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TITLE: Effectiveness of two preventive interventions for coronary heart disease in primary care.ABSTRACT: 1. To compare a patient-centred, self-directive intervention with conventional care; 2. To evaluate longitudinal within-group changes of coronary heart disease risk.Risk factor changes were evaluated in 110 men with high coronary heart disease risk attending a one year intervention study in general practice. The 22 participating general practice centres were randomly allocated to follow either a patient-centred, self-directive intervention or a conventional approach.No significant between-group differences were found in any single risk factor or in the combined risk of coronary heart disease. The improvement of total risk from screening time to conclusion of the study corresponded with changes of relative risks of CHD to 0.64 (95% CI: 0.54-0.77) and 0.65 (0.54-0.77) in the patient-centred, self-directive and the conventional care group respectively (p < 0.0001 in both groups).Everyday general practice clinical work seems as efficacious as a specific intervention method based on currently advocated behaviour change principles.

TITLE: Sulbactam/cefoperazone versus cefotaxime for the treatment of moderate-to-severe bacterial infections: results of a randomized, controlled clinical trial.ABSTRACT: We conducted a randomized, open-label, controlled, multicenter study to compare sulbactam/cefoperazone with cefotaxime in terms of efficacy and safety for the treatment of hospitalized patients with moderate-to-severe bacterial infections. More than two-thirds of the pathogens recovered from these patients produced beta-lactamase. Two hundred-seven (88.1%) of the 235 patients enrolled completed the study and were included in the efficacy and safety evaluations. One hundred-three patients received sulbactam/cefoperazone (2-4 g/d) administered in evenly divided doses every 12 hours by a 30-minute intravenous drip; 104 patients received cefotaxime (6-12 g/d) administered in evenly divided doses every 6 or 8 hours by a 30-minute intravenous drip. The overall efficacy rates (i.e., cure or markedly improved) were 95% for the sulbactam/cefoperazone group and 90% for the cefotaxime group (P = .186), whereas the bacterial eradication rates were 85% for the sulbactam/cefoperazone group and 81% for the cefotaxime group (P = .467). Both drug regimens were well tolerated. Sulbactam/cefoperazone is effective and safe for the treatment of moderate-to-severe bacterial infections caused mainly by beta-lactamase-producing organisms.

TITLE: Comparison of single-dose cefuroxime axetil with ciprofloxacin in treatment of uncomplicated gonorrhea caused by penicillinase-producing and non-penicillinase-producing Neisseria gonorrhoeae strains.ABSTRACT: A randomized, multicenter, investigator-blind trial was conducted to compare the efficacies of cefuroxime axetil and ciprofloxacin for treatment of patients with uncomplicated gonorrhea caused by penicillinase-producing Neisseria gonorrhoeae (PPNG). A total of 832 patients (434 females and 398 males) received a single oral dose of cefuroxime axetil (1,000 mg [417 patients]) or ciprofloxacin (500 mg [415 patients]). N. gonorrhoeae was eradicated from the cervix in 114 of 118 (97%) and 118 of 119 (99%) bacteriologically evaluable females treated with cefuroxime axetil and ciprofloxacin, respectively (P = 0.213; difference, -2%; 95% confidence interval, -6 to 1%), and from the urethra in 154 of 166 (93%) and 171 of 171 (100%) bacteriologically evaluable male patients treated with cefuroxime axetil and ciprofloxacin, respectively (P < 0.001; difference, -7%; 95% confidence interval, -11 to -3%). Both treatments were effective in eradicating N. gonorrhoeae in females with rectal infections (cefuroxime axetil, 29 of 30 [97%]; ciprofloxacin, 25 of 25 [100%]; P = 1.00). In small numbers of patients, cefuroxime axetil was less effective than ciprofloxacin in treating males with pharyngeal infections (eradication in 4 of 10 and in 8 of 8 patients, respectively; P = 0.013). PPNG was eradicated from the cervix in 22 of 23 (96%) and 32 of 32 (100%) bacteriologically evaluable female patients treated with cefuroxime axetil and ciprofloxacin, respectively (P = 0.418; difference, -4%; 95% confidence interval, -13 to 4%), and from the urethra in 35 of 36 (97%) and 34 of 34 (100%) bacteriologically evaluable male patients treated with cefuroxime axetil and ciprofloxacin, respectively (P = 1.00; difference, -3%; 95% confidence interval, -8 to 3%). The incidences of drug-related adverse events were similar for the two study drugs. In summary, treatment with a single oral dose of cefuroxime axetil is as effective as treatment with a single oral dose of ciprofloxacin in eradicating PPNG from males and females with uncomplicated gonorrhea (urethral and endocervical), and both regimens are well-tolerated. However, in the present study, cefuroxime axetil was less effective than ciprofloxacin in treating urethral gonococcal infections in male patients, although both study drugs were highly effective in treating cervical gonococcal infections in female patients.

TITLE: Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial.ABSTRACT: The Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial compared the efficacy and safety of intravenous hirudin with heparin as adjunctive therapy to thrombolysis and aspirin in patients with acute myocardial infarction. The primary safety end point was the occurrence of major hemorrhage or anaphylaxis.Based on experience in phase II trials, TIMI 9A used a hirudin bolus of 0.6 mg/kg followed by a fixed-dose 96-hour infusion of 0.2 mg/kg per hour. A modified weight-adjusted heparin regimen was used (5000-U bolus and infusion of 1000 U/h for patients < 80 kg or 1300 U/h for patients > or = 80 kg) with titration to a target activated partial thromboplastin time (aPTT) of 60 to 90 seconds. Because rates of hemorrhage in both treatment arms were higher than expected, randomization was suspended in TIMI 9A after 757 patients had been enrolled. Intracranial hemorrhage occurred in 1.7% of patients treated with hirudin and 1.9% of those treated with heparin (P = NS). Major spontaneous hemorrhage at a nonintracranial site occurred more frequently in hirudin--than in heparin-treated patients (7.0% versus 3.0%; P = .02), whereas major hemorrhage at instrumented sites was similar (5.2% in both hirudin and heparin groups). Patients who developed a major hemorrhage were older (P < .001) and had higher aPTT values, especially in the first 12 hours after thrombolysis (P = .001).The rate of major spontaneous hemorrhage for both heparin and hirudin in TIMI 9A was higher than that seen in TIMI 5, TIMI 6, and GUSTO 1. This was possibly a result of high levels of anticoagulation at the doses of heparin and hirudin used, low previous estimates of the hemorrhage risk at the doses of hirudin used in TIMI 9A due to the relatively small number of patients receiving that dose in earlier studies, and enrollment of patients at higher risk of hemorrhage. Because a prolonged aPTT was associated with an increased risk of major hemorrhage in both heparin- and hirudin-treated patients, it now appears important to monitor aPTT on a regular basis when using either antithrombin to identify those patients who require downward adjustment of the infusion. TIMI 9B has therefore been configured with a lower hirudin bolus (0.1 mg/kg) and infusion (0.1 mg/kg per hour) and lower heparin infusion (1000 U/h without weight adjustment). Infusions of both antithrombins will be titrated to a target aPTT of 55 to 85 seconds.

TITLE: Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study.ABSTRACT: This study was designed to determine the efficacy of intravenous amiodarone in the management of recent-onset atrial fibrillation.The optimal approach for acute atrial fibrillation has not been established. Amiodarone is a unique antiarrhythmic agent with activity in both supraventricular and ventricular tachyarrhythmias, but its value for the restoration of sinus rhythm in patients with recent-onset atrial fibrillation has not been demonstrated.Sample size was calculated to detect a 25% increase in reversion rate with amiodarone with a statistical power of 80%. One hundred consecutive patients with recent-onset (<1 week) atrial fibrillation and not taking antiarrhythmic agents were randomized to receive either intravenous amiodarone, 5 mg/kg body weight in 30 min followed by 1,200 mg over 24 h, or an identical amount of saline. Both groups received intravenous digoxin, 0.5 mg initially, followed by 0.25 mg at 2 h and 0.25 mg every 6 h thereafter, to complete 24 h while the ventricular rate was >100 beats/min. Amiodarone and digoxin blood levels were determined. Both groups were homogeneous regarding underlying heart disease, time from onset to treatment, initial ventricular rate and left atrial size.By the end of the 24-h treatment period, 34 patients (68%, 95% confidence interval [CI] 53% to 80%) in the amiodarone group and 30 (60%, 95% CI 45% to 74%) in the control group had returned to sinus rhythm (p = 0.532). Mean times (+/-SD) of conversion were 328 +/- 335 and 332 +/- 359 min, respectively (p =0.957). Among patients who did not convert to sinus rhythm, treatment with amiodarone was associated with a slower ventricular rate (82 +/- 15 beats/min in the amiodarone group vs. 91 +/- 23 beats/min in the control group, p = 0.022). After restoration of sinus rhythm, atrial fibrillation recurred during a 15-day follow-up period in 4 (12%) of 34 patients (95% CI 3% to 27%) in the amiodarone group and in 3 (10%) of 30 (95% CI 2% to 26%) in the control group (p = 0.861).Intravenous amiodarone, at the doses used in this study, produces a modest but not significant benefit in converting acute atrial fibrillation to sinus rhythm.

TITLE: Differing metabolism and bioactivity of atrial and brain natriuretic peptides in essential hypertension.ABSTRACT: Plasma concentrations of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in severe hypertension, acute myocardial infarction, and heart failure. In the current study of individuals with essential hypertension, we have documented the hemodynamic, hormonal, and endocrine effects of infusions of these two peptides given alone or in combination in equimolar doses calculated to induce increments in plasma peptides to concentrations (30 to 60 pmol/L) observed in these disease states. The metabolic clearance rate of ANP (4.56 +/- 0.62 L/min) was greater than that for BNP (3.4 +/- 0.23 L/min, P <.001). Infusions of each cardiac hormone impaired the clearance of coinfused peptide. All peptide infusions enhanced natriuresis (17% to 70% above preinfusion levels versus placebo, 6%; P <.001), lowered blood pressure (10 to 18 mm Hg fall in mean arterial pressure below placebo levels; P <.001), increased hematocrit, suppressed the renin-angiotensin-aldosterone system, and enhanced plasma norepinephrine concentrations. The natriuretic and blood pressure-lowering effects of BNP were twofold to threefold those of ANP. In contrast, ANP-induced increments in plasma and urinary second messenger (cGMP) levels were greater than those for BNP. Both peptides suppressed the renin-angiotensin-aldosterone system (approximately one-third fall in renin activity and plasma aldosterone) and enhanced plasma norepinephrine concentrations (+30%) to a similar degree. Increments in plasma ANP and BNP that occur simultaneously in cardiovascular disease states appear capable of causing hemodynamic, endocrine, and renal effects that would tend to ameliorate conditions such as hypertension or heart failure.

TITLE: Partial vs full beta-receptor agonism. A clinical study of inhaled albuterol and fenoterol.ABSTRACT: To compare the maximal extrapulmonary effects of the beta-agonists albuterol and fenoterol in eight healthy volunteers.In this double-blind study, we have examined the maximum cardiac effects (electromechanical systole [QS2I]--a measure of inotropy, heart rate, BP) and metabolic effects (plasma K+ and cyclic adenosine monophosphate [cAMP]) of repeated inhalation of albuternol and fenoterol. In eight healthy volunteers, 400 microg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (+/- 0.1 mmo l/L for K+, and +/- 10 ms for QS2I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol (ED50F) were calculated.The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs -1.03 mmol/L; p<0.002), QS2I (-71.8 vs 57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p<0.002). The dose required to produce the ED50f was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, QS2I, and cAMP, respectively. There were no significant differences between fenoterol and albuterol with respect to heart rate (Emax, 44.9 vs 32.5 beats/min; p=0.19; potency ratio, 1.98; p=0.052).These findings suggest that albuterol behaves as a partial agonist at beta-receptors when compared with fenoterol, and that when inhaled in doses currently recommended for severe asthma, albuterol will result in lesser maximum cardiac and metabolic effects than fenoterol. These findings are consistent with the hypothesis that the property of full receptor agonism may contribute to the increased risk of death associated with fenoterol.

TITLE: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome.ABSTRACT: The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy.Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation.The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P < 0.001). The probability of event-free survival for five years was 28 percent in the high-dose group and 10 percent in the conventional-dose group (P = 0.01); the overall estimated rate of survival for five years was 52 percent in the high-dose group and 12 percent in the conventional-dose group (P = 0.03). Treatment-related mortality was similar in the two groups.High-dose therapy combined with transplantation improves the response rate, eventfree survival, and overall survival in patients with myeloma.

TITLE: Patient-controlled analgesia for conscious sedation during endoscopic retrograde cholangiopancreatography: a randomized controlled trial.ABSTRACT: Adequate comfort is essential to patients undergoing invasive procedures. This study was designed to evaluate whether patient-controlled analgesia could improve sedation for ERCP.Patients were randomized to receive standard sedation (n = 31) or patient-controlled analgesia (n = 31). The patients were blinded to the randomization. After the procedure the patient, physician, and nurse each rated their satisfaction with sedation using a verbal rating scale.There was no significant difference between the patient's mean satisfaction score for the conventional and patient-controlled analgesia groups (9.3 and 9.6, respectively, p = 0.5). The physicians rated sedation higher in the conventional group compared with the patient-controlled analgesia group (8.6 and 8.2, respectively, p = 0.02). Physicians and nurses' scores correlated (r = 0.53, p = 0.0001), but there was no correlation between scores reported by either physicians or nurses and the patients' scores (r = 0.2 and r = 0.05, respectively). Oxygen saturation less than 90% occurred for more than 1 minute in three patients who received standard sedation but in none who used patient-controlled analgesia.This trial demonstrates that patient-controlled analgesia during ERCP is as effective as standard sedation with respect to patient satisfaction. Physicians and nurses, however, are not good proxies for assessing patient satisfaction.

