily be undesirable and / or unnecessary to implant tibial nerve stimulation apparatus in the contralateral limb . however , it is hereby hypothesized that such implantation may be beneficial to such subjects by providing bilateral pain relief , thereby providing pain relief in a limb that is generally less available for treatment by implantation of stimulation apparatus therein . the implantation sites and disorders described hereinabove are examples for illustrating the use of the techniques described herein . the implants described herein may be implanted at a variety of implantation sites , and the techniques described herein may be used to treat a variety of disorders . for example : stimulation of the tibial nerve ( and / or of sensory fibers that lead to the tibial nerve ), e . g ., to treat neuropathic pain and / or urge incontinence ; stimulation of sensory fibers that lead to the radial and / or ulnar nerves , e . g ., to treat tremor ( e . g ., essential tremor , and tremor associated with parkinson &# 39 ; s disease ); stimulation of the sacral and / or pudendal nerve , e . g ., to treat urge incontinence ; direct stimulation of an implantation site within the brain ( e . g ., deep brain stimulation ), such as the thalamus , e . g ., to treat tremor , obsessive - compulsive disorder , and / or depression ; stimulation of the vagus nerve , e . g ., to treat epilepsy , depression , inflammation , tinnitus , and / or congestive heart failure ( e . g ., by incorporating some or all of device 20 into an aortic stent ); stimulation of baroreceptors in a blood vessel wall ( e . g ., the wall of the carotid sinus and / or aorta , e . g ., to treat high blood pressure ; stimulation of one or more muscles ( such as shoulder muscles ), e . g ., to treat muscle pain ; stimulation of the medial nerve , e . g ., to treat carpal tunnel syndrome ; stimulation of the hypoglossal nerve and / or one or more muscles of the tongue , e . g ., to treat obstructive sleep apnea ; stimulation of cardiac tissue , e . g ., to pace and / or defibrillate the heart ( e . g ., the use of the implant as a leadless pacemaker ); stimulation of peripheral nerves of the spinal cord , e . g ., to treat chronic pain ; stimulation of the dorsal root ganglion for the treatment of chronic pain ; and it will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove . rather , the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove , as well as variations and modifications thereof that are not in the prior art , which would occur to persons skilled in the art upon reading the foregoing description .

US-201213528433-A

a bubble free , self - priming iv set for use in the administration of liquids includes a coupling assembly for attaching the delivery system to a source of liquid and includes a coupling membrane for controlling the flow of liquid and air through the coupling assembly . the system also includes a drip chamber for receiving liquid through the coupling assembly , the drip chamber having a membrane for preventing air from leaving the drip chamber . a self leveling port is disposed within a wall of the drip chamber , the port being permeable to air , but impermeable to liquid . finally , a patient conduit is in fluid communication with the drip chamber and further comprises a flow control plug disposed at the distal end of the conduit . the flow control plug is permeable to air but impermeable to liquid . use of this system allows a clinician to attach a source of fluid to a patient without significant intervention , while the system self primes .

the presently preferred embodiments of the present invention will be best understood by reference to the drawings , wherein like parts are designated by like numerals throughout . it will be readily understood that the components of the present invention , as generally described and illustrated in the figures herein , could be arranged and designed in a wide variety of different configurations . thus , the following more detailed description of the embodiments of the self - priming intravenous delivery system of the present invention , as represented in fig1 through 3 , is not intended to limit the scope of the invention , as claimed , but is merely representative of presently preferred embodiments of the invention . for this application , the phrases “ connected to ,” “ coupled to ,” and “ in communication with ” refer to any form of interaction between two or more entities , including mechanical , electrical , magnetic , electromagnetic , and thermal interaction . the phrase “ attached to ” refers to a form of mechanical coupling that restricts relative translation or rotation between the attached objects . the phrase “ attached directly to ” refers to a form of attachment by which the attached items are either in direct contact , or are only separated by a single fastener , adhesive , or other attachment mechanism . the term “ abutting ” refers to items that are in direct physical contact with each other , although the items may not be attached together . the terms “ integrally formed ” refer to a body that is manufactured integrally , i . e ., as a single piece , without requiring the assembly of multiple pieces . multiple parts may be integrally formed with each other if they are formed from a single work piece . referring to fig1 , a perspective view illustrates an intravenous ( iv ) delivery system 10 according to the invention . as shown , the iv system 10 may be connected to a source of liquid 12 , which in this configuration is an iv bag 14 . alternatively , the source of liquid 12 may be an iv bottle ( not shown ) or other container known in the art . the iv system 10 may be connected to the iv bag 12 by a coupling 20 for connecting the iv system 10 to the iv bag 14 . as shown , the coupling 20 may be a spike 22 for spiking the iv bag 14 and / or a threaded coupling ( not shown ). the iv system 10 may include a drip chamber 24 for determining the flow rate from the source of liquid 12 . the drip chamber 24 may include a top end 26 , a bottom end 28 , and a sidewall 30 extending between the top end 26 and the bottom end 28 . the top end 26 may include an inlet orifice 32 that may be shaped and sized to encourage liquid entering the drip chamber 24 to form droplets , facilitating the determination of the liquid &# 39 ; s flow rate . the bottom end 28 may also include an outlet orifice 34 that permits liquid to exit the drip chamber 24 . the drip chamber 24 may also include an access orifice 36 . the access orifice 36 may be positioned in the top end 26 or in the sidewall 30 . in some configurations , the access orifice 36 may be positioned at or near an operable liquid height 38 of the drip chamber 24 . the operable liquid height 38 of the drip chamber 24 is deep enough so that air will not be sucked from the surface of the liquid into the outlet orifice 34 , yet shallow enough that each droplet that falls from the inlet orifice 32 may be discerned in order to determine the flow rate of liquid into the drip chamber 24 . for example , the operable liquid height 38 may range from about ⅓ to about ⅔ full . however , the preferable operable liquid height 38 of drip chamber 24 may range from about ⅓ to about ½ full . a self leveling port 40 may be connected to the access orifice 36 . the access port 40 may be used to removably connect the access orifice 36 to various devices 42 , such as a cap 44 , another iv set , a syringe , and other devices known in the art . as shown , the access port 40 may be a luer fitting , known in the art . a valve 46 may also be connected to the drip chamber 24 to selectively control access to the drip chamber 24 through the access orifice 36 . the valve 46 may be a stop cock , a slide valve , a butterfly valve , or any other type of valve known in the art . the valve 46 may be opened to allow gravity to pull liquid from the source of liquid 12 into the drip chamber 24 without deforming the sidewall 30 of the drip chamber 24 to induce a vacuum . the valve 46 may remain open until the operable liquid height 38 is reached . when the valve 46 is closed , fluid may only enter and exit through the inlet orifice 32 and outlet orifice 34 . thus , when the valve 46 and the outlet orifice 34 are closed , the pressure within the drip chamber 24 may rise until the liquid is unable to enter the drip chamber 24 from the inlet orifice 32 . in configurations of the iv system 10 where the self leveling port 40 and the valve 46 are connected to the access orifice 36 , the valve 46 may be disposed to prevent fluid from the self leveling port 40 from reaching the access orifice 36 . for example , the valve 46 may be used to control the flow from another iv system connected to the self leveling port 40 into the drip chamber 24 . additionally , a filter 48 may be connected to the access orifice 36 , permitting air to flow through the filter 48 while restricting the flow of liquid . where the access orifice 36 is disposed at an operable liquid height 38 , the filter 48 may be used as a fail safe to prevent the height of liquid within the drip chamber 24 from exceeding the operable liquid height 38 of the drip chamber 24 . more specifically , once the filter 48 is covered by the liquid within the drip chamber 24 , the liquid and air in the drip chamber 24 is prevented from exiting the access orifice 36 . thus , the pressure may rise within the drip chamber 24 and prevent liquid from entering the drip chamber 24 from the source of liquid 12 . in this configuration the filter 48 results in the self leveling port 40 being permeable to air , but impermeable to liquid , and becomes impermeable to air upon contact with liquid . the iv system 10 may also include a membrane 50 disposed in the drip chamber 24 . the membrane 50 is configured such that air is prevented from leaving the drip chamber 24 . thus , the membrane 50 acts as a bubble trap to trap any air bubbles that may otherwise flow out of the drip chamber 24 into the patient conduit 52 . as illustrated in fig1 , the drip chamber 20 is connected to a patient conduit 52 . the conduit 24 is a tube used to convey fluid 14 from the drip chamber 20 and the iv bag 12 to a patient . a clamp 54 , a zero dead space access port 56 , and a flow control plug 58 may be attached to the tube 24 . the clamp 54 permits the flow of liquid 14 exiting the drip chamber 20 to be controlled and stopped . the zero dead space access port 56 permits another iv set ( not shown ) to be piggybacked onto the iv set 10 or to have medication directly added to the fluid 14 by a syringe ( not shown ). the zero dead space access port 56 is also designed not to trap air as the liquid 14 flows through it . the flow control plug 58 helps to protect an end 60 of the iv system from contamination and also helps to prevent air bubbles from moving through the tube 24 with the liquid 14 . in particular , the flow control plug 58 controls fluid flow in the patient conduit 52 during priming to reduce air bubble formation . before the iv system 10 is attached to a source of liquid 14 , the clamp 54 is typically opened , unlike conventional systems where the clamp is closed to prevent the flow of fluid through the patient conduit 52 . as shown , the clamp 54 is a roller clamp 62 . other types of clamps may be used . the clamp may be pre - programmed to allowed fluid flow at a specific rate . once the iv system 10 is attached to a source of liquid 14 , it is unnecessary to produce a vacuum by squeezing the drip chamber 24 as is conventional . referring to fig2 , a cross sectional view illustrates the iv system and specifically the drip chamber 24 of fig1 . as shown , the membrane 50 conforms to the shape of the bottom end 28 of the drip chamber 20 and completely covers the chamber outlet 64 . by positioning the membrane 50 to completely cover the chamber outlet 64 , air is prevented from being trapped between the membrane 50 and the bottom end 28 as the fluid 14 moves through the membrane 50 . while in use , air bubbles 80 are generated as the droplets 82 strike the surface 84 of the pool 86 . the membrane 50 prevents the air bubbles 80 from reaching the chamber outlet 64 so that the air bubbles 80 are able to return to the surface 84 of the pool 86 and be discharged or vented through the self leveling port 40 . also , the membrane may be made of molded open - cell foam that has a general pore size of about 10 to 20 microns with the preferred pore size being about 12 to 15 microns . also shown , the connection 90 between the patient conduit 52 and the drip chamber 24 is a zero dead space connection . in other words , the inlet end 92 is shaped to be attached flush to the chamber bottom end 28 so that air may not be entrapped at the connection 90 as the fluid 14 passes the connection 90 and purges the air from the patient conduit 52 . fig3 depicts an alternative embodiment of a self priming iv delivery system 100 used for administering an iv - solution to a patient . as illustrated above , a source of liquid 112 is provided . the liquid is located in a container 114 such as a vented rigid container or bottle , or a collapsible plastic bag , as is discussed above . . . . the iv system 100 is a hermetically sealed system and includes a solution coupling spike assembly 116 having a lancing or piercing member 118 for piercing a seal on the container 114 . as set forth above , other primary components of the iv system 10 include a drip chamber 120 , and a patient conduit 122 having a termination end 124 and supporting a flow controller such as a roller clamp 126 for controlling the flow of liquid in the patient conduit 122 . the venting conduit 126 provides a sealable opening at an outer end for communicating with the surrounding atmosphere , i . e . with the environment in which the iv system 100 is disposed . when the spike assembly 116 is connected to a rigid container 112 , such as a glass bottle , venting of the container is provided through the conduit 30 to allow the liquid to flow . if , on the other hand , the container 112 is a collapsible bag , venting is not required and the conduit 126 can remain sealed . as the liquid is drawn out by the piercing member 118 of the spike assembly 116 , the liquid flows down into a funnel - shaped portion 128 having an outlet end 130 which supports a drip orifice 132 or which otherwise directs the liquid to the drip orifice for providing the liquid , in the form of a succession of individual drops , to the drip chamber 120 . the spike assembly 116 also includes a check valve 136 disposed at an outlet end of the venting conduit 126 and an air filter 138 disposed between the check valve 136 and the surrounding atmosphere , as shown . when the venting conduit is opened , as in the case of the piercing member 118 being coupled to a rigid container 114 , the check valve allows filtered air , through air filter 138 , to enter the venting conduit to cause liquid to flow out of the container , but prevents air , and consequently , liquid , from exiting the container 112 through the venting conduit 126 . a membrane 140 , which may be configured as a fine mesh screen , is also preferably included in the spike assembly 116 . the membrane may be formed of any suitable material — such as polyamide nylon 6 , 6 , polyamide nylon 11 , or polyester - polyethylene teraphthalate with a hydrophilic coating applied by a plasma coating process — and causes a sealing off of the funnel portion 128 of the spike assembly from the fluid conduit 142 when the contents of the container 114 have been drained into the spike assembly 116 . the sealing off is caused by the surface tension of the medicament forming a barrier on the membrane 140 which will prevent air present in the container 112 from being passed through to the drip chamber 120 and to the patient conduit 122 . thus , upon emptying of the container 114 , the air present in the container will be confined to an area 144 above the membrane 140 . when a subsequent dose of medicament is required , the spike 118 of the spike assembly 116 is removed from the empty container 112 and attached to a full container . in order to start the flow of liquid from the subsequent container , the air confined in area 144 must be removed , and a venting membrane 146 is included in the spike assembly for this purpose . as liquid again flows from the second container 112 , air will be forced out through the membrane 146 . membrane 146 may be comprised of a porous hydrophobic material such as polyethylene ( pe ), polypropylene ( pp ), or polytetrafluoroethylene ( ptfe ), so that air is allowed to pass from area 144 to the surrounding atmosphere while preventing liquid in the funnel portion 128 from spilling through the membrane , such as in the event of an overflow condition . once the air is removed , the roller clamp 150 is opened to allow the fluid to flow into the patient line 122 . a check valve 148 prevents air from the surrounding atmosphere from entering area 144 through membrane 144 when fluid flows from the container 112 . the drip chamber 120 includes a top wall providing an inlet opening , a bottom wall 154 providing an outlet opening 156 , and at least one side wall 158 comprised of a transparent or translucent material so that medicament in the drip chamber can be readily viewed . a drip orifice or opening 132 may be formed on , attached to , or may depend from the top wall 150 or , alternatively , may be formed on the outlet end 130 of the spike assembly 116 . as explained above , the drip orifice 132 establishes the size of the liquid drops 134 as the liquid enters the drip chamber 120 . by adjusting the rate of flow of the drops 134 into the drip chamber 120 , and knowing the size of the individual drops which is dictated by the drip orifice size , a medicament dosage rate can be established . the drip chamber 120 also includes an opening or hole 160 formed in the side wall 158 and vertically displaced from the drip chamber bottom 154 by a predetermined amount “ x ”. the opening 160 may be formed as part of a primary molding process in which the drip chamber 120 is formed , or as a secondary process wherein the opening 160 is punched - out or otherwise removed from the side wall 158 . as explained more fully below , the opening 60 is dimensioned to accommodate a sealing off by of a vent plug 162 to provide a self - priming function to the drip chamber 120 . the term “ vent plug ” as used herein means an obstruction for sealing off the opening 160 . this can be accomplished , by way of non - limiting example , by a member dimensioned for seating within the opening 160 or by a cover or shield , such as a band of material . the vent plug may include various other types of plugs , including mechanically or chemically actuated plugs . the plug may be a bimetallic strip which is water activated . the vent plug may be activated by temperature , pressure , or chemical action . the vent plug may also be mechanically triggered . the fluid drops 134 form a reservoir 164 at the bottom of the drip chamber 120 . the liquid is then provided to the patient conduit 122 for conveying the liquid to the termination end 124 , at which an end cap 170 that may be detachably or permanently connected , allows coupling of the patient line to an iv needle ( not shown ). the end cap 170 includes a side wall 171 , a front wall 173 in which a vent 172 is formed , and a termination end vent plug 174 . also disposed on the patient conduit 122 is the roller clamp 150 having an adjustable control such as a knurled wheel 176 for regulating the flow of liquid in the patient conduit 122 . as fully discussed above , a problem with existing iv systems having drip chambers lies in the setup and “ priming ” of the drip chamber to establish a desired or prescribed medicament flow rate at which the medicament will enter the patient . as explained above , this typically requires a heath care professional , such as a nurse , to allow the medicament in the drip chamber to reach a certain level , typically ⅓ of the drip chamber volume . in order to accomplish this , the patient conduit 122 needs to be obstructed or otherwise partially closed off so that the liquid will fill the drip chamber 120 at a faster rate than the liquid enters the patient conduit 122 to form the reservoir 164 . thus , the health care professional will be required to tighten the roller clamp 150 for this purpose . moreover , to set the reservoir level at approximately ⅓ of the drip chamber volume , an equal volume of air in the drip chamber must be removed . in pre - existing iv systems , this was accomplished by squeezing the flexible drip chamber side wall 158 . in the event the squeezing of the drip chamber side wall 158 caused an excessive amount of air to be removed , this resulted in an excessive amount of liquid collected in the reservoir 164 which then needed to be removed in a tedious manner as explained above . also , if the liquid entered the reservoir and / or patient line too rapidly , air bubbles will be formed on the inner surface of the patient conduit and then have to be removed , typically by tapping the chamber 120 and / or patient conduit 122 . in accordance with the present invention , the manual priming activity previously performed by health care professionals can be eliminated by the iv system 100 . when the spike assembly 116 is first connected to a liquid container 112 , liquid will begin to flow through the liquid conduit 142 into the funnel region 128 , whereupon the drip orifice 132 will cause liquid drops 134 to be formed and fall , under the force of gravity , into the drip chamber 120 . to facilitate formation of the reservoir 164 and , specifically , to prevent the liquid from draining into the patient conduit 122 before the reservoir 164 can be formed to a desired depth relative to the drip chamber bottom 154 , liquid flow through the patient conduit 122 must be obstructed so that the medicament level will rise in the drip chamber at a rate which exceeds the flow of the medicament into the patient line . this can be accomplished by adjustment of the roller clamp 150 , such as by manipulating adjustment wheel 176 or , as is contemplated by the preferred embodiment , through the vent 172 formed in the front wall 173 of the end cap 170 . thus , if the roller clamp 150 is in its fully opened state , the narrow opening of the vent 172 will restrict liquid flow in the patient conduit 122 to a rate which is slower than the rate that the fluid enters the drip chamber 120 so that the reservoir 164 can form in the drip chamber and so that fluid will enter the patient line at a slow rate to prevent the formation of air bubbles therein . with flow in the patient conduit 122 restricted by the roller clamp 150 and / or by the end cap 170 , liquid drops 134 continue to enter the drip chamber 120 so that the reservoir 164 will rise to a height of “ x ”. this height corresponds to the opening 160 at which the vent plug 162 is disposed . in one embodiment , the vent plug 162 is comprised of an absorptive material which allows displaced air from the drip chamber 120 — which is displaced by the increased level of the reservoir 164 — to pass from the drip chamber to the surrounding atmosphere but which , upon contacting liquid , expands or swells to seal off the opening 160 . when this occurs , liquid in the reservoir 164 is prevented from escaping through the vent plug 162 and air from the surrounding atmosphere is prevented from reentering the drip chamber 120 through the vent plug 162 . in this manner , the iv system 100 functions as a self - priming device which automatically allows the reservoir to fill to a desired level ( e . g ., ⅓ of the drip chamber volume ) once the spike assembly 116 is attached to the liquid container 114 so that a health care professional no longer needs to compress the drip chamber side wall 158 to cause liquid to flow therein . because the drip chamber no longer needs to be compressed for priming , the problem of over - filling the drip chamber is avoided . consequently , the material used to form the drip chamber 120 is no longer limited to a flexible material but can now include rigid materials . suitable absorptive materials for the vent plug 162 include , by way of non - limiting example , porous pe , pp , or ptfe , embedded , doped or coated with carboxymethylcellulose ( cmc ), polyacrylate , or other known or hereafter discovered super - absorbent polymers . to allow air present in the patient conduit 122 to escape through the termination end 124 so that , upon connection of the termination end 124 to a patient , such air will not enter the patient , the termination end vent plug 174 is provided . the termination end vent plug 174 is comprised of porous pe , pp , or ptfe , embedded , doped or coated with a super - absorbent polymer and creates a barrier when liquid impinges upon it . alternatively , the termination end vent plug 174 can be formed of a hydrophobic material . once the patient conduit 122 is completely filled with liquid , all air is removed therefrom and the termination end vent plug 174 forms a barrier to prevent spillage of the liquid through the vent 172 . in this state , the iv system 100 is ready for attachment to a patient iv connection . this can be accomplished by detaching the end cap from the patient line and then coupling the line to a patient . the termination end vent plug 174 allows air from the patient conduit 122 to pass from the patient line to the surrounding atmosphere through vent 172 in the end cap 170 . however , once the termination end vent plug becomes wet through contact with the liquid in the patient conduit 126 , air is prohibited from reentering the patient line through the vent 172 . when connecting the already - primed iv system 100 to a subsequent medicament container , the health care professional simply closes the patient conduit 122 via the roller clamp 150 , disconnects the spike 118 from the empty container , and attaches it to a full container . any amount of liquid that may exist in the spike 118 during disconnection and reconnection to a medicament container is de minimis and will have little effect on the level of the reservoir 64 . once connected and the patient line reopened by opening the roller clamp , air in region 144 will be removed through membrane 146 and liquid will begin to flow into the drip chamber and into the patient conduit 122 . another benefit of the inventive self - priming iv system 100 is that the occurrence of a high liquid flow rate into the drip chamber is reduced or altogether avoided because the primary cause of such a condition — the manual compressing of the drip chamber side wall 158 — is no longer performed . nevertheless , to prevent the vent plug 162 from prematurely contacting the liquid , such as when the drops 134 enter the drip chamber 120 and cause a splatter or splashing effect against the surface of the reservoir , a splash guard 178 formed of , for example , a liquid impervious plastic shield , can be readily affixed about the vent plug 162 to the internal surface of the side wall 158 of the drip chamber . as shown , the splash guard 176 is connected to the drip chamber side wall 158 by , for example , adhesive at a location above the vent plug 162 , and extends to a point below the vent plug 162 and offset from the side wall 158 so that an opening 177 is formed to allow the rising reservoir 164 to contact the vent plug 162 in an intended manner . it should be appreciated that the inventive drip chamber 120 and the vented end cap 170 can be used together in an iv system , or can be used separately , with the benefits attributed to each such feature being realized by that feature &# 39 ; s use . for example , the drip chamber 16 can be used in conjunction with the roller clamp 150 by using the roller clamp to partially close off and restrict liquid flow in the patient conduit 126 . this allows the reservoir 164 to fill to a desired level to moisten the vent plug 162 and also allows a slow rate of liquid to fill the patient conduit 126 and expel air therefrom through the termination end 124 without causing air bubbles to form on the inner surface of patient conduit 122 . such a system , however , still requires caregiver attention because the roller clamp 150 will need to be manipulated to adjust a desired flow rate for priming the drip chamber 120 . likewise , end cap 170 can be used at the termination end of a patient conduit 122 attached to any known iv delivery system , such as a system containing a drip chamber 120 or a system containing an infusion pump ( not shown ). the end cap 170 , as explained above , will reduce the rate of liquid flow in the patient conduit 122 so that air bubbles will not be formed on the inner surface of the fluid conduit . moreover , termination end vent plug 174 will prevent seepage of the liquid from the termination end 124 once the patient line becomes filled in the intended manner . if the end cap 170 is of a removable configuration , such as via a luer - type connection as is known in the art , then once the patient conduit 122 is filled , roller clamp 150 will be closed and end cap 170 can then be removed without causing seepage of the liquid contained in the patient conduit 122 , whereupon the conduit can then be attached to the intravenous needle connected to a patient . thereafter , roller clamp 150 can be re - opened to allow intended operation of the iv system . an additional feature illustrated in fig3 is an extension conduit 180 is disposed between the spike assembly and drip chamber to transport the liquid from the spike assembly 116 , and in particular , from the outlet 130 of the funnel portion 128 , to the drip chamber 120 . the extension conduit is comprised of a flexible tube material such as plastic , having a length “ l ”, and which is preferably transparent or translucent . the extension conduit 180 has an inlet end 182 connected to the spike assembly outlet , and an outlet end 184 connected to , or otherwise disposed in , the drip chamber top wall 150 . in this embodiment the drip orifice 132 may be formed in the outlet end 184 of the conduit or , may be formed in the drip chamber top wall 150 . the length “ l ” of the conduit is sufficient to separate the relative distance between the spike assembly 116 and the drip chamber 120 so that the drip chamber is disposed at a height which is more readily viewable by the health care professional . this feature is desirable because the liquid bag or bottle may be positioned higher than the eye level of the health care professional making observation of the drip chamber and the counting of drops for flow rate adjustments will be difficult . the extension conduit 180 can be used in connection with any known iv system for separating a drip chamber from a spike assembly . the present invention may be embodied in other specific forms without departing from its structures , methods , or other essential characteristics as broadly described herein and claimed hereinafter . the described embodiments are to be considered in all respects only as illustrative , and not restrictive . the scope of the invention is , therefore , indicated by the appended claims , rather than by the foregoing description . all changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope .

US-85208007-A

the invention relates to a vaginal probe , in particular for treating incontinence and comprising an external part , an internal part , a bridge connecting said parts and processing electronics . the external part is configured as a handle and has a cavity and the internal part is a body that is rounded on all sides . said body : a ) has sensors on its surface , which are connected to the processing electronics ; b ) is symmetrical about a longitudinal central plane , which runs between the legs of a patient using said probe ; c ) has cross - sections that are perpendicular to said longitudinal central plane and to the bridge , in which the measured height dimension h of said body , which runs parallel to the longitudinal central plane , is at maximum half its measured width b , which runs perpendicular to the longitudinal central plane ; and d ) has a front sub - section that is at a distance from the external part , a central section and a rear sub - section . said central section is curved , the rear sub - section is connected to the bridge and the front sub - section and the rear sub - section are interconnected in one piece by means of the central section and are at an angle of between 170 deg – 100 deg in relation to one another .

the vaginal probe has an external portion 20 , an internal portion 22 and a crosspiece 24 that joins said two portions 20 , 22 together and is configured as a short tube . the tube has a free length of about 5 to 20 mm , preferably of about 10 mm and an outer diameter of about 5 to 7 mm . the external portion 20 is configured as a handle which is taken hold of for inserting and removing the vaginal probe . it forms a hollow space 26 for accommodating a processing electronics unit 28 , a battery 30 and at need other electronic components . a three - dimensional sensor that is responsive to the earth &# 39 ; s gravity field ( e . g ., adxl 202 of analog devices inc .) is integrated in a preferred embodiment . this sensor permits to continuously register the position of the vaginal probe in space and , as a result thereof , in situ . the hollow space 26 is accessible via a flap 27 . electrical external contacts 29 are provided for charging the built - in accumulators ( batteries ). the external portion 20 is formed substantially like a flat parallelepiped or like a cushion . it substantially consists of a thin shell so that it is as light as possible and that the hollow space 26 may be configured to be as large as possible . it is implemented so as to be quite flat for occupying but very little space between the legs . in a preferred embodiment , the external portion 20 is formed in such a manner that a clear distinction can be made between the front ( in front of the legs of a female patient ) and the back , exhibiting e . g ., an asymmetry with regard to the crosspiece 24 in its longest extension . as a result , the female patient will understand more easily that the e . g ., longer part of the external portion 20 must point vertically upward upon correct insertion of the vaginal probe . the internal portion 22 is symmetrical about a longitudinal center plane 32 . said plane passes through the central axis 33 of the rod - shaped crosspiece 24 and extends between the legs of a female patient wearing the vaginal probe . the external portion 20 has its main dimensions in this longitudinal central plane 32 . in the exemplary embodiment shown , the longitudinal central plane 32 is concurrently a plane of symmetry of the external portion 20 and of the crosspiece 24 . the internal portion 22 has cross sectional areas the cross sectional area 34 of which is shown in the figs . this cross sectional area and all the other ones are oriented at right angles to the longitudinal center plane 32 and across the longitudinal direction of the vaginal probe . the longitudinal direction is oriented parallel to the axis 33 of the rod - shaped crosspiece 24 . the cross sectional area 34 is oriented at right angles to the axis 33 of the rod - shaped crosspiece 24 . as shown in the figs ., the internal portion 22 is quite flat . it generally has a shape remotely resembling a shoespoon . the cross sectional area 34 has a height dimension h oriented in the direction of the longitudinal center plane 32 and extending across the crosspiece 24 and a width dimension b that is determined transverse to the longitudinal center plane 32 . as can be seen from the figs ., the width in the region of the cross sectional area 34 is at least six times the height h . in all the possible cross sectional areas that are parallel to the cross sectional area 34 , the width b is at least twice the height h . the height h is selected to be as small as possible , in the exemplary embodiment it is 10 mm maximum . the width varies between 43 and 20 mm . to provide a better description , the internal portion 22 will now be divided into subsections . it has a front subsection 36 , a central section 38 and a rear subsection 40 that is connected to crosspiece 24 . these subsections 36 through 40 integrally merge with each other . as more specifically shown in fig3 , in which the longitudinal center plane 32 coincides with the plane of the paper , the rear subsection 40 is oriented substantially in the direction of the crosspiece 24 . the central section 38 has a curved orientation . the front subsection 36 is inclined at an angle a of about 30 ° to the extended direction of the rear subsection 40 so that the angle between the front subsection 36 and the rear subsection 40 is of about 150 °. in the illustration of fig3 , the internal portion 22 generally has approximately the shape of an arch . in the illustration in accordance with fig2 , in which the width dimension b lies in the plane of the drawing , the width dimension , which takes departure from the rear subsection 40 , first increases on almost a straight line , passes through a respective left hand side and right hand side arched cavity 41 before decreasing again at the beginning of the front end of the central section 38 , an approximately parabolic front boundary line being given thereby , see fig2 . in the transition between the front subsection 36 and the central section 38 there is formed a u - shaped recess 42 that is bounded relative to the front portion 36 . it has an overall area that is clearly smaller than the area defined by the outer contour in the top view of fig2 , the area of the recess 42 being more specifically smaller than ⅓ , preferably smaller than ⅕ of the overall defined area in the top view . given the recess 42 , the probe is better retained within a vagina because tissue portions located both above and underneath partially pass through this recess and become superimposed . therefore , in a particular implementation of the internal portion 22 , an emitting diode ( led ) 68 and a light sensitive receiving diode 70 are mounted into the slightly opening , u - shape oriented legs of this recess 42 in such a manner that they are located directly opposite each other on the same level so that the light absorbed by the tissue can be continuously measured for registering the oxygen saturation in the tissue . the recess 42 must not be provided , it is also possible to make a vaginal probe without said recess 42 . the sensors will now be discussed herein after . in the front subsection 36 there is provided a reference sensor 44 that is configured to be circular in the exemplary embodiment , said sensor being located between the recess 42 and the front point of the internal portion 22 and having a diameter of about 15 mm . in the embodiment shown it is located on the top side of the vaginal probe that is visible in fig2 . on the same side of the vaginal probe there are two oblong parallel first sensors 46 . they are located in immediate proximity to the longitudinal center plane 32 , in the region of a concave groove 53 and in the transition area between the rear subsection 40 and the central section 38 . they form a partial grip around the urethra and are intended to register the measured signals generated by the m . sphincter urethrae externus upon contraction thereof . in the same length position but on the side of the internal portion 22 and of the respective one of the arched cavities 41 there are disposed two second sensors 48 for scanning the m . puborectalis . these sensors are also striped and extend substantially in the longitudinal direction . two third sensors 50 are mounted to the part of greatest width of the internal portion 22 . as can be seen from fig5 , they are located on the bottom side of the internal portion 22 . they are located on either side of the recess 42 and have a circular shape with a diameter of about 8 mm . they are associated with the pelvic floor muscles . in the rear subsection 40 , there is disposed a fourth sensor 51 which extends symmetrically substantially in the longitudinal direction to the longitudinal center plane 32 , said sensor coming to rest against the pars profunda of the m . sphincter ani externus , see fig5 . accordingly , the sensors 46 – 50 are provided in pairs , the sensor 51 and the reference sensor 44 being single sensors . all of the sensors 44 – 51 are disposed and configured so as to be symmetrical to the longitudinal center plane 32 . the sensors of the same type , meaning for example the first two electrodes 46 and so on , are respectively built according to the same principle . a possible construction of the vaginal probe will be explained herein after with the help of the fig6 – 8 . according to these , the internal portion 22 has an inner part 52 carrying the sensors 44 – 51 and their supply lines 58 as well as a body 54 , which is formed around said inner part 52 and is connected thereto , said body being preferably manufactured by injection molding or any other casting process and surrounding the inner part 52 except for the surfaces of its sensors 44 – 51 . the surfaces of the sensors 44 – 51 are flush with the surface of the body 54 . for making this body 54 , a suited plastic material exhibiting good adhesion to the body tissue is selected . appropriate plastic materials are those tolerated by the body such as silicone , polyethylene , acrylate and so on , in any case insulators . as shown in the fig6 – 8 , the inner part 52 consists of a flat carrier 56 and of the sensors 44 – 51 connected thereto . the carrier 56 is flat and has substantially the shape of the internal portion as viewed from the top ( see fig5 ) with slightly reduced dimensions though so that the body 54 is allowed to surround the carrier 56 with a wall of at least some millimeters thick . with their free surfaces which are visible from the top , the sensors project from the carrier 56 by this wall thickness of the body 54 . the carrier has circuit traces 58 through which the discrete sensors 44 – 51 are connected to connecting points 60 . electric lines extending through the inner hollow or , in an alternative , outside along the rod - shaped crosspiece 24 into the hollow space 26 of the external portion 20 , are connected to these connecting points 60 . the connecting points 60 are provided in the number required by the sensors for performing the function , they are eight in the exemplary embodiment if the sensors are electrodes and at least ten if the signal is acquired via electrically operated pressure elements . the inner part 52 may be manufactured in several different ways . as shown in the fig6 – 8 , the inner part 52 may be a cast plastic part that is already configured to form all the sensors 44 – 51 , electrodes in this case , including their surfaces . this plastic part is now completely coated with a conductive coating , for example by electroplating . the metallic electrodes are also formed as a result thereof . in a further step , partition lines are etched , they are for example cut out with a laser so that the electrodes are separated , one electrode being connected to but one connecting point 60 . put another way , the electrodes and the connecting points 60 are insulated against each other so that the desired conductor connections are preserved . the method of manufacturing an introitus probe , more specifically a vaginal probe , just described is suited for any probe , not only for the probe in accordance with claim 1 . the applicant makes the right of filing a divisional application for manufacturing such a probe a proviso . the method steps are the following : manufacturing a plastic part in the form of what will later be the probe , coating said plastic part with a conductive coating , more specifically by electroplating . forming partition lines in the coating for separating and defining electrodes so that one electrode is connected to at least one connecting point . in another embodiment , the discrete sensors 44 – 51 , electrodes in this case as well , are made from flat stampings of metal , such as medical grade special steel , and deposited onto a plastic carrier . they are directly connected via discrete conductors so that connecting points 60 are not necessary . in an improved embodiment , these metallic electrodes are bowl - shaped , meaning they have a rim that projects downward toward the carrier 56 only . the carrier 56 has channels mating with the rims of the electrodes engaging therein . in another embodiment , a sheet metal blank is stamped or formed in such a manner that it forms all the sensors 44 – 51 , electrodes again . it is then coated e . g ., filled , with plastic . next , material of the sheet metal blank is removed e . g ., with a laser so that the electrodes and their supply lines are separated from each other . the sensors 44 – 51 are for example pressure sensitive membranes or electronic pressure elements , preferably combined with metallic electrodes that are disposed on their outer surface . they are integrated in the surface of the vaginal probe so as to provide a form - positive fit therewith . in the combined implementation , each sensor must be supplied , besides the measuring line , by two supply lines , only two of which must lead to the electronics unit in the external portion 20 . each sensor e . g ., the sensor 44 , can be used for reference pressure . fig9 shows another exemplary embodiment the manufacturing of which is particularly advantageous . a preferably single piece molded body already having the shape of the finished probe is first produced . it forms in one piece the internal portion 22 and the crosspiece 24 . at the end of the crosspiece it advantageously has a connection piece for connection with the external portion 20 . thin electric conductor areas 72 are deposited onto this molded body . the entire molded body is for example electroplated e . g ., chromium plated . partition lines are then made using a laser , meaning the discrete conductor areas are formed and electrically separated from each other . the conductor areas have in any case a conductor region on the crosspiece 24 so that they may be contacted at the end of the crosspiece i . e ., from the external portion 20 . the conductor areas 72 are preferably larger than the areas required for the sensors 44 – 51 , they are not allowed to be smaller though . an externally surrounding layer 76 of electrically insulating material , more specifically a varnish layer , covers the conductor areas 72 and the areas exposed by the laser , but does not cover the areas of the sensors 44 – 51 which remain bare . as a result , the sensors are freely accessible from the outside . this layer 76 is only illustrated in parts in fig9 . in the front subsection 36 , it is shown completely , in the rear subsection 40 it has been removed for showing the conductor areas 72 and the partition lines 74 . the conductor areas 72 located side by side that can be seen in the upper portion of fig9 are connected to the urethra electrodes 46 or form these in parts , respectively . in still another embodiment the sensors 44 – 51 are formed by pressure sensitive membranes or electronic pressure elements that carry the electrodes on their surface and are integrated into the surface of the vaginal probe so as to provide a form - positive fit therewith . in this implementation , each sensor must be supplied , besides the measuring line , by two supply lines , only two of which must lead to the electronics unit in the external portion 20 . the sensor 44 can be used as a reference pressure . continence can also be produced by mechanical weight load . preferably , the weight of the internal portion 22 can be varied by suited means , for example by filling hollow spaces or by adding weights . the centroid is preferably provided in proximity to the urethra , meaning of the concave groove 53 . fig1 still illustrates a separate control apparatus 78 to a much reduced scale . it has a corresponding emitter and receiver and the processing electronics unit 28 and display means 80 .

US-50817005-A

dual loin knife blade members , in the form of a z - blade and two styles of j - blades , for use with knife assemblies in loin pulling machines for pork processing operations . the z - blade knife comprises a shelf portion of extended length , formed of two separately - shaped blade portions , to maximize to the allowable customer dimensional length specification for the meat shelf being cut , while not cutting into and exposing the red meat of the pork loin eye . the j - blade , of either the tabbed or non - tabbed style , includes lower sweeping radius blade portions allowing the j - blade to lie closely adjacent and generally conform to the profile of the underlying split conveyor belt bed shape . the profiles for the present z - blades and j - blades permit substantially increased yield in pork loin processing operations , reduced subsequent hand - trimming labor , as well as extended blade wear .

the present disclosure relates to dual loin knife blades that provide improved processing operating efficiencies and yields over the prior forms of z - blades and j - blades as disclosed in u . s . pat . no . 6 , 547 , 658 , and further overcomes many of the deficiencies found in the blades , and their shapes and manufacturing methods . having reference to the drawings , wherein like reference numerals indicate corresponding elements , there is shown in fig1 an illustration of a z - blade member , generally denoted by reference 20 . z - blade 20 includes ( from top to bottom in that figure ): an upper mounting portion , generally denoted by region reference 22 ; an upper central blade portion 24 ; an angle bend forming a rib bone radius portion 26 ; a shelf portion 28 comprising an upper initial or finger shelf portion 30 , a relatively short shallow - angled shelf bend portion 32 , and a lower or loin eye avoidance shelf portion 34 ( hereafter the “ las portion ”); an angle bend forming a belly cutoff radius 36 ; a belly cutoff blade portion 38 ; and a lower mount portion 40 . portions 28 , 30 , 32 , 34 , 36 and 38 , collectively , form a lower central blade portion . more specifically , the upper mounting portion 22 of z - blade 20 comprises an s curve portion 42 and an upper mount portion 44 which mounts to a loin puller apparatus &# 39 ; upper blade mount ( not shown ). it will be understood that , depending on the specific mounting block arrangement and location ( not shown ) present in a given loin pulling machine ( not shown ), there may be a need for an even larger ( or smaller ) s curve portion , or instead , no need at all for the linkage - adjusting s curve portion 42 of z - blade 20 . instead , portion 42 and upper mount portion 44 can simply be formed as an elongated straight mounting section of z - blade 20 , or even take some other configuration , again depending on the specific upper mounting requirements for the z - blade in a given application . as seen in fig1 and 2 , the cutting edge 46 runs from an upper end point 48 to a lower end point 50 . those end points 48 , 50 may be readily extended upwardly and downwardly as needed for a given loin puller machine , depending on the type and size ( i . e . live weights ) of hog carcass being processed . further , cutting edge 46 can be formed with either an inner or outer single beveled cutting edge , such as shown in fig3 and 4 , or instead , can be formed as a double bevel cutting edge , as shown in fig5 , depending on the preference of the customer . in fig2 , cutting edge 46 is shown as an inner single bevel cutting edge ( but again , that type edge is depicted merely for purposes of presentation ). upper central blade portion 24 is shown as a generally elongated straight section ending at its lower end in the rib bone radius 26 . it will be understood that upper straight blade portion 24 is positioned substantially above the entry point of the meat carcass into the blade ( such point being shown as line m - m in fig2 ). nevertheless , blade portion 24 still carries a cutting edge 46 , primarily so that if any carcasses are improperly aligned within the loin pulling machine ( not shown ), the cutting edge 46 will be present to cut through the bones and meat , so that such mis - aligned carcass section does not jam up the machine and cause unwanted downtime . the angle of the rib bone radius 26 is quite tight , and thus , relative to now the lower central blade portion , sets up an aggressive positioning of the shelf portion 28 towards the loin area , as compared to that angle in the known prior art blades , which instead typically had much larger radii , such as 114 °. that is , the angle of the present rib bone radius 26 is preferably in the range from approximately 107 ° to 111 °, and more preferably is approximately 109 °. the permitted length of a cut belly shelf on a loin is typically specified by the end user customers to be 2 . 5 inches plus or minus 0 . 2 inch . the prior art z - blades , however , purposely had only a 2 . 5 inch maximum shelf length . however , with the present invention , the shelf length ( designated as length s . l . in fig2 ) for the elongated shelf portion 28 is 2 . 7 inches , and therefore is able to cut deeper into the belly area and near the loin eye meat . that resultant elongated length of cut belly shelf thereby increases the overall weight of the loin portion , with resultant increased revenues for the processors . however , if such an extended shelf length s . l . of 2 . 7 inches were undertaken with a straight shelf blade design , such as present in the known prior art z - blades , that extended straight blade length would improperly cut right into the loin eye meat . advantageously , the present shelf 28 has been formed of two sections , namely an upper , initial finger shelf portion 30 , which is formed preferably as a straight section extending approximately 0 . 680 inch in length , and within a preferred range from approximately 0 . 650 to 0 . 710 inch in length , and then the second shelf or las section 34 , i . e . the loin avoidance shelf portion , which is also formed preferably as a straight section having a length of approximately 0 . 561 inch , and within a preferred range from approximately 0 . 531 to 0 . 591 inch in length . formed between those two shelf portions 30 and 34 is a bend angle portion 32 having a shallow bend angle α in the range of approximately 9 ° to 13 °, and preferably approximately 11 . 2 °. the radius to create angle α is approximately 4 . 8845 to 4 . 9445 inches , and preferably 4 . 9145 inches . angle α allows the las blade portion 34 to cant down slightly from the upper finger shelf portion 30 . it will be understood that if angle α is made too great , than the belly yield can be lost , i . e ., the depth of the edge of the belly is no larger as much as the customer - required depth specification of one - half inch minimum , thereby necessitating additional trimming labor to cut back the belly shelf towards the spare rib , until the required one - half inch depth dimension is again attained . on the other hand , if angle α is made too small , then there is a risk of exposing and cutting into the loin eye meat by the las section 34 . thus , by using a bend angle α within the above range , for the extended shelf s . l ., that angle α allows the las portion 34 completely to avoid interference with the red meat of the loin eye . thus , the two - part extended length shelf 28 , with intervening angle α of bend portion 32 , is a substantial improvement over the straight shelves of the prior art z - blades , because an extended shelf length of meat can now be cut , including cutting closer to the spare rib and through the finger lean , yet without cutting into the loin eye meat . this extended length shelf results in substantial yield gains of the loin portions for the meat processor . as seen in fig2 , the cutoff radius 36 has a tight angle bend created by a radius in the range from approximately 0 . 220 to 0 . 280 inches , and more preferably of approximately 0 . 2500 inch . the angle between the lower shelf portion 34 , relative to the belly cutoff blade portion 38 , is formed within the range of approximately 117 . 2 ° and 121 . 8 °, and preferably approximately 119 . 5 °. the belly cutoff blade portion 38 is thus formed as a substantially vertical portion including the cutting edge 46 and lower end point 50 , and is operable to cutoff the fatback from the belly of the pork carcass . the lower mounting portion 40 mounts within the lower mounting block ( not shown ) of the associated loin pulling machine ( not shown ); again , it can take any of several forms as needed to be held properly by such mounting blocks . thus , the shape shown for lower mounting portion 40 in fig1 and 2 is merely for purposes of illustration . the overall length ( designated as length o . l . in fig2 ), for the z - blade of the present disclosure is normally is the range from approximately 13⅞ inches to 14⅛ inches , and is preferably some 14 inches long , as measured in its finally formed shape . the range of thickness for the z - blade 20 is in the preferred range from approximately 0 . 130 inches to 0 . 150 inches , and is preferably 0 . 140 inches . as noted , the upper central blade portion 24 and belly cutoff blade portion 38 are generally parallel to one another . as an alternate form of two section shelf 28 , it could be formed as one continuous downwardly curved section , formed of a radius of preferably 7 . 287 inches , and within the preferred range from 7 . 257 inches to 7 . 317 inches . such a curved shelf blade portion of the extended 2 . 7 inch length is a substantial improvement over prior art shelf blade portions . turning to fig6 and 7 , there is shown as one aspect of the present disclosure , an improved j - blade , generally denoted by reference numeral 60 , and for use with certain types of loin puller machines . that is , certain loin puller apparatus ( not shown ) were modified into dual blade machines in the field , i . e . converted from a single hoop - style blade machine to a dual blade loin knife - type machine . due to such field modifications , including the style and location of the specific blade mounting blocks used , and the other components found in those type loin puller machines , the j - blades used with those field - modified machines are necessarily formed of a specific shape . thus , the improved j - blade 60 for use with such field - modified machines includes a dual bevel cutting edge 62 ( used for presentation purposes only in this disclosure , and again is dependent on the end user &# 39 ; s preference ), having respective upper and lower end points 64 , 66 . j - blade includes ( from top to bottom in those figures ): an upper mount portion 68 ; an upper central blade portion 70 ; a rib bone radius 72 ; a lower central blade portion having generally straight fatback trimming portion 74 , a transition area 76 , and a sweeping radius portion 78 ; a cutoff angle bend 80 ; a generally straight cutoff portion 82 ; and a lower blade mount portion 84 . more specifically , the upper central blade portion 70 comprises an s - curve portion 86 which helps properly position the upper mount portion 68 in its needed linkage position . that is , the s - curve portion 86 helps as a linkage step to properly locate ( from left to right in fig7 ) the upper mount portion 68 relative to the upper mounting block ( not shown ) of an associated field - modified loin puller machine ( not shown ). thus , again here , similar to the above - described z - blade , the blade portions 68 and 70 can take other shapes rather than the s - curve portion 86 , as needed to accommodate the proper linkage positioning with the upper blade mounting blocks . the feather bone radius 72 is preferably in the preferred range from 0 . 220 to 0 . 280 inches , and more preferably is approximately 0 . 2500 inch . that relatively tight radius allows the straight fatback trim portion 74 of the disclosed improved j - blade 60 to be aggressively positioned ( i . e . in a fairly vertical alignment and quite close to , i . e . tighter into against , the feather bones ( not shown ) of the pork carcass ), than was ever previously available with the prior art j - blades . preferably , the relative length of the straight fatback trim portion 74 is approximately 2 . 079 inches long and within the preferred range of approximately 2 . 049 to 2 . 109 . further , it will be understood that the prior art blades were formed of a flat curve along that fatback trim portion of the overall j - blade , rather than substantially straight as formed with the fatback trim portion 74 of the disclosed j - blade 60 . by having such a straight blade portion for fatback trim portion 74 , the result is that less overall fat remains on the loin portion that is pulled , and instead , more fat is cut into the fatback portion that is trimmed away . this results in better yields , and hence , in better revenues for those respective sections of the carcass when sold . there is a small transition area 76 located between the generally straight fatback trim portion 74 and the sweeping radius portion 78 of j - blade 60 . the radius for the sweeping radius portion 78 is much more aggressive , i . e . is much tighter , than that present in the prior art j - blades . that is , the radius in area 78 is preferably in the range from approximately 3 . 939 inches to 3 . 999 inches , and more preferably is approximately 3 . 9691 inch . the sweeping radius portion 78 of j - blade 60 operates to remove the fatback over the loin eye , and thus , that tight radius blade portion causes a smaller thickness of fat cover ( not shown ) to remain over the loin eye , yet that portion 78 does not enter the red meat of the loin eye . for example , the most aggressive radius present in the known prior art fatback blade portions was relatively flat , i . e . only approximately 4 . 117 inches , such that that relatively flat radius inherently created a substantial yield loss in the fatback trim portion of the carcass . the tight sweeping radius of present blade portion 78 then transitions into , and comes down low towards belt bed , due to the sharp cutoff angle bend 80 . that sharp bend 80 has a preferred radius of only approximately 1 . 875 inch , and is within a preferred range of only approximately 0 . 1575 inch to 0 . 2175 inch . the angle between the sweeping radius portion 78 relative to the cutoff portion 82 , is formed within the range of approximately 83 . 9 ° and 88 . 5 °, and preferably 86 . 2 °. stated another way , the fatback trim portion 74 comprises approximately the first two fifths of the meat cutting portion of the j - blade 60 , and the lower sweeping radius portion 78 comprises approximately the lower remaining three fifths . this aggressive shape , thus , trims the fatback over the loin eye very close in with a tight radius , and puts the blade quite close to the red meat portion of the loin , resulting in a larger piece of fatback that is now worth more , since it contains more connected weight . further , the resulting loin is thus formed to be of a very first quality , since it has only the minimal dimensional specification of remaining fat cover . if the overall meat cutting portions of the blade ( i . e . portions 74 and 78 ) were formed too tight , i . e . too close in against the loin eye , then they would expose the loin red meat , which then drops the quality and price of the loin . on the other hand , if those blade portions 74 , 78 were formed to be too loose or wide , then there is less fatback trimmed off , such that too much fat is left on the loin . that , in turn requires extra and costly subsequent “ hand knife ” labor for trimming away that , extra fatback . in effect , the tight radius of cutoff angle bend 80 allows the sweeping radius portion 78 to start right away at its lower end , such that the sweeping radius portion 78 gets up close into the loin eye area , and thereby , in effect , allows the greatest recovery of the fatback . it will be noted that fig8 , 9 and 10 , disclose , respectively , inner and outer single bevel cutting edges 63 , and a dual bevel cutting edge 62 . shown in fig1 and 12 , as an alternate aspect of the present disclosure , is a modified form of a j - blade for use with those certain different types of loin puller processing machines that need a tab for holding a diverter bar , and which machines are otherwise different from the machines which utilize the style of j - blade 60 of fig6 and 7 . thus , there is shown in fig1 and 12 , an improved tabbed - style j - blade , as generally denoted by reference numeral 90 . tabbed j - blade 90 includes a dual bevel cutting edge 92 with respective upper and lower end points 94 , 96 . the tabbed j - blade 90 includes ( from top to bottom in fig1 ): an upper mount portion 98 ; an upper central blade portion 100 , which extends generally down to that point along tabbed blade 90 as designated by carcass entry line m — m , i . e . the line at approximately which the top of the pork carcass enters the blade ; an elongated sweeping curve portion , generally designated by reference numeral 102 , which includes two separate blade portions , namely a tight upper radius or fatback trim portion 104 , as separated by a transition area 106 , and a tight lower radius or sweep radius portion 108 ( which carries the integrally - formed tab member 109 , as having an inner opening 111 to hold and retain the associated diverter bar ( not shown )); a cutoff angle bend 110 ; a generally vertical cutoff blade portion 112 ; and finally , a lower mount portion 114 . more specifically , the upper central portion 100 includes a generally shallow s - curve portion 116 which , along with the upper mount portion 98 , can be larger or smaller ( as needed ) and provides the proper positioning and linkage setup for mounting the upper end of the j - blade 90 to the mounting blocks ( not shown ) of the loin puller machines ( not shown ). again , as with the similar portion of the above - described z - blade 20 and j - blade 60 , the upper portions 98 and 100 of tabbed j - blade 90 can be formed in different configurations , as needed , to : accommodate the upper mounting block for a given loin puller machine ( not shown ). however , starting from essentially carcass entry line m - m on down , the shapes of the various blade portions for tabbed j - blade 90 are specially formed . the upper fatback trim portion 104 is preferably formed of a radius in the range of approximately 3 . 970 inches to 4 . 030 inches , and more preferably is of approximately 4 . 0 inches . this tight curvature for upper fatback trim portion 104 permits the blade 90 at that location to properly divide and trim the finger lean portions and to cut near the feather bone area of the loin , but without cutting into the loin eye meat . then , after the transition area 106 , the separate and different radius of the lower sweep radius portion 108 is within the range from approximately 3 . 470 inches to 3 . 530 inches , and more preferably , is of approximately 3 . 5 inches . as seen , those two respective and distinct radiuses blend into one another along the transition area 106 . the cutoff angle bend 110 is preferably formed of a tight radius of approximately 0 . 360 inch , and within a preferred range of from 0 . 330 inch to 0 . 390 inch . while it is of a slightly different overall shape from the corresponding portions of non - tabbed j - blade 60 ( of fig6 an 7 ), the lower meat cutting portions 104 and 108 of the tabbed j - blade 90 are still substantially more aggressive , i . e . tighter in towards the feather bones and loin eye meat , than any of the known prior art tabbed - style j - blade designs . in effect , the curved cutting portions 104 and 108 permit substantially more fatback to be trimmed from the loin meat areas , and thus , add back an otherwise lost portion of the fatback segment , thereby substantially increasing yields , over the prior art tabbed - style j - blade . as shown in fig1 , the z - blade 20 of the present disclosure is depicted in its normal operating environment , namely in operation above a split conveyor belt - type bed 116 , as shown carrying the shoulder end of the pork loin , generally depicted by reference numeral 118 . as seen , the shelf portion 28 properly cuts the finger lean meat 120 yet does not get too close to the loin meat 112 . however , as will be understood , the z - blade 20 is formed so as to leave a proper “ silver dollar ”- sized score ( not shown ) on the belly . turning to fig1 , there is shown , in the operating environment similar to fig1 , the non - tabbed j - blade 60 of the present disclosure , including the split conveyor belt bed 116 and the carcass shoulder end 118 . as seen , the sweeping radius portion 78 of non - tabbed j - blade 60 mirrors , i . e . is shaped to closely follow , the overall profile of the belt bed 116 . thus , when needed the blade , in effect , is allowed to lay down directly onto the belt bed , as it were , so as to be able to closely trim the loin shoulder end 118 . this blade profile - mirrors - bed profile feature is particularly advantageous when pulling loins of so - called “ european white ” hog carcasses , yet can be accomplished without at all cutting into the belt bed 116 . in effect , when blade 60 is so lowered , there is no “ air gap ” left between the profile of the lower sweeping radius portion 78 and the belt bed 116 . this blade profile - mirrors - bed profile feature is further accentuated by the fact that the radius formed in cutoff angle bend 80 of non - tabbed j - blade 60 is substantially sharp . thus , a substantially greater amount of fatback 124 can be cut away by the aggressive shape of the meat cutting portions of non - tabbed j - blade 60 . further , the specific configuration of j - blade 60 will not over - expose false lean at the shoulder end or over - score the ham end of the loin . turning to fig1 , there is shown the tabbed j - blade 90 of the present disclosure as depicted in its operating environment ( similar to fig1 and 17 ), and again depicting the split conveyor belt bed 116 and the loin shoulder end 118 . as noted , the angle of the cutoff angle bend 110 is not quite as sharp , i . e . not as tight ( as the corresponding angle of cutoff angle bend 80 of non - tabbed j - blade 60 ). nevertheless , the lower sweep radius portion 108 of tabbed j - blade 90 is still able to come down substantially close to , and have a generally similar profile to , the conveyor belt bed 116 . thus , here again , and contrary to the prior art tabbed j - blade designs , a substantial greater portion of the fatback 124 of the carcass is able to be cut away from the loin 122 all so as to in increase both loin and fatback yields when using the tabbed j - blade 90 of the present disclosure . further yet , the tabbed - style j - blade must not expose too much false lean , or “ over score ” the loin &# 39 ; s ham end , i . e ., beyond the desired “ silver dollar ”- size score . now , turning to the method of forming the various z - blades and j - blades of the present disclosure , it will be understood that the blades are preferably formed of d - 2 steel material , die - stamped rather than hand - formed ( as in the prior art ) for greater accuracy and consistency , and are heat treated for greatest longevity . the preferred method for forming the respective blades of the present disclosure , thus , includes the following steps : ( a ) preliminarily , when forming a tabbed - style j - blade , form a laser cut , or mill cut as desired , of the profile of the blade and attached tab , all as an integral unit formed from one piece of metal stock ( such that the tab member is not a weaker piece due to being welded later on to a separate blade member , as was done in the prior art ); ( b ) mill the outer blade profile ( either style of blade ), on a milling machine ; ( c ) machine the milled blades &# 39 ; overall cutting edge , whether as a double or single bevel edge , and whether as an inner or outer single bevel edge ; ( d ) anneal the machined blades , so as to soften them , by subjecting them in a preferred temperature range of from approximately 1060 ° f . to 1080 ° f ., in the preferred time range from approximately 85 – 95 minutes ; ( e ) die - stamp the annealed blades , so as to form the actual accurate curves , angle bends , and overall blade profile to the respective z - and j - blades ; ( f ) heat treat the die - stamped blades , to within the range on the rockwell scale of between approximately r . c . 44 – 54 ; ( g ) quality control check the blade profile of the heat - treated blades , to make sure the cutting edge profile has not changed during the earlier heat treatment step ; and ( h ) polish all surfaces of the blades to generally a substantially flawless mirror - like finish , namely to a polished surface finish within the preferred range from approximately 4 to 32 microinches . thereafter , the finished and polished blades are wrapped and shipped to the customer , whereupon the customer grinds on their own final cutting edge , to their own specific edge grinding specifications and desires . they can also then subsequently re - sharpen the blade over its lifetime of use . due to the foregoing method of forming the present z - and j - blades , a substantially superior blade member is obtained . for example , contrary to the rough surface finish established on the known prior art blades , the mirror - like polished surface finish found on the blades of the present disclosure helps to substantially reduce side load forces created by the blades as they cut through the meat carcasses . this is because the polished surface finish creates less drag on the blade - related machine components . this in turn substantially reduces blade wear , and blade - related component wear for the loin puller machines , thereby resulting in increased savings in maintenance downtime and replacement parts . further , the present tabbed - style j - blades are formed by laser cutting ( or mill - cutting , as desired ) both the blade and the tab as a single unit , i . e . all formed as an integral piece from one piece of metal stock . this is contrary to the prior art method of welding and braising on the tab as a separate item to the blade . thus , due to that difference , the present one - piece tabbed - style j - blades has a substantially longer useful life , as there is no problem in having a welded tab portion prematurely break off from the remaining blade portion . further , by heat treating the blades to be within the r . c . 44 – 54 range , the present blades are substantially stronger and result in a longer useful life . yet further , as a result of die - stamping the curves and bends of the present z - and j - blades , instead of hand forming then as done with the prior art blade , a very accurate , and consistently - formed , blade portion is achieved . by permitting with the presently - disclosed blades an additional two tenths of an inch of fatback layer to remain on the belly ( which around the time of filing the subject application was running approximately $ 1 . 23 per pound , as contrasted to the then current price for fat hand trimmings off the loin of only $ 0 . 46 per pound ), the extra two tenths of an inch , across the entire length of the pork belly , times typically some 1200 carcass pieces per hour , times two loins per animal , times the typical 16 - hour per day shifts of such pork carcass processing operations , results in additional revenue to the processor of literally tens of thousands of dollars per day . similarly , substantial revenue savings , in effect , occurs by reducing the amount of needed later “ hand trimming ” of excess fatback over the loin eye meat . from the foregoing , it is believed that those skilled in the art will readily appreciate the unique features and advantages of the present disclosure over the previous types of dual loin knife blades for meat processing operations . further , the foregoing detailed description has been given for clearness of understanding only , and no unnecessary limitation should be understood therefrom , as modifications will be obvious to those skilled in the art .

US-90084304-A

a universal asthma and emphysema medication inhaler spacer comprises a cylindrical open - ended elongated chamber having a circular opening in the inlet end of a predetermined diameter and a predetermined depth . the outlet end of the chamber has an opening in it shaped to accommodate a human mouth . at the inlet end , the opening has opposed relief offsets on opposite sides to accommodate medication dispensers which have outlets of non - circular cross - sectional shapes , as well as circular shapes .

reference now should be made to the drawing , in which the same reference numbers are used throughout the different figures to designate the same components . fig1 is a front perspective view of a spacer 20 , in accordance with a preferred embodiment of this invention . the spacer 20 is used with a metered dose inhaler 10 , which is depicted in dotted lines . the dispenser 20 has an inwardly turned right - hand outlet end with a circular opening 21 in it . the outer diameter of the spacer 20 is approximately one and one - fourth inches ; and the diameter of the opening 21 is approximately one - half inch . this permits the opening 21 readily to accommodate a human mouth for inhaling aerosol medication located within the body of the spacer 20 . the overall length of the spacer 20 is approximately three and one - fourth inches for a typical commercial application . as illustrated in fig2 the spacer 20 also is open at its left - hand or inlet end to accommodate a separate inlet end cap 25 , which is inserted into the left - hand open end of the cylindrical spacer 20 with a friction fit . an outwardly directed flange 26 limits the extent of insertion of the inlet end cap 25 into the spacer , as illustrated in fig2 . also as is most readily apparent from an examination of fig2 and 3 , the end cap 25 / 26 has a circular opening 24 extending through it . this opening has a diameter which is less than the internal diameter of the cylinder 20 by the amount of the wall thickness of the cap 25 , which extends into the hollow elongated cylindrical chamber 20 . the circular opening 24 has its center located on the central longitudinal axis of the cylindrical chamber 20 . as shown most clearly in fig3 through 7 , the circular opening 24 is shaped to accommodate the external diameter of a standard circular mouthpiece 11 ( as shown in fig1 and 5 ) of a popular brand of metered dose inhaler currently available on the market . when the mouthpiece end 11 of the inhaler is inserted into the inlet opening 24 , a friction fit between the inner wall of the circular opening 24 with the outer wall of the mouthpiece portion 11 takes place . this friction fit causes the mouthpiece 11 of the inhaler to be centered on the axis of the chamber 20 . in this position , the metered dose inhaler 10 / 11 then may be used to dispel a metered dose of inhalant through the spray nozzle included in the delivery system of the metered dose inhaler 10 / 11 . the length of the chamber 20 is selected to permit the particles of medication to be mixed with air drawn into the chamber when the used inhales through the opening 21 , such air being pulled around the exterior of the mouthpiece 11 through slight differences in the opening 24 and the outer diameter of the circular mouthpiece 11 . this causes the size of the particles released at the mouthpiece or outlet end 21 of the chamber 20 to be significantly reduced in size from those released at the inlet end 25 / 26 ; so that there is an increased potential that the medication will be carried into the airways and lungs of the user , reducing loss of medication by impaction on the inner walls of the spacer 20 and the mouth and tongue of the user . the chamber 20 and the inlet end cap 25 / 26 preferably are made of rigid clear plastic material , such as polypropylene or the like . as illustrated in fig2 these parts are shown as made in two portions , namely the cylindrical chamber 20 with the mouthpiece or outlet end 21 , and the inlet end cap 25 / 26 . the entire assembly , however , could be manufactured as a single integral unit , if desired . whether the device is made of two parts , as shown in fig2 or is made in one piece as an integral unit , cleaning is greatly facilitated . there are no soft surfaces or sharp corners where unused medication or other materials can become lodged . in addition , because of the shape and types of materials which are employed , it is easy to clean the spacer in a dishwasher , if desired . it is important for the spacer to be easily cleaned ; so that reuse of the spacer is possible without exposing the user to bacterial and viral infections which may possibly breed in a spacer if it is not regularly cleaned . by making the spacer easy to clean , the likelihood that it will be cleaned between uses is greatly increased . as illustrated in fig4 and 7 , other common metered dose inhaler dispensers currently on the market employ mouthpiece end configurations which are not the full circle 11 , which has been illustrated in fig5 and described above . three other shapes , 14 , 16 and 18 , are currently in common use . to accommodate these other shapes , the inlet end 25 / 26 of the device shown in fig1 through 3 is provided with a pair of spaced relief areas , generally in the form of substantially v - shaped notches or indentations located on opposite sides of the circular opening 24 . as illustrated in fig3 through 7 , these relief areas comprise an area consisting of two portions 28a and 28b on the right - hand side ( as viewed in all of fig3 through 7 ) and a corresponding relief area 29a / 29b on the left - hand side ( again , as shown in all of fig3 through 7 ). these relief areas extend approximately half way into the full depth of the circular opening 24 in the end cap 25 / 26 , as shown most clearly in fig2 and 3 . as a consequence , when the flattened oval mouthpiece 14 of a dispenser such as used on the tilade ® ( neocromil sodium ) inhaler is used , the pointed edges of the somewhat flattened oval shape of the mouthpiece fit into the intersection points of the two relief areas 28a / 28b and 29a / 29b , as illustrated in fig4 . the opposing corners of the flattened oval mouthpiece 14 then rest against the shoulder formed by the remaining unrelieved portion of the circular opening 24 to frictionally hold the mouthpiece 14 centered in place in the end cap 25 / 26 . similarly , another generally oval shaped mouthpiece end , with straight edges on each side of the oval , such as the mouthpiece 16 used in the atrovent ® ( ipratropium bromide ) inhaler has exterior dimensions such that the mouthpiece 16 may be fully extended into the opening 24 , with the corners or edges of the mouthpiece 16 frictionally engaging the circular portion 24 of the spacer to permit the use of an atrovent ® metered dose inhaler . the rigid opening 24 centers the mouthpiece 16 on the axis of the chamber 20 . as is readily apparent from an examination of both fig4 and 6 , when either of the tilade ® or atrovent ® inhalers are used , air is drawn into the chamber 20 from around the mouthpiece 14 or 16 to mix with the medication as the user inhales through the opening 21 of the spacer . another type of mouthpiece , which is similar in overall shape to the one described above in conjunction with fig6 is employed by the proventil ® ( albuterol ) aerosol metered dose inhaler . the proventil ® mouthpiece 18 is shown in fig7 and is generally of the same overall shape as the mouthpiece 16 of the atrovent ® inhaler , but is somewhat larger in size ; so that it fits into the relief areas 28a / 28b and 29a / 29b , as shown in fig7 to abut against the shoulder formed by these relief areas with the inner part of the circular opening 24 illustrated in fig3 . once again , air is drawn into the chamber 20 by a person inhaling through the opening 21 as the aerosol medication is dispensed into the chamber in the manner described above . it has been found that by configuring the end cap 25 / 26 with the relief areas 28a / 28b and 29a / 29b as described above , all of the different commercially available metered dose inhalers , such as the ones described above , may be universally used with the spacer 20 . since no flexible plastic material is required in the construction of the device , the same rigid polypropylene plastic is used for all parts of the spacer , which facilitates manufacture , assembly and cleaning of the device throughout its use . a typical inside diameter of the circular opening 24 is 15 / 16 inches , with the distance between the inner points of the v - shaped bottoms of the relief areas 28a / 28b and 29a / 29b being 11 / 16 inches to frictionally accommodate the tilade ® dispenser . the other dispenser mouthpieces 16 and 18 , which have been shown in conjunction with fig6 and 7 , are accommodated by these dimensions . it should be noted that all of the dispensers have relatively rigid mouthpieces , but are made of plastic which has some resilience in it ; so that the friction fits which have been described above may be effected . the foregoing description of the preferred embodiment of the invention is to be considered as illustrative and not as limiting . various changes and modifications will occur to those skilled in the art for performing substantially the same function , in substantially the same way , to achieve substantially the same result , without departing from the true scope of the invention as defined in the appended claims .

US-25150294-A

a dual slot microwave probe for tissue ablation provides axially spaced slots producing an improved heating pattern with reduced axial extent . degradation in this heating pattern caused by the addition of ceramic support elements and / or fluid cooling is realized through a feeding structure delivering separate sources of microwave energy to the different slots of the probe aligned with the slots of the probe .

referring now to fig1 , a microwave ablation system 10 suitable for use with the probe of the present invention may provide a microwave source 12 generating a microwave electrical signal in the microwave region ( typically from 1 to 3 ghz ), for example at substantially 2 . 45 ghz for the embodiment described below . a microwave signal from the microwave source 12 may be conducted along a flexible coaxial cable 14 to a connector 16 on a proximal end 18 of a microwave ablation probe 20 . the probe 20 provides a substantially rigid elongate shaft 22 whose distal end 24 may be inserted percutaneously to the skin of the patient 26 so that the distal end 24 lies within a tumor 28 . it will be appreciated that the structure of the probe 20 may also be used in open surgery without percutaneous insertion . an external cooling system 30 may connect with the probe 20 and provide for a pump 32 and heat exchanger 34 communicating via a flexible hose 36 with the connector 16 providing a cooling fluid ( such as chilled water or gas ) to the probe 20 to cool the shaft 22 of the probe 20 as will be described . a second hose 38 also communicates with the connector 16 to collect exhausted ( heated ) cooling fluid from the probe 20 for return to the pump 32 to the heat exchanger 34 . referring now to fig2 , a distal end 24 of the probe 20 provides a sharpened tip 40 directed along an axis 42 of the shaft 22 permitting insertion of the shaft 22 through tissue . the sharpened tip 40 may be part of a conductive antenna shell 44 extending in a radially symmetric manner about the axis 42 of the probe 20 , the conductive antenna shell 44 having a first antenna opening 46 proximate to the sharpened tip 40 and a second antenna opening 48 axially displaced away from the first antenna opening 46 and the sharpened tip 40 . both the first antenna opening 46 and second antenna opening 48 provide circumferential slots in the conductive antenna shell 44 separating the conductive material of the conductive antenna shell 44 into resistively isolated sharpened tip 40 , spacer conductive shell 50 ( displaced distally and spaced from the sharpened tip 40 by the first antenna opening 46 ), and shaft shell 52 ( displaced distally and spaced from the spacer shell 50 by the second antenna opening 48 ). each of the sharpened tip 40 , spacer shell 50 and shaft shell 52 may , for example , be constructed of a conductive stainless steel material providing biocompatibility and electrical conductivity . microwaves emanating through the first antenna opening 46 and second antenna opening 48 interfere to provide an axially concentrated outer sar iso - contour 54 defining an ablation region that is axially compressed encompassing a region positioned at the distal end 24 . ideally , a spherical sar is desired at applicator tip , while axially narrow sar is desired in preference to an axially elongate sar for the rest of shaft shell 52 , the latter which risks body burning and which does not comport well to typical tumor dimensions . in one embodiment , an axial length of the first antenna opening 46 may be made approximately 4 mm in axial length , the spacer shell 50 approximately 8 mm in axial length , and the second antenna opening 48 approximately 1 mm in axial length . the diameter of the shaft 22 may , for example , match that of a 17 gauge steel catheter . these dimensions will vary according to the desired shape of the ablation region , the frequency of the microwaves , and other factors including the permittivity of the tissue and are intended simply as guidance and not as a limitation to the invention . generally antenna opening widths from 1 to 10 mm separated by 1 to 20 mm may be considered and evaluated experimentally or by simulation . notably , the two antenna openings may be of different axial lengths . selection and calculation of the proper dimensions for the slots may be determined with reference to the brace paper cited above and hereby incorporated by reference . referring now to fig3 and 4 , the sharpened tip 40 , spacer shell 50 and shaft shell 52 , together providing the antenna shell 44 , form an outermost electrically active component of the probe 20 . the spacer shell 50 may be supported on tubular dielectric support 60 receiving at a distal end a cylindrical boss 62 extending from the base of the conical sharpened tip 40 and fitting into the inner diameter of the dielectric support 60 to be retained axially therein . the first antenna opening 46 may be formed by an exposed portion of the dielectric support 60 extending distally beyond the spacer shell 50 . likewise the second antenna opening 48 may be formed by a portion of the dielectric support 60 extending proximally beyond the spacer shell 50 on the opposite side of the spacer shell 50 . a proximal end of the dielectric support 60 may provide a reduced diameter section 64 fitting into the inner diameter of the shaft shell 52 which may , for example , be a standard steel catheter tube having an inner diameter of 0 . 059 inches . the dielectric support 60 will generally be electrically insulating high temperature material such as a ceramic . a feeding structure 70 fits within the cylindrical volume defined by the inner wall of the dielectric support 60 . the feeding structure 70 generally is formed from a 020 - c semirigid coaxial cable having a central center conductor 72 surrounded by an insulating dielectric layer 74 ( typically polytetrafluoroethylene ( ptfe )) with an outer surrounding coaxial conductive spacer shell 75 . in a preferred embodiment , the center conductor 72 is spaced from the sharpened tip 40 ( for example by a millimeter ) providing improved field shaping and eliminating the need for a robust mechanical connection between the conductor 72 and the sharpened tip 40 that might experience high stresses produced by material expansion with heating of the sharpened tip 40 of the probe . the portion of the feeding structure 70 beneath the spacer shell 50 provides the standard coaxial construction of the center conductor 72 surrounding dielectric layer 74 and outer conductive spacer shell 75 . a feeding opening 79 providing a microwave emission region of the feeding structure 70 is located in a portion of the feeding structure 70 aligned with the second antenna opening 48 . the feeding opening 79 is provided by removing the outer conductor of the coaxial cable of the feeding structure in the region beneath the second antenna opening 48 to allow direct broadcasting of microwave energy from the center conductor 72 radially through the feeding opening 79 and out of the second antenna opening 48 and first antenna openings 46 . the remaining length of the feeding structure 70 extending proximally away from the second antenna opening 48 again assumes the standard coaxial cable topology with the center conductor 72 , dielectric layer 74 , and outer shell 81 providing the coaxial conductive shield . a blocking wall 80 extends radially from the outer shell 81 of the feeding structure on a proximal side of the second feeding opening 79 to the inner wall of the shaft shell 52 proximal to the opening 48 to define a compartment 82 proximal to the wall 80 that may be filled with a cooling fluid 84 from the cooling system 30 shown in fig1 . for this purpose , a small supply tube 86 may be threaded into the compartment 82 to discharge cooling fluid or gas near to the wall 80 which may then flow backward through the compartment 82 to the proximal end of the shaft 22 for extraction therefrom . the cooling fluid 84 may be , for example , water providing an effective conductive short at microwave frequencies between the shell 81 and the shaft shell 52 . the blocking wall 80 may , for example , be formed of an insulating material such as epoxy or a conductive material . cooling of the shaft shell 52 outside of the ablation region further focuses the ablation toward the distal end of the probe 20 reducing body burns and skin burns . as noted , the feeding structure 70 overcomes the degradation of the ablation pattern when cooling structure and ceramic materials are added to the probe 20 . referring now to fig3 , 4 and 5 , the reduced diameter section 64 of the dielectric support 60 fitting within the shaft shell 52 may provide an effective high impedance to standing waves forming on the shaft shell 52 which may otherwise create hotspots if not suppressed . generally , the axial length of the reduced diameter section 64 fitting under the shaft shell 52 may be adjusted to provide a relative phase shift between microwave energy passing directly through the shaft shell 52 from the tip and microwave energy passing through the reduced diameter section 64 from the tip , to provide for destructive cancellation at the desired microwave frequency ( for example producing a one half wavelength phase lag ). the result is a reduction of standing waves on the shaft shell 52 and thus resistive heating of the shaft shell 52 . the outer surfaces of the probe 20 may optionally be covered by a conformal coating or lubricant material . certain terminology is used herein for purposes of reference only , and thus is not intended to be limiting . for example , terms such as “ first ”, “ second ” and other such numerical terms referring to structures do not imply a sequence or order unless clearly indicated by the context . when introducing elements or features of the present disclosure and the exemplary embodiments , the articles “ a ”, “ an ”, “ the ” and “ said ” are intended to mean that there are one or more of such elements or features . the terms “ comprising ”, “ including ” and “ having ” are intended to be inclusive and mean that there may be additional elements or features other than those specifically noted . it is further to be understood that the method steps , processes , and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated , unless specifically identified as an order of performance . it is also to be understood that additional or alternative steps may be employed . it is specifically intended that the present invention not be limited to the embodiments and illustrations contained herein and the claims should be understood to include modified forms of those embodiments including portions of the embodiments and combinations of elements of different embodiments as come within the scope of the following claims . all of the publications described herein , including patents and non - patent publications are hereby incorporated herein by reference in their entireties .

US-201213441189-A

a shipping clip is configured to secure at least one shelf within a cabinet having walls and a base . the shipping clip includes a main beam having first and second side , and a biasing tab outwardly extending from the first side at an angle . the biasing tab is configured to exert a force into the shelf to compressively secure the shelf within the cabinet during shipping .

fig5 illustrates an isometric view of a shipping clip 40 according to an embodiment of the present invention . the shipping clip 40 may be formed of various materials , such as rubber , or plastic . the shipping clip 40 includes a main beam 42 having a cabinet securing post 44 extending from a wall - abutting side 46 . the cabinet securing post 44 is configured to be retained within a securing hole ( not shown in fig5 ) within a cabinet wall ( not shown in fig5 ). a handle 48 extends from a shelf side 50 ( which is opposite the wall - abutting side ), and proximate the top of the main beam 42 . that is , the handle 48 and the post 44 extend from opposite sides 50 and 46 , respectively , of an upper portion of the main beam 42 . the handle 48 may include a vertical fin 52 extending outwardly from the side 50 . the vertical fin 52 may be integrally formed with a cylindrical post 54 . the vertical fin 52 and the cylindrical post 54 may be ergonomically configured to allow easy grasping of the handle 48 . for example , the cylindrical post 54 acts as a barrier that prevents fingers from sliding off the handle 48 in the direction of arrow a . proximate a mid - section 55 of the main beam 42 , a resilient biasing tab 56 extends outwardly from the side 50 at an angle 0 . the biasing tab 56 includes extension beam 58 integrally formed with a rounded , or blunted shelf - abutting end 60 , that is distally located from the main beam 42 . as shown in fig5 , the shelf - abutting end 60 is a turned up end of the extension beam 58 . the biasing tab 56 may be spring - biased . a shelf - stabilizing ramp 62 extends from the side 50 of the main beam 42 below the biasing tab 56 . the ramp 62 includes a lower surface 64 that extends perpendicularly from the side 50 of the main beam 50 . the lower surface 64 is integrally connected to a ramped surface 66 that extends toward the midsection 55 of the main beam 42 . the lower portion of the main beam 42 terminates in a shim 68 that extends below the ramp 62 . the shim 68 is configured to be positioned between a cabinet wall ( not shown in fig5 ) and lateral portions of shelves ( not shown in fig5 ). fig6 illustrates a front cross - sectional view of the shipping clip 40 securing a plurality of shelves 70 within a cabinet 72 according to an embodiment of the present invention . the shelves 70 are positioned on top of a base 74 of the cabinet 72 . as shown in fig6 , two shelves 70 are stacked on top of the base 74 . the shipping clip 40 is secured into the cabinet wall 76 . that is , the post 44 is secured within a reciprocal opening 78 formed in the cabinet wall 76 . the shim 68 of the shipping clip 40 is positioned between the shelves 70 and the cabinet wall 76 . the shim 68 provides a barrier between the shelves 70 and the cabinet wall 76 that prevents lateral shifting of the shelves 70 within the cabinet 72 . thus , the shelves 70 and cabinet walls 76 are protected against scratching or other damage that may be caused by the shelves 70 banging into the cabinet walls 76 during shipping . the lower surface 64 of the ramp 62 is positioned over a top edge of the top shelf 70 , while the shim 68 may overlay a lateral surface of the top shelf 70 . the ramp 62 and the shim 68 may cooperate to secure the shelves 70 from vertical and lateral shifting . the shelf - abutting end 60 of the biasing clip 56 exerts a force into the top surface of the top shelf 70 . the force exerted by the biasing clip 56 into the top shelf compresses the shelves 70 into the base 74 of the cabinet , thereby restricting movement of the shelves 70 . as shown in fig6 , the shipping clip 40 , or a plurality of shipping clips 40 , may be used to secure a plurality of shelves 70 within the cabinet 72 during shipping . for example , two or four shipping clips 40 may be used to secure a plurality of shelves 70 within the cabinet 72 . while two shelves 70 are shown in fig6 , the shipping clip 40 may be configured to secure more or less shelves 70 than those shown . also , shelf pins do not have to be used in order to secure the shelves 70 . optionally , shelf pins may be used to secure the shelves away from the base 74 . fig7 illustrates a front perspective view of the shipping clips 40 securing a plurality of shelves 70 within the cabinet 72 according to an embodiment of the present invention . as shown in fig7 , the shelves 70 are supported by a plurality of shelf pins 80 . the shelves 70 are securely retained between the shelf pins 80 and the shipping clips 40 . while four shelves 70 are shown secured between the shelf pins 80 and the shipping clips 40 , the shipping clips 40 may be configured to secure more or less shelves 70 than those shown within the cabinet 72 during shipping . thus , embodiments of the present invention provide a shipping clip capable of securing a plurality of shelves during shipping . as shown in fig6 , a plurality of shipping clips may be used to secure a plurality of shelves against a base of a cabinet . for example ; four horizontally aligned shipping clips may be used to secure a plurality of shelves within the cabinet . further , as shown in fig7 , a plurality shelves may be secured between a plurality of shipping clips and a plurality of shelf pins . for example , four horizontally - aligned shipping clips and four coplanar shelf pins may be used to secure a plurality of shelves therebetween . additionally , embodiments of the present invention provide a shipping clip that prevents shelves from banging into the cabinet walls during shipping . the shims and ramps of the shipping clips act as barriers that minimize the shelves from shifting during shipping . while various spatial terms , such as upper , lower , mid , lateral , horizontal , vertical , and the like are used to describe portions of the shipping clip with respect to a cabinet , it is understood that such terms are merely used with respect to the orientations shown in the drawings . the orientations may be inverted , rotated , or otherwise changed , such that an upper portion is a lower portion , and vice versa , horizontal becomes vertical , and the like . variations and modifications of the foregoing are within the scope of the present invention . it is understood that the invention disclosed and defined herein extends to all alternative combinations of two or more of the individual features mentioned or evident from the text and / or drawings . all of these different combinations constitute various alternative aspects of the present invention . the embodiments described herein explain the best modes known for practicing the invention and will enable others skilled in the art to utilize the invention . the claims are to be construed to include alternative embodiments to the extent permitted by the prior art . various features of the invention are set forth in the following claims .

US-43147806-A

a cabinet includes a mounting bracket which permits the attachment of the cabinet in room corners which are out of square . the bracket is adjustably slidable with respect to the cabinet so as to facilitate an attachment of the cabinet to the nonperpendicularly - aligned walls . the cabinet is trapezoidally - shaped to permit its positioning in a corner .

with reference now to the drawings , and in particular to fig1 thereof , a new and improved corner cabinet embodying the principles and concepts of the present invention and generally designated by reference numeral 10 will be described . more specifically , it will be noted that the corner cabinet 10 essentially comprises a trapezoidally - shaped housing 12 with a rear wall section of the housing 14 being truncated to define the top of the trapezoid . this truncated rear wall portion 14 facilitates a positioning of the cabinet housing 12 into an out - of - square corner . various accessories may be attached to the housing 12 to complement a use of the cabinet 10 , which such accessories including a topmost mounted light assembly 16 and a bottommost positioned towel rack 18 . the cabinet 10 may include interior shelves which are protectively covered by sliding mirror doors 20 , 22 . additionally , a plurality of through - extending apertures 24 may be provided in sidewall portions of the cabinet housing 12 , and these apertures may be utilized to receive threaded fasteners , nails , or the like , which can be directd into the walls of a corner to thus provide an additional means of mounting the cabinet 10 . referencing fig2 in conjunction with fig1 it will be noted that a novel feature of the invention 10 includes a corner mounting bracket 26 which facilitates the attachment of the cabinet 10 between non - perpendicularly aligned walls defining a corner . the bracket 26 is of a trapezoidal shape and includes a floor section 28 having upstanding flanges 30 , 32 , 34 directed around three sides thereof . the flanges 30 , 32 , 34 would normally be integrally attached to the floor section 28 . the flange portions 30 , 32 are provided with respective through - extending apertures 36 , 38 through which threaded fasteners , or the like , can be directed for attachment to the respective walls of a corner . the flange 34 is provided with an elongated slot 40 through which an additional threaded fastener , or the like , can be adjustably positioned for direct attachment to the corner if additional support of the cabinet 10 is required . the floor portion 28 of the bracket 26 includes a pair of substantially parallelably aligned , elongated slots 42 , 44 . these slots 42 , 44 , as best illustrated in fig1 are adjustably alignable with a pair of respective apertures 46 , 48 formed in the top of the housing 12 . threaded fasteners can then be directed between the openings 42 , 46 and 44 , 48 to effect a secure mounting of the bracket 26 to the housing 12 . fig3 of the drawings has been provided to illustrate the attachment of the light 16 to a topmost portion of the housing 12 . as shown , the light 16 would most likely be of an elongated design and would include a topmost positioned vent 50 to facilitate the removal of heat from the light . the light 16 could further include a manually operable on and off switch 52 and an electric plug receptacle 54 which would permit the attachment of other electrically powered appliances thereto . to complete the construction of the light 16 , a cylindrically - shaped transparent or translucent lens 56 can be provided to cover the unillustrated light bulb contained therein . fig4 and 5 of the drawings illustrate the interior construction of the corner cabinet 10 , wherein it can be seen that the respective sidewalls of the cabinet may include punched , or otherwise separably attached , upstanding tabs 58 . pairs of the tabs 58 may be positioned at varying heights along a sidewall portion of the housing 12 , with l - shaped shelf support members 60 being supportably retained between a selected pair of the tabs . with the support members 60 being positioned on opposed sidewall portions of the housing 12 , it can be appreciated that a trapezoidally - shaped shelf , which could be formed of glass , plastic or the like , may then be slid into the cabinet to be retained therein by a pair of the members 60 . with respect to the manner of usage of the corner cabinet 10 , the same should be apparent from the above description . however , a brief summary thereof will be provided . more particularly , it can be appreciated that the cabinet 10 can be positioned within a corner having out - of - square walls , and the bracket 26 may then be moved forwardly or rearwardly with respect to the cabinet housing 12 to effect a desired fit within the corner . once the bracket 26 has been moved to a desired location within the corner , it may be secured to the corner walls by the use of threaded fasteners , or the like , positioned through the apertures 36 , 38 . with the brackets 26 being adjustably held to a topmost surface of the housing 12 by threaded fasteners extending between the openings 42 , 46 and 44 , 48 , a secure attachment of the cabinet 10 to the bracket 26 can be achieved by tightening the fasteners extending though these openings . of course , the cabinet housing 12 is first slidably moved relative to the bracket 26 to achieve the best possible fit of the cabinet 10 within the out - of - square corner . with respect to the above description then , it is to be realized that the optimum dimensional relationships for the parts of the invention , to include variations in size , materials , shape , form , function and manner of operation , assembly and use , are deemed readily apparent and obvious to one skilled in the art , and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by the present invention . therefore , the foregoing is considered as illustrative only of the principles of the invention . further , since numerous modifications and changes will readily occur to those skilled in the art , it is not desired to limit the invention to the exact construction and operation shown and described , and accordingly , all suitable modifications and equivalents may be resorted to , falling within the scope of the invention .

US-88885386-A

a prosthesis for addressing pelvic organ prolapse in females comprises a frame fabricated from a shape memory material that supports a thin , flexible sheet in a stretched condition when the frame is unconstrained . the frame is shaped so as to conform to and be supported by bone structures and muscle tissue in the pelvic basin while providing needed support to pelvic organs to maintain them in a proper position . the use of a shape memory material allows the prosthesis to be rolled or folded into a reduced size for ease of placement through a small incision in the wall of the vagina , but that springs back to its memorized shape following deployment from a delivery sheath .

this description of the preferred embodiments is intended to be read in connection with the accompanying drawings , which are to be considered part of the entire written description of this invention . in the description , relative terms such as “ lower ”, “ upper ”, “ horizontal ”, “ vertical ”, “ above ”, “ below ”, “ up ”, “ down ”, “ top ” and “ bottom ” as well as derivatives thereof ( e . g ., “ horizontally ”, “ downwardly ”, “ upwardly ”, etc .) should be construed to refer to the orientation as then described or as shown in the drawings under discussion . these relative terms are for convenience of description and do not require that the apparatus be constructed or operated in a particular orientation . terms such as “ connected ”, “ connecting ”, “ attached ”, “ attaching ”, “ join ” and “ joining ” are used interchangeably and refer to one structure or surface being secured to another structure or surface or integrally fabricated in one piece , unless expressively described otherwise . referring first to fig1 , it shows a plan view of the pelvic floor repair patch 10 constructed in accordance with a first embodiment of the present invention . it is seen to comprise a sheet of mesh fabric 12 having a predetermined shape configuration . without limitation , the sheet of mesh fabric may be formed from polypropylene or ptfe , both of which have been used in the past in constructing implantable medical prostheses . while such mesh fabrics are preferred , it is also contemplated that the sheet 12 may comprise a xenograft , such as appropriately treated porcine dermis tissue . the sheet material 12 is provided with a support frame 14 for maintaining the sheet 12 in its predetermined shape configuration following placement of the patch 10 proximate the pelvic floor of a female patient . as seen in fig1 , the support frame 14 used in this embodiment is affixed to the sheet 12 , such as by closely spaced stitches 16 . the support frame 14 comprises first and second wing portions 18 and 20 that are preferably bilaterally symmetrical about an imaginary central axis 21 of the device . each of the wing portions 18 and 20 includes rounded wing tip portions 22 and 24 at first ends thereof and these wing tip portions on the first and second wing portions 18 and 20 are integrally joined to one another by a concave , arcuate segment 26 . in the embodiment of fig1 , the ends of the wing portions 18 and 20 opposite the wing tip portions 22 and 24 are generally rounded as at 28 and 30 . convex arcuate segments 29 and 31 join the wing tips 22 and 24 to their respective opposite ends 28 and 30 . the support frame 14 may comprise one or more strands of a shape memory material , multiple strands will be wound together as a cable . without limitation , the strands may be made from a shape memory metal , such as nitinol , or alternatively , from a suitable biodegradable polymer having elastic properties . the particular polymer to be used as a biomaterial in forming the frame is one that will match the mechanical properties and the time of degradation to the needs of the application . the ideal polymer for this application will not evoke an inflammatory / toxic response , is able to be metabolized in the body after fulfilling its purpose and one that leaves no significant trace , is sterilizable and can readily be processed into the desired configuration . polydioxanone is a bio - degradable polymer having a glass transition temperature in a range of from − 10 ° c . and 0 ° c . and a crystallinity of about 55 %. the presence of an ether oxygen group into the backbone of the polymer chain gives the material a good flexibility . it also exhibits a shape memory property . a monofilament of polydioxanone loses about 50 % of its initial breaking strength after three weeks and is absorbed within six months . this provides ample time for tissue ingrowth into the mesh to take place . as further seen in fig1 the sheet 12 generally follows the contour of the frame member , but with the border of the sheet material 12 extending laterally beyond the support frame . to prevent unraveling of the multiple strands comprising the cable frame 14 , it has been found expedient to apply a tubular ferrule 32 to the free ends of the strands to form a closed loop . where the frame comprises multiple strands of nitinol wire twisted together as a cable , the ferrule 32 may be laser beam welded in place surrounding the opposed ends of the strands . where the frame comprises a polymer , the free ends may be fused together by melting and then allowed to solidify . in either case , fraying of the multiple strands is prevented . with the frame 14 being fabricated from an elastic material , it is possible to roll up the device from the configuration shown in fig1 , which is generally planar , to a tubular configuration as shown in fig2 . as such , the device may then be inserted through an incision 2 - 3 cm in length in the wall of the vagina into the pelvic cavity where it is allowed to unfurl by elastic recoil and thus reassume the shape configuration shown in fig1 . the surgeon may then use his or her fingers to position the device in the appropriate pelvic plane described previously to best address the type and degree of organ prolapse that the surgery is intended to correct . because of the inherent property of the frame , it reduces bunching or crinkling of the mesh due to uneven suturing of prior art patch materials used in pelvic floor repair . such bunching or crinkling commonly results in dyspareunia during coitus . if it is desired to remove a metal frame 14 following placement of the sheet 12 and before closing the incision in the vaginal wall , the sheet may be formed so as to include a plurality of spaced - apart “ belt - loop ” like appendages thereon through which the frame 14 is strung . after being appropriately spaced , bio - degradable anchoring tacks can be used to hold the sheet 12 in place , the frame 14 can be stripped out from the belt loop appendages and removed from the patient . of course , if the frame 14 comprises a biodegradable polymer , there is no need to remove it because it will be absorbed by the body following tissue ingrowth through the sheet material during the period of three months or so post - surgery . referring next to fig3 , there is shown a superior view of the female pelvic diaphragm showing placement of the device of the present invention in treating pelvic floor herniation . when appropriately placed , the rounded wing tip portions 22 and 24 on the prosthesis frame 14 are arranged to rest against the pelvic wall in the region of the sacrospinous ligament 34 that extends between the sacral spine 36 and the sacrum 38 . the opposite end portions 28 and 30 yieldingly engage the region of the lower symphysis and adjacent inferior pubic rami 40 . when the device is so positioned , the convex arcuate portions of the frame 29 and 31 will be supported by the pelvic sidewalls in the region of the arcus tendineous fasciae pelvis 42 . this placement results in the anterior end portion of the concave arc segment 26 looping around the vagina at the level of the cervix , c . the concave segment connecting ends 28 and 30 provides clearance for the urethra , u . fig4 is an alternative embodiment of the device for addressing repair of level i and level ii support . it comprises a frame member 100 supporting a biocompatible sheet , such as a polypropylene mesh or a treated porcine dermis material 102 . as in the embodiment of fig1 , the frame is again bilaterally symmetrical about an imaginary central axis 104 . it is comprised of a plurality of generally circular arcs that are integrally joined to form a pair of wing - shaped members 106 and 108 on opposite sides of the axis 104 . the arcs define wingtip portions 110 and 112 that when placed in a female patient are arranged to abut the region of the sacrospinous ligaments . these wingtip portions are joined to one another by a concave , arcuate segment that is sized and shaped so as not to interfere with the rectum , r , and providing support to the vagina at the level of the cervix , c . the concave , arcuate portion 116 allows engagement of the implant with the lower symphysis pubis inferior pelvic rami . the convex arcuate segments 118 and 120 are designed such that they resiliently engage the pelvic sidewalls in a plane located slightly above the iscial spine , which is proximate the pelvic plane of the greatest dimensions . in the embodiment of fig4 , the frame 100 is preferably molded from a biocompatible , biodegradable polymer exhibiting shape memory properties . polyurethanes formed from a high molecular weight poly ( e - caprolactone ) and a high weight fraction of hard - segment - determining blocks exhibit a high shape - memory property . block copolymers made with polyethylene terephthalate and polyethyele oxide is also a potential candidate as are copolymers of polyglycolide ( pga ) and polylactide ( pla ). another potential candidate for the frame material is a polymer called polynorbornene . readers desiring additional information on shape memory polymers exhibiting biodegradable properties are referred to an article entitled “ shape - memory polymers ” authored by andreas lendlein and steffen kelch , angew . chem . int . ed . 2002 , 41 , pages 2034 - 2057 , the contents of which are hereby incorporated by reference . turning next to fig5 , there is shown a further embodiment in which the sheet 102 has fibers interwoven in the mesh so as to stimulate tissue ingrowth when the prosthesis is to be used for repairing level i as well as level ii vaginal support . in the area of the wingtips 110 and 112 , the mesh sheet 102 is interwoven with fibers of polyethylene terephthalate ( pet ) as identified by numeral 126 , a material known to induce fibrosis , whereby the mesh sheet 102 becomes secured prior to the loss of resiliency in the frame due to biodegradation with time . as a further option , to reduce the possibility of patient discomfort due to pressure of the resilient frame with pelvic tissue prior to its being absorbed , the frame may be formed in a molding operation to exhibit a cross section such as depicted in fig6 hereof . the polymer frame member 100 is integrally molded to exhibit a cushioning layer 122 formed of a soft , deformable foam material . the cushioning layer 122 need only span the arcuate portions 118 and 120 of the frame member 100 . the cushioning layer 122 is sufficiently resilient that it can deform to spread the contact force over a greater area , thereby reducing the contact pressure between the frame structure and the tissue that it abuts . the embodiment of fig5 and the cross - section of fig6 also show that the cushioning layer 122 may have raised tread - like projections as at 128 extending radially from the surface thereof which aid in fixing the frame in fibromuscular tissue of the pelvic side walls . these projections may be integrally molded with the cushion layer 122 . fig7 is an anterior view of the skeletal female pelvis on which the prosthesis of the present invention has been added to generally illustrate the placement of the prosthesis when addressing forms of pelvic organ prolapse . the anterior portion of the frame 100 is made to engage the inferior pubic symphysis as best seen in fig8 while the wingtip portions 110 and 112 thereof abut the sacrospinous ligament proximate the joint between the third and fourth sacral segments . as the name suggests , the sacrospinous ligament is a thin , triangular ligament attached by its apex to the ischial spine , and medially , by its broad base , to the lateral margins of the sacrum and coccyx . when the prosthesis is so positioned , the convex arcuate segments 118 and 120 of the prosthesis are somewhat elevated relative to the ischial spine and engage the region of the arcus tendineous fascia pelvis . fig9 is a schematic illustration of the condition known as cystocele in which the posterior wall of the bladder prolapses into the vaginal space due to a defect in the anterior vaginal wall fascia . in fig9 , the pubic symphysis is identified by numeral 200 and the ischial spine by numeral 202 . the urethra 204 leads to the urinary bladder 206 exhibiting a cystocele 208 or protrusion into the vaginal canal 210 leading to the uterus 212 . the rectum is identified by numeral 214 . the bladder and urethra are separated from the vagina by the pubocervical fascia . intact fascia prevents the bladder from bulging down into the vagina . females with cystocele have a defect or weakness in this fascia . fig1 is a view like that of fig9 but with the prosthesis of the present invention deployed as previously described so as to provide lateral support to the bladder 206 and repairing the cystocele . in this view , the cross - section of the frame 100 is displayed with its anterior portion engaged with the pubic symphysis or inferior rami and its posterior wingtip portions abutting the region of the sacrospinous ligaments identified in fig1 by numeral 216 . a method for the surgical repair of anterior vaginal wall prolapse , or cystocele , is described with reference to fig7 through 10 . the surgical procedure involved will , in its general description , be well recognized by workers in the field . a concomitant procedure for stress urinary incontinence ( sui ), both occult and overt , may be carried out under the same anesthetic . after standard preoperative preparation of the patient has been completed in an optimal manner , she will receive appropriate anesthesia and be placed in the so called modified lithotomy position . she will then be prepped and draped in the standard manner . this will include insertion of an indwelling bladder catheter using standard aseptic technique to allow identification of the urethra and also application of anti - thomboembolic pneumatic sequential compression stockings to the lower limbs . a weighted vaginal retractor or other suitable form of retractor such as the “ lone star ” 198 is used . two pairs of allis forceps , or similar , are then applied , in the sagittal plane about 5 cms apart , to the cystocele . the inferior pair of such forceps is placed proximate to the bladder neck . the intervening vaginal wall of the cystocele is placed on traction between the clamps and infiltrated , using a 22 gauge needle , with an adequate volume of saline containing suitable local anesthetic and vasoconstrictor agents this will facilitate optimal hydrodissection and hemostasis . while maintaining opposing traction on the allis forceps , a small incision with a maximum length of approximately 3 cms is made in the vaginal wall commencing in the region of the bladder neck and proceeding in the midline in a cephalad direction toward the vaginal apex . the use of hydrodissection allows the incision to be deep enough to reach the bladder fascia ( pubocervical fascia ) in a safe manner and thus minimize failure of wound healing with subsequent mesh extrusion . initial sharp then blunt dissection technique with the fingertip — well known to workers in the field , is then used to separate the bladder from the anterior vaginal wall and reach and identify in turn , the ischial spine and sacrospinous ligaments on both sides of the pelvis . the invention is then passed in a closed and circularly folded configuration completely through the vaginal incision in the midline toward the sacrum , between the vagina and the bladder . the device is then allowed to unfold by inherent elastic recoil and digitally positioned into the desired anatomical location previously described . on each side of the pelvis , the posterior frame of the invention will be positioned just above and proximate to the ischial spine and be gently fixed by short projections , incorporated into the polymer frame as previously described into the fibromuscular tissues of the coccygeus muscle . alternative embodiments and methods of fixation of the posterior component of the frame of the invention into the region of the coccyges muscle include for example biodegradable barbs suitable for fingertip compression . with regard fixation of the anterior component of the frame on each side of the pelvis into the fibromuscular tissues of the obturator internus muscle , similar short projections incorporated into the frame or biodegradable barbs with fingertip compression may again be utilized . the short vaginal incision may then be closed using methods familiar to gynecological surgeons . this may include a continuous non - locking suture of 2o or 3o delayed absorbable suture . using the embodiments of the present invention , the pelvic repair procedures can be carried out with a minimum of suturing . the frame structure tends to hold the mesh fabric or sheet of graft material in its deployed state and only a few bio - degradable anchor pins of the type currently being used in other surgical hernia repair procedures to secure hernia repair patches in place , will be used to secure the fabric in place should it be desired to remove the frame structure 14 prior to closing the surgically created opening in the vaginal wall . this invention has been described herein in considerable detail in order to comply with the patent statutes and to provide those skilled in the art with the information needed to apply the novel principles and to construct and use such specialized components as are required . however , it is to be understood that the invention can be carried out by specifically different equipment and devices , and that various modifications , both as to the equipment and operating procedures , can be accomplished without departing from the scope of the invention itself .

US-42111609-A

the invention provides methods and compositions for molecular resonance imaging of membrane potential . the compositions comprise an indicator moiety attached through an optional linker to a macrocycle component that binds a lanthanide . the indicator moiety changes conformation in response to alterations in membrane potential and alters the interaction of the bound lanthanide with water . this alteration produces a detectable change in mri signal , notably the t 1 value . a preferred indicator moiety is spiropyran as it exhibits membrane - potential driven interconversions between the closed - ring spiropyran conformer and the extended merocyanine conformer . a preferred macrocycle is do3a , known to bind gadolinium and an established mri contrast agent . the methods of the invention comprise in vivo and in vitro uses of compositions of the invention to obtain mri images that provide information about membrane potential .

briefly , and as described in more detail below , described herein are compositions useful as mri probes of membrane potential . the compositions comprise an indicator moiety that changes conformation in response to an electric field , linked to a macrocycle component capable of binding to a paramagnetic species commonly used in mri contrast agents . several features of the current approach should be noted . first , the compositions of the present invention act as mri probes of membrane potential because changes in the conformation of the indicator moiety affect the access of water protons to the paramagnetic species bound by the macrocycle component . second , the compositions of the invention are useful as mri probes of membrane potential when used to image cultured cells such as , e . g ., cultured neurons , myoblasts , myofibrils , or to image isolated organs or sections thereof such as , e . g ., brain , ganglia , spinal cord , retina , heart and other muscles . advantages of this approach are numerous . the invention provides for the use of mri to carry out non - invasive monitoring of membrane potential . thus , the invention provides all of the advantages of contrast - enhanced mri including , e . g ., enhanced safety as compared to use of ionizing radiation for imaging , high spatial resolution , while providing information about the membrane potential of the imaged tissues . the invention is useful for , e . g ., diagnosing and assessing the functional state of tissues , especially those that are electrically excitable , and for screening the effects of drugs on tissues that can be functionally evaluated on the basis of membrane potential . it permits early diagnosis , prior to the appearance of functional impairment of retinal disease such as age - related macular degeneration , allowing earlier treatment and prevention of blindness . in addition , the invention can be used to simultaneously image myocardial electrical activity and contractility , providing advantages to the study of cardiac normal and pathophysiology beyond what can be determined from monitoring electrical activity alone as by , e . g ., ekg recordings . terms used in the claims and specification are defined as set forth below unless otherwise specified . the term “ ameliorating ” refers to any therapeutically beneficial result in the treatment of a disease state , e . g ., a neurological or electrophysiological disease state , including prophylaxis , lessening in the severity or progression , remission , or cure thereof . the term “ in situ ” refers to processes that occur in a living cell growing separate from a living organism , e . g ., growing in tissue culture . the term “ in vivo ” refers to processes that occur in a living organism . the term “ mammal ” as used herein includes both humans and non - humans and include but is not limited to humans , non - human primates , canines , felines , murines , bovines , equines , and porcines . the term “ sufficient amount ” means an amount sufficient to produce a desired effect , e . g ., an amount sufficient to assess membrane potential using mri . an indicator moiety is a molecule that undergoes a conformational change in response to membrane potential changes . as a result of that conformational change , the indicator moiety effects an alteration of the interaction of an associated macrocycle - chelated lanthanide and water . it must be noted that , as used in the specification and the appended claims , the singular forms “ a ,” “ an ” and “ the ” include plural referents unless the context clearly dictates otherwise . “ la ” is used throughout the specification and claims to indicate a lanthanide . recited ranges are inclusive of the limits unless otherwise indicated . recited amounts , temperatures , etc . have been disclosed with care , but are intended to encompass variations on the order of ± 20 % to allow for normal experimental error and deviation , except where otherwise indicated . since its inception in the early 1970 &# 39 ; s magnetic resonance imaging ( mri ) has come to occupy a prominent place in medical diagnostics . mri excels as a noninvasive method to three - dimensionally image deep tissues in living subjects but gives little information about biochemical processes . gradual improvements in the design of image acquisition protocols and hardware have lead to the ability to probe structures in vivo at cellular resolution ( 10 μm ). recent advances in contrast agent development hold the promise that mr contrast agents can be designed to be indicators of biological processes . much as fluorescent probes opened a window to biochemistry for optical imaging techniques , one envisions that mr contrast agents will fulfill the same role for mri . depolarization of membranes is an integral component of many signal transduction cascades . abnormal changes at this level of signaling can be symptomatic of pathological conditions . in epilepsy , for example , there are changes in the pattern of nerve activity in the brain preceding and following seizures . in cardiovascular systems irregular electrical activity can indicate underlying disease states . in the visual system , lack of activity in the retina indicates dysfunction in the detection of light . the ability to generate mr images of membrane potential therefore is of use in many fields . certain atomic nuclei possess a non - zero spin , which gives rise to a net magnetic moment . the nuclear magnetic moments of water protons ( hydrogen atoms ) supply the signal in most mr imaging experiments . the sample to be imaged is placed in a strong static magnetic field that induces the sample to become slightly magnetized with a net magnetic moment in the direction of the applied field , with an energy ( angular momentum ) proportional to the applied field . to encode spatial information , other fields are applied as gradients along one or more orthogonal axes . each position in space is uniquely encoded by the energy or phase of the spins there . a radio frequency field is pulsed through the sample and the energy absorbed results in a reorientation of the net nuclear magnetization in a new direction ( typically a pulse is applied to tilt the magnetization 90 degrees ). after this perturbation , net energy loss by a variety of processes returns the net magnetization to its initial equilibrium orientation . the formation of an image from this process has a complicated dependence on a large number of factors . in a typical experiment , one modifies the imaging parameters to reduce the contributions from many of these factors . in the most typical mri experiments , signal intensity is primarily derived from proton concentration and relaxation times . relaxation times characterize the return of net magnetization to equilibrium . it is the difference in signal intensities between spatial regions that provides contrast . proton concentration can vary by a large percentage between soft tissue and bone , providing sharp contrast . differences in proton density between soft tissues is more subtle , however , and contrast more likely is derived from tissue - dependent differences in relaxation times , which depend strongly on local environment . the need to differentiate tissues or organs that are magnetically similar but histologically distinct has been a major impetus for the development of contrast enhancement agents . they are called contrast agents because signal is increased in their presence , thus improving contrast between that tissue and surrounding tissues . more than 30 % of all clinical mr exams now employ contrast agents . however , current clinical mri agents are not sensitive to biochemical events in cells or organs — rather , being always active they enhance the signal wherever they are present . distinguishing tissues relies on differential distribution of contrast agents between tissues , which does not always occur . contrast agents that are responsive to microenvironmental differences between tissues would allow discrimination based on biochemical events , extending the potential applications for mri beyond simple anatomy . paramagnetic elements , such as lanthanides , make effective contrast agents . unpaired electrons in the paramagnetic ions interact directly with surrounding water protons to dramatically reduce their relaxation times . this change in the relaxation times translates to enhanced signal . the effects of contrast agents are generally reported in terms of relaxation rates or relaxivity of the water protons , which are inversely related to the relaxation times and reflect the overall contributions of all relaxation mechanisms at work in the system . water access to the paramagnetic ions is important for the effect ( first sphere coordination ). the principles and practice of mri image formation with and without contrast enhancement are well known to those of skill in the art and are discussed in greater detail in aime , et al ., jmri 16 : 394 – 406 ( 2002 ); caravan , et al ., chem rev 99 : 2293 – 2352 ( 1999 ), and gadian , nmr and its applications to living systems , 2 nd edition , oxford science publications ( 1995 ), the entire disclosures of which are incorporated by reference in their entirety for all purposes . in very large cells , such as squid giant axons , one can insert an electrode into the cell and measure the potential across the membrane directly . for systems in which even microelectrodes would be too large , however , other means must be employed . optical techniques to measure membrane potential were first suggested in 1968 based on the discovery that changes in membrane potential may be accompanied by innate optical changes ( for some systems ). wu , j . y . & amp ; cohen , l . b . ( 1993 ) in fluorescent and luminescent probes for biological activity ( academic press , san diego ), pp . 389 – 403 . around the same time , it was found that stimulus - dependent changes were observed in the fluorescence of stained axons . this prompted a hunt for other dyes that show varying signal in response to membrane potential . today , exogenous dyes for measurement of membrane potential are a large and well - studied group of indicators . these are divided into two major classes : fast ( ms ) and slow ( s ), according to the speed of their response to electrical activity . waggoner , a . ( 1976 ) j membrane biol . 27 , 317 – 334 . dyes have been found that experience optical changes of three types : absorbance , birefringence and fluorescence . among the fast dyes , spiropyran is particularly interesting because it experiences a significant structural rearrangement in response to changes in membrane potential , resulting in a redistribution of charge . the dye molecule is believed to respond to membrane potentials by temporarily associating with the resting membrane in its neutral spiropyran form ( fig1 , upper left ), and releasing from the membrane when isomerized , in response to membrane hyperpolarization , to its charged merocyanine counterpart ( fig1 , upper right ). the merocyanine form of the molecule has absorbance in the visible range of light while the spiropyran form does not . change in membrane potential results in a measurable absorbance of light by the dye . this electrochromic behavior is associated with a redox process for the nitro group ( no 2 ). zhi , j ., baba , r ., hashimoto , k . & amp ; fujishima , a . ( 1995 ) j . photochem . photobio . a . chem 92 , 91 – 97 . interestingly , this transformation can also be triggered by illumination with light . fig1 illustrates the structural changes occurring during this redox reaction and how they can be produced by response to light or to electrical activity . the merocyanine form also thermally relaxes to the closed - ring spiropyran isomer at a temperature - dependent rate . we use spiropyran / merocyanine groups to modulate the interaction of contrast agents with membranes , and control the relaxivity properties of the contrast agents . we show that spiropyran groups , in their merocyanine form , can be engineered to shield the paramagnetic metal center of a contrast agent from water protons and that this shielding alters the contrast enhancement properties of the contrast agent in a reversible manner . in one embodiment of the compounds of the invention , couple a spiropyran moiety via a linker to a macrocycle - based lanthanide chelator . the generic molecule is shown in fig2 with gd as an exemplary lanthanide . in preferred embodiments , the linker length , n , is between 0 and 4 and preferably r 1 = c n h 2n + 2 , c n h 2n or a combination of both . as one of ordinary skill will recognize , synthesizing the alternate preferred embodiments may be accomplished by straightforward reactant substitutions in the reaction scheme shown in fig4 . for example , altering the length and character of the r 1 substituent can be done by substituting choromethyl methyl ether ( n = 1 ) at step one of the synthesis with chloroethyl methyl ether ( n = 2 ), or chloromethylene derivatives ( to generate unsaturated versions of the linker ), etc . r 2 – r 7 are independently selected from h , ch 3 , phenyl , or bulky steric - hindering groups , such as , e . g ., substituted benzyl moieties ( e . g ., nitrosobenzyl ), pyrimidine , or other planar ring type groups . reagent substitutions for altering r 2 – r 7 include , e . g ., substitution of bromoacetic acid ( r = h ) at step four of the synthesis with 2 - bromo - 2 - methylpropionic acid ( r = ch 3 ); 2 - bromo - 3 - methylbutyric acid ( r = ch 2 ( ch 3 ) 2 ); 2 - bromohexanoic acid ( r =( ch 2 ) 3 ch 3 ); 2 - bromophenylacetic acid ( r = phenyl ); 2 - bromo ( myristic , proprionoic , octanoic , tetradecanoic etc ) acid ( r = long chain alkyl ), etc . a is independently selected from coo 31 , po 3 2 − , or other lanthanide — coordinating group . reagent substitutions for altering a include , e . g ., substitution of cyclen at step four of the synthesis with cyclen containing phosphonomethyl groups in the amino functions in three positions ( phosphonomethyl groups introduced by condensation of cyclen with formaldehyde and phosphorous acid or by treatment of formyl cyclen with triethyl phosphite and paraformaldehyde ). similarly , substitutions may be made by one of ordinary skill in the art for the indicator moiety . for the exemplified spirobenzopyran , alternates such as spirobenzothiopyran and other substitutions may be made without departing from the scope of the invention . for the molecule described in the examples , below , a = coo 31 , r 1 = c n h 2n + 2 , n = 2 , and r 2 – r 7 are each h . we show that the merocyanine form of the spiropyran moiety prevents the chelated lanthanide ion from interacting with water . this is consistent with a number of observations from the literature . the merocyanine form is known to bind metals , the spiropyran form does not . chibisov , a . & amp ; görner , h . ( 1998 ) chemical physics 237 , 425 – 442 ; görner , h . & amp ; chibisov , a . k . ( 1998 ) j . chem . soc . faraday . trans . 94 , 2557 – 2564 ; wojtyk , j . t . c ., kazmaier , p . m . & amp ; buncel , e . ( 1998 ) chem . commun ., 1703 – 1704 . metal complexation is favored by 6 - nitro , 8 - methoxy - substituted spiropyran derivatives and this complexation stabilizes the merocyanine from thermal decay back to the spiropyran form . the lifetime for uncomplexed merocyanine is on the order of 12 – 60 seconds ( 25 s for the merocyanine shown in fig1 ). görner , h . & amp ; chibisov , a . k . ( 1998 ). in the presence of metal this lifetime increases significantly . the increase in merocyanine lifetime is strongly dependent on the type and concentration of metal . for example , in the presence of 0 . 15 mm pb ( ii ) the lifetime for merocyanine is 300 sec . in 1 mm pb ( ii ) the lifetime increases to 600 sec . binding of lanthanides such as europium and terbium at 0 . 15 mm results in lifetimes on the order of 300 seconds . the merocyanine form is still readily converted back to spiropyran by visible light irradiation . reports in the literature on crown ether conjugates with spiropyran indicate that the presence of a monoazacrown moiety enhances merocyanine &# 39 ; s interaction with metals . the merocyanine group interacts with metals bound by crown ethers while the spiropyran form does not . kimura , k ., yamashita , t . & amp ; yokoyama , m . ( 1992 ) chem . soc . perkin trans 2 , 613 – 619 . multinuclear nmr spectrometry indicates that the metal ion in the crown ether moiety interacts strongly with the phenolate anion of merocyanine . kimura , k ., sakamoto , h ., kado , s ., arakawa , r . & amp ; yokoyama , m . ( 2000 ) analyst 125 , 1091 – 1095 . the interaction of a spiropyran crown ether derivative with metals is illustrated in fig3 . the derivatized crown ethers show a higher affinity for multivalent metal ions than to monovalent metal ions . in spite of this metal binding , visible light irradiation triggers immediate isomerization back to the spiropyran form . syntheses of several monoazacrown conjugates are described by kimura et . al . ( 2000 ) and provide the basis for the synthesis we describe below . we modified this synthesis by substituting a macrocycle known to bind gd , e . g . do3a ( macrocycle component shown below linker moiety in the fig2 ), for the crown ether . the macrocycle component chelates the lanthanide gadolinium and the resulting metal complex acts as a contrast agent . although crown ethers behave differently from cyclens ( the four nitrogen macrocycle component of fig2 ), we have shown that this synthesis can be accomplished reasonably . the synthesis is given in fig4 , and is described in detail in example 1 , below . the ability of this agent to create contrast in an mri image depends on the interaction of water with the lanthanide such as europium , terbium or gadolinium . interaction of the phenolate anion of the merocyanine group with a lanthanide such as gadolinium occupies a coordination site on the gadolinium and thus , limits interaction with water ( fig5 ). this interaction occurs between a do3a - chelated lanthanide such as gd and the phenolate anion in the compounds of the invention . in this configuration the contrast agent does not enhance the mr image . when membrane potential changes to reverse the merocyanine form back to the spiropyran form , coordination to the lanthanide is lost so water is again free to occupy that site , activating the contrast agent . without wishing to be bound by theory , while we believe the dominant mechanism affecting efficacy of the contrast agent is the interaction between the merocyanine component and the metal , we see the potential for another mechanism to affect contrast . the spiropyran isoform is membrane - associated while the merocyanine form is free in aqueous solution , and so the spiropyran - derivatized contrast agent also likely associates with membranes . when membrane - localized , the do3a component may experience a different water environment than in the aqueous compartment and these changes in interaction with water can affect the mri signal . membrane - associated contrast agent , with limited water access , therefore can show reduced enhancement of the mr image , compared to the contrast agent when free in solution . based on the structures of the compounds of the invention , these effects may be minor . methods of the invention comprise administering or applying a sufficient amount of a compound of the invention in vivo or in situ and obtaining one or more contrast - enhanced mri images , wherein the contrast is an indication of membrane potential . methods of the invention further comprise assaying the activity of compounds of the invention in in vivo or in vitro tests to characterize the compounds of the invention . methods for diagnosing , characterizing the severity of , and staging diseases that are caused or accompanied by disturbances in the normal electrophysiological activity of excitable cells also are encompassed by the present invention . said methods of the invention include administering a sufficient amount effective amount of a compound of the invention . the compounds of the invention can be formulated in pharmaceutical compositions for in vivo administration , preferably to a mammal , more preferably to a human . these compositions can comprise , in addition to one or more of the compounds of the invention , a pharmaceutically acceptable excipient , carrier , buffer , stabiliser or other materials well known to those skilled in the art . such materials should be non - toxic and should not interfere with the function of the active compound . the precise nature of the carrier or other material can depend on the route of administration , e . g . oral , intravenous , cutaneous or subcutaneous , nasal , intramuscular , intraperitoneal routes . pharmaceutical compositions for oral administration can be in tablet , capsule , powder or liquid form . a tablet can include a solid carrier such as gelatin or an adjuvant . liquid pharmaceutical compositions generally include a liquid carrier such as water , petroleum , animal or vegetable oils , mineral oil or synthetic oil . physiological saline solution , dextrose or other saccharide solution or glycols such as ethylene glycol , propylene glycol or polyethylene glycol can be included . for intravenous , cutaneous or subcutaneous injection , or injection at the site of affliction , the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen - free and has suitable ph , isotonicity and stability . those of relevant skill in the art are well able to prepare suitable solutions using , for example , isotonic vehicles such as sodium chloride injection , ringer &# 39 ; s injection , lactated ringer &# 39 ; s injection . preservatives , stabilisers , buffers , antioxidants and / or other additives can be included , as required . the actual amount administered , and rate and time - course of administration , will depend on the nature of the compound , as well as the target area to be imaged . prescription of treatment , e . g . decisions on contrast agent dosage etc , is within the responsibility of radiologists and other medical doctors , and typically takes account of the disorder to be imaged , the condition of the individual patient , the site of delivery , the method of administration and other factors known to practitioners . examples of the techniques and protocols mentioned above can be found in remington &# 39 ; s pharmaceutical sciences , 16th edition , osol , a . ( ed ), 1980 . below are examples of specific embodiments for carrying out the present invention . the examples are offered for illustrative purposes only , and are not intended to limit the scope of the present invention in any way . efforts have been made to ensure accuracy with respect to numbers used ( e . g ., amounts , temperatures , etc . ), but some experimental error and deviation should , of course , be allowed for . the practice of the present invention will employ , unless otherwise indicated , conventional methods of synthetic organic chemistry , biochemistry , and pharmacology , within the skill of the art . such techniques are explained fully in the literature . see , e . g ., t . e . creighton , proteins : structures and molecular properties ( w . h . freeman and company , 1993 ); a . l . lehninger , biochemistry ( worth publishers , inc ., current addition ); sambrook , et al ., molecular cloning : a laboratory manual ( 2nd edition , 1989 ); methods in enzymology ( s . colowick and n . kaplan eds ., academic press , inc . ); remington &# 39 ; s pharmaceutical sciences , 18th edition ( easton , pa . : mack publishing company , 1990 ); carey and sundberg advanced organic chemistry 3 rd ed . ( plenum press ) vols a and b ( 1992 ). a compound having the structure shown as the final product in the scheme detailed in fig4 was synthesized and characterized . reaction step ( 1 ) ( shown in isolation in fig6 ) proceeds well and the product was characterized by 1 h nmr spectroscopy ( peak obtained at mw = 214 ). this product was readily purified by recrystallization from hot n - hexane . the yield of this reaction in our hands was not established . the literature value is 89 % isolated yield . l . d . taylor and r . b . davis , j . org . chem . 1963 , 28 , 1713 . reaction step ( 2 ) ( shown in isolation in fig7 ) also proceeded and the crude product was purified by recrystallization from ethanol / tetrahydrofuran . small , square - shaped orange crystals were obtained over a period of two days in ca . 12 % yield . analysis of these crystals via 1 h nmr spectroscopy suggests that their crystal structure may contain tetrahydrofuran ( see fig8 ). mass spectroscopy yielded an m / z peak at 352 . further addition of tetrahydrofuran to the ethanol mixture yielded a second crop of similar crystals . however , this second crop was coated in orange - colored viscous oil , characteristic of material that had come out of solution too quickly . this material is to be further recrystallized to improve product yield . reaction step ( 3 ) ( shown in isolation in fig9 ) was carried out under reflux ( approximately 80 ° c .) proceeded well and yielded a solid product as expected . previous attempts to synthesize this compound have yielded viscous oil . purification of the product from reaction ( 2 ) appears to lead to a purer product from reaction ( 3 ) as we obtained a solid instead of an oil . this product was analyzed by 1 h nmr and by es mass spectral analysis : fw ca . 506 , [ m ]+ 504 ( 100 %). reaction step ( 4 ) ( shown in isolation in fig1 ) was conducted overnight at ph = 10 – 11 . however , the ph dropped to a value of 9 after 24 h . thus , the ph was again raised to a value of ca . 10 and allowed to react for a further 24 h , during which time the reaction mixture maintained its ph value of ca . 10 . it appears that at least 48 hours are necessary for the reaction to go to completion as indicated by the lack of further ph change . es mass spectral analysis indicated a prominent peak at 701 ( expected mass of the ligand + na + ). reaction step 5 ( i . e ., the final reaction step shown in fig4 ) involves the insertion of the metal to the macrocycle . the sample was run through a chelex 100 column after first neutralizing the reaction mixture to ph = 7 . however , upon eluting with water , only pale yellow oil was obtained . this did not display the characteristic absorbances of ca . 510 and 550 nm upon exposure to uv - light irradiation . in addition , it was observed that a band of purple - colored material was trapped at the top of the chelex column . various solvents were used to try to pass this band through the column , and ethanol and chloroform each were found to be effective to elute the product . this purple - colored material displayed characteristic color changes expected for the final product . uv irradiation ( described in the following example ) produced a product with absorbances at ca . 510 and 550 nm . irradiation with white light eliminates these absorbance peaks . mass spec for the product from step 5 yielded a peak at 835 and also peak at 678 ( representing either free ligand or artifactual dissociation of product during electrospray ). a 5 mm nmr tube was charged with a solution of the spirobenzopyran - do3a compound ( ca . 0 . 03 g ) in 0 . 5 ml of dmso - d6 . a purple - colored solution resulted . exposing this sample to white - light ( 10 w quartz halogen lamp ) for 2 min led to a color change to give a pale yellow solution . the 1 h nmr spectrum of this yellow - colored solution indicated that both the spirobenzopyran - do3a and the merocyanine - do3a isomers were present in solution in approximately equal concentrations . to further bias the mixture to one isomer in solution , namely the spirobenzopyran - do3a isomer , the same sample was irradiated with white light for an additional 4 h . upon re - running the 1 h nmr spectrum of this sample it was clear that numerous peaks had decreased in intensity while some other peaks had grown in intensity . analysis of this spectrum allowed the full characterization of the spirobenzopyran - do3a isomer . the nmr data are as follows : 1h - nmr ( 300 mhz , dmso - δ6 ): d1 . 20 ( s , 3 ′, 3h ), 1 . 24 ( s , 3 ′, 3h ), 2 . 63 ( s , nch3 , 3h ), 3 . 35 ( m , do3a , 22h ), 4 . 21 ( s , 9 , 1h ), 4 . 22 ( s , 9 , 1h ), 6 . 00 ( d , 3 , j = 10 . 5 hz , 1h ), 6 . 63 ( d , 7 ′, j = 7 . 8 hz , 1h ), 6 . 82 ( t , 5 ′, j = 7 . 8 hz , 1h ), 7 . 00 ( d , 4 ′, j = 7 . 8 hz , 1h ), 7 . 04 ( t , 6 ′, j = 7 . 8 hz , 1h ), 7 . 23 ( d , j = 10 . 5 hz ), 1h ), 8 . 11 ( d , 5 , j = 2 . 7 hz , 1h ), 8 . 14 ( d , 7 , j = 2 . 7 hz , 1h ). fig1 shows the proton assignments derived from the nmr spectrum . a 30 ml spherical bulb containing a 0 . 84 mm aqueous solution of the spirobenzopyran - gd3 +( dota ) complex was inserted into a 5 mm nmr tube containing 0 . 3 ml of d 2 o . the sample was subjected to uv - irradiation using an 8w handheld lamp for 15 h then its t 1 value measured using standard inversion - recovery methods . a t 1 value of 2 . 703 was obtained . the sample was then irradiated with white light for 15 h and its t 1 re - evaluated and a t 1 of 2 . 652 was obtained . larger t 1 differences are expected to result from the use of more intense irradiation . the ability of the compounds of the invention to respond to membrane potentials and enhance mri contrast is initially tested in vitro . because the spiropyran - merocyanine transition can be triggered by light irradiation , the first steps of characterization can be simplified by using light as a stimulus for testing the compounds isomerization properties , rather than membrane potential . absorbance spectra for the contrast agents are measured after uv or visible light irradiation to confirm that the spiropyran - merocyanine transition is occurring for the derivatized contrast agent . the relaxivity for the complexes in solution is determined after intense uv irradiation ( to convert to the merocyanine form ) or visible irradiation ( to convert to spiropyran ). relaxivity can be measured using a relaxometer ( bruker minispec ). the agent also can be characterized by electrochemistry to ascertain its redox properties and evaluate its suitability for membrane studies . zhi , j ., baba , r ., hashimoto , k . & amp ; fujishima , a . ( 1995 ) j . photochem . photobio . a : chem 92 , 91 – 97 . relaxivity of the contrast agent also can be determined in the presence of liposomes , a model membrane system , to investigate whether membrane - localization significantly affects contrast enhancement . liposomes are generated using standard techniques by probe sonication of a buffered solution of phosphatidylcholine ( pc , 25 mm ). operative compounds of the invention localize to the liposomes . if the difference in relaxivity between uv and visible light irradiated contrast agent is unchanged in the presence of membrane , this indicate that there is little modification of the water environment about the compound when it is membrane localized . conversely , a change in the behavior of the contrast agent in the presence of liposomes compared to results in liposome - free solution indicates that difference in water interaction for membrane associated agent is significant . these data provide interesting insight to the closeness of association of the spiropyran - derivatized contrast agent with the membrane . longer linkers place the lanthanide chelator farther from the membrane and minimize the contribution from the membrane localization mechanism . the contrast agents &# 39 ; responses to membrane potentials also can be tested in the liposome system . membrane potentials can be induced in unilamellar phosphatidylcholine ( pc ) vesicles having preformed kcl gradients by the addition of valinomycin ( 20 mg / mmole pc ). cabrini , g . & amp ; verkman , a . ( 1986 ) j . membrane biol . 92 , 171 – 182 ; plasek , j . & amp ; sigler , k . ( 1996 ) j . photochem . photobio . 33 , 101 – 124 . relaxivity of water is determined in vesicle suspensions before and after the addition of valinomycin . for well - behaved contrast agents , values correlate with those obtained by light - induced isomerization of the contrast agent . the valinomycin assay is a “ one - way ” experiment in which the response of the contrast agent to hyperpolarization can be measured , but reversal to resting state cannot . to demonstrate reversibility , a cellular assay is used , as described below . the response of the contrast agents to membrane potentials as opposed to light can be assessed in cultured cells . cultured cardiac cells with contractile activity ( e . g . hl - 1 ) ( or any other spontaneously active electrically - excitable cell such as cultured pacemaker neurons ) are well suited for assaying the contrast agents of the invention . the cells are incubated with ( or without , as a control ) the contrast agents and observed by light microscopy . when incubated with operative contrast agents of the invention , the beating of the cells produces a corresponding pattern of absorbance changes in the membrane and extracellular space . short exposure images are obtained from the cells and the correlation established by analysis of the captured images . these cells also can be examined by mri microscopy . acquisition parameters are set to capture images down to hundreds of microseconds and are adjusted to best reflect the periodic change in membrane potential that will vary as a function of the particular cell type and culture condition . when cardiac myocytes are used for the assay , pharmacologic agents can be used to further evaluate the ability of the contrast agent to accurately reflect changes in membrane activity . for example , the cells can be imaged in the presence of a modulator of cardiac activity such as isoproterenol , which perturbs the synchrony of cardiomyocyte contractile activity , or phenylephrine , which increases contractile activity . jahangiri , a ., leifert , w ., patten , g . & amp ; mcmurchie , e . ( 2000 ) mol . cell . biochem . 206 , 33 – 41 ; mcwhinney , c ., hansen , c . & amp ; robishaw , j . ( 2000 ) mol . cell . biochem . 214 , 111 – 119 . cells are grown in culture and incubated with the contrast agent ± modulator , imaged using one or more of the techniques described above ( i . e ., light or mri microscopy ) and the data are analyzed to determine whether the modulator &# 39 ; s expected effect is reflected in the signal generated by the assayed contrast agent . whole dishes of cells can be imaged by mri . alternatively , cells can be grown in a three - dimensional matrix and imaged as such . cardiomyocytes can be grown as clusters in a three - dimensional cell culture system . igelmund , p ., fischer , i ., soest , j ., gryschenko , o ., fleichmann , b . & amp ; hescheler , j . ( 1997 ) pflugers archiv - eur j physiol 433 , p293 — p293 suppl . s . a number of other three - dimensional culture systems have been reported in which normally monolayer cells are grown in matrices of denatured collagen or microporous carriers . bancel , s . & amp ; hu , w . ( 1996 ) biotech progress 12 , 398 – 402 ; heermeier , k ., spanner , m ., trager , j ., gradinger , r . & amp ; schmidt , j . ( 1995 ) cells and materials 5 , 309 – 320 . diffusivity of the contrast agents of the invention through cells in three - dimensional culture provides a proxy for the ability of the agents to diffuse throughout tissues in vivo . in vivo tissue distribution of the compounds of the invention can be assessed in mouse and rat models using a radiolabeled derivative of the contrast agent . 111 indium is substituted for the lanthanide ( preferably gadolinium ) in the synthesis of the agent . 111 indium is routinely used as a radioactive substitute for gadolinium and is a gamma emitter . duncan , j . r ., franano , f . n ., edwards , w . b . & amp ; welch , m . j . ( 1994 ) inves . radiol . 29 , s58 – s61 ; jasanada , f ., urizzi , p ., souchard , j ., gaillard , f . l ., favre , g . & amp ; nepveu , f . ( 1996 ) bioconj . chem . 7 , 72 – 81 . 111 indium is employed because it has a half - life of 2 . 8 days compared to 242 days for 153 gd and has emissions about twice as energetic . a radiolabeled contrast agent of the present invention is introduced into the animal and whole body distribution is assessed at various time points after administration . a number of techniques can be used to introduce the agent to the animal including by way of example but not limitation : intravenous , intraperitoneal , intravitreal and subretinal . key organs and tissues are harvested and gamma counted . blood samples are taken and counted over time to determine blood clearance rates . systemic ( i . v , i . p ), intravitreal and subretinal delivery methods can be used to assess distribution of compounds of the invention to the eye , particularly the retina . use of compounds of the invention in an animal model of retinal degeneration an animal model is used to demonstrate the ability of a contrast agent of the present invention to produce an image of retinal activity and detect photoreceptor loss in a mouse or rat model of human retinal degeneration disease . a number of animal models of retinal degeneration are available and useful for this purpose . for example , the b6 . br - pcd strain of mice suffers from a purkinje cell defect which results in complete photoreceptor degradation in the course of one year ; sam mice experience profound loss of photoreceptors in the peripheral retina ; a number of rd mutant mice are models for retinal degeneration and retinitis pigmentosa ( rd6 mice show abnormal erg at 1 – 2 months ); and fischer 344 rats show age - related retinal degeneration . diloreto , d ., martzen , m ., delcerro , c ., coleman , p . & amp ; delcerro , m . ( 1995 ) brain res . 698 , 1 – 4 ; shoji , m ., okada , m ., ohta , a ., higuchi , k ., hosokawa , m . & amp ; honda , y . ( 1998 ) ophthalmic res 30 , 172 – 179 ; porteracailliau , c ., sung , c ., nathans , j . & amp ; adler , r . ( 1994 ) pnas 91 , 974 – 978 ; eversole - cire , p ., conception , f ., simon , m ., takayama , s ., reed , j . & amp ; chen , j . ( 2000 ) inv . opth . vis . sci . 41 , 1953 – 1961 ; hawes , n ., chang , b ., hageman , g ., nusinowitz , s ., nishina , p ., schneider , b ., smith , r ., roderick , t ., davisson , m . & amp ; heckenlively , j . ( 2000 ) inv . opth . vis . sci . 41 , 3149 – 3157 . using the most efficient injection method , as determined from the biodistribution studies described in example 5 , contrast agent is introduced to mouse or rat eyes . animals under even illumination by wavelengths of light that do not trigger the indicator group conformational change are mr imaged in small animal probes using rf surface coils designed for imaging the eye to generate high resolution mri images of the retina . the animals are imaged over time as the retina progressively deteriorates . at various time points , animals are sacrificed and the retinas prepared for histological confirmation of photoreceptor degradation and optionally , 2 - d electroretinography ( 2d - erg ). the mri results are correlated with the histological results and optionally with those from 2d - erg . while the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments , it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention . all references , issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety , for all purposes .

US-70071203-A

an intramolecularly - quenched , near infrared fluorescence probe that emits substantial fluorescence only after interaction with a target tissue is disclosed . the probe includes a polymeric backbone and a plurality of near infrared fluorochromes covalently linked to the backbone at fluorescence - quenching interaction - permissive positions separable by enzymatic cleavage at fluorescence activation sites . the probe optionally includes protective chains or fluorochrome spacers , or both . also disclosed are methods of using the intramolecularly - quenched , near infrared fluorescence probes for in vivo optical imaging .

probe backbone design will depend on considerations such as biocompatibility ( e . g ., toxicity and immunogenicity ), serum half - life , useful functional groups ( for conjugating fluorochromes , spacers , and protective groups ), and cost . useful types of backbone include polypeptides ( polyamino acids ), polyethyleneamines , polysaccharides , aminated polysaccharides , aminated oligosaccharides , polyamidoamines , polyacrylic acids and polyalcohols . a preferred backbone consists of a polypeptide formed from l - amino acids . when polylysine is used as a backbone , the ε - amino groups on the side chains of the polylysine can serve as convenient reactive groups for covalent linkage of fluorochromes and spacers ( fig1 a and 1b ). when the backbone is a polypeptide , preferably the molecular weight of the probe is from 2 kd to 1000 kd . more preferably , its molecular weight is from 4 kd to 500 kd . a backbone may be chosen or designed so as to have a suitably long in vivo persistence ( half - life ) inherently . therefore , protective chains are not necessary in some embodiments of the invention . alternatively , a rapidly - biodegradable backbone such as polylysine can be used in combination with covalently - linked protective chains . examples of useful protective chains include polyethylene glycol ( peg ), methoxypolyethylene glycol ( mpeg ), methoxypolypropylene glycol , polyethylene glycol - diacid , polyethylene glycol monoamine , mpeg monoamine , mpeg hydrazide , and mpeg imidazole . the protective chain can also be a block - copolymer of peg and a different polymer such as a polypeptide , polysaccharide , polyamidoamine , polyethyleneamine or polynucleotide . synthetic , biocompatible polymers are discussed generally in holland et al ., 1992 , &# 34 ; biodegradable polymers ,&# 34 ; advances in pharmaceutical sciences 6 : 101 - 164 . a useful backbone - protective chain combination is methoxypoly ( ethylene ) glycol - succinyl - n - ε - poly - l - lysyine ( pl - mpeg ). the synthesis of this material , and other polylysine backbones with protective chains , is described in bogdanov et al ., u . s . pat . no . 5 , 593 , 658 and bogdanov et al ., 1995 , advanced drug delivery reviews 16 : 335 - 348 . various near infrared fluorochromes are commercially available ( cy5 . 5 and cy5 ; amersham , arlington hts ., ill . ; ird41 and ird700 , li - cor , lincoln , neb . ; nir - 1 , dejindo , kumamoto , japan ; lajolla blue , diatron , miami , fla .) and can be used to construct probes according to this invention . fluorescent probes with excitation and emission wavelengths in the near infrared spectrum are used , i . e ., 650 - 1300 nm . use of this portion of the electromagnetic spectrum maximizes tissue penetration and minimizes absorption by physiologically abundant absorbers such as hemoglobin (& lt ; 650 nm ) and water (& gt ; 1200 nm ). ideal near infrared fluorochromes for in vivo use exhibit : ( 1 ) narrow spectral characteristics , ( 2 ) high sensitivity ( quantum yield ), ( 3 ) biocompatibility , and ( 4 ) decoupled absorption and excitation spectra . table 1 summarizes information on the properties of six commercially - available near infrared fluorochromes , whose structures are shown in fig2 a and 2b . table 1______________________________________near infrared fluorochromesfluoro - ( nm ) ( nm ) mol . extinct . quantumchrome excitation emission wt . coef . yield % ______________________________________cy5 . 5 675 694 1128 . 41 250 , 000 28 . 0cy5 649 670 791 . 99 250 , 000 28 . 0ird41 787 807 925 . 10 200 , 000 16 . 5ird700 685 705 704 . 92 170 , 000 50 . 0nir - 1 663 685 567 . 08 75 , 000 nalajolla 680 700 5000 . 00 170 , 000 70 . 0blue______________________________________ intramolecular fluorescence quenching by non - activated probes can occur by any of various quenching mechanisms . several mechanisms are known , including resonance energy transfer between two fluorochromes . in this mechanism , the emission spectrum of a first fluorochrome should be very similar to the excitation of a second fluorochrome , which is in close proximity to the first fluorochrome . efficiency of energy transfer is inversely proportional to r 6 , where r is the distance between the quenched chromophore and excited chromophore . self - quenching can also result from fluorochrome aggregation or excimer formation . this effect is strictly concentration dependent . quenching also can result from a non - polar - to - polar environmental change . to achieve intramolecular quenching , several strategies can be applied . they include : ( 1 ) linking a second fluorochrome , as an energy acceptor , at a suitable distance from the first fluorochrome ; ( 2 ) linking fluorochromes to the backbone at high density , to induce self - quenching ; and ( 3 ) linking polar fluorochromes in a vicinity of non - polar structural elements of the backbone and / or protective chains . fluorescence is partially or fully recovered upon cleavage of the fluorochrome from neighboring fluorochromes and / or from a particular region , e . g ., a non - polar region , of the probe . the fluorochrome can be covalently linked to a fluorochrome attachment moiety , backbone , or spacer using any suitable reactive group on the fluorochrome and a compatible functional group on the fluorochrome attachment moiety , backbone , or spacer . for example , a carboxyl group ( or activated ester ) on a fluorochrome can be used to form an amide linkage with a primary amine such as the ε - amino group of the lysyl side chain on polylysine . in some embodiments of the invention , the fluorochromes are linked directly to the backbone or linked to the backbone through nonbiodegradable spacers . in such embodiments , the fluorescence activation sites are in the backbone . some probes of this type accumulate in tumor interstitium and inside tumor cells , e . g ., by fluid phase endocytosis . by virtue of this preferential accumulation , such probes can be used to image tumor tissues , even if the enzyme ( s ) activating the probe are not tumor specific . in preferred embodiments of the invention , fluorochromes are linked to the backbone through spacers containing fluorescence activation sites . oligopeptide spacers can be designed to contain amino acid sequences recognized by specific proteases associated with target tissues . prostate specific antigen ( psa ), is a 33 kd chymotrypsin - like serine protease is secreted exclusively by prostatic epithelial cells . normally , this enzyme is primarily involved in post - ejaculation degradation of the major human seminal protein . normally , serum concentrations of psa are proportional to the volume of prostatic epithelium . the release of psa from prostate tumor cells , however , is about 30 - fold higher than that from normal prostate epithelium cells . damages basal membrane and deranged tissue architecture allow psa to be secreted directly into the extracellular space and into the blood . although high levels of psa can be detected in serum , the serum psa exists as a complex with a1 - antichymotrypsin protein , and is proteolytically inactive . free , uncomplexed , activated psa occurs in the extracellular fluid from malignant prostate tissues , and psa activity can be used as a marker for prostate tumor tissue . prostate tumor tissue is highly enriched in psa . thus , spacers containing the amino acid sequence recognized by psa can be used to produce a near infrared probe that undergoes fluorescence activation specifically in prostate tumor tissue . an example of a psa - sensitive spacer is his - ser - ser - lys - leu - gln - gly ( seq id no : 2 ). other psa - sensitive spacers can be designed using information known in the art regarding the substrate specificity of psa . see , e . g ., 1997 , denmeade et al ., cancer res . 57 : 4924 - 4930 . cathepsin d is an abundant lysosomal aspartic protease distributed in various mammalian tissues . in most breast cancer tumors , cathepsin d is found at levels from 2 - fold to 50 - fold greater than levels found in fibroblasts or normal mammary gland cells . thus , cathepsin d can be a useful marker for breast cancer . spacers containing the amino acid sequence recognized by cathepsin d can be used to produce a near infrared probe that undergoes fluorescence activation specifically in breast cancer tissue . an example of a cathepsin d - sensitive spacer is the oligopeptide : gly - pro - ile - cys - phe - phe - arg - leu - gly ( seq id no : 1 ). other cathepsin d - sensitive spacers can be designed using information known in the art regarding the substrate specificity of cathepsin d . see , e . g ., gulnik et al ., 1997 , febs let . 413 : 379 - 384 . when the fluorochromes are linked directly to the backbone , probe activation is by cleavage of the backbone . high fluorochrome loading of the backbone can interfere with backbone cleavage by activating enzymes such as trypsin . therefore , a balance between fluorescence quenching and accessibility of the backbone by probe - activating enzymes . for any given backbone - fluorochrome combination ( when activation sites are in the backbone ) probes representing a range of fluorochrome loading densities can be produced and tested in vitro to determine the optimal fluorochrome loading percentage . when the fluorochromes are linked to the backbone through activation site - containing spacers , accessibility of the backbone by probe - activating enzymes is unnecessary . therefore , high loading of the backbone with spacers and fluorochromes does not significantly interfere with probe activation . in such a system , every lysine residue of polylysine can carry a spacer and fluorochrome , and every fluorochrome can be released by activating enzymes . preferential accumulation of a probe in a target tissue can be achieved or enhanced by binding a tissue - specific targeting moiety ( targeting ligand ) to the probe . the binding can be covalent or non - covalent . examples of targeting moieties include a monoclonal antibody ( or antigen - binding antibody fragment ) directed against a target - specific marker , a receptor - binding polypeptide directed to a target - specific receptor , and a receptor - binding polysaccharide directed against a target - specific receptor . antibodies or antibody fragments can be produced and conjugated to probes of this invention using conventional antibody technology ( see , e . g ., folli et al ., 1994 , &# 34 ; antibody - indocyanin conjugates for immunophotodetection of human squamous cell carcinoma in nude mice ,&# 34 ; cancer res . 54 : 2643 - 2649 ; neri et al ., 1997 , &# 34 ; targeting by affinity - matured recombinant antibody fragments of an angiogenesis associated fibronectin isoform ,&# 34 ; nature biotechnology 15 : 1271 - 1275 ). similarly , receptor - binding polypeptides and receptor - binding polysaccharides can be produced and conjugated to probes of this invention using known techniques . after a probe is designed and synthesized , it can be tested routinely in vitro to verify a requisite level of intramolecular fluorescence quenching before activation . preferably , this is done by obtaining a fluorescence value for the intramolecularly quenched , fluorochrome - containing probe in a dilute , physiological buffer . this value is then compared to the fluorescence value obtained from an equimolar concentration of free fluorochrome in the same buffer , under the same fluorescence - measuring conditions . preferably , this comparison will be done at a series of dilutions , to verify that the measurements are taking place on a linear portion of the fluorescence vs . fluorochrome concentration curve . the molar amount of an intramolecularly - quenched fluorochrome on a probe can be determined by one of ordinary skill in the art using any suitable technique . for example , the molar amount can be determined readily by near infrared absorption measurements . alternatively , it can be determined readily by measuring the loss of reactive linking groups on the backbone ( or spacers ), e . g ., decrease in ninhydrin reactivity due to loss of amino groups . after suitable intramolecular fluorescence quenching is verified , &# 34 ; de - quenching ,&# 34 ; i . e ., fluorescence , upon exposure to an activating enzyme also can be verified in vitro . in preferred procedure , fluorescence of an intramolecularly - quenched probe is measured before and after treatment with an activating enzyme . if the probe has activation sites in the backbone ( as opposed to in spacers ), de - quenching should be tested at various levels of fluorochrome loading , where &# 34 ; loading &# 34 ; refers to the percentage of possible fluorochrome linkage sites on the backbone actually occupied by fluorochromes . in addition , cells grown in culture can be used routinely to test intramolecularly - quenched near infrared fluorescence probes . probe molecules free in cell culture medium should be non - detectable by fluorescence microscopy . cellular uptake should result in probe activation and a fluorescence signal from probe - containing cells . microscopy of cultured cells thus can be used to verify that activation takes place upon cellular uptake of a probe being tested . microscopy of cells in culture is also a convenient means for determining whether activation occurs in one or more subcellular compartments . although the invention involves novel fluorescence probes , general principles of fluorescence , optical image acquisition , and image processing can be applied in the practice of the invention . for a review of optical imaging techniques , see , e . g ., alfano et al ., 1997 , &# 34 ; advances in optical imaging of biomedical media ,&# 34 ; ann . ny acad . sci 820 : 248 - 270 . an imaging system useful in the practice of this invention can include three basic components . the first is a source of nearly monochromatic , near infrared light . this can be provided by filtered white light . for example , light from a 150 - watt halogen lamp can be passed through a suitable bandpass filter commercially available from omega optical ( brattleboro , vt .). the second basic component is a high pass filter ( 700 nm ), which separates the fluorescence emissions from the excitation light . a suitable high pass filter also can be purchased from omega optical . the third basic component is a low - light ( cooled ) ccd camera with appropriate macro lens attachments . selecting suitable components and assembling them into a suitable optical imaging system is within ordinary skill in the art . in order that the invention may be more fully understood , the following examples are provided . it should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way . we synthesized three different intramolecularly - quenched near infrared fluorescence probes by conjugating a commercially - available fluorochrome known as cy5 . 5 ( absorption = 675 nm , emission = 694 nm ; amersham , arlington heights , ill .) to pl - mpeg ( average molecular weight approx . 450 kd ). the three probes differed in attachment of the fluorochrome to the polylysine backbone . in a probe designated &# 34 ; cy - pl - mpeg ,&# 34 ; the cy5 . 5 was linked directly to the ε - amino group of the polylysine side chains at various densities , which ranged from 0 . 1 % to 70 % derivatization of the ε - amino groups . in a probe designated , &# 34 ; cy - rrg - pl - mpeg ,&# 34 ; the cy5 . 5 fluorochrome was linked to the polylysine by a a spacer consisting of arg - arg - gly . in a probe designated &# 34 ; cy - gpicffrlg - pl - mpeg ,&# 34 ; the cy 5 . 5 fluorochrome was linked to the polylysine by a a spacer consisting of gly - pro - ile - cys - phe - phe - arg - leu - gly ( seq id no : 1 ). trypsin and trypsine - like proteases are capable of cleaving the polylysine backbone of cy - pl - mpeg , when it is only partially derivatized . probes cy - rrg - pl - mpeg and cy - gpicffrlg - pl - mpeg were designed to allow fluorochrome cleavage of the spacer , but not necessarily the backbone . for example the peptide spacer rrg , sensitive to trypsin cleavage , was used to derivatize the pl - mpeg , and then cy5 . 5 was linked to the n - terminus of the rrg spacers . the cathepsin d sensitive peptide spacer , gpicffrlg ( seq id no : 1 ), was similarly used to derivatize the pl - mpeg . cy5 . 5 , commercially available as a monofunctional nhs - ester ( amersham , arlington heights , ill . ), was used according to the vendor &# 39 ; s instructions , to label free ε - amino groups of the polylysine backbone in pl - mpeg . cy5 . 5 was added to a pre - mixed mpeg - pl solution ( 0 . 2 mg pl - mpeg in 1 ml 80 mm sodium bicarbonate solution ) to a final concentration of 17 μm . after three hours , the reaction mixture was applied to a sephadex ™ g - 25 ( pharmacia ) column ( 12 cm ) for separation of the reaction product ( cy - pl - mpeg ) from the unreacted fluorochrome and other low - molecular weight components of the reaction mixture . average fluorochrome loading was about 20 %, i . e ., 11 out of 55 free amino groups on the pl - mpeg labeled with cy5 . 5 ( based on tnbs assay and absorption measurement ). fig3 a shows the excitation and emission spectra of cy5 . 5 free in solution . fig3 b shows the excitation and emission spectra of cy5 . 5 fluorochromes of cy - pl - mpeg . the excitation and emission wavelengths of cy5 . 5 are 648 nm and 694 nm , respectively . there was a marked difference in the level of fluorescence of the free cy5 . 5 and the cy - pl - mpeg . the fluorescence level of the cy - mpeg - pl was approximately 30 - fold lower than that of the unbound cy5 . 5 . in subsequent studies , we determined the effect of fluorochrome loading ( i . e ., percentage of ε - amino groups on the polylysine backbone occupied by fluorochrome ) on the optical properties of the probe . fig4 shows the relative fluorescent signal of cy ( n )- mpeg - pl ( white bars ) as a function of percentage of ε - amino groups on the polylysine backbone occupied by fluorochrome . at 20 % loading ( 11 of 55 groups ) and higher , intramolecular quenching was observed , and the fluorescence signal was lowered in comparison to probes with lower fluorochrome loading . after trypsin cleavage of the backbone , fluorescence signal was recovered , as shown by the black bars in fig4 . maximum fluorescence recovery was obtained at 20 % loading ( 15 - fold fluorescence signal increase upon activation ). recovery was reduced when at loading greater than 20 %. this may have been due to steric hinderance and the need for free lysine groups for efficient cleavage of the backbone . the next step in testing the functional imaging probe was to perform cell culture experiments . we expected that non - internalized cy - pl - mpeg would be non - detectable by fluorescence microscopy , and that cellular uptake would lead to activation of the probe , with a resulting fluorescence signal . data obtained using amelanotic b16 melanoma cells confirmed our prediction and showed that : ( 1 ) the non - activated probe is non - fluorescent , ( 2 ) the probe is taken up by this cell line , and ( 3 ) cellular uptake results in activation of the probe and fluorescence signal detection . in this experiment we compared a bright field image outlining b16 cells to : ( 1 ) the same field under near infrared fluorescence conditions when cy - mpeg - pl was added to the cells , near time - zero ; and ( 2 ) after allowing time for intracellular uptake of the probe ( data not shown ). the cells were not detectable by near infrared fluorescence near time - zero , but the cells were clearly visible ( due to intracellular fluorescence ) after cellular uptake of the probe , i . e ., at about two hours . this experiment demonstrated that our imaging probe detectably changed its optical properties in a target cell - dependent manner . in vivo mouse imaging was carried out using a system composed of three main parts : light source , platform / holder , and image recording device . a fiber optic light bundle with a 150 w halogen bulb ( fiberlite high intensity illuminator series 180 , dolan - jennen industries ) provided broad spectrum white light . a sharp cut off band pass optical filter ( omega filter corp ., brattleboro , vt .) was mounted at the end of the fiber optic bundle to create a uniform excitation source in the 610 - 650 nm range . the light was placed approximately 15 cm above the imaging platform to provide homogenous illumination of the entire mouse . the platform itself was a matte black surface that decreased the number of excitation photons reflected ( and possibly detected ) by the recording device . fluorescent ( emission ) photons were selected using a low pass filter with a sharp cut off at 700 nm ( omega filter corp .). cy5 . 5 dye has an excitation peak at approximately 670 nm , with a broad shoulder extending below 610 nm . peak emission is at 694 nm . sharp cut - off filters with more than 5 od attenuation combined with widely spaced frequencies for the filter set markedly decreased &# 34 ; cross talk &# 34 ; of incident excitation photons recorded as fluorescent emission signal . the narrow angle between light source and recording device ensured that only fluorescent emission photons or scattered photons that interacted with the mouse tissue reached the low pass filter . for image recording , the low - pass filter was mounted on a low power microscope ( leica stereozoom 6 photo , leica microscope systems , heerbrugg , switzerland ). a low light ccd ( sensys 1400 , 12 bit cooled ccd , photometrics , tuscon , ariz .) recorded the fluorescent emission images . images were transferred to a powermac 7600 / 120 pc ( apple computer , cupertino , calif .) and processed using iplab spectrum 3 . 1 software ( signal analytics corp ., vienna , va .). post processing included standard routines to exclude bad ccd pixels , and superimposition routines to overlay emission images with localization images of the entire mouse obtained using a second white light source . typical acquisition time was 30 seconds for the near infrared emission images , and 1 second for the white light ( non - selective images ). we tested the near intramolecularly - quenched infrared fluorescence probe ( cy 11 - pl - mpeg ; 20 % fluorochrome loading ) in tumor - bearing mice . nude mice bearing tumor line 9l or lx1 received 2 nmol of cy 11 - pl - mpeg intravenously . the mice were imaged by near infrared light immediately , and up to 36 hours after intravenous administration of the probe . an increase in fluorescence signal within tumor was observed as a function of time , as the probe was internalized into tumor cells and became activated by endosomal hydrolases . fig5 a is a schematic diagram of the imaged mouse , illustrating the location of tumor shown in fig5 b and 5c . fig5 b is visible light photograph of the skin covering a tumor on the side of a nude mouse into which the cy 11 - pl - mpeg probe was injected . fig5 c is a corresponding near infrared fluorescence image . the tumor is visible as an area of intense fluorescence , in contrast to the surrounding tissue . __________________________________________________________________________ # sequence listing - ( 1 ) general information :- ( iii ) number of sequences : 2 - ( 2 ) information for seq id no : 1 :- ( i ) sequence characteristics :# acids ( a ) length : 9 amino ( b ) type : amino acid ( d ) topology : linear - ( ii ) molecule type : peptide - ( xi ) sequence description : seq id no : 1 :- gly pro ile cys phe phe arg leu gly # 5 1 - ( 2 ) information for seq id no : 2 :- ( i ) sequence characteristics :# acids ( a ) length : 7 amino ( b ) type : amino acid ( d ) topology : linear - ( ii ) molecule type : peptide - ( xi ) sequence description : seq id no : 2 :- his ser ser lys leu gln gly # 5 1__________________________________________________________________________

US-7944798-A

1 - phenyl - 2 - pyridinyl alkyl alcohol compounds are effective as inhibitors of the phosphodiesterase 4 enzyme and may be used to prevent and / or treat certain diseases or conditions .