TITLE: The effects of clonidine premedication on sevoflurane requirements and anesthetic induction time.ABSTRACT: We assessed the effects of oral clonidine preanesthetic medication (4.5 microg/kg) on the vital capacity rapid-inhalation anesthetic induction time (VCRII time) and minimum alveolar anesthetic concentration (MAC) to prevent a response to a verbal command in 50% of patients (MAC-Awake) by its hypnotic effect, and on MAC-Skin incision for the analgesic effect in patients anesthetized with sevoflurane. We studied 104 adult patients (control group: n = 52, clonidine group: n = 52) aged 30-48 yr scheduled to undergo general anesthesia. Fifty-two patients received oral clonidine 4.5 microg/kg 1.5 h before arrival in the operating room (clonidine group). The patients exhaled to residual volume and took three vital capacity breaths of 5% sevoflurane in oxygen. The VCRII time was defined as the time interval between the initiation of the VCRII and the disappearance of the response to verbal command. Anesthesia was maintained with sevoflurane in oxygen and air. The end-tidal (ET) sevoflurane concentration reached a predetermined value, then the ratio of predetermined ET to inspiratory concentration was maintained at > or =0.95 for at least 15 min before skin incision. After skin incision, the patients were observed for gross purposeful muscular movements. MAC was defined as the average of the cross-over midpoints in each cross-over. After maintaining the ET sevoflurane concentration for 15 min, patients were judged to be awake or asleep. Average times for VCRII using 5% sevoflurane were achieved in 44+/-11 s (mean +/- SD) and 27+/-6 s in the control and clonidine groups, respectively (P = 0.0001). MAC-Awake values of sevoflurane were 0.66%+/-0.03% and 0.35%+/-0.02% (P = 0.0001), and MAC-Skin incision values were 1.97%+/-0.19% and 1.29%+/-0.13% (P = 0.0001) in the control and clonidine groups, respectively. These results suggest that clonidine may have a more potent hypnotic effect than analgesic effect.Oral clonidine preanesthetic medication (4.5 microg/kg) significantly reduces vital capacity rapid inhalation anesthetic induction time and minimum alveolar anesthetic concentration awake for sevoflurane.

TITLE: Emergence and clinical relevance of mutations associated with zidovudine resistance in asymptomatic HIV-1 infected patients.ABSTRACT: The dynamics leading to the emergence of a zidovudine-resistant mutation at codon 215 of the reverse transcriptase coding region was investigated in a cohort of HIV-infected individuals who received early zidovudine therapy. Clinical implications and the role of the resistance mutation at codon 41 were also assessed. Thirty-eight initially asymptomatic HIV-infected patients with a CD4+ cell count above 400 cells/mm3 were followed for a mean period of 121 weeks (20 received zidovudine and 18 matching placebo). Specific mutations in the HIV-1 reverse transcriptase coding region conferring resistance to zidovudine were detected using a selective polymerase chain reaction. During the follow-up period a mutation at codon 215 was detected in eight (40%) of the individuals in the zidovudine group, and in two of these eight subjects, a mutation at codon 41 was found. During the study, disease progression occurred in seven of the eight (88%) patients with a mutation at codon 215, compared with 7 of 18 (39%) patients assigned to the placebo group and 3 of the 12 (25%) patients receiving zidovudine treatment who did not develop a 215-mutant strain (p < 0.05). At entry, none of the patients harbored MT-2 tropic virus. Therefore, the emergence of a zidovudine-resistant mutation at codon 215 is associated with subsequent disease progression in asymptomatic HIV-infected patients who receive zidovudine monotherapy. This association suggests that the mutation at codon 215 is involved in a loss of therapeutic efficacy and, therefore, patients should be monitored during treatment with zidovudine.

TITLE: Relationships of blood pressure to fibrinolysis: influence of anthropometry, metabolic profile and behavioural variables.ABSTRACT: To investigate the relationship between blood pressure and the plasma fibrinolytic system and to verify whether this association was independent or mediated by one or more potential confounding factor.A random sample of 94 males aged 38 years subdivided into normotensives, hypertensives and those hypertensives with the highest blood pressure values.Overall and regional obesity, blood lipids, fasting and 2-h post-load glucose, C-peptide and insulin levels, and main behavioural variables, including adipose tissue fatty acid composition (an objective index of dietary fat intake), were measured. The plasma fibrinolytic system was evaluated by determining activities and total plasma concentrations of both tissue-type plasminogen activator before and after venous occlusion, and its inhibitor plasminogen activator inhibitor type-1 (PAI-1).PAI-1 activity was significantly higher in the hypertensives than in the normotensives. PAI-1 antigen tended to parallel PAI-1 activity, and levels of tissue-type plasminogen activator antigen and activity tended to be lower in the hypertensives at baseline and after venous occlusion, but not significantly different from those in the normotensives. The hypertensives also had significantly higher body mass index and body fat content (measured by bio-impedance), increased plasma triglycerides, uric acid, fasting and 2-h glucose, C-peptide and insulin concentrations. In univariate linear regression analysis both systolic and diastolic blood pressures were found to be positively correlated with PAI-1 levels (r = 0.27, P < 0.01, for both). This correlation was maintained after adjustment for total body fat, fasting glucose, fasting insulin concentration or adipose tissue alpha-linolenic acid; however, it was no longer significant after adjustment for plasma 2-h insulin, 2-h C-peptide, 2-h glucose or triglyceride levels. Multivariate regression analysis revealed that only 2-h insulin and triglyceride concentration showed an independent association with PAI-1 levels.This study confirms that, in 38-year-old males, hypertension is associated with increased PAI-1 activity. It supports the possibility that the relationship between blood pressure and PAI-1 may reflect the overall effect of the insulin resistance syndrome (in particular hyperinsulinaemia and hypertriglyceridaemia) rather than a direct effect of blood pressure on the fibrinolytic system.

TITLE: Butorphanol: an opioid for day-care paediatric surgery.ABSTRACT: The purpose of this study was to compare the side effects and efficacy of equianalgesic doses of morphine (M) and butorphanol (B) in children undergoing similar surgical procedures associated with moderate postoperative pain. We studied 156 healthy children aged 1.5-13 yr who underwent elective inguinal herniorrhaphy or orchidopexy. After induction of anaesthesia subjects were given 150 micrograms.kg-1 M or 30 micrograms.kg-1 B following a randomized, stratified, blocked and double-blind design. A standardized anaesthetic was administered, which included 1.5% halothane, vecuronium, droperidol and mechanical ventilation. The postsurgical four-hour follow-up included assessment of pain, vomiting and respiratory depression. Pain was assessed with mCHEOPS and analgesics were administered when indicated in the recovery room. Each opioid was administered to a group of 78 patients. Within each group, 25 subjects had an iv induction, 21 children had an orchidopexy and 57 had inguinal hernia repairs. The groups were similar with respect to age, weight, and length of surgery. The choice of opioid did not affect recovery times from anaesthesia. Analgesic requirements were similar among the groups. Ten minutes after arrival in the recovery room the B-subjects had a lower pain score than the M-patients. Postoperative vomiting was less among the B-subjects: 14% vs 28%, P = 0.03. Two M-patients required an unscheduled admission to hospital because of vomiting. It is concluded that butorphanol has few advantages over morphine in the population studied.

TITLE: Inner city air pollution and respiratory health and atopy in children.ABSTRACT: The impact of inner city air pollution on the development of respiratory and atopic diseases in childhood is still unclear. In a cross sectional study in Dresden, Germany, 5,421 children in two age groups (5-7 yrs and 9-11 yrs) were studied according to the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol. The prevalences of wheezing and cough as well as doctor diagnosed asthma and bronchitis were assessed by parental questionnaires. Children also underwent skin-prick testing, venipuncture for the measurement of serum immunoglobulin (Ig)E, lung function testing and a bronchial challenge test (4.5% saline) to assess airway hyperresponsiveness. Exposure was assessed on an individual basis by relating mean annual air pollution levels (SO2, NO2, CO, benzene, and O3) which had been measured on a 1 km2 grid, to the home and school address of each study subject. After adjusting for potential confounding factors an increase in the exposure to benzene of 1 microg x m3 air was associated with an increased prevalence of morning cough (adjusted odds ratio (aOR)): 1.15; 1.04-1.27) and bronchitis (aOR: 1.11; 1.03-1.19). Similar associations were observed for NO2 and CO. In turn, the prevalences of atopic sensitization, symptoms of atopic diseases and bronchial hyperresponsiveness were not positively associated with exposure to any of these pollutants. It is concluded that in this study a moderate increase in exposure to traffic-related air pollution was associated with an increased prevalence of cough and bronchitis, but not with atopic conditions in children.

TITLE: Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam.ABSTRACT: The calcium channel blockers mibefradil and isradipine inhibit CYP3A4 in vitro. However, their in vivo inhibitory effects on CYP3A4 are not known in detail, although mibefradil was recently withdrawn from the market because of serious drug interactions.The effects of mibefradil and isradipine on the pharmacokinetics and pharmacodynamics of oral triazolam, a model substrate of CYP3A4, were studied in a randomized, double-blind crossover study with three phases. Nine healthy subjects took 50 mg mibefradil, 5 mg isradipine, or placebo orally once a day for 3 days. On day 3, each subject received a single 0.25 mg oral dose of triazolam. Thereafter, blood samples were collected up to 18 hours, and pharmacodynamic effects of triazolam were measured up to 8 hours.Mibefradil increased the total area under the plasma triazolam concentration-time curve [AUC(0 - infinity)] 9-fold compared with placebo (P < .001). The peak plasma concentration of triazolam was increased 1.8-fold (3.4+/-0.1 ng/mL versus 1.8+/-0.2 ng/mL [mean +/- SEM]; P < .001), and the elimination half-life (t 1/2) was increased 4.9-fold (18.5+/-1.9 hours versus 4.0+/-0.5 hours; P < .001) by mibefradil. In addition, mibefradil was associated with increased pharmacodynamic effects of triazolam. In contrast to mibefradil, isradipine reduced the AUC(0 - infinity) and t 1/2 of triazolam by about 20% (P < .05) and had no significant effects on the pharmacodynamics of triazolam.Mibefradil but not isradipine markedly increases the plasma concentrations of triazolam and thereby enhances and prolongs its pharmacodynamic effects, consistent with potent inhibition of CYP3A4.

TITLE: Bone densitometry: a new, highly responsive region of interest in the distal forearm to monitor the effect of osteoporosis treatment.ABSTRACT: The bisphosphonates have been introduced as alternatives to hormone replacement therapy (HRT) for the treatment and prevention of postmenopausal osteoporosis. The expected increasing application in at clinical practice demands cost-effective and easily handled methods to monitor the effect on bone. The weak response at the distal forearm during antiresorptive treatment has restricted the use of bone densitometry at this region. We describe a new model for bone densitometry at the distal forearm, by which the response obtained is comparable to the response in other regions where bone densitometry is much more expensive and technically complicated. By computerized iteration of single X-ray absorptiometry forearm scans we defined a region with 65% trabecular bone. The region was analyzed in randomized, double-masked, placebo- controlled trials: a 2-year trial with alendronate (n = 69), a 1-year trial with ibandronate (n = 141) and a 2-year trial with HRT (n = 121). Bone mineral density (BMD) at the distal forearm revealed a highly statistically significant dose-related response and increased 3-5% per year with 2.5 mg ibandronate, 10 mg alendronate or HRT, whereas the decrease in the placebo groups was 1-3% (p<0.001). The response at the distal forearm was similar to the response at the lumbar spine and hip. In conclusion, trabecular bone at the distal forearm is as responsive to antiresorptive treatment as trabecular bone in other skeletal regions. Bone densitometry at the new region of interest in the distal forearm has comparable performance characteristics to more expensive and technically demanding methods. The method is more accessible clinically and has potential as an alternative for monitoring bone mass changes during antiresorptive treatment.

TITLE: Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers.ABSTRACT: The aim of the study was to investigate the potential effects of chronic digoxin or digitoxin treatment or circadian blood pressure profile in normotensive subjects.In two randomized double-blind, placebo-controlled cross-over protocols, 22 healthy normotensive subjects were enrolled, 12 subjects in either study. After adequate loading doses, digoxin 0.25 mg twice daily or digitoxin 0.1 mg daily was given for a total of 10 days. Automatic 24-h ambulatory blood pressure measurements were carried out at days 4 and 10 of either glycoside or placebo.Digoxin treatment significantly decreased heart rate (HR) and diastolic blood pressure (DBP) during the overnight sleeping phase of day 10 compared with placebo (HR, 4 beats min-1; DBP, 8 mmHg; P < 0.05). Digitoxin treatment significantly decreased heart rate and diastolic blood pressure during the overnight sleeping phase of day 4 (HR, 8 beats min-1; DBP, 7 mmHg) and day 10 (HR, 7 beats min-1; DBP, 5 mmHg) compared with placebo (P < 0.05). Neither digoxin nor digitoxin significantly affected systolic blood pressure.Both digoxin and digitoxin, within therapeutic steady-state plasma concentrations, reduced diastolic blood pressure and heart rate during overnight sleep, presumably because of increased parasympathetic activity or decreased sympathetic activity.

TITLE: Efficacy of ondansetron and prochlorperazine for the prevention of postoperative nausea and vomiting after total hip replacement or total knee replacement procedures: a randomized, double-blind, comparative trial.ABSTRACT: Limited data are available on the efficacy of ondansetron hydrochloride compared with prochlorperazine maleate for the treatment of postoperative nausea and vomiting (PONV).To evaluate the comparative efficacy of ondansetron and prochlorperazine for the prophylaxis of PONV in patients undergoing total hip replacement or total knee replacement procedures.A randomized, double-blind, comparative trial was conducted at a tertiary care, university hospital. Seventy-eight patients undergoing elective total hip or total knee replacement procedures received a single dose of ondansetron hydrochloride (n = 37), 4 mg intravenously, or prochlorperazine maleate (n = 41), 10 mg intramuscularly, at the end of the surgical procedure. Rescue therapy was administered every 4 hours as needed during the initial 48 hours. Primary outcome measures were the incidences and severity of PONV. Secondary outcome measures included the number of rescue antiemetic doses required, number of physical therapy cancellations because of PONV, length of hospital stay, and cost of antiemetic agents administered.The incidence of nausea was significantly greater in the ondansetron group compared with the prochlorperazine group (81% vs 56%; odds ratio, 3.4; 95% confidence interval, 1.2-9.4) as was the severity of nausea (P = .04). Multivariate analysis identified administration of ondansetron, history of PONV, obesity, and female sex as risk factors for a nausea event. The incidence of vomiting tended to be greater in the ondansetron group (49% vs 32%; odds ratio, 2.0; 95% confidence interval, 0.8-5.0). The need for rescue antiemetic therapy was also greater in the ondansetron group (46% vs 27%; odds ratio, 2.3; 95% confidence interval, 0.9-6.0). The mean antiemetic drug cost per patient was significantly greater for the ondansetron group ($47.56 vs $2.47; P<.001). However, the proportion of patients who were unable to participate in physical therapy because of PONV and the median length of hospital stay were similar in both groups.Prochlorperazine is associated with superior efficacy and significant cost savings compared with ondansetron for the prevention of PONV in patients undergoing total hip and total knee replacement procedures.

TITLE: Effect of diaspirin cross-linked hemoglobin on endothelin-1 and blood pressure in acute ischemic stroke in man.ABSTRACT: For almost 50 years it has been known that hemolysed blood can increase blood pressure. Although preclinical studies suggest that this pressor response is due to an interaction of hemoglobin with endothelium-derived vasoactive substances, its mechanism in humans is unknown. We investigated the involvement of endothelin-1 in the blood pressure response to the oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) in stroke patients.In a randomized phase II study, increasing doses of DCLHb (25, 50 and 100 mg/kg, n=8, 8 and 11, respectively) or placebo (n=26) were infused intravenously every 6 h for 72 h to patients with an acute ischemic stroke. Blood pressure and heart rate were measured every 15 min and plasma concentrations of endothelin-1, catecholamines, renin, vasopressin and atrial natriuretic peptide were measured before and 24 and 66 h after the start of the infusions.In the placebo group, mean arterial pressure (MAP) was 112 (109-115) mmHg (mean and 95% confidence interval) at baseline and decreased spontaneously by 11.4 (5.4-17.5) and 12.5 (5.4-19.5) mmHg after 24 and 66 h, respectively. This decrease in MAP was attenuated in patients treated with DCLHb, reaching statistical significance in the highest dose group. The plasma endothelin-1 concentration decreased slightly in the placebo group, from 4.2 (3.1-5.3) pg/ml (median and range) at baseline to 2.4 (1.9-3.7) pg/ml after 24 h (P=0.0044) and 2.8 (1.9-3.7) pg/ml after 66 h (P=0.0042), but increased dose-dependently in response to DCLHb infusion. With the highest dose of DCLHb, the plasma endothelin-1 concentration rose from 4.8 (0.1-7.8) pg/ml at baseline to 21.2 (13.4-53.2) pg/ml after 24 h (P< 0.001) and to 27.6 (11.9-47.8) pg/ml after 66 h (P< 0.001). The increases in the plasma endothelin-1 concentration and in MAP were correlated (r=0.30, P=0.02). Other vasoactive hormones were not affected by the DCLHb infusion.Infusion of DCLHb in patients with acute ischemic stroke was associated with a dose-dependent increase in plasma endothelin-1 concentration. This may underlie the attenuation by DCLHb of the natural decrease in blood pressure that we observed in these patients.

TITLE: Effects of an ionic versus a nonionic low osmolar contrast agent on the thrombotic complications of coronary angioplasty.ABSTRACT: An increasing body of evidence suggests that the potential for thrombotic complications is greater with nonionic than with ionic contrast agents. This is a particularly important consideration in the highly thrombogenic setting of percutaneous transluminal coronary angioplasty (PTCA). To explore this issue further, 500 consecutive patients undergoing PTCA were prospectively randomized to receive the low osmolality ionic ioxaglate or the nonionic agent iohexol. The number of acute thrombotic in-laboratory events was significantly less in the ioxaglate than in the iohexol group (8 versus 18; P < 0.05), but there was no significant difference between the 2 groups as regards the number of out-of-laboratory acute rethrombotic events. With multivariate analysis, use of the nonionic agent rather than the ionic agent emerged as an independent predictor of acute in-laboratory rethrombosis. These data suggest that, in the performance of PTCA, an ionic, rather than a nonionic, should be the preferred contrast agent.

TITLE: Weight gain of Kenyan school children infected with hookworm, Trichuris trichiura and Ascaris lumbricoides is improved following once- or twice-yearly treatment with albendazole.ABSTRACT: We studied growth in infected children given one dose (600 mg) or two doses of albendazole per school year. Children were examined and allocated at random within sex by descending hookworm egg count to one of three groups: placebo (n = 93), one dose (1x, n = 96) or two doses (2x, n = 95). Each child was treated and then re-examined and treated 3.6 and 8.2 mo later (Exams 2 and 3). The 1x and 2x groups gained significantly more by Exam 3 than the placebo group in weight (1.1 and 0.9 kg more, respectively), percent weight-for-age (3.3 and 2.7 percentage points more), percent weight-for-height (3.1 and 2.9 percentage points more), percent arm circumference-for-age (2.3 and 2.0 percentage points more) and triceps and subscapular skinfolds but did not differ significantly from each other. The placebo group showed significant decreases between exams (P < 0.0002) in percent weight-for-age and percent arm circumference-for-age and no change in percent weight-for-height, whereas the 1x and 2x groups exhibited significant increases (P < 0.005). At Exam 3, arithmetic mean egg reduction rates for the 1x and 2x groups were 84 and 95% for hookworm, 42 and 32% for Trichuris and 55 and 87% for Ascaris, respectively. We conclude that one or two doses of albendazole per year resulted in similar growth improvements, despite reinfection, in school-age children in an area where these helminths and poor growth are prevalent.

TITLE: Effects of enalapril on ventricular volumes and neurohumoral status after inferior wall myocardial infarction.ABSTRACT: The activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and its beneficial modification with the use of angiotensin-converting enzyme inhibin after inferior wall myocardial infarction (MI) was evaluated. Fifty patients with acute inferior MI were randomly assigned to receive 5 mg per day of either enalapril or placebo after admission. Blood tests for neurohormone levels and echocardiograms were performed at initial examination and 4 weeks later. Baseline characteristics were similar in the two groups. Four weeks after randomization, patients treated with enalapril had lower end-diastolic volume (146 +/- 29 vs 167 +/- 15 ml; p = 0.04), end-systolic volume (56 +/- 18 vs 107 +/- 17 ml; p = 0.03), serum norepinephrine levels (320 +/- 93 vs 465 +/- 77 pg/ml; p < 0.01), angiotensin II levels (18 +/- 6 vs 54 +/- 11 pg/ml; p < 0.01), and atrial natriuretic polypeptide levels (106 +/- 9 vs 122 +/- 17 pg/ml; p = 0.05) than patients given placebo. The incidence of heart failure after MI was also lower in this group (4% vs 16%; p = 0.009). Results show that there is early neurohumoral activation in the course of acute inferior wall MI. Enalapril reduces neurohumoral levels and preserves ventricular volumes. These effects were associated with a reduction in the incidence of heart failure 4 weeks after MI in these patients.

TITLE: Relationship between salt and blood pressure in hypertensive patients on chronic ACE-inhibition.ABSTRACT: We investigated the effect of a 4-day oral salt load (150 mmol NaCl extra per day) on blood pressure, erythrocyte sodium transport and the activity in the renin-angiotensin system in six males with primary hypertension, who had attained normotension on chronic enalapril treatment for 4 years. The design was a placebo-controlled, randomized, two-way cross over, double-blind study, i.e. each patient served as his own control. Intracellular erythrocyte sodium and potassium content were measured by flame photomometry. The increase in the intracellular sodium concentration during 1 h in 37 degrees C incubation of whole-blood with ouabain (compared with no-ouabain) was measured to determine the rate of active sodium efflux. 24-h blood pressure registration was performed with Space-lab equipment (SL 90202) before and at the end of the salt load. Left ventricular morphology was evaluated with echocardiography and the minimal vascular resistance of the hand vascular bed with water plethysmography at baseline and after 4 years on enalapril. Four years' enalapril treatment caused a significant decrease in blood pressure, left ventricular mass and minimal vascular resistance. During the 4-day salt load average 24-h blood pressure was significantly elevated, 129+/-3/85+/-2 mmHg as compared to 124+/-2/82+/-2 mmHg during placebo treatment (p=0.025). The change (delta) in MAP during high salt intake showed a negative relationship to delta-sodium efflux rate constant (r=-0.65, p=0.047). No significant relationship was found between the blood pressure response to the salt load and structural cardiovascular changes. In conclusion, a short-term oral salt load in hypertensive patients on chronic enalapril treatment caused a blood pressure rise, which was related to cellular sodium transport but not to structural cardiovascular changes.

TITLE: Re-evaluation of i.m. ephedrine as prophylaxis against hypotension associated with spinal anaesthesia for Caesarean section.ABSTRACT: To assess the safety and efficacy of 37.5 mg ephedrine i.m. in preventing hypotension associated with spinal anaesthesia for Caesarean section.In a double-blind randomised controlled study, 40 patients (20 in each group) were given either 37.5 mg ephedrine or placebo i.m. The following parameters were recorded: (i) blood pressure; (ii) heart rate; (iii) ephedrine i.v. supplementation; (iv) umbilical venous blood gases and neonatal Apgar scores.The incidence of hypertension in the study group was 30% compared with 20% for the control group (P:NS). There was no difference in mean highest blood pressure or mean highest heart rate between the groups. The incidence of hypotension was lower but not significantly lower in the study group (50%) than in the control group (80%) (P:NS). However, the incidence of delayed hypotension was only 10% in the study group patients compared with 50% in the control group patients (P < 0.05).Giving 37.5 mg ephedrine i.m. prior to spinal anaesthesia was not associated with reactive hypertension or tachycardia. Intramuscular ephedrine provided more sustained cardiovascular support than intravenous ephedrine.

TITLE: Insulin therapy in burn patients does not contribute to hepatic triglyceride production.ABSTRACT: Lipid kinetics were studied in six severely burned patients who were treated with a high dose of exogenous insulin plus glucose to promote protein metabolism. The patients were 20+/-2-yr-old (SD) with 63+/-8% total body surface area burned. They were studied in a randomized order (a) in the fed state on the seventh day of a control period (C) of continuous high-carbohydrate enteral feeding alone, and (b) on the seventh day of enteral feeding plus exogenous insulin (200 pmol/h = 28 U/h) with extra glucose given as needed to avoid hypoglycemia (I+G). Despite a glucose delivery rate approximately 100% in excess of energy requirements, the following lipid parameters were unchanged: (a) total hepatic VLDL triglyceride (TG) secretion rate (0.165+/-0.138 [C] vs. 0.154+/- 0.138 mmol/kg . d-1 [I+G]), (b) plasma TG concentration (1.58+/-0.66 [C] vs. 1. 36+/-0.41 mmol/liter [I+G]), and (c) plasma VLDL TG concentration (0. 68+/-0.79 [C] vs. 0.67+/- 0.63 mmol/liter [I+G]). Instead, the high-carbohydrate delivery in conjunction with insulin therapy increased the proportion of de novo-synthesized palmitate in VLDL TG from 13+/-5% (C) to 34+/-14% (I+G), with a corresponding decreased amount of palmitate from lipolysis. In association with the doubling of the secretion rate of de novo-synthesized fatty acid (FA) in VLDL TG during insulin therapy (P > 0.5), the relative amount of palmitate and stearate increased from 35+/-5 to 44+/-8% and 4+/-1 to 7+/-2%, respectively, in VLDL TG, while the relative concentration of oleate and linoleate decreased from 43+/-5 to 37+/-6% and 8+/-4% to 2+/-2%, respectively. A 15-fold increase in plasma insulin concentration did not change the rate of release of FA into plasma (8.22+/-2.86 [C] vs. 8.72+/-6.68 mmol/kg.d-1 [I+G]. The peripheral release of FA represents a far greater potential for hepatic lipid accumulation in burn patients than the endogenous hepatic fat synthesis, even during excessive carbohydrate intake in conjunction with insulin therapy.

TITLE: An oral sodium citrate-citric acid non-particulate buffer in humans.ABSTRACT: We have investigated the effect on the pH of the gastric fluid of a single dose of sodium citrate 0.3 mol litre-1 (antacid) and a solution containing sodium citrate dehydrate (100 mg ml-1) with citric acid monohydrate (66 mg ml-1) (buffer). The dose for both solutions was 0.4 ml kg-1 via a nasogastric tube. Each group comprised 10 patients undergoing neurosurgical operations of 5-7 h duration. A control group of 10 patients received no gastric solution. The pH of the gastric aspirate was measured hourly using a Metrohm 632 digital pH meter (Synectics Medical, Sweden). Mean baseline gastric pH was 2.64 (SD 1.71). In the control group, pH increased to 4.4 (1.51) at 5 h, returning to baseline at 7 h. In the antacid group, pH increased to 6.11 (0.47) at 15 min and decreased to 3.70 (1.94) at 7 h (P < 0.01). In the buffer group, pH was stable at 3.80-3.95 (0.22) over 7 h (P > 0.01). Total mean gastric aspirate was 0.5 ml kg-1.