the term “ halogen atoms ” as used herein includes fluorine , chlorine , bromine and iodine . as used herein , the expression “ linear or branched c 1 - c x alkyl ” where x is an integer greater than 1 , such as c 1 - c 6 or c 1 - c 4 alkyl , refers to straight or branched chain alkyl groups wherein the number of carbon atoms is in the range 1 to x ( e . g . 1 to 6 or 1 to 4 ). examples of alkyl groups may thus include methyl , ethyl , n - propyl , isopropyl , t - butyl , pentyl , hexyl and the like . optionally in said groups one or more hydrogen atoms can be replaced by halogen atoms , preferably chlorine or fluorine . as used herein , the expression “ c 3 - c 7 cycloalkyl ” refers to cyclic non - aromatic hydrocarbon groups containing 3 to 7 ring carbon atoms . examples of them may thus include cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl and cycloheptyl . unless otherwise provided , when referring to chiral compounds , a degree of purity “ substantially pure ” here means at least greater than about 97 % chirally pure , preferably greater than 99 % and most preferably greater than 99 . 9 %. the invention is directed to compounds acting as inhibitors of the phosphodiesterase 4 ( pde4 ) enzyme . said compounds inhibit the conversion of cyclic nucleotides , in particular cyclic adenosine monophosphate ( camp ), into their inactive 5 ′- mononucleotide forms . in the airways , the physiological responses to elevated intracellular levels of cyclic nucleotides , in particular of camp , lead to the suppression of the activity of immune and pro - inflammatory cells such as mast cells , macrophages , t lymphocytes , eosinophils and neutrophils , resulting in a decrease of the release of inflammatory mediators which include cytokines such as il - 1 , il - 3 and tumor necrosis factor - alpha ( tnf - α ). it also leads to an airway smooth muscle relaxation and a decrease in oedema . the catalytic site of pde4 has been previously identified : it mainly comprises a hydrophobic region in which two sub - pockets are present , e . g . s 0 and s 1 and a hydrophilic region containing the metal ions zn 2 + and mg 2 + , that in turn comprises the sub - pocket s 2 spreading around the metal ions and a sub - pocket s 3 which branches approximately 90 ° from the middle of the hydrophobic pocket . most of the known compounds are provided with a moiety capable of interacting with the sub - pockets s 0 and s 1 of the hydrophobic region such as a substituted cathecol group and with another moiety able of indirectly interacting with the metal ions of the s 2 sub - pocket , for example a heterocycle such as pyridine or pyrrolidone . the present invention is directed to compounds that can maintain the interactions with the sub - pockets s 0 and s 1 by means of the substituted catechol moiety and the interaction with the metal ions region by means of the pyridine ring like other known pde4 inhibitors , but differing from them , for the presence of a sulfonylamino - benzoic acid group , which enable them to establish an additional interaction with the sub - pocket s 3 . in particular the present invention relates to compounds of formula ( i ) as defined earlier , including the pharmaceutically acceptable inorganic and organic salts , hydrates , solvates or addition complexes thereof . r1 is — nhso 2 r4 , wherein r4 is methyl , r2 is — or3 , wherein r3 is cyclopropylmethyl , and n is 0 ; r1 is — nhso 2 r4 , wherein r4 is methyl , r2 is — or3 , wherein r3 is cyclopropylmethyl , and n is 1 ; r1 is linear or branched c 1 - c 6 alkyl , r2 is — nhso 2 r4 , and n is 0 ; r1 is methyl , r2 is — nhso 2 r4 , wherein r4 is methyl , and n is 0 ; r1 is linear or branched c 1 - c 6 alkyl , r2 is — nhso 2 r4 , and n is 1 ; r1 is methyl , r2 is — hnso 2 r4 , wherein r4 is methyl , and n is 1 ; r2 is linear or branched c 1 - c 6 alkyl , r1 is — nhso 2 r4 , and n is 0 ; r2 is methyl , r1 is — hnso 2 r4 , wherein r4 is methyl , and n is 0 ; r2 is linear or branched c 1 - c 6 alkyl , r1 is — nhso 2 r4 , and n is 1 ; r2 is methyl , r1 is — nhso 2 r4 , wherein r4 is methyl , and n is 1 ; r1 is — or3 wherein r3 is cyclopropylmethyl , r2 is — nhso 2 r4 and r4 is methyl , and n is 1 ; both r1 and r2 are — nhso 2 r4 , and n is 0 ; both r1 and r2 are — nhso 2 r4 , wherein r4 is methyl , and n is 0 ; both r1 and r2 are — nhso 2 r4 , and n is 1 ; and both r1 and r2 are — nhso 2 r4 , wherein r4 is methyl , and n is 1 . it will be apparent to those skilled in the art that compounds of formula ( i ) contain at least one asymmetric center , presently represented by the carbon atom with an asterisk , and therefore exist as optical stereoisomers . the present invention is directed to the compounds of formula ( i ) which are (−) enantiomers with configuration ( s ) at the carbon atom represented with an asterisk . the present invention is also directed to the intermediate compounds of formula ( ii ) wherein the carbon atom represented with an asterisk has the ( s ) configuration . the compounds of formula ( i ) show an in vitro inhibitory activity toward the pde4 enzyme in the nm range , and they are endowed with a remarkable activity in the lungs upon intra - tracheal administration in an animal model of copd . they may also exhibit sustained pulmonary levels in the lungs , being undetectable in plasma , which is an index of a short systemic action . according to preferred embodiments , the present invention provides the compounds of formula ( i ) reported below : the above compounds have been conveniently identified as (−) enantiomers which , however , have ( s ) configuration at the carbon atom marked with an asterisk . as such , these same compounds can be also identified as per the following table : advantageously , the compounds of the invention are characterized by selectivity toward lpde4 higher than that toward hpde4 , as obtained by the determination of their ic 50 values . in the case of lpde4 , the ic 50 is the molar concentration of the test compound producing 50 % inhibition of camp disappearance , assessed as described in cortijo j et al ., br . j . pharmacol ., 1993 , 108 : 562 - 568 , which is incorporated herein by reference in its entirety . in the case of hpde4 instead , the ic 50 is the molar concentration of the test compound producing 50 % inhibition of the binding of [ h 3 ] rolipram , assessed as described in duplantier a j et al ., j . med . chem ., 1996 ; 39 : 120 - 125 , which is also incorporated herein by reference in its entirety . preferably , the hpde4 / lpde4 ic 50 ratio for the compounds of the invention is higher than 5 , more preferably higher than 10 , even more preferably higher than 20 and most preferably higher than 100 . the compounds of formula ( i ) may be prepared conventionally according to known methods . some of the processes which can be used are described below and reported in scheme 1 . according to a particular embodiment of the present invention , the compounds of formula ( i ) may be prepared , for example , following the synthetic pathways described in scheme 1 . racemic alcohol ( 3 ) may be prepared by reacting aldehyde ( 1 ) with methyldichloropyridine ( 2 ). racemic alcohol ( 3 ) may be separated into (−) ( 12 ) and (+) ( 14 ) enantiomers by known methods , such as by reacting the racemic mixture with a suitable chiral auxiliary thus obtaining a mixture of diastereoisomers . such diastereoisomers may be separated by crystallization or by chromatography or by means of enzymes according to known methods . subsequently , the chiral auxiliary may be removed from diastereoisomers to give the desired chiral alcohol as a single enantiomer . alternatively , the alcohol racemic mixture may be resolved by means of chromatography with a chiral stationary phase , according to known methods ( see , “ enantiomer separation : fundamentals and practical methods ” f . toda , springer - verlag 2004 ; and “ drug stereochemistry : analytical methods and pharmacology ”, irving w . wainer , crc press , 1993 , which are both incorporated herein by reference in their entireties ). in particular , racemic alcohol ( 3 ) may be condensed with a chiral acid such as ( s )- naproxen and the obtained diastereomeric mixture ( 10 ) may be separated into the two single diastereoisomers ( 11 ) and ( 13 ) by chromatography . after cleavage of the single diastereomeric esters by hydrolysis in an aqueous solvent or by alcoholysis in an alcoholic solvent , using acidic or basic conditions , enantiomeric pure alcohol intermediates (−) ( 12 ) and (+) ( 14 ) may be obtained . racemate ( 4 ), obtained by oxidation of racemate ( 3 ) carried out according to conventional methods , may be reacted with a chiral acid such as ( s )- acetylmandelic acid so obtaining a mixture of two diastereoisomers ( 5 ). by trituration with diethyl ether and crystallization in a solvent such as isopropanol , ethanol or methanol , or by chromatographic separation , single diastereomeric esters ( 6 ) and ( 8 ) may be obtained . after cleavage of single diastereomeric esters by hydrolysis in an aqueous solvent or by alcoholysis in an alcoholic solvent , using acidic or basic conditions , enantiomeric pure alcohol intermediates (+) ( 7 ) and (−) ( 9 ) may be obtained . compounds of formula ( i ) wherein n is 0 may be prepared by reacting the proper enantiomeric alcohol (+)( 14 ) with benzoic acid ( 15 ) in the presence of a suitable strong base such as lithium diisopropylamide ( lda ), nah , or dimethylaminopyridine ( dmap ) and in the presence of a condensing agent such as 1 - ethyl - 3 -[ 3 - dimethylaminopropyl ]- carbodiimide hydrochloride ( edc ) or n - hydroxybenzotriazole ( hobt ) in a solvent such as dichloromethane . other solvents may be used , such as dimethylformamide ( dmf ), tetrahydrofuran ( thf ), chloroform , dioxane or any other aprotic solvent known to those skilled in the art . in a particular embodiment , the reaction may also be carried out in the absence of solvents . compounds of formula ( i ) wherein n is 1 may be prepared by oxidizing corresponding compounds of formula ( i ) wherein n is 0 by means of an oxidizing agent such as 3 - chloroperbenzoic acid , peracetic acid or hydrogen peroxide in solvents such as chloroform , dichloromethane or acetic acid ( route b ). alternatively , compounds of formula ( i ) wherein n is 1 may also be prepared by first oxidizing alcohol enantiomers (+) ( 14 ), by means of the aforementioned operative conditions , thus obtaining alcohol enantiomers (+) ( 7 ). subsequent reaction between the given alcohol enantiomer with a benzoic acid of formula ( 15 ), thus provides the above compounds of formula ( i ) wherein n is 0 ( route a ). separation of (+) ( 7 ) and (−) ( 9 ) enantiomers from racemic alcohol ( 4 ), which in its turn be obtained by oxidation of racemic alcohol ( 3 ), may be carried out by known methods , as described above for separation of enantiomers of racemic alcohol ( 3 ). the skilled person should be aware that optional variations to the synthetic steps reported in scheme 1 may be applied as well to the preparation of the compounds of the invention . in particular , the order of reactions may be performed so as to get the desired compounds or intermediates thereof , as well as to the choice of operative conditions being adapted , including solvents , optional oxidizing agents , condensing agents , and the like . as an example , in case chemically reactive substituents are present in any of the starting materials or intermediates thereof , that might give rise to unwanted side reactions , suitable protection of those same substituents may be carried out before the reaction takes place . by analogy , subsequent deprotection may be then carried out , so as to obtain again the above chemically reactive substituent or group in the free form . the protection and deprotection of functional groups is described in “ protective groups in organic chemistry ,” 3rd edition , t . w . greene and p . g . m . wuts , wiley - interscience ( 1999 ) and in “ protecting groups ,” p . j . kocienski , georg thieme verlag ( 1994 ) both of which are incorporated herein by reference in their entireties . according to the present process for the preparation of the compounds of the invention , and variants thereof , the starting materials of formula ( 1 ) and ( 2 ) as well as any additional reactant [( e . g . of formula ( 15 )], auxiliar of chirality , solvent or agent being employed , is known or may be easily prepared according to known methods . the present invention also provides pharmaceutical compositions of compounds of formula ( i ) in admixture with one or more pharmaceutically acceptable carriers , for example those described in remington &# 39 ; s pharmaceutical sciences handbook , xvii ed ., mack pub ., n . y ., u . s . a , which is incorporated herein by reference in its entirety . examples include diluents ( such as sucrose , mannitol , lactose , starches ) and known excipients , including suspending agents , solubilizers , buffering agents , binders , disintegrants , preservatives , colorants , flavours , lubricants and the like . time release capsules , tablets and gels are also advantageous in administering the compounds of the present invention . administration of the compounds of the present invention may be accomplished according to patient needs , for example , orally , nasally , parenterally , e . g . subcutaneously , intravenously , intramuscularly , intrasternally and by infusion , by inhalation , rectally , vaginally , topically , locally , transdermally , and by ocular administration . various solid oral dosage forms may be used for administering compounds of the invention including such solid forms as tablets , gelcaps , capsules , caplets , granules , lozenges and bulk powders . various liquid oral dosage forms may also be used for administering compounds of the invention , including aqueous and non - aqueous solutions , emulsions , suspensions , syrups , and elixirs . such dosage forms can also contain known suitable inert diluents such as water and known suitable excipients such as preservatives , wetting agents , sweeteners , flavours , as well as agents for emulsifying and / or suspending the compounds of the invention . the compounds of the invention may be injected , for example , intravenously , in the form of an isotonic sterile solution . other preparations conventionally known in the art are also possible . suppositories for rectal administration of the said compounds of the invention may be prepared by mixing the compound with a suitable excipient such as cocoa butter , salicylates and polyethylene glycols . formulations for vaginal administration may be in the form of cream , gel , paste , foam , or spray formula containing , in addition to the active ingredient , conventional carriers . for topical administration , the pharmaceutical compositions may be in the form of creams , ointments , liniments , lotions , emulsions , suspensions , gels , solutions , pastes , powders , sprays , and drops suitable for administration to the skin , eye , ear or nose . topical administration may also involve transdermal administration , e . g . by means of transdermal patches . for the treatment of the diseases of the respiratory tract , the compounds of the invention are preferably administered by inhalation . inhalable preparations include inhalable powders , propellant - containing metering aerosols or propellant - free inhalable formulations . for administration as a dry powder , single - or multi - dose inhalers known from the prior art may be utilized . in that case , the powder may be filled in gelatine , plastic or other capsules , cartridges or blister packs or in a reservoir . a diluent or carrier , generally chemically inert to the compounds of the invention , e . g . lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention . inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form . the propellant - driven formulations may also contain other ingredients such as co - solvents , stabilizers and optionally other excipients . the propellant - free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous , alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft - mist nebulizers such as respimat ®. the compounds of the invention may be administered as the sole active agent or in combination with one or more other pharmaceutical active ingredients including those currently used in the treatment of respiratory disorders , e . g . β 2 - agonists , corticosteroids and m3 antagonists . the dosages of the compounds of the invention may depend upon a variety of factors including the particular disease to be treated , the severity of the symptoms , the route of administration , the frequency of the dosage interval , the particular compound utilized , the efficacy , toxicology profile , and pharmacokinetic profile of the compound . advantageously , the compounds of formula ( i ) may be administered for example , at a dosage comprised between 0 . 001 and 1000 mg / day , preferably between 0 . 1 and 500 mg / day . when they are administered by inhalation route , the dosage of the compounds of formula ( i ) is advantageously comprised between 0 . 01 and 20 mg / day , preferably between 0 . 1 and 10 mg / day . preferably , the compounds of formula ( i ) alone or combined with other active ingredients may be administered for the prevention and / or treatment of any obstructive respiratory disease such as asthma , chronic bronchitis and chronic obstructive pulmonary disease ( copd ). however the compounds of formula ( i ) may be administered for the prevention and / or treatment of any disease wherein the activity of pde4 receptors is implicated and inhibition of pde4 receptor activity is desired , or a disease state which is mediated by pde4 activity ( for instance a disease state in which pde4 is overexpressed or overactive ). examples of such diseases include : allergic disease states such as atopic dermatitis , urticaria , allergic rhinitis , allergic conjunctivitis , vernal conjunctivitis , eosinophilic granuloma , psoriasis , inflammatory arthritis , rheumatoid arthritis , septic shock , ulcerative colitis , crohn &# 39 ; s disease , reperfusion injury of the myocardium and brain , chronic glomerulonephritis , endotoxic shock , cystic fibrosis , arterial restenosis , artherosclerosis , keratosis , rheumatoid spondylitis , osteoarthritis , pyresis , diabetes mellitus , pneumoconiosis , toxic and allergic contact eczema , atopic eczema , seborrheic eczema , lichen simplex , sunburn , itching in the anogenital area , alopecia areata , hypertrophic scars , discoid lupus erythematosus , systemic lupus erythematosus , follicular and wide - area pyodermias , endogenous and exogenous acne , acne rosacea , beghet &# 39 ; s disease , anaphylactoid purpura nephritis , inflammatory bowel disease , leukemia , multiple sclerosis , gastrointestinal diseases , autoimmune diseases , and the like . they also include neurological and psychiatric disorders such as alzheimer &# 39 ; s disease , multiple sclerosis , amylolaterosclerosis ( als ), multiple systems atrophy ( msa ), schizophrenia , parkinson &# 39 ; s disease , huntington &# 39 ; s disease , pick &# 39 ; s disease , depression , stroke , and spinal cord injury . other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof . a solution of 3 - cyclopropylmethoxy - 4 - difluoromethoxy - benzaldehyde ( 5 . 00 g ) and 3 , 5 - dichloro - 4 - methylpyridine ( 2 . 57 g ) in 50 ml dry thf was cooled to − 30 ° c . solid potassium t - butoxide ( tbuok , 1 . 96 g ) was added portionwise maintaining the temperature between − 30 ° c . and − 20 ° c ., thus obtaining a dark red solution . after completion of the addition , the mixture was stirred at − 30 ° c . for 1 hour . a saturated aqueous solution of nh 4 cl ( 50 ml ) was then added to the reaction mixture , maintaining the temperature between − 5 ° c . and − 10 ° c . the color of the reaction mixture turned to yellow . the mixture was then extracted with etoac . the organic layer was dried over na 2 so 4 and the solvent was removed by evaporation . the residue was treated with 30 ml of a mixture of petroleum ether / etoac = 8 / 2 ; the precipitate was filtered and dried , obtaining 4 . 83 g of the title compound that was employed in the next step without further purification . compound ( 3 ) ( 13 . 0 g ) was dissolved in ch 2 cl 2 ( 250 ml ) then m - chloro perbenzoic acid ( 16 . 5 g ) was added , and the resulting solution was stirred at room temperature for 2 hours . na 2 s 2 o 3 ( 25 . 4 g ) was added , and the mixture was vigorously stirred at r . t . for 1 hour . the solid residue was filtered off , the solution was washed with 1n naoh ( 3 × 100 ml ) then the organic phase was dried over na 2 so 4 and the solvent was removed by evaporation to give 10 . 3 g of the desired product ( 4 ) as a white solid that was used in the next steps without further purification . compound ( 4 ) ( 19 . 95 g ), ( s )- acetylmandelic acid ( 9 . 22 g ), 1 - ethyl - 3 -[ 3 - dimethylamino propyl ] carbodiimide hydrochloride ( 18 g ), and 4 - dimethylaminopyridine ( 2 . 89 g ) were dissolved , under n 2 atmosphere , in dry ch 2 cl 2 ( 300 ml ). the reaction mixture was stirred at room temperature overnight . a 5 % aqueous solution of nahco 3 ( 200 ml ) was added and the aqueous phase was extracted with ch 2 cl 2 ( 3 × 100 ml ). the combined organic phases were dried over na 2 so 4 and the solvent was evaporated under reduced pressure to give the title compound ( 5 ) as mixture of two diastereoisomers ( 32 g ); separation of the two diastereoisomers is described in examples 4 and 6 . the crude diastereomeric mixture ( 5 ) ( 32 g ) was triturated with et 2 o ( 100 ml ), sonicated and filtered . the procedure was repeated four times in order to obtain a solid mixture enriched in diastereoisomer ( 6 ). this solid was crystallized from iproh ( 80 ml ) and filtered to give 9 . 65 g of compound ( 6 ) with diastereomeric purity & gt ; 95 %. the diastereomeric purity was determined by hplc analysis and by analytical chiral hplc performed on chiracel od column ( isocratic elution with hexane : isopropanol 40 : 60 , flow 0 . 45 ml / min , retention time = 27 . 2 min ). ′ 1h nmr ( 300 mhz , dmso - d6 ) ppm 8 . 57 ( s , 2h ), 7 . 27 - 7 . 44 ( m , 5 μl ), 6 . 91 - 7 . 18 ( m , 1h ), 7 . 03 ( t , 1h ), 6 . 71 - 6 . 79 ( m , 2h ), 5 . 95 ( dd , 1h ), 5 . 85 ( s , 1h ), 3 . 72 ( dd , 1h ), 3 . 60 ( dd , 1h ), 3 . 41 ( dd , 1h ), 3 . 23 ( dd , 1h ), 2 . 13 ( s , 3h ), 1 . 07 - 1 . 31 ( m , 1h ), 0 . 48 - 0 . 72 ( m , 2h ), 0 . 21 - 0 . 44 ( m , 2h ) compound ( 6 ) ( 6 . 42 g ) was suspended in methanol ( 350 ml ) then a saturated solution of nahco 3 ( 175 ml ) was added . the white suspension was vigorously stirred at room temperature overnight . the reaction mixture was diluted with ch 2 cl 2 ( 700 ml ) and washed with a 5 % aqueous solution of nahco 3 ( 300 ml ); the aqueous phase was extracted with ch 2 cl 2 ( 2 × 300 ml ), the combined organic layers were dried over na 2 so 4 , and the solvent was removed by evaporation under vacuum . the crude white solid obtained was triturated with et 2 o ( 2 × 100 ml ) and filtered to give 3 . 88 g of compound ( 7 ) with enantiomeric purity & gt ; 99 %. the enantiomeric purity was determined by analytical chiral hplc performed on chiracel od column ( isocratic elution with hexane : isopropanol 30 : 70 , flow 0 . 35 ml / min , retention time = 22 . 3 min ). ′ 1h nmr ( 300 mhz , dmso - d6 ) ppm 8 . 51 ( s , 2h ), 7 . 11 ( d , 1h ), 7 . 05 ( d , 1h ), 6 . 88 ( dd , 1h ), 7 . 01 ( t , 1h ), 5 . 59 ( d , 1h ), 4 . 84 ( dd , 1h ), 3 . 89 ( dd , 1h ), 3 . 84 ( dd , 1h ), 3 . 18 ( dd , 1h ), 3 . 02 ( dd , 1h ), 1 . 03 - 1 . 35 ( m , 1h ), 0 . 46 - 0 . 67 ( m , 2h ), 0 . 24 - 0 . 46 ( m , 2h )=+ 68 ° ( c = 0 . 5 , meoh ) the crude diastereomeric mixture ( 5 ) was triturated with et 2 o ( 100 ml ), sonicated and filtered . the procedure was repeated four times , and the filtrates were collected and evaporated under reduced pressure to give a solid mixture enriched in diastereoisomer ( 8 ) that was crystallized from iproh ( 100 ml ) to give 6 . 4 g of compound ( 8 ) as a white solid with diastereomeric purity & gt ; 99 %. the diastereomeric purity was determined by hplc analysis and by analytical chiral hplc performed on chiracel od column ( isocratic elution with hexane : isopropanol 40 : 60 , flow 0 . 45 ml / min , retention time = 21 . 6 min ). 1 h nmr ( 300 mhz , dmso - d6 ) ppm 8 . 27 ( s , 2h ), 7 . 27 - 7 . 45 ( m , 5h ), 7 . 20 ( d , 1h ), 7 . 08 ( d , 1h ), 7 . 00 ( dd , 1h ), 7 . 08 ( t , 1h ), 5 . 97 ( dd , 1h ), 5 . 85 ( s , 1h ), 3 . 93 ( dd , 1h ), 3 . 89 ( dd , 1h ), 3 . 33 ( dd , 1h ), 3 . 17 ( dd , 1h ), 2 . 07 ( s , 3h ), 1 . 14 - 1 . 38 ( m , 1h ), 0 . 50 - 0 . 71 ( m , 2h ), 0 . 21 - 0 . 47 ( m , 2h ) compound ( 8 ) ( 1 . 18 g ) was suspended in methanol ( 50 ml ) then a saturated solution of nahco 3 ( 25 ml ) was added . the white suspension was vigorously stirred at room temperature for 24 hours . the reaction mixture was diluted with ch 2 cl 2 ( 700 ml ) then a 5 % aqueous solution of nahco 3 ( 300 ml ) was added , and the phases were separated . the aqueous phase was extracted with ch 2 cl 2 ( 2 × 100 ml ), the combined organic layers were dried over na 2 so 4 , and the solvent was removed by evaporation under vacuum . the crude white solid obtained was triturated twice with et 2 o ( 50 ml ) and once with ch 2 cl 2 ( 20 ml ), then was filtered to give 0 . 74 g of compound ( 7 ) with enantiomeric purity & gt ; 99 %. the enantiomeric purity was determined by analytical chiral hplc performed on chiracel od column ( isocratic elution with hexane : isopropanol 30 : 70 , flow 0 . 35 ml / min , retention time = 24 . 0 min ). ′ 1h nmr ( 300 mhz , dmso - d6 ) ppm 8 . 51 ( s , 2h ), 7 . 11 ( d , 1h ), 7 . 05 ( d , 1h ), 6 . 88 ( dd , 1h ), 7 . 01 ( t , 1h ), 5 . 59 ( d , 1h ), 4 . 84 ( dt , 1h ), 3 . 89 ( dd , 1h ), 3 . 84 ( dd , 1h ), 3 . 18 ( dd , 1h ), 3 . 02 ( dd , 1h ), 1 . 08 - 1 . 32 ( m , 1h ), 0 . 47 - 0 . 66 ( m , 2h ), 0 . 26 - 0 . 45 ( m , 2h ) 2 -( 6 - methoxy - naphthalen - 2 - yl )- propionic acid 1 -( 3 - cyclopropylmethoxy - 4 - difluoromethoxy - phenyl )- 2 -( 3 , 5 - dichloro - pyridin - 4 - yl )- ethyl ester ( 10 , mixture of diastereoisomers 11 and 13 ) compound ( 3 ) ( 12 . 0 g ) was dissolved in dmf ( 100 ml ) then ( s )- 2 -( 6 - methoxy - naphthalen - 2 - yl )- propionic acid ( 7 . 5 g ), 4 - dimethylaminopyridine ( 3 . 6 g ), and 1 - ethyl - 3 -[ 3 - dimethylaminopropyl ] carbodiimide hydrochloride ( 5 . 7 g ) was added . after stirring at rt for 4 hours , water ( 1000 ml ) is added . the mixture was extracted with etoac ( 500 ml × 2 ), the combined organic layers are dried over sodium sulphate , and the solvent was removed by evaporation under reduced pressure to afford 17 . 0 g of an oil which is crystallized from etoh thus obtaining 11 . 5 g of the title compound as mixture of diastereomers ( 11 ) and ( 13 ). 1 h nmr ( 200 mhz , cdcl 3 ) ppm 8 . 43 and 8 . 60 ( 2s , 1h each , 2h ), 7 . 51 - 7 . 68 ( m , 3h ), 7 . 10 - 7 . 23 ( m , 3h ), 6 . 85 - 6 . 97 ( m , 2h ), 6 . 51 - 6 . 68 ( m , 1h ), 6 . 22 - 6 . 97 ( t , 1h , chf 2 ), 6 . 00 - 6 . 13 ( m , 1h ), 3 . 93 - 3 . 95 ( s , 3h , och 3 ), 3 . 72 - 3 . 84 ( m , 2h ), 3 . 07 - 3 . 57 ( m , 3h ), 1 . 42 - 1 . 45 ( d , 3h , ch 3 ), 0 . 94 - 1 . 25 ( m , 1h ), 0 . 51 - 0 . 67 ( m , 2h ), 0 . 12 - 0 . 36 ( m , 2h ). the compound was isolated from the diastereomeric mixture of example 8 by hplc separation using a daisogel 10 μm , 50 × 300 mm column ; eluent : n - hexane / methyl - tert - butyl - ether / isopropyl alcohol : 90 / 9 . 9 / 0 . 1 ; flow : 80 ml / min . ; loading : 300 mg per injection ; elution time : from 11 to 20 min . the collected fractions were evaporated and the residue was crystallized from n - hexane / isopropyl - alcohol . 1 h nmr ( 200 mhz , cdcl 3 ) ppm 8 . 60 ( s , 2h ), 7 . 68 - 7 . 75 ( m , 2h ), 7 . 58 - 7 . 59 ( m , 1h ), 7 . 27 - 7 . 29 ( d , 1h ), 7 . 12 - 7 . 24 ( m , 2h ), 6 . 98 - 7 . 04 ( m , 1h ), 6 . 73 - 6 . 78 ( dd , 1h ), 6 . 67 - 6 . 68 ( d , 1h ), 6 . 60 - 7 . 35 ( t , 1h , chf 2 ), 5 . 99 - 6 . 06 ( m , 1h ), 3 . 84 - 3 . 87 ( m , 4h ), 3 . 47 - 3 . 55 ( m , 2h ), 3 . 32 - 3 . 41 ( dd , 1h ), 3 . 22 - 3 . 29 ( m , 1h ), 1 . 33 - 1 . 37 ( d , 3h , ch 3 ), 0 . 96 - 1 . 03 ( m , 1h ), 0 . 43 - 0 . 52 ( m , 2h ), 0 . 13 - 0 . 21 ( m , 2h ). the compound was isolated from the diastereomeric mixture of example 8 by hplc separation using a daisogel 10 μm , 50 × 300 mm column ; eluent : n - exane / methyl - tert - butyl - ether / isopropyl - alcohol : 90 / 9 . 9 / 0 . 1 ; flow : 80 ml / min . ; loading : 300 mg per injection ; elution time : from 7 to 10 min . the collected fractions were evaporated and the residue was crystallized from n - hexane / isopropyl - alcohol . 1 h nmr ( 200 mhz , cdcl 3 ) ppm 8 . 27 ( s , 2h ), 7 . 64 - 7 . 80 ( m , 2h ), 7 . 56 - 7 . 57 ( m , 1h ), 7 . 28 - 7 . 29 ( d , 1h ), 7 . 14 - 7 . 20 ( m , 3h ), 6 . 68 - 7 . 42 ( t , 1h , chf 2 ), 6 . 93 - 6 . 98 ( m , 2h ), 6 . 00 - 6 . 07 ( m , 1h ), 3 . 88 - 3 . 92 ( m , 4h ), 3 . 71 - 3 . 84 ( m , 2h ), 3 . 39 - 3 . 51 ( dd , 1h ), 3 . 16 - 3 . 25 ( dd , 1h ), 1 . 33 - 1 . 37 ( d , 3h , ch 3 ), 1 . 08 - 1 . 23 ( m , 1h ), 0 . 50 - 0 . 59 ( m , 2h ), 0 . 34 - 0 . 26 ( m , 2h ). to a suspension of (+)- 2 -( 6 - methoxy - naphthalen - 2 - yl )- propionic acid - 1 -( 3 - cyclopropyl methoxy - 4 - difluoromethoxy - phenyl )- 2 -( 3 , 5 - dichloro - pyridin - 4 - yl )- ethyl ester ( 13 ) ( 14 . 0 g ) in methanol ( 110 ml ), potassium tert - butoxide ( 5 . 1 g ) was added . the resulting mixture was stirred at rt for 2 hours , obtaining a clear solution . water was slowly added under stirring to incipient precipitation ( turbid solution ). after stirring for a further 60 minutes , the precipitated solid was filtered , washed with water and dissolved in chloroform ( 100 ml ). the solution was dried over sodium sulphate and the solvent removed under vacuum . the residue was crystallized in chloroform / hexane = 1 / 2 . 5 to obtain 8 . 1 g of white solid . 1 h nmr ( 200 mhz , cdcl 3 ) ppm δ 8 . 45 ( s , 2h ), 7 . 19 - 7 . 08 ( d , 1h ), 7 . 06 - 7 . 00 ( d , 1h ), 6 . 95 - 6 . 85 ( dd , 1h ), 6 . 99 - 6 . 24 ( t , 1h , chf 2 ), 5 . 18 - 5 . 00 ( m , 1h ), 3 . 98 - 3 . 78 ( m , 2h ), 3 . 54 - 3 . 35 ( m , 1h ), 3 . 31 - 3 . 15 ( m , 1h ), 2 . 04 - 1 . 94 ( d , 1h , oh ), 1 . 40 - 1 . 14 ( m , 1h ), 0 . 75 - 0 . 53 ( m , 2h ), 0 . 50 - 0 . 29 ( m , 2h ). starting from diastereoisomer ( 11 ), following the procedure of example 10 , alcohol ( 12 ) was obtained . compound ( 14 ) ( 3 . 0 g ) was dissolved in ch 2 cl 2 ( 100 ml ). 70 % m - chloro perbenzoic acid ( 5 . 4 g ) was added , and the resulting solution was stirred at room temperature for 18 hours . solid na 2 s 2 o 3 ( 5 g ) was then added , and the mixture was vigorously stirred at r . t . for 30 minutes . the solid residue was removed by filtration ; the organic solution was diluted with additional 100 ml of ch 2 cl 2 and washed with aqueous saturated nahco 3 solution ( 3 × 100 ml ). the organic phase was dried over na 2 so 4 , and the solvent was removed by evaporation . the residue was triturated in etoac ( 20 ml ) to give 1 . 9 g of the desired product 7 as a white solid , which was used in the next step without further purification . 1 h nmr ( 200 mhz , cdcl 3 ) ppm 8 . 14 ( s , 2h ), 7 . 18 - 7 . 09 ( d , 1h ), 7 . 07 - 7 . 02 ( d , 1h ), 6 . 92 - 6 . 83 ( dd , 1h ), 7 . 01 - 6 . 22 ( t , 1h , chf 2 ), 5 . 10 - 4 . 96 ( m , 1h ), 3 . 96 - 3 . 84 ( d , 2h ), 3 . 45 - 3 . 29 ( m , 1h ), 3 . 23 - 3 . 07 ( m , 1h ), 3 . 24 - 3 . 17 ( d , 1h , oh ), 1 . 41 - 1 . 67 ( m , 1h ), 0 . 75 - 0 . 53 ( m , 2h ), 0 . 50 - 0 . 29 ( m , 2h ). alcohol ( 9 ) may be obtained following the procedure described in example 13 , using alcohol ( 12 ) in place of alcohol ( 14 ) as starting material . 1 - ethyl - 3 -[ 3 - dimethylamino propyl ] carbodiimide hydrochloride ( 2 . 85 g ) was added to a solution of alcohol ( 14 ) ( 2 . 0 g ), 4 - dimethylaminopyridine ( 0 . 3 g ), 3 - cyclopropylmethoxy - 4 -( n - tert - butoxycarbonyl - n - methanesulfonyl )- amino - benzoic acid ( 2 . 0 g ) in dry ch 2 cl 2 ( 180 ml ) at r . t . under nitrogen atmosphere . after stirring at r . t . overnight , the mixture was washed with 5 % aqueous hcl ( 2 × 100 ml ); the organic phase was separated and washed with a saturated aqueous solution of nahco 3 ( 2 × 100 ml ), dried over na 2 so 4 and evaporated to dryness . the crude was purified by flash chromatography on silica gel in gradient elution ( hexane / etoac 10 / 1 to 6 / 4 ) to afford 1 . 4 g of the title compound . 3 - cyclopropylmethoxy - 4 -( n - tert - butoxycarbony - n - methanesulfonyl )- amino - benzoic acid 1 -( 3 - cyclopropylmethoxy - 4 - difluoromethoxy - phenyl )- 2 -( 3 , 5 - dichloro - pyridin - 4 - yl )- ethyl ester ( 1 . 4 g ) was dissolved in ch 2 cl 2 ( 140 ml ). a 4m solution of hcl in dioxane ( 40 ml ) was added and the resulting mixture was stirred at r . t . for 24 hours . the reaction mixture was then evaporated to dryness , and the residue was triturated in iproh ( 50 ml ) and subsequently in etoh ( 50 ml ) followed by et 2 o ( 70 ml ) to afford 0 . 880 g of compound ( c1 ). compound ( c2 ) was prepared according to the same synthetic procedure of example 15 , starting from alcohol intermediate ( 7 ). alternatively , compound ( c2 ) can be prepared starting from compound ( c1 ) as described in the following example 17 . preparation of (−)- 3 - cyclopropylmethoxy - 4 - methanesulfonylamino - benzoic acid 1 -( 3 - cyclopropylmethoxy - 4 - difluoromethoxy - phenyl )- 2 -( 3 , 5 - dichloro - 1 - oxy - pyridin - 4 - yl )- ethyl ester ( c2 ) starting from compound ( c1 ) compound ( c1 ) ( 0 . 69 g ) was dissolved in ch 2 cl 2 ( 20 ml ). 70 % m - chloro perbenzoic acid ( 0 . 355 g ) was added , and the resulting solution was stirred at room temperature for 18 hours . solid na 2 s 2 o 3 ( 0 . 244 g ) was then added , and the mixture was vigorously stirred at r . t . for 30 minutes . the solid residue was removed by filtration ; the organic solution was diluted with additional 20 ml of ch 2 cl 2 and washed with aqueous saturated nahco 3 solution ( 3 × 20 ml ). the organic phase was dried over na 2 so 4 and the solvent was removed by evaporation . the residue was triturated in etoh ( 20 ml ) to give 0 . 710 g of the desired compound ( c2 ) as a white solid . the following compounds shown in table 2 were prepared following the same route using suitable reagents . the carboxylic acid intermediates employed in the synthesis of the described final compounds are commercially available or are already known or are synthesized according to known methods . 3 - hydroxy - 4 - nitro - benzoic acid ( 10 g ) was dissolved in meoh ( 500 ml ). 96 % h 2 so 4 ( 2 ml ) was added , and the mixture was heated to 60 ° c . for 18 hours . the reaction mixture was concentrated to approx . 200 ml , diluted with etoac ( 200 ml ) and washed with an aqueous saturated solution of nahco 3 ( 2 × 20 ml ). the organic layer was dried over na 2 so 4 and the solvent was removed by evaporation to yield 10 . 5 g of the desired intermediate . 3 - hydroxy - 4 - nitro - benzoic acid methyl ester ( 10 . 5 g ) was dissolved in dry dmf ( 150 ml ) under n 2 atmosphere . k 2 co 3 ( 24 . 3 g ), ki ( 2 . 6 g ) and cyclopropylmethylbromide ( 10 . 3 ml ) were added and the mixture was stirred at 50 ° c . for 6 hours . the reaction mixture was diluted with water ( 300 ml ) and extracted with et 2 o ( 2 × 200 ml ); the combined organic layers were dried over na 2 so 4 and the solvent was removed by evaporation to yield 12 . 7 g of the desired intermediate . 3 - cyclopropylmethoxy - 4 - nitro - benzoic acid methyl ester ( 12 . 7 g ) was dissolved in meoh ( 100 ml ) and etoac ( 100 ml ); 10 % pd / c ( 1 . 0 g , suspended in 20 ml of water ) was added , and the mixture is hydrogenated in a parr apparatus ( h 2 : 20 psi ) for 5 hours . 37 % hcl was added ( 10 ml ), and hydrogenation was continued for additional 2 hours to obtain complete conversion . the catalyst was filtered over a celite pad , the mixture was diluted with etoac ( 200 ml ) and washed with an aqueous saturated solution of nahco 3 ( 2 × 100 ml ). the organic layer was dried over na 2 so 4 and the solvent was removed by evaporation to yield 10 . 7 g of the desired intermediate . methyl 3 -( cyclopropylmethoxy )- 4 - aminobenzoate ( 8 . 86 g ) was dissolved in pyridine ( 80 ml ) at room temperature under n 2 atmosphere . methanesulfonyl chloride ( 4 . 04 ml ) was added and the mixture was stirred at r . t . for 18 hours . the reaction mixture was evaporated to dryness , the crude was treated with 1n hcl ( 500 ml ) and extracted with ch 2 cl 2 ( 3 × 200 ml ). the organic layer was dried over na 2 so 4 and the solvent was evaporated off to yield 11 . 7 g of the desired intermediate . 3 - cyclopropylmethoxy - 4 - methanesulfonylamino - benzoic acid methyl ester ( 3 . 0 g ) was dissolved in ch 2 cl 2 ( 150 ml ). dimethylaminopyridine ( dmap , 1 . 22 g ) and boc 2 o ( 2 . 18 g ) were added and the mixture was stirred at r . t . for 1 hour . the reaction mixture was washed with 5 % aqueous hcl ( 2 × 50 ml ), the organic layer was dried over na 2 so 4 and the solvent was removed by evaporation . the residue was triturated in et 2 o and filtered to afford 4 . 0 g of the desired intermediate that was used in the next steps without further purification . cyclopropylmethoxy - 4 -( n - tert - butoxycarbonyl - n - methanesulfonyl )- amino - benzoic acid methyl ester ( 4 . 0 g ) was dissolved in meoh ( 100 ml ). 1n naoh ( 15 ml ) was added , and the resulting mixture was stirred at r . t . for 1 hour , then was heated to 50 ° c . for 2 hours . the reaction mixture was then diluted with etoac ( 250 ml ) and washed with 1n hcl ( 2 × 100 ml ). the organic layer was dried over na 2 so 4 and the solvent was evaporated off to give 3 . 5 g of the desired acid derivative . in vitro determination of pde4 inhibitory activity in the peripheral blood mononuclear cells ( pbmcs ) assay the assay , which is based on the known inhibitory activity exerted by pde4 inhibitors on the lipopolyshaccarides ( lps )- induced tumour necrosis factor - alpha ( tnf - α release in peripheral blood mononuclear cells ( pbmcs ), is performed according to a method previously described ( hatzelmann a et al ., j . pharmacol . exp . ther ., 2001 ; 297 : 267 - 279 ; and draheim r et al ., j . pharmacol . exp . ther ., 2004 ; 308 : 555 - 563 , both of which are incorporated herein by reference in their entireties . cryopreserved human pbmcs , ( 100 μl / well ) are incubated in 96 - well plates ( 10 5 cells / well ), for 30 minutes , in the presence or absence ( 50 microl ) of the test compounds whose concentrations range from 10 − 12 m to 10 − 6 m . subsequently , lps ( 3 ng / ml ) is added . after 18 hours incubation at 37 ° c . in a humidified incubator under an atmosphere of 95 % air and 5 % co 2 , culture medium is collected and tnf - α is measured by elisa . the results regarding compounds c1 to c6 , expressed as mean ± 95 % confidence limits of the molar concentration of the test compound producing 50 % inhibition of lps - induced tnf - α release ( ic 50 ), are comprised between 0 . 06 and 4 . 4 nm . the effects of the tested compounds are calculated as percentage of inhibition of tnf - α release , assuming lps - induced tnf - α production in the absence of inhibitor compound as 100 % and basal tnf - α production of pbmcs in the absence of lps as 0 %. evaluation of the ability to inhibit the low affinity lpde4 versus the ability to compete for the high affinity hpde4 the affinity toward lpde4 and hpde4 is assessed as previously described respectively in cortijo j et al ., br . j . pharmacol ., 1993 , 108 : 562 - 568 and duplantier a j et al ., j . med . chem ., 1996 ; 39 : 120 - 125 , both of which are incorporated herein by reference in their entireties . the concentration of the test compound ranges between 10 − 12 m and 10 − 5 m . the values of affinity toward lpde4 and hpde4 tested on compounds c1 to c6 are comprised between 82 and 477 . in the case of lpde4 , the ic 50 is the molar concentration of the test compound producing 50 % inhibition of camp disappearance , while in the case of hpde4 , the ic 50 is the molar concentration of the test compound producing 50 % inhibition of the binding of [ h 3 ] rolipram . the results indicate that the compounds of the invention inhibit lpde4 with subnanomolar affinity and are considerably more selective toward lpde4 versus hpde4 . synergistic activity of fixed dose combination of carmoterol / c1 on carbachol - induced contraction in guinea - pigs trachea zig - zag tracheal segments are obtained from male ovoalbumin ( oa )- sensitised guinea pigs and two preparations are obtained from a trachea . each preparation is placed in 20 - ml organ bath filled with oxygenated ( o 2 95 % and co 2 5 %) normal krebs - henseleit solution and maintained at 37 ° c . tracheal preparations are connected to isometric force transducers under a resting tone of 1 g . after an equilibration period of 60 minutes , tracheal preparations are pretreated for 30 minutes with c1 ( 10 - 7 m ), carmoterol ( 3 * 10 - 10 m ), the association c1 and carmoterol or vehicle , respectively , followed by cumulative administration of oa ( 10 − 10 - 10 − 5 g / ml ). at the end of the oa administration a maximal concentration of carbachol ( 10 − 5 m ) is added to obtain the maximal contraction of each preparation . the effects are expressed as percent values of the carbachol - induced maximal response ( 100 %). 30 - minute pre - treatment of the preparation with c1 ( 10 − 7 ni ) caused an inhibition of the oa - induced contraction of 23 %. similarly the inhibition produced by carmoterol ( 3 * 10 - 10 m ) is 18 %. c1 ( 10 − 7 m ) and carmoterol ( 3 * 10 − 10 m )- combination caused a reduction of the oa - induced contraction of the 93 %. this study shows that both carmoterol and c1 are potent in antagonizing carbachol - induced contraction in guinea - pig airways . moreover , in line with their complementary molecular mechanism of action , in the frame of a functional agonism - antagonism , fixed combinations display synergistic effect in the control of cholinergic contraction in guinea - pig trachealis where a numerical limit or range is stated herein , the endpoints are included . also , all values and subranges within a numerical limit or range are specifically included as if explicitly written out . 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 . all patents and other references mentioned above are incorporated in full herein by this reference , the same as if set forth at length .

US-201313930304-A

a conventional respiratory nebulizer has an emergency medication dose storage system conveniently useable in an emergency to deliver the stored medication dose directly to the nebulizing chamber quickly , reliably , and with a single impulse of manual force to a simple mechanical delivery system , thereby making the nebulizer useable in two steps : deploy the medication with a single stroke of force ; and inhale the nebulized medication . the nebulizer can be operated without disassembling the nebulizer housing so as to expose the nebulizing chamber and without manually opening the liquid medication container and , without spillage and without manual pouring of the liquid medication directly into the nebulizing chamber , and without reassembling the nebulizer housing before positioning the inhaler mouthpiece in the mouth so as to inhale the nebulized medication .

in keeping with the objects of the invention , the present invention provides a conventional nebulizer having a built - in ( and thus integral ) novel storage structure for storing a dose of liquid medication in preparation for an emergency . the liquid medication is conveniently delivered to the conventional nebulizer &# 39 ; s conventional nebulizing chamber . a conventional nebulizer is used to aerosolize liquid medication and deliver the aerosol for inhalation by a user . although both are typically used for treating pulmonary medical conditions such as asthma , a conventional nebulizer differs from hand - held inhaler sprayers in that the hand - held aerosolizer generally contains multiple doses of medication , has a propellant permanently loaded within it , and is indicated for use where a single aerosolized dispensed quantity comprises the intended dose of medication for use by a patient . it is critical to accurately time the dispensing shot from a hand - held medication inhaler to coincide with a user &# 39 ; s inspiration , so as to ensure that the medication actually reaches the lungs of a user . mistiming of the dispensing shot from a handheld inhaler can result in a short dose of medication or in no dose at all . a conventional nebulizer , in contrast , has no stored medication at all . it is comprised of a nebulizing chamber , an air pump and an inhaler . the air pump , usually electrically driven , supplies a stream of compressed air through a conduit to a nebulizer housing . the housing is generally cylindrical , has a top and bottom part that can be separated by a user , and the top part has an upwardly projecting extension that ends in an inhaler . the inhaler is generally a horizontally disposed tube with an open distal end and a proximal end that is an open - ended mouthpiece . the conventional nebulizer housing contains a nebulizing chamber . the chamber is basically a vertical cylinder with an open top for receiving a dose of liquid medication . the chamber has an air - stream inlet in the bottom . compressed air from the air pump is conveyed to the chamber &# 39 ; s bottom air inlet through a conduit . the compressed air enters the bottom of the nebulizing chamber and is then mixed with the dose of liquid medication , causing the medication to become nebulized into an aerosol . there is an open airflow between the nebulizer chamber and an upwardly extending short tube leading to a t - connection with a horizontal tube open at both ends that comprises an inhaler pipe with a breather mouthpiece at one end . one open end of the inhaler pipe comprises a distal end , opposite to a proximal end which comprises the mouthpiece shaped to fit into the mouth of a user . the inhaler pipe is in open airflow with the nebulizer chamber . when a user inhales through the proximal open end of the mouthpiece , air is urged into the open distal end and into the proximal end of the mouthpiece . the user &# 39 ; s inhalation effort also urges air from the nebulizer chamber , containing nebulized medication to rise up the connecting tube and to enter the proximal end of the mouthpiece . the user thus inhales nebulized liquid medication , and the user may do so with inhalations repeated as needed over a period of time sufficient to get relief from respiratory symptoms that put the user into acute distress , such as an asthma attack . thus an important difference between a conventional nebulizer and a hand - held inhaler is that the hand - held device is intended to deliver a single dose of medication intended to treat the entire episode of acute respiratory distress . the user must time the dispensing shot of the hand - held nebulizer to coincide with a breath inspiration or the effect of the device is defeated and the medication shot is wasted . in contrast , a conventional nebulizer provides the ability for an acute respiratory sufferer to breathe as many times as needed to receive sufficient nebulized medication into the lungs to alleviate the acute distress symptoms . the conventional nebulizer thus does a different job as compared to the hand held inhaler . in additional comparison , handheld inhalers typically contain numerous doses of medication while a conventional nebulizer contains no medication at all . a critical problem solved by the present invention is that , while medication delivered by a conventional nebulizer could be more effective than medication delivered by a hand - held inhaler due to the availability of repeated inhalations of medication with the conventional nebulizer , there remains an important shortcoming , which is addressed by the inventive step of the current invention . in order to use a conventional nebulizer it is necessary for a user , or someone assisting the user to ( 1 ) disassemble the nebulizer housing by removing its top so as to expose the nebulizing chamber ; ( 2 ) locate a separately stored container of liquid medication to be nebulized ; ( 3 ) carefully open the liquid medication container so as not to spill it ; ( 4 ) pour the liquid medication directly into the nebulizing chamber without losing any of it through spilling into the nebulizer housing ; ( 5 ) reassemble the nebulizer housing ; and ( 6 ) position the inhaler mouthpiece in the mouth so as to inhale the nebulized medication . a problem arises in that use of a nebulizer is not going to be sought until a person is already in acute respiratory distress . otherwise , problems of nebulizer overuse , overmedication , medication side effects and a search for alternate pulmonary therapy modalities will all become concerns for a patient . therefore , use of a conventional nebulizer implies that a user is experiencing acute pulmonary symptoms , is in acute distress , and is experiencing an emergency . persons suffering acute respiratory distress are routinely subject to being fearful , frightened , or fully panicked . fear , fright and panic are well known to degrade performance on tasks requiring some level of skill in eye - hand coordination tasks . when seeking the use of a conventional nebulizer , then , a user is required to locate a separate container holding a dose of liquid medication , open the nebulizer , open the medication container , pour the liquid into the nebulizer chamber , and re - assemble the nebulizer housing . the aforedescribed sequence of steps can be difficult or impossible for a fearful , frightened or panicked sufferer of acute respiratory distress . an important consideration is that there will almost certainly be occasions when a person experiencing acute need of a conventional nebulizer is alone and without anyone to assist . it is just these occasions where a conventional nebulizer may be available but be impossible for a user to operate . to solve the problem of user inability to operate a conventional nebulizer in an emergency , the present invention presents a simple solution : construct a conventional nebulizer than has a built - in stored dose of liquid medication and make that liquid dose injectable into the nebulizer chamber with either a simple twist of a screw cap ( preferred embodiment of the present invention ) or a single stroke of user force ( non - preferred embodiment ). as provided in the present invention the user will not be required to disassemble or reassemble the housing of a conventional nebulizer ; will not be required to locate a separately stored container of liquid medication ; will not be required to open the separate medication container ; and will not be required to pour the liquid medication into the nebulizer chamber . according to the present invention , a conventional nebulizer will have added to its housing a storage chamber , preferably cylindrical , for storing , in loaded - gun fashion , a dose of liquid medication on board the conventional nebulizer housing . in the preferred embodiment of the present invention the novel storage chamber for the medication capsule is a substantially cylindrical sleeve with an open top aperture projecting vertically downward from the inhaler pipe to a point slightly above the conventional nebulizer chamber within the housing of a conventional nebulizer . the sleeve &# 39 ; s diameter is small enough so as not to interfere with the conventional nebulizer &# 39 ; s free flow of air from the nebulizer chamber , up the conventional neck of a nebulizer and into the conventional inhaler pipe of a nebulizer . the medication capsule storage sleeve merely occupies a portion of the air passage between the nebulizer chamber and the inhaler pipe and thus in no way does the storage sleeve seal or impede the conventional free flow of air within what is otherwise a conventional nebulizer . in the non - preferred embodiment of the present invention the novel medication storage chamber ( as with the preferred embodiment , the storage chamber of the non - preferred embodiment is also sleeve - like ); however , instead of extending vertically as does the sleeve of the preferred embodiment , the storage chamber of the non - preferred embodiment generally projects outwardly from an inner delivery end in proximity to the nebulizing chamber , through the wall of a conventional nebulizer housing , and extends to an outer user - access end . in the non - preferred embodiment the novel structure medication storage chamber generally has a tapered - nozzle open - aperture delivery end disposed in close proximity to the nebulizing chamber so that the liquid medication , when deployed by a user , is injected reliably and directly into the nebulizing chamber . in the non - preferred embodiment ( as is also true for the preferred embodiment ) the novel medication storage chamber accepts a single disposable and user - replaceable cartridge containing a dose of liquid medication to be nebulized in an emergency . the chamber of the non - preferred embodiment is provided at its outer end with pressure means for a user to exert a stroke of physical force upon the outer end of the medication chamber so as to squeeze upon the medication cartridge . the cartridge of the non - preferred embodiment is preferably cylindrical with an inner end tapered to match and fit within the tapered nozzle of the medication storage chamber of the non - preferred embodiment . in the non - preferred embodiment an outer end of the medication cartridge is capable of accepting force from a manually - operated piston . the medication dose cartridge of the non - preferred embodiment has a seal that is capable of rupture upon application of hydraulic pressure , the seal being located at an inner end of the cartridge , disposed at or near the inner end of the medication storage chamber . the preferable emergency user - pressure means is a piston arrangement , where the piston is integral with the medication cartridge , is elastomerically sealed , and accepts a push - force from a piston rod . the easily recognized example of this is a medical syringe . the non - preferred embodiment of the present invention may be described as a medical syringe capable of receiving disposable medication dose cartridges , in combination with a conventional nebulizer . the piston arrangement ( exemplified by a medical syringe ) projects through the wall of the conventional nebulizer and has its medication delivery nozzle at or very near the conventional nebulizing chamber . conventional stop means at the outer end of the chamber prevents the piston rod from coming out of the outer end of the medication storage chamber . in another embodiment , insertion of the medication capsule within a rotatable knob cam activation assembly facilities bursting of the seal of the medication reservoir capsule . the novel combination of the present invention addresses and solves the problem of what procedure must be followed by a patient having a breathing emergency , such as a severe attack of asthma , and needs a quick reliable dose of nebulized medication , particular where ( 1 ) no other person is available to assist the patient and ( 2 ) a single - shot hand - held nebulizer is medically inappropriate for treatment . fig1 is an exploded view of a prior art conventional nebulizer housing 10 shown disassembled . conventional medication container 14 is shown adding liquid medication to conventional nebulizing chamber 15 . in the event of a respiratory emergency , a user would have to locate a separate container of liquid medication 14 , then open it , then disassemble ( as shown ) the portions of the nebulizer housing 10 , then pour the liquid medication from its separate container 14 into nebulizer chamber 15 , then reassemble nebulizer housing 10 before being able to inhale nebulized medication through proximal end of conventional mouthpiece 30 which is part of conventional breather 25 , breather 25 having an open distal end 31 opposite to proximal end 30 . when a user has pour medication into nebulizer chamber 15 and reassembled housing 10 , then conventional air supply line 20 supplies a stream of compressed air to nebulizer chamber 15 causing the liquid medication to become nebulized and urging the nebulized medication upward through connecting tube 11 so as to be available for user inhalation through proximal end mouthpiece 30 . fig2 shows a perspective view of the prior art conventional nebulizer in use . a user inserts the proximal mouthpiece end 30 of breather 25 into the mouth and inhales . nebulizer housing 10 [ concealed by the user &# 39 ; s hand in the drawing ] furnishes nebulized ( aerosolized ) medication to the user for as many repeated inhalations as the user may need for alleviation of an acute respiratory emergency . air supply lines 20 is shown extending upwardly but the user &# 39 ; s hand conceals the intersection of air supply line 20 with the bottom of the nebulizer chamber 10 . in a non - preferred embodiment of the present invention , the novel medication storage chamber generally projects outwardly from an inner delivery end in proximity to the nebulizing chamber , through the wall of a conventional nebulizer housing , and extends to an outer user - access end . fig3 shows the non - preferred embodiment of the present invention with a conventional nebulizer housing 10 fitted with novel integral ( i . e ., built - in ) medication storage chamber 35 . storage chamber 35 is capable of receiving removable medication dose cartridge 40 . both chamber 35 and matching cartridge 40 are elongated , preferably cylindrical and both have matching inner and opposite outer ends . the inner end 36 of storage chamber 35 is disposed within nebulizer housing 10 while outer end 37 of chamber 35 is outside of nebulizer housing 10 . chamber 35 is fixed in a position that places its inner end 36 in close proximity to nebulizing chamber 15 . the preferably cylindrical body of chamber 35 points radially outward from nebulizing chamber 15 so that outer end 37 of medication storage chamber 35 is outside of and spaced apart from nebulizer housing 10 . medication storage chamber 35 is provided with open - ended tapered nozzle 38 at its inner end 36 , nozzle 38 being in close proximity to nebulizing chamber 15 so as to reliably inject a dose of liquid medication from cartridge 40 upon user application of a single inwardly directed pressure stroke to pressure plate 56 of grooved piston rod 50 , disposed within medication storage chamber 35 , at the outer end 37 of said storage chamber . medication cartridge 40 is provided with tapered inner end 42 tapered to open end 45 . pressure seal 43 is located at inner end 42 of cartridge 40 while elastomerically sealed piston 44 is located at the outer end of cartridge 44 . upon user application of a single stroke of inward pressure on pressure plate 56 at the outer end of piston rod 50 ( user grasps finger engagements wings 52 for convenience ), contact is made between grooved piston rod 50 and piston 44 resulting in an increase in hydraulic pressure on seal 43 . tapered shoulders 47 of cartridge 40 contact and engage tapered nozzle 38 of medication storage chamber 35 , causing cartridge 40 to become seated firmly within cartridge 35 when a user applies manual pressure to pressure plate 56 of grooved piston rod 50 . seal 43 is manufactured so as to burst upon user force application on pressure plate 56 of grooved piston rod 50 . when seal 43 bursts , pressure from grooved piston rod 50 causes injection of liquid medication from cartridge 40 into nebulizing chamber 15 . the remainder of the nebulizing operation is conventional . fig4 shows the non - preferred embodiment of the present invention with a detail of removable medication dose cartridge 40 , having pressure seal 43 disposed at inner end 42 , open end 45 is comprised of the tapered shoulders 47 at inner end 42 of cartridge 40 and outer end 41 contains movable elastomerically sealed piston 44 . piston 44 receives pressure from grooved piston rod 50 . in response , piston 44 moves in an inward direction applying hydraulic pressure to the liquid medication contained within the body of cartridge 40 . in turn the hydraulic pressure causes seal 43 at the inner end of cartridge 40 to burst . when seal 43 ruptures , liquid medication is forced under piston pressure to be injected into nebulizing chamber 15 . fig5 shows the non - preferred embodiment of the present invention with a cut away side view detail of medication storage chamber 35 intersecting nebulizer housing 10 so as to have inner end 36 of chamber 35 in close proximity to nebulizing chamber 15 for reliable injection into chamber 15 of liquid medication from open inner end 43 of cartridge 40 upon application of a single stroke of inward user pressure upon pressure plate 56 of grooved piston rod 50 , the force being transmitted to piston 44 of cartridge 40 . stop 55 engages groove on piston rod 50 , preventing piston rod 50 from coming out of medication storage chamber 35 . as shown on fig6 and 7 , in a preferred embodiment , the novel medication storage sleeve 62 projects vertically downward from the top of horizontal inhaling pipe 70 extending downwardly into the nebulizer housing 10 to a point just above the nebulizing chamber 15 . a medication dose capsule 66 is an elongated substantially cylindrical container oriented vertically within sleeve 62 . capsule 66 is user inserted and user removed respectively to and from sleeve 62 . capsule 66 is intended to be stored in sleeve 66 until used , and then removed and replaced in preparation for a next use of the nebulizer . capsule 66 has a lower end tear off tab 64 . sleeve 62 has lower end stop means 62 c to engage tear off tab 64 to prevent tab 64 from turning when torque is applied to capsule 66 . stop means 62 a is attached by a retention means , such as bracket 62 b , within hollow sleeve 62 , allowing fluid flow of the liquid medication through lots 62 a and 62 b and then through aperture 62 d of hollow sleeve 62 . sleeve 62 accepts screw cap activating handle 68 after a user inserts capsule 66 into sleeve 62 . screw cap 68 engages projection means on capsule 66 so as to twist capsule 66 within sleeve 62 when a user applies a torque force to screw cap 68 . because the lower end tear off tab 64 of capsule 66 is prevented from twisting by the stop means 62 a within sleeve 66 , capsule 66 is caused to shear and rupture at its lower end when a user twists cap 68 . liquid medication within capsule 66 flows by gravity into nebulizing chamber 15 upon rupture of the lower end of capsule 66 . the liquid medication is then conventionally nebulized and the user gets the therapeutic benefit of the nebulizer in a conventional manner . fig6 shows an exploded view of the preferred embodiment novel medication storage sleeve 62 projects vertically downward from the top of horizontal inhaling pipe 70 extending downwardly into the nebulizer housing 10 to a point just above the nebulizing chamber 15 . a medication dose capsule 66 is an elongated substantially cylindrical container oriented vertically within sleeve 62 . capsule 66 is user inserted and user removed respectively to and from sleeve 62 . capsule 66 is intended to be stored in sleeve 66 until used , and then removed and replaced in preparation for a next use of the nebulizer . capsule 66 has a lower end tear off tab 64 . sleeve 66 has lower end stop means to engage tear off tab 64 to prevent tab 64 from turning when torque is applied to capsule 66 . sleeve 62 accepts screw cap activating handle 68 after a user inserts capsule 66 into sleeve 62 . screw cap 68 engages projection means on capsule 66 so as to twist capsule 66 within sleeve 62 when a user applies a torque force to screw cap 68 . because the lower end tear off tab 64 of capsule 66 is prevented from twisting by the stop means within sleeve 66 , capsule 66 is caused to shear and rupture at its lower end when a user twists cap 68 . liquid medication within capsule 66 flows by gravity into nebulizing chamber 15 upon rupture of the lower end of capsule 66 . the liquid medication is then conventionally nebulized and the user gets the therapeutic benefit of the nebulizer in a conventional manner . fig7 shows a detailed perspective of the preferred embodiment of the present invention . a user applies torque to screw cap 68 which in turn applies torque to medication capsule 66 seated within storage sleeve 62 . stop means 62 c engages tear off tab 64 so that applied torque causes rupture of capsule 66 , allowing its contents to flow by gravity into conventional nebulizer chamber 15 . fig8 shows the second version of the preferred embodiment , having a vertical storage sleeve 62 for a capsule 66 of liquid medication , where the capsule 66 is seated with its tear - off tab 64 in close proximity to the conventional nebulizing chamber within the housing of the conventional nebulizer . fig9 , 10 and 11 show a vertical storage sleeve 62 for the capsule 66 of liquid medication , showing a lever 69 actuating lever arm 69 a , which exerts pressure against lever arm paddle 69 b against capsule 66 , thereby moving the capsule 66 laterally , while the tear - off portion 64 of the capsule is seated and immobilized within stop means 62 c , so that lateral pushing of the capsule 66 causes a tear of the capsule 66 at the tear - off portion 64 and fluid flow through slots 62 a and 62 b adjacent to stop means 62 c , through aperture 62 d and into the fluid reservoir portion 15 of the nebulizer . fig1 - 16 show an alternate embodiment for a knob cam assembly for bursting the tear off tab 64 from capsule 66 . as shown in fig1 , capsule 66 is inserted through a port in knob activator 168 between capsule pincher blades 180 a and 180 b , down to restraining stop means 162 c , adjacent to one or more mist ports 162 a and / or 162 b , etc ., which , after bursting of the seal between capsule 66 and tear off tab 68 , medication is misted within nebulizer 15 upward to inhaling pipe 70 and mouthpiece 30 . ports 162 a and / or 162 b , as well as restraining stop means 162 c are down stream of inhaling pipe 70 , between nebulizer 15 and inhaling pipe 70 . rotation of knob activator 168 causes twisting of capsule 66 between capsule pincher blades 180 a and 180 b , and thence against cam contact protrusion elements 192 a and 192 b of cam assembly 190 , which rotates in unison with rotation of knob activator 168 , while restraining stop means holds tear off tab 64 of capsule 66 during rotation of capsule 66 within cam assembly 190 . rotation of knob activator 168 and cam assembly 190 is limited to a preferable arc of movement , such as , for example 180 degrees , by means of reciprocating stop element 194 a on inhalation pipe 70 being stopped by reciprocating stop element 194 b on the adjacent bottom of cam assembly 190 . in the foregoing description , certain terms and visual depictions are used to illustrate the preferred embodiment . however , no unnecessary limitations are to be construed by the terms used or illustrations depicted , beyond what is shown in the prior art , since the terms and illustrations are exemplary only , and are not meant to limit the scope of the present invention . it is further known that other modifications may be made to the present invention , without departing the scope of the invention , as noted in the appended claims .

US-90162807-A

apparatus is disclosed for producing relief grooves in pan - shaped bones , especially in the acetabulum of a human hip joint . the apparatus includes a drivable drive shaft having a free end section . a casing is arranged on the free end section . the casing has an exterior contour which , facing away from the drive shaft is , at most , as large as the pan - contour of the bone . at least one cutting device is arranged in the casing which is movable transversely relative to the longitudinal axis of the drive shaft . the cutting device has a cutting edge arranged in an outwardly radial direction . an adjusting device is included which cooperates with the cutting device . the cutting edge is arranged in an initial position within the casing and is radially movable outwardly by means of the adjusting device .

the apparatus 90 shown in fig1 and 2 for producing relief grooves in pan - shaped bones is illustrated and described with relation to a development and use for the creation of a groove in the acetabulum 1 of a human hip joint . the apparatus 90 has a drive shaft 91 which is drivable by a drive mechanism , not shown . on the free end section of the drive shaft 91 , there is arranged a casing 92 . the casing 92 has a lower end surface which is of spherical shape . the upper surface of the casing is covered by a removable cover 93 which is fixed to the lower part 94 of the casing 92 by screws which are not shown for the sake of clarity . the mentioned screws are screwed into tapped holes 96 of the lower part 94 . as can be seen especially from fig2 the lower part 94 of the casing 92 is provided on its upper surface with a symmetrical guide , constructed as a slot or groove 97 . this guide extends from the center towards the outer edge . the groove - shaped guide 97 serves for guiding two diametrically opposed cutting means 98 which are mirror - symmetrical with respect to each other . each of the cutting means 98 is composed of a base plate 99 on whose outer rim , the cutting edge is constructed in the shape of cutting teeth 101 . the cutting teeth 101 are located on an arc of a circle 102 whose radius r corresponds to the casing radius on the outlet point of the cutting teeth 101 . each of the cutting means 98 has a guiding head 103 which cooperates with an adjusting device as will be described further below . the guiding head 103 consists of a pin 106 which protrudes from the base plate 99 and is parallel to the longitudinal axis 104 of the drive shaft 91 . on the free end of the pin , there is arranged a guiding roller 107 which is mounted on the pin 106 , so as to be rotatably movable , but axially immovable , through a ball bearing 108 . each of the pins 106 is fixed in a collar 109 which protrudes from the base plate 99 of the cutting means 98 . each of the cutting means 98 is mounted in the casing against the restoring force of two springs 111 . these springs are coil springs and are arranged parallel to each other and spaced apart , wherein both springs 111 of each cutting means 98 are connected to each other through a stirrup 112 . each of the springs is supported on its one end on the collar 109 of the respective cutting means 98 , and on its other end on the stirrup 112 , wherein the stirrup 112 is supported by the cover 93 of the casing 92 . the adjusting device has an adjusting bush 113 which is arranged concentrically on the drive shaft 91 and is connected with the drive shaft 91 through a fine thread 114 . the diameter d of the lower end section of the adjusting bush 113 has a dimension such that the cutting means 98 is still located completely in the casing 92 during fitting of the guiding head 103 on the lower end section of the adjusting bush 113 . above the smallest diameter d of the adjusting bush 113 , there is a first conical section 116 whose largest diameter d is of such a size that the cutting teeth 101 are completely radially extended during fitting of the respective guiding head 103 , as can be seen in the portion of fig1 with solid lines and in fig2 in the left part of the drawing . the right part of the illustration according to fig2 shows the above - mentioned stage in which the cutting teeth 101 are still completely in the casing . adjacent to and directly above this first conical section 116 is a second conical section 117 with decreasing diameter whose smallest diameter , at the upper end , is approximately of the same size as the smallest diameter d of the first conical section 116 . on the upper end of the adjusting bush 113 , there is an adjusting flange 118 whose outer jacket 119 is provided with knurling for roughing and the creation of a better grip . the mode of operation of the apparatus shown in the drawings and above described , is as follows : after the acetabulum 1 has been cut with a spherical shell - end mill in a mainly uniform shape of a spherical indentation , and a centering bore for a centering pin 121 arranged on the outer side of the casing 92 has been provided in the tissue , the apparatus 90 is set in the position with retracted cutting means 98 ( in fig1 with dash - dotted illustration and in fig2 the right portion ). when the drive shaft 91 is then rotated about its longitudinal axis 104 , wherein the hand of the operating surgeon does not act on the adjusting flange 118 , the above - described stage initially is maintained . only when the operating surgeon acts with his hand on the jacket 119 of the adjusting flange 118 and moves the adjusting bush 113 downwardly relative to the drive shaft 91 by way of the thread connection 114 between the adjusting bush 113 and the drive shaft 91 does the guiding rollers 107 of the guiding heads 103 start to move upwardly along the first conical section 116 . thus , the guiding heads 103 with their pins 106 and cutting means 98 , which are fixed thereon , are radially moved outwardly against the force of the springs 111 so that the cutting teeth 101 move radially outwardly out of the casing 92 and begin to cut into the bone tissue . the operating surgeon , who can interrupt this adjusting procedure at any time in a most simple manner by releasing the adjusting flange 118 , performs this procedure as long as the guiding heads 103 have reached and exceeded the largest diameter d of the first and second conical section 116 and 117 . the guiding heads 103 then go back to approximately a diameter d along the second conical section 117 , so that the cutting teeth 101 are located again completely within the casing 92 at the end of the treatment procedure . then , the apparatus 90 can be removed from the acetabulum 1 without any trouble because there is no need of a separate step for retracting of the cutting means 98 . after the treatment procedure , the acetabulum 1 is provided with a groove - shaped recess which corresponds to the completely extracted position of the cutting teeth 101 , as can be seen by the solid lines in fig1 . subsequently , there can be inserted in the acetabulum 1 , in form - locking manner , an acetabulum pan 3 which is composed of a plastic material and is provided with tongue - shaped projections 27 . because of their elasticity , the projections 27 bend at first during the insertion , and then snap into the previously created groove . the centering bore for the centering pin 121 is filled in by a centering pin 29 which is integrally connected with the acetabulum pan . such an application needs obviously no bone cement . in any case , at most , an extremely small amount of bone cement is sufficient so that the above - mentioned disadvantages do not occur . the above advantages can be achieved , although only extremely little tissue material needs to be removed , since the groove for the projection 27 can be provided at a location low enough to prevent an excessive stress of the acetabulum rim . as has been described above , the casing of the present invention is preferably constructed symmetrically with respect to rotation and suitably has a spherical shape . thus , a specially good adjustment of the apparatus to the pan is possible when the pan has previously been treated with a correspondingly shaped shell - end mill . a good adjustment is particularly possible , when the pan is previously cut , not only in the shape of a spherical identation , but also to include a central bore , in which a centering pin can be inserted . the centering pin extends centrally from the exterior surface of the casing to the outside . the cutting means is radially guided in the casing , preferably by means of a guide which can be constructed as a slot or groove extending from the center of the casing towards the exterior surfaces . such a development is especially then suitable when the cutting means is constructed in the shape of a plate , at whose edge , located on the outside , the cutting edge is constructed in the shape of cutting teeth . further , in such a development , the cutting teeth are preferably arranged on an arc of a circle whose radius corresponds to the casing radius on the emergence point of the cutting teeth out of the casing . in order to perform the radially outward movement of the cutting means in an optimum way , each of these cutting means has a guiding head cooperating with the adjusting device which is described further below . the guiding head can consist of a pin , which is arranged parallel to the longitudinal axis of the drive shaft and extends upwardly from the plate - shaped cutting means . on the free end of the pin , there is arranged a guiding roller which is preferably mounted rotatably , but is axially immovably on the pin through a bearing , for example , a ball bearing . each of the cutting means is preferably mounted in the casing against the restoring force of at least one spring . however , two parallel springs having distance therebetween arranged between the casing and each of the cutting means are also suitable . the springs can be coil springs and can be connected by means of a spacer clamp or stirrup , or the like . the interchangeability of the cutting means which is achievable with the apparatus according to the invention , is especially important because a regrinding of the cutting edges cannot be performed in view of the necessary dimensional accuracy . if the cutting teeth are reground and respective material is removed from them , the relief groove which is produced by the cutting teeth afterwards would have a smaller exterior diameter than before the regrinding so that a respective artificial hip pan with corresponding tongue - shaped lugs would not fit anymore into the pan . the adjusting device preferably is composed essentially of an adjusting bush , arranged concentrically on the drive shaft and connected with the drive shaft through a thread which is suitably a fine thread in order to obtain a sensitive feed motion or adjustment . as further discussed above , the adjusting bush has on its lower end section a diameter which is , at most , of such a size that the cutting means is still completely located within the casing during fitting of its guiding head on the lower end section of the adjusting bush . in this position , no cutting procedure can take place and , therefore , the tissue of the bone pan cannot be damaged during positioning . furthermore , the adjusting bush has preferably a first section which extends upwardly and whose diameter increases , wherein its largest diameter is of such a size that the cutting means protrudes completely radially from the casing when its guiding head rests on this largest diameter . adjacent to and above the first section of the adjusting bush , there is preferably a second section whose diameter decreases , wherein its smallest diameter located on the upper end is approximately of the same size as the smallest diameter of the first section . the first section , as well as the second section of the adjusting bush is preferably conically constructed , so that a constant and uniform increase of the cutting radius is achieved when the adjusting device is actuated as has been described . the adjusting bush has on its upper end section preferably an adjusting flange on which the hand of the operating surgeon can selectively act , in order to move the cutting means radially outwardly . while the foregoing description and drawings represent the preferred embodiments of the present invention , it will be obvious to those skilled in the art that various changes and modifications may be made therein without departing from the true spirit and scope of the present invention .

US-4280879-A

example embodiments are directed to a method of correcting attenuation in a magnetic resonance scanner and a positron emission tomography unit . the method includes acquiring pet sinogram data of an object within a field of view of the pet unit . the method further includes producing an attenuation map based on a maximum likelihood expectation maximization of a parameterized model instance and the pet sinogram data .

various example embodiments will now be described more fully with reference to the accompanying drawings in which some example embodiments are illustrated . in the drawings , the thicknesses of layers and regions may be exaggerated for clarity . accordingly , while example embodiments are capable of various modifications and alternative forms , embodiments thereof are shown by way of example in the drawings and will herein be described in detail . it should be understood , however , that there is no intent to limit example embodiments to the particular forms disclosed , but on the contrary , example embodiments are to cover all modifications , equivalents , and alternatives falling within the scope of the example embodiments . like numbers refer to like elements throughout the description of the figures . it will be understood that , although the terms first , second , etc . may be used herein to describe various elements , these elements should not be limited by these terms . these terms are only used to distinguish one element from another . for example , a first element could be termed a second element , and , similarly , a second element could be termed a first element ; without departing from the scope of example embodiments . as used herein , the term “ and / or ” includes any and all combinations of one or more of the associated listed items . it will be understood that when an element is referred to as being “ connected ” or “ coupled ” to another element , it can be directly connected or coupled to the other element or intervening elements may be present . in contrast , when an element is referred to as being “ directly connected ” or “ directly coupled ” to another element , there are no intervening elements present . other words used to describe the relationship between elements should be interpreted in a like fashion ( e . g ., “ between ” versus “ directly between ,” “ adjacent ” versus “ directly adjacent ,” etc .). the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments . as used herein , the singular forms “ a ,” “ an ” and “ the ” are intended to include the plural forms as well , unless the context clearly indicates otherwise . it will be further understood that the terms “ comprises ,” “ comprising ,” “ includes ” and / or “ including ,” when used herein , specify the presence of stated features , integers , steps , operations , elements and / or components , but do not preclude the presence or addition of one or more other features , integers , steps , operations , elements , components and / or groups thereof . spatially relative terms , e . g ., “ beneath ,” “ below ,” “ lower ,” “ above ,” “ upper ” and the like , may be used herein for ease of description to describe one element or a relationship between a feature and another element or feature as illustrated in the figures . it will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures . for example , if the device in the figures is turned over , elements described as “ below ” or “ beneath ” other elements or features would then be oriented “ above ” the other elements or features . thus , for example , the term “ below ” can encompass both an orientation which is above as well as below . the device may be otherwise oriented ( rotated 90 degrees or viewed or referenced at other orientations ) and the spatially relative descriptors used herein should be interpreted accordingly . it should also be noted that in some alternative implementations , the functions / acts noted may occur out of the order noted in the figures . for example , two figures shown in succession may in fact be executed substantially concurrently or may sometimes be executed in the reverse order , depending upon the functionality / acts involved . unless otherwise defined , all terms ( including technical and scientific terms ) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which example embodiments belong . it will be further understood that terms , e . g ., those defined in commonly used dictionaries , should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein . portions of the example embodiments and corresponding detailed description are presented in terms of software , or algorithms and symbolic representations of operation on data bits within a computer memory . these descriptions and representations are the ones by which those of ordinary skill in the art effectively convey the substance of their work to others of ordinary skill in the art . an algorithm , as the term is used here , and as it is used generally , is conceived to be a self - consistent sequence of steps leading to a desired result . the steps are those requiring physical manipulations of physical quantities . usually , though not necessarily , these quantities take the form of optical , electrical , or magnetic signals capable of being stored , transferred , combined , compared , and otherwise manipulated . it has proven convenient at times , principally for reasons of common usage , to refer to these signals as bits , values , elements , symbols , characters , terms , numbers , or the like . in the following description , illustrative embodiments will be described with reference to acts and symbolic representations of operations ( e . g ., in the form of flowcharts ) that may be implemented as program modules or functional processes include routines , programs , objects , components , data structures , etc ., that perform particular tasks or implement particular abstract data types and may be implemented using existing hardware . such existing hardware may include one or more central processing units ( cpus ), digital signal processors ( dsps ), application - specific - integrated - circuits , field programmable gate arrays ( fpgas ) computers or the like . it should be borne in mind , however , that all of these and similar terms are to be associated with the appropriate physical quantities and are merely convenient labels applied to these quantities . unless specifically stated otherwise , or as is apparent from the discussion , terms such as “ processing ” or “ computing ” or “ calculating ” or “ determining ” of “ displaying ” or the like , refer to the action and processes of a computer system , or similar electronic computing device , that manipulates and transforms data represented as physical , electronic quantities within the computer system &# 39 ; s registers and memories into other data similarly represented as physical quantities within the computer system memories or registers or other such information storage , transmission or display devices . note also that the software implemented aspects of the example embodiments are typically encoded on some form of program storage medium or implemented over some type of transmission medium . the program storage medium may be magnetic ( e . g ., a floppy disk or a hard drive ) or optical ( e . g ., a compact disk read only memory , or “ cd rom ”), and may be read only or random access . similarly , the transmission medium may be twisted wire pairs , coaxial cable , optical fiber , or some other suitable transmission medium known to the art . the example embodiments are not limited by these aspects of any given implementation . the term model may mean any kind of attenuation atlas , anatomical attenuation model , attenuation reference image of an object , or any other reference used to estimate a pet attenuation map . moreover , a deformable model may be implemented which may capture all reasonable shapes of an attenuating object and capture all possible attenuation values at respective spatial positions . the deformable model may vary in shape and appearance . the term attenuation appearance model of a model refers to the collection of all possible attenuation coefficients at a spatial position within an object such that each spatial position may have a set of potential attenuation coefficients that may occur . an instance of the attenuation appearance model is a specific setting of attenuation coefficients , one for each spatial position of the object . fig1 shows a device 1 for superimposed mr and pet image representation that may be used in the example embodiments . the device 1 includes a known mr scanner 2 . the mr scanner 2 defines a longitudinal direction z that extends orthogonally to the drawing plane of fig1 . as shown in fig1 , a pet unit having a plurality of pet detection units 3 arranged in opposing pairs about the longitudinal direction z is disposed coaxially inside the mr scanner 2 . the pet detection units 3 include an apd photodiode array 5 preceded by an array of cerium doped lutetium orthosilicate ( lso ) crystals 4 and an electrical amplifier circuit ( amp ) 6 . however , example embodiments are not limited to the pet detection units 3 having the apd photodiode array 5 preceded by an array of lso crystals 4 , but other kinds of photodiodes , crystals and devices can equally be used for detection purposes . image processing for superimposed mr and pet image representation is performed by a computer 7 . along its longitudinal direction z , the mr scanner 2 defines a cylindrical first field of view . the plurality of pet detection units 3 defines , along the longitudinal direction z , a cylindrical second field of view . according to example embodiments , the second field of view of the pet detection units 3 essentially coincides with the first field of view of the mr scanner 2 . this is implemented by appropriately adapting the arrangement density of the pet detection units 3 along the longitudinal direction z . fig2 illustrates a method of estimating a complete pet attenuation map using mlem to reconstruct a pet image . the mlem may be any known mlem . the method of fig2 may be implemented in any pet device or hybrid device with pet modality such as the device 1 illustrated in fig1 . as shown in fig2 , a statistical model is generated at s 200 . while a statistical model is used for illustrative purposes , it should be understood that any other model that may be parameterized may be used in other example embodiments . the statistical model may be built by performing principal component analysis of deformation fields and attenuation maps resulting from coregistrations of data sets . data sets may be obtained from scans of multiple individuals and either simple attenuation maps or , corresponding pairs of mr image data and an image from which an attenuation map can be induced ( e . g ., mr and ct image pairs from each individual ). by coregistering data sets , statistical variations of a shape ( e . g ., an arm ) and attenuation values may be captured . principal component analysis allows for a more compact representation of the parameter space to be developed . principal components may be obtained from principal axis transformations of a covariance matrix of input data such as deformation parameters and attenuation parameters . the principal components are the principal eigen vectors of the covariance matrix of the input data . transforming the input data to the principal axis produces a compact linear representation of the input data , from which new instances of the model can be generated by linear combinations . varying linear combination coefficients of the principal components produce other instances of the statistical model . it should be understood that statistical analysis methods other than principal component analysis , such as clustering analysis , may be used to reduce dimensionality . the statistical model may be of the complete body or of any arbitrary body part . for example , the statistical model may be a kinematic arm model in combination with an attenuation map of human arms or a statistical atlas and statistical attenuation map of the complete body , for example . the statistical model may be similar to the model described in rueckert et al . “ automatic construction of 3d statistical deformation models using non - rigid registration .” lecture notes in computer science , vol . 2208 ( 2001 ), 77 - 84 or fenchel et al . “ automatic labeling of anatomical structures in mr fastview images using a statistical atlas .” lecture notes in computer science , vol . 5241 ( 2008 ), 576 - 84 , except that these models are based on grey value images instead of attenuation maps . the statistical model is parameterized by deformation parameters d i and attenuation appearance parameters a i for each instance i . the deformation parameters d i parameterize the shape of the object . the attenuation appearance parameters a i parameterize the attenuation coefficients at the spatial positions . examples of attenuation appearance parameters a i are attenuation values of different tissue types at their respective spatial position at 511 kev , for example , lung tissue attenuation 0 . 018 / cm . both the deformation parameters and the attenuation appearance parameters are obtained from the coregistered data sets . the covariance matrix over all input instances is then computed . from covariance matrices of the parameters , principal components are extracted . an instance of the statistical model can then be described by a linear model : where μ is the instance of the statistical model , p i are the principal components and w i is the coefficient for the i - th principal component in the linear equation . generally , the coefficients are selected from an interval of three sigma of the principal values . the coefficients w i may be the deformation parameters d i for 1 & lt ; i & lt ; m and w i may be the attenuation appearance parameters a i for m + 1 & lt ; i & lt ; n . therefore , arbitrary instances may be created by assigning different coefficients . while the example embodiment of generating and parameterizing a statistical model is described above , it should be understood that other methods may be used for other models . affine parameters a i , including spatial transformation parameters like such as rotation and translation , may be used to arbitrarily align and scale the statistical model in space . moreover , a i can be used to setup a matrix m and a translation vector t by which each spatial position may be transformed to : it should be understood that the statistical model may be parameterized by other parameters instead of , or , in addition to the deformation parameters , the attenuation appearance parameters and the affine parameters . based on the statistical model , a pet attenuation map given by the model instance μ is created at s 210 ( e . g ., an average model ). the pet attenuation map given by the model instance μ may be estimated by the computer . more specifically , the attenuation map for the model instance μ may be a function of d i , a i and a i and is defined as : l is a log likelihood of an emission image ( emitter distribution ) l ( λ , μ ) where λ is an emission image ( the spatial distribution of the positron emission ). the emission image λ is based on an initial emitter distribution image that is computed from pet sinogram data , for example , by back projection . the attenuation map given by the model instance μ is a function of the deformation parameters d i and the attenuation appearance parameters a i the affine parameters a i , as shown above . therefore , ( λ , μ ( d i , a i , a i )= arg max ( l ( λ , μ ( d i , a i , a i ))) ( 4 ) becomes the parameter setting for the maximum likelihood . furthermore , it should be understood that the emission image a may also be parameterized by a model , for example , the statistical model . moreover , it should be understood that other measures may be integrated into an extended likelihood . for example , if a statistical distribution of the model parameters is known or can be approximated , the likelihood of the model instance itself could be integrated into the likelihood measure . the larger the amount of data sets , the more comprehensive the statistical model will be and thus , the more generalized the statistical model will be . it should be understood that the statistical model is a possible embodiment of a deformable model and that each instance i of the statistical model is a function of the model parameters for that instance . for example , the deformation parameters d i and the attenuation appearance parameters a i the affine parameters a i are model parameters . pet sinogram data of an object within a field of view of a pet unit is acquired at s 215 . the pet sonogram data may be acquired by the pet unit shown in fig1 . based on the pet sinogram data , the emission image λ ( pet image ) is computed simultaneously with the model parameters . alternatively , the emission image λ and the statistical model may be computed alternatively by first keeping the emission image a fixed and updating the statistical model , then keeping the statistical model fixed and updating the emission image . the emission image λ and the model parameters for that instance are optimized at s 220 based on the pet sinogram data . the emission image λ and the model parameters for that instance are optimized in an iterative fashion . during optimization , the emission image λ is computed , the statistical model is updated and the emission image λ is recomputed until optimization has been reached . the model parameters may be the deformation parameters d i , the attenuation parameters a i and the affine parameters a i . at s 220 , the pet attenuation map given by the model instance μ and the emission image λ are reconstructed simultaneously based on a mlem function . the computer shown in fig1 may reconstruct the emission image λ and the pet attenuation map given by the model instance μ . the emission image λ and the pet attenuation map given by the model instance μ may be reconstructed and optimized based on the log - likelihood of the ( un - truncated ) measured pet emission which is defined as follows : where y i is the measured pet sinogram data and y i ′ is the estimated y i value . y i ′ is estimated by forward projecting the emission image λ and correcting attenuation by the attenuation map given by the model . l can then be optimized as a function of the parameters d i , a i and a i and λ . here , constraining the mlem to the parameter space of the model is used to estimate the complete attenuation map . the parameter space means all possible values of the parameterized statistical attenuation model . in the example embodiment shown in fig2 , the parameter space may include all model parameters , for example , all deformation , attenuation appearance and affine transformation parameters . the model parameters are optimized in an iterative fashion until a maximum likelihood has been reached . the optimum can be found by any common optimization algorithm . the optimum is the parameter setting for which the maximum likelihood reaches a maximum value . the optimum defines the most likely instance of the parameterized model for attenuation and emitter image . when the optimization algorithm at s 220 has converged , the optimum maximum likelihood has been reached . the attenuation map is then obtained directly from the model instance and the pet image from the emission image at s 225 . it should be understood that the emission image obtained at s 225 may be discarded when another pet image reconstruction is triggered using the attenuation map . fig3 illustrates a method of estimating a complete pet attenuation map using an mr based attenuation map and mlem to reconstruct a pet image according to an example embodiment . the method of fig3 may be implemented in any pet device or hybrid device with pet modality such as the device 1 illustrated in fig1 . as shown in fig3 , a statistical model is generated at s 300 . s 300 is the same as s 200 . therefore , a detailed description of s 300 will be omitted for the sake of clarity and brevity . at s 305 a , an object is scanned by an mr unit within the field of view of the mr unit to acquire mr data . the mr scanner shown in fig1 may be used to acquire the mr data . once the object is scanned , an mr based attenuation map is produced at s 305 b . the mr based attenuation map may be generated by any known method of generating an mr based attenuation map and may be produced by the computer shown in fig1 . based on the mr based attenuation map and the statistical model , a pet attenuation map for a model instance p is created at s 310 . s 310 is the same as s 210 , except that the pet attenuation map for the model instance μ is constrained by the mr based attenuation map . therefore , a detailed description of s 310 will be omitted for the sake of clarity and brevity . pet sinogram data of an object within a field of view of a pet unit is acquired at s 315 . s 315 is the same as s 215 . at s 320 , the model parameters for the instance are optimized . s 320 is the same as s 220 . the model parameters are optimized until a maximum likelihood has been reached . once a maximum likelihood of the pet attenuation map for the model instance μ and the emission image λ has been reached , the attenuation map for the model instance μ defines an optimal attenuation map for the model instance μ at s 325 . the reconstructed pet image is also produced at s 325 , but may be discarded when the optimal attenuation map for the model instance μ can be used in another reconstruction process to obtain a pet image . methods of combining mr based attenuation maps and pet attenuation maps are known in the art . therefore , for the sake of clarity and brevity , they will not be discussed . fig4 illustrates a method of refining an initial attenuation map using mlem according to an example embodiment . the method of fig4 may be implemented in any pet device or hybrid device with pet modality such as the device 1 illustrated in fig1 . as shown in fig4 , at s 400 , a statistical model is generated in the same mariner as in fig2 and 3 . at s 402 , the statistical model being parameterized is adapted to an initial attenuation map . the initial attenuation map may be generated beforehand from a low - resolution mr image or a transmission scan , for example . in another example embodiment , a parameterized model that includes anatomy which frequently extends outside a mr field of view ( e . g ., a kinematic model of the human arms ) may be added to the initial attenuation map or may be used to complete the initial attenuation map . at s 405 , an object is scanned by an mr unit within the field of view of the mr unit to produce an mr image . at s 410 , a model instance is created . the model instance is created based on a best fit of the initial attenuation map with respect to a least squares approach . for statistical models , the best fit may be computed by performing an orthogonal projection of the initial attenuation map to the linear space of the statistical model , for example . thus , the model that is created is an average instance of the statistical model scaled to the initial attenuation map . at s 415 , pet sinogram data is scanned and then the model parameters of the attenuation map for the model instance μ are optimized at s 420 . s 415 and s 420 are the same as s 215 and s 220 , respectively . therefore , s 415 and s 420 will not be described in greater detail , for the sake of clarity and brevity . at s 420 , the initial attenuation map is refined using mlem . at s 425 , a refined attenuation map is produced based on the maximum likelihood of the attenuation map for the model instance μ . a pet image is also produced . as described above , the methods may be used for estimating a complete attenuation map of an object based on a model using mlem reconstruction and / or to complete missing parts of an attenuation map which is computed with other methods before by means of a model . moreover , the example embodiments may be used for refining an attenuation map such as attenuation maps computed from mr - based attenuation map computation methods including initialization of the model and refinement to the data . the example embodiments aid in avoiding local maxima and generate valid and meaningful instances of a model within its parameter space , atlas or reference image . example embodiments 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 example embodiments , and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the example embodiments .

US-45857509-A

a composition for protecting from ultraviolet radiation is disclosed . the composition comprises a filter and an effectiveness indicator responsive to the reduction of effectiveness protection .

a reduction in the harmful effects of sunlight and ultra violet radiation , e . g . sunburn and skin cancer , occupies greater consumer emphasis than ever before . in june of 2014 , the surgeon general of the united states issued a call to action to prevent the rising problem of skin cancer . the incorporation of uva and uvb filters in cosmetic and otc ( over the counter ) products of various types is long standing . for example , skin care and cosmetic products containing known filters such as , octocrylene , avobenzone , oxybenzone , homosalate , padimate o , titanium dioxide and zinc oxide , among others are available commercially . however , it is impossible to know when it is time to re - apply such products . in other words , after quantitative exposure to sunlight and uv radiation , when are they no longer effective and when exactly should the consumer re - apply to avoid sunburn and potential skin cancer . the present invention therefore is directed to providing compounds and compositions in addition to polymer and mylar films that can be applied to the skin with adhesives that overcome the problems associated with overexposure to uva and uvb radiation . the present invention can be applied prior and beneath a commercially available sunscreen of any spf value to indicate when it is no longer active or protecting and allowing dangerous levels of uv radiation through to the skin , above the sunscreen or independently as a sun exposure indicator . the present invention can be incorporated into a sunscreen composition or as an indicator alone in forms such as creams , gels , sprays , sticks , polymer and mylar films . specifically , compounds , compositions , polymer and mylar films of the present invention reduce the risk of skin damage from the harmful effects of sunlight and sunburn by containing encapsulated ink and liquid crystals that change color ( s ) from clear to blue after the designated amount of uv radiation has been absorbed . the present compounds also reduce the risk of prolonged exposure to the sun and reduce the risk of premature aging of the skin , such as wrinkles and other visual indicia of skin aging , like the loss of skin tones and elasticity and sun spots as well as long term dna damage . it is clear that the ability to indicate when a sunscreen is no longer active or capable of absorbing uv radiation is a vast improvement to current methods and compositions . in many embodiments , a compound to protect the skin from uva and uvb radiation can be added to the composition . because both uva and uvb radiation can be damaging , a preferred sunscreen provides protection from both types of radiation . in such embodiments , the compositions protect all layers of the skin . uvb and / or uva filters typically are used in sunscreen compositions of the present invention , sunscreens can be organic and inorganic compounds . the photochromic inks and liquid crystals are added to an organic ester and surfactants to ensure their compatibility to the following ultra violet absorbers and blockers : p - aminobenzonic acid , padimate o , phenylbenzimidazole sulfuric acid , cinoxate , dioxybenzone , homosalate , octocrylene , octyl methoxycinnamate , octyl salicylate , sulisobenzone , trolamine salicylate , avobenzone , ecamsule , 4 - methylbenzyladine camphor , tinosorb m , tinosorb s , neo heliopan ap , mexoryl xl , benzophenone - 9 , uninul t 150 , uninul a plus , uvasorb heb , parasol slx , amiloxate , oxybenzone ( benzophenone - 3 ), tannic acid , uric acids , quinine salts , dihydroxynaphthalin acid , and peg - 25 paba . further , sunscreen compounds such as dioxybenzone , cinoxate , ethyl - 4 [ bis ( hy - droxypropyl )] amino benzoate , glycerol amino benzoate , homosalate , menthol anthranilate , octocrylene , octyl methoxycinnamate , octyl salicylate , padimate a , padimate o , red petrolatum , titanium dioxide , 4 - menthylbenzylidene camphor , benzophenone - 1 , benzophenone - 2 , benzophenone - 4 , benzophenone - 6 , benzophenone - 12 , isopropyl dibenzoylmethane , butyl methoxydi - benzoylmathane , zotocrylene , dea - methoxycinnamate , digalloyl trioleate , tea - salicylate , or zinc oxide can be used in the current composition . therefore , variations on the present compositions include a uv - specific compound to absorb or block uva and / or uvb radiation to protect the skin . these compounds filter a percentage of the uv spectrum depending on the type , concentration , and intensity of the chromophores used . the filter families include , alone or in combination , and not limited to , the benzotriazoles , benzophenomes , benzoic acids / paba , cinnamates , salicylates , and avobenzones , to further protect the skin against uvs and uvb damage . maximum loads of one or more uv filters in a sunscreen composition can be up to 15 - 30 % by weight . a uva and uvb filter , individually , are present in an amount of about 0 . 25 to about 3 percent by weight of the composition , when both a uva and uvb blocker are used , each typically is present in an amount of about 0 . 5 to about 1 . 5 percent , by weight . additional uv filters , including combinations of any two or more , are selected from the following categories ( with specific examples ): p - aminobenzoic acid , its salts and its derivatives ( ethyl , isobutyl , glyceryl esters ; p - dimethylaminobenzoic acid ); anthranilates ( o - aminobenzoates ; methyl , menthol , phenyl , benzyl , phenyl ethyl , linalyn , terpinyl , and cyclohexenyl esters ); salicylates ) octyl , amyl , phenyl , benzyl , menthyl , ( homosalate ) glyceryl , and dipropyleneglycol esters ); cinnamic acid derivatives ( menthyl and benzyl esters ; alpha - phenyl cinnamonitrate ; butyl cinnamoylpyruvate ); dihydroxycinnamic acid derivatives ( umbelliferone , methylumbelliferone , methylaceto - umbelliferone ); camphor derivatives ( 3 benzylidene , 4 methylbenzylidene , polyacrylamidomenthyl benzylidene , benzalkonium methosulfate , benzylidene camphor sulfuric acid , and terephthalyidene dicamphor sulfuric acid ); trihydroxycjnnamic acid derivatives ( esculetin , methylesculetin , daphnetin , and glucosides , esculin and daphnin ); hydrocarbons ( diphenylbutadiene , stilbene ); dibenzalacetone ; benzalacetophenone ; naphtholsulfonates ( sodium salts of 2 - naphthol - 3 , 6 - disulfonic and of 2 - naphthol - 6 , 8 - disulfonic acids ); dihydroxy - naphthoic acid and its salts ; o - and p - hydroxydiphenyldisulfonates ; coumarin derivatives ( 7 - hydroxy , 7 - methyl , 3 - phenyl ); diazoles ( 2 - acetyl - 3 - bromoindazole , phenylbenzoxazole , methyl naphthoxazole , various aryl benzothiazoles ); quinine salts ( bisulfate , sulfate , chloride , oleate , and tannate ); quinoline derivatives ( 8 - hydroxyquinoline salts , 2 - phenylquinoline ); hydroxy - or methoxy - substituted benzophenones ; uric acid derivatives ; vilouric acid derivatives , tannic acid and its derivatives ; hydroquin ; and benzophenones ( oxybenzone , sulisobenzoone , dioxybenzone , benzoresorcinol , octabenzone , 4 - isopropyldibenzoylmethane , butylmethoxydibenzoylmethane , etocrylene , and 4 - isopropyl - dibenzoylmethane ). the following are additional specific uv filters : 2 ethylhexyl p - methoxycinnamate , 4 , 4 - t - butyl methoxydibenzoylmethane , octyldimethyl p - aminobenzoate , digalloyltrioleate , ethyl 4 -[ bis ( hydroxypropyl )] aminobenzoate , 2 - ethylhexylsalisylate , glycerol p - aminobenzoate , 3 , 3 , 5 - trimethylcyclohexylsalisylate , and combinations thereof . sunscreen or dermatological formulations can include a variety of photoactive compounds , preferably including one or more uva photoactive compound and one or more uvb photoactive compound . in many embodiments , a sunscreen or dermatological formulation includes a photoactive compound selected from the group consisting of p - aminobenzoic acid and sals and derivatives thereof ; anthranilate and derivatives thereof ; dibenzoylmethane and derivatives thereof ; salicylate and derivatives thereof ; cinnamic acid and derivatives thereof ; dihydroxycinnamic acid and derivatives thereof ; camphor and salts and derivatives thereof ; trihydroxycjnnamic acid and derivatives thereof ; dibenzalacetone naphthosulfonate and salts and derivatives thereof ; benzalacetophenone naphtholsulfate and salts and derivatives thereof ; dihydroxy - naphthoic acid and salts and derivatives thereof ; o - hydroxydiphenyldisulfonate and salts and derivatives thereof ; p - hydroxydiphenyldisulfonate and salts and derivatives thereof ; coumarin and derivatives thereof ; diazole derivatives ; quinine derivatives and salts thereof ; quinoline derivatives , uric acid derivatives ; vilouric acid derivatives ; tannic acid and derivatives thereof ; hydroquinone ; diethyl amino hydroxybenzoyl hexyl benzoate and salts and derivatives thereof ; and mixtures thereof . the above described uv filters are commercially available . for example , suitable commercially available organic uv filters are identified by trade name and supplier in table 1 below . in addition to uva and uvb filters , a present composition can also contain a photo stabilizer for the uva and uvb filters . photostabilizers include octocrylene , methylbenzilydene camphor , and esters and polyesters of naphthalene dicarboxolic acid . alkoxy crylenes , and notably methoxy crylenes , are useful photo stabilizers . an important feature of the present invention is a topically applied compound for providing a cosmetic or therapeutic effect , in addition to a compound for protection from radiation , can be any of a wide variety of compounds either water soluble or oil soluble , as well as polymer or mylar films . more specifically , such compounds can be one of or a mixture of , a cosmetic compound , a medicinally active compound , a compound used in cosmetics or personal care , or any other compound that is useful upon topical application to the skin . such topically applied agents include , but are not limited to , skin care compounds , plant extracts , antioxidants , insect repellents , counterirritants , vitamins , steroids , antibacterial compounds , anti fungal compounds , anti - inflammatory compounds , topical anesthetics , sunscreens , and other cosmetic and medicinal topically effective compounds and the above mentioned polymers and mylar films . for example , a skin conditioner could be the topically applied compound . skin conditioning agents include , but are not limited to , humectants , such as a fructose , glucose , glycerin , propylene glycol , glycereth - 26 , mannitol , pyrrolidone carbolic acid , hydrolyzed lecithin , coco - betaine , cysteine hydrochloride , glucamine , sodium gluconate , potssiumaspartate , oleyl betaine , thiamine hydrochloride , sodium laureth sulfate , sodium hyaluronate , hydrolyzed proteins , hydrolyzed keratin , amino acids , amine oxides , water - soluble derivatives of vitamin a , e and d , selenium and derivatives thereof , amino - functional silicones , ethoxylated glycerin , alpha - hydroxy acids and salts thereof , fatty oil derivatives , such as peg - 24 hydrogenated lanolin , beta - hydroxy acids and salts thereof ) e . g ., glycol acid , and salicylic acid ), and mixtures thereof . numerous other skin conditioners are listed in the ctfa cosmetic ingredient handbook , first ed ., j . nikotakis , ed ., the cosmetic , toiletry and fragrance association ( 1988 ), ( hereafter , ctfa handbook ) pages 79 - 84 , incorporated herein by reference . the skin conditioner can also be a water - insoluble ester having at least 10 carbon atoms , and preferably 10 to about 32 carbon atoms . suitable esters include those comprising an aliphatic alcohol having about 8 to about 20 carbon atoms and an aliphatic or aromatic carboxylic acid including from 2 to about 12 carbon atoms , or conversely , an aliphatic alcohol having about 2 to about 12 carbon atoms with an aliphatic or aromatic carboxylic acid including about 8 to about 20 carbon atoms . the ester is either straight - chained or branched . suitable esters therefore include , for example , but are not limited to : ( a ) aliphatic monohydric alcohol esters , including , but are not limited to : myristyl propionate , isopropyl isostearate , isopropyl myristate , isopropyl palminate , acetyl acetate , cetyl - propionate , cetyl - stearate , isodecyl neopentatonoate , cetyl - octonoate , isocetyl stearate ; ( b ) aliphatic di - and tri - esters of polycarboxylic acid , including but not limited to : diisopropyl adipate , diisostearyl fumarate , dactyl adipate , a succinate ester , and triisostearyl citrate ; ( c ) aliphatic polyhydric alcohol esters , including but not limited to : propylene glycol dipelargonate ; ( d ) aliphatic esters of aromatic acids , including but not limited to : c12 - c15 alcohol esters of benzoic acid , octylsalicylate , sucrose benzoate , and dactylphthalate . numerous other esters are listed in the cfta handbook , at pages 24 through 26 , incorporated herring by reference . the topically applied compound can also be retinoid acid or a retinol derivative and can be applied to polymer or mylar films . similarly , topically applied drugs , like anti fungal compounds , antibacterial compounds , anti - inflammatory compounds , topical anesthetics , skin rash , skin disease and dermatitis medications , and anti - itch and irritation reducing - reducing compounds can be used as an active agent of the present composition of the present invention . for example , analgesics such as benzocaine , dyclonine hydrochloride , also vera and the like ; anesthetics such as butambem picrate , lidocaine hydrochloride , xylocaie and the like : antibacterials and antiseptics such as povidone - iodine , polymyxin b sulfate - bacitracin , zinc - neomycin sulfate - hydrocortisone , chloramphenicol , ethylbenzethonium chloride , erythromycin and the like ; antiparasitics such as lindane and essentially all dermatologicals like acne preparations such as benzoyl peroxide , erythromycin benzoyl peroxide , clindamycin phosphate , 5 , 7 - dichloro 8 - hydroxyquinoline and the like ; burn relief ointments such as o - amino - p - toluensulfonamide mono acetate and the like ; dipigmenting agents such as monobenzone ; dermatitis relief agents such as the active steroid amcinomide , diflorasone dictate , hydrocortisone and the like ; emollients and moisturizers such as mineral oil , peg - 4 dilaurate , lanolin oil , petrolatum , mineral wax and the like ; fungicides such as butocouazole nitrate , haloprogin , clotrimazole and the like ; herpes treatment drugs such as o -[( 2 - hydroxymethyl )- methyl ] guanine ; pruritic medications such as alclometasone dipropionate , betanethasone vakerate , isopropyl myristrate msd and the like ; psoriasis , seborrhea and scabicide agents such as anthralin methoxsalen , coal tar and the like ; steroids such as 2 -( acetyloxy )- 9flouro - 1 ′, 2 ′, 3 ′, 4 ′- tertrahydro - 11 - hydroxypregna - 1 , 4 - dieno -[ 16 , 17 - b ] naphthalene - 3 , 20 - dione . any other medication capable of topical administration like skin protectants such as allontoin and anti - acne agents such as salicylic acid can leo be incorporated in the composition of the present invention in the amount sufficient to perform its intended function . other topically applied compounds are listed remington &# 39 ; s pharmaceutical sciences , 17th ed ., mack publishing co ., easton , pa . ( 1985 ), pages 773 - 791 and pages 1054 - 1058 ( hereafter remington &# 39 ; s ), incorporated herein by reference . the topically active compound can also be a plant extract or natural oil . preferred plant extracts and natural oils absorb blue light and generally have a yellow , yellow - brown , or red color . numerous plant extracts are available form lipo chemicals , in . paterson , n . j . nonlimiting plant extracts are those obtained from alfalfa , aloe vera , alma fruit , angelica root , anise seed , apple , apricot , artichoke leaf , asparagus root , banana , barberry , barley sprout , bee pollen , beet leaf , bilberry fruit , birch leaf , bitter melon , black currant leaf , black pepper , black walnut , blueberry , blackberry , burdock , carrot , cayenne , celery seed , cherry , chickweed , cola nut , corn silk , cranberry , dandelion root , elderberry , eucalyptus leaf , flax oil powder , ginger root , gingko leaf , ginseng , goldenrod , goldenseal , grape , grapefruit , guava , hibiscus , juniper , kiwi , kudzu , lemon licorice root , lime malt , marigold , myrrh , olive leaf , orange fruit , orange peel , oregano , papaya fruit , papaya leaf , passion fruit , peach , pear , pine bark , plum , pomegranate , prune , raspberry , rhubarb root , rosemary leaf , sage leaf , spearmint leaf , st . john &# 39 ; s wart , strawberry , sweet cloves , tangerine , violet herb , watercress , watermelon , willow bark , wintergreen leaf , witch hazel bark , yohimbe , and yucca root . an example of a natural oil is rice bran oil . the present composition can also contain a surfactant . the surfactant can be an anionic surfactant , a cationic surfactant , a nonionic surfactant or a compatible mixture of surfactants . the surfactant can also be an ampholytic or amphoteric surfactant which have anionic or cationic properties depending upon the ph of the composition . examples of anionic surfactants include , without limitation , soaps , alkyl sulfates , anionic acyl sarcosinates , methyl acyl taurates , n - acyl glutamates , acyl isethionates , alkyl phosphate esters , ethoxylated alkyl phosphate esters , alkyl sulfosuccinates , trideceth sulfates , protein sondensates , mixtures of ethoxylated alkyl sulfates and the like . examples of anionic non soap surfactants include , without limitation , the alkali metal salts of an organic sulfate having an alkyl radical containing about 8 to about 22 carbon atoms and a sulfuric acid or sulfuric acid ester radical . examples of zwitterionic surfactants include , without limitation , derivatives of aliphatic quaternary ammonium , phosphonium , and sulfonium compounds in which the aliphatic radicals can be straight chain or branched and wherein one of the aliphatic substituents contains an anionic water - solubilizing group , e . g ., carboxyl , sulfonate , sulfate , phosphate or phosphonate . examples of amphoteric surfactants include , without limitation , derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be straight chained or branched and wherein one of the aliphatic substituents contains about 8 to about 18 carob atoms and one contains an anionic water solubilizing group , e . g ., carboxyl , sulfonate , sulfate , phosphate or phosphonate . examples of cationic surfactants include without limitation , stearyldimethylbenzyl ammonium chloride ; dedecyltrimethyl ammonium chloride ; nonylbenzylethyldimethyl ammonium nitrate and tetradecylpyridium bromide . nonionic surfactants include without limitation , compounds produced by the condensation or ethylene oxide groups with an organic hydrophobic compound , which may be aliphatic or alkyl aromatic in nature , for example , the polyethylene oxide condensates of alkyl phenols . a present composition can also contain hydrotrope . a hydrotrope is a compound that has an ability to enhance the water solubility of other compounds . specific examples of hydrotropes include but are not limited to , sodium cumene sulfonate , ammonium cumene sulfonate , ammonium xylene sulfonate , potassium toluene sulfonate , sodium toluene sulfonate , sodium xylene sulfonate , toluene sulfonic acid and xylene sulfonic acid . other useful hydrotopes include sodium polynaphthalene sulfonate , sodium polystyrene sulfonate , sodium methyl naphthalene sulfonate , sodium camphor sulfonate , and disodium succinate . a present composition can also contain an organic solvent , for example , as a component of the cosmetically acceptable barrier . the solvent can be a water - soluble organic compound containing one to six , and typically one to three hydroxyl groups , e . g ., alcohols , diols , triols , and polyols . specific examples of solvents include , but are not limited to , methanol , ethanol , isopropyl alcohol , n - butanol , n - propyl alcohol , propylene glycol , glycerol , diethylene glycol , dipropylene glycol , tripropylene glycol , hexylene glycol , butylene glycol , 1 , 2 , 6 - hexanetriol , sorbitol , peg - 4 , 1 , 5 - pentanediol , similar hydroxyl - containing compounds and mixtures thereof . the solvent can also be water or an aprotic solvent , e . g ., dimethyl sulfide or tetrahydrofuran . a present composition can also contain a thickening or gelling agent . a thickening or gelling agent can be , for example , a polymer that is water soluble or that generates a colloidal solution water . a thickening or gelling agent , therefore , can be , for example , polymers or copolymers unsaturated carboxylic acids or unsaturated esters , polysaccharide derivatives , gums , colloidal salicates , polyethylene glycols ( peg ) and their derivatives , polyvinylpyrrolidones and their derivatives , polyacrylamides and their derivatives , polyacrylonitriles , hydrophilic silica gels or mixtures thereof . specific thickening or gelling agents can be , for example , acrylic and / or methacrylic polymers or copolymers , vinyl carboxylic polymers , polyglyceryl acrylates or methacrylates , polyacrylamides derivatives , cellulose or starch derivatives , chitin derivatives , alginates , amino acids , ceramides , fatty acids , cholesterol and derivatives thereof and other natural moisturizing compounds , hyaluronic acid and its salts , chondroitin sulphates , xantham , gellan , rhamsan , karaya or guar gum , carob flour and colloidal aluminum magnesium silicates of the montmorillonite type . additional thickening or gelling agents include vinylcarboxylic polymers sold under the trade name carbopol ( lubrizol / noveon ), acrylic acid / ethyl acrylate copolymers , acrylic acid / stearyl methacrylate copolymers , carboxymethylcellulose , hydroxymethylcellulose , hydroxypropylcellulose , microcrystalline cellulose hydroxypropyl guar , colloidal rectorates , bentonites and the like . the present composition can also contain pigments , dyes , preservatives , hydrating agents and the like . the pigments can be inorganic pigments , organic pigments , or nacreous pigments . inorganic pigments include but are not limited to , titanium dioxide , black , yellow , red or brown oxide , manganese violet , ultramarine violet , ultramarine blue , chlorium oxide , and the like . among organic pigments , non limiting examples include d & amp ; c red no . 3 , no . 6 , no . 7 , no . 9 , no . 13 , no . 19 , no . 21 , no . 27 , no . 30 , or no . 38 , or alternatively carbon black . the nacreous pigments can be , for example , white nacreous pigments such as mica coated with titanium oxide or with bismuth oxychloride . colored nacreous pigments , such as titanium mica colored with iron oxides or with chromium oxide , titanium mica colored with an organic pigment of the above mentioned type , or alternatively , nacreous pigments based on bismuth oxychloride can also be used . the dye can be , for example , a water - soluble dye , such as ponceau disodium salt , alizarin green disodium salt , quinoline yellow amaranth trisodium salt , tartazine disodium salt , rhodamine monosodium salt , fuchsin do sodium salt , xanthophylls and the like . the present composition can contain fillers , such as clays of the montmorillonite , rectorate or bentonite type , or other fillers such as silicas , silicone powders , polyamides or powdered polymathymethacrylate . various white fillers such as , for example , talc , kaolin , powdered teflon ( polytetraflouroethylene ), powdered polyethylene , powdered cross linked poly 0beta - alanine and the like . other classes of optional ingredients included in a present composition can be , but not limited to , ph adjusters , chelating agents , preservatives , buffering agents , foam stabilizers , opacifiers and similar classes of ingredients known to persons skilled in the art . specific optional ingredients include inorganic phosphates , sulfates , and carbonates as buffering agents ; edta and phosphates as chelating agents ; and acids and bases as ph adjusters . nonlimiting examples of basic ph adjusters are ammonia ; mono - di -, and tri - alkyl amines ; mono -, di -, and tri - alkylanolamines ; alkali metal and alkaline earth metal hydroxides ; and mixtures thereof . specific , non limiting examples of basic ph adjusters are ammonia , sodium , potassium and lithium hydroxide ; monoethanolamine ; triethylamine ; isopropanolamine ; diethanolamine and tiethanolamine . examples of acidic ph adjusters are mineral acids and organic carboxylic acids . nonlimiting examples of mineral acids are citric acid , hydrochloric acid , nitric acid , phosphoric acid and sulfuric acid . a composition of the present invention is topically applied to the skin as needed in gel , cream , lotion , polymer or mylar films to indicate when a sunscreen of given spf value needs to be reapplied and thereby protect the skin from the harmful effects of uv radiation . typically , the composition is topically applied to the skin every 10 minutes to 90 minutes depending if the skin has no spf sunscreen applied or the maximum protection currently commercially sold . however , application of the present composition can be more or less frequent as prescribed , required or desired . the present compositions are applied to the skin by spraying , or rubbing . the preferred route of administration is rubbing onto the skin with a soft massage to ensure ultimate contact with the skin . to demonstrate the new and unexpected benefits provided by the present invention , numerous compositions were prepared with components in the ranges indicated below . the appearance of each composition was noted , and the absorbance spectra and time elapsed for the composition to change color from clear to blue were taken and analyzed . each examples group represents several examples of compositions in the ranges indicated therein . the examples further illustrate the invention but are not to be construed as limitations on the scope of the invention contemplated herein . while the invention is described with respect to specific embodiments , modifications thereof can be made by one skilled in the art without departing from the spirit of the invention . the details of said embodiments are not to be construed as limitations except to the extent indicated in the following claims .

US-201615097949-A

the invention relates to a slatted base , in particular for a bed , having a frame and having a plurality of elements which are connected to one another in an articulated manner , at least one element being pivotable in relation to the or every other element . in order to ensure with minimum outlay that , when an element is pivoted , the relative position of a person resting on the slatted base , for example in relation to a bedside cabinet or the like , does not change , the elements are designed to be horizontally displaceable in relation to the frame . an element to be pivoted is furthermore connected to the frame via at least one coupling member . when the element is pivoted , a free end thereof can be moved upwards and downwards in the vertical direction and cannot be displaced in the horizontal direction .

the slatted bases illustrated in the drawing are used , above all , for beds , hospital beds or the like . they are used to support a person lying on the bed or in a hospital bed . fig1 to 8 show a slatted base 20 according to a first exemplary embodiment of the invention in different illustrations . the slatted base 20 shown in those figures has a frame 21 and four elements 22 , 23 , 24 , 25 which are connected to one another in an articulated manner . the frame 21 does not have to be an integral part of the slatted base 20 . it may also form the body of the bed or the like on which the elements 22 , 23 , 24 , 25 are supported . the slatted base 20 is then formed essentially only from the elements 22 , 23 , 24 , 25 . two respectively adjacent elements 22 , 23 or 23 , 24 or 24 , 25 are connected to one another in each case by means of a joint 26 or 27 or 28 respectively . the frame 21 is formed by two longitudinal bars 29 extending parallel to one another and transverse bars 30 extending at right angles to the longitudinal bars 29 . the elements 22 , 23 , 24 , 25 of the slatted base 20 serve to support different parts of the body of a person ( not illustrated ) resting on the slatted base . in this case , the lateral or outer element 22 serves to support an upper body and head of the person lying on the slatted base 20 and is therefore also described as the top element . the likewise outer or lateral element 25 , in contrast , serves to support the feet and legs of the person resting on the slatted base 20 and is therefore also described as the foot element . the elements 23 , 24 are arranged between the outer or lateral elements 22 , 25 -- that is to say between the top element and foot element . the elements 23 , 24 of the slatted base 20 serve to support a seat and the thighs of the person resting on the slatted base 20 . the element 23 is therefore usually also described as the seat element , and the element 24 as the thigh element . the particular feature of the slatted base 20 is to be seen in the fact that , on the one hand , the elements 23 , 24 , 25 are designed to be displaceable in the horizontal direction in relation to the frame 21 and , on the other hand , the element 22 to be pivoted -- that is to say the top element -- is connected on both sides thereof to the frame 21 via a coupling member 31 in each case . this ensures that , when the element 22 is pivoted , a free end 32 of the element 22 is moved upwards and downwards solely in the vertical direction . the component of the movement in the horizontal direction , which usually occurs when the element 22 is pivoted , is compensated , so that the free end 32 of the element 22 cannot be displaced in the horizontal direction . to ensure the horizontal displaceability of the elements 22 , 23 , 24 , 25 in relation to the frame 21 , the element 23 -- that is to say the seat element -- is mounted on the frame 21 so as to be horizontally displaceable . for this purpose , guide rails 33 are arranged on the longitudinal bars 29 of the frame 21 and are fixed so as to be non - displaceable on the longitudinal bars 29 of the frame 21 . the element 23 is mounted so as to be horizontally displaceable in the said guide rails 33 . for this purpose , the joints 26 , 27 , which bound the element 23 laterally , engage with means which are not illustrated in detail in the guide rails 33 . it is likewise possible for the joints 26 , 27 to slide along on guide rails configured at right angles . on account of the element 23 being mounted so as to be horizontally displaceable in the guide rails 33 , all the elements 22 , 23 , 24 , 25 are displaceable in the horizontal direction in relation to the frame 21 . this results from the fact that the elements 22 , 23 , 24 , 25 , that is to say all the elements , are connected to one another by means of the joints 26 , 27 , 28 . on account of the horizontal displaceability of the element 23 and the connection of the elements 22 and 23 by means of the joint 26 , a part of the element 22 is also horizontally displaceable during the pivoting movement , even despite the free end 32 of the pivotable element 22 being non - displaceable in the horizontal direction . wherever the horizontal displaceability even of the element 22 is mentioned , this excludes the free end 32 of the element 22 which , according to the invention , can only be moved upwards and downwards essentially vertically when the element 22 is pivoted . the coupling member 31 is connected , on the one hand , to the element 22 -- that is to say to the top element -- and , on the other hand , to the frame 21 . the coupling member 31 is connected by a first end section 34 to the frame 21 , namely to the transverse bar 30 of the frame 21 , by means of a first joint 35 . the coupling member 31 is connected by a second end section 36 , located opposite the first end section 34 , to the element 22 to be pivoted -- that is to say to the top element -- by means of a second joint 37 . in this case , the first joint 35 is arranged on the frame 21 , namely on the transverse bar 30 , in a stationary manner . the second joint 37 can be pivoted in relation to the frame 21 together with the element 22 . when the element 22 is pivoted out of the horizontal position according to fig2 into the inclined position according to fig1 the element 22 , which is connected at its end located opposite the free end 32 to the element 23 in the joint 26 , is pivoted upwards about the joint 26 . on account of the element 22 being connected to the frame 21 via the coupling member 31 , a tensile force is exerted on the elements 22 , 23 , 24 , 25 of the slatted base 20 in the direction of the free end 32 of the element 22 . the element 23 guided in the guide rails 33 is thus displaced in the horizontal direction in the direction of the free end 32 of the element 22 . in the process , on account of the articulated connection of the elements 22 , 23 , 24 , 25 , all the elements 22 , 23 , 24 , 25 and joints 26 , 27 , 28 are moved in the direction of the free end 32 of the element 22 . the horizontal component of the movement of the free end 32 which usually results when the element 22 is pivoted is thus compensated . the free end 32 of the element 22 is consequently only moved upwards and downwards in the vertical direction when the element 22 is pivoted . in contrast , the free end 32 of the element 22 cannot be displaced in the horizontal direction . consequently , when the element 22 is pivoted , the coupling member 31 causes a forced displacement of all the elements 22 , 23 , 24 , 25 in the direction of the free end 32 of the element 22 . this forced displacement is made possible by the horizontal displaceability of the elements 22 , 23 , 24 , 25 . differing from the exemplary embodiment shown in accordance with fig1 - 8 , it is also possible for the coupling members 31 not to be attached by the end section 34 to the frame 21 , but to another means which cannot be pivoted in relation to the element 22 ( top element ). for instance , the coupling members 31 may also be attached by the end section 34 to a wall surface , floor surface or a foot part . a drive , which is not illustrated in detail , is used to pivot the element 22 . this drive is preferably configured as an electric motor and is positioned directly in the joint 26 . the drive is capable of absorbing all the moments and forces arising . consequently , virtually solely a tensile load acts on the coupling members 31 which cause the forced displacement of the elements 22 , 23 , 24 , 25 when the element 22 is pivoted . all other moments and forces are absorbed by the drive . consequently , the coupling members 31 may also be described as tension members . as is the case with the joint 26 , drives which are not illustrated in detail are assigned to the joints 27 , 28 in order to enable the elements 23 , 24 and 24 , 25 to be pivotable relative to each other . the fact that drives configured as electric motors are assigned respectively to the joints 26 , 27 , 28 is made clear in fig3 to 8 in that the joints 26 , 27 , 28 project clearly beyond the elements 22 , 23 , 24 , 25 . the guide rails 33 have a slightly inclined course in relation to the longitudinal bars 29 of the slatted base 20 . inclination is dimensioned so as to facilitate the horizontal displaceability of the elements 22 , 23 , 24 , 25 during a downward movement of the element 22 and thus when the element 22 is pivoted from the inclined position according to fig1 into the horizontal position according to fig2 . consequently , due to the inclined course of the guide rails 33 , a force arises which facilitates the essentially horizontal displaceability of the element 23 in the slightly inclined guide rails 33 during the downward movement of the element 22 into the position according to fig2 . this restoring force can alternatively , however , also be brought about by the use of a spring element which assists the horizontal displaceability of the elements 22 , 23 , 24 , 25 when the element 22 is pivoted into the horizontal position according to fig2 . the coupling members 31 may be configured in different ways . for instance , it is possible to configure the coupling members 31 as cables . in this case , when the element 22 -- that is to say the top element -- is pivoted into the inclined position , a tensile force is exerted by the cables in order to ensure the forced displacement of the elements 22 , 23 , 24 , 25 . however , when the element 22 is pivoted into the horizontal position , no restoring force can be transmitted by the cables . in this case , the spring elements already mentioned are provided for this purpose . the said spring elements cause the forced displacement of the other elements when the element 22 is pivoted into the horizontal position . alternatively , it is also possible for the coupling members 31 to be configured as rods . when the element 22 is pivoted into the inclined position , the rods again exert a tensile force in order to ensure the forced displacement of the elements 22 , 23 , 24 , 25 . when the element 22 is pivoted into the horizontal position , compressive forces may also be exerted by the rods in order to cause the forced displacement of the elements 22 , 23 , 24 , 25 . in this case , both tensile forces and compressive forces consequently act on the coupling members 31 configured as rods . it is likewise possible to provide the mentioned spring elements in addition to the rods , so that the rods are subjected virtually exclusively to a tensile load . a slatted base 38 according to a second exemplary embodiment of the invention is shown in fig9 to 16 . the slatted base 38 shown in those figures also has a frame 39 and four elements 40 , 41 , 42 , 43 connected to one another in an articulated manner . in each case two adjacent elements 40 , 41 or 41 , 42 or 42 , 43 are again connected to one another by a joint 44 , 45 , 46 respectively . like the frame 21 of the slatted base 20 , the frame 39 of the slatted base 38 is formed by two longitudinal bars 47 extending parallel to one another and transverse bars 48 extending transversely to the longitudinal bars 47 . the element 40 is again configured as the top element , and the element 43 as the foot element . the elements 41 , 42 are the seat elements and thigh elements already described in conjunction with the slatted base 20 according to fig1 to 8 . the elements 40 , 41 , 42 , 43 of the slatted base 38 according to fig9 to 16 can be displaced horizontally in relation to the frame 39 . for this purpose , the element 41 is mounted so as to be horizontally displaceable in guide rails 49 which are fixed to the longitudinal bars 47 of the frame 39 . with regard to details concerning the design of the guide rails 49 , reference is made to the descriptions given in relation to the guide rails 33 of the slatted base 20 according to fig1 to 8 . the element 40 to be pivoted -- that is to say the top element -- is connected on both sides to the frame 39 via a coupling member 50 . for this purpose , the coupling members 50 are connected by a first end section 51 to the frame 39 by means of a first joint 52 . each of the coupling members 50 arranged next to the element 40 is connected by an end section 53 , located opposite the first end section 51 , by means of a second joint 54 to the element 40 to be pivoted . in this respect , the slatted bases 20 and 38 are of matching design . consequently , in the slatted base 38 according to fig9 to 16 , it is also ensured that , when the element 40 is pivoted , a free end 55 of the element 40 is only moved upwards and downwards in the vertical direction , while the free end 55 cannot be displaced in the horizontal direction . the slatted base 38 according to fig9 to 16 differs from the slatted base 20 according to fig1 to 8 by the design of the drive for pivoting the elements 40 , 41 , 42 , 43 . whereas , in the slatted base 20 according to fig1 to 8 , each joint 26 , 27 , 28 of two adjacent elements 22 , 23 or 23 , 24 or 24 , 25 is respectively assigned a separate drive , in the slatted base 38 according to fig9 to 16 a single drive 56 is provided to pivot the elements 40 , 41 , 42 , 43 . the drive 56 is preferably configured as an electric motor . an axis of rotation 57 , 58 on each side passes through the drive 56 in the horizontal direction . each of the axes of rotation 57 , 58 bears on each side a lever 59 , 60 respectively . the levers 59 serve to pivot the element 40 , that is to say the top element . the levers 60 serve to pivot the element 43 , that is to say the foot element . according to fig9 to 16 , the levers 59 and 60 are attached by a first end 61 and 62 to the respective axis of rotation 57 and 58 . the levers 59 and 60 are in contact , by ends 63 , 64 , located opposite the ends 61 , 62 , with the elements 40 and 43 to be pivoted . the end section 53 of the coupling member 50 and the end 63 of the lever 59 engage on the element 40 at a common point , namely the joint 54 . the joint 54 is consequently a double joint . the levers 59 , 60 can be pivoted independently of one another by means of the drive 56 . the coupling members 50 of the slatted base 39 may again be configured in different ways . it is possible to configure the coupling members 50 as rods or cables . in this regard , reference is made to the descriptions in relation to the slatted base 20 according to fig1 - 8 . if the coupling members 31 , 50 are configured as cables , their length is to be dimensioned such that the cable is virtually taut when the top elements ( elements 22 , 40 ) have been pivoted into the inclined position .

US-7924898-A

a remotely activated door - opening mechanism is provided for a cage trap having an animal enclosure , preferably a cage trap as disclosed in u . s . publ . no . us2008 / 0115405 . the mechanism is mounted outside the enclosure of the trap and is preferably remotely activated by an ir or rf transmitter to open a door of the trap and release a trapped animal when the operator is at a safe distance away . the mechanism may also be manually set with a time delay and may be associated with either a main entry door to the trap or with a secondary escape door located at an opposite end of the trap .

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 the specific terminology so selected , and it is to be understood that each specific element includes all technical equivalents that operate in a similar manner to accomplish a similar purpose . as shown in fig1 and 2 , the remotely activated cage trap door - opening mechanism according to a first embodiment of the present invention is generally designated by reference numeral 10 and is mounted at the top rear of a cage trap as disclosed in the aforesaid &# 39 ; 085 application . the door opening mechanism 10 includes a mechanical assembly , generally designated by reference numeral 12 , and an activating assembly , generally designated by reference numeral 14 . the activating assembly and portions of the mechanical assembly are contained within a housing 16 which is mounted to the trap 18 . the mechanical assembly 12 includes a rotatable spool 20 , a toothed sprocket 22 , a latch pawl 24 , a torsion / clock spring 26 and a cable 28 with a fastening element 30 . the toothed sprocket 22 is mounted on one end of the spool 20 so as to ratchet against the latch pawl 24 within the housing . the torsion / clock spring 26 is mounted on the opposite end of the spool 20 . the cable is wound on the spool 20 with the extendible end thereof coupled to the fastening element 30 . the fastening element 30 may be embodied as a clip , such as a carbineer style clamp , by which the extendible end of the cable 28 is secured to the set lever 40 of the trap 18 . the mechanical assembly 12 also includes an attachment element 32 to secure the housing 16 to the trap 18 . this attachment element 32 may be embodied as a sliding clip element 34 ( see fig3 ), as a carbineer style clamp 33 ( see fig4 ), or as any other suitable clamp or fastening mechanism as would be understood by persons of ordinary skill in the art . according to one preferred embodiment , the activating assembly 14 includes an ir receiver generally designated by reference numeral 50 and a remote ir transmitter 52 . the receiver 50 includes a circuit board 54 , a power source such as a battery 56 , and a solenoid 58 operative to release the latch pawl 24 from the sprocket 22 when actuated by the remote ir transmitter 52 . alternatively , the receiver may be configured for rf communication with a remote rf transmitter . to use the door - opening mechanism , the housing 16 is secured to the upper rear edge 44 of the trap enclosure 42 by the attachment element 32 . the housing 16 may be secured to the trap prior to use , i . e ., prior to setting the trap , or may be attached to the trap after an animal has been trapped . if the housing 16 is secured to the trap prior to use , according to a preferred method of use , the extendible end of the cable 28 is not attached to the set lever 40 of the trap 18 until after the trap has been tripped and the animal is to be released . the trap 18 is set by moving the set lever 40 toward the rear of the trap 18 in the manner described in the &# 39 ; 085 application . as shown in fig1 , the set lever is supported on a set lever bracket 41 that is mounted on the roof transverse to a longitudinal direction of the animal enclosure . as supported on the bracket 41 , the set lever is pivotally movable in the longitudinal direction from one side of the bracket to the other side of the bracket . therefore , when the trap 18 is tripped by an animal , the set lever 40 moves toward the front of the trap , i . e ., from the side of the bracket 41 nearest the rear of the trap to the side of the bracket nearest the front of the trap , under the urging of the weight of the door 46 as conveyed through the trap cable assembly 48 . once the door is closed , the animal is trapped inside . to release the animal , the housing is secured to the upper rear edge 44 of the trap enclosure 42 , if not already secured thereto . the free end of the cable 28 is pulled out of the housing to extract the cable 28 from the spool 20 against the tension of the torsion / clock spring 26 until the fastening element 30 is positioned to be clipped onto the set lever 40 . the ratcheting of the sprocket 22 against the pawl 24 allows the extracted cable 28 to remain extended without a retraction force . with the end of the cable 28 attached to the set lever , the user may withdraw a desired distance away from the trap . once the user is at a safe distance , the user or another individual having the remotely located ir transmitter 52 , actuates the ir receiver 50 . actuation of the ir receiver 50 activates the solenoid 58 which , in turn , releases the latch pawl 24 from the sprocket 22 . once the pawl 24 is released , the spool 20 is free to spin and thereby retract the cable 28 onto the spool 20 by the stored energy in the wound tension spring 26 . the retraction of the cable 28 pulls the set lever 40 toward the rear of the trap to automatically open the door 46 . to soften any abruptness in the rapid cable retraction , a rotary dampener 60 may be added to the mechanical assembly in a manner known to those skilled in the art . as described herein , the cage trap door - opening mechanism is an independent accessory that can be easily attached to and then removed from any existing cage trap equipped with an over - center set mechanism to remotely open the door thereof . other mechanical assemblies suitable for the operation of the present invention could also be used as would be understood by persons of ordinary skill in the art . for example , the cable spool and cable could be operated by an electric motor or a hand - wound crank . retraction of the cable could also be effected by a pneumatic cylinder . similarly , as alternatives to the ir transmitter and receiver , or to an rf transmitter and receiver , other remote means of conveying a signal and of receiving the signal by a receiver or comparable device on the activating assembly are also intended to be included within the present invention . the door - opening mechanism could also be mechanical or electrically timed . activation of the door - opening mechanism could also be accomplished through the use of a wired remote or by a remote mechanical mechanism . any of the above - described assemblies for operation and activation of a remote door - opening mechanism may also be used in conjunction with a trap having a separate escape door such as that illustrated in fig5 a and 5b and generally designated by reference numeral 62 , in accordance with a second embodiment of the present invention . the separate escape door 62 is preferably positioned at the opposite end of the trap relative to the entry door 46 . since the entry door 46 of the trap shown in fig1 is described herein as being at the trap front end , then the separate escape door 62 is preferably at the rear end of the trap . alternatively , the separate escape door could be positioned on the side of the trap , preferably near the rear end . wherever its location , the separate escape door 62 may be more simply designed than the entry door , requiring only a movable panel that can be positioned and held in a closed position , as shown in fig5 a , to cover an escape opening 64 , and then moved to an opened position to uncover the escape opening , as shown in fig5 b . in the embodiment shown in fig5 a and 5b , the escape door 62 is pivotally mounted to the end wall 66 of the trap by a hinge 68 positioned at the bottom of the escape opening 64 . when the trap is in a set condition for trapping an animal as shown in fig5 a , the escape door 62 is held vertically in a closed or secured position by a door release unit generally designated by reference numeral 70 . the door release unit 70 , in the embodiment shown , includes a control assembly 72 mounted on the trap body , preferably on the roof 76 , and a catch 74 mounted on the escape door 62 so as to be adjacent the control assembly 72 when the escape door is in the closed position . alternatively , the control assembly 72 may be mounted adjacent one side of the escape door with the catch then being placed on the escape door in generally horizontal alignment with the control assembly . with this alternative placement of the release unit , the escape door may be secured to the trap by a vertical hinge ( not shown ) positioned on the opposite side of the door so that the escape door is configured to swing between opened and closed positions while remaining in a vertical orientation . the control assembly 72 includes a latching mechanism ( not shown ) for securing the catch 74 to keep the escape door in the closed or secured position until the control assembly 72 is activated . the latching mechanism can use mechanical , electrical , magnetic , or other means to keep the catch 74 engaged with the control assembly . when this engagement is released by the control assembly , the door and catch are allowed to pivot downwardly away from the control assembly to uncover the escape opening 64 . according to one preferred embodiment , the door release unit 70 is battery powered and remotely activated by a user 78 using a remote control unit 80 as shown in fig5 c . alternatively , the door release unit 70 can be designed to operate using a mechanical time release , such as that described in u . s . pat . no . 3 , 638 , 346 , by which a manually set timing device triggers the opening of the escape door after the manually set time period has elapsed . in conjunction with such a mechanical time release , the escape door may be spring loaded so as to be ready to swing open when the door release unit is triggered by the timer . however configured , the present invention provides a door - opening mechanism that is easy to use and which , through the remote control activation capability , allows the user to maintain a safe distance from the trap when releasing a trapped animal . it is to be understood that the present invention is not limited to the illustrated embodiments described herein . modifications and variations of the above described embodiments of the present invention are possible as appreciated by those skilled in the art in light of the above teachings .

US-201213610400-A

the present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of - isoproterenol , - isoproterenol dipivalate , — n - ethylnoradrenaline , — n - n - propylnoradrenaline , — n - butylnoradrenaline , — n - tert - butylnoradrenaline , 1 - dihydrooxylphenyl )- 2 -- 1 -- butanol , - 1 -- 3 - methyldopamine and - 1 -- 3 - methyldopamine suitable . the pharmaceutical composition may be for topical application to ocular tissues .

( s )- isoproterenol l - bitartrate , ( s )- noradrenaline l - bitartrate , d - mannitol , benzalkonium chloride , pivaloyl chloride ( trimethylacetyl chloride ), iodoethane , 1 - iodopropane , 1 - iodobutane , sodium borohydride , methyl trifluoromethanesulfonate , 2 - chloro - 3 , 4 - dihydroxyacetophenone , 1 , 4 - dioxane , p - toluoyl chloride , disodium sulfate , chlorobutanol , aminocaproic acid , sodium perchlorate , [ glu 1 ]- fibrinopeptide b , ( r )- isoproterenol hydrochloride , isoetharine mesylate , di - tert - butyl dicarbonate , triethylamine , acetyl chloride , 2 - propanol , dimethylformamide , tert - butylamine , isobutyryl chloride , benzoyl chloride , cetylpyridinium chloride , and povidone ( k30 ) were obtained from sigma - aldrich ( oakville , ontario , canada ). acetone , methylene chloride , ethyl acetate , glacial acetic acid , disodium carbonate , sodium chloride and naoh were from emd science ( gibbstown , n . j ., usa ). disodium edetate , trifluoroacetic acid ( tfa ), and water were purchased from j . t . baker ( phillipsburg , n . j ., usa ). 1 . 0m hcl was obtained from vwr ( montreal , quebec , canada ). water for mass spectrometry was purchased from anachemia ( lachine , qc , canada ). formic acid was purchased from riedel de haën ( oakville , ontario , canada ). acetonitrile and hexane were from fisher scientific ( nepean , ontario , canada ). ag ® 4 - x4 resin , 100 - 200 mesh , free base form was purchased from bio - rad laboratories , inc ( hercules , calif ., usa ). all the chemicals were used without further purification . cetylpyridinium trifluoroacetate was prepared from cetylpyridinium chloride . to a solution of sodium trifluoroacetate in methanol was added trifluoroacetic acid . the resulting methanolic solution of tfa - na was then added dropwisely the solution of cetylpyridinium chloride in ethanol with stirring . after 30 min , precipitated nacl was filtered off and evaporated with rotary evaporator (& lt ; 40 ° c .). the residue was dissolved in dichloromethane and insoluble components were filtered off . after evaporation , tert - butanol was added and lyophilized to obtain as a white crystal . cetylpyridinium acetate was prepared from cetylpyridinium chloride . cetylpyridinium chloride was dissolved in methanol , and acetic acid and sodium acetate were added . after evaporating the solvent , the residue was dissolved in methylene chloride . cetylpyridinium acetate was soluble in methylene chloride , whereas sodium chloride was precipitated and removed by filtration . the solvent was evaporated and the absence of chloride ion was confirmed as no precipitate was formed when silver nitrate solution was added to the product . this compound is used in the synthesis of ( s )— n - ethylnoradrenaline hydrochloride , ( s )— n - propylnoradrenaline hydrochloride , and ( s )— n - butylnoradrenaline hydrochloride . to a solution of ( s )- noradrenaline bitartrate ( 3 . 83 g , 12 mmol ) in 100 ml of tetrahydrofuran ( thf )- water ( 1 : 1 v / v ) was added sodium bicarbonate ( 3 . 3 g , 40 mmol ), and stirred vigorously . di - tert - butyl dicarbonate ( 2 . 9 g , 13 . 2 mmol ) in thf ( 10 ml ) was then added dropwise at room temperature . the reaction mixture was stirred for 3 hrs . the product ( s )— n - boc - noradrenaline was extracted with 50 ml of dichloromethane ( dcm ) three times . the combined extract was washed with water ( 50 ml ) and brine ( 50 ml ). the product solution was dried over sodium sulfate , filtered and then evaporated to dryness , yielding the desired product . the product showed over 95 % purity based on the hplc profile ( an analytical waters hplc ( waters symmetryshield ™ 3 . 5 μm ; 4 . 6 × 50 mm c 18 - reverse phase column ). a gradient 10 - 90 % acetonitrile in water , 0 . 1 % trifluoroacetic acid ( tfa ), for 9 min at a flow rate of 2 ml / min ( system a ) was used . the product was further used without purification . c 13 h 19 no 5 ; white solid ; rt = 4 . 9 min ( system a ). hrms : calcd . for [ m + h + ]= 270 . 1341 . found = 270 . 1342 . esi - ms / ms ( collision energy ( ce )= 2 ): m / z (% relative intensity ): 270 ( m + h + , 94 ), 252 ( 100 ), 214 ( 1 . 3 ), 196 ( 51 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 6 . 80 ( s , 1h ), 6 . 73 ( d , j = 8 hz , 1h ), 6 . 67 ( d , j = 7 hz , 1h ), 4 . 54 ( dd ( br ), j = 5 , 7 hz , 1h ), 3 . 24 ( dd , j = 5 , 13 hz , 1h ), 3 . 16 ( dd , j = 7 , 14 hz , 1h ), 1 . 43 ( s , 9h ). to a mixture of ( s )— n - boc - noradrenaline ( 3 . 0 g , 11 mmol ) and triethylamine ( 5 ml , 36 mmol ) in dcm ( 100 ml ) was slowly added pivaloyl chloride ( 2 . 9 ml , 24 mmol ) at 0 ° c . under nitrogen . the reaction mixture was stirred for 15 min at 0 ° c ., and then for 2 hrs at room temperature . the product solution was washed with water ( 50 ml ), dried over sodium sulfate and concentrated . silica gel column chromatography ( using a gradient of 20 - 40 % ethyl acetate / hexane ) afforded pure product ( 2 . 40 g , 46 % yield from ( s )- noradrenaline bitartrate ) as a viscous liquid . c 23 h 35 no 7 ; viscous liquid ; rt = 9 . 0 min ( system a ). hrms : calcd . for [ m + h + ]= 438 . 2492 . found = 438 . 2482 . esi - ms / ms ( ce = 2 ): m / z (% relative intensity ): 438 ( m + h + , 100 ), 420 ( 2 . 3 ), 382 ( 86 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 7 . 29 ( d , j = 7 hz , 1h ), 7 . 17 ( s , 1h ), 7 . 14 ( d , j = 9 hz , 1h ), 4 . 74 ( t ( br ), j = 8 hz , 1h ), 3 . 28 ( dd , 1h ), 3 . 22 ( dd , j = 8 , 15 hz , 1h ), 1 . 44 ( s , 9h ), 1 . 36 ( s , 9h ), 1 . 34 ( s , 9h ). to a solution of ( s )— n - boc - noradrenaline dipivalate ( 2 . 4 g , 5 . 5 mmol ) in dry methanol ( 100 ml ) was added dropwise acetyl chloride ( 8 ml , 110 mmol ) at 0 ° c . the reaction mixture was stirred for 15 min at 0 ° c . and then at room temperature . the reaction was monitored by tlc . after completion of the reaction ( 3 hrs . ), the solvent was evaporated under reduced pressure and the product was purified by high performance displacement chromatography ( hpdc ) ( 0 . 1 % tfa / water , 4 g / l of cetylpyridinium trifluoroacetate as eluent ). the product was further used in the preparations of ( s )— n - ethylnoradrenaline dipivalate hydrochloride , ( s )— n - propylnoradrenaline dipivalate hydrochloride , and ( s )— n - butylnoradrenaline dipivalate hydrochloride as described below . c 18 h 28 no 5 cl ; white solid ; rt = 6 . 0 min ( system a ). hrms : calcd . for [ c 18 h 27 no 5 + h + ]= 338 . 1967 . found = 338 . 1983 . esi - ms / ms ( ce = 13 ): m / z (% relative intensity ): 338 ( m + h + , 5 . 9 ), 320 ( 100 ), 236 ( 26 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 7 . 36 ( dd , j = 2 , 8 hz , 1h ), 7 . 27 ( d , j = 2 hz , 1h ), 7 . 20 ( d , j = 8 hz , 1h ), 4 . 94 ( dd , j = 4 , 9 hz , 1h ), 3 . 20 ( dd , j = 4 , 13 hz , 1h ), 3 . 04 ( dd , j = 9 , 13 hz , 1h ), 1 . 36 ( s , 9h ), 1 . 35 ( s , 9h ). to a solution of ( s )— noradrenaline dipivalate hydrochloride ( 0 . 37 g , 1 . 0 mmol ) and triethylamine ( 0 . 4 ml , 3 . 0 mmol ) in 10 ml of dry dimethylformamide ( dmf ) was added iodoethane ( 0 . 12 ml , 1 . 5 mmol ). the reaction mixture was stirred for 24 hrs at room temperature under nitrogen and lyophilized . the mixture was taken up in ethyl acetate ( 30 ml ) and extracted with nah 2 po 3 buffer ( 4 × 20 ml , ph 3 ). the organic layer was extracted again with water ( 3 × 20 ml ). combined buffer extracts and water extracts were adjusted to ph 11 using 1 . 0n naoh and extracted with ethyl acetate ( 3 × 20 ml ). the separated organic phase was further washed with water ( 20 ml ) and brine ( 20 ml ), dried over sodium sulfate and concentrated . crude mixture was purified by hpdc ( 0 . 1 % tfa / water , 4 g / l of cetylpyridinium trifluoroacetate as eluent ). the isolated compound was treated with excess of 1 . 0n hcl and lyophilized to give a solid mono - ethylation product ( 0 . 11 g , 27 % yield ). c 20 h 32 no 6 cl ( mono - ethylation ); white solid ; rt = 6 . 2 min ( system a ). hrms : calcd . for [ c 20 h 31 no 6 + h + ]= 366 . 2280 . found = 366 . 2268 . esi - ms / ms ( ce = 15 ): m / z (% relative intensity ): 366 ( m + h + , 55 ), 348 ( 100 ), 264 ( 24 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 7 . 37 ( dd , j = 2 , 8 hz , 1h ), 7 . 27 ( d , j = 2 hz , 1h ), 7 . 20 ( d , j = 8 hz , 1h ), 4 . 98 ( dd , j = 3 . 10 hz , 1h ), 3 . 24 ( dd , j = 3 , 13 hz , 1h ), 3 . 12 ( m , 3h ), 1 . 36 ( s , 9h ), 1 . 35 ( s , 9h ), 1 . 34 ( t , j = 7 hz , 3h ). to a solution of ( s )— n - ethylnoradrenaline dipivalate hydrochloride ( 50 mg , 125 μmol ) in dry methanol ( 3 ml ) was added excess solid sodium borohydride and the reaction mixture was monitored by hplc until no unreacted starting material remained . the solvent was evaporated to dryness giving white solid . crude mixture was purified by preparative hplc using 0 . 1 % tfa / water as eluent . the residue was treated with excess 1 . 0n hcl and lyophilized to give desired product as a white solid ( 22 mg , 76 % yield ). c 10 h 16 no 3 cl ; white solid ; rt = 0 . 53 min ( system a ). hrms : calcd . for [ c 10 h 16 no 3 + h + ]= 198 . 1130 . found = 198 . 1128 . esi - ms / ms ( ce = 8 ): m / z (% relative intensity ): 198 ( m + h + , 48 ), 180 ( 100 ). nmr : 1 h nmr ( 500 mhz , dmso - d 6 ): δ 8 . 99 ( s ( br ), 1h ), 8 . 96 ( s ( br ), 1h ), 6 . 79 ( s , 1h ), 6 . 72 ( d , j = 8 hz , 1h ), 6 . 61 ( d , j = 9 hz , 1h ), 5 . 92 ( s ( br ), 1h ), 4 . 77 ( d , j = 10 hz , 1h ), 2 . 94 ( m ( br ), 3h ), 2 . 87 ( t , j = 12 hz , 1h ), 1 . 21 ( t , j = 7 hz , 3h ). to a mixture of ( s )- noradrenaline dipivalate hydrochloride ( 0 . 37 g , 1 . 0 mmol ) and triethylamine ( 0 . 4 ml , 3 . 0 mmol ) in dry dmf ( 10 ml ) was added iodopropane ( 0 . 15 ml , 1 . 5 mmol ) and stirred for 24 hrs at room temperature under nitrogen . the resulting mixture was lyophilized . the mixture was taken up in ethyl acetate ( 30 ml ) and extracted with nah 2 po 3 buffer ( 4 × 20 ml , ph 3 ). the organic layer was extracted again with water ( 3 × 20 ml ). combined buffer extracts and water extracts were adjusted to ph 11 using 1 . 0n naoh and extracted with ethyl acetate ( 3 × 20 ml ). the separated organic phase was further washed with water ( 20 ml ) and brine ( 20 ml ), dried over sodium sulfate and concentrated . crude mixture was purified by hpdc ( 0 . 1 % tfa / water , 4 g / l of cetylpyridinium trifluoroacetate as eluent ). the isolated compound was treated with excess of 1 . 0n hcl and lyophilized to give a solid product ( 0 . 09 g , 22 % yield ). c 21 h 34 no 6 cl ; white solid ; rt = 6 . 4 min ( system a ). hrms : calcd . for [ c 21 h 33 no 6 + h + ]= 380 . 2437 . found = 380 . 2421 . esi - ms / ms ( ce = 15 ): m / z (% relative intensity ): 380 ( m + h + , 78 ), 362 ( 100 ), 278 ( 20 ), 250 ( 0 . 9 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 7 . 38 ( d , j = 8 hz , 1h ), 7 . 28 ( s , 1h ), 7 . 20 ( d , j = 8 hz , 1h ), 5 . 01 ( dd , j = 3 . 10 hz , 1h ), 3 . 26 ( d , j = 13 hz , 1h ), 3 . 14 ( t , j = 10 hz , 1h ), 3 . 03 ( t , j = 8 hz , 2h ), 1 . 76 ( m ( br ), 2h ), 1 . 36 ( s , 9h ), 1 . 35 ( s , 9h ), 1 . 04 ( t , j = 7 hz , 3h ). to a solution of ( s )— n - propylnoradrenaline dipivalate hydrochloride ( 40 mg , 96 μmol ) in dry methanol ( 3 ml ) was added excess solid sodium borohydride and the reaction mixture was monitored by hplc until no unreacted starting material remained . the solvent was evaporated to dryness giving white solid . crude mixture was purified by preparative hplc using 0 . 1 % tfa / water as eluent . the residue was treated with excess 1 . 0n hcl and lyophilized to give desired product as a white solid ( 15 mg , 63 % yield ). c 11 h 18 no 3 cl ; white solid ; rt = 0 . 57 min ( system a ). hrms : calcd . for [ c 11 h 17 no 3 + h + ]= 212 . 1286 . found = 212 . 1280 . esi - ms / ms ( ce = 8 ): m / z (% relative intensity ): 212 ( m + h + , 63 ), 194 ( 100 ). nmr : 1 h nmr ( 500 mhz , dmso - d 6 ): δ 8 . 96 ( s ( br ), 1h ), 8 . 93 ( s ( br ), 1h ), 6 . 78 ( s , 1h ), 6 . 72 ( d , j = 8 hz , 1h ), 6 . 62 ( d , j = 9 hz , 1h ), 5 . 93 ( d ( br ), j = 3 hz , 1h ), 4 . 76 ( d , j = 9 hz , 1h ), 2 . 99 ( m ( br ), 1h ), 2 . 87 ( m ( br ), 2h ), 2 . 72 ( m ( br ), 1h ), 1 . 65 ( m , 2h ), 0 . 89 ( m , 3h ). to a mixture of ( s )- noradrenaline dipivalate hydrochloride ( 0 . 56 g , 1 . 5 mmol ) and triethylamine ( 0 . 6 ml , 4 . 5 mmol ) in dry dmf ( 15 ml ) was added iodobutane ( 0 . 26 ml , 2 . 25 mmol ) and stirred at room temperature under nitrogen for 24 hrs . the resulting mixture was lyophilized . the mixture was taken up in ethyl acetate ( 40 ml ) and extracted with nah 2 po 3 buffer ( 4 × 20 ml , ph 3 ). the organic layer was extracted again with water ( 3 × 20 ml ). combined buffer extracts and water extracts were adjusted ph to 11 using 1 . 0n naoh and extracted with ethyl acetate ( 3 × 20 ml ). the separated organic phase was further washed with water ( 20 ml ) and brine ( 20 ml ), dried over anhydrous sodium sulfate and concentrated . crude mixture was purified by hpdc ( 0 . 1 % tfa / water , 4 g / l of cetylpyridinium trifluoroacetate as eluent ). the isolated compound was treated with excess of 1 . 0n hcl and lyophilized to give a solid product ( 0 . 22 g , 34 % yield ). c 22 h 36 no 6 cl ; white solid ; rt = 6 . 7 min ( system a ). hrms : calcd . for [ c 22 h 36 no 6 + h + ]= 394 . 2593 . found = 394 . 2582 . esi - ms / ms ( ce = 15 ): m / z (% relative intensity ): 394 ( m + h + , 100 ), 376 ( 34 ), 292 ( 4 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 7 . 37 ( dd , j = 2 , 8 hz , 1h ), 7 . 28 ( d , j = 2 hz , 1h ), 7 . 21 ( d , j = 8 hz , 1h ), 5 . 00 ( dd , j = 3 . 10 hz , 1h ), 3 . 25 ( dd , j = 3 , 12 hz , 1h ), 3 . 14 ( dd , j = 10 , 12 hz , 1h ), 3 . 06 ( t , j = 8 hz , 2h ), 1 . 71 ( m ( br ), 2h ), 1 . 46 ( m , 2h ), 1 . 36 ( s , 9h ), 1 . 35 ( s , 9h ), 1 . 01 ( t , j = 7 hz , 3h ). to a solution of ( s )— n - butylnoradrenaline dipivalate hydrochloride ( 50 mg , 120 μmol ) in dry methanol ( 3 ml ) was added excess solid sodium borohydride and the reaction mixture was monitored by hplc until no unreacted starting material remained . the solvent was evaporated to dryness giving white solid . thf ( 10 ml ) and saturated nacl solution ( 10 ml ) were added to the solid and extracted with thf ( 4 × 15 ml ). combined organic extracts were dried over anhydrous sodium sulfate , filtered , dried in vacuo . the residue was treated with excess 1 . 0n hcl and lyophilized to give desired product as a white solid ( 25 mg , 80 % yield ). c 12 h 20 no 3 cl ; white solid ; rt = 0 . 84 min ( system a ). hrms : calcd . for [ c 12 h 19 no 3 + h + ]= 226 . 1443 . found = 226 . 1437 . esi - ms / ms ( ce = 8 ): m / z (% relative intensity ): 226 ( m + h + , 78 ), 208 ( 100 ). nmr : 1 h nmr ( 500 mhz , dmso - d 6 ): δ 8 . 95 ( s ( br ), 1h ), 8 . 93 ( s ( br ), 1h ), 6 . 78 ( d , j = 2 hz , 1h ), 6 . 72 ( d , j = 9 hz , 1h ), 6 . 62 ( dd , j = 2 , 9 hz , 1h ), 5 . 93 ( d ( br ), j = 3 hz , 1h ), 4 . 75 ( d , j = 9 hz , 1h ), 2 . 99 ( dd , j = 3 , 13 hz , 1h ), 2 . 89 ( m , 3h ), 1 . 61 ( m , 2h ), 1 . 31 ( m , 2h ), 0 . 89 ( t , j = 8 hz , 3h ). to a solution of ( r )- isoproterenol hydrochloride ( 123 . 6 mg , 0 . 5 mmol ) in methanol ( 5 ml ) was added methyl trifluoromethanesulfonate ( 220 μl , 2 . 0 mmol ) at room temperature , and stirred overnight . after adding another methyl trifluoromethanesulfonate ( 220 μl , 2 . 0 mmol ), the solution was stirred again overnight . the solvent was removed using evaporator . then the residue was purified by preparative hplc ( vydac c18 , 5 × 25 cm column , isocratic solvent ( 0 . 1 % tfa in 5 % acetonitrile / water ), flow rate 20 ml / min ). the purified product was treated with 0 . 05n hcl ( 10 ml ), and lyophilized to give ( r )— o - methylisoproterenol hydrochloride ( 62 . 3 mg 0 . 24 mmol , 48 % yield ) as a pale brown solid . c 12 h 20 no 3 cl ; pale brown solid ; rt = 4 . 6 min ( system b ). hrms : calcd . for [ c 12 h 19 no 3 + h + ]= 226 . 1443 . found = 226 . 1440 . esi - ms / ms ( ce = 10 ): m / z (% relative intensity ): 226 ( m + h + , 23 ), 194 ( 100 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 6 . 79 ( m , 2h ), 6 . 69 ( dd , j = 3 , 8 hz , 1h ), 4 . 34 ( dd ( br ), j = 3 , 10 hz , 1h ), 3 . 40 ( sept , j = 6 hz , 1h ), 3 . 23 ( s , 3h ), 3 . 04 - 3 . 16 ( m , 2h ), 1 . 34 ( d , j = 6 hz , 3h ), 1 . 32 ( d , j = 6 hz , 3h ). to a solution of ( s )- isoproterenol bitartrate ( 361 mg , 1 . 0 mmol ) in methanol ( 1 ml ), was slowly added methyl trifluoromethanesulfonate ( 1 ml , 8 . 0 mmol ) at room temperature , and stirred for 4 hrs . the solvent was rapidly removed using evaporator and the product was then purified by preparative hplc ( vydac c18 , 5 × 25 cm column , gradient elution ( 0 - 40 %, acetonitrile / water ( 0 . 1 % tfa ) with flow rate 20 ml / min ). the purified compound was treated with 0 . 1n hcl ( 10 ml ) and lyophilized to give ( s )— o - methylisoproterenol hydrochloride as a white solid . the product was analyzed by an analytical waters hplc ( waters symmetryshield ™ 3 . 5 μm ; 4 . 6 × 50 mm c 18 - reverse phase column ). a gradient 0 - 90 % acetonitrile in water , 0 . 1 % trifluoroacetic acid ( tfa ), for 12 min at a flow rate of 2 ml / min ( system b ) was used . c 12 h 20 no 3 cl ; white solid ; rt = 4 . 6 min ( system b ). hrms : calcd . for [ c 12 h 19 no 3 + h + ]= 226 . 1443 . found = 226 . 1432 esi - ms / ms ( ce = 10 ): m / z (% relative intensity ): 226 ( m + h + , 17 ), 194 ( 100 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 6 . 75 ( m ( br ), 2h ), 6 . 64 ( d ( br ), j = 6 hz , 1h ), 4 . 33 ( d ( br ), j = 8 hz , 1h ), 3 . 36 ( m ( br ), 1h ), 3 . 19 ( s , 3h ), 3 . 00 - 3 . 12 ( m , 2h ), 1 . 29 ( t ( br ), j = 7 hz , 6h ). to a solution of w - chloro - 3 , 4 - dihydroxyacetophenone ( 5 g , 26 . 8 mmol ) in dioxane ( 10 ml ), was added tert - butylamine ( 8 . 4 ml , 80 mmole ), and stirred for 3 hrs at 70 - 80 ° c . the reaction was monitored by hplc until no unreacted starting material remained . to the product amino ketone base was added 10 % hcl . after cooling overnight at room temperature , the solid was filtered , washed with acetone , and dried to give amino ketone hydrochloride ( 5 . 62 g , 81 % yield ; m . p . 233 - 235 ° c .). to a stirred solution of co - tert - butylamino - 3 , 4 - dihydroxyacetophenone hydrochloride ( 900 mg , 3 . 5 mmol ) in methanol ( 20 ml ), was slowly added nabh 4 ( 266 mg , 7 mmol ) at room temperature . the reaction was monitored by hplc until no unreacted starting material remained ( 4 hrs ). the solvent was evaporated and the product was further lyophilized , giving a crude free base ( 1 . 32 g ). the crude free base ( 500 mg ) was dissolved in 2 . 5 ml of water and adjusted to ph 9 - 10 with 10 % hcl . after filtration , the resulting brown solution was eluted with 40 % methanol / water on rp - 18 column chromatography . the collected fractions were combined and dried in vacuo afforded a brown product , which was subjected to ag ® 4 - x4 resin ( 100 - 200 mesh ) column chromatography using pure water as eluent . after lyophilization , pure n - tert - butyl - noradrenaline was obtained as a yellowish crystal . c 12 h 19 no 3 ; yellowish crystal ; rt = 4 . 5 min ( system b ). hrms : calcd . for [ c 12 h 19 no 3 + h + ]= 226 . 1443 . found = 226 . 1432 . esi - ms / ms ( ce = 10 ): m / z (% relative intensity ): 226 ( m + h + , 100 ), 208 ( 60 ), 152 ( 9 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 6 . 63 ( d , j = 2 hz , 1h ), 6 . 50 - 6 . 60 ( m , 2h ), 4 . 66 ( t , j = 7 hz , 1h ), 3 . 00 ( d , j = 7 hz , 2h ), 1 . 33 ( s , 9h ). to a solution of ( s )- isoproterenol bitartrate ( 1 . 0 g , 3 mmol ) in dmf ( 15 ml ), were added triethylamine ( 1 . 25 ml , 9 mmol ) and boc 2 o ( 0 . 67 g , 3 mmol ) at room temperature . the mixture was vigorously stirred overnight and the reaction was monitored by hplc . the crude material was extracted with dcm ( 3 × 50 ml ). the combined extract was washed with water ( 3 × 50 ml ), and brine ( 50 ml ) and dried over anhydrous sodium sulfate . the resulting residue was evaporated to dryness to obtain 0 . 96 g of pale brown solid . the product was used further without purification . to a mixture of ( s )— n - boc - isoproterenol ( 0 . 96 g , 3 mmol ) and triethylamine ( 0 . 98 ml , 7 mmol ) in dcm ( 10 ml ) was dropwisely added isobutyryl chloride ( 0 . 65 ml , 6 mmol ) over 10 min at 0 ° c . under nitrogen and stirred for 2 hrs at room temperature . the crude material was extracted with dcm ( 3 × 50 ml ), washed with water ( 3 × 50 ml ) and brine ( 50 ml ), and dried over anhydrous sodium sulfate . the resulting solution was evaporated to dryness to provide ( s )— n - boc - isoproterenol diisobutyrate as a white crystal ( 1 . 2 g ), which was used further without purification . to a solution of ( s )— n - boc - isoproterenol diisobutyrate ( 1 . 2 g , 2 . 6 mmol ) in isopropanol ( 10 ml ) was added acetyl chloride ( 1 . 88 ml , 26 mmol ) at 0 c and stirred for 1 . 5 hrs at room temperature . the reaction was monitored by hplc . after removing the solvent , the product ( s )- isoproterenol diisobutyrate was purified by hpdc ( 0 . 1 % tfa / water , 4 g / l of cetylpyridinium trifluoroacetate as eluent ) to afford 319 mg ( 32 % overall yield ). c 19 h 30 no 5 cl : white solid : rt = 5 . 8 min ( system a ). hrms : calc . for [ c 19 h 29 no 5 + h + ]= 352 . 2124 . found = 352 . 2119 . nmr : 1 h nmr ( cd 3 od ): δ 7 . 40 ( d , j = 8 hz , 1h ), 7 . 34 ( brs , 1h ), 7 . 24 ( d , j = 8 hz , 1h ), 5 . 02 ( dd , j = 3 , 11 hz , 1h ), 3 . 47 ( m , 1h ), 3 . 25 ( dd , j = 3 , 12 hz , 1h ), 3 . 13 ( dd , j = 10 , 12 hz , 1h ), 2 . 83 ( m , 2h ), 1 . 37 ( d , j = 7 hz , 6h ), 1 . 30 ( d , j = 3 hz , 12h ). to a solution of ( s )- isoproterenol bitartrate ( 1 . 0 g , 3 mmol ) in dmf 15 ml , were added triethylamine ( 1 . 25 ml , 9 mmol ) and boc 2 o ( 0 . 67 g , 3 mmol ) at room temperature . the mixture was vigorously stirred overnight and the reaction was monitored by hplc . the product was extracted with dcm ( 3 × 50 ml ), washed with water ( 3 × 50 ml ) and brine ( 50 ml ), and dried over anhydrous sodium sulfate . the residue was further evaporated to dryness to obtain 0 . 85 g of pale brown solid . the product was used further without purification . to a mixture of ( s )— n - boc - isoproterenol ( 0 . 85 g , 2 . 7 mmol ) in dcm ( 10 ml ) and triethylamine ( 0 . 89 ml , 6 . 4 mmol ) was dropwisely added benzoyl chloride ( 0 . 63 ml , 5 . 4 mmol ) over 10 min at 0 ° c . under nitrogen and stirred for 2 hrs at room temperature . the product was extracted with dcm ( 3 × 50 ml ), washed with water ( 3 × 50 ml ) and brine ( 50 ml ), and dried over anhydrous sodium sulfate . the resulting solution was evaporated to dryness , providing ( s )— n - boc - isoproterenol dibenzoylate as a white crystal ( 1 . 43 g ). to a solution of ( s )— n - boc - isoproterenol dibenzoylate ( 1 . 43 g ) in isopropanol ( 10 ml ) was added acetyl chloride ( 2 . 01 ml , 28 mmol ) at 0 ° c . and stirred for 1 . 5 hrs at room temperature . after removal the solvent , the desired ( s )- isoproterenol dibenzoylate was purified by hpdc ( 0 . 1 % tfa - h2o , 4 g / l of cetylpyridinium trifluoroacetate as eluent ) to yield 806 mg ( 64 % overall yield ). c 25 h 26 no 5 cl : white solid : rt = 6 . 3 min ( system a ). hrms : calc . for [ c 25 h 25 no 5 + h + ]= 420 . 1811 . found = 420 . 1815 . nmr : 1 h nmr ( cd 3 od ): δ 8 . 03 ( m , 4h ), 7 . 63 ( m , 2h ), 7 . 60 ( d , j = 6 . 6 hz , 1h ), 7 . 49 ( d , j = 7 . 8 hz , 1h ), 7 . 49 ( brs , 1h ), 7 . 44 ( m , 4h ), 5 . 14 ( dd , j = 3 , 10 hz , 1h ), 3 . 53 ( m , 1h ), 3 . 33 ( dd , j = 16 . 6 hz , 1h ), 3 . 21 ( dd , j = 10 , 12 hz , 1h ), 1 . 41 ( d , j = 6 . 7 hz , 6h ). to a solution of ( s )- isoproterenol bitartrate ( 1 . 0 g , 3 mmol ) in dmf 15 ml , were added triethylamine ( 1 . 25 ml , 9 mmol ) and boc 2 o ( 0 . 67 g , 3 mmol ) at room temperature . the mixture was vigorously stirred overnight , and the reaction was monitored by hplc . ( s )— n - boc - isoproterenol was extracted with dcm ( 3 × 50 ml ), washed with water ( 3 × 50 ml ) and brine ( 50 ml ), and dried over anhydrous sodium sulfate . the solvent was evaporated to dryness to obtain 0 . 91 g of pale brown solid . to a mixture of ( s )— n - boc - isoproterenol ( 0 . 91 g , 2 . 9 mmol ) in dcm ( 10 ml ) and triethylamine ( 0 . 94 ml , 6 . 8 mmol ) was dropwisely added toluoyl chloride ( 0 . 77 ml , 5 . 4 mmol ) over 10 min at 0 ° c . under nitrogen and stirred for 2 hrs at room temperature . the product was extracted with dcm ( 3 × 50 ml ), washed with water ( 3 × 50 ml ) and brine ( 50 ml ), and dried over anhydrous sodium sulfate . the solution was evaporated to dryness to provide ( s )— n - boc - isoproterenol ditoluoylate as a white crystal ( 1 . 52 g ). to a solution of ( s )— n - boc - isoproterenol ditoluoylate ( 1 . 52 g ) in isopropanol ( 10 ml ) was added acetyl chloride ( 2 . 04 ml , 28 mmol ) at 0 ° c . and stirred for 1 . 5 hrs at room temperature . after removal the solvent , the desired ( s )- isoproterenol ditoluoylate was purified by hpdc ( 0 . 1 % tfa - h 2 o , 4 g / l of cetylpyridinium trifluoroacetate as eluent ) to afford 715 mg ( 55 % overall yield ). c 27 h 30 no 5 cl : white solid : rt = 6 . 8 min ( system a ). hrms : calc . for [ c 27 h 29 no 5 + h + ]= 448 . 2124 . found = 448 . 2109 . nmr : 1 h nmr ( cd 3 od ): δ 7 . 89 ( d , j = 8 hz , 4h ), 7 . 53 ( d , j = 8 hz , 1h ), 7 . 50 ( d , j = 8 hz , 1h ), 7 . 45 ( brs , 1h ), 7 . 24 ( d , j = 7 hz , 4h ), 5 . 06 ( dd , j = 3 , 10 hz , 1h ), 3 . 49 ( m , 1h ), 3 . 31 ( dd , j = 10 hz , 1h ), 3 . 19 ( dd , j = 10 , 13 hz , 1h ), 2 . 38 ( s , 6h ), 1 . 38 ( d , j = 7 hz , 6h ). to a solution of isoetharine mesylate ( 1 . 68 g , 5 mmol ) in acetone ( 25 ml ) was added 1 . 0n naoh ( 25 ml , 25 mmol ) at room temperature and stirred for 10 sec , followed by addition of pivaloyl chloride ( 2 . 47 ml , 20 mmol ) in one portion . the reaction solution was stirred for additional 15 sec . and then quenched with 1 . 0n hcl ( 20 ml ). the product was extracted with dcm ( 3 × 100 ml ), washed with 10 % sodium bicarbonate ( 100 ml ) and brine ( 50 ml ), dried over anhydrous sodium sulfate , filtered and concentrated in vacuo . crude product was purified by hpdc ( 0 . 1 % tfa / water , 4 g / l of cetylpyridinium trifluoroacetate as eluent ) yielding white solid ( 1 . 0 g , 45 % yield ). c 23 h 38 no 5 cl ; white solid ; rt = 6 . 6 min ( system a ). hrms : calcd . for [ c 23 h 37 no 5 + h + ]= 408 . 2750 . found = 408 . 2732 . esi - ms / ms ( ce = 15 ): m / z (% relative intensity ): 408 ( m + h + , 100 ), 390 ( 16 ), 348 ( 0 . 8 ), 306 ( 2 . 3 ). nmr : 1 h nmr ( 500 mhz , cd 3 od ): δ 7 . 39 ( dd , j = 2 , 9 hz , 1h ), 7 . 32 ( d , j = 2 hz , 1h ), 7 . 21 ( d , j = 9 hz , 1h ), 5 . 17 ( d , j = 4 hz , 1h ), 3 . 60 ( sept , j = 6 hz , 1h ), 3 . 42 ( m , 1h ), 1 . 69 ( m , 1h ), 1 . 59 ( m , 1h ), 1 . 44 ( s , 3h ), 1 . 43 ( s , 3h ), 1 . 36 ( s , 9h ), 1 . 35 ( s , 9h ), 0 . 87 ( t , j = 7 hz , 3h ). the purity of ( s )- isoproterenol dipivalate hydrochloride was examined by waters analytical hplc system ( 600 - ms controller , 600e pump , 717 autosampler , 996 photodiode array detector ). the optical purity of ( s )- isoproterenol bitartrate and ( s )- isoproterenol dipivalate hydrochloride was examined by using another waters hplc system ( 600 controller , 600e pump , 717 autosampler , an d2996 photodiode array detector ). high performance displacement chromatography ( hpdc ) was also carried out by using the latter system . nmr spectra were measured by bruker avance 500 mhz nmr . high - resolution mass spectra were measured by micromass waters q - tof ultima ™ global mass spectrometer ( mississauga , ont , canada ) with nanolockspray ([ glu 1 ]- fibrinopeptide b as a reference compound ). huvecs were purchased from cedarlane laboratories ( burlington , canada ) and maintained in endothelial cell basal medium - 2 ( ebm - 2 ) supplemented with egm - 2 growth factor mixture ( clonetics ) and 2 % foetal bovine serum . the cells were cultured at 37 ° c . under a humidified 95 %/ 5 % ( v / v ) mixture of air and co 2 . matrigel endothelial cell tube formation assays were performed using bd matrigel ™ ( becton , dickinson ). bd matrigel ™ was thawed at 4 ° c ., and 150 μl were quickly added to each well of a 48 - well plate and allowed to solidify for 60 min at 37 ° c . huvecs ( 7 × 10 4 cells / ml ) in ec basal medium - 2 ( ebm - 2 ) were seeded 250 μl per well onto the surface of the solid bd matrigel ™ in the presence of the compounds to be tested . the cells were incubated for 22 h at 37 ° c . in a 5 % co 2 incubator . tube formation was monitored by using a leitz labovert ( leitz , wetzlar , germany ) inverted microscope . two randomly selected microscopic fields were photographed with a digital camera ( nikon , coolpicks 995 ). the total length of tube structures in each photograph was measured using imagej ™ free software ( http :// rsb . info . nih . gov / ij /) and was normalized to that of control with no test compound . each reported value represents the average of total six photographs from three independent experiments . invasion of endothelial cells was measured using bd biocoat ™ growth factor reduced matrigel ™ invasion chambers ( beckton - dickinson ; 8 mm pore size ). ebm - 2 medium ( 500 μl each ) was placed into the lower wells . huvecs ( 2 . 5 × 10 4 ) in ebm - 2 serum - free medium ( 500 μl ) were seeded into each of the upper wells and incubated in the presence of a test compound . huvecs were allowed to migrate for 36 h at 37 ° c . in an atmosphere of 95 % air / 5 % co 2 . huvecs that remained on the upper surface of the filter were removed using a cotton swab . huvecs that had migrated to the lower surface of the filters were fixed with methanol , stained with 0 . 1 % crystal violet / 20 % ( v / v ) methanol and examined using a leitz labovert ( leitz , wetzlar , germany ) inverted microscope after mounting on a slide . three randomly selected microscopic fields were digitally captured using a nikon coolpicks ™ 995 digital camera and the number of huvecs in each photograph was directly counted . each reported value represents the average and standard deviation of total four photographs from two independent experiments . ( s )- isoproterenol dipivalate hydrochloride used in the animal study was synthesized from ( s )- isoproterenol bitartrate . pivaloyl chloride ( trimethylacetyl chloride ) ( 4 . 1 mmol , 500 ml ) was added to a solution of ( s )- isoproterenol bitartrate ( 1 . 0 mmol , 361 . 3 mg ) in 50 % 1 . 0n naoh aq / acetone ( 5 . 5 ml / 5 . 5 ml ). the mixture was allowed to react at room temperature for 1 h . the solution was acidified to ph 3 - 5 using 1 . 0n hcl . after washing with n - hexane ( fisher , nepean , ontario , canada ), the solution was extracted with dcm . the organic layer was washed with 10 % na 2 co 3 aqueous solution , dried over anhydrous sodium sulfate , and concentrated under reduced pressure . the residue was purified by high performance displacement chromatography ( column ; shiseido capcell ™ pak c18 aq 5 μm ; 250 × 4 . 6 mm ; 4 . 0 mg / ml cetylpyridinium acetate 0 . 1 % acetic acid in water , flow rate ; 1 . 0 ml / min ). the product was eluted out by a displacer , 4 . 0 mg / ml cetylpyridinium acetate 0 . 1 % acetic acid in water . after salt exchange using 0 . 1n hcl and lyophilization , ( s )- isoproterenol dipivalate hydrochloride was obtained in 32 ± 4 % yield and 97 . 2 ± 0 . 7 % purity based on quantification of impurities described below . c 21 h 34 no 5 cl ; white solid ; rt = 6 . 6 min ( system a ). hrms : calcd . for [ c 21 h 33 no 5 + h + ]= 380 . 2437 . found = 380 . 2426 . 1 h nmr ( 500 mhz , cd 3 od ) δ 7 . 33 ( dd , j = 7 . 2 , 1 . 9 hz , 1h ), 7 . 24 ( d , j = 1 . 9 hz , 1h ), 7 . 15 ( d , j = 7 . 2 hz , 1h ), 4 . 96 ( dd , j = 9 . 9 , 3 . 1 hz , 1h ), 3 . 40 ( m , 1h , 3 . 18 ( dd , j = 12 . 3 , 3 . 1 hz , 1h ), 3 . 07 ( dd , j = 12 . 62 , 9 . 9 hz , 1h ), 1 . 32 ( d , j = 7 . 0 hz , 6h ), 1 . 30 ( s , 9h ), 1 . 29 ( s , 9h ). the optical isomers of ( s )- isoproterenol bitartrate and ( s )- isoproterenol dipivalate hydrochloride were separated by hplc using shiseido chiral cd - ph column ( 250 × 4 . 6 mm ; 5 μm ; isocratic 60 : 40 of 0 . 5m sodium perchlorate / water and acetonitrile ; flow rate , 1 . 0 ml / min ). the elution profile was monitored by the absorption at 223 nm for isoproterenol bitartrate and 264 nm for isoproterenol dipivalate hydrochloride . the optical impurities were quantitated by the absorbance at 223 nm for isoproterenol bitartrate and 264 nm for isoproterenol dipivalate hydrochloride and by using a curve fitting software tablecurve2d ( systat ). the impurities of ( r )- isoproterenol bitartrate and ( r )- isoproterenol dipivalate hydrochloride were estimated as 2 . 0 ± 0 . 3 % and 3 . 3 ± 0 . 2 %, respectively . thus , the racemization induced during synthesis and purification was minimal , if it occurred . ( s )- isoproterenol hydrochloride and ( s )- isoproterenol dipivalate hydrochloride used in in vitro studies have 99 . 9 % or higher optical purity . in vivo studies : ( s )- isoproterenol dipivalate hydrochloride was used to study diabetic retinopathy in a rat model . another advantage of adrenalines is the formulation , i . e ., commercial eye drop dipivefrin is a prodrug of ( r , s )- adrenaline . it is more lipophilic than adrenaline , is still water soluble and stable in eye drop solution . adrenaline is released when it passes through cornea , and pivalic acid , cleaved form of the blocking group , has a wide margin of safety , even at large oral administration . dipivefrin enhances the ocular absorption 17 times better than adrenaline , allowing one to reduce the amount of the dose and the potential side effects ( mandell et al ., 1978 ). the same formulation of prodrug was successfully applied to isoproterenol ( hussain & amp ; truelove , 1975 ). thus , the effect of the formulated ( s )- isoproterenol dipivalate hydrochloride on diabetic retinopathy with rat model was examined . active ingredient in the eye drop is 0 . 10 % ( w / v ) ( s )- isoproterenol dipivalate hydrochloride , and inactive ingredients are 1 . 84 % ( w / v ) d - mannitol , 0 . 005 % ( w / v ) disodium edetate , 0 . 10 % ( w / v ) chlorobutanol , 0 . 16 % ( w / v ) ε - aminocaproic acid , 0 . 5 % ( w / v ) sodium chloride , 0 . 003 % ( w / v ) benzalkonium chloride , and 0 . 20 % ( w / v ) povidone . the ph of the eye drop was adjusted to 5 . 5 with 1 . 0n hcl . the control eye drop has the same inactive ingredients , but lacks the active ingredient . the eye drop was freshly prepared every month and was stored at 4 ° c . no degradation of the active and inactive gradients was detected based on their hplc profiles after one month of storage at 4 ° c . the volume of each eye drop was 50 μl . prevention of diabetic retinopathy by ( s )- isoproterenol dipivalate eye drop was studied using a rat model . two - month - old male sprague - dawley rats were purchased from charles river , canada . they were housed in the biotechnology research institute ( bri )- animal facility . housing and all experimental manipulations were approved by the bri animal care committee that functions under the guidelines of the canadian council of animal care . diabetes was induced in male sprague - dawley rats weighing approximately 200 to 250 g by a single intraperitoneal injection of the beta - cell toxin , streptozotocin ( stz ) ( sigma , st . louis , mich . ), at a dose of 60 mg / kg body weight in 0 . 1m citrate buffer ph 4 . 5 . non - diabetic control rats received citrate buffer only . one week following induction of diabetes , glucose levels were determined in the blood sampled from the tail vein using a blood glucose monitoring system ( ascensia elite blood glucose meter , bayer inc , toronto , on , canada ). since the limit of detection of the blood glucose meter was 33 mm , any value above that has been assigned a maximum value of 35 mm . only animals with blood glucose levels higher than 15 mm were retained in the study . animals were thus allocated into one of four groups : group i ( n ˜ 20 ): non - diabetic rats - receiving vehicle ; group ii ( n ˜ 20 ): non - diabetic rats - receiving eye drops containing ( s )- isoproterenol dipivalate ; group iii ( n ˜ 20 ): diabetic rats - receiving vehicle ; group iv ( n ˜ 20 ): diabetic rats - receiving eye drops containing ( s )- isoproterenol dipivalate . eye drops or vehicle were administered twice a day , seven days a week , on the cornea of different groups of rats , with a minimum interval of 7 h between the two treatments . to promote weight gain and limit hyperglycemia , diabetic rats were injected sub - cutaneously with 2 iu ultralente insulin ( humulin , eli lilly , toronto , on , canada ) three times a week . animal weights were monitored every week . the effects of ( s )- isoproterenol on diabetic retinopathy were studied by staining retinal capillaries with antibodies against lectin . the capillary density at the retinal center , corresponding to the macula of the human eye , was analyzed . diabetes induces glycation in retina . since ( s )- isoproterenol is a potent anti - glycation agent , penetration of ( s )- isoproterenol reduces glycation in diabetic retinal capillaries . thus , the retinas , which were stained with antibodies against lectin , were also stained with antibodies against glycated bovine serum albumin , and the degree of glycation of retinal capillaries was analyzed . anti - angiogenic activity of catecholamines and related compounds was measured by inhibiting capillary tube formation of ( huvecs in matrigel assay ( fig1 ). the potency of ( s )- isoproterenol is around 10 μm under the angiogenic assay condition used in fig1 . as dopamine showed comparable potency in the same assay ( fig2 a ) and showed effective anti - angiogenic activity at 1 μm ( basu et al ., 2001 ), the in vivo potency of ( s )- isoproterenol could be lower than 10 μm . the anti - angiogenicity of some anti - angiogenic agents of the present invention is listed in table 1a . table 1b lists dopamine , a known anti - angiogenic compound , and some catecholamines that do not show anti - angiogenic effects . fig2 a is the quantitative expression of the anti - angiogenicity of these compounds and fig2 b are some photographs used in the analysis . dopamine is an anti - angiogenic agent through dopamine d2 receptor ( basu et al ., 2001 ), whereas ( r )- adrenalines ( belonging to the catecholamine class of compounds ) are angiogenic through β2 - adrenergic receptor ( thaker et al ., 2006 ). it was surprising and unexpected that ( s )- noradrenaline , which is structurally homologous to dopamine , was not anti - angiogenic , whereas ( s )- isoproterenol , which is less homologous to dopamine than ( s )- noradrenaline , was anti - angiogenic . moreover , even less homologous ( r , s )— n - tert - butylnoradrenaline was anti - angiogenic , despite ( r )— n - tert - butylnoradrenaline being an agonist of β2 - adrenergic receptor ( walker et al ., 1985 ). consequently , anti - angiogenic activity of the compounds listed in table 1a is unexpected . ( r )- isoproterenol is known to be angiogenic and competes with the anti - angiogenic activity of ( s )- isoproterenol as racemic mixture ( r , s )- isoproterenol did not show anti - angiogenic activity . thus , the optical purity of ( s )- isoproterenol required to express anti - angiogenic activity was examined with various optical purity of ( s )- isoproterenol ( fig3 ). anti - angiogenic activity was observed with 97 % w / w or higher optical purity of ( s )- isoproterenol , while 95 % w / w optically pure ( s )- isoproterenol was in the transition from non - antiangiogenic to anti - angiogenic . consequently , at least 97 % w / w optically purity of ( s )- isoproterenol is preferred , more preferably at least 99 . 9 % w / w , even more preferably at least 99 . 99 % w / w , because the in vivo expression of β2 - adrenergic receptor in the targeted tissue could be higher than that in huvecs used in the assay , requiring further elimination of ( r )- isoproterenol in the drug . some ( s )- adrenalines listed in tables 1a and 1b are ( s )- noradrenaline , ( r , s )- adrenaline , ( s )— n - ethylnoradrenaline , ( s )— n - propylnoradrenaline , ( s )— n - butylnoradrenaline , ( r , s )— n - tert - butylnoradrenaline ( colterol ), and isoetharine . the least lipophilic ( s )- noradrenaline was not anti - angiogenic , whereas more lipophilic ( s )— n - ethylnoradrenaline , ( s )— n - propylnoradrenaline , ( s )- isoproterenol , ( s )— n - butylnoradrenaline showed anti - angiogenic activity . in racemic mixture , relatively lipophilic ( r , s )- adrenaline and ( r , s )- isoproterenol showed no anti - angiogenic activity . however , more lipophilic ( r , s )— n - tert - butylnoradrenaline and isoetharine showed anti - angiogenic activity . since ( r )- isoform of these adrenalines is angiogenic through their 82 - adrenergic receptor agonist activity , anti - angiogenic activity of ( s )- isoform of these adrenalines might be enhanced as their lipophilicity is increased . examples of some other ( s )- adrenalines useful in the present invention are listed in fig7 . since ( s )- isoproterenol and its analogs are anti - glycation agents ( yeboah et al ., 2005 ) and we have now found that they are anti - angiogenic , these activities may show synergy effects when both glycation and angiogenesis are contributing to the disease , for example diabetic retinopathy . for such applications , the compounds and their prodrugs with anti - glycation activity and anti - angiogenic activity , but lacking adrenergic activity are preferred . more specifically , ( s )- isoproterenol and its prodrugs are in particular interest . some prodrugs listed in fig9 are ( s )— n - ethyladrenaline dipivalate , ( s )— n - propylnoradrenaline dipivalate , ( s )— n - n - butylnoradrenaline dipivalate , ( s )- isoproterenol dipivalate , ( s )- isoproterenol diisobutyrate , ( s )- isoproterenol dibenzoylate , ( s )- isoproterenol ditoluoylate , and isoetharine dipivalate . anti - angiogenic activity was measured on some prodrugs , resulting no or weak anti - angiogenic activity as shown in fig1 . considering that a part of some prodrugs may be hydrolyzed to anti - angiogenic ( s )- isoproterenol during 22 hrs of the incubation period , the prodrugs in fig1 would be non - antiangiogenic or very weak anti - angiogenic agents . tumor cell invasion is a process involved in the late stage of cancer development where tumor migrates from one tissue to other tissues . the present invention provides a novel activity of ( s )- isoproterenol to prevent tumor cell invasion . fig3 shows that ( s )- isoproterenol ( 20 μm ) reduced the invasion of huvecs in matrigel by 60 %. in contrast , its optical isomer ( r )- isoproterenol did not show any anti - invasion activity . together with anti - angiogenic activity , ( s )- isoproterenol has dual activities to treat tumor metastasis . the present invention excludes the use of the compounds with β2 - adrenergic agonist activity such as ( r )- isoproterenol as β2 - adrenergic agonists are angiogenic ( thaker et al ., 2006 ), unless anti - angiogenic activity of the ingredients exceeds the angiogenic activity of the β2 - adrenergic agonist component ( s ) and the β2 - adrenergic activity does not interfere the therapeutic effects of the present invention and does not provide adrenergic adverse effects . the present invention includes the use of prodrugs of ( s )- isoproterenol and its analogs , where the aromatic hydroxyl group ( s ) are modified . the prodrugs may enhance and accelerate the tissue absorption and penetration due to its high lipophilicity . the prodrugs also protect the aromatic hydroxyl group ( s ) from chemical reactions such as oxidation during storage . the prodrugs are also less uv - light sensitive compared with the corresponding drugs . in case that a high optical purity is desired for anti - angiogenic activity and for minimizing adverse adrenergic effects , prodrugs reduce the racemization during storage . table 2 describes the optical purities of ( s )- isoproterenol and ( s )- isoproterenol dipivalate after incubation in various eye drop formulations for 10 days at 55 ° c . and compared with those before incubation . the incubation for 10 days at 55 ° c . corresponds to the incubation for 167 days at 22 ° c . the average optical purity of ( s )- isoproterenol after incubating 10 days at 55 ° c . was 97 . 35 ± 0 . 52 %, resulting in conversion of 2 . 55 % of ( s )- isoproterenol to ( r )- isoproterenol . this corresponds to a reduction of optical purity of ( s )- isoproterenol from 99 . 90 % to 90 % after 655 days of storage at room temperature . on the contrary , the average optical purity of ( s )- isoproterenol dipivalate after incubating 10 days at 55 ° c . was approximately 99 . 85 ± 0 . 08 %, resulting in 0 . 02 % of ( s )- isoproterenol dipivalate conversion to the corresponding ( r )- isoform . this implies that the optical purity of ( s )- isoproterenol dipivalate is reduced from 99 . 87 % to 99 . 78 % after 2 years of storage at room temperature . since a high optical purity of ( s )- isoproterenol is greatly desired for anti - angiogenic activity , prodrug formulation is preferred . prodrug formulation is not limited to pivalate esters . examples of some protecting groups of the aromatic hydroxyl groups are listed in fig8 . streptozotocin was used to induce diabetes in rats . the blood glucose levels were monitored once a week over a 27 week period for non - diabetic and diabetic rats . control group i ( receiving vehicle ) and group ii ( receiving prodrug ) of non - diabetic animals ( filled diamond ) have a steady blood glucose level of 5 . 1 ± 0 . 4 and 5 . 1 ± 0 . 4 mm , respectively ). an increase in blood glucose levels was noted for group iii ( receiving vehicle ) and group iv ( receiving prodrug ) diabetic rats , during the first 2 weeks of diabetes induction . the glucose levels then stabilized at 28 ± 4 and 27 ± 5 mm , respectively . as the glucose level at around 5 mm is considered normal , rats in group i and group ii are non - diabetic . rats are considered diabetic when the blood glucose level exceeds 15 mm . thus , all of the rats in group iii and group iv are diabetic . the consistency of the blood glucose level between groups i and ii and between groups iii and iv shows that ( s )- isoproterenol does not affect the blood glucose level and diabetes . another potential adverse effect of ( s )- isoproterenol on body weight loss / gain was monitored . the weight gain during the experiments is essentially the same between group i ( non - diabetic rats receiving vehicle ) in fig5 a and group ii ( non - diabetic rats receiving prodrug ) in fig5 b , suggesting that no effect of ( s )- isoproterenol in weight gain / loss of non - diabetic rats . the weight gain is much less in the diabetic rats compared to those of non - diabetic rats ( chen et al ., 2004 ); however , the weight gain of group iii ( diabetic rats receiving vehicle ) in fig5 a is essentially the same as that of group iv ( diabetic rats receiving prodrug ) in fig5 b , showing no effect of ( s )- isoproterenol in weight gain / loss of diabetic rats . while rats are not an appropriate model organism for studying anti - angiogenicity directly , they may be used to study the ability of a drug to penetrate to the retina of an eye . it is known that ( s )- isoproterenol is a potent anti - glycation agent ( yeboah et al ., 2005 ). the delivery of ( s )- isoproterenol into retina was demonstrated by inhibiting retinal glycation with ( s )- isoproterenol dipivalate eye drops . antibodies against glycated bovine serum albumin stained glycated retinal proteins in red fluorescence . the glycation of retinal capillaries was evaluated by superimposing the red fluorescence of anti - glycation antibodies with the above green fluorescence of anti - lectin antibodies , resulting green to light orange fluorescence of healthy retinal capillaries with less glycation and red fluorescence of highly glycated retinal capillaries . the retinal capillaries of non - diabetic rat eyes with least glycation showed green to light orange fluorescence . similar healthy capillaries were observed in diabetic rat eye with ( s )- isoproterenol dipivalate . the retinal capillaries in diabetic rat eye with vehicle were stained in red fluorescence and were also damaged as less number of capillaries were stained . fig6 quantifies the effect by normalizing the red fluorescence intensity of ages by the retinal capillary density , resulting 0 . 43 ± 0 . 15 , 0 . 44 ± 0 . 17 , and 0 . 76 ± 0 . 14 for non - diabetic rats , diabetic rats with ( s )- isoproterenol dipivalate treatment , and diabetic rats with vehicle , respectively . the p values are 0 . 052 , 0 . 068 , and 0 . 971 for non - diabetic rats vs . diabetic rats with vehicle , diabetic rats with ( s )- isoproterenol dipivalate vs . diabetic rats with vehicle , and non - diabetic rats vs . diabetic rats with ( s )- isoproterenol dipivalate , respectively . it should be noticed that acellular capillaries , which are enriched in diabetic retina with vehicle , are expected to be highly glycated such that the degree of glycation for diabetic rats with vehicle would be greater than 0 . 76 ± 0 . 14 in fig6 , demonstrating that ( s )- isoproterenol dipivalate effectively delivered ( s )- isoproterenol into retina and significantly reduced the glycation in retinal capillaries . since ( s )- isoproterenol can be effectively delivered to the retina of an eye where it can exert its anti - angiogenic effect , it is expected to be useful in the treatment and / or prevention of diabetic retinopathy . in one preferred embodiment , the present invention provides a novel use of ( s )- isoforms of isoproterenol and its analogs , for preventing and / or treating diseases related to angiogenesis and / or invasion . these compounds satisfy several criteria important for this application . first of all , the anti - angiogenic activity of ( s )- isoproterenol and its analogs is high . the anti - angiogenic activity at cellular level must be observable at or below 1 mm , preferably at or below 100 μm , more preferably at or below 20 μm . secondly , the adrenergic activity , which is characteristic of the ( r )- isoform is insignificant for the ( s )- isoform . the adrenergic activities of the ( s )- isoform of adrenalines are much lower than that of the corresponding ( r )- isoform ( patil et al ., 1974 ). in particular , topical administration of up to 20 % ( s )- isoproterenol hydrochloride did not show any indication to lower intra - ocular pressure in the human eye ( kass et al ., 1976 ). the ( s )- isoform of isoproterenol and its analogs are considered to be adrenergically inert and be safe for topical and systemic administration . the evidence that most commercial drugs of adrenergic agonists are racemic mixtures provides strong practical reason for the inertness of the ( s )- isomers ( boulton & amp ; fawcett , 2002 ). preparations according to one preferred embodiment of the present invention contain only the ( s )- isoform of isoproterenol and its analogs in order to reduce potential adverse effects through stimulation of adrenergic receptors . isoproterenol is known to have a duration long enough for a reasonable frequency of administration such as a twice - a - day administration , e . g ., when 2 . 47 % ( r , s )- isoproterenol was instilled to normal human eyes , a 20 % reduction in ocular tension was observed , lasting at least 12 h ( ross & amp ; drance , 1970 ). once ( s )- isoproterenol gets into blood circulation system , it is metabolized to 3 - methyl -( s )- isoproterenol and its plasma half - life is in the range from 3 . 0 to 4 . 1 min ( conway et al ., 1968 ), minimizing the possibility of any systemic adverse effects of ( s )- isoproterenol . the contents of the entirety of each of which are incorporated by this reference . basu , s . ; nagy , j . a . ; pal , s . ; vasile , e . ; eckelhoefer , i . a . ; bliss , v . s . ; manseau , e . j . ; dasgupta , p . s . ; dvorak , h . f . ; mukhopadhyay , d . the neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor / vascular endothelial growth factor . nat . med . ( 2001 ), 7 , 569 - 574 . bentley , g . a . ; starr , j . the antinociceptive action of some β - adrenoceptor agonists in mice . br . j . pharmacol . ( 1986 ) 88 , 515 - 521 . boulton , d . w . ; fawcett , j . p . β2 - agonist eutomers : a rational option for the treatment of asthma ? am . j . respir . med . ( 2002 ), 1 , 305 - 311 . chen , a . s . ; taguchi , t . ; sugiura , m . ; wakasugi , y . ; kamei , a . ; wang , m . w . ; miwa , i . pyridoxal - aminoguanidine adduct is more effective than aminoguanidine in preventing neuropathy and cataract in diabetic rats . horm . metab . res . ( 2004 ) 36 , 183 - 187 . conway , w . d . ; minatorya , h . ; lnds , a . m . ; shekosky , j . m . absorption and elimination profile of isoproterenol iii . the metabolic fate of dl - isoproterenol - 7 - 3h in the dog . j . pharm . sci . ( 1968 ) 57 , 1135 - 1141 . chalothorn , d . ; zhang , h . ; clayton , j . a . ; thomas , s . a . ; faber , j . e . catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia . am . j . physiol . heart circ . physiol . ( 2005 ) 289 , h947 - h959 . dejgaard , a . ; hilsted , j . ; christensen , n . j . noradrenaline and isoproterenol kinetics in diabetic patients with and without autonomic neuropathy . diabetologia . ( 1986 ) 29 , 773 - 777 . jarvinen , t . ; jarvinen , k . prodrugs for improved ocular drug delivery . adv . drug delivery rev . ( 1996 ), 19 , 203 - 224 . kass , m . a . ; reid , t . w . ; neufeld , a . h . ; bausher , l . p . ; sears , m . l . the effect of d - isoproterenol on intraocular pressure of the rabbit , monkey , and man . invest . ophthalmol . ( 1976 ), 15 , 113 - 118 . kyselova , z . ; stefek , m . ; bauer , v . pharmacological prevention of diabetic cataract . j . diabetes complications . ( 2004 ) 18 , 129 - 140 . lands , a . m . ; luduena , f . p . ; tullar , b . f . the pharmacologic activity of the optical isomers of isoproterenol compared with that of the optically inactive analog 1 -( 3 , 4 - dihydroxyphenyl )- 2 - isopropylaminoethane hcl . j . pharmacol . exp . ther . ( 1954 ), 111 , 469 - 474 . mandell , a . 1 . ; stentz , f . ; kitabchi , a . e . dipivalyl epinephrine : a new pro - drug in the treatment of glaucoma . ophthalmology ( 1978 ) 85 , 268 - 275 . mullick , a . ; konishi , y . anti - diabetic cataract compounds and their uses . international publication number wo 2007 / 109882 , oct . 4 , 2007 . patil , p . n . ; miller , d . d . ; trendelenburg u . molecular geometry and adrenergic drug activity . pharmacol . rev . ( 1974 ), 26 , 323 - 392 . ross , r . a . ; drance , s . m . effects of topically applied isoproterenol on aqueous dynamics in man . arch . ophthal . ( 1970 ) 83 , 39 - 46 . seidehamel , r . j . ; dungan , k . w . ; hickey , t . e . specific hypotensive and antihypertensive ocular effects of d - isoproterenol in rabbits . am . j . ophthalmol . ( 1975 ), 79 , 1018 - 1025 . thaker , p . h . ; han , l . y . ; kamat , a . a . ; arevalo , j . m . ; takahashi , r . ; lu , c . ; jennings , n . b . ; armaiz - pena , g . ; bankson , j . a . ; ravoori , m . ; merritt , w . m . ; lin , y . g . ; mangala , l . s . ; kim , t . j . ; coleman , r . l . ; landen , c . n . ; yang li , y . ; felix , e . ; sanguino , a . m . ; newman , r . a . ; lloyd , m . ; gershenson , d . m . ; kundra , v . ; lopez - berestein , g . ; lutgendorf , s . k . ; cole , s . w . ; sood , a . k . chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma . nat . med . ( 2006 ), 12 , 939 - 944 . walker , s . b . ; kradjan , w . a . ; bierman , c . w . bitolterol mesylate : a beta - adrenergic agent . chemistry , pharmacokinetics , pharmacodynamics , adverse effects and clinical efficacy in asthma . pharmacotherapy ( 1985 ), 5 , 127 - 137 . wang , b . c . ; bloxham , d . d . ; goetz , k . l . effect of dipivalyl derivatives of catecholamines on cardiovascular function in the conscious dog . j . pharmacol . exp . ther . ( 1977 ) 203 , 442 - 448 . yeboah , f . ; konishi , y . ; cho , s . j . ; lertvorachon , j . ; kiyota , t . ; popek , t . anti - glycation agents for preventing age -, diabetes -, and smoking - related complications . us patent publication 2005 / 0043408 , feb . 24 , 2005 . other advantages that are inherent to the structure are obvious to one skilled in the art . the embodiments are described herein illustratively and are not meant to limit the scope of the invention as claimed . variations of the foregoing embodiments will be evident to a person of ordinary skill and are intended by the inventor to be encompassed by the following claims .

US-201615150835-A

a method and apparatus for removing grease from meat includes a mesh basket for holding the partially cooked meat , a pressure plate for exerting a sustained force on the meat within the mesh basket , one or more spacers for placing on top of the pressure plate , a container for holding the mesh basket with the one or more spacers partially extending beyond an opening in the container and a lid that can be pressed onto the container , sealing the opening and placing sustained force on the spacers , thereby placing sustained force on the pressure plate , thereby compressing the partially cooked meat and extracting grease and excess liquids from the meat through the mesh basket and into the bottom of the container . a handle is provided to hold the container so as to pour out the grease and excess liquids through a flow conducting member , perhaps a spout .

reference will now be made in detail to the presently preferred embodiments of the invention , examples of which are illustrated in the accompanying drawings . throughout the following detailed description , the same reference numerals refer to the same elements in all figures . referring to fig1 , an external view of the present invention is shown . in this , a container 110 is shown having a lid 160 that may be secured to the container by a latch 150 / 152 . in this embodiment , a twist latch is shown comprising a hook 150 and a receptor 152 that engage by placing the lid 160 onto the top rim of the container 110 and twisting the lid 160 until the hook 150 engages with the receptor 152 . in other embodiments , other means known in the industry of securing the lid 160 to the container 110 may be used including , but not limited to , a retaining wires and pressure fits . a lid grip 165 may be included in some embodiments to help in placing and removing the lid 160 . the container 110 may also have a grip 140 for gripping the container . also shown is a flow conducting member or spout 130 to help direct the outward flow of grease and excess fluids through an opening in the side of the container 110 . referring now to fig2 , an expanded view of the present invention is shown . in this the container 110 is shown having a lid 160 that may be secured to the container by a latch 150 / 152 . in this embodiment , a twist latch is shown comprising a hook 150 and a receptor 152 that engage by placing the lid 160 onto the top rim of the container 110 and twisting the lid 160 until the hook 150 engages with the receptor 152 . in other embodiments , other means known in the industry of securing the lid 160 to the container 110 may be used including , but not limited to , a retaining wires and pressure fits . a lid grip 165 may be included in some embodiments to help in placing and removing the lid 160 . the container 110 may also have a grip 140 for gripping the container . also shown is a flow conducting member or spout 130 to help direct the outward flow of grease and excess fluids from the container 110 . in this view , a mesh basket 210 for holding partially cooked meat is shown . this basket may be constructed from a wire mesh such as used to form a kitchen strainer or colander or may be a perforated metal ( or other sturdy material such as plastic or teflon ) container whereas the wire mesh or perforations are sized large enough to allow grease and excess juices to flow through the openings yet retain most of the meat . the basket is sized to fit within the container 110 and provide sufficient clearance from the interior surface 290 of the container 110 such that grease and excess juices may flow along the interior surface 290 of the container 110 when the container 110 is tilted . configured to fit within the mesh basket 210 is a pressure plate 240 for pressing against the partially cooked meat . it is preferred that the pressure plate 240 is a solid material , substantially disk - like in shape and having a diameter slightly smaller than the inside diameter of the mesh basket 210 , such that it fits snuggly within the mesh basket 210 . configured to fit above the pressure plate 240 are one or more spacers ( two are shown 220 / 230 ). the spacers are configured to fit within the mesh basket 210 and fill the void between the pressure plate 240 and the lid 160 when the lid 160 is closed . it is preferred that the spacer ( s ) extend above the top annular rim 205 of the container 110 before the lid 160 is closed , possibly an inch or so above the annular rim 205 , thereby placing a sustained pressure on the contents of the mesh basket when the lid 160 is closed and latched . the spacers 220 / 230 may be substantially disk - like in shape and have a diameter smaller than the inside diameter of the mesh basket , though they may not fit as snuggly as the pressure plate 240 . referring now to fig3 , an expanded view of the present invention is shown . in this the container 110 is shown having a grip 140 for gripping the container . also shown is a flow conducting member 130 to help direct the outward flow of grease and excess fluids from the container 110 . in this view , a mesh basket 210 for holding partially cooked meat 310 is shown . this basket may be constructed from a wire mesh such as used to form a kitchen strainer or colander or may be a perforated metal ( or other sturdy material such as plastic ) container whereas the wire mesh or perforations are sized large enough to allow grease and excess juices to flow through the openings yet retain most of the meat . the basket is sized to fit within the container 110 and provide sufficient clearance from the interior surface 290 of the container 110 such that grease and excess juices may flow along the interior surface 290 of the container 110 when the container 110 is tilted . in this embodiment , the mesh basket 210 has a lip 350 that engages with a stop 360 that extends from the inside surface of the container 110 . the lip 350 and stop 360 may hold the mesh basket 210 at or above the bottom surface 330 of the container 110 . in some embodiments , the bottom of the container 110 is raised slightly in the center , forming a raised bottom 320 for the mesh basket 210 to rest upon . some embodiments may not have a lip 350 and stop 360 and rely only upon the raised bottom 320 to support the mesh basket 210 . some embodiments may not have the raised bottom 320 and only have a lip 350 and stop 360 to support the mesh basked 210 . some embodiments may have both the raised bottom 320 and the lip 350 / stop 360 to provide extra support for the mesh basket 210 . configured to fit within the mesh basket 210 is a pressure plate 240 for pressing against the partially cooked meat 310 . it is preferred that the pressure plate 240 is a solid material , substantially disk - like in shape and having a diameter slightly smaller than the inside diameter of the mesh basket 210 , such that it fits snuggly within the mesh basket 210 . configured to fit above the pressure plate 240 are one or more spacers ( two are shown 220 / 230 ). the spacers are configured to fit within the mesh basket 210 and fill the void between the pressure plate 240 and the lid 160 when the lid 160 is closed . it is preferred that the spacer ( s ) extend above the top annular rim 205 of the container 110 before the lid 160 is closed , possibly an inch or so above the annular rim 205 , thereby placing a sustained pressure on the partially cooked meat 310 that is held in the mesh basket when the lid 160 is closed and latched . the spacers 220 / 230 may be substantially disk - like in shape and have a diameter smaller than the inside diameter of the mesh basket , though they may not fit as snuggly as the pressure plate 240 . referring now to fig4 , an expanded view of the present invention is shown with the mesh basket 210 inserted into the container 110 . in this the container 110 is shown having a grip 140 for gripping the container . also shown is a flow conducting member 130 to help direct the outward flow of grease and excess fluids from the container 110 . in this view , a mesh basket 210 for holding partially cooked meat 310 is shown inserted into the container 110 . this basket may be constructed from a wire mesh such as used to form a kitchen strainer or colander or may be a perforated metal ( or other sturdy material such as plastic ) container whereas the wire mesh or perforations are sized large enough to allow grease and excess juices to flow through the openings yet retain most of the meat . the basket is sized to fit within the container 110 and provide sufficient clearance from the interior surface 290 of the container 110 such that grease and excess juices may flow along the interior surface 290 of the container 110 when the container 110 is tilted . in this embodiment , the mesh basket 210 has a lip 350 that engages with a stop 360 that extends from the inside surface of the container 110 . the lip 350 and stop 360 may hold the mesh basket 210 at or above the bottom surface 330 of the container 110 . in some embodiments , the bottom of the container 110 is raised slightly in the center , forming a raised bottom 320 for the mesh basket 210 to rest upon . some embodiments may not have a lip 350 and stop 360 and rely only upon the raised bottom 320 to support the mesh basket 210 . some embodiments may not have the raised bottom 320 and only have a lip 350 and stop 360 to support the mesh basked 210 . some embodiments may have both the raised bottom 320 and the lip 350 / stop 360 to provide extra support for the mesh basket 210 . configured to fit within the mesh basket 210 is a pressure plate 240 for pressing against the partially cooked meat 310 . it is preferred that the pressure plate 240 is a solid material , substantially disk - like in shape and having a diameter slightly smaller than the inside diameter of the mesh basket 210 , such that it fits snuggly within the mesh basket 210 . configured to fit above the pressure plate 240 are one or more spacers ( two are shown 220 / 230 ). the spacers are configured to fit within the mesh basket 210 and fill the void between the pressure plate 240 and the lid 160 when the lid 160 is closed . it is preferred that the spacer ( s ) extend above the top annular rim 205 of the container 110 before the lid 160 is closed and optionally latched , possibly an inch or so above the annular rim 205 , thereby placing a sustained pressure on the partially cooked meat 310 that is held in the mesh basket when the lid 160 is closed and latched . the spacers 220 / 230 may be substantially disk - like in shape and have a diameter smaller than the inside diameter of the mesh basket , though they may not fit as snuggly as the pressure plate 240 . referring now to fig5 , an expanded view of the present invention is shown with the mesh basket 210 inserted into the container 110 and the lid 160 closed . in this the container 110 is shown having a grip 140 for gripping the container . also shown is a flow conducting member 130 to help direct the outward flow of grease and excess fluids from the container 110 . in this view , a mesh basket 210 for holding partially cooked meat 310 is shown inserted into the container 110 with a lip 350 engaged with a stop 360 that extends from the inside surface of the container 110 and the mesh basket 210 resting upon the raised bottom 320 to support it . shown in fig5 within the mesh basket 210 is a pressure plate 240 for pressing against the partially cooked meat 310 . above the pressure plate 240 are two spacers 220 / 230 that are exerting a sustained pressure on the partially cooked meat 310 , pressing out grease and excess liquids 510 , thereby allowing the grease and excess liquids 510 to collect at the bottom of the container 110 and later be poured from the container 110 through the flow conducting member 130 when the container 110 is tilted . referring now to fig6 , a top view of the lid 160 of the present invention is shown with a grip 165 . the lid 160 is preferably disk - shaped and is configured to fit tightly onto the top annular surface of the container 110 , thereby substantially sealing the container so that grease and excess liquids 510 can flow out of the flow conducting member 130 without leaking between the lid 160 and the container 110 . this seal will help in the use of the present invention , but , in some embodiments , may be a partial seal or a weak seal being that by slowly pouring the grease and excess liquids 510 out of the flow conducting member 130 may prevent the grease and excess liquids 510 from reaching the lid 160 and leaking between the lid 160 and the container 110 . equivalent elements can be substituted for the ones set forth above such that they perform in substantially the same manner in the same way for achieving the same result . it is believed that the system and method of the present invention and many of its attendant advantages will be understood by the foregoing description . it is also believed that it will be apparent that various changes may be made in the form , construction and arrangement of the components thereof without departing from the scope and spirit of the invention or without sacrificing all of its material advantages . the form herein before described being merely exemplary and explanatory embodiment thereof . it is the intention of the following claims to encompass and include such changes .

US-10006205-A

the present invention relates to a method for synthesis of optically pure 4 - alkenyl or 4 - alkanyl - 2 - hydroxytetronic acids from an optically pure aldehyde . the invention further relates to the use of such optically pure compounds as potent inhibitors of platelet aggregation by working at the level of cyclooxygenase . the invention further relates to the pharmaceutical use of such compounds in the treatment of coronary artery diseases , especially in the treatment and / or prevention of atherosclerosis .

in a first embodiment , the present invention relates to optically pure 4 - alkenyl - or 4 - alkanyl - 2 - hydroxytetronic acid compounds of the general formulae ia or ib ## str2 ## wherein r is an alkenyl group of 2 - 20 carbon atoms or an alkanyl group of 9 - 20 carbon atoms , and , when an alkenyl group , contains one or more degrees of unsaturation . in a composition aspect , the present invention encompasses novel pharmaceutical compositions comprising the optically pure compound of the general formulae ia and ib , together with a physiologically acceptable carrier or excipient , in an amount sufficient to have antilipidemic or antiaggregatory activities in an animal or patient . the compounds and their compositions of the present invention are thus useful in the treatment or prevention of atherosclerotic disorders . as used herein , the term &# 34 ; alkenyl group of 2 - 20 carbon atoms containing one or more degrees of unsaturation &# 34 ; means an organic , alkanyl group containing one or more double bonds and which can optionally be substituted by one or more halogen , lower alkanyl , alkoxy , aromatic or heteroaromatic groups . examples of unsubstituted alkenyl groups include those such as 3 - octadecenyl , 3 , 6 , 9 , 12 - octadecatetraenyl , and the like . examples of alkanyl groups of 9 - 20 carbon atoms include hexadecanyl , heptadecanyl , octadecanyl , nonadecanyl and eicosanyl , as well as their corresponding branched - chain analogs thereof . examples of substituted lower alkenyl groups include those such as halogen substituted alkenyl , e . g ., fluoro , chloro , bromo and iodo - substituted alkenyl ; alkanyl - substituted alkenyl , e . g ., methanyl -, ethanyl and similar alkenyl ; and alkoxy substituted alkenyl , e . g ., methoxy , ethoxy and similar - alkenyl . as used herein , the term &# 34 ; lower alkanyl &# 34 ; means straightor branched - chain saturated aliphatic hydrocarbon groups preferably containing 1 - 6 carbon atoms . representative of such groups are methyl , ethanyl , isopropanyl , isobutanyl , butanyl , pentanyl , hexanyl and the like . the term &# 34 ; alkoxy &# 34 ; means a lower alkanyl group attached to the remainder of the molecule by oxygen . examples of alkoxy are methoxy , ethoxy , propoxy , isopropoxy and the like . the term &# 34 ; aryl &# 34 ; means phenyl or benzyl , optionally substituted by one or more halogen atoms , e . g ., fluoro , chloro , bromo or iodo , or lower alkanyl groups . a second embodiment of the present invention relates to a process for making optically pure 4 - substituted - 2hydroxytetronic acid compounds of formula i : ## str3 ## wherein r &# 39 ; is an alkenyl or alkanyl group of 2 - 20 carbon atoms , and , when an alkenyl group , contains one or more degrees of unsaturation , or an aryl group . ( a ) coupling of α - allyloxyacetic acid with the optically pure alkanyl ester of the formula ii ## str4 ## or its corresponding isomer , wherein r &# 39 ; is as hereinbefore defined and alk is a lower alkanyl group of 1 - 6 carbon atoms in the presence of dcc ( n , n 1 - dicyclohexylcarbodiimide ) and an acid acceptor such as 4 - pyrrolidinopyridine or dimethyl aminopyridine , to obtain an α - allyloxy acetyl ester of the formula iii ## str5 ## or its corresponding isomer , wherein alk and r &# 39 ; are as hereinbefore defined ; ( b ) cyclizing the allyl ester of formula iii with lihmda to afford the allyloxy aci - reductone of the formula iv ## str6 ## wherein r &# 39 ; is as hereinbefore defined , or its corresponding isomer ; ( c ) isomerizing the allyloxy aci - reductone of formula iv with hydrogen and an iridium catalyst to yield the corresponding 1 - propenyl ether of the formula v ## str7 ## or its corresponding isomer , wherein r &# 39 ; is as hereinbefore defined ; and ( d ) hydrolysis of the enol ether of formula v , or its corresponding isomer with aqueous acid , to afford the desired compound of formula i . the coupling of step ( a ) is typically conducted in an anhydrous solvent , such as methylene chloride , under an inert atmosphere . preferably , the reaction is conducted at temperatures of about 5 ° c . to room temperature , for periods of 6 - 24 hours . the coupling reagents used are preferably dcc or hydroxybenzotriazine ( hobt ) or the like in combination with a catalytic nucleophile such as 4 -( n , n - dimethylamino ) pyridine ( dmap ), 4 - pyrrolidinopyridine or another typically utilized for this purpose . the cyclization of step ( b ) is typically conducted in an anhydrous solvent such as tetrahydrofuran under an inert atmosphere . preferably , this reaction is conducted at temperatures of about - 78 ° c . for periods of 1 - 4 hours . lihmda is typically utilized as a sterically hindered non - nucleophilic base , but other similar sterically hindered bases can be substituted . the isomerization of step ( c ) is preferably conducted in an anhydrous solvent , such as tetrahydrofuran , under an inert atmosphere . typically , the reaction is conducted at room temperatures , with reaction times being approximately 1 - 4 hours . the hydrolysis of step ( d ) is conducted with an aqueous acid , preferably 50 % acetic acid , at reflux temperatures . the invention also provides for pharmaceutical compositions comprising the optically pure compounds of the general formula i above , as well as their physiologically acceptable salts ( such as , for example , na + , k + , nh 4 + ). the compounds of the invention have antilipidemic and antiaggregatory activity and are useful in the treatment or prevention of atherosclerotic disorders . the invention accordingly further provides optically pure compounds of the general formula i and their physiologically acceptable salts for use in the therapy or prophylaxis of atherosclerotic disorders . when tested according to the methods described in the art , the ( s )- isomers of formula ib having the formula ## str8 ## wherein r is as hereinbefore defined , have been found to possess markedly superior properties when compared to their corresponding ( r )- isomers . the r - and s - enantiomers were tested as inhibitors of arachidonic acid - induced aggregation in human platelet - rich plasma . data for individual experiments ( 2 separate donors ) are given as pic 50 ( log molar inhibitory concentration of each drug which blocks aggregation to arachidonic acid by 50 %) inhibitors were preincubated for 1 minute prior to addition of arachidonic acid ( 200 - 400 μm ). changes in light transmission were measured as an index of aggregation and quantified after 4 minutes . table 1______________________________________ ( r )- 3 , 4 - dihydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone ( μm ) raw data - 1 × log ( 0 . 000001 × data ) ______________________________________764 . 500 3 . 117538 . 000 3 . 269657 . 000 3 . 182653 . 167 ave 3 . 189113 . 299 std 0 . 07765 . 413 sem 0 . 04417 . 346 c v 2 . 4003 n 3371 . 695 - 95 % cl 2 . 999934 . 639 + 95 % cl 3 . 380back - transformed / data : ( geometric mean ) 646 . 510 ave417 . 291 - 95 % cl1001 . 640 + 95 % cl______________________________________ table 2______________________________________ ( s )- 3 , 4 - dihydroxy - 5 ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone ( μm ) raw data - 1 × log ( 0 . 000001 × data ) ______________________________________0 . 319 6 . 4964 . 300 5 . 3672 . 200 5 . 6582 . 273 ave 5 . 8401 . 992 std 0 . 5871 . 150 sem 0 . 33987 . 616 c v 10 . 0433 n 3 - 2 . 675 - 95 % cl 4 . 3837 . 221 + 95 % cl 7 . 297back - transformed / data : ( geometric mean ) 1 . 445 ave0 . 050 - 95 % cl41 . 405 + 95 % cl______________________________________ the compounds of the invention may be formulated in a conventional manner , optionally together with one or more other active ingredients , for administration by any convenient route for example of oral , intravenous or intramuscular administration . thus , according to another aspect , the invention provides a pharmaceutical composition comprising a compound of formulae ia or ib and / or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient . for oral administration , the pharmaceutical composition may take the form of , for example , tablets , capsules , powders , solutions , syrups or suspensions prepared by conventional means with physiologically acceptable excipients . the compounds may be formulated for intravenous or intramuscular administration in dry form for reconstitution before use , or as a sterile solution or suspension . a proposed daily dose based on similar pharmacokinetic parameters to chta for administration to man is 10 to 25 mg / kg , for example 1 gm daily to 70 kg , which may be conveniently administered in 1 to 3 doses per day . the precise dose administered will , of course , depend on the age and condition of the patient . melting points were determined in open capillaries with a thomas - hoover uni - melt apparatus and are uncorrected . infrared spectra were recorded by a laser precision analytical rfx - ftir spectrometer ( model tsi - 400 ). nuclear magnetic resonance spectra were obtained with either an ibm - bruker model nr / 250 , 270 or 500 ft nmr spectrometer . tetramethylsilane ( tms ) in cdcl 3 , acetone - d 6 , or cd 3 od was used as internal standard . chemical shifts were reported on the δ scale with peak multiplicities : s , singlet ; d , doublet ; dd , doublet of doublets ; ddd , doublet of doublets of doublets ; t , triplet ; q , quartet ; m , multiplet . tetrahydrofuran ( thf ) was distilled from na / benzophenone ketyl and ch 2 cl 2 was dried over p 2 o 5 . optical rotations were taken on a perkin - elmer model 241 polarimeter using a 10 cm , 1 ml cell . mass spectra were acquired with either a kratos ms25rfa or a vg 70 - 250s mass spectrometer . elemental analyses were performed by galbraith laboratories , inc ., knoxville , tenn . 3 , 6 , 9 - pentadecatriyn - 1 - ol . in a 1 l three - necked , flame - dried round . bottom flask fitted with a reflux condenser and a rubber septum was placed 3 . 86 g ( 159 mmol ) of magnesium in 250 ml of anhydrous tetrahydrofuran . bromoethane ( 17 . 3 g ; 1586 mmol ) in 250 ml anhydrous tetrahydrofuran was added dropwise , under argon , and the reflux rate was controlled with the aid of an ice - water bath . the mixture was heated to reflux and stirred for 1 hour . 3 - butyn - 1 - ol ( 5 . 56 g , 79 . 3 mmol ), dissolved in 150 ml of anhydrous tetrahydrofuran , was slowly added dropwise with stirring ( 2 hours ). following addition , the reaction was heated to reflux . after stirring for 90 minutes , 0 . 5 g ( 2 . 63 mmol ) of cuprous ( i ) iodide was added . after 75 minutes 9 . 0 g ( 39 . 65 mmol ) of 1 - bromo - 2 , 5 - undecadiyne dissolved in 150 ml of anhydrous tetrahydrofuran was added . the mixture was heated at reflux for 12 h and an additional 0 . 25 g ( 1 . 32 mmol ) of cuprous ( i ) iodide was added . the mixture was heated at reflux for 7 hours , cooled and quenched by addition of 400 ml of ice - water saturated with ammonium chloride . after filtration ( celite ), the filtrate was extracted with 3 × 400 ml of ether . the ether layers were washed with 2 × 300 ml of saturated ammonium chloride solution , 3 × 200 ml of water , 250 ml of brine , dried ( na 2 so 4 ), and concentrated in vacuo to yield 6 . 2 g of yellow - brown oil . the residue was partially purified by crystallization ( petroleum ether ) at - 20 ° c . to produce 5 . 75 g ( 75 %) of an unstable yellow oil ( room temperature ) which was utilized immediately in the next reaction . ir ( neat , cm - 1 ) 3365 , 2956 , 2933 , 2225 ; 1 h nmr ( cdcl 3 ) δ 3 . 70 ( t , j = 6 . 2 hz , 2h ), 3 . 17 - 3 . 13 ( m , 4h ), 2 . 45 ( dt , j = 1 . 5 , 5 . 9 , 12 . 0 hz , 2h ), 2 . 15 ( dt , j = 2 . 1 , 6 . 9 , 13 . 9 hz , 2h ), 1 . 68 ( br , 1 h ), 1 . 55 - 1 . 43 ( m , 2h ), 1 . 43 - 1 . 26 ( m , 4h ), 0 . 89 ( t , j = 6 . 9 hz , 3h ); hrms calculated for c 15 h 20 o ( m + ) 216 . 1514 , found 216 . 1519 . ( 3z , 6z , 9z )- 3 , 6 , 9 - pentadecatriene - 1 - ol . 3 , 6 , 9 - pentadecatriynol ( 5 . 75 g , 26 . 6 mmol ), 5 % palladium on barium sulfate ( 0 . 5 g ) and 5 drops of 3 % quinoline in methanol were added to a 500 ml hydrogenation flask . hydrogen , at an initial pressure of 72 psi , was taken up over 30 minutes . the mixture was filtered ( celite ) and the filtrate was evaporated in vacuo to produce 5 . 7 g of crude triene which was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) yielding 5 . 5 . g ( 93 %) of light yellow oil : ir ( neat , cm - 1 ) 3336 ( br ), 3012 , 2958 , 2927 , 1652 , 719 ; 1 h nmr ( cdcl 3 ) δ 5 . 60 - 5 . 28 ( m , 6h ), 3 . 67 ( t , j = 6 . 4 hz , 2h ), 2 . 88 - 2 . 79 ( m , 2h ), 2 . 43 - 2 . 33 ( m , 2h ), 2 . 12 - 1 . 98 ( m , 2h ), 1 . 68 - 1 . 53 ( m , 2h ), 1 . 53 - 1 . 23 ( m , 6h ), 0 . 89 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 15 h 26 o ( m + ) 222 . 1984 , found 222 . 1990 . ( 3z , 6z , 9z )- 1 - bromo - 3 , 6 , 9 - pentadecatriene . to a 250 ml three - necked round bottom flask was added under nitrogen 9 . 46 g ( 36 . 1 mmol ) of triphenylphosphine dissolved in 150 ml of anhydrous acetonitrile . after cooling to 0 ° c . ( ice - salt bath ), bromine ( 5 . 77 g , 36 . 1 mmol ) was added dropwise with stirring . the mixture was warmed to room temperature and stirred for 30 minutes . 3 , 6 , 9 - pentadecatrienol ( 6 . 16 g , 27 . 75 mmol ), dissolved in 50 ml of anhydrous acetonitrile , was added dropwise ( 15 minutes ) and stirred for approximately 4 hours . upon reaction completion acetonitrile was removed in vacuo and the residue was dissolved in 75 ml of ether . hexanes were utilized to precipitate the triphenylphosphorane side product which was removed by filtration . the crude residue , obtained after concentration of the filtrate in vacuo , was purified over silica gel using ethyl acetate : hexanes ( 1 : 9 ) as eluant . the product 7 . 0 g ( 90 %) was obtained as a light yellow oil . ir ( neat , cm - 1 ) 2958 , 2927 , 1652 , 1267 , 723 ; 1 ih nmr ( cdcl 3 ) δ 5 . 69 - 5 . 28 ( m , 6h ), 3 . 38 ( t , j = 7 . 1 hz , 2h ), 2 . 89 - 2 . 75 ( m , 4h ), 2 . 75 - 2 . 52 ( m , 2h ), 2 . 12 - 1 . 93 ( m , 2h ), 1 . 49 - 1 . 31 ( m , 6h ), 0 . 89 ( t , j = 6 . 8 hz , 3h ); 13 c nmr ( cdcl 3 ) δ 131 . 0 , 130 . 6 , 128 . 9 , 127 . 4 ( 2c ), 126 . 3 , 32 . 2 , 31 . 5 , 30 . 9 , 29 . 3 , 27 . 3 , 25 . 8 , 25 . 7 , 22 . 6 , 14 . 0 ; hrms calculated for c 15 h 25 br ( m + ) 284 . 1139 , found 284 . 1 . 101 . ( 3z , 6z , 9z )- 3 , 6 , 9 ,- pentadecatrieyl ! triphenyl - phosphonium bromide . bromo - 3 , 6 , 9 - pentadecatriene ( 7 . 0 g , 24 . 6 mmol ) was treated with 7 . 5 g ( 28 . 6 mmol ) of triphenylphosphine in 25 ml of acetonitrile . the mixture was heated to 70 ° c . under nitrogen atmosphere . following reaction completion ( monitor salt formation by tlc ; 72 hours ) the mixture was dried for 36 hours under reduced pressure to ensure removal of traces of acetonitrile . the resultant yellow residue , 13 . 45 g , was used in the next reaction without further purification : ir ( neat , cm - 1 ) 3010 , 2958 , 1652 , 1191 , 723 ; 1 h nmr ( cdcl 3 ) δ 7 . 93 - 7 . 61 ( m , 15 h ), 5 . 69 - 5 . 12 ( m , 6h ), 4 . 02 - 3 . 91 ( m , 2h ), 2 . 69 - 2 . 48 ( m , 4h ), 2 . 09 - 1 . 92 ( m , 2h ), 1 . 89 - 1 . 72 ( m , 2h ), 1 . 46 - 1 . 25 ( m , 6h ), 0 . 88 ( t , j = 6 . 9 hz , 3h ). ( s )- 2 , 2 - dimethyl - 4 - oxo - l , 3 - dioxolane - 5 - acetyl chloride . to 20 g ( 1149 mmol ) of ( s )- 2 , 2 - dimethyl - 4 - oxo - 1 , 3 - dioxolane - 5 - acetic acid in a dry 250 ml round bottom flask was added under argon and at room temperature 75 ( 630 mmol ) of thionyl chloride and 2 drops of dmf . the reaction mixture was stirred until evolution of gaseous hcl ceased ( oil bubbler ; approximately 2 hours ). the excess thionyl chloride was distilled in vacuo and remaining traces were removed under reduced pressure ( 9 hours ). the acid chloride ( 22 . 1 g ) thus obtained was utilized without further purification in the next step : ir ( neat , cm - 1 ) 2998 , 1793 , 1751 , 989 , 958 ; 1 h nmr ( cdcl 3 ) δ 4 . 69 ( dd , j = 3 . 6 , 6 . 4 hz , 1 h ), 3 . 56 ( dd , j = 3 . 6 , 18 . 1 hz , 1 h , 3 . 36 ( dd , j = 6 . 4 , 18 . 1 hz , 1 h ), 1 . 65 ( s , 3h ), 1 . 58 ( s , 3h ). ( s )- 2 , 2 - dimethyl - 4 - oxo - 1 , 3 - dioxolane - 5 - acetaldehyde . to a 500 ml three - necked flask equipped with a mechanical stirrer , reflux condenser and gas inlet dispersion tube was added 22 . 1 g ( 115 mmol ) of crude ( s )- 2 , 2 - dimethyl - 4 - oxo - 1 , 3 - dioxolane - 5 - acetyl chloride dissolved in 250 ml of anhydrous xylenes . to this solution was added 2 . 0 g of 5 % palladium on barium sulfate and 0 . 2 ml of stock quinoline - sulfur poison solution ( prepared by refluxing 1 g of sulfur with 5 ml of quinoline for 6 hours and diluting to a final volume of 70 ml with anhydrous xylenes ). hydrogen gas was bubbled through the stirred reaction mixture and the hydrogen chloride gas generated was trapped in 175 ml of water containing a few drops of phenolphthalein indicator . the mixture was heated at 135 ° c . and monitored by titration of the hydrogen chloride solution with 5m sodium hydroxide solution . on completion ( approximately 3 hours ), the reaction mixture was cooled to room temperature and 1 . 5 g of norit was added . the mixture was filtered ( celite ) and the filtrate concentrated under reduced pressure . the residue was purified over silica gel using ethyl acetate : hexanes ( 1 : 3 ) to furnish 16 . 2 g ( 89 %) of white solid : mp 37 °- 38 ° c . ; α ! d 25 1 . 4 ° ( c = 4 . 54 , ch 3 oh ); ir ( neat , cm - 1 ) 2994 2744 , 1793 , 1725 , 1386 ; 1 h nmr ( cdcl 3 ) δ 9 . 78 ( s , 1h ), 4 . 80 ( dd , j = 3 . 6 , 6 . 8 hz , 1h ), 3 . 10 ( dd , j = 3 . 6 , 18 . 3 hz , 1h ); 2 . 92 ( dd , j = 6 . 9 , 18 . 3 hz , 1h ), 1 . 63 ( s , 3h ), 1 . 58 ( s , 3h ); hrms calculated for c 7 h 10 o 4 ( m + ) 158 . 0579 , found 158 . 0572 . ( s )- 5 -( 3 - methoxyallyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolane - 4 - one . in a dry 500 ml three - necked round bottom flask under argon was dissolved 14 . 2 g ( 126 . 58 mmol ) of potassium t - butoxide in 300 ml of anhydrous tetrahydrofuran . the solution was cooled to 0 ° c . and 44 g ( 126 . 6 mmol ) of methoxymethyltriphenylphosphine chloride was added slowly and with stirring ( 20 minutes ). the resulting orange - red solution was stirred at 0 ° c . for 45 minutes and 10 g ( 63 . 3 mmol ) of ( s )- 2 , 2 - dimethyl - 4 - oxo - 1 , 3 - dioxolane - 5 - acetaldehyde in 50 ml of anhydrous tetrahydrofuran was added dropwise ( 15 minutes ). the mixture was allowed to stir at ambient temperature for 1 hour and quenched by addition of 100 ml of brine . following stirring for 1 hour , the mixture was extracted with 3 × 250 ml of ether . the combined ether extract was washed with 2 × 150 ml of brine , dried ( na 2 so 4 ) and filtered . the filtrate was evaporated under reduced pressure to yield 18 g of a crude brown colored liquid ( contaminated with the triphenylphosphorane ). this residue was purified over silica gel using ethyl acetate : petroleum ether ( 1 : 9 ) to give 9 . 2 g ( 78 %) of a mixture of inseparable e : z enol ethers as a colorless liquid : α ! d 25 - 3 . 2 ° ( c = 2 . 8 , ch 3 oh ); ir ( neat , cm - 1 ) 2994 , 2938 , 1793 , 1658 ; 1 h nmr ( cdcl 3 ) δ for the e - enol ether ( 75 %) 6 . 42 ( d , j = 12 . 7 hz , 1h ), 4 . 49 - 4 . 34 ( m , 2h ), 3 . 53 ( s 3h ), 2 . 72 - 2 . 32 ( m , 2h ), 1 . 60 ( s , 3h ), 1 . 54 ( s , 3h ), for the z - enol ether ( 25 %) 6 . 04 ( d , j = 6 . 1 hz , 1h ), 4 . 78 - 4 . 61 ( m , 2h ), 3 . 61 ( s , 3h ), 2 . 72 - 2 . 32 ( m , 2h ), 1 . 60 ( s , 3h ), 1 . 54 ( s , 3h ); hrms calculated for c 9 h 14 o 4 ( m + ) 186 . 0892 , found 186 . 0894 . methyl ( 2s )- tetrahydro - 5 - methoxy - 2 - furoate . to the enol ethers , ( s )- 5 -( 3 - methoxyallyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one ( 4 . 0 g , 21 . 5 retool ), dissolved in 150 ml of anhydrous methanol was added 5 - 6 drops of concentrated h 2 so 4 . the resultant solution was heated for 6 hours and cooled to room temperature . sodium bicarbonate ( 0 . 5 g ) was added , and the methanol was removed in vacuo . the residue was dissolved in 250 ml of ch 2 cl 2 and washed with 2 × 100 ml of saturated sodium bicarbonate solution and 2 × 125 ml of brine . the organic extract was dried ( na 2 so 4 ) and the solvent removed under reduced pressure to produce a colorless liquid which was purified over silica gel using ethyl acetate : hexanes ( 1 : 1 ) as eluant to provide 2 . 93 g ( 86 %) of a colorless liquid as a 3 : 1 mixture of diastereomers : α ! d 25 27 . 3 ° ( c = 1 . 2 , ch 3 oh ); ir ( neat , cm - 1 ) 2958 , 1739 , 1213 , 1105 ; 1 h nmr ( cdcl 3 ) δ for diastereomer a ( 66 %) 5 . 21 ( m , 1h ), 4 . 64 - 4 . 52 ( m , 1h ), 3 . 77 ( s , 3h ), 2 . 44 - 1 . 83 ( m , 4h ); for diastereomer b ( 33 %) 5 . 08 ( m , 1h ), 4 . 64 - 4 . 52 ( m , 1h ), 3 . 77 ( s , 3h ), 3 . 42 ( s , 3h ), 2 . 44 - 1 . 83 ( m , 4h ); hrms calculated for c 7 h 12 o 4 ( m + ) 160 . 0735 , found 160 . 0718 . methyl ( 2s )- tetrahydro - 5 - hydroxy - 2 - furoate . methyl ( 2s )- tetrahydro - 5 - methoxy - 2 - furoate ( 2 . 93 g , 18 . 3 retool ) was stirred with 500 ml of 25 % aqueous acetic acid for approximately 10 hours ( monitor by tlc ). upon reaction completion the aqueous acetic acid was removed in vacuo and the residue was purified over silica gel using ethyl acetate : hexane ( 1 : 1 ) to give 2 . 4 g ( 90 %) of a colorless liquid as a 5 . 8 : 4 . 2 diastereomeric mixture : α ! d 25 9 . 3 ° ( c = 2 . 7 , ch 3 oh ); ir ( neat , cm - 1 ) 3457 ( br ), 2956 , 1735 , 1062 , 1010 1 h nmr ( cdcl 3 ) δ for diastereomer a ( 58 %) 5 . 62 ( m , 1h ), 4 . 60 ( dd , j = 6 . 5 , 8 . 1 hz , 1h ), 3 . 78 ( s , 3h ), 2 . 46 - 1 . 93 ( m , 4h ); for diastereomer b ( 42 %) 5 . 75 ( m , 1h ), 4 . 73 ( dd , j = 3 . 8 , 8 . 5 hz , 1h ), 3 . 76 , ( s , 3h ), 2 . 46 - 1 . 93 ( m , 4h ); hrms calculated for c 6 h 10 o 4 ( m + ) 146 . 0579 , found 146 . 0574 . methyl ( s )- 2 - hydroxyarachiodonate . to a flame - dried , 500 ml three - necked flask , fitted with a low temperature thermometer and a rubber septum , was added under argon 12 . 35 g ( 22 . 57 mmol ) of 3 , 6 , 9 - pentadecatrienetriphenylphosphine bromide and 350 ml of anhydrous tetrahydrofuran . the solution was cooled to - 35 ° c . and 14 . 1 ml of 1 . 6 m n - buli in hexanes ( 22 . 56 mmol ) was added dropwise with stirring . the dark red solution was warmed to room temperature , stirred for an additional 30 minutes and cooled to - 35 ° c . the solution was cooled to - 60 ° c ., and methyl ( 2s )- tetrahydro - 5 - hydroxy - 2 - furoate ( 1 . 65 g , 11 . 28 mmol ) dissolved in 25 ml of anhydrous tetrahydrofuran was added dropwise ( approximately 15 minutes ). the mixture was stirred at - 60 ° c . for 2 hours and warmed to room temperature . upon completion ( tlc monitoring , approximately 8 - 9 hours ), the reaction was quenched by the addition of 100 ml of 10 % aqueous hcl solution and extracted with 3 × 300 ml of ethyl acetate . the organic layers were washed with 3 × 250 ml of water , 2 × 200 ml of brine , dried ( na 2 so 4 ), filtered and concentrated in vacuo . the residue contaminated with the triphenylphosphorane , was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) as eluant to provide 3 . 1 g ( 82 %) of yellow oil : α ! d 25 10 . 2 ° ( c = 5 . 4 , ch 3 oh ); ir ( neat , cm - 1 ) 3477 ( br ), 3012 , 2956 , 1739 , 1652 , 721 ; 1 h nmr ( cdcl 3 ) δ5 . 45 - 5 . 25 ( m , 8h ), 4 . 20 ( dd , j = 4 . 0 , 7 . 6 hz , 1h ), 3 . 79 ( s , 3h ), 2 . 92 - 2 . 74 ( m , 4h ), 2 . 35 - 1 . 92 ( m , 4h ), 1 . 91 - 1 . 62 ( m , 2h ), 1 . 49 - 1 . 24 ( m , 6h ), 0 . 89 ( t , j = 6 . 4 hz , 3h ); hrms calculated for c 21 h 34 o 3 ( m . sup . +) 334 . 2507 , found 334 . 2509 ; analysis calculated for c 21 h 34 o 3 : c , 75 . 41 ; h , 10 . 25 . found c , 75 . 36 ; h , 10 . 13 . ( r )- 2 , 2 - dimethyl - 4 - oxo - 1 , 3 - dioxolane - 5 - acetyl chloride was prepared as for the s - isomer of example a from r - malic acid in similar yield : ir ( neat , cm - 1 ) 2996 , 1793 , 1751 , 989 958 ; 1 h nmr ( cdcl 3 ) δ 4 . 69 ( dd , j = 3 . 6 , 6 . 4 hz , 1h ), 3 . 53 ( dd , j = 3 . 6 , 18 . 1 hz , 1h ) 3 . 35 ( dd , j = 6 . 4 , 18 . 1 hz , 1h ) 1 . 65 ( s , 3h ), 1 . 58 ( s , 3h ). ( r )- 2 , 2 - dimethyl - 4 - oxo - 1 , 3 - dioxolane - 5 - acetaldehyde was prepared as for the s - isomer from ( r )- 2 , 2 - dimethyl - 4 - oxo - 1 , 3 - dioxolane - 5 - acetyl chloride in similar yield : mp 37 °- 38 ° c . ; α ! d 25 3 . 7 ° ( c = 5 . 12 , ch 3 oh ); ir ( neat , cm - 1 ) 2996 , 2746 , 1791 , 1727 , 1388 ; 1 h nmr ( cdcl 3 ) δ9 . 78 ( s , 1h ), 4 . 80 ( dd , j = 3 . 6 , 6 . 8 hz , 1h ), 3 . 11 ( dd , j = 3 . 6 , 18 . 3 hz , 1h ), 2 . 93 ( dd , j = 6 . 9 , 18 . 3 hz , 1h ), 1 . 63 ( s , 3h ), 1 . 58 ( s , 3h ); hrms calculated for c 7 h 10 o 4 ( m + ) 158 . 0579 , found 158 . 0574 . ( r )- 5 -( 3 - methoxyallyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one was prepared as for the s - isomer from ( r )- 2 , 2 - dimethyl - 5 - oxo - 1 , 3 - dioxolane - 4 - acetaldehyde in similar yield : α ! d 25 3 . 1 ° ( c = 3 . 07 , ch 3 oh ); ir ( neat , cm - ) 2992 , 2740 , 1793 , 1656 ; 1 h nmr ( cdcl 3 ) for the e - enol ether ( 72 %) δ 6 . 42 ( d , j = 12 . 7 hz , 1h ), 4 . 49 - 4 . 34 ( m , 2h ), 3 . 53 ( s , 3h ), 2 . 72 - 2 . 32 ( m , 2h ), 1 . 61 ( s , 3h ), 1 . 54 ( s , 3h ); for the z - enol ether ( 28 %) 6 . 05 ( d , j = 6 . 1 hz , 1h ), 4 . 78 - 4 . 65 ( m , 2h ), 3 . 61 ( s , 3h ), 2 . 72 - 2 . 32 ( m , 2h ), 1 . 61 ( s , 3h ), 1 . 54 ( s , h ); hrms calculated for c 9 h 14 o 4 ( m + ) 186 . 0892 , found 186 . 0891 . methyl ( 2r )- tetrahydro - 5 - methoxy - 2 - furoate was prepared as for the s - isomer from ( r )- 5 -( 3 - methoxyallyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolane - 4 - one in similar yield : α ! d 25 - 28 . 33 ° ( c = 0 . 1 , ch 3 oh ); ir ( neat , cm - 1 ) 2956 , 1754 , 1209 , 1105 ; 1 h nmr ( cdcl 3 ) diastereomer a ( 66 %) δ 5 . 21 ( m , 1h ), 4 . 64 - 4 . 52 ( m , 1h ), 3 . 77 ( s , 3h ), 3 . 38 ( s , 3h ), 2 . 42 - 1 . 84 ( m , 4h ) for diastereomer b ( 33 %) 5 . 08 ( m , 1h ), 4 . 64 - 4 . 52 ( m , 1h ), 3 . 77 ( s , 3h ), 3 . 42 ( s , 3h ), 2 . 42 - 1 . 84 ( m , h ); hrms calculated for c 7 h 12 o 4 ( m + ) 160 . 0735 , found 160 . 0750 . methyl ( 2r )- tetrahydro - 5 - hydroxy - 2 - furoate was prepared as for the s - isomer from methyl ( 2r )- tetrahydro - 5 - methoxy - 2 - furoate in similar yield : α ! d 25 - 9 . 2 ° ( c = 1 . 8 , ch 3 oh ); ir ( neat , cm - 1 ) 3543 ( br ), 2956 , 1741 , 1068 , 1010 ; 1 h nmr ( cdcl 3 ) for diastereomer a ( 58 %) a 5 . 62 ( m , 1h ), 4 . 67 ( dd , j = 6 . 5 , 8 . 1 hz , 1h ), 3 . 78 ( s , 3h ), 2 . 46 - 1 . 93 ( m , 4h ); for diastereomer b ( 42 %) δ 5 . 75 ( m , 1h ), 4 . 73 ( dd , j = 3 . 8 , 8 . 5 hz , 1h ), 3 . 76 ( s , 3h ), 2 . 46 - 1 . 93 ( m , 4h ); hrms calculated for c 6 h 10 o 4 ( m + ), 146 . 0579 , found 46 . 0577 . methyl ( r )- 2 - hydroxyarachidonate was prepared as for the s - isomer from methyl ( 2r )- tetrahydro - 5 - hydroxy - 2 - furoate in similar yield : α ! d 25 - 10 . 5 ° ( c = 0 . 9 , ch 3 oh ); ir ( neat , cm - 1 ) 3504 ( br ), 3012 , 2956 , 1739 , 1652 , 723 ; 1 h nmr ( cdcl 3 ) δ 5 . 45 - 5 . 25 ( m , 8h ), 4 . 20 ( dd , j = 4 . 0 , 7 . 7 hz , 1h ), 3 . 79 ( s , 3h ), 2 . 92 - 2 . 74 ( m , 4h ); 1 . 90 - 1 . 62 ( m , 2h ), 1 . 49 - 1 . 24 ( m , 6h ), 0 . 89 ( t , j = 6 . 4 hz , 3h ), hrms calculated for c 21 h 34 o 3 ( m + ), 334 . 2507 , found 334 . 2506 . pentadecyltriphenylphosphonium bromide . under nitrogen atmosphere 1 - bromopentadecane ( 6 . 5 g , 22 . 4 mmol ) was treated with 5 . 87 g ( 22 . 4 mmol ) of triphenylphosphine in 15 ml of acetonitrile and heated to 135 ° c . the reaction was monitored by tlc ( salt formation , about 18 hours ), and the mixture was dried under reduced pressure ( 24 hours ) to ensure removal of traces of acetonitrile and provided 12 . 3 g of a colorless solid which was utilized in the next reaction without further purification . methyl ( 2s , 5z )- 2 - hydroxy - 5 - eicosenoate . to a flame - dried 500 ml three - necked flask fitted with a low temperature thermometer and a rubber septum , was added under argon 12 . 2 g ( 22 . 06 mmol ) of pentadecyltriphenylphosphonium bromide and 300 ml of anhydrous tetrahydrofuran . following cooling to - 35 ° c ., 13 . 8 ml of 1 . 6 m n - buli in hexanes ( 22 . 06 mmol ) was added dropwise and with stirring . the orange solution was warmed to room temperature and stirred for an additional 30 minutes . the mixture was cooled to - 35 ° c ., and 18 . 5 g ( 103 . 3 mmol ) of hexamethylphosphoramide was added slowly . the reaction mixture was stirred for 45 minutes and cooled to - 60 ° c . methyl ( 2s )- tetrahydro - 5 - hydroxy - 2 - furoate ( 1 . 6 g , 11 . 03 mmol ) and dissolved in 25 ml of anhydrous tetrahydrofuran was added dropwise , and stirring was continued for 1 hour at - 60 ° c . the mixture was warmed to room temperature ; reaction completion was monitored using tlc . the reaction was quenched by addition of 100 ml of 10 % aqueous hcl solution and extracted with 3 × 300 ml of ethyl acetate . the organic layers were washed with 3 × 250 ml of water , 2 × 200 ml of brine , dried ( na 2 so 4 ), filtered and evaporated in vacuo . the residue , contaminated with triphenylphosphorane , was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) to yield 2 . 98 g ( 80 %) of colorless oil : α ! d 25 + 8 . 9 ° ( c = 1 . 4 , ch 3 oh ); ir neat , cm - 1 ) 3475 ( br ), 3006 , 2925 , 1739 , 721 ; 1 h nmr ( cd 3 cocd 3 ) δ 5 . 48 - 5 . 24 ( m , 2h ), 4 . 20 ( m , 1h ), 3 . 79 ( s , 3h ), 2 . 72 ( d , j = 5 . 3 hz , 1h ), 2 . 32 - 2 . 15 ( m , 2h ), 2 . 15 - 1 . 98 ( m , 2h ), 1 . 92 - 1 . 64 ( m , 2h ), 1 . 48 - 1 . 21 ( m , 24h ), 0 . 88 ( t , j = 6 . 3 hz , 3h ); 13 c nmr ( cd 3 cocd 3 ) δ 175 . 7 , 131 . 5 , 127 . 9 , 70 . 0 , 52 . 4 , 34 . 4 , 31 . 9 , 29 . 7 ( 5c ), 29 . 6 ( 2c ), 29 . 3 ( 3c ), 27 . 2 , 22 . 7 ( 2c ), 14 . 0 ; hrms calculated for c 21 h 40 o 3 ( m + ) 340 . 2977 , found 340 . 2977 ; analysis calculated for c 21 h 40 o 3 : c , 74 . 07 ; h , 11 . 84 : found : c , 74 . 13 ; h , 11 . 91 . methyl ( 2r , 5z )- 2 - hydroxy - 5 - eicosenoate was prepared as for the s - isomer from methyl ( 2r )- tetrahydro - 5 - hydroxy - 2furoate in similar yield : α ! d 25 - 8 . 8 ° ( c = 2 . 1 , ch 3 oh ); ir ( neat , cm - 1 ) 3482 ( br ), 3006 , 2925 , 1739 , 721 ; 1 h nmr ( cd 3 cocd 3 ) δ 5 . 48 - 5 . 24 ( m , 2h ), 4 . 20 ( m , 1h ), 3 . 79 ( s , 3h ), 2 . 72 ( d , j = 5 . 3 hz , 1h ), 2 . 32 - 2 . 15 ( m , 2h ), 2 . 15 - 1 . 98 ( m , 2h ), 1 . 92 - 1 . 64 ( m , 2h ), 1 . 48 - 1 . 21 ( m , 24h ), 0 . 88 ( t , j = 6 . 3 hz , 3h ); 13 c nmr ( cd 3 cocd 3 ) δ 175 . 7 , 131 . 5 , 127 . 9 , 70 . 0 , 52 . 3 , 34 . 4 , 31 . 9 , 29 . 7 ( 5c ), 29 . 6 ( 2c ), 29 . 3 ( 3c ), 27 . 2 , 22 . 7 ( 2c ), 14 . 0 ; hrms calculated for c 21 h 40 o 3 ( m + ) 340 . 2977 , found 340 . 2970 . methyl ( s )- 2 -( allyloxy ) acetyloxy arachidinoate . to a dry two - necked round bottom flask fitted with a rubber septum was added , under argon , 1 . 5 g ( 4 . 49 retool ) of methyl ( s )- 2 - hydroxyarachidonate dissolved in 125 ml of anhydrous ch 2 cl 2 . the solution was cooled to 10 ° c . ( ice bath ) and 1 . 30 g of allyloxyacetic acid ( 11 . 23 mmol ) dissolved in 15 ml of anhydrous ch 2 cl 2 and 0 . 133 g ( 0 . 90 mmol ) of 4 - pyrrolidinopyridine dissolved in 2 ml of anhydrous ch 2 cl 2 was added . a solution of 2 . 32 g ( 11 . 23 mmol ) of dcc in 25 ml of ch 2 cl 2 was added dropwise with stirring , warmed to room temperature , and stirred overnight . ch 2 cl 2 was removed by distillation under reduced pressure and the residue was chromatographed on silica gel using ethyl acetate : hexanes ( 1 : 5 ) as eluant to furnish 1 . 79 g ( 92 %) of yellow oil : α ! d 25 - 8 . 1 ° ( c = 0 . 1 , ch 3 oh ); ir ( neat , cm - 1 ) 3012 , 2956 , 1751 , 1652 ; 1 h nmr ( cdcl 3 ) δ 5 . 94 - 5 . 82 ( m , 1h ), 5 . 41 - 5 . 22 ( m , 10h ), 5 . 11 ( t , j = 6 . 3 hz , 1h ), 4 . 23 ( d , j = 16 . 6 hz , 1h ), 4 . 22 ( d , j = 16 . 6 hz , 1h ), 4 . 12 ( d , j = 1 . 3 , 5 . 7 hz , 2h ), 3 . 75 ( s , 3h ), 2 . 89 - 2 . 68 ( m , 4h ), 2 . 32 - 1 . 89 ( m , 2h ), 1 . 42 - 1 . 31 ( m , 6h ), 0 . 89 ( t , 6 . 5 hz , 3h ); hrms calculated for c 26 h 40 o 5 ( m + ) 432 . 2875 , found 432 . 2856 ; analysis calculated for c 26 h 40 o 5 : c , 72 . 19 ; h , 9 . 32 : found : c , 71 . 90 ; h , 9 . 11 . ( s )- 3 -( allyloxy )- 4 - hydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone . to a flame - dried , three - necked , 250 ml round bottom flask under argon fitted with a low temperature thermometer and a septum was added 1 . 23 g ( 7 . 59 mmol ) of hexamethyldisilazane in 100 ml of anhydrous tetrahydrofuran . the contents were cooled to - 25 ° c . ( dry ice , ccl 4 ) and 4 . 75 ml of 1 . 6 m ( 7 . 59 mmol ) n - buli in hexanes was added dropwise with stirring while maintaining the temperature below - 15 ° c . the stirred reaction mixture was warmed to - 5 ° c ., the contents maintained between - 5 ° c . and 0 ° c . for 45 minutes , and cooled to - 78 ° c . ( dry ice / acetone ). methyl ( s )- 2 - hydroxyarachidonate , ( allyloxy ) acetate ( 1 . 56 g , 3 . 61 mmol ) in 30 ml of anhydrous tetrahydrofuran was added dropwise with stirring while maintaining the temperature below - 68 ° c . following addition , the mixture was stirred at - 78 ° c . for 75 minutes and quenched by addition of 40 ml of 10 % aqueous hcl solution . ether ( 125 ml ) was added , the mixture warmed to room temperature , and extracted with 3 × 100 ml of ether . the ether extract was washed with 2 × 75 ml of brine , dried ( na 2 so 4 ) and concentrated in vacuo to yield 1 . 34 g of crude product which was purified over silica gel using 10 % methanol in chloroform as eluant to provide 1 . 28 g ( 89 %) of yellow oil : α ! d 25 - 9 . 7 ° ( c = 0 . 2 , ch 3 oh ); ir ( neat , cm . sup . - 1 ) 3081 ( br ), 3012 , 2956 , 1747 , 1670 , 723 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 05 - 5 . 89 ( m , 1h ), 5 . 44 - 5 . 14 ( m , 10h ), 4 . 72 ( dd , j = 3 . 5 , 7 . 7 hz , 1h ), 4 . 48 ( dt , j = 1 . 2 , 5 . 6 hz , 2h ), 2 . 89 - 2 . 69 ( m , 6h ), 2 . 38 - 1 . 88 ( m , 4h ), 1 . 71 - 1 . 21 ( m , 8h ), 0 . 87 ( t , j = 6 . 6 hz , 3h ); ms ( fab ) ( m + 1 ) + 401 ; hrms calculated for c 25 h 36 o 4 m + 400 . 2614 ), found 400 . 2606 ; analysis calculated for c 25 h 36 o 4 + h 2 o : c , 71 . 74 ; h , 9 . 15 : found : c , 71 . 90 ; h , 9 . 11 . ( s )- 4 - hydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 3 - ( e )- propenyloxy !- 2 ( 5h )- furanone . to a flame - dried , three - necked 250 ml round bottom flask was added , under argon , 0 . 254 g ( 0 . 30 mmol ) of bis -( methyldiphenylphosphine )! ( 1 , 5 - cyclooctadiene ) iridium ( 1 ) hexafluorophosphate suspended in 50 ml of freshly distilled peroxide free anhydrous tetrahydrofuran . the flask was evacuated and the argon displaced with hydrogen . the red colored suspension turned to a colorless solution and after 5 minutes the flask was evacuated and replaced with argon . the ( s )- 3 -( allyloxy ) - 4 - hydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone ( 0 . 6 g , 1 . 5 mmol ), dissolved in 25 ml of peroxide free tetrahydrofuran , was added and reaction completion monitored using tlc ( approximately 3 hours ). the solvent was evaporated under reduced pressure and the residue was purified over silica gel using 10 % methanol in chloroform as eluant to furnish 0 . 47 g ( 79 %) of dark yellow oil : α ! d 25 - 11 . 2 ° ( c = 0 . 2 , ch 3 oh ); ir ( neat , cm - 1 ) 3081 ( br ), 3012 , 2956 , 1745 , 1662 , 721 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 42 - 6 . 35 ( m , 1h ), 5 . 49 - 5 . 23 ( m , 8h ), 5 . 05 - 4 . 89 ( m , 1h ), 4 . 77 ( dd , j = 3 . 5 , 7 . 9 hz , 1h ), 2 . 92 - 2 . 74 ( m , 4h ), 2 . 31 - 1 . 57 ( m , 6h ), 1 . 51 ( dd , j = 1 . 6 , 6 . 9 hz , 3h ), 1 . 45 - 1 . 28 ( m , 8h ), 0 . 87 ( t , j = 6 . 4 hz , 3h ); ms ( fab ) ( m + 1 ) + 401 , ( m + na )+ 423 ; hrms calculated for c 25 h 36 o 4 ( m + ) 400 . 2614 , found 400 . 2616 ; analysis calculated for c 25 h 36 o 4 + h 2 o ): c , 71 . 74 ; h , 9 . 15 : found : c , 71 . 70 ; h , 9 . 06 . ( s )- 3 , 4 - dihydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone . to a 100 ml round bottom flask was added , under nitrogen , 0 . 3 g ( 0 . 74 mmol ) of ( s )- 4 - hydroxy - 5 ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 3 - ( e - propenyloxy !- 2 ( 5h )- furanone dissolved in 60 ml of 50 % aqueous acetic acid . the stirred solution was heated a reflux ( oil bath ) for 15 minutes , cooled , and concentrated in vacuo . the residue was chromatographed on silica gel using 12 % methanol in chloroform as eluant to provide 0 . 26 g ( 95 %) of yellow oil : α ! d 25 - 13 . 5 ° ( c = 0 . 2 , ch 3 oh ); ir ( neat , cm - 1 ) 3220 ( br ), 3012 , 2956 , 1751 , 1670 , 1652 , 723 , 694 ; 1 h nmr ( cd 3 cocd 3 ) δ 5 . 48 - 5 . 34 ( m , 8h ), 4 . 68 ( dd , j = 3 . 4 , 7 . 9 hz , 1h ), 2 . 85 - 2 . 72 ( m , 4h ), 2 . 25 - 2 . 19 ( m , 2h ), 2 . 18 - 1 . 97 ( m , 4h ), 1 . 65 - 1 . 52 ( m , 1h ), 1 . 48 - 1 . 28 ( m , 7h ), 0 . 87 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 22 h 32 o 4 ( m + ) 360 . 2301 , found 360 . 2308 ; analysis calculated for c 22 h 32 o 4 + 0 . 33 h 2 o : c , 72 . 1 ; h , 8 . 98 : found : c , 72 . 18 ; h , 8 . 93 . methyl ( r )- 2 -( 2 - allyloxy ) acetyloxyarachidonate was prepared as for the s - isomer from methyl ( r )- 2 - hydroxyarachidonate in similar yield : α ! d 25 7 . 0 ° ( c = 0 . 1 , ch 3 oh ); ir ( neat , cm - 1 ) 3012 , 2956 , 1756 , 1648 ; 1 h nmr ( cdcl 3 ) δ 5 . 94 - 5 . 82 ( m , 2h ), 5 . 45 - 5 . 22 ( m , 10h ), 5 . 11 ( t , j = 6 . 3 hz , 1h ); 4 . 23 ( d , j = 16 . 6 hz , 1h ), 4 . 22 ( d , j = 16 . 6 , 1h ), 4 . 12 ( dt , j = 1 . 3 , 5 . 7 hz , 2h ), 3 . 75 ( s , 3h ), 2 . 89 - 2 . 68 ( m , 4h ), 2 . 28 - 1 . 89 ( m , 6h ), 1 . 61 - 1 . 49 ( m , 2h ), 1 . 42 - 1 . 31 ( m , 6h ), 0 . 89 ( t , j = 6 . 5 hz , 3h ); hrms calculated for c 26 h 40 o 5 ( m + ), 432 . 2875 , found 432 . 2858 . ( r )- 3 -( allyloxy )- 4 - hydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone was prepared as for the s - isomer from methyl ( r )- 2 - hydroxyarachidonate , ( allyloxy ) acetate in similar yield : α ! d 25 9 . 4 ° ( c = 0 . 3 , ch 3 oh ); ir ( neat , cm - 1 ) 3081 ( br ), 3012 , 2956 , 1749 , 1670 , 723 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 05 - 5 . 89 ( m , 1h ), 5 . 44 - 5 . 14 ( m , 10h ), 4 . 74 ( dd , j = 3 . 5 , 7 . 7 hz , 1h ), 4 . 48 ( dt , j = 1 . 1 , 5 . 7 hz , 2h ), 2 . 87 - 2 . 69 ( m , 6h ), 2 . 42 - 1 . 88 ( m , 4h ), 1 . 71 - 1 . 21 ( m , 8h ), 0 . 87 ( t , j = 6 . 6 hz , 3h ); ms ( fab ) ( m + 1 ) + 401 ; hrms calculated for c 25 h 36 o 4 ( m + ) 400 . 2614 , found 400 . 2607 . ( r )- 4 - hydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 3 - ( e )- propenyloxy !- 2 ( 5h )- furanone was prepared as for the s - isomer from ( r )- 3 -( allyloxy )- 4 - hydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone in similar yield : α ! d 25 11 . 7 ° ( c = 0 . 2 , ch 3 oh ); ir ( neat , cm - 1 ) 3081 ( br ), 3012 , 2956 , 1749 , 1664 , 696 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 42 - 6 . 35 ( m , 1h ), 5 . 49 - 5 . 23 ( m , 8h ), 5 . 05 - 4 . 89 ( m , 1h ) 4 . 77 ( dd , j = 3 . 5 , 7 . 9 hz , 1h ), 2 . 92 - 2 . 74 ( m , 4h ), 2 . 31 - 1 . 57 ( m , 6h ), 1 . 51 ( dd , j = 1 . 6 , 6 . 9 hz , 3h ), 1 . 45 - 1 . 28 ( m , 8h ), 0 . 87 ( t , j = 6 . 4 hz , 3h ); ms ( fab ) ( m + i ) + 401 , ( m + na ) + 423 ; hrms calculated for c 25 h 36 o 4 ( m + ) 400 . 2614 , found 400 . 2615 . ( r )- 3 , 4 - dihydroxy - 5 - all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 2 ( 5h )- furanone was prepared as for the s - isomer from ( r )- 4 - hydroxy - 5 - ( all - z )- 3 , 6 , 9 , 12 - octadecatetraenyl !- 3 - ( e )- propenyloxy !- 2 ( 5h )- furanone in similar yield : α ! d 25 13 . 2 ° ( c = 0 . 2 , ch 3 oh ); ir ( neat , cm - 1 ) 3241 ( br ), 3012 , 2956 , 1751 , 1675 , 1652 , 723 , 694 ; 1 h nmr ( cd 3 cocd 3 ) δ 5 . 48 - 5 . 34 ( m , 8h ), 4 . 68 ( dd , j = 3 . 4 , 7 . 9 hz , 1h ), 2 . 85 - 2 . 72 ( m , h ), 2 . 35 - 2 . 19 ( m , 2h ), 2 . 18 - 1 . 97 ( m , 4h ), 1 . 65 - 1 . 52 ( m , 1h ), 1 . 48 - 1 . 28 ( m , 7h ), 0 . 87 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 22 h 32 o 4 ( m + ) 360 . 2301 , found 360 . 2305 ; analysis calculated for c 22 h 32 o 4 + 0 . 5 h 2 o : c , 71 . 51 ; h , 9 . 00 ; found : c , 71 . 52 ; h , 9 . 14 . methyl ( 2s , 5z )- 2 -( 2 - allyloxy ) acetyloxy - 5 - eicosenoate . to a dry 100 ml three - necked round bottom flask fitted with a rubber septurn was added , under argon , 0 . 65 g ( 1 . 91 mmol ) of methyl ( 2s , 5z )- 2 - hydroxy - 5 - eicosenoate and 50 ml of anhydrous ch 2 cl 2 . following cooling to 10 ° c . ( ice bath ), 0 . 45 g ( 3 . 82 mmol ) of allyloxyacetic acid dissolved in 15 ml of anhydrous ch 2 cl 2 and 0 . 028 g ( 0 . 19 mmol ) of 4 - pyrrolidinopyridine dissolved in 2 ml of anhydrous ch 2 cl 2 were added . a solution containing 0 . 79 g ( 3 . 82 mmol ) of dcc in 15 ml of ch 2 cl 2 was added dropwise and the stirred mixture was warmed to room temperature and stirred for an additional 8 hours . ch 2 cl 2 was evaporated in vacuo and the product was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) as eluant to furnish 0 . 78 g ( 93 %) of colorless oil : α ! d 25 - 6 . 5 ° ( c = 1 . 6 , ch 3 oh ); ir ( neat , cm - 1 ) 3006 , 2923 , 1758 , 721 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 01 - 5 . 86 ( m , 1h ), 5 . 51 - 5 . 24 ( m , 4h ), 5 . 10 ( t , j = 6 . 3 hz , 1h ), 4 . 22 ( d , j = 16 . 6 hz , 1h ), 4 . 23 ( d , j = 16 . 6 hz , 1h ), 4 . 13 ( dt , j = 1 . 1 , 5 . 7 hz , 2h ), 3 . 75 ( s , 3h ), 2 . 26 - 2 . 12 ( m , 2h ), 2 . 07 - 1 . 87 ( m , 4h ), 1 . 42 - 1 . 28 ( m , 24h ), 0 . 88 ( t , j = 6 . 3 hz , 3h ); hrms calculated for c 26 h 46 o 5 ( m + ), 438 . 3345 found 438 . 3330 . ( s )- 3 - allyloxy - 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone . to a flame - dried , three - necked 250 ml round bottom flask fitted with a low temperature thermometer and a septum was added , under argon , 0 . 648 g ( 4 . 02 mmol ) of hexamethyldisilazane in 50 ml of anhydrous tetrahydrofuran . the contents were cooled to - 25 ° c . ( dry - ice / ccl 4 ), and 2 . 51 ml of 1 . 6 m ( 4 . 02 mmol ) of n - buli in hexanes was added dropwise with stirring while maintaining the temperature below - 15 ° c . the mixture was warmed to - 5 ° c . and the contents maintained between - 5 ° c . and 0 ° c . for 45 minutes . the mixture was cooled to - 78 ° c . ( dry ice / acetone ) and 0 . 84 g ( 1 . 91 mmol ) methyl ( 2s , 5z )- 2 -( 2 - allyloxy ) acetyloxy - 5 - eicosenoate in 20 ml of anhydrous tetrahydrofuran was added dropwise with stirring while maintaining the temperature below - 68 ° c . following addition , the mixture was stirred at - 78 ° c . for 75 minutes and quenched with 10 ml of 10 % aqueous hcl solution . ether ( 75 ml ) was added , and the reaction mixture was warmed to room temperature and extracted with 3 × 75 ml of ether . the ether extracts were washed with 2 × 50 ml of brine , dried ( na 2 so 4 ) and concentrated in vacuo to provide 0 . 75 g ( 97 %) of residue . purification over silica gel using 10 % methanol in chloroform as eluant provided 0 . 69 g ( 89 %) of white solid : mp 51 °- 54 ° c .,; α ! d 25 - 9 . 0 ° ( c = 0 . 6 , ch 3 oh ); ir ( neat , cm - 1 ) 3079 ( br ), 3002 , 2915 , 1741 , 1654 , 734 , 719 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 04 - 5 . 89 ( m , 1h ), 5 . 47 - 5 . 15 ( m , 4h ), 4 . 72 ( dd , j = 3 . 5 , 7 . 6 hz , 1h ), 4 . 48 ( dt , j = 1 . 1 , 5 . 9 hz , 2h ), 2 . 21 - 1 . 54 ( m , 6h ), 1 . 45 - 1 . 28 ( m , 24h ), 0 . 87 ( t , j = 6 . 8 hz , 3h ); hrms calculated for c 25 h 42 o 4 ( m + ) 406 . 3083 , found 406 . 3084 ; analysis calculated for c 25 h 42 o 4 : c , 73 . 85 ; h , 10 . 41 . found : c , 73 . 52 ; h , 10 . 27 . ( s )- 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 3 - ( e )- propenyloxy !- 2 ( 5h )- furanone . to a flame - dried , three - necked 250 ml round bottom flask under argon was added 0 . 172 g ( 0 . 20 mmol ) of bis ( methyldiphenylphosphine )! ( 1 , 5 - cyclooctadiene ) iridium ( 1 ) hexafluorophosphate suspended in 35 ml of freshly distilled peroxide free anhydrous tetrahydrofuran . the flask as evacuated and the argon displaced with hydrogen . the red suspension turned to a colorless solution after 5 minutes . the flask was evacuated , and the hydrogen replaced with argon . ( s )- 3 - allyloxy - 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone ( 0 . 415 g , 1 . 02 mmol ) was dissolved in 25 ml of peroxide free tetrahydrofuran and added to the activated catalyst . on completion ( tlc ; approximately 3 hours ) the solvent was evaporated in vacuo and purified over silica gel using 10 % methanol in chloroform as eluant to provide 0 . 33g ( 79 %) of white waxy solid : mp 42 °- 45 ° c . ; α ! d 25 - 13 . 0 ° ( c = 0 . 3 , ch 3 oh ); ir ( neat , cm - 1 ) 3079 ( br ), 3004 , 2919 , 1739 , 1681 , 1658 , 738 , 721 ; 1 h nmr ( cd 3 cocd 3 δ 6 . 43 - 6 . 36 ( m , 1h ), 5 . 49 - 5 . 31 ( m , 2h ), 5 . 05 - 4 . 91 ( m , 1h ), 4 . 77 ( dd , j = 3 . 5 , 7 . 8 hz , 1h ), 2 . 24 - 1 . 62 ( m , 6h ), 1 . 51 ( dd , j = 1 . 7 , 6 . 9 hz , 3h ), 1 . 44 - 1 . 24 ( m , 24h ), 0 . 87 ( t , j = 6 . 8 hz , 3h ); hrms calculated for c 25 h 42 o 4 ( m + ) 406 . 3083 , found 406 . 3083 . ( s )- 3 , 4 - dihydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone . to a 100 ml round bottom flask was added , under nitrogen , 0 . 2 g ( 0 . 49 mmol ) ( s )- 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 3 - ( e )- propenyloxy !- 2 ( 5h )- furanone was dissolved in 60 ml of 50 % aqueous acetic acid . the solution was heated at reflux ( oil bath ) for 15 minutes , cooled , and the aqueous acetic acid removed in vacuo . the residue was purified over silica gel using 12 % methanol in chloroform as eluant to give 0 . 17 g ( 95 %) of white waxy solid : mp 64 °- 66 ° c . ; α ! d 25 - 9 . 9 ° ( c = 0 . 5 , ch 3 oh ); ir ( neat , cm - 1 ) 3421 ( br ), 2917 , 2850 , 1754 , 1668 , 719 ; 1 h nmr ( d 3 cocd 3 ) δ 5 . 49 - 5 . 28 ( m , 2h ), 4 . 67 ( dd , j = 3 . 4 , 7 . 8 hz , 1h ), 2 . 32 - 1 . 88 ( m , 4h ), 1 . 69 - 1 . 51 ( m , 2h ), 1 . 44 - 1 . 25 ( m , 24h ), 0 . 87 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 22 h 38 o 4 ( m + ) 366 . 2770 , found 366 . 2780 ; analysis calculated for c 22 h 38 o 4 + 0 . 33 h 2 o : c , 70 . 93 ; h , 10 . 46 ; found : c , 70 . 73 ; h , 10 . 31 . methyl ( 2r , 5z )- 2 -( 2 - allyloxy ) acetyloxy - 5 - eicosenoate was prepared as for the s - isomer from methyl ( 2r , 5z )- 2 - hydroxy - 5 - eicosenoate ( as prepared as example d ) in similar yield : α ! d 25 6 . 4 ° ( c = 1 . 4 , ch 3 oh ); ir ( neat , cm - 1 ) 3006 , 2921 , 1756 , 721 ; 1 h nmr ( cd 3 cocd 3 δ 6 . 01 - 5 . 86 ( m , 1h ), 5 . 51 - 5 . 24 ( m , 4h ), 5 . 10 ( t , j = 6 . 3 hz , 1h ), 4 . 22 ( d , j = 16 . 6 hz , 1h ), 4 . 23 ( d , j = 16 . 6 hz , 1h ), 4 . 13 ( dt , j = 1 . 1 , 5 . 7 hz , 2h ), 3 . 75 ( s , 3h ), 2 . 26 - 2 . 12 ( m , 2h ), 2 . 07 - 1 . 87 ( m , 4h ), 1 . 42 - 1 . 28 ( m , 24h ), 0 . 88 ( t , j = 6 . 3 hz , 3h ); hrms calculated for c 26 h 46 o 5 ( m + ) 438 . 3345 , found 438 . 3347 . ( r )- 3 - allyloxy - 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone was prepared as for the s - isomer from methyl ( 2r , 5z )- 2 -( 2 - allyloxy ) acetyloxy - 5 - eicosenoate in similar yield : mp 49 °- 53 ° c . ; α ! d 25 8 . 9 ° ( c = 0 . 8 , ch 3 oh ); ir ( neat , cm - 1 ) 3079 ( br ), 3002 , 2915 , 1741 , 1654 , 734 , 719 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 04 - 5 . 89 ( m , 1h ), 5 . 47 - 5 . 15 ( m , 4h ), 4 . 72 ( dd , j = 3 . 5 , 7 . 6 hz , 1h ), 4 . 48 ( dt , j = 1 . 1 , 5 . 9 hz , 2h ), 2 . 21 - 1 . 54 ( m , 6h ), 1 . 45 - 1 . 28 ( m , 24h ), 0 . 87 ( t , j = 6 . 8 hz , 3h ); hrms calculated for c 25 h 42 o 4 ( m + ), 406 . 3083 found 406 . 3094 . ( r )- 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 3 - ( e )- propenyloxy !- 2 ( 5h )- furanone was prepared as for the s - isomer from ( r )- 3 - allyloxy - 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone in similar yield : mp 42 °- 45 ° c . ; α ! d 25 12 . 8 ° ( c = 0 . 3 , ch 3 oh ); ir ( neat , cm - 1 ) 3079 ( br ), 3004 , 2919 , 1739 , 1681 , 1658 , 738 , 721 ; 1 h nmr ( cd 3 cocd 3 ) δ 6 . 43 - 6 . 36 ( m , 1h ), 5 . 49 - 5 . 31 ( m , 2h ), 5 . 05 - 4 . 91 ( m , 1h ), 4 . 77 ( dd , j = 3 . 5 , 7 . 8 hz , 1h ), 2 . 24 - 1 . 62 ( m , 6h ), 1 . 51 ( dd , j = 1 . 7 , 6 . 9 hz , 3h ), 1 . 44 - 1 . 24 ( m , 24h ), 0 . 87 ( t , j = 6 . 8 hz , 3h ); hrms calculated for c 25 h 42 o 4 ( m + ) 406 . 3083 , found 406 , 3076 . ( r )- 3 , 4 - dihydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone was prepared as for the s - isomer from ( r )- 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 3 - ( e )- propenyloxy !- 2 ( 5h )- furanone in similar yield : mp 65 °- 67 ° c . ; α ! d 25 9 . 5 ° ( c = 0 . 5 , ch 3 oh ); ir ( neat , cm - 1 ) 3421 ( br ), 2917 , 2850 , 1754 , 1666 , 734 , 719 ; 1 h nmr ( cd 3 cocd 3 ) δ 5 . 49 - 5 . 28 ( m , 2h ), 4 . 67 ( dd , j = 3 . 4 , 7 . 8 hz , 1h ), 2 . 32 - 1 . 88 ( m , 4h ), 1 . 69 - 1 . 51 ( m , 2h ), 1 . 44 - 1 . 25 ( m , 24h ), 0 . 87 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 22 h 38 o 4 ( m + ), 366 . 2770 found 366 . 2780 ; analysis calculated for c 22 h 38 o 4 + 0 . 33 h 2 o : c , 70 . 93 ; h , 10 . 46 : found : c , 70 . 53 ; h , 10 . 25 . methyl ( 2s , 5z )- 2 -( 2 - benzyloxy ) acetyloxy - 5 - eicosenoate . to a two - necked , flame - dried 100 ml round bottom flask was added , under argon , 0 . 275 g ( 0 . 81 mmol ) of methyl ( 2s , 5z )- 2 - hydroxy - 5 - eicosenoate in 40 ml of anhydrous ch 2 cl 2 and 0 . 20 g ( 1 . 09 mmol ) of benzyoxyacetyl chloride . the solution was cooled to 0 ° c . ( ice - salt bath ), and pyridine ( 0 . 086 g , 1 . 09 mmol ) was added dropwise . the mixture was stirred for 30 minutes at 0 ° c ., warmed to room temperature , and stirred for an additional 8 hours . the reaction was quenched with 10 ml of ice - water . ch 2 cl 2 ( 20 ml ) was added , and the mixture stirred for 6 hours . the ch 2 cl 2 layer was washed with 3 × 20 ml 10 % aqueous hcl solution , 3 × 15 ml of saturated sodium bicarbonate solution , 2 × 25 ml of brine , dried ( na 2 so 4 ) and concentrated under reduced pressure . the residue was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) as eluant to yield 0 . 34 g ( 87 %) of white solid : α ! d 25 - 5 . 4 ° ( c = 0 . 5 , ch 3 oh ); ir ( neat , cm - 1 ) 3006 ( br ), 2923 , 1756 , 1455 , 734 , 698 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 40 - 7 . 26 ( m , 5h ), 5 . 48 - 5 . 22 ( m , 2h ), 5 . 12 ( t , j = 16 . 7 hz , 1h ); 4 . 17 ( d , j = 16 . 7 hz , 1h ), 3 . 76 ( s , 3h ), 2 . 20 - 1 . 87 ( m , 6h ), 1 . 49 - 1 . 21 ( m , 24h ), 0 . 88 ( t , j = 6 . 4 hz , 3h ); hrms calculated for c 30 h 48 o 5 ( m + ), 488 . 3501 , found 488 . 3501 . ( s )- 3 - benzyloxy - 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone . to a flame - dried , three - necked 100 ml flask equipped with a low temperature thermometer was added , under argon , 0 . 302 g ( 1 . 87 mmol ) of hexamethyldisilazide in 25 ml of anhydrous tetrahydrofuran . the solution was cooled to - 25 ° c . and 1 . 17 ml of 1 . 6 m n - buli ( 1 . 87 mmol ) in hexanes was added dropwise with stirring while maintaining the temperature below - 15 ° c . the reaction was held between - 3 ° c . and - 5 ° c . for 45 minutes , cooled to - 78 ° c ., and 0 . 434 g ( 0 . 89 mmol ) of methyl ( 2s , 5z )- 2 - hydroxy - 5 - eicosenoate , ( benzyloxy ) acetate in 8 ml of anhydrous tetrahydrofuran was added dropwise . the reaction was stirred for 2 hours and quenched at - 78 ° c . with 10 ml of cooled 10 % aqueous hcl solution . ether ( 15 ml ) was added , and the mixture was warmed to room temperature and extracted with 3 × 50 ml of ether . the organic layers were washed with 3 × 25 ml of brine , dried ( na 2 so 4 ) and concentrated under reduced pressure . the residue was purified over silica gel using 10 % methanol in chloroform as eluant to furnish 0 . 34 g ( 84 %) of white solid : mp 76 °- 79 ° c . ; α ! d 25 - 13 . 8 ° ( c = 0 . 3 , ch 3 oh ); ir ( kbr , cm - 1 ) 3033 ( br ), 3004 , 2917 , 1739 , 1660 , 1402 , 1342 , 738 , 728 , 696 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 43 - 7 . 29 ( m , 5h ), 5 . 48 - 5 . 27 ( m , 2h ), 5 . 06 ( d , j = 11 . 3 hz , 1h ), 5 . 01 ( d , j = 11 . 3 hz , 1h ); 4 . 69 ( dd , j = 3 . 5 , 7 . 6 hz , 1h ), 2 . 28 - 1 . 51 ( m , 6h ), 1 . 42 - 1 . 27 ( m , 24h ), 0 . 86 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 29 h 44 o 4 ( m + ), 456 . 3239 ; analysis calculated for c 29 h 44 o 4 + 0 . 2 h 2 o : c , 75 . 68 ; h , 9 . 72 ; found : c , 75 . 57 ; h , 9 . 68 . ( s )- 3 , 4 - dihydroxy - 5 - octadecyl - 2 ( 5h )- furanone . to a 250 ml hydrogenation bottle was added 0 . 02 g of 10 % palladium on carbon in 5 ml methanol . to this suspension was added 0 . 1 g ( 0 . 219 mmol ) of ( s )- 3 - benzyloxy - 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone dissolved in 15 ml methanol . hydrogenation was initiated at 40 psi and at room temperature . the reaction was monitored for completion by tlc ( approximately 5 - 6 hours ), filtered ( celite ) and evaporated under reduced pressure . the residue was purified over silica gel using 10 % methanol in chloroform as eluant to generate 58 mg ( 72 %) of white solid : mp 110 °- 112 ° c . ; α ! d 25 - 6 . 8 ° ( c = 0 . 3 , ch 3 oh ); ir ( kbr , cm - 1 ) 3380 ( br ), 2917 , 2848 , 1741 , 1668 ; 1 h nmr ( cd 3 cocd 3 ) δ 4 . 67 ( dd , j = 3 . 5 , 7 . 3 hz , 1h ), 2 . 01 - 1 . 88 ( m , 1h ), 1 . 57 - 1 . 47 ( m , 1h ), 1 .. 42 - 1 . 23 ( m , 322 ), 0 . 87 ( t , j = 6 . 8 hz , 3h ); hrms calculated for c 22 h 40 o 4 ( m + ), 368 . 2927 , found 368 . 2928 ; analysis calculated for c 22 h 40 o 4 + 0 . 5 h 2 o : c , 69 . 99 ; h , 10 . 95 ; found : c , 70 . 27 ; h , 11 . 22 . methyl ( 2r , 5z )- 2 -( 2 - benzyloxy ) acetyloxy - 5 - eicosenoate was prepared as for the s - isomer from methyl ( 2r , 5z )- 2 - hydroxy - 5 - eicosenoate in similar yield : α ! d 25 5 . 2 ° ( c = 0 . 5 , ch 3 oh ); ir ( neat , cm - 1 ) 3006 , 2923 , 1756 , 1455 , 734 , 698 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 40 - 7 . 26 ( m , 5h ), 5 . 48 - 5 . 22 ( m , 2h ), 5 . 12 ( t , j = 6 . 4 hz , 1h ); 4 . 66 ( s , 2h ), 4 . 25 ( d , j = 16 . 7 hz , 1h ); 4 . 17 ( d , j = 16 . 7 hz , 1h ), 3 . 76 ( s , 3h ), 2 . 20 - 1 . 87 ( m , 6h ), 1 . 49 - 1 . 21 ( m , 24h ), 0 . 88 ( t , j = 6 . 4 hz , 3h ); hrms calculated for c 30 h 48 o 5 ( m + ), 488 . 3501 , found 488 . 3501 . ( r )- 3 - benzyloxy - 4 - hydroxy - 5 - ( z )- 3 - octadecenyl !- 2 ( 5h )- furanone was prepared as for the s - isomer from methyl ( 2r , 5z )- 2 -( 2 - benzyloxy ) acetyloxy - 5 - eicosenoate in similar yield : mp 76 °- 79 ° c . α ! d 25 13 . 5 ° ( c = 0 . 5 , ch 3 oh ); ir ( kbr , cm - 1 ) 3033 ( br ), 3004 , 2917 , 1739 , 1660 , 1400 , 1342 , 738 , 730 ; 696 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 43 - 7 . 29 ( m , 5h ), 5 . 48 - 5 . 27 ( m , 2h ), 5 . 06 ( d , j = 11 . 3 hz , 1h ); 5 . 01 ( d , j = 11 . 3 hz , 1h ); 4 . 67 ( dd , j = 3 . 5 , 7 . 6 hz , 1h ), 2 . 28 - 1 . 51 ( m , 6h ), 1 . 42 - 1 . 27 ( m , 24h ), 0 . 86 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 29 h 44 o 4 ( m + ), 456 . 3239 , found 456 . 3243 . ( r )- 3 , 4 - dihydroxy - 5 - 3 - octadecyl !- 2 ( 5h )- furanone was prepared as for the s - isomer from ( r )- 3 - benzyloxy - 4 - hydroxy - 5 - z )- 3 - octadecenyl !- 2 ( 5h )- furanone in similar yield : mp 114 °- 117 ° c . ; α ! d 25 5 . 2 ° ( c = 0 . 2 , ch 3 oh ); ir ( kbr , cm - 1 ) 3411 ( br ), 2917 , 2848 , 1754 , 1668 ; 1 h nmr ( cd 3 cocd 3 ) δ 4 . 67 ( dd , j = 3 . 5 , 7 . 3 hz , 1h ), 2 . 01 - 1 . 88 ( m , 1h ), 1 . 57 - 1 . 47 ( m , 1h ), 1 . 42 - 1 . 23 ( m , 32h ), 0 . 87 ( t , j = 6 . 8 hz , 3h ); hrms calculated for c 22 h 40 o 4 ( m + ), 368 . 2927 , found 368 . 2927 ; analysis calculated for c 22 h 40 o 4 + 0 . 5 h 2 o : c , 69 . 99 ; h , 10 . 95 ; found c : 69 . 71 ; h , 11 . 09 . methyl ( s )- 3 - phenyllactate . in a 250 ml round bottom flask fitted with a reflux condenser , 3 . 0 g ( 18 . 07 mmol ) of s - phenyllactic acid in 225 ml of methanol containing 4 drops of concentrated sulfuric acid was heated at reflux for 7 hours . the reaction mixture was cooled , 0 . 6 g of sodium bicarbonate was added , and the methanol was evaporated under reduced pressure . the residue was taken up in 200 ml of ether , and the ether layer was washed with 2 × 75 ml of water , 2 × 100 ml of saturated sodium bicarbonate solution and 2 × 75 ml of brine , dried ( na 2 so 4 ) and evaporated under reduced pressure to provide 3 . 12 g of crude product which was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) to furnish 2 . 92 g ( 90 %) of white crystalline solid : mp 46 °- 47 ° c ., ir ( kbr , cm - 1 ) 3473 ( br ), 3029 , 2954 , 1739 , 1496 , 1454 ; 1 h nmr ( cdcl 3 ) δ 7 . 34 - 7 . 19 ( m , 5h ), 4 . 50 - 4 . 43 ( m , 1h ), 3 . 77 ( s , 3h ), 3 . 14 ( dd , j = 4 . 4 , 13 . 9 hz , 1h ); 2 . 96 ( dd , j = 6 . 8 , 13 . 9 hz , 1h ), 2 . 72 ( d , j = 6 . 2 hz , 1h ); hrms calculated for c 10 h 12 o 3 ( m + ), 180 . 0786 , found 180 . 0786 . methyl ( s )- 2 -( 2 - benzyloxy ) acetyloxy - 3 - phenyllactate . to a two - necked , flame - dried 250 ml round bottom flask , under argon , was added 2 . 92 g ( 16 . 2 mmol ) of methyl ( s ) 3 - phenyllactate in 80 ml of anhydrous ch 2 cl 2 . benzyloxyacetyl chloride ( 4 . 49 g , 24 . 33 mmol ) was added with stirring and the solution was cooled to 0 ° c . in an ice - salt bath . pyridine ( 1 . 93 g , 24 . 33 mmol ) was added dropwise and reaction contents were stirred for 30 minutes at 0 ° c ., warmed to room temperature , and stirred for an additional 3 hours . the reaction was quenched with 40 ml of ice - water and 75 ml of ch 2 cl 2 was added . following stirring overnight the ch 2 cl 2 layer was washed with 3 × 75 ml of 10 % aqueous hcl solution , 3 × 100 ml of saturated sodium bicarbonate under reduced pressure . the crude product was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) to yield 4 . 68 g ( 88 %) of white crystalline solid : mp 51 °- 52 ° c ., α ! d 25 - 14 . 3 ° ( c = 2 . 4 , ch 3 oh ); ir ( kbr , cm - 1 ) 2948 , 2886 , 1766 , 1745 , 1455 , 1434 ; 1 h nmr ( cdcl 3 ) δ 7 . 36 - 7 . 19 ( m , 10h ), 5 . 36 ( dd , j = 4 . 5 , 8 . 7 hz , 1h ); 4 . 57 ( s , 2h ), 4 . 19 ( d , j = 16 . 7 hz , 1h ); 4 . 09 ( d , j = 16 . 7 hz , 1h ), 3 . 74 ( s , 3h ), 3 . 23 ( dd , j = 4 . 5 , 14 . 3 hz , 1h ), 3 . 11 ( dd , j = 8 . 7 , 14 . 3 hz , 1h ); hrms calculated for c 19 h 20 o 5 ( m + ), 328 . 1311 , found 328 . 1269 . ( s )- 5 - benzyl - 3 - benzyloxy - 4 - hydroxy - 2 ( 5h )- furanone . to a flame - dried three - necked argon - purged 100 ml flask equipped with a low temperature thermometer was added 2 . 38 g ( 14 . 73 mmol ) of hexamethyldisilazide in 35 ml of anhydrous tetrahydrofuran . the solution was cooled to - 25 ° c ., and 5 . 9 ml of a 2 . 5 m n - buli ( 14 . 73 mmol ) solution in hexanes was added dropwise while maintaining the temperature below - 15 ° c . following the addition , the reaction was stirred and held between - 3 ° and - 5 ° c . for 45 minutes and cooled to - 78 ° c . methyl ( s )- 2 -( 2 - benzyloxy ) acetyloxy - 3 - phenyllactate ( 2 . 3 g , 7 . 01 mmol ) in 10 ml of anhydrous tetrahydrofuran was added dropwise . the reaction was stirred for 75 minutes and quenched at - 78 ° c . with 25 ml of precooled 10 % aqueous hcl solution . after warming to room temperature , the aqueous layer was extracted with 3 × 80 ml of ether and the combined organic layers washed with 3 × 100 ml of brine and dried ( na 2 so 4 ). the ether was evaporated under reduced pressure to provide 1 . 98 g of crude white solid which was recrystallized using ether / petroleum ether to give 1 . 82 g ( 85 %) of white crystalline solid : mp 181 °- 182 ° c . ; α ! d 25 - 57 . 1 ° ( c = 0 . 9 , ch 3 oh ); ir ( kbr , cm - 1 ) 3031 ( br ), 2719 , 1743 , 1662 , 1454 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 34 - 7 . 29 ( m , 5h ), 7 . 29 - 7 . 21 ( m , 5h ), 4 . 96 ( dd , j = 3 . 7 , 6 . 5 hz , 1h ), 4 . 87 ( d , 18 . 2 hz , 1h ), 4 . 79 ( d , j = 18 . 2 hz , 1h ), 3 . 26 ( dd , j = 3 . 7 , 14 . 5 hz , 1h ), 2 . 88 ( dd , j = 6 . 5 , 14 . 5 hz , 1h ); 13 c nmr ( cd 3 cocd 3 ) δ 169 . 0 , 160 . 2 , 138 . 2 , 136 . 4 , 130 . 6 ( 2c ), 129 . 2 ( 2c ), 129 . 1 ( 2c ), 129 . 0 ( 2c ), 128 . 8 , 127 . 6 , 121 . 9 , 76 . 0 , 73 . 6 , 38 . 6 ; hrms calculated for c 18 h 16 o 4 ( m + ), 296 . 1048 , found 296 . 1045 ; analysis calculated for c 18 h 16 o 4 : c , 72 . 96 ; h , 5 . 44 ; found c : 72 . 59 ; h , 5 . 53 . ( s )- 5 - benzyl - 3 , 4 - dihydroxy - 2 ( 5h )- furanone . in a 250 ml argon - flushed hydrogenation bottle was suspended 0 . 2 g of palladium on 10 % carbon in 10 ml methanol . to this suspension was added 2 . 0 g ( 6 . 76 mmol ) of ( s )- 5 - benzyl - 3 - benzyloxy - 4 - hydroxy - 2 ( 5h )- furanone and 25 ml methanol . the mixture was shaken at room temperature under hydrogen ( 35 psi ) and monitored by tlc ( about 5 - 6 hours ). after filtration ( celite pad ) the filtrate was evaporated under reduced pressure , and the residue was purified by recrystallization from acetone / hexanes to furnish 1 . 25 g ( 90 %) of a white crystalline solid : mp 142 °- 144 ° c . ; α ! d 25 - 40 . 2 ° ( c = 2 . 1 , ch 3 oh ); ir ( kbr , cm - 1 ) 3334 ( br ), 1762 , 1681 , 1455 , 1319 ; 1 h nmr ( cd 2 cocd 3 ) δ 7 . 28 - 7 . 21 ( m , 5h ), 4 . 93 ( dd , j = 3 . 5 , 6 . 7 hz , 1 h ), 3 . 29 ( dd , j = 3 . 5 , 14 . 5 hz , 1h ), 2 . 88 ( dd , j = 6 . 5 , 14 . 5 hz , 1h ); hrms calculated for c 11 h 10 o 4 ( m + ), 206 . 0579 , found 206 . 0583 ; analysis calculated for c 11 h 10 o 4 : c , 64 . 08 ; h , 4 . 82 ; found c : 63 . 99 ; h , 4 . 89 . methyl ( r )- 3 - phenyllactate was prepared in similar yield as for the corresponding s - isomer from ( r )- phenyllactic acid : mp 47 ° c . ; ir ( kbr , cm - 1 ) 3479 ( br ), 3029 , 2954 , 1739 , 1496 , 1454 ; 1 h nmr ( cdcl 3 δ 7 . 34 - 7 . 19 ( m , 5h ), 4 . 50 - 4 . 43 ( m , 1h ), 3 . 78 ( s , 3h ), 3 . 14 ( dd , j = 4 . 3 , 13 . 9 hz , 1h ), 2 . 97 ( dd , j = 6 . 8 , 13 . 9 hz , 1h ), 2 . 72 ( d , j = 6 . 2 hz , 1h ); hrms calculated for c 10 h 12 o 3 ( m + ), 180 . 0786 , found 180 . 0795 . methyl ( r )- 2 -( 2 - benzyloxy ) acetyloxy - 3 - phenyllactate was prepared in similar yield as for the corresponding s - isomer from ( r )- 3 - phenyllactate : mp 49 °- 50 ° c . ; α d 25 14 . 7 ° ( c = 0 . 4 , ch 3 oh ); ir ( kbr , cm - 1 ) 2948 , 2886 , 1766 , 1745 , 1455 , 1434 , 1 h nmr ( cdcl 3 ) δ 7 . 35 - 7 . 19 ( m , 10h ), 5 . 36 ( dd , j = 4 . 5 , 8 . 7 hz , 1h ), 4 . 57 ( s , 2h ), 4 . 19 ( d , j = 16 . 7 hz , 1h ), 4 . 09 ( d , j = 16 . 7 hz , 1h ), 3 . 74 ( s , 3h ), 3 . 23 ( dd , j = 4 . 5 , 14 . 3 hz , 1h ), 3 . 11 ( dd , j = 8 . 7 , 14 . 3 hz , 1h ); hrms calculated for c 19 h 20 o 5 ( m + ), 328 . 1311 , found 328 . 1303 . ( r )- 5 - benzyl - 3 - benzyloxy - 4 - hydroxy - 2 ( 5h )- furanone was prepared in similar yield as for ( s )- 5 - benzyl - 3 - benzyloxy - 4 - hydroxy - 2 ( 5h )- furanone from methyl ( r )- 2 -( 2 - benzyloxy ) acetyloxy - 3 - phenyllactate : mp 182 °- 183 ° c . ; α ! d 25 57 . 8 ° ( c = 0 . 4 , ch 3 oh ); ir ( kbr , cm - 1 ) 3029 ( br ), 2717 , 1743 , 1660 , 1454 , 1 h nmr ( cd 3 cocd 3 ) δ 7 . 34 - 7 . 29 ( m , 5h ), 7 . 29 - 7 . 21 ( m , 5h ), 4 . 96 ( dd , j = 3 . 7 , 6 . 5 hz , 1h ), 4 . 86 ( d , 18 . 4 hz , 1h ), 4 . 79 ( d , j = 18 . 4 hz , 1h ), 3 . 26 ( dd , j = 2 . 7 , 14 . 4 hz , 1h ), 2 . 88 ( dd , j = 6 . 5 , 14 . 4 hz , 1h ); hrms calculated for c 18 h 16 o 4 ( m + ) δ 296 . 1048 , found 296 . 1045 . ( r )- 5 - benzyl - 3 , 4 - dihydroxy - 2 ( 5h )- furanone was prepared in similar yield as for the corresponding s - isomer from ( r )- 5 - benzyl - 3 - benzyloxy - 4 - hydroxy - 2 ( 5h )- furanone : mp 142 °- 144 ° c . ; α ! d 25 40 . 8 ° ( c = 0 . 8 , ch 3 oh ); ir ( kbr , cm - 1 ) 3336 ( br ), 1762 , 1679 , 1455 , 1319 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 28 - 7 . 22 ( m , 5 ), 4 . 93 ( dd , j = 3 . 6 , 6 . 7 hz , 1h ), 3 . 29 ( dd , j = 3 . 6 , 14 . 5 hz , 1h ), 2 . 88 ( dd , j = 6 . 7 , 14 . 5 hz , 1h ); hrms calculated for c 11 h 10 o 4 : c , 64 . 08 ; h , 4 . 82 . found : c , 63 . 93 , h , 4 . 86 . ( s )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one . in a 500 ml flame - dried round bottom flask fitted with a septum and under argon was placed 11 . 0 g ( 63 . 2 mmol ) of the dioxolanate of ( s )- malic acid ( prepared by reaction of commercially available ( s )- malic acid with excess dimethoxypropane and p - toluenesulfonic acid as a catalyst ) dissolved in 200 ml anhydrous tetrahydrofuran . the reaction was cooled (- 20 ° c . to - 30 ° c .) and 70 ml of 1 m borane - tetrahydrofuran complex was added dropwise over 2 h . following addition the reaction vessel was placed in a refrigerator at 4 ° c . for 11 h , warmed to room temperature , stirred at room temperature for 9 h and chromatographed ( silica gel ) using acetone as eluant . following evaporation under reduced pressure , the residue was chromatographed as before to generate 9 . 1 g ( 90 %) of the alcohol as a colorless unstable liquid which was dried under reduced pressure and utilized as such in the next reaction : ir ( neat , cm - 1 ) 3480 ( br ), 2994 , 2940 , 2888 , 1791 , 1220 ; 1 h nmr ( cdcl 3 ) δ 4 . 58 ( dd , j = 5 . 1 , 7 . 0 hz , 1h ), 3 . 91 - 3 . 79 ( m , 2h ), 2 . 28 - 2 . 13 ( m , 1h ), 2 . 13 - 1 . 97 ( m , 1h ), 1 . 64 ( s , 3h ), 1 . 57 ( s , 3h ). ( s )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one p - toluenesulfonate . dried ( s )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolane - 4 - one ( 9 . 0 g , 59 . 2 mmol ) was dissolved in 100 ml of anhydrous pyridine under argon and cooled to - 4 ° c . to this solution maintained at approximately 0 ° c . was added dropwise 11 . 3 g ( 59 . 22 mmol ) of p - toluenesulfonyl chloride dissolved in 100 ml of pyridine . following addition , the mixture was placed in the refrigerator ( 0 °- 4 ° c .) overnight . water ( 150 ml ) was added , and the aqueous mixture extracted with 4 × 200 ml of ether . the ether layers were combined , washed with 3 × 150 ml of water , 3 × 150 ml of saturated copper sulfate solution ( until no dark blue color remained ), 2 × 100 ml of water , 3 × 150 ml of brine , dried ( na 2 so 4 ), filtered , and evaporated under reduced pressure . the crude tosylate was purified by column chromatography using ethyl acetate : hexanes ( 1 : 1 ) to provide the title compound , 16 . 7 g ( 95 %) as white solid : mp 48 °- 49 ° c . ; α ! d 25 - 3 . 7 ° ( c = 0 . 3 , ch 3 oh ); ir ( kbr , cm - 1 ) 2989 , 1785 , 1390 , 1357 , 1278 1 h nmr ( cdcl 3 ) δ 7 . 80 ( d , j = 8 . 3 hz , 2h ), 7 . 36 ( d , j = 8 . 3 hz , 2h ), 4 . 43 ( dd , j = 4 . 4 , 8 . 1 hz , 1h ), 4 . 27 - 4 . 14 ( m , 2h ), 2 . 46 ( s , 3h ), 2 . 3 - 2 . 17 ( m , 1h ), 2 . 09 - 1 . 92 ( m , 1h ), 1 . 58 ( s , 3h ), 1 . 51 ( s , 3h ); hrms calculated for c 14 h 18 o 6 s ( m + ), 314 . 0824 , found 314 . 0817 . ( s )- 5 - hexyl - 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one . to a flame - dried 500 ml three - necked round bottom flask under nitrogen containing a suspension of 4 . 85 g ( 25 . 48 mmol ) of cuprous iodide in 200 ml of anhydrous ether and held at - 30 ° c . was added dropwise 31 . 85 ml of 1 . 6 m n - buli ( 50 . 96 mmol ) in hexanes . the dark red - brown solution was stirred at - 30 ° c . to - 40 ° c . for 2 h and cooled to - 78 ° c . ( s )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one p - toluenesulfonate ( 4 . 0 g , 12 . 74 mmol ), dissolved in 30 ml of anhydrous ether and 10 ml of anhydrous tetrahydrofuran , was added dropwise while maintaining the temperature below - 70 ° c . the reaction mixture was stirred for 18 h at - 78 ° c . following completion ( tlc monitoring ), the reaction was warmed to - 10 ° c . and quenched by the addition of 125 ml of precooled saturated ammonium chloride solution . ether ( 100 ml ) was added and the mixture filtered over celite . the aqueous phase was extracted with 3 × 175 ml ether . the combined ether extract was washed with 2 × 125 ml of saturated ammonium chloride solution , 1 × 75 ml of water and 2 × 100 ml of brine , dried ( na 2 so 4 ), filtered and concentrated under reduced pressure . the product was purified ( silica gel ) using ethyl acetate : hexanes ( 1 : 5 ) as eluant to give 2 . 44 g ( 95 %) of the title compound as a colorless oil : α ! d 25 0 . 6 ° ( c = 1 . 9 , ch 3 oh ); ir ( kbr , cm - 1 ) 2958 , 2933 , 2861 , 1797 ; 1 h nmr ( cdcl 3 ) δ 4 . 39 ( dd , j = 4 . 4 , 7 . 1 hz , 1h ), 1 . 95 - 1 . 81 ( m , 1h ), 1 . 81 - 1 . 62 ( m , 1h ), 1 . 61 ( s , 3h ), 1 . 54 ( s , 3h ), 1 . 49 - 1 . 38 ( m , 2h ), 1 . 35 - 1 . 29 ( m , 6h ), 0 . 89 ( t , j = 6 . 6 13 c nmr ( cdcl 3 ) δ 173 . 3 , 110 . 2 , 74 . 2 , 31 . 7 , 31 . 6 , 28 . 8 , 25 . 8 , 24 . 8 , 22 . 5 , 13 . 9 ; hrms calculated for c 11 h 20 o 3 ( m + ), 200 . 1412 , found 200 . 1422 . methyl ( s )- 2 - hydroxyoctanoate . in a 250 ml round bottom flask fitted with a reflux condenser was placed 2 . 4 g ( 12 mmol ) of ( s )- 5 - hexyl - 2 , 2 - dimethyl - i , 3 - dioxolan - 4 - one in 150 ml of methanol containing 2 drops of concentrated sulfuric acid . following heating at reflux for 6 hours , the reaction mixture was cooled , and 0 . 5 g of sodium bicarbonate was added . the solvent was evaporated under reduced pressure and the residue dissolved in 200 ml of ch 2 cl 2 . the solution was washed with 2 × 75 ml of water , 2 × 100 ml of saturated sodium bicarbonate solution , and 2 × 75 ml of brine , and dried ( na 2 so 4 ). the ch 2 cl 2 solvent was evaporated under reduced pressure to provide 2 . 07 g of crude product which was purified over silica gel using ethyl acetate : hexanes ( 1 : 5 ) to furnish 2 . 0 g ( 96 %) of the title compound as a pale yellow oil : α ! d 25 2 . 9 ° ( c = 0 . 8 , ch 3 oh ); ir ( neat , cm - 1 ) 3475 ( br ), 2925 , 2857 , 1739 ; 1 h nmr ( cdcl 3 ) δ 4 . 19 ( m , 1h ), 3 . 79 ( s , 3h ), 2 . 73 ( d , j = 4 . 8 hz , 1h ), 1 . 89 - 1 . 75 ( m , 1h ), 1 . 72 - 1 . 56 ( m , 1h ), 1 . 55 - 1 . 39 ( m , 2h ), 1 . 39 - 1 . 28 ( m , 6h ), 0 . 88 ( t , j = 6 . 6 hz , 3h ); hrms calculated for c 19 h 18 o 3 ( m + ), 174 . 1255 , found 174 . 1255 . methyl ( s )- 2 -( 2 - benzyloxy ) acetyloxyoctanoate . in a two - necked , flame - dried 250 ml round bottom flask , under argon , was added 4 . 28 g ( 25 . 0 mmol ) of methyl ( s )- 2 - hydroxyoctanoate in 100 ml of anhydrous ch 2 cl 2 . benzyloxyacetyl chloride ( 6 . 82 ; 36 . 9 mmol ) was added and the mixture was cooled to 0 ° c . in an ice - salt bath . pyridine ( 2 . 92 g , 36 . 9 mmol ) was added dropwise . the mixture was stirred for 30 minutes at 0 ° c ., warmed to room temperature , stirred for an additional 3 hours , and quenched with 30 ml of ice - water . an additional 50 ml of ch 2 cl 2 was added . following stirring overnight , the ch 2 cl 2 layer was separated and extracted with 3 × 50 ml of 10 % aqueous hcl solution , 3 × 75 ml of saturated sodium bicarbonate solution , and 2 × 100 ml of brine , dried ( na 2 so 4 ) and concentrated under reduced pressure . the residue was purified over silica gel ethyl acetate : hexanes ( 1 : 6 ) as eluant to give 6 . 7 g ( 88 %) of the title compound as a pale yellow liquid : α ! d 25 - 10 . 9 ° ( c = 0 . 3 , ch 3 oh ); ir ( neat , cm - 1 ) 2927 , 2859 , 1735 , 1455 ; 1438 ; 1 h nmr ( cdcl 3 ) δ 7 . 36 - 7 . 29 ( m , 5h ), 5 . 11 ( t , j = 6 . 5 hz , 1h ), 4 . 66 ( s , 2h ), 4 . 23 ( d , j = 16 . 7 hz , 1h ), 4 . 17 ( 2 , j = 16 . 7 hz , 1h ), 3 . 75 ( s , 3h ), 1 . 87 - 1 . 72 ( m , 2h ), 1 . 42 - 1 . 15 ( m , 8h ), 0 . 87 ( t , j = 6 . 6 hz , 3h ); hrms calculated for c 18 h 26 o 5 ( m + ), 322 . 1780 , found 322 . 1760 . ( s )- 3 - benzyloxy - 5 - hexyl - 1 - 4 - hydroxy - 2 ( 5h )- furanone . in a flame - dried three - necked argon purged 100 ml flask equipped with a low temperature thermometer was added 2 . 1 g ( 13 . 04 mmol ) of hexamethyldisilazide in 35 ml of anhydrous tetrahydrofuran . following cooling to - 25 ° c ., 5 . 3 ml of a 2 . 5 m n - buli in hexanes ( 13 . 04 mmol ) was added dropwise and with stirring while maintaining the temperature below - 15 ° c . the mixture was stirred and held between - 3 ° c . and - 5 ° c . for 45 minutes and cooled to - 78 ° c . methyl ( s )- 2 -( 2 - benzyloxyl ) acetyloxyoctanoate ( 2 . 0 g ; 6 . 21 mmol ) in 10 ml of anhydrous tetrahydrofuran was added dropwise . the reaction was stirred for 75 minutes and quenched at - 78 ° c . with 30 ml of precooled 10 % aqueous hcl solution . after warming to room temperature the product was extracted with 3 × 80 ml of ether , and the organic layer was washed with 3 × 100 ml brine , dried ( na 2 so 4 ) and evaporated under reduced pressure to give 1 . 65 g of crude white product which was recrystallized using ether / petroleum ether to furnish 1 . 53 g ( 85 %) of white crystals : mp 74 °- 75 ° c . ; α ! d 25 - 18 . 9 ° ( c = 2 . 0 , ch 3 oh ); ir ( kbr , cm - 1 ) 3035 ( br ), 2950 , 2921 , 1735 , 1646 , 1465 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 43 - 7 . 29 ( m , 5h ), 5 . 06 ( d , 16 . 1 hz , 1h ), 5 . 01 ( d , j = 16 . 1 hz , 1h ), 4 . 69 ( dd , j = 3 . 7 , 7 . 0 hz , 1h ), 1 . 90 - 1 . 82 ( m , 1h ), 1 . 61 - 1 . 45 ( m , 1h ), 1 . 38 - 1 . 15 ( m , 8h ), 0 . 87 ( t , j = 6 . 8 hz , 3h ); 13 c nmr ( cd 3 cocd 3 ) δ 171 . 6 , 169 . 4 , 161 . 2 , 138 . 3 , 129 . 2 ( 2c ), 129 . 1 ( 2c ), 128 . 9 , 120 . 9 , 75 . 9 , 73 . 4 , 32 . 6 , 32 . 4 , 24 . 4 , 23 . 2 , 14 . 3 ; hrms calculated for c 17 h 22 o 4 ( m + ), 290 . 1518 ; found 290 . 1538 ; analysis calculated for c 17 h 22 o 4 c 70 . 36 , h 7 . 50 ; found c 70 . 32 , h 7 . 64 . ( s )- 5 - hexyl - 3 , 4 - dihydroxy - 2 ( 5h )- furanone . in a two - necked 100 ml round bottom flask was added , under argon , 0 . 7 g ( 2 . 41 mmol ) of ( s )- 3 - benzyloxy - 4 - hydroxy - 3 ( 5h )- furanone , 0 . 7 g of 10 % pd / c , and 4 . 96 g ( 660 . 35 mmol ) of cyclohexene in 50 ml of absolute ethanol . the mixture was stirred and heated at reflux , filtered ( celite ) and the solvent removed under reduced pressure . the residue was recrystallized from acetone / hexanes to provide 0 . 362 g ( 75 %) of white solid : mp 100 °- 101 ° c . ; α ! d 25 - 14 . 1 ° ( c = 0 . 4 , ch 3 oh ); ir ( kbr , cm - 1 ) 3426 ( br ), 2921 , 1766 , 1662 ; 1 h nmr ( cd 3 cocd 3 ) δ 4 . 56 ( dd , j = 3 . 4 , 7 . 0 hz , 1h ), 1 . 98 - 1 . 84 ( m , 1h ), 1 . 57 - 1 . 43 ( m , 1h ), 1 . 42 - 1 . 22 ( m , 8h ), 0 . 90 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 10 h 16 o 4 ( m + ), 200 . 1049 ; found 200 . 1049 ; analysis calculated for c 10 h 16 o 4 : c 60 . 05 , h 8 . 05 . ( r )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one was prepared in similar yield as for the corresponding s - isomer from the dioxolanate of ( s )- malic acid : ir ( neat , cm - 1 ) 3453 ( br ), 2994 , 2940 , 2888 , 1791 , 1220 ; 1 h nmr ( cdcl 3 ) δ 4 . 58 ( dd , j = 5 . 1 , 7 . 0 hz , 1h ), 3 . 91 - 3 . 79 ( m , h ), 2 . 28 - 2 . 13 ( m , 1h ), 2 . 12 - 1 . 97 ( m , 1h ), 1 . 64 ( s , 3h ), 1 . 57 ( s , 3h ). ( r )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one p - toluenesulfonate was prepared in similar yield for the corresponding s - isomer from ( r )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolane - 4 - one : mp 52 °- 53 ° c . ; α ! d 25 3 . 8 ° ( c = 1 . 1 , ch 3 oh ); ir ( kbr , cm - 1 ) 2992 , 1785 , 1388 , 1357 , 1278 ; 1 h nmr ( cdcl 3 ) δ 7 . 80 ( d , j = 8 . 3 hz , 2h ), 7 . 36 ( d , j = 8 . 3 hz , 2h ), 4 . 43 ( dd , j = 4 . 4 , 8 . 1 hz , 1h ), 4 . 27 - 4 . 14 ( m , 2h ), 2 . 46 ( s , 3h ), 2 . 30 - 2 . 18 ( m , 1h ), 2 . 09 - 1 . 93 ( m , 1h ), 1 . 58 ( s , 3h ), 1 . 51 ( s , 3h ); hrms calculated for c 14 h 18 o 6 s ( m + ), 314 . 0824 ; found 314 . 0830 . ( r )- 5 - hexyl - 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one was prepared in similar yield as for the corresponding s - isomer from ( r )- 5 -( 2 - hydroxyethyl )- 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one : α ! d 25 - 2 . 9 ° ( c = 1 . 3 , ch 3 oh ); ir ( neat , cm - 1 ) 2958 , 2931 , 2859 , 1793 ; 1 h nmr ( cd 3 cl 3 ) δ 4 . 39 ( dd , j = 4 . 4 , 7 . 1 hz , 1h ), 1 . 95 - 3 . 81 ( m , 1h ), 1 . 81 - 1 . 62 ( m , 1h ), 1 . 61 ( s , 3h ), 1 . 54 ( s , 3h ), 1 . 49 - 1 . 38 ( m , 2h ), 1 . 24 - 1 . 28 ( m , 6h ), 0 . 89 ( t , j = 6 . 6 hz , 3h ); hrms calculated for c 11 h 20 o 3 ( m + ), 200 . 1412 ; found 200 . 1431 . methyl ( r )- 2 - hydroxyoctanoate was prepared in similar yield as for the corresponding s - isomer from ( r )- 5 - hexyl - 2 , 2 - hexyl - 2 , 2 - dimethyl - 1 , 3 - dioxolan - 4 - one : α ! d 25 2 . 7 ° ( c = 0 . 3 ch 3 oh ); ir ( neat , cm - 1 ) 3496 ( br ), 2929 , 2859 , 1749 ; 1 h nmr ( cdcl 3 ) δ 4 . 19 ( m , 1h ), 3 . 79 ( s , 3h ), 2 . 73 ( d , j = 4 . 8 hz , 1h ), 1 . 89 - 1 . 75 ( m , 1h ), 1 . 72 - 1 . 57 ( m , 1h ), 1 . 55 - 21 . 39 ( m , 2h ), 1 . 39 - 1 . 28 ( m , 6h ), 0 . 88 ( t , j = 6 . 6 hz , 3h ); hrms calculated for c 9 h 18 o 3 ( m + ), 174 . 1255 ; found 174 . 1256 . methyl ( r )- 2 -( 2 - benzyloxy ) acetyloxy was prepared in similar yield as for the corresponding s - isomer from methyl ( r )- 2 - hydroxyoctanoate : α ! d 25 10 . 8 .° ( c = 1 . 1 , ch 3 oh ); ir ( kbr , cm - 1 ) 2925 , 2857 , 1733 , 1455 , 1436 ; 1 h nmr ( cdcl 3 ) δ 7 . 36 - 7 . 29 ( m , 5h ), 5 . 10 ( t , j = 6 . 5 hz , 1h ), 4 . 65 ( s , 2h ), 4 . 23 ( d , j = 16 . 7 hz , 1h ), 4 . 17 ( d , j = 16 . 7 hz , 1h ), 3 . 74 ( s , 3h ), 1 . 87 - 1 . 72 ( m , 2h ), 1 . 42 - 1 . 15 ( m , 8h ), 0 . 87 ( t , j = 6 . 6 hz , 3h ); hrms calculated for c 18 h 26 o 5 ( m + ), 322 . 1780 ; found 322 . 1782 . ( r )- 3 - benzyloxy - 5 - hexyl - 4 - hydroxy - 2 ( 5h )- furanone was prepared in similar yield as for the corresponding s - isomer from methyl ( r )- 2 -( 2 - benzyloxy ) acetyloxyoctanoate : mp 86 °- 87 ° c . ; α ! d 25 18 . 8 ° ( c = 0 . 9 , ch 3 oh ); ir ( kbr , cm - 1 ) 3035 ( br ), 2950 , 2921 , 1735 ; 1646 ; 1465 ; 1 h nmr ( cd 3 cocd 3 ) δ 7 . 43 - 7 . 29 ( m , 5h ), 5 . 07 ( d , 16 . 2 , 1h ), 5 . 01 ( d , j = 16 . 2 , 1h ), 4 . 69 ( dd , j = 3 . 7 , 7 . 0 , 1h ), 1 . 90 - 1 . 82 ( m , 1h ), 1 . 61 - 1 . 45 ( m , 1h ), 1 . 61 - 1 . 45 ( m , 1h ), 1 . 38 - 1 . 15 ( m , 8h ), 0 . 87 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 17 h 22 o 4 ( m + ), 290 . 1518 , found 290 . 1505 . ( r )- 5 - hexyl - 3 , 4 - dihydroxy - 2 ( 5h )- furanone was prepared in similar yield as for the corresponding s - isomer from ( r )- 3 - benzyloxy - 5 - hexyl - 4 - hydroxy - 2 ( 5h )- furanone : mp 98 °- 99 ° c . ; α ! d 25 14 . 2 ° ( c = 1 . 9 , ch 3 oh ); ir ( kbr , cm - 1 ) 3423 ( br ), 2921 , 1768 , 1660 ; 1 h nmr ( cd 3 cocd 3 ) δ 4 . 57 ( dd , j = 3 . 4 , 7 . 0 hz , 1h ), 1 . 98 - 1 . 84 ( m , 1h ), 1 . 57 - 1 . 43 ( m , 1h ), 1 . 42 - 1 . 22 ( m , 8h ), 0 . 90 ( t , j = 6 . 7 hz , 3h ); hrms calculated for c 10 h 16 o 4 ( m + ), 200 . 1049 ; found 200 . 1049 .

US-24561594-A

the present invention concerns a space holder , especially for vertebrae or intervertebral discs for implantation into human or animal organisms , having a cylinder - like body and , at the ends of the cylinder - like body , means provided for connecting to adjacent body parts , said cylinder - like body essentially being formed as a solid cylinder from at least one material that is elastically deformable under the conditions of use , such that the space holder is compressible and extensible in the axial direction and , with reference to means provided at the ends for connecting the space holder to adjacent body parts , can bend about a radial axis of rotation .

fig1 shows a 3d view of a first embodiment of the space holder of the invention with a cylindrical body 1 having provision for two connecting rings 2 at the ends of the cylindrical body 1 for connecting the space holder to the adjacent body parts , e . g . bones or cartilage in , for example , the human body . cylindrical body 1 is made as a solid cylinder from an elastic polymer , such as high molecular polyethylene or medical grade silicone , with cylinder - shaped body 1 being made up of two parts , namely a cylindrical core 8 and a cylinder pipe - shaped sleeve or cover 7 , which is arranged coaxially around core 8 . due to the two - component structure of core 8 and sleeve 7 , different materials having different properties , such as strength , elasticity etc , can be used for optimally adjusting the mechanical properties of cylinder - shaped body 1 to requirements . connecting rings 2 , which are arranged at the ends of cylinder - shaped body 1 , have identical shapes in the sample embodiment shown , but may also have different shapes . connecting rings 2 possess an inner diameter that roughly corresponds to the outer diameter of cylinder - shaped body 1 such that they can be pushed over the ends of cylinder - shaped body 1 . the outer diameter of cylinder - shaped body 1 can be made somewhat larger than the inner diameter of connecting ring 2 in order that tensioning of the cylinder - shaped body 1 and / or connecting ring 2 may cause the connecting ring to sit firmly by non - positive means on cylinder - shaped body 1 . in this selected variant , connecting rings 2 project by a thickness d 1 , which corresponds to the wall thickness of connecting ring 2 , over the body surface of cylinder - shaped body 1 . furthermore , connecting rings 2 are arranged on cylindrical body 1 such that they project by a height h 1 in the axial direction beyond the ends of cylinder - shaped body 1 . it is thus possible for serrations 3 provided for at the side ends of connecting rings 2 to engage with adjacent body tissue at the site of the implantation . connecting rings 2 in the embodiment shown in fig1 are formed such that triangular cavities 5 at the two ends of connecting ring 2 create trapezoidal serrations 3 , provision for which is made at the side opposite cylinder - shaped body 1 for engaging with and clinging onto adjacent body tissue . in addition , connecting ring 2 has diamond - shaped cavities 4 , provision for which is made such that they are adjacent to each other around the entire ring . as a result , connecting ring 2 is formed again to itself by a number of diamond - shaped interconnected fillets 6 , with the tips of the diamonds formed by fillets 6 cut - off so that trapezoidal serrations 3 are formed . since connecting ring 2 in the sample embodiment shown projects over cylindrical body 1 approximately from the centre of the diamonds 4 , each diamond - shaped cavity 4 in the ring 2 shown in the lower part of fig1 has an upper region 10 in which only a recess as far as the cylindrical body 1 is formed due to diamond - shaped cavity 4 , whereas provision is made in lower region 11 for a fully open aperture ( correspondingly in upper ring 2 ). both recess 10 and aperture 11 enable the space holder to grow into and knit together with the body tissue . aside from the force fit or snug fit of the connecting rings on cylindrical body 1 , there are other ways of effecting a permanent and especially non - twisting connection between connecting rings 2 and cylindrical body 1 . for example it is possible to make provision for protrusions ( not shown ) on the inside of connecting rings 2 and to also mould , for example , the connecting rings 2 or the protrusions during the manufacture of cylinder - shaped body 1 by injection moulding into cylinder - shaped body 1 , in which case the projections would then be enveloped and occluded by the plastic compound of cylinder - shaped body 1 , as a way of effecting the permanent connection between cylinder - shaped body 1 and connecting rings 2 . in addition , however , a large number of other connecting means and techniques are conceivable . through forming the cylinder - shaped body 1 as a solid body and especially as a two component body with core 8 and sleeve 7 , optimum load distribution and load accommodation are possible , with , especially by forming core 8 and sleeve 7 differently as regards mechanical properties , a desired property profile capable of being set . for example , core 8 can be designed to be more rigid than jacket 7 such that , given flexural stress on the space holder about the radial axis 13 shown by way of example , the especially highly extended or compressed external areas of sleeve 7 exhibit extensive yielding capability , whereas core 8 , which only has to accommodate less extensive extension or compression , exhibits greater rigidity such that the space holder overall has the property of readily facilitating minor bending , while increasing bending is met with a disproportionate increase in resistance . but also axial extension or compression along longitudinal axis 12 is optimally effected by the elastic solid cylinder 1 of the embodiment shown in fig1 . fig2 shows a second embodiment of a space holder of the object of the invention in an illustration corresponding to fig1 . therein , the same or similar components with identical references are shown so that , with the exception of the differences described below , the considerations above also apply here . in the embodiment of fig2 , cylindrical body 1 is also made from an elastic polymer , with the exception that it is a single - piece body made from one component , i . e . cylinder - shaped body 1 is made from a single material in a single piece . however , the ends of cylinder - shaped body 1 have a reduced diameter for a limited length of the longitudinal axis 12 of cylinder - shaped body 1 such that a shoulder 9 is formed . the diameter is thereby reduced by twice the thickness d 2 , which corresponds to the wall thickness of connecting ring 2 , such that connecting ring 2 arranged at shoulder 9 is flush with the body surface of cylinder - shaped body 1 . in this embodiment , also , the connecting rings 2 are formed such that , in the arrangement in shoulder 9 of cylinder - shaped body 1 , they project over the ends of cylinder - shaped body 1 by a height h 2 in order again to give the spikes 3 formed at the ends the possibility of engaging with adjacent body tissue at the site of implantation . the embodiment shown in fig2 also differs from the embodiment shown in fig1 as regards the shape of connecting rings 2 . the connecting rings 2 used here are notable for the fact that they have a wave - like or a zigzag shaped arrangement of fillets 6 , such that triangular cavities 5 are formed between the fillets 6 at the ends and trapezoidal spikes 3 are again present between triangular cavities 5 . by virtue of the arrangement of connecting rings 2 in shoulders 9 of cylinder - shaped body 1 , the triangular grooves 5 on the side facing cylinder - shaped body 1 form recesses 10 with cylinder - shaped body 1 that again enable the space holder to grow into the body tissue . on the upper connecting ring 2 of fig2 is shown by way of example the manner in which , for example , a connection may be effected between connecting rings 2 and cylinder - shaped body 1 by rods 15 projecting radially inward . in this regard and also by way of example is shown in connecting ring 2 aperture 14 , through or into which rod 15 can be pushed or screwed such that it projects radially inward inside connecting ring 2 . rod 15 can be fixed to connecting ring 2 by suitable means of attachment , such as thread and counter - nut . connecting rings 2 prepared in this way can , for example , then be inserted into an injection mould so that cylinder - shaped body 1 can then be moulded from a bio - compatible polymer . radially inwardly projecting rods 15 of connecting rings 2 are then occluded in cylinder - shaped body 1 and produce a permanent , especially also a non - twisting connection between connecting rings 2 and cylinder - shaped body 1 . admittedly , it is also conceivable to produce cylinder - shaped body 1 beforehand , to push connecting rings 2 onto shoulders 9 and and then to press rods 15 through apertures 14 into cylinder - shaped body 1 or into the polymer material of cylinder - shaped body 1 or to guide them into corresponding holes and then to secure rod 15 in a suitable way , e . g . via screw connections on connecting ring 2 . in addition to the connecting possibilities described explicitly here for connecting connecting rings 2 and cylinder - shaped body 1 , numerous other suitable connecting techniques are conceivable . fig3 shows a side view of an alternative connecting ring 2 with several rows of diamond - shaped cavities that are offset to each other in the axial direction by a half diamond . as indicated by the dashed line 14 in fig3 , a connecting ring 2 designed in this way can be shortened to the corresponding desired length by cutting along cutting line 14 of connecting ring 2 such that spikes 3 are again formed at the point of separation by diamond - shaped connected fillets 6 . fig4 and 5 are schematic cross - sectional diagrams of the different cross - sectional shapes of cylinder - like body 1 , with fig4 showing an oval cross - sectional shape and fig5 a pea - shaped cross - section .

US-201113021135-A

a device for projecting ice cubes onto a roof to scare away birds , especially pigeons . the use of ice is environmentally friendly and will not jam gutters .

other objects , features and advantages of the invention will become apparent from a consideration of the following detailed description and the accompanying drawing . referring to the figure , it can be understood that the present invention is embodied in a device 10 which catapults ice cubes 20 when activated . the device can be located and oriented to catapult ice cubes onto the roof of a house to scare away birds roosting on the roof . the ice cubes will eventually melt and the water will drain away in the gutter system harmlessly and in an environmentally friendly manner . the device can be activated by means of a timer , or a remote control or a simple on / off switch as is convenient . it is noted that the details of the motor along with the mechanical elements associated therewith are not important to the invention and those skilled in the art will understand the motor and its mechanical elements based on the teaching of this disclosure . as such , these details will not be provided or claimed . device 10 includes a housing 30 having a hollow interior 32 in which is located an ice cube making system which includes a mold 34 fluidically connected to a water intake 36 and to an ice cube dispensing system having an ice cube dispensing port 38 located in a channel 40 . ice cubes formed in the ice cube making system are dispensed from port 38 for a purpose which will be understood from the teaching of this disclosure . a motor ( not seen in the figure ) is located in portion 42 of the housing and is powered from cord 50 and is controlled using arm 54 in the manner of an off / on switch . a catapult assembly 60 is located in channel 40 and includes a spring system 62 having spring arms 64 and 66 mounted on the housing in channel 40 and having a coil spring 68 mounted on one arm 66 with a catapult arm 70 pivotally mounted at proximal end 72 thereof to the housing and connected to spring 68 to be strongly biased toward a catapulting position shown in fig1 and adapted to be forced back into channel 40 and held therein by a lock element 80 releasably engaging distal end 82 of the catapult arm . lock element 80 moves between a locking position in which the distal end of the catapult arm is engaged by the lock element to hold the arm against the bias of spring 68 and an unlocking position in which the lock element is moved away from engagement with the distal end of the catapult arm whereby the arm will be released to be moved by spring 68 toward the catapulting position of that arm . an ice cube holding portion 86 of the catapult arm is located adjacent to ice cube dispensing port 38 when the catapult arm is in a loaded orientation in the channel whereby ice cubes 20 will be catapulted when the lock element is moved by the motor to release the arm so the bias of the spring system will move it from a loaded orientation in the channel to the catapulting position . spring 68 is selected to have a spring constant sufficient to force the catapult arm from its cocked position into the catapulting position with force sufficient to throw ice cubes located on the catapult arm off of that arm and at least one story ( approximately ten feet ) into the air above the device whereby such catapulted ice cubes will be thrown far and high enough to land on the roof of a building and frighten birds off of that roof . the spring can also be selected to catapult ice cubes higher than one story as well without departing from the scope of this disclosure . once the catapult arm is in the catapulting position , it is moved back into the loaded position by a system which includes a monorail element 100 that is slidably mounted on the housing via a track 102 and is operated by the motor . movement of the monorail element from one end 104 of the track to the other end 106 of the track will force the catapult arm from the catapulting position shown in fig1 back to the loaded position in the channel . a heating coil 110 is included to ensure that water will flow through the appropriate conduits which may be located closely adjacent to a cooling unit associated with the ice cube making system . device 10 is located and oriented to catapult ice cubes onto a roof adjacent to birds on the roof so the landing ice cubes will scare the birds away and then move from the roof into the gutter system of the structure . the device can be manually operated using arm 54 or it can be connected to a timer system or to a remote control system as desired . while various embodiments of the invention have been described , it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of this invention . accordingly , the invention is not to be restricted except in light of the attached claims and their equivalents .

US-93040711-A

a device and method of training bank personnel utilizing game techniques . the game board comprises several connected continuous circuits . the circuits have spaces which direct the players to stacks of question and answer cards . the winner is determined by the player who answers the most questions or certain specified questions . the game also instructs in proper procedural and ethical conduct .

the present invention is directed to a device for both initial and refresher training of bank personnel . as illustrated by fig1 , 3 , 4 , 5 and 6 the device is comprised of a game board 2 ; playing cards &# 34 ; b &# 34 ;, i . e . b 1 , b 2 , b 3 , &# 34 ; c &# 34 ;, i . e . c 1 , c 2 , c 3 , and &# 34 ; d &# 34 ;, i . e . d 1 , d 2 , d 3 ; space advancement or professionalization cards 4 ; chance mechanism or dice 6 ; and player markers 8 . referring in particular to fig1 the game board 2 contains a course or circuit which is composed of at least two continuous branches that meet at a common space on the board . each branch is divided into a number of spaces . the majority of the spaces in each branch requires the player to select a card from a particular stack of cards such as one of the &# 34 ; b &# 34 ;, &# 34 ; c &# 34 ; or &# 34 ; d &# 34 ; cards and answer the question written thereon . the answers to the questions are contained on the reverse side of the cards . the number of groups or question and answer cards should preferably correspond to the number of branches in the course . each group of cards also preferably is comprised of a number of subgroups , i . e . group &# 34 ; b &# 34 ; is comprised of subgroups b 1 , b 2 and b 3 . the number of groups and subgroups of cards is not critical nor is the number of cards in each subgroup , usually about 20 . the groups and subgroups of question and answer cards can differ from each other in subject matter and / or level of difficulty . fig2 and 6 illustrate different groups and subgroups of cards that can be employed if the game is to be employed in the training of tellers . the game is particularly suited for the training of tellers , new accounts personnel , item processing personnel , load documentation personnel and those involved with basic credit responsibilities . the following are sample question and answer cards which illustrate the wide range of concepts that can be taught utilizing the game of the present invention : 1 . what is the name of the contract that is a written promise to pay back to the bank the amount of a loan ? a . the data a note falls due or when it is payable . a . the length of time from the date to the due ( maturity ) date . a . the borrower has signed a security agreement giving the bank the right to sell certain of the borrower &# 39 ; s property if he fails to repay the loan . a . the guarantor assumes responsibility for the amount of a note plus any future loans the borrower makes . 3 . how often does the bank usually send a checking account statement to its customers ? a . all the activity in the account for the preceding month . all deposits made and checks paid , the service charge , if any , and any other debits and credits posted to the account . 5 . what is the service charge on a budget account if 9 of the customer &# 39 ; s checks are paid during the month and his minimum balance is $ 325 . 00 ? 1 . what is the maximum amount allowed by law in a commercial savings account ? 2 . what is the name of the savings account offered to businesses ? 5 . what is the rate of interest paid on 6 - month money market certificates ? a . the rate changes weekly and is based on the average discount rate on 6 - month u . s . treasury bills . 1 . how does a customer activate the line of credit on a captain &# 39 ; s account ? a . by writing a check in excess of the account balance or by requesting that a certain amount be deposited in the account . 4 . how soon after a series ee bond is issued can it be redeemed ? 5 . in what situation can you cash a check made payable to a company ? those spaces in each branch which are not question and answer spaces are occupied by playing instructions . those spaces denoted by the letter &# 34 ; e &# 34 ; provide illustrations of proper ethical and procedural conduct and allow the player to take an additional turn . examples of appropriate phrasology for these spaces are : you have a perfect balancing record for the month . take another turn . you receive a $ 200 stolen check from a man passing as a customer and are able to delay him until the police arrive . take another turn . those spaces denoted by the letter &# 34 ; f &# 34 ; contain illustrations of improper ethical and procedural conduct and require the player to return a question card that may have been acquired . examples of appropriate phrasology for these spaces are : while working on night deposits , a customer approaches , your phone rings and a co - worker asks an urgent question . you come unglued . turn in any 1 situation card . an auditor finds your cash drawer over its limit . turn in a cash question card . those spaces denoted by the letter &# 34 ; p &# 34 ; contain instructions to obtain a professionalism card . these cards may be retained and as shown in fig3 allow the player to skip a roll of the dice . they provide the player flexibility in avoiding and landing on specific spaces . the training device is used in the manner of a recreational game . to commence the training exercise each player ( at least two ) places his marker on the first space of one of the circuits which is the head of an arrow . in sequence each player rolls the dice 6 and moves his marker 8 along any one of the circuit branches the same number of spaces as he has rolled on the dice . if the marker lands on an &# 34 ; e &# 34 ;, &# 34 ; f &# 34 ; or &# 34 ; p &# 34 ; space , then the instructions on such spaces are followed . should the marker fall on a question space , then the player must take a card from the appropriate stack and answer the question . if the answer is correct , then the player is permitted to keep possession of the card . if the answer is incorrect , the next player is given the opportunity to answer the question . this passing of the card continues until one of the players provides the correct answer and that player is entitled to the card . whenever a player lands on &# 34 ; want ads &# 34 ;, he must roll a 2 or 6 in order to move on to the next branch . a player may choose to travel on any of the branches , including those which he has already covered . the preferred object of the game is for a player to obtain and maintain possession of at least one card from each subgroup or to obtain the largest number of cards . the &# 34 ; f &# 34 ; spaces require the returning of cards to their respective stacks and the &# 34 ; e &# 34 ; spaces and professionalism cards can provide a strategic advantage in obtaining specific cards . these special boxes help emphasize the importance of proper procedural and ethical conduct . they also provide an element of unexpectability to the exercise . in order to win a player must have superior knowledge and cannot win simply through &# 34 ; luck &# 34 ;. the device is extremely effective in training personnel in a positive manner . although it appears as a common game , the players absorb the subject matter by listening to the questions and answers as cards are drawn . the concentration level is naturally very high since it is important to answer questions correctly in order to win . the question cards are only obtainable by providing correct answers and never through &# 34 ; luck &# 34 ; or another player &# 39 ; s misfortune . not only is operational procedure taught but also professionalism is emphasized and rewarded . the game is versatile since it can be used by different levels of employees and be used to teach different bank functions . the game structure and objectives are dissimilar to conventional games which is important in order to achieve the teaching objectives of the device . the invention may be embodied in other specific forms within departing from the spirit or essential characteristics thereof . the present embodiments are therefore to be considered in all respects as illustrative and not restrictive , the scope of the invention being indicated by the appended claims rather than by the foregoing description , and all charges which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein .

US-27179681-A

the invention relates to a method and a device for the production of portions from at least one continuous strand of a food product , in particular for the production of meatballs . the machine comprises : an extrusion device which can deliver a continuous strand in a vertical direction , and a portioning device that includes at least one cutting system . the cutting system comprises cutting elements which can be moved transversely to the vertical direction between an open position , in which the strand passes between the cutting elements , and a closed position for cutting the strand and forming portions of the food product . in addition , each cutting system comprises ejection means for ejecting the forming portions downwards from the cutting elements . the ejection means include at least one lower channel that is fluidly connected to a compressed fluid such that compressed fluid can be injected into the lower channel when the lower channel is in a closed position . the lower channel is formed in a body of the corresponding cutting element .

the machine illustrated in the figures is intended for the production of meatball type portions from three continuous strands , said machine enabling automatic packaging of the meatballs in trays . with reference to fig1 and 3 , the machine comprises an extrusion device 1 , a portioning device and a retrieval device 2 , also known as a packaging or tray packaging device . in the present embodiment , the extrusion device 1 comprises three extrusion heads or nozzles 11 , individually referenced 11 1 , 11 2 , 11 3 , having a main vertical axis a 1 , a 2 , a 3 for the continuous extrusion of three cylindrical strands . the portioning device comprises three cutting systems 3 , individually referenced 3 1 , 3 2 , 3 3 , one cutting system being arranged below each extrusion head . the packaging device comprises an endless conveyor belt arranged below the cutting systems and intended to convey on the upper belt thereof trays b in a substantially horizontal feed direction f . the extrusion device comprises a push rod 12 , known per se , for delivering via an outlet 12 a a continuous flow of a food product , for example a minced meat flow . the outlet 12 a is connected by means of a tube 13 , for example a flexible tube , to the inlet 14 a of a distributor 14 . the distributor , known per se , equally distributes to three outlets 14 b the incoming flow of food product . the distributor is mounted on a support frame 7 . an extrusion head 11 is connected to each outlet 14 b by means of a flexible tube , represented schematically under the reference 15 in fig1 and 3 between an outlet of the distributor and the nozzle referenced 11 3 . the heads are movably mounted in vertical translation on the support frame , overhanging the conveyor . with reference to fig3 and 5 , the frame comprises two overhanging arms 71 , between which an upper plate 72 is mounted . each head is slidably mounted on a head support 73 assembled on the plate 72 . the support 73 comprises two lateral vertical members 73 a assembled on each side of a base 73 b whereby the support is assembled with the plate . said vertical members have ribs sliding in corresponding grooves of the head body 110 . each head is slidably mounted above a circular opening 72 a of the plate . the heads are mounted such that the main axes a 1 , a 2 , a 3 thereof are offset from each other in the direction f , and the horizontal direction perpendicular to the direction f . an actuating system 6 is suitable for simultaneously moving the three heads according to a vertical to - and - fro movement between a low position illustrated in fig6 a and a high position illustrated in fig6 b . this actuating system comprises an actuating bar 61 movably mounted in horizontal translation , parallel with the feed direction , between the two arms 71 . the bar is provided with a rack 62 engaging with the pinion of a motor 63 . each head is provided with an actuating piece 64 arranged perpendicular to the direction f and sliding in a vertical slot of the base 73 b of the head support . an l - shaped lever 65 is pivotally mounted on the base 73 b about an axis perpendicular to the direction f . a first arm of the lever 65 has at the end an oblong slot wherein the pin 64 for actuating the head is inserted , and the second arm thereof is connected via a piece to the bar 61 . the horizontal to - and - fro movement of the bar by the motor 63 triggers , via the levers , the vertical to - and - fro movement of the heads . the motor is suitable for being controlled to move the bar between the right position , illustrated in fig6 a wherein the heads are in a low position , and a left position , illustrated in fig6 b , wherein the heads are in the high position . each extrusion head 3 is associated with a cutting system 3 for cutting the continuous strand delivered by said head into portions . each cutting system is a diaphragm type system , having a central passage closing and opening progressively . with reference to fig8 to 11 , each cutting system 3 comprises in this case six cutting elements 30 mounted in sliding contact with each other in the recess 41 of a support housing 40 . each cutting element is formed from a body having a general hexahedral shape , comprising an upper surface 31 and a lower surface 32 , mutually parallel and overall trapezoidal , and four vertical lateral surfaces . of these four lateral surfaces , a first surface and a second surface which are adjacent , referred to as inner sliding surfaces 33 , 34 join along an edge 35 . a first outer surface 36 forms an edge with the second inner sliding surface 34 and extends parallel with the first inner sliding surface 33 . the second outer surface 37 , referred to as the outer sliding surface , forms an edge with the inner sliding surface , optionally via a chamfered edge 38 . the recess 41 has a hexagonal side wall 42 and a rear wall 43 provided with a through central circular opening 44 . the cutting elements are mounted in the recess of the housing , each cutting element is in sliding contact via the lower surface 32 thereof against the rear wall 43 of the recess , and via the outer sliding surface 37 thereof against one face of the side wall 42 . the cutting elements are in sliding contact with each other via the inner sliding surfaces 33 , 34 thereof , each cutting element being in contact via the first inner sliding surface thereof with the second inner sliding surface of an adjacent element and via the second inner sliding surface thereof with the first inner sliding surface of the other adjacent element . in a so - called open position of the cutting system , as illustrated in fig6 a , the cutting elements are in contact against the wall of the recess via the outer surfaces 36 , 37 thereof , a central passage is formed by the exposed parts of the first inner sliding surfaces 33 of the cutting elements . the passage has in this open position a sufficient cross - section so that the extruded strand can pass , without contact with the cutting elements . the sliding of the cutting elements along the faces of the side wall of the recess gives rise to a progressive reduction of the central passage until the closure of said passage in a so - called closed position of the cutting system , illustrated in fig6 b and 12 , wherein the cutting elements come substantially into contact with each other via the edge 35 thereof . the cutting system is maneuvered from the closed position to the open position by moving one of the cutting elements , referred to as the driving cutting element , along the side wall by means of an actuating piece 39 attached to the outer sliding surface , by means of screws screwed into an insert 30 a , housed in a recess of said cutting element , said piece sliding in a slot 45 of the side wall of the recess of the housing . the sliding via the piece of said driving cutting element results in sliding of the other cutting elements . in the present embodiment , each cutting element has a pointed shape towards the edge 35 thereof . the angle formed by the two inner sliding surfaces 33 , 34 and the upper surface 31 is cut to form an upper inclined surface 31 a . similarly , the angle formed by the two inner sliding surfaces 33 , 34 and the lower surface 32 is cut to form a lower inclined surface 32 a . these lower and upper inclined surfaces have a concave shape in this instance , such that in the closed position , the lower inclined surfaces form a lower cavity with a semi - spherical surface or a spherical segment surface , and the upper inclined form a cavity with a semi - spherical surface or a spherical segment surface . each cutting element thus has an edge 35 having a reduced height in relation to the height of the cutting element which is defined between the upper surface and the lower surface . these cutting elements with a pointed portion enable more progressive clamping of the strand at the end of closure of the central passage and shaping of the portions . the cutting systems 3 are assembled with the upper plate 72 , against the lower surface thereof . for the assembly thereof , the cutting systems are mounted for example by means of screws between the upper plate and a lower plate 74 , the whole being attached to the arms via the lower plate . each cutting system is centred in relation to the main axis of a head , an opening 72 a of the upper plate , and an opening of the lower plate . the cutting systems 3 and the heads 11 are moved in synchronicity , such that the cutting systems are in the open position when the heads are in the low position , and in the closed position when the heads are in the high position . the cutting systems are in this instance moved between the two positions thereof by means of the actuating system 6 used for moving the heads , the pieces 39 of the driving cutting elements of the three cutting systems being assembled with the actuating bar 61 mentioned above . according to the invention , each cutting system further comprises ejection means for ejecting the portions downwards when the cutting systems are in the closed position . these ejection means are in this instance pneumatic , and comprise injection channels 5 or lower channels formed in the cutting elements . with reference to fig9 to 12 , each cutting element comprises a channel 5 opening via a lower orifice 51 onto the concave lower inclined surface 32 a and opening via a connection orifice 52 onto the upper surface 31 . the channel comprises a first segment 53 extending from the connection orifice 52 , perpendicular to the upper surface , and extended by a second segment 54 to the lower inclined surface . with reference in particular to fig4 and 7b , the connection orifice is connected to an air injection system ( not shown ) by a flexible tube ( not shown ), this connection being made by means of a connector 55 ( fig4 ). to enable the movement of the cutting elements , the upper plate is provided with slots 75 wherein the connectors slide . the air injection system is suitable for injecting air into said channels 5 , via the flexible tubes , when the cutting systems are in the closed position , to form an air flow from the lower orifices . according to one embodiment , this air injection commences immediately before the cutting systems have reached the closed position thereof , and is discontinued immediately after the cutting systems have started to return to the open position thereof . in the present embodiment , said second segment 54 is inclined and forms an angle that is different to zero in relation to the horizontal , such that the air flow from the channel is directed downwards , the segment forming for example an angle of approximately 10 ° in relation to the horizontal . a guiding system is further provided under each cutting system to guide the portions on the dropping thereof . fig3 a and 7a illustrate a guiding system 8 associated with a cutting system . this guiding system comprises cylindrical rods 81 , for example three in number , extending downwards from the cutting system while moving same closer to each other to form together a passage centred along the main axis of the head associated with the cutting system , and wherein the cross - section decreases from top to bottom . the rods are arranged at regular angular intervals and comprise an inclined segment extending from the cutting system while approaching the main axis and a vertical segment parallel with the main axis , the cross - section of the passage at these segments corresponding substantially to the cross - section at the strand diameter . the conveyor 2 comprises an endless belt , on the upper belt whereof trays are positioned , in succession . in the present embodiment , the trays comprise three rows of meatballs , the rows being parallel with the feed direction . each cutting system associated with an extrusion head forms the meatballs for one row of the tray . preferably , the trays are trays including compartments , each compartment being intended to receive one meatball . the tray has bosses separating the compartments from each other , said bosses serving to guide the meatballs towards the compartments on the dropping thereof and also for holding the meatballs in the compartments when the trays are put on sale , after sealing , in an inclined position at substantially 45 °. in operation , each head extrudes a strand of a food product continuously in the vertical direction . the heads being in the low position , and the cutting systems in the open position , the strands pass through the central passage of the cutting systems and extend beyond said cutting systems . the cutting systems are moved by the actuating system 6 towards the closed position thereof in order to progressively clamp the strands . simultaneously , the heads are moved towards the high position thereof such that the feed rate of the strand in contact with the cutting systems is zero . just before the cutting systems reach the closed position thereof , air is injected into the lower channels . the meatballs formed are thus ejected from the lower cavities . the meatballs ejected from the cutting systems are guided by the guiding systems 8 into the empty compartments of the trays . the cutting systems are moved to the open position thereof and simultaneously the heads are returned to the low position , in order to pass the strands through the central passages such that they extend below the cutting systems to form the next meatballs . simultaneously , the trays are moved forward by one step by the conveyor to position the next empty compartments of the rows to be filled in the trays below the cutting systems . air injection into the channels is preferably stopped during this movement of the cutting systems from the closed position to the open position . fig1 illustrates the cutting elements 130 of a cutting system 103 according to one alternative embodiment , suitable for use in the machine described above instead of the cutting systems 3 . as above , the cutting system 103 comprises cutting elements 130 mounted in sliding contact with each other in the recess of the support housing ( not shown ). with reference to fig1 to 16 , each element is formed from a body having a general hexahedral shape , comprising an upper surface 131 and a lower surface 132 , a first inner sliding surface 133 and second inner sliding surface 134 joined along an edge 135 , a first outer surface 136 , and a second outer sliding surface 137 . each cutting element also has a concave upper inclined surface 131 a and a concave lower inclined surface 132 a . the cutting system is maneuvered between the closed position thereof and the open position thereof via a driving cutting element , as above . each cutting element comprises in this instance a plurality of so - called lower injection channels 105 , opening via lower orifices 151 onto the lower inclined surface 132 a for ejecting the portions , and a plurality of so - called upper injection channels 109 opening via upper orifices 191 onto the upper inclined surface 131 a in order to form an air cushion at said upper inclined surface and prevent the strand from adhering to said surface , particularly on opening the central passage . the upper 109 and lower 105 channels are formed in an insert 146 housed in a recess 130 b opening onto the upper inclined surface 131 a and onto the lower inclined surface 132 a . the insert 146 comprises an upper part 147 , having a concave outer surface 147 a and an inner surface 174 b , a lower part 148 having a concave outer surface 148 a and an inner surface 148 b , and a central part 149 connecting the upper part and the lower part together via the inner surfaces 147 b , 148 b thereof . the upper channels 109 are formed in the upper part 147 , and open onto the inner surface 147 a thereof via orifices 192 and onto the outer surface 147 a via the upper orifices 191 . the lower channels 105 are formed in the lower part 148 , opening onto the inner surface 148 b thereof via orifices ( not shown ), and onto the outer surface 148 a thereof via the lower orifices 191 . when the insert 146 is housed in the recess 130 b thereof , the outer surfaces 147 a , 148 a of the upper and lower parts form a continuous concave surface respectively with the upper inclined surface 131 a and the lower inclined surface 132 a , and the upper and lower channels are arranged perpendicular to the upper and lower surfaces of the cutting element . for the vertical hold of the insert , the upper part 147 comprises a shoulder 147 c bearing against a shoulder of the recess 130 b . these upper and lower channels are supplied with air by the same so - called main channel 155 . the main channel 155 opens via a connection orifice 152 on the upper surface and via an orifice 156 ( fig1 ) in the recess 130 b , said orifice being arranged between the inner surfaces 147 b , 148 b of the insert . the main channel comprises a first segment 153 extending from the connection orifice 152 , perpendicular to the upper surface , and extended by a second segment 154 to the recess 130 b . the connection orifice is equipped with a connector 155 for the connection thereof to an air injection system by means of a flexible tube . once mounted in the housing thereof , the cutting elements have lower 105 and upper 109 channels arranged vertically , for respectively creating downward vertical air flows for ejecting the portions and upward vertical air flows for preventing the strand from adhering to the cutting elements . the air injection system is suitable for injecting air into said lower and upper channels , via the main channel , when the cutting systems are in the closed position . the air injection commences immediately before the cutting systems have reached the closed position thereof , and is discontinued immediately after the cutting systems have started to return to the open position thereof . according to one alternative embodiment , the insert 146 provided with upper and lower channels is replaced by an insert made of porous material , for example made of plastic or sintered metal , in particular sintered stainless steel , allowing fluid to pass . although the invention has been described in relation to one particular embodiment , it is obvious that it is in no way restricted and that it includes any technical equivalents of the means described and the combinations thereof if they fall within the scope of the invention . the machine according to the invention may also be used for the production of filled portions comprising an outer layer of a main material encompassing an inner layer of a filling material , the extrusion heads comprising two inlets for the coextrusion of the main material and the filling material . in the embodiment illustrated , the extrusion heads comprise a side inlet , and a central inlet sealed in this instance by a cap . for coextrusion , the cap is removed and a conduit is mounted in the main passage of the head body . the side inlet is fed as above by the push rod 12 and the distributor 14 , with the main material . the conduit is fed with filling material via a second push rod associated with a second distributor . the connection of the conduit to an outlet of the distributor is also performed by means of a flexible conduit to enable the movement of the extrusion heads vertically to - and - fro . fig1 a and 17b illustrate such a spherical filled portion , or filled ball , obtained with coextrusion heads , and cutting systems illustrated in the figures . fig1 a and 18b illustrate an elongated filled portion that may also be obtained using the cutting systems illustrated in the figures , timing for example the return of the coextrusion heads to the high position thereof when they are in the low position , so as to obtain longer portions . fig1 a and 19b illustrate a filled portion suitable for being obtained with cutting systems comprising cutting elements wherein the lower inclined portions form a lower cavity of a different shape to that illustrated in the figures , and with no upper inclined portions .

US-201314385749-A

the disclosure relates to a nose splint usable to erect the lateral walls of the bony vault of the nose in a precise manner upon fracture thereof due to accident or rhinoplasty .

as best seen in fig2 the human nose 10 comprises the bony vault 12 , the upper cartilaginous vault 14 and the lower cartilaginous vault 16 . the vaults 12 , 14 and 16 have a common supporting partition , the bony and cartilaginous septum 18 . the bony vault 12 is made up of upward projections of the frontal process of the maxilla 20 , from which a pair of nasal bones 21 and 22 extend to form an arch at the union thereof . the upper cartilaginous vault 14 is made up of paired , triangular cartilages 31 and 32 that extend from the bony vault 12 and are attached along the dorsal border of the septum by a dense fibrous union . the cartilages 31 and 32 are attached to the undersurface of the lateral walls of the bony vault 12 by a membrane . the dorsal segment 23 or upper edge of the upper cartilaginous vault 14 is a bridge that connects the two upper lateral cartilages 31 and 32 . the lower cartilaginous vault 16 forms the base of the nose 10 and is made up of tissues caudal to the free edge of the upper lateral cartilages 31 and 32 . the lower vault 16 shares with the vaults 12 and 14 the dorsal edge 23 of the septum 18 and the connective tissue attachments to the upper lateral cartilages 31 and 32 . upon the occurrence of an accident or incident to rhinoplasty , the septum 18 is separated from the dorsal edge 23 of the bony and cartilaginous vaults 12 and 14 . until healing occurs , the cartilaginous vaults 12 and 14 collectively define an open pyramid and must rely on the remaining attachment to the nasal bones 21 and 22 for their support and lateral distraction . in order to close the open pyramid or reconstruct a smaller pyramid , the nasal bones 21 and 22 must be positively supported at their bases . therefore , the nasal bones 21 and 22 are fractured to reform the nasal pyramid 10 . as best seen in fig3 and 5 , a splint 40 in accordance with a constructed embodiment of the instant invention , is made from relatively ductile metallic sheet material , for example , aluminum which inherently also has some degree of flexibility and resiliency . the splint 40 is cut to the configuration best seen in fig4 comprising an elongate bridge portion 42 of inverted u - shape in cross section and contoured to conform at least generally to the outer configuration of the human nose ( fig3 ) with elongated wing portions 44 and 46 extending laterally from the base thereof . the bridge portion 42 is of pyramid configuration in the sense that it comprises a broad - base structure that disposes the lower side edges of the bridge portion against the patient &# 39 ; s cheeks at the base of the nose , as also shown in fig3 and it is provided with a series of spaced slits 48 and 50 at the top and bottom thereof to faciliate forming the contour of the bridge to a particular patient &# 39 ; s nose . it is to be noted that the wings 44 and 46 are tapered and displaced downwardly , as seen in fig4 from the center of the bridge 42 to maximize a patient &# 39 ; s visual capability and they incline slightly upwardly from the lower side edges of the bridge portion 42 as shown in fig5 so that in the normal unstressed condition the wings clear or are spaced from the patient &# 39 ; s cheeks . as been seen in fig5 the bridge portion 42 is arched , the underside of the arch being padded with a layer of foam rubber 52 . the wings 44 and 46 have reentrantly folded lower edge flanges 60 and 62 that function to stiffen the wings 44 and 46 and provide for positioning of the line of action of an external elastic 63 , as will be described . the stiffening flanges 60 and 62 are folded about axes extending at substantially right angles to the axis of folding of the apex of the bridge portion 42 and they have fingers 64 and 66 extending therefrom , respectively , for the acceptance of a gauze supporting rubber sling 68 . pointed outer end portions or extensions 70 and 72 here shown on the stiffening flanges 60 and 62 of the wings 44 and 46 have barbs 74 and 76 thereon for penetration and retention of the end portions 78 and 80 of the elastic band 63 that extends from the points 70 and 72 under the patient &# 39 ; s neck and the extensions 70 and 72 are bendable transversely of the wings to adjust and control the area of the patient &# 39 ; s nose at which the elastic band 63 concentrates pressure imposed by the bridge 42 and to place a pre - determined downward pressure on the wings 44 and 46 which causes the lower edges of the bridge portion 42 to press against the patient &# 39 ; s cheeks at the base of the nose . in practice , tincture of benzoine is applied to the forehead and nasal bridge of the patient and allowed to dry . surgical tape is then applied to the nasal skin after which the splint of the instant invention is superimposed over the patient &# 39 ; s nose . the line of pressure of the splint on the nose is controlled by increasing or decreasing the angle of the reentrantly folded portions 60 and 62 of the wings 44 and 46 thereby to move the pointed end portions 70 and 72 upwardly or downwardly ; viz ., longitudinally with respect to the bridge portion 42 , as seen in fig4 of the drawing . it is to be noted that the relatively long lever arms provided by the wings 44 and 46 cause the lower edges of the bridge portion 42 to apply what may be termed a pinching action downwardly against the patient &# 39 ; s cheeks and inwardly against the base of the nose through the padding layer 52 , thereby to apply controlled pressure on the base of the nasal pyramid . both the degree of pinching and total downward pressure of the splint is adjusted by first attaching one end of the elastic strap over either the point 70 or 72 of the splint 40 . the elastic strap 63 is passed behind the patient &# 39 ; s head and under the ears and stretched approximately 2 . 5 centimeters . another slit is cut in the strap 63 at the point of engagement with the opposite wing , after which the strap 63 is engaged therewith . stretching or extension of the elastic strap 63 in the manner described exerts a bias on the wings 44 and 46 to press the foam rubber lining 52 at the juncture of the bridge 42 and the wings 44 and 46 against the patient &# 39 ; s cheeks adjacent to the nose and simultaneously to contract the bridge portion 42 so as to reduce the base dimension of the pyramid defined by the bridge portion and thereby exert a pinching action against the nose at the juncture thereof with the patient &# 39 ; s cheeks as perhaps best shown in fig3 . gauze is held in place under the patient &# 39 ; s nose by placing a pad sized approximately 1 inch by 4 inch under the nostrils and thereafter attaching the rubber sling 68 to the tabs 64 and 66 on the wings 44 and 46 . from the foregoing it should be apparent that the splint of the instant invention provides for a plurality of adjustments to assure proper positioning and retention of the bones of the nasal pyramid , as well as to provide for adjustment of the lines of force of the supplementary resilient members at the base and at opposite sides of the nose so as to prevent or at least inhibit bleeding into the operated area in the case of rhinoplasty . at the same time , the padding layer 52 at the juncture of the bridge portion 42 and the wings 44 and 46 provides a soft or yielding pressure that prevents pressure sores from developing at and along the lines of force . adjustment is easily achieved by field bending of the splint 40 both to the particular contours of a patient &# 39 ; s face and to accommodate the particular fracture or surgical process . while it will be apparent that the preferred embodiment of the invention disclosed is well calculated to fulfill the objects above stated , it will appreciated that the invention is susceptible to modification , variation and change without departing from the proper scope of fair meaning of the subjoined claims .