TITLE: A randomised, double-blind, parallel-group study to compare the efficacy and safety of ondansetron (GR38032F) plus dexamethasone with metoclopramide plus dexamethasone in the prophylaxis of nausea and emesis induced by carboplatin chemotherapy.ABSTRACT: A double-blind, parallel-group study in 189 ovarian cancer patients compared the efficacy of ondansetron 8 mg i.v. (OND) and metoclopramide 60 mg i.v. (MET) both in combination with dexamethasone 20 mg i.v. in the prevention of carboplatin-induced emesis. On day 1, complete or major control of emesis (0-2 emetic episodes) was observed in 97% patients from the OND group compared with 74% patients from the MET group (p < 0.001). Similarly, a worst-day analysis over days 1-3 showed complete or major control of emesis in 87% patients (OND) compared wth 66% patients (MET) (p < 0.001). Similar findings in favour of the OND group were observed for nausea grade on day 1 and the worst-day grade during days 1-3. OND was better tolerated than MET. Fewer patients from the OND group (13%) reported adverse events compared with the MET group (21%). Extrapyramidal type symptoms were observed in 6 (6%) patients from the MET group (paraesthesia, involuntary movement of the jaw and tongue, and restlessness), compared with none from the OND group. Ondansetron plus dexamethasone is a highly effective and well-tolerated treatment and is significantly superior to metoclopramide plus dexamethasone in the prevention of carboplatin-induced emesis.

TITLE: Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. Swedish Breast Cancer Cooperative Group.ABSTRACT: Postsurgical treatment with tamoxifen has been shown to improve overall survival among patients with early stage breast cancer. However, the optimal duration of tamoxifen treatment remains controversial.A multicenter, randomized trial was initiated in Sweden in the early 1980s to compare 2 years with 5 years of adjuvant tamoxifen in the treatment of postmenopausal women younger than 75 years of age who had early stage, axillary lymph node-negative or -positive, invasive disease.The trial was planned and organized by the Swedish Breast Cancer Group, and it involved five regional breast cancer study organizations (South Sweden, South-East Sweden, Stockholm, Uppsala-Orebro, and North Sweden). During the period from 1983 through 1991, a total of 3887 patients were entered in the trial; 3545 (91%) women remained alive and recurrence free at 2 years and could thus contribute meaningful information to the 2-year (n = 1801) versus 5-year (n = 1744) comparison. Primary surgery consisted of either modified radical mastectomy or breast-conserving surgery. Radiation therapy was indicated for patients with lymph node-positive disease and was generally offered to all women who were treated with breast-conserving surgery. Only 89 (2.5%) of the 3545 women who were recurrence free at 2 years received adjuvant chemotherapy concurrently with tamoxifen. Twenty-milligram daily doses of tamoxifen were used at two centers, and 40-mg daily doses were used at the remaining three centers. Estrogen receptor status of the tumor was known for 2987 women (77% of the entered patients). Primary end points in the trial were event-free survival (local-regional recurrence, distant metastasis, contralateral breast cancer, or death) and overall survival. Survival curves were estimated by use of the life-table method. The Cox proportional hazards model was used to make comparisons between the 2- and 5-year treatment groups.Patients assigned to receive 5 years of tamoxifen, compared with 2 years of tamoxifen, experienced statistically significant improvements in event-free survival (relative hazard = 0.82; 95% confidence interval [CI] = 0.71-0.96) and overall survival (relative hazard = 0.82; 95% CI = 0.69-0.99). These findings translate into an 18% relative reduction in both first events (95% CI = 4%-29%) and mortality (95% CI = 1%-31%) with the longer treatment. Overall survival at 10 years was estimated to be 80% among patients in the 5-year tamoxifen group who were alive and recurrence free at 2 years, compared with 74% among corresponding patients in the 2-year treatment group. The benefit associated with the longer treatment extended to women with lymph node-positive as well as lymph node-negative disease, but it appeared to be restricted to women whose tumors were classified as estrogen receptor positive.Five years of adjuvant tamoxifen is more beneficial than 2 years in the treatment of postmenopausal women with estrogen receptor-positive, early stage, invasive breast cancer.

TITLE: Hemodynamic effects of the class III antiarrhythmic drug, d-sotalol, in patients with congestive heart failure.ABSTRACT: In contrast to Vaughan Williams class I drugs, class III drugs, such as d-sotalol, may not be negative inotropic. These drugs block potassium ion channels and prolong repolarization, theoretically leading to improved contractility. We investigated the hemodynamic actions of acute intravenous administration of 1.5 mg/kg of d-sotalol in 28 patients with congestive heart failure randomized to receive placebo (n = 10) or active drug (n = 18) in a double-blind study. A Swan-Ganz catheter was placed in all patients > or = 16 hours before drug administration. All hemodynamic variables were assessed at baseline and 30 minutes and 1, 2, 4, 8, and 12 hours after administration of the drug. Electrocardiograms were obtained before and 1, 2, 4, and 12 hours after drug administration. The QT interval increased from 370 +/- 9 to 426 +/- 14 ms at 1 hour, whereas the QTc increased from 433 +/- 5 to 470 +/- 12 ms (both p < 0.001). The increase was still statistically significant at 12 hours. There was no change in the placebo group. Although heart rate decreased in the d-sotalol group (84 +/- 2 to 76 +/- 2 at 1 hour, p < 0.001), there were no changes in blood pressure or right atrial pressure. Cardiac index decreased slightly (2.0 +/- 0.2 to 1.9 +/- 0.1 mm Hg), consistent with the lower heart rate. Pulmonary capillary wedge pressure decreased from 18.9 +/- 2.4 to 17.9 +/- 1.9 mm Hg at 1 hour despite reduced cardiac index. We conclude that in contrast to class I, II, and IV antiarrhythmic drugs, d-sotalol exerts no clinically important acute hemodynamic actions at doses that produce electrophysiologic effects.

TITLE: Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group.ABSTRACT: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma.To compare the clinical benefit of montelukast, a once-daily oral leukotriene receptor antagonist; placebo; and inhaled beclomethasone.Randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 12-week study.36 sites worldwide.895 patients 15 to 85 years of age with chronic asthma and an FEV1 50% to 85% of predicted.Montelukast, 10 mg once daily at bedtime; inhaled beclomethasone, 200 microg twice daily, administered with a spacer device; or placebo.Primary end points were daytime asthma symptom score and FEV1. Secondary end points were peak expiratory flow rates in the morning and evening, as-needed beta-agonist use, nocturnal awakenings, asthma-specific quality of life, and worsening asthma episodes.Over the 12-week treatment period, the average percentage change from baseline in FEV1 was 13.1% with beclomethasone, 7.4% with montelukast, and 0.7% with placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). The average change from baseline in daytime symptom score was -0.62 for beclomethasone, -0.41 for montelukast, and -0.17 for placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). Each agent improved peak expiratory flow rates and quality of life, reduced nocturnal awakenings and asthma attacks, increased the number of asthma-control days, and decreased the number of days with asthma exacerbations (P < 0.001 for each active treatment compared with placebo for each end point; P < 0.01 for beclomethasone compared with montelukast for each end point). Although beclomethasone had a greater mean clinical benefit than montelukast, montelukast had a faster onset of action and a greater initial effect. The two agents caused similar decreases in peripheral blood eosinophil counts (P < 0.05 for each agent compared with placebo). Both agents had tolerability profiles similar to that of placebo over the 12-week study.Although beclomethasone had a larger mean effect than montelukast, both drugs provided clinical benefit to patients with chronic asthma. This finding is consistent with the use of these agents as controller medications for chronic asthma.

TITLE: The contribution of the swallowed fraction of an inhaled dose of salmeterol to it systemic effects.ABSTRACT: Salmeterol is approximately eight times as potent as salbutamol for systemic effects. This may be because the drug is eight times more potent on receptors or there may be differences in systemic bioavailability. The systemic effects of salbutamol are limited by its fairly high first-pass metabolism, but the oral bioavailability of salmeterol is unknown. The contribution of the swallowed fraction of an inhaled dose of salmeterol to its systemic effects were analysed in a randomized, double-blind, crossover study. Twelve healthy subjects were given inhaled salmeterol 400 microg, inhaled salmeterol 400 microg plus oral activated charcoal or inhaled placebo plus oral activated charcoal on three separate days. Cardiac frequency (fC), Q-T interval corrected for heart rate (QTc), plasma potassium and glucose concentrations were measured for 4 h following the inhaled drug. Salmeterol with and without oral charcoal produced significant changes for all measures compared to placebo. The magnitude of effect following salmeterol alone was significantly greater than that following salmeterol plus charcoal for fC and glucose (mean (95% confidence interval) differences 8 (2-13) beats x min(-1), 0.59 (0.04, 1.13) mmol x L(-1), respectively) and nonsignificantly greater for QTc interval and potassium concentration. The differences between salmeterol given with and without charcoal suggest that 28-36% of the systemic response to salmeterol administered from a metered-dose inhaler are due to drug absorbed from the gastrointestinal tract. Thus, most of the systemic effects are due to the inhaled fraction of the drug.

TITLE: Corticosteroid treatment of erythema multiforme major (Stevens-Johnson syndrome) in children.ABSTRACT: The effectiveness of systemic corticosteroids in erythema multiforme major (EMM) is controversial. We therefore evaluated the efficacy of corticosteroids in the treatment of EMM in a prospective study of 16 children with EMM admitted to our department within 3 days from the onset of rash. Ten patients (group A) received bolus infusions of methylprednisolone (4 mg/kg/day) while six had only supportive treatment (group B). The early use of corticosteroids compared to supportive treatment resulted in: (1) significant reduction of the period of fever (4.0 +/- 1.9 vs 9.5 +/- 4.2 days P = 0.01); (2) reduction of the period of acute eruption (7.0 +/- 3.3 versus 9.8 +/- 3.0 days P = 0.08); and (3) milder signs of prostration. Complications were minimal in both groups.The early and short course of corticosteroids favourably influences the course of erythema multiforme major in children.

TITLE: Triazolam is ineffective in patients taking rifampin.ABSTRACT: Triazolam is metabolized predominantly by cytochrome P450 3A4 (CYP3A4). Rifampin (rifampicin) is a potent inducer of CYP3A4 and it is known to markedly reduce plasma concentrations and effects of drugs such as midazolam. The possible interaction between rifampin and triazolam was examined in this study.The pharmacokinetics and pharmacodynamics of triazolam were investigated in a randomized, double-blind crossover study with two phases. Ten young healthy volunteers took either 600 mg rifampin once daily or placebo for 5 days. On the sixth day, 0.5 mg triazolam was administered orally. Timed blood samples were collected and the effects of triazolam were measured with five psychomotor tests for 10 hours.The area under the plasma triazolam concentration-time curve in the rifampin phase was only 5.1% of that in the placebo phase (0.74 +/- 0.14 versus 14.8 +/- 1.0 ng.hr/ml [mean +/- SEM; p < 0.001]). Rifampin pretreatment decreased the maximum plasma concentration of triazolam to 12.4% of the control value (i.e., from 2.9 +/- 0.2 to 0.36 +/- 0.06 ng/ml [p < 0.001]) and the elimination half-life from 2.8 +/- 0.1 to 1.3 +/- 0.1 hours (p < 0.001). All psychomotor tests showed markedly reduced effects (p < 0.01) of triazolam after rifampin pretreatment.Triazolam is ineffective during rifampin treatment. This is most likely due to increased metabolism of triazolam after induction of CYP3A4 in the gut wall and liver by rifampin. It is advisable to use hypnotic agents that are not metabolized by CYP3A4 during treatment with rifampin or other potent inducers of CYP3A4.

TITLE: Post-partum urinary retention: a comparison between two methods of epidural analgesia.ABSTRACT: To compare two methods of epidural labor analgesia regarding the incidence of post-partum urinary retention.One thousand parturients who requested epidural analgesia for the relief of labor pain received, at random, either bupivacaine 0.25% with adrenaline 1:200 000 (n = 500) or bupivacaine 0.125% with 10 micrograms sufentanil (n = 500). During the same observation period all women with clinically significant urinary retention (> 500 ml, requiring indwelling catheter) were registered.Altogether 30/3.364 parturients had clinically significant urinary retention. Twenty-seven of these had received epidural analgesia (EDA) (17 with bupivacaine/adrenaline and ten with bupivacaine/sufentanil, a non-significant differences). The number of parturients with urinary retention was highly increased following EDA (27/1000) as compared to those not receiving EDA (3/2364), P < 0.001 (Fisher's exact test). In patients with EDA and urinary retention there were no difference between the groups in the incidence of instrumental deliveries or vaginal/perirectal tears. All parturients regained normal bladder function.EDA significantly increased the risk of post-partum urinary retention but no difference was found between the two epidural techniques.

TITLE: Use of tunneled femoral catheters to prevent catheter-related infection. A randomized, controlled trial.ABSTRACT: The risk for catheter-related infection seems higher with femoral catheters than with catheters inserted at other sites.To evaluate the effect of catheter tunneling on femoral catheter-related infection in critically ill patients.Randomized, controlled trial.Three intensive care units at academic hospitals in Paris, France.345 adult patients requiring a femoral venous catheter for more than 48 hours.Tunneled or nontunneled femoral catheters.Time to occurrence of systemic catheter-related sepsis, catheter-related bloodstream infection, and quantitative catheter tip culture with a cutoff of 10(3) colony-forming units/mL.Of 345 randomly assigned patients, 336 were evaluable. Probable systemic catheter-related sepsis occurred in 15 of 168 patients who received a nontunneled femoral catheter (controls) and in 5 of 168 patients who received a tunneled femoral catheter (estimated absolute risk reduction, 6% [95% CI, 0.9% to 11%]). Time to occurrence of catheter-related bloodstream infection was not significantly modified (relative risk, 0.28 [CI, 0.03 to 1.92]; P = 0.18); 3 events occurred in the control group and 1 event occurred in the tunneled-catheter group. After stratification by treatment center and adjustment for variables that were prognostic (use of broad-spectrum antimicrobial agents at catheter insertion) or imbalanced between both groups (mechanical ventilation at insertion), tunnelized catheterization reduced the proportion of patients who developed systemic catheter-related sepsis (relative risk, 0.25 [CI, 0.09 to 0.72]; P = 0.005) and positive quantitative culture of the catheter tip (relative risk, 0.48 [CI, 0.23 to 0.99]; P = 0.045).The incidence of femoral catheter-related infections in critically ill patients can be reduced by using subcutaneous tunneling.