US-22200181-A

the present invention is a cosmetic or dermatological formulation , comprising iminodisuccinic acid or a salt thereof and a polyol , and a method of applying same to the skin to moisturize the skin . the present invention also includes methods of increasing the skin - moisturizing properties of polyols by using iminodisuccinic acid or a salt thereof .

according to the invention , the iminodisuccinic acid or its salts are used to increase the skin - moisturizing action of polyols . according to the invention , the increase in the skin - moisturizing action of polyols is at least 25 % if 2 hours have passed after application of the formulation to the skin and if the skin moisture content is determined as follows : measurement conditions : 21 ° c .± 1 ° c . and 50 ± 5 % atmospheric humidity at least 15 min acclimatization time the cosmetic or dermatological formulations according to the invention can advantageously be used as skin care products , as face care products and as sunscreen compositions . in the context of the invention , “ skin care products ” are understood here as meaning , inter alia , skin creams , skin lotions , milks , ointments , oils , balsams and sera which are used for care of the skin . face care products are used as a special form of skin care products for care of facial skin . they are used in particular to prevent developing or to reduce already existing wrinkles and folds . according to the invention , face care products also include decorative cosmetics , the main purpose of which is to change the color of skin and skin appendages ( e . g . eyelashes , eyebrows ). sunscreen compositions in the context of the invention are to be understood as meaning all forms of formulations which comprise at least one uv light protection filter . they furthermore include so - called “ aftersun products .” these are intended to cool the skin after sunbathing and to improve its moisture retention capacity , the imparting of the cooling effect playing a central role . this cooling effect is as a rule achieved by large amounts of ethanol and water , which evaporates spontaneously when the formulation is spread on the skin . the preparations furthermore usually comprise moisturizing agents , such as glycerol or propylene glycol , and anti - inflammatory compounds , such as , for example , allantion , α - bisabolol , panthenol or aloe vera extract . the following examples are intended to illustrate the present invention without limiting it . unless stated otherwise , all the amounts data , contents and percentage contents are based on the weight and the total amount or on the total weight of the formulations . [ 0024 ] w / o emulsions 1 2 3 4 5 triglycerol diisostearate 1 . 0 0 . 5 0 . 25 2 . 0 3 . 0 diglycerol dipolyhydroxystearate 1 . 0 1 . 5 1 . 75 3 . 0 2 . 0 paraffin oil 12 . 5 10 . 0 8 . 0 5 . 0 17 . 5 vaseline 8 . 0 6 . 0 5 . 0 12 . 0 2 . 5 hydrogenated coconut glycerides 2 . 0 1 . 0 2 . 5 5 . 0 0 . 25 decyl oleate 0 . 5 0 . 75 1 . 0 2 . 0 0 . 25 octyldodecanol 0 . 5 1 . 0 0 . 75 3 . 0 0 . 25 aluminum stearate 0 . 4 0 . 3 0 . 6 1 . 0 0 . 05 dicaprylyl carbonate 0 . 1 0 . 05 0 . 15 0 . 5 1 . 0 hydrogenated castor oil 0 . 5 0 . 75 1 . 0 2 . 5 5 . 0 iminodisuccinic acid 0 . 5 — — — 0 . 1 magnesium sulfate 0 . 5 0 . 6 0 . 5 0 . 7 1 . 0 glycerol 3 . 0 5 . 0 10 . 0 15 . 0 1 . 5 tetrasodium iminosuccinate — 0 . 6 1 . 5 0 . 4 — perfume q , s . q , s , q , s , q , s , q , s , ethanol 2 . 0 — 5 . 0 — — caprylic / capric acid triglyceride 2 . 0 2 . 5 3 . 0 5 . 0 0 . 5 methyl paraben 0 . 4 0 . 15 0 . 05 0 . 3 0 . 4 propyl paraben 0 . 3 0 . 4 0 . 25 0 . 15 — iodopropynyl butyl carbamates — — 0 . 05 — 0 . 1 water to 100 to 100 to 100 to 100 to 100 6 7 8 9 10 peg - 30 dipolyhydroxystearate — 0 . 5 0 . 25 — 3 . 0 lanolin alcohol 1 . 0 1 . 5 1 . 75 3 . 0 — paraffin oil 12 . 5 10 . 0 8 . 0 5 . 0 17 . 5 vaseline 8 . 0 6 . 0 5 . 0 12 . 0 2 . 5 hydrogenated coconut glycerides 2 . 0 1 . 0 2 . 5 5 . 0 0 . 25 hydrogenated polyisobutene 0 . 5 0 . 75 1 . 0 2 . 0 0 . 25 octyldodecanol 0 . 5 1 . 0 0 . 75 3 . 0 0 . 25 aluminum stearate 0 . 4 0 . 3 0 . 6 1 . 0 0 . 05 dicaprylyl carbonate 0 . 1 0 . 05 0 . 15 0 . 5 1 . 0 hydrogenated castor oil 0 . 5 0 . 75 1 . 0 2 . 5 5 . 0 sorbitol 12 . 5 1 . 0 0 . 75 0 . 25 0 . 1 magnesium sulfate 0 . 5 0 . 6 0 . 5 0 . 7 1 . 0 glycerol — 5 . 0 — 15 . 0 5 . 5 tetrasodium iminosuccinate 1 . 5 0 . 6 3 . 0 0 . 4 1 . 0 perfume q , s , q , s , q , s , q , s , q , s , 1 , 3 - butylene glycol — — 5 . 0 — 7 . 5 caprylic / capric acid triglyceride 2 . 0 2 . 5 3 . 0 5 . 0 0 . 5 methyl paraben 0 . 4 0 . 15 0 . 05 0 . 3 0 . 4 propyl paraben 0 . 3 0 . 4 0 . 25 0 . 15 — water to 100 to 100 to 100 to 100 to 100 w / s emulsion 11 12 13 14 15 cetyl dimethicone copolyol 1 . 0 — — 3 . 0 5 . 0 cyclomethicone + dimethicone copolyol 10 . 0 12 . 5 25 — — cyclomethicone 12 . 5 15 28 . 0 25 . 0 17 . 5 dimethicone 5 . 0 13 . 0 5 . 0 12 . 0 15 . 0 hydrogenated polyisobutene 0 . 5 0 . 75 1 . 0 2 . 0 0 . 25 octyldodecanol 0 . 5 1 . 0 0 . 75 3 . 0 0 . 25 panthenol 0 . 5 1 . 0 0 . 75 0 . 25 0 . 1 magnesium chloride 2 . 0 0 . 6 2 . 5 0 . 7 1 . 0 glycerol 25 . 0 5 . 0 10 . 0 15 . 0 57 . 5 tetrasodium iminosuccinate 0 . 6 0 . 1 1 . 2 0 . 15 5 . 0 perfume q , s , q , s , q , s , q , s , q , s , methyl paraben 0 . 4 0 . 1 0 . 05 0 . 3 0 . 4 butylene glycol — 5 . 0 — — 7 . 5 propyl paraben 0 . 3 0 . 4 0 . 25 0 . 15 — cetyldimethicone 0 . 5 — 0 . 7 — — iodopropynyl butyl carbamate — — 0 . 05 — 0 . 1 modified starch — 2 . 5 — 0 . 15 — water to 100 to 100 to 100 to 100 to 100 o / w emulsions 16 17 18 19 20 glyceryl stearate citrate 2 — — — — glyceryl stearate — 5 2 3 — peg - 40 stearate — — 1 — — triglycerol methylglucose distearate — — — — 3 sorbitan stearate — — — — 1 cetearyl glucoside — — — 2 — behenyl alcohol — — — — 1 stearyl alcohol 2 1 — — — cetylstearyl alcohol — — 2 — — hydrogenated coconut fatty glycerides 2 — — 1 — shea butter — 2 — — — butylene glycol dicaprylate / dicaprate 1 — — — — caprylic / capric triglyceride — 4 — — 1 ethylhexyl coconut fatty acid ester 3 — — — — octyldodecanol — — 5 8 — mineral oil 8 1 — — 5 tetrasodium iminosuccinate 1 0 . 5 2 . 5 0 . 3 0 . 75 vaseline 4 — — 2 — octamethyltetrasiloxane 5 1 3 1 3 dimethylpolysiloxane — 3 1 3 2 dicarprylyl carbonate 10 1 8 5 2 glycerol 3 . 0 — 25 12 . 5 30 butylene glycol 18 15 — — — methyl paraben 0 . 3 — — 0 . 2 0 . 4 iodopropynyl butyl carbamates 0 . 1 0 . 2 0 . 2 0 . 05 — perfume q . s . q . s . q . s . q . s . q . s . water to 100 to 100 to 100 to 100 to 100 21 22 23 24 25 glyceryl stearate citrate 5 — — — — glyceryl stearate — 5 — — — peg - 40 stearate — 2 — — — polyethylene glycol ( 21 ) stearyl ether — — 2 — — polyethylene glycol ( 2 ) stearyl ether — — 1 — — cetearyl glucoside — — — 2 — stearic acid — — — — 2 . 5 behenyl alcohol — — — — 2 stearyl alcohol 2 1 — 5 — cetylstearyl alcohol — — 2 — 1 hydrogenated coconut fatty glycerides 2 — — 3 1 shea butter — 2 — 3 — butylene glycol dicaprylate / dicaprate 1 — 8 — 2 caprylic / capric triglyceride — 4 2 — — ethylhexyl coconut fatty acid ester 3 6 — — 2 octyldodecanol — — 1 9 — mineral oil 9 1 1 1 3 vaseline 4 2 5 0 . 5 0 . 75 glycerol 7 . 5 15 65 25 — sorbitol 3 . 5 — — — 15 tetrasodium iminosuccinate 1 0 . 5 2 . 5 1 . 25 0 . 75 octamethyltetrasiloxane — 1 2 5 — dimethylpolysiloxane 0 . 5 0 . 75 1 . 25 — 1 dicarprylyl carbonate 6 2 10 0 . 5 4 methyl paraben 0 . 3 — 0 . 1 — 0 . 05 iodopropynyl butyl carbamate 0 . 1 0 . 2 0 . 1 0 . 2 0 . 15 perfume q . s . q . s . q . s . q . s . q . s . water to 100 to 100 to 100 to 100 to 100

US-79091004-A

a pharmaceutical composition for topical administration including 2 , 3 - dimethyl - 6 -- 6h - indolo - quinoxaline or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier . the composition is useful for the treatment of herpes virus infections of the skin or mucous membranes in a mammal subject .

and may be prepared e . g . as described in wo87 / 04436 , the contents of which is incorporated herein by reference . pharmaceutically acceptable salts of b - 220 may be formed using any organic or inorganic , pharmaceutically acceptable acid , such as are well - known to the person of ordinary skill in the art . pharmaceutically acceptable acid addition salts according to the invention are salts that are safe and effective for topical use in mammals and that possess the desired biological activity , e . g . hydrochloride , hydrobromide , hydroiodide , nitrate , sulfate , bisulfate , phosphate , acid phosphate , isonicotinate , acetate , lactate , salicylate , citrate , tartrate , pantothenate , bitartrate , ascorbate , succinate , maleate , gentisinate , fumarate , gluconate , glucaronate , saccharate , formate , benzoate , glutamate , methanesulfonate , ethanesulfonate , benzensulfonate , or p - toluenesulfonate salts . the pharmaceutical composition of the invention comprises b - 220 and at least one pharmaceutically acceptable excipient . in one embodiment of the invention , the pharmaceutical composition comprises b - 220 or a pharmaceutically acceptable salt thereof in a pharmaceutical carrier suitable for topical delivery of the active ingredient . in one embodiment , the pharmaceutical composition comprises b - 220 or a pharmaceutically acceptable salt thereof and an additional therapeutically active ingredient , suitable for topical administration , e . g . selected from antiviral agents , antibiotics , anaesthetic agents , analgesic agents , antiphlogistic agents and anti - inflammatory agents . in one embodiment , the additional therapeutically active ingredient comprises or is an antiviral agent . the antiviral agents suitable for the purposes of the present invention are topically acceptable antiviral compounds , which in addition to being specific inhibitors of herpes virus multiplication also are active after topical administration and in addition are pharmaceutically acceptable for topical administration . this means that the toxicity of the antivirals must be sufficiently low to allow for a continuous contact with the human body and in particular with the skin and mucous membranes . examples of antiviral agents are substances within the group comprising compounds acting on viral dna polymerase , such as nucleoside analogues after phosphorylation to their triphosphate forms ; phosphonoformic and phosphonoacetic acids and their analogues ; and other antiviral compounds having a different mechanism of action . as examples of antiviral agents which can be used in the combination of the invention can be mentioned acyclovir ( acv ), acv - phosphonate , brivudine ( bromovinyldeoxyuridine , bvdu ), carbocyclic bvdu , buciclovir , cdg ( carbocyclic 2 ′- deoxyguanosine ), cidofovir ( hpmpc , gs504 ), cyclic hpmpc , desciclovir , edoxudine , famciclovir , ganciclovir ( gcv ), gcv - phosphonate , genivir ( dip - 253 ), h2g ( 9 -[ 4 - hydroxy - 2 -( hydroxy - methyl ) butyl ]- guanine ), hpmpa , lobucavir ( bishydroxymethylcyclobutylguanine , bhcg ), netivudine ( zonavir , b w882c87 ), penciclovir , pmea ( 9 -( 2 - phosphonylmethoxy - ethyl ) adenine ), pmedap , sorivudine ( brovavir , bv - arau ), valacyclovir , 2242 ( 2 - amino - 7 -( 1 , 3 - dihydroxy - 2 - propoxymethyl ) purine ), hoe 602 , hoe 961 ; bpfa ( batyl - pfa ), paa ( phosphonoacetate ), pfa ( phosphonoformate ); arildone , amantadine , bild 1263 , civamide ( capsaicin ), crt , isis 2922 , peptide t , tromantadine , virend , 1 - docosanol ( lidakol ) and 348u87 ( 2 - acetylpyridine - 5 -[ 2 - chloro - anihno - thiocarbonyl ]- thiocarbono - hydrazone ). preferred antiviral agents are those with specific antiviral activity such as herpes specific nucleoside analogues which are preferentially phosphorylated in virus - infected cells and have very low or non - existent incorporation into cellular dna as well as other compounds with specific antiviral activity . acyclovir , for instance , has a selectivity ratio for the inhibitory activity against hsv - 1 in vitro of about 2000 . among said preferred substances can in addition to acyclovir be mentioned brivudine , cidofovir , desciclovir , famciclovir , ganciclovir , hoe 961 , lobucavir , netivudine , penciclovir , pmea , sorivudine , valacyclovir , 2242 , bpfa , pfa , paa . a suitable antiphlogistic agent , i . e . an agent capable of reducing inflammation , pain and / or fever , e . g . may be a non - steroidal anti - inflammatory drug ( nsaid ), such as diclofenac ( iupac name 2 -( 2 , 6 - dichloranilino ) phenylacetic acid ), or ibuprofen , ( iupac name ( rs )- 2 -( 4 -( 2 - methylpropyl ) phenyl ) propanoic acid ), or a pharmaceutically acceptable salt thereof , e . g . a sodium , potassium or diethylamine salt thereof . a suitable anaesthetic agent e . g . may be lidocaine ( iupac name 2 -( diethylamino )- n -( 2 , 6 - dimethylphenyl ) acetamide ). a suitable antiinflammatory agent e . g . may be adenosine ( iupac name : ( 2r , 3r , 4s , 5r )- 2 -( 6 - amino - 9h - purin - 9 - yl )- 5 -( hydroxymethyl ) oxolane - 3 , 4 - diol . the antiinflammatory agent also may be selected from antiinflammatory glucocorticoids . a suitable glucocorticoid can be either naturally occurring or synthetic and can be selected from any of the group i - id glucocorticoids , according to a classification system for topical glucocorticoids used in the nordic countries , corresponding to less potent , low or moderately potent glucocorticoids . examples of glucocorticosteroids are alclometasone , amicinonide , beclomethasone , betamethasone , budesonide , ciclesonide , clobetasone , clocortolone , cloprednol , cortison , desonide , desoximethasone , dexamethasone , diflorosane , diflucortolone , difluprednate , fludrocortisone , fludroxycortid , flumethasone , flunisolide , fluocinolone acetonide , fluocinonide , fluocortin , fluocortolone , fluprednidene , fluticasone , halcinonide , halobetasol , halometasone , hydrocortisone , methylprednisolone , mometasone , paramethasone , prednisolone , prednicarbate , prednisone , prednylidene , rofleponide , tipredane and triamcinolone and their esters , salts and solvates , that is hydrates , where applicable . some preferred glucocorticoids are hydrocortisone , alclometasone , desonide , fluprednidene , flumethasone , hydrocortisone butyrate , clobetasone , triamcinolone acetonide , betamethasone , budesonide , desoximethasone , diflorosane , fluocinolone , fluocortolone , fluticasone , methylprednisolone aceponate , mometasone and rofleponide ; in particular hydrocortisone , budesonide and fluticasone . a suitable antibiotic e . g . may be selected from clindomycin , erythromycin , mupirocin , bacitracin , polymyxin and neomycin . the carrier of the pharmaceutical composition should be stable and pharmaceutically acceptable and suitable for topical application . it should also enable incorporation of sufficient amounts of b - 220 or of the pharmaceutically acceptable salt thereof , and optionally additional active ingredient ( s ). in addition to conventional ingredients in creams , lotions , gels or ointments , aerosolizable liquids , and foams , compositions based on phospholipids , including sphingolipids can be advantageous . in a cream or ointment formulation the carrier may be white petrolatum . a liquid carrier may include water , alcohols or glycols or water - alcohol / glycol blends , in which effective amounts of the active ingredient ( s ) according to the invention can be dissolved or dispersed , optionally with the aid of non - toxic surfactants . adjuvants such as fragrances and antimicrobial agents can be added to optimize the properties for a given use . thickeners such as synthetic polymers , fatty acids , fatty acid salts and esters , fatty alcohols , modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes , gels , ointments , creams etc ., for application directly to the skin and / or mucous membrane of the user . a pharmaceutical composition of the invention can be used for the prophylaxis and / or treatment of herpes virus infections in mammals including man . in a preferred embodiment the composition is used for the treatment of primary or recurrent herpes virus infections . the treatment of infection should take place during the virus replication , preferably from the first appearance of redness / lesion or prodromal symptoms and for a period of 3 - 4 days at least . the formulation may be repeatedly applied , e . g . up to every two hours , during the whole episode until healing . prophylactic treatment may be performed in patients having regularly recurrent disease . in this case the formulation is applied to the area where a recurrence is expected before the appearance of the first symptoms . the compositions of the invention can be used to treat all types of herpes virus that replicate in the skin or the mucous membrane , e . g . hsv - 1 , hsv - 2 and vzv . the pharmaceutical compositions for topical administration according to the present invention are preferably creams , lotions , gels , sprays , foams , ointments or drops . the pharmaceutical compositions can be incorporated into plasters or patches to be applied to the skin of a patient to be treated for herpes infections or into pens or sticks for application to the skin or mucous membranes . liquid compositions can be applied from absorbent pads , used to impregnate bandages and other dressings , or sprayed onto the affected area using pump - type or aerosol sprayers . topical administration refers in this context to dermal or mucosal administration to the skin or mucous membrane . the person of ordinary skill in the art will be well able to select suitable excipients in view of the selected formulation and form of administration , referring to e . g . handbooks such as remington : the science and practice of pharmacy 21st edition . philadelphia , pa . lippincott williams & amp ; wilkins . 2005 . in embodiments where a glucocorticoid is included in the pharmaceutical composition of the invention , care must be taken to define the optimal dose of the respective components , due to the herpes virus - stimulating effects of glucocorticoids . too high a dose of the glucocorticoid might stimulate virus multiplication to an extent that can not be inhibited by the antiviral agent . with too low a dose the desired reduction of the symptoms of inflammation might not be achieved . a pharmaceutical composition according to the present invention should contain a therapeutically effective amount of b - 220 . for example , the relative amount of b - 220 in a pharmaceutical composition according to the present invention can be within the range of 0 . 1 - 10 % ( w / w ), preferably 0 . 5 - 5 % ( w / w ), e . g . about 1 % ( w / w ). in embodiments where an additional therapeutically active ingredient , such as any of the above - mentioned agents , is present in the composition , its concentration can be e . g . within the range of 0 . 005 - 5 % ( w / w ), or within the range of 0 . 01 - 2 % ( w / w ) or 0 . 25 - 1 % ( w / w ). in still another aspect , the present invention refers to a method of prophylactic and / or curative treatment of herpes virus infections of the skin or mucous membranes in a mammal subject , e . g . a human , comprising topical administration , in combination or in sequence , of a therapeutically effective dose of b - 220 or a pharmaceutically acceptable salt thereof , and at least one additional pharmaceutically active ingredient as mentioned herein above . b - 220 ( 1 part ) was mixed with white petrolatum ( 99 parts ) in a homogenizer to provide a preparation in the form of an ointment , free of other components . this ointment is stable for more than 24 months and accordingly no stabilizers or conditioners had to be added . variants of this preparation , e . g . containing a higher percentage of b - 220 , such as 2 . 5 % ( w / w ) may be prepared in the same way . an ointment containing 1 % by weight b - 220 in white petrolatum was administered topically to 10 volunteers suffering from recurrent herpes labialis . the administration was performed repeatedly every day by applying a thin layer of the ointment to affected areas . all test subjects reported that pain surprisingly disappeared or was substantially alleviated within 1 - 2 days and redness disappeared or were substantially reduced within 2 - 4 days .

US-201213984105-A

an exercising device comprising an elastic cord forming a continuous loop whereon three movable rings are disposed for forming a triangular stretching device defining three adjustable loops . two lower loops form stirrups to receive and hold each foot of the user in a side - by - side relationship and a loop at the apex can be adjusted to receive and exercise the neck or head , or be gripped by the hands . a variety of muscle - toning exercises for the back , neck , arms , stomach , thighs and legs can be performed , and the loop can take numerous shapes and arrangements adaptable for a wide variety of exercises .

fig1 illustrates a preferred embodiment of applicant &# 39 ; s basic gymnastic exercising device 10 comprising a stretchable and elastic cord formed in a preferably permanent continuous loop 12 having ends permanently joined as at 14 , a pair of flexible tubular hand grips 16 , and three preferably moveable and slidable plastic , fabric ( or the like ) or metal rings 18 , 18 &# 39 ; and 18 &# 34 ;. as shown in fig1 the rights 18 &# 39 ; and 18 &# 34 ; can be positioned onto the elastic loop 12 in such an arrangement as to form a triangle . as shown , the continuous loop 12 extends through first ring 18 from a first inside wall 18a to a first outside wall 18b to define a first stirrup loop 20 adjacent the first outer wall 18a . similarly , the continuous loop 12 extends through second ring 18 &# 39 ; from a second inner wall 18 &# 39 ; a to a second outer wall 18 &# 39 ; b to define a second stirrup loop 21 adjacent the second outer wall 18 &# 39 ; b . the continuous loop 12 , as shown for example , in fig1 also has a first portion 12 &# 39 ; and a second portion 12 &# 34 ; extending between the first inner wall 18a of first ring 18 and second inner wall 18 &# 39 ; a of second ring 18 &# 39 ;. the first portion 12 &# 39 ; extends through the third ring 18 &# 34 ; from the third inner wall 18 &# 34 ; a to the third outer wall 18 &# 34 ; b to define an apex loop 22 adjacent the third outer wall 18 &# 34 ; b . the flexible tube 16 positioned within the apex loop 22 can serve two purposes : ( a ) to cover joined ends of the elastic cord to form the loop 12 , and ( b ) to serve as a hand grip means . the inside diameter of the flexible tube 16 is optionally equal to the diameter of the elastic cord comprising the loop 12 , thus preferably restricting its unintentional displacement from any desired positions along the cord or arm or any optionally enlarged junction of the ends of the cord . as shown in the drawing , the tube 16 may be a pair of hand grips 16 &# 39 ; and 16 &# 34 ;. in preferred embodiments of the present invention the hand grips are movable on the loop 12 so they may be positioned at appropriate locations as required for any particular exercise . the circumferential length of the loop 12 is advantageously approximately ten feet . this length has been found to form a loop most adaptable to persons of varying heights . fig2 and 3 illustrate a preferred method of adjusting the exercising device 10 for use by persons of short stature and / or for increasing or decreasing its resistive tension . by gripping the handle 16 at the apex loop 22 and inserting the feet in the stirrup loops 20 and 21 and separating the feet in a side - by - side disposition , the resistive tension in the cord sections 24 and 26 is increased . it should also be noted that the height of the apex loop 22 is simultaneously decreased , thereby enabling a person of shorter stature to utilize the device with greater facility and advantage . ( see fig3 ). as clearly depicted in fig3 the exercising device 10 is thereby capable of self - adjusting . as the elastic loop 12 is stretched , the rings 18 forming the stirrup loops 20 and 21 , which are preferrably loosely constructed with respect to the diameter &# 34 ; d &# 34 ; at the loop 12 and arranged to slide toward the feet , thus tightening the stirrup loops around the instep of each foot . fig2 and 3 also illustrate the position the person can assume to perform the basic exercise for toning the muscles in the arms , chest and legs . the hands gripping the apex loop 22 can be pulled apart aginst the tension of the elastic cord to exercise the arm and chest muscles . to exercise the thigh and leg muscles , the right foot in the stirrup loop 20 is lifted and lowered against the tension of the cord sections at 24 and 26 . the left foot , for example , in the stirrup loop 21 can be lifted and lowered against the tension of the cord sections at 28 and 24 to achieve a similar benefit to the left leg muscles . in fig4 a simple exercise for the back , arm and shoulder muscles is illustrated . the hands grip the apex loop 22 and are raised upward against the resistive tension in cord sections 26 and 28 . in such position , the body may be bent at the torso to stretch the midriff and thus increase the benefits of this exercise . fig5 illustrates a method for exercising the neck muscles by inserting the head through the apex loop 22 and then rotating the head forward and backward , and from side to side . fig6 illustrates a method for exercising the stomach muscles by the user lying on his or her back with the exercising device 10 mounted as shown in fig5 . by lifting and lowering the legs , the muscles in the legs and abdominal region are also toned , tensioned and exercised . by assuming the position shown in fig7 a left leg - lift exercise can be performed with the device 10 . by gripping the cord sections 26 and 28 tightly at a position closer to the foot stirrups 20 and 21 , a variable and optionally greater force will be required to stretch the cord section 24 . keeping the leg stiff and raising it against the resistive tension in the cord section 24 will involve and exercise the muscles of the thigh and buttock regions . such reclining position is reversed ( lying on the left side ) for exercising the opposite ( right ) leg . fig8 illustrates the body position assumable with the exercise device 10 fitted on the head of the user and the feet maintained in the stirrups 20 and 21 . this exercise will exert pressure on the neck muscles as well as the stomach muscles , as the upper torso is moved forwardly and backwardly . although six different body - shaping exercises have been illustrated in this disclosure , many other exercises can be performed with the present invention . by maintaining the feet in the stirrups 20 and 21 and bringing the portion 12 &# 39 ; of loop 12 between the legs and across the back of the user , additional exercises can be performed either in the standing position or lying , e . g ., on the stomach . the illustrations in fig2 through 8 were used to depict the versatility of the exercising device 10 disclosed herein . the variety of muscle - toning exercises , however , is only limited by the imagination and / or energy expended by the person using said device . the instant fitness device is characterized by its simplicity and wide capability of use by almost everybody . the three rings can snap and fasten the feet and the body of the user in any desired position , and can adjust the length of the stretch cord from five feet in height ( 10 feet circumference ) down to three feet . the enormous versatility and wide utility of the invention can be seen from an examination of the following possible uses : in fig1 with the rings as shown in the drawing , insert the right foot in stirrup loop 20 and the left foot in stirrup loop 21 . then hold the hand grip 16 positioned in apex loop 22 with the hands positioned in the middle of the cord ( fig2 ). depending on the user &# 39 ; s height , he or she can adjust the desired length and stretch by moving the feet apart or bringing them closer together . in this way , the workout can be heavier or lighter , depending upon the user &# 39 ; s physical condition . once the user has established the desired length , he or she can tension - up the stretch cord and the rings 18 &# 39 ; and 18 &# 34 ; will be locked in , fastening the feet . in this position , for example , the user can exercise arm curls with one arm or both . the basic position can be used to strengthen shoulders for golf , tennis or other sports , by stretching over the head , swinging the arms and twisting the body . also , from this standing position ( fig2 ) the stretch cord may be placed around the neck ( fig5 ), securing the ring 18 , exercising the legs , abdomen , waist , hips and neck , side trunk bends , forward and backward bends , side leg raises , back and forward leg swings , knee lifts , and many more . in a variation of this position , by removing the upper ring 18 &# 34 ;, holding the stretch cord at the chest level and positioning the rings 18 and 18 &# 39 ; to provide a desired tension , the user can work out the chest muscle , abdomen , shoulders and back . for example : cross body -- arms swinging , arms raised over the head , and so forth . still another variation of this position is to restore the ring 18 and put the stretch cord between the legs and behind the shoulders . the ring 18 holds the stretch cord in place and prevents it from sliding down from the back of the shoulders . now the user can exercise the neck , abdomen , back , hips , thighs and shoulders doing lateral body bending , forward bending , body twisting , and so on -- almost ad infinitum . with the hands ( palms oriented upward ) the user can remove the stretch cord from the shoulders and exercise the triceps and shoulders by doing curls behind the head , or by fully extending the arms upwardly . the user can then assume the initial position ( fig2 ) with the stretch cord and ring 18 &# 34 ; at the chest level . with a little imagination the user can develop more and more exercises from standing or any other position once he or she gets confidence and feels secure with the positioning capability of the three rings 18 , 18 &# 39 ; and 18 &# 34 ;. by moving from standing to sitting position , the user can position the rings 18 and 18 &# 39 ; adjacent the feet , and the apex loop 22 around the head ( fastened with the ring 18 &# 34 ;), can exercise the neck forward , backward , laterally and in circles . additionally , the user can remove the stretch cord from the head and put it around the neck , using the ring 18 &# 34 ;. the user can also adjust the desired tension and length by opening or closing his or her feet . another suggested use of the device is to hold the hands , palms oriented downwardly , with the stretch cord between the feet in stirrup loop 20 and stirrup loop 21 and the apex loop 22 around the neck , the user lying on his or her back . from this position , the user can do sit - ups , the device being capable of sliding and stretching through the rings . this type of sit - up is excellent for the back , abdomen , neck , chest , arms and legs . getting back once again to the initial position , people with less strength or more advanced age can use the segments above the feet for rowing . for stronger use , remove ring 18 , hold loops 20 , 21 and 22 with both hands , position rings 18 and 18 &# 39 ;, and adjust the desired length by opening or closing the distance between the feet . in this manner , one could exercise rowing , curls , back , biceps , triceps , abdomen , legs and chest . coming back to the initial position ( fig2 ) and restored apex loop 22 , holding hand grips 16 in the hands or put around the neck ( whatever fits more comfortably ), position rings 18 and 18 &# 39 ;, insert feet in stirrup loops 20 and 21 and lie down on the back . raise the legs fully extended and do lateral swings , separating and bringing together the feet . turn on one side and exercise the abdomen , thighs and back , raising the upper leg and bringing it up and down , or moving forward and backward parallel with the ground . there are many other such exercises which require just a little imagination . another major group of exercises can be performed by lying face down : with the rings 18 and 18 &# 39 ; in place , stretch the cord from the back of the body and put apex loop 22 around the back of the shoulders , fastening it with ring 18 &# 34 ;. to execute leg curls or full extension of the legs and arms -- roll on the stomach with the legs and arms high up . the same exercise may be done by removing the stretch cord from around the back of the shoulders with both hands ( palms oriented upward ) fully extended forward , and by stretching the cord and increasing the tension . if more tension is needed , stretch the legs apart until the desired tension is obtained . to exercise the legs , back , shoulders , neck and chest , do leg curls , arm curls , rolling on the stomach and swinging the legs . the invention , as set forth , is usable by older people , by people with limited motion or in rehabilitational programs ( joint surgeries or other kinds of surgeries in which water exercises could be replaced by this stretching cord device ). sitting on a chair , the user can exercise more safely than in the water -- the back , abdomen , legs , knees , etc . users are adjusting more easily to this device and the results are much faster , eliminating the fear of water , the time , and all the hassles involved in finding a pool and a therapist . additionally , this stretch cord device can be used during lunch breaks , coffee breaks or the like , in any house and in any room of almost any size . the device of this invention can be transported everywhere and can be stored any place and under any conditions . the device of this invention is preferrably made by a stretch cord having a relaxed diameter of a minimum 3 / 8 of an inch , with a stretch expansion between 65 % to 100 %, and a relaxed circumferential length of ten feet ; and could be made adjustable for any person with heights of from 4 &# 39 ; 8 &# 34 ; to 6 &# 39 ; 3 &# 34 ; with the help of three plastic or metal rings . the rings preferrably are rigid and have an inner diameter ( for the 3 / 8 &# 34 ; diameter stretch cord ) of one inch to allow sliding movement on the cord 12 . the device weighs about 1 / 4 of a pound ( approximately 120 gr .). the invention described above is susceptible to many variations , modifications and changes . it should be understood that all such variations , modifications and changes are within the spirit and scope of the invention and the appended claims . similarly , it will be understood that it is intended to cover all changes , modifications and variations of the examples of the invention herein disclosed for the purpose of illustration which do not constitute departures from the spirit and scope of the invention .

US-66184991-A

a self - drilling bone fusion screw apparatus is disclosed which includes at least first and second sliding boxes . a first screw member having a tapered end and a threaded body is disposed within the first sliding box , and a second screw member having a tapered end and a threaded body disposed within the second sliding box . an adjuster adjusts the height of the sliding boxes . the screw members are screwed into vertebral bodies in order to fuse the vertebral bodies together . a plurality of the self - drilling bone fusion screw apparatuses may be attached together and / or integrated via a plate or cage . also disclosed is a cervical facet staple that includes a curved staple base and at least two prongs attached to the bottom surface of the curved staple base .

referring to fig1 - 6 , the above described problem can be solved in the thoracic and lumbar spine by insertion into the denuded intervertebral disc space multiple embodiments of screw box constructs with bdft screws . fig1 a - d illustrate three - dimensional views of the lumbar intervertebral expandable screw box 100 with two bdft screws 101 , 102 ; one lateral and one medially oriented ( embodiment ia ). fig1 e illustrates a sagittal - oblique view of the lumbar intervertebral expandable screw box 120 with two lateral oriented bdft screws 121 , 122 ( embodiment ib ). the expandable box 100 consists of top and bottom triangular sliding bases 103 , 104 ( fig1 - d ). the superior and inferior segments of the height / depth adjusting screw 105 are integrated and connected to the two separate top and bottom triangular bases 103 , 104 , respectively . by turning this adjusting screw 105 back and forth i . e . clock - wise , and counter clockwise , the sliding rails 106 of the top triangular base 103 ( fig1 d ) slide up and down the rail inserts 107 on the bottom triangular base 104 ( fig1 d ). this action will simultaneously alter the intervertebral height and depth of the screw box 100 allowing individualized custom fitting of the screw box 100 conforming to the dimensions of the disc space . transvertebral screw 101 penetrates the top base 103 , and transvertebral screw 102 traverses the bottom base 104 of the screw box 100 . the two screws 101 , 102 traverse the screw box 100 in opposing directions , bi - directionally ( whether they are lateral or medially oriented ). the external edges of the triangular bases 103 , 104 in contact with vertebral body surfaces include ridges 107 . this facilitates the screw box &# 39 ; s 100 incorporation into and fusion with the superior and inferior vertebral bodies ( fig1 a - e ). both top and bottom screw box bases 103 , 104 are perforated with holes 108 to allow bone placement for fusion . the entire construct , furthermore , is hollow to allow bone filling . hence this device functions as both an intervertebral bone fusion spacer and bi - directional transvertebral screw fusion device . fig2 a - c illustrate three - dimensional views of the lumbar intervertebral non - expandable screw box 200 with two bdft screws 201 , 202 ( embodiment ii ). screws 201 and 202 perforate and orient in opposing , superior and inferior directions . there are holes 208 and hollow spaces allowing packaging with bone . there are also holes which allow the traversal of screws . the superior and inferior edges include ridges 207 to facilitate integration and fusion with superior and inferior vertebral bodies . the expandable screw box 200 may include a screw insert 209 to attach a horizontal mini - plate ( not shown ). the self - contained internalized drill guides are at a 25 degree angle . the screw boxes can be designed with the internalized drill guides with different angles and / or different positions within the box . fig3 illustrates a three - dimensional view of left and right lumbar intervertebral non - expandable screw boxes 300 a , 300 b with one bdft screw 301 or 302 ( embodiment iii ). it is roughly half the width of embodiments i and ii . screw 301 is inserted into screw box 300 a ( left ) and screw 302 is inserted into screw box 300 b ( right ). there are holes 308 and hollow spaces allowing packing of bone to achieve biological fusion . the combined effect of one superior oriented and one inferior oriented screw fuses the superior and inferior vertebral bodies with small constructs . this also enables placement of larger dimension screws compared to embodiments i and ii . fig4 a and b illustrate three - dimensional views of the horizontal intervertebral zero profile mini - plate 400 with two non - expandable lumbar intervertebral screw boxes 300 a , 300 b housing two bdft screws 301 , 302 . fig4 a illustrates the perforations 401 within the plate 400 through which small plate securing screws 310 will be inserted to connect it to the built - in screw holes of the screw box 300 a , 300 b ( fig4 b ). the horizontal mini - plate 400 together with the top surfaces of left and right screw boxes 300 a , 300 b provide a physical barrier between the underlying bone placed beneath it ( not illustrated ), and the thecal sac and nerve roots above it ( not illustrated ). fig4 c illustrates two screw boxes 300 c , 300 d within a circumferential cage 420 ( 2 in 1 ) construct which is designed for anterior placement into the lumbar spine . there are slots 308 a , 308 b for bone graft placement , both outside and inside the boxes . the circumferential cage 420 has perforations 401 a for the placement of transvertebral screws ( not shown ). fig5 a - c illustrate three - dimensional views of the external drill / screw guide - box expander 500 which assists in screw trajectory and box expansion ( embodiments ia - b ). for embodiments ii and iii , the same instrument is utilized ; however , an expanding allen key component is not used . the key components of this device include an allen key 501 , a spring 502 , a handle 503 , a griper 504 and a screw guide 505 . the allen key 501 when inserted in the insertion 514 and turned , turns the screw adjuster ( fig5 c ) which in turn regulates top and bottom triangular screw box base sliding , and hence box 200 width and depth . the griper 504 has griper prongs 506 which insert into grooves of the screw guide 505 and the screw box 200 ( fig5 a - d ) thus perfectly aligning them . fig5 d illustrates a superior oblique view of the screw guide 505 demonstrating insertions 509 for griper prong 506 , built - in trajectory guides 511 , 512 for insertions of screws 101 and 102 , and the allen key 501 . fig5 e - g illustrate three - dimensional views of the sequential steps necessary for the external guide assembly . fig5 e illustrates the insertion of the allen key 501 into the handle 503 . fig5 f illustrates the insertion of the handle 503 through the spring 502 and griper 504 . fig5 g illustrates insertion of the griper 504 into the screw guide 505 . fig5 h - i illustrate three - dimensional views of a positioning tool 500 a for impaction and placement of two transvertebral screws 201 , 202 in the non - expandable screw box 200 . the driver assembly 550 consists of a screw driver 551 , a flexible shaft 552 and a square recess bit 553 . this facilitates turning the screws 201 , 202 into the bone . the flexible shaft 552 facilitates the avoidance of spinous processes which might hinder the screw driving if the shaft 552 were straight . the positioning tool 500 a can have a rectangular handle , embodiment i ( fig5 h ), or a circular handle , embodiment ii ( fig5 i ). this serves to position the screw box within the intervertebral space , and screws 201 , 202 within the screw box . once positioned , the screw box can be impacted by tapping the handle with a mallet ( not shown ). the positioning tool &# 39 ; s 500 a griper handle inserts into the screw guide and the box , which maintains alignment . fig6 a illustrates a three - dimensional view of insertion of the construct ( embodiment i ) into the lumbar intervertebral disc space . fig6 b illustrates a three dimensional lateral view of insertion of the construct ( embodiment i ) into the disc space with short screws . placement with longer screws would capture more bone . fig7 a and b illustrate three - dimensional views of the two - pronged cervical facet staple 700 ( embodiment i ). there is a staple base 701 which is contoured to align with the curved surface of the cervical facet joints . there is a superior impactor threaded insert 702 . an impactor can be screwed into this insert 702 and then impacted with a mallet . the two spikes 703 , 704 perforate the inferior and superior facets of the superior and inferior vertebral bodies hence leading to cervical facet joint fusion . the spikes can be designed with ridges and / or fishhooks to facilitate irreversible extraction . fig8 a - c illustrate three - dimensional views of the four - pronged cervical facet staple 800 ( embodiment ii ). likewise it has a staple base 805 contoured specifically for the surface of the facet joint . it also has an impactor insert 806 . the insertion of a device with four prongs 801 - 804 instead of two prongs further limits the degrees of motion of the joint hence making the fusion more rigid . fig9 a - b illustrate a three - dimensional view of the two - pronged cervical staple impactor 900 . it has a handle 901 , a stem 902 , and a screw insert 903 which can be screwed into the threaded staple insert . the impactor has two wings 904 which keep the staple base edges in place facilitating staple impaction . the handle 901 of the impactor 900 is broad in order to allow impaction by a mallet . fig1 a - c illustrate three - dimensional views of the four - pronged cervical staple impactor 1000 ( embodiment ii ). it has the same features as the two - pronged impactor 900 , except its wings 1004 are broader accommodating the broader staple base . the impactor 1000 also includes a handle 1001 , a stem 1002 , and an impact screw 1003 . fig1 a illustrates a three - dimensional view of placement of the two pronged cervical facet staple 700 into a cervical spine model having vertebral body 1103 and lamina 1104 . one staple 700 is perched on the joint 1101 prior to impaction . the other staple 700 is impacted . fig1 b illustrates a three - dimensional view of placement of the four pronged cervical facet staple 800 into a cervical spine pre and post impaction . fig1 c illustrates the concept of modularity and incremental diminution of movement of the joint by the modular placement of different combinations and permutations of varying numbers of two and four pronged cervical facet staples 700 , 800 . if one wishes to have the most flexible ( least rigid ) fusion , one would place a unilateral two pronged staple 700 . one can increase i . e . calibrate increasing degrees of rigidity by increasing the number of prongs penetrating the facet joints bilaterally . in fig1 c each facet joint is fused using a total number of six prongs . one side this is accomplished by using three two pronged staples 700 , and on the other side using one four pronged staple 800 and one two pronged staple 700 . these two embodiments can be mixed and matched unilaterally or bilaterally to vary the degree of rigidity and conversely flexibility of fusion . the most flexible fusion at one level would be accomplished by one staple 700 ( 2 prongs ). the highest level of rigidity would be achieved by placing two four pronged staples 800 on both sides totaling sixteen prongs . intermediate degrees of relative joint motion can be modulated by insertion into the cervical facet joints staples in two - four prong increments from 2 - 16 . each additional prong further limits the degree of facet joint motion hence increasing rigidity , and conversely decreasing flexibility . thus the novel modular use of these embodiments heralds an era of flexible cervical spine fusion . fig1 a - b illustrate a lumbar facet joint staple 1200 in open and closed positions and having staple prongs 1203 . this lumbar facet staple has been thoroughly described in our previous co - pending patent application ser . no . 11 / 536 , 815 , filed on sep . 29 , 2006 , and ser . no . 11 / 208 , 644 , filed on aug . 23 , 2005 , the relevant portion of each of which is hereby incorporated by reference hereinafter . the new improvement of this device includes a ratchet 1201 . the staple 1200 can be incrementally closed with increased ratcheting over increasing number of spurs 1202 . this achieves increasing calibrated levels of lumbar facet joint fusion , and conversely diminishing joint flexibility . this new designs further enhances the capacity to achieve flexible fusions in the lumbar spine . exemplary surgical steps for practicing one or more of the foregoing embodiments will now be described . the posterior lumbar spine implantation of all the screw box 100 , 200 , 300 embodiments , with bdft screws , and horizontal mini - plate 400 can be implanted via previously described posterior lumbar interbody fusion ( plif ) or posterior transforaminal lumbar interbody fusion ( tlif ) procedures . the procedures can be performed open , microscopic , closed tubular or endoscopic . fluoroscopic guidance can be used with any of these procedures . after adequate induction of anesthesia , the patient is placed in the prone position . a midline incision is made for a plif procedure , and one or two parallel paramedian incisions or a midline incision is made for the tlif procedure . for the plif , a unilateral or bilateral facet sparing hemi - laminotomy is created to introduce screw box 100 , 200 , 300 embodiments i - iii into the disc space , after it is adequately prepared . for the tlif procedure , after unilateral or bilateral dissection and drilling of the inferior articulating surface and the medial superior articulating facet the far lateral disc space is entered and a circumferential discectomy is performed . the disc space is prepared and the endplates exposed . then one screw box 100 , 200 , 300 of either embodiments i - iii is placed on either right , left or both sides . then another screw box of embodiments 100 , 200 , 300 i - iii is placed on the contralateral side . for embodiment i the external screw guide 505 / box expander is attached to the screw box ( fig5 a - h ). first the allen key 501 is screwed until the box conforms perfectly to the height and depth of the space . then a pilot hole can be drilled or an awl can start a pilot hole in the vertebral bodies . then a transvertebral screw is screwed into the vertebral body via the built - in box screw guides 505 . for difficult angles , an angled screw driver can be employed . for embodiments ii - iii the same method is used for placing screws , except the allen key 501 is not utilized in the absence of plate expansion . if bilateral constructs have been inserted , bone is packed into the intervertebral space , as well as within the device . then the horizontal intervertebral zero profile mini - plate 400 is slid beneath the thecal sac and is secured to both left and right screw boxes with small mini - plate screws 210 ( fig4 a - b ). this prevents bone intrusion into the thecal sac and hence possible nerve root compression . fig6 a and b illustrate the process of insertion and final placement of the construct into the lumbar spine . the mini - plates 400 can come in different horizontal lengths and widths to accommodate different intra and inter - patient disc space diameters . the bdft screws can come in different widths , lengths and thread designs . the anterior thoracic and lumbar spine implantation of one , two or three screw box constructs 100 , 200 , 300 and bdft screws can be performed in a similar manner to the posterior application . likewise , a horizontal mini - plate 400 can be used to cap two or three screw box constructs 100 , 200 , 300 ( one placed midline deeply , one placed left and one placed right , forming a triangulation ). alternatively two screw box constructs may be placed into a circumferential ring for anterior placement . anterior placement of these devices can be performed into the l4 / 5 and l5 / s1 spaces on the supine anesthetized patient via previously described open microscopic or endoscopic techniques . once the disc space is exposed and discectomy and space preparation are performed , placement of one , two or three screw box embodiments 100 , 200 , 300 ( i - iii ) or a 2 in 1 construct can be placed . the screw placement is facilitated by the internal screw guides , and different positioning tools (( fig5 ). a right angled screw driver and / or ratchet could alternatively be employed a capping mini - plate 400 may be applied if desirable . the mechanism of screw placement and mini - plate 400 attachment are identical to what was described above . the posterior placement of screw box constructs 100 , 200 , 300 alone or combined with horizontal mini - plates 400 into the thoracic spine can be performed via previously described transpedicular approaches ; open or endoscopic . the anterior placement into the thoracic spine can be accomplished via a trans - thoracic approach . once the disc space is exposed via either approach , any combination of the above mention embodiments ( i - iii ) can be inserted . engagement of the devices is identical to what was mentioned above . for posterior placement of cervical facet staple 700 , 800 embodiments , after adequate induction of anesthesia the patient is flipped prone and his head and neck secured . a single midline or two para - median incisions are made for unilateral or bilateral or multilevel placement of staples . ultimately the facet joint is exposed . alternatively and preferably this can be performed percutaneously under fluoroscopic guidance with intravenous sedation . the staple 700 , 800 ( embodiments i or ii ) is loaded into the impactor 900 , 1000 . the staple 700 , 800 is placed on the two articulating cervical facets , and then impacted into the joint . to achieve modular calibrated fusion different combinations and permutations of cervical facet stales can be inserted ranging from a single unilateral two pronged staple providing a high degree of flexibility to a total of four bilaterally placed four pronged staples 800 ( 16 prongs ) leading to the highest degree of rigidity . additional bone may or may not be placed in its vicinity to facilitate permanent and solid fusion . this procedure can be performed open , closed , percutaneously , tubulary , endoscopically or microscopically . fig1 a - c illustrates placement of the staples 700 , 800 in the cervical spine . we have previously described surgical placement of the lumbar facet joint staple in our two co - pending patents . the surgical procedure for this device is identical to that which has been previously mentioned . the present inventions may provide effective and safe techniques that overcome the problems associated with current transpedicular based cervical , thoracic and lumbar fusion technology , and for many degenerative stable and unstable spine disease . these inventions could replace much pedicle screw - based instrumentation in many but not all degenerative spine conditions . the speed and simplicity of placement of cervical and lumbar facet staples , and placement of lumbar screw box - bdft constructs far exceeds that of current pedicle screw technology . furthermore , these devices have markedly significantly decreased risk of misguided screw placement , and hence decreased risk of neural and vascular injury , and blood loss . in the lumbar spine bdft screw constructs and facet staples could be applied modularly in different combinations to achieve different degrees of rigidity ( flexibility ). patients having these devices would have decreased recovery and back to work time . these devices most likely lead to similar if not equal fusion with significantly less morbidity , and hence overall make them a major advance in the evolution of spinal instrumented technology leading to advances in the care of the spinal patient . another major novelty and advance is the introduction of simple and safe modular calibrated cervical flexible fusion . to our knowledge neither a similar device nor a similar mathematical concept of modular joint flexibility / fusion calibration has been postulated for the cervical spine or for any other articulating joint . to our knowledge there have not been any previously described similar posterior lumbar and thoracic combined spacer and screw constructs . these devices can similarly be modified to stabilize bone fractures throughout the entire body . to our knowledge the description of zero to subzero profile anterior or posterior horizontal spinal plates which traverse the diameter of the disc space has not been previously described .

US-201113108982-A

the present invention is related to an improved method for her2 gene test by using quantitative real - time pcr technique . our invention streamlines test process , and incorporates quality control for each major step , including sample , reagent , operation , and data report . we eliminate the need for reference genes which is hard to standardize in her2 pcr test . we develop a cutoff reference point by using the statistical mean of tumor tissue population , and adopt a simplified scoring scheme for evaluation of her2 status . our invention produces consistent result across machines and labs , and has proven to be clinically successful in her2 test .

sample collection — immediately after biopsy or surgery , the tumor specimen can be preserved in formalin - fixed paraffin embedded ( ffpe ), freshly frozen in liquid nitrogen or in optimal - cutting temperature compound ( oct ). rna extraction — the total rna is extracted from 25 mg of frozen sample or from ten 10 - μm sections by using a commercial rna isolation kit . the total rna concentration was determined by a spectrophotometer or fluorometer . reagent content — reagents are stored at − 20 ° c . in two groups . her2 sdna is a synthetic single - stranded oligo nucleotide , and has a molecular weight of 22570 . 6 . control rna is prepared from breast cancer cell lines . assay and plate design — a her2 test contains the reactions : i ) sdna solutions and one ntc in duplicate for generation of standard curve ; ii ) unknown sample rna in triplicate , plus one no rt well for each sample ; iii ) control rna in triplicate plus one no rt well . refer to the user manual of real - time pcr machine for the procedures of assigning plate wells for the above reactions . choose ‘ fam ’ for collect fluorescence data and ‘ rox ’ as reference dye . see fig1 for an example of plate setup . running rt and pcr — real - time pcr assay consists of two consecutive steps , i . e ., reverse transcription ( rt ) and polymerase chain reaction ( pcr ). in rt process , mrna is converted to a single stranded cdna which is then amplified with a specific pair of primers in pcr process . the quantity of amplified dna fragments is monitored with a fluorescence - labeled oligo probe in each pcr cycle . the c t value is recorded for each amplification curve , and is used for calculation of gene expression level in sample . following are detailed steps . 1 . take out rt mix , rt enzyme , trna , and water from pack a , and thaw them on ice ; meanwhile , take out sdna solutions from pack b and put them on a separate ice bath . invert each vial several times after thawing reagent . 2 . determine the number of reactions for your assay and calculate the quantity of rt mix and rt enzyme . for each reaction , including standard , unknown , ntc and no rt , you need 5 . 9 μl rt mix and 0 . 1 μl rt enzyme , but in no rt control , add 0 . 1 μl water to replace rt enzyme . mix solution by pipeting up and down for several times . do not vortex . 3 . load 6 μl of the above solution to each well uniformly . it is not necessary to change tip after each loading . 4 . determine rna concentration for each sample and adjust to 25 ng / μl . add 4 μl of rna sample to each unknown or no rt well , the total rna in each reaction will be 100 ng ; meanwhile , add 4 μl of control rna to each ‘ control rna ’ well . 5 . add 4 μl of sdna solution to each corresponding standard well . in ntc well , add 4 μl of trna to replace sdna . the total volume of each rt reaction is 10 μl . 6 . seal pcr plate tightly with membrane across plate edges and around each well . put the plate into real - time pcr machine and perform rt reaction using a thermal profile : 50 ° c . for 30 min , and 72 ° c . for 5 min , then cool down to 20 ° c . or room temperature . 7 . when running rt , take out pcr mix and pcr enzyme from pack a . thaw the reagents on ice , and re - suspend the reagents by inverting vials several times . 8 . calculate the quantity of pcr mix and pcr enzyme needed for your assay . for each pcr reaction , you need 39 . 8 μl of pcr mix and 0 . 2 μl of pcr enzyme . add appropriate amount of pcr enzyme to pcr mix , and pipet solution up and down several times . do not vertex solution . 9 . load 40 μl of above solution to each well . seal pcr plate again with membrane and ensure that the edges and wells are tightly sealed . the total volume of solution in each well will be 50 μl . 10 . put the plate back to a real - time pcr machine and set up thermal profile to : 95 ° c . for 1 min / 40 cycles of 95 ° c . for 12 s / 55 ° c . for 1 min / 72 ° c . for 30 s . 11 . collect data after running , and trash the plate in a different location to avoid potential contamination to the future assays . data analysis and test requirements — our method offers a tool for accurate measurement of her2 expression level in breast cancer cells , as well as a tool for identification of cancer patients who might benefit from herceptin treatment . tests of breast tumor samples lead to establishment of a cutoff reference point for her2 positive tumors . following is detailed discussion on obtaining high quality test results . 1 . threshold setup . threshold is defined as a fluorescence intensity level , above which the fluorescence signal is considered to be significantly higher than the background . software provided with real - time machine setup a threshold following each pcr run for calculation of sample c t . however , the threshold will vary in different assays . our tests indicate that sdna at 0 . 002 ng / μl has an average c t of 21 . 65 ( table 1 ); accordingly , setup of a threshold to yield a c t value of 21 . 65 for 0 . 002 sdna will produce consistent results across assays . 2 . validation of standard curve . standard curve is a plot of the initial template quantity in the standard wells ( x - axis ) versus the c t ( threshold cycle ). usually , a least mean square curve fitting algorithm is adopted to generate a standard curve . r 2 is a key parameter used to evaluate the quality of a standard curve . the highest value of r 2 is 1 . standard curve that has a r 2 value higher than 0 . 95 is considered valid . 3 . amplification efficiency . amplification efficiency measures the percentage of the template molecules which are doubled every cycle , and is a comprehensive parameter that reflects the overall quality of assay reagents and conditions . in a real - time pcr , amplification efficiency is estimated from standard curve using the equation : efficiency = 10 (− 1 / slope ) − 1 . a valid assay should have an amplification efficiency above 95 %. 4 . replicate variation . replicates are wells which contain the same rna sample , and , theoretically , should have the same c t value . therefore , variation among the replicates would represent the errors of assay operations . a valid test should have a replicate variation of less than 0 . 5 c t units . 5 . false positive . if a sample contains normal level of her2 mrna but displays a significantly low c t , this phenomenon is termed as ‘ false positive ’. a major cause of false positive sample is dna contamination , which may come from many different sources , such as reagents and amplified products from neighboring wells or previous assay plates . a “ no template control ’ ( ntc ) is included in the test for each sample , and should have no amplification signal or no c t under normal conditions . 6 . false negative . if a sample contains an over - expression level of her2 mrna but displays a normal or even higher c t , this phenomenon is termed as ‘ false negative ’. the sample quality is a major cause of false negative results . for example , the presence of pcr inhibitors or rna degradation can lead to high shift of c t value . our tests indicate that effects of both pcr inhibitors and rna degradation are highly sensitive to sample dilution . if a sample at two different concentrations shows consistent result , then , it is considered having acceptable quality . 7 . control rna . test also incorporates control rnas which are isolated from breast cancer cell lines . these rnas are used as true controls for her2 positive and her2 negative . inclusion of these rnas also monitors reagent quality and assay operation . under standard test conditions , control rnas show constant delta c t value ( δc t ) against cutoff reference point . 8 . cutoff reference point . prior to routine her2 pcr testing , a her2 cutoff reference point ( s ) ( crp ) must be established in order to compute the cδc t which is equal to crp — c t ( unknown sample ); if cδc t & gt ; 1 , the test result is her2 positive ; else , negative . crp is derived from the statistical mean of a breast tumor tissue population , and is monitored by a synthetic dna ( sdna ) in each test . validation with fish test — her2 gene amplification was determined by the fda - approved pathway her2 dna probe kit ( vysis / abbott , usa ). according to the manufacturer &# 39 ; s instruction , her2 gene was considered non - amplified if an average her2 ( red ) to cep17 ( green ) ratio was & lt ; 2 . 0 , and low amplification between 2 . 0 and 4 . 0 , and highly amplified if the ratio was & gt ; 4 . 0 . for comparison purpose , the samples with a ratio of ≧ 2 . 0 were classified as her2 positive ; otherwise , as her2 negative . fish tests were conducted either at ncku pathology lab or by an outsourced reference lab . fish test were done selectively ( mostly for ihc 2 + samples ), not for all the samples . testing procedure flow chart — fig2 is included to demonstrate the essence of the quality assurance and result validation before and after the pcr run with the invented cutoff point method . test data and result analysis — table 1 shows establishment of her2 standard curve baseline and calculation of cδc t , for the determination of her2 expression status in breast tissue samples . as detailed in ‘ claim 10 ’, if cδc t is greater than 1 , then her2 test is positive ; otherwise , the her2 test will be negative . the cutoff reference point ( crp ) for the tissues preserved in optimal - cutting temperature compound ( oct ) is 21 . 65 , for the tissues in formalin - fixed paraffin embedded ( ffpe ) is 25 . 13 . tissue samples from sources , such as oct vs . ffpr , can be tested in the same pcr run . distribution of her2 mrna expression in breast tissues — table 2 shows that her2 mrna gene expression in both tumor and normal tissues exhibits a normal distribution , regardless the tissue processing methods . analysis also shows that her2 expression in the tumor in normal tissues belongs to different populations . showing a normal distribution of her2 mrna expression offers a statistical basis for establishment of cutoff reference point ( crp ) for her2 pcr testing . establishment of cutoff reference point ( crp ) by using the statistical mean of breast tumor her2 mrna expression level . table 3 shows adoption of a c t value as cutoff reference point that is around the statistical mean of her2 mrna expression level in the tumor samples and is equivalent the statistical mean of normal tissue minus 3 . 5 standard deviation . given that the statistical mean varies by sample sources , such as oct vs . ffpe , different crp is used for different tissue sources accordingly . table 3 also shows that crp may be monitored by a defined quantity of sdna ( a synthetic single - stranded dna ) in each test for easy calculation of cδct in a real - time manner , which is further described in ‘ claim 10 ’. test result validation , pcr vs . fish — table 4 shows the detail test results of the invented method and fish method on different types and sources of breast tumor samples . table 5 is included to summarize the agreement score between the invented method and the existing fish method . given that the sample acquisition in this study is random and non - consecutive slicing between the pcr test and the fish test for the same patient , the agreement score of 90 % reported here is conservative . with reference to fig1 , it will be noted that ‘ standard ’ is the well containing different amount of her - 2 sdna for generation of standard curve ; ‘ unknown ’ is the well that contains sample rna , and each sample is run in triplicate ; ‘ ntc ’ is a control which contains all the reaction components except sdna ; ‘ no rt ’ is a control which contains rna and all other reaction components , but no rt enzyme ; ‘ control rna ’ is included as control for the quality of both rt and pcr reactions .

US-201313765701-A

the invention relates to cyclic peptides of 3 - 9 amino acids comprising 2 - 7 aliphatic and 0 - 2 polar amino acids that are capable of self - assembling , wherein said aliphatic amino acids are arranged in decreasing hydrophobicity from n - to c - terminus and at least a portion of the cyclic peptide has to have its amino acids in alternating d - and l - configuration , as well as their use in hydrogels as well as co - gels or co - hydrogels . the hydrogels of the invention may be used in nanomedicine or drug delivery , cell culture or alternatively in electronic devices .

we have previously described ultrashort peptide sequences ( 3 - 7 residues ) which have an innate tendency to self - assemble into helical fibers that ultimately result in hydrogel formation , see e . g . wo 2011 / 123061 , us 2014 / 0093473 a1 , wo 2014 / 104981 a1 of the inventors , and hauser et al . ( 2011 ), mishra et al . ( 2011 ). the microarchitecture of these nanofibrous hydrogels resemble extracellular matrix , opening avenues for widespread applications as biomimetic scaffolds for tissue engineering and three - dimensional cell culture . furthermore , the ultrashort peptide hydrogels demonstrate remarkable mechanical stiffness , thermostability , biocompatibility , in vitro and in vivo stability . in particular , the stability of these hydrogels offer attractive advantages to applications such as developing injectable therapies for degenerative disc disease and other tissue engineering applications requiring the construct to provide structural support over long durations . however , in developing these hydrogels for shorter - term applications , such as injectable matrices for drug and gene delivery , it is desirable to precisely control the drug release rate . however , when a co - hydrogel , containing a bioactive compound and the peptide was formulated , only a burst release could be observed , a sustained release was never achieved . this application describes a novel class of self - assembling aliphatic cyclic peptides . inspired by the structure of previously mentioned class of ultrashort self - assembling peptides , the cyclic peptides represent a head to tail macrocylized form of these peptides . however , to achieve self - assembly of cyclic peptide , the peptide contains alternate l - and d - amino acids ( with regards to the absolute configuration , fig1 ). in comparison to this , the parent peptides only contain one amino acid stereo isomer ( all l or all d ). although the self - assembling properties of cyclic peptides are well known ( mandal et al ., 2014 ; montenegro et al ., 2013 ; li et al ., 2012 ), most of the reported systems do not form hydrogels . hydrogel formation could this far only be achieved using rigid structures . recently several groups independently report on the hydrogel formation using functionalized cyclic dipeptides . however , a cyclic dipeptide not only represents the smallest possible cyclic peptide , but is often better described as a diketopiperazine unit , and can thus be not considered as a macrocyclic peptide . gelation of diketopiperazine is achieved through additional functionalization of the amino acid side chain and cannot be seen as an intrinsic molecular behavior ( manchineella and govindaraju , 2012 ; hoshizawa et al ., 2013 ; kleinsmann and nachtsheim , 2013 ). to the best of our knowledge no macrocyclic peptide which can self - assemble to form hydrogels is reported this far . in this disclosure we describe the synthesis of macrocyclic peptides which can self - assemble in water to form hydrogels made of nano - tubular fibres . these peptides are made entirely of aliphatic α - amino acids , and self - assembly is only achieved through non - covalent interaction . all fmoc protected amino acids , o -( b enzotriazol - 1 - yl )- n , n , n ′, n ′- tetramethyluronium tetrafluoroborate ( tbtu ), benzotriazol - 1 - yl - oxytripyrrolidinophosphonium hexafluorophosphate ( pybop ) were purchased from gl biochem ( shanghai ) ltd . dimethylformamide ( dmf ) ( analytical grade ) was purchased from fisher scientific uk . acetic anhydride ( ac 2 o ) and dimethyl sulfoxide ( dmso ) was purchased from sigma aldrich . n , n - diisopropylethylamine ( dipea ), dichloromethane ( dcm ), trifluoroacetic acid ( tfa ) and tis ( triisopropylsilane ) were purchased from alfa aesar , a johnson matthey company . piperidine was purchased from merck schuchardt ohg . diethyl ether ( et 2 o ) was purchased from tedia company inc . all chemicals were used as received . all peptide based compounds were purified on an agilent 1260 infinity preparative hplc system equipped with a phenomenex lunar c18 column ( 150 × 21 . 2 mm 5 μm ). the hplc was coupled over an active splitter to a sq - ms for mass triggered fraction collection . milliq water and hplc grade acetonitrile , both containing 0 . 1 % formic acid , were used as eluents . 1 h and 13 c nmr spectra were recorded on a bruker av - 400 ( 400 mhz ) instrument and all signals were referenced to the solvent residual peak . h - livags - oh was synthesized on wang resin ( gl biochem ) using spps following standard peptide synthesis protocols ( kirin et al ., 2007 ). the de - protection of fmoc was achieved by treating the resin with piperidine in dmf . the supernatant was filtered off and the resin washed with dmf . coupling of the appropriate fmoc - protected amino acid to the resin was done by treating the resin with a combined solution of the amino acid ( 3 equivalent ), tbtu ( 3 equivalent ) and dipea ( 3 equivalent ) in dmf . the filtering - cum - washing , de - protection , and coupling cycle was then repeated until all the amino acids of the peptide were linked . the fmoc deprotected peptide was cleaved from the resin using a mixture of tfa / h20 / tis ( 95 : 2 . 5 : 2 . 5 ). after precipitation with et 2 o the solid was collected by centrifugation washed with et 2 o and dried . cyclization was carried out in solution at a concentration of 0 . 5 mg / ml in dmf using a threefold access of tbtu and dipea . the cyclization reaction was followed by hplc - ms and if required , more coupling reagent was added to achieve full cyclization . afterwards the solvent was removed , and the product was purified by hplc - ms . see fig5 to 7 for nmr and esi - ms spectra . clk6 was synthesized using standard solid phase cyclization reactions procedure ( abbour and baudy - floc ′ h , 2013 ). in short : fmoc - lys - oallyl ( 1 . 05 mmol ) was coupled to 2 - chlorotrityl resin ( 2 . 1 g ) in dmf / ch2cl2 ( 1 : 3 ). for this purpose , ctc resin was washed once with ch 2 cl 2 , afterwards , fmoc - lys - oallyl , dissolved in dmf and ch 2 cl 2 was added followed by 5 equivalents of dipea . after 5 min an additional equivalent of dipea was added . the reaction was allowed to proceed for 30 min . afterwards , the resin was quenched with meoh to avoid side reactions . the following peptide was synthesized as described above . after fmoc - d - leu - oh was added , the allyl group was removed using pd ( pph4 ) 4 ( 0 . 1 mmol ) and 10 equivalents of phsih 3 . the reaction was allowed to proceed in ch2cl2 in an open vessel for 1 hours . hplc - ms confirmed full deprodection . afterwards , the resin was washed 5 times with dmf followed by fmoc deprodection . final cyclization was carried out in dmf on the resin using pybop ( 4 equiv . ), hoat ( 4 equiv .) and dipea ( 4 equiv .) as coupling reagent . small amounts of resin were cleaved to follow the reaction by hplc - ms . once complete cyclization was achieved , the peptide was cleaved from the resin as described above . after purification by hplc - ms the pure product was obtained by lyophilization . see fig8 to 10 for nmr and esi - ms spectra . hydrogel samples were shock frozen and kept at − 80 ° c . frozen samples were then freeze - dried . lyophilized samples were fixed onto a sample holder using a carbon conductive tape and sputtered with platinum from both the top and the sides in a jeol jfc - 1600 high resolution sputter coater . the coating current was 20 ma and the process lasted for 50 sec . the surface of interest was then examined with a jeol jsm - 7400f field emission scanning electron microscopy ( fesem ) system using an accelerating voltage of 2 kv . as discussed above , we have previously reported a new class of aliphatic amphiphilic ultrashort peptides which have an innate tendency to self - assemble in water to form biomimetic , nanofibrous hydrogels with very high mechanical strength and are extremely stable in vitro and in vivo . in this patent application , we explore the possibility of conduction a head to tail macro cyclization reaction to obtain cyclic peptides . to achive this goal , the previously reported peptides sequences , which have been proven to form hydrogels , can be cyclized . however , to facilitate self - assembly of cyclic peptides a peptide containing alternate absolute stereo configurations of the amino acids have to be synthesized ( fig1 ). two parent peptide sequences were chosen to conduct a proof of concept study : firstly , ac - livags - oh [ seq id no . 21 ] was used , since it can be cyclized in solution as an unprotected peptide . for this purpose h 2 n - livags - oh was synthesized by standard fmoc - solid phase peptide synthesis ( see above for details ), whereby leucine and valine was used in d - absolute configuration . it has to be noted , that glycine does not have a stereocenter and thus no l or d stereoisomer exists . cyclization of h 2 n - livags - oh was performed in solution using standard reaction conditions yielding clivags (= cls 6 ). see fig2 a . since solution was cyclization resulted in low yield , the cyclic analog of ac - livagk - nh 2 [ seq id no . 16 ] was synthesized entirely on the solid phase . for this purpose , an orthogonal synthetic approach was used , whereby fmoc - lys - oallyl was the starting amino acid . after the entire fmoc protected peptide was synthesized , the allyl protection group can be removed without cleaving the peptide from the resin . this allows that the final cyclization reaction is carried on solid phase and the cyclic peptide , clivagk (= clk 6 ) can be cleaved from the resin and purified by hplc - ms ( see above ). see fig2 b . in order to determine the minimum gelation concentration in water , the cyclic peptides were attempted to be dissolved in milliq water . as cls6 displayed a low solubility in water , the minimum gelation concentration could not be determined . however , to prove , that cls6 is able to self - assemble in water , cls6 was dissolved in hexafluoroisopropanol ( hfip ) and dropped slowly into water . a gelatinous “ precipitate ” is formed when cls6 is dropped into water proving the ability of the cyclic peptide to self - assemble in water . the low solubility of cls6 in water can be attributed to the absence of a charged amino acid residue . in order to introduce a charged amino acid residue clk6 was synthesized and its ability to form hydrogels was investigated . for this purpose clk6 was dissolved at a concentration of 10 mg / ml in water . however , full solubility was only achieved , when the peptide solution was heated at 60 ° c . for about 2 h . after standing at room temperature , an opaque sol gel was formed . in contrast , when a 5 mg / ml solution of clk6 was prepared in the same way , a clear hydrogel was formed overnight ( see fig3 ). further reduction of the peptide concentration only resulted in an increase in viscosity , but no hydrogel formation could be observed . our previous studies on the parent peptide ac - livagk - nh2 have shown stimuli responsive behaviour to salt , which allows to reduce the minimum gelation concentration by 50 %. to test , whether clk6 displays stimuli response to salt concentration , a 5 mg / ml 1 × pbs solution was prepared . for this purpose , clk6 was dissolved in 9 parts of water and afterwards 1 part of 10 × pbs solution was added . after vortexing , only peptide aggregation , resulting in precipitation of clk6 was observed ( fig3 ). morphological characterization of the cls 6 hydrogel scaffolds was done by field emission scanning electron microscopy ( fesem ) and representative images are shown in fig4 . a fibrillization of cls 6 is clearly visible in both images , confirming the ability of the compound to self - assemble in water . we report here the synthesis of two cyclic peptides which are derived from a class of ultrashort aliphatic peptides . the cyclic peptides were synthesized though a head to tail cyclization reaction , either in solution or on solid support . although one example , cls6 displays limited water solubility , the compounds still displays self - assembling properties , when a solution of cls6 dissolved in hfip is added drop wise to water . to increase the water solubility clk6 was synthesized , whereby the lysine residue bares a positive charge , which should increase the water solubility . upon solubilizing clk6 in water at 60 ° c . a hydrogel is formed after about 2 h standing at room temperature an opaque sol gel was formed . in contrast , when a 5 mg / ml solution of clk6 was prepared in the same way , a clear hydrogel was formed overnight . further reduction of the peptide concentration only resulted in an increase in viscosity , but no hydrogel formation could be observed . fesem studies of cls6 confirmed a fibre structure of the hydrogels proving its ability to self - assemble in water . this new material can be used for drug delivery , nano printing , as nano template , for nano wires and as additive in other peptide based hydrogels . it is to be understood that the described embodiment ( s ) have been provided only by way of exemplification of this invention , and that further modifications and improvements thereto , as would be apparent to persons skilled in the relevant art , are deemed to fall within the broad scope and ambit of the present invention described herein . s . abbour and m . baudy - floc &# 39 ; h , tetrahedron letters , 2013 , 54 , 775 - 778 . c . a . e . hauser , r . deng , a . mishra , y . loo , u . khoe , f . zhuang , d . w . cheong , a . accardo , m . b . sullivan , c . riekel , j . y . ying and u . a . hauser , proceedings of the national academy of sciences , 2011 , 108 , 1361 - 1366 . h . hoshizawa , y . minemura , k . yoshikawa , m . suzuki and k . hanabusa , langmuir , 2013 , 29 , 14666 - 14673 . s . i . kirin , f . noor , n . metzler - nolte and w . mier , journal of chemical education , 2007 , 84 , 108 . a . j . kleinsmann and b . j . nachtsheim , chemical communications , 2013 , 49 , 7818 - 7820 . l . li , h . zhan , p . duan , j . liao , j . quan , y . hu , z . chen , j . zhu , m . liu , y .- d . wu and j . deng , advanced functional materials , 2012 , 22 , 3051 - 3056 . s . manchineella and t . govindaraju , rsc advances , 2012 , 2 , 5539 - 5542 . d . mandal , a . nasrolahi shirazi and k . parang , organic & amp ; biomolecular chemistry , 2014 , 12 , 3544 - 3561 . mishra , y . loo , r . deng , y . j . chuah , h . t . hee , j . y . ying and c . a . e . hauser , nano today , 2011 , 6 , 232 - 239 . j . montenegro , m . r . ghadiri and j . r . granja , accounts of chemical research , 2013 , 46 , 2955 - 2965 . m . r . reithofer , k .- h . chan , a . lakshmanan , d . h . lam , a . mishra , b . gopalan , m . joshi , s . wang and c . a . e . hauser , chemical science 2014 , 5 , 625 - 630 .

US-201615551116-A

a balloon catheter having concentric , elongate lumen and guide tubes defining a lumen therebetween . an annular balloon has its proximal end secured to the lumen tube and its distal end secured to the guide tube . relative axial movement of the tubes adjusts the balloon between retracted and extended positions . processes for using the balloon catheter are also disclosed including performing angioplastic procedures on a plurality of stenoses of differing longitudinal extents during a single catheterization procedure , implanting self expanding stents in blood vessels treating occluded blood vessels and apply medications to diseased blood vessels .

referring to the drawings and to fig1 and 2 in particular , one embodiment of a catheter is shown generally at 10 . the catheter 10 utilizes the usual guide wire 12 . an elongate tubular guide tube 14 surrounds the guide wire . in use the guide tube 14 is slidable longitudinally of the guide wire for insertion into and withdrawal from a blood vessel of a patient being treated . an elongate cylindrically contoured lumen tube 15 is concentrically disposed about the guide tube 14 . a catheter control structure 16 has an elongate through guide tube receiving passage 17 . the control structure is fixed to the proximal end of the lumen tube 15 . the control structure 16 also includes an inflation / deflation port 18 communicating through passage 19 with a lumen 20 . the lumen 20 is an annular passage with its perimeter delineated by the lumen tube 15 and its inner circumference by the guide tube 14 . the control structure carries an annular seal 22 which circumscribes the guide tube 14 . an annular thumb screw 24 is threaded into the control structure 16 for controllably compressing the seal 22 to effect a fluid tight seal between the structure and the guide tube 14 . the guide tube 14 has a plurality of position indicating indicia 25 near its proximal end . the indicia 25 function to indicate to an operator relative longitudinal spacing of the distal ends of the guide and lumen tubes 14 , 15 . an annular angioplasty balloon 26 is provided . the balloon 26 has a proximal end connected to the distal end of the lumen tube at 28 . the distal end of the balloon 26 is connected to the distal end of the guide tube 14 at 30 . as indicated by a comparison of fig1 and 2 , the guide tube is relatively moveable , when the seal 22 is released , between a retracted position as shown in fig1 and an extended position as shown in fig2 . thus , the balloon is adjustable between the position of fig1 where the balloon is folded on itself and the position of fig2 where the balloon 26 is fully extended . the effect of this adjustment is to vary an inflation / deflation volume 32 which is essentially fully defined by the balloon 26 in the retracted position of fig1 . the inflation space 32 is perimetrically defined by the balloon 26 with its inner circumference defined by the guide tube 14 when the guide tube and balloon are in their fully extended positions as shown in fig2 . fig1 a is a foreshortened , sectional view of an alternate embodiment of the catheter 10 &# 39 ;. modified parts as contrasted with the embodiment of fig1 and 2 , are identified by like reference numerals with a &# 34 ;&# 39 ;&# 34 ; added , while identical parts carry the same reference numerals . as will be seen by an examination of fig1 a , the balloon 26 &# 39 ; rather than being folded on itself in a direction forwardly of the catheter when in its shortened position , is folded on itself rearwardly to surround and overlie the lumen tube 15 . to this end the connection 30 &# 39 ; of the distal end of the balloon 26 &# 39 ; and the guide tube 14 &# 39 ;, is not folded on itself as it is in the embodiments of fig1 and 2 . when the catheter 10 or 10 &# 39 ; is to be used to treat a patient , the thumb screw 24 is loosened and the guide tube 14 is retracted relative to the lumen tube 15 and the control structure 16 or the lumen tube and the structure are advanced relative to the guide tube to position the balloon in its retracted position of fig1 or fig1 a and in a deflated condition . the balloon is then inserted into a sterilization tube 34 as shown in fig3 . the catheter is then subjected to the usual sterilization procedures utilizing ethelene oxide gas at elevated temperatures . the effect of the sterilization procedures is that the thermoplastic material of which the balloon 26 is composed is temporarily set in its compressed and deflated condition through the heat of sterilization . in practice angioplasty balloons are made of a variety of thermoplastic materials , including nylon , pet and polyethylene . for the present disclosure nylon is the preferred material . one of the outstanding advantages of the present invention is that in effect one has a single catheter to accomplish what previously took a set of catheters of a range of sizes . with the catheter of this invention , a plurality of stenoses may be treated with a single catheterization . turning first to fig5 and 7 , a guide wire 12 is inserted into a blood vessel 35 . the guide and lumen tubes are then advanced as a unit by pushing the control structure 16 toward the patient . the advance along the guide wire is continued until the balloon 26 in its collapsed and retracted position is within an atheroma 36 of relatively short length longitudinally of the vessel 35 as depicted in fig5 . fluid under pressure is then directed through the port 18 . the fluid is communicated through the lumen 20 into the space 32 within the balloon 26 until the balloon achieves the inflated condition of fig6 . the balloon distends the plaque of the atheroma 36 and the wall of the vessel 35 to relieve the stenosis . once the angioplasty procedure to distend the atheroma 36 has been completed , the balloon is deflated and the catheter 10 is moved , fig7 . at this juncture if there is a second stenosis to be treated , the balloon is moved to a second and longer atheroma 38 , fig8 . at a time which might either proceed or follow the positioning relative to the second atheroma 38 , the thumb screw 24 is loosened to relax the seal 22 . the guide tube 14 is then shifted axially relative to the lumen tube 15 and the control structure 16 to adjust the balloon to an appropriate length . as shown in fig8 and 9 , the adjustment has been to substantially the fully extended length of the balloon . once the length adjustment has been completed , the thumb screw 24 is tightened to compress the seal and fix the tubes 14 , 15 in their newly adjusted relative positions . once this adjustment has been completed and the balloon 26 is appropriately located within the atheroma 38 , the balloon is again inflated , this time to distend the atheroma 38 and the vessel 35 to the condition indicated in fig9 . when the angioplastic plaque expansion procedure has been completed , the balloon is again deflated . if there are further stenoses in the same blood vessel 35 to be treated , the length adjustment and repositioning procedure will be repeated . if there are no further stenoses to treat , the catheter is withdrawn from the vessel 35 . where a stenosis of intermediate length as shown at 40 in fig4 is present , the balloon length will be adjusted to an intermediate length as indicated in fig4 . preferably the sequence of stenosis treatment when there are three or more is to , referring to the illustrations , treat the short stenosis 36 of fig5 to 7 , the intermediate stenosis 40 of fig4 and thereafter the longest stenosis 38 of fig8 to 10 . where the potential for re - occlusion and restenosis is relatively high , it has become accepted practice to insert a stent into a section of the blood vessel that has been expanded through an angioplastic procedure . self expanding stents are useful for certain clinical indications . the balloon catheter of this invention is highly suitable for implanting such stents with the catheter of the alternate embodiment being preferred when the vessel to be treated is of sufficient diameter . referring now to fig1 to 14 , a self expanding stent 42 is shown in a compressed condition in fig1 . for illustrative purposes fig1 to 14 show the stent being positioned within the expanded long stenosis 38 of fig8 through 10 . prior to insertion of the catheter 10 to implant the stent 42 , the stent is telescoped over the lumen tube 15 . the catheter is adjusted to position the balloon in its retracted position of fig1 a . the stent is compressed to a diameter small enough to position it within the balloon 26 &# 39 ; and adjacent the distal end of the lumen tube 15 . when so positioned the balloon functions to constrain the stent 42 in its compressed condition . preferably the balloon is fully deflated to the point where the balloon is longitudinally folded on its self to provide inner and outer contacting layers circumscribing and constraining the stent . after the stent has been compressed and positioned within the balloon , the catheter is inserted until the stent is located within the expanded atheroma 36 . once the balloon is appropriately positioned , the seal 22 is relaxed to the extent necessary to permit relative axial movement of the tubes 14 , 15 as illustrated in fig1 and 13 . the lumen tube is then held stationary as the guide tube is advanced . the advance of the guide tube 14 is continued to literally peel the balloon from the stent , allowing it to expand to the position of fig1 . where some return or restenosis has been experienced , the balloon may be positioned within the stent and inflated to return the plaque of the stenosis 36 to its expanded condition , as illustrated in fig1 . thereafter the catheter is withdrawn . when the stent implantation process dictates a smaller profile than the arrangement of fig1 - 14 , the arrangement depicted in fig2 - 24 is used . referring now to fig2 - 24 , a self expanding stent 42 is shown in a compressed condition in fig2 . for illustrative purposes fig2 - 24 show the stent being positioned within the expanded small stenosis 36 of fig5 through 7 . prior to insertion of the catheter 10 to implant the stent 42 , the stent is telescoped over the lumen tube 15 . the catheter is adjusted to position the balloon in its retracted position of fig1 . the stent is compressed to a diameter small enough to position it within the balloon 26 and against the distal end of the guide tube 14 . when so positioned the balloon functions to constrain the stent 42 in its compressed condition . preferably the balloon is fully deflated to the point where the balloon is longitudinally folded on its self to provide inner and outer contacting layers circumscribing and constraining the stent . after the stent has been compressed and positioned within the balloon , the catheter is inserted until the stent is located within the expanded atheroma 36 . once the balloon is appropriately positioned , the seal 22 is relaxed to the extent necessary to permit relative axial movement of the tubes 14 , 15 as illustrated in fig2 and 24 . the lumen tube is then retracted as the guide tube is maintained stationary and engagement with the stent 42 to resist retractive motion of the stent . the retraction of the lumen tube 15 is continued to literally peel the balloon from the stent , allowing it to expand to the position of fig2 . where some return or restenosis has been experienced , the balloon may be positioned within the stent and inflated to return the plaque of the stenosis 36 to its expanded condition , as illustrated in fig1 . thereafter the catheter is withdrawn . referring to fig1 - 17 , a process for relieving an obstruction in an occluded vessel is shown . the catheter is advanced along the guide wire 12 until the balloon 26 is positioned adjacent an atheroma 46 to be treated . at this juncture the guide tube 14 is in its fully retracted condition such that the balloon distal end connection 30 is immediately adjacent the proximal end connection 26 . as the balloon is inflated it expands against vessel walls adjacent the occlusion and in so doing anchors the balloon against retraction as the balloon is further inflated . as inflation continues the guide tube 14 is advanced slowly either manually or by overcoming friction between the seal 22 and the guide tube with the fluid pressure in the balloon . as the inflation and advance occur , the balloon works its way axially through the atheroma 46 , as illustrated in fig1 , until the balloon has worked its way fully through the atheroma 46 as illustrated in fig1 . after the balloon has advanced through the atheroma the balloon is deflated and the catheter is withdrawn leaving the occlusion opened such that blood flow through the vessel 35 is restored . alternately where conditions permit , an alternate a first step in the process a guide wire 12 &# 39 ; is fed through the vessel . the guide wire 12 &# 39 ; is preferably of the type which has an enlarged tip 45 , known as an &# 34 ; olive &# 34 ; due to its shape having a physical resemblance to an olive fruit . referring now to fig1 - 21 , a local drug delivery system is illustrated . with this procedure the alternate embodiment of fig1 a is utilized . a medication carried by a hydrogel or other carrier 50 is applied to that section of the external surface of the balloon 26 &# 39 ; which is adjacent and surrounding the lumen tube 15 when the balloon 26 &# 39 ; is in its collapsed and foreshortened position as shown in fig1 . thus , the external surface of the balloon when it is in the condition illustrated in fig1 , is free of the medication in order that the medication will not be inadvertently administered other than to the specific diseased region to be treated . this diseased region is illustrated at 52 in fig1 - 21 . in the drug delivery process the catheter 10 &# 39 ; with the balloon 26 &# 39 ; in its collapsed condition of fig1 , is inserted into a blood vessel 54 to be treated . the insertion is continued until the balloon has passed through the diseased region 52 . the guide tube 14 is restrained in the location depicted in fig1 . the balloon is then partially expanded as illustrated in fig1 to anchor the catheter 10 &# 39 ; in its position with the balloon immediately past the diseased region 52 . as a next step , the lumen 15 is retracted , while the guide tube 14 is maintained longitudinally fixed in the blood vessel 54 . as the lumen tube 15 is withdrawn the balloon inflation is continued as the guide tube withdrawal continues , fig2 , until the balloon is in its fully extended and inflated condition of fig2 to apply the drug to , but essentially only to , the diseased region 52 . thereafter the balloon is deflated and the catheter is withdrawn from the vessel 54 . although the invention has been described in its preferred form with a certain degree of particularity , it is understood that the present disclosure of the preferred form has been made only by way of example and that numerous changes in the details of construction , operation and the combination and arrangement of parts may be resorted to without departing from the spirit and the scope of the invention as hereinafter claimed .

US-98457697-A

to practice the method of this invention , a large stainless steel tank having a conical bottom is utilized for the mass cooking of corn to produce masa . connected to the conical bottom of the tank is a multiplicity of steam rings interconnected by a manifold to an external source of steam . a conical screen is positioned closely adjacent the conical bottom to facilitate the injection of steam for heating the contents and selective injection of air for stirring the corn in the cooking or steeping process . interspersed closely adjacent to the steam rings are air injection rings receiving compressed air from the surge tank connected to a compressor . selective injection of compressed air sequentially from the inner air ring followed by injection through the intermediate air ring and the outer air ring stirs the liquid and corn content of the tank in the process of cooking or steeping . the steps of the method of the process of this invention include heating and steeping of corn , water , and calcium hydroxide mixture for predetermined period . selective injection of air through the bottom of the container stirring the steeping mixture , the pumping of fluid from the bottom of the container and discharging the fluid into the top of the container followed by sequential repetition of the foregoing steps until the corn content is cooked or steeped to a desired texture for producing masa followed by the processing the corn into masa .

for a description of the construction and utilization of the preferred embodiment , reference is made to the attached drawings . the steeping tank 10 of fig1 was constructed utilizing fourteen gauge stainless steel to form the outer shell . the seams were welded with heliarc welding and polished smooth . the frame structure 11 , partially illustrated in fig1 , and 4 , is of stainless steel construction welded to and supporting the tank 10 . the conical bottom 12 of the tank was constructed of fourteen gauge stainless steel generally projecting at an angle of approximately 45 degrees downward from the outer wall of the tank 10 . a series of steam rings comprising a first steam ring 14 , a second steam ring 15 , and a third steam ring 16 are formed from stainless steel angle iron spaced and welded to the conical bottom 12 substantially as illustrated in fig1 and 4 . a series of 1 / 8 &# 34 ; steam inlet holes 17 were drilled through the interior of the conical bottom 12 projecting into the various steam rings . the number of these steam inlet holes 17 might vary ; however , in the preferred embodiment , sixty - four evenly spaced 1 / 8 &# 34 ; apertures were utilized in the third steam ring 16 . the total area of all the steam inlet holes 17 preferably equals the area of the steam inlet opening from the manifold 18 into the steam rings 14 , 15 and 16 . interconnecting the various steam rings 14 , 15 and 16 was a steam manifold as best illustrated in fig1 and 5 . this steam manifold 18 is connected to the external source of steam 20 which is controlled by steam valves 19 . the steam components of this device are utilized in the initial heating or cooking step of the method of this invention . secured to the conical bottom 12 of this device are multiple air rings illustrated in the various views . the first air ring 22 , the second air ring 23 , and the third air ring 24 are perhaps best illustrated in fig1 and 6 . these various air rings are spaced from the wall of conical bottom 12 and are interconnected to the device by means of air inlet risers 26 . these risers project through the conical bottom of the tank 12 and terminate adjacent the interior surface of conical screen 45 as illustrated in fig4 . as a part of the compressed air system , an air reservoir or surge tank 27 is employed . supplying air to the air surge tank 27 is an external air compressor 28 . this external air compressor 28 is a large capacity compressor employing a 25 horsepower electric motor and is of the type that might be utilized in hospitals for supplying highly purified air for utilization in respirators and related medical uses . the air compressor employs a multiplicity of filters to remove foreign particles from the air . all oil is removed and a refrigerated filter removes all moisture from the air . the air admitted to the device of this invention is and must meet the highest food processing standards . interconnecting the air reservoir surge tank 27 is a first air pipe 29 , second air pipe 30 , and third air pipe 30 into which is positioned first air valve 32 , a second air valve 33 , and a third air valve 34 . these valves , as illustrated in fig1 - 7 , are manually operated ; however , solenoid control valves could be utilized with appropriate timers controlling their cycle operation as shown and described subsequently in conjunction with fig8 and 9 . first , air hose 36 interconnects first air pipe 29 with first air ring 22 . a similar arrangement is employed in interconnecting the second air hose 37 and the third air hose 38 to their corresponding air rings 23 and 34 . hoses 36 , 37 and 38 are in pairs to distribute air 180 degrees apart for more uniform air injection . in the overall utilization of this device , steeping tank 10 could be manually loaded ; however , an inlet conveyor 40 could be utilized . positioned in the lower apex of a conical bottom 12 of the tank is an outlet butterfly valve 41 which communicates with an outlet conduit 42 which is preferably six inches in diameter to insure the even flow of the processed corn and liquid from steeping tank 10 . an auxiliary water supply 43 may be interconnected to the outlet conduit 42 . in the process of cooking or steeping the corn to produce the masa meal , a cycle of operation of approximately 24 hours is required . interspersed in the various steps of the method or process , it is desirable to periodically recirculate the cooking or steeping liquid within the tank . water is taken from the area between the conical screen 45 and the conical bottom 12 utilizing the water recirculation means 46 as illustrated in fig1 . fluid recirculating pump 47 employs a centrifugal pump component driven by a three horsepower electric motor . fluid recirculation pump 47 receives the fluid from water ring 48 which communicates with the interior of the tank 10 through four evenly spaced water apertures 49 in conical bottom 12 . elevator pipe 50 projects upward to the top of steeping tank 10 where it discharges over a spreading cone 51 . in the method or process of this invention which will be later described , water recirculation means 46 is activated for a period of approximately three minutes interspersed between the various air injection cycles . a positive displacement pump 56 is interconnected to outlet conduit 42 and discharges corn and liquid from the steeping tank 10 through the conical bottom 12 . this pump , powered by a ten horsepower electric motor , moves the liquid and corn from steeping tank 10 through outlet conduit 42 to the water - corn separator 58 . the liquid and corn are separated , and the corn passes through a washer 59 . the corn may be conveyed by a screw elevator ( not illustrated ) into a metering device ( not shown ) which supplies the masa corn to stone grinder 64 . the moist , cooked , processed corn , which contains a quantity of absorbed water approximately equal to the weight of the corn , is ground by a stone grinder 64 and produces a dough - like masa which is collected into a masa bin 66 . this masa is passed through extruder rollers 68 and cut into tortillas , which are deposited on a cooling conveyor 71 . the conveyor passes through an oven 70 and conveyor 71 continues on a multi - level serpentine path to permit the tortillas to cool slightly . the conveyor passes the tortillas to packaging stand where the product may be packaged and boxed . the foregoing , overall process and components for mass cooking and mass production of the tortillas is not considered to be the particular novel portion of this invention . the novelty primarily is believed to reside in the various components and arrangements pertaining to the cooking or steeping tank 10 and the associated steam and air injection rings operably associated with the conical bottom 12 . the arrangements of the components permitting the air stirring of large quantities of corn and liquid ranging from 50 to 150 bushels permitting a slow steeping , cooking , or cooling process produces a superior masa of outstanding quality . in the utilization and operation of the device of this invention , a large cooking or steeping tank 10 may be filled with 50 to 150 bushels of corn , depending on the quantity desired . the tank 10 is then filled with cold water into which is mixed a desired quantity of calcium hydroxide to remove the husks from the corn kernals . when the cooking or steeping tank 10 is filled with the desired quantity of corn and liquid , steam is admitted to the system by opening steam valve 19 leading to the steam manifold 18 resulting in the injection of steam through the steam inlet holes 17 of the various steam rings 14 , 15 and 16 . steam is injected into the system until the temperature of the liquid and corn is raised to just at the point of boiling , which is approximately 212 degrees fahrenheit , at which point the steam is cut off . the mass is allowed to cook and steep in a stationary position for one hour . at this point in the method or process , the air injection step is initiated to insure uniform cooling of the mass . the contents of the tank 10 is stirred by first opening the first air valve 32 admitting air to the first air ring 22 into the bottom center of tank 10 and the air bubbles or flows upward . this process is followed by opening of the second air valve 33 admitting air to the second air ring 23 for a period of time sufficient to cause a bubbling or rolling of the contents of steeping tank 10 . this is followed by the step of opening the third air valve 34 admitting air to the third air ring 24 . this latter step is continued for a sufficient length of time to create a bubbling up or rolling of the liquid and corn contents of the tank 10 . following this initial air injection process , the water recirculation means 46 is activated for a period of two minutes . this series of steps is repeated again in fifteen minutes . this fifteen minute cycle continues for four hours . the air injection sequence is then reduced to once every half hour for the next four hours . following this four hour cycle , the air injection and water recirculation steps are taken once every hour for the next four hours . after a period of approximately sixteen hours of steeping or cooling , the masa is ready for the final step of milling and processing . cyclic step of cooking or steeping corn to produce masa is approximately twenty - four hours . if the corn is a new crop or moist corn , a shorter cooking cycle or steeping cycle may be employed . drier corn , or an old crop of corn stored in elevators for longer periods of time , require a longer cooking or steeping cycle . referring now to fig8 of the drawings , there is shown a schematic diagram of an automatic control system that can be utilized in the operation of the previously described mechanical system for producing the masa . these controls are for the cooking tank 10 prior to discharging of a corn and liquid through positive displacement pump 56 shown in fig7 . referring to fig8 standard household voltage of 110 - 120 volts ac is connected between input terminals 100 and 102 . one line is protected by fuse 104 in a manner well - known in the industry . past fuse 104 is a normally closed off switch 106 , which is connected in series with a normally opened on switch 108 . upon pushing the on switch 108 , start relay r1 is activated . the activation of start relay r1 closes normally opened r1 contacts 110 . this latches relay r1 in the on position even after on switch 108 is released until off switch 106 is pushed . simultaneously with activating start relay r1 , relay r2 is activated through normally closed contact 112 of delayed timer t1 - d . timer t1 has a double pole , double throw contact with an instantaneous portion represented by the letter &# 34 ; i &# 34 ; and the delayed portion represented by the letter &# 34 ; d &# 34 ;. this same nomenclature will be used for other timers having an instantaneous portion and a delay portion . the activation of relay r2 closes normally opened r2 contacts 114 , which in turn activates solenoid valve v1 to open a valve and allow the steam to blow through the line into a drainage to empty condensate out . this only occurs for a couple of seconds because normally opened contact 116 of relay 102 has simultaneously activated relay timer t7 . after a matter of seconds , timer t7 closes normally opened contacts 118 of delay timer t7 thereby activating valve v2 to give steam into the tank 10 . operation of steam valve 19 shown in fig1 is essentially the same as a three - way valve . by activation of v1 as previously described , valves 120 and 122 are opened and valve 124 is closed . by activation of v2 , valve 124 is opened . when neither v1 nor v2 is activated , valves 122 and 124 are closed as well as possibly valve 120 . obviously many other types of three - way valving arrangements may be utilized . it is only important that the steam condensate in the line be blown through to the drain , and not into the tank 10 . the timing for delay timer t7 is normally about two seconds , but it is a variable timer that has a range of 0 - 10 seconds . the length of the steam line would determine the time delay that should be set in by timer t7 . simultaneously with the operation of relays r1 and r2 in fig8 timer t1 has been activated and the delay portion t1 - d starts timing . the delay portion of timer t1 - d may be set over a range , but typically the period of time would be 30 - 45 minutes for cooking of the corn . when the delay portion set into timer t1 has expired , normally closed contact 112 will open deactivating relay r2 . upon deactivating relay r2 , contact 116 opens deactivating timer t7 , contact 114 opens deactivating valve v1 and contact 118 of timer t7 opens deactivating valve v2 . also , normally opened contact 126 of timer t1 - d is closed thereby starting timer t2 with immediate activation of the instantaneous portion and starting the timing of the delay portion . normally closed contact 128 of timer t2 - i is opened . until timer t2 - d has timed out , the corn that has previously been heated by steam will simply sit and steep . during steeping , the corn is still cooking due to the heat previously applied during the steaming cycle . steeping is basically letting something sit in a hot condition . the steeping or the delay set in by timer t1 - d may range from 30 - 60 minutes . the timer t2 - d can be varied from 1 minute to 99 minutes . normally for older corn , the steeping would be for a longer period of time than it would be for new corn . after timer t2 - d has timed out , normally opened contact 130 will be closed thereby providing current flow through contactor 132 of manual / auto switch 134 . thereafter , a current path is provided through normally closed contact 136 of timer t4 - d to timer t3 - i . also current path is provided through normally closed contact 138 of timer t3 - d to the coil for timer t3 - d . when timer t3 - d times out , normally closed contact 138 will open and normally opened contact 140 will close thereby providing a current path to the coil of timer t4 - i , and through contact 142 of timer t4 - d , to the coil of t4 - d . activation of timer t4 - i closes normally opened contact 144 of timer t4 - i . by the arrangement just described , timers t3 and t4 operate so that one is on during the period of time that the other is off . after timer t3 - d has timed out , timer t4 - i closes normally opened contact 146 to activate impulse relay r7 . the activation of impulse relay r7 switches the state of contacts 148 and 150 . at all times , either contact 148 or 150 will be closed and the other opened . these contacts 148 and 150 will remain in that condition until another impulse is received by impulse relay r7 . three pole , double throw relay r9 operates each time that timer t3 - i is activated via normally opened contact 152 and normally closed contact 154 of timer t4 - i . also three pole , double throw relay r9 is activated instantaneous upon turning on power through normally opened contact 156 of relay r2 . also upon applying power through the on switch 8 , if the manual / auto switch 134 is in the automatic position , current is supplied through contactor 158 to timer t5 via normally closed contact 160 of relay r3 , to timer t6 upon activating relay r3 via normally opened contact 162 , and to relay r3 via normally closed contact 164 of timer t6 in conjunction with either normally opened contact 166 of timer t5 or normally opened contact 168 of relay r3 . timer t5 is a delay timer , as well as timer t6 . when timer t5 activates after its delay , normally opened contact 166 will be closed thereby activating relay r3 . the connections in conjunction with timers t5 , t6 and relay r3 operate in such a manner that if t5 is on , t6 is off , and vice versa in a manner similar to timers t3 and t4 previously described . the amount of time that the air is on is controlled by timer t5 and the amount of time that the air is off is controlled by timer t6 . timer t5 normally has a delay of approximately 0 . 5 seconds and may range anywhere from a quarter of a second to a second . timer t6 has a delay of approximately 5 seconds . from the time power is turned on by on switch 108 until it is turned off by off switch 106 , timers t5 and t6 will be cycling as long as the manual / auto switch 134 is in the auto position . this simultaneously causes stepping switch 170 to operate as the center of diode bridge 172 with diode 174 being connected thereacross . stepping switch 107 operates contacts 176 , 178 and 180 in sequential order . contact 176 will close for approximately one - half second thereby activating relay r4 for approximately one - half second , after a ten second delay , contact 178 will close operating r5 for approximately one - half second , and after another ten second delay , contact 180 will close for approximately one - half second thereby activating relay r6 . this occurs continually as long as power is on and manual / auto switch 134 is in the auto position . activation of relay r4 closes r4 contact 182 for approximately one - half second , activation of relay r5 closes r5 contact 184 for approximately one - half second , and activation of relay r6 closes r6 contact 186 for approximately one - half second . therefore , if three pole , double throw relay r9 is activated so that its contacts 188 , 190 and 192 are closed , valves v3 , v4 and v5 will be activated to give sequential blasts of air into the tank 10 every 10 seconds . valves v3 , v4 and v5 correspond to valves 32 , 33 and 34 , respectively . by use of the blast of air , the corn inside of the tank 10 is rolled in a manner that does not create damage . particularly note that the corn is periodically rolled during the period of time that steam is being applied because relay r9 is activated through contact 156 of relay r2 . also , when timer t3 - i is activated closing contact 152 , relay r9 is again activated thereby allowing periodic blasts of air to the corn . it is only during stepping that air is not periodically applied to roll the corn . in the present system , it is envisioned that as many as four tanks will be operated simultaneously ; however , it can be any particular number of tanks . these various tanks are referred to as unit no . 2 , unit no . 3 and unit no . 4 . any one of these particular units may provide the inputs to operate timers t5 and t6 as shown . also , connections a , b and c as pictorially illustrated are electrical connections that would operate valves for other tanks simultaneously with the operation of the valves v3 , v4 and v5 for the unit described hereinabove . there is also provided a pump switch 194 that may be operated in either the automatic or manual mode . the pump switch 194 , when operating in the manual mode , will simply be turned on when it is necessary to pump an excess amount of water off of the corn . in the automatic mode , the pump 194 would be activated during the time that timer t3 - d was timing out . whether operated automatically or manually , activation of relay r8 will close normally open contact 196 of relay r8 thereby operating the motor m which corresponds with pump 47 . operation of pump 47 will circulate the fluid inside of tank 10 . after the cooling step has occurred , then power is turned off by pushing off switch 106 . if the operator wants to stir the corn during steeping , the operator may switch manual / auto switch 34 to the manual mode at which time blasts of air through valves v3 , v4 and v5 will roll the corn as previously described in conjunction with the stepping switch 170 . this depends upon whether or not the operator deems it desirable to stir the corn by blasts of air during steeping . likewise , fluid inside of tank 10 may be circulated by pump 47 by moving pump switch 194 to the manual position . referring now to fig9 there is shown a timing chart illustrating the sequence of steps used in producing corn masa in accordance with the teachings of the present invention . the chart is divided into four parts with each part having a steam cycle represented by the letter &# 34 ; a &# 34 ;, a steeping cycle represented by the letter &# 34 ; b &# 34 ;, and a cooling and soaking cycle represented by the letter &# 34 ; c &# 34 ;. it should be realized that the times may be varied according to the type of product that is to be produced . referring first to part i , a cooking time &# 34 ; a &# 34 ; of approximately 18 minutes is provided . the corn may or may not be rolled during the cooking time of 18 minutes . thereafter , the corn is allowed to steep for approximately 60 minutes . after steeping for approximately 60 minutes , the corn is cooled and soaked as indicated by &# 34 ; c &# 34 ; for approximately 6 hours alternating three minute air cycles for stirring the corn after 35 minutes of dwell throughout the 6 hour cycle . the three minute air blasts are indicated by marks 200 on the timing chart . referring next to part ii , a typical taco shell called happy jose made from white corn is shown . the cooking time &# 34 ; a &# 34 ; of 35 minutes is provided . the corn may or may not be stirred during this cooking cycle . thereafter , the corn is allowed to steep for approximately 16 hours as indicated by the letter &# 34 ; b &# 34 ;. next , the corn is allowed to cool and soak as indicated by the letter &# 34 ; c &# 34 ; for approximately 16 hours with alternating blasts of air for approximately 3 minutes after 35 minutes of dwell throughout the 16 hour cycle . referring to part iii of the timing chart , there is shown the cycle for making taco shells , such as happy jose , from yellow corn . the cooking time &# 34 ; a &# 34 ; is approximately 30 minutes . the corn may or may not be rolled by blasts of air during the cooking time . thereafter , the corn is steeped for approximately 60 minutes as indicated by the letter &# 34 ; b &# 34 ;. next , during cooling and soaking of approximately 16 hours as indicated by the letter &# 34 ; c &# 34 ;, the corn is rotated by alternating three minute blasts of air after thirty minutes of dwell throughout the cooling and soaking cycle . referring to part iv , a typical cooking cycle of an amigo &# 39 ; s brand taco shell is shown . the cooking time is approximately 47 minutes and corn may be rolled during the cooking time by periodic blasts of air . next , during the steeping as indicated by the letter &# 34 ; b &# 34 ;, the corn is basically inactive for approximately 60 minutes . next , during cooling and soaking indicated by the letter &# 34 ; c &# 34 ;, for approximately 24 hours there are alternating 5 minute air blasts after 60 minutes of dwell throughout the 24 hour cycle .

US-15548980-A

this invention provides a spring assembly for use in a chair tilt control mechanism . the tilt control mechanism is one that can recline and return a backrest for a chair . the spring assembly includes a cylindrical block that has first and second ends and a central bore . a pair of end caps is located at each of the first and second ends of the block . each end cap has a receiving section that can rotate within the central bore of the block . each end cap also has a hole extending through it that provides a coupling point for the chair backrest . the spring assembly also includes at least one steel coil spring around the block . the spring has one terminal end coupled to the tilt control mechanism and the other end coupled to one of the end caps . the end caps rotate within the block as the chair backrest is reclined or returned . the force needed to rotate the end caps is a sum of the spring force provided by the spring and the frictional relationship between the block and the end caps .

this invention provides a spring assembly for a tilt control mechanism used on chairs . the spring assembly allows an occupant to exert a force on the backrest of the chair to recline the backrest . the spring assembly also biases the chair to an upright position when the reclining force is relieved . as described below , the spring assembly also provides dwell in the action of the backrest without resort to a rubber torsion spring . with initial reference to fig1 a chair on which the mechanism embodying the principles of the invention can be used is generally indicated by reference numeral 10 . chair 10 is equipped with a base assembly 12 . base 12 preferably has a number of castors 14 operably supported on the outer ends of a corresponding number of support legs 16 . support legs 16 converge to a pedestal column 18 . column 18 supports a gas cylinder 20 that allows the height of the chair to be adjusted by an occupant , as is known to those of skill in the art . the construction of the base 12 and column 18 is well known to those of skill in the chair industry . with continued reference to fig1 a tilt control mechanism 22 is coupled at one point to gas cylinder 20 . tilt control mechanism 22 is also coupled to a seat 24 and a chair backrest 26 . preferably , a pair of armrests 28 is also coupled to tilt control mechanism 22 or seat 24 or back 26 . having briefly described the basic elements of chair 10 , a more detailed description of the various elements of tilt control mechanism 22 is described below . fig2 , and 4 show various components of tilt control mechanism 22 . tilt control mechanism 22 has a base housing or chassis 30 . chassis 30 is preferably a stamped metal piece that provides the overall structure for holding the various components of the mechanism as described below . chassis 30 has a pair of spaced - apart sides , each of which has a hole 32 . hole 32 is used to hold a bearing 34 in place , such as by a press - fit relationship . bearing 34 is preferably steel and has a hole as well . a bushing 36 is located within the hole of bearing 34 , as best seen in fig4 . the bushing 36 has a polygonal hole formed therein , the importance of which is described below . as seen in the figures , the hole is preferably a hexagonal hole . bushing 36 has an outer diameter that closely matches the diameter of the hole in the bearing 34 , such that the bushing 36 can rotate relative to the bearing 34 . in a preferred embodiment , bushing 36 is made from a plastic material . the mechanism 22 also includes an elongated rod 38 that is held within the bushings 36 . more specifically , the shape of rod 38 matches the shape of the hole through the bushings 36 . in the preferred embodiment , the shape of rod 38 and the shape of the hole of bushing 36 are hexagonal . rotation of the rod 38 rotates the bushings 36 within the bearings 34 . rod 38 is used to hold and operate a spring assembly 40 and to attach tilt control mechanism 22 to the frame of chair 10 . as would be understood by those of skill in the art , only the basic components of the tilt control mechanism 22 that relate to the spring assembly 40 are shown in the figures . other components , such as a height adjustment mechanism or a tilt lock - out mechanism could be incorporated into mechanism 22 , as would be understood by those of skill in the art . returning to the spring assembly 40 , fig6 most clearly shows the construction , which includes an end cap 42 on each end of the assembly 40 . end caps 42 are preferably made of a metal material , including steel , a sintered metal , a cast metal , or another material of comparable strength . each end cap 42 has a cap section 44 that extends radially beyond a receiving section 46 that extends axially inward from cap section 44 . each end cap 42 also has a spring fulcrum section 47 . as best seen in fig4 cap section 44 has a notch 48 formed in a part thereof , the importance of which is described more - fully below . a polygonal hole 51 extends through both cap section 44 and receiving section 46 . hole 51 is shaped to match the shape of rod 38 . in the preferred embodiment the hole 51 is hexagonal . the spring assembly 40 also includes a block 52 . block 52 has a hole 54 that extends axially through the entire length of the block 52 . the hole 54 is used to hold the block 52 on the receiving section 46 of the end caps . each receiving section 46 extends into the hole 54 . the hole 54 has an inner diameter that closely matches the outer diameter of the receiving section 46 . block 52 also has a pair of raised spring fulcrum sections 56 that are separated by a radially extending spring separator section 58 . as best seen in fig2 spring separator section 58 is preferably shaped to separate a pair of coil springs 60 . in another embodiment best shown in fig7 the spring assembly 40 further includes a bearing 49 located within hole 54 of block 52 . bearing 49 is able to rotate within hole 54 . in this embodiment each end cap 42 has a truncated receiving section 45 that extends into the hole 54 . a polygonal hole 51 extends through each end cap 42 , including truncated receiving sections 45 . further , a polygonal hole 53 extends through bearing 49 . polygonal holes 51 and 53 are shaped to match the shape of rod 38 . in this embodiment , hole 54 is used to hold the block 52 on the bearing 49 and on the truncated receiving sections 45 of the end caps . hole 54 has an inner diameter that closely matches the outer diameter of the bearing 49 . preferably , bearing 49 is made of a plastic material . each coil spring 60 has a longer tail end 62 and a shorter tail end 64 . in - between the tail ends 62 and 64 are a number of spring coils 66 . the short tail 64 has a notch 68 that is located and shaped to mate with the notch 48 in the end cap 42 . as best seen in fig2 and 6 , springs 60 are held in place on block 52 and are separated from one another by spring separator section 58 . longer tail end 62 and shorter tail end 64 pivot upon fulcrum sections 56 and 47 , respectively , allowing coil spring 60 to coil with minimum restriction . preferably , springs 60 are made of steel . the tension within springs 60 is preferably adjustable with a tension adjustment mechanism 70 . as best seen in fig5 the long tails 62 of springs 60 are held within a receiving bracket or nut 72 . the receiving bracket or nut 72 is threaded onto a threaded rod 74 . rod 74 terminates at a large bevel gear 76 that mates with a smaller bevel gear 78 . the smaller bevel gear 78 is mounted on the end of a rod 80 that terminates at a handle 82 . by rotating the handle 82 , the user can move the bracket 72 upwardly or downwardly to adjust the initial tension on springs 60 . the tension in springs 60 determines the force necessary to recline the backrest 26 of chair 10 . spring assembly 40 is held in place within tilt control mechanism 22 by rod 38 . more specifically , springs 60 are placed over the spring fulcrum sections 56 and 47 of block 52 and end caps 42 , respectively . the receiving sections 46 or 45 of the end caps 42 are placed in hole 54 of block 52 . rod 38 then slides through bushing 36 , into the hole 51 of end caps 42 and out the other bushing 36 . the outwardly extending ends of rod 38 are then coupled to backrest 26 . as would be understood by those of skill in the art , many configurations are available for the attachment of the backrest 26 to the rod 38 . the attachment is made such that reclining the backrest causes rotation of the rod 38 . as shown in fig3 and as discussed above , receiving sections 46 of end caps 42 are placed within hole 54 of block 52 . preferably , block 52 is made from a material that creates a desired frictional relationship with end caps 42 . the desired relationship creates a frictional force such that dwell is achieved in the action of spring assembly 40 . again , one such material that may be used for block 52 is nylon in connection with a metal end cap 42 . it will be understood that any materials that create the desired frictional relationship and have properties necessary to maintain the frictional relationship may be chosen for end caps 42 and block 52 . one spring 60 is disposed over spring fulcrum sections , 47 and 56 , with the notch 68 of short tail 64 located within notch 48 of the end cap 42 . the long tail 62 is held within the receiving bracket 72 . in another embodiment as shown in fig7 and as discussed above , truncated receiving sections 45 and bearing 49 are placed within hole 54 of block 52 . it is preferable that block 52 is made from a material that creates a desired frictional relationship with bearing 49 . in another embodiment it is preferable that block 52 is made from a material that creates a desired frictional relationship with end caps 42 and bearing 49 . in operation , a user can adjust the energy in springs 60 , which adjusts the force required to recline backrest 26 . the restoring torque exerted by springs 60 against the rotation of rod 38 can be adjusted by changing the position of the long tails 62 . rotation of the handle 82 causes the receiving bracket 72 to move linearly along the axis of the rod 74 , which in turn moves tails 62 to the desired radial location . preferably , the gear ratio of the bevel gears 76 , 78 is such that a minimal amount of effort is required to adjust springs 60 to vary the initial restoring torque of the springs and , thereby , control the rate at which backrest 26 tilts rearwardly and returns to an upright position . when the user reclines , rod 38 rotates . this rotation causes bushing 36 to rotate within bearing 34 and causes end caps 42 to rotate relative to block 52 . the friction between the end caps 42 and the block 52 adds to the reclining force , such that the force required to recline the backrest is greater than the return force of the backrest . in another embodiment the rotation of rod 38 further causes bearing 49 to rotate relative to block 52 . in this embodiment the friction between bearing 49 and block 52 adds to the reclining force . in another embodiment the friction between both bearing 49 and end caps 42 with block 52 adds to the reclining force . the steel spring assembly 40 can achieve roughly the same reclining force and dwell action as the traditional rubber torsion springs . the springs 60 are more durable than the rubber springs , and offer a more consistent spring assembly . the action of backrest 26 may be adjusted by altering the materials and dimensions of the components of spring assembly 40 . as suggested above , different materials may be used for end caps 42 and block 52 to adjust the frictional relationship between these two components . the desired frictional relationship between end caps 42 and block 52 may also be altered by adjusting the dimensions of these elements . for example , the diameter of receiving section 46 can be altered to provide more or less clearance from block 52 . in addition , the outer diameter of receiving section 46 ( fig3 ), or the outer diameter of truncated receiving section 45 and bearing 49 ( fig7 ), along with the inner diameter of hole 54 of block 52 may be altered to adjust the amount of force necessary to recline the chair . springs 60 may also be adjusted to vary their resistance . the dimensions of springs 60 and the number of coils 66 may be altered as desired . such adjustments are also applicable to the embodiment including bearing 49 . from the foregoing , it will be seen that this invention is one well adapted to attain all the ends and objects hereinabove set forth together with other advantages which are obvious and which are inherent to the structure . it will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations . this is contemplated by and is within the scope of the claims . since many possible embodiments may be made of the invention without departing from the scope thereof , it is to be understood that all matter herein set forth or shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense .

US-39167903-A

a device for the protection of a high heel is disclosed which is adjustable to adapt to various shoe heel diameters and is barely visible during use .

while this invention is susceptible to embodiment in many different forms , there is shown in the drawings and will herein be described in detail specific embodiments , with the understanding that the present disclosure of such embodiments is to be considered as an example of the principles and not intended to limit the invention to the specific embodiments shown and described . in the description below , like reference numerals are used to describe the same , similar or corresponding parts in the several views of the drawings . this detailed description defines the meaning of the terms used herein and specifically describes embodiments in order for those skilled in the art to practice the invention . the term “ comprising ” is not intended to limit inventions to only claiming the present invention with such comprising language . any invention using the term comprising could be separated into one or more claims using “ consisting ” or “ consisting of ” claim language and is so intended . the terms “ a ” or “ an ”, as used herein , are defined as one or as more than one . the term “ plurality ”, as used herein , is defined as two or as more than two . the term “ another ”, as used herein , is defined as at least a second or more . the terms “ including ” and / or “ having ”, as used herein , are defined as comprising ( i . e ., open language ). the term “ coupled ”, as used herein , is defined as connected , although not necessarily directly , and not necessarily mechanically . reference throughout this document to “ one embodiment ”, “ certain embodiments ”, and “ an embodiment ” or similar terms means that a particular feature , structure , or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention . thus , the appearances of such phrases or in various places throughout this specification are not necessarily all referring to the same embodiment . furthermore , the particular features , structures , or characteristics may be combined in any suitable manner in one or more embodiments without limitation . the term “ or ” as used herein is to be interpreted as an inclusive or meaning any one or any combination . therefore , “ a , b or c ” means any of the following : “ a ; b ; c ; a and b ; a and c ; b and c ; a , b and c ”. an exception to this definition will occur only when a combination of elements , functions , steps or acts are in some way inherently mutually exclusive . the drawings featured in the figures are for the purpose of illustrating certain convenient embodiments of the present invention , and are not to be considered as limitation thereto . term “ means ” preceding a present participle of an operation indicates a desired function for which there is one or more embodiments , i . e ., one or more methods , devices , or apparatuses for achieving the desired function and that one skilled in the art could select from these or their equivalent in view of the disclosure herein and use of the term “ means ” is not intended to be limiting . as used herein the term “ woman &# 39 ; s stiletto ” or “ high heel ” is the standard tapered woman &# 39 ; s shoe heel as depicted in the figures and well known in the art . it is the generally non - replaceable part of the shoe heel . while a variety of different diameters and tapering exist ( which has created the problem solved herein ) the general style of heel is shown and well known . as used herein , the “ lower portion of the stiletto or high heel ” is the very bottom portion of the heel just above the replaceable heel ( heel cap or heel tip ) which is usually some sort of leather , rubber , or plastic portion that is worn down during walking and can be easily replaced by a cobbler . the upper portion of the heel is where the heel is attached to the rest of the shoe . the heel is essentially permanently attached to the shoe and is generally not replaceable . for purposes of this invention , the non - replaceable heel will have a lower portion that extends from the replaceable heel portion upwards to a desired height , such as ¾ , half or a quarter , up the entire heel as necessary . the heel will have a diameter that varies depending on the distance from the replaceable heel but generally tapered as well . the problem being solved by the present invention is in part dealing with this variable diameter and taper of the heel and still making the device unobtrusive and effective . as used herein the term “ clear plastic film ” refers to a polymer film that is see tough and flexible enough to wrap around the stiletto heel in use . examples of polymers suitable for the present invention include polyurethane but based on this disclosure , others are taught . the polymer has an adhesive backing . the adhesive is one that is compatible with the polymeric film and sticks to the material the outer surface of the heel is made of so for example it may need to be compatible with leather , plastic coatings or the like . as an example silicone adhesive could be used . other adhesives could be used or found with little experimentation based on the disclosure herein . the polymeric film will have a lower portion of an essentially trapezoid shape ( including a rectangle shape ) having a fixed height and width or tapered width in a manner to match the stiletto or high heel shape ( tapered heel ). generally the width of the present invention will be greater than the height but may change depending on the exact heel to be adapted . in order to be useful on a wide variety of heels , the straight or tapering sides have one or more adjustable features , for example , perforations which allow the width and taper to be adjusted to fit the circumference of the heel and taper of the heel and make a fit with little or no bulge . perforations can be done in any convenient manner such as between about 2 perforations to about 12 perforations per inch . for example , perforations could be 0 . 07 ″ cut to 0 . 08 ″ cut and 0 . 01 ″ tear to 0 . 02 ″ tear . it will have an upper portion that is tapered and is adjustable in height . again , adjustability can be by perforations which adjust the height of the upper portion . the circumference of the heel is the distance around the heel as shown in the figures , however , a wide variety of heels could be produced for a variety of heels but all can be made adjustable within the scope of the present invention . in one embodiment , there is a non - adhesive backing to protect the adhesive backing until the film is applied to the heel of choice . in applying the device of the present invention to a heel , the device &# 39 ; s middle line is aligned with the center back of the heel and is positioned around the stiletto heel and portions of the side and top portion removed excess device until wrapping it around the heel matches the circumference and / or taper of the heel . then the removable backing is removed and the device &# 39 ; s side is placed against the heel ( as shown in the figures ), wrapped around the heel , and smoothed to remove any air bubbles and make sure it matches . in one embodiment , the seam created by the device is placed where it is least likely to be seen , that is facing the toe of the stiletto or high heel shoe . now referring to the figures , fig1 is a frontal profile of the device of the present invention . protective wrap 1 is shown having trapezoid bottom portion 10 having parallel top 3 and bottom 2 and parallel sides 4 and 5 . ( this example depicts a rectangle but nonparallel sides are also contemplated .) the device has left side 7 and right side 6 which are tapering from the top side 3 to the bottom side 2 to form a trapezoidal shape when torn on 8 a . in order to adjust the width of the device 1 , diagonal perforations 8 a and 8 b are shown in the rectangular portion . in fig1 the device 1 has diagonal perforation 8 a being which can be torn to remove that piece and narrow the width as well as perforating for adjusting the height of lower portion 10 . it is clear there can be one or more perforations as desired to narrow the width of the device and the perforations can be angled as needed . one skilled in the art in view of this disclosure , could easily determine placement of perforations . also shown is backing 9 which in this drawing is in the process of being pulled off the back side of device 1 which is being shown from the front side 15 . an adhesive would be on the back side . fig1 shows tapered upper portion 11 . the upper portion 11 is tapered from the lower portion 10 down to the rounded top 12 . perforations 13 and 14 are also shown for adjusting height . fig2 a , 2 b , and 2 c are a perspective series of the device 1 being wrapped around the lower portion of stiletto heel 23 on shoe 24 . also shown is the replaceable heel cap 25 . while the wrapping is such that the seam will be to a side of the shoe 24 , in one embodiment , the seam is positioned to face shoe toe 26 ( as shown in fig3 ). fig3 shows a perspective of the device completely wrapped around heel 23 without seems or bulges . notice that it is mounted on the lower portion of the heel 23 but any height of the heel can be chosen especially with the adjustable height feature . when in place , it protects the heel from scuffing or damage and can be removed and replaced with a new device easily and quickly . fig4 depicts another embodiment of the present invention . in this view the device 1 has additional vertical width adjusts perforations 20 and 21 which extend from the tapered portion 11 to the trapezoidal portion 10 . also shown is notch 22 for making it easier to peel backing ( not shown in this view ) off of device 1 . those skilled in the art to which the present invention pertains may make modifications resulting in other embodiments employing principles of the present invention without departing from its spirit or characteristics , particularly upon considering the foregoing teachings . accordingly , the described embodiments are to be considered in all respects only as illustrative , and not restrictive , and the scope of the present invention is , therefore , indicated by the appended claims rather than by the foregoing description or drawings . consequently , while the present invention has been described with reference to particular embodiments , modifications of structure , sequence , materials and the like apparent to those skilled in the art still fall within the scope of the invention as claimed by the applicant .

US-201314031873-A

a system and method for using an individual &# 39 ; s unique golf club parameters in the design and manufacture of custom golf club sets at a single work station . the invention accurately measures and cuts the head and butt ends of a complete set of golf club shafts in a single step , permits uniform installation of grips , and precise adjustment of loft and lie and of swing weight distribution .

of the mechanisms included within the apparatus of applicant &# 39 ; s invention , those relating to cutting the shafts of golf club sets are depicted in fig1 a . a production table 10 serves as the mounting platform for a table saw 12 which is used in cutting the shafts of each golf club set . a fiber disk is to be used with the table saw 12 as such a disk achieves the smoothest cut for golf club shafts . referring to fig1 b , 2 , and 3a , a step stop 14 is slidably mounted along two channels 16 formed in the work surface of the production table 10 . the step stop 14 serves to position the shafts of a complete set of golf clubs on the work surface of the production table 10 such that the butt end and tip end cuts may each be made in a single step using the table saw 12 . corresponding to the 1 / 2 inch difference in length between successive clubs in a golf club set , the surface of the step stop 14 against which the ends of the shafts rest during the cutting operation is formed into a stair step - like configuration having &# 34 ; steps &# 34 ; for as many as ten shafts . by positioning an end of each of the 8 to 10 shafts respectively against each of the &# 34 ; steps &# 34 ; of the step stop 14 , the single , straight - line cut which is made by the table saw 12 results in a complete set of golf club shafts having the proper 1 / 2 inch increments of length . referring principally to fig1 b and 2 , a ruler 18 is mounted on the work surface of the production table 10 immediately adjacent to the step stop 14 . the ruler 18 is positioned such that the desired length of the 2 - iron ( the longest of the irons and the club from which the relative measurements of the other clubs in a set are measured ) may be easily selected by aligning the 2 - iron &# 34 ; step &# 34 ; ( the innermost step closest to the ruler with the desired measurement indication on the ruler 18 . for securing the step stop 14 in a desired position , a bolt and wing nut combination 20 passes through the step stop 14 and one of the channels 16 . the step stop 14 is kept in proper alignment with the channels 16 by two runners ( not shown in the drawings ) which are mounted on the underside of the step stop 14 and which are sized for nesting within their respective channels 16 . in cutting a golf club shaft , cuts made at the shaft &# 39 ; s butt end are solely for arriving at a desired length , whereas cuts may at the tip end are for arriving at a desired altered shaft flexibility . when received from the manufacturer , if left uncut at the tip end , a golf club shaft will have its greatest degree of flexibility which exceeds that of the normal golf club shaft . segments of the tip end are removed to achieve a normal flexibility , with larger segments being removed to achieve a stiffer shaft . once the desired flexibility is achieved , segments of the shafts , butt ends are removed to complete the length reduction needed to achieve the desired overall shaft length . the length of the butt end and tip end segments removed during the shaft cutting operation will be in standard , one - half inch increments throughout a golf club shaft in all but very unusual situations . use of the step stop 14 facilitates such uniform cuts at both head and butt ends of the shafts . referring to fig3 b and 4b , to permit a certain degree of mass production using applicant &# 39 ; s invention , viz ., manufacturing a number of 2 irons , then 3 irons , and so on , applicant &# 39 ; s preferred embodiment provides a flat stop 26 . as its name implies , the flat stop 26 has no &# 34 ; steps &# 34 ; and thus is used to cut an identical length from each shaft aligned against it . the flat stop 26 has two pegs which are inserted in stop holes 28 situated at one inch intervals corresponding to cutting shafts ranging from 38 inches to 47 inches in length . referring to fig3 c , 4a and 4b , two guide blocks 22 are used to align a full set of shafts and secure them against the work surface of the production table 10 during use of either the step stop 14 or the flat stop 26 . each guide block has ten semi - circular grooves 24 corresponding in number and size to the maximum number of shafts which will be cut in each single cutting operation . the guide blocks 22 are , in turn , securely held in place over the shafts by two surface - mounted locking clamps 24 . referring to fig1 a and ib , to facilitate performing each step in the manufacturing process for a number of golf club sets , the production table 10 is provided with shaft rack members 30 complimentarily arranged on either long side of the production table 10 . each shaft rack member 30 has a number of semi - circular cutaways 32 generally sized for accommodating the shafts included in one golf club set . prior to installing the head on a golf club shaft , one should abrade approximately one inch of the outer surface of the golf club shaft immediately adjacent to the shaft &# 39 ; s tip end . this enhances the action of adhesives used in mounting heads on golf club shafts . referring to fig1 a , the preferred embodiment of applicant &# 39 ; s invention includes a belt sander 34 useful in abrading the surfaces of shafts . the belt sander 34 is also useful in removing burrs created during the cutting operations . the preferred embodiment of applicant &# 39 ; s invention also includes a shaft crimper 36 . the upper and lower members of the shaft crimper 36 each has an indentation defining one half of the space occupied by a golf club shaft at its tip end . a small protrusion ( usually in the form of a partially embedded ball bearing but not visible in the drawings ) is positioned in each of the indentations . the shaft crimper 36 designed as just - described serves to contour the tip end of a shaft for achieving a more positive joinder between the shaft and the head placed thereon . when producing golf clubs according to the methods of applicant &# 39 ; s invention , the shaft crimper 36 is used immediately after belt sander 34 , unless the swing weight of a club is to be altered . in the latter event , a weight ( to be discussed hereinafter ) is inserted in the tip end of the shaft before crimping . referring to fig1 a , the preferred embodiment of applicant &# 39 ; s invention includes a vise 38 mounted on the work surface of the production table 10 adjacent to the shaft crimper 36 . the vice 38 is principally used in practicing applicant &# 39 ; s invention for holding either a woods retainer 40 or an irons retainer 42 . the retainers 40 and 42 are used for securely maintaining the shafts of a golf club set with their heads installed thereon in uniform orientations for properly and easily installing a golf club set &# 39 ; s grips with emblems and markings on each grip being oriented identically to those on every other grip within the set . referring to fig7 and 8 , the woods retainer 40 comprises a woods head piece 44 , a woods mid - piece 46 , a woods tail piece 48 , a mounting board 50 and a vice rail 52 . the woods head piece 44 , mid - piece 46 , and tail piece 48 are each coated with a smooth , non - abrasive surface to prevent scratching shaft surfaces during use . referring to fig5 and 6 , the irons retainer 42 includes parts corresponding to those of the woods retainer 40 . the irons retainer 42 includes an irons head piece 54 , mid - piece 56 , tail piece 58 , mounting board 60 and vise rail 62 . unlike the woods retainer 40 , the mid - piece 56 of the irons retainer 42 is designed to be adjustable to accommodate the highly - variable shaft / head offset which results from the many - differing irons head designs . a slot 63 in the irons &# 39 ; mid - piece 56 allows the mid - piece 56 move relative to a bolt and wing nut combination 64 for aligning with any given club &# 39 ; s shaft . like their corresponding members for the woods retainer 40 , the head piece 54 , mid - piece 56 , and tail piece 58 of the irons retainer 42 are coated for presenting a non - abrasive surface to club shafts . use of the words retainer 40 or irons retainer 42 as appropriate in producing golf clubs provides a considerable advantage , not only in convenience , but in reducing product &# 34 ; casualty rate .&# 34 ; because vices are often used to hold golf clubs for grip installation , shafts are often collapsed or bent by excessive or uneven force applied thereon . also , holding a golf club shaft with a vise provides no guaranteed uniformity in grip position as does the irons retainer 42 or the woods retainer 40 . once a club is secured by either the woods retainer 40 or the irons retainer 42 , installing the club &# 39 ; s grip is accomplished according to known procedures -- two inch double sided grip tape is wrapped about the shaft where the grip is to be placed , naphtha or an equivalent solvent is placed on the tape to &# 34 ; activate &# 34 ; the glue , and the grip is positioned on the shaft . referring again to fig1 a , the preferred embodiment of applicant &# 39 ; s invention includes a loft / lie gauge and retainer 66 mounted on the work surface of the production table 10 adjacent to the vise 38 . the loft / lie gauge and retainer 66 is used for measuring the extent to which the shaft of a club must be bent to achieve the requested loft and / or lie characteristics of the club . the loft / lie gauge and retainer 66 incorporated into applicant &# 39 ; s preferred embodiment is scotland loft and lie machine distributed exclusively by ocean club , inc . of san antonio , tex . the loft / lie gauge and retainer 66 holds the head of a club securely enough to allow the shaft to be bent while situated within the retainer 66 . adjacent to the loft / lie gauge and retainer 66 is a golf club scale 68 . the scale 68 is primarily used when a particular non - standard swing weight has been requested . when a particular swing weight has been requested , a practitioner of applicant &# 39 ; s invention will , immediately after the shaft cutting operation , temporarily place each club &# 39 ; s head and grip on the shaft for measuring the swing weight . when the amount of corrective weight is determined using the scale 68 , a weight of applicant &# 39 ; s design ( to be discussed hereinafter ) is inserted into the tip end of each shaft prior to using the shaft crimper 36 ( the deformation of the shaft operating to secure the weight within the shaft ). referring to fig9 applicant &# 39 ; s invention includes a weight 70 of novel design for altering the swing weight of golf clubs . the weight 70 will be manufactured in a number of weight increments to achieve any specific desired extent of swing weight correction . each weight 70 is sized for telescopic insertion into the tip end of a shaft . weights 70 will be sized for use in woods and irons shafts of the various materials presently available for golf club shafts . each weight 70 has an annular flange 72 formed at one end . the flange 72 is slightly larger than the interior diameter of a golf club shaft , but is of slightly lesser diameter than the hosel of a golf club head . the flange 72 serves in concert with the head of the golf club to maintain the weight 70 at the tip end of the shaft . a hole 74 is formed opening at either end of the weight 70 in an axial orientation . the hole 74 permits air within the hosel of a club head to escape while installing the head on the shaft having the weight 70 therein . without the hole 74 , the air within the hosel would be compressed as the head is placed on the shaft and would tend to force the head from the shaft before the epoxy used in mounting the head fully cures . use of the weight 70 in altering the swing weight of a golf club is considerably more convenient and precise then the presently practiced lead shot or powder / cork method . referring again to fig1 a , the second terminal end of the production table 10 opposite the shaft cutting apparatuses is outfitted for stockpiling completed golf club sets to await packaging for shipment or presentment to a purchaser . a number of 1 inch × 1 / 2 inch × 96 inch wood strips 76 are mounted on the work surface of the production table 10 parallel with the length of the table 10 and with each other . the wood strips 76 are separated from each other by approximately 31 / 4 inches . carpet strips 78 are attached , preferably by gluing , to the working surface of the production table 10 between the wood strips 76 . six inch long pegs 80 are placed at six inch intervals on a wall or upright member immediately to the rear of the production table 10 and longitudinally coextensive with the wood strips 76 and carpet strips 78 . the pegs 80 are positioned approximately thirty two inches above the production table &# 39 ; s 10 work surface . the combination of the wood strips 76 , the carpet strips 78 , and the pegs 80 permit a large number of golf clubs to be stockpiled in a manner which prevents scratching or scarring of the shafts or of the heads of the finished clubs . although the invention has been described with reference to specific embodiments , this description is not meant to be construed in a limited sense . various modifications of the disclosed embodiments , as well as alternative embodiments of the inventions will become apparent to persons skilled in the art upon the reference to the description of the invention . it is , therefore , contemplated that the appended claims will cover such modifications that fall within the scope of the invention .

US-17824988-A

the present invention is a kit and a method of using a kit for treating bone including a fill material mixture made of osteoconductive material , osteoinductive material and a lubricating carrier , a porous container to receive the fill material mixture and a tool that flowably introduces the fill material mixture into the porous container .

the allograft mixture may generally be comprised of three components : non - demineralized cortical cancellous allograft granules or other suitable osteoconductive material , demineralized bone matrix (“ dbm ”) or other suitable osteoinductive material and sodium hyaluronan ( ha ), or other suitable lubricating carrier . the non - demineralized cortical cancellous allograft granules may generally be 200 - 2000 microns in size and may have an aspect ratio of about 1 . 5 longer than wide . the dbm may generally be 100 - 1000 microns in size and tends to be more uniform and rounded in shape . the lubricating carrier may generally be a viscous liquid , for example , sodium hyaluronan in varying molecular weights , alginate , dextran , gelatin , collagen and others . the dbm is more likely than the non - demineralized granules to be suspended in the lubricating carrier due to the geometric and size difference between the dbm and the non - demineralized granules . ceramic materials may be added as alternatives to the cortical cancellous granules . the ceramics are also load bearing , load sharing , and osteoconductive . the ceramic material formulation may include , for example , calcium hydroxyapatite , tricalcium phosphate and calcium sulfate among others . calcium hydroxyapatite resorbs very slowly , over a period of years . tricalcium phosphate resorbs slowly , in about 3 - 6 months . calcium sulfate resorbs more quickly , in less than 3 months . as shown in fig1 , the tendency for the dbm to flow with the carrier is particularly noticeable when the mixture is delivered and packed into the mesh container 10 . the dbm particles flow through the mesh pores under the force applied by the emptying of the filled tube into the confined mesh container . the smaller of the dbm particles flow through the mesh pores into the bony defect . these dbm particles are the sole osteoinductive elements in the mixture . as the dbm is forced through the mesh pores , the dbm makes intimate contact with the irregular surfaces of the bony defect and consequently causes new bone to grow precisely at the surfaces where bony fusion is intended . the mesh pores , generally about 250 - 5000 microns , may act as a sieve or filter that preferentially retains the non - demineralized granules . this filtering feature may allow the larger , irregularly shaped granules to pack tightly together within the mesh while the fluid component , also carrying the particles of dbm , may fill the interstices of the packed granules and flow through the pores of the mesh . the relationship between the sizes of the dbm , the mesh pores and the granules may generally be described as follows : if the granules have a size equal to x , then the dbm size may generally be in the range of 0 . 3 - 0 . 7x and the pore size may generally be in the range of 0 . 5 - 2 . 5x . the formulation of the mixture may generally be in the range of about 2 parts dbm , 8 parts non - demineralized allograft granules and 8 parts lubricating carrier . the non - demineralized granules are primarily osteoconductive ( supporting bone growth on the surface , but not strongly inducing growth ), while the dbm is both osteoconductive and osteoinductive ( encourages bone to grow ). because the dbm is osteoinductive , as the dbm flows out of the mesh pores in the fluid carrier , the dbm creates an increased potential for bone growth surrounding the mesh container , at the host - mesh interface , which may help to speed bony healing , or incorporation of the mesh and graft into the host bone structure . as shown in fig2 , a single mesh container 10 may have varying pore sizes , resulting in a differential porosity . that is , where the pores are larger , more fill material will flow out of the pores and where the pores are smaller less fill material will flow out of the pores . this differential porosity allows the surgeon to direct the flow of material out of the mesh pores and thus optimize the placement of the osteoinductive dbm more precisely to promote bony growth at the defect site . fig3 shows a preferred tool 20 , patented as u . s . pat . no . 6 , 620 , 169 to spineology , inc , that may be used to process and inject the fill material mixture . in a preferred embodiment , the tool 20 shown in fig3 is used to process the fill material mixture and inject the mixture into fill tubes . fig4 shows the preferred embodiment where the fill material mixture is extruded from a fill tube 30 having at least one opening to direct the flow of the fill material mixture into the porous container 10 for optimal fill material placement . additional components , for example , bone morphogenic protein , vascular endothelial growth factor , platelet derived growth factor , insulin - like growth factor , chondrocyte growth factor , fibroblast growth factor , antiviral agents , antibiotic agents and others may be added to the formulation .

US-75438810-A

a method of dynamically measuring parameters within a series of images using image processing is disclosed . a sequence of ultrasound images is generated by means of an ultrasound system . a user determines at least one region of interest within a first image . then , at least one parameter for each region of interest is evaluated , e . g . the number of pixels exceeding a pre - defined intensity are counted . a new region of interest within a sequential image is searched within a search area around the predefined region of interest which best matches the region of interest . this is done for all images of a sequence whereby the new region of interest which best matches the region of interest of the previous image is used as a region of interest for the following image .

fig1 is a block diagram of an ultrasound system that produces sequential images of an object of interest and comprises a transducer . the ultrasonic transducer 100 comprises an array of piezoelectric crystals that deliver ultrasonic energy into a patient and receive ultrasonic echoes from the patient . electrical signals representative of the echoes produced by the transducer 100 are delivered to transmit / receiver unit 110 where they are selectively combined to produce an indication of the echo intensity along a particular direction or beam in the patient . the data produced by the transmit / receiver unit 110 are fed to an echo processor 120 that calculates an echo parameter at each position along a beam . the echo processor may incorporate a beam former and may scan convert the data parameters . furthermore , the echo processor may calculate a doppler shift , the power of a doppler shift , the echo intensity of a fundamental , the echo intensity of all non - linear components , the echo intensity of harmonic or sub - harmonic components , the strain , attenuation or thermal properties , etc . of the echoes received along a particular beam . data from the echo processor 120 is fed to a scan converter 130 that converts the data into a form that can be readily displayed on a video monitor . this arrangement generates a series of images with a specified frame rate . the data produced by the scan converter is stored in an image processor 140 , for example , on a hard drive , where an additional processing , such as adding color , may be performed prior to displaying the images on a video monitor 160 . the image processor may include one or more processor sub - systems including digital signal processors ( dsps ) and / or general purpose processors for further enhancement and / or processing . controlling the operation of the above - referenced parts are one or more central processing units 150 . the central processing units 150 also receive commands from a user through a variety of controls ( not shown ) that allow the user to adjust the operation of the ultrasound machine . a light pen , trackball , a mouse input device 170 or any other input device is coupled with the central processing unit 150 to allow a user to define specific points of interest on the screen 160 . the system can further be equipped with a voice recognition system to activate and / or control features of the present invention . fig2 a shows a typical set up screen . firstly , a sequence of ultrasound images using the b - mode and / or doppler - mode of the global region within , e . g . a patient is taken . therefore , ultrasound waves are sent via the transducer 100 into a body and are reflected by tissue , organs , etc . the reflected waves are processed within the echo processor 120 and further processed by scan converter 130 and image processor 140 to form a visual image of the examined area . a series of images with a predefined frame rate can be stored , e . g . on a hard disk or processed in real - time . secondly , the user defines in a setup screen that displays a first image of an image series or the initial scan in case of a real - time operation one or more regions of interest ( roi ) by means of an input device 170 , such as a mouse , a light pen , a graphic tablet , touch screen , etc . in fig2 a , e . g . two roi 200 and 210 have been defined . the rois according to fig2 have a square or rectangular shape . within these pre - defined roi 200 and 210 lie , e . g . a blood vessel or a specific organ or part of an organ . the region of interest can have a square , rectangular , circular , elliptic , polygon or user - defined shape . a user can choose which shape is the most appropriate for the respective region of interest . size and shape may depend on the respective object of interest . regions of interest ( roi ) are placed in the doppler or b - mode image over selected vasculature . the signal intensity is measured from the image by summing the image values ( doppler or b - mode ) in the roi . graphs of the roi values over time are plotted to demonstrate the time history of the blood flow . parameters derived from the graphs may be used to quantitate blood flow . now follows the evaluation of the pre - defined rois . therefore , each roi is examined by an examination routine . within this routine , for example a threshold for b - mode images is set . the routine then counts every pixel within the roi whose intensity exceeds the pre - defined threshold . in another embodiment multiple parameters within one roi can be determined by a plurality of ranges . if certain characteristics lie within a specific intensity range , different parameters can be separated by different intensity ranges . to define an intensity range multiple registers can store the respective range values . the registers can be hardware registers or can be represented by specific memory locations within the main memory of the image processor . to enhance the echos sent back from the examined blood vessel or organ , in addition contrast agents may be used . furthermore , different methods of image processing can be applied . for example , instead of using the fundamental echo waves for gray - scale intensity imaging , the so - called harmonic imaging technique can be used . especially contrast agents reflect ultrasound waves with harmonics which can be filtered out to distinguish them from tissue reflections which have less or no harmonics . another method is called the phase inversion method that uses two ultrasound waves with an inverted phase . thus , the reflected ultrasound waves are combined to eliminate or minimize the fundamental component of the received signal and only the remaining non - linear components contribute to the images sent to the image processor . if a doppler - mode is used with or without the b - mode , usually the doppler - mode results are displayed in color on the screen to distinguish it from the b - mode picture . in this case the routine counts the colored pixels within the roi indicating the amount of blood and / or contrast agent within a blood vessel or organ . again , multiple parameters can be separated by means of different intensity ranges if appropriate . the result of this evaluation can be depicted in a graph , for example , at the bottom of the screen . as a next step , the evaluation of the image series is started . for each following image in the sequence it is first evaluated whether the roi 200 and 201 have moved . fig2 b shows a sequential ultrasound image with moved roi 201 and 211 . the calculation of the new rois can be done by means of an image comparison routine . a suitable method is described in u . s . pat . no . 5 , 575 , 286 which is hereby incorporated by reference . for example , a search area around the roi of a first image is defined and a best match within this search area of the second image is calculated and establishes a new roi . the new rois will be used for the following ultrasound image , etc . in the shown example of fig2 b the object , e . g . the blood vessel or organ , would have moved out of the initial roi and therefore without the method according to the present invention a false evaluation would have taken place . fig2 b is an exaggerated display of a movement of an object which could actually occur over time , in other words over a series of images . a suitable image comparison routine , for example , defines a search area around a roi . the roi may have the size of n pixel points in lateral direction and m pixel points in axial direction for the first b - mode image . as mentioned above , any kind of shape , such as polygon , circular , etc . can be established for a roi . the search regions will be defined for the succeeding image with the size of n + 2δn pixel points in lateral direction and m + 2δm pixel points in axial direction for the second b - mode image . the following search will be done for each roi at 2δn by 2δm locations . at each location , a sum - absolute - difference ( sad ) value is computed , whereby each sad roi has m × n points . the sad value is evaluated for each ( i , j ) until a minimum of sad occurs which will be the best match of the respective roi of the first and second image . these values also represent the new roi for a following image and new values are calculated in the same manner for all following images of a series . the respective equation may be represented by : sad  ( i , j ) = ∑ n = 1 n   ∑ m = 1 m    i m , n - j m + i , n + j  where i and j are the grade levels ( b - mode image intensities ) at the user specific locations from these two b - mode images . the parameters i and j are within the following ranges : − δn & lt ;= i & lt ;= δn , − δm & lt ;= j & lt ;= δm . the displacements in both lateral and axial directions are given by x 1 = id and y 1 = jd , whereby d is the image pixel size . this result of this coarse - scale search is usually precise enough for the purpose of tracking a specific pre - defined area containing , e . g . a blood vessel or organ . for ideal cases , where noise signals are relatively small compared to the echo signals , the accuracy of this search is mainly limited by the pixel size of the b - image . for example , using a 2 . 5pl20 probe for cardiac imaging in vivo with a depth of 80 . 0 mm , the pixel size is about 0 . 17 mm , which is much smaller than other uncertainties caused by other artifacts , such as the variation of speed of sound or the organs complex motion . instead of the sum - absolute - difference method ( sad ) a sum square difference ( ssd ), or a cross correlation method or any other suitable image comparison can be used . also all methods can also be used as normalized methods . once the new rois are established the evaluation routine as described above takes place again to determine , for example the amount of blood and / or contrast agent in the respective investigated object . the resulting data will again be displayed in the above - mentioned graph . fig5 shows a sample graph for a fully computed image sequence . the shown graph represents a time intensity parametric curve . multiple regions are represented by different graphs ( only one shown in fig5 ). in addition , certain characteristic parameters , such as rise time , decay time , peak value of the curve can be displayed to give further information to a user . many other parametric values are possible . fig3 shows an example of a series of three rois 205 , 206 , and 207 taken out of an ultrasound image sequence . in this example the b - mode is combined with doppler - mode , wherein the result of the doppler - mode is overlayed in color on top of the b - mode image . the color is represented by shaded areas 255 , 256 , and 257 . it represents the amount of blood / contrast agents flowing through object 225 , e . g . a blood vessel . the different rois 205 , 206 , and 207 represent different stages within a series of ultrasound images taken , for example as shown in fig5 at times t 1 , t 2 , and t 3 , respectively . fig4 shows a similar sequence of rois of an ultrasound image sequence applying the b - mode . in this sequence a pre - defined threshold is set by a user . the threshold separates the object of interest , e . g . blood , contrast agent , etc . from other representations , such as tissue , bones , etc . the roi evaluation routine will count the pixels whose brightness level is above the pre - defined threshold and display it in a similar manner as described a with respect to fig3 . fig6 depicts a flow chart diagram showing a typical evaluation of an ultrasound image series according to the present invention . after an image sequence has been recorded one or more rois are defined by a user in step 600 . in step 610 one or more rois are evaluated as described above and in step 620 the results are stored and / or displayed . step 630 determines whether the last image of an ultrasound image has been processed . if yes , the routine ends , if no , then the next image of the ultrasound image sequence is fetched in step 640 . in step 650 one or more new rois are calculated and the routine repeats step 610 - 650 until the whole sequence has been processed . the method according to the present invention is also not limited to the described post - processing . instead , a real time application is easily feasible . after the ultrasound transducer has been placed on , e . g . the patient by one hand , the user defines the roi ( s ) either before or after the collection of the image sequence ., for example , by means of a light pen or mouse operated with his other hand . once the roi ( s ) have been defined the method according to the present invention keeps track of the roi ( s ) and the graph ( fig5 ) can be displayed in real - time . furthermore the tracking can be performed in a forward time direction or in a reverse mode . also , if suitable an image within a sequence may be deleted or skipped from consideration or edited if the motion is too large . in another embodiment , if the tracking algorithm does not identify the roi in a specific image of the sequence it can automatically skip this image . the threshold value for skipping an image , or in other words the quality of a specific image may be defined by a user . furthermore , if an automatic image match is not found with the search algorithm , a user can manually define a region location . this method is in particular suitable within any kind of post - processing . any type of image comparison technique can be applied in step 650 . for example , a certain preferably static characteristics , such as a static shape or brightness transitions can be vectorized and its position can be compared in the following images thus defining reference coordinates which are used to define the position of the rois . as described any type of blood flow imaging technique such as doppler - mode , harmonic - mode , phase - inversion - mode , etc . can be used to provide proper data for the evaluation of a roi . any type of image comparison technique which is able to track an object is applicable . the present invention is not limited to the use of ultrasound and can also be applied to any type of ultrasound , radiology or mr system . the present invention avoids any motion effect on the accuracy of an estimation of a time intensity curve .

US-54303000-A

a cigarette is provided having a variable length . a filter or mouthpiece slides within a sleeve attached to the cigarette , or a sleeve attached to the filter or mouthpiece slides over the cigarette . a single band is adhered to one element and a pair of bands is adhered to the other element . the single band is captive between the pair of bands so that the cigarette can be lengthened or shortened within the range allowed by the pair of bands , but the filter or mouthpiece cannot be removed from the cigarette . the variable length mechanism can be made to additionally provide variable dilution or variable flavorant .

in the discussion that follows , when the distances of two bands from a particular point are compared , the distances are to be measured to the adjacent or abutting edges of the bands in question . a first embodiment 10 of a cigarette according to this invention is shown in fig1 and 2 . cigarette 10 includes a cigarette rod 11 and a filter plug 12 circumscribed by peripheral layer 13 . peripheral layer 13 could be traditional plug wrapping or an extruded covering , or it could be the outer self - supporting ( e . g ., fused ) layer of an unwrapped filter plug . as shown , cigarette rod 11 is simply a tobacco rod , including a charge of tobacco 14 wrapped in cigarette paper 15 . however , cigarette rod 11 could include an additional filter segment ( not shown ) at the end adjacent filter plug 12 , so that the cigarette as a whole has a tobacco rod and a segmented filter plug . filter plug 12 is circumscribed by three bands 21 , 22 , 23 of tipping paper or similar material , in sequence . first band 21 and third band 23 are adhered to peripheral layer 13 by adhesive bands 24 , 25 , respectively . the distance of first band 21 from the rod end of filter plug 12 exceeds the distance of third band 23 from the rod end of filter plug 12 by more than the width of second band 22 . second band 22 is not adhered to peripheral layer 13 and is thus free to slide along filter plug 12 between first and third bands 21 , 22 . first band 21 is overwrapped by first tipping paper section 16 , which is adhered to band 21 by adhesive band 17 . second tipping paper section 18 overlaps the remainder of filter plug 12 and a portion of cigarette rod 11 , and is adhered to second band 22 by adhesive band 19 and to cigarette rod 11 by adhesive band 101 . adhesive band 19 is at least as far from the end of cigarette rod 11 adjacent filter plug 12 as first band 21 is from the rod end of filter plug 12 . second tipping paper section 18 and second band 22 thus form a sleeve in which filter plug 12 can move longitudinally . first and third bands 21 , 23 serve as stops to prevent plug 12 from moving too far in either direction . third band 23 prevents the removal of plug 12 from cigarette 10 , while first band 21 prevents plug 12 from moving too close to cigarette rod 11 . as shown in fig1 and 2 , first band 21 is positioned to stop plug 12 as it reaches cigarette rod 11 , but it could be positioned to stop plug 12 at a finite distance from cigarette rod 11 , if desired . a second embodiment 30 of a cigarette according to this invention is shown in fig3 and 4 . cigarette 30 also has a cigarette rod 11 and a filter plug 12 circumscribed by peripheral layer 13 . again , cigarette rod 11 is shown as being simply a tobacco rod , but could also include an additional filter segment . in this embodiment , cigarette rod 11 is circumscribed by first , second and third bands 31 , 32 , 33 , in sequence . first and third bands 31 , 33 are adhered to cigarette rod 11 by adhesive bands 34 , 35 respectively . first band 31 is adhered to cigarette rod 11 at a first preselected distance from the end of cigarette rod 11 adjacent filter plug 12 and third band 33 is adhered to cigarette rod 11 at a second preselected distance from the end of cigarette rod 11 adjacent filter plug 12 which exceeds the first preselected distance by more than the width of second band 32 . second band 32 is not adhered to cigarette rod 11 and is thus free to slide along cigarette rod 11 between first and third bands 31 , 33 . filter plug 12 and first , second and third bands 31 , 32 , 33 are overwrapped by tipping paper 36 , which is adhered to peripheral layer 13 by adhesive band 37 and to second band 32 by adhesive band 38 . the distance from the mouth end of filter plug 12 to adhesive band 38 is greater than the sum of the length of filter plug 12 and the first preselected distance , and also greater than the sum of the length of filter plug 12 and the difference between the second and first preselected distances . tipping paper 36 and second band 32 thus form a sleeve with which filter plug 12 is longitudinally slidably mounted on cigarette rod 11 . first and third bands 31 , 33 serve as stops to prevent filter plug 12 from moving too far in either direction . first band 31 prevents the removal of filter plug 12 from cigarette rod 30 . third band 33 prevents filter plug 12 from moving too close to cigarette rod 11 . as shown in fig3 and 4 , third band 33 is positioned to stop filter plug 12 as it reaches cigarette rod 11 , but it could be positioned to stop filter plug 12 at a finite distance from cigarette rod 11 , if desired . a third embodiment 50 of a cigarette according to this invention is shown in fig5 and 6 . cigarette 50 has a cigarette rod 51 circumscribed at its mouth end by a mouthpiece 52 of plastic or relatively stiff paper . as shown , cigarette rod 51 is shown as a tobacco rod 53 and a filter segment 54 , joined together by tipping paper 55 , but it can also be simply a tobacco rod . in this embodiment , cigarette rod 51 is circumscribed by first , second and third bands 61 , 62 , 63 , in sequence . first and third bands 61 , 63 are adhered to cigarette rod 51 by adhesive bands 64 , 65 , respectively . first band 61 is adhered to cigarette rod 51 at a first preselected distance from the mouth end of cigarette rod 51 , and third band 63 is adhered to cigarette rod 51 at a second preselected distance from the mouth end of cigarette rod 51 which exceeds the first preselected distance by more than the width of second band 62 . second band 62 is not adhered to cigarette rod 51 and is thus free to slide along cigarette rod 51 between first and third bands 61 , 63 . mouthpiece 52 and first , second and third bands 61 , 62 , 63 are overwrapped by tipping paper 56 , which is adhered to mouthpiece 52 by adhesive band 57 and to second band 62 by adhesive band 58 . the distance from the mouth end of mouthpiece 52 to adhesive band 58 is greater than the first preselected distance and greater than the sum of the length of mouthpiece 52 and the difference between the second and first preselected distances . tipping paper 56 and second band 62 thus form a sleeve with which mouthpiece 52 is longitudinally slidably mounted on cigarette rod 51 . first and third bands 61 , 63 serve as stops to prevent mouthpiece 52 from moving too far in either direction . first band 61 prevents the removal of mouthpiece 52 from cigarette rod 51 . third band 63 prevents mouthpiece 52 from moving too far toward the coal end of cigarette rod 51 . as shown in fig5 and 6 , third band 63 is positioned to stop mouthpiece 52 when it is flush with the mouth end of cigarette rod 51 , but it could be positioned to stop mouthpiece 52 before it is flush with rod 51 , leaving some minimum recess . cigarettes 10 , 30 , 50 have all been shown with circular cross sections . it is within the scope of this invention to produce a variable length cigarette having an ovoid or other non - circular cross section . in fig1 a , cigarette 100 is shown having an ovoid cross section . cigarette 100 is similar to cigarette 10 except for its cross - sectional shape , having an ovoid cigarette rod 111 , and an ovoid filter plug 112 circumscribed by peripheral layer 113 , first and second bands 121 , 122 , third band 123 ( not shown ), and first and second tipping paper sections 116 , 118 , all adhered as in cigarette 10 . the extendable portions of cigarettes according to this invention having circular cross sections can also be rotated . the extendable portions of cigarettes according to this invention having ovoid or other non - circular cross sections may or may not be rotatable . if they are constructed like cigarettes 10 , 20 or 100 , they cannot be rotated because the tipping paper sleeve is fixed in shape by being adhered to the filter plug . however , if they are constructed like cigarette 30 , they may be rotatable if mouthpiece 52 is sufficiently deformable to follow the changing contours as the extendable portion is rotated . in addition to providing variable length , the extendable portion of a cigarette according to this invention can also provide variable dilution or variable flavorant . variable dilution is shown in cigarettes 10 , 30 , and it can also be provided in cigarette 50 . as seen in fig1 and 2 , second tipping paper section 18 has a circumferential row of holes 70 overlying third band 23 . third band 23 and the underlying peripheral layer 13 have an array 71 of holes underlying row 70 . each row in array 71 has a different number of holes . row 70 has the same number of holes as the row in array 71 with the greatest number of holes . as shown in fig1 when the cigarette is at its maximum extended length , row 70 is in registry with the maximum row of array 71 providing maximum dilution by allowing a maximum amount of air to enter the smoke stream of cigarette 10 . as shown in fig2 cigarette 10 is at its minimum length and row 70 is in registry with the minimum row of array 71 , providing minimum dilution . in this embodiment , array 71 is movable and row 70 is stationary , but the reverse is also possible . as shown in fig3 and 4 , cigarette 30 has a row 72 of holes in first band 31 and the underlying cigarette paper 15 , and an array 73 of holes in tipping paper 36 . in this embodiment , maximum dilution is provided with cigarette 30 at its minimum length , and minimum dilution is provided with cigarette 30 at its maximum length . here too , the row of holes is shown as stationary , and the array of holes is shown as movable , but the reverse is also possible . other methods of dilution are possible in the construction shown in cigarette 10 . peripheral layer 13 can be made air - permeable . in such a case , as cigarette 10 is lengthened , more of permeable peripheral layer 13 is exposed to the air , increasing dilution . another method that could be used is to provide two longitudinally elongated slits , one in the tipping paper and one in the peripheral layer , which register in varying degrees as the cigarette is lengthened and shortened . in any embodiment , at least one of the tipping paper and peripheral layer must be substantially air - impermeable for effective control of dilution . no dilution mechanism is shown for cigarette 50 , but it is possible to provide one . if a particular embodiment is capable of rotation as well as extension , as discussed above , the dilution holes can be registered and deregistered by rotation as well as by extension . variable flavorant is shown in cigarettes 10 , 30 , and can also be provided in cigarette 50 . as shown in fig1 and 3 , cigarettes 10 , 30 have crushable capsules 80 of flavorant between movable filter plug 12 and the end of cigarette rod 11 . as filter plug 12 is moved forward on cigarette rod 11 , capsules 80 are burst , releasing their flavorant . as an alternative , microcapsules ( not shown ) can be coated onto surfaces that move relative to adjacent surfaces , such as the inside of tipping paper 18 at 81 , the inside of tipping paper 36 at 82 , or the inside of mouthpiece 52 at 83 . as these sections move relative to adjacent structures , the microcapsules are ruptured by friction . other flavor trapping media can also be used . when a single large capsule is used , as in fig1 it is relatively easy to burst , and all the flavorant is released at once . the burst capsule is shown in fig2 . when several smaller capsules are used , as in fig3 they are harder to break and do not all break at once , allowing the smoker to release additional flavorant by applying additional pressure . as shown in fig4 only some of the capsules have been burst . when microcapsules are used , they are even harder to break , and more flavorant is released with each extension or shortening of the cigarette , as more capsules rupture because of friction . as an alternative to capsules or microcapsules , a flavorant can be mixed with a carrier that will release it on contact with water vapor or other smoke constituents . the mixture can be coated onto surfaces that are exposed in varying amounts to the smoke flow as the cigarette is lengthened and shortened . many different flavorants can be used . flavorants which can be added to the smoke during the course of smoking the entire cigarette , such as menthol , can be used . alternatively , flavorants which would be overwhelming if added during the course of smoking the entire cigarette , but which would be refreshing and effective as a &# 34 ; last puff freshener &# 34 ; if added during the last few puffs , such as anise or orange , could be used . if a &# 34 ; last puff freshener &# 34 ; is used , the smoker would be instructed not to lengthen or shorten the cigarette until he was almost ready to finish it . a preferred flavor capsule for use in the cigarette of the present invention has a shell of 80 % vinyl acetate and 20 % algin and is filled with menthol in peppermint oil . the fill makes up 70 % of the capsule weight . the capsule diameter is from about 1 , 100 microns to about 2 , 500 microns . the capsule has an average break force of 272 grams . other capsules which can be used with this invention can have shells of paraffin or polyvinyl acetate with polyvinyl alcohol and can be filled with compounded flavors in coconut oil . the fill can make up 20 - 80 % of the capsule weight , and the capsule diameter can be from about 800 microns to about 2 , 600 microns . the break force can range from about 60 grams to about 600 grams . other types of capsules will be apparent to one skilled in the art . thus a cigarette is provided having a variable length which can also be provided with variable dilution and variable flavorant . one skilled in the art will appreciate that the present invention can be practiced by other than the described embodiments , which are presented for purposes of illustration and not of limitation , and the present invention is limited only by the claims which follow .

US-85304986-A

a beverage package having a blow molded plastic container of a single resin that is filled with a beverage product and sealed . the sealed container is wrapped in an oxygen barrier film to prevent oxygen from contacting the container and permeating through the container wall and thereby spoiling the beverage . the wrap is separable from the container before the beverage is consumed resulting in two separate , single material components for easy recycling . the molded container includes an upright side wall having a recessed groove sized to receive and store a telescoping straw for use in drinking the contents of the container .

the beverage package of the present invention includes a blow molded container 10 shown in fig1 . container 10 includes a bottom wall 12 , an upright side wall 14 and a top wall 16 . the general configuration of the container 10 is rectangular , however other shapes can be used as desired . the top wall 16 includes an opening 18 through which the container 10 is filled with a beverage and through which the beverage is withdrawn when consumed . a strippable seal member 20 formed for example of a foil material or the like , is secured by an adhesive to the top wall 16 around the periphery of the opening 18 to close and seal the container . the container side wall 14 is formed with a recessed groove 22 which is used to house a straw 24 for use in drinking the beverage from the container 10 . the straw 24 , shown in fig3 and 4 , is a telescoping straw having an inner tube 26 and an outer tube 28 . by telescopically collapsing the straw as shown in fig3 the overall length of the straw is less than the height of the container 10 . this permits the straw to be contained within the recessed groove 22 and eliminates the need for a bendable straw . the straw 24 is preferably contained within a sealed plastic wrap , not shown , to keep the straw 24 clean . resilient projections 23 formed in the groove 22 are used to hold the straw within the groove . alternatively , a small amount of adhesive can be used to mount the straw . the container 10 is molded with a bottom flash 30 and a top flash 32 , as shown in fig5 extending below and above the container . the top flash 32 is formed so as to close the opening 18 , leaving the container sterile and sealed as it exits from the blow molding machine . the sealed container is conveyed into a clean room having a controlled environment . the top flash 32 is removed to open the sterile container inside the clean room . the container is then filled with a beverage product and is closed with the seal member 20 . the container side wall 14 has three distinct portions , a lower portion 19 , a main central portion 21 and an upper portion 25 . in the base portion 19 , the side wall tapers outwardly and upwardly from the bottom wall 12 as best seen in fig5 . in the main portion 21 , the horizontal cross sectional size and shape of the side wall is substantially constant . in the upper portion 25 , the side wall gradually tapers in cross sectional size toward the top wall 16 . the top wall 16 is smaller than the bottom wall 12 . this provides the container with increased vertical strength around the opening 18 so that the container can withstand the vertical load applied when the seal 20 is placed on the top wall . in addition , the opening 18 substantially consumes the top wall 16 , having a diameter that is at least as large as half of the length of the top wall 16 . this ensures that the vertical load on the container when the seal member is applied to the top wall is applied near the side wall where the top wall is supported . further processing occurs after the filled and sealed container exits the clean room . the straw 24 is mounted in the groove 22 and a label 34 is wrapped around the main central portion 21 of the container . the final step in the packaging process is the application of the barrier film wrap . with reference to fig6 three filled containers 10 are shown being inserted into a film wrap 36 . the film wrap 36 is in the form of a sleeve having two open ends 38 and 40 . after the containers are inserted into the film wrap 36 , one end of the film wrap 36 is closed and sealed as shown in fig7 . the air within the wrap 36 is withdrawn by vacuum pump and the other end 38 of the film wrap 36 is closed and sealed . the film wrap 36 presents a barrier to oxygen and hermetically seals the wrapped containers . the film wrap prevents oxygen from contacting the permeable plastic containers and permeating through the containers to spoil the beverage product . by preventing oxygen permeation , the unrefrigerated shelf life of the beverage is significantly increased . in addition to forming an oxygen barrier , the wrap 36 also joins multiple containers together in a package . while three containers are shown wrapped together in the film wrap 36 , it will be appreciated that any number of containers can be contained within one film wrap . the barrier film wrap is removed from the containers prior to consumption of the beverage . with the barrier film removed , the separate components , i . e . the blow molded container 10 and the barrier film wrap 36 can be easily recycled as each component contains a single material . the beverage package of the present invention is therefore advantageous when compared to current paper juice boxes having several layers of different materials laminated together . a second embodiment of the blow molding container is shown in fig9 and 10 and indicated generally at 50 . container 50 , like container 10 , includes a bottom wall 12 , an upright side wall 14 and a top wall 16 . the top wall 16 includes an opening 18 for filling the container with a beverage product . container 50 differs from container 10 in two major respects . the container 50 includes a recessed straw groove 52 in each major face 54 formed by the generally rectangular side wall 14 . by providing a straw groove in both major faces of the side wall , there is no longer a correct and an incorrect orientation of the container on a conveyor line . regardless of which face is positioned toward the straw insertion equipment , there will be a groove for receiving the straw . the presence of the straw groove acts to increase the column stiffness of the side wall which is important during the application of the seal 20 on the opening 18 . the container thus benefits structurally from the unused straw groove . the straw groove 52 differs from the groove 22 shown in container 10 . the groove 52 does not extend through the top wall 16 of the container . rather , the upper end 56 of the straw groove is below the top wall 16 . this strengthens the side wall 14 from inward deflection of the major faces 54 . the straw grooves act as creases in the side wall which facilitate inward deflection of the side wall . by terminating the groove short of the top wall 16 , the top wall provides a transverse flange extending across the groove providing resistance to inward deflection of the major faces 54 . the grooves 52 have spaced sides 56 and 58 which project into the container . resilient projections 60 , like projections 23 , are formed which extend into the groove to frictionally engage the straw 24 and hold it in the groove . while the invention of the recyclable beverage package includes the blow molding container with an oxygen barrier wrap , it will be appreciated that the blow molded container with a groove for a straw has utility by itself . the container can be made of other plastic materials such as polyethylene terephthalate ( pet ) which do not need a barrier wrap or the container can be blow molded with a multiple resin layer structure in which one resin layer provides the necessary oxygen permeability barrier . obviously , it is preferred to use a single material in the blow molding container to facilitate recycling . it is to be understood that the invention is not limited to the exact construction illustrated and described above , but that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the following claims .

US-31353994-A

the described system provides a folding and self - contained truss based entertainment technology support system designed for rapid deployment . embodiments disclose a system incorporating folding truss technology in conjunction with lighting , dimming , power and data distribution systems encompassing a complete and integrated mobile and rapid deployment lighting and lighting support system . further embodiments describe truss systems used for the rapid deployment , installation and removal of entertainment systems including but not restricted to lighting , sound , video and scenic equipment .

preferred embodiments of the present invention are illustrated in the figures , like numerals being used to refer to like and corresponding parts of the various drawings . embodiments of the present invention generally relate to entertainment technology systems and , in particular , to truss systems necessary to install and support entertainment systems including but not restricted to lighting , sound , video and scenic equipment in entertainment environments such as arenas , convention centers , hotel ballrooms , and theatres . the disclosed invention provides a structure and method to facilitate the rapid deployment and removal of an entertainment technology truss system designed to support entertainment technology equipment such as luminaires , dimmers , power distribution systems , loudspeakers , microphones , projectors , scenery or other entertainment technology equipment as well known in the art . in one exemplary embodiment of the invention as illustrated in fig5 , the entertainment technology equipment may be a plurality of luminaires 110 , dimming systems 130 , 132 , 134 , 136 , 138 and power distribution 114 along with all cabling to interconnect these devices . fig5 illustrates an entire truss system 100 in a partially unfolded state so that the individual components are easier to distinguish . five sections of truss 120 , 122 , 124 , 126 , 128 are herein illustrated ; however the invention is not so limited and further embodiments of the invention may use any number of connected truss sections . all the entertainment technology equipment 110 , 130 , 132 , 134 , 136 , 138 , 114 may be pre - installed into truss sections 120 , 122 , 124 , 126 , 128 along with all necessary cabling to interconnect the equipment . each of the truss sections 120 , 122 , 124 , 126 , 128 may be of a short length so as to be convenient to store and move around a venue . in one embodiment the truss sections 120 , 122 , 124 , 126 , 128 are each 8 ft in length , however the invention is not so limited and the truss sections can be of any length without departing from the spirit of the invention . each truss section is permanently connected to the adjacent truss section through hinges 150 , 152 , 154 , 156 such that each truss section may rotate through an angle from lying parallel to the adjacent truss section to aligning axially with the adjacent truss section . to facilitate this action hinges 150 , 152 , 154 , 156 , 158 need to allow approximately 180 ° of rotation at each joint and must be designed so that the hinge does not interfere with such rotation . further hinges 150 , 152 , 154 , 156 , 158 are mounted on alternate faces on each adjacent truss section such that the truss sections will fold in a ‘ z ’ pattern . for example on truss section 124 first hinge 152 connecting to truss section 122 is on the bottom corner of truss 124 while second hinge 154 connecting to truss section 126 is on the top corner of truss 124 . the use of hinges to connect the truss sections provides a permanent connection between the truss sections and further allows a dedicated path for cabling to be installed to connect the items of entertainment technology equipment with both electrical power and control data . this cabling may be permanently installed within the truss system and provide links and connections between all sections of truss . as the cabling runs between truss sections it is routed adjacent to the hinges such that it does not interfere with the operation of said hinges and so that no strain or load is placed on the cabling . in the illustrated embodiment such cabling may connect together the power distribution unit 114 , dimming systems 130 , 132 , 134 , 136 , 138 and the plurality of luminaires 110 such that external connections to system 100 may be limited to a power supply cable and a data control cable . truss system 100 may be fitted with wheels or casters 104 such that it is easily moved around a venue or on and off vehicles for transport . casters 104 may be fixed or removable and may be elevated or recessed . each truss section may be fitted with a stop or bumper 140 , 142 , 144 , 146 , 148 which provides a secure and structurally sound resting point for the adjacent truss section to rest on when the system is folded . fig6 illustrates an embodiment of the truss system 100 in its folded , undeployed , state so that it may be stored and transported in the most compact configuration . the height and width of the folded system may be chosen so as to allow the system to pass through standard doorways and to be transported in standard vehicles . for example it may be constructed so as to be less than 8 ft in height so that it would easily be transported within a standard shipping container and pass through a typical loading dock door . the height and width of each truss section also may be selected so as to contain the required entertainment technology equipment within the structure of the truss section ( s ). the truss system may be deployed in a number of manners depending on the floor space and venue height available . two methods will be described ; however other installation techniques are possible and the techniques of installation are not a limitation of the invention . we first consider an installation technique for a venue where we have a limited floor space available , but sufficient height . to deploy the truss system in these circumstances the folded system 100 is positioned under a hoist suspension point and the first truss section 128 is connected to a hoist by suspension line 116 as illustrated in fig6 . the choice of suspension point and hoist is outside of the scope of this invention and such suspension points and hoists may be provided from chain hoists , counterweight systems , powered rigging hoists , manual winches or any other rigging suspension hoist as well known in the art . suspension line 116 may then be raised such that first truss section 128 is lifted and rotates around hinge 156 which connects it to second truss section 126 so as to raise first truss section 128 to a vertical position as shown in fig7 . suspension line 116 may then be lowered again such that first truss section 128 continues to rotate about hinge 156 and is lowered until it is axially aligned with second truss section 126 as illustrated in fig8 . first truss section 128 and second truss section 126 may now be connected together at point 166 by use of a pin through the spigot , bolt , clamp or other method well known in the art such that first truss section 126 and second truss section 128 are connected and behave as a single longer truss section and hinge 156 is constrained from rotation . suspension line 116 may now be raised again and will lift first truss section 128 and second truss section 126 as a single combined unit to the vertical position illustrated in fig9 . as suspension line 116 continues to lift it will start to raise third truss section 124 which will rotate around hinge 152 until it also is vertical as shown in fig1 . second truss section 126 and third truss section 124 may now be connected together at point 164 by use of a pin through the spigot , bolt , clamp or other method well known in the art such that first truss section 126 , second truss section 128 and third truss section 124 are connected and behave as a single longer truss section and hinge 154 is constrained from rotation . similarly suspension line 116 may now be further raised such that fourth truss section 122 is also raised vertically and is secured at point 162 so that four sections are connected as shown in fig1 . finally , suspension line 116 may be further raised such that fifth truss section 120 is also raised vertically and secured at point 160 so that all five truss sections are connected as shown in fig1 and all hinges 150 , 152 , 154 , 156 are constrained from further rotation . at this point a second suspension line 118 may be connected to the truss system and the entire system raised and rotated as a single unit until it is horizontal in its final deployed orientation as illustrated in fig1 . although two suspension points 116 , 118 are here shown on the first and fifth truss sections the invention is not so limited and any number , positioning and layout of suspension points may be used in further embodiments of the invention . the installation technique shown in fig6 to 13 provides installation in a minimum of floor space in a very efficient and simple manner . at all times the truss system 100 remains a single connected structure so that at no point are any truss sections separated from each other . the technicians have only to install the connections 160 , 162 , 164 , 166 that prevent truss rotation . although the methodology for five truss sections is disclosed in this embodiment the technique may be extended in further embodiments and any number of hinged truss sections may similarly be deployed and attached to one another , thus extending the overall truss length . in a further embodiment hinges 150 , 152 , 154 , 156 may be provided with a locking mechanism through a pin , bolt , clamp or other device such that further security is provided to prevent rotation and movement at the hinge points . we now consider a second installation technique for a venue where we have sufficient floor space available to accommodate the entire length of the truss system but a low height . to deploy the truss system in these circumstances the folded system 100 is positioned under a hoist suspension point and the first truss section 128 is connected to a hoist by suspension line 116 as illustrated in fig1 . the choice of suspension point and hoist is outside of the scope of this invention and such suspension points and hoists may be provided from chain hoists , counterweight systems , powered rigging hoists , manual winches or any other rigging suspension hoist as well known in the art . suspension line 116 may then be raised such that first truss section 128 is lifted and rotates around hinge 156 which connects it to second truss section 126 so as to raise first truss section 128 to a vertical position as shown in fig1 . suspension line 116 may then be lowered again such that first truss section 128 continues to rotate about hinge 156 and is lowered until it is axially aligned with second truss section 126 as illustrated in fig1 . the unfolding truss stack , being on casters , rolls and stays directly under the lift point while it unfolds . first truss section 128 and second truss section 126 may now be connected together at point 166 by use of a pin , bolt , clamp or other method well known in the art such that first truss section 126 and second truss section 128 are connected and behave as a single longer truss section and hinge 156 is constrained from rotation . a second suspension line 117 may now be connected to second truss section 126 and first suspension line 116 and second suspension line 117 raised together such that first truss section 128 and second truss section 126 are raised and third truss section 124 will be rotated to a vertical position around hinge 152 as shown in fig1 . suspension lines 116 and 117 may now be lowered together while simultaneously moving the remaining truss sections 120 and 122 on casters 104 such that third truss section 124 continues to rotate and lower until it is axially aligned with both second truss section 126 and fourth truss section 122 as illustrated in fig1 . second truss section 126 and third truss section 124 may now be connected together at point 164 and third truss section 124 and fourth truss section 122 may be connected together at point 162 . at this point the first , second , third and fourth truss sections are connected together and may be further raised as a single unit by suspension lines 116 and 117 as illustrated in fig1 until the fifth truss section 120 is raised into a vertical position by rotating around hinge 150 . a third suspension line 118 may now be connected to fifth truss section 120 which may subsequently be raised until fifth truss section 120 is axially aligned with fourth truss section 122 and can be connected together at point 160 to form the final deployed system as illustrated in fig2 . all five truss sections are securely connected and all hinges 150 , 152 , 154 , 156 are constrained from further rotation . although three suspension points 116 , 117 , 118 are here shown on the first , second and fifth truss sections the invention is not so limited and any number , positioning and layout of suspension points may be used in further embodiments of the invention . the installation technique shown in fig1 to 20 provides installation in a minimum of ceiling height space in a very efficient and simple manner . at all times the truss system 100 remains a single connected structure so that at no point are any truss sections separated from each other . the technicians have only to install the connections 160 , 162 , 164 , 166 that prevent truss rotation . although the methodology for five truss sections is disclosed in this embodiment the technique may be extended in further embodiments and any number of hinged truss sections may similarly be deployed and attached to one another , thus extending the overall truss length . in a yet further embodiment hinges 150 , 152 , 154 , 156 may be provided with a locking mechanism through a pin , bolt , clamp or other device such that further security is provided to prevent rotation and movement at the hinge points when the truss system is deployed . such locking mechanism may take the applied load and relieve the hinge of the loaded stress . in all embodiments described herein the entertainment technology items installed in the truss system such as a lighting system comprising luminaires , dimming system and power distribution may subsequently be connected to existing or temporary distribution systems in the venue so as to connect to main data and power distribution . this may , in some embodiments , be accomplished through a single connection for power and a single connection for data providing an extremely simple and rapid installation of the entire system . fig2 illustrates a perspective view of an embodiment of the invention 200 showing the truss sections unfolding . fig2 illustrates views of a yet further embodiment of the system 300 with entertainment technology devices installed within the truss sections . the embodiments disclosed provide a means for entertainment technology rigging that is both rapid to deploy and remove , and provide a safe integrated system at all times . the truss may also be installed with a minimum of labor and installation time while causing a minimum of inconvenience to other users of the space . while the disclosure has been described with respect to a limited number of embodiments , those skilled in the art , having benefit of this disclosure , will appreciate that other embodiments may be devised which do not depart from the scope of the disclosure as disclosed herein . while the disclosure has been described in detail , it should be understood that various changes , substitutions and alterations can be made hereto without departing from the spirit and scope of the disclosure .

US-34805509-A

a cleaning brush for golf clubs , and in particular , a cleaning brush for cleaning the face and grooves of a golf club , is provided . the brush can be clamped securely to the retractable legs of a golf bag , which golf bag preferably has an integral support stand . the brush design allows the golfer to clean their clubs without needing to handle the cleaning brush . an improved method for cleaning golf clubs is thus obtained .

the brush of the present invention can be a wide variety of shapes and sizes , such as , for example , a flat brush of about 6 to 15 cm in length . in a preferred embodiment of the invention , the brush comprises a series of outwardly facing bristles so as to enable the golfer to clean irons or woods . in a most preferred embodiment , the present invention provides a brush which is a cylindrical tube having a plurality of radially extending bristles . the cylindrical tube can be a solid piece to which the bristles are attached , or it might be a foraminated cylinder , eg . having a perforated structure , through which the bristles held on the inside of the brush , would extend . the bristles of the brush can be made of any suitable material which will remain rigid enough to clean the grooves of the club face , without begin so hard and / or rigid that they would damage the surface or grooves of the club . preferably , the bristles are made of a polymeric material such as nylon , or polyethylene , but might also be made of a soft metal material , such as , for example , brass . the remaining parts of the brush can be made of materials which are preferably light - weight , and can withstand the rigors of prolonged use in an outdoor environment . plastic materials such as polyethylene , polypropylene , polystyrene , and the like might be used as well as wood , or metal components made of steel , brass , aluminum or the like . the brush would have a clamping system which would firmly lock the brush in place . a preferred clamping system would comprise a clamp at a proximate end and a distal end of the brush , so that both ends of the brush could be firmly clamped in place . the clamping system might be releasable , or it might be fixed to the bag , stand or other support . a preferred clamping system would comprise , however , a worm - gear driven adjustable screw clamp located at each end of the cylindrical brush . the brush can be attached directly to the golf bag , but more preferably is affixed to one of the legs of a retractable support stand . alternatively , the brush can be affixed to a golf pull cart , and in a preferred feature of this embodiment , would comprise a releasable clamping system so that the brush could be moved from pull cart to pull cart , as desired . in a further embodiment , the brush might be attached to a support post , such as those used to support ball washers at each tee , for example , and thus provide cleaning brushes at specified locations on the golf course , the golf driving or practice range , or the like . the support post might also be used to support a source of water or cleansing solution , such as a water tub , for wetting the surface of the club to be cleaned . the brush is preferably mounted so that it is closer to the bottom of the golf bag rather than the top of the bag , and thus , in operation , is typically less than 0 . 5 meters from the ground , and more preferably , less than 0 . 3 meters from the ground . at this height , the golfer can stand erect , hold the golf club by the grip , and brush the club face across the surface of the brush which is locked into position at the lower end of the bag , or otherwise held in a position near the ground . additionally , and / or optionally , the golfer can carry a spray bottle of water or cleaning solution in order to wet the surface of the club face to be cleaned . in a most preferred embodiment , though , the brush is clamped at or near the lower end of one of the legs of a golf bag support stand . although the golf bag stand may be removably attached to the golf bag , preferably , the golf bag stand is integral with the golf bag . accordingly , the present invention provides a golf bag with an integral , retractable golf bag stand having at least two legs , and a cleaning brush wherein said cleaning brush is attached to a leg of the retractable stand , and preferably at a lower end of said leg of said retractable stand , wherein said brush is effectively fixed into position . preferably , the brush has a proximate end and a distal end , and clamps at each end of said brush , wherein said clamps at each end of said brush are used to fix the brush into position . in a golf bag system where the brush is included as part of an integral cleaning system for a retractable support stand golf bag , various clamping systems might be included on the brush , the bag , or the support stand , in order to lock the brush into position on the bag or the support legs . it should be noted though , that it is a key feature of the present invention , that the brush be essentially fixed in position so that the golfer can clean the club face surface without needing to hold the brush in place . this would allow the golfer to keep one or both hands on the club grip as the club was being cleaned , and would eliminate the need for the golfer to touch or otherwise handle the cleaning brush being used . various embodiments of the golf club cleaning brush of the present invention will now be described by reference to the following drawings wherein : [ 0025 ] fig1 is a perspective view of one possible cleaning brush according to the present invention ; and [ 0026 ] fig2 is a perspective view of the cleaning brush of fig1 which has been affixed to a retractable leg of a golf bag support stand , which legs are , in turn , integral components of a golf bag . other features of the present invention , as well as other objects and advantages attendant thereto , are set forth in the following description and the accompanying drawings in which like reference numerals depict like elements . in fig1 a cleaning brush generally designated as 10 is shown which includes a , hollow , foraminated steel cylinder 12 . at the centre of cylinder 12 is a wire support rod ( not shown ) to which a series of bristles 14 are attached . bristles 14 extend from the support rod through the holes , or perforations , in steel cylinder 12 and then extend radially away from the surface of steel cylinder 12 . as such , bristles 14 extend from the entire surface of cylinder 12 . at each end of cylinder 12 is a support bracket 16 , each of which has an opening 18 through which a worm - gear driven attachment clamp 19 can be inserted . clamps 19 are used to hold each end of brush 10 in place on a support mechanism . in fig2 the cleaning brush 10 of fig1 is shown in use on a golf bag , generally depicted as 20 . the golf bag includes a hollow shell 22 for holding the golf clubs , and an integral , retractable , golf bag support stand 24 having retractable legs 26 and 28 . cleaning brush 10 could be affixed to either leg 26 or 28 , but in this example , is shown as being affixed to a lower region of leg 28 . it should be noted , however , that brush 10 would not interfere with the normal retraction of leg 28 , and thus , use of the golf bag would not be adversely affected by addition of cleaning brush 10 . the brush shown is generally circular in cross - section . however , the brush might also be modified to include a grove on the surface of the brush and / or the support brackets , which would correspond to the diameter of the retractable leg on the golf bag support stand , and thus further prevent the brush from moving . in operation , the golf bag would be left standing on the ground after a shot has been played . the golfer would hold the club by the grip , typically in one hand , and would brush the club face across the surface of cleaning brush 10 so that bristles 14 would extend into the grooves of the club face and thus remove any foreign matter from the grooves and / or the face of the club . thus , it is apparent that there has been provided , in accordance with the present invention , a golf club cleaner which fully satisfies the means , objects , and advantages set forth hereinbefore . therefore , having described specific embodiments of the present invention , it will be understood that alternatives , modifications and variations thereof may be suggested to those skilled in the art , and that it is intended that the present specification embrace all such alternatives , modifications and variations as fall within the scope of the appended claims . additionally , for clarity and unless otherwise stated , the word “ comprise ” and variations of the word such as “ comprising ” and “ comprises ”, when used in the description and claims of the present specification , is not intended to exclude other additives , components , integers or steps .

US-98598401-A

a method according to one embodiment may provide access to an articular surface of a bone . the method includes forming a passage through at least a portion of the bone . the passage provides an opening in the articular surface . the method further includes inserting a tether through the passage . the tether inserted through the passage can be coupled to at least one device from an insertion site remote from the articular surface . the tether can be withdrawn through the passage to convey the device to a location proximate the articular surface .

as a general overview , the present disclosure may provide a system and method for replacing at least a portion of an articular surface of a joint . the present disclosure may allow instruments and / or other devices to be delivered to a target area , e . g . an articular surface or portion thereof , within a joint . according to one aspect , the present disclosure may allow instruments and / or other devices to be delivered to a target area that is obscured from direct frontal or axial access . furthermore , consistent with the system and method herein , the instruments and / or devices delivered to the target area may be used to perform a diagnostic and / or therapeutic procedure on a target area obscured from direct frontal or axial access . according to one embodiment , a method is provided for repairing a defect in an articular surface of a joint . the method herein may be useful , for example , for repairing defects on portions of an articular surface of a joint that are obstructed from direct access by mating joint surfaces and / or other anatomical features . such obstructed articular surfaces may be accessed and / or repaired without requiring complete dislocation of the joint . accordingly , the present disclosure may provide a less invasive system and method for repairing an articular joint surface . embodiments of the present disclosure are described in the context of repairing a region of the articular surface of a femoral head . specifically , the illustrated and described embodiment is directed at the retrograde access , implant site preparation , and delivery of a prosthetic resurfacing device to the femoral head . those having skill in the art will appreciate , however , that the principles herein may be utilized for accessing target areas other than the femoral head and may be used in connection with procedures other than prosthetic resurfacing of an articular surface . without intending to limit the claimed subject , in addition to providing retrograde delivery of implants , diagnostic devices , surgical instruments , etc ., to the superior or medial femoral head , the method herein is equally suitable for retrograde delivery to sites such as , cut not limited to , the medial humeral head , tibial surface and patella . similarly , the method herein may be used for thru - bone delivery of prosthetic implants , diagnostic devices , surgical instruments devices , etc . to sites such as the glenoid , acetabulum , trochlear groove , etc . referring to fig1 , the system is depicted with reference to a femoral head 10 . a region of the articular surface of the femoral head 10 to be replaced , i . e ., the target area 12 , is indicated by broken lines . according to one embodiment , a method herein may include drilling a passage along a predetermined working axis 13 through the femur 11 towards the target area 12 on the femoral head 10 . the passage through the femur 11 may provide access to the target area 12 of the femoral head 10 . in the case of the illustrated embodiment , the origin of the drill site may be on the body of neck of the femur 11 directed toward the target area 12 on the femoral head 10 . the passage through the femur 11 may be oriented generally normal to the articular surface of the femoral head 10 in the vicinity of the target area 12 . as shown in fig1 , a drill guide 14 may be used to orient an access passage generally normal to the target area 12 of the articular surface of the femoral head 10 . the drill guide 14 may include a locating ring 16 and a drill bushing 18 . the drill bushing 18 may be connected to the locating ring 16 by an arm 15 of the drill guide 14 . the arm 15 of the drill guide 14 may orient the drill bushing 18 in a generally coaxial relationship relative to the locating ring 16 along the working axis 13 . as depicted , the locating ring 16 may include a generally annular member . as such , when the locating ring 16 is disposed on the arcuate surface of the femoral head 10 , the locating ring 16 may attain an orientation generally normal to the surface of the femoral head 10 . the coaxial orientation of the drill bushing 18 and the locating ring 16 may allow a passage to be drilled through the femoral head 10 , and guided by the drill bushing 18 , to be substantially normal to the articular surface of the femoral head 10 at the target area 12 . consistent with the present disclosure , a drill axis defined by the drill bushing 18 may have an orientation that is not normal to the femoral head 10 in the target area 12 . turning to fig2 , a passage 20 is shown provided through the femur 11 , extending trough the femoral head 10 in the region of the target area 12 . as discussed above , the passage 20 may be formed by drilling through the femur 11 using a drill bit guided by the drill bushing 18 of the drill guide 14 . a tether 22 , such as a wire , suture , thread , etc ., may be inserted through the passage 20 so that the tether 22 may extend from the femoral head 10 . the tether 22 may be advanced though the passage 20 with the aid of a guide pin 24 . for example , the guide pin 24 may be a cannulated rod and the tether 22 may be at least partially disposed in a lumen of the guide pin 24 . according to an alternative embodiment , the guide pin 24 may simply be a rod that may be used to push , or otherwise advance , the tether 22 through the passage 20 . as shown , the tether 22 may include a loop 26 on the distal end thereof . the loop 26 or feature may be used for attaching instruments , devices , etc ., to the tether 22 . accordingly , various attachment features other than a loop may suitably be employed herein . the tether 22 may be used to ferry , shuttle , or otherwise convey various diagnostic devices , surgical instruments , prosthetic devices , etc . from a remote insertion site , e . g ., exterior to the joint , to the target area 12 . in one embodiment , the tether 22 may be used to convey instruments , devices , etc ., to the target area 12 without requiring direct and / or axial access to the target area 12 . for example , referring the fig3 , the tether 22 may be coupled to a reamer 28 outside of the joint . the reamer 28 may include a body 31 and one or more cutting features 29 and may be used for excising a portion of the femoral head 10 in the region of the target area 12 . the tether 22 may be advanced or pulled through the femur 11 and out from the joint area to allow the reamer 28 to be attached to the tether 22 at the remote insertion site . advancing the tether 22 from femoral head 10 may include pulling the distal end of the tether 22 completely from the body of a patient , e . g ., in an embodiment in which the remote insertion site it outside of the patient . the loop 26 at the distal end of the tether 22 may be coupled to a cooperating feature 30 on an underside of the reamer 28 . the reamer 28 may be conveyed to the target area 12 by withdrawing the tether 22 back through the passage 20 , thereby pulling and or guiding the reamer 28 to the target area 12 . withdrawing the tether 22 back through the passage 20 may transport the reamer 28 to the target area 12 and / or may generally center the attachment feature 30 of the reamer 28 relative to the passage 20 . turning to fig4 , once the reamer 28 has been transported to the target area 12 , the reamer 28 may be coupled to a drive shaft 32 disposed extending at least partially through the passage 20 . in one embodiment , the drive shaft 32 may be a cannulated shaft that may be threaded over the tether 22 . the reamer 28 and the drive shaft 32 may include cooperating features allowing the driveshaft 32 to transmit torque to the reamer 28 . the cooperating features of the drive shaft 32 and the reamer 28 may include torque transmitting features such as cooperating a cooperating socket and plug , e . g ., a mating hex shaft and hex socket . consistent this variety of torque transmitting coupling the wire 22 may be used to pull the reamer 28 towards in the drive shaft 32 in order to maintain the connection between the cooperating features of the drive shaft 32 and the reamer 28 . alternatively , the cooperating features of the drive shaft 32 and the reamer may be releasably securable to one another . according to one such embodiment , the cooperating features of the drive shaft 32 and the reamer 28 may include cooperating threaded components that screw together , cooperating snap - fit features , etc . at least a portion of the femoral head 10 in the general region of the target area 12 may be excised by rotatably driving the reamer 28 and pulling the reamer 28 into the femoral head 10 . the reamer 28 may be rotatably driven manually and / or using a drive motor , for example using a drill . the reamer 28 may be pulled into the femoral head 10 by withdrawing the drive shaft 32 , in an embodiment in which the drive shaft 32 and the reamer 28 are releasably secured to one another . additionally , and / or alternatively , the reamer 28 may be pulled into the femoral head by withdrawing or pulling on the tether 22 , which may , in some embodiments , remain coupled to the reamer 28 during the excision operation . in addition to conveying the reamer 28 to the target area 12 , the tether 22 may also be used to transport various other devices and / or instruments to the target area 12 . devices and / or instruments transported to the target area 12 by the tether 22 may also be centered about the passage 20 through the femur 11 similar to the reamer 28 . for example , in an embodiment consistent with the present disclosure , also in the general context of an articular surface repair procedure , the tether 22 may be used to shuttle or transport an anchoring device , such as a screw 33 , fig5 a and 5b , to the target area 12 . the screw 33 may be provided having an internal driving feature 34 , e . g ., a hex socket feature , a torx ™ socket , etc . the tether 22 may be threaded through a cannulated driver 35 which may be inserted through the passage 20 . the tether 22 may be used to convey the screw 33 to the target area 12 and center the screw 33 relative to the passage 20 . the driver 35 may be engaged with the driving feature 34 of the screw 33 and a holding force may be applied to the screw 33 via the tether 22 , thereby maintaining the engagement between the driver 34 and the screw 33 . with the driver 34 and the screw 33 maintained in engagement with one another , the screw 33 may be threadably driven into the passage 20 at the target area 12 . in a related manner , the tether 22 , alone and / or in conjunction with various suitably configured shafts and / or driving elements extending through the passage 20 , may be used to transport and operate or install other instruments and devices . ultimately , the tether 22 may be used to shuttle a prosthetic implant to the target area 12 and install the implant into an implant site , such as may be created using the reamer 28 . consistent with the foregoing disclosure , a system and method may be provided for replacing at least a portion of an articular surface of a joint that is obscured from axial approach . according to one aspect , a method herein may permit the retrograde delivery of instruments and devices from an insertion site to a target area on the articular surface . according to an embodiment , the method may include drilling a passage from an accessible region of a bone removed from a target articular surface . the passage may extend toward the target articular surface . a tether , such as a wire , may be introduced through the passage , and positioned having a distal end extending from a distal opening of the passage at the target articular surface . the distal end of the tether may be coupled to a prosthetic device , a surgical instrument , diagnostic device , etc . the tether may then be drawn back toward the articular surface , thereby transporting / carrying the prosthetic device , surgical instrument , diagnostic device , etc . to the articular surface . according to another aspect , after the a prosthetic device , surgical instrument , diagnostic device , etc ., has been transported to the articular surface , the prosthetic device , surgical instrument , diagnostic device , etc . may be engaged by a shaft or pin extending through said passage to said articular surface . the shaft or pin may be used for applying a rotational and / or axial force to the prosthetic device , surgical instrument , diagnostic device , etc . using this methodology , a procedure may be performed on a target are without direct axial or frontal access to the target area . those having skill in the art will appreciate that the method herein may be used for transporting numerous additional instruments , devices , etc . to a working surface having impeded direct axis . further is should be understood that a variety of pins , shafts , catheters , etc . may be inserted through the passage for acting on , interacting with , or co - acting with instruments and / or devices transported to a target area consistent with above aspects of the disclosure . finally , it should also be understood that the embodiments disclosed herein are susceptible for use in procedures in addition to the repair of articular cartilage at a joint . accordingly , it should be understood that the embodiments that have been described herein are but some of the several contemplated within the scope of the claimed subject matter , and are set forth here by way of illustration , but not of limitation . it is obvious that many other embodiments , which will be readily apparent to those skilled in the art may be made without departing materially from the spirit and scope of the claimed subject matter .

US-99445304-A

the invention relates to product , method and system for materials handling apparatus and more particularly to an integrated design of a vessel for combining sterilization , storage , transport and presentment of dental or surgical instruments or implants using a uniquely designed sterilization tray . fabrication of the tray and the number of parts required can be greatly cost reduced , due to the simplicity of the design .

for the purpose of representing the principles of the invention , reference will now be made to 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 application of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art are included as part of the present invention . fig1 shows the tray [ 110 ] component with a generally rectangular base [ 115 ], attached to a front wall [ 120 ], a right wall [ 125 ], a left wall [ 130 ] and a rear wall [ 135 ] that contact each other and are nearly perpendicular to the base [ 115 ] and to each other . the base [ 115 ] has multiple apertures [ 140 ] which may be of various shapes , sizes and locations . the rear wall [ 135 ] has one or more tray orientation perforations [ 145 ] and the front wall [ 120 ] has a wall hook [ 150 ]. fig1 a identifies sidewall lip features [ 175 ] molded or added on to four corners at the intersection of the wall [ 120 , 125 , 130 , 135 ] either in contact with the base [ 115 ] or not in contact with the base . fig2 illustrates the flexible elastomeric lid [ 200 ] preferably produced with silicone rubber or other high heat resistant elastomers , with a multiplicity of upper apertures [ 205 ] through the lid top [ 210 ] which is joined perpendicularly to the front flange [ 215 ], the right flange [ 220 ], the left flange [ 225 ] and the rear flange [ 230 ]. the surface of the lid top [ 210 ] contains four stacking corner tabs [ 235 ]. multiple lid pull tabs [ 240 ] protrude from the right flange [ 220 ] and the left flange [ 225 ]. cupped corners [ 245 ] are formed such that the front flange [ 215 ], right flange [ 220 ], left flange [ 225 ] and rear flange [ 230 ] turn down to form the curvilinear cupped corners [ 245 ]. one or more attaching loop ( s ) [ 250 ] is part of the front flange [ 215 ]. the rear flange [ 230 ] also contains cupped corners [ 245 ] at each end . additionally , a hollow tube [ 255 ] may be added to the lid top [ 210 ] for the insertion of an optional rigid rod [ 260 ] for structural integrity during stacking . fig3 provides a pictorial representation of the lid [ 200 ] shown upside down with the top lid , inner [ 310 ] surface exposed and showing details of the cupped corners [ 245 ] and optional instrument locating brackets [ 315 ] with securing tabs [ 320 ] and surgical or dental instruments [ 325 ] placed in the locating brackets [ 315 ] and a lid guide notch [ 330 ]. fig4 shows the relationship between the tray [ 110 ] and the lid [ 200 ]. within the lid [ 200 ] is an optional resilient retention member [ 410 ] that may be optionally molded into the lid [ 200 ] or as a separate component , assembled through one or several upper apertures [ 205 ]. when the lid [ 200 ] of the tray [ 110 ] is closed the retention member [ 410 ] compresses against any medical or dental instruments [ 325 ] that may be placed in the tray brackets [ 415 ] projecting upwards from the base [ 115 ], thereby securing the medical or dental instruments [ 325 ] in the desired locations . the tray brackets , [ 415 ] may optionally have securing tabs [ 320 ]. orientation nubs [ 420 ] are located on the inside surface of the rear flange [ 230 ] for insertion into the tray orientation perforations [ 145 ]. fig5 illustrtates the medical or dental sterilization tray assembly [ 500 ] in the closed position with an elastomeric lid [ 200 ] and rigid tray [ 110 ]. details of the assembly process are noted below : the lid [ 200 ] orients onto the tray [ 110 ] by inserting the orientation nubs [ 420 ] into the tray orientation perforations [ 145 ] and by inserting the cupped corners [ 245 ] located on the rear flange [ 230 ] around the corners of the rear wall [ 135 ]. the lid [ 200 ] is then grasped by the cupped corners [ 245 ] located on the front flange [ 215 ] and rotatably stretched over the front wall [ 120 ] corners thereby securing the lid [ 200 ] to the tray [ 110 ] creating a tray assembly [ 500 ]. the attaching loop [ 250 ] is then stretched over the wall hook [ 150 ] to secure the lid [ 200 ] to the tray [ 110 ]. removal of the lid [ 200 ] from the tray [ 110 ] is accomplished by grasping the pull tabs [ 240 ] and rotatably stretching the lid [ 200 ] from the front flange [ 215 ] toward the rear flange [ 230 ] and disassociating the cupped corners [ 245 ] from the front wall [ 120 ]. fig6 references an alternative embodiment of an elastomeric lid [ 200 ]. this bracket lid [ 600 ] embodiment has integral tray instrument retention brackets [ 610 ], elastomeric gripping protrusions [ 615 ], and an instrument retention bracket [ 620 ] similar to the retention member [ 410 ]. fig7 references an alternative embodiment of an elastomeric lid [ 200 ]. this finger mat lid [ 700 ] embodiment has an integral finger mat [ 710 ]. another embodiment includes slight separations at each corner of the elastomeric lid [ 200 ] or the tray [ 110 ].

US-26836305-A

the nasal catheter system will provide an improvement over existing devices that do not fill the recesses of the nose , do cause significant pain and still do not stop nosebleeds very effectively . the objectives are achieved through the design of a version of the device that has two inflatable bags , which in the preferred embodiment are not elastic balloons . the anterior bag is much larger in volume than the anterior nasal cavity . the design of the bag is generally cylindrical but has deep ridges projecting outward producing a “ pleated ” design with ribs running along and parallel to the axis of the catheter . alternate designs include a circumferential ring or capillary tube fingers projecting outward . any surface projection that serves to create additional surface area or any projection that winds and flows into the meatus recesses of the nasal cavity with greater ease will accomplish some aspect of the desired objective .

referring to fig1 - 16 , a nasal catheter system 10 includes a catheter 12 having a first anterior fluid channel 14 , a first anterior output opening 16 , a first anterior input port 18 , and a first external section 20 . the first anterior bag 22 is securely attached to the catheter 12 . this simplest version with one first anterior bag 22 is illustrated in fig1 . the nasal catheter system 10 can be more complex and have a second anterior bag 24 and a posterior bag 26 attached to the catheter 12 as shown in fig1 a , 2 b . the nasal catheter system 10 is inserted into a first anterior nasal cavity 32 and when the catheter 10 is filled with a fluid 30 via the first anterior input port 18 , the fluid 30 flows through the first anterior fluid channel 14 and into the first anterior bag 22 , thereby expanding the first anterior bag 22 and producing pressure upon the first anterior nasal cavity 32 . the first anterior fluid channel 14 ends at about the first anterior output opening 16 . when included a second anterior bag 24 is inserted into the second anterior nasal cavity 34 and the first anterior bag 22 is inserted into a first anterior nasal cavity 32 , as shown on fig4 . the posterior bag 26 is inserted into the posterior nasal cavity 36 that is behind the first and second anterior nasal cavity 32 , 34 . the first anterior bag 22 has a first anterior chamber 40 , a first outer surface 42 , a first front end 44 , a first middle portion 46 and a first rear end 48 . a plurality of first anterior elongated ridges 50 are attached to the first outer surface 42 and span over about the first middle portion 46 . the plurality of first anterior elongated ridges 50 have a plurality of first anterior ridge cavities 52 . the first anterior ridge cavities 52 are connected to and in communication with the first anterior chamber 40 . the preferred fluid 30 is water 54 . when water 54 is injected into the first anterior fluid channel 14 it passed through the first anterior output opening 16 into the first anterior ridge cavities 52 and the first anterior chamber 40 . the water 54 creates pressure upon the first anterior ridge cavities 52 and the first anterior chamber 40 causing them to expand and producing pressure upon the first anterior nasal cavity 32 . when the posterior bag 26 is included then the catheter 10 has a posterior fluid channel 58 that has a posterior section 60 , a first posterior input port 62 and a posterior output opening 66 . a second posterior input port 64 can be added , in which case , the posterior fluid channel 58 would be extended and the second posterior input port 64 attached to the posterior fluid channel 58 . both the first posterior input port 62 and second posterior input 64 port provide fluid 30 or water 54 to the posterior output opening 66 . either the first posterior input port 62 or second posterior input port 64 can be used for convenience . the posterior bag 26 is attached to the catheter 10 near the posterior output opening 66 . the posterior bag 26 is filled when water 54 or fluid 30 is inserted into the first posterior input port 62 or the second posterior input port 64 and the water 54 flows though the posterior fluid channel 58 and through the posterior output opening 66 into the posterior bag 26 . the posterior fluid channel 58 generally parallels and adjoins the first anterior fluid channel 14 and the second anterior fluid channel 74 . the posterior bag 26 has a posterior chamber 70 that fills with water 54 and expands the posterior bag 26 and produces pressure upon the posterior nasal cavity 36 . in some patients the physician cannot ascertain from which anterior nasal cavity 32 , 34 the bleeding is occurring . the solution is to provide a second anterior bag 24 attached to the catheter 12 . filling of the second anterior bag 24 is accomplished by adding to the catheter 12 ; a second anterior fluid channel 74 having a second anterior output opening 76 , a second anterior input port 78 , and a second external section 80 . referring particularly to fig2 a , 2 b ; the second anterior bag 24 is attached to the second anterior fluid channel 74 , the second anterior bag has a second anterior chamber 82 , a second outer surface 84 , a second front end 86 , a second middle portion 88 and a second rear end 90 . attached to the second outer surface 84 are a plurality of second anterior elongated ridges 92 that span over about the second middle portion 88 . the plurality of second anterior elongated ridges 92 have a plurality of second anterior ridge cavities 94 . the second anterior ridge cavities 94 are connected to and are in communication with the second anterior chamber 82 . fig1 c and fig1 c show the nasal catheter system 10 being coiled or wrapped for insertion . the second anterior bag 24 may be inserted into a second anterior nasal cavity 34 and when the catheter 12 is filled with a fluid 30 , the fluid 30 flows through the second anterior fluid channel 74 and into the second anterior bag 24 , which expands the second anterior bag 24 and producing pressure upon the second anterior nasal cavity 32 . referring to fig2 b , to secure the nasal catheter system 10 within the nasal cavity 28 a nasal plug 95 is used to receive the first external section 20 and a second nasal plug 95 ′ secures the second external section 80 . the first external section 20 can then be clamped by a clamping device 97 and the second external section 80 is secured by clamping device 97 ′, thus securing the nasal catheter system 10 within the nasal cavity 28 . pressure is placed upon the meatus recesses 96 of the nasal cavity 28 when the nasal catheter system 10 is inserted into a nasal cavity 28 and a fluid 30 is inserted into the first anterior input port 18 of the catheter 12 , and the fluid 30 passes through the catheter 12 and passes through the first anterior output opening 16 into the first anterior bag 22 . this expands the first anterior chamber 22 and the plurality of first anterior ridge cavities 52 . the expansion causes the plurality of first anterior ridge cavities 52 to press against the interior walls of the nasal cavity 28 and flow into additional open spaces of the meatus recesses 96 . since the first anterior ridge cavities 52 will search for a path of least resistance , the first anterior ridge cavities 52 will wind and flow into the meatus recesses 96 thereby producing pressure upon the nasal cavity 28 and meatus recesses 96 that is much more effective and less painful than conventional methods . fig5 a , 10 a illustrates the meatus recesses 96 . they are the superior meatus 142 , middle meatus 144 and inferior meatus 146 . the meatus recesses 142 , 144 , 146 are deep and winding recesses that are not easily accessed by traditional round or ovoid inflatable balloons 104 . referring to fig3 and fig4 the insertion of the three - bag embodiment into the nose 116 requires more than just pushing it into either or both nostrils 106 , 107 . when the second anterior bag 24 is included it is necessary to pull the first anterior bag 22 and catheter 12 through the second anterior nasal cavity 34 , the posterior nasal cavity 36 and into the throat 38 in order to reach the first anterior nasal cavity 32 . the catheter system 10 must be inserted into the second nostril 107 on one side of the nose 116 and advanced into the posterior nasal cavity 36 and then brought into the opposite first posterior nasal airway 112 and out through the first anterior nasal cavity 32 and first nostril 106 . to accomplish this the leading end , external section , of the device &# 39 ; s catheter 12 is elongated by eighteen to twenty - four inches which allows the insertion of the elongated section 108 of the catheter 12 into the second nostril 107 . the elongated section 108 is brought out the mouth by advancing the catheter 12 through the nose 116 until it can be visualized looking through the mouth 110 into the throat 38 and grasped with a hemostat 162 to pull it from the throat 38 and out of the mouth 110 . although the maneuver as depicted on fig3 puts the catheter system 10 into the second nostril 107 and brings it out the mouth 110 , it does not result in the catheter 12 being brought out the other first posterior nasal airway 112 . to do this a second and separate tube depicted as secondary member 114 needs to be inserted into the opposite first nostril 106 and advanced into the back of the throat 38 and pulled from the throat 38 and out the mouth 110 . this secondary member 114 does not have any inflatable bag . the secondary member 114 can be a second catheter . its only purpose is to attach to the elongated portion 108 of the catheter 12 and pull the catheter system 10 from the back of the throat 38 into the first posterior nasal airway 112 of the opposite side of the nose 116 and out through the first anterior nasal cavity 32 and first nostril 106 . fig4 illustrates how the secondary member 114 is inserted into the second nostril 107 , is brought through the mouth 110 and attaches to the elongated section 108 of the catheter 12 with a small circular clamp device 97 ′. a circular clamp device 97 ′ or other commonly used clamping medical device can be used to attach the secondary member 114 to the elongated portion 108 of the catheter 12 . the catheter 12 is then pulled into the nose 116 by pulling the secondary member 114 which pulls the catheter 12 into the second nostril 107 , then to the back of the nose 116 and then forward into the opposite first anterior nasal cavity 32 and out through the opposite first nostril 106 . the elongated section 108 is discarded by cutting the catheter 12 as it exits from the first nostril 106 of the nose 116 . the three bags 22 , 24 , 26 are inflated with water 54 and secured at the nostrils 106 , 107 by clamping the common catheter 12 over the nasal plugs 95 . the catheter 12 is depicted with an elongated section 108 where the secondary member 114 is used to pull the nasal catheter system 10 through the nasal cavity 28 when a second anterior bag 24 is used . in a variation the secondary member 114 can be attached directly to a lengthened first external section 20 or second external section 80 of the catheter 12 , depending on the design . the secondary member 114 is cut and discarded once the procedure is complete . the catheter 12 is inserted through the second anterior nasal cavity 34 , the posterior nasal cavity 36 and into the throat 38 where the secondary member 114 is then attached . the secondary member 114 may be inserted through the first anterior nasal cavity 32 , the posterior nasal cavity and into the throat 38 . the secondary member 114 is then attached to the elongated section 108 of the catheter 12 . the secondary member 114 is pulled back through the first anterior nasal cavity 32 , pulling the catheter 12 , the posterior bag 26 , the first anterior bag 22 and the second anterior bag 24 into the posterior nasal cavity 36 , first anterior nasal cavity 32 , and second anterior nasal cavity 34 . although not illustrated , rather than using the three bag nasal catheter system 10 that requires pulling portions of the nasal catheter system 10 through the throat 38 ; an alternative is to use an embodiment where two nasal catheter system 10 are used that consist of a catheter 12 with a first anterior bag 22 and a posterior bag 26 , with a second nasal catheter system 10 consisting of just a second anterior bag 24 and separate catheter 12 . the two systems 10 are not connected so they can be inserted separately into the first anterior nasal cavity 32 and the second anterior nasal cavity 34 . this alleviates the need to pull the first anterior bag 22 all the way through the second anterior nasal cavity 34 and the posterior cavity 36 , in order to reach the first anterior nasal cavity 32 . the advantage of the three bag nasal catheter system 10 is that once inserted into the nasal cavity 28 the posterior bag 26 , the first anterior bag 22 and the second anterior bag 24 are all connected and serve to hold each other firmly and securely into proper position . the nasal catheter system 10 can be constructed of various materials . materials commonly used in the medical industry for catheter 12 are acceptable . in the preferred embodiment the first anterior bag 22 , second anterior bag 24 and posterior bag are made of medical grade silicone with the appropriate expandability for accessing the meatus recesses 96 and providing adequate pressure to stop the nose bleed . referring to fig1 b , 2 b ; surface projections attach to the first and second anterior bag 22 , 24 . the surface projections may vary in configuration . an effective design of the surface projections is with a plurality of first anterior elongated ridges 50 and second anterior elongated ridges 92 that are capable of effectively accessing the meatus recesses 96 without creating painful pressure within the nasal cavity 28 . the plurality of first anterior elongated ridges 50 span from about the first front end 44 to about the first rear end 48 including the first middle portion 46 of the first anterior bag 22 . the plurality of second anterior elongated ridges 92 span from about the second front end 86 to about the second rear end 90 including the second middle portion 88 of the second anterior bag 24 . when the catheter 12 is filled with a fluid 30 , the fluid 30 flows through the first anterior fluid channel 14 and into the first anterior bag 22 , thereby expanding the first anterior bag 22 and first anterior elongated ridge cavities 52 producing pressure upon the first anterior nasal cavity 32 . the plurality of first anterior elongated ridges 50 shown in fig1 b , 2 b and second anterior elongated ridges 92 may vary in placement quantity , circumference , shape , length and other characteristics . other variations of the surface projections include circumferencial ridges 118 , 122 shown in fig1 a - c and capillary tubes 128 , 138 shown in fig1 a - c that also may vary in placement quantity , circumference , shape , length and other characteristics . fig1 a , 15 b illustrates the plurality of first anterior circumferencial ridge 118 attached to the first outer surface 42 and axially positioned in circumferencial rings about the first long axis 126 and spanning over about the first middle portion 46 . the plurality of first anterior circumferencial ridge 118 have a plurality of first anterior circumferencial ridge cavities 120 . the first anterior circumferencial ridge cavities 120 are in communication with the first anterior chamber 40 . in a similar arrangement , the second anterior bag 24 includes a plurality of second anterior circumferencial ridges 122 attached to the second outer surface 84 and axially positioned in circumferencial rings about the second long axis 127 . the plurality of second anterior circumferencial ridges 122 span over about the second middle portion 89 . fig1 c shows the plurality of second anterior circumferencial ridges 122 having a plurality of second anterior circumferencial ridge cavities 124 , the second anterior circumferencial ridge cavities 124 are in communication with the second anterior chamber 82 . the first anterior circumferencial ridges 118 and second anterior circumferencial ridges 122 are similar in most all characteristics and function , other than which anterior bag 22 , 24 they are associated with . fig1 a , 16 b , 16 c show another variation of the surface projections is a plurality of first anterior capillary tubes 128 . the first anterior bag 22 includes a plurality of first anterior capillary tubes 128 attached to the first outer surface 42 having a first open end 132 and a first closed end 134 and attached to the first outer surface 42 . the first anterior capillary tubes 128 take the form of finger - like projections extending generally perpendicular from the first outer surface 42 and spanning over about the first middle portion 46 . the plurality of first anterior capillary tubes 128 having a plurality of first anterior capillary tube cavities 130 . the first open end 132 of the first anterior capillary tube cavities 130 are in communication with the first anterior chamber 40 . as shown in fig1 c ; in a similar arrangement , the second anterior bag 24 includes a plurality of second anterior capillary tubes 138 attached to the second outer surface 84 . the plurality of second anterior capillary tubes 138 have a plurality of second anterior capillary tube cavities 140 that are in communication with the second anterior chamber 82 . the first anterior capillary tubes 128 and second anterior capillary tubes 138 are similar in most all characteristics and function , other than which anterior bag 22 , 24 they are associated with . fig1 a shows the plurality of first anterior capillary tubes 128 spanning from about the first front end 44 to about the first rear end 48 including the first middle portion 46 . the plurality of second anterior capillary tubes 138 span from about the second front end 86 to about the second rear end 90 including the second middle portion 88 . parts of the nasal catheter system 10 can be manufactured from medical grade silicone , rubber or any other sufficiently expandable materials that are safe for usage internally within the patient . fig5 a shows the difficult to access crevices of the nasal cavity 28 . these crevices are the superior meatus 142 , middle meatus 144 and inferior meatus 146 , which are separated by the superior turbinate 148 , middle turbinate 150 and inferior turbinate 152 . the nasal septum 154 separates the first anterior nasal cavity 32 from the second anterior nasal cavity 32 . fig5 b shows the first anterior nasal cavity 32 and posterior nasal cavity 36 . fig7 a , 7 b , 7 c illustrates the prior art method of gauze 156 being placed into the nose . fig7 a and 7 b show the anterior gauze 156 is packed into the anterior nasal cavity 32 , 34 . fig7 c shows one of the early methods for treatment for an “ anterior ” nose bleed , where gauze is placed into either the right or left side of the nose , whichever is bleeding or at times both sides of the nose . a “ posterior ” gauze pack 158 is placed into the nose 116 in addition to the “ anterior ” gauze packing 156 . a roll of gauze is inserted into the back of the nose and secured to a second roll of gauze at the opening of the nose 116 with a string 160 so the posterior gauze roll 158 will not fall into the throat . this method is now seldom used since the foley catheter method was developed . fig8 shows the standard urological catheter ( foley catheter ) with a balloon 104 that is expanded with water 54 to put pressure in the back of nose , in the common space posterior nasal cavity 36 to the center wall ( septum ). this balloon 104 also allows the physician to insert gauze into the front of the nose 116 with less concern that the packing will “ fall ” into the throat 38 and obstruct the airway . the catheter 12 is clamped at the inlet of the nose to keep the balloon 104 from moving backwards into the throat 38 . the balloon 104 of the foley catheter produces excessive pressure and pain when inflated in an attempt to fill the posterior nasal cavity 36 . fig9 shows the xomed ™ epistat ™, which represents the latest technology used to attempt to stop the persistent nosebleed . the xomed ™ epistat ™ uses a catheter 12 traversing through the right or left chamber of the nose . you could put one in each side of the nose . two balloons 104 , 105 are inflated with water . the larger balloon 104 is meant to put pressure in the anterior nasal cavity which is divided into right and left side . the small balloon 105 is meant to put pressure in the posterior nasal cavity 36 of the nose 116 , this is the common chamber . as shown in fig1 a and fig1 a the xomed ™ epistat ™ has inflatable balloons 104 , 105 which can never conform to the shapes of the nasal cavities 28 , especially the anterior nasal cavity 32 , 34 . the anterior nasal cavity 32 , 34 is the hardest to fill with a balloon 104 . the expanding spherical or ovoid balloon 104 will put minimal pressure in the crevices of the meatus recesses 96 . likewise , the posterior nasal cavity 36 is not a sphere and the expanding bulb will not conform to the anatomical space . in an attempt to control the bleeding , the physician will put more and more pressure in the balloons 104 , 105 and this causes a significant amount of pain because of the expanding pressure inside the nose 116 . the pain is produced because the balloon 104 is expanded with much more pressure than needed to compress a bleeding vessel . the increased pressure is used to try to “ drive ” the balloon into the crevices or “ serpentine meatus recesses ” 96 of the nose 116 . regardless of how much pressure is put into the balloon , the balloon will not “ flow ” into the crevices of the nose . fig1 a and 11 a show how the xomed ™ epistat ™ balloon 104 expands producing a round or ovoid configuration while producing significant pressure in a very small area , with significant pain , and not filling any of the major area of the nose such as the superior meatus 142 , middle meatus 144 and inferior meatus 146 crevices . there is ineffective filling of the posterior nasal cavity 36 by the posterior balloon of the xomed ™ epistat ™. the balloon can only expand in a sphere and takes on a modified configuration only with significant pressure in the balloon and still does not fill the posterior nasal cavity 36 . fig1 b and 11 b show complete filling of the superior meatus 142 , middle meatus 144 and inferior meatus 146 by the second anterior bag 24 of the present invention . the posterior bag 26 is designed to the shape of the anatomical space in the posterior cavity 36 . it is slightly larger than this space to effect pressure in all areas and completely fills the posterior nasal cavity 36 . fig1 a , 12 b , 13 a and 13 b show the catheter 10 with the first anterior fluid channel 14 to the first anterior bag 22 and posterior fluid channel 58 to the posterior bag 26 that allows them to be filled individually , clamped individually and then both clamped by a single clamp 97 around the common catheter 12 as it exits the nasal plug 95 to produce a completed intra nasal catheter system 10 . fig1 b shows the posterior bag 26 filed with water 54 and the posterior fluid channel 58 to the posterior bag 26 individually clamped . fig1 a show both the posterior bag 26 and first anterior bag 22 filled with water 54 . the posterior fluid channel 58 and anterior fluid channel 14 are then individually sealed with clamps 97 , 97 ′. the redundancy of size and ridge projections will flow into all areas fig1 b illustrates both bags 26 , 22 filled with water and the entire system “ snugged ” with firmness by pulling on the combined dual common catheter 10 while pressing inward on the nasal plug 95 and clamping the dual common catheter 10 with one clamp 97 . filling the variation with three bags 22 , 24 , 26 would be carried out in a similar manner once the nasal catheter system 10 was in place inside the nose 116 . the posterior bag 26 would be filled from the left nostril through the first posterior input port 62 while the second posterior input port 64 to the posterior bag 26 is individually clamped . the first and second anterior bags 22 , 24 would then be filled and individually clamped . a common clamp 97 would then be applied to the common catheter 10 coming out each nostril and through the nasal plug 95 . the least complex version has one first anterior bag 22 , this device would be more effective and more convenient than other devices now available to stop the milder anterior nosebleeds . although the present invention has been described in considerable detail with regard to the preferred versions thereof , other versions are possible . therefore , the appended claims should not be limited to the descriptions of the preferred versions contained herein .

US-65393300-A

a garment adapted for wear by persons desiring to maintain their arms in a fixed position along their upper body . the garment includes an upper portion , such as a shirt , adapted for wear on the upper body , and at least one hand portion , such as a glove . the shirt is preferably made of a loop material and the glove includes a region of hook material . utilizing the loop and hook materials , the glove can be releasably attached to the shirt to maintain the user &# 39 ; s hand in a fixed position along the user &# 39 ; s upper body . the garment is primarily intended for maintaining one or both of the user &# 39 ; s arms close against the body to facilitate relaxation while in cramped or tight positions , such as in an airplane seat . however , the garment may also be used in a wide variety of applications wherein it is desired to support one or both of the user &# 39 ; s arms in a releasably fixed position .

larger individuals are often uncomfortable while seated on vehicles such as airplanes , buses or trains because their arms tend to extend over the armrests and contact adjacent passengers or passersby . as a result , many individuals have found it helpful to place their arms in a folded position across their chest . this position effectively narrows their body width and helps to avoid contact with others . unfortunately , however , this position can be very difficult to maintain , particularly during longer trips . therefore , a need exists for a garment system that provides users with the ability to releasably secure their hands or arms at selectable locations along their upper body . such a device would help prevent muscle strain and thereby significantly increase the user &# 39 ; s comfort during travel . such a device would also be useful in a wide variety of other applications , such as for maintaining a user &# 39 ; s hands or arms in a fixed position during rehabilitation after an injury or to help control body tremors resulting from neurological disorders . to be practical , the garment system must be reliable , convenient and easy to transport . to address these needs , the present invention provides a new and improved garment adapted for providing users with the ability to releasably secure their hands or arms along their upper body . referring now to fig1 – 2 , for purposes of illustration , a preferred embodiment of the present invention provides a garment 10 including , generally , an upper portion 12 and a pair of hand portions 14 . the upper portion 12 is worn over the torso and can take a variety of different forms , such as , for example , a shirt , a vest or a sweater . the upper portion 12 is preferably made of a material that provides a first attachment means , such as , for example , a loop material . alternatively , patches of material can be sewn or otherwise attached to the upper portion of the garment to provide first attachment means in specific locations . the hand portions 14 preferably comprise a pair of gloves with open fingers for comfort and convenience . however , it will be appreciated that the hand portions may take a variety of different forms . furthermore , the hand portions may be worn on the wrists or forearms and therefore the term “ hand portions ” should not be construed as limited to articles adapted for wear only on the hands . the hand portions 14 include at least a region of material , such as , for example , a hook material , that provides a second attachment means . in the illustrated embodiment , each of the hand portions 14 is provided with a region of material 16 along the palm . the second attachment means releasably adheres to the first attachment means for providing the user with the ability to affix at least one hand to his or her upper body at a selectable location . fig2 illustrates the embodiment of fig1 during use wherein the garment 10 provides a comfortable and convenient means for maintaining the user &# 39 ; s hands in a fixed position along his or her upper body . as discussed above , this garment is particularly well suited for larger people while traveling on vehicles , such as on airplanes , buses , or trains , wherein the seats are often too narrow for their body size . by enabling the user to easily maintain his or her arms in a desired position along his or her upper body , the user &# 39 ; s arms are prevented from contacting adjacent passengers or passersby and therefore the user can relax or sleep in comfort . still referring to fig2 , when the user places his or her palms against his or her upper body in the desired location , the region of material 16 along the palm of each of the hand portions 14 removably adheres to the material on the upper portion 12 . thus , the user can relax his or her shoulders and arms and permit the garment to bear the load of the dead weight of the arms . as a result , muscle strain and tendonitis in the arms and shoulders can be avoided . the first and second attachment means are chosen to be sufficiently strong such that the dead weight of the arms will not cause the first and second attachment means to separate disadvantageously . as discussed below , this garment can take many different forms ; however , each of the forms is manufactured to be capable of providing the user with a reliable means to support of one or both arms . additional components may be attached to the upper portion 12 of the garment 10 of fig1 . for example , as illustrated in fig3 , a neck pad 16 may be provided for enhanced head and neck support . the neck pad 16 is preferably provided with at least a region 18 of second attachment means , as illustrated in fig3 , for adhering to the upper portion 12 along the front shoulder region . the neck pad 16 can include an additional region 19 of second attachment means for attachment along the back of the user &# 39 ; s collar on the upper portion 12 . the neck pad may take a variety of forms , such as , for example , a stuffed pillow or an inflatable tube . fig4 illustrates the neck pad 16 of fig3 during use . in addition , similar pads may be attached to other areas of the upper portion 12 of the garment , such as , for example , along the forearms , elbows or on a shoulder , for enhancing the user &# 39 ; s comfort . furthermore , pockets ( not shown ) may be attached to the upper portion at selectable locations for a wide variety of different purposes . fig5 illustrates an alternative embodiment of a garment according to the present invention wherein the upper portion comprises a crossing strap 20 . the crossing strap 20 preferably attaches to itself at attachment location 17 to form a loop . the loop of the crossing strap 20 is placed over the head and is provided with first attachment means at least along the strap ends 22 . a significant feature of this embodiment is the ability to take the crossing strap 20 on and off quickly and easily , as compared with a sweater or vest . the crossing strap 20 illustrated in fig5 may include a padded neck region 24 for enhanced head and neck support . hand portions 14 similar to the gloves illustrated in fig1 and 2 may be used with the crossing strap 20 , as illustrated during use in fig6 . fig7 illustrates another embodiment of a garment according the to present invention wherein the upper portion is provided in the form of a non - crossing strap 21 . the strap 21 is placed around the back of the neck and lays over the front region of the shoulders . the strap 21 is provided with a first attachment means at least along the strap ends 23 . the strap 21 illustrated in fig7 also includes a padded neck region 25 for enhanced head and neck support . hand portions 14 similar to the gloves illustrated in fig1 and 2 may be used with the strap 21 , as illustrated during use in fig8 . fig9 and 10 illustrate alternative embodiments of hand portions comprising straps that are worn around the hands or wrists . fig9 illustrates an embodiment of the hand portions comprising palm straps 26 that wrap around the palm region of the hand . each palm strap 26 includes an attachment region 28 provided with a second attachment means . fig1 illustrates an embodiment of the hand portions comprising wrist straps 30 . each wrist strap 30 includes an attachment region 32 provided with a second attachment means . fig1 illustrates yet another embodiment of the garment that is particularly well suited for immobilizing a victim &# 39 ; s arm , such as , during rehabilitation after an injury . in the embodiment illustrated in fig1 , the upper portion of the garment comprises a shoulder strap 34 adapted for wear across one shoulder . a region of first attachment means is provided at least along a region 36 on the exterior of the shoulder strap 34 . during use , the user wears a hand portion , such as one of the wrist straps 30 illustrated in fig1 , provided with a second attachment means adapted to releasably attach to the first attachment means 36 of the shoulder strap 34 at a selectable location . the embodiment illustrated in fig1 is particularly advantageous for applications wherein a sling may be impractical or cumbersome . this embodiment also advantageously allows the user to quickly and easily detach the wrist strap 30 from the shoulder strap 34 and thereby free the injured arm when necessary . in contrast , it is much more difficult to remove a conventional sling and then replace the arm in the sling when finished . a significant feature of this embodiment is the ability to select the attachment position of the arm according to the particular needs of the user . to illustrate this feature , fig1 shows the embodiment of fig1 during use , but with a wrist strap 30 attached to the shoulder strap 34 at a different location . fig1 illustrates yet another alternative embodiment that is particularly well - suited for use in maintaining a user &# 39 ; s hands or arms in a fixed location while laying on a stretcher or cot . in this embodiment , the upper portion of the garment comprises a chest strap 38 adapted for wear around the user &# 39 ; s chest . a region of first attachment means is provided at least along a region 40 on the front exterior of the chest strap 38 . hand portions , such as the wrist straps 30 shown in fig1 , provide second attachment means for releasable attachment to the chest strap 38 . the combination of the wrist straps 30 and the chest strap 38 provides the ability to affix the user &# 39 ; s hands or arms along his or her upper body in a quick and easy manner . fig1 illustrates yet another alternative embodiment wherein wrist straps 42 , 44 are provided with attachment means on both the top and bottom sides . using the wrist straps 42 , 44 in combination with the chest strap 38 , a first wrist strap 42 may be attached to the chest strap 38 while a second wrist strap 44 is attached to the first wrist strap 42 . fig1 illustrates yet another alternative embodiment wherein the upper portion of the garment comprises a harness 46 adapted for wear along the user &# 39 ; s torso . this embodiment provides an upper portion that can be snugly fitted to the user . the harness 46 includes second attachment means 48 along the front exterior . in each of the embodiments described above , the upper portion is adapted for wear along the torso region of the body is provided with a first attachment means , such as a durable fabric comprising a loop material . as discussed above , the upper portion may be manufactured in a variety of different forms including , but not limited to , a shirt , sweater , vest or strap . furthermore , the upper portion may be manufactured to be very durable for long - term use or may be manufactured to be disposable , such as for one - time use by passengers on an airplane , train or bus . the entire upper portion may be made of a loop material fabric or , alternatively , the fabric may be provided along only a limited desired region . in addition , the upper portion may have loop material along one or both sides ( i . e ., it may be single or double - sided ). an upper portion manufactured from a double - sided loop material may be reversible and may also provide the ability to attach articles , such as pockets , along both the exterior and interior of the upper portion . the upper portion may also include a zipper in the front , preferably made of a plastic material for increased comfort and for avoiding detection by metal detectors . the fabric used in the manufacture of the upper portion is preferably breathable , lightweight , washable , flame - retardant , waterproof and has a soft surface for comfort against the skin . in one preferred embodiment , the fabric comprises a laminated loop material such as veltex ® manufactured by velcro usa , inc . veltex ® provides a relatively soft and even surface that is aesthetically pleasing and can be manufactured into a functional garment that can be worn for warmth or style in nearly any environment . in another preferred embodiment , the loop material comprises a medical grade laminate that provides increased attachment strength and improved duty cycles for durability over long periods . medical grade laminates generally comprise a soft breathable foam substrate with knitted nylon loop provided along one or both surfaces thereof . velcro usa , inc . provides a wide variety of medical grade laminates that are suitable for use with the present invention . the hand portions of the garment are preferably manufactured to include a region of hook material , at least along the palm or inner wrist , for providing a second attachment means for attachment with the first attachment means . as discussed above , the hand portions may be manufactured for wear along the hands , wrists or forearms . the gloves may be open - fingered for increased comfort and functionality , similar to weight lifting gloves ( e . g ., as illustrated in fig1 ). although the first and second attachment means of the preferred embodiments are described above with respect to hook and loop materials , it will be appreciated that alternative first and second attachment means may also be used . for example , the invention may be used with attachment devices such as buttons , hooks , snaps and clasps or any other device wherein the first attachment means may be releasably attached to a second attachment means in a quick and easy manner . furthermore , it will be appreciated that , when hook and loop materials are used , the hooks may be provided on the upper portion while the loops are provided on the hand portions , or vice versa . from the foregoing , it will be appreciated that the garment system of the present invention is very convenient to use . due to the minimal number of components and ease of use , the garment may be easily transported or stored in small area . in addition , the garment system of the present invention is very versatile and can be used in a broad range of applications at home or during travel . in certain applications , the garment system is usable by two or more persons . for example , in one application , the upper portion ( e . g ., a vest ) is worn by a motorcycle rider while the hand portion ( e . g ., gloves ) is worn by a passenger . in this application , the garment provides a safety mechanism by helping to ensure that the passenger &# 39 ; s hands are firmly secured to the rider &# 39 ; s upper body . in other applications , the upper portion and hand portions may be used for instructional purposes , such as hand placement during dancing , or for a wide variety of other instructional or recreational purposes , such as games and the like . while particular forms of the invention have been illustrated and described , it will also be appreciated that various additional modifications can also be made without departing from the spirit and scope of the invention .

US-93843304-A

a method for a roulette game played by at least one player and a roulette wheel and ball to cooperate with the roulette wheel to indicate a winning number may include the steps of : providing a first area to provide a winning number only based on the winning number indicated by the ball in the roulette wheel in a first operation of the ball and roulette wheel ; providing a second area defining a group of winning numbers to provide the player to advance to a second operation of the ball and roulette wheel which would provide another chance for a winning number .

in the game of roulette , a roulette wheel 101 with a multitude of colored and numbered areas 103 , e . g ., depressions , delineated cages , etc . may be positioned around the roulette wheel 101 , is spun on its vertical axis after which a ball is introduced upon the moving rotating wheel surface until the ball ultimately comes to rest upon one of such numbered areas . the roulette numbered areas 103 may be substantially identical in order to achieve a substantially equal probability that the ball will end up within any one of the numbered areas 103 and the numbered areas 103 may be randomly numbered around the wheel surface . there may be two types of roulette wheels . the first type may have 37 independent slots on a “ european ” roulette wheel while a second type may have 38 independent slots on the “ american ” version of a roulette wheel . of the 37 slots on the european wheel , 1 of the slots is numbered “ 0 ” and identified by the background color green , while the remaining 36 slots are numbered 1 - 36 , and are identified in alternating background colors of red and black . of the 38 slots on the american wheel , 2 of the slots may have a background color green and marked with the numbers “ 0 ” and “ 00 ”, while the remaining 36 slots may be numbered 1 - 36 , and are identified in alternating background colors of red and black . other types of wheels may be possible . another feature of a casino style roulette table is that there is a designated betting board area 105 generally rectangular in shape and with a defined perimeter and divided with generally square or rectangular betting areas 107 corresponding to the roulette wheel &# 39 ; s numbers and colors and on which betting areas the players place chips in order to register their bets on the outcome of the wheel spin . the betting areas 107 are either won or lost in a single or first roll of the ball on the roulette wheel 101 . the establishment operating the roulette wheel 101 may collect the losing bets or pay off the winning bets in accordance with the number that the ball finally comes to rest in . for these players , there is no opportunity for the bet to be extended to a second operation of the roulette wheel 101 . this does not extend the excitement and enjoyment of the betting experience . the players sit adjacent to this betting area while the croupier generally sits or stands across from the players and the wheel at the other tableside . players may place , modify or remove chips at any time prior to the “ no more bets ” call by either having the croupier do so or by actually moving their hands across the periphery of the betting area and manipulating the chips into or away from the individual betting areas . obviously , the croupier has to closely monitor these player actions and be sure no betting takes place after the “ no more bets ” call . the layout 100 is modified from a conventional roulette layout by adding a predefined group of betting numbers which may be a multiple of betting numbers which may range from two to a predetermined number . fig1 illustrates a first group 131 which may include the numbers 13 , 36 , 24 , 3 , 15 which may be substantially adjacent to each other . a second group 133 may include the numbers 12 , 29 , 25 , 10 . a third group 135 may include the numbers 6 , 18 , 31 . a fourth group 137 may include the numbers 14 , 35 , 23 , 4 , 16 . a fifth group 139 may include the numbers 11 , 30 , 26 , 9 . a sixth group 141 may include the numbers 32 , 17 , 5 and a seventh group 143 which may include the numbers 34 , 22 , 20 , 7 , 33 , 21 , 19 , & amp ; 8 which may not be all adjacent to each other and which may have a smaller subset of numbers which may be adjacent and may be positioned at different locations on the roulette wheel 101 . an eighth group 145 may include the numbers 28 , 0 , 2 , 27 , 00 , 1 . which may not be all adjacent and may be positioned at different locations on the roulette wheel 101 . the group of numbers 131 , 133 , 135 , 137 , 139 , 141 , 143 may be identified by a common feature on the roulette wheel 101 which may be a common color such as blue , orange , yellow , etc , a common special symbol such as $, & amp ;, % etc , or any other image . additional betting areas may be positioned on the betting board area 105 such as the first betting area 109 may be for placing the bets for the fourth group 137 , the second betting area 111 may be for placing the bets for the second group 133 , the third betting area 113 may be for placing bets for the third group 135 , the fourth betting area 115 may be for placing bets for the sixth group 141 , the fifth betting area 117 may be for placing bets for the fifth group 139 , the sixth betting area 119 may be for placing bets for the first group 139 , and a seventh betting area 121 may be for placing bets for the seventh group 143 . the present invention provides additional betting options with predetermined sections of group numbers on the roulette wheel 101 which may be known as “ neighborhoods ”. these neighborhood sections may be identified by any additional coloring other than the already utilized red , black , and green colors . on the american version of the roulette wheel 101 , one alternative may be to group the total 38 independent spots into the following sections : 2 neighborhoods having 3 roulette numbered areas 103 each ; 2 neighborhoods of 4 roulette numbered areas 103 each ; 2 neighborhoods of 5 roulette numbered areas 103 each ; 1 neighborhood of 6 roulette numbered areas 103 ; and 1 neighborhood of 8 roulette numbered areas 103 . on the european version of the wheel , the 37 independent roulette numbered areas 103 would be divided into the following sections : 2 neighborhoods consisting of 3 roulette numbered areas 103 each ; 2 neighborhoods of 4 roulette numbered areas 103 each ; 3 neighborhoods of 5 roulette numbered areas 103 each ; and 1 neighborhood of 8 roulette numbered areas 103 . as a result of these neighborhood additions to each version of the roulette wheel , corresponding sections to identify the respective neighborhoods would be added to the betting layout and paid a fraction of true odds to winning bets . the present invention provides for a bet which would not lose as long as the ball does not land on one of the numbers within the numbered group . for example , a third group 135 may include the numbers 6 , 18 , and 31 , and if the ball should land on any one of these numbers for example 31 , the bet wins and is paid a fraction of odds . if the ball would land outside of these numbers , then the bet also would not necessarily lose . this bet would only lose if the ball should land in any of the numbers of the seventh group 143 for example 19 . all other non - winning neighborhood wagers are allowed to remain on the betting layout and considered to “ push ”, thus allowing the bettor the option of utilizing the “ pushed ” wager at his / her discretion . in conclusion , this enhancement would create a “ multiple roll ” version of the game of roulette because every wager would not be won or lost on a single - roll outcome . conversely , if a bettor places a wager on seventh group 143 on the layout in betting area 121 , the outcome must result in the ball landing on any number of the seventh group 143 on the first roll . for example , if the ball lands in the number 8 , the winning wager would be paid a fraction of true odds . if the ball lands on any other number not included in the seventh group 143 , for example 12 , then the bet loses . bettors place bets for the game of roulette . some bettors place bets on non - group betting areas and bettors place bets on the first group 131 . the ball is dropped on a rotating roulette wheel 101 . it is well recognized that as the wheel slows in speed and the movement of the ball moving and / or bouncing along the wheel &# 39 ; s surface slows as well , observers , e . g ., those bettors playing the game , have a better idea , that is , heightened odds , of choosing which of the numbered or colored areas the ball will ultimately come to rest upon thus determining the winner . the casino employee , dealer or croupier overseeing the table normally controls the movement when no more bets may be placed on the outcome of where the ball will rest and this call or decision is made on the basis of experience and judgment and preferably before the wheel slows to a point where the players can see where or which area of the wheel the ball is going to ultimately rest upon . the croupier thus has to observe the ball , the wheel , their relative speeds and movements and provides a “ no more bets ” announcement . for example , the ball lands on the area corresponding to the number 31 , and the bettors who had placed a bet on number 31 in the traditional manner are paid . the bettor who placed a bet on the first betting area 109 does not lose but may push his bet to the next roll of the ball on the roulette table 101 . while the invention is susceptible to various modifications and alternative forms , specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail . it should be understood , however , that the description herein of specific embodiments is not intended to limit the invention to the particular forms disclosed .

US-201213430482-A

disclosed is a method for the culture of higher eukaryotic cells which are dependent for survival on an exogenous factor . the method involves co - culturing the factor - dependent cells with an immortalized eukaryotic cell that has been engineered to secrete the requisite factor . also disclosed is a cell line of non - stromal cell origin which secretes interleukin - 7 .

fig1 is a diagram of the il - 7 expression vector , pbail7 . fig2 is a graph showing lymphocyte proliferation on three different adherent mammalian cell lines . fig3 is a representation of a series of micrographs showing b - lymphocytes cultured on an adherent layer of ( a ) primary bone marrow - derived feeder cells , ( b ) nail - 7 feeder cells , and ( c ) nih 3t3 feeder cells . there now follows one example of an immortalized mammalian cell line ( i . e ., the nail - 7 cell line ) which has been engineered to produce and secrete a factor ( i . e ., il - 7 ) and a description of its use as a feeder layer for the culture of hematopoietic cells ( i . e ., b - lineage cells ) which are dependent for their survival upon both the factor and cell - cell contact . this example is presented for the purpose of illustrating , not limiting , the invention . the pbail - 7 expression plasmid and the nail - 7 cell line were constructed as follows . a cdna library was first prepared . mrna was extracted from the spleen of a swiss mouse by the guanidinium isothiocyanate method of chirgwin ( biochemistry 18 : 5294 , 1976 ), and cdna produced from this rna using the cdna synthesis kit of boehringer - mannheim ( indianapolis , ind .) and the recommendations of the manufacturer . oligodeoxynucleotide pcr primers were designed based on the published il - 7 sequence of namen et al . ( nature 333 : 571 , 1988 ) and generated by an applied biosystems 380a dna synthesizer ( applied biosystems , foster city , calif .). the sequences of the primers corresponded to nucleotides 525 - 551 of the il - 7 positive sense strand and 1158 - 1184 of the il - 7 negative sense strand . in addition , four nucleotides , ggtc , were included at the 5 &# 39 ; end of each primer to create a sali restriction enzyme recognition site in the pcr product . 0 . 1 × 10 9 moles of each pcr primer were mixed with 4 μg of spleen cdna , and an il - 7 cdna molecule was amplified by the polymerase chain reaction ( pcr ) procedure of the cetus corporation ( perkin - elmer cetus gene amp kit , norwalk , conn .). pcr - amplified reaction products were treated with polynucleotide kinase to add 5 &# 39 ; terminal phosphate groups and the fragments were ligated to smai - digested , pbluescript ks ( stratagene , la jolla , calif .). e . coli strain dh5α was transformed with the ligation mixture and ampicillin - resistant cells ( i . e ., those cells harboring a recombinant plasmid ) were selected and propagated in culture by standard techniques ( see , e . g ., ausubel et al ., current protocols in molecular biology , wiley publishing , new york , n . y ., 1987 ). plasmid dna was prepared by standard techniques ( ausubel et al ., supra ), and the sequences of the cdna inserts were determined by the method of sanger ( sanger et al ., proc . natl . acad . sci . usa 74 : 5463 , 1977 ). clone pil - 7 . 16 was shown to contain a full - length il - 7 coding sequence and was used for all subsequent subcloning procedures . to direct expression of il - 7 in nih3t3 cells , the il - 7 cdna was inserted downstream of ( i . e , under the transcriptional control of ) the human β - actin enhancer and promoter , transcriptional control elements which have been shown to be highly active in nih3t3 cells ( gunning et al ., proc . natl . acad . sci . usa 84 : 4831 , 1987 ). the expression plasmid was constructed as follows . pil7 . 16 was digested with sali , and a 668 base pair fragment containing the il - 7 cdna was isolated by agarose gel electrophoresis ( ausubel et al ., supra ). this fragment was ligated to sali - digested phbapr - 1 ( gunning et al ., proc . natl . acad . sci . usa 84 : 4831 , 1987 ) and used to transform e . coli dh5α host cells as described above . plasmid dna was prepared from several independent colonies and was screened by restriction digestion analysis using the published il - 7 and phbapr - 1 sequences described above . a recombinant plasmid with the il - 7 cdna in the appropriate orientation was selected and termed pbail - 7 ( β - actin / il - 7 ). pbail - 7 was introduced into cultured mammalian nih3t3 cells as follows . 20μg of scai - digested pbail - 7 and 1 μg of ecori - digested psv7neo ( murphy et al ., proc . natl . acad . sci . usa 83 : 2939 , 1986 ) were mixed with 10 7 nih3t3 fibroblasts ( atcc accession number crl - 6442 ) in 0 . 5 ml of phosphate buffered saline . psv7neo confers resistance to g418 , and cells transfected with this plasmid may be dominantly selected ( ausubel et al ., supra ). cells were electroporated by standard techniques using a biorad gene pulser machine ( 0 . 25 kv , 960 uf ) ( biorad , hercules , calif . ; ausubel et al ., supra ), incubated for two days in nonselective medium ( i . e ., dulbecco &# 39 ; s modified eagle medium , or dmem , supplemented with 2mm glutamine , 50 u / ml penicillin , 50 μg / ml streptomycin , and 10 % bovine calf serum ; gibco , grand island , n . y . ), and then incubated for 11 days in selective medium ( i . e ., dmem containing 400 μg / ml g418 ; geneticin ; life technologies inc ., grand island , n . y .). twelve g418 - resistant clones were selected and transferred to individual plates with a capillary tube . clones were propagated for several generations in selective medium , aliquots of cells were then propagated in non - selective medium , and their culture supernatants were assayed for the production of il - 7 by the method of namen et al . ( j . exp med . 164 : 988 - 1002 , 1988 ). in addition , rna was prepared from samples of the clones by the method of chirgwin ( biochemistry 18 : 5294 , 1976 ) and assayed for the presence of il - 7 mrna by rnase protection ( by the method of krieg et al ., nucl . acids res . 12 : 7035 - 56 , 1984 ) using an il - 7 - specific probe including nucleotides 525 to 656 of the antisense strand of pil7 . 16 . one cell line shown to express il - 7 mrna and secrete active il - 7 was chosen for experiments described herein . this cell line was termed nail - 7 ( nih3t3 / β - actin / il - 7 ). a monolayer of nail - 7 cells was used to support the growth of b - lineage lymphocytes and the efficacy of such a nail - 7 feeder layer was compared to that of a parental nih3t3 cell layer and a primary stromal cell layer . primary stromal cell feeder layers were prepared by the method of whitlock et al . ( j . imm . meth . 67 : 353 - 369 , 1984 ). nail - 7 and nih3t3 cell feeder layers were prepared by treating confluent cultures of each cell type with mitomycin - c ( 10 μg / ml for 2 - 4 hr ., sigma chemical co ., st . louis , mo .) to block cell division . following treatment , cells were replated at 5 × 10 4 cells / cm 2 . feeder - dependent b - lineage lymphocytes were prepared from balb / c mice by the method of whitlock et al ., ( j . imm . meth . 67 : 353 , 1984 ) and were plated at 10 5 cells / ml in dishes containing monolayers of either stromal cells , mitomycin - c - treated nih3t3 cells , or mitomycin - c - treated nail - 7 cells ( each prepared as described above ). at 3 - 4 day intervals , the cultures were alternately supplemented with a half - volume of selective medium , or resuspended vigorously , aspirated , and replenished with one volume of selective medium . the cells in the aspirates were counted by standard techniques . results presented in fig2 show the number of b - lymphocytes in cultures grown on either nail - 7 cells (), nih3t3 cells (), or bone marrow stromal cells (). fig3 shows feeder - dependent lymphocytes grown for 10 days on either nail - 7 cells ( middle panel , b ) or nih3t3 cells ( right panel , c ). fig3 also shows a six week culture of bone marrow stromal cells ( left panel , a ). fig2 and 3 indicate that feeder - dependent lymphocytes cultured on primary bone marrow stromal cells or on nail - 7 cells proliferated vigorously while the same lymphocytes plated on nih3t3 cells grew very poorly , if at all . fig2 further shows that b - lymphocytes grow rapidly and to a higher density on nail - 7 cells than on a stromal cell feeder layer or on an nih3t3 cell layer . certain aspects of this method may be altered without destroying the efficacy of the culture system . for example , although it is preferable to routinely transfer aliquots of the cultured b - lymphocytes to plates containing freshly mitomycin c - treated nail - 7 cell layers ( e . g ., once a week to once a month ), a continuous culture of b - lymphocytes may be successfully propagated on a single layer of treated nail - 7 cells for many months . to date , b - lymphocytes have been cultured for up to eight continuous months on the same layer of mitomycin - c treated nail - 7 cells . b - lymphocytes have also been propagated on a nail - 7 cell line which was not treated with mitomycin - c . culture was carried out as described above ( i . e ., using equivalent medium lacking mitomycin - c ) except that the nail - 7 feeder layer was plated at a very low initial density ( e . g ., at 1 / 10 confluence or approximately 10 4 cells or less / 10 cm 2 plate ). the length of continuous culture time is limited by the rapid growth of the untreated nih3t3 feeder layer and the resultant exhaustion of culture nutrients . the method of the invention can be used to culture factor - dependent cells remote from b - lineage lymphocytes and can utilize feeder cell layers other than il - 7 - producing nih3t3 cells . the following examples illustrate that such feeder cells and such factor - dependent cells may be either adherent or non - adherent . these examples are designed to provide guidance and should not be construed as limiting . in a first example , adherent factor - dependent cells are propagated with non - adherent feeder cells the factor - dependent cells are plated on a solid support , e . g ., on a tissue culture dish , under conditions and for a period of time which allow adherence to the solid support . feeder cells are then suspended in the culture medium , where they secrete factors which promote adherent cell growth . harvesting the factor - dependent cells involves removal of the feeder cells by aspiration of the culture supernatant followed , where necessary , by one or more washing steps with , e . g ., phosphate buffered saline . the factor - dependent cells are then collected following their release from the solid support , e . g ., by brief treatment with trypsin ( by standard methods ; see , e . g ., ausubel et al ., supra ). in particular , this method of this first example may be used for the propagation of adherent factor - dependent endothelial cells with engineered non - adherent hematopoietic cells , e . g ., lymphocytes . the endothelial cells and hematopoietic cells are cultured by standard techniques ( see , e . g ., andus et al ., pharm . res . 7 : 435 , 1990 ; and methods described herein , respectively ). the hematopoietic cells are engineered to produce a factor which stimulates endothelial cell growth , such as fibroblast growth factor , transforming growth factor - e , transforming growth factor - β , or the c - kit ligand ( see , e . g ., folkman et al ., science 235 : 442 , 1987 ; ingber et al ., j . cell biol . 109 : 317 , 1989 ). following propagation , the endothelial cells are harvested as described above . in a second example , both the factor - dependent cells and the feeder cells are adherent . in this case , cells are plated simultaneously and allowed to adhere to a solid support ( preferably , a tissue culture dish , as generally described above ). the factor - dependent cells are stimulated to divide by growth factors produced by the adherent feeder cells . following propagation , the factor - dependent cells and the feeder cells are simultaneously harvested by brief treatment with trypsin ( as described above ). factor - dependent cells are isolated from the mixed population by physical methods designed to differentiate between the two cell types , e . g ., elutriation or density gradient centrifugation ( beckman publications ds 534 ; beckman instruments , columbia , md . ; ausubel et al ., supra ; respectively ). the factor - dependent cells may also be isolated by immunological methods , such as binding to cell type - specific monoclonal antibodies attached to plastic plates or magnetic beads ( wysocki and sato , proc . natl . acad . sci . usa 75 : 2844 , 1978 ; dynal , inc , great neck , n . y . ), or to fluorescent molecules for fluorescence activated cell sorting ( jovin et al ., trends biochem . sci . 5 : 214 , 1980 ; herzenberg et al ., sci . am . 234 : 108 , 1976 ; ortho diagnostics systems , inc ., westwood , mass .). in specific examples , this method is useful for the culture of factor - dependent endothelial cells or factor - dependent nerve cells on an engineered nih3t3 feeder layer . in the first case , the feeder layer cells are engineered to produce endothelial cell growth factors such as fibroblast growth factor , transforming growth factor - α , transforming growth factor - β , or kit ligand ( see , e . g ., folkman et al ., 1987 , supra ; ingber et al ., 1989 , supra ). in the second case , the immortalized adherent cells are engineered to produce a nerve cell growth factor such as nerve growth factor ( ngf ) ( see , e . g ., bienenstock et al ., int . arch . allergy appl . immunol . 87 : 238 , 1987 ; carbonetto et al ., j . physiol . ( paris ) 82 : 258 , 1987 ). cells are grown using standard methods of endothelial cell or nerve cell culture ( see , e . g ., audus et al ., pharm . res . 7 : 435 , 1990 ; and lander , mol . neurobiol . 1 : 213 , 1987 ; bunge et al ., prog . brain res . 78 : 321 , 1988 ; azmitia et al ., neurobiol of aging 9 : 743 , 1988 , respectively ). the factor - dependent cells are separated by physical or immunological methods as described above . finally , both the factor - dependent cells and the feeder cells may be non - adherent . in this case , factor - dependent cells and feeder cells are cultured as a mixed population in solution ( e . g ., in a test tube or culture bottle ). once propagated , the factor - dependent cells are harvested by physical or immunological separation from the feeder cells , using , for example , the methods described above . alternatively , factor - dependent cells not requiring cell - cell contact may be grown in solution with feeder cells , under conditions where the factor - dependent cells remain separated from the feeder cells by some physical barrier , e . g ., a semi - permeable membrane . such a physical barrier must prevent cells from mixing but must allow factor ( s ) to pass from the feeder cells to the factor - dependent cells . preferably , the physical barrier used for this type of culturing is provided by a millicell - cm ( millipore , bedford , mass .). in a specific example , this method is used for the culture of factor - dependent b - lymphocytes with engineered t - lymphocyte feeder cells . cells are grown using standard methods of lymphocyte cell culture ( see , e . g ., methods described herein ). the feeder cells are engineered to produce a b - lymphocyte growth factor , such as il - 7 ( as described herein ). if the factor - dependent and feeder cells are cultured together in suspension , the factor - dependent cells are separated by physical or immunological methods as described above . alternatively , if the factor - dependent cells and feeder cells are cultured on opposite sides of a semi - permeable membrane , the need for later separation is circumvented , and the factor - dependent cells may be harvested directly from suspension . for all of the above examples , the choice of culture conditions ( e . g ., choice of growth medium ) will vary slightly according to the types of feeder and factor - dependent cells involved ; appropriate conditions are well known by those skilled in the art . where necessary , culture conditions are adjusted to accommodate the growth condition requirements ( e . g ., media requirements ) of both the feeder cells and the factor - dependent cells , the modifications are generally minor and should not be an impediment to the success of the culture method . mitomycin - c treatment is not necessary to the success of the instant culture method . mitomycin - c treatment facilitates the use of feeder layers capable of rapid proliferation ; however , as described above , untreated feeder layers have been used successfully ( even very rapidly - dividing nih3t3 feeder layers ). moreover , since mitomycin - c treatment simply slows feeder layer proliferation , it may be eliminated when the culture system makes use of a slowly - dividing feeder layer . the method of the invention may be used for the propagation of human cells , for example , b - or t - lineage lymphocytes . because the culture system provides the opportunity to define the growth conditions , particular growth factors may be provided by the feeder layer which stimulate maturation of , e . g ., blood cells from progenitor cells . alternatively , omission of a growth factor which triggers cell differentiation ( e . g ., one which is normally secreted by primary cell layers , such as stromal cells ) allows the large - scale propagation of cell precursors , e . g ., stem cells . in one particularly useful application , human cells are isolated from a patient , e . g ., stem cells or blood cells from an immunodeficient or immunocompromised patient . the cells are propagated using the in vitro method of the instant invention , harvested , and re - introduced ( e . g ., intravenously ) into the patient to bolster or restore immune function .

US-34264394-A

a vacuum cleaner current - carrying hose connection system is disclosed having a female connection end on a first vacuum cleaner current - carrying hose adapted for receiving a male connection end on a second vacuum cleaner current - carrying hose . the male connection has at least two male receptor plugs configured for inserting into female receptor holes in the female connection end . a vacuum cleaner hose connection system is further disclosed having a male connection end that has at least two male receptor plugs for transmitting current , a female connection end having at least two female receptor holes for receiving the male receptor plugs , and the male and female connection ends being rotatably movable , about the longitudinal axis of at least one of the female connection end and the male connection end , between an unengaged position and an engaged position .

throughout the following description , specific details are set forth in order to provide a more thorough understanding of the invention . however , the invention may be practiced without these particulars . in other instances , well known elements have not been shown or described in detail to avoid unnecessarily obscuring the invention . accordingly , the specification and drawings are to be regarded in an illustrative , rather than a restrictive , sense . fig1 and 2 show a male connection end 10 and a female connection end 80 of a current - carrying hose system made in accordance with a preferred embodiment of the invention . the male connection end 10 and the female connection end 80 are both connected to a flexible vacuum hose 20 having a current - carrying cord wound round in a helix . the male connection end 10 has a hard shell 30 that is snugly attached to the male connection end &# 39 ; s contoured leading lip 40 . two male receptor plugs 50 protrude from the contoured leading lip 40 . an inner vacuum tube member 60 protrudes out of the male connection end 10 and has a guide button 70 on each side . female connection end 80 has a hard protective shell 90 attached snugly to the female connection end &# 39 ; s contoured leading lip 100 . fig3 shows a top view of the male connection end 10 according to the preferred embodiment of the invention , and shows a screw 110 that is used to attach the hard protective cover 30 to the remainder of the male connection end 10 . fig4 shows a top view of the female connection end 80 according to a preferred embodiment of the invention , showing screw 120 that is used to attach the hard protective cover 90 to the remainder of the female connection end 80 . the inner portions of the male and female connection ends 010 and 80 are best illustrated with reference to fig5 to 8 showing the protective hard covers 30 and 90 removed . fig5 and 6 show the alternate side views for the male connection end 10 . the male connection end 10 has a short flange 210 and a long flange 220 , each protecting and attached to a circuit board 230 . each circuit board 230 is attached to two conducting leads 240 , and each conducting lead 240 is in contact with one of four conducting loops 250 . the four conducting loops 250 are spaced apart by insulating non - conducting loops 260 . the conducting loops 250 and the insulating loops 260 extend circumferentially around the vacuum hose . the front portion of the male connection end 10 , including the contoured leading lip 40 and the short and long flanges 210 and 220 , is freely rotatable around a longitudinal axis extending through the inner vacuum tube member 60 . vacuum tube 60 extends into pipe 20 through a seal member . as the front end of the male connection end 10 rotates , the conducting leads 240 remain at all times in contact with the conducting loops 250 . spacer knobs 310 extend out of the short and long flanges 210 and 220 , through the short and long circuit boards 230 . the spacer knobs 310 hold the circuit boards 230 in position and help prevent the circuit boards 230 from touching the conducting loops 250 . each conducting loop 250 is attached to one wire from the helix of wires in the current - carrying cord 20 . each conducting loop 250 is also connected to one conducting lead 240 , which in turn is connected via a wire on the circuit board 230 to an insulated wire 270 . for each conducting lead 240 on each circuit board 230 , the electrical connection travels on an opposite side of the circuit board 230 to a separate insulated wire 270 . each insulated wire 270 is connected to one of the male receptor plugs 50 . the connection between the insulated wires 270 and the male receptor plugs 50 is shown as a welded joint in fig5 , 7 , and 8 and is shown using female electric push / slide connectors 265 in fig6 . it is to be understood that the connection between the insulated wires 270 and the male receptor plugs 50 can be by any suitable means . the male receptor plugs 50 are attached firmly to the front portion of the male connection end 10 by a plug mounting cover 280 , which in turn is held in place by a plug mounting screw 285 attached to a mounting screw receptacle 287 . a screw 290 and nut 300 combination are shown in fig5 to 8 for firmly connecting two halves of the male receptor end , if the male receptor end is made by two pieces . while fig5 and 6 are similar , they illustrate opposite sides of the male connection end 10 . the configuration of the insulating wires 270 and the location of the short and long flanges 210 and 220 are slightly different for each side . fig7 shows the male connection end and the female connection end in a partially engaged position . to achieve this position , the guide buttons 70 on the male connection end 10 are first slid through the guide button receiving channels 400 in female connection end 80 , as illustrated in fig9 . with the guide buttons 70 in position , a twisting action will result in the male receptor plugs 50 being guided into place within the female receptor holes 130 each time the ends are connected . a guide button receptor 410 helps keep the male and female connection ends 10 and 80 held together when in fully engaged position . fig8 shows the male and female connection ends 10 and 80 in fully engaged position . female receptor leads 350 contact the male receptor plugs 50 when the male and female connection ends 10 and 80 are in the fully engaged position . the female receptor leads 350 are in electrical communication with insulated receptor wires 270 via electrical circuit pathways 360 . the remaining inner workings of the female connection end 80 are similar to the male connection end 10 , including conducting loops 250 , insulating loops 260 , short and long flanges 210 and 220 , and conducting leads 240 . fig1 shows a handle part 500 along with a female connection end 80 . the handle part 500 has male receptor plugs 50 and an inner vacuum tube member 60 with a guide button 70 , all similar to the male connection end 10 . the handle part 500 has a leading end 510 and a hard protective cover 520 . the handle part 500 is further shown with an on / off switch 540 and with an inner vacuum tube pipe 550 . as can be appreciated with references to fig1 to 10 , the preferred embodiment uses the same type of connection between the vacuum cleaner current - carrying hose 20 and a second or third vacuum cleaner extension hose as it does with the handle part 500 . this will allow for easy operation with a single vacuum hose or with any number of extensions of similar vacuum hoses , which may or may not be of similar length to the first hose . as described briefly above , the front portion of the connection ends 10 and 80 , including the hard covers 30 and 90 are freely rotatable about the longitudinal axis of the connection end . the preferred embodiment provides a simple and easy to use mechanism to connect a vacuum hose to a handle part 500 or to a second vacuum hose without requiring the pushing of buttons or straight pulling apart of connections . engaging and unengaging the connection can be carried out by twisting . inner vacuum tube pipe 550 is in communication with inner vacuum tube member 60 and may form a single tube . fig1 and 12 show a male connection end 580 and a female connection end 590 according to a second embodiment of the invention . the male receptor end has four male receptor plugs 620 , a straight leading lip 610 , and a hard protective shell 600 . the female receptor end has female receptor holes ( not shown ) that will line up with the male receptor plugs 620 . the female connection end has a connection mechanism 650 in communication with a connection mechanism button 660 . the connection mechanism 650 fits into a corresponding receptor hole ( not shown ) in the male connection end 580 . fig1 and 14 show top views of the male and female connection ends according to the second embodiment . fig1 shows a handle part 700 with a female connection end 590 according to the second embodiment of the invention . the handle part 700 has male receptor plugs 620 , an inner vacuum tube member 60 and guide buttons 70 similar to the male connection end 580 . the handle part 700 has a leading lip 710 and a hard shell cover 720 . the handle part 700 further shows an on / off button 740 and an inner vacuum tube pipe 750 . as will be appreciated with references to fig1 to 15 , the second embodiment has a straight leading edge connection between the male and female parts . the use of the uniform male and female connection end system allows the easy insertion or removal of an extension hose between a first vacuum hose and a handle part . a basic implementation of the invention requires a male / female connection system at one end of the main hose . the connection system can connect the hose to a vacuum cleaner body or to a wall outlet of a built in vacuum cleaner at one end and / or it could connect the hose to the handle part . this description has described the connection system applying between a hose and a handle part , however it is to be understood that this system could be used between a hose and a vacuum cleaner &# 39 ; s main body or a wall outlet . it is further possible to have a connection system at both ends of the main hose , in which case the main hose would likely have one male connection end and one female connection end according to this invention . implementing the connection system at both ends of the main vacuum cleaner hose , namely to connect to the handle part and to the main body , would allow a main hose to have both a male connection end and a female connection end , allowing main and extension hoses to be interchangeable . connecting two hoses together according to the invention provides a swivel at the join of the hoses , which reduces or eliminates kinking in the middle of the extended hose . the ease of opening the join between two hoses further facilitates access to any clogs that may have occurred in the extended hose . as will be apparent to those skilled in the art in the light of the foregoing disclosure , many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof . for example , current - carrying vacuum hoses have been described as having a current - carrying cord wound round in a helix , however it is to be understood that this invention can be practiced with cords that carry a relatively straight current - carrying cord inside or outside the vacuum cord . accordingly , the scope of the invention is to be construed in accordance with the substance defined by the following claims .

US-66512703-A

a tillage with an auto - reset mechanism and system adapted for tripping when a tool encounters an obstacle in the field , and automatically resetting when the obstacle is cleared . the mechanism is adapted for mounting various ground - working tools , such as shank - mounted chisels , which typically operate slightly below the ground surface and are thus susceptible to damage from submerged obstacles , such as rocks , buried timber and tree roots .

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 , which may be embodied in various forms . 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 in virtually any appropriately detailed structure . certain terminology will be used in the following description for convenience in reference only and will not be limiting . for example , up , down , front , back , right and left refer to the invention as oriented in the view being referred to . the words “ inwardly ” and “ outwardly ” refer to directions toward and away from , respectively , the geometric center of the embodiment being described and designated parts thereof . said terminology will include the words specifically mentioned , derivatives thereof and words of similar meaning referring to the drawings in more detail , the reference numeral 2 generally designates an implement , e . g ., a multi - gang tillage tool , embodying an aspect of the present invention and generally including numerous tilling tool arm assemblies 4 with auto - reset mechanisms 8 . without limitation on the generality of useful applications of the present invention , the implement 2 can comprise a tillage tool assembly 4 including coulters , discs , knives , chemical applicators and other ground - working equipment components 10 , 12 , which can be chosen for particular tasks associated with factors such as field conditions , crops , ground moisture , field trash , debris , etc . the tillage tool generally includes a toolbar 22 , which can be connected to a tractor by a conventional three - point hitch , a drawbar or other suitable connection mechanisms . the toolbar 22 mounts one or more “ gangs ” of ground - working tool arm assemblies 4 . without limitation , the multiple gangs correspond to the rows of crops in an agricultural field which are treated in a single pass . for example , eight - gang tillage tools are relatively common . greater working widths corresponding to more crop rows can be accommodated with other aspects of the present invention , such as a stack - fold and flat - fold configurations , which can include a center section and two side sections configured for hydraulically folding up and over the center section . a tool arm assembly 4 includes an arm 18 with a first , proximal section 15 and a second , distal section 17 , which can be joined at a 90 ° elbow 19 . other possible configurations of the arm 18 include different angles between the sections and different arm geometries . various configurations and shapes of the arm 18 could be functional in the tool arm assembly 4 , provided similar connections to other components , geometries and ranges - of - motion are maintained . an auto - reset mechanism or system 8 includes a bracket subassembly 20 pivotally mounting the tool arm assembly proximal section 15 on the toolbar 22 for swinging upwardly to clear obstructions , and thereafter automatically resetting to a working , subsurface - engaging position . the bracket assembly 20 includes a bracket mount 26 with a pair of bracket mount plates 27 , which are positioned in spaced relation and notched to receive the toolbar 22 . the bracket mount 26 is mounted on the toolbar 22 by u bolts 28 for removal and reinstallation if needed . alternatively , the bracket mounts 26 could be welded onto the toolbar 22 in fixed positions , or mounted using some other suitable attachment means . an upper linkage arm subassembly 30 includes a pair of linkage arms 31 pivotally connected at their front ends to the upper ends of the bracket mount plates 27 by a front pivot bolt 34 . the linkage arms 31 are pivotally connected at their back ends to the upper end of the arm proximate section 15 by a rear pivot bolt 36 . the tool arm 18 is thus adapted to pivot about a pivotal axis through the rear pivot bolt 36 . a reset spring assembly 24 includes a spring mounting bracket 32 pivotally attached to a lower end of the arm proximate section 15 by a bolt retainer 40 . the spring mounting bracket 32 includes a pair of coil springs 42 each mounted on a respective side of the arm proximal section 15 . the springs 42 are linked to the front bracket mount 26 by a pair of torsion rods 44 , which are pivotally connected at their front ends to the bracket mount 26 lower end and extend through respective spring guides 46 at their back ends , which threadably receive nuts 48 whereby spring tension is adjustable . suitable pivot bushings 50 can be provided at the pivotal connections for reducing friction and wear on the moving parts . alternatively , the pivotal connections could utilize other bearing devices , configurations and / or lubricants . a variety of tools can be mounted on the tool arm assemblies 4 for specific agricultural operations . without limitation , knives 14 are mounted on shanks 13 extending through shank receivers 29 located on the arm distal sections 17 . each arm proximal section 15 also mounts a depth gauge wheel 12 which extends forwardly and downwardly from a wheel mounting plate 58 on the elbow 19 formed by the arm sections 15 and 17 . the depth gauge wheel 12 can mount an optional coulter disk 62 . a pair of row cleaners 10 is mounted between the depth gauge wheels 12 and the shanks 13 . fig2 and 3 show a tool arm assembly 4 in exploded and constructed views , respectively . the elements are combined for easy disassembly for cleaning or modification , such as attaching different tool types . fig4 shows the tillage tool arm assembly 4 in normal operation with the knife 14 embedded in the ground and the depth gauge wheel 12 maintaining the depth of the knife 14 . a subsurface obstacle 25 , shown in fig5 - 10 , is located in front of the knife 14 and generally in its path . fig5 shows the depth gauge wheel 12 passing over the obstacle 25 . fig6 shows the row cleaners 10 clearing the obstacle 25 . fig7 shows the knife 14 hitting the obstacle 25 , causing the tool arm 18 to rotate counterclockwise , as shown further in fig8 and 9 , and again in more detail in fig1 . an attachment bar receiver 52 is located at the proximal end of the proximal section 17 of the tool arm 18 . this receiver allows for connection of additional ground - working tools in the form of a secondary tool attachment 54 , such as shown in fig4 . a spring - loaded absorber 56 connects the main arm 66 of the secondary tool attachment 54 to a mounting bracket assembly 60 similar to bracket assembly 20 discussed above . in the example shown , a secondary coulter blade 62 and tilling tool 64 are connected via the secondary tool attachment 54 , and would be lifted by the reset spring assembly 24 . it is to be understood that the invention can be embodied in various forms , and is not to be limited to the examples discussed above . the range of components and configurations which can be utilized in the practice of the present invention is virtually unlimited .

US-201414281748-A

an assembly for angle adjustment is disclosed and shown for use with agriculture equipment such as planters , applicators and tillage equipment wherein deployment of a coupler upon a shaft to allow introduction of an angle is beneficial . a closing wheel assembly incorporating the assembly for angle adjustment allows control of the angle of a closing wheel to improve soil gathering action for delivery of more or less soil to the seed slot / open furrow generated by the opener or opener assembly of a planter row unit . exemplary applications of the assembly for angle adjustment include row unit closing wheel assemblies , fertilizer applicators and strip tillage closing systems .

before the present closing wheel adjusting assembly is disclosed and described , it is to be understood that the assembly for angle adjustment 30 is not limited to specific methods , specific components , or to particular implementations . 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 . also , it is to be understood that phraseology and terminology used herein with reference to device or element orientation ( such as , for example , terms like “ front ”, “ back ”, “ up ”, “ down ”, “ top ”, “ bottom ”, and the like ) are only used to simplify description of the present closing wheel adjusting assembly , and do not alone indicate or imply that the device or element referred to must have a particular orientation . in addition , terms such as “ first ”, “ second ”, and “ third ” are used herein and in the appended claims for purposes of description and are not intended to indicate or imply relative importance or significance . as used in the specification and the appended claims , the singular forms “ a ,” “ an ,” and “ the ” include plural referents unless the context clearly dictates otherwise . ranges may be expressed herein as from “ about ” one particular value , and / or to “ about ” another particular value . when such a range is expressed , another embodiment includes from the one particular value and / or to the other particular value . similarly , when values are expressed as approximations , by use of the antecedent “ about ,” it will be understood that the particular value forms another embodiment . it will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint , and independently of the other endpoint . “ optional ” or “ optionally ” means that the subsequently described event or circumstance may or may not occur , and that the description includes instances where said event or circumstance occurs and instances where it does not . throughout the description and claims of this specification , the word “ comprise ” and variations of the word , such as “ comprising ” and “ comprises ,” means “ including but not limited to ,” and is not intended to exclude , for example , other components , integers or steps . “ exemplary ” means “ an example of ” and is not intended to convey an indication of a preferred or ideal embodiment . “ such as ” is not used in a restrictive sense , but for explanatory purposes . disclosed are components that can be used to perform the disclosed closing wheel adjusting assembly . these and other components are disclosed herein , and it is understood that when combinations , subsets , interactions , groups , etc . of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed , each is specifically contemplated and described herein , for all closing wheel adjusting assembly . this applies to all aspects of this application including , but not limited to , components of an assembly for angle adjustment 30 . thus , if there are a variety of additional components that can be added it is understood that each of these additional components can be added with any specific embodiment or combination of embodiments of the disclosed assembly for angle adjustment 30 . referring now to the drawings , wherein like reference numerals designate identical or corresponding parts throughout the several views , fig1 is a top view of a closing wheel assembly 20 of the prior art which may be mounted upon a row unit 11 ( not shown ) of a planter , drill or air - seeder 1 . one of ordinary skill will appreciate that a planter , drill or air - seeder 1 of the prior art upon which the closing wheel assembly 20 of the present disclosure may be mounted are well known . as shown in appendix a , the air - seeder 1 is similar to a model built and sold by case - ih , which is also branded and sold as new - holland . the general design is similar to many models on the market upon which the assembly for angle adjustment 30 may be applied to allow introduction and control of an angle of the closing wheels 23 . planter row units 11 of the type depicted in fig8 and appendix a are generally mounted to a tool bar 4 or similar structure using linkage 5 and may be oriented in either a parallel or non - parallel arrangement . the planter row unit 11 generally includes an opener assembly 14 to open a furrow in the ground surface ( shown as disc 15 ), a down pressure member ( shown as a spring 17 ) for applying a biasing force to the opener assembly 14 , a depth regulator 18 for regulating the depth of the furrow , a seed delivery mechanism 13 for delivering seed to the opened furrow ( shown as a hose ), a closing wheel assembly 20 for closing the furrow , at least one hopper 6 for holding seed , and a row unit frame 12 to which various elements of the planter row unit 11 are mounted . ( see appendix a for linkage 5 , hopper 6 , and row unit frame 12 ) as shown , fig2 illustrates a detailed view of the closing wheel assembly 20 of one particular air - seeder row unit 11 , particularly the opener ( disc ) 15 and closing wheel 23 . the model shown is a row unit offered by cnh and marketed as a case - ih 500 / 500t and by new holland as a 2080 / 2085 . as those practiced in the art will appreciate , the closing wheel assembly 20 shown in fig1 - 2 allows the closing wheel 23 to raise or lower , relative to the air - seeder row unit and row unit opener , to allow the closing wheel 23 to follow the soil surface . the closing wheel assembly 20 shown herein includes a closing wheel torsion spring 24 and closing wheel torsion spring rack 25 that function to adjust the pressure upon the closing wheel 23 and thus the amount of soil compression and the potential soil engaging depth of the closing wheel 23 . typically , increasing pressure upon the closing wheel 23 increases the scraping action of the closing wheel 23 on the ground surface 8 thereby increasing the dirt or soil moved during planting for delivery to the open furrow 9 to improve closing of the furrow . ( see also fig9 and appendix along with discussion herein ) applicant has studied the prior art closing wheel assembly 20 as depicted by fig1 - 2 and ascertained that in operation the preferred and beneficial amount of soil is many times not delivered to the furrow 9 opened by row unit opener 15 resulting in poor closing of the furrow , poor soil to seed contact and generally poor conditions for germination and growth of seeds . the closing wheels 23 and closing wheel assembly 20 as pictured in fig1 and 2 are an illustrative example of a configuration in which the closing wheel 23 when operated across a field does not have enough “ soil gathering action ” to effectively close the furrow / seed slot , particularly in moist field and soil conditions . to address and correct this failure to deliver soil 10 ( not shown ) in a direction 10 a ( see fig9 ) to the open furrow / seed slot 9 , thus improving soil gathering action , for a closing wheel assembly 20 of the type depicted herein , an assembly for angle adjustment 30 incorporated into the closing wheel assembly 20 is beneficial . as depicted in fig3 - 9 , an assembly for angle adjustment 30 comprised of a coupler 31 is mounted to the closing wheel shaft 22 of the closing wheel assembly 20 . the coupler 31 has a hollow body and is configured with a first end ( shaft end 31 a ) that mounts to the closing wheel shaft 22 by sliding onto and over the closing wheel shaft 22 , after removal of the closing wheel 23 . ( see fig5 a & amp ; 5b ) a tapped ( timed ) hole 32 is configured in the body of the coupler 31 proximate the first or shaft end 31 a of the coupler and is typically threaded and configured for engagement with a set screw 34 . the second end of coupler 31 b is configured as a cap having a bore 37 creating a straight passage through the coupler 31 with a special face and end 36 a configured therein which applicant has named a “ d - hole ” 36 as the interior barrel of the d - hole is made up of indexing and non - indexing edges , referenced respectively as , 36 b and 36 c as illustrated in fig6 c . the d - hole 36 and bore 37 are concentric at the cap end and pass straight through the body of the coupler 31 . the face ( d - hole face ) 36 a of the cap end may be angled up to 12 degrees as illustrated throughout and particularly by fig6 b . further , the d - hole 36 has an angled face 36 a which correspondences to the range of angle allowed by the closing wheel adjustment assembly 30 , which as disclosed is 0 - 12 degrees . rotating the coupler 31 upon the shaft 22 changes the angle 23 a between shaft 22 and closing ( rotatable ) wheel 23 while maintaining even contact between closing wheel 23 and angled face 36 a to support smooth rotation of closing ( rotatable ) wheel 23 . a bolt 33 , specially configured for the coupler 31 is configured for insertion in the coupler 31 . ( see fig6 a and 6b ) the angled bolt is comprised of three sections as illustrated throughout but particularly in fig6 b . a first section — the shaft ( receiver ) end 33 a is straight and is threaded and is configured for insertion inside to interlock with the mating threads 22 a ( not shown ) inside closing wheel shaft 22 of the prior art . ( see fig2 ) the first section is generally parallel with the body of the coupler 31 . an indexing barrel 33 c forms the second section and interconnects the first section and the third sections , referenced respectively as , 33 a and 33 b as illustrated in fig6 a and 6b . the indexing barrel 33 c has locking or indexing edges which correspond to the interior shape of the d - hole 36 to index the bolt 33 in the d - hole 36 . the third section is the angled end 33 b which is also threaded and is angled relative to the first section of the bolt and the indexing barrel 33 . the assembly for assembly for angle adjustment 30 comprising coupler 31 and bolt 33 are typically constructed from high quality galvanized steel to inhibit corrosion and increase run life . the above - referenced elements may , however , be constructed of any material known to those skilled in the art or later developed , which material is appropriate for the specific application of the assembly for angle adjustment 30 without departing from the spirit and scope of the present disclosure . one of ordinary skill will also appreciate that the actual mating shape of the d - hole 36 and locking edges ( 36 b , 36 c ) of the indexing barrel ( 33 c ) are inconsequential , i . e . shapes other than a “ d ” may be chosen without departure from the present disclosure , but that the indexing nature of the design disclosed provides additional benefits in operation and adjustment . one of ordinary skill will also appreciate that although applicant has disclosed the assembly for angle adjustment 30 having two components including coupler 31 and bolt 33 , one of ordinary skill will appreciate the end of an axle could be figured as bolt 33 for engagement with coupler 31 to allow for a similar end result and function , rotation to allow for angle introduction and control , without departure from the scope , spirit and intent of the present disclosure . use and operation using the assembly for angle adjustment 30 is illustrated by fig3 and fig9 as incorporated into a closing wheel assembly 20 . the opener assembly unit pictured in fig3 is a right - hand ( rh ) opener , and the timed hole 32 of the coupler 31 is pointing straight backwards ( towards the user ), assuming the user is positioned posterior of the closing wheel assembly 20 in fig3 . for example , and by way of illustration and without limitation , positioning the set - screw 34 straight backwards on a rh opener , as shown , allows the maximum closing wheel adjustment angle of 12 degrees . further , if the coupler 31 is rotated further so the set - screw 34 is now pointed straight downwards ( for a rh opener ) the closing wheel angle 23 a is now neutral . finally , if the coupler 31 is rotated further ( so the set - screw 34 is pointing straight forward ( or away from the user ), on a rh opener ), the closing wheel angle 23 a becomes negative at the maximum angle ( not desired as it doesn &# 39 ; t gather the soil to close the open furrow 9 . fig9 is a rear view of a right mounted closing wheel assembly with the assembly for angle adjustment 30 of the present disclosure incorporated therein . the closing wheel 23 is adjusted to approximately to an angle 23 a having a value of 10 . 4 degrees and soil 10 ( not shown ) is moving right to left ( soil direction 10 a ) for a right handed ( rh ) opener towards the furrow 9 ( not shown ) to be closed . ( see fig1 for illustrative example of an open furrow 9 ) when the coupler 31 is installed on the closing wheel shaft 22 , the assembly for angle adjustment 30 is infinitely adjustable allowing an angle 23 a operating range of − 12 and + 12 degrees to the open furrow 9 ( aka seed slot ) ( when viewed from above , with the closing wheel arm 21 in the horizontal position ). one of ordinary skill will appreciate that a closing wheel 23 positioned with a negative angle 23 a typically is not desirable as the closing wheel 23 does not gather sufficient soil to close the open furrow 9 so the operating range for a closing wheel angle 23 a is 0 - 12 degrees . applicant has found that 12 degrees of closing wheel angle 23 a is best suited for higher moisture clay soils , especially with no - till conditions . the maximum 12 degree angle is achieved when the set screw 34 is positioned straight backwards on a closing wheel arm 22 that &# 39 ; s horizontal when viewed from the side . as the coupler is rotated downwards , the closing wheel angle 23 a is reduced . the reduced angle is better suited for looser soils , drier soils or when operating at higher speeds where increased soil throw is common . when the coupler 31 is adjusted so the set screw 34 points straight downwards , the closing wheel 23 will run parallel to the open furrow 9 with little to no closing wheel action which is typically undesirable for this particular application . after setting the desired closing wheel angle 23 a , the lock nut on the axle and the set screw 34 on the coupler 31 are both tightened to lock the coupler 31 in position . the opener assembly unit pictured in fig3 is a right - hand ( rh ) opener , and the set screw 34 is pointing straight backwards ( towards the user ). the settings are the same with the left - handed ( lh ) opener as the coupler 31 is reversed on the opposite side . indicator marks 35 are provided on the coupler 31 to ensure all couplers 31 are positioned at a consistent angle within all of the closing wheel arm shafts 22 across the drill / planter / seeder 1 . fig7 is a perspective view of another embodiment of the assembly for angle adjustment 30 wherein indicator marks 35 have been positioned around the outer circumference of the body of the coupler 31 . one of ordinary skill will appreciate that the assembly for angle adjustment 30 may be configured for use and operation adjacent a plurality of closing wheel assemblies 20 attached to a plurality of corresponding planter row units 10 attached to a tool bar 4 to form a contiguous planter unit ( not shown ). furthermore , the assembly for angle adjustment 30 may be adapted for use with non - symmetrical closing wheels ( not shown ), or walking style closing wheels ( not shown ), or multiple point closing wheels ( shown ), independent of the styles or types of closing wheels shown or disclosed herein . fig8 is a perspective view of another embodiment of the assembly for angle adjustment 30 wherein an annular groove 39 has been positioned in the interior of the coupler ( shaft end 31 a ) with a rubber o - ring 40 positioned therein to inhibit intrusion of soil , dirt , water and dust between the coupler shaft end 31 a and shaft 22 . having described the preferred embodiments , other features of the will undoubtedly occur to those versed in the art , as will numerous modifications and alterations in the embodiments as illustrated herein , all of which may be achieved without departing from the spirit and scope of the assembly for angle adjustment 30 disclosed herein . accordingly , the methods and embodiments pictured and described herein are for illustrative purposes only , and the scope of the present disclosure extends to all method and / or structures for providing increased functionality , comfort , and / or longevity to shoes and / or components thereof . furthermore , the methods and embodiments pictured and described herein are no way limiting to the scope of the assembly for angle adjustment 30 unless so stated in the following claims . it should be noted that the assembly for angle adjustment 30 is not limited to the specific embodiments pictured and described herein , but is intended to apply to all similar apparatuses and methods for providing the various benefits and / or features of a assembly for angle adjustment 30 . modifications and alterations from the described embodiments will occur to those skilled in the art without departure from the spirit and scope of the assembly for angle adjustment 30 . it is understood that the assembly for angle adjustment 30 as disclosed herein extends to all alternative combinations of one or more of the individual features mentioned , evident from the text and / or drawings , and / or inherently disclosed . all of these different combinations constitute various alternative aspects of the assembly for angle adjustment 30 and / or components thereof . the embodiments described herein explain the best modes known for practicing the assembly for angle adjustment 30 and / or components thereof and will enable others skilled in the art to utilize the same . the claims are to be construed to include alternative embodiments to the extent permitted by the prior art . while the assembly for angle adjustment 30 has been described in connection with preferred embodiments and specific examples , it is not intended that the scope be limited to the particular embodiments set forth , as the embodiments herein are intended in all respects to be illustrative rather than restrictive . unless otherwise expressly stated , it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order . accordingly , where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order , it is no way intended that an order be inferred , in any respect . this holds for any possible non - express basis for interpretation , including but not limited to : matters of logic with respect to arrangement of steps or operational flow ; plain meaning derived from grammatical organization or punctuation ; the number or type of embodiments described in the specification . it will be apparent to those skilled in the art that various modifications and variations can be made without departing from the scope or spirit . other embodiments will be apparent to those skilled in the art from consideration of the specification and practice disclosed herein . it is intended that the specification and examples be considered as illustrative only , with a true scope and spirit being indicated by the following claims .

US-201514738133-A

endoscopic biopsy forceps that allows a non - deformed , high - quality tissue specimen to be readily collected from the correct target position . needles that extend forward to project into a pair of forceps cups are offset from the center of said pair of forceps cups .

embodiments of the invention are described below with reference to the accompanying drawings . fig3 shows endoscopic biopsy forceps according to a first embodiment of the invention . the forceps comprises a flexible sheath 1 to be inserted into or removed from the forceps channel in an endoscope ( not shown ) and a manipulating wire 2 that extends through the entire length of the flexible sheath 1 and which is free to advance and retract along the longitudinal axis . a manipulating section 3 for controlling the manipulating wire 2 to either advance or retract is coupled to the basal end of the sheath 1 ( which is the closer to the operator ). an actuating tip 10 that can be driven with the manipulating wire 2 is coupled to the distal end of the sheath 1 . fig1 and 2 show the actuating tip 10 in enlarged form . fig2 is a side view with part taken away , and fig1 is a plan view in partial section . the sheath 1 consists of a coil pipe 1 a covered with a flexible tube 1 b ; the coil pipe 1 a may be formed of a fine stainless steel wire that is wound in close turns in a specified diameter . if desired , either the coil pipe 1 a or the flexible tube 1 b may be omitted . coupled securely to the tip of the sheath 1 is a tip assembly 13 having a large slit 12 formed in the front portion . a support shaft 14 is mounted in the tip assembly 13 in such a way that it crosses the neighborhood of the distal end of the slit 12 . a pair of forceps cups 11 are supported rotatably on the shaft 14 so that they can open and close like beaks by rotating about the shaft 14 . a known link mechanism 15 is provided within the slit 12 such that it is driven by the manipulating wire 2 to open and close the forceps cups 11 . the link mechanism 15 is a pantograph consisting of four links joined pivotally in parallelogram form and the two front links are an integral part of the pair of forceps cups 11 so that they pivot on the support shaft 14 . a driving rod 16 is coupled to the rear end of the link mechanism 15 . the distal end of the manipulating wire 2 is securely coupled to the driving rod 16 so that the link mechanism 15 can be actuated by remote control from the basal end of the sheath 1 . if the manipulating wire 2 is pushed forward , the pair of forceps cups 11 open as indicated by one - long - and - two - short dashed lines in fig2 ; if the manipulating wire 2 is pulled toward the operator , the cups close as indicated by solid lines . two needles 20 extend forward from the distal end of the tip assembly 13 so that they project into the pair of forceps cups 11 . each of the needles 20 is an integral projecting part of a mount seat 21 in thin plate form ; the support shaft 14 is passed through the holes in the mount seats 21 so that they are in engagement with the tip assembly 13 . a securing projection 21 a erected at the rear end of each mount seat 21 is fitted into a hole made in each side wall of the tip assembly 13 ; as a result , the mount seats 21 are secured in position so that they will not rotate about the support shaft 14 . as fig2 shows , the two needles 20 lie in the same plane as the surface of engagement between the two forceps cups 11 . it should , however , be noted that both needles are offset from the longitudinal axis 50 through the center of the forceps cups 11 so that they are symmetrical with respect to said longitudinal axis . to collect a tissue specimen for biopsy using the endoscopic biopsy forceps according to the first embodiment of the invention , the following procedure may be taken . first , the sheath 1 is passed through the treatment tool insertion channel in an endoscope ( not shown ) so that the actuating tip 10 is guided into a body cavity . a pair of forceps cups 11 are opened , the needles 20 are pierced through the mucous membrane of the diseased part so that the actuating tip 10 is fixed in position , and subsequently the manipulating wire 2 is pulled toward the operator to close the pair of forceps cups 11 . the needles 20 pierced through the mucous membrane of the diseased part allow the actuating tip 10 to be positively secured on the mucosal surface so that a specimen of the diseased part can be easily detached from the right position and collected into the forceps cups 11 . since the needles 20 are not pierced in the central part of the tissue specimen but in positions offset from the center , the collected specimen is not deformed and by microscopic examination of it , the doctor can determine correctly if the diseased part is malignant or not . the present invention is by no means limited to the foregoing embodiment and it may be applied to other techniques of biopsy , for example , “ hot biopsy ” in which a specimen for biopsy is collected with a radio - frequency current being applied to the forceps cups 11 via the manipulating wire 2 . in the first embodiment , the needles 20 project into the forceps cups 11 but this is not the sole case of the invention . as shown in fig4 and 5 which show endoscopic biopsy forceps according to a second embodiment of the invention , the needles 20 may project along the peripheries of the forceps cups 11 . in this case , relief grooves la must be formed in the forceps cups 11 to avoid interference with the needles 20 . also note that the mount seats 21 in the second embodiment are formed to be larger than in the first embodiment . fig6 shows a third embodiment of the invention in which it is applied to so - called bipolar radio - frequency biopsy forceps . in this embodiment , two insulated conductor wires are used as manipulating wires 2 , each consisting of a lead wire 2 a and an insulation coat 2 b . a pair of forceps cups 11 are electrically insulated from each other and connected to different lead wires 2 a . because of this arrangement , high - frequency cautery and coagulation can be performed with the two forceps cups 11 serving as a positive and a negative electrode in the absence of any counter electrode . in the third embodiment , two needles 20 also extend forward from the distal end of the tip assembly 13 to project into the pair of forceps cups 11 . again , the needles may be adapted to be movable along the peripheries of the forceps cups as in the second embodiment . it should also be noted that the present invention is by no means limited to the three embodiments described above and various modifications may be made . for instances only one needle 20 may be used or , alternatively , three or more needles may be employed . all that is required is that the needle or needles should be offset from the center of the pair of forceps cups 11 .

US-51985400-A

various forms of a cable fixation device , instrumentation , kit , and methods useful for repairing the skeletal system are introduced . the system utilizes a clamp housing fixing a butt end of a surgical cable therein . in an operative configuration the cable is looped around a damaged bone segment and reentered through a lock aperture in the clamp housing then through a collet and lock cap residing within the lock aperture . the cable loop and each aforementioned component comprise a central axis aligned within a single plane . a sliding interface situated between the lock cap and collet prevent twisting of the surgical cable . the locking mechanism is non - destructive to the cable despite repeated unlocking and relocking of the fixation device . the axis for tensioning of the cable is coincident with the locking axis . a counter torque instrument has a torsional input shaft generally perpendicular to the elongated axis of the instrument .

referring to the figures , wherein like numerals indicates like or corresponding parts throughout the several views , numerals of different embodiments are separated by 1000 . similarly , corresponding axes of different embodiments are indicated with a repeated letter . an embodiment of a cable fixation device 100 is illustrated in fig1 . the device comprises a clamp housing 200 , a cable collet 300 , a lock cap 400 , and a cerclage cable assembly 500 . as illustrated in fig3 , the cable fixation device 100 is useful during surgery to secure segments of bone together by encircling the cerclage cable assembly 500 around the bone then tensioning and securing the cable . the long axis of the bone is situated generally coaxial with axis e of the loop as illustrated in fig2 . in one embodiment , cerclage cable assembly 500 ( fig1 and 2 ) comprises a cable 502 ( fig2 ), a butt 102 , a cable drum 501 ( fig2 and 23 ), and a cable lead generally indicated at 101 ( fig2 ). the word ‘ cable ’ used herein may refer to many different elongate tensioning forms . for example , in alternative embodiments cable 502 may be in the form of a wire or line . each component of the cable fixation device and instruments is made of biocompatible materials typically titanium or stainless steel alloys although polymers such as peek may be utilized as well . cable 502 in preferred embodiments is approximately 1 . 8 mm in diameter and woven from a blend of titanium or titanium alloy strands for a predetermined blend of flexibility and strength . cable lead 101 is preferably tapered and formed with a smooth surface to keep all cable strands tightly wound for eased entry into cable apertures or channels of housing 200 and through instruments and to prevent injury to the patient or surgeon . for example , lead 101 may be swaged . the butt 102 opposes lead 101 ( fig2 ) on cable 502 and comprises the cable end configured for anchoring within clamp housing 200 . in preferred embodiments the butt 102 ( fig2 ) comprises an enlarged terminal portion illustrated here in the form of a cable drum 501 pressed on the cable . the drum 501 comprises a cylindrical sleeve with one or more entry faces 103 that are tapered or radiused . the clamp wall 104 diameter of drum 501 is sized to impart sufficient friction at the cable surface to prevent being pulled off due to tensioning of cable 502 or due to other forces imparted by the patient &# 39 ; s skeletal system . other methods may be used to secure drum 501 on cable 502 and may include for example welding , crimping , or molding . in alternate embodiments the butt may take other forms such as simply the cut end of the cable wherein a portion of the clamp housing is crimped on the cable . each component of the cable fixation device 100 partially resides within clamp housing 200 . as seen in fig3 - 7 , the housing 200 comprises a block body generally indicated at 218 . formed on body 218 is a pair of opposing side surfaces 208 , a front end or leading surface 209 , a rear end surface or trailing surface 211 , an upper surface 207 , and a bottom surface 216 . to assist in proper fit of housing 200 on the bone surface , the bottom surface 216 is concave as generally indicated at 217 of fig5 . in this embodiment , the radius of the concave is less than the radius of the bone surface onto which it will be seated . further in this embodiment , bottom surface 216 is concave between opposing side surfaces 208 as generally indicated at 214 of fig4 . together , the concave surface at 217 and 214 define feet 215 at each corner of bottom surface 216 of body 218 . these feet 215 may be sharpened or extended into the form of teeth in some embodiments and may penetrate the bone surface to prevent slippage of the clamp housing 200 across the outer surface of the bone when cable fixation device is in an operative configuration wherein cable 502 is secured in a loop around the bone segments with cable tensioned and secured to a pre - determined tension utilizing lock cap 400 advanced on cable collet 300 . extending into the trailing surface 211 of body 218 along axis ‘ a ’ is a drum channel generally shown at 212 . drum channel 212 defines drum wall 205 . drum channel 212 is shaped and sized to house cable drum 501 ( fig2 , 22 ) of cerclage cable assembly 500 . cable shelf 219 with drum stop surface 220 ( fig6 ) contain drum 501 in drum channel 212 preventing it from being pulled out of housing 200 when the cable 502 is tensioned . cable slot generally indicated at 213 provides for the loading of cable 502 into drum channel 212 then provides for seating of the cable drum 501 into the drum channel 212 upon pulling of the free end of cable 502 . in alternative embodiments , the butt 102 of cable 502 is secured in housing 200 by way of methods described earlier . a lock aperture generally shown at 203 ( fig2 & amp ; 3 ) is defined by a series of walls with various diameters . passage wall 201 is sized in diameter to freely pass cable 502 , the cable collet 300 , and the lock cap 400 . step 210 transitions between passage wall 201 and fixation wall 202 . fixation wall 202 comprises features to fix the lock cap 400 in place . in this embodiment these fixation features are in the form of threads ( not shown ) formed in the surface of fixation wall 202 for co - engagement with threads ( not shown ) formed in fixation face 406 of lock cap 400 ( fig1 ). alternatively , other co - engagement configurations may be utilized for fixation between the lock cap and clamp housing such as for example a bayonet connection . compression wall 204 ( fig2 , 3 , 7 ) is tapered and complements lock wall 305 ( fig8 - 9 ) of cable collet 300 wherein when lock cap 400 is advanced along axis b , lock wall 305 is also driven causing collet 300 to compress and clamp on cable 502 thereby fixing cable in place . inlet wall 206 ( fig4 ) is sized sufficiently large to freely pass cable 502 while small enough to prevent passage of collet 300 . in alternative embodiments , compression wall 204 may assume other forms such as a smaller diameter step to serve a similar function of compressing collet . cable collet 300 is illustrated in fig8 - 10 . in this embodiment , the collet 300 comprises a curved body 311 with clamp surface 301 extending therethrough along axis ‘ c ’. clamp surface 301 defines central aperture 306 sized sufficient in diameter to pass cable 502 . formed in curved body 311 is a bottom face 307 , a top face 303 , a lock wall 305 , and a head face 302 . the curved body 311 may comprise one or more tapered face 304 . extending from the top face 303 are a plurality of top compression gaps 309 and extending from the bottom face 307 are bottom compression gaps 308 . these gaps 308 and 309 are defined by gap walls 310 . in this embodiment the gaps are cut linear along axis c and the gaps 308 radially alternate with gaps 309 . in alternate embodiments these gaps may take other forms such as a spiral . at the bottom of each gap is a resilient wall 312 which flexes therein providing for central aperture 306 to reduce in diameter for cable clamping . in alternative embodiments collet 300 may be spherical . lock cap 400 ( fig1 - 12 ) comprises a cylindrical body 410 with central aperture 401 extending along axis d . drive surfaces 407 define drive pocket 408 which extend into cylindrical body 410 from top surface 411 . drive pocket 408 is configured in shape to receive cannulated driver tip 602 ( fig1 ). at the bottom of drive pocket 408 is pocket base 409 . cable wall 402 defines central aperture 401 . aperture 401 has sufficient diameter to pass cable 502 through drive wall 412 . fixation face 406 engages fixation wall 202 of clamp housing 200 for locking . in this embodiment , fixation face 406 is threaded as is wall 202 ( threads not shown ). threads on face 406 may include a lead in taper 405 to ease starting of threads . step 404 decreases diameter of drive wall 412 to prevent interference with threads during assembly . in preferred embodiments , drive wall 412 drives with sliding engagement against top face 303 of collet 300 during locking . due to this sliding engagement , a rotation of the lock cap 400 does not cause rotation of the collet 300 and therefore cannot induce rotation between clamp surface 1301 and cable 1502 . in addition , the sliding engagement between lock cap 400 and collet 300 provides for pushing of the collet 300 linearly along axis c such that clamp surface 301 slides along the cable until the collet collapses down therein locking cable 1502 in place . as an alternative , lock cap 400 and collet 300 may be unitary wherein rotation of lock cap 400 will cause 1 : 1 rotation of the collet 300 . this approach is less preferred and is noted in the prior art . here , the clamp surfaces within the collet induce a twist on the cable 502 as the collet 300 tightens around it that can lead to abrasion and fraying of the cable . in addition , the cable surface has inherent irregularities which become bound in the collet prematurely therein causing the cable to be pushed distally during locking and leading to an undesired reduction in cable cerclage tension . fig1 - 15 illustrate cannulated driver 600 . this instrument is used to advance lock cap 400 . the driver 600 comprises a drive shaft 603 with central cable aperture 601 extending the length of the instrument for passage of cable 502 . at the distal end of drive shaft 603 is driver tip 602 with drive faces 609 configured to be received in drive pocket 408 . drive faces 609 will transmit torsional forces applied by the user at the handle 605 into drive surfaces 407 in the lock cap for advancement toward collet 300 for locking or away from collet for unlocking . distal stop surface 608 and proximal stop surface 610 are advanced in to drive pocket 408 until seated against top surface 411 or pocket base 409 . drive shaft 603 may be configured as a singular shaft extending through handle 605 or as illustrated may be configured in segments to include proximal shaft 612 . in this configuration , each shaft comprises fixation bosses 604 and 606 to seat within and assemble within handle 605 . one or more fixation holes 613 may house pins or screws holding handle to drive shaft 603 . located at the proximal end of proximal shaft 612 is tensioner face 611 for interfacing with a tensioner instrument . fig1 - 18 illustrates a preferred alternative clamp housing 1200 comprising many of the same features of clamp housing 200 . again , corresponding parts are offset by 1000 . for example , opposing side surfaces 208 on clamp housing 200 are identified as opposing side surfaces 1208 on the clamp housing 1200 . extending into each opposing side surface 1208 is a pair of opposed control slots 1228 traveling parallel yet offset from axis bb . control slots 1228 house control tabs 708 extending from clamp base 701 ( fig2 ). control slots 1228 are bounded by opposed upper tilt wall 1225 and lower tilt wall 1226 and medially by steering wall 1227 . projecting from bottom surface 1216 are a plurality of teeth 1229 illustrated here in the form of elongated sharps 1230 extending between opposing side surfaces 1208 . the concave curvature shown at 1217 of bottom surface 1216 remains in this embodiment , however concave surface 214 illustrated in fig4 is absent . the elongate sharps 1230 and bottom surface 1216 are generally linear between opposing side surfaces 1208 as illustrated in fig1 . fig2 illustrates an alternative collet 1300 having ⅓ rd less bottom compression gaps 1308 and top compression gaps 1309 . in this embodiment , rather than terminating in a squared corner , each compression gap terminates in a rounded corner to improve flexibility and prevent stress concentrations . in some embodiments these rounded corners are formed by edm machining . fig2 illustrates cable fixation device 1100 with cerclage cable assembly 1500 formed into a loop as if wrapped around bone segments . as in previous embodiments , the cerclage cable assembly 1500 resides in a single plane here shown as plane f and generally perpendicular to axis e . this single plane alignment is further illustrated in fig2 a and is responsible for the absence of torsional forces on the clamp housing 200 that may cause it to cant on the bone when cable 1502 is tensioned and locked in the operative configuration . on competing devices wherein the cable loop is not aligned in a single plane , the instrumentation utilized to hold the clamp housing during insertion to the surgical site and during tensioning and locking will counteract torsional forces on the clamp housing to keep the housing aligned . however , the clamp housing will cant on the bone causing a loss in cable tension as soon as the instrumentation is removed . this leads to a reduction in the stability provided by the cable and clamp construct . illustrated in fig2 is a cross section of cable fixation device 1100 through plane f also illustrating the internal components of the assembly having a co - planar elongate axis . as noted earlier , some embodiments of the clamp housing include control slots for attachment of a counter torque locker . a preferred embodiment of a counter torque locker 700 is illustrated in fig2 with attached cerclage cable assembly 1500 . fig2 illustrates an exploded view of counter torque locker 700 for viewing of internal parts . clamp base 701 serves to contain several parts of the assembly . worm rod 702 is situated generally perpendicular within the proximal end of clamp base 701 and is generally co - axial with axis h . worm shaft 703 is situated generally co - axial with axis g within clamp base 701 . hat 704 is situated within the proximal portion of clamp base 701 and is also generally co - axial with axis g . worm retainer 705 is generally co - axial with axis h as is drive bar 706 . a cross sectional view of clamp base 701 is illustrated in fig2 b . control arm 715 extends from base 701 at the distal end . opposing containment walls 707 are spaced to house opposing side surfaces 208 of clamp housing 200 therebetween . control tabs 708 extend parallel to axis g and are sized and positioned to fit in control slots 1228 of clamp housing 1200 . the control tabs 708 comprise mating walls positioned to mirror with the upper tilt wall 1225 , lower tilt wall 1226 and steering wall 1227 of clamp housing 1200 . these mating walls are the upper minor 709 , lower minor 710 , and steering minor 711 . proximal to control arms 715 is stop wall 712 situated to abut clamp housing 200 when the clamp base 701 is fully engaged with it and lock cap 1400 is fully advanced to locking . clamp base 701 comprises an internally positioned shaft guide 713 extending down the length of base 701 sized to house worm shaft 703 therein . along axis h , worm guide 714 extends through a proximal portion of clamp base 701 . at the proximal end of clamp base 701 resides hat seat 717 for seating hat 704 thereagainst . inset the proximal end of clamp base 701 is hat guide 716 sized and shaped to house hat 704 therein . fig2 illustrates the internal gear mechanisms . worm rod 702 resides within worm guide 714 and rotates freely therein . worm shaft 703 resides within shaft guide 713 and also rotates freely therein . the worm rod 702 comprises a worm helix 721 ( shown in location only ) on its outer surface for functioning as a worm drive . the worm rod 702 comprises a worm shoulder 725 for securing the worm drive against one of the worm walls 718 . a worm retainer 705 is removabley positioned on worm rod 702 opposite the worm shoulder 725 to secure the worm rod 702 in a predetermined position within clamp base 701 . interior to worm shaft 703 is cannula 724 which extends the entire length along axis g and is sized to pass cable 502 . at the distal end of worm shaft 703 is drive boss 723 with complementing surfaces for residing within drive pocket 1408 and transmitting torsional forces to drive surfaces 407 to advance lock cap 400 . alternatively , worm shaft 703 may be configured with a drive bit detachable from worm shaft 703 such that the drive bit is replaceable as it wears . in one form this drive bit will be backed by a spring biasing the drive bit distally such that as lock cap 1400 is advanced distally the drive bit will stay entirely engaged in the drive pocket 408 . at the proximal end of worm shaft 703 are radially placed worm teeth 722 ( shown in location only ) shaped to inter - digitate or otherwise mesh with the worm helix 721 formed on worm rod 702 to provide a worm and worm gear relationship . hat 704 comprises a hat base 726 sized for secure fit within hat guide 716 of clamp base 701 and positioned by hat lip 728 abutting hat seat 717 . hat tunnel 727 extends through hat 704 along axis g and is sized for passing cable 502 therethrough . hat pod 720 provides a proximal surface against which a distal end of a cable tensioning instrument ( fig3 ) may be placed . drive bar 706 comprises internal drive surfaces ( not shown ) for acting on complementing worm drive 719 surfaces of worm rod 702 . torsional forces imparted by the user on drive bar 706 causes rotation of the worm rod 702 . these forces are imparted through the worm helix 721 to worm teeth 722 therein causing the drive boss 723 to advance lock cap 1400 in a direction that will cause either tightening or loosening of collet 1300 around cable 1502 . the instruments disclosed for tensioning cable 1502 and advancing lock cap 1400 are generally co - aligned along axis b during operation . this feature simplifies the surgical procedure by eliminating the need for handling of a cable tensioner positioned on one axis and the use of a cap locking instrument on a different axis . this co - alignment also provides a minimally invasive approach for completing the surgery as it reduces the size of incision required to operate the instrumentation . in addition , the cable fixation device 100 disclosed herein utilizing the collet 300 and lock cap 400 fixes the cable 502 at the tension applied by the tensioner without loss of tension . the cable fixation device 100 will preferably be packaged pre - assembled with collet 300 loosely seated within compression walls 204 and lock cap 400 loosely threaded within fixation wall 202 . the cable drum 501 is pre - seated within drum walls 205 . a surgical kit may be provided for use in the surgical suite comprising the cable fixation device , the cannulated driver , the counter torque locker , a cable passer , and a cable tensioner . the cable fixation device 100 is utilized by passing the free end of the cable around the bone or bone segments to be stabilized . a cable passer 800 ( fig3 ) may be utilized for this purpose . the passer typically comprises a passer handle 802 connected to a passer shaft 803 for guiding a semi - circular passer tube 801 around the outer surface of the bone . the surgical cable is fed into the passer tube 801 until exposed out the other side . the passer 800 may then be removed leaving the cable 1502 encircled around the bone . the lead 1101 of cable 1502 is then fed through inlet wall 1206 of clamp housing 1200 , through the central aperture 1306 of the collet 1300 , and through the cable wall 1402 of lock cap 1400 . in an optional provisional locking step , the surgeon may choose to use cannulated driver 600 ( fig1 ) to temporarily secure the cable . in this event , the cable lead 1100 is fed through central cable aperture 601 of driver tip 602 until the lead 1101 exits tensioner face 611 . the driver tip 602 is then seated in drive pocket 1408 . grasping the cable lead , the surgeon snugs the cable to a desired cable tension then applies hand torque on handle 605 to advance lock 1400 until cable collet 1300 compresses around cable 1502 to secure the loop . the surgeon may choose to move on to secure other cables before returning to perform final locking . in preferred methods , driver 600 is then removed and replaced with counter torque locker 700 . the cable lead 1100 is fed though cannula 724 of worm shaft 703 until lead 1101 exits hat tunnel 727 . drive boss 723 of counter torque locker 700 is seated in drive pocket 1408 and control tabs 708 are seated within control slots 1228 of clamp housing 1200 . the lead 1101 of the cable 1502 is then fed into a standard surgical cable tensioner ( fig3 ). the counter torque locker 700 is used to loosen lock cap 1400 and the cable is tensioned to a predetermined tension therein causing the cerclage loop around the bone to tighten and elongated sharps 1230 to engage the bone surface . the surgeon then applies torque to drive bar 706 therein causing rotation of worm rod 702 , worm shaft 703 , and final advancement of lock cap 1400 therein forcing collet 1300 to collapse about cable 1502 securing the cable fixation device 100 at a predetermined cable tension . if the surgeon chooses , drive bar 706 or handle 605 may be derotated to loosen and remove the cable fixation device 100 , 1100 or to retension to an alternative tension level before relocking without damage to cable 502 , 1502 . the tensioner and counter torque locker 700 may then be removed and excess cable lead trimmed . in an alternative method , portions of the cable fixation device 100 may be assembled during surgery . in preferred embodiments the butt of the cable is configured in size to be passable through the cable passer then assembled with the clamp housing 200 after the passer instrument is removed . this feature provides for the cable 1502 to be passed in either direction through passer tube 801 . in cases where introducing the passer instrument from one side of the bone is easier than the other , the surgeon may be forced with prior art systems to introduce the passer from the more difficult side to assure the clamp housing 200 is positioned in a convenient direction for tensioning and locking . this assembled in surgery feature ensures the surgeon will be able to enjoy the convenience of introducing the passer instrument around the bone from either entry position while also being assured the clamp housing will be directed in a convenient direction for tensioning and locking . assembly in preferred embodiments is completed by passing the cable around the bone then dropping cable 1502 through cable slot 1213 . cable 1502 is pulled until cable drum 1501 is seated in drum channel 1212 and against drum stop surface 1220 . this assembly during surgery feature is made possible by cable slot 1213 as it provides a path for cable drum 1501 to be seated in drum channel 1212 without requiring the cable lead 1101 to pass through the drum channel 1212 first . in an alternative method , the provisional lock step using driver 600 is not performed . once the cable is passed around the bone and through the clamp housing , the surgeon may immediately use the counter torque locker 700 , with cable tensioner if she so chooses , to perform provisional or final locking . in another alternative method , the surgeon may choose not to use a counter torque locker 700 when it is believed sufficient final locking can be achieved without it . in this method the surgeon may choose to use driver 600 with clamp housing 200 or 1200 to achieve final locking . driver 600 may also be used with a cable tensioning device . the foregoing invention has been described in accordance with the relevant legal standards , thus the description is exemplary rather than limiting in nature . variations and modifications to the disclosed embodiment may become apparent to those skilled in the art and fall within the scope of the invention .

US-201414216913-A

methods and apparatus for diagnosing and treating disorders of the lung are provided , which may include any number of features . in one embodiment , a method comprises obtaining diagnostic information relating to a patient &# 39 ; s lungs , compiling a list of potential treatment plans for lung volume reduction in the first and second lungs , excluding treatment plans from the list of potential treatment plans that propose treatment of a lung segment that falls within a segment exclusion rule , and identifying at least one preferred treatment plan from the list of potential treatment plans that targets sufficiently diseased lung segments while also targeting a preferred combined volume of the first and second lungs .

vapor ablation of lung tissue can be used to treat lung disorders , such as emphysematous tissue . application of vapor to emphysematous tissue can damage the tissue to create lvr . compared to the techniques described above , the ablation of microvasculature with vapor results in elimination of diseased tissue supplied by that microvasculature . since vapor travels along the airway tree and into the parenchyma , the vapor can shrink and cause fibrosis of the lung tissue , which can result in volume reduction in the presence of collateral ventilation . vapor can be delivered preferentially to the most diseased segments within a lobe . tissue - to - air ratio ( tar ) can be used as a surrogate marker for extent of hyperinflation and degree of gas exchange deficiency . tar can be derived from a hrct scan . fig1 - 2 show one embodiment of a system 10 and system components for generating and delivering vapor to lung tissue to be treated . the system 10 generally comprises a vapor generator 12 , hand - piece 14 , and delivery catheter 16 . the vapor generator 12 can be attached to hand - piece 14 by tube 18 . the generator can comprise a pressure vessel 20 containing liquid water ( or other biocompatible liquid , such as saline ) and a heating element ( not shown ) configured to heat the water or other biocompatible liquid to generate condensable vapor . in some embodiments , the vapor generator can further comprise sensors , such as temperature sensors , pressure sensors , and / or flow rate sensors , and valves to control the flow of vapor . hand piece 14 can be coupled to the proximal end 22 of catheter 16 . the vapor generator can further include a processor or electronic controller operatively connected to the vapor generator , the delivery catheter , and to sensors in the catheter and / or in the body of the patient , and the processor or electronic controller can be configured to control all aspects of vapor delivery from the generator through the catheter to a target tissue . vapor generation and delivery can be controlled by the processor or controller based on a number of factors , including parameters of the system , of the vapor , or of the body of the patient sensed by the sensors or alternatively , based on an input from a user such as flow rate , dosage , or total volume of vapor to be delivered . the catheter is generally used to deliver the heated condensable vapor ( e . g ., steam ) to a targeted segment or sub - segment of the subject &# 39 ; s lung containing the diseased lung tissue . the catheter 16 generally comprises flexible shaft 24 and occlusion balloon 26 located at or slightly proximal to the distal end 28 of the catheter . the distal end 28 of the catheter can include vapor ports for delivering the vapor to the targeted tissues . when the occlusion balloon 26 is expanded within a targeted segment or sub - segment of the lung , the delivered vapor is allowed to propagate distally into the lung , but not proximally past the occlusion balloon . in some embodiments , the catheter can be introduced to a lung segment via the airway using a bronchoscope . once a target airway with the diseased lung tissue is reached , vapor can be delivered from the catheter to ablate the lung tissue using the airway as a delivery channel or the open parenchymal space . this can be done with and without the occlusion balloon shown in fig1 - 2 . one limitation of the bronchoscope method is the diameter of the scope , since a bronchoscope cannot access airways smaller in diameter than the outer diameter of the bronchoscope . one method of delivering a more precise treatment is to access a more distal ( and smaller ) airway . to do this , a pulmonary navigation system could be used . there are a number of ways to implement this . in one embodiment , system 10 of fig1 - 2 can further include a navigation catheter with a working channel . first , the navigation catheter can be navigated to the target airway using its navigation system . after the target airway is reached , the vapor catheter 16 can be pushed through the working channel to the target airway and to deliver vapor to ablate the tissue . another method is to incorporate the navigation system described above into the vapor catheter 16 of system 10 . in this embodiment , the vapor catheter 16 is navigatable to the target tissue , without the need for a separate navigation catheter or bronchoscope to access the target site of the lungs . in this embodiment , the catheter is navigated to the target and then vapor is delivered to ablate the lung tissue . the vapor is generally heated to between about 100 ° c . to about 200 ° c . in the vapor generator . vapor generated in a remote boiler will typically have a lower temperature upon delivery , but the vapor will still have a temperature at or above at least 100 ° c . referring again to fig1 - 2 , the vapor catheter is preferably non - reusable and supplied sterile . the catheter can comprise components for occluding the target airway and delivering a dose of vapor from the vapor generator to the targeted lung segment or sub - segment . the catheter shaft can be adapted to allow delivery of the catheter through a bronchoscope , and the catheter comprises a balloon near the distal end of the catheter shaft to allow proper sealing of the targeted bronchi . a general method of delivering vapor to the lung includes advancing the catheter into the region of the lung targeted for treatment , such as a segment or sub - segment of the lung . the balloon 26 at or near the distal end of the catheter tip can be inflated to seal the airway . the vapor can then delivered from the distal end of the catheter to the targeted tissue . after treatment , the balloon can then deflated to allow for withdrawal of the catheter . fig3 illustrates one method of treating a patient &# 39 ; s lung 40 embodying features of the invention that includes delivering a heated condensable vapor 42 to the airways 48 of lung tissue , so as to create necrosis of the tissue of the nodule , the tissue of terminal bronchioles , and parenchymal tissue . in one embodiment , the catheter - based system of fig1 - 2 can be used to access the lung tissue , either with or without the aid of a bronchoscope . the distal tip of the catheter can be placed in proximity to the target lung tissue . vapor generated by generator 12 can be delivered through the catheter to ablate the targeted tissue of the lung nodule . a method of determining a treatment plan for lvr will now be described . in some embodiments , the treatment can include delivery of vapor to ablate the lung tissue once the treatment plan has been determined . first , a tissue - to - air ratio ( tar ) of each lung segment of the lungs can be calculated by dividing the tissue mass of a segment by the air volume of that segment . the tar can be calculated , for example , by a processor or electronic controller of the system described above , based segmental tissue and air volumes derived from imaging or a diagnostic evaluation of the lungs . alternatively , a physician or medical provider can calculate the tar of each lung segment . the tar of each lung segment can be used to quantitatively characterize a disease state of the lung tissue . the tar of each lung segment can be used to calculate a heterogeneity index ( hi ) of the segments , which is the ratio of the tar of the ipsilateral lobe to the tar of the segment . a further diagnostic evaluation of the patient &# 39 ; s lungs can determine additional parameters of the patient &# 39 ; s lung , including the mass of each lung segment and the volume of each lung segment . after the tar of each lung segment has been calculated , the electronic controller of the system , or a physician , can compile a list of potential treatments that include a first treatment that targets a first segment of a first lobe of the first lung , and a second treatment that targets a second segment of a second lobe of the second lung . since this list of potential treatments can include several potential treatment plans ( dozens or more ), a logic workflow can be used to determine the optimal segment selection for treatment . this disclosure describes various methodologies that can be used to exclude treatment plans from the list of potential treatment plans to identify the safest and most effective treatment plan for lvr therapy . in one exemplary treatment plan , one lobe in a patient lung is treated ( e . g ., with condensable vapor to ablate the lung tissue ). for example , in one embodiment vapor can be delivered in a first treatment to one segment , preferably the most diseased segment , of an upper lobe of a patient &# 39 ; s lung . after treatment of the first lobe , the treatment plan typically requires a period of time for healing and reaction from this treatment to occur ( typically 3 months ). next , vapor can be delivered in a second treatment to one or two segments of a lobe in the opposite lung . generally , the first treatment targets 50 %+/− 20 % ( absolute ) volume reduction of the first lobe , and the second treatment targets 60 %+/− 20 % ( absolute ) volume reduction of this second ( and possibly third ) lobes . although the preferred treatment of lung tissue includes delivering condensable vapor to the tissue to ablate the lung tissue , other treatment methods , such as those described above in the background section , may be used in accordance with the treatment planning described herein . the overall volume reduction target sum of the lung volume reduction percentages between the first and second treatments can be approximately 110 %+ 20 %/− 15 % ( absolute ). this treatment plan considers the tar of the lobes to be treated as a first priority ; however , the further the most diseased segment is from the targeted volume reduction , the greater chance that another lobe would be selected . the treatment plans described herein typically provide for treatment of the superior ( upper ) lobes of the lungs . however , a similar methodology can be applied to treat the inferior ( lower ) lobes of the lungs in other embodiments . according to the treatment plan described in the paragraph above , the following rules can be used for selecting the optimal segment ( s ) to treat during the first and second treatments . these rules can be applied to select the optimal segments and lobes to treat for each particular patient so as to maximize the effectiveness of the vapor therapy for that patient . the human body comprises two lungs , and a total of five lobes . the right lung has three lobes , including the superior ( upper ), middle , and inferior ( lower ) lobes , and the left lung has two lobes , the superior and inferior lobes . each lobe of the lungs includes several lung segments . as described above , patients with severe emphysema typically have lung segments within a lobe that are significantly more diseased than other segments within that lobe . since not all segments in each lobe are typically diseased , a treatment plan needs to be devised so as to not treat healthy lung segments . the flowchart of fig4 a - 4b describes the methodology taken to exclude healthy lung segments from treatment , according to one embodiment of a method of treating a lung with vapor . all method steps described in fig4 a - 4b can be performed or carried out by a processor or electronic controller of the system described above . the data with which the processor can determine which segments to exclude can be based on a diagnostic evaluation of the patient &# 39 ; s lungs , e . g ., diagnostic imaging of the lungs . alternatively , the method can be carried out by a physician or medical provider . step 402 of the flowchart of fig4 a aims to exclude individual healthy lung segments from treatment . referring to step 403 a of fig4 a , lung segments can be excluded from the list of potential treatment plans if they have a heterogeneity index less than a threshold heterogeneity value . in one embodiment , lung segments can be excluded if the hi is less than 1 . 2 . as defined above , the hi considers the tissue - to - air ratio of the particular segment in relation to the average of all the segments in the same lobe . according to one embodiment , a hi less than 1 . 2 is an indication that the segment being evaluated is “ healthy ” based on tar . the controller or processor of the system can evaluate the hi of each lung segment and exclude the segment from treatment if the hi is less than the threshold heterogeneity value ( e . g ., less than 1 . 2 ). alternatively , this evaluation can be made by a physician . in step 403 b of fig4 a , lung segments can be excluded from treatment if they have a mass less than a minimum threshold mass . in one embodiment , segments can be excluded if they have a mass less than 13 g . the mass of the segment being considered can be determined based on imaging of the lung , either by the controller of the system or by a physician , and the controller or the physician can made the determination to exclude the segment based on the mass of the segment . lung segments with a mass of less than 13 g can be excluded from treatment because segments this small typically require such a short treatment time ( less than 3 seconds ). referring to step 403 c of fig4 a , segments can also be excluded by either the controller of the system or a physician if the tissue volume ( computed from its mass , assuming 1 gram of tissue mass = 1 ml of tissue volume ) plus the air volume of the segment being evaluated is greater than a threshold value . in one embodiment , the segment can be excluded if the tissue mass in grams ( assuming 1 g of tissue = 1 ml of tissue volume ) plus air volume in ml is greater than 1700 . finally , referring to step 403 d of fig4 a , a segment can be excluded by a controller of the system or a provider if the segment mass is greater than a maximum threshold mass . in one embodiment , the segment can be excluded from treatment if the mass is greater than 48 g . segments with masses greater than the maximum threshold mass can be excluded from treatment since they require treatment times longer than is desirable for the patient ( e . g ., treatment times greater than 10 sec ). step 404 of fig4 b provides methodology for evaluating the feasibility of a treatment plan as a whole ( first and second treatments ) in view of the individual segment exclusions from step 402 . as described above , a first treatment typically treats a first segment in a first lobe of a first lung , and the second treatment can treat a second segment ( and sometimes a third segment ) in a second lobe of the second lung . for example , a first treatment can comprise delivering vapor to one segment in the upper lobe of the left lung , and a second treatment can comprise delivering vapor to two segments in the upper lobe of the right lung . at step 404 of fig4 , a controller or provider can evaluate all possible treatment plans ( first and second treatments ) after individual segments have been excluded ( from step 402 ) and can further exclude the remaining available segments according to the following rules . in step 405 a of fig4 b , if a segment to be treated in the first treatment makes up a volume that falls outside of a predetermined volume range of the entire lobe , then that segment can be excluded from the list of possible treatment plans . in one embodiment , if the first treatment would require treating a segment that falls outside of 30 - 70 % of the total volume of the lobe ( e . g ., the segment is less than 30 % of the volume of the lobe or greater than 70 % of the volume of the lobe ) the segment can be excluded from the list of possible treatment plans . for example , if a segment in a potential first treatment makes up 25 % of the lobe , then the segment falls outside of the range of 30 - 70 % and can be excluded . similarly , referring to step 405 b , if a segment to be treated in the second treatment makes up a volume that falls outside of a predetermined volume range of the entire lobe , then the segment can be excluded from the list of possible treatment plans . in one embodiment , if the second treatment would require treating a segment that falls outside of 40 - 80 % of the total volume of the lobe ( e . g ., the segment is less than 40 % of the volume of the lobe or greater than 80 % of the volume of the lobe ) the segment can be excluded from the list of possible treatment plans . for example , if a segment in a potential second treatment makes up 85 % of the lobe , then the segment falls outside of the range of 40 - 80 % and can be excluded . in step 405 c , if the first or second treatment would result in a total treated mass ( in grams ) plus volume ( in ml ) greater than a threshold mass plus volume ( such as 1700 ), then it can be excluded . in step 405 d , treatment options can be excluded if the combined percentage of the segments to be treated with respect to the total volume of both lobes falls outside a predetermined range of the total volume of both lungs . the percentage range can be taken on a scale of 200 % ( e . g ., 100 % for the first lung plus 100 % of the second lung ) for the combined first and second treatments . if a segment to be treated in the first treatment plus a segment to be treated in the second treatment falls outside of the predetermined range , then the options of segments being evaluated can be excluded . in one embodiment , if the first and second treatments would result in treatment of the lungs falling outside a range of 95 %- 130 %, then the segment options can be excluded . for example , if first treatment would result in treatment of 30 % of the first lobe , and the second treatment would result in treatment of 40 % of the second lobe , the combination of the first and second treatments would treat only 70 % ( out of 200 %) of the two lobes / lungs . this combined treatment volume of 70 % falls outside of the preferred volume range of 95 - 135 % in step 405 d . steps 402 and 404 above eliminate all segments ( or combinations of segments ) for the list of possible treatment plans . after all possible treatment plans have been determined , the available treatment plans can be ranked according to the rules described in fig5 . once again , these determinations undertaken in the flowchart of fig5 can be performed by a processor or electronic controller of the vapor system described above . alternatively , they can be determined by a physician or medical provider . first , referring to step 502 of fig5 , the electronic controller or medical provider can determine if a significant difference in density or segment tar in the available segments of each lobe exists . this determination aims to find the balance between treating the most diseased segment in the lobes and treating the appropriate volume of the lobes . in one embodiment , a significant difference in density or segment tar can be defined as greater than 2 % difference between the segments in each lobe . as described above , the tar of the various lung segments can be used to quantify a disease state of the lung tissue . in the present example , a difference of 2 % absolute difference is used as significant quantifier of a diseased state in the lung tissue , but any difference could be used as significant depending on the treatment modality , patient type , and understanding of the disease . if at step 502 , it is determined that there exists a significant difference in segment tar between the available segments , then at step 504 the controller or medical provider can conditionally eliminate any available treatment plans from the list of potential treatment plans that use the “ least diseased ” ( e . g ., highest tar ) segment in that lobe . for an example of steps 502 and 504 , if a first segment rb1 has a tar of 7 %, a second segment rb2 has a tar of 10 %, and a third segment rb3 has a tar of 8 %, by this definition , there is a significant difference in segment tar between the segments because there exists a 3 % difference between any two of the three segments within the lobe ( here , the 3 % difference exists between rb1 and rb2 ). applying step 504 to this example , least diseased segment ( the second segment rb2 with a tar of 10 %) can be conditionally eliminated from the list of available treatment plans . thus , the controller or medical provider will determine not to treat the least diseased segment , but will still consider treating the remaining segments ( in this example , the remaining segments have tars of 7 % and 8 %). advancing from step 504 of fig5 ( or directly from step 502 if there is an insignificant difference in segment tar ) arrives at step 506 of fig5 . at step 506 , the controller or provider can calculate a combined tar of all possible treatment plans from the remaining options , determine the lowest combined tar value , and can select all treatment plans having a combined tar within a specified range of the lowest combined tar value . a combined tar is defined as the mass of all segments in each treatment option , divided by the volume of all segments in that treatment option . in some embodiments , the combined tar can be an average of the segments , or alternatively it can be weighted based on the volume and / or mass of segments . a combined tar will typically evaluate 1 segment from the first lobe to be treated ( during the first treatment ), and then will evaluate 1 - 2 segments from the second lobe to be treated ( during the second treatment ). the combined tar for the first and second treatments can then be determined . in one embodiment , as shown in step 508 of fig5 , all treatment plan options having a combined tar within a threshold range of the lowest combined tar can be selected . in one embodiment , the threshold range can be 0 . 3 %. if multiple treatment plan options satisfy the criteria of step 508 , then the remaining options can be ranked at step 510 of fig5 based on treatment plans that would result in treating a total volume of the lung closest to a preferred volume are selected as the primary option . in one embodiment , the ideal total volume to be treated between both lungs is 110 % of a lobe ( out of 200 % for two lobes combined ). at step 512 of fig5 , if multiple treatment plans have a combined tar within the threshold range of the lowest combined tar , and also would treat a total volume at or near the ideal total volume to be treated , then the treatment plan with the lowest combined tar is preferred . if the method described above does not result in three available treatment plans , then the controller or provider can select the next lowest combined tar , and repeat the steps above to arrive at 3 treatment planning options . by way of example to understand steps 506 - 512 , in one example at step 506 a patient has potential treatment plans with a combined tar of 8 %, 9 %, and 10 %, respectively . in this example , the lowest combined tar averages to 9 %. next , the controller or the provider can , at step 508 , look for any other treatment plans falling within the threshold range ( e . g ., 0 . 3 %) of this lowest combined tar . thus , treatment plans for this patient with a combined tar average of 8 . 8 %, and of 9 . 3 %, would fall within the threshold range . once the available treatment plans within the threshold range of the lowest combined tar are identified , preference is given , at step 510 , to the treatment plan that is closest to the ideal total volume to be treated ( e . g ., closest to 110 %). the best treatment plan available is a treatment plan that falls within the threshold range of the lowest combined tar , that is closest to the ideal total volume to be treated . given the example of this paragraph , if the treatment plan having a combined tar average of 9 % would treat 105 % of the two lobes , but a different treatment plan having a combined tar average of 9 . 3 % would treat 110 % of the two lobes , then the latter treatment plan is preferred . the intent of this methodology is to rank treatment options closest to the ideal total volume to be treated ( thought at the time of this writing to be approximately 110 %). the methods described above refer to segments of the lung . however , it should be understood that the methods can also be applied to subsegments of the lungs as well . fig6 a - 6d will walk through one example of determining a treatment plan according to the principles laid out above . fig6 a shows all the different combinations of segments to be treated in the upper lobes of a patient . in this example , the left upper lobe ( lul ) can include segments lb1 , lb2 , lb3 , and lb1 + 2 , and the right upper lobe ( rul ) can include segments rb1 , rb2 , and rb3 . referring still to fig6 a , method 1 ( treatment plan option 1 ) would provide a first treatment to segment rb1 of the right upper lobe , followed by a second treatment to segments lb1 and lb2 of the left upper lobe . the segment treated in the first treatment is indicated by the number “ 1 ” in the chart , and the segment ( s ) treated in the second treatment are indicated by the “ 2 ” ( and where applicable , “ 3 ”). method 2 ( treatment plan option 2 ) would provide a first treatment to rb1 and a second treatment to lb1 and lb3 . the various permutations of possible treatments are shown in the remaining methods 3 - 33 of fig6 a . fig6 b illustrates the various parameters of each segment that will be used for treatment planning , including the tar of each segment , the hi of each segment , the air volume of each segment , the mass of each segment , the total volume of each segment , the percentage of the lobe that each segment comprises , and the ll tar , or lower lobe tar of each lung . fig6 c applies the exclusionary rules outlined above in fig4 to the individual segments in each possible treatment plan . for example , in fig6 c , methods 5 - 8 , 16 - 18 , 27 - 30 and 33 can be excluded from the list of treatment plans because the first treatment ( tx . 1 ) of delivering vapor to rb2 , with a percentage of the lobe of 24 %, falls below the range of 30 - 70 % defined in step 404 of fig4 above . ( in an output or display , these and other excluded blocks can be marked with red text and / or shading to show an exclusion .) similarly , methods 13 - 15 can be excluded since the first treatment of delivering vapor to lb1 + 2 would fall above the range of 30 - 70 %. as seen in fig6 c , methods 28 - 33 can also be excluded since they require the second treatment ( tx . 2 ) to deliver vapor to lobes falling below the range of 40 - 80 % defined above . the remainder of columns in fig6 c show each of the exclusions defined above , including eliminating treatment plans that treat less than 95 % or greater than 130 % of the two lobes , or have a segmental hi and mass greater than 48 g . the methods lacking any exclusions are methods 1 - 3 , 9 , 19 , 20 , 22 and 23 . these methods may be marked with green shading in an output or display . fig6 d identifies the least diseased segments in which there is a significant difference in tar between the available segments . as described above in fig5 , these segments can be excluded from treatment . the data in fig6 a - 6d results in only a single method , method 1 , that does not conditionally eliminate any “ least diseased ” segments and satisfies the other requirements of fig4 and 5 . method 1 therefore becomes the preferred , or best treatment plan . as described above , 3 total options are desired , so the controller or provider can return to the list , select the next lowest “ combined tar ” and repeat the steps described above including any previously conditionally eliminated options . going through this process for the data of fig6 a - 6d results in the selection of method 2 as the 2nd best option and method 22 as the 3rd best option . there may be patients for whom the treatment planning methodology outlined above concludes that no treatment is possible , i . e ., all potential treatment plans are excluded . for such patients , revisiting one or more of the exclusion criteria on a subsegmental basis may result in an acceptable treatment plan . for example , a lung segment treatment plan that was excluded on the basis of the segment &# 39 ; s tissue mass in grams plus air volume in milliliters is greater than 1700 may be recalculated for a subsegment of that lung segment . if the subsegment qualifies , then that subsegment can be treated . as for additional details pertinent to the present invention , materials and manufacturing techniques may be employed as within the level of those with skill in the relevant art . the same may hold true with respect to method - based aspects of the invention in terms of additional acts commonly or logically employed . also , it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently , or in combination with any one or more of the features described herein . likewise , reference to a singular item , includes the possibility that there are plural of the same items present . more specifically , as used herein and in the appended claims , the singular forms “ a ,” “ and ,” “ said ,” and “ the ” include plural referents unless the context clearly dictates otherwise . it is further noted that the claims may be drafted to exclude any optional element . as such , this statement is intended to serve as antecedent basis for use of such exclusive terminology as “ solely ,” “ only ” and the like in connection with the recitation of claim elements , or use of a “ negative ” limitation . unless defined otherwise herein , all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . the breadth of the present invention is not to be limited by the subject specification , but rather only by the plain meaning of the claim terms employed .

US-201414504042-A

a coffee maker includes a housing , the housing of the coffee maker shaped and configured to fit within a wall cavity inside a wall and attach to one or more wall structures , the housing including an integral mounting structure having engagement structures to engage the one or more wall structures . the coffee maker unit further includes an in - line water heater located within the housing to receive a supply of water from plumbing that is external to the housing and a brewing area located within the housing to contain a supply of coffee grounds and to receive water from the water heater . the coffee maker farther includes a coffee pot receptacle configured to support a coffee pot at least partially within the wall cavity such that the coffee pot is located to receive coffee from the brewing area .

fig1 is a perspective view of an in - wall coffee maker 10 mounted within a wall cavity in a kitchen area according to one embodiment of the present invention . the basic advantages of this invention are evident from fig1 . particularly , as illustrated , the in - wall coffee maker 10 does not occupy any space on top of the counter 13 . furthermore , the amount of above - counter space it occupies is minimal or none . in the embodiment shown , only a small semicircular projection 14 protrudes into the room from the wall panel 12 . in an alternative embodiment , the face 17 can be configured to lie flush with the wall 12 . in that embodiment , no above - counter space is occupied by the in - wall coffee maker 10 . also according to this invention , no cabinet space is occupied by the in - wall coffee maker 10 . accordingly , the in - wall coffee maker 10 of this invention leaves counter , above - counter , and cabinet space available for activities or other kitchen appliances . the specific features of the in - wall coffee maker 10 will now be more fully discussed with reference to fig2 - 4 . fig2 is a perspective view , and fig3 and 4 are a side elevation and a top plan view , respectively , of the in - wall coffee maker 10 of the present invention according to the embodiment of fig1 . referring to fig2 - 4 , according to one embodiment , the in - wall coffee maker 10 includes a mounting structure , such as a mounting box 20 , that receives a coffee maker unit 15 . the coffee maker unit 15 is attached to the mounting box 20 using attachment structures . in this embodiment , the attachment structures include flanges 60 ( see fig6 ) in the mounting box 20 having holes 16 a that allow fasteners , such as screws , to be threaded through mating holes 16 in the face 17 of the coffee maker unit 15 into the wall panel 2 . of course , it should be evident that any type of attachment between the coffee maker unit 15 and the mounting box 20 is within the contemplation of this invention , including , but not limited to , mechanical attachment via screws , rivets , bolts , nails , clips , latches , snap engagement , hook and eye material ( i . e ., velcro ®), etc ., or chemical attachment via glue or other adhesives . referring specifically to fig3 and 4 , dashed lines represent the position of the wall panel 12 when the coffee maker 10 is mounted within a wall cavity . as illustrated by fig3 and 4 , when mounted , most of the coffee maker 10 is retained within the wall cavity . specifically , the coffee maker 10 of this preferred embodiment extends approximately four inches into the wall cavity while protruding only about two and one - half inches from the wall 12 at the center of its semicircular projection 14 . only a small portion of the coffee maker 10 , therefore , protrudes from an outside face of the wall 12 after installation . as noted previously , another embodiment has a front face that lies flush with the wall . in - wall mounting is therefore extremely advantageous because it frees up countertop and above - counter space for other things . unlike conventional home coffee makers , the coffee maker unit 15 of this invention also preferably includes a self - filling capability . fig5 is a schematic diagram showing the components of the coffee maker of fig1 for providing the self - filling capability . self - filling coffee makers having various cup capacities are within the contemplation of this invention , including , for example , four , ten , and twelve cup embodiments . in the self - filling coffee maker , the user actuates a fill selector 71 to select the desired amount of coffee to be brewed , up to the maximum amount for that particular embodiment . after a user selects the desired cup amount for the coffee maker to produce , a water meter 75 ( such as a solenoid valve connected to a timer ) operates to regulate a supply of water from an incoming water line 70 , generally from a cold water source , to provide the selected amount of water to the coffee maker unit 15 . specifically , a water metering system 75 is provided that can be controlled by a program on an electronic circuit or directly by a user . the water metering system 75 can be used in combination with a traditional heated water reservoir 72 or it can be used in an in - line heating system ( not shown ). in a water reservoir system , the meter 75 regulates a supply of water into the water reservoir 72 . the water reservoir 72 typically contains a heating element 76 for heating the water to the desired temperature for brewing the coffee in the drip cone 74 . in an in - line system , however , an in - line heating system ( rather than a heated water reservoir 72 ) is used to heat water in route from the metering system 75 to a brewing area such as a drip cone 74 for brewing the coffee . a preferred water metering system is electric , but a water pressure - driven meter could also be used . another feature of this embodiment is the provision of electrical power outlets 26 located on the face 17 of the coffee maker unit 15 . the outlets 26 are wired to an electrical power source through an electrical junction box 50 ( see fig6 ) in the mounting box 20 . these outlets 26 allow other electrical appliances to be plugged in and receive electrical power through the coffee maker unit 15 . the coffee maker unit 15 also preferably includes conventional coffee maker features known in the art . some of these features include a programming control 21 for an on / off timer , a manual on / off switch 22 , a 24 - hour digital clock 24 , and a power indicator 25 all located on the face 17 . also , a coffee pot 35 can be removably supported within a coffee pot cavity 30 on a warming plate 32 . the on / off timer of the coffee maker unit 15 is preferably fully programmable to allow automatic starting at any desired time . another preferable feature is a two - hour automatic shutoff . the specific details regarding the provision of these and other electronic features is known to those of skill in the art . fig6 is a front perspective view of one embodiment of the mounting box 20 , into which the in - wall coffee maker unit 15 is installed , according to this invention . referring to fig6 , the mounting box 20 is preferably a rough - in sheet metal box that includes a top wall 40 , a bottom wall 42 , two side walls 44 , 46 , and a rear wall 48 . preferred dimensions for the mounting box 20 for a ten - twelve cup coffee maker 10 are approximately 27 . 9 cm wide × 27 . 9 cm tall by 10 . 16 cm deep . for a four cup embodiment , the preferred dimensions are approximately 20 . 32 cm wide by 20 . 32 cm tall by 7 . 62 deep . flanges 60 or tabs are provided along a front portion of each of the top , bottom , and side walls 40 , 42 , 44 , 46 of the mounting box 20 . the flanges 60 provide attachment members for attaching the mounting box 20 to the coffee maker unit 15 . fasteners can be used to secure the coffee maker unit 15 to the mounting box 20 via the flanges 60 . if screws are used as the fasteners , each of the flanges 60 preferably contains one or more holes 16 a for receiving the screws from mating holes 16 in the coffee maker unit 15 . as noted previously , the attachment members according to this invention are not limited to the flanges 60 with screw holes 16 a of this embodiment . rather , any type of attachment that is sufficient to secure the coffee maker unit 15 to the mounting structure 20 is within the scope of this invention . the attachment , however , is preferably non - permanent , such that the coffee maker unit 15 can be easily removed from the mounting box 20 for maintenance , repair , or replacement . furthermore , in some embodiments , no attachment members are required at all . for instance , the coffee maker unit 15 can rest within the mounting box 20 ( or on a mounting shelf ) without being secured thereto and still satisfy the requirements of this invention . the mounting box 20 also preferably includes engagement members in the form of tabs 54 formed from cut out portions of the top 42 , bottom 44 and side walls 46 , 48 . the tabs 54 are cut from the sheet metal box 20 in such a way that they can be bent outwardly from the box 20 to engage a wall panel 12 ( see fig1 ), such as sheet rock , wood paneling , etc . specifically , the tabs 54 can be rectangular - shapes cut out along three edges or triangular shapes cut out along two edges , among others . redundant or alternative securing can be provided by engagement members in one of the side walls 44 , 46 used to fasten the mounting box 20 to a wall stud 84 ( see fig8 ). for example , mechanical fasteners such as nails , screws , bolts , etc ., 85 can be applied through holes 56 to secure the mounting box 20 to the wall stud 84 . a chemical engagement member , such as an adhesive strip , or any of a number of other types of engagement members could also be used to secure the mounting box to the stud 84 , obviating the need for holes 56 . still referring to fig6 , an electrical junction box 50 is provided along one of the side walls 44 of the mounting box 20 . the junction box 50 can be formed along any of the walls 40 , 42 , 44 , 46 , 48 . the electrical junction box 50 can be a conventional single gang outlet box configured to allow hardwiring between the in - wall coffee maker 10 and power supply lines of the building or vehicle in which the coffee maker 10 is installed . the power supply lines may provide ac ( i . e ., 110v or 220v ) or dc ( i . e ., 12v ) power , depending on the power available . for situations where hardwiring is impracticable or undesirable , the electrical junction box can comprise a power cord that allows the coffee maker 10 to be plugged into an existing power outlet . the coffee maker unit 15 is electrically connected to power connections in the junction box 50 . the electrical connection between the coffee maker unit 15 and the junction box 20 can be established through hardwiring or a power cord can be provided on the coffee maker unit 15 that plugs into a conventional - type outlet in the junction box 50 . yet another possible embodiment would include having a simple male / female interface between a power connector on the coffee maker unit 15 and a power connector in the electrical junction box 50 . in this way , the coffee maker unit 15 could simply be inserted into the mounting box 20 such that its power connector ( e . g ., a plug ) slides into engagement with the power connector ( e . g ., a receptacle ) of the junction box 50 , without the need for additional wiring . besides receiving power for the coffee maker unit 15 itself , the in - wall coffee maker 10 can include power lines routed from the junction box 50 to electrical outlets 26 on the front face 17 of the coffee maker unit 15 to provide electrical power to external devices . yet another alternative embodiment is provided by extending an edge of face 17 of the coffee maker unit 15 beyond the side wall 44 of the mounting box 20 and by providing a slidable plug on the face 17 which can be plugged directly into an electrical wall socket located proximal with the coffee maker 10 . in a self - filling embodiment , described again with reference to fig6 , an incoming water line 70 enters the mounting box 20 through a hole 52 in one of the walls 40 , 42 , 44 , 46 , 48 thereof . as with the junction box 50 , the hole 52 can be located within any one of the walls 40 , 42 , 44 , 46 , 48 , although , in this embodiment , it is located in the same side wall 44 as the junction box 50 . the hole 52 for receiving the incoming water line 70 is provided with a rubber grommet 53 to protect the water line 70 from being damaged by the sharp edges of the sheet metal mounting box 20 . alternatively , a plumbing fixture , such as an “ i ” connector , could be used in the hole 52 to allow the incoming water source line 70 to be connected to an outside end of the connector and a water reservoir line to be connected to an opposite end of the connector on the inside of the mounting box 20 . the water reservoir line receives water from the incoming water source line 70 through the connector and supplies water to the water reservoir through a metering system 75 . yet another embodiment that can further simplify installation includes male / female plumbing connectors on the coffee maker unit 15 and the mounting box 20 . the male / female plumbing connectors allow the coffee maker unit 15 to be connected directly to the incoming water supply line 70 without requiring tubing between the mounting box 20 and the coffee maker unit 15 . although the preferred material for the mounting box 20 is sheet metal because of its ease of manufacture and adaptability , other materials , such as plastic , wood , etc ., could also be used for the mounting box 20 . the use of other materials would require only minor modifications to the mounting box 20 . tabs 54 of the sheet metal box , for instance , in a plastic or wood box , could be replaced by other types of engagement structures such as clips or other fasteners . also , although the mounting structure of the foregoing embodiments was a mounting box 20 , it should be noted that any mounting structure that is capable of supporting the coffee maker unit 15 in place within the wall cavity is within the contemplation of this invention . for instance , a mounting bracket , a mounting shelf , a mounting hook ( s ), etc ., could all be used for this purpose . a sheet rock screw can also be used to secure the box from either a side , top , or bottom location . metal bars ( i . e ., “ t ”, “ l ”, or “ i ” bars ) could also be added behind the box to secure it . fig7 is an exploded perspective view of the coffee maker unit 15 and the mounting box 20 illustrating an interface between them . as illustrated by fig7 , the mounting box 20 receives and supports the coffee maker unit 15 within a wall cavity and provides the necessary water 52 and power 50 interconnections . specifically , an incoming water line 70 a provides water to the mounting box 20 through hole ( or plumbing fixture ) 52 . an internal water line 70 b ( either the same as line 70 a or connected thereto via a plumbing fixture ) supplies water to a water meter 75 of the coffee maker unit 15 . also , electrical power is provided to the junction box 50 of the mounting box 20 by an external power cable 99 a . power from the junction box 50 to the coffee maker unit 15 is supplied via an internal power cable 99 b . although the embodiments described so far have included a separate mounting structure , it should be noted that one embodiment of this invention can include a coffee maker unit provided with an integral mounting structure to mount with a wall structure that has the necessary water and power interconnections provided directly thereon . in such an embodiment , a separate mounting structure would be unnecessary . a method for installing the in - wall coffee maker of fig1 - 7 will now be described in detail with reference to fig6 , and 8 . it should be noted , however , that most of the following steps need not be performed in the order in which they are described . the first step is to locate an area for installation . the installation area for a self - filling coffee maker should be near a water source 90 , such as is typically found near a sink , dishwasher , or refrigerator ( if plumbed for ice / water ), to facilitate easy routing of the incoming water line 70 . the installation area should also be located near a power source 92 . the width between wall studs 84 at the installation area should be checked to make sure that the coffee maker 10 will fit between them . specifically , the opening between studs 84 , or cavity width , should not be less than 27 . 9 cm wide for the ten - twelve cup embodiment and not less than 20 . 32 cm wide for the four cup embodiment . also , the power outlet area 92 should not be within the cavity width . once a suitable location has been selected , a template corresponding to the desired size of the wall cut out is used to properly mark a cut out area on the wall panel 12 . the cut out area should be above the typical 10 . 16 cm back splash 82 . if the back splash 82 is higher than typical and is noticeably in the way , the installation location may have to be altered , or a professional may need to be hired , to install the unit . otherwise , the back splash 82 can be modified by cutting around the necessary areas to facilitate installation . once the cut out area is marked , the marked area of the wall panel 12 can be cut out using any suitable cutting tool , such as a saw , and then removed . at this point , an area directly below counter 13 height from the cut out area should be located , and a 1 . 27 cm hole should be drilled through the wall at this location . holes adjacent to this hole should also be drilled along the wall 12 in the direction of the water source 90 . these holes should be spaced a few inches apart to enable the person installing the unit to run the water line 70 ( preferably 0 . 635 cm ) to the installation area . once all the holes are finished , the water line 70 is routed from the water source 90 to the installation location . plenty of line length should be left at both ends to make sure that a proper connection can be made . no excess line should be cut off at this point . a cold water valve at the cold water source 90 is now turned off . an “ i ” connection ( preferably either 0 . 952 cm by 0 . 635 cm or 0 . 635 cm by 0 . 635 cm ) can be used to tie in the water line 70 to the mounting box 20 . alternatively , the water line 70 can be run through the hole 52 in the mounting box 20 and connected to the coffee maker unit 15 using an “ i ” connection . the water should not be turned back on yet . the electrical junction box 50 should next be connected to the power source 92 , either with a power cord connection or hardwire integration . hardwire integration may require a professional electrician and is described in further detail below . in the case of a hardwire connection , a nearby power source 92 ( i . e ., an electrical outlet ) is found . this outlet 92 should be located within one stud cavity away from the installation area . the power to this outlet 92 is then turned off to prevent the risk of electrocution . any necessary holes in the studs 84 should then be drilled in order to route a power cable 99 a from the power source 92 to the junction box 50 . next , the necessary cable length is cut and fed into the outlet box . the outlet 92 is disconnected so the wire can be safely pulled into the outlet box . the power cable 99 a can then be routed into the mounting box 20 and the power lines tied to the junction box 50 . referring still to fig6 , and 8 , once the power lines and water line 70 are connected to the mounting box 20 , the mounting box 20 is placed in the wall cavity so that the opening of the mounting box 20 is flush with the wall panel 12 . when the entrance to the mounting box 20 is flush against the outside of the wall panel , the tabs 54 are bent outwardly to secure the box 20 to the wall panel 12 . if necessary , a side wall of the mounting box 20 can be further fastened to a wall stud 84 with fasteners such as nails 85 . of course , any other type of fastener such as screws , glue , etc ., may be used . next , the coffee maker unit 15 is installed into the mounting box 20 . to do this , the coffee maker unit 15 is electrically connected to the power source at the junction box 50 and also connected to the incoming water line 70 a . the electrical connection between the coffee maker unit 15 and the junction box 50 can be a plug - in connection or a hardwire connection , among others . the connection to the water line can be through a separate internal water line 70 b and a plumbing fixture or directly between the unit 15 and the external line 70 a , among others . the coffee maker unit 15 should not be fully secured within the mounting box 20 until the water is checked and verified to be running properly . the cold water source 90 should therefore be turned on and the connections should be checked for leaks . if any leaks appear , they should be fixed . if there are no leaks , the unit 15 is then attached to the mounting box 20 via mating screw holes 16 in the unit 15 and flanges 60 . other types of attachment between the box 20 and the unit 15 are also acceptable . also alternatively , the coffee maker unit 15 can have an integral mounting structure to allow it to be directly fastened to the wall panel 12 and be directly supplied with power and water without the need for a separate mounting box 20 . in any event , once the coffee maker 10 is completely installed , the power can be turned on and the coffee maker unit 15 can be operated . installation of the in - wall coffee maker 10 of this invention in boats and motor homes is relatively the same as for buildings such as houses , hotels , offices , and apartments . because tabs 54 are provided in the rough - in box 20 that can be bent over to engage a wall panel 12 , a wall opening of sufficient size to house the unit is the only requirement for installation . the tabs 54 will generally provide enough strength to hold the coffee maker 10 in place . furthermore , additional holes 56 are available for securing the mounting box 20 to other wall structures if alternative or additional securing is needed . a few of the many other possible embodiments of this invention will now be described in general terms . at the outset , it should be noted that ease of installation and maintenance are important considerations for designing a system according to this invention . it is desirable to have the installation as easy as possible and to have the ability to change out the unit quickly and easily if problems occur ( such as a water leak or a malfunction with the unit itself ). it is also important to make the face flush ( or substantially flush ) with the wall to provide the advantage of freeing countertop space . other important considerations include avoiding problems associated with the water supply or power supply issues through reliable connections . although the primary embodiment includes a rough - in sheet metal box with hardwired power and water connections , there are numerous other possible ways to accomplish the objects of this invention . for instance , an enclosure made of plastic , wood , or other material can be built inside a wall cavity and provided with a water metering system . a conventional countertop coffee maker can then be fitted within the enclosure , connected to a power source , and receive water into its water reservoir from the water metering system . a slide - in unit is also contemplated where the water and power sources are supplied through male to female connectors that engage each other as the unit is slid into place . yet another alternative is to frame - in and sheet rock an alcove area and place a water dispenser and outlet inside this area . a conventional coffee maker could then be placed within the alcove . another alternative includes providing a frame , similar to a picture frame , to an existing coffee pot to support it within a wall cavity . the coffee pot is connected to a water supply and a power supply and placed within the wall cavity , using the frame to support it in place . furthermore , a mounting bracket or a shelf could be used instead of a mounting box to support the in - wall coffee maker within the wall cavity according to this invention . still other embodiments are possible which are not described here but are within the spirit of the invention and should be considered to be within the scope of the claims . having described and illustrated the principles of the invention in various embodiments thereof , it should be apparent that the invention can be modified in arrangement and detail without departing from such principles . i claim all modifications and variations coming within the spirit and scope of the following claims .