TITLE: A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic subjects receiving regular salmeterol or formoterol.ABSTRACT: Regular treatment with inhaled, long-acting beta2 -agonists is associated with subsensitivity for bronchoprotective effects. It is not known whether a high dose of short-acting beta2 -agonist could overcome this subsensitivity.The objective of this study was to investigate the acute effects of a high dose of inhaled albuterol on methacholine-induced bronchoconstriction in patients receiving regular treatment with salmeterol or formoterol.Ten stable asthmatic subjects (mean age, 34 years; FEV1, 77% of predicted value), all taking inhaled corticosteroids (methacholine PD20 < 500 microg), were recruited into a randomized, single-blind, crossover study. After an initial 1-week run-in period, subjects underwent 3 separate treatment periods each of 9 days (separated by a washout of at least 5 days) comprising inhaled placebo twice daily, inhaled salmeterol dry powder 50 microg twice daily, or inhaled formoterol dry powder 12 microg twice daily. Methacholine challenge was performed 1 hour after the first dose and after 7 days of treatment. After 9 days of treatment, a third methacholine challenge was performed 1 hour after inhalation of a single 1600 microg dose of albuterol dry powder.There was significant (P <.001) improvement in geometric mean PD20 after the first dose of active treatment as compared with placebo (78 microg) versus salmeterol (266 microg, a 3.4-fold difference [95% CI 1.9 to 6.1]) and versus formoterol (318 microg, a 4.1-fold difference [95% CI 2.3 to 7.3]). This bronchoprotection diminished with regular treatment, although it remained significant (P <.01) compared with placebo (68 microg) versus salmeterol (144 microg, a 2.1-fold difference [95% CI 1.2 to 3.8]) and versus formoterol (230 microg, 3.4-fold difference [95% CI 1.9 to 6.2]). After 9 days, the protection afforded by a single dose of albuterol after placebo pretreatment (889 microg) was significantly (P =.005) higher in comparison with albuterol protection after salmeterol pretreatment (338 microg, a 2.7-fold difference [95% CI 1.1 to 6.8]) and after formoterol pretreatment (247 microg, a 3.6-fold difference [95% 1.4 to 9.1]).Thus in stable asthmatic subjects receiving regular salmeterol or formoterol, bronchoprotective subsensitivity was not overcome by administering a high dose of albuterol. Further studies are required to evaluate the clinical relevance of this pharmacologic phenomenon when albuterol is used in acute asthma.

TITLE: Serum S100beta release after coronary artery bypass grafting: roller versus centrifugal pump.ABSTRACT: Microemboli generated during cardiopulmonary bypass (CPB) are implicated in the cerebral injury seen after coronary artery bypass grafting. Centrifugal pumps generate fewer microemboli than roller pumps. Increased S100beta levels have been reported after coronary artery bypass grafting, with levels greater than 1 ng/mL resulting in poorer neuropsychologic outcome. This study investigated the potential neurologic benefits of centrifugal pumps, by using S100beta as a marker for cerebral injury.Thirty-two patients who had coronary artery bypass grafting were randomly assigned to two groups. Serial blood samples (preoperative, end of bypass, 30 minutes, and 2 and 24 hours after cardiopulmonary bypass) were taken and the serum analyzed for S100beta using a new immunoluminometric assay.Both groups were matched for age, number of grafts, and cardiopulmonary bypass and cross-clamp times. Postoperative serum S100beta levels were significantly higher in both groups than preoperative levels. Peak S100beta levels did not correlate with cardiopulmonary bypass time; however, 24-hour S100beta levels correlated with intubation time r = 0.40, p = 0.04). Th ere was no significant difference in S100beta levels between the groups at any of the time points.S100beta levels increased after coronary artery bypass grafting. Centrifugal pumps do not significantly decrease S100beta release. Persistently increased S100beta levels are associated with longer intubation times.

TITLE: A vitamin E concentrate rich in tocotrienols had no effect on serum lipids, lipoproteins, or platelet function in men with mildly elevated serum lipid concentrations.ABSTRACT: Tocotrienols, lipid-soluble antioxidants with vitamin E activity, have been reported to lower LDL-cholesterol concentrations and platelet aggregation in men, but results are contradictory.To examine in detail the effects of a vitamin E concentrate rich in tocotrienols on serum lipoproteins and on platelet function in men at risk for cardiovascular disease.In this randomized, double-blind, placebo-controlled parallel trial, 20 men received daily for 6 wk 4 capsules, each containing 35 mg tocotrienols and 20 mg alpha-tocopherol; 20 other men received 4 capsules daily, each providing 20 mg alpha-tocopherol. All men had concentrations of serum total cholesterol between 6.5 and 8.0 mmol/L or lipoprotein(a) concentrations > 150 mg/L.Compliance was confirmed by changes in serum tocopherol and tocotrienol concentrations. Serum LDL cholesterol in the tocotrienol group was 4.80 mmol/L before and 4.79 mmol/L after intervention, and increased from 4.70 to 4.86 mmol/L in the placebo group (95% CI for the difference: -0.54, 0.19 mmol/L; P = 0.333). Also, changes in HDL cholesterol, triacylglycerol, lipoprotein(a), and lipid peroxide concentrations did not differ between the groups. After adjustment for differences in initial values, no effects were found on collagen-induced platelet aggregation velocity, maximum aggregation, or thromboxane B2 formation in citrated whole blood. ATP release, however, was lower in the tocotrienol group. Urinary thromboxane B2 and 11-keto-thromboxane B2 concentrations and coagulation and fibrinolytic measures did not change.The tocotrienol supplements used had no marked favorable effects on the serum lipoprotein profile or on platelet function in men with slightly elevated lipid concentrations.

TITLE: Clonidine premedication modifies responses to adrenoceptor agonists and baroreflex sensitivity.ABSTRACT: To evaluate the effects of clonidine on responses to adrenoceptor agonists and baroreflex sensitivity, we examined arterial blood pressure (AP) responses to phenylephrine and heart rate (HR) responses to isoproterenol and baroreflex sensitivity (HR response to AP changes due to phenylephrine or nitroglycerin).We studied 60 anaesthetized patients who either did or did not receive 5 micrograms.kg-1 clonidine po before they were anaesthetized. After induction of general anaesthesia, the patients received 3 micrograms.kg-1 phenylephrine, 0.02 microgram.kg-1 isoproterenol, or 2-3 micrograms.kg-1 nitroglycerin, and haemodynamic measurements were taken. Baroreflex sensitivity was expressed as the slope of the linear regression line (msec.mmHg-1; in msec of R-R interval change vs mmHg change in systolic arterial pressure) following the administration of phenylephrine and nitroglycerin.Patients who received clonidine had greater augmented responses in AP to phenylephrine and in HR to isoproterenol (47.2 +/- 15.6% vs 23.7 +/- 11.9% for increase in systolic AP and 59.8 +/- 22.6% vs 26.2 +/- 11.0% for increase in HR, P < 0.05 respectively). There were no differences between the baroreflex sensitivities in the pressor (phenylephrine) test groups (3.77 +/- 1.08 vs 4.41 +/- 1.66 msec.mmHg-1). In contrast, the slopes of depressor (nitroglycerin) test groups were decreased in patients receiving clonidine (1.98 +/- 0.73 vs 3.68 +/- 1.72 msec.mmHg-1, P < 0.05).The results suggest that premedication with clonidine might enhance critical hypotension during anaesthesia and surgery, but restoration both of AP and HR decrease can be achieved effectively by phenylephrine and isoproterenol i.v., respectively.

TITLE: Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex hormone receptor activity--a controlled crossover trial.ABSTRACT: Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages including cholesterol reduction, antioxidant activity, and possibly a reduced cancer risk. However, the concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic subjects underwent two 1-month low-fat metabolic diets in a randomized crossover study. The major differences between the test and control diets were an increase in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000 kcal/d and a doubling of the soluble fiber intake. Fasting blood samples were obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the end of each phase. Soy foods increased urinary isoflavone excretion on the test diet versus the control (3.8+/-0.7 v 0.0+/-0.0 mg/d, P < .001). The test diet decreased both oxidized LDL measured as conjugated dienes in the LDL fraction (56+/-3 v 63+/-3 micromol/L, P < .001) and the ratio of conjugated dienes to LDL cholesterol (15.0+/-1.0 v 15.7+/-0.9, P = .032), even in subjects already using vitamin E supplements (400 to 800 mg/d). No significant difference was detected in ex vivo sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high-isoflavone foods was associated with reduced levels of circulating oxidized LDL even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular disease risk without increasing the risk for hormone-dependent cancers.

TITLE: Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland)ABSTRACT: Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and beta-carotene might be associated with reduced risk of colorectal cancer.We tested the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a double-blind, placebo-controlled trial among 29,133 50-69-year-old male cigarette smokers. Participants were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or a placebo daily for 5-8 years. Incident colorectal cancers (n = 135) were identified through the nationwide cancer registry, and 99% were histologically confirmed. Intervention effects were evaluated using survival analysis and proportional hazards models.Colorectal cancer incidence was somewhat lower in the alpha-tocopherol arm compared to the no alpha-tocopherol arm, but this finding was not statistically significant (relative risk (RR) = 0.78, 95% confidence interval (CI) 0.55-1.09; log-rank test p = 0.15). Beta-carotene had no effect on colorectal cancer incidence (RR = 1.05, 95% CI 0.75-1.47; log-rank test p = 0.78). There was no interaction between the two substances.Our study found no evidence of a beneficial or harmful effect for beta-carotene in colorectal cancer in older male smokers, but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect. The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk.

TITLE: Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.ABSTRACT: Patients with precapillary pulmonary hypertension (PH) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries. By causing the pulmonary artery to dilate, inhaled nitric oxide (NO) may allow an increase in exercise capacity in patients with PH.On 2 separate days, 3 days apart, 14 patients with precapillary PH (10 primary PH, 4 residual PH after correction of an intracardiac shunt; age, 40+/-12 years; mean pulmonary artery pressure, 60+/-23 mm Hg) performed exercise, with and without inhalation of 20 ppm NO, on a cycle ergometer. The work rate was increased 15 W/min until their symptom-limited maximum, with breath-by-breath gas analysis. Patients were randomly and blindly selected to inhale NO on either their first or second test. Peak exercise load and anaerobic threshold tended to increase, but not significantly. Peak oxygen consumption (f1.gif" BORDER="0">O(2)) and Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio increased significantly, by 18% and 22%, respectively (peak f1.gif" BORDER="0">O(2), 13.6+/-3.6 to 16.0+/-4. 1 mL. kg(-1). min(-1); Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio, 5. 8+/-2.4 to 7.1+/-2.3 mL. kg(-1). min(-1). W(-1); both P<0.01). Peak f1.gif" BORDER="0">O(2) increased >10% in 12 of the 14 patients. However, respiratory quotient at peak exercise decreased from 1. 22+/-0.15 to 1.09+/-0.15 (P<0.01).Inhaled NO substantially increases oxygen consumption at the same workload during exercise. This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH.

TITLE: Pulmonary effects of short-term exposure to low levels of toluene diisocyanate in asymptomatic subjects.ABSTRACT: Isocyanates may be involved in the development of chronic obstructive airway disease among exposed workers. A short-term exposure to toluene diisocyanate (TDI) at concentrations near the permissible levels was investigated to examine whether there was an association with changes in pulmonary function tests and in potential markers of airway injury and inflammation in bronchial lavage (BL) and bronchoalveolar lavage (BAL). Seventeen subjects without respiratory symptoms (eight smokers and nine nonsmokers) were exposed once to ambient air and once to TDI (5 parts per billion (ppb) for 6 h followed by 20 ppb for 20 min) in a randomized, single-blind sequence. Pulmonary function tests were repeatedly assessed during exposure and BAL was performed 1 h after each exposure. Biochemical studies on lavage fluids included albumin, immunoglobulins, antiproteases (alpha2-macroglobulin and alpha1-proteinase inhibitor), potential indicators of epithelial cell function (secretory component and Clara cell protein), and cytokines (tumour necrosis factor-alpha, interleukin (IL)-4, IL-5, IL-6, and IL-8). Exposure to TDI caused a modest decrease in specific airway conductance (sGaw) (p=0.053) and in maximal expiratory flow at 25% of forced vital capacity (MEF25%) (p=0.015) when compared with ambient air. Exposure to TDI resulted in a slight increase in BAL albumin level (TDI: 26.4+/-12.5 versus air: 21.8+/-8.6 microg x mL(-1), p=0.044) and in BL alpha2-macroglobulin concentration (TDI: 0.07+/-0.061 versus air: 0.05+/-0.04 microg x mL(-1), p=0.021). This study suggests that exposure to low toluene disocyanate concentrations is associated with minimal but detectable changes in airway calibre and in epithelial barrier permeability. The pulmonary effects of long-term exposure to low levels of isocyanates require further investigation.

TITLE: Oestrogen has no short-term effect on intestinal strontium absorption in healthy postmenopausal women.ABSTRACT: Impaired intestinal calcium absorption in postmenopausal women is often indirectly linked to decreased serum 1,25(OH)2D or to intestinal resistance to its action rather than directly to low circulating oestrogen levels following the menopause. The purpose of this clinical study was to investigate the short-term effect of oral 17 beta-oestradiol on intestinal calcium absorption, with strontium as a marker.Twenty-five healthy postmenopausal women participated in this randomised double blind placebo controlled clinical trial. Twelve women received oestradiol therapy (2 mg/day) and thirteen placebo for 2 months. Fractional strontium absorption (Fc240) was assessed at baseline and after 2 months of oestradiol/placebo therapy.Intestinal strontium absorption (Fc240) was unchanged after treatment with 17 beta-oestradiol (10.1 +/- 5.0 vs. 10.2 +/- 3.8(%)). Serum total calcitriol (1,25(OH)2D) was unchanged after treatment with placebo (88 +/- 22 vs. 79 +/- 21 (pmol/l)) but increased after treatment with oestradiol (88 +/- 30 vs. 116 +/- 33 (pmol/l); P < 0.005). Serum vitamin D binding protein (DBP) increased after oestradiol but not after placebo treatment. The free serum 1,25(OH)2D index was calculated. This index did not change after oestrogen therapy (1.6 +/- 0.5 vs. 1.8 +/- 0.5).In healthy postmenopausal women, short-term suppletion with exogenous oral oestrogen did not influence intestinal calcium absorption as measured by the strontium absorption test.

TITLE: Comparative efficacy and safety of calcium carbasalate plus metoclopramide versus ergotamine tartrate plus caffeine in the treatment of acute migraine attacks.ABSTRACT: This randomized, double-blind, double-dummy, multicenter, parallel-group study aimed at comparing the efficacy and safety of calcium carbasalate (equivalent to 900 mg aspirin) plus metoclopramide 10 mg (CM) with ergotamine tartrate 1 mg plus caffeine 100 mg (EC) administered in the treatment of 2 acute migraine attacks. A total of 296 patients fulfilling the International Headache Society diagnostic criteria for migraine were enrolled. In total, one or two migraine attacks were treated in 268 and 235 patients, respectively. The primary endpoint for the first treated attack was headache relief, with intensity decreasing from moderate or severe to mild or absent 2 h after drug intake. Usual secondary efficacy endpoints were assessed. A superiority of CM over EC was observed for both treated attacks for the main endpoint: success in 54 versus 36%, p = 0.003 for the first attack and 60 versus 44%, p = 0.02 for the second attack. CM was also significantly superior to EC during the first attack for complete headache relief (20 vs. 8%, p = 0.006), nausea (42 vs. 63%, p = 0. 007) and willingness to take the drug again (90 vs. 80%, p = 0.043). The global efficacy evaluation, rated by the investigators, was significantly more favorable to CM for both attacks (p = 0.001 for the first attack and p = 0.02 for the second). The patients' evaluation was significant for the first attack (p = 0.002). The global incidence of adverse events was 45% higher with EC, though not significant (32 vs. 22%, p = 0.075). They were most often unspecific and mild to moderate in intensity. Gastrointestinal side effects were significantly less frequent with CM than EC (7 vs. 21%, p = 0.001). Thus, CM is more effective and has a better gastrointestinal safety than EC in the acute treatment of migraine attacks.

TITLE: Benzalkonium chloride in a decongestant nasal spray aggravates rhinitis medicamentosa in healthy volunteers.ABSTRACT: A randomized double-blind parallel study with 20 healthy volunteers was performed to research the effect of a preservative in a decongestant nasal spray on the development of rhinitis medicamentosa. Ten subjects received oxymetazoline nasal spray with benzalkonium chloride and the others used oxymetazoline nasal spray without the preservative three times daily for 30 days. Before starting the course of treatment and after its conclusion, recordings of the mucosal surface positions were made with rhinostereometry followed by histamine challenge tests. Symptoms of nasal stuffiness were estimated on visual analogue scales (0-100) in the morning and the evening just before using the nasal spray. After 30 days, rebound swelling and nasal stuffiness were found in both groups. In the group receiving oxymetazoline nasal spray with benzalkonium chloride the mean rebound swelling was 1.1 mm and the estimated mean evening symptom score for nasal stuffiness was 43. In the group without benzalkonium chloride the corresponding variables were significantly less marked, with a mean rebound swelling of 0.5 mm (P < 0.05) and a mean evening symptom score of 25 (P < 0.05). The increase in histamine sensitivity in both groups was interpreted as a sign of nasal hyperreactivity. A new type of nasal spray bottle was used that has been shown to prevent bacterial contamination. In conclusion, the long-term use of benzalkonium chloride in oxymetazoline nasal spray accentuates the severity of rhinitis medicamentosa in healthy volunteers.

TITLE: Randomized comparison of oral misoprostol and oxytocin for labor induction in term prelabor membrane rupture.ABSTRACT: To compare labor induction intervals between oral misoprostol and intravenous oxytocin in women who present at term with premature rupture of membranes.One hundred eight women were randomly assigned to misoprostol 50 microg orally every 4 hours as needed or intravenous oxytocin. The primary outcome measure was time from induction to vaginal delivery. Sample size was calculated using a two-tailed alpha of 0.05 and power of 80%.Baseline demographic data, including maternal age, gestation, parity, Bishop score, birth weight, and group B streptococcal status, were similar. The mean time +/-standard deviation to vaginal birth with oral misoprostol was 720+/-382 minutes compared with 501+/-389 minutes with oxytocin (P = .007). The durations of the first, second, and third stages of labor were similar. There were no differences in maternal secondary outcomes, including cesarean birth (eight and seven, respectively), infection, maternal satisfaction with labor, epidural use, perineal trauma, manual placental removal, or gastrointestinal side effects. Neonatal outcomes including cord pH, Apgar scores, infection, and admission to neonatal intensive care unit were not different.Although labor induction with oral misoprostol was effective, oxytocin resulted in a shorter induction-to-delivery interval. Active labor intervals and other maternal and neonatal outcomes were similar.

TITLE: The safety and efficacy of prophylactic ondansetron in patients undergoing modified radical mastectomy.ABSTRACT: We aimed to evaluate the antiemetic efficacy, safety, and clinical utility of prophylactic ondansetron administered at the end of the surgery for the prevention of postoperative nausea and vomiting (PONV) in a homogenous population of 54 women undergoing modified radical mastectomy (MRM). A standard general anesthetic and perioperative analgesic technique were used. After surgery, patients received either saline placebo or ondansetron 4 mg IV. Episodes of PONV, as well as rescue antiemetic requirements, were recorded for the first 24 h after surgery. The 24-h incidence of PONV (33.3% vs 81.5%; P = 0.0010) was significantly lower in the ondansetron group. The severity of PONV, evaluated by the number of emetic episodes per patient (1.59+/-1.90 vs 0.29+/-0.66; P = 0.0029), and the rescue antiemetic requirement (59.2% vs 14.8%; P = 0.0019) was significantly lower, in the ondansetron group. Patient satisfaction scores and number needed to prevent PONV (2.07) were significantly better and therapeutically more favorable in the ondansetron group. The incidence of adverse events such as headache, dizziness, and increased liver enzyme levels (number needed to harm = infinity) was similar in both groups. Administered at the end of the surgery in adult female patients undergoing general anesthesia for MRM, ondansetron 4 mg is effective and safe in preventing PONV. We recommend the clinical practice of routine prophylactic ondansetron to prevent PONV after MRM, as it significantly improves perioperative patient satisfaction and outcome.We evaluated the antiemetic efficacy, safety, and routine use of prophylactic ondansetron, a "gold standard" antiemetic, in women undergoing radical breast surgery who were at a high risk of postoperative vomiting. We analyzed more meaningful "true" and "therapeutic" outcome measures, and we conclude that prophylactic ondansetron is safe and effective and that its routine use is justified.

TITLE: Effect of chronic magnesium supplementation on magnesium distribution in healthy volunteers evaluated by 31P-NMRS and ion selective electrodes.ABSTRACT: The role of magnesium (Mg) intake in the prevention and treatment of diseases is greatly debated. Mg biodistribution after chronic Mg supplementation was investigated, using state-of-the-art technology to detect changes in free ionized Mg, both at extra- and intracellular levels.Thirty young healthy male volunteers participated in a randomised, placebo (P)-controlled, double-blind trial. The treated group (MgS) took 12 mmol magnesium lactate daily for 1 month. Subjects underwent in vivo 31P-NMR spectroscopy and complete clinical and biological examinations, on the first and last day of the trial. Total Mg was measured in plasma, red blood cells and 24 h urine ([Mg]U ). Plasma ionized Mg was measured by ion-selective electrodes. Intracellular free Mg concentrations of skeletal muscle and brain tissues were determined noninvasively by in vivo 31P-NMR at 3T. NMR data were automatically processed with the dedicated software MAGAN.Only [Mg]U changed significantly after treatment (in mmol/24 h, for P, from 4.2+/-1.4 before to 4.1+/-1.3 after and, for MgS, from 3.9+/-1.1 before to 5. 1+/-1.1 after, t=2.15, P=0.04). The two groups did not differ, either before or after the trial, in any other parameter, whether clinical, biological or in relation with the Mg status.Chronic oral administration of Mg tablets to young healthy male volunteers at usual pharmaceutical doses does not alter Mg biodistribution. This study shows that an adequate and very complete noninvasive methodology is now available and compatible with the organization of clinical protocols which aim at a thorough evaluation of Mg biodistribution.

TITLE: Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome.ABSTRACT: In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (> or =20 microU/mL), our aim was to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular normal menses. A second aim was to assess the effects of weight loss versus other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third aim was to assess associations between PCOS, 4G/5G polymorphism in the promoter sequence of the plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal hemoglobin A1C (HgA1C); onlythree (7%) had type 2 diabetes mellitus. Metformin (1.5 to 2.25 g/d) was given for 6.1+/-5.1 months (range, 1.5 to 24), to 16 patients for less than 3 months, to 12 for 3 to 6 months, and to 15 for at least 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups (P<.1) or among dose groups (P>.1). The body mass index (BMI) decreased from 36.4 + 7 Kg/m2 at study entry to 35.1+/-6.7 on Metformin (P=.0008). Of 43 patients, 28 (67%) lost weight (1 to 69 pounds), with nine (21%) losing at least 12 pounds. On Metformin, the median fasting serum insulin decreased from 26 microU/mL to 22 (P=.019), testosterone decreased from 61 ng/dL to 47 (P=.003), and estradiol increased from 41 pg/mL to 71 (P=.0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone decrease, P<.002; estradiol increase, P<.0004). The change in response variables on Metformin did not differ (P>.05) between those who lost weight and those who did not, excepting Lp(a), which increased 4 mg/dL in those who lost weight and decreased 9 mg/dL in those who did not (P = .003). The change in response variables on Metformin did not differ among the five quintiles of weight loss, excepting fasting glucose (P<.05), which increased 6 mg/dL in those who lost the least weight on Metformin versus those in the 60th to 80th percentile for weight loss, in whom glucose decreased 33 mg/dL. Although the pretreatment fasting serum insulin was not significantly correlated with testosterone (r=.24, P=.13) or androstenedione (r=.27, P=.09), on Metformin, the change in insulin correlated positively with the change in testosterone (r=.35, P=.047) and with the change in androstenedione (r=.48, P=.01). Patients were more likely than normal controls (83% v 64%, P=.016) to be heterozygous or homozygous for 4G polymorphism of the PAI-1 gene and were also more likely to have high PAI-Fx (> or =22 U/mL, 28% v3%, chi(2)=10.1, P=.001). Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.

TITLE: CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline.ABSTRACT: The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.

TITLE: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group.ABSTRACT: To confirm the promising phase II results of docetaxel monotherapy, this phase III trial was conducted of chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC) who had previously failed platinum-containing chemotherapy.A total of 373 patients were randomized to receive either docetaxel 100 mg/m(2) (D100) or 75 mg/m(2) (D75) versus a control regimen of vinorelbine or ifosfamide (V/I). The three treatment groups were well-balanced for key patient characteristics.Overall response rates were 10.8% with D100 and 6.7% with D75, each significantly higher than the 0.8% response with V/I (P =.001 and P =.036, respectively). Patients who received docetaxel had a longer time to progression (P =.046, by log-rank test) and a greater progression-free survival at 26 weeks (P =.005, by chi(2) test). Although overall survival was not significantly different between the three groups, the 1-year survival was significantly greater with D75 than with the control treatment (32% v 19%; P =.025, by chi(2) test). Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel, nor did it impact survival. There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2. Toxicity was greatest with D100, but the D75 arm was well-tolerated.This first randomized trial in this setting demonstrates that D75 every 3 weeks can offer clinically meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy.

TITLE: Human vascular renin-angiotensin system and its functional changes in relation to different sodium intakes.ABSTRACT: A growing body of evidence supports the existence of a tissue-based renin-angiotensin system (RAS) in the vasculature, but the functional capacity of vascular RAS was not investigated in humans. In 28 normotensive healthy control subjects, the metabolism of angiotensins through vascular tissue was investigated in normal, low, and high sodium diets by the measurement of arterial-venous gradient of endogenous angiotensin (Ang) I and Ang II in two different vascular beds (forearm and leg), combined with the study of 125I-Ang I and 125I-Ang II kinetics. In normal sodium diet subjects, forearm vascular tissue extracted 36+/-6% of 125I-Ang I and 30+/-5% of 125I-Ang II and added 14.9+/-5.1 fmol x 100 mL(-1) x min(-1) of de novo formed Ang I and 6.2+/-2.8 fmol x 100 mL(-1) x min(-1) of Ang II to antecubital venous blood. Fractional conversion of 125I-Ang I through forearm vascular tissue was about 12%. Low sodium diet increased (P<.01) plasma renin activity, whereas de novo Ang I and Ang II formation by forearm vascular tissue became undetectable. Angiotensin degradation (33+/-7% for Ang I and 30+/-7% for Ang II) was unchanged, and vascular fractional conversion of 125I-Ang I decreased from 12% to 6% (P<.01). In high sodium diet subjects, plasma renin activity decreased, and de novo Ang I and Ang II formation by forearm vascular tissue increased to 22 and 14 fmol x 100 mL(-1) x min(-1), respectively (P<.01). Angiotensin degradation did not significantly change, whereas fractional conversion of 125I-Ang I increased from 12% to 20% (P<.01). Leg vascular tissue functional activities of RAS paralleled those of forearm vascular tissue both at baseline and during different sodium intake. These results provide consistent evidence for the existence of a functional tissue-based RAS in vascular tissue of humans. The opposite changes of plasma renin activity and vascular angiotensin formation indicate that vascular RAS is independent from but related to circulating RAS.