US-42687206-A

the present invention provides novel salts of raltegravir , processes for their preparation and pharmaceutical compositions comprising them . the present invention also provides crystalline sodium salt of raltegravir , process for its preparation and pharmaceutical compositions comprising it . the present invention further provides a process for the preparation of amorphous sodium salt of raltegravir . the present invention further provides a process for the preparation of raltegravir potassium crystalline form h 1 .

according to one aspect of the present invention , there is provided a barium salt of raltegravir , that is , raltegravir barium . the term “ raltegravir barium ” as used herein means any salt comprising raltegravir anions and barium cations . the raltegravir barium may preferably be a solid . the powdered x - ray diffractogram ( pxrd ) of amorphous raltegravir barium is shown in fig1 . amorphous raltegravir barium of present invention is further characterized by a differential scanning calorimetry ( dsc ) thermogram as shown in fig2 . according to another aspect of the present invention , there is provided a process for the preparation of raltegravir barium , which comprises : a ) reacting raltegravir with barium hydroxide in a suitable solvent ; b ) heating the contents to an elevated temperature ; c ) slurrying the solution obtained in step ( b ); and d ) isolating raltegravir barium . the suitable solvent used in the process may preferably be a solvent or mixture of solvents selected from the group consisting of water ; an alcoholic solvents such as methanol , ethanol and isopropyl alcohol ; an ester solvents such as ethyl acetate , methyl acetate , isopropyl acetate , tert - butyl methyl acetate and ethyl formate ; a nitrile solvents such as acetonitrile , propionitrile , butyronitrile and benzonitrile ; dimethylformamide ; dimethylsulfoxide ; an aromatic hydrocarbon solvents such as benzene , toluene and xylene ; a halogenated hydrocarbon solvents such as methylene chloride , chloroform , carbontetrachloride and ethylene dichloride ; a ketonic solvents such as acetone , methyl ethyl ketone , methyl isobutyl ketone and diethyl ketone ; an ether solvents such as tetrahydrofuran , 1 , 4 - dioxane , tert - butyl methyl ether and diethyl ether . more preferable solvent is water , alcoholic solvents and nitrile solvents , and still more preferable solvent is water , methanol , ethanol and acetonitrile . the term “ elevated temperature ” refers to temperature at above 25 ° c . preferably the contents are heating in step ( b ) at about 60 to 70 ° c . isolation of raltegravir barium in step ( d ) may preferably be performed by conventional techniques such as centrifugation and filtration . according to another aspect of the present invention , there is provided a pharmaceutical composition that comprises raltegravir barium and pharmaceutically acceptable carriers , diluents or excipients and optionally other therapeutic ingredients . the salt may preferable be conveniently formulated into tablets , capsules , suspensions , dispersions , injectables and other pharmaceutical forms . according to another aspect of the present invention , there is provided a calcium salt of raltegravir , that is , raltegravir calcium . the term “ raltegravir calcium ” as used herein means any salt comprising raltegravir anions and calcium cations . the powdered x - ray diffractogram ( pxrd ) of amorphous raltegravir calcium is shown in fig3 . amorphous raltegravir calcium of present invention is further characterized by a differential scanning calorimetry ( dsc ) thermogram as shown in fig4 . according to another aspect of the present invention , there is provided a process for the preparation of raltegravir calcium , which comprises : a ) reacting raltegravir with calcium acetate in a suitable solvent ; b ) heating the contents to an elevated temperature ; c ) removing the solvent from the solution obtained in step ( b ) to obtain a residual mass ; d ) slurrying the residual mass obtained in step ( c ) with aliphatic hydrocarbon solvent ; and e ) isolating raltegravir calcium . the suitable solvent used in step ( a ) may preferably be a solvent or mixture of solvents selected from the group consisting of water ; an alcoholic solvents such as methanol , ethanol and isopropyl alcohol ; an ester solvents such as ethyl acetate , methyl acetate , isopropyl acetate , tert - butyl methyl acetate and ethyl formate ; a nitrile solvents such as acetonitrile , propionitrile , butyronitrile and benzonitrile ; dimethylformamide ; dimethylsulfoxide ; an aromatic hydrocarbon solvents such as benzene , toluene and xylene ; a halogenated hydrocarbon solvents such as methylene chloride , chloroform , carbontetrachloride and ethylene dichloride ; a ketonic solvents such as acetone , methyl ethyl ketone , methyl isobutyl ketone and diethyl ketone ; an ether solvents such as tetrahydrofuran , 1 , 4 - dioxane , tert - butyl methyl ether and diethyl ether . more preferable solvent is water , alcoholic solvents and nitrile solvents , and still more preferable solvent is water , methanol , ethanol and acetonitrile . the term “ elevated temperature ” refers to temperature at above 25 ° c . preferably the contents are heating in step ( b ) at about 60 to 70 ° c . removal of the solvent may be carried out in step ( c ) at atmospheric pressure or at reduced pressure . removal of the solvent may preferably be carried out until the solvent is almost completely distilled off . the aliphatic hydrocarbon solvent used in step ( d ) may preferably be a solvent or a mixture of solvents selected from cyclohexane , hexane and n - heptane . more preferable aliphatic hydrocarbon solvent is n - heptane . isolation of raltegravir calcium in step ( e ) may preferably be performed by conventional techniques such as centrifugation and filtration . according to another aspect of the present invention , there is provided a pharmaceutical composition that comprises raltegravir calcium and pharmaceutically acceptable carriers , diluents or excipients and optionally other therapeutic ingredients . the salt may preferable be conveniently formulated into tablets , capsules , suspensions , dispersions , injectables and other pharmaceutical forms . according to another aspect of the present invention , there is provided a lithium salt of raltegravir , that is , raltegravir lithium . the term “ raltegravir lithium ” as used herein means any salt comprising raltegravir anions and lithium cations . the raltegravir lithium may preferably be a solid and more preferable solid is crystalline raltegravir lithium . the powdered x - ray diffractogram ( pxrd ) of crystalline raltegravir lithium is shown in fig5 . crystalline raltegravir lithium of present invention is further characterized by a differential scanning calorimetry ( dsc ) thermogram as shown in fig6 . according to another aspect of the present invention , there is provided a process for the preparation of raltegravir lithium , which comprises : a ) reacting raltegravir with lithium hydroxide in a suitable solvent ; b ) heating the contents to an elevated temperature ; c ) removing the solvent from the solution obtained in step ( b ) to obtain a residual mass ; d ) slurrying the residual mass obtained in step ( c ) with alcoholic solvent ; and e ) isolating raltegravir lithium . the suitable solvent used in step ( a ) may preferably be a solvent or mixture of solvents selected from the group consisting of water ; an alcoholic solvents such as methanol , ethanol and isopropyl alcohol ; an ester solvents such as ethyl acetate , methyl acetate , isopropyl acetate , tert - butyl methyl acetate and ethyl formate ; a nitrile solvents such as acetonitrile , propionitrile , butyronitrile and benzonitrile ; dimethylformamide ; dimethylsulfoxide ; an aromatic hydrocarbon solvents such as benzene , toluene and xylene ; a halogenated hydrocarbon solvents such as methylene chloride , chloroform , carbontetrachloride and ethylene dichloride ; a ketonic solvents such as acetone , methyl ethyl ketone , methyl isobutyl ketone and diethyl ketone ; an ether solvents such as tetrahydrofuran , 1 , 4 - dioxane , tert - butyl methyl ether and diethyl ether . more preferable solvent is water , alcoholic solvents and nitrile solvents , and still more preferable solvent is water , methanol , ethanol and acetonitrile . the term “ elevated temperature ” refers to temperature at above 25 ° c . preferably the contents are heating in step ( b ) at about 60 to 70 ° c . removal of the solvent may be carried out in step ( c ) at atmospheric pressure or at reduced pressure . removal of the solvent may preferably be carried out until the solvent is almost completely distilled off . the aliphatic hydrocarbon solvent used in step ( d ) may preferably be a solvent or a mixture of solvents selected from cyclohexane , hexane and n - heptane . more preferable aliphatic hydrocarbon solvent is n - heptane . isolation of raltegravir lithium in step ( e ) may preferably be performed by conventional techniques such as centrifugation and filtration . according to another aspect of the present invention , there is provided a pharmaceutical composition that comprises raltegravir lithium and pharmaceutically acceptable carriers , diluents or excipients and optionally other therapeutic ingredients . the salt may preferable be conveniently formulated into tablets , capsules , suspensions , dispersions , injectables and other pharmaceutical forms . according to another aspect of the present invention , there is provided crystalline sodium salt of raltegravir . according to another aspect of the present invention , there is provided a process for the preparation of crystalline raltegravir sodium , which comprises : a ) suspending raltegravir in an alcoholic solvent ; b ) adding sodium hydroxide to the suspension obtained in step ( a ); c ) slurrying the reaction mass obtained in step ( b ) at about 25 to 30 ° c . ; and d ) isolating crystalline raltegravir sodium . the alcoholic solvent used in step ( a ) may preferably be a solvent or mixture of solvents selected from methanol , ethanol and isopropyl alcohol . more preferable alcoholic solvent is ethanol . isolation of crystalline raltegravir sodium in step ( d ) may preferably be performed by conventional techniques such as centrifugation and filtration . according to another aspect of the present invention , there is provided a process for the preparation of crystalline form 1 of raltegravir sodium , which comprises : a ) suspending raltegravir in an alcoholic solvent ; b ) adding sodium hydroxide to the suspension obtained in step ( a ); c ) slurrying the reaction mass obtained in step ( b ) for 10 to 12 hours at about 25 to 30 ° c . ; and d ) isolating raltegravir sodium crystalline form 1 . raltegravir sodium crystalline form 1 , which is characterized by peaks in the powder x - ray diffraction spectrum having 2θ angle positions at about 7 . 2 , 8 . 0 , 18 . 0 , 18 . 5 and 21 . 8 ± 0 . 2 degrees . the powdered x - ray diffractogram ( pxrd ) of raltegravir sodium crystalline form 1 is shown in fig7 . the alcoholic solvent used in step ( a ) may preferably be a solvent or mixture of solvents selected from methanol , ethanol and isopropyl alcohol . more preferable alcoholic solvent is ethanol . isolation of raltegravir sodium crystalline form 1 in step ( d ) may preferably be performed by conventional techniques such as centrifugation and filtration . according to another aspect of the present invention , there is provided a process for the preparation of crystalline form 2 of raltegravir sodium , which comprises : a ) suspending raltegravir in an alcoholic solvent ; b ) adding sodium hydroxide to the suspension obtained in step ( a ); c ) slurrying the reaction mass obtained in step ( b ) for 30 to 35 hours at about 25 to 30 ° c . ; and d ) isolating raltegravir sodium crystalline form 2 . raltegravir sodium crystalline form 2 , which is characterized by peaks in the powder x - ray diffraction spectrum having 2θ angle positions at about 8 . 4 , 17 . 0 , 17 . 9 , 18 . 3 , 21 . 3 , 21 . 8 and 23 . 7 ± 0 . 2 degrees . the powdered x - ray diffractogram ( pxrd ) of raltegravir sodium crystalline form 2 is shown in fig8 . the alcoholic solvent used in step ( a ) may preferably be a solvent or mixture of solvents selected from methanol , ethanol and isopropyl alcohol . more preferable alcoholic solvent is ethanol . isolation of raltegravir sodium crystalline form 2 in step ( d ) may preferably be performed by conventional techniques such as centrifugation and filtration . according to another aspect of the present invention , there is provided a pharmaceutical composition that comprises crystalline raltegravir sodium and pharmaceutically acceptable carriers , diluents or excipients and optionally other therapeutic ingredients . the salt may preferable be conveniently formulated into tablets , capsules , suspensions , dispersions , injectables and other pharmaceutical forms . according to another aspect of the present invention , there is provided a process for the preparation of amorphous raltegravir sodium , which comprises : a ) reacting raltegravir with sodium hydroxide in a suitable solvent ; b ) heating the contents to an elevated temperature ; c ) removing the solvent from the solution obtained in step ( b ) to obtain a residual mass ; d ) slurrying the residual mass obtained in step ( c ) with alcoholic solvent ; and e ) isolating amorphous raltegravir sodium . the powdered x - ray diffractogram ( pxrd ) of amorphous raltegravir sodium is shown in fig9 . amorphous raltegravir sodium of present invention is further characterized by a differential scanning calorimetry ( dsc ) thermogram as shown in fig1 . the suitable solvent used in step ( a ) may preferably be a solvent or mixture of solvents selected from the group consisting of water ; an alcoholic solvents such as methanol , ethanol and isopropyl alcohol ; an ester solvents such as ethyl acetate , methyl acetate , isopropyl acetate , tert - butyl methyl acetate and ethyl formate ; a nitrile solvents such as acetonitrile , propionitrile , butyronitrile and benzonitrile ; dimethylformamide ; dimethylsulfoxide ; an aromatic hydrocarbon solvents such as benzene , toluene and xylene ; a halogenated hydrocarbon solvents such as methylene chloride , chloroform , carbontetrachloride and ethylene dichloride ; a ketonic solvents such as acetone , methyl ethyl ketone , methyl isobutyl ketone and diethyl ketone ; an ether solvents such as tetrahydrofuran , 1 , 4 - dioxane , tert - butyl methyl ether and diethyl ether . more preferable solvent is water , alcoholic solvents and nitrile solvents , and still more preferable solvent is water , methanol , ethanol and acetonitrile . the term “ elevated temperature ” refers to temperature at above 25 ° c . preferably the contents are heating in step ( b ) at about 60 to 70 ° c . removal of the solvent may be carried out in step ( c ) at atmospheric pressure or at reduced pressure . removal of the solvent may preferably be carried out until the solvent is almost completely distilled off . the aliphatic hydrocarbon solvent used in step ( d ) may preferably be a solvent or a mixture of solvents selected from cyclohexane , hexane and n - heptane . more preferable aliphatic hydrocarbon solvent is n - heptane . isolation of amorphous raltegravir sodium in step ( e ) may preferably be performed by conventional techniques such as centrifugation and filtration . according to another aspect of the present invention , there is provided a process for the preparation of raltegravir potassium crystalline form h1 , which comprises : a ) suspending raltegravir in an alcoholic solvent ; b ) adding potassium hydroxide to the suspension obtained in step ( a ); c ) slurrying the reaction mass obtained in step ( b ) at about 25 to 30 ° c . ; and d ) isolating raltegravir potassium crystalline form h1 . the alcoholic solvent used in step ( a ) may preferably be a solvent or mixture of solvents selected from methanol , ethanol and isopropyl alcohol . more preferable alcoholic solvent is ethanol . isolation of raltegravir potassium crystalline form h1 in step ( d ) may preferably be performed by conventional techniques such as centrifugation and filtration . the invention will now be further described by the following examples , which are illustrative rather than limiting . raltegravir ( 100 gm ), ethanol ( 600 ml ), acetonitrile ( 400 ml ) and barium hydroxide ( 42 gm ) were added at 25 to 30 ° c . the contents were heated to 60 to 65 ° c . to obtain a solution . the solution was cooled to 25 to 30 ° c . and stirred for 18 hours at 25 to 30 ° c . the solid obtained was collected by filtration and dried to obtain 108 gm of raltegravir barium . raltegravir ( 10 gm ), methanol ( 60 ml ), acetonitrile ( 40 ml ) and barium hydroxide ( 4 . 2 gm ) were added at 25 to 30 ° c . the contents were heated to 60 to 65 ° c . to obtain a solution . the solution was cooled to 25 to 30 ° c . and stirred for 20 hours at 25 to 30 ° c . the solid obtained was collected by filtration and dried to obtain 10 gm of raltegravir barium . raltegravir ( 100 gm ) was suspended in ethanol ( 600 ml ) and then added barium hydroxide ( 42 gm ) at 25 to 30 ° c . the contents were heated to 60 to 65 ° c . to obtain a solution . the solution was cooled to 25 to 30 ° c . and stirred for 18 hours at 25 to 30 ° c . the solid obtained was collected by filtration and dried to obtain 105 gm of raltegravir barium . raltegravir ( 100 gm ) was suspended in acetonitrile ( 400 ml ) and then added barium hydroxide ( 42 gm ) at 25 to 30 ° c . the contents were heated to 60 to 65 ° c . to obtain a solution . the solution was cooled to 25 to 30 ° c . and stirred for 18 hours at 25 to 30 ° c . the solid obtained was collected by filtration and dried to obtain 105 gm of raltegravir barium . raltegravir ( 10 gm ), ethanol ( 60 ml ), acetonitrile ( 40 ml ), water ( 2 ml ) and calcium acetate ( 4 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added n - heptane ( 50 ml ) and again distilled to obtain residue . n - heptane ( 100 ml ) was added to the residue and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 10 . 2 gm of raltegravir calcium . raltegravir ( 10 gm ), methanol ( 60 ml ), acetonitrile ( 40 ml ), water ( 2 ml ) and calcium acetate ( 4 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added n - heptane ( 50 ml ) and again distilled to obtain residue . n - heptane ( 100 ml ) was added to the residue and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 9 . 8 gm of raltegravir calcium . raltegravir ( 10 gm ), ethanol ( 60 ml ), acetonitrile ( 40 ml ), water ( 2 ml ) and calcium acetate ( 4 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added cyclohexane ( 50 ml ) and again distilled to obtain residue . cyclohexane ( 100 ml ) was added to the residue and stirred for 5 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 10 gm of raltegravir calcium . raltegravir ( 10 gm ) was suspended in ethanol ( 60 ml ) and then added a solution of calcium acetate ( 4 gm ) in water ( 2 ml ) at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added n - heptane ( 50 ml ) and again distilled to obtain residue . n - heptane ( 100 ml ) was added to the residue and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 9 . 9 gm of raltegravir calcium . raltegravir ( 10 gm ) was suspended in acetonitrile ( 40 ml ) and then added a solution of calcium acetate ( 4 gm ) in water ( 2 ml ) at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added n - heptane ( 50 ml ) and again distilled to obtain residue . n - heptane ( 100 ml ) was added to the residue and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 9 . 8 gm of raltegravir calcium . raltegravir ( 10 gm ), ethanol ( 60 ml ), acetonitrile ( 40 ml ), water ( 2 ml ) and lithium hydroxide ( 0 . 7 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added ethanol ( 50 ml ) and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 10 . 1 gm of raltegravir lithium . raltegravir ( 10 gm ), methanol ( 60 ml ), acetonitrile ( 40 ml ), water ( 2 ml ) and lithium hydroxide ( 0 . 7 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added ethanol ( 50 ml ) and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 9 . 8 gm of raltegravir lithium . raltegravir ( 10 gm ) was suspended in ethanol ( 60 ml ) and then added a solution of lithium hydroxide ( 0 . 7 gm ) in water ( 2 ml ) at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added ethanol ( 50 ml ) and stirred for 5 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 10 gm of raltegravir lithium . raltegravir ( 10 gm ) was suspended in acetonitrile ( 40 ml ) and then added a solution of lithium hydroxide ( 0 . 7 gm ) in water ( 2 ml ) at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added ethanol ( 50 ml ) and stirred for 5 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 9 . 9 gm of raltegravir lithium . raltegravir ( 50 gm ) was suspended in ethanol ( 500 ml ) and then added a solution of sodium hydroxide ( 5 gm ) in water ( 10 ml ) at 25 to 30 ° c . the reaction mass was stirred for 11 hours at 25 to 30 ° c . and filtered . the solid obtained was dried under vacuum at 60 ° c . for 7 hours to obtain 52 gm of raltegravir sodium crystalline form 1 . raltegravir ( 50 gm ) was suspended in ethanol ( 500 ml ) and then added sodium hydroxide ( 5 gm ) at 25 to 30 ° c . the reaction mass was stirred for 12 hours at 25 to 30 ° c . and filtered . the solid obtained was dried under vacuum at 60 ° c . for 7 hours to obtain 50 gm of raltegravir sodium crystalline form 1 . raltegravir ( 100 gm ) was suspended in ethanol ( 1000 ml ) and then added a solution of sodium hydroxide ( 10 gm ) in water ( 20 ml ) at 25 to 30 ° c . the reaction mass was stirred for 32 hours at 25 to 30 ° c . and filtered . the solid obtained was dried under vacuum at 60 ° c . for 8 hours to obtain 105 gm of raltegravir sodium crystalline form 2 . raltegravir ( 100 gm ) was suspended in ethanol ( 1000 ml ) and then added sodium hydroxide ( 10 gm ) at 25 to 30 ° c . the reaction mass was stirred for 34 hours at 25 to 30 ° c . and filtered . the solid obtained was dried under vacuum at 60 ° c . for 8 hours to obtain 102 gm of raltegravir sodium crystalline form 2 . raltegravir ( 10 gm ), ethanol ( 60 ml ), acetonitrile ( 40 ml ), water ( 2 ml ) and sodium hydroxide ( 1 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added n - heptane ( 50 ml ) and again distilled to obtain residue . n - heptane ( 100 ml ) was added to the residue and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 10 gm of amorphous raltegravir sodium . raltegravir ( 50 gm ), ethanol ( 300 ml ), acetonitrile ( 200 ml ), water ( 10 ml ) and sodium hydroxide ( 5 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added cyclohexane ( 250 ml ) and again distilled to obtain residue . cyclohexane ( 500 ml ) was added to the residue and stirred for 5 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 48 gm of amorphous raltegravir sodium . raltegravir ( 10 gm ), methanol ( 60 ml ), acetonitrile ( 40 ml ), water ( 2 ml ) and sodium hydroxide ( 1 gm ) were added at 25 to 30 ° c . the contents were heated to 65 to 70 ° c . and distilled off solvent completely under vacuum at 45 ° c . to obtain residue . to the residue was added n - heptane ( 50 ml ) and again distilled to obtain residue . n - heptane ( 100 ml ) was added to the residue and stirred for 6 hours at room temperature . the solid obtained was collected by filtration and dried to obtain 9 . 8 gm of amorphous raltegravir sodium . raltegravir ( 50 gm ) was suspended in ethanol ( 500 ml ) and then added a solution of potassium hydroxide ( 8 gm ) in water ( 10 ml ) at 25 to 30 ° c . the reaction mass was stirred for 16 hours at 25 to 30 ° c . and filtered . the solid obtained was dried under vacuum at 60 ° c . for 9 hours to obtain 52 gm of raltegravir potassium crystalline form h1 . raltegravir ( 50 gm ) was suspended in ethanol ( 500 ml ) and then added potassium hydroxide ( 8 gm ) at 25 to 30 ° c . the reaction mass was stirred for 18 hours at 25 to 30 ° c . and filtered . the solid obtained was dried under vacuum at 60 ° c . for 9 hours to obtain 50 gm of raltegravir potassium crystalline form 1 - 11 . raltegravir ( 50 gm ) was suspended in isopropyl alcohol ( 500 ml ) and then added a solution of potassium hydroxide ( 8 gm ) in water ( 10 ml ) at 25 to 30 ° c . the reaction mass was stirred for 17 hours at 25 to 30 ° c . and filtered . the solid obtained was dried under vacuum at 60 ° c . for 9 hours to obtain 48 gm of raltegravir potassium crystalline form h1 .

US-201013699368-A

a toaster has a casing , a carrier for supporting a slice of bread , the carrier being movable between an upper position to expose the slice of bread outside the casing and a lower position to render the slice of bread inside the casing , a heating element provided inside the casing for heating the slice of bread when the carrier is in the lower position , an internal operating mechanism for moving the carrier , the operating mechanism including a spring assembly for resiliently biasing the carrier upwards and holding means including a stationary solenoid for holding the carrier in the lower position , and a time for controlling the time period during which the slice of bread is to be heated by the heating element wherein the holding means is releasable by a user at point other than the solenoid or with a force relatively smaller than the holding force of the solenoid in order to release the carrier from the lower position at any time during the time period .

referring to the drawings , there is shown an internal operating mechanism 10 of a toaster embodying the invention , which operating mechanism 10 is installed inside one end of the toaster . as partially shown , the toaster has a tray - like base 9 and a fixed transversely - extending vertical partition 8 standing on the base 9 . the toaster further includes a rectangular cuboidal casing , as in conventional toasters , in which ( as shown ) the partition 8 defines on its rear side a toasting compartment 7 and on its front side a comparatively much thinner end compartment 11 for accommodating the operating mechanism 10 . although this is not shown in the drawings , the toasting compartment 7 houses a vertically slidable carriage for supporting two slices of bread to be toasted and heating elements located on opposite sides of the slices of bread so supported for heating the bread . the top wall of the casing has a longitudinally - extending slot through which the slices of bread can be inserted into or removed from the toaster . the operating mechanism 10 has four principal parts , namely a carriage - moving unit 12 for moving the bread carriage , a holding unit 13 for holding the carriage - moving unit 12 and hence the bread carriage in a lowermost position for bread toasting , a switching unit 14 for controlling the operation of the bread heating elements ( and an electro - magnetic solenoid 28 to be introduced later ), and a timer ( not shown ). referring firstly to the carriage - moving unit 12 ( best shown in fig2 ), it is formed by a fixed vertical pole 35 extending from top to bottom of the toaster casing , and inner and outer sliders 15 and 16 mounted on the pole 35 for vertical movement therealong . each of the sliders 15 and 16 has top and bottom backward flanges through which the pole 35 extends . the outer slider 16 is relatively longer than the inner slider 15 and is arranged to embrace the inner slider 15 between its top and bottom flanges 17 , lying close thereto . the partition 8 has a central vertical slot 6 , from which the pole 35 is laterally off - set . the bread carriage has a part passing through the slot 6 from behind and secured to the inner slider 15 , and is thus movable by and at the same time with the inner slider 15 . the inner slider 15 is vertically and freely slidable between the top and bottom flanges 17 of the outer slider 16 , and has a normal rest position sitting internally on the outer slider &# 39 ; s bottom flange 17 under the action of its own weight and the weight of the bread carriage ( and the weight of a handle bar 31 to be introduced later ) a compression spring 22 is disposed on the bottom half of the pole 35 , acting resiliently to urge the outer slider 16 and hence the inner slider 15 and the bread carriage upwards into a normal top position , as shown in fig1 c , 3a , 3b and 5c . the outer slider 16 has a large aperture 18 through which three integral arms 19 to 21 of the inner slider 15 extend forward . immediately under the aperture 18 , the outer slider 16 has three integral arms 23 to 25 extending forward . the inner slider &# 39 ; s middle arm 20 is aligned with the gap formed between the middle and the right - side arms 24 and 25 of the outer slider 16 . a hook member 26 is located in the gap between the arms 24 and 25 , freely hinged about a horizontal axis . the hook member 26 has an integral hooking portion 27 , and assumes a normal rest angular position in which its hooking portion 27 points horizontally forward . the arm 20 of the inner slider 15 has a bottom profile matching with the top profile of the hook member 26 directly below . in the rest position of the inner slider 15 relative to the outer slider 16 , the arm 20 engages from above with the hook member 26 , thereby holding the hook member 26 firmly in its rest angular position against pivoting downwards , with their matching profiles being in a fit inter - engagement behind the hinging axis of the hook member 26 . a handle bar 31 is secured to the right - side arm 21 of the inner slider 15 , extending horizontally forward . the holding unit 13 is now specifically referred to , which is formed in part by the middle arm 20 of the inner slider 15 and the hook member 26 on the outer slider 16 . the holding unit 13 further includes an electro - magnetic solenoid 28 and a hook 29 which is hinged on the solenoid 28 about a horizontal axis to pivot freely within a limited extent . the hook 29 normally points vertically upwards under its own weight , and has a hooking portion 30 which extends in a horizontal direction when the hook 29 is in the normal vertical position . a soft - iron plate ( not shown ) is fixed on the bottom of the hook 29 , which is arranged to be magnetically attracted by the solenoid 28 , and thus bearing against it , when the solenoid 28 is energized in order to maintain by force the hook 29 in its normal vertical position . the hooking portion 27 of the hook member 26 above and the hooking portion 30 of the hook 29 below are aligned with each other such that when the upper hooking portion 27 is moved downward with the outer slider 16 against the action of the spring 22 ( as described below ) to and against the lower hooking portion 30 , the hook 29 will give way by pivoting backwards against the magnetic attraction force of the solenoid 28 , as illustrated in fig6 -- the hooking portions 27 and 30 have rounded inter - engaging profiles to facilitate this action . when this happens , the hooking portion 30 will ride round the forthcoming hooking portion 27 and subsequently engage rigidly therewith when the hook 29 has eventually returned to its normal vertical position under the persistent magnetic attraction of the solenoid 28 . the solenoid attraction is sufficiently strong to hold the hook 29 in such a returned normal vertical position , against the action of the spring 22 acting indirectly upon the hook member 26 . throughout this engagement action , the inner slider 15 remains resting on the bottom flange 17 of the outer slider 16 . as a result , the hook member 26 on the outer slider 16 is at all time being held firmly in its rest angular position by the arm 20 of the inner slider 15 , as described above , and will therefore not disengage from the hook 29 . in the resulting condition , the outer slider 16 is held against the action of the spring 22 into a bottom position , as shown in fig1 a , 4a , 4b and 5a , through interengagement between the co - operating hooking portions 27 and 30 . the switching unit 14 is now referred to , which is arranged to control the supply of electrical power to the solenoid 28 as well as the heating elements . an integral y - shaped member 32 formed on the right side of the outer slider 16 provides one of the two parts of the switching unit 14 . the outer part is provided by a series of four upwardly - pointing and spaced - apart switch contacts , forming two adjacent pairs 33 and 34 . the series of switch contacts 33 and 34 is symmetrically aligned with the y - shaped member 32 above . when the y - shaped member 32 is moved downwards with the outer slider 16 , it will enter into the gap between the two inner switch contacts 33 and 34 and then urge them further apart and eventually against the corresponding two outer switch contacts 33 and 34 , thereby closing the two pairs of switch contacts 33 and 34 at the same time . this results in simultaneous switching - on of the heating elements and the solenoid 28 . referring finally to the timer , which is triggered to start running upon switching - on of the heating elements and the solenoid 28 . the timer then counts a pre - determined or selected period of time , and at the end of the counted time period operates automatically to cut off the power supply to the solenoid 28 by means of an electrical switch or switching arrangement ( not shown ). the timer can be either a mechanical wind - up spring timer or an electronic digital timer or the like , as in conventional toasters or other electrical appliances . as the core of the present invention does not reside in the construction and / or configuration of the timer , it will not be described in further detail here . in operation , a user is to move the bread carriage , supporting thereon one or two slices of bread , downwards by pressing on the handle bar 31 . as the handle bar 31 is secured to the inner slider 15 and the inner slider 15 is resting internally on the outer slider 16 , the outer slider 16 is moved downwards with the inner slider 15 remaining and being maintained in its rest position relative to the outer slider 16 . immediately before the outer slider 16 reaches its bottom position , the y - shaped member 32 comes into action and closes both switch contact pairs 33 and 34 , thereby switching on the heating elements and the solenoid 28 . when the outer slider 16 finally reaches its bottom position , the hook member 26 and the hook 29 then come into inter - engagement in order to hold the outer slider 16 in the bottom position and hence the bread carriage and in turn the bread slices wholly inside the toaster for treatment by the heating elements . at the same time , the timer is triggered . throughout this action , the inner slider 15 remains resting internally on the outer slider 16 , and is therefore holding the hook member 26 firmly in its rest angular position to maintain its engagement with the hook 29 . at the end of the toasting period , the electrical switch or switching arrangement controlled by the timer operates to cut off the power supply to the solenoid 28 . the hook 29 is thus released from the solenoid &# 39 ; s magnetic attraction , and consequently pivots backwards to give way to the hook member 26 . as a result , the outer slider 16 is released to return to its top position under the action of the spring 22 , carrying therewith the inner slider 15 , the bread carrier and the toasted bread slices . during bread toasting , it is sometimes necessary to stop the toaster to avoid over - heating caused by an excessively long timer setting , or in the interim to check the condition of the bread . with the use of a conventional toaster , this can be done by lifting the handle bar up to forcefully separate the internal movable assembly from the holding solenoid against magnetic attraction . this action often causes undesirable jerking of the toaster because the handle bar lifting force must overcome the solenoid &# 39 ; s magnetic attraction , and it is usually necessary for the user to hold the toaster body stable beforehand . with the use of the toaster of the subject invention , the premature or interim stopping of the toaster is done also by lifting the handle bar 31 upwards . but in this case , the upward movement of the handle bar 31 does not act against the magnetic attraction of the solenoid 28 , because the inner slider 15 connected to the handle bar 31 is not being physically held in position by the solenoid 28 . instead , the inner slider 15 is merely resting on the outer slider 16 under its own weight and the weight of the handle bar 31 , the bread carrier and the bread slices . when the inner slider 15 is lifted up , its arm 20 disengages vertically from the hook member 26 of the outer slider 16 . upon release , the hook member 26 instantly pivots downwards to disengage from the hook 29 and thus allow the outer slider 16 to carry the inner slider 15 , the bread carrier and the bread slices to move upwards under the action of the spring 22 . it is appreciated that the manual uplifting force acted upon the handle bar 31 needs only to overcome the combined weight of the inner slider 15 , the handle bar 31 , the bread carrier and the bread slices , which is considerably smaller than the magnetic attraction force of the solenoid 28 . accordingly , with the provision of a soft - touch release mechanism provided by the subject invention , it is not necessary for the user to hold the toaster body stable when the toaster is stopped in the middle of bread toasting . the invention has been given by way of example only , and various other modifications of and / or air & amp ; rations to the described embodiment may be made by persons skilled in the art without departing from the scope of the invention as specified in the appended claims .

US-51661995-A

an intravascular imaging guidewire which can accomplish longitudinal translation of an imaging plane allowing imaging of an axial length of a region of interest without moving the guidewire . the imaging guidewire comprises a body in the form of a flexible elongate tubular member . an elongate flexible imaging core is slidably received within the body . the imaging core includes a shaft having an imaging device mounted on its distal end . the body and the imaging core are cooperatively constructed to enable axial translation of the imaging core and imaging device relative to the body . the body has a transparent distal portion extending an axial length over which axially translatable imaging may be performed . the imaging guidewire has a maximum diameter over its entire length sized to be received within a guidewire lumen of an intravascular catheter .

referring to fig1 - 3 , an imaging guidewire 10 is depicted according to the present invention . in general , the guidewire 10 must be flexible enough to traverse a circuitous path through the vascular system , and yet have sufficient pushability to transmit a pushing force from a remote proximal end 12 of the guidewire 10 , along a winding path , to a distal end 14 of the guidewire 10 . the imaging guidewire 10 must also have sufficient torsional stiffness to reliably transmit rotational force applied at the proximal end 12 to the distal end 14 so that the guidewire 10 can be steered through the branches of vessels of the vascular system . the imaging guidewire 10 comprises a guidewire body 16 in the form of a flexible , elongate tubular member which slidably and rotatably houses an elongate , flexible , rotating imaging core 18 . the imaging guidewire 10 has a substantially uniform diameter and no component along the entire length of the guidewire 10 exceeds a predetermined diameter . this maximum diameter is preferably 0 . 035 &# 34 ; because guidewire lumens of typical catheter sized to be inserted into smaller vessels are sized to receive a guidewire having a maximum diameter of 0 . 035 &# 34 ;. the overall length of the guidewire 10 varies depending on the intended application but may preferably range between 40 cm and 300 cm . the guidewire body 16 includes a main body 20 having a proximal end 22 and a distal end 24 . the main body 20 extends from a connector 40 of the imaging core 18 at its proximal end 22 to a predetermined distance , preferably approximately 15 to 20 cm , from the distal end 14 of the guidewire 10 at its distal end 24 . the main body 20 is preferably formed of nitinol hypotube because it exhibits strength and flexibility properties desired in a guidewire body . nitinol is also preferred because it minimizes kinking , has a convenient transition temperature below which it transitions to a &# 34 ; soft &# 34 ; state , and is a memory metal such that it returns to its original shape after being bent under specific temperature conditions . those skilled in the art would appreciate that other materials including other superelastic materials , other metal alloys , and plastics may also be used . it is to be understood that where nitinol is specified as the preferred material , other materials , including alternative superelastic materials , metal alloy , and plastics may also be utilized . the nitinol main body 20 preferably has an outer diameter of approximately 0 . 035 &# 34 ;. an imaging portion 26 of the guidewire body 16 is connected to the distal end 24 of the main body 20 and extends to the distal end 14 of the guidewire body 16 . the imaging portion 26 is substantially transparent to imaging signals transmitted and / or received by an imaging device 42 of the imaging core 18 . in a preferred form , the imaging portion 26 is formed of a polyethylene plastic tube which is interference fit onto the distal end 24 of the main body 20 . alternatively , any other suitable attachment method may be employed such as adhesives , mechanical connectors , etc . a floppy tip 28 is placed inside , and at the distal end , of the imaging portion 26 . the floppy tip 28 provides a flexible tip to assist in maneuvering the imaging guidewire 10 through a patient &# 39 ; s vessels . the floppy tip 28 can be aimed in different directions by rotating the catheter or by actuating a steering mechanism ( not shown ). the floppy tip 28 is preferably formed from a flexible coil spring which is radiopaque so as to be visible under fluoroscopy . the floppy tip 28 is held in place by thermally forming the imaging portion 26 over the floppy tip 28 or alternatively using any other suitable attachment technique such as adhesives , press fit , connectors , fasteners , etc . in an alternative form , the guidewire 10 is constructed without the floppy tip 28 leaving the distal extremity greater flexibility . in this case , a radiopaque maker band is placed at the distal end of the imaging portion 26 . the imaging core 18 principally comprises a tubular drive shaft 44 having an imaging device 46 attached to a distal end of the drive shaft 44 and the connector 40 attached to a proximal end of the drive shaft 44 . the drive shaft 44 may be composed of a single tubular member ( not shown ), or preferably , it may be several elements attached together as shown in fig1 - 3 . a telescope portion 48 of the drive shaft 44 is preferably formed of a nitinol tube having an outer diameter of approximately 0 . 022 &# 34 ;. the telescope portion 48 acts as a telescoping extension of the drive shaft 44 and is of a length approximately the same as the desired length of axial translation of the imaging device 46 , preferably around 15 cm . the telescope portion 48 is connected to the connector 40 at its proximal end and extends distally to a distal end which is attached to a proximal end of a drive cable 50 . the drive cable 50 is preferably of a counterwound , multifilar coil construction as best shown in fig3 and described in u . s . pat . no . 4 , 951 , 677 , to crowley et al ., the disclosure of which is incorporated herein by reference . the telescope portion 48 is attached to the drive cable 50 using a coupler 52 . one end of the coupler 52 is attached to the telescope portion 48 using an interference fit . the interference fit may be accomplished by cooling the nitinol telescope portion 48 below its transition temperature such that it becomes soft . the coupler 52 is then slid onto the telescope portion 48 and when warmed above the transition temperature , a secure interference fit results . the other end of the coupler 52 is attached to the drive cable 50 , preferably using an adhesive , although any suitable attachment means is contemplated . the coupler 52 also functions as a stop which interferes with a stop collar 46 attached to the inside of the proximal end 22 of the main body 20 which limits the proximal axial translation of the imaging core 18 relative to the guidewire body 16 . the stop collar 46 may also be interference fit into the nitinol main body 20 using the same method just described for attaching the coupler 52 to the telescope portion 48 . the imaging device 46 is attached to the distal end of the drive cable 50 . the imaging device 46 may be any type device which creates a high quality imaging signal of the body tissue to be imaged , but is preferably an ultrasound imaging device . the imaging device 46 includes a housing into which an ultrasound transducer 56 is mounted . the design , construction and use of ultrasound imaging devices is generally known in the art and therefore a detailed description is not included herein . the ultrasound transducer 56 is oriented to image in a radially outward direction and when rotated with the drive shaft 44 creates a 360 degree radial scan of the surrounding tissue . alternatively , the ultrasound transducer 56 may be oriented such that it images in a forward looking or backward looking direction or any angle in between . to transmit the imaging signal from the imaging device 46 to the connector 40 , a coaxial cable 58 is attached to the imaging device 42 which runs down the center of the drive shaft 44 where the other end of the coaxial cable 58 is attached to the connector 40 . the connector 40 detachably connects to a drive unit ( not shown ) and / or imaging signal processing equipment ( not shown ). turning now to fig2 the innovative connector 40 will be described in detail . overall , the connector 40 is cylindrically shaped and has a maximum diameter not exceeding the diameter of the remainder of the guidewire 10 , which is preferably 0 . 035 &# 34 ; in diameter . the distal end of the connector 40 is composed of a conductive ring 60 which is attached to the proximal end of the telescope portion 48 by an interference fit as shown , or by any other suitable attachment method . the conductive ring 60 is filled with conductive epoxy 62 through a fill hole 80 to cover the outer lead 64 of the coaxial cable 58 thereby electrically connecting the conductive ring 60 to the outer lead 64 and completing one pole of the imaging device 42 circuit . the conductive ring 60 may have a second hole 82 to observe the amount of epoxy being inserted to ensure that it does not overfill and electrically connect to a second conductor 66 . the second conductor 66 has a stepped tubular section 70 and a ball - shaped end 72 . the stepped tubular section 70 is covered with an insulator 74 such as a piece of shrink tubing . the stepped tubular section 70 covered with the insulator 74 inserts into the conductive ring 60 and is bonded in place using an adhesive such as cyanoacrylate . the insulator 74 electrically insulates the conductive ring 60 from the second conductor 66 . the inner lead 68 and insulation 76 of the coaxial cable 58 extend through the first conductive epoxy 62 and through the stepped tubular section 70 . the inner lead 68 further extends into a cavity in the ball - shaped end 72 . the cavity in the ball - shaped end 72 is filled with a second conductive epoxy 78 to conductively connect the second conductor 66 to the inner lead 68 completing the other pole of the imaging device 42 circuit . hence , connector 40 provides a detachable electrical and mechanical attachment to the drive unit ( not shown ) which rotates the imaging core 18 and to the signal processing electronics ( not shown ). the detachability feature allows the guidewire 10 to be quickly and easily disconnected so that catheters may be inserted over the guidewire 10 and , then just as easily , the guidewire 10 can be reconnected . the imaging core 18 is slidably and rotatably received within the guidewire body 16 such that the imaging core 18 may be axially translated relative to the guidewire . in this way , the imaging device 42 can be axially translated along the imaging portion 26 of the guidewire body 16 thereby enabling imaging along an axial length of a region of tissue without moving the guidewire body 16 . hence , the proper positioning of the guidewire 10 within the patient &# 39 ; s body is maintained so that it may effectively serve as a guidewire for the insertion of catheters . an alternative embodiment of an imaging guidewire 90 is shown in fig4 - 5 . the imaging guidewire 90 is similar to , and includes many of the features and elements as , the imaging guidewire 10 described above . throughout the description and figures , like reference numerals refer to like elements and therefore , some elements are not explicitly described for all figures . the main differences of the imaging guidewire 90 are the use of a single polymer sheath 94 for the guidewire body 92 , and a modified imaging core 96 . the guidewire body 92 is formed of a single piece polymer sheath 94 having a proximal end 98 and a distal end 100 . preferred polymer sheath materials include polyimide and peek . the sheath 94 extends from the connector 40 to the distal end of the guidewire 90 . a nonrotating union collar 104 may be inserted between the rotatable connector 40 and the nonrotating sheath 94 to limit wear of the polymer sheath at the intersection between the connector 40 and the sheath 94 . the imaging core 96 comprises a drive cable 102 having the imaging device 42 attached to its distal end and the connector 40 attached to its proximal end . the drive cable 102 is preferably a counterwound , multifilar coil as described above . a stiffening sleeve 106 preferably formed of a flexible tube such as a nitinol tube , is disposed between the drive cable 102 and the sheath 94 . the polymer sheath 94 may not provide sufficient rigidity and pushability to the guidewire and therefore , the stiffening sleeve 106 gives the guidewire these properties . the stiffening sleeve 106 is received into the union collar 104 and extends distally to the imaging device 42 . in an alternative form , the stiffening sleeve 106 could extend distally to a predetermined distance short of the imaging device 42 , preferably about 15 cm short . the stiffening sleeve 106 preferably does not rotate with the drive cable 102 . the method of using the imaging guidewire 90 is virtually identical to that described above for imaging guidewire 10 . fig6 - 7 show an imaging guidewire 10 having an improvement in the transition from the stiffer main body 20 of the guidewire body 16 to the softer , more pliable imaging portion 26 according to the present invention . a relatively large difference in the stiffness of the main body 20 and the imaging portion 26 can create a stress riser at the connection point which tends to cause the more flexible imaging portion 26 to bend sharply and / or kink when the guidewire is routed through small radius paths . to relieve this condition , instead of bonding the imaging portion 26 directly to the main body 20 as described above , a graduated transition 120 comprising a short transition tube 108 is attached to the distal end 24 of the main body 20 and the imaging portion 26 is attached to the other end of the transition tube 108 . the transition tube is made of a material , and is configured , such that it has a stiffness between that of the main body 20 and the imaging portion 26 . fig8 - 9 show an alternative configuration for the graduated transition 120 between the main body 20 and the imaging portion 26 similar to that described with respect to fig6 - 7 , except that the distal end of the transition tube 110 is left free . the outer diameter of the main body 20 is reduced from that described above to accommodate a full length jacket 112 comprising a thin layer of plastic , preferably polyethylene , to be formed over the entire length of the main body 20 . the preferred reduced thickness of the main body 20 is preferably about 0 . 032 &# 34 ; corresponding to a jacket 110 thickness of about 0 . 003 &# 34 ;. the imaging portion 26 and the jacket 112 may be formed from a single varying thickness piece of material . in this configuration , the transition tube 110 is similar in construction and materials to the transition tube 108 described above . another variation of a graduated transition 120 between the main body 20 and the imaging portion 26 is shown in fig1 - 11 . the imaging guidewire 10 of fig1 - 11 is identical to that shown in fig1 - 3 except that the distal end 24 of the main body 20 is constructed in a spiral form 114 with increasing pitch as it extends distally . then , the imaging portion 26 extends over the spiral form 114 . the spiral form 114 creates a more flexible portion of the main body 20 which performs the graduated transition function similar the that described above . fig1 - 13 depict yet another embodiment of an imaging guidewire 10 having a graduated transition 120 . the imaging guidewire 10 of fig1 - 13 is identical to that of fig1 - 11 except that the spiral form 114 is replaced with a tapered finger section 116 . still another embodiment of graduated transition 120 on an imaging guidewire 10 is shown in fig1 - 15 . in this embodiment , a reinforcing braided section 118 is placed over the connection between the imaging portion 26 and the main body 20 . the braided section 118 may be made of plastic such as polyethylene , co - extruded polymer materials , or any other suitable material . the braided section 118 performs similarly to the graduated transitions described above . except for the varying graduated transition configurations of the guidewire body 16 , the imaging guidewires 10 of fig6 - 15 are identical to the imaging guidewire described for fig1 - 3 . in addition , the method of using the imaging guidewires is the same as previously described . thus , the reader will see that the present invention provides an improved imaging guidewire . while the above description contains many specifics , these should not be construed as limitations on the scope of the invention , but rather as an examples of particular embodiments thereof . many other variations are possible . accordingly , the scope of the present invention should be determined not by the embodiments illustrated above , but rather , the invention is to cover all modifications , alternatives and legal equivalents falling within the spirit and scope of the appended claims .

US-93931597-A

a depth control system particularly useful for single point depth control on an agricultural implement includes a valve and actuator mounted directly to the pivotal connection areas of a hydraulic cylinder that controls height . cylinder motion directly controls valve actuation independently of complicated linkages to reduce the size and cost of the system and substantially overcome hysteresis problems .

referring now to fig1 and 2 , therein is shown a portion of an agricultural implement 10 having a tool - supporting frame 12 supported for forward movement over a field by lift wheel structure 16 . hydraulic cylinder structure 20 is connected through a lift linkage 22 to the wheel structure 16 to selectively raise and lower the frame 12 . tools ( not shown ) can be mounted on the frame for vertical movement therewith between field - working and transport positions . depth control for soil engaging elements is provided by the vertical movement of the frame 12 . a rockshaft 24 extending transversely to the forward direction of the travel of the implement is rotatably mounted on the frame 12 by bearing block support structure 26 . a lever or arm 28 is fixed to and extends upwardly from the rockshaft 24 closely adjacent the support structure 26 for rotation with the rockshaft about a transversely extending axis . the lift linkage 22 includes a tension link 32 pivotally connected at a forward end 34 to the arm 28 . the link 32 includes an aft end 36 pivotally connected to an upright arm 38 on the wheel structure 16 . as the forward end 34 of the link 32 is moved in the fore - and - aft direction , the wheel structure 16 is pivoted relative to the frame 12 to raise and lower the frame . the cylinder 20 includes a rod end 40 pivotally connected by elongated cylinder pin structure 42 to the rockshaft arm 28 rearwardly and below the pivotal connection at the forward end 34 to the arm 28 . the cylinder 20 includes a base end 44 pivotally connected by a second elongated cylinder pin structure 46 to an aft end of a cylinder support bracket structure 48 . the cylinder support bracket 48 includes an angle support 50 having a forward end connected to the bearing block support structure 26 . the aft end of bracket 48 is connected by a u - bolt assembly 52 to a transversely extending frame tube 12 t . the rod and base ends of the cylinder 20 are connected by hydraulic lines 56 and 58 , respectively , to a controlled source of hydraulic fluid for extending and retracting the cylinder . the base end line 58 is connected to a lower output port on a control valve 60 which is mounted directly on the rod end cylinder pin structure 42 . the control valve 60 includes a forwardly directed inlet port connected through a manual lock - up valve 66 and fluid line 68 to a controlled source of hydraulic fluid on the towing vehicle ( not shown ). the control valve 60 includes an outwardly biased valve actuator 70 , which when in the position shown in fig2 allows generally unrestricted flow between the base end of the cylinder 20 and the source . the actuator 70 , when depressed against the bias , blocks flow between the cylinder 20 and the source . the valve 66 is normally open during field operations but can be closed to lock the cylinder 20 in a selected position such as the extended position during transport of the implement 10 . valve actuator structure 80 is supported from the rod and base ends 40 and 44 of the cylinder 20 and includes a tube or guide 82 slidably received through mating apertures in the cylinder pin structures 42 and 46 . a spring 84 is captured on the base end of the guide 82 between pin and washer structure 86 and the pin structure 46 , and an aft end pin 88 prevents the guide 82 from sliding forwardly out from the aperture in the pin structure 46 . the forward end of the guide 82 extends through and freely slides within the aperture in the rod end pin structure 42 while the base end of the guide normally remains fixed relative to the base end pin structure 46 . in case of binding , over - retraction of the cylinder 20 or improper adjustment of the actuator structure 80 , the spring 84 can compress to allow the guide 82 to slide rearwardly relative to the pin structure 46 to prevent bending or breaking of the actuator structure 80 . the actuator structure 80 includes a plate or contact member 90 slidably supported on the guide 82 . an adjustment rod 94 is rotatably supported from the guide 82 by a forward rod bracket 96 and an aft rod bracket 98 below and parallel to the guide 82 . the guide 82 is supported generally parallel to cylinder axis 20 a and remains parallel to the cylinder axis with extension and retraction of the cylinder . the rod 94 has a threaded central portion received through a threaded aperture at the lower end of the contact member 90 . by rotating the rod 94 , the contact member 90 can be adjustably positioned along a central portion of the guide 82 . indices 102 are provided along the central portion to provide the operator with a visual indication of the adjusted position of the contact member 90 . as the cylinder 20 is retracted by opening the hydraulic line 68 to reservoir , the frame 12 lowers . the valve 60 moves with the rod end pivot structure 42 rearwardly relative to the contact member 90 as the forward end of the guide slides through the pin structure 42 . the valve 60 and contact member 90 converge generally along a straight path parallel to the cylinder axis 20 a until the member 90 depresses the valve actuator 70 and blocks flow from the base end of the cylinder 20 through the line 58 to establish an adjusted frame position dependent on the adjusted position of the contact member 90 along the guide 82 . to raise the frame , the operator pressurizes the line 68 using a control valve on the towing vehicle and a one - way check valve ( not shown ) in the valve 60 allows hydraulic fluid to enter the base end of the cylinder 20 to extend the cylinder rod and raise the frame . having described the preferred embodiment , it will become apparent that various modifications can be made without departing from the scope of the invention as defined in the accompanying claims .

US-28144302-A

an elongate access sheath comprises a proximal portion and a lumen . the proximal portion supports a control handle , a brake pad , a tension gear , and a locking trigger . a deflector filament extends through the lumen and is coupled to the tension gear . the tension gear includes an outside and an inner engagement portion . the brake pad comprises a slot and an outside engagement portion . the locking trigger includes a pin disposed within the brake pad slot . the control handle includes a lever and an engagement portion . upward movement of the lever engages the engagement portion with the outside engagement portion of the tension gear to rotate the tension gear in a first direction and slides the deflector filament to bend the lumen distal portion . translation of the locking trigger engages the brake pad and the tension gear to prevent rotation of the tension gear in an opposite second direction .

the embodiments described in this disclosure will be discussed generally in relation to the use of deflectable sheaths in the manipulation and guidance of operating and imaging tools in urological procedures such as lithotripsy , but the disclosure is not so limited and may be applied to the use of other deflectable medical devices in procedures in other vasculature or other body vessels or lumens . in the present application , the term “ proximal ” refers to a direction that is generally closest to the operator of the device during a medical procedure , while the term “ distal ” refers to a direction that is furthest from the operator of the device . the present deflectable access sheath operates to allow the controlled deflection of the distal end of the deflectable access sheath away from a linear conformation . in particular , the deflectable access sheath may provide for a locking mechanism that locks the angle of the deflectable end of the deflectable access sheath . this locking mechanism allows for better control and use of the device during the procedure and allows the user to perform various other procedures during the ureteroscopy . the locking mechanism can be released to allow for the increased deflection of the deflectable end or for the deflectable end to return to a linear conformation . the deflectable access sheath may further allow the deflection of the deflectable end while the deflectable access sheath is in a locked position . in one example , a ratcheting mechanism allows the incremental deflection of the deflectable end . each incremental deflection is locked into place by the locking mechanism . this ratchet aspect allows the user on - the - spot modification of the deflection angle of the deflectable end . once the desired angle of the distal end of the deflectable access sheath is achieved , accessories and / or other medical devices , such as laser fibers , optical fibers , wire guides , stone - breakers , and / or stone removal tools , can be inserted through the working channel and used for that particular procedure . the present device provides a handle design that allows the user to access the sheath closer to hip - level which allows the user to transfer more torque to twist the device and grip power to actuate the device . this results in less fatigue of the user . the handle design of the present device is more fully described with reference to u . s . application serial no . 29 / 461 , 908 ( filed jul . 29 , 2013 ) and commonly assigned to the assignee of this application , which is hereby incorporated by reference in its entirety . as described more fully below with regard to fig1 - 3 , the sheath handle assembly 100 has a control handle 120 that accomplishes the above functions . the sheath handle assembly 100 is composed of four main parts — a sheath housing 110 , a control handle 120 , a locking trigger 150 and a gear locking system 160 that is composed of a tension gear 130 and a brake pad 140 . in operation , the sheath housing 110 is held by the user and the control handle 120 is compressed in an upward direction . this upward compression translates into a clockwise rotational movement of the tension gear 130 . the movement of the tension gear 130 translates into the longitudinal movement of the tension wire 170 which causes deflection of the distal end of the sheath handle assembly 100 ( not pictured here ). the locking trigger 150 is actuated by a downward movement that engages the gear locking system 160 . this engagement brings the outer teeth of the brake pad 140 in contact with the inner teeth of the tension gear 130 . subsequent compression of the control handle 120 results in the incremental movement of the tension wire 170 as defined by the inner teeth of the tension gear 130 . this provides for incremental adjustment of the deflection of the distal end of the sheath handle assembly 100 ( not pictured here ), while preventing the return of the distal end to a linear configuration . fig1 - 3 illustrate an embodiment of the sheath handle assembly 100 . fig4 - 7 illustrate components of an embodiment of the sheath handle assembly 100 . fig8 a - b illustrate the sheath handle assembly 100 as it is operated by a user to deflect the distal end of the sheath handle assembly 100 . fig9 - 11 illustrate the sheath handle assembly 100 as the gear locking system 160 is actuated . fig1 a - b illustrate an alternative embodiment of the gear locking system 160 of fig1 . fig1 a - b show the multiple components of the sheath handle assembly 100 as they are interconnected . fig1 a provides a proximal view of the sheath handle assembly 100 with sheath housing 110 , control handle 120 , and a portion of the locking trigger 150 . connected to the distal end of the sheath handle assembly 100 is a lumen with a deflectable end ( not pictured here ) that will be further discussed in fig8 a - b . fig1 b shows a cross - sectional view of the sheath handle assembly 100 that includes a sheath housing 110 , a control handle 120 , a gear locking system 160 which is made up of the tension gear 130 and the brake pad 140 , a locking trigger 150 , and a tension wire 170 . each of the individual components of the sheath handle assembly 100 will be described in further detail below . fig2 a - b provide enlarged cross - sectional views of the locking mechanism 200 of the sheath handle assembly 100 and the interconnections of the various components of the sheath handle assembly 100 . the locking mechanism 200 includes the control handle 120 , the gear locking system 160 which is made up of the tension gear 130 , the brake pad 140 , and the locking trigger 150 . fig3 provides a cross - sectional view of the sheath housing 110 with receptors built into the inside of the sheath housing 110 to provide for the containment and controlled movement of the various components in the sheath handle assembly 100 as described in fig1 - 2 . the control handle 120 is rotatably connected to the sheath housing 110 through a pin that is inserted through the control handle 120 and fits into the handle slot 310 . the pin connected through the handle slot 310 allows the control handle 120 rotational movement about the pin . the movement of the control handle 120 is further controlled by a pin that fits into handle movement slot 320 of the sheath housing 110 , described in further detail below . the locking trigger 150 and the tension gear 130 is rotatably connected to the sheath housing 110 by a pin that is connected through the slot 330 of the sheath housing 110 . as will be described in further detail , the pin at slot 330 fits through the tension gear locking trigger 150 which is disposed about the tension gear 130 . the brake pad 140 is connected to the sheath housing 110 through a pin that is rotatably connected to the sheath housing 110 through a pin that is inserted through the brake pad 140 and fits into the brake slot 340 of the sheath housing 110 . the pin connected through the brake slot 340 allows the brake slot 340 rotational movement about the pin . as will be discussed further , movement of the locking trigger 150 rotates the brake pad 140 to bring it in contact with tension gear 130 . the sheath housing 110 of fig3 also provides for other connections that allows for the actuation of the locking trigger 150 . the actuating braking slot 360 provides for the protrusion of the locking mechanism actuator ( not pictured here ) to protrude from the sheath housing 110 so that it is visible to the user . the distal end of the locking trigger 150 fits into the locking trigger indicator slot 350 which limits the extent of the movement of the distal end of the locking trigger 150 . the locking trigger pin indicator 380 allows for the distal end of the locking trigger indicator slot 350 to be visible when the locking trigger 150 is actuated . the locking trigger 150 is prevented from moving by the locking trigger protrusion 370 which keeps the proximal end of the locking trigger 150 in either the non - actuated or actuated position . fig4 - 7 illustrate the individual components of an embodiment of the sheath handle assembly 100 . fig4 a - b provide a side and perspective view of the tension gear 130 of the gear locking system 160 of fig1 b and 2 a - b . in the present embodiment , the tension gear 130 has an outer surface 420 and an inner surface 410 . the tension gear 130 is rotatably connected to the sheath housing 110 through the opening 405 which is disposed about a pin that is connected to slot 330 of fig3 . the outer surface 420 includes an outer engagement portion 470 and a portion for engaging the tension wire 170 of fig1 b . the outer engagement portion 470 is comprised of more than one tooth 440 and more than one tooth receiving end 445 . this outer engagement portion 470 engages a series of teeth on a portion of the control handle 120 which cause the outer engagement portion 470 to rotate when the control handle 120 is actuated . the outer surface 420 also includes a filament anchor 430 which protrudes from the outer surface 420 . the tension wire 170 of fig1 b is attached to the filament anchor 430 at the filament connection 480 and rests in the filament receptor 490 . the filament receptor 490 is disposed between the filament anchor 430 and one end of the outer engagement portion 470 . the length of the filament receptor 490 is at least equal to the length of the tension wire 170 needed to cause the maximum deflection of the lumen . the inner surface 410 has an inner engagement portion 460 that is composed of teeth to engage the teeth portion of the brake pad 140 shown in fig5 a - b . the inner engagement portion 460 includes more than one sawtooth 450 and more than one sawtooth receiving end 455 . as will be discussed below , when the inner engagement portion 460 is engaged , a ratcheting device is created . the shape of the sawtooth 450 and the sawtooth receiving end 455 , provide for movement in a single direction and restricts movement in a counterclockwise direction at each sawtooth 450 . fig5 a - b provide a side and perspective view of the brake pad 140 of the gear locking system 160 of fig1 b and 2 a - b . in the present embodiment , the brake pad 140 has an outer surface 510 and two points of connection to the sheath housing 110 — an opening 520 and a slot portion 530 that define and restrict the movement of the brake pad 140 . the brake pad 140 is rotatably connected to the sheath housing 110 through the opening 520 which is disposed about a pin that can be fit into the brake slot 340 . as will be further described below , the slot portion 530 is disposed about a pin that fits into the locking trigger 150 . when the locking trigger 150 is actuated in either an upward or downward direction , the brake pad 140 is rotated a limited distance as defined by the slot portion 530 . the outer surface 510 of the brake pad 140 includes a ratchet portion 540 for engaging the inner engagement portion 460 of the tension gear 130 . the ratchet portion 540 is comprised of more than one tooth 550 and more than one tooth receiving end 560 . as described above , the shape of the tooth 550 and the tooth receiving end 560 act as a ratchet against the inner surface 410 of the brake pad 140 . when the ratchet portion 540 of the brake pad 140 is brought into contact with the inner surface 410 of the tension gear 130 , the tension gear 130 is allowed to move in a single direction , but the tooth 550 and the tooth receiving end 560 interact with the sawtooth 450 and sawtooth receiving end 455 of the tension gear 130 to prevent movement of the tension gear 130 in a counterclockwise direction at each sawtooth 450 and sawtooth receiving end 455 of the tension gear 130 . fig6 a - b provide a side and perspective view of the control handle 120 of fig1 b and 2 a - b . in the present embodiment , the control handle 120 has a lever portion 650 , an engagement portion 620 on the outer surface 610 and two points of connection to the sheath housing 110 — an opening 660 and a slot portion 670 that define and restrict the movement of the control handle 120 . the control handle 120 is rotatably connected to the sheath housing 110 through the opening 660 which is disposed about a pin that can fit into the handle slot 310 . the range of movement of the control handle 120 is limited by the slot portion 670 . a pin fits into the handle movement slot 320 of the sheath housing 110 and the slot portion 670 is disposed about this pin . when the lever portion 650 of the control handle 120 is pulled in an upward direction , the rotational movement of the control handle 120 is limited by the length of the slot portion 670 . any or all embodiments of the lever portion 650 may be provided with gripping features that provide secure and / or ergonomic gripping of the handles by the user . any or all of the handles may further be provided with a mechanism or ability to provide the user with tactile feedback while gripping and / or operating the handle . the engagement portion 620 lies on the outer surface 610 of the control handle 120 . engagement portion 620 is composed of more than one input tooth 630 and more than one input tooth receiving end 640 . as will be discussed , the input tooth 630 and the input tooth receiving end 640 of the engagement portion 620 interact with the more than one tooth 440 and more than one tooth receiving end 445 of the outer engagement portion 470 of the tension gear 130 to cause the tension gear 130 to rotate . when the gear locking system 160 is not engaged , actuating of the lever portion 650 causes the engagement portion 620 of the control handle 120 to interact with the outer engagement portion 470 of the tension gear 130 and rotation of the tension gear 130 in a clockwise direction when the lever portion 650 is compressed upwards and rotation of the tension gear 130 in a counterclockwise direction when the lever portion 650 is released . fig7 a - 7 b provide a side and perspective view of the locking trigger 150 . in the present embodiment , the locking trigger 150 is composed of elements that control the movement of the locking trigger 150 and elements that actuate the gear locking system 160 . the locking trigger 150 has a locking mechanism actuator 710 , a tension gear engagement slot 720 , a brake pad engagement slot 730 , a locking trigger movement pin 740 and a distal pin 750 . the locking trigger 150 is rotatably connected to the sheath housing 110 through the tension gear engagement slot 720 which is disposed about a pin that connects to the slot 330 of the sheath housing 110 . the locking trigger 150 is disposed about the tension gear 130 such that the pin that fits into slot 330 of the sheath housing 110 fits through both the tension gear engagement slot 720 and the opening 405 of tension gear 130 . the brake pad engagement slot 730 is operatively connected to the brake pad 140 by a pin that extends through the slot portion 530 of the brake pad 140 . the pin is connected on either end to the brake pad engagement slot 730 of the locking trigger 150 . the locking mechanism actuator 710 provides the user with control of the movement of the locking trigger 150 and the engagement of the gear locking system 160 . the locking mechanism actuator 710 protrudes from the sheath housing 110 at the actuating braking slot 360 to allow the user to actuate the locking mechanism actuator 710 in the actuating braking slot 360 . before the gear locking system 160 is engaged , the pin connected to the brake pad engagement slot 730 is adjacent to the slot top portion 532 of the brake pad 140 . the user can engage the gear locking system 160 by actuating the locking mechanism actuator 710 which moves the locking trigger 150 so that the pin connected to the brake pad engagement slot 730 is now adjacent to the slot bottom portion 534 of the brake pad 140 . the movement brings the brake pad 140 in contact with the tension gear 130 . as discussed above , this engages the gear locking system 160 and creates a ratcheting movement . the brake pad 140 allows movement of the tension gear 130 in a clockwise direction , but prevents the tension gear 130 from moving in a counterclockwise direction . as will be discussed below , when the gear locking system 160 is engaged , subsequent movement in a clockwise direction is limited in increments by the sawtooth 450 on the tension gear 130 . the locking trigger 150 is prevented from moving — whether in its actuated state or non - actuated state — by the locking trigger protrusion 370 of fig3 . when the locking mechanism actuator 710 is actuated to engage or disengage the gear locking system 160 , the locking trigger movement pin 740 moves above and below either end of the locking trigger protrusion 370 of fig3 which protrudes above the surface of the sheath housing 110 . this protrusion prevents the locking trigger movement pin 740 from migrating , and therefore keeps the gear locking system 160 from unintentionally engaging or disengaging . the distal end of the locking trigger 150 and the distal pin 750 is housed in the locking trigger indicator slot 350 of the sheath housing 110 . when the locking mechanism actuator 710 has been actuated to engage the gear locking system 160 , the distal pin 750 moves so that it rests in the locking trigger pin indicator 380 of the sheath housing 110 . the locking trigger pin indicator 380 is an opening in the sheath housing 110 that allows the distal pin 750 to be visible from outside the sheath housing 110 . when the locking mechanism actuator 710 has been actuated to engage the gear locking system 160 , the visibility of the distal pin 750 at the locking trigger pin indicator 380 provides the user with a visual cue that the gear locking system 160 has been engaged . the sheath handle assembly 100 functions to deflect the distal end of the lumen attached to the distal end of the sheath handle assembly 100 . fig8 a - 8 b illustrate the lumen 820 and the deflectable end 810 as it is deflected away from a linear position . as seen in fig8 a , the control handle 120 can be compressed to bring it closer to the body of the sheath housing 110 . the engagement portion 620 of the control handle 120 interacts with the outer engagement portion 470 of the tension gear 130 to turn the tension gear 130 in a clockwise direction . the proximal end of the tension wire 170 is attached to the filament anchor 430 of the tension gear 130 and the distal end of the tension wire 170 is attached to the lumen 820 . as the tension gear 130 moves in a clockwise direction , the tension wire 170 moves in a proximal direction which causes the deflectable end 810 to deflect away from the linear configuration . as seen in fig8 b , the deflectable end 810 can deflect in a single direction away from the linear configuration . when the control handle 120 is released so that it moves in a direction away from the sheath housing 110 , the tension gear 130 moves in a counterclockwise direction . the attached tension wire 170 then moves in a distal direction which causes the deflectable end 810 of the lumen 820 to return to a linear configuration . the angle of deflection of the deflectable end 810 can be held in place , or adjusted in increments by engaging the gear locking system 160 . fig9 - 11 illustrate the sheath handle assembly 100 as the gear locking system 160 is engaged . fig9 a illustrates a cross - section of the sheath handle assembly 100 before the gear locking system 160 is engaged . as can be seen , before the gear locking system 160 is engaged , the pin in the brake pad engagement slot 730 of the locking trigger 150 is located adjacent to the slot top portion 532 of the slot portion 530 of the brake pad 140 . in this configuration , the ratchet portion 540 of the brake pad 140 has not engaged the inner engagement portion 460 of the tension gear 130 . this allows the control handle 120 to move freely in either direction — to turn the tension gear 130 in a clockwise or a counterclockwise direction ( depending on whether the control handle 120 is being compressed or released ). this movement slides the tension wire 170 in either a proximal or distal direction to cause the deflectable end 810 of the lumen 820 of fig8 b to either deflect away from linear or to return to its linear configuration . fig9 b illustrates a cross - section of the sheath handle assembly 100 after the gear locking system 160 is engaged . the locking mechanism actuator 710 is actuated in a downward direction . this movement causes the pin in the brake pad engagement slot 730 to move downward so that it lies adjacent to the slot bottom portion 534 of the slot portion 530 of the brake pad 140 . this causes the brake pad 140 to rotate about the pin in the opening 520 so that the ratchet portion 540 of the brake pad 140 is brought in contact with the inner engagement portion 460 of the tension gear 130 . the distal pin 750 moves upward so that it comes in contact with the locking trigger pin indicator 380 . as mentioned above , this serves as an indicator to the user that the gear locking system 160 is engaged . the distal pin 750 may be colored differently than the sheath housing 110 or have some marking to provide a visual indicator to the user . the locking trigger movement pin 740 interlocks with the locking trigger protrusion 370 to prevent unintentional movement of the locking trigger 150 . the locking trigger protrusion 370 is sloped to allow sliding of the locking trigger movement pin 740 into either configuration . however , without external force , the locking trigger movement pin 740 cannot move into another configuration . when the gear locking system 160 is engaged , the shape of the teeth on the inner engagement portion 460 of the tension gear 130 and the teeth on the ratchet portion 540 of the brake pad 140 are sloped in a direction that prevent movement of the tension gear 130 in a counterclockwise direction . however , because of the sloped direction of the teeth , the control handle 120 can still be incrementally compressed to allow movement of the tension gear 130 in a clockwise direction . the angle of deflection of the deflectable end 810 can be secured at each increment on the inner engagement portion 460 as represented by each individual sawtooth 450 . when the gear locking system 160 is disengaged , the locking mechanism actuator 710 is actuated in a upward direction which causes the pin in the brake pad engagement slot 730 to move upward so that it lies adjacent to the slot top portion 532 of the slot portion 530 of the brake pad 140 . when the gear locking system 160 is disengaged , the angle of deflection of the deflectable end 810 is no longer maintained and the control handle 120 is able to move freely . the tension gear 130 is able to move in both a clockwise and counterclockwise direction to either deflect the deflectable end 810 of the lumen 820 or to return the deflectable end 810 back into a linear configuration . fig1 provides an enlarged side view of the gear locking system 160 when it is engaged and the ratchet portion 540 of the brake pad 140 is in contact with the inner engagement portion 460 of the tension gear 130 . fig1 a - b provide a partial side view of the sheath handle assembly 100 before and after the gear locking system 160 has been engaged . fig1 a shows the locking mechanism actuator 710 of the locking trigger 150 positioned within the actuating braking slot 360 before the gear locking system 160 is engaged . fig1 b shows the locking mechanism actuator 710 of the locking trigger 150 within the actuating braking slot 360 after the gear locking system 160 is engaged . fig1 a - b also show the locking trigger pin indicator 380 which is visible to the user to indicate whether the gear locking system 160 is engaged . fig1 a - b provide a side view and a partial bottom view ( wherein the friction tension gear 1210 is transparent for better viewing ) of an alternate embodiment of the gear locking system 160 . the friction gear locking system 1200 of fig1 a and b is the same as the gear locking system 160 except the friction tension gear 1210 does not have any teeth on the surface of its inner surface 1220 and the friction brake pad 1250 does not have any teeth to engage the friction tension gear 1210 on its outer surface 1260 . the friction tension gear 1210 has all the features of the tension gear 130 except for the inner engagement portion 460 of fig4 a - b . the friction tension gear 1210 pictured in fig1 a - b has an inner surface 1220 and an outer surface 1230 . the inner surface 1220 has a filament receptor 1280 that the tension wire 170 of fig1 b rests upon . the outer surface 1230 has a chamfered edge 1240 that provides the friction tension gear 1210 with a better grip of the friction brake pad 1250 that it interacts with . the friction brake pad 1250 has all the features of the tension gear 130 except it lacks the ratchet portion 540 of fig5 a - b . the friction brake pad 1250 pictured in fig1 a - b has an outer surface 1260 with a friction pad 1270 disposed partially over the outer surface 1260 . the friction pad 1270 may be composed of any soft elastomeric material such as rubber , polyisoprene , or thermoelastomers . the friction gear locking system 1200 has the same function as the gear locking system 160 except that , in place of teeth , when the friction gear locking system 1200 is engaged , the friction pad 1270 of the outer surface 1260 is brought in contact with the chamfered edge 1240 of the inner surface 1220 of the friction tension gear 1210 . the friction force between the friction pad 1270 of the friction brake pad 1250 and the chamfered edge 1240 of the friction tension gear 1210 prevents the friction tension gear 1210 from moving in a counterclockwise direction . this embodiment does not have the discrete increments of the gear locking system 160 and therefore does not offer ratcheting . however , it provides for greater flexibility in controlling the deflectable end 810 of the lumen 820 . while particular elements , embodiments , and applications of the present invention have been shown and described , it is understood that the invention is not limited thereto because modifications may be made by those skilled in the art , particularly in light of the foregoing teaching . it is therefore contemplated by the appended claims to cover such modifications and incorporate those features which come within the spirit and scope of the invention .

US-201414520448-A

a training device for skiers includes an inverted v - shaped support defining an apex . one leg is rotatable about an upwardly inclined axis along a first angle and the other leg extends at a different angle from the apex . the free end of the other leg supports a platform for supporting the skier &# 39 ; s feet . the other leg together with the platform swing in pendulum fashion about the apex and seek an equilibrium position under the action of gravity when the skier is not on the platform .

fig1 shows a device 1 for simulating the movements and forces occurring in connection with alpine skiing . this device comprises a frame 2 to be placed on the floor . the frame 2 may be replaced by a plate , or it can be coupled with a plate by means of lugs 3 having screw holes formed therethrough . such a plate can have a larger width and contribute to the stability of the device . the device also comprises a carrying member 4 in the form of a plate on which a user places his feet . the carrying member is movable to and fro between two extreme positions in a path determined by guiding means described hereinafter , the carrying member being coupled with the frame 2 by means of the guiding means . a frame plate 5 is fixed to the frame and supports two rotation bearings 6 at a first angle relative to the frame . in a simpler embodiment , the bearing means may comprise a sleeve - bearing having a nylon lining as the bearing element . bearings 6 rotatably carry a first support shaft part 7 which supports a second support shaft part 8 at a second angle relative to the frame . the second support shaft part carries at its free end a nylon bearing sleeve 9 cooperating with a bearing spindle 10 coupled with the plate 4 . the plate carries at its lower side two stop pins 11 each provided with a resilient envelope or sleeve . the rotation axis of plate 4 in the rest position is determined by gravity and lies in a substantially vertical plane . frame 2 further carries two support pins 12 on which a support brace 13 can be placed . support brace 13 includes a pair of vertically extending tubular portions which are adapted to be gripped by the hands of a user . the second support shaft part 8 consists of a first part 14 connected to the first support shaft part 7 and a second part 15 telescopically shiftable over said first part 14 . fig2 shows in cross - section the construction in more detail . a securing screw 16 serves to secure second part 15 against longitudinal displacement and rotation relative to first part 14 . in order to prevent rotation , part 14 is provided with a groove 14 with which screw 16 cooperates . fig3 shows an alternative embodiment in which a frame plate 18 is connected with frame 2 by means of a hinge 19 . in order to adjust the angle of the frame plate , frame 2 includes stop ribs 20 adapted to cooperate with the adjustable end part 21 of the frame plate . the end part 21 can be fixed in different positions by means of screws 22 . accordingly , the first angle , indicated in fig3 by numeral 23 can be adjusted . in the embodiment shown in fig3 the second angle 26 between the first support shaft part 24 and the second support shaft part 25 is adjustable . a plate 27 having perforations 28 , 29 is present at the free end of the first support shaft part 24 . screws 28 &# 39 ; and 29 &# 39 ; cooperate with these perforations and the second support shaft part 25 to fix part 25 to plate 27 in different positions . fig4 shows a modified construction . in this case , the second support shaft part 34 carries the bearing sleeve 9 by means of a plate 32 provided with perforations 30 and 31 . with the construction shown in fig4 the angle between the axes of the second support shaft part 34 and the bearing sleeve 9 as well as bearing spindle 10 can be adjusted into a plurality of discrete positions . as seen in fig4 each of pins 11 is provided with a resilient coating layer 35 therearound . in a very practical and simple embodiment , this layer consists of a part of a rubber hose . fig4 also shows a bearing ball 36 serving as a bearing for spindle 10 in bearing sleeve 9 . in this manner , very low rotation friction is ensured . should , however , some friction be desired , this ball 36 can be left out and the bearing may comprise a friction bearing , the friction of which can be increased , if necessary , by providing a braking strip which may or may not be adjustable . a similar construction can be added in place of the rotation bearings 6 previously described . a locking screw 39 can be turned into a blind hole 40 provided in plate 4 . in this manner , the plate can be coupled in a fixed position to the second support shaft part 34 . fig5 shows a second support shaft part 37 carrying a bearing sleeve 9 fixedly connected thereto . the bottom of the carrying member 4 is provided with ears 38 journalling the pivot shaft 37 &# 39 ; to which the spindle 10 is attached and is pivotally received in the bearing sleeve 9 . this construction introduces an additional degree of freedom , which however will mainly be reserved for the more experienced skier . in this simple embodiment , the second support shaft part 37 is the stop limiting the two extreme positions of wobbling movement of plate 4 . it should be noted that stop pins 11 may be adjustable by means of slot holes and bolts or the like . in the embodiment of fig1 the carrying plate may be removed from the bearing sleeve and the pins positioned rearwardly of the apparatus so that the stop pins 11 become inoperative . the support structure 7 , 14 in fig1 and 24 , 25 in fig3 defines in each case an inverted v - shaped structure . taking fig1 as an example , parts 7 and 14 lie in a common plane and their juncture point or apex lies uppermost at rest with no user supported on the carrying plate 4 . because the apex acts as a pendulum point when the part 7 rotates about its axis , the remote end of the part 14 with its extension 15 , 9 , swings freely along a path of concave form centered at the apex as is indicated by the arrow a in fig1 . the equilibrium position ( no skier on the plate 4 ) is with the juncture point uppermost and the axis of member 10 in a vertical plane , under the influence of gravity . similarly in fig3 the shaft 24 is at an upwardly inclined angle defining the first acute angle 23 with respect to the supporting surface and the part 25 is inclined at another angle 26 with respect to the supporting surface . more importantly , these two parts define an inverted v shape in which , once again , the apex remains in fixed position ( except for rotation of the part 24 ). part 25 which carries plate 4 seeks an equilibrium position under the influence of gravity and no load on the plate which places the swivel axis of the plate in a vertical plane . when there is a load on the platform , part 25 acts as a pendulum and swings back and forth along a concave path centered at the apex . in operation , a user places his feet on the carrying plate and grasps one of the vertical tubes of support brace 13 in each hand . the user then shifts his body laterally of the device in the same manner that he would in making turns in a skiing run . the device will provide motions and positions for the user that closely duplicate those encountered during parallel skiing . accordingly , the apparatus enables a user to practice all the movements involved and the proper technique in making a normal ski run .

US-15158688-A

provided herein are compounds of the formula : as well as pharmaceutically acceptable salts thereof , wherein the substituents are as those disclosed in the specification . these compounds , and the pharmaceutical compositions containing them , are useful for the treatment of diseases such as , for example , type ii diabetes mellitus and metabolic syndrome .

the present invention pertains to inhibitors of 11β - hsd1 . in a preferred embodiment , the invention provides for pharmaceutical compositions comprising sulfonyl piperidines of the formula i : as well as pharmaceutically acceptable salts thereof , that are useful as inhibitors of 11β - hsd1 . it is to be understood that the terminology employed herein is for the purpose of describing particular embodiments , and is not intended to be limiting . further , although any methods , devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention , the preferred methods , devices and materials are now described . in this specification the term “ aryl ” is used to mean a mono - or polycyclic aromatic ring system , in which the rings may be carbocyclic or may contain one or more atoms selected from o , s , and n . examples of aryl groups are phenyl , pyridyl , benzimidazolyl , benzofuranyl , benzothiazolyl , benzothiophenyl , cinnolinyl , furyl , imidazo [ 4 , 5 - c ] pyridinyl , imidazolyl , indolyl , isoquinolinyl , isoxazolyl , naphthyl , [ 1 , 7 ] naphthyridinyl , oxadiazolyl , oxazolyl , phthalazinyl , purinyl , pyidazinyl , pyrazolyl , pyrido [ 2 , 3 - d ] pyrimidinyl , pyrimidinyl , pyrimido [ 3 , 2 - c ] pyrimidinyl , pyrrolo [ 2 , 3 - d ] pyrimidinyl , pyrrolyl , quinazolinyl , quinolinyl , quinoxalinyl , tetrazolyl , thiadiazolyl , thiazolyl , thiophenyl , triazolyl , and the like . as used herein , the term “ alkyl ” means , for example , a branched or unbranched , cyclic or acyclic , saturated or unsaturated ( e . g . alkenyl or alkynyl ) hydrocarbyl radical which may be substituted or unsubstituted . where cyclic , the alkyl group is preferably c 3 to c 12 , more preferably c 5 to c 10 , more preferably c 5 to c 7 . where acyclic , the alkyl group is preferably c 1 to c 10 , more preferably c 1 to c 6 , more preferably methyl , ethyl , propyl ( n - propyl or isopropyl ), butyl ( n - butyl , isobutyl or tertiary - butyl ) or pentyl ( including n - pentyl and isopentyl ), more preferably methyl . it will be appreciated therefore that the term “ alkyl ” as used herein includes alkyl ( branched or unbranched ), substituted alkyl ( branched or unbranched ), alkenyl ( branched or unbranched ), substituted alkenyl ( branched or unbranched ), alkynyl ( branched or unbranched ), substituted alkynyl ( branched or unbranched ), cycloalkyl , substituted cycloalkyl , cycloalkenyl , substituted cycloalkenyl , cycloalkynyl and substituted cycloalkynyl . as used herein , the term “ lower alkyl ” means , for example , a branched or unbranched , cyclic or acyclic , saturated or unsaturated ( e . g . alkenyl or alkynyl ) hydrocarbyl radical wherein said cyclic lower alkyl group is c 5 , c 6 or c 7 , and wherein said acyclic lower alkyl group is c 1 , c 2 , c 3 or c 4 , and is preferably selected from methyl , ethyl , propyl ( n - propyl or isopropyl ) or butyl ( n - butyl , sec - butyl , isobutyl or tertiary - butyl ). it will be appreciated therefore that the term “ lower alkyl ” as used herein includes lower alkyl ( branched or unbranched ), lower alkenyl ( branched or unbranched ), lower alkynyl ( branched or unbranched ), cycloloweralkyl , cycloloweralkenyl and cycloloweralkynyl . the alkyl and aryl groups may be substituted or unsubstituted . where substituted , there will generally be , for example , 1 to 3 substituents present , preferably 1 substituent . substituents may include , for example : carbon - containing groups such as alkyl , aryl , arylalkyl ( e . g . substituted and unsubstituted phenyl , substituted and unsubstituted benzyl ); halogen atoms and halogen - containing groups such as haloalkyl ( e . g . trifluoromethyl ); oxygen - containing groups such as alcohols ( e . g . hydroxyl , hydroxyalkyl , aryl ( hydroxyl ) alkyl ), ethers ( e . g . alkoxy , aryloxy , alkoxyalkyl , aryloxyalkyl ), aldehydes ( e . g . carboxaldehyde ), ketones ( e . g . alkylcarbonyl , alkylcarbonylalkyl , arylcarbonyl , arylalkylcarbonyl , arycarbonylalkyl ), acids ( e . g . carboxy , carboxyalkyl ), acid derivatives such as esters ( e . g . alkoxycarbonyl , alkoxycarbonylalkyl , alkylcarbonyloxy , alkylcarbonyloxyalkyl ), amides ( e . g . aminocarbonyl , mono - or di - alkylaminocarbonyl , aminocarbonylalkyl , mono - or di - alkylaminocarbonylalkyl , arylaminocarbonyl ), carbamates ( e . g . alkoxycarbonylamino , arloxycarbonylamino , aminocarbonyloxy , mono - or di - alkylaminocarbonyloxy , arylaminocarbonyloxy ) and ureas ( e . g . mono - or di - alkylaminocarbonylamino or arylaminocarbonylamino ); nitrogen - containing groups such as amines ( e . g . amino , mono - or di - alkylamino , aminoalkyl , mono - or di - alkylaminoalkyl ), azides , nitriles ( e . g . cyano , cyanoalkyl ), nitro ; sulfur - containing groups such as thiols , thioethers , sulfoxides and sulfones ( e . g . alkylthio , alkylsulfinyl , alkylsulfonyl , alkylthioalkyl , alkylsulfinylalkyl , alkylsulfonylalkyl , arylthio , arysulfinyl , arysulfonyl , arythioalkyl , arylsulfinylalkyl , arylsulfonylalkyl ); and heterocyclic groups containing one or more , preferably one , heteroatom , ( e . g . thienyl , furanyl , pyrrolyl , imidazolyl , pyrazolyl , thiazolyl , isothiazolyl , oxazolyl , oxadiazolyl , thiadiazolyl , aziridinyl , azetidinyl , pyrrolidinyl , pyrrolinyl , imidazolidinyl , imidazolinyl , pyrazolidinyl , tetrahydrofuranyl , pyranyl , pyronyl , pyridyl , pyrazinyl , pyridazinyl , piperidyl , hexahydroazepinyl , piperazinyl , morpholinyl , thianaphthyl , benzofuranyl , isobenzofuranyl , indolyl , oxyindolyl , isoindolyl , indazolyl , indolinyl , 7 - azaindolyl , benzopyranyl , coumarinyl , isocoumarinyl , quinolinyl , isoquinolinyl , naphthridinyl , cinnolinyl , quinazolinyl , pyridopyridyl , benzoxazinyl , quinoxalinyl , chromenyl , chromanyl , isochromanyl , phthalazinyl and carbolinyl ). the lower alkyl groups may be substituted or unsubstituted , preferably unsubstituted . where substituted , there will generally be , for example , 1 to 3 substitutents present , preferably 1 substituent . as used herein , the term “ alkoxy ” means , for example , alkyl - o — and “ alkoyl ” means , for example , alkyl - co —. alkoxy substituent groups or alkoxy - containing substituent groups may be substituted by , for example , one or more alkyl groups . as used herein , the term “ halogen ” means , for example , a fluorine , chlorine , bromine or iodine radical , preferably a fluorine , chlorine or bromine radical , and more preferably a fluorine or chlorine radical . as used herein , the term “ pharmaceutically acceptable salt ” means any pharmaceutically acceptable salt of the compound of formula ( i ). salts may be prepared from pharmaceutically acceptable non - toxic acids and bases including inorganic and organic acids and bases . such acids include , for example , acetic , benzenesulfonic , benzoic , camphorsulfonic , citric , ethenesulfonic , dichloroacetic , formic , fumaric , gluconic , glutamic , hippuric , hydrobromic , hydrochloric , isethionic , lactic , maleic , malic , mandelic , methanesulfonic , mucic , nitric , oxalic , pamoic , pantothenic , phosphoric , succinic , sulfuric , tartaric , oxalic , p - toluenesulfonic and the like . particularly preferred are fumaric , hydrochloric , hydrobromic , phosphoric , succinic , sulfuric and methanesulfonic acids . acceptable base salts include alkali metal ( e . g . sodium , potassium ), alkaline earth metal ( e . g . calcium , magnesium ) and aluminum salts . the compounds of the present invention can be prepared by any conventional means . suitable processes for synthesizing these compounds are provided in the examples . generally , compounds of formula i can be prepared according to scheme 1 , scheme 2 or scheme 3 ( see below ). the sources of the starting materials for these reactions are also described . compounds of formula 1 can be prepared from nipecotic acid ( 2 ) according to scheme 1 by sulfonylation to give a sulfonamide of formula 4 followed by an amide coupling reaction to give the compound of formula 1 . the first reaction can be carried out by reacting the compound of formula 2 with a sulfonyl chloride of formula 3 in an inert solvent such as a halogenated hydrocarbon ( such as methylene chloride ) or an ether ( such as tetrahydrofuran or dioxane ) or an ester solvent such as ethyl acetate . the reaction is conveniently carried out in the presence of an organic base ( such as triethylamine or diisopropylethylamine ) or an inorganic base ( such as sodium hydroxide or sodium carbonate ). when an inorganic base is used , the reaction is conveniently carried out in the additional presence of water , and the co - solvent should be stable to the aqueous base . the reaction can be carried out at a temperature between about 0 degrees and about room temperature , preferably at around room temperature . additionally , a number of aryl - sulfonyl - nipecotic acid derivatives of formula 4 are available commercially , and some of these are shown in the table : name supplier 1 -[( 2 , 4 , 6 - trimethylphenyl ) sulfonyl ]- asinex , moscow , russia 3 - piperidinecarboxylic acid 1 -[( 2 - nitrophenyl ) sulfonyl ]- 3 - ambinter , paris , france piperidinecarboxylic acid 1 -[( 4 - bromophenyl ) sulfonyl ]- 3 - interchim , montlucon , france piperidinecarboxylic acid 1 -[( 4 - ethoxyphenyl ) sulfonyl ]- 3 - enamine , kiev , ukraine piperidinecarboxylic acid 1 -[( 4 - fluorophenyl ) sulfonyl ]- 3 - interchim , montlucon , france piperidinecarboxylic acid 1 -[( 4 - methoxyphenyl ) sulfonyl ]- 3 - chemdiv , san diego , usa piperidinecarboxylic acid 1 -[( 4 - methylphenyl ) sulfonyl ]- 3 - akos consulting , basel , piperidinecarboxylic acid switzerland 1 -[( 4 - nitrophenyl ) sulfonyl ]- 3 - interchim , montlucon , france piperidinecarboxylic acid 1 -[[ 4 -( acetylamino ) phenyl ] sulfonyl ]- enamine , kiev , ukraine 3 - piperidinecarboxylic acid the coupling of carboxylic acids of formula 4 with amines of formula 5 , according to scheme 1 , can be achieved using methods well known to one of ordinary skill in the art . for example , the transformation can be carried out by reaction of carboxylic acids of formula 4 or of appropriate derivatives thereof such as activated esters , with amines of formula 5 or their corresponding acid addition salts ( e . g ., the hydrochloride salts ) in the presence , if necessary , of a coupling agent , many examples of which are well known per se in peptide chemistry . the reaction is conveniently carried out by treating the carboxylic acid of formula 4 with the hydrochloride of the amine of formula 5 in the presence of an appropriate base , such as diisopropylethylamine , a coupling agent such as o -( benzotriazol - 1 - yl )- 1 , 1 , 3 , 3 - tetramethyluronium hexafluorophosphate , and in the optional additional presence of a substance that increases the rate of the reaction , such as 1 - hydroxybenzotriazole or 1 - hydroxy - 7 - azabenzotriazole , in an inert solvent , such as a chlorinated hydrocarbon ( e . g ., dichloromethane ) or n , n - dimethylformamide or n - methylpyrrolidinone , at a temperature between about 0 degrees and about room temperature , preferably at about room temperature . alternatively , the reaction can be carried out by converting the carboxylic acid of formula 4 to an activated ester derivative , such as the n - hydroxysuccinimide ester , and subsequently reacting this with the amine of formula 5 or a corresponding acid addition salt . this reaction sequence can be carried out by reacting the carboxylic acid of formula 4 with n - hydroxysuccinimide in the presence of a coupling agent such as n , n ′- dicyclohexylcarbodiimide in an inert solvent such as tetrahydrofuran at a temperature between about 0 degrees and about room temperature . the resulting n - hydroxysuccinimide ester is then treated with the amine of formula 5 or a corresponding acid addition salt , in the presence of a base , such as organic base ( e . g ., triethylamine or diisopropylethylamine or the like ) in a suitable inert solvent such as n , n - dimethylformamide at around room temperature . compounds of the invention of formula 1 can also be prepared according to scheme 2 , which differs from scheme 1 in the order of the incorporation of the aryl - sulfonyl and amine groups into the molecule . in this process , the nitrogen of the compound of formula 2 is protected to give a compound of formula 6 where pg represents a protective group , many appropriate examples of which are known to one of skill in the art , as discussed below . the compound of formula 6 is then converted to an amide of formula 7 , the protective group is then cleaved to give an amine of formula 8 and this compound is then reacted with a sulfonyl chloride of formula 3 to give the compound of formula 1 . it will be readily apparent to one of skill in the art that scheme 2 affords the possibility to prepare compounds of the invention in which one of r 1 or r 2 represents hydrogen on solid - phase by using a resin - bound amine 5 . many protective groups pg are known to those of skill in the art of organic synthesis . for example , several suitable protective groups are enumerated in “ protective groups in organic synthesis ” [ greene , t . w . and wuts , p . g . m ., 2nd edition , john wiley & amp ; sons , n . y . 1991 ]. preferred protective groups are those compatible with the reaction conditions used to prepare compounds of the invention . examples of such protective groups are tert - butoxycarbonyl ( boc ), benzyloxycarbonyl ( cbz ), and 9 - fluorenylmethoxycarbonyl ( fmoc ). some examples of intermediates of formula 6 are available commercially , as shown in the table below . further examples of intermediates of formula 6 can be prepared as described in the subsequent paragraph . compound name supplier ( 3r )- 1 -( 9 - fluorenylmethoxycarbonyl )- 3 - fluka chemical corp ., piperidinecarboxylic acid milwaukee , wi ( 3r )- 1 -( tert - butoxycarbonyl )- 3 - fluka chemical corp ., piperidinecarboxylic acid milwaukee , wi ( 3s )- 1 -( tert - butoxycarbonyl )- 3 - digital specialty chemicals , piperidinecarboxylic acid dublin , nh 1 -( 9 - fuorenylmethoxycarbonyl )- 3 - fluka chemical corp ., piperidinecarboxylic acid milwaukee , wi 1 -( tert - butoxycarbonyl )- 3 - aldrich chemical company , piperidinecarboxylic acid milwaukee , wi 1 -[( benzyloxy ) carbonyl ]- 3 - maybridge plc , tintagel , piperidinecarboxylic acid cornwall , uk intermediates of formula 6 can be prepared by reacting the compound of formula 2 with an alkoxycarbonylating reagent such as di - tert - butyl dicarbonate , 2 -( tert - butoxycarbonyloxyimino )- 2 - phenylacetonitrile , benzyl chloroformate , 9 - fluorenylmethyl pentafluorophenyl carbonate , n -( 9 - fluorenylmethoxycarbonyloxy ) succinimide , or the like , in the presence of a base which may be organic ( for example , triethylamine ) or inorganic ( for example , sodium hydroxide , sodium or potassium carbonate , or sodium hydrogen carbonate ) in an inert solvent such as water or dioxane or tetrahydrofuran , or in a mixture of inert solvents such as a mixture of water and acetone , water and dioxane , or water and tetrahydrofuran . the reaction is conveniently carried out at a temperature between about 0 degrees and about room temperature , preferably at about room temperature . where the intermediate of formula 6 is not stable to basic conditions , as in the case of a compound of formula 6 in which pg represents fmoc ( 9 - fluorenylmethoxycarbonyl ), care should be taken that this intermediate is not exposed to strongly basic conditions during attempts to prepare it . it will be readily apparent to one of skill in the art that the selection of protective group depends on the nature of the target compound 1 , so that for example , the functionalities present in the nr1r2 moiety are compatible with the conditions used to accomplish the removal of the protective group in the conversion of the compound of formula 7 to the compound of formula 8 . because there exist a number of different choices for the protective group pg , with complementary methods of deprotection , there is no difficulty in selecting a protective group for the synthesis of any of the compounds of the invention according to scheme 2 . the coupling of a carboxylic acid of formula 6 with an amine of formula 5 , according to scheme 2 , can be achieved using methods well known to one of ordinary skill in the art . for example , the transformation can be carried out by reaction of a carboxylic acid of formula 6 or of an appropriate derivative thereof such as an activated ester , with an amine of formula 5 or its corresponding acid addition salt ( e . g ., the hydrochloride salt ) in the presence , if necessary , of a coupling agent , many examples of which are well known per se in peptide chemistry . the reaction is conveniently carried out by treating the carboxylic acid of formula 6 with the hydrochloride of the amine of formula 5 in the presence of an appropriate base , such as diisopropylethylamine , a coupling agent such as o -( benzotriazol - 1 - yl )- 1 , 1 , 3 , 3 - tetramethyluronium hexafluorophosphate , and in the optional additional presence of a substance that increases the rate of the reaction , such as 1 - hydroxybenzotriazole or 1 - hydroxy - 7 - azabenzotriazole , in an inert solvent , such as a chlorinated hydrocarbon ( e . g ., dichloromethane ) or n , n - dimethylformamide or n - methylpyrrolidinone , at a temperature between about 0 degrees and about room temperature , preferably at about room temperature . alternatively , the reaction can be carried out by converting the carboxylic acid of formula 6 to an activated ester derivative , such as the n - hydroxysuccinimide ester , and subsequently reacting this with the amine of formula 5 or a corresponding acid addition salt . this reaction sequence can be carried out by reacting the carboxylic acid of formula 6 with n - hydroxysuccinimide in the presence of a coupling agent such as n , n ′- dicyclohexylcarbodiimide in an inert solvent such as tetrahydrofuran at a temperature between about 0 degrees and about room temperature . the resulting n - hydroxysuccinimide ester is then treated with the amine of formula 5 or a corresponding acid addition salt , in the presence of a base , such as organic base ( e . g ., triethylamine or diisopropylethylamine or the like ) in a suitable inert solvent such as n , n - dimethylformamide at around room temperature . the removal of the protective group in the conversion of the compound of formula 7 to the amine of formula 8 is carried out according to procedures that are well known in the arts of synthetic chemistry and peptide chemistry and which depend on the nature of the protective group pg . many examples of suitable procedures are listed in “ protective groups in organic synthesis ” [ greene , t . w . and wuts , p . g . m ., 2nd edition , john wiley & amp ; sons , n . y . 1991 ]. for example , in the case where the protective group is fmoc ( 9 - fluorenylmethoxycarbonyl ), the group can be conveniently removed by treating the compound of formula 7 with an organic base ( such as piperidine , morpholine , or ethanolamine ) in an inert solvent such as n , n - dimethylformamide or dichloromethane at about room temperature . in the case where the protective group is benzyloxycarbonyl ( cbz ), the group can be removed under hydrogenolytic conditions , for example by hydrogenation in the presence of a noble metal catalyst such as palladium - on - carbon , or palladium black , in the presence of an inert solvent ( for example , an alcohol such as ethanol ) at about room temperature and under atmospheric pressure , or at elevated pressure ( such as 50 psi of hydrogen ) if required . as a further example , in the case where the protective group is tert - butoxycarbonyl ( boc ), the group can be removed by treatment of the compound of formula 7 with acid ( either organic or inorganic ) in an inert solvent . for example , the boc group can be removed by treatment of the compound of formula 7 with trifluoroacetic acid in dichloromethane at about room temperature , or it can be removed by treatment of the compound of formula 7 with hydrochloric acid in an alcoholic solvent ( e . g ., methanol or ethanol ) or an ether ( e . g ., dioxane ) or ethyl acetate , also at about room temperature . the compound of formula 8 is conveniently converted to the compound of the invention of formula 1 by sulfonylation with a sulfonylating reagent of formula 3 . the reaction can be carried out by reacting the compound of formula 8 with a sulfonyl chloride of formula 3 in an inert solvent such as a halogenated hydrocarbon ( such as methylene chloride ) or an ether ( such as tetrahydrofuran or dioxane ) or an ester solvent such as ethyl acetate . the reaction is conveniently carried out in the presence of an organic base ( such as triethylamine or diisopropylethylamine ) or an inorganic base ( such as sodium hydroxide or sodium carbonate ). when an inorganic base is used , the reaction is conveniently carried out in the additional presence of water , and the co - solvent should be stable to the aqueous base . the reaction can be carried out at a temperature between about 0 degrees and about room temperature , preferably at around room temperature . many sulfonyl chlorides of formula 3 are commercially available , or can be synthesized according to the many different processes as discussed above . in the case where a resin - bound amine of formula 5 was used , an additional step is required for the conversion of the resin - bound compound of formula 1 into the compound of the invention ; namely , the compound of the invention must be cleaved from the resin . this can be done using any conventional conditions , many of which are known to one of skill in the art of solid - phase organic synthesis , and which conditions will depend on the nature of the linker attaching the product to the solid support . for example , in the case where fmbp resin was used , the cleavage is conveniently effected by treating the resin - bound compound of formula 1 with an organic acid , preferably trifluoroacetic acid , in an inert solvent such as dichloromethane at room temperature . compounds of the invention of formula 1 can also be prepared according to scheme 3 , which differs from scheme 1 in that there are an additional two steps in the sequence — a protection step and a deprotection step . in this process , the carboxyl group of the compound of formula 2 is protected to give a compound of formula 9 where r 3 represents a protective group , many appropriate examples of which are known to one of skill in the art , as discussed below . the compound of formula 9 is then converted to sulfonamide of formula 10 , the protective group is then cleaved to give a carboxylic acid of formula 4 and this compound is then coupled with an amine of formula 5 to give the compound of formula 1 . it will be appreciated by one of skill in the art that scheme 3 affords the possibility to carry out the sulfonylation reaction ( the conversion of a compound of formula 9 to a compound of formula 10 ) on solid - phase by using a polymer - supported r 3 group . many protective groups r 3 are known to those of skill in the art of organic synthesis . for example , several suitable protective groups are enumerated in “ protective groups in organic synthesis ” [ greene , t . w . and wuts , p . g . m ., 2nd edition , john wiley & amp ; sons , n . y . 1991 ]. preferred protective groups are those compatible with the reaction conditions used to prepare compounds of the invention . examples of such protective groups are lower alkyl straight - chain or branched esters ( e . g ., methoxy ( r 3 ═ och 3 ), ethoxy ( r 3 ═ och 2 ch 3 ), or tert - butoxy ( r 3 ═ oc ( ch 3 ) 3 ) esters ), or the benzyl ester ( r 3 ═ och 2 c 6 h 5 ), or a resin commonly used in solid - phase synthesis ( e . g ., wang resin or rink resin ), and these can be made by any conventional methods . for example , they may conveniently be made from the corresponding carboxylic acid of formula 2 by any esterification reaction , many of which are well known to one of ordinary skill in the art . for example , a compound of formula 9 in which r 3 represents methoxy can be prepared from a compound of formula 2 by treatment with an ethereal solution of diazomethane . the reaction is conveniently carried out in an inert solvent such as an ether ( e . g ., diethyl ether or tetrahydrofuran ) or an alcohol ( e . g ., methanol ), at a temperature of between about 0 degrees and about room temperature , preferably at about 0 degrees . in the case where r 3 represents the wang resin , the compound of formula 9 is conveniently prepared by treating the resin with the compound of formula 2 in the presence of a coupling agent ( such as diisopropylcarbodiimide ) and in the presence of a catalytic amount of n , n - dimethylaminopyridine ( dmap ) in an inert solvent such as n , n - dimethylformamide at about room temperature . the sulfonylation reaction can be carried out by reacting the compound of formula 9 with a sulfonyl chloride of formula 3 in an inert solvent such as a halogenated hydrocarbon ( such as methylene chloride ) or an ether ( such as tetrahydrofuran or dioxane ) or an ester solvent such as ethyl acetate . the reaction is conveniently carried out in the presence of an organic base ( such as triethylamine or diisopropylethylamine ) or an inorganic base ( such as sodium hydroxide or sodium carbonate ). when an inorganic base is used , the reaction is conveniently carried out in the additional presence of water , and the co - solvent and protective group should be stable to the aqueous base . the reaction can be carried out at a temperature between about 0 degrees and about room temperature , preferably at around room temperature . many sulfonyl chlorides of formula 3 are commercially available , or can be synthesized according to many different processes as discussed above . for the removal of the protective group from a compound of formula 10 to give the carboxylic acid of formula 4 , any conventional means can be used . for example , in the case where r 3 represents an unbranched lower alkoxy group ( e . g ., methoxy ), the reaction may be carried out by treating the compound of formula 10 with an alkali methyl hydroxide , such as potassium hydroxide , sodium hydroxide or lithium hydroxide , preferably lithium hydroxide , in an appropriate solvent , such as a mixture of tetrahydrofuran , methanol and water . the reaction is conveniently carried out at a temperature between about 0 degrees and about room temperature , preferably at about room temperature . in the case where r 3 represents wang resin or rink resin , the cleavage can be effected using trifluoroacetic acid in dichloromethane at about room temperature . the coupling of a carboxylic acid of formula 4 with an amine of formula 5 to give the compound of the invention of formula 1 according to scheme 3 , can be achieved as mentioned above , using methods well known to one of ordinary skill in the art . for example , the transformation can be carried out by reaction of carboxylic acids of formula 4 or of appropriate derivatives thereof such as activated esters , with amines of formula 5 or their corresponding acid addition salts ( e . g ., the hydrochloride salts ) in the presence , if necessary , of a coupling agent , many examples of which are well known per se in peptide chemistry . the reaction is conveniently carried out by treating the carboxylic acid of formula 4 with the hydrochloride of the amine of formula 5 in the presence of an appropriate base , such as diisopropylethylamine , a coupling agent such as o -( benzotriazol - 1 - yl )- 1 , 1 , 3 , 3 - tetramethyluronium hexafluorophosphate , and in the optional additional presence of a substance that increases the rate of the reaction , such as 1 - hydroxybenzotriazole or 1 - hydroxy - 7 - azabenzotriazole , in an inert solvent , such as a chlorinated hydrocarbon ( e . g ., dichloromethane ) or n , n - dimethylformamide or n - methylpyrrolidinone , at a temperature between about 0 degrees and about room temperature , preferably at about room temperature . alternatively , the reaction can be carried out by converting the carboxylic acid of formula 4 to an activated ester derivative , such as the n - hydroxysuccinimide ester , and subsequently reacting this with the amine of formula 5 or a corresponding acid addition salt . this reaction sequence can be carried out by reacting the carboxylic acid of formula 4 with n - hydroxysuccinimide in the presence of a coupling agent such as n , n ′- dicyclohexylcarbodiimide in an inert solvent such as tetrahydrofuran at a temperature between about 0 degrees and about room temperature . the resulting n - hydroxysuccinimide ester is then treated with the amine of formula s or a corresponding acid addition salt , in the presence of a base , such as organic base ( e . g ., triethylamine or diisopropylethylamine or the like ) in a suitable inert solvent such as n , n - dimethylformamide at around room temperature . racemic nipecotic acid is commercially from suppliers such as aldrich chemical company , inc ., milwaukee , wisc . ; tci america , portland , oreg . ; and lancaster synthesis ltd ., lancashire , uk . the optically active nipecotic acids are also commercially available . for example , both ( r )-(−)- nipecotic acid and ( s )-(+)- nipecotic acid are available from the following suppliers : aldrich chemical company , inc ., milwaukee , wisc . digital specialty chemicals , dublin , n . h . tci japan , tokyo , japan yamakawa chemical industry co ., ltd ., tokyo , japan . in addition , the individual enantiomers of nipecotic acid can be prepared by chiral chromatography ( see j . s . valsborg and c . foged , j . labelled compd . radiopharm . 1997 , 39 , 401 ) or by resolution . the following publications describe methods for the preparation by resolution of ( r )-(−)- nipecotic acid and ( s )-(+)- nipecotic acid or their acid addition salts : m . akkerman et al . recueil trav . chim . pays - bas 1951 , 70 , 899 p . magnus and l . s . thurston j . org . chem . 1991 , 56 , 1166 x . zheng et al . chirality 1995 , 7 , 90 s . schleich and g . helmchen , eur . j . org . chem . 1999 , 2515 chung , y . j . et al . j . am . chem . soc . 2000 , 122 , 3995 s . h . gellman and b . r . huck , u . s . pat . no . 6 , 710 , 186 e . d . moher et al , wo 2002068391 k . a . ismail and s . c . bergmaier , eur . j . med chem . 2002 , 37 , 469 sulfonyl chlorides of formula 3 can be purchased or they can be prepared using one of a large variety of different synthetic procedures well known in the field of organic synthesis , as outlined below . the synthetic approaches to sulfonyl chlorides are often complementary and offer access to sulfonyl chlorides with many different substitution patterns in the aryl ring system . more than 100 sulfonyl chlorides of formula 3 are commercially available from suppliers such as aldrich chemical company , inc . ( milwaukee , wisc . ), lancaster synthesis ltd . ( lancashire , uk ), tci america ( portland , oreg . ), and maybridge plc ( tintagel , cornwall , uk ). for the purposes of illustration , a number of commercially available sulfonyl chlorides are shown in the table below . many other examples can be found by consulting the available chemicals directory ( mdl information systems , san leandro , calif .) or scifinder ( chemical abstracts service , columbus , ohio ). name supplier 1 - naphthalene - sulfonyl chloride tci america , portland , or 2 , 4 - difluoro - benzene - sulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 2 , 5 - dichloro - benzene - sulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 2 - chloro - 6 - methylbenzene - sulfonyl lancaster synthesis ltd ., chloride lancashire , uk 2 - chloro - benzene - sulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 2 - mesitylene - sulfonyl chloride lancaster synthesis ltd ., lancashire , uk 3 - chloro - 2 - methylbenzene - sulfonyl maybridge plc , tintagel , chloride cornwall , uk 3 - nitro - benzene - sulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 3 - pyridinesulfonyl chloride combi - blocks , llc , hydrochloride san diego , ca 4 - methoxy - 2 , 3 , 6 - trimethyl - benzene - lancaster synthesis ltd ., sulfonyl chloride lancashire , uk 8 - quinoline - sulfonyl chloride maybridge plc , tintagel , cornwall , uk o - toluene - sulfonyl chloride tci america , portland , or sulfonyl chlorides of formula 3 can also be made by reactions that are well known in the field of organic synthesis , such as those outlined below . for example , sulfonyl chlorides of formula 3 can be made from a sulfonic acid of formula 11 as shown in scheme 4 . the chlorination of an arylsulfonic acid , or a salt thereof , of formula 11 can be accomplished conveniently by treating it with a chlorinating agent such as thionyl chloride or phosphorus oxychloride or phosphorus pentachloride , in the optional additional presence of a catalytic amount of n , n - dimethylformamide , at a temperature between about 0 degrees and about 80 degrees depending on the reactivity of the chlorinating agent . many examples of this reaction are known in the literature , such as those listed in the following table isoquinoline - 5 - sulfonyl chloride a . morikawa et al . j . med . chem . 1989 , 32 , 42 2 - ethoxycarbonyl - benzenesulfonyl x . baucherel et al . chloride wo 2002100810 4 - n - butoxybenzenesulfonyl chloride v . p . sandanayaka et al . u . s . pat . no . 2002 / 0099035 benzothiazole - 6 - sulfonyl chloride s . a . kunda et al . u . s . pat . no . 6 , 140 , 505 5 - dimethylamino - 2 - methyl - c . wu j . org . chem . benzenesulfonyl chloride 1998 , 63 , 2348 sulfonyl chlorides of formula 3 can be made by electrophilic aromatic substitution of an aromatic compound of formula 12 as shown in scheme 5 . as is known to one of average skill in the art , this process is suitable for the preparation of arylsulfonyl chlorides with particular substitution patterns , such as for example where there is an ortho / para directing substituent in a benzene ring ortho or para to the site of introduction of the sulfonyl group . the reaction is conveniently carried out by treating the aromatic compound of formula 12 with chlorosulfonic acid in the absence of solvent and then heating the mixture at a temperature between about 70 degrees and about 100 degrees . many examples of this reaction are known in the literature , such as those listed in the following table 5 - acetyl - 3 - thiophenesulfonyl a . arduini et al . tetrahedron chloride lett . 2003 , 44 , 5755 3 - bromo - 5 - isobutyl - thiophene - 2 - v . derdau et al . j . org . chem . sulfonyl chloride 2003 , 68 , 5168 2 - chloro - 4 - ethyl - thiazole - 5 - r . wischnat et al . wo 03002546 sulfonyl chloride 4 -( 1 , 3 - dihydro - 1 , 3 - dioxo - 2h - l . m . lima et al . bioorg . med . isoindol - 2 - yl )- chem . 2002 , 10 , 3067 benzenesulfonyl chloride 2 , 3 - dihydro - 6 - methoxy - 1h - indene - m . a . aboud - gharbia 5 - sulfonyl chloride u . s . pat . no . 4 , 857 , 644 5 -( 1 , 1 - dimethylethyl )- 2 - methyl - y . christidis benzenesulfonyl chloride u . s . pat . no . 4 , 948 , 827 4 - fluoro - 2 - methyl - benzenesulfonyl m . pal et al . j . med . chem . chloride 2003 , 46 , 3975 1 - methyl - 1h - pyrazole - 4 - sulfonyl p . j . dollings et al . chloride u . s . pat . no . 6 , 103 , 708 [ 4 -( chlorosulfonyl ) phenyl ]- b . p . clark carbamic acid , methyl ester u . s . pat . no . 6 , 482 , 824 1 , 2 , 3 , 4 - tetrahydro - 6 - methyl - 2 , 4 - v . v . makarov et al . dioxo - 5 - pyrimidinesulfonyl chloride ru 2 , 204 , 555 ( chemical abstracts can 140 : 93843 ) sulfonyl chlorides of formula 3 can also be made from anilines of formula 13 by a diazotization / sulfonylation reaction sequence as shown in scheme 6 . the diazotization reaction is conveniently carried out by treating the aniline of formula 13 or an acid addition salt thereof ( such as the hydrochloride salt ) in aqueous solution in the presence of a mineral acid such as hydrochloric acid or sulfuric acid with an alkali metal nitrite salt such as sodium nitrite at a temperature less than 10 degrees , preferably around 0 degrees . the diazonium salt obtained in this way can be converted directly to the sulfonyl chloride using a variety of reagents and conditions which are known in the field of organic synthesis . examples of suitable reagents include sulfur dioxide and copper ( i ) chloride or copper ( ii ) chloride in acetic acid / water , or thionyl chloride and copper ( i ) chloride or copper ( ii ) chloride in water , according to the procedure of p . j . hogan ( u . s . pat . no . 6 , 531 , 605 ). for example , the sulfonylation reaction can be carried out by adding the solution of the diazonium salt , prepared as described above , to a mixture of sulfur dioxide and copper ( ii ) chloride in a suitable inert solvent , such as glacial acetic acid , at a temperature around 0 degrees . many examples of this reaction are known in the literature , such as those listed in the following table 4 - methyl - benzenesulfonyl chloride n . ikemoto et al . tetrahedron 2003 , 59 , 1317 3 , 4 , 5 - trimethoxy - benzenesulfonyl c . binisti et al . eur . j . med . chloride chem . 2001 , 36 , 809 2 - fluoro - 6 - trifluoromethyl - m . a . gonzalez and e . w . benzenesulfonyl chloride otterbacher u . s . pat . no . 6 , 433 , 169 2 - methoxy - pyridine - 5 - sulfonyl s . l . gwaltney et al . bioorg . chloride med . chem . lett . 2001 , 11 , 871 3 - nitro - benzenesulfonyl chloride m . meier and r . wagner u . s . pat . no . 5 , 436 , 370 4 - benzyloxy - 2 - nitro - benzenesulfonyl r . j . cherney et al . j . med . chloride chem . 2003 , 46 , 1811 4 - acetyl - benzenesulfonyl chloride a . s . wagman et al . j . org . chem . 2000 , 65 , 9103 sulfonyl chlorides of formula 3 can also be made from an aryl benzyl sulfide of formula 14 by an oxidative chlorination reaction as shown in scheme 7 . the reaction is conveniently carried out by bubbling chlorine gas into a solution or suspension of the aryl benzyl sulfide of formula 14 in a suitable solvent such as a mixture of acetic acid and water at a temperature around room temperature . 4 -( chlorosulfonyl )- 3 - nitro - benzoic s . p . andrews et al .. org . acid , methyl ester chem . 2003 , 68 , 5525 4 , 7 - dichloro - quinoline - 6 - sulfonyl r . h . baker et al . j . am . chloride chem . soc . 1946 , 68 , 2636 1 , 3 - dioxo - 2 , 3 - dihydro - 2 - methyl - 1h - j . v . hay et al . isoindol4 - 4 - sulfonyl chloride u . s . pat . no . 4 , 521 , 241 2 , 3 - dihydro - 1 - oxo - 1h - indene - 5 - j . j . howbert and t . a . sulfonyl chloride crowell synthetic commun . 1990 , 20 , 3193 5 -( 2 - chlorosulfonyl - phenyl )- 3 - w . j . barry and i . l . finar j . methyl - 1 - phenyl - 1h - pyrazole - 4 - chem . soc . 1954 , 138 carboxylic acid ethyl ester 3 - methyl - 4 - nitro - benzenesulfonyl j . c . baum et al . can . chloride j . chem . 1990 , 68 , 1450 sulfonyl chlorides of formula 3 can also be made as shown in scheme 8 from an aryl bromide of formula 15 by metal - halogen exchange , followed by reaction of the organometallic intermediate with sulfur dioxide to give an arylsulfonate salt , followed by reaction with sulfuryl chloride to give the arylsulfonyl chloride . the reaction can be carried out by treating the aryl bromide with an organometallic reagent such as n - butyl lithium or preferably sec - butyl lithium , in the optional additional presence of tetramethylethylenediamine ( tmeda ) in a suitable inert solvent such as tetrahydrofuran ( thf ) or diethyl ether at low temperature ( for example , around − 78 degrees ) to give the aryllithium intermediate . this can then be reacted , without isolation , with a mixture of sulfur dioxide and a solvent such as diethyl ether , again at low temperature , such as for example between about - 78 degrees and about − 60 degrees . the resulting arylsulfonate salt can then be converted to the arylsulfonyl chloride , again without isolation of the intermediate , by treatment with sulfuryl chloride at a temperature around 0 degrees . many examples of this reaction are known in the literature , such as those listed in the following table 2 - benzyloxy - 5 - methyl - benzenesulfonyl g . papageorgiou et al . chloride tetrahedron 1999 , 55 , 237 [ 2 , 2 ′] bithiophenyl - 5 - sulfonyl chloride m . f . chan et al . bioorg . med . chem . 1998 , 6 , 2301 2 ′- methoxy - biphenyl - 4 - sulfonyl w . r . ewing et al . j . med . chloride chem . 1999 , 42 , 3557 4 -( 2 - phenyl - 2h - tetrazol - 5 - yl )- y . tamura et al . j . med . benzenesulfonyl chloride chem . 1998 , 41 , 640 3 -( 2 - p - tolyl - vinyl )- thiophene - 2 - b . raju et al . bioorg . med sulfonyl chloride chem . lett . 1997 , 7 , 939 3 - trifluoromethyl - benzenesulfonyl t . hamada and o . yonemitsu chloride synthesis 1986 , 852 sulfonyl chlorides of formula 3 can be made from an aryl thiol of formula 16 by oxidation using chlorine as shown in scheme 9 . for example , the reaction can be carried out by treating the aryl thiol of formula 16 with a solution of chlorine in an inert solvent such as glacial acetic acid at a temperature around 0 degrees . for example , 4 -( 1h - tetrazol - 1 - yl ) phenyl ] sulfonyl chloride could be prepared using this procedure from the thiophenol 4 -( 1h - tetrazol - 1 - yl )- benzenethiol which is known ( w . v . curran et al . u . s . pat . no . 3 , 932 , 440 ). several examples of this reaction are known in the literature , such as those listed in the following table 2 - benzothiazolesulfonyl chloride e . vedejs et al . j . org . chem . 2000 , 65 , 2309 5 -( chlorosulfonyl )- 1 - methyl - 1h - f . suzuki et al . jp 06056792 pyrazole - 4 - carboxylic acid , chemical abstracts can 122 : 31573 ethyl ester 5 - amino - 1h - 1 , 2 , 4 - triazole - 3 - r . b . shankar sulfonyl chloride u . s . pat . no . 4 , 937 , 350 2 - methyl - benzenesulfonyl chloride g . e . lepone u . s . pat . no . 4 , 454 , 135 sulfonyl chlorides of formula 3 can be made from a phenol of formula 17 through a sequence of reactions outlined in scheme 10 . the phenol of formula 17 can be converted to the o - aryl - n , n ′- dialkylthiocarbamate of formula 18 by reaction with an n , n ′- dialkylthiocarbamoyl chloride in an inert solvent in the presence of a base . the resulting o - aryl - n , n ′- dialkylthiocarbamate of formula 18 can be rearranged to the s - aryl - n , n ′- dialkylthiocarbamate of formula 19 by heating neat at high temperature such as at around 250 degrees . the s - aryl - n , n ′- dialkylthiocarbamate of formula 19 can then be converted to the sulfonyl chloride of formula 3 by oxidation using chlorine in a suitable inert solvent such as a mixture of formic acid and water at a temperature around 0 degrees . an example of the use of this process for the preparation of sulfonyl chlorides can be seen in v . percec et al . j . org . chem . 2001 , 66 , 2104 . amines of formula 5 can be purchased or they can be prepared using one of a large variety of different synthetic procedures well known in the field of organic synthesis , as outlined below . several thousand amines of formula 5 are commercially available from suppliers such as aldrich chemical company , inc . ( milwaukee , wisc . ), lancaster synthesis ltd . ( lancashire , uk ), tci america ( portland , oreg . ), and maybridge plc ( tintagel , cornwall , uk ). other examples of amines are found in the available chemicals directory ( mdl information systems , san leandro , calif .) or scifinder ( chemical abstracts service , columbus , ohio ). amines of formula 5 can also be made by reactions that are well known in the field of organic synthesis , such as those outlined in “ comprehensive organic transformations : a guide to functional group preparations ” [ r . c . larock , vch publishers , inc ., n . y . 1989 , pages 385 - 438 ] and in “ advanced organic chemistry ” [ j . march , 3 rd edition , wiley interscience , ny , 1985 ]. resin - bound amines of formula 5 in which r 2 represents a resin to which an amine can be attached can be prepared by reactions that are familiar to one of average skill in the art of solid - phase organic synthesis . for example , an amine of formula 5 where r 2 represent the fmpb resin can be prepared according to scheme 11 by treating fmpb resin ( 20 ) with a primary amine of formula 21 in the presence of a reducing agent such as sodium triacetoxyborohydride in an inert solvent such as a halogenated hydrocarbon ( such as 1 , 2 - dichloroethane ) at room temperature . some examples of amines that can be prepared by known methods are shown in the table below : tetrahydro - n - methyl - 3 - thiophenamine , b . loev j . org . chem . 1 , 1 - dioxide 1961 , 26 , 4394 tetrahydro - 3 - thiophenamine , thomas p . johnston et al . 1 , 1 - dioxide j . med . chem . 1971 , 14 , 600 2 - cyclohex - 1 - enyl - ethylamine r . s . coleman and j . a . shah synthesis 1999 , 1399 n -[( 4 - fluorophenyl ) methyl ]- s . casadio bollettino chimico benzeneethanamine , hydrochloride farmaceutico 1978 , v117 , p83 - 9 chemical abstracts can 90 : 16185 3 - isopropoxypropylamine j . c . little u . s . pat . no . 3 , 372 , 195 endo - norbornylamine r . f . borch et al . j . am . chem . soc . 1971 , 93 , 2897 n - cyclopropyl - n -( 2 - thienylmethyl )- n . r . easton de 1 , 568 , 438 amine bis -( 2 - methoxy - ethyl )- amine monsanto chm . co . u . s . pat . no . 2 , 876 , 243 in addition , a series of aminomethylpyrazoles can be prepared using the reductive amination procedure described by borch et al ( r . f . borch et al . j . am . chem . soc . 1971 , 93 , 2897 ), starting from pyrazole - carboxaldehydes that are commercially available , as shown in the table below : amine aldehyde aldehyde supplier 1 , 3 , 5 - trimethyl - 1h - 1 , 3 , 5 - trimethyl - 1h - maybridge plc , pyrazole - 4 - methylamine pyrazole - 4 - tintagel , carbaldehyde cornwall , uk 1 , 5 - dimethyl - 1h - 1 , 5 - dimethyl - 1h - fluorochem ltd ., pyrazole - 4 - methylamine pyrazole - 4 - old glossop , carbaldehyde derbyshire , uk 1 , 3 - dimethyl - 1h - 1 , 3 - dimethyl - 1h - acros organics pyrazole - 4 - methylamine pyrazole - 4 - usa , morris carbaldehyde plains , nj 5 - chloro - 1 , 3 - dimethyl - 5 - chloro - 1 , 3 - dimethyl - key organics 1h - pyrazole - 4 - 1h - pyrazole - 4 - limited / bionet methylamine carbaldehyde research , camelford , uk 4 - chloro - 1 - methyl - 1h - 4 - chloro - 1 - methyl - 1h - butt park ltd ., pyrazole - 3 - methylamine pyrazole - 3 - carbaldehyde bath , uk 4 - bromo - 1 - methyl - 1h - 4 - bromo - 1 - methyl - 1h - apollo scientific pyrazole - 3 - methylamine pyrazole - 3 - carbaldehyde ltd ., stockport , uk 1 - methyl - 1h - pyrazole - 4 - 1 - methyl - 1h - pyrazole - 4 - fluorochem ltd ., methylamine carbaldehyde old glossop , derbyshire , uk 1 - ethyl - 5 - methyl - 1h - 1 - ethyl - 5 - methyl - 1h - fluorochem ltd ., pyrazole - 4 - methylamine pyrazole - 4 - carbaldehyde old glossop , derbyshire , uk 1 - ethyl - 3 - methyl - 1h - 1 - ethyl - 3 - methyl - 1h - fluorochem ltd ., pyrazole - 4 - methylamine pyrazole - 4 - carbaldehyde old glossop , derbyshire , uk 1 - ethyl - 1h - pyrazole - 4 - 1 - ethyl - 1h - pyrazole - 4 - fluorochem ltd ., methylamine carbaldehyde old glossop , derbyshire , uk 1 - ethyl - 1h - pyrazole - 1 - ethyl - 1h - pyrazole - 2 , 5 - n . d . zelinsky 2 , 5 - dimethyl - 4 - dimethyl - 4 - carbaldehyde institute , methylamine moscow , russia 1 , 3 - dimethyl - 1h - 1 , 3 - dimethyl - 1h - maybridge plc , pyrazole - 5 - methylamine pyrazole - 5 - carbaldehyde tintagel , cornwall , uk 3 - methyl - 1 - propyl - 1h - 3 - methyl - 1 - propyl - 1h - ost - west pyrazole - 4 - methylamine pyrazole - 4 - carbaldehyde handelsservice , zepernick , germany 4 - bromo - 1 - methyl - 1h - 4 - bromo - 1 - methyl - 1h - maybridge plc , pyrazole - 5 - methylamine pyrazole - 5 - carbaldehyde tintagel , cornwall , uk 5 - chloro - 3 - ethyl - 1 - 5 - chloro - 3 - ethyl - 1 - oakwood products , methyl - 1h - pyrazole - 4 - methyl - 1h - pyrazole - 4 - inc ., west methylamine carboxaldehyde columbia , sc amines of formula 5 in which r 1 represents hydrogen and r 2 represents unsubstituted or substittued adamantane are either commercially available or can be made by methods that are well known to one of average skill in the art . examples of commercially available adamantan - 1 - yl - amines are shown in the table below . name supplier 1 - adamantanamine aldrich chemical company , inc ., milwaukee , wi 2 - adamantanamine hydrochloride aldrich chemical company , inc ., milwaukee , wi 3 , 5 , 7 - trimethyl - 1 - adamantanamine chemdiv , inc ., san diego , ca 3 , 5 - bis ( 1 - methylethyl )- 1 - microchemistry ltd ., adamantanamine hydrochloride moscow , russia 3 - amino - 1 - adamantanol aldrich chemical company , inc ., milwaukee , wi 3 - cyclohexyl - 1 - adamantanamine microchemistry ltd ., moscow , hydrochloride russia 3 - ethyl - 1 - adamantanamine apin chemicals ltd ., hydrochloride abingdon , uk 3 - ethyl - 5 , 7 - dimethyl - 1 - microchemistry ltd ., moscow , adamantanamine hydrochloride russia 3 - ethyl - 5 - methyl - 1 - adamantanamine microchemistry ltd ., moscow , hydrochloride russia 3 - isopropyl - 1 - adamantanamine chembridge , san diego , ca 3 - methyl - 1 - adamantanamine ambinter , paris , france hydrochloride 3 - n - propyl - 1 - adamantanamine chemdiv , inc ., san diego , ca 3 - trifluoromethyl - 1 - adamantanamine interchim , montlucon , hydrochloride france 4 - amino - 1 - adamantanol microchemistry ltd ., moscow , russia 5 - amino - 2 - adamantanol microchemistry ltd ., moscow , russia 5 - amino - 3 , 7 - dimethyl - adamantan - 1 - ol microchemistry ltd ., moscow , russia ( 5 - amino - 3 - methyl - adamantan - 1 - yl )- chemdiv , inc ., methanol san diego , ca memantine hydrochloride sigma , st . louis , moi amines of formula 5 in which r 1 represents hydrogen and r 2 represents unsubstituted or substituted adamantane which are not commercially available can be made using a number of different reactions known in the literature . for example , 2 - adamantanamine derivatives can be prepared from the corresponding adamantan - 2 - ones by conversion of the ketone to the oxime followed by reduction to the amine . such reactions can be carried out using the procedures described in k . banert et al . chem . ber . 1986 , 119 , 3826 - 3841 . 2 - adamantanamines can also be prepared from 4 - alkyl - 4 - protoadamantanols by a ritter reaction with acetonitrile in the presence of sulfuric acid to give the acetamide which is then hydrolyzed to give the 2 - adamantanamine , as described in d . lenoir et al . j . org . chem . 1971 , 36 , 1821 - 1826 . adamantanamines can be prepared from the corresponding 1 - adamantane - carboxamides using a hoffmann rearrangement or similar reaction . a variety of conditions for effecting this reaction are known in the art , and there have been a number of publications disclosing the application of this reaction for the preparation of 1 - adamantanamines . among these are the hypervalent iodine - mediated hoffmann rearrangement described in r . m . moriarty et al . synth . commun . 1988 , 18 , 1179 and g . loudon et al . j . org chem . 1984 , 49 , 4272 - 4276 , and the hypochlorite - mediated reaction reported in g . l . anderson et al . synth . commun . 1988 , 18 , 1967 . 1 - adamantanamines can also be prepared using the ritter reaction starting from the corresponding 1 - adamantanol and treating with chloro - acetonitrile under acidic conditions , followed by hydrolysis of the amide . the preparation of 1 - adamantanamine using such a process has been described by a . jirgensons et al . in synthesis 2000 , 1709 - 1712 . alternatively , 1 - adamantanamines can be prepared from the corresponding 1 - bromo - adamantanes using either ritter - like conditions followed by hydrolysis ( see k . gerzon et al . j . med . chem . 1963 , 6 , 760 - 763 or o . cervinka et al . collect . czech chem . commun . 1974 , 39 , 1592 - 1588 ), or by reaction of the 1 - bromo - adamantanes with acetamide followed by hydrolysis ( see k . gerzon et al . j . med . chem . 1967 , 10 , 603 - 606 ). the 1 - bromo - adamantanes are readily available by bromination of the hydroxy - adamantanes using bromine / triphenylphosphine or from the adamantane using bromine ( see j . g . henkel et al . j . med chem . 1982 , 25 , 51 - 56 ). 1 - adamantanamines can also be prepared from the corresponding 1 - adamantanols by displacement of the hydroxy group by azide under acidic conditions , followed by reduction of the azide ( see t . sasaki et al . j . org . chem . 1977 , 42 , 3741 - 3743 ). in the practice of the method of the present invention , an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt thereof , is administered via any of the usual and acceptable methods known in the art , either singly or in combination . the compounds or compositions can thus be administered orally ( e . g ., buccal cavity ), sublingually , parenterally ( e . g ., intramuscularly , intravenously , or subcutaneously ), rectally ( e . g ., by suppositories or washings ), transdermally ( e . g ., skin electroporation ) or by inhalation ( e . g ., by aerosol ), and in the form or solid , liquid or gaseous dosages , including tablets and suspensions . the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum . the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid , or in the form of a biodegradable sustained - release composition for subcutaneous or intramuscular administration . useful pharmaceutical carriers for the preparation of the compositions hereof , can be solids , liquids or gases ; thus , the compositions can take the form of tablets , pills , capsules , suppositories , powders , enterically coated or other protected formulations ( e . g . binding on ion - exchange resins or packaging in lipid - protein vesicles ), sustained release formulations , solutions , suspensions , elixirs , aerosols , and the like . the carrier can be selected from the various oils including those of petroleum , animal , vegetable or synthetic origin , e . g ., peanut oil , soybean oil , mineral oil , sesame oil , and the like . water , saline , aqueous dextrose , and glycols are preferred liquid carriers , particularly ( when isotonic with the blood ) for injectable solutions . for example , formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient ( s ) which are prepared by dissolving solid active ingredient ( s ) in water to produce an aqueous solution , and rendering the solution sterile . suitable pharmaceutical excipients include starch , cellulose , talc , glucose , lactose , gelatin , malt , rice , flour , chalk , silica , magnesium stearate , sodium stearate , glycerol monostearate , sodium chloride , dried skim milk , glycerol , propylene glycol , water , ethanol , and the like . the compositions may be subjected to conventional pharmaceutical additives such as preservatives , stabilizing agents , wetting or emulsifying agents , salts for adjusting osmotic pressure , buffers and the like . suitable pharmaceutical carriers and their formulation are described in remington &# 39 ; s pharmaceutical sciences by e . w . martin . such compositions will , in any event , contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient . the dose of a compound of the present invention depends on a number of factors , such as , for example , the manner of administration , the age and the body weight of the subject , and the condition of the subject to be treated , and ultimately will be decided by the attending physician or veterinarian . such an amount of the active compound as determined by the attending physician or veterinarian is referred to herein , and in the claims , as an “ effective amount ”. for example , the dose of a compound of the present invention is typically in the range of about 10 to about 1000 mg per day . the invention will now be further described in the examples below , which are intended as an illustration only and do not limit the scope of the invention . the following reagents were obtained from the vendors listed in the table , unless otherwise indicated in the experimental descriptions . starting material supplier 4 - acetamido - benzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 1 - adamantanamine aldrich chemical company , inc ., milwaukee , wi 1 - aminoindan aldrich chemical company , inc ., milwaukee , wi 2 - amino - 1 - methoxybutane tci america , portland , or benzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi benzylamine aldrich chemical company , inc ., milwaukee , wi 4 - bibenzenesulfonyl chloride fluka chemical corp ., milwaukee , wi 4 - n - butyl - benzenesulfonyl chloride maybridge plc , tintagel , cornwall , uk 4 - tert - butylcyclohexylamine tci america , portland , or 2 - chlorobenzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 2 - chlorobenzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 3 - chlorobenzenesulfonyl chloride lancaster synthesis ltd ., lancashire , uk 4 - chlorobenzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 2 - chloro - benzylamine aldrich chemical company , inc ., milwaukee , wi 3 - chloro - 4 - fluoro - benzenesulfonyl alfa aesar , ward hill , ma chloride 3 - chloro - 2 - methyl - benzenesulfonyl aldrich chemical company , chloride inc ., milwaukee , wi 2 -( 3 - chlorophenyl ) ethylamine aldrich chemical company , inc ., milwaukee , wi cyclohexylamine eastman kodak , rochester , ny cyclopentylamine lancaster synthesis ltd ., lancashire , uk decahydroisoquinoline aldrich chemical company , inc ., milwaukee , wi trans - decahydroisoquinoline tci america , portland , or decahydroquinoline aldrich chemical company , inc ., milwaukee , wi decahydroquinoline aldrich chemical company , inc ., milwaukee , wi 2 , 4 - dichlorobenzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 2 , 4 - dichlorobenzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 1 -( 3 - dimethylaminopropyl )- 3 - advanced chemtech , ethylcarbodiimide hydrochloride louisville , ky n , n - dimethylaminopyridine aldrich chemical company , inc ., milwaukee , wi 4 - fluoro - benzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 1 -( 4 - fluorophenyl ) ethylamine aldrich chemical company , inc ., milwaukee , wi 2 -( 2 - fluorophenyl ) ethylamine aldrich chemical company , inc ., milwaukee , wi 2 -( 4 - fluorophenyl ) ethylamine aldrich chemical company , inc ., milwaukee , wi hexamethyleneimine aldrich chemical company , inc ., milwaukee , wi hexamethyleneimine aldrich chemical company , inc ., milwaukee , wi 1 - hydroxybenzotriazole hydrate acros organics usa , morris plains , nj 4 - hydroxypiperidine aldrich chemical company , inc ., milwaukee , wi 4 - hydroxy - piperidine fluka chemical corp ., milwaukee , wi isoamylamine aldrich chemical company , inc ., milwaukee , wi isoamylamine aldrich chemical company , inc ., milwaukee , wi isobutylamine aldrich chemical company , inc ., milwaukee , wi isopropylamine aldrich chemical company , inc ., milwaukee , wi 4 - isopropyl - benzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi lithium hydroxide monohydrate aldrich chemical company , inc ., milwaukee , wi 4 - methoxy - benzenesulfonyl chloride aldrich chemical company , inc ., milwaukee , wi 2 - methoxy - benzylamine aldrich chemical company , inc ., milwaukee , wi 2 -( methoxycarbony )- benzenesulfonyl alfa aesar , ward hill , ma chloride 2 -( 2 - methoxyphenyl ) ethylamine tci america , portland , or 3 - methoxypropylamine lancaster synthesis ltd ., lancashire , uk methylamine aldrich chemical company , inc ., milwaukee , wi 2 - methyl - benzylamine aldrich chemical company , inc ., milwaukee , wi dl - alpha - methylbenzylamine aldrich chemical company , inc ., milwaukee , wi 4 - methylpiperidine aldrich chemical company , inc ., milwaukee , wi 4 - methyl - piperidine aldrich chemical company , inc ., milwaukee , wi morpholine aldrich chemical company , inc ., milwaukee , wi 2 -( 4 - morpholino )- ethylamine tci america , portland , or 1 - naphthalenemethylamine aldrich chemical company , inc ., milwaukee , wi 2 - naphthylsulfonyl chloride aldrich chemical company , inc ., milwaukee , wi nipecotic acid ethyl ester aldrich chemical company , inc ., milwaukee , wi phenethylamine aldrich chemical company , inc ., milwaukee , wi 2 - phenyl - propylamine aldrich chemical company , inc ., milwaukee , wi 3 - phenyl - propylamine aldrich chemical company , inc ., milwaukee , wi 8 - quinolinesulfonyl chloride lancaster synthesis ltd ., lancashire , uk 1 , 2 , 3 , 4 - tetrahydro - 1 - naphthylamine aldrich chemical company , inc ., milwaukee , wi thiophene - 2 - sulfonyl chloride aldrich chemical company , inc ., milwaukee , wi thiophene - 2 - sulfonyl chloride aldrich chemical company , inc ., milwaukee , wi triethylamine aldrich chemical company , inc ., milwaukee , wi 2 -( trifluoromethyl )- benzylamine aldrich chemical company , inc ., milwaukee , wi chlorobenzenesulfonyl chloride ( 0 . 25 ml , 1 . 8 mmol ) was added to a solution of ( r )-(+)- nipecotic acid ethyl ester ( available from aldrich chemical company ; inc ., milwaukee , wisc . ; 250 mg , 1 . 6 mmol ) and triethylamine ( 0 . 5 ml , 3 . 6 mmol ) in dichloromethane ( 5 ml ) under argon . an additional portion of dichloromethane ( 10 ml ) was added and the solution was stirred for five days at room temperature . the reaction mixture was washed with water and the water layer was back - extracted with dichloromethane . the combined organic layers were washed with 80 % saturated brine , dried ( magnesium sulfate ), filtered and evaporated to give ( 3r )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ethyl ester ( 561 mg ) as a colorless viscous oil , which was used directly in the next step . nmr indicated the presence of the desired product along with a small amount of dichloromethane . 1 m aqueous lithium hydroxide solution ( 3 . 5 ml ) was added to a solution of ( 3r )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ethyl ester ( from step 1 ; 560 mg ) in tetrahydrofuran ( 10 ml ). the reaction mixture was stirred overnight at room temperature , the solvent was evaporated , the residue was diluted with water and the solution was acidified to ph 1 . the solution was extracted three times with ethyl acetate , and the combined organic layers were washed with 80 % saturated brine , dried ( magnesium sulfate ), filtered and evaporated to give ( 3r )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 450 mg , 92 %) as a colorless semisolid . ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid was prepared from 2 - chlorobenzenesulfonyl chloride and ( s )-(+)- nipecotic acid ethyl ester ( available from aldrich chemical company , inc ., milwaukee , wisc . ; 166 mg , 1 . 1 mmol ) using the procedure described for the preparation of intermediate a1 . ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid was prepared from 2 - chlorobenzenesulfonyl chloride and ( rac )- nipecotic acid ethyl ester using the procedure described for the preparation of intermediate a1 . ( 3r )- 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid was prepared from 4 - chlorobenzenesulfonyl chloride and ( r )-(+)- nipecotic acid ethyl ester ( available from aldrich chemical company , inc ., milwaukee , wisc .) using the procedure described for the preparation of intermediate a1 . ( 3s )- 1 -( 2 , 4 - dichloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid was prepared from 2 , 4 - dichlorobenzenesulfonyl chloride and ( s )-(−)- nipecotic acid ethyl ester ( available from aldrich chemical company , inc ., milwaukee , wisc .) using the procedure described for the preparation of intermediate a1 . ( 3s )- 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid was prepared from 4 - chlorobenzenesulfonyl chloride and ( s )-(−)- nipecotic acid ethyl ester ( available from aldrich chemical company , inc ., milwaukee , wisc .) using the procedure described for the preparation of intermediate a1 . ( 3r )- 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid was prepared from thiophene - 2 - sulfonyl chloride and ( r )-(+)- nipecotic acid ethyl ester ( available from aldrich chemical company , inc ., milwaukee , wisc . ; 166 mg , 1 . 1 mmol ) using the procedure described for the preparation of intermediate a1 , with the following modification . a second equivalent of thiophene - 2 - sulfonyl chloride from a different bottle and a second equivalent of triethylamine were added to the reaction mixture because it was determined by nmr that the sulfonyl chloride had hydrolyzed . ( 3s )- 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid was prepared from thiophene - 2 - sulfonyl chloride and ( s )-(+)- nipecotic acid ethyl ester ( available from aldrich chemical company , inc ., milwaukee , wisc . ; 166 mg , 1 . 1 mmol ) using the procedure described for the preparation of intermediate a1 , with the following modification . a second equivalent of thiophene - 2 - sulfonyl chloride from a different bottle and a second equivalent of triethylamine were added to the reaction mixture because it was determined by nmr that the sulfonyl chloride had hydrolyzed . a solution of 2 - methylcyclopentanone ( 11 ml , 100 mmol ), hydroxylamine hydrochloride ( 17 . 76 g , 250 mmol ), and triethylamine ( 42 . 5 ml , 300 mmol ) in ethanol ( 150 ml ) was heated at reflux overnight . the solvent was evaporated and the residue was diluted with water and acidified to ph 1 . the mixture was extracted three times with ethyl acetate , and the combined organic layers were washed with water and brine , dried ( magnesium sulfate ), filtered and evaporated to give 2 - methylcyclopentanone oxime ( 10 g , 88 %) as a pale yellow oil . a solution of ethanolic hcl was prepared by adding acetyl chloride ( 2 ml ) to ethanol ( 100 ml ) at 5 degrees , then removing the cooling bath and allowing the solution to stir for 1 h at room temperature . 2 - methylcyclopentanone oxime ( from step 1 , 550 mg ) was added to this solution along with 10 % palladium - on - carbon ( two spatulas - full ). the mixture was hydrogenated overnight at atmospheric pressure , and then filtered through celite . the celite was washed well with ethanol , and the solvents were removed under vacuum . recrystallization from ethyl acetate gave 2 - methyl - cyclopentylamine hydrochloride as a brown solid ( 330 mg , 50 %). isoamylamine ( 0 . 12 ml , 1 . 0 mmol ) was added to a solution of ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a1 ; 248 mg , 0 . 8 mmol ), 1 - hydroxybenzotriazole hydrate ( 146 mg , 1 . 1 mmol ), n , n - dimethylaminopyridine ( 202 mg , 1 . 7 mmol ), and 1 -( 3 - dimethylaminopropyl )- 3 - ethylcarbodiimide hydrochloride ( 205 mg , 1 . 1 mmol ) in dichloromethane ( 10 ml ). the solution was stirred at room temperature for 5 days , and then diluted with dichloromethane , washed with 1 m hcl ( 20 ml ) and then brine ( 30 ml ), dried ( magnesium sulfate ), filtered and evaporated . the crude product was purified using an isco sg100c rs - 40 column , eluting with 15 - 50 % ethyl acetate / hexanes to give ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide ( 192 mg , 64 %) as a white solid . mass spectrum ( es ) mh += 373 . ( 3r )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide was prepared from ( 3r )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and isoamylamine using the procedure described for the preparation of example 1 . white solid . yield : 74 %. mass spectrum ( es ) mh += 373 . ( 3r )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide was prepared from ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a3 ) and 4 - hydroxypiperidine using the procedure described for the preparation of example 1 . white solid . yield : 67 %. mass spectrum ( es ) mh += 387 . ( 3r )- 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide was prepared from ( 3r )- 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a7 ) and cyclopentylamine using the procedure described for the preparation of example 1 . off - white solid . yield : 73 %. mass spectrum ( es ) mh += 343 . ( 3s )- 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide was prepared from ( 3s )- 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a8 ) and cyclopentylamine using the procedure described for the preparation of example 1 . off - white solid . yield : 73 %. mass spectrum ( es ) mh += 343 . ( 3r )- 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide was prepared from ( 3r )- 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a4 ) and cyclopentylamine using the procedure described for the preparation of example 1 . white solid . yield : 80 %. mass spectrum ( es ) mh += 371 . ( 3s )- 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide was prepared from ( 3s )- 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a4 ) and cyclopentylamine using the procedure described for the preparation of example 1 . white solid . yield : 69 %. mass spectrum ( es ) mh += 371 . ( rac )-[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]-( octahydro - quinolin - 1 - yl )- methanone was prepared from ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a3 ) and decahydroquinoline using the procedure described for the preparation of example 1 . white solid . yield : 87 %. mass spectrum ( es ) mh += 425 . ( rac )- azepan - 1 - yl -[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]- methanone was prepared from ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a3 ) and hexamethyleneimine using the procedure described for the preparation of example 1 . white solid . yield : 65 %. mass spectrum ( es ) mh += 385 . ( rac )-[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]-( 4 - methyl - piperidin - 1 - yl )- methanone was prepared from ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a3 ) and 4 - methylpiperidine using the procedure described for the preparation of example 1 . white solid . yield : 77 %. mass spectrum ( es ) mh += 385 . ( rac )-[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]-( 4 , 4 - dimethyl - piperidin - 1 - methanone was prepared from ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a3 ) and 4 , 4 - dimethylpiperidine ( prepared by the reduction of 3 , 3 - dimethyl - glutarimide using lithium aluminum hydride ; see d . hoch and p . karrer helv . chim . acta 1954 , 37 , 397 ) using the procedure described for the preparation of example 1 . white solid . yield : 82 %. mass spectrum ( es ) mh += 399 . ( 3s )- 1 -( 2 , 4 - dichloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide was prepared from ( 3s )- 1 -( 2 , 4 - dichloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a5 ) and cyclopentylamine using the procedure described for the preparation of example 1 . white solid . yield : 60 %. mass spectrum ( es ) mh += 405 . ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid adamantan - 1 - ylamide was prepared from ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and 1 - adamantanamine using the procedure described for the preparation of example 1 . white solid . yield : 86 %. mass spectrum ( es ) mh += 437 . ( 3 s )-( 7 - aza - bicyclo [ 2 . 2 . 1 ] hept - 7 - yl )-[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]- methanone was prepared from ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and 7 - aza - bicyclo [ 2 . 2 . 1 ] heptane hydrochloride ( tyger scientific inc ., ewing , n . j .) using the procedure described for the preparation of example 1 . white solid . yield : 76 %. mass spectrum ( es ) mh += 383 . ( 3s )-[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]-( octahydro - quinolin - 2 - yl )- methanone was prepared from ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and decahydroisoquinoline using the procedure described for the preparation of example 1 . white solid . yield : 84 %. mass spectrum ( es ) mh += 425 . ( 3s )-( 4ar , 8as )- rel -[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]-( octahydro - quinolin - 2 - yl )- methanone was prepared from ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and racemic - trans - decahydroisoquinoline ( tci america , portland , oreg .) using the procedure described for the preparation of example 1 . white solid . yield : 90 %. mass spectrum ( es ) mh += 425 . ( rac )-[ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]- morpholin - 4 - yl - methanone was prepared from ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and morpholine using the procedure described for the preparation of example 1 . white foam . yield : 56 %. mass spectrum ( es ) mh += 373 . ( 3s )-([ 1 -( 2 - chloro - benzenesulfonyl )- piperidin - 3 - yl ]-[( cis )- 1 , 3 , 3a , 4 , 7 , 7a - hexahydro - isoindol - 2 - yl ]- methanone was prepared from ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and cis - 2 , 3 , 3a , 4 , 7 , 7a - hexahydro - 1h - isoindole ( prepared by the procedure described in r . d . otzenberger et al . j . org . chem . 1974 , 39 , 319 ) using the procedure described for the preparation of example 1 . pale yellow semi - solid . yield : 41 %. mass spectrum ( es ) mh += 409 . ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - methyl - cyclopentyl )- amide was prepared from ( 3s )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a2 ) and 2 - methyl - cyclopentylamine hydrochloride ( of intermediate b1 ) using the procedure described for the preparation of example 1 . pale white solid . yield : 35 %. mass spectrum ( es ) mh += 385 . fmpb resin ( calbiochem - novabiochem corp ., san diego , calif . ; 4 -( 4 - formyl - 3 - methoxyphenoxy ) butyryl am resin , 50 - 100 mesh , loading 0 . 98 mmol / g ) was loaded into the irori minikans ( discovery partners international , san diego , calif . ; 85 mg of resin per can ). minikans to react with the same amine were combined together in one reaction vessel and suspended in a mixture of 1 , 2 - dichloroethane , sodium triacetoxyborohydride ( 7 eq . ), and the appropriate amine ( 7 eq .) and allowed to react overnight at room temperature . after the reaction solution was drained from each reaction vessel , minikans were washed twice with methanol and once with 10 % ( v / v ) triethylamine / dichloromethane . at this stage all minikans from different reaction vessels ( i . e . reacted with different amines ) were combined together and washed sequentially with dmf ( once ), methanol ( once ), and dichloromethane ( once ), and then with dmf ( twice ), methanol ( twice ), and dichloromethane ( twice ). the minikans were dried under vacuum overnight . the minikans from the previous step were suspended in a 50 / 50 mixture of dichoromethane and dmf , and then n - fmoc nipecotic acid ( chem - impex international , inc ., wood dale , ill . ; 7 eq . ), bromotris ( pyrrolydino ) phophonium hexafluorophosphate ( pybrop ; calbiochem - novabiochem corp ., san diego , calif . ; 7 eq .) or o - benzotriazole - n , n , n ′, n ′- tetramethyl - uronium - hexafluoro - phosphate ( hbtu ; alfa aesar , ward hill , mass . ; 7 eq . ), and diisopropylethylamine ( 7 eq .) were added . the reaction was carried out at room temperature overnight . after the reaction solution was drained from the reaction vessel , minikans were washed and dried as described above . the minikans were suspended in dmf solution of acetic anhydride ( 3 eq .) and diisopropylethylamine ( 6 eq .) and allowed to react for 2 hours at room temperature . after 2 hours the capping solution was drained and minikans were washed and dried as described above . the minikans were suspended in 20 % ( v / v ) piperidine / dmf solution and allowed to react for 2 hours at room temperature . after 2 hours the reaction solution was drained and minikans were washed and dried as described above . the minikans were sorted on the irori sorter for the sulfonylation reaction . minikans to react with the same sulfonyl chloride were combined together in one reaction vessel and suspended in dichloromethane . then the appropriate sulfonyl chloride ( 7 eq .) and diisopropylethylamine ( 7 eq .) were added and the reaction was allowed to go overnight at room temperature . after the reaction solution was drained from each reaction vessel , minikans were washed with dichloromethane in each individual reaction vessel . at this stage all minikans from different reaction vessels ( i . e . reacted with different sulfonyl chlorides ) were combined together and washed as described above . the minikans were then dried under vacuum overnight . the minikans were sorted on the irori sorter for cleavage . the final products were cleaved from the solid support on the irori cleavage station as follows : tfa / dichloromethane ( 50 / 50 , v / v ; 3 ml ) was added to each well . after 3 hours the solution was drained and collected , and each well containing a minikan was rinsed with dichloromethane ( 3 ml ) for 20 minutes . the rinse was combined with the solution from the cleavage step and the combined solution was evaporated to dryness on the genevac . the products were analyzed by lc - ms . compounds with purity less than 85 % were purified as follows : samples were dissolved in mixtures of methanol , acn and dmso and purified using the following instruments : sciex 150 ex mass spec , gilson 215 collector , shimadzu prep hplc system , leap autoinjector . all compounds were purified using tfa buffers lc / ms in the positive ion detection : solvent ( a ) 0 . 05 % tfa / h20 ( b ) 0 . 035 % tfa / acn , using the appropriate linear gradient mode in 10 minutes , with a c - 18 column , 2 . 0 × 10 cm eluting at 20 ml / min and mass directed collection the following compounds were prepared by solid phase synthesis , using the amines and sulfonyl chlorides indicated : m + h example structure sulfonyl chloride amine name observed 20 2 -( methoxycarbonyl )- benzenesulfonyl chloride 2 - phenyl - propylamine 2 -[ 3 -( 2 - phenyl - propylcarbamoyl )- piperidine - 1 - sulfonyl ]- benzoic acid methyl ester 445 21 2 -( methoxycarbonyl )- benzenesulfonyl chloride cyclohexyl - methylamine 2 -[ 3 - ( cyclohexyl - methyl - carbamoyl )- piperidine - 1 - sulfonyl ]- benzoic acid methyl ester 423 22 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl chloride 2 -( 2 - methoxy - phenyl )- ethylamine 1 -( 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - methoxy - phenyl )- ethyl ]- amide 485 23 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 471 24 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl chloride cyclopropyl - methylamine 1 -( 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 405 25 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl chloride n -( 3 - aminopropyl )- n - methylaniline 1 -( 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 3 -( methyl - phenyl - amino )- propyl ]- amide 498 26 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 2 , 4 - dichloro - 5 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 461 27 2 , 5 - dimethyl - 4 - chloro - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 4 - chloro - 2 , 5 - dimethyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 451 28 2 , 5 - dimethyl - 4 - chloro - benzenesulfonyl chloride cyclopentylamine 1 -( 4 - chloro - 2 , 5 - dimethyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 399 29 2 . 5 - dimethyl - chloro - benzenesulfonyl chloride cyclopropyl - methylamine 1 -( 4 - chloro - 2 , 5 - dimethyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 385 30 2 , 5 - dimethyl - 4 - chloro - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 4 - chloro - 2 , 5 - dimethyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 441 31 2 - chloro - 4 - trifluoromethyl - bezenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 2 - chloro - 4 - trifluoromethyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 481 32 2 - chloro - 5 - trifluoromethyl - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 2 - chloro - 5 - trifluoromethyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 491 33 2 - chloro - 5 - trifluoromethyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 2 - chloro - 5 - trifluoromethyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 481 34 2 - chloro - 6 - methyl - benzenesulfonyl chloride 2 -( 2 , 3 - dimethoxy - phenyl )- ethylamine 1 -( 2 - chloro - 6 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 , 3 - dimethoxy - phenyl )- ethyl ]- amide 481 35 2 - chloro - 6 - methyl - benzenesulfonyl chloride 2 -( 2 - methoxy - phenyl )- ethylamine 1 -( 2 - chloro - 6 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - methoxy - phenyl )- ethyl ]- amide 451 36 2 - chloro - 6 - methyl - benzenesulfonyl chloride 2 -( morpholin - 4 - yl )- ethylamine 1 -( 2 - chloro - 6 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - morpholin - 4 - yl - ethyl )- amide ; compound with trifluoro - acetic acid 430 37 2 - chloro - 6 - methyl - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 2 - chloro - 6 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 437 38 2 - chloro - 6 - methyl - benzenesulfonyl chloride cyclopropyl - methylamine 1 -( 2 - chloro - 6 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 371 39 2 - chloro - 6 - methyl - benzenesulfonyl chloride n -( 3 - aminopropyl )- n - methylaniline 1 -( 2 - chloro - 6 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 3 -( methyl - phenyl - amino )- propyl ]- amide ; compound with trifluoro - acetic acid 464 40 2 - chloro - 6 - methyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 2 - chloro - 6 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 427 41 2 - chloro - benzenesulfonyl chloride 1 -( 4 - fluorophenyl ) ethyl - amine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 1 -( 4 - fluoro - phenyl )- ethyl ]- amide 425 42 2 - chloro - benzenesulfonyl chloride 1 - aminoindan 1 -( 2 - chloro - benzenesulfonyl )- benzenesulfonyl )- piperidine - 3 - carboxylic acid indan - 1 - ylamide 419 43 2 - chloro - benzenesulfonyl chloride 1 - naphthalenemethyl - amine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( naphthalen - 1 - ylmethyl )- amide 443 44 2 - chloro - benzenesulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 425 45 2 - chloro - benzenesulfonyl chloride 2 -( 4 - fluorophenyl ) ethyl - amine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 4 - fluoro - phenyl )- ethyl ]- amide 425 46 2 - chloro - benzenesulfonyl chloride 2 - ( trifluoromethyl )- benzylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - trifluoromethyl - benzylamide 461 47 2 - chloro - benzenesulfonyl chloride 2 - chloro - benzylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - chloro - benzylamide 427 48 2 - chloro - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 423 49 2 - chloro - benzenesulfonyl chloride 2 - methyl - benzylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 407 50 2 - chloro - benzenesulfonyl chloride 2 - phenyl - propylamine 1 -( 2 - chloro - benzenesulfonyl )- benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - phenyl - propyl )- amide 421 51 2 - chloro - benzenesulfonyl chloride 3 - phenyl - propylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - phenyl - propyl )- amide 421 52 2 - chloro - benzenesulfonyl chloride benzylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid benzylamide 393 53 2 - chloro - benzenesulfonyl chloride cyclohexyl - methylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 399 54 2 - chloro - benzenesulfonyl chloride cyclohexylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 385 55 2 - chloro - benzenesulfonyl chloride cyclopentamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 371 56 2 - chloro - benzenesulfonyl chloride cyclopropyl - methylamide 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 357 57 2 - chloro - benzenesulfonyl chloride dl - alpha - methylbenzyl - amine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 1 - phenyl - ethyl )- amide 407 58 2 - chloro - benzenesulfonyl chloride isoamylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 373 59 2 - chloro - benzenesulfonyl chloride isobutylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid isobutyl - amide 359 60 2 - chloro - benzenesulfonyl chloride phenethylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid phenethyl - amide 407 61 2 - chloro - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 413 62 2 - methoxycarbonyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 2 -[ 3 -( 2 - thiophene - 2 - yl - ethylcarbamoyl )- piperidine - 1 - sulfonyl ]- benzoic acid methyl ester 437 63 2 - methoxycarbonyl - thiophene - 3 - sulfonyl chloride 2 - methoxy - benzylamine 3 -[ 3 -( 2 - methoxy - benzylcarbamoyl )- piperidine - 1 - sulfonyl ]- thiophene - 2 - carboxylic acid methyl ester 453 64 2 - methoxycarbonyl - thiophene - 3 - sulfonyl chloride thiophene - 2 - ethylamine 3 -[ 3 -( 2 - thiophen - 2 - yl - ethylcarbamoyl )- piperidine - 1 - thiophene - 2 - carboxylic acid methyl ester 443 65 2 - methyl - benzenesulfonyl chloride 2 -( 2 - methoxy - phenyl )- ethylamine 1 -( toluene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - methoxy - phenyl )- ethyl ]- amine 417 66 2 - methyl - benzenesulfonyl chloride 2 -( acetamido )- ethylamine 1 -( toluene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - acetylamino - ethyl )- amide 368 67 2 - methyl - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( toluene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 403 68 2 - methyl - benzenesulfonyl chloride cyclopentylamine 1 -( toluene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 351 69 2 - methyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( toluene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl )- ethyl )- amide 393 70 2 - naphthylsulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( naphthalene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 441 71 2 - naphthylsulfonyl chloride 2 - methyl - benzylamine 1 -( naphthalene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 423 72 2 - naphthylsulfonyl chloride 3 - phenyl - propylamine 1 -( naphthalene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 3 - phenyl - propyl )- amide 437 73 2 - naphthylsulfonyl chloride cyclohexylamine 1 -( naphthalene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 401 74 2 - naphthylsulfonyl chloride isoamylamine 1 -( naphthalene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 389 75 3 - chloro - 2 - methyl - benzenesulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 439 76 3 - chloro - 2 - methyl - benzenesulfonyl chloride 2 -( 2 - methoxy - phenyl )- ethylamine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - methoxy - phenyl )- ethyl ]- amide 451 77 3 - chloro - 2 - methyl - benzenesulfonyl chloride 2 -( 4 - fluorophenyl ) ethyl - amine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 4 - fluoro - phenyl )- ethyl ]- amide 439 78 3 - chloro - 2 - methyl - benzenesulfonyl chloride 2 -( morpholin - 4 - yl )- ethylamine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - morpholin - 4 - yl - ethyl )- amide ; compound with trifluoro - acetic acid 430 79 3 - chloro - 2 - methyl - benzenesulfonyl chloride 2 - methyl - benzylamine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 421 80 3 - chloro - 2 - methyl - benzenesulfonyl chloride 3 - phenyl - propylamine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - phenyl - propyl )- amide 435 81 3 - chloro - 2 - methyl - benzenesulfonyl chloride cyclopentylamine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 385 82 3 - chloro - 2 - methyl - benzenesulfonyl chloride cyclopropyl - methylamine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 371 83 3 - chloro - 2 - methyl - benzenesulfonyl chloride n -( 3 - aminopropyl )- n - methylaniline 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 3 -( methyl - phenyl - amino )- compound with trifluoro - acetic acid 464 84 3 - chloro - 2 - methyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 3 - chloro - 2 - methyl - benzenesulfonyl )- pipendine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 427 85 3 - chloro - 4 - fluoro - benzenesulfonyl chloride 2 -( 2 - methoxyphenyl ) ethyl - amine 1 -( 3 - chloro - 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - methoxy - phenyl )- ethyl ]- amide 455 86 3 - chloro - 4 - fluoro - benzenesulfonyl chloride 2 -( pyrrolidin - 1 - yl )- ethylamine 1 -( 3 - chloro - 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - pyrrolidin - 1 - yl - ethyl )- amide ; compound with trifluoro - acetic acid 418 87 3 - chloro - 4 - fluoro - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 3 - chloro - 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 441 88 3 - chloro - 4 - fluoro - benzenesulfonyl chloride cyclopentylamine 1 -( 3 - chloro - 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 389 89 3 - chloro - 4 - fluoro - benzenesulfonyl chloride cyclopropyl - methylamine 1 -( 3 - chloro - 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 375 90 3 - chloro - 4 - fluoro - benzenesulfonyl chloride n -( 3 - aminopropyl )- n - methylaniline 1 -( 3 - chloro - 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 3 -( methyl - phenyl - amino )- propyl ]- amide ; compound with trifluoro - acetic acid 468 91 3 - chloro - 4 - methyl - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 3 - chloro - 4 - methyl - benzenesulfonyl )- methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 437 92 3 - chloro - 4 - methyl - benzenesulfonyl chloride 3 -( n , n - diisopropylamino )- propylamine 1 -( 3 - chloro - 4 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - diisopropylamino - ethyl )- amide ; compound with trifluoro - acetic acid 444 93 3 - chloro - 4 - methyl - benzenesulfonyl chloride pyridine - 4 - methylamine 1 -( 3 - chloro - 4 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( pyridin - 4 - ylmethyl )- amide ; compound with trifluoro - acetic acid 408 94 3 - chloro - 4 - methyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 3 - chloro - 4 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 427 95 3 - chloro - 6 - methoxy - benzenesulfonyl chloride cyclopentylamine 1 -( 5 - chloro - 2 - methoxy - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 401 96 3 - chloro - benzenesulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( 3 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 425 97 3 - chloro - benzenesulfonyl chloride 2 -( 4 - fluorophenyl ) ethyl - amine 1 -( 3 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 4 - fluoro - phenyl )- ethyl ]- amide 425 98 3 - chloro - benzenesulfonyl chloride 2 - methyl - benzylamine 1 -( 3 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 407 99 3 - chloro - benzenesulfonyl chloride 3 - phenyl - propylamine 1 -( 3 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - phenyl - propyl )- amide 421 100 3 - chloro - benzenesulfonyl chloride cyclohexyl - methylamine 1 -( 3 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 399 101 3 - chloro - benzenesulfonyl chloride cyclohexylamine 1 -( 3 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 385 102 3 - fluoro - 4 - methyl - benzenesulfonyl chloride 2 -( 2 , 3 - dimethoxy - phenyl )- ethylamine 1 -( 3 - fluoro - 4 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 , 3 - dimethoxy - phenyl )- ethyl ]- amide 465 103 3 - fluoro - 4 - methyl - benzenesulfonyl chloride cyclopentylamine 1 -( 3 - fluoro - 4 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 369 104 3 - fluoro - 6 - methyl - benzene - sulfonyl chloride 2 -( 2 - methoxy - phenyl )- ethylamine 1 -( 5 - fluoro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - methoxy - phenyl )- ethyl ]- amide 435 105 3 - fluoro - 6 - methyl - benzene - sulfonyl chloride 2 - methoxy - benzylamine 1 -( 5 - fluoro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 421 106 3 - fluoro - 6 - methyl - benzene - sulfonyl chloride cyclopentylamine 1 -( 5 - fluoro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 369 107 4 - acetamido - benzenesulfonyl chloride cyclohexyl - methylamine 1 -( 4 - acetylamino - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 422 108 4 - acetamido - benzenesulfonyl chloride cyclohexylamine 1 -( 4 - acetylamino - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 408 109 4 - bibenzenesulfonyl chloride 2 -( 4 - morpholino )- ethylamine 1 -( biphenyl - 4 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - morpholin - 4 - yl - ethyl )- amide ; compound with trifluoro - acetic acid 458 110 4 - bibenzenesulfonyl chloride 2 - phenyl - propylamine 1 -( biphenyl - 4 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - phenyl - propyl )- amide 463 111 4 - bibenzenesulfonyl chloride cyclohexyl - methylamine 1 -( biphenyl - 4 - sulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 441 112 4 - bibenzenesulfonyl chloride cyclohexylamine 1 -( biphenyl - 4 - sulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 427 113 4 - bibenzenesulfonyl chloride cyclopentamine 1 -( biphenyl - 4 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 413 114 4 - bibenzenesulfonyl chloride isoamylamine 1 -( biphenyl - 4 - sulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 415 115 4 - chloro - benzenesulfonyl chloride 1 , 2 , 3 , 4 - tetrahydro - 1 - naphthylamine 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 1 , 2 , 3 , 4 - tetrahydro - naphthalen - 1 - yl )- amide 433 116 4 - chloro - benzenesulfonyl chloride 2 -( trifluoromethyl )- benzylamine 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - trifluoromethyl - benzylamide 461 117 4 - chloro - benzenesulfonyl chloride 2 - phenyl - propylamine 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - phenyl - propyl )- amide 421 118 4 - chloro - benzenesulfonyl chloride cyclohexyl - methylamine 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 399 119 4 - chloro - benzenesulfonyl chloride cyclohexylamine 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 385 120 4 - chloro - benzenesulfonyl chloride cyclopentamine 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 371 121 4 - chloro - benzenesulfonyl chloride isoamylamine 1 -( 4 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 373 122 4 - fluoro - 2 - methyl - benzenesulfonyl chloride 2 - methoxy - benzylamine 1 -( 4 - fluoro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 421 123 4 - fluoro - 2 - methyl - benzenesulfonyl chloride cyclopentylamine 1 -( 4 - fluoro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 369 124 4 - fluoro - 2 - methyl - benzenesulfonyl chloride cyclopropyl - methylamine 1 -( 4 - fluoro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 355 125 4 - fluoro - 2 - methyl - benzenesulfonyl chloride thiophene - 2 - ethylamine 1 -( 4 - fluoro - 2 - methyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 411 126 4 - fluoro - benzenesulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 409 127 4 - fluoro - benzenesulfonyl chloride 2 -( 4 - fluorophenyl ) ethyl - amine 1 -( 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 4 - fluoro - phenyl )- ethyl ]- amide 409 128 4 - fluoro - benzenesulfonyl chloride 2 - methyl - benzylamine 1 -( 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 391 129 4 - fluoro - benzenesulfonyl chloride 3 - phenyl - propylamine 1 -( 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - phenyl - propyl )- amide 405 130 4 - fluoro - benzenesulfonyl chloride cyclohexylamine 1 -( 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 369 131 4 - fluoro - benzenesulfonyl chloride isomaylamine 1 -( 4 - fluoro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 357 132 4 - isopropyl - benzenesulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( 4 - isopropyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 433 133 4 - isopropyl - benzenesulfonyl chloride 2 - methyl - benzylamine 1 -( 4 - isopropyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 415 134 4 - isopropyl - benzenesulfonyl chloride cyclohexyl - methylamine 1 -( 4 - isopropyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 407 135 4 - isopropyl - benzenesulfonyl chloride cyclohexylamine 1 -( 4 - isopropyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 393 136 4 - methoxy - benzenesulfonyl chloride 1 - naphthalene - methylamine 1 -( 4 - methoxy - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( naphthalen - 1 - ylmethyl )- amide 439 137 4 - methoxy - benzenesulfonyl chloride 2 - phenyl - propylamine 1 -( 4 - methoxy - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 2 - phenyl - propyl )- amide 417 138 4 - methoxy - benzenesulfonyl chloride cyclohexyl - methylamine 1 -( 4 - methoxy - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 395 139 4 - methoxy - benzenesulfonyl chloride cyclohexylamine 1 -( 4 - methoxy - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamine 381 140 4 - methoxy - benzenesulfonyl chloride isoamylamine 1 -( 4 - methoxy - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 369 141 4 - methyl - 3 , 4 - dihydro - 2h - benzp [ 1 , 4 ] oxazone - 7 - sulfonyl 2 - methoxy - benzylamine 1 -( 4 - methyl - 3 , 4 - dihydro - 2h - benzo [ 1 , 4 ] oxazine - 7 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamine ; compound with trifluoro - acetic acid 460 142 4 - methyl - 3 , 4 - dihydro - 2h - benzo [ 1 , 4 ] oxazine - 7 - sulfonyl cyclopropyl - methylamine 1 -( 4 - methyl - 3 , 4 - dihydro - 2h - benzo [ 1 , 4 ] oxazine - 7 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide ; compound with trifluoro - acetic acid 394 143 4 - methyl - 3 , 4 - dihydro - 2h - benzo [ 1 , 4 ] oxazine - 7 - sulfonyl thiophene - 2 - ethylamine 1 -( 4 - methyl - 3 , 4 - dihydro - 2h - benzo [ 1 , 4 ] oxazine - 7 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide ; compound with trifluoro - acetic acid 450 144 4 - n - butyl - benzenesulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( 4 - butyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 447 145 4 - n - butyl - benzenesulfonyl chloride 2 - methyl - benzylamine 1 -( 4 - butyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 429 146 4 - n - butyl - benzenesulfonyl chloride cyclohexyl - methylamine 1 -( 4 - butyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 421 147 4 - n - butyl - benzenesulfonyl chloride isopropylamine 1 -( 4 - butyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid isopropylamide 367 148 4 - n - butyl - benzenesulfonyl chloride methylamine 1 -( 4 - butyl - benzenesulfonyl )- piperidine - 3 - carboxylic acid methylamide 339 149 5 - chloro - 3 - methyl - benzo [ b ] thiophene - 2 - sulfonyl chloride cyclopentylamine 1 -( 5 - chloro - 3 - methyl - benzo [ b ] thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 441 150 5 - chloro - thiophene - sulfonyl chloride 2 -( 2 - methoxy - phenyl )- ethylamine 1 -( 5 - chloro - thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - methoxy - phenyl )- ethyl ]- amide 443 151 5 - chloro - thiophene - sulfonyl chloride 2 - methoxy - benzylamine 1 -( 5 - chloro - thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 429 152 5 - chloro - thiophene - sulfonyl chloride cyclopentylamine 1 -( 5 - chloro - thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 377 153 5 - chloro - thiophene - sulfonyl chloride thiophene - 2 - ethylamine 1 -( 5 - chloro - thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 419 154 8 - quinolinesulfonyl chloride 1 - aminoindan 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid indan - 1 - ylamide 436 155 8 - quinolinesulfonyl chloride 1 - naphthalenemethyl - amine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid ( naphthalen - 1 - ylmethyl )- amide 460 156 8 - quinolinesulfonyl chloride 2 -( 2 - fluorophenyl ) ethyl - amine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 442 157 8 - quinolinesulfonyl chloride 2 -( 3 - chlorophenyl ) ethyl - amine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 3 - chloro - phenyl )- ethyl ]- amide 458 158 8 - quinolinesulfonyl chloride 2 - chloro - benzylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - chloro - benzylamide 444 159 8 - quinolinesulfonyl chloride 2 - phenyl - propylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - phenyl - propyl )- amide 438 160 8 - quinolinesulfonyl chloride 4 - tert - butylcyclohexyl - amine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid 4 - tert - butyl - cyclohexyl )- amide 458 161 8 - quinolinesulfonyl chloride cyclohexyl - methylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 416 162 8 - quinolinesulfonyl chloride cyclohexylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 402 163 8 - quinolinesulfonyl chloride cyclopentamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopentylamide 388 164 8 - quinolinesulfonyl chloride isoamylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 390 165 8 - quinolinesulfonyl chloride isobutylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid isobutyl - amide 376 166 8 - quinolinesulfonyl chloride phenethylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid phenethyl - amide 424 167 benzenesulfonyl chloride 1 -( 4 - fluoro - phenyl ) ethyl - amine 1 - benzenesulfonyl )- piperidine - 3 - carboxylic acid [ 1 -( 4 - fluoro - phenyl )- ethyl ]- amide 391 168 benzenesulfonyl chloride 1 , 2 , 3 , 4 - tetrahydro - 1 - naphthylamine 1 - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 1 , 2 , 3 , 4 - tetrahydro - naphthalen - 1 - yl )- amide 399 169 benzenesulfonyl chloride 1 - aminoindan 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid indan - 1 - ylamide 385 170 benzenesulfonyl chloride 1 - naphthalene - methylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid ( naphthalen - 1 - ylmethyl )- amide 409 171 benzenesulfonyl chloride 2 -( 2 - fluoro - phenyl ) ethylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 391 172 benzenesulfonyl chloride 2 -( trifluoromethyl )- benzylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid 2 - trifluoromethyl - benzylamide 427 173 benzenesulfonyl chloride 2 - amino - 1 - methoxybutane 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid ( 1 - methoxymethyl - propyl )- amide 355 174 benzenesulfonyl chloride 2 - chloro - benzylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid 2 - chloro - benzylamide 393 175 benzenesulfonyl chloride 2 - methyl - benzylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid 2 - methyl - benzylamide 373 176 benzenesulfonyl chloride 2 - phenyl - propylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid ( 2 - phenyl - propyl )- amide 387 177 benzenesulfonyl chloride 3 - methoxypropyl - amine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid ( 3 - methoxy - propyl )- amide 341 178 benzenesulfonyl chloride 3 - phenyl - propylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid ( 3 - phenyl - propyl )- amide 387 179 benzenesulfonyl chloride cyclohexyl - methylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 365 180 benzenesulfonyl chloride cyclohexylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid cyclohexylamide 351 181 benzenesulfonyl chloride cyclopentamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid cyclopentylamide 337 182 benzenesulfonyl chloride isoamylamine 1 - benzenesulfonyl - piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 339 183 biphenyl - 4 - sulfonyl cyclopropyl - methylamine 1 -( biphenyl - 4 - sulfonyl )- piperidine - 3 - carboxylic acid cyclopropylmethyl - amide 399 184 quinoline - 8 - sulfonyl chloride n -( 3 - aminopropyl )- n - methylaniline 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid [ 3 -( methyl - phenyl - amino )- propyl ]- amide ; compound with trifluoro - acetic acid 467 185 quinoline - 8 - sulfonyl chloride thiophene - 2 - ethylamine 1 -( quinoline - 8 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - thiophen - 2 - yl - ethyl )- amide 430 186 thiophene - 2 - sulfonyl chloride 1 -( 4 - fluoro - phenyl ) ethylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid [ 1 -( 4 - fluoro - phenyl )- ethyl ]- amide 397 187 thiophene - 2 - sulfonyl chloride 1 , 2 , 3 , 4 - tetrahydro - 1 - naphthylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 1 , 2 , 3 , 4 - tetrahydro - naphthalen - 1 - yl )- amide 405 188 thiophene - 2 - sulfonyl chloride 1 - aminoindan 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid indan - 1 - ylamide 391 189 thiophene - 2 - sulfonyl chloride 1 - naphthalene - methylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( naphthalen - 1 - ylmethyl )- amide 415 190 thiophene - 2 - sulfonyl chloride 2 -( 2 - fluoro - phenyl ) ethylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid [ 2 -( 2 - fluoro - phenyl )- ethyl ]- amide 397 191 thiophene - 2 - sulfonyl chloride 2 -( trifluoromethyl )- benzylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - trifluoromethyl - benzylamide 433 192 thiophene - 2 - sulfonyl chloride 2 - chloro - benzylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - chloro - benzylamide 399 193 thiophene - 2 - sulfonyl chloride 2 - methoxy - benzylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid 2 - methoxy - benzylamide 395 194 thiophene - 2 - sulfonyl chloride 2 - phenyl - propylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 2 - phenyl - propyl )- amide 393 195 thiophene - 2 - sulfonyl chloride 4 - tert - butylcyclohexyl - amine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 4 - tert - butyl - cyclohexyl )- amide 413 196 thiophene - 2 - sulfonyl chloride cyclohexyl - methylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclohexylmethyl - amide 371 197 thiophene - 2 - sulfonyl chloride cyclohexylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid cyclohexylamide 357 198 thiophene - 2 - sulfonyl chloride cyclopentamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxyhc acid cyclopentylamide 343 199 thiophene - 2 - sulfonyl chloride dl - alpha - methylbenzyl - amine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 1 - phenyl - ethyl )- amide 379 200 thiophene - 2 - sulfonyl chloride isoamylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid ( 3 - methyl - butyl )- amide 345 201 thiophene - 2 - sulfonyl chloride phenethylamine 1 -( thiophene - 2 - sulfonyl )- piperidine - 3 - carboxylic acid phenethyl - amide 379 3 , 5 , 7 - trimethyl - 1 - adamantanamine ( which can be prepared by the procedure described in j . g . henkel and j . t . hane j . med chem . 1982 , 25 , 51 - 56 ) ( approx . 1 . 0 equiv ) is added to a solution of ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a1 ; approx . 0 . 8 equiv ), 1 - hydroxybenzotriazole hydrate ( 1 . 1 equiv ), n , n - dimethylaminopyridine ( approx . 1 . 7 equiv ), and 1 -( 3 - dimethylaminopropyl )- 3 - ethylcarbodiimide hydrochloride ( approx . 1 . 1 equiv ) in dichloromethane ( approx . 10 ml per equivalent ). the solution is stirred for 24 h , and then diluted with dichloromethane , washed with 1 m hcl and then brine , dried ( magnesium sulfate ), filtered and evaporated . the crude product is purified by column chromatography , eluting with ethyl acetate / hexanes to give ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 , 5 , 7 - trimethyl - adamantan - 1 - yl )- amide . amino - 1 - adamantanol ( aldrich chemical company , inc ., milwaukee , wisc .) ( approx . 1 . 0 equiv ) is added to a solution of ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( of intermediate a1 ; approx . 0 . 8 equiv ), 1 - hydroxybenzotriazole hydrate ( 1 . 1 equiv ), n , n - dimethylaminopyridine ( approx . 1 . 7 equiv ), and 1 -( 3 - dimethylaminopropyl )- 3 - ethylcarbodiimide hydrochloride ( approx . 1 . 1 equiv ) in dichloromethane ( approx . 10 ml per equivalent ). the solution is stirred for 24 h , and then diluted with dichloromethane , washed with 1 m hcl and then brine , dried ( magnesium sulfate ), filtered and evaporated . the crude product is purified by column chromatography , eluting with ethyl acetate / hexanes to give ( rac )- 1 -( 2 - chloro - benzenesulfonyl )- piperidine - 3 - carboxylic acid ( 3 - hydroxy - adamantan - 1 - yl )- amide . the in vitro inhibition of 11β - hsd1 by compounds of the present invention were demonstrated by means of the following test : purified human hsd1 was diluted in 50 mm tris - hcl , 100 mm nacl , 0 . 1 mg / ml bsa , 0 . 02 % lubrol , 20 mm mgcl2 , 10 mm glucose 6 - phosphate , 0 . 4 mm nadph , 60 u / ml glucose 6 - phosphate dehydrogenase to a concentration of 1 . 5 ug / ml ( enzyme solution ). cortisone ( 100 um ) in dmso was diluted to 1 um with 50 mm tris - hcl , 100 mm nacl ( substrate solution ). testing compounds ( 40 um ) in dmso was diluted 3 fold in series in dmso and further diluted 20 fold in substrate solution . enzyme solution ( 10 ul / well ) was added into 384 well microtiter plates followed by diluted compound solutions ( 10 ul / well ) and mixed well . samples were then incubated at 370 c for 30 min . edta / biotin - cortisol solution ( 10 ul / well ) in 28 mm edta , 100 nm biotin - cortisol , 50 mm tris - hcl , 100 mm nacl was then added followed by 5 ul / well of anti - cortisol antibody ( 3 . 2 ug / ml ) in 50 mm tris - hcl , 100 mm nacl , 0 . 1 mg / ml bsa and the solution was incubated at 37 degrees for 30 min . five ul per well of eu - conjugated anti - mouse igg ( 16 nm ) and apc - conjugated streptavidin ( 160 nm ) in 50 mm tris - hcl , 100 mm nacl , 0 . 1 mg / ml bsa was added and the solution was incubated at room temperature for 2 hours . signals were quantitated by reading time - resolved fluorescence on a victor 5 reader ( wallac ). percent inhibition of hsd1 activity by an agent at various concentrations was calculated by the formula % inhibition = 100 *[ 1 −( fs − fb )/( ft − fb )], where : fs is the fluorescence signal of the sample which included the agent , fb is the fluorescence signal in the absence of hsd1 and agent , ft is the fluorescence signal in the presence of hsd1 , but no agent . the inhibitory activities of test compounds were determined by the ic 50 s , or the concentration of compound that gave 50 % inhibition . the results of the in vitro inhibition of 11β - hsd1 by representative compounds of the present invention are shown in the following table : compound hhsd1 ic 50 ( μm ) example 2 0 . 29 example 43 0 . 025 example 50 0 . 031 example 73 0 . 047 example 80 12 example 128 3 example 135 0 . 39 example 157 0 . 91 example 169 0 . 39 example 173 0 . 94 example 175 3 example 187 0 . 19 the in vivo inhibition of 11β - hsd1 by compounds of the present invention can be demonstrated by means of the following test : the compound of the invention is formulated in 7 . 5 % modified gelatin in water and is administered ip at 100 mg / kg to mice ( male c57b1 / 6j , age ˜ 97 days ). after 30 minutes , cortisone formulated in gelatin is administered by s . c . injection at 1 mg / kg . after a further 40 minutes , blood samples are taken from the mice and are analyzed using lc - ms for the concentrations of cortisone , cortisol , and drug . percent inhibition of hsd1 activity by the inhibitor is calculated by the following formula : c veh is the conversion of cortisone to cortisol when the animal is dosed with vehicle , and c inh is the conversion of cortisone to cortisol when the animal is dosed with inhibitor , where the conversion c is given by the formula c =[ cortisol ]/([ cortisol ]+[ cortisone ]). it is to be understood that the invention is not limited to the particular embodiments of the invention described above , as variations of the particular embodiments may be made and still fall within the scope of the appended claims .

US-36505306-A

a torque - transmitting , variably - flexible insertion device includes a hollow body having a proximal end with an entrance for receiving an instrument and a distal end with a tip for protrusion of the instrument . a vacuum - activated device transitions the hollow body between a relatively flexible condition and a relatively stiff condition . a torque braid transmits torque from the proximal end toward the distal end . a method for transmitting torque and variably flexing the insertion device includes transmitting torque along the hollow body with the torque braid , applying suction to create a vacuum in the hollow body for placing the hollow body in the relatively stiff condition , and relieving the vacuum for placing the hollow body in the relatively flexible condition .

referring now to the figures of the drawings in detail and first , particularly , to fig1 thereof , there is seen a steerable , variably - flexible insertion device 1 according to the invention . the insertion device 1 has a hollow body with a proximal end 2 for manipulation by an operator and for receiving an instrument such as an endoscope or a colonoscope . the insertion device 1 also has a distal end 3 for insertion into a patient and for protrusion of the instrument . a handle 4 of the hollow body for control by the operator is disposed at the proximal end 2 . the handle 4 has a vacuum connection or nipple 5 for controlling stiffness of the device , as will be explained below . an outer jacket 41 of the hollow body , which is disposed between the handle 4 and a tip 7 of the hollow body at the distal end 3 , is not shown in fig1 . the outer jacket 41 , which is shown in fig1 , provides a flexible section with a given length extending beyond the handle 4 . whereas fig1 shows the hollow body steered to the right , fig2 shows it steered to the left and fig3 shows the hollow body in perspective . a steering assembly 10 of the device 1 includes five vertebrae 13 - 17 shown as being disposed along the hollow body . however , more or fewer vertebrae can be provided in dependence on the length , diameter and use of the hollow body . eight tendons are shown as being equally spaced apart about the circumference of the hollow body . a first four of those tendons , identified as non - steering tendons and indicated by reference numeral 11 , extend only between the handle 4 and the vertebra 17 where they are fixed in place . a second four of those tendons , identified as steering tendons and indicated by reference numeral 12 , are spaced apart by 90 ° circumferentially and extend between the handle 4 and the distal - most vertebra 13 where they are fixed in place . once again , a greater or lesser number of tendons may be used , as needed . the tendons may have a rounded or flattened cross section or a flattened cross section twisted along its length . the vertebrae to which the tendons are fixed may be referred to as weld rings since the tendons may be welded thereto . for example , all of the tendons 12 are fixed to the vertebra 13 , such as by welding . at the vertebra 16 , for example , the steering tendons 12 are permitted to slide , but the non - steering tendons 11 are welded or otherwise fixed in place . when welding is used for fixation , the tendons and vertebrae are normally made of stainless steel . however , the tendons and vertebrae may also be formed of plastic which is bonded or adhesively connected where desired . both metal and plastic tendons and vertebrae may be used in one device . four knobs 6 are each slideably disposed within a respective slot 8 in the handle 4 . each of the steering tendons 12 extend between the vertebra 13 and a respective one of the knobs 6 . each steering tendon 12 extends through a respective knob 6 and is connected to a respective stop 9 . when a knob 6 is slid proximally , it pushes a stop 9 and pulls a steering tendon 12 to steer the hollow body . in the condition shown in fig1 , the knob 6 at the right has been slid proximally so that the tip 7 of the hollow body has been steered to the right . in the condition shown in fig2 , the knob 6 at the left has been slid proximally so that the tip 7 of the hollow body has been steered to the left . a similar result shown in fig3 has been accomplished by sliding one of the knobs 6 proximally . when the knobs 6 are forced distally , the knobs can freely slide independently of the steering tendons 12 to prevent buckling of the steering tendons 12 . it will be readily understood that if two of the knobs are slid proximally , the tip 7 will move in a direction between the two directions that each one of the knobs would have moved the tip if moved individually . fig4 shows the device 1 with the handle 4 removed , from which it can be seen that the steering tendons 12 of the steering assembly 10 continue toward the handle from the tip 7 , whereas the non - steering tendons 11 stop . it is also possible , as shown in fig5 , to provide stiffness zones within the steering assembly 10 . for example , a stiffness zone a closest to the distal tip 17 has four tendons , a stiffness zone b has eight tendons and a stiffness zone c closest to the handle 4 has sixteen tendons . a zone with more tendons will be stiffer than a zone with fewer tendons . the number of tendons and their location within the zones as well as the number of zones can be increased or decreased , depending on the application of the device . the vertebrae are also shown . the four tendons in the zone a are all fixed at the upper most vertebra but are free to slide elsewhere . four of the eight tendons in zone b , which do not extend to zone a , are fixed at the vertebra between zones a and b but are free to slide elsewhere . similarly , eight of the sixteen tendons in zone c , which do not extend into zones a and b , are fixed at the vertebra between zones b and c but are free to slide elsewhere . fig6 shows a cross - sectional view of the handle 4 of fig1 - 3 , in which the connection or nipple 5 , knobs 6 and slots 8 are not shown . the handle 4 has an inner handle 19 disposed within an outer handle 18 , defining an annular vacuum plenum volume 24 therebetween which extends in longitudinal direction of the handle 4 . a vacuum inlet / outlet hole or port 25 is formed in the body of the outer handle 18 and communicates with the volume 24 . a sliding so - called tire valve thumb grip 20 encircles the outer handle 18 and is sealed thereto by o - ring seals having o - rings 21 in recesses 22 in the grip 20 . the grip 20 also has a vacuum inlet / outlet 23 for the connection or nipple 5 . when the grip 20 is slid toward an annular stop 26 as shown , the vacuum inlet / outlet 23 is not in alignment with the vacuum inlet / outlet hole 25 . however , when the grip 20 is slid toward an annular stop 27 , the vacuum inlet / outlet 23 and the vacuum inlet / outlet hole 25 are aligned , providing communication between the connection or nipple 5 and the volume 24 . therefore , during operation , the grip 20 is slid toward the stop 27 to apply vacuum to stiffen the hollow body or to vent the vacuum to the atmosphere or supply air at atmospheric pressure to make the hollow body flexible again . the grip 20 is slid toward the stop 26 to maintain the stiffened or flexible condition of the hollow body attained by vacuum or venting or air supply through the connection or nipple 5 . an end cap 28 is inserted into a proximal end of the outer handle 18 for insertion of an instrument , such as an endoscope or a colonoscope . end caps with various sized openings may be used in dependence on the instrument being used . the instrument passes through the hollow body and emerges at the distal tip 7 . a diaphragm seal or so - called septum 29 is disposed between the end cap 28 and the inner handle 19 . a dot - dash line 30 represents an instrument inserted through the handles . fig7 and 8 show a handle 4 with an outer vacuum valve handle 35 which is ergonomically configured with a so - called handlebar shape to be gripped by the hand of an operator of the device . a tire valve thumb grip 20 as is seen in fig6 is also provided in the embodiment of fig6 and 7 , but has been omitted for clarity . the outer handle 35 is an alternative to the outer handle 18 . as can be seen from the cross section of fig8 , a vacuum source may be connected to a port 36 in the outer handle 35 and the vacuum inlet / outlet 23 of the tire valve thumb grip 20 may communicate with a vacuum inlet / outlet hole 37 leading to an annular vacuum plenum volume 39 between the outer handle 35 and an inner handle 38 . when the tire valve thumb grip 20 is slid so that the vacuum inlets / outlets 23 and 37 are misaligned , vacuum is supplied from the port 36 to the vacuum plenum volume 39 . when the tire valve thumb grip 20 is slid so that the vacuum inlets / outlets 23 and 37 are aligned , the plenum 39 is vented to the atmosphere . an end cap 34 is also shown . fig9 illustrates a torque sheath or braided inner liner 40 of the insertion device 1 . the torque braid 40 is a woven tube formed of fabric , plastic , metal or a combination thereof , such as a metallized material . steel or a polymer , such as polyethylene terephthalate or pet ( sold under the trademark mylar ) or peek ( polyether ether ketone ) are particularly useful . the purpose of the torque braid 40 is to transmit torque applied by the operator of the device at the proximal end 2 along the length of the hollow body up to the tip 7 . therefore , the torque braid must be non - linearly compliant , that is it has a limited elongation in the linear direction . as is shown in the perspective view of fig1 , the torque braid 40 may be disposed in a space 44 between an outer jacket 41 and an inner sleeve 42 . in the illustrated embodiment , the torque braid 40 is disposed above the vertebra 15 , but the tendons have been omitted for clarity . the torque braid 40 may be placed in various locations , as will be described below with reference to fig1 - 15 . the purpose of the torque braid 40 is to allow twisting of the hollow body as well as steering of the hollow body by the tendons while inserting the insertion device into the body . the torque braid 40 is typically provided over the full length of the hollow body , but may also be omitted at the tip 7 for additional flexibility or doubled , for instance , near the handle 4 for additional stiffness . fig1 also shows a coil 43 of the hollow body which is provided within the inner sleeve 42 of the hollow body for supporting the inner sleeve . the coil may be a wire which is teflon - or hydrophilic - coated to ease insertion of an endoscope or colonoscope . the stiffness or spring constant k of the coil 43 tends to maintain the device 1 in a straight condition and is used to maintain the round cross section of the device 1 while it is flexed . fig1 shows an alternative embodiment of the torque braid 40 and the tendons 11 , 12 , in which the tendons are intermittently woven through the torque braid to eliminate the need for the vertebrae 13 - 17 . the tendons 11 , 12 travel under the torque braid 40 for about 2 inches and then are woven through one loop of the torque braid 40 to create weave points . this is repeated along the length of the device . the weave points act like the vertabrae in “ attaching ” the tendons 11 , 12 to the body of the device but letting the tendons slide through . using the torque braid in this way eliminates the need for the vertabrae thus decreasing the outer diameter of the device , lowering the cost of the device and simplifying the structure thereof . it is noted that the tendons are shown as being flexed as they weave through the torque braid for clarity of the illustration . in actuality there will be some amount of flex in both the torque braid and the tendons , but mostly on the part of the torque braid . the tendons could also be woven in the opposite way , that is laid on top of the braid and woven down into it . fig1 - 15 are cross - sectional views of the device , in which the torque braid 40 is placed in various locations . in each of the figures , as seen from the exterior toward the interior , the insertion device 1 includes the outer jacket 41 , the space 44 , the vertebrae 13 - 17 ( reference numeral 15 is used as an example ), the inner sleeve 42 and the coil 43 , although the latter is merely shown in outline form for the sake of clarity . it is also seen that the vertebrae 13 - 17 have channels 45 formed therein permitting movement of the tendons 11 , 12 which are not fixed in place . in the embodiment of fig1 , the torque braid 40 is disposed between the coil 43 and the inner sleeve 42 . in the embodiment of fig1 , the torque braid 40 is disposed between the inner sleeve 42 and the vertebra 15 . in the embodiment of fig1 , the torque braid 40 is disposed between the vertebra 15 and the outer jacket 41 . in the embodiment of fig1 , the torque braid 40 is disposed within the coil 43 . the operation of the variably flexible insertion device 1 will now be described below by making reference to the above - described figures . the device 1 is flexed against the stiffness or spring constant k of the coil 43 , for example upon traversing the rectosigmoid junction , by sliding one or more of the knobs 6 . if it is desired to maintain that flexed condition for guiding an endoscope , such as a colonoscope , vacuum is applied at the connection or nipple 5 in the embodiment of fig6 or at the vacuum port 36 in the embodiment of fig8 . when suction is applied to create the vacuum , it causes the inner sleeve 42 and the outer jacket 41 to firmly contact each other with the tendons 11 , 12 sandwiched and frictionally locked therebetween . therefore , the vacuum connection or nipple 5 or the vacuum port 36 acts as a device for transitioning the hollow body 4 / 35 , 7 , 19 / 38 , 41 , 42 , 43 between a relatively flexible condition and a relatively stiff condition through the application of a vacuum . as long as the vacuum is applied , the device 1 maintains its flexed condition . the positions of the knobs 6 in fig1 - 3 show that in the flexed condition , the tendons 12 at the outer periphery of the bend become shorter and the tendons 12 at the inner periphery of the bend become longer , since they are all fixed in place at the first vertebra 13 . the tendons or wires are passive elements which are not in tension at any time . the tendons float within the hollow body when it is in the flexible condition , except where they are fixed to vertebra , such as at the distal end . the tendons are frictionally locked by the inner sleeve 42 and the outer jacket 41 when the hollow body is in the stiff condition . however , in both the relatively flexible condition and the relatively stiff condition , the tendons have no active control imposed on them and are not pulled or constrained . when it is desired to resume flexibility of the device 1 , the vacuum is vented or replaced by air at ambient or positive pressure . this causes the inner sleeve 42 and the outer jacket 41 to release the tendons and allows the stiffness or spring constant k of the coil 43 to place the device 1 into its normally flexible condition . the device is intended to be used in a manner similar to prior art devices . therefore , the device will be placed over the endoscope . the endoscope will then be inserted into the rectum . the device will then be pushed in its flexible condition , to follow the curvature of the scope . the device will then be stiffened , allowing the scope to be pushed forward with less pressure exerted on the colon of the patient . this procedure can be repeated until the scope reaches the cecum . an alternative use of the device is to aid in small bowel endoscopy . the device is placed over the endoscope . the endoscope is inserted into the patient transorally , through the stomach and then partially into the small bowel . the device is then pushed in its flexible condition , to follow the curvature of the scope . the device is then stiffened , allowing the scope to be pushed forward without the scope looping in the stomach . another use of the device is for aiding in access to internal body parts , such as the gallbladder , through an opening of an internal body cavity , such as the stomach . the device is placed over the endoscope . the endoscope is inserted into the patient transorally , through the stomach and then up against the internal surface of the stomach . the device is then pushed in its flexible condition , to follow the curvature of the scope . the device is then stiffened , allowing the surgeon to create an opening in the stomach wall without the scope looping in the stomach . once the opening is created , the device and the scope can be advanced outside the stomach . the device can then be stiffened to create a stable platform to perform surgical procedures outside of the stomach . the device could contain one or more features ( i . e . balloons ) for sealing the outer periphery of the device to the stomach wall to prevent gastric fluids from exiting the stomach . in each of these procedures described above , the knobs and tendons are used to steer the insertion device within the body as needed , while the torque braid allows the device to be twisted as needed .

US-80484307-A

this invention discloses method of treating or inhibiting cancer in a human having at least one of an exon 19 del e746 - a750 and / or an exon 21 point mutation comprising administering to said human gefitinib and / or iressa alone or in combination with other cytotoxic agents or chemotherapeutic agents and an effective amount of egfr kinase inhibitor .

for the purpose of defining the scope of this invention , an egfr kinase inhibitor is defined as a molecule that inhibits the kinase domain of the egfr . it is preferred that the egfr kinase inhibitor irreversibly inhibits egfr kinase , typically by possessing a reactive moiety ( such as a michael acceptor ) that can form a covalent bond with egfr . the egfr inhibitor may also have activity as a her - 2 inhibitor . for purposes of this invention the egfr kinase inhibitor includes , the following : quinazolines of this application , are disclosed in u . s . pat . nos . 6 , 384 , 051 b1 and 6 , 288 , 082 , both of which examples are hereby incorporated by reference . these compounds can be prepared according to the methodology described in u . s . pat . nos . 6 , 384 , 051 b1 and 6 , 288 , 082 , which is hereby incorporated by reference . the structure of the egfr kinase inhibitors of formula 1 are as follows : x is cycloalkyl of 3 to 7 carbon atoms , which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups ; or is a pyridinyl , pyrimidinyl , or phenyl ring ; wherein the pyridinyl , pyrimidinyl , or phenyl ring may be optionally mono - di -, or tri - substituted with a substituent selected from the group consisting of halogen , alkyl of 1 - 6 carbon atoms , alkenyl of 2 - 6 carbon atoms , alkynyl of 2 - 6 carbon atoms , azido , hydroxyalkyl of 1 - 6 carbon atoms , halomethyl , alkoxymethyl of 2 - 7 carbon atoms , alkanoyloxymethyl of 2 - 7 carbon atoms , alkoxy of 1 - 6 carbon atoms , alkylthio of 1 - 6 carbon atoms , hydroxy , trifluoromethyl , cyano , nitro , carboxy , carboalkoxy of 2 - 7 carbon atoms , carboalkyl of 2 - 7 carbon atoms , phenoxy , phenyl , thiophenoxy , benzoyl , benzyl , amino , alkylamino of 1 - 6 carbon atoms , dialkylamino of 2 to 12 carbon atoms , phenylamino , benzylamino , alkanoylamino of 1 - 6 carbon atoms , alkenoylamino of 3 - 8 carbon atoms , alkynoylamino of 3 - 8 carbon atoms , and benzoylamino ; r 1 , r 2 , r 3 , and r 4 are each , independently , hydrogen , halogen , alkyl of 1 - 6 carbon atoms , alkenyl of 2 - 6 carbon atoms , alkynyl of 2 - 6 carbon atoms , alkenyloxy of 2 - 6 carbon atoms , alkynyloxy of 2 - 6 carbon atoms , hydroxymethyl , halomethyl , alkanoyloxy of 1 - 6 carbon atoms , alkenoyloxy of 3 - 8 carbon atoms , alkynoyloxy of 3 - 8 carbon atoms , alkanoyloxymethyl of 2 - 7 carbon atoms , alkenoyloxymethyl of 4 - 9 carbon atoms , alkynoyloxymethyl of 4 - 9 carbon atoms , alkoxymethyl of 2 - 7 carbon atoms , alkoxy of 1 - 6 carbon atoms , alkylthio of 1 - 6 carbon atoms , alkylsulphinyl of 1 - 6 carbon atoms , alkylsulphonyl of 1 - 6 carbon atoms , alkylsulfonamido of 1 - 6 carbon atoms , alkenylsulfonamido of 2 - 6 carbon atoms , alkynylsulfonamido of 2 - 6 carbon atoms , hydroxy , trifluoromethyl , cyano , nitro , carboxy , carboalkoxy of 2 - 7 carbon atoms , carboalkyl of 2 - 7 carbon atoms , phenoxy , phenyl , thiophenoxy , benzyl , amino , hydroxyamino , alkoxyamino of 1 - 4 carbon atoms , alkylamino of 1 - 6 carbon atoms , dialkylamino of 2 to 12 carbon atoms , aminoalkyl of 1 - 4 carbon atoms , n - alkylaminoalkyl of 2 - 7 carbon atoms , n , n - dialkylaminoalkyl of 3 - 14 carbon atoms , phenylamino , benzylamino , r 5 is alkyl of 1 - 6 carbon atoms , alkyl optionally substituted with one or more halogen atoms , phenyl , or phenyl optionally substituted with one or more halogen , alkoxy of 1 - 6 carbon atoms , trifluoromethyl , amino , nitro , cyano , or alkyl of 1 - 6 carbon atoms groups ; r 6 is hydrogen , alkyl of 1 - 6 carbon atoms , or alkenyl of 2 - 6 carbon atoms ; r 8 is hydrogen , alkyl of 1 - 6 carbon atoms , aminoalkyl of 1 - 6 carbon atoms , n - alkylaminoalkyl of 2 - 9 carbon atoms , n , n - dialkylaminoalkyl of 3 - 12 carbon atoms , n - cycloalkylaminoalkyl of 4 - 12 carbon atoms , n - cycloalkyl - n - alkylaminoalkyl of 5 - 18 carbon atoms , n , n - dicycloalkylaminoalkyl of 7 - 18 carbon atoms , morpholino - n - alkyl wherein the alkyl group is 1 - 6 carbon atoms , piperidino - n - alkyl wherein the alkyl group is 1 - 6 carbon atoms , n - alkyl - piperidino - n - alkyl wherein either alkyl group is 1 - 6 carbon atoms , azacycloalkyl - n - alkyl of 3 - 11 carbon atoms , hydroxyalkyl of 1 - 6 carbon atoms , alkoxyalkyl of 2 - 8 carbon atoms , carboxy , carboalkoxy of 1 - 6 carbon atoms , phenyl , carboalkyl of 2 - 7 carbon atoms , chloro , fluoro , or bromo ; z is amino , hydroxy , alkoxy of 1 - 6 carbon atoms , alkylamino wherein the alkyl moiety is of 1 - 6 carbon atoms , dialkylamino wherein each of the alkyl moieties is of 1 - 6 carbon atoms , morpholino , piperazino , n - alkylpiperazino wherein the alkyl moiety is of 1 - 6 carbon atoms , or pyrrolidino ; any of the substituents r 1 , r 2 , r 3 , or r 4 that are located on contiguous carbon atoms can together be the divalent radical — o — c ( r 8 ) 2 — o —; r 2 is a pyridinyl , optionally substituted pyrimidine , thiazole , or an optionally substituted phenyl ring wherein the phenyl or pyrimidine ring may be unsubstituted , mono - substituted , or di - substituted ; and r 3 is — o — or — s —; or a pharmaceutically acceptable salt thereof . with respect to the quinazolines , the pharmaceutically acceptable salts are those derived from such organic and inorganic acids as : acetic , lactic , citric , tartaric , succinic , maleic , malonic , gluconic , hydrochloric , hydrobromic , phosphoric , nitric , sulfuric , methanesulfonic , and similarly known acceptable acids . the compounds herein may be administered orally , by intralesional , intraperitoneal , intramuscular or intravenous injection ; infusion ; liposome - mediated delivery ; topical , nasal , anal , vaginal , sublingual , uretheral , transdermal , intrathecal , ocular or otic delivery . in order to obtain consistency in providing the compound of this invention it is preferred that a compound of the invention is in the form of a unit dose . suitable unit dose forms include tablets , capsules and powders in sachets or vials . such unit dose forms may contain from 0 . 1 to 300 mg of a compound of the invention and preferably from 2 to 100 mg . the compounds of the present invention can be administered orally at a dose range of about 0 . 01 to 100 mg / kg . such compounds may be administered from 1 to 6 times a day times a day . the effective amount will be known to one of skill in the art ; it will also be dependent upon the form of the compound . one of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and thus determine what dosage to administer . the compound of the present invention may be delivered locally via a capsule that allows a sustained release of the compound over a period of time . controlled or sustained release compositions include formulation in lipophilic depots ( fatty acids , waxes , oils ). the administration can take the form of dosing a reversible egfr kinase inhibitor , for example but not limited to gefitinib or iressa alone until resistance is detected during clinical monitoring at which time an effective amount of an irreversible egfr kinase inhibitor , for example but not limited to ekb or hki is administered . the administration can also take the form of dosing a reversible egfr kinase inhibitor , for example but not limited to gefitinib or iressa alone until resistance is detected during clinical monitoring at which time an effective amount of an irreversible egfr kinase inhibitor , for example but not limited to ekb or hki is administered followed by another round of dosing with the reversible egfr kinase inhibitor as exemplified herein . the alkyl portion of the alkyl , alkoxy , alkanoyloxy , alkoxymethyl , alkanoyloxymethyl , alkylsulphinyl , alkylsulphonyl , alkylsulfonamido , carboalkoxy , carboalkyl , alkanoylamino aminoalkyl , alkylaminoalkyl , n , n - dicycloalkylaminoalkyl , hydroxyalkyl , and alkoxyalkyl substituents include both straight chain as well as branched carbon chains . the cycloalkyl portions of n - cycloalkyl - n - alkylaminoalkyl and n , n - dicycloalkylaminoalkyl substituents include both simple carbocycles as well as carbocycles containing alkyl substituents . the alkenyl portion of the alkenyl , alkenoyloxymethyl , alkenyloxy , alkenylsulfonamido , substituents include both straight chain as well as branched carbon chains and one or more sites of unsaturation . the alkynyl portion of the alkynyl , alkynoyloxymethyl , alkynylsulfonamido , alkynyloxy , substituents include both straight chain as well as branched carbon chains and one or more sites of unsaturation . carboxy is defined as a — co 2 h radical . carboalkoxy of 2 - 7 carbon atoms is defined as a — co 2 r ″ radical , where r ″ is an alkyl radical of 1 - 6 carbon atoms . carboalkyl is defined as a — cor ″ radical , where r ″ is an alkyl radical of 1 - 6 carbon atoms . alkanoyloxy is defined as a — ocor ″ radical , where r ″ is an alkyl radical of 1 - 6 carbon atoms . alkanoyloxymethyl is defined as r ″ co 2 ch 2 — radical , where r ″ is an alkyl radical of 1 - 6 carbon atoms . alkoxymethyl is defined as r ″ och 2 — radical , where r ″ is an alkyl radical of 1 - 6 carbon atoms . alkylsulphinyl is defined as r ″ so — radical , where r ″ is an alkyl radical of 1 - 6 carbon atoms . alkylsulphonyl is defined as r ″ so 2 — radical , where r ″ is an alkyl radical of 1 - 6 carbon atoms . alkylsulfonamido , alkenylsulfonamido , alkynylsulfonamido are defined as r ″ so 2 nh — radical , where r ″ is an alkyl radical of 2 - 6 carbon atoms , an alkenyl radical of 2 - 6 carbon atoms , or an alkynyl radical of 2 - 6 carbon atoms , respectively . when x is substituted , it is preferred that it is mono -, di -, or tri - substituted , with monosubstituted being most preferred . it is preferred that of the substituents r 1 , r 2 , r 3 , and r 4 , at least one is hydrogen and it is most preferred that two or three be hydrogen . an azacycloalkyl - n - alkyl substituent refers to a monocyclic heterocycle that contains a nitrogen atom on which is substituted a straight or branched chain alkyl radical . a morpholino - n - alkyl substituent is a morpholine ring substituted on the nitrogen atom with a straight or branch chain alkyl radical . a piperidino - n - alkyl substituent is a piperidine ring substituted on one of the nitrogen atoms with a straight or branch chain alkyl radical . a n - alkyl - piperidino - n - alkyl substituent is a piperidine ring substituted on one of the nitrogen atoms with a straight or branched chain alkyl group and on the other nitrogen atom with a straight or branch chain alkyl radical . the term alkyl includes both straight and branched chain alkyl moieties , preferably of 1 - 6 carbon atoms . the term alkenyl includes both straight and branched alkenyl moieties of 2 - 6 carbon atoms containing at least one double bond . such alkenyl moieties may exist in the e or z conformations ; the compounds of this invention include both conformations . the term alkynyl includes both straight chain and branched alkynyl moieties containing 2 - 6 carbon atoms containing at least one triple bond . the term cycloalkyl refers to an alicyclic hydrocarbon group having 3 - 7 carbon atoms . the term halogen is defined as cl , br , f , and 1 . alkoxy , alkylthio , alkoxyalkyl , alkylthioalkyl , alkoxyalkyloxy and alkylthioalkyloxy are moieties wherein the alkyl chain is 1 - 6 carbon atoms ( straight or branched ). the term alkylamino refers to moieties with one or two alkyl groups wherein the alkyl chain is 1 - 6 carbons and the groups may be the same or different . the alkyl groups ( the same or different ) bonded to the nitrogen atom which is attached to an alkyl group of 1 - 3 carbon atoms . the compounds herein may contain an asymmetric carbon ; in such cases , the compounds of formula 1 cover the racemate and the individual r and s entantiomers , and in the case were more than one asymmetric carbon exists , the individual diasteromers , their racemates and individual entantiomers . for purposes of this invention an egfr kinase inhibitor of interest having a structure of formula 1 includes ( 4 - dimethylamino - but - 2 - enoic acid [ 4 -( 3 - chloro - 4 - fluoro - phenylamino )- 3 - cyano - 7 - ethoxy - quinolin - 6 - yl ]- amide ) (“ ekb - 569 ”). for purposes of this invention cancer includes non - small cell lung cancer . report on 2 patients with non - small cell lung cancer ( nsclc ) who received ekb - 569 . a 63 year old male with a smoking history bi 720 ( 20 × 38 years ) having adenocarcinoma and ct0nom1 ( multiple pulmonary metastasis ). exon 19 deletion e746 - a750 is identified . herception test score was 0 + and egfr score 2 +. the patient was given 25 mg / day ekb - 569 for 9 months . a 49 year old female with a smoking history of bi 30 ( 10 × 3 years ) having adenocarcinoma performance status 1 , ct0n3m1 ( pulmonary , brain and bone ). exon 21 point mutation l858r . herceptest score +, egfr score 3 +, ekb - 569 35 mg / day for 4 months . epidermal growth factor receptor ( egfr ) mutations in nsclc correlate with clinical response and predict prolonged survival after gefitinib ( paez j g , et al , science , 2004 ; lynch t j , et al , n engl j med , 2004 ). phase 1 dose - escalation study of ekb - 569 was completed in japanese patients with advanced - stage malignancies known to overexpress egfr . ekb - 569 was effective in these two patients after treatment with gefitinib and recurrence of nsclc . in some cases , re - treatment with gefitinib is effective when nsclc recurs in patients treated with gefitinib ( kurata t , et al , ann oncol , 2004 ). acquired resistance to gefitinib is associated with a second mutation in exon 20 encoding the egfr kinase domain ( pao w , et al , plos med , 2005 ) 387 , 785 , a specific and irreversible anilinoquinazoline egfr inhibitor , strongly inhibited the activity of egfr encoded by a gene containing a second mutation in the kinase domain ( kobayashi s , et al , n engl j med , 2005 ) ekb - 569 , another irreversible egfr inhibitor , may abrogate the resistance mechanism to gefitinib . one patient had exon 19 del e746 - a750 , and the other had exon 21 point mutation .

US-40317006-A

a hydrocolloid confectionery product that includes , as a gelling agent , comprising iota - carrageenan or a mixture of carrageenans containing more than 50 % iota - carrageenan in an amount sufficient to provide characteristics and properties of the product that are essentially the same as in hydrocolloid confectionery products that include gelatin as a gelling agent . also , a process for making the hydrocolloid confectionery .

hydrocolloid confectionery products include sugar gels and water gels , for example , hard , soft and foamed gums , wine gums , laces , tubes and corrugated strips , jujubes , fruit leathers , fruit pastilles , lemon slices , pastilles , turkish delight , gummi bears , jelly babies , table jellies , savoury gels , etc . carrageenan is a polysaccharide gelling agent that is usually extracted from seaweed and the extraction usually yields a mixture of at least two types , i . e . two or more of the iota , kappa and lambda types , the amounts of each depending on the seaweed used and the extraction conditions . carrageenan usually also contains salt in an amount up to about 3 % by weight . in this invention , a mixture of carrageenans containing at least 60 % iota - carrageenan is advantageously used , with preferably at least 70 %, more preferably at least 80 % and especially at least 90 % iota - carrageenan by weight based on the total weight of the carrageenan utilized in the hydrocolloid confectionery product . the iota - carrageenan gives the dominant gelatin like behavior to the hydrocolloid confectionery product . the amount of carrageenan in the hydrocolloid confectionery product may be from 0 . 1 % to 5 . 0 %, preferably from 0 . 25 % to 4 % and more preferably from 0 . 5 % to 3 % by weight based on the weight of the hydrocolloid confectionery product . if desired , one or more other hydrocolloids may be present together with the carrageenan in the hydrocolloid confectionery product , e . g ., agar agar , xanthan gum , locust bean gum , gellan gum , gum arabic , pectin , gelatin , kappa - carrageenan , guar gum , or modified or unmodified starches , e . g . maize or potato starch . the use of one or more other hydrocolloids together with the carrageenan enables the creation of different gelling characteristics as desired and / or may be used to manipulate the textural properties . the hydrocolloid confectionery product of the present invention typically comprises in addition to iota - carrageenan , conventional amounts of water , sugar , glucose syrup , gelatin , other carrageenans and / or other hydrocolloids , color , flavor and food grade acids . when the hydrocolloid confectionery product of the present invention is a sugar gel , this usually contain from 30 % to 90 %, preferably from 40 % to 70 % of a sugar syrup by weight based on the weight of the hydrocolloid confectionery product e . g ., corn syrup , glucose syrup , invert syrup , high fructose syrup , sucrose , fructose , maltose , and / or sugar replacers , e . g . isomalt , maltitol , sorbitol , mannitol , lactitol , or trehalose . different types of sugar systems can be used to manipulate the final textural properties of the hydrocolloid confectionery product . this is used to influence the viscosity and processing parameters e . g . depositing temperature . in addition to the carrageenan and the sugar systems and optionally together with other hydrocolloids , the hydrocolloid confectionery product may contain the usual ingredients such as a food - acceptable acid , e . g . lactic acid , malic acid , tartaric acid , ascorbic acid , hydrochloric acid or citric acid in an amount of from 0 . 5 % to 5 % and preferably from 1 % to 2 . 5 % by weight based on the weight of the hydrocolloid confectionery product ; a food - acceptable acid salt in an amount of from 0 . 25 % to 2 . 5 % and preferably from 0 . 5 % to 1 . 5 % by weight based on the weight of the hydrocolloid confectionery product ; a humectant such as glycerol , flavor , color , protein , e . g . egg white , or milk protein in the case of aerated system , in an amount of from 0 . 1 % to 1 % and preferably from 0 . 2 to 0 . 5 % by weight based on the weight of the hydrocolloid confectionery product ; and water . the amount of water in the finished hydrocolloid confectionery product may be from 10 % to 25 % and preferably is from 12 . 5 % to 22 . 5 % by weight based on the weight of the hydrocolloid confectionery product . the hydrocolloid confectionery sugar gel products of the present invention may be prepared by conventional methods . for example , the ingredients may be blended to form a syrup , then cooked , shaped and , if necessary , dried . drying is usually required to achieve the final total solids and the final texture is influenced by drying process . drying is not required if the liquor is deposited at the total solids of the finished products or if it is processed by starchless molding . as for the ingredients , the processing method will affect the final texture of products . the ingredients may be blended with agitation , e . g ., stirring . a syrup of the sugars , carrageenan , and water are preferably blended first followed by the addition of the remaining components , e . g , acid , flavor , color , humectants , etc . to give a syrup mixture having a solids content of from 60 % to 90 % and preferably from 65 % to 75 % by weight based on the weight of the syrup . the syrup mixture may be cooked by open pan boiling , in a jet cooker , coil cooker , plate heat exchanger or a cooker extruder . depending on the cooking equipment , ingredients used in the formulation , and their concentrations at forming , the operating conditions will vary . the selection of optimum processing conditions is well within the level of a skilled artisan . the shaping may be carried out , for instance , by filling molds by casting , depositing ( starch or starchless ) or injection , slabbing ( flat or contoured ), layering or extrusion . the iota - carrageenan or mixture of carrageenans containing more than 50 % iota - carrageenan sets rapidly or instantly and causes a quick forming during the depositing step . the setting time depends on parameters such as the temperature , concentration , ph , ionic strength etc . the setting temperature is preferably at least 95 ° c . the shaped product may be dried , for instance by stoving which is a dehydration process at a specific temperature , humidity and time which parameters may be readily selected by skilled artisans . depending on whether or not the cooked syrup mixture is subjected to a stoving process , different gumminess and / or elasticity properties may be obtained . the product may also be subjected to one or more of other finishing treatments as desired depending on the product and the requirements , e . g . washing , destarching , steaming , sanding , crystallization , and oiling and polishing , or engrossing with other sugar confectionery products . the final solids content may be from 75 % to 90 % and preferably from 77 . 5 % to 87 . 5 % by weight based on the weight of the hydrocolloid confectionery . by using different mixtures of ingredients , different processing methods or different shaping methods , hydrocolloid confectionery products with completely novel textures can be produced . the hydrocolloid confectionery water gel products of the present invention may be prepared by blending to form a syrup , boiling and , if necessary , drying . the following examples further illustrate the preferred embodiments of the present invention . pre heat glucose syrup and water ( with tri - sodium citrate added ), to 600 c ., then add the carrageenan ( genugel carrageenan type x - 8300 ) to the solution while stirring with a high speed mixer to ensure complete dispersion , and then heat to boil . add sugar to the slurry and boil to the required total solids . the total solids of liquors may be in the range from 60 - 90 % depend on the subsequent forming and moulding methods . the gummi type product has an elastic , bouncy , non - sticky , long - lasting and cohesive eating property . the texture is similar to a gummi product prepared using gelatin . a similar procedure to that described in example 1 is followed but with the addition of 1 % of modified maize starch . the texture is similar to confectionery having a hard gum characteristic . a similar procedure to that described in example 1 is followed but using a carrageenan of predominantly kappa type instead of the carrageenan there used . the product does not have the elastic and bouncy texture but rather a short or less stringy texture which is not acceptable .

US-82390701-A

swimming goggles that are shaped by approximately profiling the goggles to the swimmer &# 39 ; s head resulting in the goggles having a minimal tendency to be pulled off or pulled ajar from the swimmer &# 39 ; s head by hydrodynamic forces while exhibiting minimal hydrodynamic drag . optical arrays molded into the lenses of the goggles permit standard vision both underwater and above the water .

fig1 - 4 show prior art goggles which are discussed in the background of the invention . the present invention relates to lenses which are used in swimming and diving goggles which essentially hold the lenses in position with respect to the eyes and face of the wearer . it is within the purview of the present invention to be used in connection with any means which hold lenses in position . in one embodiment illustrated by fig5 , fig6 , and fig7 , swimming goggles 10 are shown having lens frames 11 , 12 , lenses 13 , 14 , nose - bridge 15 , head strap 16 , and eye seals 17 . the lenses are shown having an exterior surface and incorporating optical arrays as part of both the inner surfaces 20 , 21 and the outer surfaces 18 , 19 of the exterior surfaces of the lenses 13 , 14 , respectively . each optical array of goggles 10 consists of refractive surfaces alternating with return surfaces . the inner optical array for the right lens 14 consists of refractive surfaces 600 that are generally flat and parallel with each other and are approximately parallel to the inner refractive surfaces 605 of the inner optical array of the left lens 13 . the outer refractive surfaces 610 on the right lens 14 are generally flat and also parallel with each other and are approximately parallel to the outer refractive surfaces 615 on the left lens 13 . the inner refractive surfaces 600 , 605 are not necessarily parallel to the outer refractive surfaces 610 , 615 . for example , as shown in lens 30 in fig8 , the outer refractive surfaces 31 are parallel to other outer refractive surfaces on each lens , but are not parallel to the inner refractive surfaces 32 . the left and right lenses also need not be mirror images of each other . the number of inner refractive surfaces does not need to be the same as the number of outer refractive surfaces of the lens . rays , for example 640 and 650 , observed by the swimmer both underwater and above water pass through the refractive surfaces 610 and 600 , and 615 and 605 respectively . two rays that are parallel with each other before passing through the goggle lenses are also parallel with each other after passing through the lenses . this is true both for rays coming from straight ahead such as 640 and 650 , and for rays coming from the side , as depicted by 770 and 780 in fig7 . the optical rays 770 and 780 are shown in fig7 with underwater refraction angles . the direction cosine of a ray may change after passing through a lens of the goggles . however , the change in the direction cosine will be approximately the same for an optical ray that will be entering the left lens as for a ray that will be entering the right lens if these two rays are parallel to each other before they enter the lenses . parallel rays remain parallel after passing through the lenses of these goggles . this is true when the parallel rays are either both underwater or both above water . referring to fig5 - 7 , the size of the outer refractive surfaces 615 and the size of the outer return surfaces 625 may be reduced while the number of such surfaces is increased to ensure that the maximum distance between any point on the outer surface and a specified profile 660 is arbitrarily small . any profile , for example profile 660 , may be approximated to any degree of accuracy using only flat and parallel refractive surfaces 615 connected by return surfaces 625 . referring to fig1 . this figure illustrates nomenclature . shown is a ray 1140 entering the outer lens surface 1100 of a portion of a lens . the normal 1160 to the outer surface 1100 at the point that ray 1140 enters the outer lens surface is shown . after refracting at the outer lens surface 1100 the ray , now labeled as 1130 , passes through the lens . after being refracted at the inner lens surface 1110 the ray , now labeled as 1120 , is shown on a trajectory to intersect the center of rotation 1180 of the eye . also shown is the normal 1150 to the inner refractive surface 1110 at the point the ray 1120 exits the inner refractive surface . for simplicity of illustration , details of the cornea and eye lens structures are not shown ; the eye including the cornea and eye lens are shown contained within a portion of a sphere . optical rays of interest will always be assumed to start at an object , enter the outer surface of a lens , pass through the lens , exit the inner surface of the lens , and then enter the eye . flat and parallel refractive lens surfaces are one embodiment . a more general embodiment that also provides for standard vision goggle lenses is illustrated by referring to fig1 . for two parallel rays 1245 and 1240 that refract at the left 1205 and right 1200 outer surfaces of the left and right lenses respectively with the left ray , now labeled as 1295 , passing through the left lens section and the right ray , now labeled as 1290 , passing through the right lens section , and the left ray 1295 refracting at the inner surface 1215 of the left lens and the right ray 1290 refracting at the inner surface 1210 of the right lens , with the left ray , now labeled as 1225 , shown as the ray that is on a trajectory to intersect the center of rotation 1285 of the left eye and the right ray , now labeled as 1220 , shown as the ray that is on a trajectory to intersect the center of rotation 1280 of the right eye . after the two parallel rays 1245 and 1240 pass through the lenses and exit as rays 1225 and 1220 respectively two constraints assure that rays 1225 and 1220 are parallel . firstly , that the normals to the outer lens surfaces 1265 and 1260 are parallel to each other and secondly that the normals to the inner lens surfaces 1255 and 1250 are parallel to each other . this assures standard vision both above and below the surface of the water when the left and right lenses of the goggles are both underwater or are both above water . another special case of the parallel normal constraint assuring standard vision is illustrated by fig9 . in this example , the refractive surfaces are sections of approximately spherical lenses with the center of curvature of the spherical surfaces approximately at the center of rotation of each eye . here the right lens normals at the points of intersection are not just parallel with the respective left lens normals at the points of intersection . here the lens normals at the points of intersection are also coincident with the respective rays . the optical arrays as described in the instant invention with respect to the goggle embodiments of fig5 - 12 exhibit several characteristics . each optical array has at least two refractive surfaces . the change in direction of a ray crossing through a refractive surface may be zero degrees such as when a ray is normal to the refractive surface . see for example fig9 . refractive surfaces are smooth or piecewise smooth , but not necessarily flat . refractive surfaces are regions of the goggles through which visual images are observed . adjacent refractive surfaces may be connected by return surfaces or may abut one another . the refractive surfaces of these optical arrays differ from two transparent sections of goggles which are adjacent to each other in the prior art in two ways . firstly , at least two adjacent refractive surfaces are connected by a return surface . secondly , for two parallel rays passing through the left and right lenses which are then on trajectories to intersect with the centers of rotation of the left and right eyes respectively , the normals to the outer surfaces of the lenses at the points of entry of the respective rays with the left and right outer lens surfaces differ by less than 15 degrees , and preferably by less than 5 degrees . thirdly , for two parallel rays passing through the left and right lenses which are then on trajectories to intersect with the centers of rotation of the left and right eyes respectively , the normals to the inner surfaces of the lenses at the points of exit of the respective rays with the left and right inner lens surfaces differ by less than 15 degrees , and preferable by less than 5 degrees . the center of rotation 685 of the left eye and the center of rotation 680 of the right eye are shown in fig5 - 7 . the center of rotation 885 of the left eye is shown in fig8 . the center of rotation 985 of the left eye and the center of rotation 980 of the right eye are shown in fig9 . referring to fig1 , 1310 is a contour line through a hydrodynamically streamlined profile . 1320 is a contour line through another useful profile . this profile represented by contour line 1320 will increase drag , but will also increase the inward hydrodynamical force applied to the lenses . this helps keep the goggles in the correct position particularly during a diving entry . the profile illustrated by contour line 1320 does not present corners that stick out into the free stream such as those exhibited by the 4 , 051 , 557 goggles , for example , as shown in prior art goggles of fig3 . pressure profile devices such as spoilers , airfoils , hydrofoils , flaps , and slats can be appended to the goggle profile to help provide retention of the goggles to the head . for ease of plastic injection molding these goggles may be configured to provide for an approximately uniformly thick lens section . the refractive surfaces 600 , 610 may vary in shape . for example , refractive surfaces 43 , 44 may have hexagonal or other shapes as shown in fig1 . optically blackening , opaquing or dulling one or more of the return surfaces 620 , 630 , 625 , and 635 may generate less glare for the swimmer . blackening or dulling the return surfaces does not restrict the region of view . it only reduces the glare within the region of view . the techniques disclosed in the instant invention are most useful for the region of binocular vision . for peripheral vision outside of the binocular region simple curved sections of clear material that match the desired outer profile may be acceptable . for many people the limits of binocular vision is about 30 degrees to each side . lenses of the present invention may be fabricated from clear or tinted plastic or from clear or tinted glass . examples of suitable plastics include polycarbonate and acrylic . eye seals or eye cups may be fabricated from an elastomer , an elastomeric foam , or soft plastic that minimizes leakage of water into the area adjacent to the eyes . six materials commonly used for this purpose are chloroprene rubber , chloroprene foam rubber , epdm , epdm foam rubber , silicone rubber , and plasticized pvc . fabrication and sealing techniques known to those skilled in the art may be used to fabricate a complete set of goggles including a bridge connecting the left and right lenses together and an elastomeric head strap for holding the goggles to the head . commonly used materials for bridges are polyethylene , polypropylene , polybutylene , acrylic , polycarbonate , polyurethane , plasticized pvc , or elastomers such as silicone rubber , natural rubber , chloroprene rubber , or epdm . head straps are commonly constructed from elastomers such as natural rubber including natural latex rubber , chloroprene rubber , epdm , silicone rubber , or thermoplastic polymers such as polyurethane or plasticized pvc . as many changes are possible to the swimming goggle and lens embodiments of this invention , utilizing the teachings thereof , the description above and the accompanying drawings should be interpreted in the illustrative and not in the limited sense .

US-201313874858-A

an expandable medical implant is provided with an implantable cage body . the proximal and distal ends of the cage body may each be provided with a tapered or cam portion . the implant may further include a proximal flexure , a distal flexure , a proximal plug member having a tapered portion configured to mate with the tapered portion of the proximal end of the cage body , and a distal plug member having a tapered portion configured to mate with the tapered portion of the distal end of the cage body . the proximal plug member may be configured to move longitudinally such that the distal flexure moves and the circumference of the proximal end of the cage body resiliently expands . the distal plug member may be configured to move longitudinally such that the proximal flexure moves and the circumference of the distal end of the cage body resiliently expands . methods are also disclosed .

referring to fig1 - 3 , a series of lateral views of vertebral segments 50 and 52 are shown , depicting the insertion and expansion of one embodiment of uec ( universally expanding cage ). the depicted vertebral bodies 50 and 52 have an average 8 mm gap between vertebral end plates , representing an average intervertebral space 54 . in a typical implementation , a complete discectomy is performed prior to the insertion of the uec 56 . the intervertebral disc occupying space 54 is removed using standard techniques including rongeur , curettage , and endplate preparation to bleeding subcondral bone . the posterior longitudinal ligament is divided to permit expansion of the intervertebral space . the intervertebral space 54 may be distracted to about 10 mm using a rotating spatula ( not shown ). this is a well - known device that looks like a wide screw driver that can be placed into the disc space horizontally and turned 90 degrees to separate the endplates . a novel feature of the uec is that after intervertebral disc space expansion and preparation ( by curetting or ideally arthroscopically facilitated disc material removal ), the uec implant per se can be inserted through any orifice or angle that does not cause injury to nerves or other structures , positioned at the immediate implant location and consequent expansion platform to yield both the best fusion and angular correction results . in the example implementation depicted in fig1 - 3 , uec 56 is inserted posteriorly ( in the direction of arrow 58 ) between vertebral bodies 50 and 52 , as shown in fig1 . the vertebral space 54 depicted is meant to represent any vertebral space in which it is desired to insert the uec ( sacral , lumbar , thoracic and / or cervical ), and from any direction permitted by the surrounding anatomy . in accordance with an aspect of the disclosure , the uec is reduced to a small size in its unexpanded state to enable it to be inserted through into the intervertebral space 54 as shown in fig1 . fig2 shows uec 56 inserted between vertebral bodies 50 and 52 , with uec 56 still in its unexpanded state . in one exemplary embodiment , dimensions of an unexpanded uec are : 10 - 12 mm wide , 10 mm high and 28 mm long to facilitate insertion and thereby minimize trauma to the patient and risk of injury to nerve roots . these dimensions may accommodate the flat external surfaces . once in place , the exemplary uec 56 may be expanded to 140 percent of its unexpanded size ( as shown in fig3 ), enabling 20 degrees or more of spinal correction depending on the 3d clinical pre - operation anatomic analysis . it should be noted that while the exemplary uec 56 depicted in fig1 - 3 is an implant intended to ideally fill the warranted space , other shapes of implants such as those shown in later figures and / or described herein may be used . in various embodiments , the implants may have a transverse cross - section that is circular , oval , elliptical , square , rectangular , trapezoidal , or other shape suited to fill the implant site and transmit the required loads . the implants may straight , curved , bean - shaped , and / or include other shapes and aspect ratios . additionally , the external surfaces may be smooth , spiked , threaded , coated and / or further adapted as subsequently described in more detail . the uec can be used at any spinal level the surgeon deems in need of fusion , and may be placed at any position and angle relative to the vertebral endplates as may be needed . one , two , or more uecs may be placed at any particular level to achieve the desired height and angles between vertebral bodies . as will be later described , multiple uecs may be used to adjust the overall cranio - caudal height , the anterior - posterior angle , and the medio - lateral angle between adjacent vertebral bodies . uecs may be implanted at multiple levels to obtain or restore the desired three dimensional curvature and positioning of the spine . referring to fig4 - 9 , a first embodiment of an exemplary uec 100 according to aspects of the disclosure is shown . fig4 is an enlarged perspective view which shows details of uec 100 . for ease of understanding , a proximal end 104 and a distal end 106 of uec 100 can be defined as shown in fig4 . it should be noted that while the distal end 106 of uec 100 is typically inserted first into a patient and proximal end 104 is typically closest to the surgeon , other orientations of this exemplary device and other devices described herein may be adopted in certain procedures despite the distal and proximal nomenclature being used . referring to fig5 , an exploded perspective view shows the individual components of uec 100 . in this first embodiment , uec 100 includes a cylindrically - shaped cage body 108 , a proximal plug 110 , a distal plug 112 , a threaded actuator 114 , and a washer 116 . the terms “ plug ” and “ plug member ” are used interchangeably herein . actuator 114 has a shank sized to slidably pass through a central bore within proximal plug 110 when uec 100 is assembled . actuator 114 also has threads on its distal end for engaging with a threaded central bore within distal plug 112 . proximal plug 110 and distal plug 112 each have outer surfaces that are inwardly tapered to match inwardly tapered surfaces within cage body 108 ( as best seen in fig9 ) with this arrangement , actuator 114 may be rotated in a first direction to draw distal plug 112 toward proximal plug 110 to outwardly expand cage body 108 , as will be subsequently described in more detail . referring to fig6 , this perspective view shows details of cage body 108 of the first exemplary embodiment of uec 100 . in this embodiment , cage body 108 includes eight longitudinally extending beam portions 118 , each separated from an adjacent beam portion 118 by a longitudinally extending gap 120 . in other embodiments ( not shown ), the cage body may include fewer or more than eight beam portions , and / or beam portions having a different or varying cross - section or shape . cage body 108 of the current embodiment also includes eight circumferentially extending connector portions 122 . the connector portions 122 interconnect the ends of the beam portions 118 . four of the connector portions 122 are located at the proximal end 104 of cage body 108 , and the other four connector portions 122 are located at the distal end 106 . the connector portions 122 located at the proximal end 104 are staggered in relation to the connector portions 122 located at the distal end 106 such that each pair of adjacent beam portions 118 are connected at only one end by a connector portion 122 . with this arrangement the beam portions 118 and connector portions 122 form a continuous serpentine or repeating s - shaped pattern . the beam portions 118 and or the connector portions 122 are configured to resiliently flex to allow the cage body 108 to increase in diameter when urged radially outward by plugs 110 and 112 ( shown in fig4 ). when plugs 110 and 112 are not urging cage body 108 radially outward , the resiliency of beam portions 118 and or connector portions 122 allows cage body 108 to return to its original reduced diameter . it can be appreciated that as beam portions 118 and or connector portions 122 flex outwardly , gaps 120 become wider at their open ends opposite connector portions 122 . the outwardly facing surfaces of beam portions 118 may each be provided with one or more points or spikes 123 as shown , to permit cage body 108 to grip the end plates of the vertebral bodies . referring to fig7 , an end view of the proximal end 104 of uec 100 is shown . the enlarged head at the proximal end of actuator 114 may be provided with a recessed socket 124 as shown for removably receiving a tool for turning actuator 114 . proximal plug 110 ( and distal plug 112 , not shown ) may be provided with radially outwardly extending protuberances 126 that reside in one or more gaps 120 and abut against the side of beam portions 118 . this arrangement prevents plugs 110 and 112 from rotating when actuator 114 is turned , thereby constraining plugs 110 and 112 to only move axially toward or away from each other . proximal plug 110 ( and distal plug 112 ) may be provided with through holes and or recesses 128 to allow for bony ingrowth from the vertebral bodies for more solidly healing / fusing uec 100 in place . longitudinally extending slots 130 ( shown in fig4 ) may also be provided for this purpose , and or for packing plugs 110 and 112 with autograft , allograft , and / or other materials for promoting healing / fusion . referring to fig8 and 9 , a side view and side cross - sectional view , respectively , are shown . in operation , uec 100 is expanded by inserting a tool such as a hex key wrench or driver ( not shown ) into the recessed socket 124 at the proximal end of actuator 114 and turning it clockwise . as best seen in fig9 , the distal end of actuator 114 is threaded into the central bore of distal plug 112 . turning actuator 114 clockwise causes the distal end of actuator 114 to pull distal plug 112 towards the center of cage body 108 while the enlarged head at the proximal and of actuator 114 pushes proximal plug 110 towards the center . this movement in turn causes the ramped surfaces 132 of plugs 110 and 112 to slide inwardly along the ramped surfaces 134 located along the inside of beam portions 118 and connector portions 122 to cause these elements to flex and expand radially outward as previously described . this process may be reversed by turning actuator 114 counterclockwise . the resilient inward forces from the beam portions 118 and or connector portions 122 ( and or the compressive forces from adjacent vertebral bodies ) against plugs 110 and 112 causes the two plugs to separate axially , thereby allowing uec 100 to return to its non - expanded state . referring to fig1 - 15 , a second embodiment of an exemplary uec 200 according to aspects of the disclosure is shown . fig1 is a perspective view which shows details of uec 200 . uec 200 includes a proximal end 204 and a distal end 206 , and shares many of the same features of previously described uec 100 , which are identified with similar reference numerals . referring to fig1 , an exploded perspective view shows the individual components of uec 200 . in this second embodiment , uec 200 includes an elongated cylindrical cage body 208 , a proximal plug 210 , and a distal plug 212 . distal plug 212 includes an integrally formed actuator rod 214 that extends along the internal central axis of cage body 208 towards proximal plug 210 when uec 200 is assembled . proximal plug 210 and distal plug 212 each have outer surfaces that are threaded and inwardly tapered to match threaded and inwardly tapered surfaces within cage body 208 ( as best seen in fig1 ). with this arrangement , each plug 210 and 212 may be independently rotated to move the particular plug axially toward the middle of cage body 208 to outwardly expand that particular end 204 or 206 of cage body 208 , as will be subsequently described in more detail . as shown in fig1 and 12 , cage body 208 includes eight longitudinally extending beam portions 218 , each separated from an adjacent beam portion 218 by a longitudinally extending gap 220 . in other embodiments ( not shown ), the cage body may include fewer or more than eight beam portions , and / or beam portions having a different or varying cross - section or shape . cage body 208 of the current embodiment also includes eight circumferentially extending connector portions 222 . the connector portions 222 interconnect the ends of the beam portions 218 . four of the connector portions 222 are located at the proximal end 204 of cage body 208 , and the other four connector portions 222 are located at the distal end 206 . the connector portions 222 located at the proximal end 204 are staggered in relation to the connector portions 222 located at the distal end 206 such that each pair of adjacent beam portions 218 are connected at only one end by a connector portion 222 . with this arrangement the beam portions 218 and connector portions 222 form a continuous serpentine or repeating s - shaped pattern . the beam portions 218 and or the connector portions 222 are configured to resiliently flex to allow the cage body 208 to increase in diameter when urged radially outward by plugs 210 and 212 . when plugs 210 and 212 are not urging cage body 208 radially outward , the resiliency of beam portions 218 and or connector portions 222 allows cage body 208 to return to its original reduced diameter . it can be appreciated that as beam portions 218 and or connector portions 222 flex outwardly , gaps 220 become wider at their open ends opposite connector portions 222 . the outwardly facing surfaces of beam portions 218 may each be provided with one or more points or spikes 223 as shown , to permit cage body 208 to grip the end plates of the vertebral bodies . referring to fig1 , an end view of the proximal end 204 of uec 200 is shown . the proximal plug 210 may be provided with a recessed socket 224 as shown for removably receiving a tool for turning proximal plug 210 in either direction , such as a five - lobed driver ( not shown ). alternatively , other suitable types of recessed sockets , slots , protruding and / or keyed features may be utilized with a mating driver . the proximal end of actuator shaft 214 ( which extends proximally from distal plug 212 inside cage body 208 ) may be accessed through a central bore 225 in proximal plug 210 . the proximal end of actuator shaft 214 may be shaped as shown to be received within a mating driver socket ( such as a five - lobed socket , not shown ), which can be removably extended into the center of cage body 208 through central bore 225 . with this arrangement , both the proximal plug 210 and the distal plug 212 can be independently accessed and rotated from the proximal end of uec 200 so that the proximal end 204 and the distal end 206 of uec 200 can be expanded or contracted independently . referring to fig1 , an end view of the distal end 206 of uec 200 is shown . by comparing fig1 and 14 , it can be appreciated that connector portions 222 at the proximal end 204 of uec 200 are staggered ( i . e . rotated 45 °) in relation to the connector portions 222 at the distal end 206 of uec 200 . referring to fig1 , a side cross - sectional view of uec 200 is shown . in operation , the proximal end 204 of uec 200 may be independently expanded by inserting a tool such as a five - lobed driver ( not shown ) into the recessed socket 224 of proximal plug 210 and turning it clockwise . turning proximal plug 210 clockwise causes the threaded ramped surfaces 232 of plug 210 to translate inwardly ( to the right in fig1 ) along the threaded ramped surfaces 234 located along the inside of beam portions 218 and connector portions 222 to cause these elements to flex and expand radially outward as previously described . this process may be reversed by turning proximal plug 210 counterclockwise , thereby allowing the proximal end 204 of uec 200 to return to its non - expanded state . similarly , the distal end 206 of uec 200 may be independently expanded by inserting a tool such as a five - lobed socket ( not shown ) through the central bore 225 in proximal plug 210 until it engages with the proximal end of actuator 214 , which is attached to distal plug 212 . turning distal plug 212 counterclockwise ( from the perspective of the proximal end ) causes the threaded ramped surfaces 232 of plug 212 to translate inwardly ( to the left in fig1 ) along the threaded ramped surfaces 234 located along the inside of beam portions 218 and connector portions 222 to cause these elements to flex and expand radially outward as previously described . this process may be reversed by turning distal plug 212 clockwise , thereby allowing the distal end 206 of uec 200 to return to its non - expanded state . the adjustment tools described above ( not shown ) for turning proximal plug 210 and distal plug 212 may be inserted one at a time into uec 200 . alternatively , the two tools may be nested together , with the tool for turning the distal plug 212 passing through a central bore in the tool for turning the proximal plug , as will be subsequently shown and described in relation to other embodiments . with this arrangement , both tools may be turned simultaneously or individually . in some embodiments , both proximal plug 210 and distal plug 212 are provided with right - handed threads , so that when both tools are simultaneously turned in the same direction , one end of uec 200 expands while the other end contracts , thereby changing the outer surface angle of uec 200 without substantially changing its overall diameter ( i . e . without substantially changing the diameter or height of the midpoint of uec 200 .) for example , by turning the two tools in the same direction , the lordotic angle between two vertebral bodies can be changed by uec 200 without substantially changing the height between the two vertebral bodies . in other embodiments , one of the plugs 210 or 212 may be provides with a right - handed thread and the other plug provided with a left - handed thread . in these embodiments , when both adjustment tools are simultaneously turned in the same direction , both ends 204 and 206 of uec 200 expand or contact together without substantially changing the outer surface angle of uec 200 . for example , by turning the two tools in the same direction , the height between the two vertebral bodies can be changed by uec 200 without substantially changing the lordotic angle between two vertebral bodies . in some embodiments , plugs 210 and 212 may each be provided with threads having a different pitch from the other . such an arrangement allows both the height and the angle between adjacent vertebral bodies to be adjusted simultaneously in a predetermined relationship when both adjustment tools are turned together in unison . for example , proximal plug 210 may be provided with right - handed threads of a particular pitch while distal plug 212 may be provided with finer , left - handed threads having half the pitch of the proximal plug threads . in this embodiment , when both adjustment tools are turned together in a clockwise direction , both ends of uec 200 expand at the same time but the proximal end 204 expands at twice the rate of the distal end 206 . this allows the surgeon to increase the height between adjacent vertebral bodies and at the same time angle the bodies away from him or her . one or both of the tools may then be turned individually to more finely adjust the height and angle between the vertebral bodies . in some embodiments the above - described adjustment tools may be removed from uec 200 before the surgical procedure is completed . in some embodiments the above adjustment tools may remain in place after the procedure is completed . in some embodiments , uec 200 is 50 mm long , has an unexpanded diameter of 10 mm , and an expanded diameter of 14 mm . in other embodiments , the uec may be configured to expand to about 11 , 12 , or 13 mm , or more than 14 mm . in still other embodiments , the uec may be configured with dimensions larger or smaller than these to conform to a particular anatomy or procedure . referring to fig1 - 20 , a third embodiment of an exemplary uec 300 according to aspects of the disclosure is shown . fig1 is a perspective view which shows details of uec 300 . uec 300 includes a proximal end 304 and a distal end 306 , and shares many of the same features of previously described uecs 100 and 200 , which are identified with similar reference numerals . referring to fig1 , an exploded perspective view shows the individual components of uec 300 . in this third embodiment , uec 300 includes a rectangular cage body 308 , a proximal plug 310 , a distal plug 312 , a proximal plug adjustment tool 313 , and a distal plug adjustment tool 314 . as in the previously described uec 200 , both plugs 310 and 312 are threaded and tapered , and each end of cage body 308 is provided with an inwardly tapered and threaded bore configured to receive one of the plugs 310 or 312 . adjustment tools 313 and 314 are similar in construction and operation to the adjustment tools previously described ( but not shown ) in reference to uec 200 . proximal plug 310 includes a mating recess on its proximal end ( not shown ) configured to removably receive the splined distal end of proximal plug adjustment tool 313 for rotating proximal plug 310 . distal plug 312 includes a smaller mating recess on its proximal end ( not shown ) configured to removably receive the smaller splined distal end of distal plug adjustment tool 314 for rotating distal plug 312 . both proximal plug adjustment tool 313 and proximal plug 312 are provided with central bores that permit the distal end of distal plug adjustment tool 314 to pass therethrough , through the center of cage body 308 , and partially into distal plug 312 . in this exemplary embodiment , the proximal ends of adjustment tools 313 and 314 each have a hexagonally - shaped head that permits them to be turned together in unison or individually ( as previously described in relation to uec 200 ), using wrench ( es ), socket ( s ) ( not shown ) and / or by hand . as shown in fig1 and 17 , cage body 308 includes eight longitudinally extending beam portions 318 , each separated from an adjacent beam portion 318 by a longitudinally extending gap 320 . in other embodiments ( not shown ), the cage body may include fewer or more than eight beam portions , and / or beam portions having a different or varying cross - section or shape . it can be seen that in this embodiment , four of the gaps 320 are formed through the middle of the four faces of cage body 308 , and the other four gaps 320 are formed along the corner edges of cage body 308 . cage body 308 also includes eight circumferentially extending connector portions 322 . the connector portions 322 interconnect the ends of the beam portions 318 . circular apertures 321 may be provided as shown between the ends of gaps 320 and the connector portions 322 to relieve stress concentrations at those locations as connector portions 322 flex . four of the connector portions / flexures 322 are located at the proximal end 304 of cage body 308 ( across the corner edges of cage body 308 ), and the other four connector portions / flexures 322 are located at the distal end 306 ( across the distal end of the faces of cage body 308 .) the connector portions 322 located at the proximal end 304 are staggered in relation to the connector portions 322 located at the distal end 306 such that each pair of adjacent beam portions 318 are connected at only one end by a connector portion 322 . as with previously described embodiments , the beam portions 318 and connector portions 322 form a continuous serpentine or repeating s - shaped pattern . the beam portions 318 and or the connector portions 322 are configured to resiliently flex to allow the cage body 308 to increase in circumference when urged radially outward by plugs 310 and 312 . when plugs 310 and 312 are not urging cage body 308 radially outward , the resiliency of beam portions 318 and or connector portions 322 allows cage body 308 to return to its original reduced circumference . it can be appreciated that as beam portions 318 and or connector portions 322 flex outwardly , gaps 320 become wider at their open ends opposite connector portions 322 . the outwardly facing surfaces of beam portions 318 may each be provided with one or more points or spikes 323 as shown , to permit cage body 308 to grip the end plates of the vertebral bodies . in this exemplary embodiment , spiked or knurled surfaces are provided along the top and bottom of uec 300 while the side surfaces are left smooth . referring to fig1 and 19 , a side view and a side cross - sectional view , respectively , of uec 300 are shown . in operation , the proximal end 304 of uec 300 may be independently expanded by inserting proximal plug adjustment tool 313 into the mating recessed socket of proximal plug 310 ( as shown in fig1 ) and turning it clockwise . turning proximal plug 310 clockwise causes the threaded ramped surfaces 332 of plug 310 to translate inwardly ( to the left in fig1 and 19 ) along the threaded ramped surfaces 334 located along the inside of beam portions 318 and connector portions 322 to cause these elements to flex and expand radially outward as previously described . this process may be reversed by turning proximal plug 310 counterclockwise , thereby allowing the proximal end 304 of uec 300 to return to its non - expanded state . similarly , the distal end 306 of uec 300 may be independently expanded by inserting a tool such as a five - lobed socket ( not shown ) through the central bore 325 in proximal plug 310 until it engages with the proximal end of actuator 314 , which is attached to distal plug 312 . turning distal plug 312 counterclockwise ( from the perspective of the proximal end ) causes the threaded ramped surfaces 332 of plug 312 to translate inwardly ( to the right in fig1 and 19 ) along the threaded ramped surfaces 334 located along the inside of beam portions 318 and connector portions 322 to cause these elements to flex and expand radially outward as previously described . this process may be reversed by turning distal plug 312 clockwise , thereby allowing the distal end 306 of uec 300 to return to its non - expanded state . referring to fig2 a - 20c , a series of sides views depicts the progression from a fully retracted and a fully expanded uec 300 . in fig2 a , cage body 308 is shown in a fully retracted position . in this figure , the height of each end of cage body 308 is labeled as 100 % of retracted cage height . in fig2 b , the proximal end 304 of cage body 308 has been fully expanded while the distal end 306 remains fully retracted . in this exemplary embodiment , each end is capable of being expanded to a height ( and therefore also a width ) that is 140 % of the fully retracted height , as shown . in fig2 c , the distal end 306 has also been expanded by 40 %. in some embodiments , uec 300 has a cage length of 50 mm , an unexpanded cage height of 10 mm , and an expanded cage height of 14 mm . the overall length of uec 300 with adjustment tools 313 and 314 in place and in the unexpanded state may be 75 mm . in other embodiments , the uec may be configured to expand to about 11 , 12 , or 13 mm , or more than 14 mm . in still other embodiments , the uec may be configured with dimensions larger or smaller than these to conform to a particular anatomy or procedure . in some embodiments , the uec can form an included angle between its top and bottom surfaces of at least 20 degrees . referring to fig2 , a fourth embodiment of an exemplary uec 400 according to aspects of the disclosure is shown . fig2 is a perspective view which shows details of uec 400 . uec 400 includes a proximal end 404 , a distal end 406 , cage body 408 , proximal plug 410 , distal plug 412 , proximal plug adjusting tool 413 , and distal plug adjusting tool 414 . other than cage body 408 having a circular cross - section rather than a square cross - section , uec 400 is essentially identical in construction and operation to previously described uec 300 . in other embodiments ( not shown ), the uec may have a cross - section transverse to the central longitudinal axis that is rectangular , trapezoidal , oval , elliptical or other shape . referring to fig2 - 25 , a fifth embodiment of an exemplary uec 500 according to aspects of the disclosure is shown . fig1 is a perspective view which shows details of uec 500 . uec 500 includes a proximal end 504 and a distal end 506 , and shares many of the same features of previously described uecs 100 - 400 , which are identified with similar reference numerals . uec 500 includes three components : a generally cylindrical , unitary cage body 508 ; a proximal actuator screw 510 ; and a distal actuator screw 512 . the heads of actuator screws 510 and 512 may be referred to as plug members . cage body 508 includes two longitudinal , off - center slots 550 which each extend about three - quarters of the length of cage body 508 , and emanate from opposite ends and opposite sides of cage body 508 . cage body 508 is also provided with two transverse slots 552 , each located adjacent to the closed end of one of the longitudinal slots 550 . each transverse slot 552 extends from the outer circumference of cage body 508 and approaches the base of a longitudinal slot 550 . each of the two pairings of a longitudinal slot 550 with a transverse slot 552 defines a cantilevered arm 554 that is connected with the remainder of the cage body 508 by a living hinge 556 near the closed ends of the two slots 550 and 552 . each living hinge 556 allows its associated arm 554 to flex outwardly against a vertebral body . the open ends of longitudinal slots 550 are outwardly tapered to receive the enlarged , tapered heads of an actuator screw 510 or 512 , as best seen in fig2 . the opposite ends of actuator screws 510 and 512 extend through longitudinal slots 550 and thread into the opposite ends of cage body 508 . with this arrangement , each actuator screw 510 and 512 may be turned independently of the other , causing the screw to move axially relative to bone cage 508 . this axial movement causes the head of the screw to urge the tapered tip of the associated arm 554 outward , or allowing it to flex back inward when the screw is turned in the opposite direction . if both actuator screws 510 and 512 are turned in the same direction the same amount , uec 500 expands uniformly and increases the height between adjacent vertebral bodies . if one of the two actuator screws 510 or 512 is turned more than the other , the surgeon is able to change the angle between the vertebral bodies . as best seen in fig2 , a slot 558 or other suitable feature may be provided in the end of each actuator screw 510 and 512 at the opposite end from the screw head . a hole 560 may also be provided through each end of cage body 508 to allow access to each of the two slots 558 . this arrangement allows both of the actuator screws 510 and 512 to be turned from either end 504 and / or 506 of cage body 508 . referring to fig2 - 28 , an example implementation utilizing two uecs 56 in tandem is shown . each uec 56 may be inserted as previously described in relation to fig1 - 3 . in this implementation , uecs 56 are placed non - parallel to one another . as best seen in fig2 , this arrangement allows the surgeon to adjust the angle between the vertebrae about two different axes , and also translate the vertebrae with respect to one another about another axis . fig2 is an oblique anterior view showing placement of an anterior column implant 56 on a vertebral body 52 . in this implementation , implant 56 is placed laterally across the vertebral body 52 , forward of the lateral midline . after adjustment of implant 56 , its plugs are flush with or recessed within the outer perimeter of the endplate of vertebral body 52 so as not to impinge upon adjacent tissue . referring to fig3 , a human spine 76 is shown that exhibits scoliosis . according to aspects of the disclosure , dual uecs may be placed at various levels of the spine to treat the condition . for example , a single uec or pairs of uecs may be implanted at the levels depicted by reference numerals 78 , 80 , 82 and 84 shown in fig3 . by using the adjustments described above relative to fig2 , the curvature of the spine may be adjusted in three dimensions at these four levels to a correct alignment , as shown in fig3 . fig3 a - 32c are anterior , lateral and oblique views , respectively , showing adjacent vertebral bodies 50 and 52 having misalignments / uneven spacing . fig3 a - 33c are anterior , lateral and oblique views , respectively , showing the vertebral bodies 50 and 52 of fig3 a - 32c with the misalignments / uneven spacing corrected according to aspects of the disclosure . the implants can be made of , for example , such materials as titanium , 64 titanium , or an alloy thereof , 316 or 321 stainless steel , biodegradeable and biologically active materials , e . g . stem cells , and polymers , such as semi - crystalline , high purity polymers comprised of repeating monomers of two ether groups and a ketone group , e . g . polyaryetheretherketone ( peek )™, or teflon ™. to prevent movement of proximal and distal plugs or actuators after implantation , in some implementations a biocompatible adhesive or thread locking compound may be applied to one or more of the moving parts . in some embodiments ( not shown ) a pin may be inserted radially or axially between the plug / actuator and the cage body to lock the parts in place post operatively . in some embodiments , a ratchet , spring loaded detent , or other locking mechanism may be provided for this purpose . in general , as disclosed in the above embodiments , the cage body is cut with openings at every other end of each slot , like a sine wave , allowing expansion when the center of the cage becomes occupied with a cone or mandrill shaped unit . the cage body &# 39 ; s series of alternating slots allows the expansion to take place while keeping the outside of the uec one single piece . the slots plus the teeth on the surface allow for a solid grip on the bone surfaces and plenty of opportunities for good bone ingrowth . also , by allowing the surgeon to make one end of the uec thicker than the other , the effects of the cone ( mandrill ) introduction vary from uniform to selective conduit expansion . the uec expansion mechanism is adaptable to both fixed fusion and mobile ‘ motion preservation ’ implants , with exteriors of the expanding implant per surgeon &# 39 ; s choice ( round , flat , custom , etc .) as such , in some implementations , relative motion may be preserved between the vertebral bodies adjacent the implanted uec ( s ). in other implementations , it may be desirable to fuse the adjacent vertebral bodies around the implanted uec ( s ). to provide motion preservation between adjacent vertebrae , robust compressible materials may be used between the uec and one or both of the vertebral endplates , and / or one or more components of the uec may comprise such materials . these materials may replicate the load distributing and shock absorbing functions of the annulus and nucleus of a natural disk . for example , in some embodiments the uec may be provided with tapered plugs made of a resilient polymer to allow the uec to compress and expand to accommodate relative motion of the adjacent vertebrae . examples of biocompatible materials suitable for some uec embodiments include bionate ®, a thermoplastic polycarbonate - urethane ( pcu ) provided by dsm biomedical in exton , pa ., and chronoflex ®, a pcu provided by advansource biomaterials in wilmington , mass . the uec provides advantages over currently existing technology that include correction of coronal plane deformity ; introduction of interbody lordosis and early stabilization of the interbody space with rigidity that is greater than present spacer devices . this early stability may improve post - operative pain , preclude the need for posterior implants including pedicle screws , and improve the rate of successful arthrodesis . importantly , the uec provides improvement of space available for the neural elements while improving lordosis . traditional implants are limited to spacer effects , as passive fillers of the intervertebral disc locations awaiting eventual fusion if and when bone graft in and around the implant fuses . by expanding and morphing into the calculated shape which physiologically corrects spine angulation , the uec immediately fixes the spine in its proper , painless , functional position . as infused osteoinductive / osteoconductive bone graft materials heal , the patient becomes well and the implant becomes inert and quiescent , embedded in bone , and no longer needed . in some embodiments , the external surface of the uec may be 3d printed to not only fit into the intervertebral space per se , but to match the surface topography at each insertion location . in other words , a 3d printed endplate may be utilized , computer calculated to fit and expand the disc space of the individual patient , resulting in both best ‘ goodness of fit ’ for fusion , and improved axial skeletal alignment . by creating to ‘ maps ’ that fit e . g . as a precisely congruent superior and inferior surface to fit into a particular patients disc space , and placing these uec end plates on either side the novel uec expansion mechanism , a patient &# 39 ; s disc space and overall spine alignment will be ideally treated toward best fusion ( or motion preservation ) and alignment . “ method of surgery ” instructions may recommend the surgeon and // or robotic unit deploy expansion as programmed to insert the uec into a particular disc level of pathology , to achieve best results . for example , preoperative patient scans / films can predict ideal uec surgeon use , such as “ turn knob a a certain number of rotations clockwise ,” to maximize visible , palpable , and roentgenographic ‘ goodness of fit ’. with this approach , post activation , the uec implant fits the location , entering at the predetermined best angle ( in 3 axes ) using the proprietary method of surgery and uec insertion tools provided . in some embodiments , the uec may be coated with hydroxyapatite . in some embodiments , toothed or 400 μm beaded surfaces may be utilized to promote bony ingrowth . inflatable chambers may be provided within the endplate that can expand after being implanted . this approach addresses the 3 - d congruence to proximate disc pathology . it can also allow for intervertebral arthrodesis or arthroplasty treatment and overall improved spinal alignment , integrating the internal proprietary expansion with the variable external endplate shapes and their contents . uec inflatable endplates of polymer may be employed , such as tiny vacuoles , “ bubblewrap ”, and multiple or singular bladder constructs . if a portion of the disk space were collapsed , that region could be aptly elevated or expanded by the uec endplate variation in material and / or inflation . the inflatable chambers may contain compressible gas ( such as air ,) granules as pharmacologics , and / or stem cells that are delivered via liquids . in cases where the uec is compressible or force absorbing , the material and / or chamber could be used as a cushion or to ‘ selectively direct and protect chondrocytes ’ toward improvement of existing pathophysiology via best drug use or regeneration . the ‘ preparation ’ of the uec insertion site will vary per surgeon . in some implementations , an arthroscopic burr may be advisable for removing 0 . 5 mm of cortical bone along with all aberrant disc contents under digital arthroscopic camera control . in other implementations , the surgeon may just carefully curette the intervertebral space to ‘ clean it out ’ in preparation for the uec implant insertion . the uec may be inserted directly into the insertion site , or may be inserted through proprietary or commercially available insertion tube . the insertion tube typically will have a blunt distal tip so that it can be inserted through an incision without causing tissue damage . the tube can be used with or without additional tissue retractors . the uec may be preloaded into the insertion tube , or placed into the tube after the tube has been introduced into the insertion site . a pusher rod or other device may be utilized to deploy the uec from the insertion tube into the insertion site . in some procedures , the placement of the uec may be arthroscopically assisted . note that regardless of the endplate preparation , in the deformed , aging , pathologic spine there will be pathology to correct . according to various aspects of the present disclosure , the uecs provided herein may accomplish this in several ways as pertains to the external implant composition . for example , the uec can expand as an externally threaded conduit , either uniformly end to end resulting in same diameters at each end post - operatively ( such as 40 % overall expansion ), or precisely at either end , thus creating an overall conical albeit expanded uec . also , the uec can be flat superiorly and inferiorly as shown in the above drawings , thus more likely matching the rather flat vertebral body end plates . however , according to further aspects of the present disclosure , special care should be taken to consider both the peripheral end plate boney rim as thicker more prominent cortical bone at the vertebral end plates with a sunken or concave thinner interior ( thus subject to potential subsidence ). the uec mos ( method of surgery ) contemplated herein considers the preoperative findings ( e . g . mri , 3d ct scan , x - rays ) to integrate information on bone density , specific disc space and longitudinal spine anatomy , topography and alignment . the various expanding cages disclosed herein and variations thereof are not limited to use in the spinal column but may be used between other bone segments throughout the human or animal body . for example , a uec can be used during arthrodesis of a metatarsal joint . the uec can aid in setting the orientation of the toe to a desired angle before fusion of the apposing bone segments occurs . similarly , a uec may be utilized in the knee , elbow or other body joints , or between two or more bone segments that have been fractured by trauma . 1 ) the uec corrects spine surgical pathology both locally via horizontal ( disc ) and longitudinal vertical axial ( scoliotic / kyphotic ) spine deformity improvements . a ) arthrodesis ( fusion ) or b ) arthroplasty ( motion preservation ) c ) drug / cell therapy delivery 3 ) the uec can expand uniformly throughout implant length , and / or expand only proximally ( toward the surgical incision ) or distally , thus enabling clinical adjustments favorable to spine diseased or injured patients for local and overall spondylopathies . 4 ) the uec can be surgically inserted via outpatient mis ( minimally invasive — outpatient surgery ) as safe , efficacious implants “ doing no harm ” applying advantages from a ) materials thicknesses for height differentials or b ) expansion adjustments surgically controlled ( before / during or after implantation ) or via prefabricated portals or injections — programing implant ‘ mapped ’ corrections using c ) polymers durometrically calculated with variable compressions , permanent or biodegradable activations at will . d ) inflation of the implant as via uec surface chambers or bladder ( s ). e ) adding endplate biologics , foam , or other adaptables for best results . f ) uec expansion can adapt to expand variable external surface parameters including flat , round , or customized external maximally congruent surfaces to interface as with proximate endplates . 5 ) delivery either via uec materials per se ( eluding substances — cells or pharmacologics ) or through extrusion from a uec container or delivery vesicle / depot / chamber / portal will enable not only immediate surgically correction but long term enhanced bone in growth and local / general therapeutic and / or regenerative clinical benefits . while the disclosure has been described in connection with example embodiments , it is to be understood that the disclosure is not limited to the disclosed embodiments and alternatives as set forth above , but on the contrary is intended to cover various modifications and equivalent arrangements included within the claim scope .

US-201514939905-A

a leaf vacuum and mulching implement for attachment by three - point - hitch to a farm tractor and driven by mechanical connection to the tractor &# 39 ; s power tack - off unit . the implement utilizes a broad vacuum deck having polymeric skirts in near proximity with the ground and a floating three - point - hitch system for lifting the vacuum deck and allowing it to follow the ground contour . high velocity fans blow debris collected by the vacuum deck to a unique , rotating , multifaceted , conical shredding rotor prior to directional dispersion .

as first depicted in fig1 the vacuum mulching and dispersion unit is a farm implement adapted to any common farm tractor 12 for high - speed operation and maneuverability . the mulching apparatus is capable of vacuuming leaves and fine debris in large swaths of from 8 to 10 feet wide before mulching and dispersing the debris 11 back on the ground adjacent the mulching apparatus 10 . as seen in fig2 the mulching implement 10 is attached to the tractor by a three - point - hitch arrangement 16 capable of lifting the implement clear of the ground for easy turn - around and is further fitted with a flexible upper connection element 18 , such as chain , commonly utilized in the art for allowing the implement to float or follow the contour of the ground . adjustable height , swivel wheels 20 located at each corner of the vacuum deck 22 maintain ground clearance and further allow the mulching apparatus 10 to pivot as the tractor maneuvers around obstacles . looking now at fig3 we see that the vacuum deck 22 is fitted with polymeric skirts 24 located below the deck 22 and extending the full width of the deck 22 , thereby providing a relatively large vacuum box below the deck 22 . since no mower blades are utilized with this apparatus , a more positive vacuum can be maintained . large fan ducts 26 draw debris from openings in the vacuum deck 22 into the intakes of twin high velocity induction fans 28 connected in tandem with their outlets connected to the rotor housing 30 . much of the drive mechanism is concealed by the cover 32 , seen in fig3 and is therefore better seen exposed in fig4 . a drive shaft assembly 34 connectable to the output shaft of the tractor &# 39 ; s pto drive running at 540 rpm is connected to a gear box 36 having a 4 to 1 ratio , thereby increasing the gear box 36 output to 2 , 160 rpm . pulleys attached to the gearbox &# 39 ; s output shaft are then used to drive both the dual high velocity fans 28 at 5 , 220 rpm and the mulching rotor assembly 38 , seen in fig7 at 2 , 160 rpm . the drive arrangement is best seen in fig5 which illustrates a belt - driven series of pulleys utilizing a 50 percent pulley speed reduction that is utilized to drive the common fan shaft 40 , shown in cut - a - way with one of the fans removed . the output shaft of the gear box 36 is fitted with a dual pulley 42 having an 8 - inch diameter pulley and a 4 - inch diameter , the 8 - inch pulley having a belt 46 connected to a 4 - inch pulley located on fan shaft 40 . the 4 - inch drive pulley is then connected by belt 48 through a system of idler pulleys in a right angle manner upwards to the rotor pulley 50 . leaves and other debris vacuumed from the ground by the high velocity fans are blown into the rotor housing 30 , seen in fig6 where mulching takes place due to repeated contact with the conical - shaped multifaceted rotor assembly 38 prior to being discharged by a fan located in a fan housing or shroud 54 connected to the rotor housing 30 at flange 56 . the rotor assembly 38 sizes the materials passing through the rotor housing 30 to between approximately 50 micron up to one inch with the average size being approximately ¼ inch . the rotor housing 30 is a truncated conical shape and has a flattened portion near the truncation for making connection by flange mounting with the dual fan outlet ducts 58 . the fan ducts 58 to rotor housing connection is structurally sufficient to support the rotor housing 30 in a cantilever manner . the rotor assembly includes a central shaft 60 supported within the rotor housing 30 by a flange bearing 62 at the upper or narrow end and by a collar bearing 64 and support member 66 connected diametrically across the opening at the wide or lower end . the central shaft 60 has a portion extending a distance beyond the collar bearing 64 where a fan blade assembly 52 is mounted thereon . the rotor assembly 38 , as seen in fig7 includes at least 4 elongated lattices 68 emanating from collars 67 attached to the central shaft 60 and bound by bands 70 and 71 holding the parallel bands 76 in compression . each lattice 68 includes a doubling bar 72 having an offset portion 74 located at the wide or base end of the conical shaped lattice . each lattice is composed of a series of horizontal bands 76 of approximately { fraction ( 3 / 32 )} inch thick arranged with intersecting planes , which may not necessarily be at repetitive angles , as seen in fig8 . the leading edges of each of the lattice bands 76 are sharpened , as seen in fig8 a . the rotor assembly is rotationally balanced between shaft centers by adding lead weights as necessary , the process commonly known within the art . a more detailed view of the major component parts is shown exploded in fig9 , and 11 . in fig9 we see the vacuum deck 22 fitted with the 4 swivel type wheels 20 located at each corner . brackets 80 are provided for pivotal connection to the tractor 12 in three - point hitch arrangement whereby the tractor lifting arms 16 are capable of lifting the entire deck assembly 22 off the ground and whereby the clevis and chain assembly 18 provides for angular adjustment of the deck assembly , allowing the deck to pivot upwards at the trailing end but not allowing downward travel of the trailing end beyond a preset height established by the chain . fan ducts 26 are mounted to the vacuum deck 22 over openings 27 therein and connect at their upper ends to the intakes of the high velocity fans 28 . the gearbox is mounted to the vacuum deck in a manner whereby the drive shaft 34 , seen in fig3 and 4 , can easily make a sliding spline connection to the tractor &# 39 ; s pto output drive shaft . as seen in fig1 , we see an end view of the rotor housing 30 in which a screen element 80 is inserted in the flange 56 . this provides a retaining baffle for the finely mulched leaves to collect behind prior to discharge to insure particle sizing as low as possible usually between 50 microns and 1 inch long . in addition to the general rotor assembly 38 , as seen in fig1 , a directional nozzle housing 82 may be added for directing the fine particles downward or to either side of the tractor path if desired by simply orienting the nozzle 82 . because many varying and different embodiments may be made within the scope of the inventive concept herein taught , and because many modifications may be made in the embodiments herein detailed in accordance with the descriptive requirement of the law , it is to be understood that the details herein are to be interpreted as illustrative and not in any limiting sense .

US-13784102-A

the invention involves a device and method for ascertaining the functioning of the respiratory system and determining whether a pulmonary embolism is present . the device comprises an apparatus containing sensors for measuring the oxygen and carbon dioxide concentrations as well as the volume of air inhaled and exhaled by a patient . from this data , a processor computes the ratio of carbon dioxide to oxygen for the volume of expired air and displays the results on a screen . by comparing the results to predetermined normal values , an accurate determination can be made regarding the presence of a pulmonary embolism .

referring now to the drawing in which like reference numerals refer to like parts throughout , there is seen in fig1 a representation of lungs 10 free from any pulmonary occlusions . in healthy lungs 10 , blood flows freely from the pulmonary arteries 12 into the capillaries 14 surrounding the individual alveoli 16 of the lungs 10 . when inhaled air 18 is drawn into the lungs 10 and alveoli 16 , oxygen is transferred from the inhaled air 18 to the blood stream and carbon dioxide is transferred out . inhaled air 18 typically contains an oxygen partial pressure of approximately one hundred ( 100 ) torr and a carbon dioxide partial pressure of zero ( 0 ) torr . once the inhaled air 18 reaches the alveoli 16 , the oxygen content decreases while the carbon dioxide content increases until an equilibrium with blood gas levels in the pulmonary arteries 12 is reached . the inhaled air 18 is then , as seen in fig2 expired as exhaled air 20 . exhaled air 20 from properly functioning lungs typically contains a partial pressure of oxygen of about eighty ( 80 ) torr and a partial pressure of carbon dioxide of about forty ( 40 ) torr . fig3 depicts the functioning of a respiratory system afflicted with a pulmonary embolism 22 which , as an example , occludes blood flow to an afflicted lung 24 . as a result , there is a reduction in the number of alveoli 16 that participate in gas exchange . this volume of space available in the alveoli 16 that is lost from participation is commonly referred to as alveolar deadspace . due to the deadspace and loss of total alveolar volume available for gas exchange , afflicted lung 24 does not exchange gases as readily as the healthy lung 10 . accordingly , exhaled air 26 contains a higher partial pressure of oxygen and lower partial pressure of carbon dioxide than air exhaled from a healthy lung . in the example depicted in fig3 , exhaled air 26 exiting the respiratory system contains a partial pressure of oxygen of about eighty - five ( 85 ) torr and a partial pressure of carbon dioxide of about twenty ( 20 ) torr . thus , the ratio of carbon dioxide to oxygen in exhaled air 26 from afflicted lung 24 ( i . e ., 20 : 85 ) is smaller than the ratio in exhaled air 20 from healthy lung 10 ( i . e ., 40 : 80 ) as seen in fig2 . as seen in fig4 a system 28 for measuring and diagnosing pulmonary disorders comprises a measuring unit 30 in combination with a data processing unit 50 and a display screen 60 . measuring unit 30 determines the overall flow of air inhaled into and exhaled out of the lungs while simultaneously determining the partial pressure of oxygen and carbon dioxide . data processing unit 50 computes the concentrations of carbon dioxide , oxygen , and nitrogen from the partial pressures and determines the ratio of carbon dioxide to oxygen from the raw data obtained by measuring unit 30 . the ratio of carbon dioxide to oxygen is then plotted against expired volume on display screen 60 . by comparing the carbon dioxide ratios to average readings , the likelihood that a given patient has a pulmonary embolism can be determined . measuring unit 30 comprises a patient mouthpiece 32 connected in fluid communication to a breathing tube 34 having an open end 42 through which air can be inhaled or exhaled . measuring unit 30 further comprises three sensors ; a pneumotach 36 , a capnometer 38 , and an oxygen monitor 40 . the three sensors are situated in series and in - line with breathing tube 34 for simultaneously measuring the flow , carbon dioxide , and oxygen levels of inhaled and exhaled air . infrared and paramagnetic type sensors are preferred respectively . sensors using spectrometric techniques may also work for both oxygen and carbon dioxide measurements providing they can supply data with rapid enough response time for breath - to - breath , real - time plotting . the mainstream technique for measuring the inhaled or exhaled air is preferred , but the sidestream technique may also be effective . as seen in fig5 a t - piece adaptor 70 may optionally be provided at open end 42 of breathing tube 34 for use with patients that are oxygen dependant . t - piece adapter 70 contains an inlet valve 72 and an outlet valve 74 which properly direct the passage of inhaled and exhaled air through the breathing tube 34 . by connecting an oxygen dependant patient &# 39 ; s supply to the intake valve 72 , inhaled air can first be passed through the three sensors 36 , 38 , 40 to establish baseline readings of the oxygen and carbon dioxide concentrations for comparison to exhaled air , since an oxygen dependent patient receives air that has different concentrations than present in ambient air . data processing unit 50 comprises a commercially available computer processor programmed with software for the interpretation of the data obtained from measuring unit 30 and background comparison data . software can be specifically developed to perform the necessary calculations to determine the partial pressures and carbon dioxide to oxygen ratios or software can optionally be purchased commercially and , if necessary , modified to run the appropriate algorithms . after additional research , the background comparison data can be updated based on data obtained from use of the invention to further refine expected normal values . display screen 60 comprises a cathode ray tube or other visual display for displaying computerized data . screen 60 can optionally display graphs representing predetermined reference or background data for test populations against which the current readings can be plotted for a visual comparison . in addition to displaying the carbon dioxide to oxygen ratios as a function of time calculated by data processing unit 50 , screen 60 may optionally display a plot of the expired oxygen and carbon dioxide partial pressures . using this display , a physician may estimate the efficiency of alveolar ventilation in patients with acute respiratory distress syndromes to assist in deciding the mechanical ventilation settings . in addition to the three primary sensors 36 , 38 , 40 , data processing unit 50 may optionally be connected to a pulse oximeter 44 that measures arterial oxygen saturation of hemoglobin in the arterial blood . from this data , and the additional measurement of ph and hemoglobin concentration in a peripheral venous blood sample , the cardiac output of the patient can be calculated according to the fick equation . in order to perform the fick equation , the average total oxygen consumed , the arterial oxygen content and venous oxygen content must be determined . the average total oxygen consumed can be determined from the oxygen tension and flow curves over a predetermined time period . for the purposes of determining cardiac output , a one minute time period is sufficient . the arterial oxygen content can be estimated by multiplying the arterial oxygen saturation ( measured by pulse oximeter 44 ) by the hemoglobin concentration ( determined from the venous blood sample ). the venous oxygen content can be calculated by determining the nadir ( mean lowest ) oxygen tension measured during expiration over the predetermined time period . from the nadir oxygen tension , venous oxygen saturation can be estimated according to published oxygen binding curves for the measured ph . the venous oxygen content is then calculated by multiplying the venous oxygen saturation by the venous hemoglobin ( measured from the venous blood sample ). once these calculations have been made , the cardiac output is determined by dividing the total oxygen consumed by the difference between the arterial oxygen content and the venous oxygen content . the algorithm for the fick calculation can be programmed into the data processing unit software and the results displayed on screen 60 . the cardiac output measurement is useful for assisting the physician in determining the success or failure of treatment designed to relieve pulmonary vascular obstructions , or to treat circulatory shock . device 28 is used by having a patient breathe ( inhale and exhale a predetermined number of times in succession ) through mouthpiece 32 of the measuring unit 30 . as the patient inhales and exhales the pneumotach flow sensor 36 , capnometer 38 , and oxygen monitor 40 perform their respective readings , which are then electrically transmitted via wires or cabling to data processing unit 50 . the programmable software loaded into data processing unit 50 convert the measurements into volume and concentration readings , calculate the carbon dioxide to oxygen ratio , and display this ratio on screen 60 in the form of a graph against the volume of air expired . readings may be optimized by requiring the patient to hold in inhaled air for several heartbeats before exhaling through the mouthpiece 32 of the measuring unit 30 . it has been determined through testing that patients without a pulmonary embolism will normally have a carbon dioxide to oxygen ratio of 0 . 30 or greater while patients with a pulmonary embolism will have a carbon dioxide to oxygen ratio of 0 . 25 or less . device 28 may also be used for the detection of whole - body oxygen consumption and determination of the adequacy of oxygen delivery during resuscitation from shock . during conditions of systemic inflammation the body will extract oxygen at higher levels than normal , resulting in an increase in the carbon dioxide to oxygen ratio in exhaled air . by using t - piece 70 in the manner explained above , the concentration of the oxygen provided to the patient and the concentration of the oxygen exhaled can be determined . as illustrated in fig6 when the level of oxygen delivery ( i . e ., the amount provided minus the amount exhaled ) observed at two inspired oxygen concentrations reaches normal levels a physician has visual conformation that the resuscitation performed is adequate . one method of determining the adequacy of resuscitation is to determine oxygen delivery at both relatively low fixed concentrations of oxygen and at relatively high fixed concentration . relatively low concentrations include from about twenty - one to thirty percent ( 21 - 30 %) oxygen and relatively high oxygen concentrations involve about forty - five to fifty percent ( 45 - 50 %) oxygen . the difference between oxygen delivery at relatively low concentrations verses relatively high concentrations can be compared against a nomogram for healthy patients of similar age , body mass , body mass index , and gender and used to assess the adequacy of fluid and vasopressor resuscitation . data processing unit 50 can additionally be programmed to display on screen 60 any of the individual measurements taken by sensors 36 , 38 , 40 , and 44 , or combinations thereof for diagnostic purposes . for example , a plot of the expired carbon dioxide and oxygen concentration over time could be used to estimate the efficiency of alveolar ventilation in patients with acute respiratory distress syndrome . additionally , the plotted data from sensors 36 , 38 , 40 , and 44 could be used to assist in deciding how to properly adjust mechanical ventilators setting , such as the degree of positive end - expiratory pressure , minute ventilation , and peak inspiratory pressure settings , to optimize patient care . for example , data from sensors 36 , 37 , 40 , and 44 , can be plotted individually in patients who are being mechanically ventilated . by simultaneously plotting the partial pressures of oxygen and carbon dioxide as a function of volume of each breath , the amount of carbon dioxide released and percentage of oxygen extracted can be determined . if the barometric pressure is known or inputted into data processing unit 50 , the efficiency of alveolar ventilation during each tidal volume breath can be calculated . this information can then be used to adjust mechanical ventilation to optimize alveolar efficiency or breathing alveolar ventilation efficiency .

US-96530301-A

a pellet dispenser wherein pellets are loaded into a cylindrical cap having a centrally - located tube . the tube contains a guide and a flange end . the dispenser includes a base having an inclined skirt bounded by an external flange with a post to be inserted into the tube . the post is provided with a circumferential shoulder and a guideway . insertion of the post into the tube orients the cap and base and permits relative rotation . the assembled dispenser is inverted for use .

referring now to fig1 the present invention is shown in preferred form which includes a cap 12 fitted in contact with base structure 14 . the cap is dimensioned to fit against the base at the bottom of flange 15 . a centrally - located post 16 is provided with a circumferential sealing flange 34 which contacts the adjacent portion of the cap . in fig1 the device is shown in the closed position with the toxic material in pelletized form contained within the device . while the embodiment described contains pellets , it should be noted that other shapes or forms of solid toxicants can be used if desired . the cross sectional view of fig2 shows the device filled with rodenticide pellets 18 . the side wall of cap 12 extends downwardly to the base of flange 15 and , in the closed position , rests in circumferential groove 36 . the groove provides a seal to prevent any of the toxic material contained in the device from migrating outwardly from the base structure during shipment and handling . the rodenticide pellets are friable and may self - abrade during movement thereby creating a powder which tends to fall to the bottom of the device . since the contained materials are toxic , any leakage of material is highly undesirable even when the device is packaged . the post 16 is provided with a sealing flange 34 which inhibits loss of material through the central opening of cap 12 . thus , the pellets and any generated powder are confined until the device is placed in operation . as shown in fig2 the cap 12 threadedly engages post 16 for helical movement in relation to the base to the open position . the structure of base 14 is seen more clearly in fig3 wherein the central post 16 is shown with vertical ribs 31 projecting from its side surface . the post extends from a central platform 21 . the platform is horizontal and is connected to a skirt 20 which extends outwardly and downwardly therefrom terminating in circumferential groove 36 . as mentioned previously , groove 36 receives the bottom edge of the cap 12 when the device is in the closed position . the guide 38 on post 16 travels within a mating guideway 43 formed on thickened wall portion 44 of the inner wall 40 of tube 41 in the cap . guideway 43 begins at an edge of the wall portion 44 and terminates at its upper end with the circumferential shoulder 42 . each guide 38 formed on the post 16 moves within a corresponding guideway to control the helical movement of the cap in relation to the base structure . the upward rotation of the cap is limited by the contacting of the shoulder 42 by flange 34 which together form a stop to define the full - open position . the closed position wherein the cap 12 enters the groove 36 is established by the opposing vertical ribs 31 on post 16 contacting the thickened wall portion 44 of the tube beneath the shoulder as seen in fig6 . the wall portion 44 serves as a vertical stop projecting inwardly . in the closed position , the stop prevents rotational forces from causing the guides 38 to be driven out of the respective guideways when force is misapplied to the device . the vertical ribs 31 on the post 16 also serve to register to cap and base structure during assembly . the opening of the embodiment of fig1 to provide access to the rodenticide pellets contained therein is shown in fig2 . in order to open the device , cap 12 is rotated in relation to the base structure 14 thereby causing the guides to move along the guideways . as the cap rises above the base structure , a circumferential opening is provided therebetween to establish a 360 ° feeding opportunity for rodents . the pelletized material 18 contained in the cap is fed by the force of gravity downwardly and outwardly along the inclined skirt 20 . the outermost pellets rest against the flange 15 and none of the bait contacts the ground . the vermin can feed on the exposed material without entering the device thereby reducing the opportunity for contamination or marking of the bait by the vermin . as material is consumed , the pellets continue to move downwardly and outwardly to continuously provide a toxicant supply until the material in the cap is consumed . the limiting of the full - open position prevents the pellets from flowing out of the trough formed by the flange 15 and the adjacent skirt 20 . in the preferred embodiment , the limit of vertical movement of cap 12 is preferably set to prevent the cap from moving more than the thickness of the pellet above the edge of flange 15 . as a result , the outward flow of pellets can be prevented . in use , the device is mounted on a surface and removably affixed by an adhesive pad which may be affixed to the bottom of the support member 22 . during assembly , the molded cap is inverted and the pellets are added . the cap and base structure are made of thin walled flexible plastic so that the post 16 and flange 34 combination can be urged through the tube to the point where the guide 38 enters the guideway 43 and the sealing flange 34 emerges at the opening in the top of the cap . to provide the rotational alignment between cap and base structure , the alignment tabs 24 and 25 are molded on the bottom of the base structure as shown in fig5 . also , alignment sockets 26 are formed in the top of the cap as seen in fig7 . the alignment tabs and sockets are located on the device in accordance with the assembly apparatus used to urge the base structure into the inverted cap . also , the vertical ribs 31 projecting from the opposing sides of post 16 contact the thickened wall portion containing the guideway 43 in cases of misalignment during assembly . as seen in fig2 and 4 , the vertical ribs 31 have a chamfer at one corner . the chamfer is provided to aid in registration of cap 12 and base 14 during assembly by imparting a slight rotation should the end of the thickened wall 44 contact the chamfer . during operation , the opposing side of vertical rib 31 contacts the thickened wall portion 44 containing the guideway 43 to define the open position . the angled guideways deflect the ribs into the alignment position without damage to the assembled device . the guideways 43 are formed in a thickened wall portion of the tube 41 so that the lowermost section of the guideway terminates at the vertical stop established by wall portion 44 which locates and defines the full closed position of the device . the thickened wall portion 44 is shown in fig4 as extending on each side of guideway 43 and terminating at the recess 48 defining the inner wall thickness . as shown in fig3 and 5 , the center post 16 and the central platform 21 are reinforced by the circular support member 22 extending downwardly from the platform . the central platform 21 is orthogonal to the post 16 and the inclined skirt 20 extends to terminate at groove 36 . the flange 15 extends outwardly from the skirt , preferably at an angle greater than 90 °, to serve as a retaining wall for the pellets . by limited the vertical movement of the cap to a position which is less than the thickness of the stored material above the edge of the flange , spillage is avoided during normal use . the rotation of the cap in the reverse direction allows the device to be closed if vermin control at this location is to be suspended . the device can be transported to another location without fear of spillage of the contents of the cap . since residual material is likely to reside outside the cap , care must be taken to prevent it from being spilled during placement at another location . while the above description has referred to a specific embodiment of the invention , it is to be noted that variations and modifications may be made therein without departing from the scope of the invention as claimed .

US-38726895-A

in one embodiment , a method electrically stimulates an area in a spinal disc . the method comprises : implanting at least one steerable lead at a placement site for stimulating a spinal disc such that the lead is disposed exterior and immediately adjacent to and circumferentially along an annulus of the spinal disc , the at least one lead including a plurality of electrodes distributed along a majority of a circumference of the annulus ; connecting the lead to a signal generator ; and generating electrical stimulation pulses using the generator to stimulate targeted portions of the spinal disc , wherein the stimulation of the targeted portion of the spinal disc sufficiently stimulates nerve tissue within the spinal disc to prevent communication of pain signals originating in the spinal disc without damaging tissue of the spinal disc .

the present invention treats the nerve - containing portion of the intervertebral disc for the indication of discogenic low back pain . the epidemiology of discogenic low back pain has been described by deyo and tsui - wu in “ descriptive epidemiology of low - back pain and its related medical care in the united states ,” and schwarzer , et . al ., in “ the sacroiliac joint in chronic low back pain ” which are incorporated by reference here in full . pain can be derived from degeneration or tearing of the intervertebral disc , especially in its posterior or posterolateral portions . there is innervation of the intervertebral disc near the surface of the disc and also within its outer portion , known as the annulus fibrosus . fissures or cracks within the discs , which appear with age , mechanical trauma or disc degeneration are believed to be associated with painful symptoms . it is thought that nerve fibers grow into such painful fissures or cracks and can even reach the outer part of the disc nucleus . electrical stimulation of the disc at a specified placement site is configured to stimulate these nerve fibers and therefore negate unpleasant sensations originating in the disc . such a placement site may be interior or adjacent to the disc in question . prior treatments for such discogenic low back pain relating to disc degeneration included a technique for heating portions of the annulus fibrosus with an intradiscal radiofrequency electrode . these treatments were performed for treatment of some forms of discogenic low back pain . this method typically heats or vaporizes a portion of the disc , possibly relieving interior disc pressure , thereby possibly relieving some associated disc pain . however , this procedure leads to a burning or scaring of the nerves associated with the disc , causing the pain relief to be temporary at best . in the present invention , electrical stimulation of the nerve fibers associated with a disc is the primary methodology for pain relief . the patterns and spread of stimulation often invariably mimic the pattern of discogenic pain . typically , for example in the lumbar region , this involves the spread of stimulation to involve the axial spine and the buttocks . if the voltage is increased , the spread can include the lower limbs . previous attempts to stimulate the area of the axial spine have encountered difficulties . these difficulties , that despite complex multiple electrode systems , obtaining coverage of central discogenic pain can be difficult to cover , are well known in the art . certain dual electrode systems have been developed by advanced neuromodulation systems , inc ( ans ) to address these difficulties . these dual electrode systems are typically passed into the epidural space , to lie in the dorsolumbar area . stimulation can be obtained in the buttock and lower limbs by classical spinal cord stimulation with epidural leads placed in the epidural space . however , central discogenic low back pain can be difficult to cover . typically , for analgesia to occur , the stimulated area must cover the area of the pain . the present invention uses direct stimulation of the intervertebral disc providing coverage of axial pain , which can provide greater certainty of coverage of these painful areas . there are three main risks encountered from intradiscal manipulation , including nerve injury , migration of the lead away from the placement site to involve sensitive neural structures , and disc space infection . certain studies have shown that the risk of disc space infection is considered to be approximately one in two thousand cases . this can be reduced by the injection of antibiotic into the disc at the time of implantation . the risk of nerve injury can be greatly reduced by very careful attention to surgical technique . the risk of migration of the lead can be minimized by the use of new materials for fixation of devices in or just adjacent to the disc space . additionally , the risk can be minimized by placing the lead at a placement site that is adjacent to the disc in question , proximal to the injury site . to additionally minimize the risks mentioned above , one embodiment of the present invention uses a configuration of a needle introducer to approach and enter the intervertebral disc . a lead is then inserted through the introducer . this configuration helps to adequately reach the posterior and posterolateral or any other desired portions of the intervertebral disc and places the lead at the correct placement site where the desired stimulation will occur . thus , proper placement of the lead occurs and disc disruption is minimized using this embodiment . another embodiment of the present invention uses a configuration of the needle introducer to approach the desired location of the disc and place the lead , inserted through the introducer , at a placement site adjacent to the disc . this configuration helps to adequately reach the proper placement site where the desired stimulation will occur , without entering the intervertebral disc . the placement site corresponds to the location where lead placement optimizes disc pain relief . for safety , it is desirable that the surgeon has quantitative information about the placement of the introducer and the stimulating lead as it is placed near the placement site in or just outside the disc . additionally , risk of the lead kinking within the disc or straying outside the disc , which could result in damage to the probe or injury to the patient should be taken into account when considering the placement site . one embodiment of the present invention that minimizes the risk of kinking and allows for greater flexibility of choosing a placement site retains the lead in or adjacent to the intervertebral disc and prevents its migration . in the present invention , prior to insertion of a permanent lead into or adjacent to the disc , a trial period is typically conducted for hours , days or even sometimes weeks . trial insertion and stimulation can be conducted at the same time as the injection of radiographic contrast material into the disc . this provides the surgeon with information on fissures or cracks within the disc ( i . e . discography ) and the response of the nerves to electrical stimulation . one embodiment of the present invention envisions that each patient who is diagnosed with discogenic low back pain , often by means of magnetic resonance imaging and discography , will undergo a trial period of stimulation . in this embodiment of the present invention , a trial lead will be inserted percutaneously at the placement site in the disc via an introducer and retained for a period while stimulation is conducted . the x - ray coordinates of the position and the electrical parameters of stimulation are noted during this period before complete removal of the trial stimulating device . it is envisaged that such a trial stimulation lead will be similar to those currently utilized for periods of trial stimulation with ans leads in the epidural space . the period of trial implantation could be short , lasting only a few hours or days , to minimize the chance of disc space infection or may be longer depending on the needs of the procedure and patient . after due consideration of the results of the trial stimulation , a permanent lead is inserted at the placement site in or just outside the intervertebral disc for long term stimulation purposes . as shown in fig7 , lead 10 , whether trial or permanent , will be connected to either a fully implanted , battery driven , stimulating device 60 that can last many years , or alternatively to a system for passage of external electrical energy through a coil or similar device often utilizing radiofrequency current . stimulating device 60 is coupled to lead 10 , which is place at the placement site . one embodiment of the present invention , stimulating device 60 is an implantable rechargeable device connected to the lead . recharging of this device will be conducted by positioning of an external charging device adjacent to the implanted stimulator for a period of hours . it is envisaged that the patient will require intermittent assessment with regard to patterns of stimulation . different electrodes on the lead can be selected by suitable computer programming , such as that described in u . s . pat . no . 5 , 938 , 690 , which is incorporated by reference here in full . utilizing such a program allows an optimal stimulation pattern to be obtained at minimal voltages . this ensures a longer battery life for the implanted systems . such programming will be conducted in a similar fashion to the current method of changing parameters for ans stimulating systems . one embodiment of the present invention uses a curved introducer to approach the placement site of the intervertebral disc via a percutaneous insertion point in the patient . the introducer is placed in or adjacent to the disc , depending on the actual location of the placement site , and a lead is passed through the introducer and pushed to the placement site in or adjacent to the intervertebral disc space . appropriate steering of the lead will place the device at the placement site in close proximity to the tears and fissures so that the nerves innervating these fissures can be electrically stimulated . the stimulating lead used in the present invention has a flexible configuration and is visible under image intensifier or ct x - ray monitoring . it is envisaged that in one embodiment , the lead passes through the intervertebral foramen , to exit the skin in the lumbar region . it is connected to an internal or external stimulating device so that variations of electrode configuration and electrical stimulation can be accomplished in a trial . various embodiments of a permanent lead are considered . in one embodiment a lead , which can be either monopolar ( unipolar ) or bipolar arrangement , can be inserted surgically , preferably by an endoscopic technique . this is typically performed in a similar fashion to endoscopic sympathectomy for lower limb ischaemia or endoscopic spinal fusion . this lead will have an unexpanded and an expanded position . the lead will be either inserted into the disc or placed adjacent to the disc so that it will expand into a position preventing migration onto adjacent sensitive neural structures . the lead can have multiple electrical contacts or a single contact . it is then connected to a stimulating device , which is either fully implanted or powered by an external radiofrequency source , in the same fashion that current ans devices are powered . it is envisaged that the lead will be constructed of biocompatible materials and designed such that it will resist migration and yet not prevent ultimate removal , if required . such a anti - migration design includes an inflatable miniature balloon , surgical fixation device or a device consisting of material with elastic memory , such as silicon , polymers , polyurethane materials , or nitinol or nitinol coated with a biocompatible material . alternative techniques of placement of a permanent electrode or lead are envisaged , which are performed percutaneously . such approaches involve the lateral portion of the disc to avoid placement of the lead adjacent to a nerve root or other sensitive neural structures . additionally , the lead may lie just adjacent to the outer confines of the disc so that nerve fibers inside the annulus fibrosis are recruited . it is envisaged that such placements would be performed under x - ray control and possibly in the same manner that permanent leads are placed in the epidural space . connection of the stimulating leads in the disc would then be made to either a permanent implanted power source or a coil powered by an external device . referring to fig1 , one embodiment of the stimulating system in accordance with the present invention is generally illustrated . in this illustration , a trial lead 10 is passed across the posterior aspect of the annulus fibrosus 15 so that electrodes in the lead are near the placement site and can make contact with the requisite pain nerve fibres in the disc 20 . lead 10 typically contains more than one electrode 5 , and often can have 8 , 16 or more electrodes , which provide the direct stimulation of the nerves in the disc area during system operation . during implantation , the introducer 30 is passed closely adjacent to the facet joint 40 of the spinal column 50 and into the outer portion 15 of the disc or the annulus . introducer 30 can be shielded or unshielded . shielding may be used for impedance monitoring during insertion , which assists in determine the insertion depth into the annulus . once the lead is properly placed at the placement site , introducer 30 is then removed . a connector 55 connects lead 10 to a power source or generator 60 , which may be either external or implanted . introducer 30 has a curved tip 70 to facilitate placement of the lead to the placement site . the lead with stimulating electrodes can be placed both across the posterior portion of the disc or alternatively around the periphery in any configuration to allow juxtaposition of the electrodes at the placement site to the requisite nerve fibres . in fig2 c , one embodiment of the components of a trial lead are illustrated . those skilled in the art will recognize that the lead described in each of the figures , including fig2 a - 2c , can be either a trial lead or a permanent lead . lead 10 with its flexible shaft 220 and connector 55 is connected to an impedance monitor and stimulation / power generator 60 . lead 10 contains one or more electrodes 5 thereon , which provide the direct stimulation to the placement site during operation . this stimulating lead is passed down an introducer 30 with a curved tip 70 and a hub 90 to facilitate steering as shown in fig2 a . this is performed after the stylette 100 as shown in fig2 b of the introducer 30 is removed . the stylette 100 also has a connecting hub 110 . fig3 a - 3c illustrate the possible placement , for certain embodiments , of a permanent implanted lead at the placement or stimulating site . it is envisaged that the introducer 30 is to be passed into the disc 20 in a more lateral position to avoid any conflict with the nerve root . in fig3 a - 3c , the introducer 30 is aimed to pass into or adjacent to the anterior portion of the disc 20 so that the lead 10 curves around the annulus 15 from the anterior portion to the posterior portion of the disc . lead 10 , as shown in fig3 a , contains at least one or more electrodes 5 therein , which provide the direct stimulation during operation of the lead , once connected to generator 60 . this will achieve the same juxtaposition of lead 10 and pain nerve fibres in disc 20 at the trial stimulating lead placement site as described previously in fig1 . introducer 30 for the permanent lead 10 also has a curved tip 70 and a hub 90 for steering . it is envisaged that the lead will have a central stiffening stylette 120 which will be removed in the case of the trial lead but may be partly retained in the implanted lead 10 . the central stylette 130 will have a modification in the permanent lead 10 such that after the stylette 130 is advanced further into or around the disc 20 than lead 10 itself , then a portion of the central stylette 130 will be removed allowing the retained portion 140 to curl in upon itself and act as a locking or anchoring device for the permanent lead at the placement site in the disc . this prevents displacement and migration of the lead 10 away from the placement site . it is envisaged that lead 10 can be removed in the future if the portion of the central stylette 130 that is removed is replaced , thus straightening the retained portion of stylette 140 . in one embodiment of the present invention , the retained portion of stylette 140 can have a metallic memory such that it can adopt a predetermined shape to anchor the lead and prevent lead migration . it is envisaged that the retained portion of stylette 140 will act as an anchor by adapting to a pre - stressed shape . alternatively , other forms of anchoring the electrode could be utilized such as an inflatable balloon or surgical fixation . lead 10 is connected via an implanted connector 150 to a stimulator or generator 160 . generator 160 may be an implantable device with an internal power source , or alternatively , a radiofrequency receiving coil which is also fully implanted . such a receiving coil receives power transmitted through the skin . in a further embodiment , a permanent lead could be physically separated from the power generator by a transmitting and receiving coil . this will prevent the need for direct connecting leads that exit the disc . fig4 shows one embodiment of the present invention during implantation of the lead in the nucleus . as mentioned , it is believed that nerve endings that are involved in disc pain can appear at or in the nucleus . in fig4 , the introducer 30 inserts the lead 10 through the annulus 15 , and into the nucleus . once in the nucleus , the lead is placed near the placement site and the anchor 150 is locked into position to anchor the lead in the proper location . one further reason to locate the lead in the nucleus is to ensure that the electrodes are near the proper location , should the pain sensation transmitted via the nerves near the annulus / nucleus interface or in the edge of the annulus near the nucleus interface . fig5 shows one embodiment of the present invention during implantation of the lead in the nucleus . in fig5 , the introducer 30 inserts the lead 10 partially through the annulus 15 so that the lead is place in between the annulus and the nucleus . once at the placement site in between the annulus and the nucleus , the lead is anchored by anchor 150 and locked into position to anchor the lead in the proper location . one further reason to locate the lead in the nucleus or at the nucleus / annulus interface is to ensure that the electrodes are near the proper location , should the pain be caused from nerves near the annulus / nucleus interface or in the edge of the annulus near the nucleus interface . fig8 a and 8b show another embodiment of the present invention during implantation of the lead at the placement site adjacent to the disc . because of the proximal location of the nerve endings to the placement site exterior to the disc , placement of the lead at this location will allow the nerve endings to benefit from the stimulation effect , without having to enter into the disc . this has safety implications , by reducing the chance of disc space infections , because the leads are not interior to the disc . in fig8 a , either one or two leads 10 are placed around the outside of the disc annulus 15 at the desired placement site or affected area . fig8 a shows a percutaneous approach from the patient &# 39 ; s posterior side . fig8 b shows an endoscopic approach ( from the anterior side ). it is important to note that either one or both leads may be applied to either side of the affected disc , depending on the location for the desired stimulation or placement site . fig9 a , 9 b and 10 show a lateral view of an affected disc and a lead placement on the outside of such a disc . in fig9 a , a healthy disc is shown with a healthy disc annulus 15 . fig9 b shows a narrowing of a degenerated disc 20 . fissures have narrowed the disc and there is no clear delineation between the disc annulus and the nucleus . additionally , end plate ( modic ) changes have occurred . fig1 , shows a lateral view of lead 10 located at the placement site in the narrowed degenerated disc . fig1 could represent either lead 10 located within the disc annulus or nucleus , as described herein , or lead 10 can be located outside the disc annulus as shown in fig8 a or 8 b ( fig1 showing a posterior placement in this case ). fig6 illustrates the methodology of the present invention . in step 310 , the doctor inserts the introducer into or just adjacent to a disc . as mentioned above , the introducer has a curved tip to assist in the introduction of the lead . next , in step 320 the doctor positions the tip of the introducer in or adjacent to the disc according to x - ray coordinates and impedance monitoring . in step 330 , the doctor inserts the flexible stimulation lead into or alongside the disc . positioning the lead at the placement site is accomplished using the x - ray coordinates and the stimulation parameters . the stimulation parameters are determined during the trial insertion procedure to provide the optimal stimulation settings . finally , in step 340 , the introducer is removed and the lead remains in or adjacent to the disc . the lead is then connected to the external or internal power source . the power source will have the stimulation parameters loaded into its memory . once connected , stimulation of the disc can begin . as such , an apparatus and method for making such apparatus is described . in view of the above detailed description of the present invention and associated drawings , other modifications and variations will now become apparent to those skilled in the art . it should also be apparent that such other modifications and variations may be effected without departing from the spirit and scope of the present invention as set forth in the claims which follow .

US-201113336593-A

the invention is directed to formulations of pharmaceutical compounds , such as the cyclohexylamines and aminoadamantanes which have antimicrobial properties . in particular , it is directed to aqueous based formulations with reduced amounts of preservatives which allow safe and convenient administration and flexible dosing and which , in the case of oral formulations , are easy to swallow . optionally , the compositions contain components that provide the requisite stability and shelf life while reducing or avoiding incrustation of the composition around the container closure which leads to leaks and difficulty in opening the container .

in accordance with the present invention , an aqueous liquid based pharmaceutical composition is provided for the administration of a cyclohexylamine or an aminoadamantane to a human or animal subject , where the composition includes a cyclohexylamine or an aminoadamantane compound and is in solution , suspension or gel form . representative compositions of the invention may be a cyclohexylamine or a aminoadamantane useful in the treatment of cns diseases , including but not limited to the treatment of alzheimer &# 39 ; s disease ( u . s . pat . nos . 5 , 061 , 703 and 5 , 614 , 560 ) parkinson &# 39 ; s disease , aids dementia ( u . s . pat . no . 5 , 506 , 231 ), neuropathic pain ( u . s . pat . no . 5 , 334 , 618 ), epilepsy , glaucoma , hepatic encephalopathy , multiple sclerosis , stroke , depression ( u . s . pat . no . 6 , 479 , 553 ), and tardive dyskinesia ( parsons et al ., 1999 ), malaria , borna virus , hepatitis c ( u . s . pat . nos . 6 , 034 , 134 , and 6 , 071 , 966 ). additional pathologies are disclosed in u . s . pat . nos . 5 , 614 , 560 and 6 , 444 , 702 . each of the foregoing documents is incorporated herein by reference in its entirety . an aqueous based composition for oral administration which comprises a substance selected from the class of cyclohexylamines and aminoadamantanes and derivatives thereof wherein the composition is substantially free of preservatives . an aqueous based composition for oral or parenteral use which comprises a substance selected from the class of cyclohexylamines and aminoadamantanes and derivatives thereof and at least one preservative , wherein the concentration of the preservative is less than the concentration required to effectively preserve the corresponding placebo composition . as used herein , cyclohexylamine and aminoadamantane derivatives are chemically described by the formula ( i ): wherein r * is -( a ) n -( cr 1 r 2 ) m — nr 3 r 4 , a is selected from the group consisting of linear or branched lower alkyl ( c 1 - c 6 ), linear or branched lower alkenyl ( c 2 - c 6 ), and linear or branched lower alkynyl ( c 2 - c 6 ), r 1 and r 2 are independently selected from the group consisting of hydrogen , linear or branched lower alkyl ( c 1 - c 6 ), linear or branched lower alkenyl ( c 2 - c 6 ), linear or branched lower alkynyl ( c 2 - c 6 ) aryl , substituted aryl and arylalkyl , r 3 and r 4 are independently selected from the group consisting of hydrogen , linear or branched lower alkyl ( c 1 - c 6 ), linear or branched lower alkenyl ( c 2 - c 8 ), and linear or branched lower alkynyl ( c 2 - c 6 ), or together form alkylene ( c 2 - c 10 ) or alkenylene ( c 2 - c 10 ) or together with the n form a 3 - 7 - membered azacycloalkane or azacycloalkene , including substituted ( alkyl ( c 1 - c 6 ), alkenyl ( c 2 - c 6 )) 3 - 7 - membered azacycloalkane or azacycloalkene ; or independently r 3 or r 4 may combine with r p , r q , r r , or r s to form an alkylene chain — ch ( r 6 )—( ch 2 ) t —, wherein t = 0 or 1 and r 6 is selected from the group consisting of hydrogen , linear or branched lower alkyl ( c 1 - c 6 ), linear or branched lower alkenyl ( c 2 - c 6 ), linear or branched lower alkynyl ( c 2 - c 6 ), aryl , substituted aryl and arylalkyl ; or independently r 3 or r 4 may combine with r 5 to form an alkylene chain represented by the formula — ch 2 — ch 2 — ch 2 —( ch 2 ) t —, or an alkenylene chain represented by the formulae — ch ═ ch — ch 2 —( ch 2 ) t —, — ch ═ c ═ ch —( ch 2 ) t — or — ch 2 — ch ═ ch —( ch 2 ) t —, wherein t = 0 or 1 : r 5 is independently selected from the group consisting of hydrogen , linear or branched lower alkyl ( c 1 - c 6 ), linear or branched lower alkenyl ( c 2 - c 6 ), and linear or branched lower alkynyl ( c 2 - c 6 ), or r 5 combines with the carbon to which it is attached and the next adjacent ring carbon to form a double bond , r p , r q , r r , and r s , are independently selected from the group consisting of hydrogen , linear or branched lower alkyl ( c 1 - c 6 ), linear or branched lower alkenyl ( c 2 - c 6 ), linear or branched lower alkynyl ( c 2 - c 6 ), cycloalkyl ( c 3 - c 6 ) and aryl , substituted aryl and arylalkyl or r p , r q , r r , and r s independently may form a double bond with u or with y or to which it is attached , or r p , r q , r r , and r s may combine together to represent a lower alkylene —( ch 2 ) x — or a lower alkenylene bridge wherein x is 2 - 5 , inclusive , which alkylene bridge may , in turn , combine with r 5 to form an additional lower alkylene —( ch 2 ) y — or a lower alkenylene bridge , wherein y is 1 - 3 , inclusive , the symbols u , v , w , x , y , z represent carbon atoms ; including the respective optical isomers , diastereomers , polymorphs , enantiomers , hydrates , pharmaceutically acceptable salts , and mixtures of compounds according to formula ( i ). non - limiting examples of 1 - aminocyclohexane compounds used according to the invention include the 1 - aminoalkylcyclohexane derivatives selected from the group consisting of : 1 - amino - 1 , 3 , 5 - trimethylcyclohexane , 1 - amino - 1 ( trans ), 3 ( trans ), 5 - trimethylcyclohexane , 1 - amino - 1 ( cis ), 3 ( cis ), 5 - trimethylcyclohexane , 1 - amino - 1 , 3 , 3 , 5 - tetramethylcyclohexane , 1 - amino - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexane ( neramexane ), 1 - amino - 1 , 3 , 5 , 5 - tetramethyl - 3 - ethylcyclohexane , 1 - amino - 1 , 5 , 5 - trimethyl - 3 , 3 - diethylcyclohexane , 1 - amino - 1 , 5 , 5 - trimethyl - cis - 3 - ethylcyclohexane , 1 - amino -( 1s , 5s ) cis - 3 - ethyl - 1 , 5 , 5 - trimethylcyclohexane , 1 - amino - 1 , 5 , 5 - trimethyl - trans - 3 - ethylcyclohexane , 1 - amino -( 1r , 5s ) trans - 3 - ethyl - 1 , 5 , 5 - trimethylcyclohexane , 1 - amino - 1 - ethyl - 3 , 3 , 5 , 5 - tetramethylcyclohexane , 1 - amino - 1 - propyl - 3 , 3 , 5 , 5 - tetramethylcyclohexane , n - methyl - 1 - amino - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexane , n - ethyl - 1 - amino - 1 , 3 , 3 , 5 , 5 - pentamethyl - cyclohexane , n -( 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexyl ) pyrrolidine , 3 , 3 , 5 , 5 - tetramethylcyclohexylmethylamine , 1 - amino - 1 - propyl - 3 , 3 , 5 , 5 - tetramethylcyclohexane , 1 amino - 1 , 3 , 3 , 5 ( trans )- tetramethylcyclohexane ( axial amino group ), 3 - propyl - 1 , 3 , 5 , 5 - tetramethylcyclohexylamine semihydrate , 1 - amino - 1 , 3 , 5 , 5 - tetramethyl - 3 - ethylcyclohexane , 1 - amino - 1 , 3 , 5 - trimethylcyclohexane , 1 - amino - 1 , 3 - dimethyl - 3 - propylcyclohexane , 1 - amino - 1 , 3 ( trans ), 5 ( trans )- trimethyl - 3 ( cis )- propylcyclohexane , 1 - amino - 1 , 3 - dimethyl - 3 - ethylcyclohexane , 1 - amino - 1 , 3 , 3 - trimethylcyclohexane , cis - 3 - ethyl - 1 ( trans )- 3 ( trans )- 5 - trimethylcyclohexamine , 1 - amino - 1 , 3 ( trans )- dimethylcyclohexane , 1 , 3 , 3 - trimethyl - 5 , 5 - dipropylcyclohexylamine , 1 - amino - 1 - methyl - 3 ( trans )- propylcyclohexane , 1 - methyl - 3 ( cis )- propylcyclohexylamine , 1 - amino - 1 - methyl - 3 ( trans )- ethylcyclohexane , 1 - amino - 1 , 3 , 3 - trimethyl - 5 ( cis )- ethylcyclohexane , 1 - amino - 1 , 3 , 3 - trimethyl - 5 ( trans )- ethylcyclohexane , cis - 3 - propyl - 1 , 5 , 5 - trimethylcyclohexylamine , trans - 3 - propyl - 1 , 5 , 5 - trimethylcyclohexylamine , n - ethyl - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexylamine , n - methyl - i - amino - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexane , 1 - amino - i - methylcyclohexane , n , n - dimethyl - 1 - amino - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexane , 2 -( 3 , 3 , 5 , 5 - tetramethylcyclohexyl ) ethylamine , 2 - methyl - 1 -( 3 , 3 , 5 , 5 - tetramethylcyclohexyl ) propyl - 2 - amine , 2 -( 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexyl - i )- ethylamine semihydrate , n -( 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexyl )- pyrrolidine , 1 - amino - 1 , 3 ( trans ), 5 ( transytrimethylcyclohexane , 1 - amino - 1 , 3 ( cis ), 5 ( cis )- trimethylcyclohexane , 1 - amino -( 1r , 5s ) trans - 5 - ethyl - 1 , 3 , 3 - trimethylcyclohexane , 1 - amino -( 1s , ss ) cis - 5 - ethyl - 1 , 3 , 3 - trimethylcyclohexane , 1 - amino - 1 , 5 , 5 - trimethyl - 3 ( cis )- isopropyl - cyclohexane , 1 - amino - 1 , 5 , 5 - trimethyl - 3 ( trans )- isopropyl - cyclohexane , 1 - amino - 1 - methyl - 3 ( cis )- ethyl - cyclohexane , 1 - amino - 1 - methyl - 3 ( cis )- methyl - cyclohexane , 1 - amino - 5 , 5 - diethyl - 1 , 3 , 3 - trimethyl - cyclohexane , 1 - amino - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexane , 1 - amino - 1 , 5 , 5 - trimethyl - 3 , 3 - diethylcyclohexane , 1 - amino - i - ethyl - 3 , 3 , 5 , 5 - tetramethylcyclohexane , n - ethyl - i - amino - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexane , n -( 1 , 3 , 5 - trimethylcyclohexyl ) pyrrolidine or piperidine , n -[ 1 , 3 ( trans ), 5 ( trans )- trimethylcyclohexyl ] pyrrolidine or piperidine , n -[ 1 , 3 ( cis ), 5 ( cis )- trimethylcyclohexyl ] pyrrolidine or piperidine , n -( 1 , 3 , 3 , 5 - tetramethylcyclohexyl ) pyrrolidine or piperidine , n -( 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexyl ) pyrrolidine or piperidine , n -( 1 , 3 , 5 , 5 - tetramethyl - 3 - ethylcyclohexyl ) pyrrolidine or piperidine , n -( 1 , 5 , 5 - trimethyl - 3 , 3 - diethylcyclohexyl ) pyrrolidine or piperidine , n -( 1 , 3 , 3 - trimethyl - cis - 5 - ethylcyclohexyl ) pyrrolidine or piperidine , n -[( 1s , ss ) cis - 5 - ethyl - 1 , 3 , 3 - trimethylcyclohexyl ] pyrrolidine or piperidine , n -( 1 , 3 , 3 - trimethyl - trans - 5 - ethylcyclohexyl ) pyrrolidine or piperidine , n -[( 1r , 5s ) trans - 5 - ethyl , 3 , 3 - trimethylcyclohexyl ] pyrrolidine or piperidine , n -( 1 - ethyl - 3 , 3 , 5 , 5 - tetramethylyclohexyl ) pyrrolidine or piperidine , n -( 1 - propyl - 3 , 3 , 5 , 5 - tetramethylcyclohexyl ) pyrrolidine or piperidine , n -( 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexyl ) pyrrolidine , their optical isomers , diastereomers , enantiomers , hydrates , their pharmaceutically acceptable salts , and mixtures thereof . neramexane ( 1 - amino - 1 , 3 , 3 , 5 , 5 - pentamethylcyclohexane ) is disclosed , e . g ., u . s . pat . no . 6 , 034 , 134 , which is incorporated herein by reference in its entirety . certain 1 - aminocyclohexane derivatives of general formula ( i ) including the case where three axial alkyl substituent , e . g ., r p , r r and r 5 all together form a bridgehead to yield compounds ( so called 1 - aminoadamantanes ) illustrated by the formulae iib and iid below : certain 1 - aminocyclohexane derivatives of formula ( i ) wherein n + m = 0 , u , v , w , x , y and z form a cyclohexane ring , and one or both of r 3 and r 4 are independently joined to said cyclohexane ring via alkylene bridges formed through r p , r q : r r , r s or r 5 are represented by the following formulae iiia - iiic : wherein r q , r r , r s , r r and r 5 are as defined above for formula ( i ), r 6 is hydrogen , linear or branched lower alkyl ( c 1 - c 6 ), linear or branched lower alkenyl ( c 2 - c 6 ), linear or branched lower alkynyl ( c 2 - c 6 ), aryl , substituted aryl or arylalkyl , y is saturated or may combine with r 6 to form a carbon - hydrogen bond with the ring carbon to which it is attached , i = 0 or 1 and k = 0 , 1 or 2 and represents a single or double bond . non - limiting examples of 1 - aminocyclohexane compounds used according to the invention include 1 - amino adamantane ( amantadine ) and its derivatives selected from the group consisting of : 1 - amino - 3 - phenyl adamantane , 1 - amino - methyl adamantane , 1 - amino - 3 , 5 - dimethyl adamantane ( memantine ), 1 - amino - 3 - ethyl adamantane , 1 - amino - 3 - isopropyl adamantane , 1 - amino - 3 - n - butyl adamantane , 1 - amino - 3 , 5 - diethyl adamantane , 1 - amino - 3 , 5 - diisopropyl adamantane , 1 - amino - 3 , 5 - di - n - butyl adamantane , 1 - amino - 3 - methyl - 5 - ethyl adamantane , 1 -( dimethylaminoethoxyacetamido ) adamantane ( tromantadine ), 1 - n - methylamino - 3 , 5 - dimethyl adamantane , 1 - n - ethylamino - 3 , 5 - dimethyl adamantane , 1 - n - isopropyl - amino - 3 , 5 - dimethyl adamantane , 1 - n , n - dimethyl - amino - 3 , 5 - dimethyl adamantane , 1 - n - methyl - n - isopropyl - amino - 3 - methyl - 5 - ethyl adamantane , 1 - amino - 3 - butyl - 5 - phenyl adamantane , 1 - amino - 3 - pentyl adamantane , 1 - amino - 3 , 5 - dipentyl adamantane , 1 - amino - 3 - pentyl - 5 - hexyl adamantane , 1 - amino - 3 - pentyl - 5 - cyclohexyl adamantane , 1 - amino - 3 - pentyl - 5 - phenyl adamantane , 1 - amino - 3 - hexyl adamantane , 1 - amino - 3 , 5 - dihexyl adamantane , 1 - amino - 3 - hexyl - 5 - cyclohexyl adamantane , 1 - amino - 3 - hexyl - 5 - phenyl adamantane , 1 - amino - 3 - cyclohexyl adamantane , 1 - amino - 3 , 5 - dicyclohexyl adamantane , 1 - amino - 3 - cyclohexyl - 5 - phenyl adamantane , 1 - amino - 3 , 5 - diphenyl adamantane , 1 - amino - 3 , 5 , 7 - trimethyl adamantane , 1 - amino - 3 , 5 - dimethyl - 7 - ethyl adamantane , 1 - amino - 3 , 5 - diethyl - 7 - methyl adamantane , 1 - n - pyrrolidino and 1 - n - piperidine derivatives , 1 - amino - 3 - methyl - 5 - propyl adamantane , 1 - amino - 3 - methyl - 5 - butyl adamantane , 1 - amino - 3 - methyl - 5 - pentyl adamantane , 1 - amino - 3 - methyl - 5 - hexyl adamantane , 1 - amino - 3 - methyl - 5 - cyclohexyl adamantane , 1 - amino - 3 - methyl - 5 - phenyl adamantane , 1 - amino - 3 - ethyl - 5 - propyl adamantane , 1 - amino - 3 - ethyl - 5 - butyl adamantane , 1 - amino - 3 - ethyl - 5 - pentyl adamantane , 1 - amino - 3 - ethyl - 5 - hexyl adamantane , 1 - amino - 3 - ethyl - 5 - cyclohexyl adamantane , 1 - amino - 3 - ethyl - 5 - phenyl adamantane , 1 - amino - 3 - propyl - 5 - butyl adamantane , 1 - amino - 3 - propyl - 5 - pentyl adamantane , 1 - amino - 3 - propyl - 5 - hexyl adamantane , 1 - amino - 3 - propyl - 5 - cyclohexyl adamantane , 1 - amino - 3 - propyl - 5 - phenyl adamantane , 1 - amino - 3 - butyl - 5 - pentyl adamantane , 1 - amino - 3 - butyl - 5 - hexyl adamantane , 1 - amino - 3 - butyl - 5 - cyclohexyl adamantane , their optical isomers , diastereomers , enantiomers , hydrates , n - methyl , n , n - dimethyl , n - ethyl , n - propyl derivatives , their pharmaceutically acceptable salts , and mixtures thereof . memantine ( 1 - amino - 3 , 5 - dimethyl adamantane ), for example , is the subject matter of u . s . pat . nos . 4 , 122 , 193 and 4 , 273 , 774 . the 1 - amino adamantane compounds of formulae iib and iid , including memantine , are generally prepared by alkylation of halogenated adamantanes , preferably bromo - or chloroadamantanes . the di - or tri - substituted adamantanes are obtained by additional halogenation and alkylation procedures . the amino group is introduced either by oxidation with chromiumtrioxide and bromination with hbr or bromination with bromine and reaction with formamide followed by hydrolysis . the amino function can be alkylated according to generally - accepted methods . methylation can , for example , be effected by reaction with chloromethyl formate and subsequent reduction . the ethyl group can be introduced by reduction of the respective acetamide . for more details on synthesis see , e . g ., u . s . pat . nos . 5 , 061 , 703 and 6 , 034 , 134 . additional synthetic techniques for the foregoing compounds can be found in provisional applications ser . no . 60 / 350 , 974 filed nov . 7 , 2001 , ser . no . 60 / 337 , 858 filed nov . 8 , 2001 , and ser . no . 60 / 366 , 386 filed mar . 21 , 2002 , all incorporated by reference in their entirety . according to the invention , the 1 - aminocyclohexane derivatives of formula ( i ) may be applied as such or used in the form of their pharmaceutically acceptable salts . suitable salts of the compound include , but are not limited to , acid addition salts , such as those made with hydrochloric , methylsulfonic , hydrobromic , hydrolodic , perchloric , sulfuric , nitric , phosphoric , acetic , propionic , glycolic , lactic pyruvic , malonic , succinic , maleic , fumaric , maleic , tartaric , citric , benzoic , carbonic cinnamic , mandelic , methanesulfonic , ethanesulfonic , hydroxyethanesulfonic , benezenesulfonic , p - toluene sulfonic , cyclohexanesulfamic , salicyclic , p - aminosalicylic , 2 - phenoxybenzoic , and 2 - acetoxybenzoic acid ; salts made with saccharin ; alkali metal salts , such as sodium and potassium salts ; alkaline earth metal salts , such as calcium and magnesium salts ; and salts formed with organic or inorganic ligands , such as quaternary ammonium salts . in a preferred embodiment , the salt is memantine hydrochloride ( c 12 h 21 n . hcl , mw 215 . 77 ). in another preferred embodiment , the salt is neramexane mesylate ( c 11 h 23 n . ch 4 o 3 s , mw 265 . 42 ). the term “ salts ” can also include addition salts of free acids or free bases . all of these salts ( or other similar salts ) may be prepared by conventional means . all such salts are acceptable provided that they are non - toxic and do not substantially interfere with the desired pharmacological activity . the present invention further includes all individual enantiomers , diastereomers , racemates , and other isomers of those compounds wherein such structural variations are possible . the invention also includes all polymorphs and solvates , such as hydrates and those formed with organic solvents , of these compounds . such isomers , polymorphs , and solvates may be prepared by methods known in the art , such as by crystallization from different solvents , by regiospecific and / or enantioselective synthesis and resolution , based on the disclosure provided herein . the present invention includes derivatives of the compound of the present invention . examples of derivatives applicable to the invention include , but are not limited to , structurally related compounds composed of a tricyclic 10 - carbon ring bearing an amino group such as nitroxy - memantine derivatives ( such as nitroprusside , nitroglycerin , or an no - enerating derivative of nitroprusside or nitroglycerin in u . s . pat . nos . 5 , 234 , 956 and 5 , 455 , 279 ). cyclohexylamines and aminoadamantanes , and thus the compositions of the present invention , are useful for the prevention and / or treatment of a number of diseases and conditions affectng the central nervous system ( cns ), including dementia , alzheimer &# 39 ; s disease , parkinson &# 39 ; s disease , aids - related dementia , neuropathic pain , epilepsy , and depression . other diseases in which the compositions are beneficial include glaucoma , hepatic encephalopathy , multiple sclerosis , stroke , dyskinesia , malaria , and viral infections such as hepatitis c . in a preferred embodiment , the compositions are used for the management of alzheimer &# 39 ; s disease and other types of dementia . optionally , the composition may further comprise another active ingredient which is preferably not a cyclohexylamine or aminoadamantane derivative . as used herein , an active ingredient is a pharmaceutically acceptable compound or mixture of compounds useful for the diagnosis , prevention , or treatment of a symptom , disease , or condition . the terms “ active compound ”, “ active ingredient ”, “ drug ”, and “ drug substance ” may be used interchangeably . in one embodiment , this other active ingredient is effective in the management of cns - related conditions or diseases . these conditions may be the same as the one which is to be treated by the cyclohexylamine or aminoadamantane derivative , such as alzheimer &# 39 ; s disease or other types of dementia ; or it may be useful for the management of other symptoms and conditions which are frequently present in patients suffering from alzheimer &# 39 ; s disease or dementia . alternatively , the other active ingredient may be suitable to treat common side effects of nmda receptor antagonists &# 39 ; for example , a patient suffering from alzheimer &# 39 ; s disease may also have to be treated with an antidepressant , antipsychotic , anti - parkinson agent , or sedative . other drug classes from which the other active ingredient may be selected include acetylcholinesterase inhibitors such as donepezil , galantamine , rivastigmine , or tacrine . as used herein , aqueous liquid pharmaceutical compositions by definition include liquid solutions and dispersions , such as emulsions , and semi - solid forms such as suspensions , creams , ointments and gels . more preferably , the composition of the invention is a liquid solution . an aqueous liquid composition is a liquid preparation whose major liquid component is water . optionally , the aqueous liquid composition may further comprise other liquid components , such as pharmaceutically acceptable organic solvents . examples of such other liquid components are ethanol , glycerol , propylene glycol , and polyethylene glycol . in a preferred embodiment , water is the only liquid component of the composition of the invention . such pharmaceutical compositions comprise a therapeutically effective amount of one or more of the foregoing active ingredients dissolved in a pharmaceutically acceptable solvent , optionally a taste masking agent and optionally an antimicrobial and / or preservative agent . the taste masking component may be a sweetener . the taste masking component may further comprise a flavorant . a solubilizer may also be included to keep ingredients with a tendency to crystallize from doing so . additional optional excipients that may be added include solvents , flavorings , carriers , stabilizing agents , binders , colorants , antioxidants , and buffers ( all pharmaceutically acceptable ). in one embodiment , the active ingredient is memantine hydrochloride . the active ingredient is present in amounts ranging broadly from about 0 . 05 to about 5 % w / v , particularly ranging from about 0 . 1 to about 2 . 0 % w / v based on the total volume of the solution . in another embodiment , the active ingredient is present in an amount of about 0 . 2 % w / v . in yet another embodiment , the active ingredient is present in about 1 . 0 % w / v . in another embodiment , the active ingredient is neramexane and its salts , e . g ., hcl or mesylate . the active ingredient is present in amounts ranging broadly from about 0 . 05 to about 5 % w / v , particularly ranging from about 0 . 1 to about 2 % w / v based on the total volume of the solution . in another embodiment , the active ingredient is present in an amount of about 0 . 2 % w / v ( 2 mg / ml ). in another embodiment , the active ingredient is present in about 0 . 5 % w / v ( 5 mg / ml ). in yet another embodiment , the active ingredient is present in about 1 . 0 % w / v ( 10 mg / ml ). in another embodiment , the active ingredient is present in about 2 . 0 % w / v ( 20 mg / ml ). according to one of the embodiments , the composition comprises memantine or a salt thereof as nmda receptor antagonist . memantine may be present in the form of a hydrochloride salt . in another embodiment , the nmda receptor antagonist is neramexane , or a salt of neramexane , optionally neramexane mesylate . while the antimicrobial effectiveness may somewhat differ between the various cyclohexylamines and aminoadamantane compounds and their respective salts , it has been observed that in general , concentrations of less than about 1 mg / ml are not as effective in preserving liquid aqueous formulations . marked antimicrobial activity is typical at a concentration of about 1 - 2 mg / ml , and becomes further pronounced at concentrations of about 5 mg / ml . in a composition wherein memantine hydrochloride is selected as active ingredient , the drug concentration in the composition may be in the range from about 5 mg / ml to about 50 mg / ml . a concentration of about 10 mg / ml provides both effective preservation and convenient dosing . in a composition wherein neramexane mesylate is selected as active ingredient , the drug concentration in the composition may be in the range from about 2 mg / ml to about 100 mg / ml . a concentration in the range from about 5 mg / ml to about 10 mg / ml provides both effective preservation and convenient dosing . according to the invention , aqueous compositions comprising cyclohexylamines and aminoadamantanes can be formulated without preservatives , and preferably also without excipients having antimicrobial activity . surprisingly , aminoadamantane and cyclohexylamine drugs such as memantine , tromantadine and neramexane have been found to exhibit significant antimicrobial activity at concentrations which are useful for pharmaceutical formulation purposes . in one embodiment , the composition of the invention is substantially free of preservatives . in this context , substantially free of preservatives means that preservatives are not detectable in the composition , or only in concentrations which are generally considered irrelevant with regard to any preservation effects . according to the present invention , preservatives are defined as excipients having substantial antimicrobial activity . substantial antimicrobial activity means that the activity is sufficient to ensure the microbiological quality of a product at a low concentration , such as at concentrations of 2 - 3 % ( w / v ) or less , or at a concentration at which the preservative is physiologically acceptable in relation to the volume in which the product is administered . in another embodiment , the composition comprises at least one preservative , but at a concentration which is insufficient to effectively preserve the corresponding placebo composition . as used herein , a placebo composition is a formulation which is substantially free of active ingredients . a corresponding placebo composition is defined as a drug - free composition whose properties and other ingredients are largely the same as those of the drug - containing reference composition . whether a composition is effectively preserved may be determined with appropriate tests , such as the test for preservative efficacy ( usp & lt ; 51 & gt ;), wherein five challenge organisms are tested at defined time intervals , depending on the product category . conducted in appropriate series , such testing may also be performed in order to determine the minimally effective concentration of a specific preservative for a given composition , such as a drug - free composition corresponding to a composition according to the invention . for example , it may be found that in order to effectively preserve a particular placebo composition with sorbic acid , the preservative must be present at a concentration of at least about 0 . 1 % ( w / v ). in this case , the reference composition which comprises the cyclohexylamine or aminoadamantane derivative , if it is a composition of the invention , could contain sorbic acid at a substantially lower concentration , such as about 0 . 05 % ( w / v ) or less . in another embodiment , the concentration of the preservative is selected to be not more than about a fifth , and more preferably not more than about a tenth , of the concentration needed to effectively preserve a corresponding placebo composition . since the microbiological quality of the composition of the invention is ensured fully or in part by the active compound itself , the composition is potentially superior to conventional formulations in terms of tolerability and safety . representative preservatives in such pharmaceutical preparations may include methyl paraben , ethyl paraben , propyl paraben , benzoic acid , sodium benzoate , propionic acid , sodium propionate , sorbic acid , potassium sorbate , bronopol , chlorbutol , benzyl alcohol , phenol , thiomersal , cetylpyridinium and benzalkonium chloride , to mention only a few . the concentrations and conditions at which preservatives effectively prevent microbial growth may differ widely and are understood in the art . for example , methyl paraben is typically effective at a concentration of about 0 . 1 to about 0 . 2 % ( w / v ), whereas propyl paraben can be incorporated at a concentration of only about 0 . 02 to about 0 . 03 % ( w / v ) to produce the same preservative effect . the ph of the liquid to be preserved may also play an important role . for example , sorbic acid , potassium sorbate , benzoic acid , and sodium benzoate are much more effective at an acidic ph than in neutral environments . in one embodiment , a combination of methylparaben : propylparaben is used in a ratio of 10 : 1 . in certain embodiments , methyl paraben is present in amounts ranging broadly from about 0 . 05 % to about 2 . 0 % w / v , optionally from about 0 . 1 to about 1 . 0 % w / v , more particularly in an amount of about 0 . 1 % w / v . in certain embodiments , propylparaben is present in amounts ranging broadly from about 0 . 005 % to about 0 . 02 % w / v , optionally from about 0 . 005 to about 0 . 01 % w / v , more particularly in an amount of about 0 . 01 % w / v . other excipients which are usually not classified as preservatives may possess antimicrobial activity at somewhat higher concentrations such as above 15 or 20 % ( v / v ), for example ethanol . nevertheless , in formulations which contain substantial amounts of any of these excipients , the use of other preservatives may not be necessary . in a composition designed for oral administration , it is recommended to incorporate one or more excipients which improve the taste of the formulation . this is particularly true for neramexane mesylate . for example , at least one sweetener may be incorporated . furthermore , one or more excipients selected from the group of flavors , flavor enhancers , and taste masking - agents may be added . sweeteners , as used herein , are natural or synthetic compounds which have a sweet taste and are physiologically acceptable . prominent examples of natural sweeteners include common sugars and sugar alcohols such as sucrose , glucose , fructose , maltose , maltitol , xylitol , lactitol , mannitol , and sorbitol . preferably , a sugar alcohol is used to improve the flavor of the composition of the invention , in particular sorbitol . a useful concentration range for sorbitol or other sugars and sugar alcohols is from about 5 % ( w / v ) to about 40 % ( w / v ), and more preferably around 10 - 30 % ( w / v ). in another embodiment , an artificial sweetener is incorporated in the composition in addition to , or instead of , a natural sweetener . useful artificial sweeteners include saccharin - sodium , saccharin , sodium cyclamate , acesulfame k , neohesperidin dihydrochalcone , and aspartame , as well as any other sweeteners whose safety in human use is established . appropriate concentrations depend on the individual sweetener which is selected . the oral pharmaceutical composition of the invention may be in the form of a “ taste - masked ” or “ taste - neutral ” form . as certain forms of the active ingredient may have bitter taste ( i . e ., memantine hydrochloride ), the solutions may contain any pharmaceutically acceptable sweeteners and / or flavoring agent . flavorings may be used as necessary , including for example natural peppermint # 104 , artificial cherry # 10641 , artificial grape # 255 , orange n & amp ; a 583k or artificial grape bubble gum # 998 . these are commercially available , e . g ., from virginia dare ( brooklyn , n . y .). in one embodiment , flavorings are added in a concentration ranging from about 0 . 04 to about 5 % w / v , preferably from about 0 . 05 to about 2 . 0 % w / v , most preferred in an amount of about 0 . 05 % w / v to the final formulation . in another embodiment , a flavoring concentration of about 0 . 5 % is the most preferred amount . in another embodiment , flavoring concentration of about 1 % w / v to the final formulation is the most preferred amount . the flavor enhancers useful for practicing the invention may typically be sweetness enhancers , such as the n & amp ; a flavor enhancer or inositol . for example , the taste masking agent may be selected from the group of physiologically acceptable natural or synthetic gums . for reproducible product quality and reliable stability , it is further preferred that the composition is adjusted to a specific ph by incorporating one or more appropriate excipients selected from the group consisting of physiologically acceptable acids , bases , and acidic and alkaline salts . for example , the combination of citric acid and sodium citrate may be used for buffering the ph of the composition at a value selected in the range from about ph 5 to about ph 8 . more preferably , the ph is adjusted to a value from about ph 5 . 5 to about ph 7 . one or more buffers are used as necessary , but preferably in amounts ranging from about 1 mg / ml to about 10 mg / ml . for example , citric acid may be present in an amount ranging broadly from about 0 . 1 to about 0 . 4 % w / v , preferably in an amount ranging from about 0 . 15 to 0 . 23 % w / v , most preferably in an amount of about 0 . 19 % w / v . sodium citrate may be present in an amount ranging broadly from about 0 . 75 to about 2 % w / v , preferably from about 0 . 84 to about 1 . 0 % w / v , most preferred in an amount of about 0 . 88 % w / v . further excipients which are routinely used in pharmaceutical formulations may be incorporated as may seem appropriate to adjust the composition to the specific requirements of a particular drug candidate , or to a specific use or target population . examples of potentially suitable excipients are thickeners such as soluble gums including carrageenan , alginate , xanthan , and soluble cellulose esters ; coloring agents ; stabilizers , such as antioxidants , or crystallization inhibitors , such as glycerol , propylene glycol , or polyvinylpyrrolidone . the formulation of the present invention also contains solubilizers that serve to enhance solubility of the parabens , sorbitol , and flavoring agents , and thus serve to reduce or eliminate closure locking . the amount of solubilizer should be carefully adjusted , however , to prevent or reduce the chance of leakage of the composition from the container through the closure such as might be experienced on transportation or upon tipping during storage or use . appropriate solubilizers include propylene - glycol , polyethylene glycol , and glycerin . preferably , glycerin is used . the preferred amounts used will be specific for each formulation . solubilizers may be used in amounts generally ranging from about 1 mg / ml to about 200 mg / ml . for example , propylene glycol , when used , is present in an amount ranging broadly from about 1 to about 4 % w / v , preferably from about 2 to about 3 % w / v , most preferred in an amount of about 2 . 5 %. glycerol , when used , is present in an amount ranging broadly from about 8 to about 12 % w / v , preferably from about 9 to about 11 % w / v , most preferably in an amount of about 10 % w / v . the use of a solubilizer may affect the ph of the solution . in that case , ph should be adjusted to be in the range of about 4 to about 7 , preferably in the range of about 4 . 5 to about 6 . 5 , most preferably about 5 . 5 . in a preferred embodiment , the vehicle for the formulation may be purified water or mixtures of water and ethanol . preferably , solvents are used qs . in certain embodiments , the oral solutions of the present invention are in two strengths for memantine , 2 mg / ml and 4 mg / ml . in other embodiments , the oral solution of the neramexane mesylate is in four strengths , 2 mg / ml , 5 mg / ml , 10 mg / ml and 20 mg / ml . any appropriate bottle known in the art may be used for packaging . any suitable screw cap closure can be used , preferably , a child resistant screw cap closure with a laminated seal activated by heat . preferably , the packaging for the oral solutions includes six configurations , 120 ml , 360 ml , and 480 ml amber pet oblong shaped bottles with a child resistant heat seal cap or 20 ml , 50 ml , and 100 ml round brown glass bottles with a dropper and closure cap . in addition to the high microbiological stability of the composition which has been discussed above in detail , it is another advantage of the invention that the composition can be manufactured easily and economically using standard equipment . cyclohexylamine or aminoadamantane derivatives are usually available in salt forms which are water soluble , such as memantine hydrochloride and neramexane mesylate . the same is true for many other preferred excipients mentioned herein , so that the composition can usually be prepared from the active compound , the solid excipients and purified water simply by mixing the components under some agitation . in most cases , no heating or homogenization will be necessary . in other cases , depending on the specific selection of excipients , some heating may be recommended . in a composition designed for parenteral use , the excipients , and in particular the water , should be sterile ( e . g . water for injection ) or have a low level of microbial contamination ( bio - burden ). the manufacturing process must be designed , validated , and conducted to ensure the high quality level which is generally required for parenteral products , and to comply with current gmp standards . usually , the process will include a step of sterilization of the product within its final container . the standards and the regulatory guidances relating to the manufacture of sterile products are well known to persons skilled in this art . according to one of the embodiments , the composition is designated for oral administration . in this case , the composition is preferably filled into containers which hold a plurality of doses . appropriate containers will hold a volume in the range from about 5 ml or 5 g to about 1 , 000 ml or 1 , 000 g , and more preferably from about 10 ml ( or g ) to about 500 ml ( or g ). the volume is selected in consideration of the strength of the specific formulation and the time period for which the product is to be used . for example , a container may be selected to accommodate the medication needed for several days , weeks , or months . in one of the preferred embodiments , the container is selected to hold sufficient medication for at least about 4 weeks . in another embodiment , the container is selected to hold about 50 ml ( or g ), about 100 ml ( or 9 ), about 200 ml ( or 9 ), about 250 ml ( or g ), or about 500 ml ( or g ). appropriate containers may be of glass or a suitable plastic material , such as polypropylene or polyethylene , and will usually have a container closure system which is reclosable . optionally , the closure system is child - proof . the container may further comprise a means for measuring and / or dispensing defined doses of the composition . a conventional measuring means is , for example , a dropper , i . e . a glass tube fitted with a rubber bulb which is integrated in the closure and removed when opening the container . alternatively , a non - removable dropper may be integrated in the bottle neck . in another embodiment , the container closure system , comprises a dosing cup that provides markings indicating the amount of liquid to be taken for the most common doses . for example , the markings may range from about 0 . 5 ml to about 10 ml , and more preferably from about 1 ml to about 5 ml , or instead of volumes they may indicate the dose in grams of formulation , or in mg of drug substance . the measuring cup may be part of the container closure system , or it may be provided as a separate device within the secondary package in which the container is presented . a representative aqueous liquid composition of the instant invention includes an effective amount of memantine or neramexane to provide from about 1 mg / day to about 100 mg / day , preferably from about 5 mg / day to about 80 mg / day most preferably from about 10 to about 60 mg / day . smaller initial doses can be used , eventually increased to at least about 10 mg within the aforementioned ranges . the drug may be administered once a day , bid or more often . the formulated solution of the present invention is preferably a sugar - free , alcohol - free , palatable liquid solution stable enough for long - term use . a “ therapeutically effective amount ” of a drug is an amount effective to demonstrate a desired activity of the drug . according to the instant invention , in one embodiment a therapeutically effective amount of memantine is an amount effective to treat cns disorders , i . e ., dementia or neuropathic pain . as used herein , the term “ pharmaceutically acceptable ” refers to a biologically or pharmacologically compatible for in vivo use , and preferably means approved by a regulatory agency of the federal or a state government or listed in the u . s . pharmacopela or other generally recognized pharmacopeia for use in animals , and more particularly in humans . the term “ about ” or “ approximately ” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art , which will depend in part on how the value is measured or determined , i . e ., the limitations of the measurement system . for example , “ about ” can mean within 1 or more than 1 standard deviations , per the practice in the art . alternatively , “ about ” can mean a range of up to 20 %, preferably up to 10 %, more preferably up to 5 %, and more preferably still up to 1 % of a given value . alternatively , particularly with respect to biological systems or processes , the term can mean within an order of magnitude , preferably within 5 - fold , and more preferably within 2 - fold , of a value . where particular values are described in the application and claims , unless otherwise stated the term “ about ” meaning within an acceptable error range for the particular value should be assumed . the following examples are presented to further illustrate the invention . however , they are not to be construed as to limit the scope thereof . memantine hydrochloride ( 5 . 0 g ) was dissolved in purified water ( ph . eur ., 10 l ) to prepare a solution of 0 . 5 mg / ml . no preservative was added . the solution was filled into 10 ml glass bottles with screw closures . samples were drawn for conducting the test for preservative efficacy according to ph . eur . the test involved a challenge of the samples with the following species : the initial contamination and its changes in the subsequent 28 d were quantified as colony - forming units per ml ( cfu / ml ) as shown in table 1 . neramexane mesylate ( 5 . 0 g ) was dissolved in purified water ( ph . eur ., 10 l ) to prepare a solution of 0 . 5 mg / ml . no preservative was added . the solution was filled into 10 ml glass bottles with screw closures . samples were drawn and tested as described in example 1 . the results of the microbial challenge test are given as cfu / ml in table 2 . preservative - free aqueous solutions of memantine hydrochloride with concentrations of 5 mg / ml , 10 mg / ml , 20 mg / ml , and 40 mg / ml were prepared using purified water ( ph . eur .). no preservatives were added . samples were drawn and tested as described in example 1 . the results are shown as cfu / ml in table 3 ( for 5 mg / ml ), table 4 ( for 10 mg / ml ), table 5 ( for 20 mg / ml ), and table 6 ( for 40 mg / ml ). preservative - free aqueous solutions of neramexane mesylate with concentrations of 5 mg / ml , 10 mg / ml , 50 mg / ml , and 250 mg / ml were prepared using purified water ( ph . eur .). no preservatives were added . samples were drawn and tested as described in example 1 . the results are shown as cfu / ml in table 7 ( for 5 mg / ml ), table 8 ( for 10 mg / ml ), table 9 ( for 50 mg / ml ), and table 10 ( for 250 mg / ml ). this example demonstrates the process of making a memantine oral solution . the following ingredients in table 11 were combined according to the process described below . for each composition strength , purified water was heated to 85 ° c ., and then cooled to 20 - 30 ° c . in a 1000 gallon tank . in a separate batch tank , sorbitol 70 % was mixed with purified water , qs to approximately 2500 l . to the sorbitol - water solution , citric acid and sodium citrate were added and mixed . glycerin was then added , followed by memantine hydrochloride . in a separate 55 gallon tank , a sub - solution of propylene glycol , methyl paraben , propyl paraben , and natural peppermint flavor # 104 was mixed . the sub - solution was then added to the batch tank , which was subsequently qs to 3785 l with the purified water from the 1000 gallon tank . the final solution was cooled below 30 ° c ., then to 20 - 25 ° c . the solution was filtered , filled into bottles and then capped . the formulations were tested for taste . the taste evaluation study was performed with four healthy subjects . since memantine has a characteristics bitter taste , the subjects were asked to rate the formulation . each subject took a tea spoon ( about 5 ml ) of solution and rated the product as follows : taste of both the 4 mg / ml and 2 mg / ml formulation was good and devoid of bitter after taste . in the present example , the stability of the solutions made in example 5 was tested for percent of memantine , methyl paraben , propyl paraben , degradation and ph . the stability study of the 4 mg / ml scale up batch was initiated at 40 ° c ./ 75 % relative humidity using 120 cc oval amber bottles , 24 / 400 crc with heat seal liner . the stability of the solutions were determined using a hplc method , using an hplc system with autosampler , column - temperature - controller , uv detector , and hplc syringe pump for postcolumn reagents . the eluted drug , which is derivatized with o - phthaldehyde after hplc separation is detected and quantitated using uv detection at 340 nm . the column rp8 ( waters xterra ) is packed with octylesilane chemically bonded with embedded polar reversed - phased ligand utilizing hybrid particle technology . the packing material are porous spherical with pore size of 125 a with a size of 3 . 5 μm . the hplc conditions were as follows : column : waters xterra , rp8 hplc , 3 . 0 × 100 mm , 3 . 5 μm or equivalent column temperature : 50 ° c . flow rate : 0 . 75 ml / min injection volume : 20 μl uv detector : 340 nm run time : 5 minutes injector washing methanol : water , [ 50 : 50 ( v : v )] solution : ( recommended ) mobile phase : 0 . 1 % tfa and 20 % ( v / v ) acetonitrile in water reagent : 5 g / l o - phthaldehyde ( opa ) and 5 ml / l 3 - marcaotoproprionic acid ( mpa ) in 1 : 9 ( v / v ) acetonitrile : 0 . 3 m ph 10 . 4 borate buffer flow rate : 0 . 25 ml / min reagent pre - heating coil : 1 , 575 μl ( alltech p / n : 35896 ) reactor coil : 700 μl ( alltech p / n : 35886 ) reactor temperature : 50 ° c . the formulation was still found to be stable after 6 months . results of assay , ph , and preservative show that values are between 90 to 110 % showing excellent stability of the solution at accelerated 40 ° c ./ 75 % relative humidity conditions for six months . in addition , degradation products are not detected . although the scaled - up batch showed good results , similar measurements were conducted as an in - use stability study where bottles were handled to mimic in - use conditions . 8 bottles of memantine oral solution , 4 mg / ml were stored at room temperature without humidity control . bottles were opened daily ( 5 days / week ) for 5 minutes to stimulate conditions during normal use . after 5 minutes , the bottles were closed . the samples were analyzed after 2 , 4 , and 6 weeks to determine assay of antimicrobials , parabens , degradation products , ph and preservative effectiveness . results are shown in table 13 below . antimicrobial effectiveness testing was conducted to demonstrate that the formulations contained antimicrobial preservatives to protect the formulation from microbiological growth or from microorganisms that were introduced inadvertently or subsequent to manufacturing process . the testing was performed in accordance with the usp & lt ; 51 & gt ; using the culture conditions for inoculum specified in the test conditions . the antimicrobial effectiveness testing ( referred to later in the text as ape or antimicrobial effectiveness ) is performed as described in usp 26 , the united states pharmacopeial convention , inc . ( rockville , md ., 2002 ; pp . 2002 - 2004 ). the test is conducted in five sterile ; capped bacteriological containers into which a sufficient volume of product has been transferred . test organisms include candida albicans ( atcc no . 10231 ), aspergillus niger ( atcc no . 16404 ), escherichia coli ( atcc no . 8739 ), pseudomonas aeruginosa ( atcc no . 9027 ), staphylococcus aureus ( atcc no . 6538 ). each container is inoculated with one of the prepared and standardized inoculum , and mix . the concentration of test microorganisms that is added to the product are such that the final concentration of the test preparation after inoculation is between 1 × 10 5 and 1 × 10 6 cfu per ml of the product . the inoculated containers are incubated at 22 . 5 ± 2 . 5 ° c ., and sampled at the appropriate intervals specified in the monograph . the number of cfu present in each test preparation is determined by the plate - count procedure , specified in the monograph , for the applicable intervals . using the calculated concentrations of cfu per ml present at the start of the test , the change in log 10 values of the concentration of cfu per ml for each microorganism is calculated at the applicable test intervals , and the changes in terms of log reductions is expressed . results are evaluated in accordance with the product category for oral products made with aqueous bases or vehicle . the antimicrobial test results for pseudomonas aeruginosa ( atcc 9027 ), escherichia coli ( atcc 8739 ), staphylococcus aureus ( atcc 6538 ), candida albicans ( atcc 10231 ), and aspergillus niger ( atcc 16404 ) are listed in table 14 below . the products met the usp & lt ; 51 & gt ; criteria for antimicrobial effectiveness for all inoculums . the solution product was found to be stable for the entire study period based on the antimicrobial effectiveness testing . in the present example , the selection of the anti - caplocking agent is described . as discussed earlier , sorbitol 70 % solution was added as a sweetener in the formulation . it has a tendency to crystallize on the threads of the bottle cap and interferes with cap removal , which results in caplocking , or with hermetic closure which may result in leakage . glycerin reduces the tendency of sorbitol to crystallize . to determine the optimal concentration of glycerin required to minimize cap - locking for a 10 mg / ml memantine formulation , a caplocking study was conducted on a memantine solution of 1 % w / v ( 10 mg / ml ) and 0 . 2 %, 2 mg / ml . the compositions of 10 mg / ml solution and test results are shown in tables 15 and 16 . the compositions and test results for 0 . 2 % w / v ( 2 mg / ml ) are shown in tables 17 and 18 . for each formulation , the necks of 25 bottles were dipped in the solution prior to applying caps . application torque was measured using kaps - all electronic torque tester ( kaps - all electronic torque tester , model eb550 , riverhead , n . y .). the torque testing was performed according to manufacturer &# 39 ; s instructions . five bottles were used to determine the initial removal torque and the remaining bottles were put in a 50 ° c . oven . bottles were withdrawn after 1 , 2 , 3 and 4 wks . removal torque was measured at each time point . formulations with 0 , 2 . 5 and 5 % glycerin showed high removal torque and a white film of crystallized sorbitol was also evident around the neck of the bottle . in formulations containing 10 % glycerin no film was formed around the neck of the bottle and caps could be removed easily . however , at a concentration of 15 % and above , caps were loose which could lead to leakage . based on these tests , it was determined that 8 % w / v to 12 % w / v glycerin formulations effectively prevented caplocking . data are presented in table 16 . the caplock study was repeated for the 2 mg / ml memantine formulation . glycerin was added in concentration of 0 , 5 , 10 and 15 % to the formulation and caplocking tendency was measured as above . the compositions tested are shown in table 17 . the data pertaining to torque values are shown in table 18 . in formulations containing 10 % glycerin , no film was formed around the heck of the bottle , and caps could be remove easily . however , at a concentration of 15 %, caps were rendered free which could lead to leakage of contents and hence is not desirable . based on the data , it was determined that 10 % w / v of glycerin for both 2 mg / ml and 4 mg / ml formulations are appropriate to prevent closure locking and leaking . indeed , given the high solubility of the active ingredient based on the data , it is determined that 8 % w / v to 12 % w / v of glycerin is appropriate to prevent closure locking and leaking of memantine solutions . the present example demonstrates the process of making a neramexane oral solution in 2 , 5 , 10 , and 20 mg / ml strengths . the following ingredients in table 19 were combined according to the process described below . preparation process for one - liter batch was as follows . sorbitol 70 % was mixed with purified water in a suitable stainless steel container . to the sorbitol - water solution , glycerin was added and mixed . citric acid and sodium citrate were then added , followed by neramexane mesylate . all the above ingredients were mixed to dissolve in the batch tank . in a separate container , a sub - solution of propylene glycol , methylparaben , propylparaben , and natural peppermint flavor # 104 was mixed . the subsolution was then added to the batch tank , which was subsequently qs to desired volume with purified water . the solution was filled into bottles and then capped . in the present example , the stability of the 10 mg / ml solutions made in example 8 were tested for percent of neramexane , methyl paraben , propyl paraben , and ph using the same procedures described in example 6 . the data are presented below in table 20 . in the present example , the antimicrobial effectiveness was measured in the neramexane oral solutions . the same testing procedures outlined in example 6 were used . table 21 provides the test results for different strengths of neramexane mesylate oral solution ( 2 , 5 , and 10 mg / ml ) without preservative . in these batches , methylparaben and propylparaben level were zero . the results show that the test complies with the usp requirement . this shows that neramexane itself has sufficient preservative efficacy . the same tests were run on 10 mg / ml neramexane mesylate oral solution with preservatives at different levels . the results are shown in table 22 . in these experiments , formulations were prepared with different levels of methylparaben : propylparaben . these were : 0 . 05 : 0 . 005 ; 0 . 08 : 0 . 008 and 0 . 1 : 0 . 01 . the formulations show preservative effectiveness at all levels as they pass usp requirement . the present invention is not to be limited in scope by the specific embodiments described herein . indeed , various , modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description . such modifications are intended to fall within the scope of the appended claims . all patents , applications , publications , test methods , literature , and other materials cited herein are hereby incorporated by reference .