TITLE: A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group.ABSTRACT: Critically ill patients who require mechanical ventilation are at increased risk for gastrointestinal bleeding from stress ulcers. There are conflicting data on the effect of histamine H2-receptor antagonists and the cytoprotective agent sucralfate on rates of gastrointestinal bleeding, ventilator-associated pneumonia, and mortality.In a multicenter, randomized, blinded, placebo-controlled trial, we compared sucralfate with the H2-receptor antagonist ranitidine for the prevention of upper gastrointestinal bleeding in 1200 patients who required mechanical ventilation. Patients received either nasogastric sucralfate suspension (1 g every six hours) and an intravenous placebo or intravenous ranitidine (50 mg every eight hours) and a nasogastric placebo.The patients in the two groups had similar base-line characteristics. Clinically important gastrointestinal bleeding developed in 10 of 596 (1.7 percent) of the patients receiving ranitidine, as compared with 23 of 604 (3.8 percent) of those receiving sucralfate (relative risk, 0.44; 95 percent confidence interval, 0.21 to 0.92; P=0.02). In the ranitidine group, 114 of 596 patients (19.1 percent) had ventilator-associated pneumonia, as compared with 98 of 604 (16.2 percent) in the sucralfate group (relative risk, 1.18; 95 percent confidence interval, 0.92 to 1.51; P=0.19). There was no significant difference between the groups in mortality in the intensive care unit (ICU) (23.5 percent in the ranitidine group and 22.9 percent in the sucralfate group) or the duration of the stay in the ICU (median, nine days in both groups).Among critically ill patients requiring mechanical ventilation, those receiving ranitidine had a significantly lower rate of clinically important gastrointestinal bleeding than those treated with sucralfate. There were no significant differences in the rates of ventilator-associated pneumonia, the duration of the stay in the ICU, or mortality.

TITLE: The course of labor with and without epidural analgesia.ABSTRACT: Our purpose was to measure effects of epidural analgesia on labor compared with boluses of meperidine in a cohort of women with similar clinical circumstances.One hundred ninety-nine nulliparous women who were delivered spontaneously at term and who received oxytocin for labor augmentation before the initiation of analgesia were identified for analysis. All these women were managed in a low-risk labor unit according to a standardized protocol. This management protocol encouraged early amniotomy and the use of oxytocin when ineffective labor was diagnosed.The demographic characteristics of the two study groups were similar with respect to age, height, weight, and maternal age. The two groups had the same cervical dilatation on admission (3.3 cm) and at the time of analgesia administration (4.1 vs 4.2 cm), indicating similar progress of labor before oxytocin administration. The length of the active phase of labor was longer in the epidural group (7.9 vs 6.3 hours, p = 0.005), as was the second stage (60 vs 48 minutes, p = 0.03). The mean and maximal rates of oxytocin infusion were similar between the two study groups; however, the amount of oxytocin required for each centimeter of cervical change was more in the epidural group (22 vs 16 mU per cm of cervical change, p = 0.009). Neonatal outcomes were unaffected by the type of labor analgesia.Epidural analgesia decreases uterine performance during oxytocin-stimulated labor, resulting in an increase in the length of the first and second stages of labor.

TITLE: Associations between carcinogen-DNA damage, glutathione S-transferase genotypes, and risk of lung cancer in the prospective Physicians' Health Cohort Study.ABSTRACT: DNA damage from polycyclic aromatic hydrocarbons (PAH) and other aromatic/hydrophobic compounds has been implicated in case-control studies as a risk factor for lung cancer, as have common polymorphisms in the glutathione S-transferase (GST) genes involved in carcinogen detoxification. However, their joint effects have not been evaluated in prospective studies, leaving open questions about predictive value of these biomarkers. In this matched case-control study nested within the prospective Physicians' Health Study, we evaluated whether biomarkers measured in white blood cells (WBC) significantly predicted risk, alone and in combination, after controlling for level of smoking. The biomarkers reported here are aromatic/hydrophobic-DNA adducts and polymorphisms in genes coding for the GSTM1 and GSTP1 enzymes. Our study population was composed of 89 cases of primary lung cancer and 173 controls, matched in a 1:2 ratio on smoking, age and duration of follow up. Adducts were measured in WBC DNA by the nuclease P1-enhanced (32)P-post-labeling method. Genotypes (GSTM1 null versus non-null and GSTP1 Val versus GSTP1 Ile) were determined by genomic amplification and restriction fragment length polymorphism analysis. Among current smokers, adducts were significant predictors of lung cancer risk (after adjusting for GST genotypes, OR = 3.10, 95% CI 1.07, 9.01). The combined GSTM1 null/GSTP1 Val genotype was associated with lung cancer overall and especially among former smokers, before and after adjusting for adducts (OR for former smokers = 4.21, CI 1.08, 16.41; adjusted OR = 4.68, CI 1.17, 18.71). Among cases only, adducts were significantly higher among current or former smokers with the GSTM1 non-null/GSTP1 Ile genotype. The two risk factors (adducts and genotypes) appear to be independent predictors of risk. The findings underscore the complex and important role of biological susceptibility as a determinant of risk from carcinogens found in tobacco smoke and other environmental compounds.

TITLE: A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study.ABSTRACT: To assess the possible benefit of hormone replacement therapy (HRT) in the secondary prevention of ischaemic heart disease.A prospective randomised trial of transdermal HRT in women with definite ischaemic heart disease.A regional cardiac unit.Postmenopausal women with angiographically proven ischaemic heart disease.A total of 255 postmenopausal women with angiographically proven ischaemic heart disease were recruited and randomised; 134 were treated with transdermal HRT and 121 acted as controls. The women were seen at six monthly intervals. The primary end points, which were determined by a blinded assessor, were admission to hospital with unstable angina, proven myocardial infarction or cardiac death. A total of 53 (40%) patients withdrew from the HRT group and eight (7%) from the control group. The mean duration of follow up was 30.8 months.Admission to hospital with unstable angina, proven myocardial infarction or cardiac death.During follow up, there were 53 primary end-point events in the HRT group and 37 in the control group. Using an intention-to-treat analysis, the primary end-point event rate was 15.4 events per 100 patient years for the HRT group compared with 11.9 for the control group (event rate ratio 1.29 (95% CI 0.84-1.95, P = 0.24)). Using a per-protocol analysis, there was an event rate ratio of 1.49 (0.93-2.36, P = 0.11) for the HRT arm compared with the control arm. Particularly during the first two years of follow up, the HRT group had a higher, but not statistically significant, event rate than the control group.Our findings suggest that transdermal HRT should not be commenced for the purpose of secondary prevention in postmenopausal women with angiographically proven ischaemic heart disease.

TITLE: Calcium and zinc absorption from lactose-containing and lactose-free infant formulas.ABSTRACT: Calcium absorption is enhanced by the presence of lactose, but the quantitative significance of this effect in infant formulas is uncertain. It is also not known whether lactose affects zinc absorption.We measured the absorption of calcium and zinc from infant formulas by using a multitracer, stable-isotope technique.Eighteen full-term infants (aged 8-12 wk at enrollment) were fed 2 partially hydrolyzed whey-protein-based formulas ad libitum for 2 wk per formula. The carbohydrate source was lactose in one formula and glucose polymers in the other (lactose-free). Infants were studied in a blinded crossover fashion after 2 wk of adaptation to each formula. Isotope absorption studies were conducted with a 4-tracer method in which (70)Zn and (44)Ca were provided orally and (67)Zn and (46)Ca intravenously. Zinc and calcium absorption was measured from the fractional excretion of the oral and intravenous isotopes in urine.Fractional and total calcium absorption was significantly greater from the lactose-containing formula than from the lactose-free formula. For total calcium absorption, the mean difference between formulas was 10.3% (P = 0.002) and 60 mg/d (P = 0.006). For zinc, fractional absorption (32 +/- 11%), total absorption, and intake did not differ significantly between the 2 formulas.The presence of lactose in a formula based on cow-milk protein increases absorption of calcium but not of zinc. Absorption of calcium from a lactose-free infant formula is, however, adequate to meet the calcium needs of full-term infants when the formula's calcium content is similar to that of lactose-containing, cow-milk-based infant formulas.

TITLE: The dose-sparing effect of clonidine added to ropivacaine for labor epidural analgesia.ABSTRACT: To determine the effects of clonidine with ropivacaine during epidural labor analgesia, we studied 66 nulliparous women in early active labor. Women were randomized to receive ropivacaine 0.1% 8 mL plus 75 microg of clonidine (Group 1), ropivacaine 0.2% 8 mL plus 0.5 mL of NaCl 0.9% (Group 2), or ropivacaine 0.2% 8 mL plus 75 microg of clonidine (Group 3) 5 min after a bupivacaine 7.5 mg with epinephrine 15 microg test dose. Upon request, additional analgesia with ropivacaine 0.1% 8 mL followed by ropivacaine 0.2% 8 mL/h was administered. With clonidine, duration of analgesia was increased (132 +/- 48 min [Group 1] and 154 +/- 42 min [Group 3] versus 91 +/- 44 min [Group 2]; P < 0.05), and total ropivacaine dose over the first 4 h was significantly reduced (40.5 +/- 15 mg [Group 1] and 47.0 +/- 16 mg [Group 3] versus 72.5 +/- 18 mg [Group 2]; P < 0.01). The incidence of more profound motor block was more frequent in Group 2 (P < 0.05). Although there was a trend for more women receiving clonidine to require ephedrine for treatment of hypotension, this did not seem to have an impact on fetal outcome or incidence of cesarean deliveries for nonreassuring fetal heart rate tracings. This study demonstrates the dose-sparing effect of clonidine when added to ropivacaine.The effect of adding 75 microg of clonidine to ropivacaine for epidural labor analgesia was studied. Clonidine increased analgesia duration and produced dose sparing compared with ropivacaine alone. Despite a tendency for hypotension in women receiving clonidine, there was no apparent effect on delivery mode or neonatal outcome.

TITLE: Increased presence of anti-HLA antibodies early after allogeneic granulocyte colony-stimulating factor-mobilized peripheral blood hematopoietic stem cell transplantation compared with bone marrow transplantation.ABSTRACT: We have recently shown that the use of allogeneic granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood hematopoietic stem cell transplantation (PBHSCT), as compared with bone marrow transplantation (BMT), is associated with increased titers of antibodies (Abs) directed against red blood cell ABO antigens. To further evaluate the influence of a G-CSF-mobilized PBHSCT graft on alloimmune Ab responses, we examined the frequency of anti-HLA Abs after transplantation in the setting of the same randomized study, comparing PBHSCT with BMT in adults. Anti-HLA Ab presence was determined by complement-dependent cytotoxicity assay (CDC) and flow cytometry in the recipient before and 30 days after transplantation as well as in the donor before graft donation. The use of PBHSCT was significantly associated with increased detection of anti-HLA immunoglobulin G (IgG) Abs early after transplantation as evidenced by flow cytometry (11 of 24 versus 4 of 27 transplant recipients, P =.03) and, less so, by CDC (5 of 24 versus 1 of 27 transplant recipients, P =.09). The difference between PBHSCT and BMT was further heightened when analysis was restricted to anti-HLA IgG Ab-negative donor/recipient pairs. In such a setting, early anti-HLA Ab was never detected after BMT but was repeatedly detected after PBHSCT (flow cytometry, 6 of 18 versus 0 of 17 transplant recipients, P =.02; CDC, 4 of 23 versus 0 of 26 transplant recipients, P =.04). Importantly, the PBHSCT-associated increase in anti-HLA Ab detection was observed despite a reduction in the median number of platelet-transfusion episodes per patient in PBHSC transplant versus BM transplant recipients (3 platelet-transfusion episodes [range, 1-21] in PBHSCT group vs 6 platelet-transfusion episodes [range, 3-33] in the BMT group; P =.02). In conclusion, this study strongly suggests that G-CSF-mobilized PBHSCT results in an increased incidence of circulating anti-HLA Abs and further confirms that the use of such a graft alters alloimmune Ab responses.

TITLE: Midodrine in neurally mediated syncope: a double-blind, randomized, crossover study.ABSTRACT: Neurally mediated syncope is the most frequent cause of syncope in patients without structural heart disease. Its most common trigger is a reduction in venous return to the heart due to excessive venous pooling in the legs. We conducted a double-blind, randomized, crossover trial to investigate the efficacy of midodrine, a selective alpha-1 adrenergic agonist that decreases venous capacitance, in preventing neurally mediated syncope triggered by passive head-up tilt. Twelve patients with history of recurrent neurally mediated syncope, which was reproduced during head-up tilt, were randomized to receive a nonpressor dose of midodrine (5mg) or placebo on day 1 and the opposite on day 3. One hour after drug or placebo administration, patients underwent 60-degree head-up tilt lasting 40 minutes (unless hypotension or bradycardia developed first). In the supine position, midodrine produced no significant change in blood pressure or heart rate. The responses to head-up tilt were significantly different on the midodrine and the placebo day: on the placebo day, 67% (8/12) of the subjects suffered neurally mediated syncope, whereas only 17% (2/12) of the subjects developed neurally mediated syncope on the midodrine day (p < 0.02). These results indicate that midodrine significantly improves orthostatic tolerance during head-up tilt in patients with recurrent neurally mediated syncope.