US-57876504-A

a water - wiping blade for wiping water from surfaces having projecting regions from the surface is based on a flexible panel having an upper and a lower long edge , with a handle interface along the upper long edge , and a lip formed along the lower long edge , the lip ending in a sharp line at the end away from the flexible panel . in a preferred embodiment a handle is attached by the handle interface along the upper long edge . by rotating the flexible panel around the handle length and urging the panel into a surface , the lip can be caused to wrap around regions projecting from the surface with the sharp line of the lip in contact with the surface . translating the panel then is effective in wiping standing water from the surface even in the presence of such surface deformities , such as rivet heads and the like . in some embodiments handle extensions may be used to allow positioning the flexible panel in hard - to - reach places . also in some embodiments a lip is provided to both sides of the flexible panel so either side may be used for wiping water , and lips of various shapes are taught .

fig1 is a perspective exploded view of a hand - held water blade 11 in an embodiment of the present invention , illustrating three main elements of the assembly of water blade 11 . a two - part handle consists of a first section 15 adapted to fasten to a second section 17 with a blade insert 13 captured between the handle sections . with the handle sections joined and the blade captured , a functioning water blade 11 is formed . in a preferred embodiment of the present invention , handle sections 15 and 17 are molded from polypropylene in an injection molding process . injection molding is well known in the art of fabricating various plastics and is considered by the inventor , in this instance , to be a preferred process for manufacturing water blade 11 . in other embodiments , other fabrication methods may be employed such as gluing various parts together , or perhaps plastic welding techniques may be employed . it will be apparent to one with skill in the art that various materials may be used to fabricate handle sections 15 and 17 such as delrin , nylon , and others . metals , wood , and the like may be used in other embodiments . a t - shaped top portion 18 is provided in blade insert 13 wherein opposite sides of the &# 34 ; t &# 34 ; fit snugly into opposite blade slots provided in handle sections 17 and 15 . a blade retaining slot 12 is shown in handle section 15 , and a similar slot is provided in section 17 , though not shown in fig1 . handle sections 15 and 17 are designed to fit together to form a handle grip that retains the wiper blade , is comfortable to hold , and is of light weight . in a preferred embodiment , special texture areas are provided around the outer edges of each handle section , although this is not required . recesses may be molded into handle sections 15 and 17 for the purpose of supporting decals , logos , and the like . in the embodiment shown a method is provided for attachment of handle sections 15 and 17 whereby handle section 15 has assembly brackets such as bracket 14 that are designed to accept rivets such as rivet 19 that are to be inserted through access points shown in handle section 17 , such as the access point shown roughly in line with rivet 19 and bracket 14 illustrated by the directional arrows . bracket 14 may be formed in the molding process or may be mounted to handle section 15 after molding . bracket 14 may be fabricated from aluminum , sheet metal , or any other suitable material known in the art and of suitable strength to provide a secure attachment . in the embodiment shown by fig1 the method of attachment is riveting . however , other methods of attachment may be used as well , such as screws , snap inserts and the like . in another embodiment there may be no brackets or recesses but rather grooves provided and adapted for the installation of outer snap rings . it will be apparent to one with skill in the art that many methods , well known in the art , may be employed for attaching handle sections together without departing from the spirit and scope of the present invention as described above . in still other embodiments a one - piece handle may be provided with a t - slot adapted to engage t - section 18 of blade 13 , wherein the blade may be threaded into the slot of the one - piece handle . an advantage in this embodiment is that there is no need for separate sections or fasteners . in still other embodiments handles may be formed in other ways , ad some of these other ways are described in more detail below . in a preferred embodiment of the present invention length dimension d1 is about 12 inches , width dimension d2 is approximately 7 / 8 of an inch , and height dimension d3 is approximately 11 / 4 of an inch . it will be apparent to one with skill in the art that dimensions with respect to length , width , and height of the grip handle formed by handle sections 15 and 17 may vary . for example , handles of different sizes may be provided along with blades of different sizes for use under certain circumstances . large sizes for large trucks and trailers , for example , and smaller models for such as compact cars . fig2 is a broken elevation view of blade insert 13 of fig1 in an embodiment of the present invention showing approximate dimensions and various molded features , some of which are important to unique functionality of wiper blades in embodiments of the present invention . fig3 is a section view of blade insert 13 taken along section lines 3 -- 3 of fig2 wherein further dimensioning is illustrated . a lip region 21 is provided along the longitudinal bottom edge of blade insert 13 with lip elements extending laterally from the bottom edge . this lip region may be formed in several different ways in different embodiments of the invention . in a preferred embodiment the lip region is formed at an angle from the blade element as described below in more detail . in a preferred embodiment of the present invention blade insert 13 is molded from a silicon rubber material via injection molding process for similar reasons stated as stated above with respect to the molding of handle sections 17 and 15 . it will be apparent to one with skill in the art that blade insert 13 may be molded from other materials known in the art and of suitable flexibility . in this instant embodiment , the inventor prefers silicon rubber with a flexibility rating of approximately 30 to 70 durometer , depending on thickness of the blade . the flexibility of blade insert 13 can be more or less than 30 to 70 durometer , depending on a number of factors that also affect functionality , such as blade thickness , taper , grooving , blade height , and the like . a unique and critical function provided by unique characteristics of blade insert 13 is it &# 39 ; s capability of conforming around sometimes compound and / or radical curves in the body of an automobile , such as in a fender section . it is an object of the present invention is to provide for eliminating standing water in these areas in a safe and efficient manner . this unique capability is made possible in part by the approximate dimensional proportions of blade insert 13 with respect to length and height . referring to fig2 and fig3 blade 13 has a height d4 that is a significant fraction of length d1 . the ability of blade 13 to form around curved surfaces in wiping water from such surfaces is largely due to the height of the blade relative to the length , and this feature is enlarged upon below . in one preferred embodiment of the present invention , d12 , which is the effective height of the blade extending from a handle , is about 21 / 2 inches . this dimension is the free flexible height from bottom of blade insert 13 to the bottom of the grip handle formed by handle sections 15 and 17 of fig1 . in this embodiment d1 is about 12 inches . the ratio of free height to length in this case is about 0 . 21 , or about 20 twenty percent . the inventor has discovered empirically that this ratio need to be about ten percent or more for the water blade to be really useful for automobiles with considerable curved surfaces . it will be understood that d1 is used in this embodiment both as the length of the handle sections and the wiper blade , as the lengths are substantially the same . in some other embodiments handle elements and wiper blades will be of different dimensions . it has been found by experiment that in this embodiment , the dimensions 2 . 5 inches for height d12 and 12 inches for d1 , with a thickness of material of approximately 3 / 16 of an inch produces a useful and preferable result . in other embodiments wherein the overall dimensions of water blade 11 are larger or smaller , a material with a more suitable hardness and perhaps thickness may be employed to aid in achieving desirable flexing properties of water blade 11 . providing a significant height for blade insert 13 increases the area of contact around a curved automobiles surface such as a fender , and the like . the ratio of height to length of blade insert 13 is important to the function of water blades in various embodiments of the present invention , and will be described in more detail in below . another important characteristic in blade insert 13 is a capability to direct standing water from a surface and to move it in an efficient manner whereby virtually no water residue remains behind on the automobile surface . this directing effect is accomplished by lip 21 which is formed along the longitudinal bottom edge of blade insert 13 and extends in the embodiment shown in the form of a tapered angle on either side . angled lip 21 produces a rolling action to the water and forces it to ride up on the angled surface of the lip effectively separating the water from the surface of the automobile . it is known to the inventor that some windshield wiper blades incorporate a similar design , and it is well known in the art that this design is effective in removing standing water . the angled lip characteristic is unique in conjunction with the height of the blade , in providing a lipped blade with an ability to conform to compound and radical curves in the surface of an automobile . in the embodiment shown in the figures a series of molded indentions 23 is provided along the length of blade insert 13 . the object of these indentions is to minimize the amount of material required to mold blade insert 13 . it is known in the art that silicon rubber is relatively expensive when compared to other materials , therefore , considerable savings can be realized by employing such material reducing techniques . in the embodiment shown these indentions are equally spaced approximately 1 / 2 inch ( d13 ) from center line to center , for 24 indentions . the uniform height of these indentions is approximately 17 / 8 inches ( d1 ), and the dimension from the bottom of the indentions to the bottom of blade insert 13 is approximately 1 / 2 of an inch ( d10 ). even though indentions as described immediately above may be used for saving weight and material volume , in most preferred embodiments the sides of blade 13 are smooth , rather than grooved , and the inventor has found that the smooth embodiment actually provides enhanced water - wiping function compared to blades with the grooved surface . a groove 25 is shown running the entire length of blade insert 13 . groove 25 , described briefly with reference to fig1 is formed around the perimeter of blade insert 13 , providing the shape of t - section 18 . these grooves provide a secure locking arrangement when handle sections 15 and 17 of fig1 are closed , thereby stopping blade insert 13 from moving up or down with respect to the grip handle . the overall thickness of blade insert 13 is approximately 1 / 2 of an inch ( d5 ). a minor thickness of blade insert 13 shown from the inside diameter of t - slot 25 and extending down to the upper shoulder of angled lip 21 is approximately 3 / 16 of an inch ( d6 ). overall height of blade insert 13 is approximately 2 and 7 / 8 inches ( d4 ). the width of grooves 25 of and the height of angled lip 21 are approximately 1 / 8 of an inch ( d7 and d8 respectively ). the approximate angle of angled lip 21 in the preferred embodiment shown is 30 degrees ( d9 ). in some embodiments the angle at which lip 21 joins the body of the blade is different , and in some embodiments the lip may be on one side only . the inventor has found that a sharp edge 24 at the end of lip 21 provides a superior wiping action . various dimensions as described herein are approximate only and are meant to illustrate preferred size relationships of features of blade insert 13 in a preferred embodiment of the present invention . it will be apparent to one with skill in the art that many changes can be made with respect to dimensioning water blade 11 without departing from the spirit and scope of the present invention . for example , a larger water blade may be used on a larger vehicle such as a semi - trailer rig and so on . in one embodiment a water blade with an added height to its blade insert may be used , for example , if a particular type of vehicle contains more curved features that are pronounced . fig4 a - 4c illustrate the unique action of water blade 13 in conforming to a curved surface 29 . fig4 a illustrates a section view of a curved surface , which could be the curvature of a fender , and a water blade 11 including a rigid handle positioned so that lip 21 is just in contact with the curved surface , but flexible blade element 13 is not deformed . fig4 b is a view in the direction of arrow 27 of fig4 a , showing water blade 11 in contact with curved surface with blade element 13 not deformed . in this example , the contact of the blade element with the surface is just a narrow line . this is the situation that will always exist with a blade having little or no height d12 ( fig2 ). fig4 c is the same section view of a curved surface 29 as shown in fig4 a , with water blade 11 in contact with surface 29 , and fig4 d is a view in the direction of arrow 31 . in this example , blade 11 has been rotated somewhat around the longitudinal axis of the handle , and the blade has been urged toward curved surface 29 in the direction of arrow 33 . this movement is applied by a user holding the blade in his or her hand . the result of moving the water blade into surface 29 is deformation of blade element 11 , bringing the sharp edge of lip region 21 into contact with the surface , and causing flexible blade element 13 to wrap around the curvature of the surface to a significant degree . in this example , width of the contact area ( fig4 c ) is from point 35 to point 37 . the significantly wide contact line around the curvature of the surface is a result of the height d12 ( fig2 ) of flexible blade element 13 . the arc length that may be accomplished by blade element 13 around a curved surface in practicing the present invention is a function of both the height of the blade element and the curvature of the surface . as surface curvature may be varied and compound , rather than simple , the calculations can be complex . a simplified example is given here assuming that the curvature is circular of radius r . given radius r for the curvature of the surface , and a height h for dimension d12 of blade element 13 , and assuming that the water blade is urged into the curved surface until the handle is proximate the surface ( which is a max situation , not actually encountered in practice ), the angle α can be determined by the formula : the potential length of the contact line to the curved surface from point 35 to point 37 in this situation can then be calculated as that portion of the circumference of a circle of radius r subtended by twice the angle α taken around the center of the curvature . it is apparent in the above analysis that for the potential length of the contact line to be realized , the overall length of the flexible blade element must be at least equal to the potential length . if the length of the blade element is more than the potential contact length , then part of the blade element will not make contact , as is shown in fig4 c . as is described above , in the preferred embodiment shown , the height of the blade element is about 3 inches , and the length is about 12 inches . this relationship has been found by the inventor to be useful for most automobile bodies . it will be apparent to those with skill in the art that there are many alterations that might be made in the embodiments shown and described without departing from the spirit and scope of the present invention . in the area of handle provision for water blades in particular , many variations have been developed . fig5 a is a perspective view of one such alternative embodiment . in fig5 a a water blade 39 according to an embodiment of the present invention is molded from material such as silicone material of a single durometer , and a handle portion 41 is molded integrally from the same material . in the molding process a lengthwise passage 43 opening to either or both ends is molded into the water blade . after molding a rigid stiffener 45 of about the length of the water blade is inserted into the lengthwise passage , and provides rigidity and the function of the rigid handle added according to fig1 . fig5 b shows yet another handle alternative for a water blade 47 . in the embodiment of fig5 b material of two different durometers are molded in one mold . a blade region 49 is molded of a material soft enough for the needed flexibility , and a more rigid material is molded as a handle region 51 . procedures for such molding are well - known known in the art . in an other aspect of the invention , the lip area of water blade insert 13 , shown as element 21 in fig1 is especially implemented to provide for effective water removal ( displacement ) when used on surfaces that have projections emanating from the surface , such as rivet heads , raised ornamental patterns , and the like . fig6 is an exploded and broken view of lip 21 of water blade insert 13 of fig1 according to an embodiment of the present invention wherein lip 21 is not orthogonal to the height of the blade , but at other than a right angle . it was mentioned above that some windshield wiper blades , known to the inventor , have lip regions that are similar in design to lip 21 of fig1 and are known to be effective for removing standing water . however , it is also known and accepted in the art that a windshield wiper is limited by design and rigidity of material in that it is effective for a slightly curved and smooth surface such as a windshield . it was also mentioned above that the shape of lip 21 combined with the height of blade insert 13 is unique in it &# 39 ; s ability to conform to and remove water from compound and radical curves in the surface of an automobile . this unique capability of water removal inherent to lip 21 , as previously taught , is not limited only to contours and curves such as are common to surfaces of automobiles , trucks and other vehicles , but also extends , in some embodiments , to projections from surfaces as found in rivets , diamond plate , and other ornamental features found on some automobile surfaces , airplane surfaces , truck surfaces , and many other like surfaces that may or may not be associated with a type of vehicle , as is taught below . the flexing capabilities of blade insert 13 and lip 21 also play a major roll in the ability of water blade 11 to remove water from more difficult surfaces such as surfaces exhibiting rivet heads , diamond pattern , and so forth . for example , with the applied action of water blade 11 over a given surface that may be contoured and have a raised pattern such as a diamond head pattern , blade insert 13 will conform to the contour while the contact side of lip 21 will conform to and around the edges of the diamond pattern effectively removing water . lip 21 , for example , may be specially designed with the required length ( extension from the body of blade 13 ) for extending more than the total raised height of an ornamental pattern or an array of rivets and so on . fig7 a is a perspective view of the water blade of fig1 removing ( displacing ) water from a surface having rivet - head projections according to an embodiment of the present invention . in this embodiment , a user urges water blade 11 across a surface 61 having projecting rivet heads 63 in the direction of the arrows while , at the same time , keeping a sufficient downward force on surface 61 to cause the lip to conform to the shape of the raised rivet heads . as one side ( contact side ) of lip 21 passes over a rivet head 63 , the flexible material conforms to the shape of each of the raised regions . in this fashion , water is displaced from all areas exposed to lip 21 including regions in between raised rivet heads of surface 61 . fig7 b is an elevation view of water blade11 and rivet - studded surface 61 of fig7 a . when viewing water blade 11 and surface 61 in the direction of motion as indicated by the directional arrows of fig7 a , one can see how tightly lip 21 conforms around raised regions such as those present on surface 61 . this unique ability is due to the flexibility of the material and design of lip 21 wherein sufficient length and flexibility is provided for conforming around such shapes . it will be apparent to the skilled artisan that one angular side or portion of lip 21 may be formed of a substantially greater length than the opposing side so that dual use is provided to water blade 11 without departing from the spirit and scope of the present invention . for example , one side having a longer extension may be used for surfaces having raised regions while the opposing shorter side used for smooth surfaces and so on . in alternative embodiments alternate designs are provided to the lip section of blade 11 to conform to even more complex surface features as taught below . fig8 a is an end view of a lip shape according to another embodiment of the present invention . in this example , a lip section 65 is formed having a v shape configuration on each opposing end . as is the case with lip 21 of fig1 the v form is made to extend along the longitudinal edge of blade insert 13 of fig1 . this v formation produces a double - edge effect providing a second swipe at a surface during one initial pass of water blade 11 . fig8 b is an end view of a lip design according to yet another embodiment of the present invention . in this example , a lip section 67 is formed having a v shape similar to lip 65 of fig8 a accept that the opposing formations are much closer together . such a formation may be used , for example , when raised areas or portions of a surface are not particularly high therefore not requiring substantial length with regard to lip formation . fig8 c is an end view of a lip design according to still another embodiment of the present invention . in this example , a lip 69 is formed having a half - moon shape on opposing ends and a substantially straight bridge connecting the half - moon shapes to each other . as with the previous two examples , there are now two swiping edges that are able to make contact with a surface during one pass with blade 11 . a formation such as seen in this embodiment may be useful for a surface that has a series of rounded rows forming a ribbed surface . the formation shown here would allow bi - directional motion of water blade 11 such as across the rows and down the rows wherein water removal is successful in either direction . fig9 is an end view of yet another , and simpler , embodiment of the present invention . in this embodiment the lip is a simple straight projection forming an orthogonal t - bar at the bottom of blade 13 , the t - bar having essentially constant wall thickness . it will be apparent to one with skill in the art that examples shown in fig8 a - c and 9 are merely a few of many possible lip - design variations that may be implemented without departing from the spirit and scope of the present invention to provide for conforming to complicated shapes on surfaces to be processed with a wiper blade as taught herein . in another example of alternative embodiments , larger or smaller water blades may be desirable for certain situations . for example , larger blades may be provided for use with large vehicles , such as tractor / trailer rigs and the like , or for vans and other trucks . in some embodiments , especially for use with large vehicles or other entities with large body areas , interfaces may be provided for handle extensions and the like , to allow a user to present the blade to otherwise hard - to - reach areas . such interfaces might include such as ball and socket joints for flexibility in positioning a water blade in relationship to a handle . as another example , many different materials that could be used in the fabrication of a water blade in different embodiments . in other embodiments blade inserts may be of differing heights and lengths and may be sold separately to be inserted into one handle grip and so forth . the breadth of the present invention is limited only by the claims that follow .

US-5966198-A

methods , systems , and apparatus for delivering drugs and other substances to extraluminal tissue surrounding a body lumen are described . catheters are used to inject the drug or other substance intraluminally into tissue surrounding a stent or other luminal scaffold . the drug or other substance is injected in an amount sufficient to cause diffusion back through the tissue to the stent . an absorptive structure , reservoir , or the like , on the stent then absorbs excess drug as it passes from the luminal tissue . in this way , the stent is first loaded with drug . after time , as the stent becomes fully loaded and the tissue becomes depleted , drug will be begin to flow back from the stent into the surrounding luminal tissue .

the methods , systems , and apparatus of the present invention can be used to deliver a wide variety of therapeutic and other agents to extra luminal tissue surrounding body lumens , particularly the adventitial layer and other perivascular tissues surrounding arteries and blood vessels , particularly coronary arteries . these agents include antineoplastic agents , antiproliferative agents , immunosuppressive agents , anti - inflammatory agents , macrolide antibiotics , antibiotics , antifungals , antivirals , antibodies , lipid lowering treatments , gene therapy agents , anti - sense drugs , metalloproteinase inhibitors , growth factor inhibitors , cell cycle inhibitors , angiogenesis drugs , anti - angiogenesis drugs , and / or radio - opaque contrast media for visualization of the injection under guided x - ray fluoroscopy . each of these therapeutic agents has shown promise in the treatment of cardiovascular disease , restenosis , and / or vulnerable plaque lesions . antiproliferative agents , immunosuppressive agents , and anti - inflammatory agents , including but not limited to avi - 4126 , sirolimus , tacrolimus , everolimus , cortisone , dexamethasone , and cyclosporine , interfere with the pathological proliferative response after coronary angioplasty to prevent intimal hyperplasia , smooth muscle cell activation and migration , and neointimal thickening . antineoplastic agents , including but not limited to paclitaxel and actinomycin d , interfere with the pathological proliferative response after coronary angioplasty to prevent intimal hyperplasia , smooth muscle cell activation and migration , and neointimal thickening . macrolide antibiotics , including but not limited to sirolimus , tacrolimus , everolimus , azithromycin , clarithromycin , and erythromycin , inhibit or kill microorganisms that may contribute to the inflammatory process that triggers or exacerbates restenosis and vulnerable plaque . in addition , many macrolide antibiotics , including but not limited to sirolimus and tacrolimus , have immunosuppressive effects that can prevent intimal hyperplasia , neointimal proliferation , and plaque rupture . antibiotics , including but not limited to sirolimus , tacrolimus , everolimus , azithromycin , clarithromycin , doxycycline , and erythromycin , inhibit or kill microorganisms that may contribute to the inflammatory process that triggers or exacerbates restenosis and vulnerable plaque . antifungals , including but not limited to sirolimus , everolimus , and tacrolimus , inhibit or kill microorganisms that may contribute to the inflammatory process that triggers or exacerbates restenosis and vulnerable plaque . antivirals , including but not limited to acyclovir , ganciclovir , fancyclovir and valacyclovir , inhibit or kill viruses that may contribute to the inflammatory process that triggers or exacerbates restenosis and vulnerable plaque . antibodies may be developed to inhibit or kill microorganisms that may contribute to the inflammatory process that triggers or exacerbates restenosis and vulnerable plaque or to inhibit specific growth factors or cell cycle regulators . lipid - lowering treatments , including but not limited to statins , modify plaques , reducing inflammation and stabilizing vulnerable plaques . gene therapy agents achieve overexpression of genes that may ameliorate the process of vascular occlusive disease or the blockade of the expression of the genes that are critical to the pathogenesis of vascular occlusive disease . anti - sense agents , including but not limited to avi - 4126 , achieve blockade of genes and mrna , including but not limited to c - myc , c - myb , pcna , cdc 2 , cdk 2 , or cdk 9 s , through the use of short chains of nucleic acids known as antisense oligodeoxynucleotides . metalloproteinase inhibitors , including but not limited to batimastat , inhibit constrictive vessel remodeling . cell cycle inhibitors and modulators and growth factor inhibitors and modulators , including but not limited to modulators of vegf , igf , and tubulin , inhibit or modulate entry of vascular smooth muscle cells into the cell cycle , cell migration , expression of chemoattractants and adhesion molecules , extracellular matrix formation , and other factors that trigger neointimal hyperplasia . angiogenesis genes or agents increase microvasculature of the pericardium , vaso vasorum , and adventia to increase blood flow . anti - angiogenesis genes or agents inhibit factors that are associated with microvascularization of atherosclerotic plaque and which directly or indirectly also induce smooth muscle cell proliferation . referring now to fig1 , 2 , and 5 , a catheter 12 having a microneedle 14 suitable for injection of substances into luminal walls according to the methods of the present invention is illustrated . as shown in fig2 , the microneedle 14 is retracted within an involuted section of the catheter at its distal end 13 . the mirconeedle 14 may be advanced in a radial direction so that it penetrates into a region 22 of extra vascular tissue through wall 21 of an artery , as best shown in fig5 . in particular , the portion of the catheter which carries the needle is inflated , as described in more detail in co - pending u . s . application ser . nos . 09 / 961 , 080 , filed on sep . 20 , 2001 , and 09 / 961 , 079 , also filed on sep . 20 , 2001 , incorporated herein by reference . the systems of the present invention will further comprise stents , grafts , or other scaffold structures having absorbable structures , reservoirs , or the like , for imbibing liquid substances after they are injected into the luminal tissues . as shown in fig3 , the stent may comprise a helical scaffold 30 , which may have any conventional helical stent structure , with an absorptive polymer layer 32 , formed over at least part of its exterior surface . polymer layer 32 will be porous or alternatively comprise a hydratable gel or similar material which is capable of imbibing the drug or other liquids substance which has been injected into the luminal wall as said substance is shed or expressed from the wall . in particular , the polymer material 32 will be able to absorb the liquid drug or other substance and then release the substance back into the luminal wall over time . as shown in fig4 , a helical stent 34 has open reservoirs 36 formed over at least a portion of its exterior surface . the reservoirs 36 are covered with porous membranes 38 which permit entry of the liquid substance into the reservoir as the substance is released from the surrounding luminal wall ( after the stent has been deployed in the target lumen ). as with the absorptive material of fig3 , the liquid substance in the reservoirs 36 will first be collected within the reservoirs and subsequently released from the reservoirs back into the luminal wall over time . referring again now to fig5 , the catheter 12 will be deployed in the blood vessel and the microneedle 14 passed into the adventitial space 22 through openings in a stent 23 . the stent 23 may have the structures of either fig3 or 4 , or any other structure which has been modified to have the desired absorption capability of the present invention . the stents may be employed by conventional means , including balloon expansion , release of self - expanding stents from constraint , or combinations thereof . after deployment of the stent 32 , and penetration of the microneedle 14 into the target luminal tissue , the liquid substance will be delivered into the tissue through the microneedle , typically from a port 40 located at a proximal end of the catheter 12 ( fig1 ). remaining ports 42 and 44 are available for expansion of the catheter in order to employ the microneedle , advance of a guidewire , or the like . initially , a small bolus of material is delivered so that it forms a small plume 31 ( fig6 ). further injection of the material causes diffusion of the material both in a longitudinal direction 32 ( fig7 ) and eventually in a circumferential direction 34 ( fig8 ). after the tissue becomes saturated , excess liquid substance will diffuse back toward the lumen , eventually passing through the arterial or other luminal wall and into the absorptive structures or reservoirs of the stent 23 . after the stent is loaded , and in particular after the concentration of the drug within the surrounding tissue lowers , the liquid substance will begin to flow back into the luminal tissue because of the growing concentration gradient . in this way , maintenance of a reservoir of the drug adjacent to the tissue will be maintained for relatively long periods of time to enhance treatment . desired drugs or other therapeutic agents can exist in particulate , nanoparticulate , liquid , suspended , or aqueous states . as the drug exits the delivery needle , the longitudinal length of diffusion will depend principally on the amount of drug injected and secondarily on the lipophilicity of the drug . in the case of vascular delivery , the dispersion will further depend on the nature of the vaso vasorum to transfer the drug into the different layers of the blood vessel wall and surrounding tissue . similar factors will influence the rate of diffusion of the drug back into the stent absorptive structures and reservoirs of the present invention . while the above is a complete description of the preferred embodiments of the invention , various alternatives , modifications , and equivalents may be used . therefore , the above description should not be taken as limiting the scope of the invention which is defined by the appended claims .

US-61079003-A

an apparatus for preparing and distributing alimentary products formed of a portion of ice - cream , mousse , or the like contained between two biscuits , wafers , waffles or other bakery products comprises at least a biscuits dispenser ; a container suited to receive the product ; means suited to drive biscuits from said dispenser to said container ; means for compressing the product and means 4 for ejecting the final product ; as well as a lever or an equivalent means suited to control the movement of the above - mentioned elements .

referring to fig1 and 3 , there is shown the apparatus for manufacturing and distributing ice - cream sandwiches according to the present invention comprising a piece 5 formed by a couple of equal and parallel circular sectors firmly connected to each other by pivots 5 a and 5 b . such a piece 5 is integral with a control lever ( not shown in the drawing ) pivoted on a lateral face of the apparatus , and drives components 6 and 7 , one of which being shown in fig4 , to rotate around pivot 11 of the lever . component 7 is made up of a couple of equal and parallel compensators , firmly connected by pivot 12 and placed externally to the two circular sectors that form piece 5 . this component 7 is linked to components 1 and 3 through buttonholes and countershafts . component 1 is made up of a couple of equal and firmly connected parallel carriages , each provided with two wheels sliding on guides formed at the apparatus base in such a way as to be able to translate horizontally . this carriage 1 is provided at the top with a pusher 1 a having the function of individually pushing the biscuits out of one of dispensers 13 . the apparatus is in fact provided at the top with a plate ( not shown in the drawing ) that can be manually rotated and on which several biscuits dispensers 13 are placed , each for every type . such dispensers 13 consist of containers opened at the top , in order to be easily rechargeable , and provided at the base of a lateral wall with two openings mutually facing in such a way as to let pusher 1 a enter one of them and to let a biscuit exit from the other one . carriage 1 is firmly connected to two parallel supports 1 b sliding underneath said plate and acting as guides for inserting into a container 3 each biscuit extracted from dispenser 13 . the latter is formed of a cylinder opened at the top that ends with a cylinder 3 a having a shorter radius . cylinder 3 a , extending nearly to the base of the apparatus , contains a stem 4 which pushes a small plate 4 b to translate vertically . this small plate 4 b , located inside container 3 , forms the lower mobile base of container 3 . stem 4 is linked to cylinder 3 a through a mechanism which allows these two pieces to be firmly connected or to reciprocally translate as will be described further . component 6 , placed between the two circular sectors that form piece 5 , is a sector provided with a toothed profile engaging an helical profile formed on a shaft 8 , thus controlling both translational and rotatory motion thereof . shaft 8 , supported by a sleeve 8 a , is placed between cylinder 3 a and pivot 11 and is firmly connected to plunger 2 through an arm 2 a and an l - shaped element 9 . this l - shaped element 9 ends with a nose which , as a result of the rototranslatory motion of shaft 8 , gets into a buttonhole of an element 10 acting as a linkage between cylinder 3 a and stem 4 . the preparation of ice - cream sandwiches according to the present invention is carried out in four steps to which three different conditions of the apparatus correspond : the first step is the biscuit dispensing step to which corresponds the first apparatus condition , named dispensing mode ; after having reset the apparatus in the resting mode , the second step is carried out , i . e . the step of inserting ice - cream inside the container ; the third step consists in rearranging the apparatus in the dispensing mode so as to place a second biscuit on the ice - cream portion ; finally the fourth step is carried out wherein the apparatus is arranged in pressing mode during which the product is subjected to compression and then ejected from the apparatus . the passage from a mode to another one occurs by moving the control lever from a position to another . with reference to fig2 and 3 , there is shown how the first step is carried out . the arrows indicate the rotation or translation sense of the various elements . by rotating counterclockwise the control lever with respect to the starting position corresponding to the resting mode , and by so positioning it in the dispensation mode , the circular sector 5 , integral with the control lever , rotates in the sense indicated by arrow , thus driving also compensator 7 to rotate through pivot 5 b . the counterclockwise stroke of the circular sector 5 is , anyway , short enough to not risk to drive also toothed sector 6 to rotate through pivot 5 b . compensator 7 has a first arm , 7 a provided with a buttonhole , and a second arm , 7 b provided with a countershaft 7 c , at which , on cylinder 3 a and on carriage 1 there are respectively a countershaft 3 b and a buttonhole through which compensator 7 is connected to components 1 and 3 a . these linkages work in such a way that , when compensator 7 rotates , cylinder 3 a , and thus container 3 , that in this step is integral therewith , moves vertically upwards thanks to countershaft 3 b which changes the rotatory motion of compensator 7 into a translatory motion of cylinder 3 a . in the same time , carriage 1 , thanks to countershaft 7 c , moves horizontally in the direction indicated by the arrow . as carriage 1 moves , also pusher 1 a integral therewith , moves pushing the last biscuit of the stack outside the biscuits dispenser 13 . since also supports 1 b are integral with element 1 , as pusher 1 a pushes the biscuit , the latter lays on these supports 1 b which gradually move forward together with the same pusher 1 a and drive the biscuit until it comes exactly over container 3 . at this point , coinciding with the point in which pusher 1 a reaches the stop , a suitable device opens the two supports 1 b so to let the biscuit drop in the underneath container 3 , which meanwhile has been lifted through the mechanism described above . the biscuit is preferably put down on a special wrapping , previously placed on the bottom of container 3 , which wrapping is intended to avoid that the operator cleans the apparatus after having prepared each ice - cream sandwich , and that the final product comes into contact with the hands of the operator when he gives it to the consumer . once the first biscuit has been placed into container 3 , the operator can rearrange the lever in resting mode . this allows the compensator 7 to rotate clockwise as returned by a spring not shown in the drawing . in this way pusher 1 , driven by compensator 7 , moves back until it comes to the starting position , and container 3 , and thus cylinder 3 a together with stem 4 fixed thereto , lower again . at this point the second preparation step of the product is carried out . this step consists of manually inserting the ice - cream on the surface of the biscuit placed inside container 3 , with an appropriate proportioner spoon which , to this end , is leant at an appropriate gap formed on the lateral surface of container 3 . the third preparation step of the product consists of dispensing the second biscuit on the inserted ice - cream portion , and accordingly the procedure is the same as in the first step by arranging the lever in the distributing mode . with reference to fig1 and 3 , there is shown how the last step , i . e . the pressing step wherein the lever is rotated clockwise so as to arrange it in the pressing mode , is carried out . the rotation of the lever in this direction makes circular sector 5 to rotate in the sense opposite to the one in which the same sector 5 rotates in the distributing step . sector 5 , through pivot 5 a , drives toothed sector 6 to rotate . the latter , together with the helicoidal profile formed on shaft 8 , constitutes a gear mechanism . therefore the rotation of toothed sector 6 causes a rototranslation of shaft 8 that is transmitted also to plunger 2 which , by rotating , comes over container 3 , and by moving downwards presses the product contained therein . simultaneously , since l - shaped element 9 is integral with shaft 8 , it also moves with a rototranslatory motion so to be inserted into the buttonhole located at one end of element 10 . this element 10 is thus caused , by the motion of l element 9 , to move horizontally in the direction bringing it near to shaft 8 . this movement releases stem 4 , up to this moment integral with cylinder 3 a thanks to a removable catch , and , as the lever is rearranged in the resting mode , a spring pushes upwards the stem 4 . since the latter is integral with plate 4 b , it pushes also the final product upwards and hence outside container 3 , thus making it easy for the operator to take it and deliver it to the consumer . simultaneously , the toothed sector 6 is brought back in resting position by a spring 14 . the latter is located in the area of toothed sector 6 opposite to the toothed profile with respect to pivot 11 . this spring 14 , having the other end fixed to the frame of the apparatus , is drawn during the pressing step and then released when the lever is rearranged in the resting mode while dragging with it the toothed sector 6 . in order to avoid that the latter , once returned by the spring , goes on rotating thus going beyond the desired position , a locking device ( not shown in the figure ) is used . the toothed sector 6 causes in turn shaft 8 , through the gear mechanism , to move upwards and , with it , also arm 2 a , plug 2 , and l - shaped element 9 , which element is in this way removed from the buttonhole of piece 10 . the latter gets back in the starting position through a spring . at this point it is sufficient to push plate 4 b on the bottom to get the apparatus ready for preparing another ice - cream sandwich . possible variations and / or additions can be made by those skilled in the art to the embodiment here described and illustrated without departing from the scope of the invention . for example it could be envisaged to substitute supports 1 b by guides fixed to the frame , which bend inwardly to let the biscuit drop when the pusher reaches the stop . it could be also envisaged to automate the apparatus by providing it with devices for the automatic control of the sequence of various steps . the apparatus could further be provided with electric or pneumatic actuators instead of the manually working lever . for constructing the apparatus according to the present invention it is possible to utilize any known material regarded as suitable to construct apparatuses of conventional type . it should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art . such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages . it is therefore intended that such changes and modifications be covered by the appended claims .

US-52682405-A

the invention relates to avocado powder and to the method of obtaining the same . avocado powder is a novel product which enables the avocado to be preserved for an extended period of time at ambient temperature , such as to conserve the characteristic properties of the product , with the additional advantage of being 100 % natural and occupying less physical storage space , thereby eliminating the post - processing cold chain . the method of obtaining avocado powder comprises a series of operations or steps that terminate in the pulverization and packing of the end product .

the characteristic details from this novel product and process are clearly shown in the following description and the accompanying tables . the physical state of avocado powder is a porous solid and its organoleptic characteristics are a green color identical to that of avocado in its natural state . the characteristic odor of avocado is preserved in avocado powder due to the fact that the chemical compounds that confer odor are not altered , on the other hand , avocado flavor , once re - hydrated is identical to the natural flavor . in powdered avocado , the nutrient content is very similar to that of natural avocado , it can be seen that proteins , fats , carbohydrates , and fibers have a percentage similar to that of avocado in its natural state . since the treatment , which is described below , prevents that nutrients contained in avocado from being lost , this was confirmed using scientific methods . the technique that was used for protein determination was the kjeldahl method , to determine the fat content in avocado the soxhlet extraction method was used , moisture was determined using the gravimetric technique of constant weight , the amount of fiber present was determined by the crude fiber method . the powdered avocado is obtained by a process consisting of the following steps : i . avocado selection , in this step the fruits are separated depending on the industrial application pretended for avocado powder , if it is pretended for the cosmetic industry , the fruit should have a high content of fat , which is determined by performing bromatological analysis to the different avocado varieties , in addition to discarding any fruit which is damaged . the selected fruit for processing should be a ripe fruit , free of diseases and / or pests typical of avocado , because if the avocado is not ripe the flavor of the paste changes . ii . removal of pit and hull from avocado flesh , which can be done manually , or by means of automatic equipment depending on the scale in which the work is carried out . this process step is performed in order to conditioning or preparing the fruit for the next process step . iii . milling of the avocado pulp , which can be manually or automatically depending on the scale in which the work is carried out . in this step , as a result , a paste having a density of 904 g / cm 3 is obtained , with a green color that is identical to the color of natural avocado . this step is performed in order to conditioning the avocado pulp and to increase both the mass transfer area , and the heat transfer area , and in this way to obtain more efficient results , and in a lower cost en steps v and vi of the process . iv . application of avocado paste to the dehydrator vessels . the paste obtained in step iii is placed in the dehydrator vessels , taking care that the paste does not exceed a 2 centimeters thickness . this is to ensure that dehydration will be uniform throughout the paste . the time used to perform steps iii and iv should be short , e . g . less than 30 min , because if the exposition time of the avocado paste to environment increases , the paste begins to oxidize due to contact with oxygen and light . the time used in steps iii and iv could be increased to more than 2 hours if additives such as antioxidants such as : ascorbic acid , sodium ascorbate ( 0 . 01 ), citric acid ( 0 . 01 to 1 . 5 %) are added , but our goal is to obtain a natural product ; another way to reduce oxidation of the paste is performing step iii in cold conditions at temperatures from 1 ° c . to 5 ° c . v . cooling prior to dehydration , in this step a refrigeration chamber is used which must meet the requirements of temperature needed such that a proper previous cooling can be carried out . said cooling can be effected in two ways : by means of fast cooling , with liquid nitrogen , or a freezing mixture consisting of dry ice and ethanol , for 2 to 5 minutes ; or otherwise , by means of a slow cooling in a refrigeration chamber ( 1 ° c . to 5 ° for a minimum of 1 hr ): during fast cooling small ice crystals are formed within the avocado pulp matrix whereas during slow cooling large ice crystals are formed in the avocado pulp matrix . in our experiment , we use both cooling methods and we achieved excellent results . the pre - cooling should have a minimum duration that ensures water solidification , that is crystal formation from water contained in the avocado paste at a temperature that prevents the formation of eutectics which are detrimental to the process , during this period of time , the vessels should be rotated continuously in order to ensure a uniform cooling . in this step the enzymatic activity is inhibited by virtue of the low temperatures that are used , preventing , therefore , the oxidation of the avocado paste . vi . avocado paste dehydration . this step relies on the principle of sublimation , that is , having the water passing from solid state to vapor state without passing through the liquid phase , this is achieved working with low pressures and low temperatures . this kind of dehydration is carried out in a freeze dryer that works under the principle of sublimation . the vessels containing the avocado paste are placed in the dryer . during dehydration the parameters to be controlled are ; a vacuum pressure lower than atmospheric from between 450 × 10 − 3 to 50 × 10 − 3 in the freeze dryer vacuum chamber , a freeze dryer condenser temperature of − 40 ° c . as minimum . an additional parameter to be controlled is heat applied to the avocado paste - containing vessels which should be kept at a temperature close to ambient temperature , because if said temperature is lower than 20 ° c ., more time will be needed to sublimate all of the ice present in the avocado paste , if the temperature applied to the vessels containing the avocado paste is greater than 35 ° c ., the avocado &# 39 ; s nutritional and organoleptic properties are affected by the applied heat , greater then 35 ° c . the dwelling time of the avocado paste in the freeze dryer was from 1 hr to 10 hrs . said time depends on the parameters which are employed . all parameters mentioned in this step should be strictly controlled to achieve a successful dehydration . finally a porous solid having a color identical to that of avocado is obtained , with a moisture content lower than 1 %, having odor and flavor typical of avocado , and retaining the nutrients contained in avocado . the freeze drying method is used for food stuffs that are degradable o that experiences changes in their structure , texture , appearance or flavor as consequence from the high temperatures employed in the conventional drying methods , therefore , the present method was used to dehydrate avocado . in the experiments , the drying time was in different time intervals . all the obtained samples were analyzed for its nutrimental components , confirming that regardless of time the nutrients are conserved in avocado powder . said stability can be seen in the following tables ( 1 , 2 , 3 , 4 , 5 ). all the results from tables ( 1 , 2 , 3 , 4 , 5 ) are on a dry basis , these tables come from experimentation on drying which was performed in triplicate as well as the bromatological analysis . vii . finally , the dehydrated avocado is removed from the containers , pulverized and packaged . this packing should be in oxygen and light - impervious containers to avoid discoloration and rancidity of fats from avocado . the packing should be carried out in a controlled atmosphere and not under vacuum . once the above described method concludes , an amount of powdered avocado from between 30 % to 35 % relative to the mass of avocado applied is obtained ; said percentage will depend on the type of avocado which is used and on the duration of dehydration . powdered avocado allows for a reduction in transportation cost , and in storage space costs since that a lesser amount of space and power is required to store the avocado powder due to it does not contain water anymore and it does not need refrigeration , and the residence time or shelf life of powdered avocado is extended , at least 1 year , the latter due to the fact that the percentage of water in powdered avocado is less than 1 %, thereby preventing the proliferation of microorganisms ( due to the low water activity ). the avocado powder can be used in the food industry for human consumption , as raw material for the making of other food products , such as creams , shakes , ice cream base , mousse , buttermilks , jams , milk shakes , guacamoles , in the form of deep , sauces . also as a raw material in textile industry from the pigment , that is , the natural colorant obtained from powdered avocado , in the cosmetics industry as raw material using the oil contained in the avocado powder for the making of creams , exfoliating creams , shampoo , baby oil , perfumes , and in pharmaceutical industry in the extraction of active ingredients since it does not contain any additive that modifies its characteristics . to the product obtained by the present process , certain type of additive can be added , that is , it can be fortified , with vitamins , minerals , proteins , antioxidants , preservers , thickeners , colorants or any other chemical that is added to the final product . meaning that this powdered avocado is a natural product , however , the powdered avocado is ready to be added with nutritive substances based on the requirements of the companies from the food industry , which requires so . during the process of production of powdered avocado , the step of dehydration using the freeze dryer is a crucial step , the optimal dehydration times varying from 4 hrs to 6 hrs , for several reasons : first , after 6 hrs of dehydration the product becomes highly hygroscopic causing that more energy than necessary should be expended and that after the drying process this removed moisture would be recovered by the product , if left from 1 to 3 hrs , more heat will need to be applied , that is , greater than 35 ° c . which will cause damage to the nutrients and characteristic compounds from avocado .

US-81681206-A

a medical appliance disposal container is disclosed having at least one opening for insertion of medical appliances , the opening being covered by at least one slotted plastic membrane for insertion of the desired medical appliance into the disposal container . in at least one of the openings at the end of the slot is a bending means whereby needles may be bent while attached to a syringe and the bent needle - syringe assembly inserted through the slot into the disposal container . in another embodiment , laminated plastic screens can be color - coded to aid in sorting and counting of medical appliances , such as scalpel blades , following surgery . the disposal container of this invention provides for the direct intact disposal of a wide variety of medical appliances while providing an inexpensive container for placement at a large number of locations throughout a health care facilty . the medical appliance disposal container disclosed reduces the risk of contents spillage should the container be upset during use .

fig1 shows medical appliance disposal container 10 with an enclosed body portion of side walls 11 , bottom 12 , and top 13 . it is apparent that the container top may be of separate construction or may be part of the body construction . top 13 has container opening 14 of sufficient size for insertion of a needle - syringe assembly therethrough into the inside of the container . in association with and of the same general size as container opening 14 , is syringe disposal opening 21 in bending means plate 17 . as best seen in fig3 syringe disposal opening 21 is covered or spanned by at least one plastic membrane 15 . plastic membrane 15 has slot 16 of sufficient size to permit insertion of the desired medical appliance into disposal container 10 . slot 16 extends substantially to the end of bending means guide slot 18 in bending means plate 17 . at the end of bending means guide slot 18 is bending means orifice 19 wherein a needle mounted on a syringe may be readily bent , prohibiting further use . it is thus seen from fig1 and 3 that the needle of an intact needle - syringe assembly may be inserted through slot 16 , moved along guide slot 18 to bending orifice 19 , easily bent , moved back out of guide slot 18 and the entire needle and syringe , while still assembled , deposited into the disposal container through slot 16 . in a similar fashion , a bending plate may have the configuration as shown in fig4 wherein the bending means orifice 19 has a bending orifice ferrule 20 extending therefrom to provide yet easier bending of the needle and to make possible the use of thinner and less stiff material for bending plate 17 . in another embodiment of this invention , medical appliance disposal container 10 may be a molded plastic container such as shown in fig5 having side walls 11 , bottom 12 and separate top 13 . in the embodiment as shown in fig5 it is readily seen that top 13 is covered by bending means plate 17 with syringe disposal opening 21 , bending means guide slot 18 , and bending means orifice 19 , all covered by membrane 15 having slot 16 extending the length of the guide slot to the bending orifice 19 . again , any medical appliance which will fit through slot 16 may be placed in disposal container 10 and needles of needle - syringe assemblies may be inserted into slot 16 to about half their length , moved along guide slot 18 to bending orifice 20 where the needle is readily bent , and the assembly moved back along slot 16 with the needle being below membrane 15 to the central portion of syringe disposal opening 21 where the syringe body may be inserted into disposal container 10 . fig2 shows the layout of a collapsible container according to one embodiment of this invention which provides a full liner for the container . the collapsible container shown collapsed in fig2 has the assembled shape of the container shown in fig1 with side walls 11 , bottom 12 and top 13 , side wall liners 11a , bottom liner 12a and two top liners 13a . in a collapsible container of this type which may be readily and cheaply constructed of cardboard , bending means plate may be aligned with container opening 14 and sandwiched between top panel 13 and liner panel 13a , or between the liner panels , preferably with adhesive means to retain the bender plate in alignment with top hole 14 . medical appliance disposal container 10 shown in fig1 in addition to the syringe needle bending opening and syringe disposal opening previously described also has medical appliance insertion openings 30 . the medical appliance insertion openings 30 may be of any suitable shape to receive particular medical appliances . the medical appliance insertion openings 30 , like syringe disposal opening 21 , have a slotted plastic membrane covering the opening with the slot being of sufficient size to permit insertion of the desired medical appliance into the disposal container . for different medical appliances , it is convenient to have rows of openings 30 for each type of medical appliance . further , it is particularly desirable to have the plastic membranes covering the medical appliance insertion openings 30 color - coded so that the membrane at each opening will indicate disposal of a medical appliance through that opening providing accurate count of appliances used and disposed of as will be further discussed below . from the above general description of the medical appliance disposal container of this invention , it is apparent that a wide variety of shapes and sizes of containers may be used to fit a wide variety of specific use situations . for example , a disposal container as shown in fig1 and 2 may be fabricated from inexpensive cardboard in appropriate sizes to accommodate use in private hospital rooms , large wards , nursing stations , and specific treatment or operating rooms , as well as emergency vehicles , ambulances , and the like . the cardboard container may be coated on its interior with an absorbent material to absorb liquids or it may be coated on its interior with an absorbent resistant material to prevent liquid of liquids . likewise , the exterior may be coated with a plastic to prevent liquid absorption and to provide easy and effective cleaning . it is readily seen that synthetic polymeric sheet material of sufficient stiffness may be substituted for cardboard in the disposal box shown in fig1 . currently available blow molded plastic containers such as bottles having the shape generally shown in fig5 may also be used instances where the disposal container needs to be liquid - proof . use of the plastic bottle - type disposal container as shown generally in fig5 permits utilization of a wide number of different disposal openings by simply providing different inserts for seating beneath cap 13 . bending means plate 17 is used in connection with container openings 14 through which it is desired to dispose of needle - syringe assemblies . as described above , the bending plate provides bending orifice 19 for bending the needle while attached to the syringe and syringe disposal opening 21 of sufficient size to permit passage of the syringe body therethrough . there are many shapes and sizes of bending plates which would be suitable for use with the disposal containers of this invention as is readily apparent to one skilled in the art upon reading this disclosure . generally , for durability , it is desirable that the bending plate be of a metallic material , but synthetic polymeric materials may also be used , particularly glass fiber reinforced sheet materials , such as glass reinforced nylon or durable plastics such as lexan , a polycarbonate . for thinner bending plates and for bending plates constructed of materials which are less durable , it is preferable to provide bending orifice ferrule 20 , as shown in fig4 of metal to provide a durable bending orifice permitting direct one - handed bending and disposal of a needle - syringe assembly . also , as shown in fig4 the bending means plate may have multiple bending orifices each with their appropriate guide slot for reception of different size or different types of needles . syringe disposal opening 21 is completely covered by at least one slotted plastic membrane . plastic membrane 15 preferably has a single slot 16 which extends substantially across bending means opening 21 , along bending means guide slot 18 and bending orifice 19 . plastic membrane 15 is preferably sheet reticulated synthetic polymeric foam of a type which returns to its original condition following spreading of slot 16 upon insertion of a medical appliance . suitable such films include reticulated polyurethane foam and polyvinylchloride . multiple layers of spaced plastic membranes may be used , such as one or each side of a bending means plate or attached to container opening 14 and different top liners 13a as shown most clearly in fig2 . multiple membranes , such as two or three , assure closure of the membrane following insertion of the medical applicance therethrough and provide additional strength to the open enclosure when the disposal container may be accidentally turned upside down . the single slot 16 also aids in retention of medical appliances within the disposal container when it is turned upside down . the surface of plastic membrane 15 facing the exterior of the disposal container may be a laminated smooth polymeric film for ease of cleaning . medical appliance insertion openings 30 , used for medical appliances other than needle - syringe assemblies , may be constructed in the same fashion as described above except that the disposal opening need not provide the bending means guide slot 17 and bending means orifice 19 . a bending means plate 17 is not necessary for such insertion openings . the plastic membrane may be constructed in a similar fashion and adhered directly to the bottom of container top 13 or preferably between top 13 and top liner 13a or between two layers of top liner 13a . medical appliance insertion openings 30 , of suitable shape for particular medical appliances , may be arranged in convenient rows for each type of medical appliance and slot 16 may be covered with a thin colored layer of sheet material which must be broken for insertion of the medical appliance and thus using a different hole for each medical appliance , the number of specific medical appliances inserted into the disposal container may be readily ascertained , as is necessary in various medical practices , such as insertion of scalpels from an operating procedure . it is also apparent that the opening or openings for disposal of medical appliances may also be located in the upper portion of the sides of the disposal container . a suitable durable adhesive coated seal may be provided on the side or top of the disposal container for fully covering the openings in the top of the container for disposal of the complete container containing the disposed medical appliances . any suitable means may be used to cover the container openings and the medical appliance disposal container then safely disposed of in accordance with recommended procedures , depending upon its contents . contagious medical waste may be disposed of in containers according to this invention which can be autoclaved as required prior to final disposal . an improved medical appliance disposal container has been described which protects health service personnel from needle puncture wounds , the most prevalent hospital accident . further , the disposal container of this invention provides direct intact disposal of a wide variety of medical appliances ; renders needles inoperable ; reduces risk of contents spillage ; and provides an inexpensive disposal container for wide usage in the health care industry . while in the foregoing specification this invention has been described in relation to certain preferred embodiments thereof , and many details have been set forth for purpose of illustration , it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention .

US-35495182-A

the instant invention is a beverage container having a primary purpose of lowering the temperature of a beverage directly before consumption . the device is used in combination with a conventional beverage cup defined by an outer sleeve which operates in association with the beverage cup to form a passageway for the convection of heat to lower the temperature of beverage passing through the passageway . in operation the beverage cup is placed in an inverted sealed position thereby maintaining the beverage in a hot or cold serving temperature for a longer period of time . the passageway further prevents spills and lessens the possibility of skin burning by limiting the amount of beverage that can be spilled as well as providing a radiant cooling affect for lowering of beverage temperature . a lid is further provided for concealing the beverage cup and sleeve formed passageway providing a free air space for uninhibited beverage consumption .

although the invention is to be described in terms of a particular embodiment it will be readily apparent to those skilled in this art that various modifications , rearrangements and substitutions can be made without departing from the spirit of the invention . the scope of the invention is defined by the claims appended hereto . fig1 is a pictorial view of the instant invention 10 consisting of an outer sleeve 12 which conceals a conventional beverage cup , having a sidewall surface area 14 including a spiral shaped indentation extending from a bottom surface 16 to a removable lid 18 . the lid 18 includes a perimeter edge 20 available for coupling to an upper rim of said outer sleeve 12 and includes a provision for accessing fluid beneath the lid 18 through use of drinking aperture disposed beneath lift tab 22 . vent 24 allows air displacement as necessary . the outer sleeve 12 and lid 18 can be constructed from a nominal sidewall of reusable plastic , or disposable styrofoam and / or paper . spiral shaped indentation 14 may be v - shaped or have a square configuration with a primary purpose of providing sufficient surface area for the dissipation of heat through said sidewall . now referring to fig2 shown is a cross - sectional side view of the invention wherein the outer sleeve 12 with the spiral sidewall 14 is shown winding a fluid passageway 26 from an inner surface 28 along the lower end 16 of the outer sleeve 12 allowing beverage fluid 200 to equalize in depth by allowing fluid to flow into passageway 26 along opening 30 . conventional cup 32 is shown in an inverted position having continuous side wall 34 and end wall 36 . cup 32 may be formed from paper , styrofoam , plastic , ceramic , or the like material capable of holding extremely hot or cold beverages . when cup 32 is placed in an inverted position , the beverage 200 is allowed to flow against the inner side wall 28 of the end 16 for entrance into aperture passageway 26 along opening 30 . lid 18 is depicted locked onto the free end 40 of the sleeve 12 assimilating a conventional beverage cup with a spill resistant lid . as shown in fig3 in operation when the device 10 is tilted , the beverage 200 is inhibited from flowing out of end 36 of the inner cup 32 and is forced to travel through passageway 26 into opening 42 where it may be consumed through the opening 44 located beneath the lid 22 . in this embodiment the cup 32 utilizes the inner surface area side wall 46 to originally hold the beverage and when placed in a inverted position operates to confine the beverage 200 within the side wall 46 . the bottom wall 36 now operates as a top wall to maintain heat from escaping thus maintaining the beverage in a hot or cold state for a lower period of time than what is possible with an open beverage . it is further noted that cola &# 39 ; s retain their carbonation for the gas cannot escape through the inverted wall . for this reason the device 10 may also be used as a cold thermos wherein the beverage 200 can be maintained in a cool condition by the same principles as previously described . in addition , ice cubes are maintained along the top surface thereby not impeding flow into the passageway 26 . this is especially beneficial to young children as an ice cube cannot flow through the passageway 26 thus preventing lodgement into a child &# 39 ; s throat . the passageway 26 is thus formed by an outer surface 48 of the side wall 34 against an inner surface 50 of said sleeve . the free space 42 allows sufficient area between the bottom surface 52 of end 36 and the inner surface 54 of lid 18 . in operation , the consumer is only able to consume as much fluid as found in the free space 42 and fluidly communicated passageway 26 . this does not inhibit normal drinking practices but will inhibit an attempt to chug the entire beverage at one setting . the container 10 must be placed back into an upright position allowing the beverage 200 to refill the passageway 26 by displacing with air for subsequent tilting and consumption . this limited amount of fluid prevents a large spill of the beverage should the device be tipped even if the lid 18 is not in use . for instance , if the device is dropped , the only amount of beverage that can spill is that located in the free space 42 and adjoining fluidly communicated passageway 26 . similarly , if the lid 18 is maintained in place and only the lift tab 22 is open , should the beverage be dropped then the amount of spillage is dependent upon the positioning of the opening 44 . if the opening 44 is in an upright position then no fluid would escape , should the opening 44 be at a ninety degree angle relative to a horizontal plane then again no spillage would be predicted as the opening 26 and free space 42 should be sufficient to hold the beverage in position . if the opening 44 is closest to the surface in a horizontal plane then the amount of fluid leakage is limited to that found in the free space 42 and passageway 26 as the beverage within the inner cup 32 cannot flow through the passageway as some of the spiral passageway is at a position higher than the fluid level . in this embodiment inner surface 48 and outer surface 50 fictionally engage each other to prevent the cup 32 from movement along the surface of said sleeve . the upper edge 56 of the now inverted cup 32 may be positioned by the use of a positioning mound , not shown , which would prevent the upper edge 56 from contacting the inner surface 28 of the bottom 16 . as previously noted , the opening to the passageway 26 is depicted by numeral 30 and extends to the inner surface 28 of the bottom wall 16 making it difficult to completely seal under normal conditions . in operation the cup 32 need only be inserted partially into the outer sleeve 12 providing sufficient free air space 42 as shown by way of illustration . now referring in general to fig4 and 5 shown is an exploded view of the instant invention having a conventional cup 32 defined by an interior surface wall 46 formed by side wall 34 and bottom wall 36 . the outer surface 48 of the side wall 34 is sized to accommodate frictional engagement with the inner side wall 50 of sleeve 12 . as noted by way of illustration , the sleeve 12 has a plurality of ridges 14 placed at dissimilar positions across the circumference of the sleeve 12 which are operatively associated with the side wall surface 48 so as to perform the aforementioned passageways fluidly communicating one portion of the sleeve to be enclosed with an open portion of the sleeve which would be opened for attachment and sealing by lid 18 . lid 18 assimilates a conventional beverage cover constructed from plastic having a ventilation hole 24 and a perimeter ridge 20 available for coupling to free edge 40 of the sleeve 12 . a drinking aperture is formed with cut lines 60 and 62 allowing the drinking aperture to be exposed by lifting of tab 22 where it can be biased in a position allowing free access to the aperture along hinge line 64 or alternatively the hinge 64 can be torn from its position allowing free access to the aperture . as shown by way of illustration in fig4 the cup 34 can be used in its conventional manner with a beverage 200 placed therein . should the consumer choose to take the beverage to a location where open top cooling is not acceptable , the sleeve 12 can be placed in a position as depicted and slid over the top of the cup 34 with excess air expelled through the passageways as formed by placement of inner side wall 50 against outer side wall 48 . once the sleeve 12 has been inserted over the length of the cup 34 , the cup 34 and sleeve 12 are inverted and the end 36 of the cup 34 pushed inward approximately a quarter of an inch or as provided by a stop mechanism within the sleeve at which time the beverage is allowed to flow into the now formed passageways surrounding the cup 34 . the passageways operate to increase surface area to allow convection cooling of the beverage using ambient temperatures as well as the consumer &# 39 ; s hand further propagating the cooling of only the beverage contained within the passageways . the lid 18 is then available for placement over the open end and locked onto rim 40 . now referring to fig6 shown is an alternative embodiment 70 of the instant invention . the cross sectional view of the assembled invention shows an inverted cup 72 in the same format as previously mentioned having an outer sleeve 74 forming an interior chamber 76 with an aperture opening 78 leading into aperture passageway 80 . as previously described beverage may flow through the passageway 80 and is directed into free air space 82 through the aperture opening 84 . in this embodiment an outer sleeve 86 is positioned providing a smooth outer surface 88 wherein convection of heat is transpired through the apertures 80 through free air space apertures 90 for convection through sidewall 88 . the free air space further operates to dissipate heat and reduce condensation . the flat sidewall provides a more conventional type beverage holder and can be formed integral to the aperture formation of inner sleeve 74 . lid 92 is available for attachment to the inner sleeve 74 and / or the outer sleeve 86 . now referring to fig7 shown is still another embodiment of the instant invention having a similar array of components as previously described in fig6 with an inner cup 100 set forth in an inverted position having an interior chamber 102 fluidly communicated with aperture inlet 104 to passageway 106 which communicates to free air space 108 at aperture outlet 110 . in this embodiment the sleeve 112 which creates passageway 106 includes an outer sleeve 114 providing a secondary aperture passageway 116 . resealable opening such as tape 118 is placed beneath lid 120 allowing the consumer to insert cream , milk , or the like commonly admixed fluid into the passageway 106 . by insertion of fluid through this aperture opening 122 the fluid will flow to a pin hole orifice 124 to allow admixing of the fluid with the beverage contained in the passageway 106 . the orifice will only release fluid when the beverage is flowing past the orifice opening . it is to understood that while i have illustrated and described certain forms of my invention , it is not to be limited to the specific forms or arrangement of parts herein described and shown . it will be readily apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown in the drawings and described in the specification .

US-35644494-A

the invention concerns a composition for brightening , gloss improvement and , optionally , dyeing of human hair , in particular of permanently waved hair , which contains 0 . 5 to 12 % by weight hydrogen peroxide , and optionally , at least one direct - acting hair dye in an aqueous carrier , having a brookfield viscosity of 1 , 000 to 10 , 000 mpa . s at 25 ° c .

the following examples illustrate the invention and its effects in detail . ______________________________________cetylstearyl alcohol 3 . 0 (% by weight ) sodium cetylstearyl sulfate 0 . 3stearic acid monoethanolamide 0 . 5coconut fatty acid monoethanolamide 0 . 6coconut fatty acid monoethanolamide , 0 . 2ethoxylated with 4 moles eohydroxyethyl cellulose 0 . 2sodium lauryl sulfate 0 . 2chelating agent 0 . 1ammonium chloride 0 . 1ascorbic acid 0 . 1horse chestnut extract 0 . 2wheat protein hydrolyzate 0 . 2perfume 0 . 2hydrogen peroxide 4 . 0water @ 100 . 0ph - value : 4 . 5viscosity at 25 ° c . : 2000 mpa . s ( measured in a brookfield viscosimeter rvt with spindle no . 4at 20 rpm . ) ______________________________________ composition i was applied on a moistened dark - brown strand of human hair and was rinsed out and dried after 30 minutes . in a comparative test , an identical strand of hair was treated with an identical composition , which did not contain any hydroxyethyl cellulose and only had a viscosity of 250 mpa . s at 25 ° c . composition i , which contained in addition 0 . 1 % by weight of the direct hair dye disperse violet 4 ( with removal of 0 . 1 % by weight of water ), was applied in the half - side test to one half of permanently waved hair having a greyish color which had been pre - fixed with a conventional 6 % hydrogen peroxide solution . the other half was treated with an identical composition , whose viscosity however had been adjusted to 100 mpa . s at 25 ° c . after 15 minutes , rinsing and drying results were compared on both halves . the half of the hair which was treated with the inventive composition showed a glossy silver coloring , whereas the comparison composition led to a grey color showing no lustre . a mixture of direct hair dyes was added to composition i , with a corresponding reduction of the share of water : ______________________________________basic blue 99 0 . 01 (% by weight ) basic brown 16 0 . 02basic brown 17 0 . 03basic yellow 57 0 . 04______________________________________ this composition was applied in the half - side test to moist , medium blonde hair ; an identical composition with a viscosity adjusted to & lt ; 100 mpa . s at 25 ° c . was applied to the other half of this hair . after 15 minutes , the hair was rinsed , dried and the appearance of the two halves of the hair was compared . whereas the half of the hair treated with the inventive composition i had a bright and glossy , gold - yellow coloring , the half with the comparison composition showed a dull blond tone . in a further half - side test , one half of the hair of a test person with medium brown hair was treated with composition i , which contained the following combination of direct hair dyes : ______________________________________basic blue 99 0 . 12 (% by weight ) basic brown 16 0 . 17basic brown 17 0 . 07hc yellow 5 0 . 12hc red 3 0 . 20 ( weight - balanced by reduction of the water content ). ______________________________________ the other hair half was treated with an identical composition which , however , had a reduced viscosity of 100 mpa . s at 25 ° c . the comparison of the two halves of the hair showed after 20 minutes of treatment and subsequent rinsing and drying for the hair half treated with the inventive composition a glossy , strong red - brown coloring , whereas the hair - half treated with the low viscosity composition only had a dull , reddish - brown color tone . ______________________________________hydrogen peroxide 2 . 2 (% by weight ) hydroxypropyl trimonium guar 1 . 2polyethylene glycol 10 000 6 . 0polypropylene glycol - 30 / 1 . 0polyethylene glycol - 150wheat protein hydrolysate 0 . 3potassium sorbate 0 . 1water @ 100 . 0viscosity at 25 ° c . ( brookfield rvt , spindle 4 at 20 rpm ): 3500 mpa . sph - value : 6 . 8______________________________________ this composition was applied on a moistened strand of medium brown human hair , which was rinsed and dried after 20 minutes of treatment . a glossy light brown color was obtained ; the hair had good combability , volume and resilience . an identical composition , which only had a viscosity of 10 mpa . s at 25 ° c . by the omission of the thickening agent , effected after the same treatment in an unchanged dull brown color , the combability , volume and elasticity were significantly lower than that of the strands treated with the inventive compisition . in a further half - side test the medium blonde hair of a test subject was divided into two halves , curled , subjected to a normal permanent wave treatment , and rinsed . one half was treated with a fixing agent of composition iii comprising : ______________________________________hydrogen peroxide 2 . 6 (% by weight ) disodium hydrogen phosphate 0 . 2polyquaternium - 10 0 . 3ethylene oxide / propylene 0 . 5oxide condensatehydrogenated polyethyleneglycol - 10 0 . 2castor oilperfume 0 . 2distearyl dimethyl ammonium chloride 0 . 4hydroxypropylmethyl cellulose 1 . 5water @ 100 . 0phosphoric acid for adjustment to ph 3 . 5viscosity at 25 ° c . ( brookfield rvt , spindle 4 at 20 rpm ): 2300 mpa . s______________________________________ the other half was treated with an identical composition , the viscosity of which , however , was only 150 mpa . s at 25 ° c . after 10 minutes and subsequent rinsing the curlers were removed , and the hair was dried . the hair half fixed with the inventive composition showed a bright gloss and better combability and was more flexible and fluffier than the hair which was fixed with the low - viscous composition .

US-92178697-A

provided are methods for the treatment of various neural disorders including non - demyelinating neural disorders , such as alzheimer &# 39 ; s disease , as well as methods for the treatment of various autoimmune or immune - mediated disorders , such as scleroderma . also provided are methods for restoring or improving one or more nerve functions , such as neural transmission , in a human with a neural disorder , such as a non - demyelinating neural disorder . each of these methods comprise the administration of a serum composition obtained from a goat after challenge with an immunogen , in particular hiv or a lysate thereof .

a goat was inoculated by intramuscular injection with lysed hiv viral cocktail and formulated with freund &# 39 ; s adjuvant . the virus was previously heat killed at 60 ° c . for 30 minutes . blood samples were drawn after an appropriate interval , such as two weeks , for initial assessment . in the optimised procedure , the goat is injected every week for four weeks , then at six weeks the animal is bled to obtain the reagent . approximately 400 cc of blood is drawn from the goat under sterile technique . the area for needle extraction is shaved and prepared with betadine . an 18 - gage needle is used to draw approximately 400 cc of blood from the animal . of note is that the animal can tolerate approximately 400 cc of blood drawn without the animal suffering any untoward effects . the animal does not have to be sacrificed . the animal can then be re - bled in approximately 10 to 14 days after it replenishes its blood volume . the presence of potentially useful antibodies was confirmed , having regard to the desired antibody activity . once the presence of such reagents was confirmed , blood was then taken from the goat at between 4 - 6 weeks . the base blood product in order to create the reagent is then centrifuged to create the serum . 300 ml of serum was then filtered to remove large clots and particulate matter . the serum was then treated with supersaturated ammonium sulphate ( 45 % solution to room temperature ), to precipitate antibodies and other material . the resulting solution was centrifuged at 5000 rpm for five minutes , after which the supernatant fluid was removed . the precipitated immunoglobulin was resuspended in phosphate - buffered saline ( pbs buffer , see sambrook et al , ‘ molecular cloning : a laboratory manual ’, 1989 ) sufficient to redissolve the precipitate . the solution was then dialysed through a membrane with a molecular weight cut off of 10 , 000 daltons . dialysis was carried out in pbs buffer , changed every four hours over a period of 24 hours . dialysis was carried out at 4 ° c . after 24 hours of dialysis the contents of the dialysis bag were emptied into a sterile beaker . the solution was adjusted such that the mass per unit volume 10 mg per ml . the dilution was carried out using pbs . the resulting solution was then filtered through a 0 . 2 micron filter into a sterile container . after filtration , the solution was aliquoted into single dosages of 1 ml and stored at 22 ° c . prior to use . the composition is referred to herein as aimspro serum . acute optic neuritis is a common manifestation of multiple sclerosis . it presents as an episode of monocular blurring of central vision , with a pronounced effect on colour discrimination . while spontaneous resolution usually follows , successive attacks may result in irreversible and often slowly progressive , visual loss 1 . no medication has been available to improve visual function in these chronically affected patients . here we present evidence of a promising approach to therapy along with electrophysiological indications of a remarkable rapidity of onset . six multiple sclerosis patients with stable visual dysfunction due to chronic optic neuropathy ( 2 males , 4 females , aged from 32 to 42 years , disease duration 8 to 16 years ) were treated with a product referred to as aimspro , which is obtained from purified goat serum as described above and in wo03 / 004049 and wo03 / 064472 . administration of the drug was 1 ml by sub - cutaneous injection , generally self - administered after the first or second dose . the frequency of administration , adjusted according to response , varied from once , to three times weekly . no patient had received the product previously , but one ( case 2 ) had been taking interferon beta - 1a ( rebif ) for nearly a year : this treatment was ceased the day prior to treatment with aimspro . recordings were carried out immediately prior to the first injection , and at approximately one hour , one week and 4 to 7 weeks thereafter . prior to treatment , all subjects described that their vision had slowly and progressively deteriorated over periods of from 3 to 14 years , and none could recall intervening periods of what may have represented acute optic neuritis . corrected distance acuity ( snellen chart ) and colour vision ( square root of total error score from the farnsworth - munsell 100 - hue test 2 ) data , acquired under standardized lighting conditions , are presented ( table ). monocular visual evoked potential ( vep ) studies were carried out on each occasion . perimetry was not performed . sub - lingual temperature was monitored and showed no significant variability , within subjects , over time . data from left and right eyes were considered to be independent for analysis and colour vision scores were treated as non - parametric for statistical purposes . comparison of pre - treatment and follow - up distance acuities showed no significant change and in only two eyes ( case 2 left eye and case 5 right eye ) was there an improvement of one line or more on the snellen chart . a repeated measures analysis of variance ( anova ) test on the colour vision scores , however , yielded f =( 2 . 16 , 23 . 73 )= 8 . 52 , p = 0 . 001 . within approximately one hour of injection , there was significant improvement in colour vision ( p = 0 . 008 , z =− 2 . 667 , wilcoxon signed ranks test ). comparison of pre - treatment and “ one week ” values showed no significant difference ( p = 0 . 055 , z =− 1 . 923 ) but comparison of pre - treatment and follow up data ( at 4 to 7 weeks ) showed significant benefit ( p = 0 . 003 , z =− 2 . 981 ). no significant side effects other than local pain and swelling at injection sites over the first two to three weeks , in three patients , were encountered . for cases 5 and 6 , vep response latencies lay towards the upper limits of normal . pre - treatment vep studies from all but one of the remaining eyes showed delay in the p100 response , consistent with demyelination within visual pathways . in only one instance ( case 4 right eye ) was no response obtainable prior to treatment and this was the only eye from the entire series to show a significant change in averaged cortical responses at any time during the observation period . this 42 year old female with secondary progressive multiple sclerosis of spinal onset in 1992 , had complained of gradually deteriorating vision since 1998 . there had been four periods of 3 to 7 days &# 39 ; duration of resolving blurring of vision between 1993 and 1997 , but there had been no more recent episodic visual features in the history . examination showed bilateral optic atrophy and marked impairment of distance and colour vision . pre - treatment full field pattern reversal vep studies at 15 : 02 hrs yielded no reproducible tracings from the right eye ( see fig1 ). a test dose of aimspro ( 0 . 1 ml ) was administered subcutaneously at 15 : 13 hrs , followed by an additional 0 . 9 ml at 15 : 25 hrs . a markedly delayed but reproducible p100 response could now be obtained at 15 : 43 hrs , at 171 ms ( see fig2 ). the scalp leads had remained attached throughout the study and test conditions , including body temperature , were monitored . while this neurophysiological finding was consistent with reversal of conduction block in severely demyelinated fibres 3 , it was not accompanied by a clinically significant improvement in acuity data . the fact that no improvement in p100 latency could be detected from any eye over the study period argues against there having been significant remyelination during this time , further but observations at perhaps 6 months would be needed to assess this adequately . in summary , non - blinded , uncontrolled observations in 6 patients with slowly progressive visual dysfunction due to optic neuritis , show a significant improvement in colour vision over the course of between 4 and 7 weeks of treatment with a novel medication , aimspro . neurophysiological data from one affected eye in a patient with a five year history of marked visual deficit are consistent with an interpretation that the drug administration caused a reversal of axonal conduction block . moreover , while this phenomenon was shown to have occurred within 30 minutes of treatment , a clinical observation by the author ( unpublished observation ) on a 38 year old female patient with a “ spinal ” relapse of relapsing remitting multiple sclerosis , suggests that “ unblocking ” may be seen within as little as ten minutes . a further clinical observation ( unpublished observation ) on a patient with 18 years of stable motor deficit following severe guillain - barré syndrome suggests that the effect may pertain to the peripheral nervous system as well . visual deficit in acute optic neuritis ( as gauged by clinical and neurophysiological examination ) is thought to reflect axonal conduction block related to local inflammatory demyelinating activity 4 , 5 , 6 , but inflammation seems unlikely to be a persisting factor in chronically affected cases such as the six patients described above . a direct effect of a component of the medication on nerve transmission is , therefore , suspected . basic neurophysiological techniques are now being harnessed with a view to clarifying the mechanism of action . aimspro is a serum product initially intended to provide high titer neutralizing antibodies for use in hiv patients . characterization of the serum has revealed a high titer of anti - hla class 2 antibodies which are able to inhibit a variety of mixed lymphocyte reactions ( unpublished observations ). as increased hla class 2 expression on brain cells and lymphocytes is recognized to be a major factor in the inflammatory process in multiple sclerosis , it was postulated that the polyclonal serum may be beneficial in multiple sclerosis and similar conditions ( for review see reference 1 ). indeed , monoclonal antibodies against hla class 2 are under development by several companies . however , the rapidity of the clinical responses seen here suggests that other mechanisms may be operating in vivo . a delay in the inactivation of sodium channels , and the blockade of potassium channels have both been shown to improve conduction in experimentally demyelinated axons 7 . alternatively , a removal of blockade of axonal sodium channels by endogenous substances such as nitric oxide may explain the rapidity of the drug effect . it is therefore possible that in addition to any effects that the serum may have in influencing immunological events , it may also affect the security of axonal conduction directly . the aimspro product may also be used for treatment of autoimmune disorders as follows . a 1 ml aliquot of serum , prepared as described , is adjusted to provide a dose of 0 . 1 mg / kg , and injected subcutaneously to a patient suffering from an autoimmune disease selected from the group comprising lupus , psoriasis , eczema , thyroiditis , and polymyositis . the product was given to a patient as follows . the male patient experienced psoriasis de nova with a first presentation which started on the hands but spread over most of lower legs and arms . the treating physician prescribed timodine , then mometasone . by the end of the month , the condition was widespread . prescribed polytar emollient and referred to consultant dermatologist who confirmed acute psoriasis , and prescribed mometasone , polytar and exorex . the treatment had little effect , with psoriasis worst on arms and legs . commenced aimspro product an day 1 , 1 ml weekly . day 5 , psoriasis started improving . day 23 , exfoliating much improved . increase in dose to 2 amps weekly . after 2 months , patient much improved , and by 3 months and 18 days , psoriasis now considered resolved , and the patient wished to stop treatment . thus given 1 amp weekly for 4 / 52 , 2 amps weekly for 12 / 52 ; in total 28 amps over 16 weeks . there were no side effects reported . 2 . farnsworth d . the farnsworth - munsell 100 - hue and dichotomous tests for color vision . j opt soc am , 33 , 568 ( 1943 ). 3 . mcdonald w i , sears t a . the effect of experimental demyelination on conduction in the central nervous system . brain 1970 ; 93 , 583 - 598 . 4 . hawkins c p , et al . duration and selectivity of blood - brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied by gadolinlum - dtpa and protein markers . brain 1990 ; 113 , 365 - 378 . 5 . katz d , taubenberger j , raine c , mcfarlin d , mcfarland h . gadolinium - enhancing lesions on magnetic resonance imaging , ann neurol 1990 ; 28 , 243 . 6 . youl b d , et al the pathophysiology of acute optic neuritis : an association of gadolinium leakage with clinical and electrophysiological deficits . brain 1991 ; 114 ; 2437 - 2450 . 7 . smith k j , mcdonald w i . the pathophysiology of ms : the mechanisms underlying the production of symptoms and the natural history of disease . philos trans r soc lond b biol sci 1999 ; 354 : 1649 - 1673 . 8 . redford e j , kapoor r and smith k j . nitric oxide donors reversibly block axonal conduction : demyelinated axons are especially susceptible . brain part 12 ( december 1997 ) 2149 - 57 .

US-201514968889-A

portable therapeutic devices and methods for employing them are provided by this invention . the devices include a flexible containment bag including a fluid chamber containing a fluid medium and a self - contained pumping means disposed within the device for causing the fluid medium to circulate within the fluid chamber to provide a therapeutic effect upon contacting the device with a patient . in preferred embodiments of this invention , integral electromagnetic transducer assemblies are employed to create a pumping action within serpentine fluid channels , and solid state heat pumps are employed to control the temperature of the fluid during therapy . the devices of this invention are ideal for treating lower back pain and post - operative conditions associated with spinal surgery , as well as veterinarian treatments .

with reference to the figures , and particularly to fig1 there is shown a preferred therapeutic pad 100 of this invention . the pad 100 includes a preferred moisture absorbent face 10 disposed to lie on the rectangularly shaped front portion of the pad 100 . the moisture absorbent face forms a comfortable surface against the skin of a patient . preferably , this absorbent face 10 contains a fabric - like covering , such as non - woven polyethylene fabric . one suitable commercial product for this application is 6725 scott ( 28 gm / yd 2 ), which can be folded around a portion of the pad and is preferably ultrasonically bonded or heat sealed together with the backing layer 11 . the non - woven fabric can include an embossed surface , and is preferably water - resistant while also being permeable to sweat or water condensation forming on the skin of the patient . the preferred non - woven fabric of this invention includes a thickness of about 1 - 5 mils . the backing layer 11 is preferably constructed of a waterproof thermoplastic film or sheet material such as polyethylene , rubber hydrochloride , vinyl , mylar , or any other suitable thermoplastic . if the therapeutic pad 100 of this invention is designed to be used for heat circulation therapy , certain heat - resistant plastics can be employed for the moisture absorbent face 10 and the backing layer 11 . these materials can contain , for example , polyester , vinyl - ester , polyetheretherketone ( peek ), and polyphenylene sulfide ( pps ), nylon and fluorocarbons , such as polytetrafluoroethylene ( ptfe ). metal foils can also be used , such as those containing aluminum or tin . the therapeutic pad 100 also preferably includes a mechanism for strapping it to a body portion of a patient . one preferred attachment means is a velcro ® strap 12 disposed through slots on either transverse end of the pad 100 . the preferred velcro ® attachment means includes a loop connector 14 and hook connector 16 which can be used over and over again , as the need arises . the device is light - weight , weighing less than about 5 pounds , and preferably less than about one pound . with reference to fig2 the control mechanism of the preferred therapeutic pad 100 of this invention will now be described . the pad 100 preferably includes at its heart , a microcontroller 24 which is used to regulate the temperature sensors 22 , solid state heat pump 26 , and circulation device 28 . the microcontroller 24 can consist of a conventional microprocessor chip of the type normally employed in memory devices and computers . a power supply 30 is also necessary . the device can be internally powered with a rechargeable battery , or externally , with an a . c . power cord . preferably , the microcontroller 24 also includes means for varying the temperature and pumping parameters , such as an external control programmer 20 . in one preferred embodiment , the microcontroller 24 includes a pin array which is exposed on the outside of the pad 100 so that the control functions can be reprogrammed easily . the preferred solid state heat pump 26 and circulation device 28 will now be described with reference to fig3 and 4 . the solid state heat pump 26 of this invention is preferably of the thermoelectrical heating / cooling variety . one such solid state device is available from iti ferrotec , chelmsford , mass . this device is a thermoelectric heating or cooling product , which , being completely solid state , has no moving parts to wear out or cause unnecessary vibration . it therefore can provide both heating or cooling ability to the medium disposed in the fluid channel 40 or 44 . this device typically has a size of about 1 . 7 inches in length by 0 . 58 inches in width by 0 . 15 inches in height , to about 1 . 56 inches in length by 1 . 56 inches in width by 0 . 15 inches in height . numerous other configurations are also possible . one or more thermoelectric devices may be placed in contact with the fluid medium , or more preferably , in contact with the channel walls 38 of the therapeutic pad 100 . they can then be electrically activated so as to produce a temperature gradient between the internal thermal spreader 34 and the external thermal spreader 35 . the internal thermal spreader 34 contacts one or more channel walls so as to collect or dissipate heat energy from the fluid medium passing within the channel 40 . the external thermal spreader 35 collects or dissipates heat energy to the environment away from the patient . an insulating laminate 36 separates the thermal spreaders 34 and 35 from each other in order to improve thermal efficiency . the device acts as a heat pump by transferring heat energy from one thermal spreader to the other . the transfer is accomplished in a non - mechanical way using known solid state technology . the direction of heat transfer is determined by electrical polarity which may be reversed to selectively reverse the direction of the heat transfer to or from the fluid medium . although thermoelectric devices , such as the described solid state heat pump are preferred , this invention contemplates the use of a resealable opening in the containment bag 101 for receiving a preheated or precooled fluid medium , for example , ice water or boiling water . in such circumstances , the heat pump can be eliminated from the device , and the medium can be employed for as long as it takes it to reach room temperature , and then it could be replaced . moreover , other heating devices can be employed , such as resistive heating elements , or the like , instead of a heat pump . with reference to fig4 the preferred circulation device 28 will now be described . this circulation device 28 desirably includes an electromagnetic transducer assembly 48 coupled to the back channel wall 38 of the therapeutic pad 100 . the electromagnetic transducer assembly 48 includes a coil and magnetic assembly 51 , a diaphragm 50 , and a support 49 . the support 49 carl have a magnet attached to it which is held at a fixed distance away from the channel wall 38 . the coil is preferably attached to the diaphragm 50 so that it may move freely about the magnet . the diaphragm 50 transmits a motion of the coil about the magnet to the channel wall 38 creating a pumping action . the pumping action forces fluid from the pumping chamber 47 and over the downstream flow direction control valve 46 . the upstream flow direction control valve 43 is forced closed by reverse pressure acting upon it . the continuous pumping action of the diaphragm 50 effectively forces fluid consecutively through subsequent chambers in a circulating motion -- the flow of which is directly proportional to the frequency of the diaphragm pumping action created by the electrical signal driving the coil and magnet assembly 51 . although the preferred circulation device comprises an electromagnetic transducer pump , a microelectric motor , impeller system 55 , shown in fig6 or equivalent device , could be similarly employed to circulate the fluid medium throughout the operative fluid channels 54 . a series of circulation devices 28 and solid state heat pumps 26 of this invention can be disposed along the perimeter of the containment bag 101 as described in fig5 . the preferred containment bag 101 includes a perimeter seal 52 disposed around the edge of the containment bag 101 to prevent the leakage of any fluid medium employed in the therapeutic pad 100 . preferably , the solid state heat pumps 26 and circulation devices 28 are alternatively spaced so as to provide uniform heating and pumping of the fluid medium during use . the preferred operative fluid channels 54 can take on any uniform , continuous configuration , such as a serpentine rectangular shape , or a swirling circular shape . of course , if sufficient turbulence or fluid flow can be derived , for example , by the use of an impeller , the individual channel arrangement can be eliminated entirely , in favor of an open containment area , such as that usually employed in ice packs and the like . the fluid medium of this invention can contain any liquid or gaseous medium that is sufficient to retain and transfer a therapeutic temperature , either above or below body temperature . suitable fluid media include anti - freezes , such as methanol , denatured ethanol , glycerol , and ethylene glycol . these anti - freezes can be admixed with water to form a solution or used in their pure state . anti - freeze formulations should be capable of efficient heat - transfer , anti - boiling , and freeze - depressing characteristics . from the foregoing , it can be realized that this invention provides therapeutic pads that are both light - weight and self - contained . the pads of this invention are relatively portable , and can be used more discretely and conveniently than recirculation devices that employ large cumbersome pumping mechanisms . although various embodiments have been illustrated , this was for the purpose of describing , and not limiting the invention . various modifications , which will become apparent to one skilled in the art , are within the scope of this invention described in the attached claims .

US-39881695-A

a convertible seat - bed includes a pair of plates pivotally connected to the seat support and back support of the seat - bed . an arm is pivotally connected between the pivot plates and acts as a control link .

the preferred embodiment herein described is not intended to be exhausitve or to limit the invention to the precise form disclosed . it is chosen and described to explain the principles of the invention and its application and practical use to thereby enable others skilled in the art to utilize the invention . the seat - bed 10 shown in the drawings includes a support frame 12 which has spaced upright u - shaped supports 14 connected by a horizontal rectangular frame member 16 . frame member 16 includes a front frame part 17 , a rear frame part 19 , and side frame parts 21 . a seat support 18 carries a seat cushion 20 and is supported upon frame member 16 . a back support 22 carries a back cushion 24 as shown . seat support 18 is connected to back support 22 by a pivot mechanism 25 located at each side of the seat - bed frame 12 . each pivot mechanism 25 includes a mounting plate 26 secured to the rear of seat support 18 by bolts 29 and a mounting plate 28 secured to the lower end of back support 22 by bolts 31 . mounting plates 26 , 28 are secured to one another by pivot bolt 27 . a pivot plate 30 is connected at one end to seat support mounting plate 26 by a fastener 32 and at its other end to frame part 16 by a pivot pin 34 . a pivot plate 36 is connected at one end to back support mounting plate 28 by fastener 38 and at its other end to frame part 16 by pivot pin 40 . a pivot arm 42 is connected to pivot plate 30 between its ends by fastener 44 and to pivot plate 36 between its ends by fastener 46 . seat support 18 includes a detent part 48 . fig3 - 5 depict the conversion of seat - bed 10 from its seat position ( fig3 ) into its bed position ( fig5 ). with seat - bed 10 in the seat position of fig1 and 3 , detent part 48 compressively engages front frame member 16 to secure the seat - bed against undesired shifting of the bed into its bed position . to convert the seat - bed 10 into the bed position , a person lifts seat support 18 in the direction of arrow 50 to disengage detent part 48 from front frame member 16 . seat support 18 is then pulled forwardly of frame member 16 to cause pivot plate 30 to be shifted along arm 42 in the direction of arrow 52 ( fig3 ) until the seat - bed is in the bed position of fig5 . to return seat - bed 10 to its seat position , one simply lifts up on back support 22 to shift pivot plates 30 , 36 back to the position of fig3 . seat support 18 is then pushed downwardly until detent part 48 compressively engages frame member 16 to lock the seat support in the seat position . it is understood that the above description does not limit the invention to the precise given details but may be modified within the scope of the appended claims .

US-84775686-A

a fundus camera in which control parts of its devices are simplified , thereby ensuring improved operability . the fundus camera is provided with a monitor , an observation device , a photographing device , a storage device , a mode selection device , and an input device . the observation device photographs an image of the fundus illuminated with infrared illumination light for observation , and display the image on the monitor . the photographing device has a photoelectric photographing element and a focusing lens movable in a direction of an optical axis to focus the image of the fundus on the photoelectric photographing element , and photograph an image of the fundus illuminated with illumination light for photographing . the storage device stores the image of the fundus photographed by the photographing device . the mode selection device selects one mode from a plurality of modes including at least one of a photographing mode for photographing the image of the fundus , a playback mode for playing back and displaying the photographed image of the fundus on the monitor , and a control mode for controlling the stored image of the fundus . the input device inputs a signal specific to the selected mode .

a detailed description of preferred embodiments of a fundus camera consistent with the present invention will now be given referring to the accompanying drawings . fig1 is an external view of a fundus camera according to the present invention . fig1 a is its side view and fig1 b is its elevation as viewed from the side of an examiner . a face support unit 51 is attached to a base 50 on the side of an examinee . a mobile base 52 movable in backward / forward and right / left directions is attached on the top surface of the base 50 . a photographing part 53 containing an optical system for photographing is mounted on the mobile base 52 such that the photographing part 53 is movable in the up / down directions . a joystick 54 is provided to the mobile base 52 on the side of an examiner such that he may manipulate the joystick 54 to move the mobile base 52 in the forward / backward and right / left directions and to move the photographing part 53 in the up / down directions . a photographing switch 54 a is provided at the top of the joystick 54 . a liquid crystal color monitor 56 and a control panel part 55 are arranged on the photographing part 53 on the side of the examiner . provided on the control panel part 55 are a group of switches 60 , a ten key switch 61 , a control lever 63 used for many purposes , a rotation knob 65 a for adjusting intensity of illumination light for observation , a rotation knob 65 b for adjusting intensity of illumination light for photographing , and the like . the control lever 63 may be tilted either laterally or vertically ( including midway between the two directions ) to input control signals for each direction . in addition , it may be possible to design the control lever 63 to be tilted in eight directions . fig2 shows an optical system provided within the photographing part 53 of the present fundus camera , and the optical system comprises an illumination optical system 1 , a photographing optical system 2 , an observation optical system 3 , and a focus target projection optical system 45 . a halogen lamp 10 is an illumination light source for observation , and the light emitted from the lamp 10 is converted into infrared light by an infrared filter 11 . the infrared light then passes through a condenser lens 12 and is reflected by a half mirror 15 to illuminate a ring slit 16 . a flash lamp 13 is an illumination light source which emits visible light for photographing . the visible light emitted from the lamp 13 passes through a condenser lens 14 , is transmitted by the half mirror 15 to be synthesized coaxially with the infrared light for observation , and then illuminates the ring slit 16 . ring - slit light ( the light from the ring slit 16 ) passes through a relay lens 17 a , a mirror 18 , a black - dot plate 19 with a small black dot on its center , a beam splitter 48 , and a relay lens 17 b , and forms an intermediate image in the vicinity of an aperture of an apertured mirror 21 . the ring - slit light is then reflected by a peripheral surface of the mirror 21 to be made coaxial with an optical axis of the photographing optical system 2 . once the ring - slit light reflected by the apertured mirror 2 is converged by an objective lens 20 in the vicinity of the pupil of an eye e to be examined , the light is diffused to illuminate a fundus ef of the eye e uniformly . the visible light reflected from the fundus ef passes through the objective lens 20 , the aperture of the apertured mirror 21 , a photographing diaphragm 22 , a focusing lens 23 , an image forming lens 24 , and a dichroic mirror 25 . the visible light then enters a digital color ccd camera 26 for photographing a still - frame image , so that an image of the fundus ef is formed on a photographing surface of the camera 26 . the dichroic mirror 25 has a property of reflecting infrared light and transmitting visible light . the observation optical system 3 shares optical parts ranging from the objective lens 20 to the dichroic mirror 25 with the photographing optical system 2 , and the dichroic mirror 25 bifurcates an optical path of the infrared light . the infrared light reflected from the fundus ef by the dichroic mirror 25 passes through a relay lens 30 to be reflected by a mirror 31 . the infrared light then enters a ccd camera 32 for observation which has sensitivity to the infrared region , so that the image of the fundus ef is formed on a photographing surface of the camera 32 . it should be noted that the focusing lens 23 is movable along an optical path shared between the photographing optical system 2 and the observation optical system 3 . this accommodates a refractive error according to refractive power of the eye e . the focusing lens 23 is fixed on a rack 42 engaged with a pinion 41 fixed on a rotation shaft of a stepping motor 40 . rotation of the motor 40 moves the pinion 41 and the rack 42 , which moves the focusing lens 23 along the optical axis to bring the image of the fundus ef into focus on the photographing surfaces of the cameras 26 and 32 . the focus target projection optical system 45 comprises a target plate 47 , a led 46 emitting infrared light for illumination , and the beam splitter 48 . the target plate 47 and the led 46 are designed to be movable in synchronization with the focusing lens 23 . once the light for projecting a target from the target plate 47 is reflected by the apertured mirror 21 to form an image on a plane conjugate with the fundus ef , the light is projected onto the fundus ef via the objective lens 20 . since the image of the focus target projected onto the fundus ef is projected in infrared light , the light reflected from the image is reflected by the dichroic mirror 25 to be photographed by the camera 32 together with the image of the fundus ef . fig3 is a block diagram of a control system . the respective outputs from the cameras 32 and 26 are inputted to a main processing control part 70 connected to a monitor 56 , so that moving images to be observed from the camera 32 are displayed on the monitor 56 . a still - frame image from the camera 26 is stored in memory 71 for temporary storage included in the main processing control part 70 , and the image stored in the memory 71 is displayed on the monitor 56 . connected to the main processing control part 70 are the control switches 60 and 61 on the control panel 55 , a data storage part 72 , a drive control part 73 which controls each driving part of the optical system , and the photographing switch 54 a . the drive control part 73 receives signals for driving each of the driving parts of the optical system so as to control actuation of the motor 40 , the flash lamp 13 , and the like . next , description will now be given to operations performed in the above - described configuration . at the time of photographing , among the switches 60 , a mode switch 60 a is used to select a photographing mode . a state of operational mode in the devices is indicated on an upper left corner of the screen on the monitor 56 . when the photographing mode is selected , the halogen lamp 10 is turned on to illuminate the eye e in infrared light . an image of the eye e illuminated in infrared light is formed in the camera 32 to be displayed on the monitor 56 . an examiner observes the display on the monitor 56 and performs alignment of the photographing part 53 with respect to the eye e . besides , he makes the eye e gaze at an unillustrated fixation target to guide its line of sight . in the photographing mode , the control lever 63 is set to function as a control switch for moving the focusing lens 23 . when the control lever 63 is tilted to either the right or left , its control signals are inputted to the drive control part 73 via the main processing control part 70 . the drive control part 73 controls the actuation of the motor 40 such that the focusing lens 23 is moved toward the eye e when the control lever 63 is tilted to the left and such that the same lens is moved away from the eye e when the control lever 63 is tilted to the right . by manipulating the control lever 63 to move the focusing lens 23 , the examiner can achieve proper focus with respect to the fundus ef . a state of movement of the focusing lens 23 is indicated by an indicator 80 appearing in a lower left corner of an alignment screen displayed on the monitor 56 ( see fig3 ). the alignment performed by moving the focusing lens 23 utilizes the image of the focus target ( an image of the target plate 47 ) photographed by the camera 32 together with the image of the fundus ef . while the examiner observes on the monitor 56 the images of the fundus ef and of the focus target photographed by the camera 32 , he manipulates the control lever 63 to bring the focus target image into focus . a state of focus is detected as the examiner observes the focus target image on the monitor 56 . alternatively , it may be possible that the main processing control part 70 conducts image processing on image signals from the camera 32 so as to detect the focus target image , and that the examiner is informed of the focus state based on information about the detected image . after correct focus has been obtained on a desired part on the fundus ef to be photographed , the photographing switch 54 a is depressed to input its signals to the drive control part 73 via the main processing control part 70 . consequently , the drive control part 73 lights the flash lamp 13 to illuminate the fundus ef in visible light . the visible light reflected from the fundus ef passes through the optical path of the photographing optical system 2 , and forms an image in the camera 26 whereby an image of the fundus ef is photographed . the obtained fundus image is stored in the memory 71 for temporary storage . after the photographed image ( the fundus image ) has been obtained , the main processing control part 70 exercises control such that the photographing mode is automatically shifted to an image playback - viewing mode . as a result , the still - frame fundus image stored in the memory 71 is displayed on the monitor 56 . fig4 is an example of a screen at this point , which shows a main screen in the image playback - viewing mode . with this screen on display , the f 1 switch 60 b is depressed to shift the screen on the monitor 56 to a zoom screen in a zoom playback - viewing mode for zooming in / out on a photographed image . fig5 is an example of the zoom screen , on which the main processing control part 70 exercises control so as to bring a cursor 101 into view for specifying a reference position for zooming in / out ( i . e . a center of zoom ). with the zoom screen on display , the control lever 63 is set to function as a control switch for shifting the cursor 101 on the screen . that is , when the control lever 63 is tilted either vertically or laterally , its control signals are inputted to the main processing control part 70 , which then controls the cursor 101 such that its position displayed on the monitor 56 shifts with reference to the inputted control signals . the examiner thus specifies the reference position in the image on which to zoom in / out . next , when he depresses the f 1 switch 60 b shown in fig5 which functions as a switch for zooming in on an image in the zoom playback viewing mode , image data are computed to scale up its display at 200 percent with reference to the position of the cursor 101 . consequently , the image thus enlarged is displayed on the monitor 56 . to reduce the image having been enlarged , he depresses a f 2 switch 60 c , which functions as a switch for zooming out on an image in the zoom playback - viewing mode . this time , the image data are computed to scale down the display by one half with reference to the position of the cursor 101 . consequently , the image thus reduced is displayed on the monitor 56 . with the zoom screen on display , the mode switch 60 a is depressed to shift the screen on the monitor 56 to the main screen shown in fig4 . to save the photographed image in the data storage part 72 , with the main screen on display , a f 4 switch 60 e is depressed to call up a screen for “ save ” ( not illustrated ), where a file name in numerals is entered through a ten key , and the image data stored in the memory 71 is then saved into the data storage part 72 . fig6 is an example of a screen in an image data control mode for displaying and editing plural sets of image data stored in the data storage part 72 . the mode switch 60 a is also used to select this mode . on the monitor 56 , the screen appears with a list of id numbers and a line cursor 102 . the id numbers in a one - to - one correspondence with the sets of image data stored in the data storage part 72 , and the line cursor 102 is used to select any of the sets of image data . it should be noted that , in advance of photographing , a new id number and its last few digit number are entered in an id number entry screen , so that these numbers are stored and controlled associated with the corresponding photographed image . in addition , while the screen display is in this mode , the control lever 63 functions as a control switch to input signals for control information , for example , selecting a set of data on an image to be played back , or a screen jump . when the control lever 63 is tilted either up or down , control signals for the direction are inputted to the main processing control unit 70 so as to control the cursor 102 to be shifted up and down on the id list of the image data according to the direction in which the lever 63 is tilted . after one of the sets of the image data has been selected by shifting the cursor 102 , the selected image is loaded from the data storage part 72 by depressing the f 1 switch 60 b . the main processing control part 70 then exercises control to shift the screen display on the monitor 56 to display a played back image so that the loaded image is displayed thereon ( not illustrated ). the screen for image playback may be shifted to the screen for zoom display by depressing the f 1 switch 60 b as is in fig4 . in the image data control mode shown in fig6 the control lever 63 is tilted to the right to put the list of the image data forward by one screen , and the same lever is tilted to the left to put the same list backward by one screen . this step allows the examiner to select a screen of the list containing desired image data . as described up to this point , according to the present embodiment , a signal from the control lever 63 in the photographing mode is intended as a signal for moving the focusing lens 23 . however , the control lever 63 may be intended to function for adjusting the intensity of light from the halogen lamp 10 for observation , or from the flash lamp 13 for photographing , or from both . since the control lever 63 is capable of receiving control signals for the four directions of up / down and right / left , for example , the right / left directions may be intended to adjust the intensity of light for observation , and the up / down directions may be intended to adjust the intensity of light for photographing . the light intensity of each light source is controlled by the drive control part 73 . in addition , in the image playback - viewing mode , the control lever 63 may be used zoom in / out on a photographed image . instead of the control lever , it may be possible to use another signal input means such as a track boll or a switch . moreover , a plurality of monitors may be provided to display an observed image , a photographed image , a control screen , and the like individually thereon . having fully been described , according to the present invention , the control parts of the devices may be simplified , thereby ensuring improved operability . the foregoing description of the preferred embodiments of the invention has been presented for purposes of illustration and description . it is not intended to be exhaustive or to limit the invention to the precise form disclosed , and modifications and variations are possible in the light of the above teachings or may be acquired from practice of the invention . the embodiments chosen and described in order to explain the principles of the invention and its practical application to enable one skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated . it is intended that the scope of the invention be defined by the claims appended hereto , and their equivalents .

US-98287601-A

a mask and harness system for use in providing breathing oxygen and protection from pollutants for the eyes and respiratory system as might be encountered in high altitude aviation environments . in one preferred embodiment , the mask system has a face seal , a soft flexible lens , a pneumatically - actuated harness , and a regulator with microphone to control the flow of oxygen and to facilitate communications in aircraft flight decks and other aircraft compartments . the system is designed for required five - second donning with one hand and because of the flexible lens , is capable of storage in the relatively preferred on crowded flight decks . it is connected to an oxygen source and , optionally , with aircraft communications . the regulator controls the flow rate of oxygen to the wearer based on altitude and physiological requirements . the regulator includes a valve for purging the condensation - prone moist gases from the lens area and provides positive pressure in the mask . a second preferred embodiment molds the lens and mask seal of a single material having sufficient optical quality and flexibility to accomplish both purposes .

as shown in the exemplary drawings , a first presently preferred embodiment of the present invention is embodied in a flexible , full face coverage mask for use by aircraft flight crews which includes a flexible lens sealingly molded in to the face seal . the mask also incorporates an inflatable harness which is inflated by the breathing oxygen regulated by a regulator incorporated into the face mask . the mask also provides for purging of the interior of the flexible lens by gas from the regulator in order to retard fogging and other obscuration of the view out of the lens by the wearer . the entire assembly is capable of being rolled up into a relatively small package , which facilitates its installation within the limited available space readily at hand to the seated crewmember on the flight deck . in a second presently preferred embodiment , the entire flexible mask portion , including the lens , can be formed of a single unit , either through use of an insert molded into the balance of the mask or by use of an elastomeric transparent material for the entire face mask portion of the assembly . fig1 illustrates a general arrangement of a first preferred embodiment of the present invention . the mask assembly 10 includes a face seal molding 12 formed to fit around the periphery of the face of the wearer and receive a flexible lens 14 which is bonded or inserted into the elastomeric face seal 12 . the lower forward portion of the face seal 12 incorporates a portion which includes an oxygen supply regulator assembly 16 removably attached to the lower forward portion of the mask . the regulator 16 supplies breathing oxygen to the mask wearer through ports internal to the lower forward portion of the face seal 12 , and also supplies oxygen or other breathing gas mixtures to an inflatable harness 18 connected to the breathing gas regulator and the face seal 12 via suitable gas passages and connectors in the mask . connecting straps 20 and 22 are then similarly connected at their extremities to a connector 24 which may also be adjustable to provide means to adjust for the size and comfort of the mask once inflated . a further connector 26 connects strap 20 to the inflatable portion 18 of the harness assembly . in a presently preferred embodiment , a clear flexible elastomeric lens 14 is either bonded or inserted into a receptacle in the elastomeric face seal 12 . the use of the flexible lens in concert with the elastomeric face seal of the invention serves to improve the ability of the mask to seal out toxic or vision impairing gases . these improved face sealing characteristics also improve the oxygen consumption performance of the mask , as there is less leakage over a wider variety of face configurations . the oxygen supply for the mask is provided by oxygen supply tube 28 connected to regulator 16 . in order to facilitate communication , the mask may also incorporate a microphone ( not shown ) which is connected to the aircraft communication system by electrical wiring 30 , which may be concurrently routed with oxygen supply tube 28 . certain benefits of the present invention may be better understood by reference to fig2 which illustrates the difference in size and configuration of the present invention as compared to prior art aircraft emergency crew masks incorporating rigid lens assemblies . as illustrated in the prior art , fig2 a , a mask 32 incorporating a rigid lens assembly 34 of necessity requires a fairly large enclosure 36 into which the mask must fit to account for the inflexibility of the lens , regardless of the flexibility of the balance of the mask assembly . in contrast , by use of the flexible lens , flexible face seal and inflatable harness of the present invention , as illustrated in fig2 b , the mask may be rolled so that lens 14 and face seal 12 consume a substantially smaller volume 38 as compared to prior art masks . this feature of the invention allows the mask to be mounted in a considerably smaller space within the aircraft and possibly be placed more conveniently to hand of the crewmember during times of emergency . in light of the increased complexity and sophistication of modern aircraft , and the use of fewer crewmembers compared to previous equally complex aircraft , flight deck volume has been in short supply and thus the smaller envelope of the stowed mask of the present invention represents a substantial advantage over prior art emergency crew masks . referring to fig3 fig3 a illustrates how the present invention readily adapts to faces of various sizes more easily than prior art masks . more specifically , referring to fig3 a , which illustrates both large 40 and small 42 heads which may be required to be accommodated by emergency flight crew masks assemblies , it may be seen that a conventional rigid mask lens assembly 34 incorporated into conventional mask face seal 44 cannot accommodate this range of head sizes without highly compliant seals provided at the edges of the lens and at the edges of the face seal comparing the flexibility of the present lens assembly and the face seal illustrated in phantom as 46 shows the relatively small amount of flexibility available in a prior art lens assembly to accommodate the range of head sizes desired . referring to fig3 b , it may be seen that the same head sizes 40 and 42 may be more readily accommodated by the present invention . more specifically , it can be seen that the flexible integrated mask and lens assembly 48 can deflect over a substantially greater range as illustrated in phantom by dotted lines 50 to more easily accommodate the required range of head sizes . furthermore , such accommodation is accomplished without the requirements for high compliance seals at the edges of the lens assembly in order to bridge the difference in rigidity between a rigid lens and a soft face seal , and the stresses on the seal between the lens and the face seal are substantially reduced by the increased flexibility of the lens of the present invention . because of the lens flexibility in the present invention , the entire face seal can then flex more to varying head and face sizes . another benefit of the present invention is that since the soft lens is intentionally flexed with the face seal by the combination to the face of the user in response to the inflatable harness , less face seal frame structure is needed than in hard lens designs which must include an adequate structure to support the rigid lens . fig4 is a cross sectional view of the flexible mask and lens assembly of the present invention , illustrating the ease with which the mask both accommodates to the face of the user and provides a seal with the user &# 39 ; s face . referring to fig4 which illustrates a cross sectional view of the mask assembly of the present invention on the face of the user , it can be seen that the flexible face seal portion 12 conforms closely with the face of the wearer 52 , thereby providing an excellent seal for the mask for a variety of face configurations and surfaces . flexible lens 14 is sealingly attached to face seal 12 at positions 54 , 56 , allowing face seal 12 to conform closely to the wearer &# 39 ; s face by deflecting to accommodate any of a variety of facial configurations . a nose bridge seal portion 58 is molded into the face seal 12 in order to provide a particularly compliant configuration for sealing across the nose bridge of the wearer . fig5 is an illustration of a vertical aspect illustrating the field of view of a wearer , and showing the superior accommodation of fields of view of a wearer by the present invention . the wearer 60 , whose eyeballs 62 are capable of a field of view e is ordinarily limited by the field of view of a rigid lens of the type utilized in the prior art 64 . such a rigid or semi - rigid lens , while providing good optical quality , does not allow for a broad field of view and this may have certain important limitations , particularly in the event of emergency circumstances for a flight crew in an aircraft . by contrast , the present invention lens 14 is capable of deflection over a far wider region of the wearer &# 39 ; s face while maintaining acceptable optical quality , thus allowing for a full view through the optical portion of the mask of the field of view e of the user &# 39 ; s eyes 62 . this wide field of view is further enhanced by the ability to provide a closely fitting mask on the side portions of the face by use of the flexible lens 14 and flexible face seal 12 which can conform tightly with the forward side portions of the wearer &# 39 ; s face . fig6 through 9 illustrate a variety of configurations which may be used for the inflatable harness in order to provide close fitting and comfort for the wearer of the mask of the present invention . the inflatable portion of fig6 includes both a lateral wraparound elastomeric tube 66 and a central circular elastomeric tube 68 which are connected to one another by a harness connection 70 and into the mask by adjustable straps 72 . a similar configuration is illustrated in fig7 in which a single inflatable tube 66 is configured to assume a similar shape to that of fig6 by connectors 74 , thereby gaining the benefit of a single continuous tube to be used for the inflatable harness assembly . similarly to fig6 the inflatable portion of the harness is then attached to the face seal by straps 72 . fig8 illustrates a further variation in which the inflatable assembly consists of both a top and bottom lateral tube 66 , 76 connected by a vertical tube 80 , all of which are supplied with air via the regulator in the forward portion of the mask . fig9 illustrates yet another configuration for the harness which may be advantageously used with the invention . in this embodiment elastomeric tubes 82 , 84 are attached to mask face seal 12 by connectors 86 and are held in place in the crossed position behind the wearer &# 39 ; s head by retainer 88 . a strap 90 also serves to preserve the shape of the harness during use . it is important that the lens of the present system have sufficient optical quality and resistance to abrasion and other damage to function similarly to the rigid and semi - rigid lenses of prior art masks . it is well known that a number of formulations of silicone exist that provide resistances to yellowing and other optical degradation sufficient for use in a mask which must be stored for long periods of time prior to use . one such material which should be suitable for this purpose as a lens material is general electric se6800 - d2 silicone in the “ clear ” peroxide cured molding grade . other clear , flexible plastic materials with optical transmittance in the 80 % range may also be suitable , depending on the detail design of the mask . there are also scratch resistant additives and coatings that are available for silicone formulations which enhance the ability of the lens to maintain optical quality when subject to abrasion . one such scratch resistant coating involves the coating of the lens with urethane . in a presently preferred embodiment , the invention involves the use of a urethane coated silicone lens bonded to the silicone based face seal by use of the following process . the lens is premolded out of silicone and coated with an abrasion resistive coating , such as urethane . the lens is then placed in a mold which is designed to receive the lens and mold the liquid mask material around the lens and other inserts , if any , such as the harness mounting hardware and regulator mounting assembly . the lens perimeter and mask seal is cleaned with methyl ethyl ketone and the lens with hexane . an adhesive such as 34d manufactured by synthetic surfaces , scotch plains , n . j . is then used to adhere the lens to the face seal . the mask is then cured , depending upon the requirements of the particular silicone , and the completed mask is removed from the mold . an important aspect of the invention is the ability to combine the flexibility of the mask seal and lens with the inflatable harness in order to provide previously unavailable levels of lens field of view , storability , comfort , wearability and sealing in a mask that is also providing sufficient optical quality for use under high stress conditions by flight crews . while a variety of regulators may be used , in a presently preferred embodiment , one regulator suitable for use with the mask is the puritan - bennett oxygen pressure regulator previously utilized in the puritan - bennett sweep on 2000 crew mask , available without a lens but with an inflatable harness made of silicone tubing overlaid with nomex ® braided material . this demand regulator also provide the ability to adjust the pressure in the inflatable harness , and thus the comfort of the harness , by access to a crew control knob or lever on the side of the demand regulator assembly . the demand regulator assembly also provides for a means to provide purging air to the inside of the lens assembly via suitably arranged passages in the mask . a second presently preferred embodiment addresses the desirable benefits , for cost , reliability and manufactureability reasons , to manufacture the mask as a single piece lens and face seal assembly out of transparent silicone of the type suitable for use as a flexible lens material . it has been found that such a configuration further simplifies the design of the mask by eliminating the manufacturing step of sealing the lens with the balance of the face seal , and avoiding irregularities in flexibility associated with discontinuities between materials and the transition between the lens and the face seal . similarly to the previously described embodiments , the forward lower portion of the face seal is molded to accommodate the demand flow regulator and the attach points of the inflatable harness straps to provide a complete assembly . in this alternative method of construction , the area of the mold representing the lens is finished to a sufficiently high optical accuracy for the intended purpose and the mold is configured to provide appropriate thickness to the lens area in comparison to the balance of the mask . then , an optical quality clear silicone is used to mold the mask and to thus provide an integrally formed mask and lens assembly . in a presently preferred embodiment , a general electric silicone known as 454 - 3243 ultra tufel “ water clear , fast cure can be used to mold such a mask and provide acceptable clarity , flexibility , strengths and damage resistance capabilities . from the forgoing , it will be appreciated that the crew emergency mask assembly of the present invention allows for a substantially improved field of view and stowability while still providing a comfortable and highly effective mask for use in hazardous circumstances in the flight deck of a high performance aircraft . while several forms of the invention have been illustrated and described , it will also be apparent that various modifications can be made without departing from the spirit and scope of the invention . accordingly , it is not intended that the invention be limited except as by the appended claims .

US-56001100-A

a nutritional composition comprising a partially hydrolyzed milk protein having a degree of hydrolysis between 15 and 25 % and 50 to 1000 nanograms of tgf - β per 100 ml of ready to consume composition and methods for the primary prevention of allergic reactions to newly introduced dietary protein at weaning and the prevention of development of atopic diseases in a young mammal at weaning comprising feeding to the young mammal a therapeutic amount of the composition are disclosed .

“ atopic disease ” means the clinical manifestations of allergic sensitisation and includes atopic dermatitis , atopic eczema , allergic rhinitis and asthma ; “ degree of hydrolysis ” or “ dh ” of a protein means the number of peptide bonds in the intact protein which are cleaved during the hydrolysis divided by the number of peptide bonds in the intact protein expressed as a percentage ; “ follow - on formula ” means compositions intended for use by infants aged over four months and constituting the principal liquid element in the progressively diversified diet of such infants ; “ oral tolerance ” means an active state of immunological hyporesponsiveness to antigens delivered via the oral route ; “ primary prevention of allergic reaction to a dietary protein ” means prevention of establishment of such allergic reaction and includes reduction of risk of such an allergic reaction ; “ tgf - β ” or “ transforming growth factor β designates a group of at least five distinct but closely related bioactive peptides designated tgf - β1 , tgf - β2 etc and found inter alia in human milk ( tgf - β1 and tgf - β2 ) ( li et al , transforming growth factor - β regulation of immune responses , annu . rev . immunol . 2006 24 : 99 - 146 ); “ weaning ” means the introduction into the diet of a young mammal of foods other than its mother &# 39 ; s milk or milk - based substitute such as infant formula ; “ weaning period ” means that period in the life of a young mammal starting with the introduction of foods other than its mothers milk or milk - based substitute therefore and ending with the cessation of breast feeding or administration of infant formula or follow - on formula . the invention provides a nutritional composition comprising a partially hydrolysed milk protein having a degree of hydrolysis between 15 and 25 % and 50 to 1000 nanograms of tgf - β per 100 ml of ready to consume composition . the milk protein may be whey protein , casein protein or a mixture thereof but preferably is whey protein . if whey protein is used , the degree of hydrolysis is preferably between 15 and 19 %. preferably , the partially hydrolysed milk protein has a residual antigenicity at least 100 times less than that of intact whey protein . the residual allergenicity of the partially hydrolysed milk protein may be measured by the technique described by fritsche et al ( int . arch . aller and appl imm ., 93 , 289 - 293 , 1990 ). such a partially hydrolysed milk protein and products containing it may be described as hypoallergenic in accordance with the provisions of eu directive 96 / 4 / ec . compositions according to the invention may be used in the weaning of young mammals including human infants and toddlers as well as the young of companion animals such as dogs and cats . preferably the nutritional composition of the invention is an infant formula , more preferably a follow - on formula for use by infants aged over four months . the milk protein may be hydrolysed in any suitable manner known in the art . in the case of whey protein , a suitable process is described in european patent no . 322 , 589 , the contents of which are incorporated herein by reference . if the whey fraction used as the starting material is substantially lactose free , it is found that the protein suffers much less lysine blockage during the hydrolysis and subsequent thermal processing . this enables the extent of lysine blockage to be reduced from about 15 % by weight of total lysine to less than about 10 % by weight of lysine ; for example about 7 % by weight of lysine blockage which greatly improves the nutritional quality of the protein source . the source of the whey protein may be acid whey , sweet whey , whey protein isolate or mixtures thereof . preferably , however , the protein source is based on whey protein isolate or modified sweet whey . sweet whey is a readily available by - product of cheese making and is frequently used in the manufacture of infant formulas based on cows &# 39 ; milk . however , sweet whey includes a component which is undesirably rich in threonine and poor in tryptophan called caseino - glyco - macropeptide ( cgmp ). removal of the cgmp from sweet whey results in a protein fraction with a threonine content closer to that of human milk . a process for removing cgmp from sweet whey is described in ep 880902 . if modified sweet whey or whey protein isolate is used as the protein source , it is preferably supplemented by free histidine in an amount of from 0 . 1 to 3 % by weight of the protein . an infant formula of the present invention may comprise from 1 . 0 to 2 . 0 grams of partially hydrolysed whey protein per 100 ml of ready to consume formula , more preferably from 1 . 5 to 1 . 9 g / 100 ml . a follow - on formula of the present invention contains from 50 to 1000 nanograms of tgf - β per 100 ml of ready to consume formula , more preferably from 50 to 500 nanograms per 100 ml and most preferably 200 to 300 nanograms per 100 ml . preferably , a follow - on formula of the present invention contains both tgf - β1 and tgf - β2 , more preferably in a ratio between 1 : 5 and 1 : 50 . tgf - β may be added to the formula in the form of a whey protein fraction enriched in these bioactive peptides such as tm0301 or xp - 828l from armor protéines , france or in the form of a polypeptide growth factor isolated from milk as described for example in ep 313515 or wo 92 / 00994 . alternatively , a recombinant tgf - β may be used if preferred . a follow - on formula according to the present invention may contain a carbohydrate source . any carbohydrate source conventionally found in infant formulae such as lactose , saccharose , maltodextrin , starch and mixtures thereof may be used although the preferred source of carbohydrates is lactose . preferably the carbohydrate source contributes between 35 and 65 % of the total energy of the formula . a follow - on formula according to the present invention may contain a source of lipids . the lipid source may be any lipid or fat which is suitable for use in infant formulas . preferred fat sources include palm olein , high oleic sunflower oil and high oleic safflower oil . the essential fatty acids linoleic and α - linolenic acid may also be added as may small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils . in total , the fat content is preferably such as to contribute between 30 to 55 % of the total energy of the formula . the fat source preferably has a ratio of n - 6 to n - 3 fatty acids of about 5 : 1 to about 15 : 1 ; for example about 8 : 1 to about 10 : 1 . the follow - on formula may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts . minimum requirements have been established for certain vitamins and minerals . examples of minerals , vitamins and other nutrients optionally present in the infant formula include vitamin a , vitamin b1 , vitamin b2 , vitamin b6 , vitamin b12 , vitamin e , vitamin k , vitamin c , vitamin d , folic acid , inositol , niacin , biotin , pantothenic acid , choline , calcium , phosphorous , iodine , iron , magnesium , copper , zinc , manganese , chloride , potassium , sodium , selenium , chromium , molybdenum , taurine , and l - carnitine . minerals are usually added in salt form . the presence and amounts of specific minerals and other vitamins will vary depending on the intended infant population . if necessary , the formula may contain emulsifiers and stabilisers such as soy lecithin , citric acid esters of mono - and di - glycerides , and the like . the formula may optionally contain other substances which may have a beneficial effect such as lactoferrin , nucleotides , nucleosides , and the like . finally , the formula may contain indigestible oligosaccharides such as galacto - oligosaccharides for example in an amount of from 0 . 3 to 7 %. the formula may be prepared in any suitable manner . for example , it may be prepared by blending together the partially hydrolysed milk protein , the carbohydrate source , and the fat source in appropriate proportions . if used , the emulsifiers may be included at this point . the tgf - β may also be added at this point . the vitamins and minerals may be added at this point but are usually added later to avoid thermal degradation . any lipophilic vitamins , emulsifiers and the like may be dissolved into the fat source prior to blending . water , preferably water which has been subjected to reverse osmosis , may then be mixed in to form a liquid mixture . the temperature of the water is conveniently about 50 ° c . to about 80 ° c . to aid dispersal of the ingredients . commercially available liquefiers may be used to form the liquid mixture . the liquid mixture is then homogenised ; for example in two stages . the liquid mixture may then be thermally treated to reduce bacterial loads , by rapidly heating the liquid mixture to a temperature in the range of about 80 ° c . to about 150 ° c . for about 5 seconds to about 5 minutes , for example . this may be carried out by steam injection , autoclave or by heat exchanger ; for example a plate heat exchanger . then , the liquid mixture may be cooled to about 60 ° c . to about 85 ° c . ; for example by flash cooling . the liquid mixture may then be again homogenised ; for example in two stages at about 10 mpa to about 30 mpa in the first stage and about 2 mpa to about 10 mpa in the second stage . the homogenised mixture may then be further cooled to add any heat sensitive components ; such as vitamins and minerals . the ph and solids content of the homogenised mixture are conveniently adjusted at this point . the homogenised mixture is transferred to a suitable drying apparatus such as a spray drier or freeze drier and converted to powder . the powder should have a moisture content of less than about 5 % by weight . the tgf - β may be added at this point by dry mixing if not added previously . if a liquid product is preferred , the homogenised mixture may be sterilised then aseptically filled into suitable containers . an example of the composition of a follow - on formula according to the present invention is given below . this composition is given by way of illustration only . it should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art . such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages . it is therefore intended that such changes and modifications be covered by the appended claims .

US-201313773933-A

systems and methods for providing biologically compatible pockets or envelopes that can contain chips and other circuit elements and can make electrical connection between those elements and living organisms . the assembled biologically compatible pockets and circuit components can have biomedical applications , such as bioimplantable devices such as retinal , cochlear and cortical prosthesis implants , muscular stimulators , and other uses . in various embodiments , the described technology explains how to make and use pocket systems for dealing with chips having connectors on one or two surfaces , and with other circuit components such as resistors , capacitors , inductors and transistors . operation of chips encapsulated according to the described technology is demonstrated . accelerated life testing suggests that the pocket systems described will survive for years at 37 degrees c .

in this invention , it is believed that the innovation is to use a new “ pocket ” technology to facilitate the connection and packaging of various different components for use as biomedical implants . to use the technology , pockets ( or envelopes ) having predesigned sizes to accommodate chips / components , and having pre - metalized electrical connections are made . the chips and correspondent chips / components are then inserted into the pockets with alignment so the metal pads on the pockets and the metal pads on the chips are aligned . electrical connections between the pockets and the chips / components can be made by applying conductive epoxy or other conductive polymers . these conductive epoxy / polymers can be biocompatible or not , depending on the applications . the end product , however , of this exercise is one or more well connected chips / components on a pocketed substrate or even a completely free - standing flexible substrate , e . g ., made of parylene or other polymers . in other terms , after circuitry is inserted into and connected to traces present in the pocket or envelope , the pocket or envelope is sealed closed other than at possible locations where electrical contact with a living organism or biological object needs to be made , such as a the electrically active locations on probes . in some embodiments , communication with the contents of the sealed pocket or envelope from devices external to the living organism or biological object is accomplished using electromagnetic waves using coils . communication with an implanted device can be performed using either percutaneous connectors or wireless communication methods . an advantage of a wireless communication method over a percutaneous connector is the elimination of issues relating to possible infection or irritation related to devices that perforate the skin . however , wireless communication in the vicinity of living organisms also poses problems that need to be solved , such as avoidance of local heating , potential concerns relating to subjecting a living organism to long term electromagnetic radiation , and transmission of electromagnetic signals in living media . some of the kinds of signals that are communicated between an implanted device and an external device include power signals and data signals . power signals can include signals that provide power from an external power supply to an implanted device , so that a battery present in the implanted device can be maintained in a suitable state of charge , or so that a battery can be eliminated from the implanted device . for some conventional devices having batteries , surgery may become necessary to replace the device because its battery is expected to reach the end of its useful life . any surgery poses a health risk and unnecessary surgery is best avoided if possible , especially in persons who already have health issues . accordingly , implantable devices that do not have to be replaced because of a battery are advantageous . data signals can include data signals from an external detector to an implanted device ( such as providing an electrical signal corresponding to an audible signal received by a microphone to a cochlear implant for communication by way of a person &# 39 ; s nervous system to the person &# 39 ; s brain ), control signals from an external detector to an implanted device that provide the ability to control the implanted device by using such signals ( e . g ., controlling the state of operation of the implanted device to meet the needs of the person ), and data signals from the implanted device to an external device to monitor the condition and operation of the implanted device itself , to monitor the condition of the person ( such as pulse rate , cardiac signals , or other signals relating to the condition being treated ) and conditions in the vicinity of the implanted device ( such as physiological signals , e . g ., temperature , pressure , ph ), or to monitor the signals the implanted device is applying to the person . in some embodiments , data signals can be used to “ tune ” or “ reprogram ” the implanted device to take advantage of improvements in understanding of the person &# 39 ; s condition and the intervention , assistance , or treatment that the person should have , or provide improvements in the implantable device operation and control procedures or operational software that are developed after the device is implanted . here we present a design and initial testing results from high electrode density , silicon based arrays system with an integrated parylene cable . the greatly reduced flexible rigidity of the parylene cable is believed to relief possible mechanical damages due to relative motion between a brain and its skull . regardless of the particular technology used to accomplish neural prosthesis , an ideal wired multi - electrode array would comprise ( 1 ) biocompatible materials ; ( 2 ) high density electrodes with high signal - to - noise ratio ; ( 3 ) reliable , high density cables and a percutaneous interconnect to communicate with peripherals ; and ( 4 ) ability to accommodate integrated circuitries for on - probe signal amplification . we describe a parylene coated silicon probe that has the potential to overcome the difficulties presented by the current technology . a major improvement of the current device over prior devices is the complete encapsulation of the array with parylene . the previous generation of bioimplantible prostheses consisted of a silicon substrate that was exposed on all sides except the front side , significantly reducing the biocompatibility of the device . we have chosen to use parylene c ( poly - para - xylylene c , also referred to hereinafter as “ parylene ”) due to its insulational capability , flexibility , biocompatibility , and its prior use in medical applications . furthermore , our flexible parylene - based cable has a cross section that is 500 μm wide and 15 μm thick and is designed to route the signals acquired with a 32 channel array . an important feature of our device that the cabling is not a component that is later attached to the array . rather , it is an integrated extension of the parylene structure of the array itself . the resulting manufacturing simplification is expected to significantly improve the reliability of our device . finally , this monolithically micromachined cable — probe system is able to accommodate future chip integrations through the addition or modification of the silicon pieces on the silicon probe . as a result , we are able to fabricate silicon probe devices that are highly customizable , fully biocompatible , and easy to mass fabricate . it is expected that this technology will facilitate manufacture and use of neural prosthetic systems . a flexible parylene lift - off technology allows us to fabricate 2 - d 32 channel flexible cabled electrode array devices , as illustrated in fig1 . fig3 , fig4 , fig5 , and fig6 are images that illustrate features of the silicon bioimplantible array of fig1 . fig2 shows illustrative an unpackaged cabled silicon probe and its bonding interface . these devices can be expanded to 3 - d 32n channel structures by probe stacking of n number of 2d probes , as shown in fig7 . platinum electrodes on each of the eight silicon shanks can be spaced at configurable intervals and two reference electrodes are located on two of the longer shanks . the shank lengths range from 3 mm to 12 mm and are 150 μm thick and 60 μm wide towards the tip of the shank . the tip of the shank forms a 10 degree angle to facilitate the insertion into the brain . fig2 , fig8 and fig9 show the bonding interface for connecting a cable to external connection points . in one embodiment , the circular platinum rings arranged in a 60 degree y shape pattern on the end of device are used to electrically bond to commercial available connectors with conductive epoxy on a circular pc board . the 7 cm long parylene cables are 15 μm thick and have 34 traces lines of 10 μm wide and spaced 10 μm apart connect the distal electrodes directly to external connectors , for example as shown in fig1 . the high density silicon probes are fabricated on double side polished wafers with drie ( deep reactive ion etching ) technology . fig1 shows the steps performed in carrying out the probe fabrication process . first , a layer 1104 of 0 . 5 μm of parylene c is deposited on one side of the double side polished wafer 1102 and is melted in an oven at 350 ° c . the parylene layer 1104 is then patterned by oxygen plasma to leave areas for adhesion enhancement between the parylene / silicon interface . a sacrificial photoresist layer 1106 of 1 μm thickness is then coated to facilitate the final release of the device . a layer 1108 of parylene c ( 6 . 5 μm ) is then deposited . this is followed by a layer 1110 of lift - off electron - beam evaporated platinum ( 0 . 25 μm ) to define the trace lines , the electrodes and connector pads . the top layer 1112 of parylene c ( 6 . 5 μm ) is deposited to complete the parylene - metal - parylene sandwich structure ( see fig1 ). electrode sites and the device definition are then etched by a two step rie with o 2 plasma process . silicon probe shanks ( on the right side of each panel of fig1 ) are subsequently defined and etched by drie from both sides of the wafer . the bottom drie etching duration defines the thickness of the probe . by depositing and painting protective photoresist die by die , the thickness of every probe on the wafer can be controlled very precisely . the devices are then released in photoresist stripper to provide structures as shown in fig1 , and coated on all sides with parylene 1116 . finally , the pads corresponding to the electrodes are opened and the device is annealed at 200 ° c . for two days to bond the sandwiching parylene layers . the total coating of the probe and the cable was done by covering the connector pads with hand - painted photoresist and conformal coating 1 μm of parylene c over the entire device . the device is covered with photoresist again to protect the cables and the rest of the device , leaving the silicon probe section exposed . this structure is then etched directionally with rie to re - open the parylene coated electrodes , as shown in fig5 . this device is later released in acetone and photoresist stripper solution . the silicon probe was dipped into a silicon etchant after the rie etching to test for total coating . the silicon was not etched after 1 minute of dipping , which validates the coating is still intact and thus full biocompatibility is achieved . in previous versions of the device , xef 2 was used to roughen the surface of silicon substrate to enhance the mechanical adhesion of the parylene / silicon interface . however , due to the isotropic nature of xef 2 etching of silicon , the depth , undercut and the shape of the resulting surface becomes hard to control . this may result in broken metal lines as well as thermal stress cracks on the border lines during the high temperature electron beam evaporation of platinum . the melted parylene alternative was used to enhance the adhesion of the desired area . device testing was performed in three phases : in - vitro measurements in saline solution , in - vivo probe penetration testing and accelerated life testing . in the first phase , we used the setup shown in fig1 to conduct in - vitro impedance tests with channel electrodes having mean dimensions 22 μm × 22 μm . the measured distribution of areas of these electrodes was determined to lie within ± 9 . 1 μm 2 of the nominal value under sem measurements . impedance measurements of channel electrodes resulted in values of 670 kω ± 33 kω at 1 khz whereas the reference electrodes with areas approximately 25 , 000 μm 2 resulted in impedances in the range of 20 kω . to test the electrode &# 39 ; s ability to pick up signal different signal types , sine waves and pre - recorded action potentials were applied across a saline solution and were successfully recorded with the fabricated electrodes , as illustrated in fig1 and fig1 . impedance tests were also performed on the parylene flexible cable to determine the stray capacitances . results presented in fig1 show a clear linear relationship on a log - log scale , which allows us to derive the impedance of the cross - talk and the leakage to be approximately 27 . 4 mω and 11 . 7 mω respectively at 1 kω in a second set of operational tests , the devices were inserted through the pia and into the cortex of live rats to test penetration ability . results show a full insertion of the probe was successful without any bending , buckling or breakage by observing the shanks under a surgical microscope during insertion . finally , the devices underwent accelerated life testing in saline to determine the mean time to failure . failure modes include the failure of the silicon to parylene adhesion as well as the delamination between the parylene layers . soaking test results illustrated in fig1 show that the parylene - silicon adhesion is able to withstand more than five weeks in 90 ° c . saline before delamination occurs . furthermore , the parylene cable quality is uncompromised for the four weeks of soaking in the same environment with a cable only device , as illustrated in fig1 . we have developed and performance tested a fully parylene c encapsulated , high electrode density silicon based array with an integrated flexible cable . a 3 - d packaging scheme with commercial connectors and a percutaneous pedestal is also presented . electrode impedances were characterized and pre - recorded action potentials were recorded through these devices . in vivo insertion capability of the silicon probes have also been verified . high temperature accelerated life time testing in saline indicates the stability of both the cable and the probe - cable interface for more than four weeks in 90 ° c . saline . from the testing results , this high density silicon probe is a neural probe that is expected to be useful in chronic cortical prosthetic applications . we now describe a packaging technique that utilizes a simple , flexible parylene pocket that can accommodate and make connection to a chip , the pocket being supported on a silicon substrate with metal pads . this pocket can house an ic chip or a discrete component inside and provide electrical connections to it . we also demonstrate an 8 - shank silicon probe array integrated with a fully functional 16 - channel amplifier cmos chip . a totally biocompatible packaging / integration solution to embed amplifiers near the recording sites would be advantageous . desirable and advantageous criteria for a well - packaged device for implantation would include avoidance of infections and inflammatory responses ; the ability to withstand the harsh physiological environment of the human body ( or an animal body ); ease of fabrication ; and as low a cost as possible . we describe a new packaging technique that utilizes a flexible parylene pocket on silicon substrate with metal pads . this pocket can house an ic chip and provide electrical connections to it , and can be totally integrated with silicon probes . by application of this technology , one can make the chips and probes separately and later package them together , which is an advantage in ic / probe integration . the pocket size and the configuration of the electrodes can be modified to suit different chips and applications and is not sensitive to dry etching flatness . fig1 shows the drawing of a wireless parylene pocket integration scheme . the whole bonding structure is conformally coated and sealed with parylene - c ( poly - para - xylylene - c ), and with medical grade epoxy to achieve total encapsulation for biocompatibility . we are able to fabricate ic - cabled packages that are highly customizable , fully biocompatible , and easy to mass fabricate . the parylene pockets presented now have been designed to accommodate a 300 μm thick , 0 . 5 mm × 0 . 5 mm sized commercial ic chip . the parylene c cable and pocket thickness is 12 μm with gold metal connection traces embedded . it is believed that gold electrodeless plating is an alternative pad - to - pad interconnection technique . the two openings on two sides of this pocket were designed to provide stress relief during the insertion . the edge of the pocket has a 1 mm wide melted parylene adhesion layer section to provide the adhesion between the parylene and the silicon substrate . this structure also comprises a parylene pocket integrated with a 2 - d 32 channel flexible cabled electrode array device shown in fig7 ), which can be expanded to 3 - d 32 × n channel structures by probe stacking . the silicon base of the pocket is 0 . 8 mm × 0 . 8 mm in size and is 500 μm thick . in one embodiment , the parylene pocket is connected to a 7 cm cable with a 60 degree y shape pattern at the end , as illustrated in fig2 . these are circular platinum rings arranged to be electrically bonded to commercial available connectors with conductive epoxy on a circular pc board . the silicon shank is 150 μm thick and has length of 5 . 1 mm , 4 . 6 mm , 4 . 1 mm and 3 . 6 mm from longest to shortest , respectively , as shown in fig2 . the parylene pocket structures are fabricated on double side polished wafers with drie ( deep reactive ion etching ) technology . fig2 shows the fabrication process . on a polished surface 2202 of a silicon wafer , a sacrificial photoresist layer 2206 is spin - coated for pocket releasing . a layer 2208 of parylene - c ( 6 μm ) is then deposited , followed by a layer 2210 of cr / au ( 0 . 05 / 0 . 2 μm ) lift - off process with electron beam evaporation to provide electrical connection . the top layer 2212 of parylene - c ( 6 μm ) is deposited to complete the parylene - metal - parylene sandwich structure . electrode sites 2214 , 2214 ′ and the device definition are then opened by a two - step rie with o 2 plasma ( reactive ion etching ) process . the outline of the parylene pocket structure 2216 is subsequently etched by drie from both sides of the wafer . in the final step , the devices are released in photoresist stripper and dried . the completed open pocket has at least one electrical contact configured to be accessible on an internal surface thereof , as shown in the lowest panel on the right side of fig2 , in which open pocket 2216 has opening 2214 on the right through which a conductive epoxy can connect metal layer 2210 to a pad on a chip that is inserted in pocket 2216 . as will be seen in other embodiments described hereinbelow ( see for example fig3 , fig3 and fig4 ), similar open pockets provided by the invention also have at least one electrical contact configured to be accessible on an internal surface of the pocket . an 1 c chip is then inserted into the parylene pocket as illustrated in fig2 . it is aligned with the traces in the pocket as shown in fig2 . the chip 2420 is bonded with conductive epoxy as illustrated in fig2 and fig2 to make electrical connection between a conductor 2410 of the pocket with a selected connection pad or electrical terminal on a surface of the chip 2420 . fig2 is an illustrative example that shows a pocket in which a chip 2420 is in contact with a conductive epoxy bonding surface on one side , and situated in a pocket defined by a layer of parylene 2408 , a conductive layer 2410 , and a second layer parylene 2412 . a conductive epoxy drop is placed so as to contact conductive layer 2410 and a conduction pad on the chip 2420 . in alternative embodiments , all of the electrical contacts can be made from one side of a chip 2420 , or electrical contacts can be made at predefined locations on two sides of a single chip , as illustrated by the pocket structure illustrated in cross - section in fig3 l . as appropriate , the structure can be totally coated with parylene - c again for complete encapsulation and to ensure biocompatibility . device testing was performed in two phases : chip integration testing for both conduction and amplifier chips , which are illustrated in fig2 , and accelerated life testing in a saline environment . the embedded cmos amplifier chip used is a scalable 16 - channel pre - amplifier and buffer chip with an in - band gain of 35 . 5 db . this chip was tested using a function generator on a pocket only structure , as shown in fig2 . both sine waves and square waves with frequency of 0 . 5 khz , 1 khz , 2 khz and 5 khz and amplitude of 5 mv were passed into the chip . the amplified output , shown in fig2 , from the oscilloscope concludes a successful functionality testing of our packaging technology . the conduction chip was bonded in a silicon probe integrated pocket and the impedances of the electrodes were measured . an on - going accelerated soaking life - time test was also performed on the parylene pocket structure to determine the mean time to failure . testing shows the pocket structure with the embedded amplifier chip sealed by 1 . 5 mm of biocompatible epoxy is able to function after soaking in 90 ° c . saline for more than 30 days , which translates to a lifetime of years in saline at 37 ° c . ( normal body temperature ), based on the conventional understanding that reaction rates double for every increase in temperature by 10 ° c . in addition to the totally integrated silicon probe array , a second design was developed . it comprises a probe device with 36 electrodes and 2 reference electrodes separated from the parylene pocket structure , which is illustrated in fig3 . the probe device has identical geometry as that of the totally integrated device previously described . by separating the probe structure from the parylene pocket structure , a user would be able to test the pocket structure with the integrated ic chip before connecting it to the electrodes on the silicon probe , resulting in an advantage in terms of yielding and reliable testing . the assembled device is shown in fig3 . we use conductive epoxy as the medium for bonding the probe to the chip encapsulated in the parylene pocket . we have described , reduced to practice , and tested a new parylene - pocket packaging technology to fabricate a silicon probe array with an ic chip close to its recording sites . the packaging schemes and the fabrication details are presented . a commercial amplifier chip was used and its full functionality after packaging was verified . high - temperature accelerated life - time saline soaking testing shows satisfactory performance in both the pocket structure and the overall system . it is expected that this new packaging technique will be useful for application in complex integrated biomedical implants needed for neural prosthesis research . we now describe a biocompatible packaging technique that utilizes a complete flexible parylene chip pocket with metal pads . this pocket can both house an ic chip or any discrete components and provide electrical connection to it . as a demonstration , a fully functional 16 - channel amplifier cmos chip has been bonded and tested with this structure . this work also integrates an 8 - shank silicon probe array with the pocket , of which the electrode impedance was successfully measured . an important goal in neural prosthesis is to be able to decode the movement intention in the parietal cortex from neurons by implanting neuroprobes . while 3 - d integrated silicon probes have been successfully manufactured , the degradation of the signal to noise ratio ( snr ) is still a major challenge because electronics are too far away from the recording site . thus , a biocompatible packaging / integration solution to embed amplifiers near the recording sites would provide an advantage . we describe a new packaging technique that utilizes a totally flexible parylene chip pocket with metal pads . this pocket can both house an ic chip inside and provide electrical connections to it , and can be integrated with silicon probes . by application of the technology we now describe , one can make the chips and probes separately and later package them together , which is an advantage over direct ic / probe integration . the pocket size and the electrodes can be modified to suit different chips and applications as illustrated in fig1 and is not sensitive to dry etching flatness . the whole bonding structure is conformally coated and sealed with parylene - c ( poly - para - xylylene - c ), and with medical grade epoxy to achieve total encapsulation for biocompatibility . as a successful demonstration , a 16 - channel amplifier cmos chip embedded with parylene pocket is described . the parylene pocket configuration is fabricated with rie technology ( reactive ion etching ) as illustrated in the process illustrated in fig3 . first , a bottom layer 3204 of 5 μm thick parylene - c is deposited on a silicon wafer 3202 . a layer 3206 of sacrificial photoresist of 1 μm is then coated , which when removed will serve to define the parylene pocket structure . another layer 3208 of parylene - c ( 5 μm ) is deposited . a layer 3210 of cr / au ( 0 . 05 / 0 . 2 μm ) is deposited using a lift - off process to provide electrical connection . the top layer 3212 of parylene - c ( 2 μm ) is deposited to complete the structure . electrode sites 3214 , 3214 ′ and the device definition are then created by a two - step rie with o 2 plasma process . the devices are released in photoresist stripper . an ic chip ( see fig2 ) is then inserted by hand into the parylene pocket , aligned ( see fig2 ), bonded with conductive epoxy ( see fig2 ) and totally coated with 10 μm of parylene . device testing was done in several phases . first , the embedded cmos amplifier chip was tested using a function generator on the pocket only structure , shown in fig3 . sine and square waves of different frequencies were passed into the chip . the amplified output was measured and plotted , as illustrated in fig2 . a conduction chip was then bonded with a silicon probe ( see fig3 ) to form an integrated pocket structure , as illustrated in fig3 . the impedances of the probe electrodes were successfully measured , which indicates a successful functionality testing of our packaging technique . finally , an on - going accelerated soaking life - time test was done on the packaged structure to determine the mean - time - to - failure . testing shows the pocket structure with 1 . 5 mm of epoxy is able to function after soaking in 90 ° c . saline for more than 30 days , which should translate to years of lifetime in saline at 37 ° c . we believe that the technology provides quick and simple packaging technology for all biological implants that require signal amplification in close proximity to the location where signals are obtained . we expect that the technology will facilitate a totally wireless biocompatible insertion system for neural prosthesis application , as we next describe . fig3 is a diagram showing the steps performed in fabricating a self supporting parylene pocket structure that provides contacts to chips having contact pads on two opposite surfaces . this capability will allow the use of chips that are expected to have greater functionality as compared to chips having contacts on only one surface . as shown in fig3 a , a silicon wafer 3502 having a polished surface is provided as a support structure . as illustrated in fig3 b , a first layer of parylene 3504 is applied to the deposited on selected areas of the parylene layer 3504 . as required , the first metal layer 3506 may comprise more than one metal structure , such as parallel lines configured to provide conductor traces and / or multiple connector pads . as illustrated in fig3 d , a second layer of parylene 3508 is deposited to cover and encapsulate the first metal layer 3506 . the second layer of parylene 3508 can extend to a substantially similar extent as the first parylene layer 3504 . as illustrated in fig3 e , an opening 3510 is created ( for example by etching ) in the second parylene layer 3508 to provide a path to make contact to a contact pad in the first metal layer 3506 . as illustrated in fig3 f , a layer of photoresist 3512 is provided that covers the opening 3510 and that represents a sacrificial volume that when opened , provides a space into which a chip may be inserted . as illustrated in fig3 g , a third parylene layer 3514 is provided over the photoresist layer 3512 . the third parylene layer 3514 can extend to a substantially similar extent as the first parylene layer 3504 . as illustrated in fig3 h , a second layer of metal 3516 is deposited on selected areas of the third parylene layer 3514 . as required , the second metal layer 3514 may comprise more than one metal structure , such as parallel lines configured to provide conductor traces and / or multiple connector pads . as illustrated in fig3 i , a fourth parylene layer 3518 is deposited to cover and encapsulate the second metal layer 3516 . the fourth parylene layer 3518 can extend to a substantially similar extent as the first parylene layer 3504 . as illustrated in fig3 j , one or more openings 3520 are provided to allow access to the contact pads in the second metal layer 3516 . in one embodiment , the openings are created using reactive ion etching ( rie ) methods . as illustrated in fig3 k , openings 3522 , 3522 ′ are etched through the structure to allow electrical access to all of the contact pads . as illustrated in fig3 l , the self supporting parylene pocket structure is released from the silicon wafer 3502 and the sacrificial layer of photoresist 3512 is removed , leaving a free - standing self supporting parylene pocket structure having metal contacts and leads that can be connected to contact pads on two opposite sides of a chip , such as an ic chip or a chip having desired electronic , computational , or other capabilities . the leads in the parylene pocket can be used to make electrical connection to circuitry , probes , or other electrical or electronic devices that allow communication with the encapsulated chip . we now describe the design , fabrication and functional testing of a fully implantable , flexible , parylene - enabled neurostimulator that features single channel wireless stimulation capability . the system comprises a cmos stimulator chip , a fold - and - bond rf coil , two platinum electrodes , and discrete capacitors . the mems components are fabricated with a parylene - metal skin technology , and the system assembly is achieved by interconnecting individual components together on a parylene substrate with silver epoxy . the functionality of the integrated system has been verified using a telemetry link setup , and single - phase pulses with amplitudes ranging from 7 to 8 . 5 v have been detected . we describe flexible wireless neural implants , employing parylene - based mems devices integrated with other discrete components , such as application specific integrated circuits ( asics ) and chip capacitors . a parylene - metal skin technology allows us to microfabricate rf coils and multielectrode arrays in a process compatible way . we describe the integration of such a coil and an electrode array with a single channel stimulator chip to build a fully functional system for neural stimulation . for the first embodiment , mems devices are fabricated separately , and assembled with other system components using biocompatible silver epoxy . parylene - c serves as a substrate and packaging material , and therefore the final system is highly flexible and biocompatible for medical implantation . fig3 a depicts the system schematic of a single channel stimulator , which comprises a bion1 - 3 cmos chip , two capacitors , a specially designed rf mems coil for wireless power and data transmission from an external personal trainer , as well as a carrier substrate . the flexible carrier has interconnection leads and contact pads for system assembly , and two electrodes of which one serves as the stimulating electrode while the other is the floating ground . the overall physical dimensions of the mems coil and the carrier substrate are to meet specifications used in retinal implantation , which are determined based on surgical implantation results in canine eyes . the bion chip is a single - channel stimulator which is initially developed to mimic muscle spindle function , and to treat patients suffering from muscle paralysis . once implanted into paralyzed muscles , the chip can receive both power and command signals through inductive coupling over a 480 khz ˜ 500 khz power carrier generated in an external unit , allowing the chip to emit precisely timed stimulation pulses with highly regulated amplitude and pulse - width . the bion chip has physical dimensions of ˜ 1 mm in width , ˜ 2 . 33 mm in length , and ˜ 257 μm in thickness . there are five pads on the chip with sizes of approximately 120 μm × 74 μm . the distance between two adjacent pads is about 110 μm . two ceramic chip capacitors ( avx corporation , myrtle beach , s . c ., usa ) are incorporated in the integration system to tune the circuit . as seen from the circuit layout fig3 b , c 1 is a frequency tuning capacitor in parallel with the receiving coil to achieve a resonant frequency of ˜ 500 khz . c 2 is a charge storage capacitor which has a capacitance of ˜ 22 nf , provided by dr . gerald loeb &# 39 ; s group at the university of southern california . these capacitors are about 1 mm × 0 . 5 mm × 0 . 56 mm in size . the fabrication is divided into three steps : carrier substrate fabrication , rf mems coil fabrication , and final system assembly and packaging . to build the flexible substrate , a 200 nm layer of platinum is e - beam evaporated on a parylene - c coated silicon substrate . then the metal is patterned using lift - off to form connection pads , interconnection leads , and electrode sites . platinum is selected as the electrode material for optimal simulation capability . no adhesion metal layer is need in this case because platinum and parylene are known to have good mutual adhesion . after metal patterning , another layer of parylene - c is deposited to seal the entire structure , followed by oxygen plasma etching in a reactive ion etching ( rie ) system with a photoresist mask to define the outer geometry of the substrate , as well as to open the electrode sites and the contact vias . finally , the device is peeled off from the silicon substrate in a water bath . fig3 illustrates the detailed process for making the carrier substrate , where steps 37 b through 37 d describe the lift - off technology for platinum patterning . in fig3 a , a polished silicon wafer 3702 has a layer of parylene 3704 deposited thereon . in fig3 b , layers of a lor3b resist 3706 and a regular photoresist 3708 are deposited and patterned . in fig3 c a metal 3710 is deposited over the patterned resists . in fig3 d , the resists are removed , leaving metal 3710 in predefined locations on the parylene layer 3704 . in fig3 e additional parylene is deposited . in fig3 f the separated substrate is illustrated . fig3 presents a fabricated carrier substrate . the microscope image shows a special chip site design where parylene ribbons are etched in a way such that the chip can be held in place and self - aligned to the contact vias on the substrate during system assembly . the array site contains a 450 μm diameter tack hole so that the array can be attached to the retina using a retinal tack . to fabricate the mems coil , a fold - and - bond technology is involved , in which two coils are placed in series , and made of a single 3 μm layer of gold to achieve low resistance and high q factor . then the device is folded into two layers and stacked together with the assistance of two glass slides . aluminum sheets are inserted between the parylene surface and the class slides to prevent parylene sticking on the glass . after that , the stacked coil is placed in a vacuum oven with a chamber pressure of ˜ 10 torr for bonding . the oven temperature ramps from room temperature to 250 ° c . the device is then soaked at the bonding temperature for 2 days , followed by a slow cool - down to room temperature . nitrogen backfill is introduced during the thermal bonding process to equalize the chamber temperature . a fabricated coil is shown in fig3 , comprising two layers of metal with 10 turns in each layer . in - and - out leads are connected to the carrier substrate from the center , facilitating the surgical procedure . through vias are designed to overlap with the contact pads , so that the interconnections to the carrier substrate can be formed from either side . the electrical properties of this coil are measured , showing an inductance of approximately 2 . 24 μh and a dc resistance of approximately 15 . 82ω , which results in a q factor of 0 . 45 at 500 khz . for hybrid system assembly , individual components ( the bion chip , the coil and the capacitors ) are aligned to the corresponding interconnection vias on the carrier substrate . a small amount of biocompatible silver epoxy epo - tek h20e ( epoxy technology , billerica , mass ., usa ) is then applied on the contacts and cured at 80 ° c . for 3 hours in a convection oven . the conductive epoxy serves two purposes : to form the interconnections between the components as well as to bond the components onto the substrate . finally , parylene - c is coated on the entire system just leaving the electrode sites open in order to protect the circuitry from the corrosive eye fluids and to improve the durability of the epoxy contacts . fig4 illustrates an assembled single channel stimulator system . fig4 shows close - up views on the interconnections for each component . because the bion chip has only 5 pads , hand assembly using epoxy interconnection is quick and easy . however , a main problem encountered during the fabrication is the lack of control of the epoxy amount when applied by hand . short circuits can be created if too much epoxy is applied . epoxy reflow can also happen during high temperature curing , resulting in short circuits . for chips with high density pad layouts , this hand assembly is no longer applicable , and thus a wafer level integration technology is necessary . after the assemble system is made , its functionality is verified using a telemetry link setup , shown in fig4 . the primary stage is shown in fig4 , which comprises a personal trainer unit , a class - e coil driver and a hand - wound transmitting coil , can generate a power carrier of approximately 500 khz . the personal trainer stores command programs personalized for individual subjects , records the time and duration of treatment , and transfers this information to an external computer for real time monitoring . up to three programs can be preloaded into the memory of the personal trainer . the coil driver is connected to the personal trainer through a custom made adapter . the transmitting coil has an inductance of ˜ 46 . 4 μh and a q factor of ˜ 118 at 500 khz . litz wires 1025 - 44 spn are used for winding the primary coil to reduce the skin effect and proximity effect losses . the transmitting coil is built in a solenoid shape to establish a more uniform electromagnetic field inside the coil . additionally , ferrite cores are inserted in the transmitting coil to magnify the electromagnetic field and therefore to improve voltage transfer efficiency . in vitro measurements have been conducted using this setup , and output signals of the integrated stimulator are monitored by connecting two electrodes directly to an hp 54645a oscilloscope ( hp / agilent technologies inc ., santa clara , calif ., usa ). the distance between the two coils is varied during testing , and a maximum detectable range of ˜ 4 mm is found . the recorded stimulating pulses at the different separation distances are given in fig4 , showing a pulse width of approximately 500 μs , and amplitudes varying from 7 to 8 . 5 v . in order to estimate the power transfer capability of the mems coil , the voltage across the receiving coil terminals and the current delivered to the chip are measured . fig4 shows typical waveforms of the transferred voltage and current , indicating a resonant frequency of ˜ 505 khz and a ˜ 25 degree phase drift between voltage and current . as mentioned earlier , the tuning capacitor is a commercially available chip capacitor , which has limited options of capacitance values . therefore , it is difficult to fine tune the resonant circuit to achieve precise synchronization . the delivered power at the different separation distances are also investigated , as shown in fig4 . the mems coil can transfer a maximum power of ˜ 43 mw through this inductive link at the separation distance of 1 mm . as the separation distance increases to 2 mm , the power drops by 62 %, which is mainly limited by the low q factor of the receiving coil . the functionality of the integrated system has been successfully demonstrated in air . however , the short detectable distance would restrict the practicality of this system in actual applications . further improvement can be achieved by optimizing coil design , such as increasing metal thickness and / or the number of metal layers , in order to enhance the coil q factor and the power transfer efficiency . the verification of system functionality through implantation in rabbit eyes is underway . a single channel neural stimulator has been designed , and one embodiment has been successfully fabricated and tested . test results demonstrate that the bion chip can be driven by the mems coil within a 4 mm separation distance . output pulses with a pulse width of ˜ 500 μs as and amplitudes of more than 7 v are measured from the simulating electrode , indicating that system can be operated in vitro . current state - of - the - art technologies for retinal and cortical prosthetics suffer greatly from complicated ic packaging with high lead count , for example , more than 60 leads . there is also a lack of high density capability . we describe a novel biocompatible packaging technique that utilizes a flexible parylene pocket with metal pads on silicon substrate in order to overcome these challenges and to accommodate the increasing number of prosthetic chips . this pocket can be designed to house any ic chip or discrete component and provide electrical connection to it . as a demonstration , a high density , 128 - channel conduction chip along with surface mount capacitors , resistors and inductors have been bonded and tested with this structure . it is believed that this new technique can be further scaled to achieve 10 , 000 connections in an area of 1 cm 2 . as illustrated in fig4 , the parylene pocket structure is fabricated with a combination of rie ( reactive ion etching ) and drie ( deep reactive ion etching ) processes . on a polished surface 4702 of a silicon wafer , a sacrificial photoresist layer 4706 is spin - coated for pocket releasing . a layer 4708 of parylene - c ( 6 μm ) is then deposited , followed by a layer 4710 of cr / au ( 0 . 05 / 0 . 2 μm ) lift - off process with electron beam evaporation to provide electrical connection . the top layer 4712 of parylene - c ( 6 μm ) is deposited to complete the parylene - metal - parylene sandwich structure . electrode sites 4714 , 4714 ′ and the device definition are then opened by a two - step rie with o 2 plasma ( reactive ion etching ) process . a drie backside etch is used to define the back surface dimensions as defined by etched trenches 4720 and 4720 ′. after the excess silicon is released , the parylene pocket structure 4716 is opened in photoresist stripper and the structure is dried . an ic chip is then inserted into the parylene pocket as illustrated in fig4 . it is aligned with the traces in the pocket as shown in fig4 and fig5 . the chip is bonded with conductive epoxy as illustrated in fig5 . as appropriate , the structure can be totally coated with parylene - c again for complete encapsulation and to ensure biocompatibility . after the fabrication process , the devices are released from the wafer . an ic chip is then inserted into the parylene pocket , in some embodiments by hand , aligned as shown in fig4 and fig5 , and bonded with a conductive epoxy squeegee process , as shown in fig5 . it is then totally coated with parylene for overall biocompatibility . in the epoxy squeegee process , a commercially available conductive epoxy is mixed and applied globally on the surface of the chip . a rubber squeegee is then used to push excess epoxy off the target surface of the chip pad bonding area . pulsed laser annealing with an ultra - violet laser is then utilized to cure the epoxy connections locally , which enhances the physical strength and stiffness of the bond . finally , acetone is used to wash away the uncured conductive epoxy , which leaves the surface of the bonding pad relatively clean and the space between pads free of unwanted short circuit conductions , as shown in fig5 and fig5 . the profile of the bonding epoxy bumps has been examined . the result illustrated in fig5 shows that the maximum height is ˜ 25 μm . as illustrated in fig5 , discrete components such as diodes and capacitors can be connected to this parylene - pocket structure . device testing is performed in two stages . the first stage is chip integration testing and the second stage accelerated life testing . a dummy chip with dimensions of 5 mm × 5 mm × 500 μm is inserted into the pocket and bonded with the laser annealing technique to test the functionality of the structure . the pads on the dummy chip have minimum distances of 140 μm and maximum distances of 500 μm . commercial discrete components such as capacitors , resistors and inductors ( coils ) are connected to the pads on the parylene layer and are tested with a function generator . sine waves of different frequency were passed into the chip and the components . fig5 illustrates the successful functionality testing of the packaging technology . finally , accelerated life - time soaking test is conducted to determine the mean - time - to - failure of the devices . testing shows the pocket structure with 1 . 5 mm of biocompatible silicone is able to function after soaking in 90 ° c . saline for more than 30 days , which should translate to years of lifetime in saline at 37 ° c . it is expected that one will be able to integrate data and power coils on this platform to provide a total integrated system that will be implanted in vivo . it is expected that the rapid , inexpensive and efficient method of bonding a high density chip as described herein will provide a totally wireless biocompatible system for various applications , one of which is expected to be a retinal prosthesis application . many different pocket architectures are possible , and different forms of pockets may be most suitable for different applications . examples include a pocket on a silicon substrate ; an all - parylene pocket ; pockets designed to encapsulate specific commercially available chips ; pockets designed to encapsulate discrete components ; pockets designed to encapsulate pcbs ; a single layer pocket ; a double layer pocket ; a multi layer pocket ; pocket stacking to achieve a 3d structure ; a pocket with parylene cable connected thereto ; a pocket with a mems coil ; a pocket with mems capacitors and pockets comprising materials other than parylene . interconnection has been demonstrated using several procedures , including the squeegee method ; the hand paint method ; methods involving use of conductive epoxy ; and a laser annealing method , in which laser - assisted annealing and curing of the conductive epoxy / polymer has been successfully demonstrated . many different materials can be used in fabricating pockets as described herein . while parylene has been described as a material that is well suited to pocket architectures that are intended for implantation in living organisms , it is believed that many thin - film polymers , such as pmma , teflon , silicone and polyimide , can be used to make pockets for the same or similar applications . in fact , any thin - film polymer that can have metals provided as internal metal surfaces can be used to make pockets for applications involving packaged chips and / or electronic and electrical circuit components . recording the results from a data collection operation , e . g ., obtaining and recording a signal representing data or information , or obtaining and recording an image , such as for example , recording results in one or more dimensions , using one or more colors or hues , or at a particular frequency or wavelength , is understood to mean and is defined herein as writing output data to a storage element , to a machine - readable storage medium , or to a storage device . the recorded information can be analog information and / or digital information , as a particular embodiment may suggest or require . machine - readable storage media that can be used in the invention include electronic , magnetic and / or optical storage media , such as magnetic floppy disks and hard disks ; a dvd drive , a cd drive that in some embodiments can employ dvd disks , any of cd - rom disks ( i . e ., read - only optical storage disks ), cd - r disks ( i . e ., write - once , read - many optical storage disks ), and cd - rw disks ( i . e ., rewriteable optical storage disks ); and electronic storage media , such as ram , rom , eprom , compact flash cards , pcmcia cards , or alternatively sd or sdio memory ; and the electronic components ( e . g ., floppy disk drive , dvd drive , cd / cd - r / cd - rw drive , or compact flash / pcmcia / sd adapter ) that accommodate and read from and / or write to the storage media . as is known to those of skill in the machine - readable storage media arts , new media and formats for data storage are continually being devised , and any convenient , commercially available storage medium and corresponding read / write device that may become available in the future is likely to be appropriate for use , especially if it provides any of a greater storage capacity , a higher access speed , a smaller size , and a lower cost per bit of stored information . well known older machine - readable media are also available for use under certain conditions , such as punched paper tape or cards , magnetic recording on tape or wire , optical or magnetic reading of printed characters ( e . g ., ocr and magnetically encoded symbols ) and machine - readable symbols such as one and two dimensional bar codes . recording image data for later use ( e . g ., writing an image to memory or to digital memory ) can be performed to enable the use of the recorded information as output , as data for display to a user , or as data to be made available for later use . such digital memory elements or chips can be standalone memory devices , or can be incorporated within a device of interest . “ writing output data ” or “ writing an image to memory ” is defined herein as including writing transformed data to registers within a microcomputer . the term “ image ” can be understood to mean either a “ picture ,” whether visible to a human observer or to an instrument ( e . g ., a visible image , an infrared image , or a digital representation of such an image , whether in black and white or in color ), or alternatively , a “ copy ”, as in “ an image of a hard disk ,” whether a duplicate copy , a compressed copy , or an encrypted copy . “ microcomputer ” is defined herein as synonymous with microprocessor , microcontroller , and digital signal processor (“ dsp ”). it is understood that memory used by the microcomputer , including for example an imaging or image processing algorithm coded as “ firmware ” can reside in memory physically inside of a microcomputer chip or in memory external to the microcomputer or in a combination of internal and external memory . similarly , analog signals can be digitized by a standalone analog to digital converter (“ adc ”) or one or more adcs or multiplexed adc channels can reside within a microcomputer package . it is also understood that field programmable array (“ fpga ”) chips or application specific integrated circuits (“ asic ”) chips can perform microcomputer functions , either in hardware logic , software emulation of a microcomputer , or by a combination of the two . apparatus having any of the inventive features described herein can operate entirely on one microcomputer or can include more than one microcomputer . general purpose programmable computers useful for controlling instrumentation , recording signals and analyzing signals or data according to the present description can be any of a personal computer ( pc ), a microprocessor based computer , a portable computer , or other type of processing device . the general purpose programmable computer typically comprises a central processing unit , a storage or memory unit that can record and read information and programs using machine - readable storage media , a communication terminal such as a wired communication device or a wireless communication device , an output device such as a display terminal , and an input device such as a keyboard . the display terminal can be a touch screen display , in which case it can function as both a display device and an input device . different and / or additional input devices can be present such as a pointing device , such as a mouse or a joystick , and different or additional output devices can be present such as an enunciator , for example a speaker , a second display , or a printer . the computer can run any one of a variety of operating systems , such as for example , any one of several versions of windows , or of macos , or of unix , or of linux . computational results obtained in the operation of the general purpose computer can be stored for later use , and / or can be displayed to a user . at the very least , each microprocessor - based general purpose computer has registers that store the results of each computational step within the microprocessor , which results are then commonly stored in cache memory for later use . many functions of electrical and electronic apparatus can be implemented in hardware ( for example , hard - wired logic ), in software ( for example , logic encoded in a program operating on a general purpose processor ), and in firmware ( for example , logic encoded in a non - volatile memory that is invoked for operation on a processor as required ). the present invention contemplates the substitution of one implementation of hardware , firmware and software for another implementation of the equivalent functionality using a different one of hardware , firmware and software . to the extent that an implementation can be represented mathematically by a transfer function , that is , a specified response is generated at an output terminal for a specific excitation applied to an input terminal of a “ black box ” exhibiting the transfer function , any implementation of the transfer function , including any combination of hardware , firmware and software implementations of portions or segments of the transfer function , is contemplated herein . although the theoretical description given herein is thought to be correct , the operation of the devices described and claimed herein does not depend upon the accuracy or validity of the theoretical description . that is , later theoretical developments that may explain the observed results on a basis different from the theory presented herein will not detract from the inventions described herein . any patent , patent application , or publication identified in the specification is hereby incorporated by reference herein in its entirety . any material , or portion thereof , that is said to be incorporated by reference herein , but which conflicts with existing definitions , statements , or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material . in the event of a conflict , the conflict is to be resolved in favor of the present disclosure as the preferred disclosure . while the present invention has been particularly shown and described with reference to the preferred mode as illustrated in the drawing , it will be understood by one skilled in the art that various changes in detail may be affected therein without departing from the spirit and scope of the invention as defined by the claims .

US-65753910-A

this invention relates to an odor control liquid and aerosolized composition for deodorizing and controlling odor of animal wastes by contact therewith , comprising a non - aqueous volatile carrier and an odor control agent . the liquid and aerosolized composition can be applied in liquid form directly to the animal litter and / or the animal container and / or the animal waste . a related object of this invention is to provide a method for preventing sticking and contamination on the surfaces of a litter container , comprising applying to the container an effective amount of a powdered release agent or powdered odor control agent in a non - aqueous volatile carrier .

the odor control composition of this invention utilizes an odor control agent in a non - aqueous volatile carrier . according to this invention , an odor control agent can be any compound ( s ) that function ( s ) to mask odorous material , or any compound that reacts with odor - causing material to form non - odorous compounds . the odor control agent can be in a solid or liquid form . some examples of odor control agents can be an acrylic ester such as lauryl methacrylate , ( sold under trade name metazene by pestco company ), sodium bicarbonate , benzalkonium chloride , bisulfite complexes of aldehydes and ketones , boric acid , borax , menthol , camphor , sodium bisulfate , lemon oil , and pine oil . odor control agents can also be a powdered compounds such as magnesium silicates ( talc ), inorganic silicone and magnesium powders , sodium bicarbonate , chlorophyll , sodium dihydrogen phosphate , potassium acid phthalates , or other powdered odor control agents known to those skilled in the art , or mixtures thereof , which compounds also act as release agents . when the odor control agent is an acrylic ester , such as lauryl methacrylate , for example , the concentration of the acrylic ester component can vary from about 1 % by weight to about 70 % by weight , preferably from about 1 % to about 7 % by weight , and most preferably from about 1 % to about 3 . 5 % by weight , of the total composition . those skilled in the art will adjust the compositional levels of the odor control agent to ensure effective odor control and cost effectiveness . in another embodiment of this invention , the odor control composition further comprises from about 0 . 01 % to about 20 % by weight of an antibacterial agent . effective odor prevention for longer periods of time can be obtained with the use of an antibacterial agent added to the composition . antibacterial agents can act to prevent the buildup of microorganisms that can develop over time , and may also act as a preservative for long term storage of the liquid composition . although any broad spectrum antibacterial agent is suitable for use herein , preferred antibacterial agents are the halogenated aromatic hydrocarbons . suitable examples are p - chloro - m - cresol , hexachlorophene , 2 , 4 , 4 ′- trichloro - 2 ′- hydroxydiphenyl ether ( also known as triclosan , commercially available under the tradename microban from clinitex corporation , trichlorocarbanilide , 2 , 4 - dichloro - m - xylenol , 3 , 4 , 5 - tribromosalicylanilide , 3 , 5 , 3 ′, 4 ′- tetrachlorosalicylanilide , 3 , 5 , 3 ′, 5 ′- tetrachlorodiphenyl sulfide , and mixtures thereof . due to the effectiveness of these antibacterial agents , these materials can be used at very low levels that an effective product can be obtained without the high cost or toxicity being significant factors of consideration . the antibacterial agent is preferably present at from about 0 . 01 % by weight to 20 % by weight of the total composition , and more preferably , at from about 0 . 3 % to about 10 % by weight , of the total composition . in yet another embodiment of this invention , the odor control composition can further comprise a powdered release agent . release agents such as magnesium silicates ( talc ) can be defined as a compound that can provide benefits of stick prevention , contamination prevention , and quicker drying time , visual indication of coverage , as well as provide a coating or physical barrier to odorous compounds on porous materials . more preferably , the release agent will also be an odor absorbing powder such as , for example , inorganic silicone and magnesium powders , sodium bicarbonate , chlorophyll , sodium dihydrogen phosphate , potassium acid phthalates , or mixtures thereof . the powdered release agent can be present at about 0 . 1 % by weight to about 10 % by weight of the total composition . the non - aqueous volatile carrier of this invention should have a volatility greater than water . preferably , the nonaqueous volatile carrier is acetone , which when sprayed on a substrate , will dry most quickly and not have the potential problems of clumping if sprayed onto absorbent or adsorbent particulate materials . another preferable non - aqueous volatile carrier is isopropanol . optionally , a fragrance may be added to the composition . representative examples of fragrance components generally include , but are not limited to : volatile phenolic substances ( such as iso - amyl salicylate , benzyl salicylate , and thyme oil red ); essence oils ( such as geranium oil , patchouli oil , and petitgrain oil ); citrus oils ; extracts and resins ( such as benzoin siam resinold and opoponax resinold ); “ synthetic ” oils such as bergamot 37 and 430 , geranium 76 and pomeransol 314 , and powder mask ce - 32907 ); aldehydes and ketones ( such as beta - methyl naphthyl ketone , p - tert - butyl - a - methyl hydrocinnamic aldehyde and p - tert - amyl cyclohexanone ); polycyclic compounds ( such as coumarin and beta - naphthyl methyl ether ); esters ( such as diethyl phthalate , phenylethyl phenylacetate ). fragrances also include esters and essential oils derived from floral materials and fruits , citrus oils , absolutes , aldehydes , etc . and alcohols ( such as dimyrcetol , phenylethyl alcohol and tetrahydromuguol ). thus , the odor control compositions of this invention can be used as a premixed litter container additive for domesticated animals and pets to effectively eliminate and prevent the development of unpleasant odors in animal litter containers for extended periods of time . the odor control composition can be applied directly to the litter container , or directly to particles of an absorbent or adsorbent litter substrate , and / or directly to the litter container . any absorbent or adsorbent litter substrate material that is commercially available can be contacted with the odor control composition of this invention . some examples of absorbent litter substrates include minerals , typically clay such as kaolinites , montmorillonites , or bentonites ; fly ash as obtained from the burning of coal ; pelletized absorbent materials ( e . g . sawdust or polyurethane foam ); and the like . in addition to being used in animal litter containers , the compositions can be used in many environments , including animal containment areas , living areas , production areas , work areas and automobiles , for example . to produce an odor control animal litter , the odor control composition of this invention is applied directly to the absorbent or adsorbent litter substrate in an effective amount . for litter containers , it is most preferred that powdered release agents such as talc are used . in this respect , the talc acts not only as a stick preventive , but also coats the surface and fills the pores of the litter container , thereby forming a physical barrier to the prevent contamination and / or absorption of odorous materials . an odor control composition of this invention can be made as follows : to a batch tank , add 66 . 1 weight percent acetone and begin high speed agitation to form a vortex in the acetone . add 0 . 3 weight percent 2 - hydroxy - 2 ′, 4 , 4 ′- trichlorodiphenyl ether and magnesium silicate talc into the vortex , which results in a milky white solution . add 3 . 5 weight percent of lauryl methacrylate , and optionally 0 . 1 weight percent of powder mask fragrance ( ce - 32907 ) to the center of the vortex . close the batch lid and continue mixing at a high speed for 10 minutes , then reduce mixing to a moderate mixing speed . maintain a moderate mixing speed during filling to ensure that the talc stays suspended in the acetone . the liquid compositions of this invention can be adapted for discharge from a pressurized container to form an aerosol spray . when formulated as an aerosol spray , propellants such as propane , butane , or other known propellants , can be used . the odor control composition is preferably applied in the form of a liquid , or as an aerosol spray . an aerosol composition generally means an odor control liquid composition adapted for discharge from a pressurized container to form an aerosol spray . according to this invention , the aerosol composition comprises a non - aqueous volatile carrier , an odor control agent , and a propellant . “ applying ” the odor control composition in this invention means wetting at least a significant portion of the surface area of the solid absorbent or adsorbent material and / or container therefor , with the odor control composition , which could include spraying , soaking , or impregnating . the liquid or aerosol composition can be applied directly to the litter or litter container . when applied in either the liquid or aerosolized form , a mist of wet film is applied , whereafter the solvent quickly evaporates for fast drying . when the odor control composition is applied in aerosolized form , an even distribution of the odor control agent can be achieved over the desired area . preferably , when the liquid odor control composition comprising a an odor control agent , a powdered release agent , and a nonaqueous volatile carrier is sprayed onto a porous litter container , sticking and contamination of the container and litter can be prevented . more preferably , the liquid composition comprises an odor control agent and a powdered release agent in a nonaqueous carrier , adapted for discharge from a pressurized container to form an aerosol spray . aerosol application of the composition of this invention is advantageous for several reasons , such as : ( 1 ) because an aerosol droplet is typically a small particle size ( typically 5 - 30 micron in diameter ), a fine mist can be applied with an even distribution on the applied surfaces ; ( 2 ) after application , the small droplets have a much faster drying time ; ( 3 ) a large number of particles are released every second , providing a greater likelihood of impacting the odor molecules ; and ( 4 ) high likelihood of absorption into a porous substrate or surface ; to name a few . economically , due to the ability to perform an efficient application with an aerosol spray , the cost of the product is less and product waste is minimized , compared to typical dry powder applications . compositions comprising the powdered release agent can be easily seen for proper application , and easily removable at the time of cleaning . aerosol application also allows for a more even distribution of the odor control agent over applied areas , the amount of the odor control composition applied should be sufficient to effectively eliminate or control the odor , and at the same time , not be toxic or harmful to the environment or animal occupants .

US-34414699-A