TITLE: Improved suppression of recurrent atrial fibrillation with dual-site right atrial pacing and antiarrhythmic drug therapy.ABSTRACT: We compared the safety, tolerance and effectiveness of overdrive high right atrial (RA), dual-site RA and support (DDI or VDI) pacing (SP) in patients with symptomatic atrial fibrillation (AF) and bradycardias.Optimal pacing methods for AF prevention remain unclear.Patients (n = 118) were randomized to each of three pacing modes in a crossover trial.Mode adherence was superior for dual-site RA (5.8 months) compared with SP (3.3 months; p < 0.001) and high RA pacing (4.7 months; p = 0.006). Adverse event-free survival improved with dual-site RA (p = 0.007 vs. SP) and was comparable to high RA (p = 0. 75). AF-free survival trended to improve with dual-site RA (hazard ratio [HR] 0.715, p = 0.07 vs. SP) but not high RA (HR = 0.71, p = 0.19) or when dual-site RA was compared with high RA (HR = 0.835, p = 0.175). Time-to-recurrence was longer in dual-site RA (1.77 months) compared with high RA (0.62 months, p < 0.09) or SP (0.44 months, p < 0.05). In antiarrhythmic drug-treated patients, dual-site RA reduced recurrence risk compared with SP (HR = 0.638, p = 0.011) and high RA (HR = 0.669, p = 0.06). In patients with < or =1 AF event/week, dual-site RA improved AF suppression (HR = 0.464, p = 0.004 vs. SP; HR = 0.623, p = 0.006 vs. high RA). Dual-site RA improved AF-free and mode survival (p < 0.03 vs. high RA, p < 0.001 vs. SP) and reduced asymptomatic AF (p < 0.01 vs. high RA).Dual-site RA is safe and better tolerated than high RA and SP. In patients on antiarrhythmics, dual-site RA prolonged and high RA trended to prolong time-to-recurrent AF compared with SP. Dual-site RA provides superior symptomatic and asymptomatic AF prevention compared with high RA in patients with symptomatic AF frequency of < or =1/week.

TITLE: Two-site phacotrabeculectomy with intraoperative mitomycin-C: fornix- versus limbus-based conjunctival opening in fellow eyes.ABSTRACT: To prospectively compare the influence of fornix-based and limbus-based conjunctival flaps on the final outcome and complications of 2-site phacotrabeculectomy with mitomycin-C in fellow eyes of patients with bilateral open-angle glaucoma (OAG). Glaucoma Unit, Department of Ophthalmology, University of Crete, Crete, Greece.Twenty-two patients with bilateral primary OAG and 8 patients with bilateral exfoliative glaucoma had 2-site phacotrabeculectomy in both eyes. Eyes were randomly assigned to the fornix-based flap or limbus-based flap group by the use of random tables. The intraocular pressure (IOP) decreased significantly in both groups (P <.01); however, there was no statistically significant difference between the groups in the amount of IOP decrease or the number of postoperative antiglaucoma medications after a 1-year follow-up. Faster improvement in visual acuity was observed in the fornix-based group during the first week. The mean time of surgery was 3.5 minutes less in the fornix-based group. An increased incidence of fibrin exudation, pupillary membrane formation, and capsule opacification was found in eyes with exfoliative glaucoma. The early bleb leakage was 3 times more frequent in the fornix-based group. The type of conjunctival flap in a 2-site phacotrabeculectomy did not seem to influence the final outcome. The main advantage of the fornix-based conjunctival flap is the shorter surgical time and the relatively faster improvement in vision postoperatively. The main disadvantage is more frequent early bleb leakage.

TITLE: Ofloxacin for the treatment of urinary tract infections and biofilms in spinal cord injury.ABSTRACT: Forty two paraplegic and quadriplegic hospitalized spinal cord injured patients with urinary tract infections (UTI) were included in a double blind, randomized treatment study comparing 7 days ofloxacin (300 mg bd) with trimethoprim-sulphamethoxazole (TMPSMX; 160-800 mg bd) or an alternative, chosen because of resistance to TMPSMX. The 4-day clinical cure rate, defined as an asymptomatic patient with sterile urine, was 90% (19/21) with ofloxacin, significantly greater than 48% (10/21) for the comparison group (P=0.003) and the rate at end of therapy was 90% (19/21) with ofloxacin, against 57% (12/21) (P=0.015). Bacterial biofilms were detected on bladder epithelial cells in 39/41 (95%) patients. The biofilm score fell significantly following ofloxacin therapy (P < 0.001) or alternative therapy (P < 0.001). Ofloxacin treatment led to significantly more biofilm eradication than the other antibiotic group on day 4 (62 vs. 24%) (P=0.005) and day 7 (67 vs. 35%) (P=0.014). The study showed that ofloxacin was better than TMPSMX and alternatives at relieving clinical infection and eradicating bladder cell biofilms.

TITLE: Early identification of neutropenic patients at risk of grampositive bacteraemia and the impact of empirical administration of vancomycin.ABSTRACT: The aim of this multicentre randomised trial was to determine whether it was possible to predict grampositive bacteraemia, and whether the empirical use of vancomycin would lead to reduced morbidity and mortality. 35 of 113 patients (31%; confidence interval, CI 8.5), who presented with a skin or soft tissue infection and had received empirical vancomycin in addition to either ceftazidime or piperacillin-tobramycin, had initial bacteraemia with a single gram-positive bacterium compared with 135 of the 784 (17%; CI 2.6), who presented with another infection and who had been given ceftazidime or piperacillin-tobramycin without vancomycin (P < 0.001). Empirical vancomycin resulted in a higher rate of eradication (P = 0.033, relative risk 1.2), but not a better clinical outcome and was associated with more toxicity (P = 0.042, relative risk 1.6). Irrespective of the initial treatment regimen, fever lasted an average of 8 days, the empirical regimen was modified in more than 50% of cases and mortality attributed to gram-positive infection was less than 2%. Incorporating vancomycin in the initial empirical antibiotic regimen for febrile neutropenic patients does not appear necessary, even for skin and soft tissue infections associated with gram-positive bacteraemia.

TITLE: Effect of flumazenil on ventilatory drive during sedation with midazolam and alfentanil.ABSTRACT: Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid.Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug.Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l.min-1.mmHg-1 (x +/- SE, P < 0.05), and decreased the minute ventilation at P(ET)CO2 = 50 mmHg (VE50) from 19.7 +/- 1.2 to 14.8 +/- 0.9l.min-1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l.min-1.mmHg-1 (P < 0.05) and 11.7 +/- 0.8 l.min-1 (P < 0.05), respectively. With addition of flumazenil, slope and VE50 increased to 1.47 +/- 0.37 l.min-1.mmHg-1 (P < 0.05) and 16.4 +/- 2.0l.min-1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l.min-1.mmHg-1 and 12.5 +/- 1.2 l.min-1 did not differe significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at P(ET)CO2 = 46 +/- 1 mmHG, were affected similarly, with flumazenil showing a significant improvement compared to placebo.Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.

TITLE: Effects of the new class III antiarrhythmic drug dofetilide on the atrial and ventricular intracardiac monophasic action potential in patients with angina pectoris.ABSTRACT: The class III antiarrhythmic drug dofetilide is known to prolong action potential duration by specific blockade of the delayed rectifier potassium channel Ik. As dofetilide is likely to be used in the treatment of atrial arrhythmias it is important to determine the relative sensitivity of the atrium and ventricle in man. Twelve male patients underwent monophasic action potential and refractory period recordings from the high right atrium and right ventricular septum. The patients received either 8 micrograms.kg-1 dofetilide or placebo intravenously. The mean QTc was prolonged by 11% (SD 5%, P < 0.00001) in the active group; the mean monophasic action potential increased by 31% (SD 15%, P < 0.0005) in the atrium and 27% (SD 9%, P < 0.00005) in the ventricle; the mean effective refractory period increased by 30% (SD 16%, P < 0.0005) in the atrium and 20% (SD 6%, P < 0.0001) in the ventricle. No significant change occurred in the placebo group. There was no significant difference in effect between the two chambers. The change in QTc did not accurately reflect acute changes in refractory period or monophasic action potential duration. This has important implications for the use of QT prolongation to assess the acute effect of class III drugs.

TITLE: Changes in the cerebral arteriovenous oxygen content difference by surgical incision are similar during sevoflurane and isoflurane anaesthesia.ABSTRACT: To investigate changes of cerebral arteriovenous oxygen content difference (AVDO2) induced by surgical incision and to determine carbon dioxide (CO2) reactivity of the cerebral circulation during sevoflurane and isoflurane anaesthesia.Twenty-one ASA 1-2 patients undergoing elective surgery for supratentorial tumours were randomly allocated to receive either 1.3 MAC sevoflurane/N2O anaesthesia (n = 10) or equi-MAC isoflurane/N2O anaesthesia (n = 11). Before and after incision, haemodynamic measurements and AVDO2 determinations were performed. After opening the dura, AVDO2 was determined before and after the respiration rate was increased by 50%.Incision produced an increase in mean arterial pressure from 69 +/- 11 to 97 +/- 22 mmHg (mean +/- SD) (P < 0.0005) and from 71 +/- 6 to 89 +/- 12 mmHg (P < 0.0001) in the sevoflurane and isoflurane groups, respectively, whereas the heart rate increased from 60 +/- 9 to 72 +/- 8 bpm (P < 0.001) and from 65 +/- 6 to 70 +/- 7 bpm (P < 0.001), respectively. Arterial carbon dioxide tension (PaCO2) was increased from 33.6 +/- 2.3 to 34.6 +/- 1.8 mmHg (P < 0.05) with incision in the sevoflurane group. The AVDO2 was decreased from 6.5 +/- 1.6 to 5.3 +/- 1.6 vol% (P < 0.0005) in the sevoflurane group and from 6.7 +/- 1.1 to 6.0 +/- 1.1 vol% (P < 0.01) in the isoflurane group. The % change of AVDO2 was larger in the sevoflurane group than in the isoflurane group (-18.3 +/- 8.4% vs -9.1 +/- 9.0%; P < 0.05) but no difference remained after the post-incisional AVDO2 value of the sevoflurane group was corrected for pre-incisional PaCO2. Carbon dioxide reactivity, calculated as the percent change in AVDO2 per mmHg change in PaCO2, was 6.1 +/- 3.0%.mmHg-1 in the sevoflurane group and 5.9 +/- 2.4%.mmHg-1 in the isoflurane group (P = NS).Sevoflurane and isoflurane are associated with similar impairment of cerebral flow-metabolism coupling at incision, while CO2 reactivity is maintained during both anaesthetics.

TITLE: The effect of glimepiride on pancreatic beta-cell function under hyperglycaemic clamp and hyperinsulinaemic, euglycaemic clamp conditions in non-insulin-dependent diabetes mellitus.ABSTRACT: The comparative effects of glimepiride (Amaryl; HOE 490) and glibenclamide on insulin and glucose metabolism under hyperglycaemic and hyperinsulinaemic, euglycaemic clamp conditions were studied in a double-blind, placebo-controlled, cross-over trial. Patients with sulfonylurea-controlled non insulin-dependent diabetes were allocated in random order to placebo, glimepiride (5 mg) or glibenclamide (5 mg) and received one week treatment of each with no wash-out period. At the end of each treatment week a clamp study was performed. Two protocols were used. Protocol 1 used a 5 h hyperglycaemic clamp at 10.9 mmol/l whole blood glucose concentration and Protocol II used a 3 h hyperinsulinaemic, euglycaemic damp at 3.5 mmol/l whole blood glucose concentration. Both glimepiride and glibenclamide exhibited a hypoglycaemic effect. A significant reduction in fasting whole blood glucose concentration was observed after one-week treatment of each active agent (fasting glucose: glimepiride v. placebo, 9.3 +/- 0.7 v. 10.7 +/- 0.8 mmol/l, p < 0.02; glibenclamide v. placebo, 8.9 +/- 0.9 v. 10.7 +/- 0.8 mmol/l, p < 0.005). This hypoglycaemic action of both preparations administered in equivalent daily dose appeared comparable. Glimepiride and glibenclamide stimulated beta-cell secretion and in the basal state both beta-cell secretory products insulin and C-peptide, were elevated in the plasma (basal C-peptide concentration: glimepiride v. placebo, 0.79 +/- 0.08 v. 0.68 +/- 0.07 nmol/l, p < 0.01; glibenclamide v. placebo, 0.79 +/- 0.07 v. 0.68 +/- 0.07 nmol/l, p < 0.004). This insulinotropic effect appeared to be comparable with no demonstrable difference in the efficacy of the two preparations. Under steady-state hyperglycaemic conditions both agents promoted insulin release (stimulated C-peptide concentration; glimepiride v. placebo, 1.39 +/- 0.16 v. 1.11 +/- 0.20 nmol/l, p < 0.006; glibenclamide v. placebo. 1.60 +/- 0.18 v. 1.11 +/- 0.20 nmol/l, p < 0.001) and there was no statistically significant difference between active treatments. Under steady-state euglycaemia both preparations continued to stimulate insulin release as evidenced by the mean plasma C-peptide concentrations (glimepiride v. placebo, 0.69 +/- 0.10 v. 0.28 +/- 0.06 nmol/l, p < 0.01; glibenclamide v. placebo, 0.76 +/- 0.12 v. 0.28 +/- 0.06 nmol/l, p < 0.01). Both glimepiride and glibenclamide had a comparable and significant enhancing effect on glucose metabolism (Protocol II: M: glimepiride v. placebo 4.4 +/- 1.3 v. 1.3 +/- 0.7 mg/kg.min, p < 0.05; glibenclamide v. placebo 4.7 +/- 1.3 v. 1.3 +/- 0.7 mg/kg min, p < 0.03) and improved tissue sensitivity to the action of insulin as determined by the quantity of glucose metabolised per unit insulin (Protocol II: M/l ratio: glimepiride v. placebo, 0.09 +/- 0.03 v. 0.03 +/- 0.01 kg.min per mU/l, p < 0.02; glibenclamide v. placebo, 0.1 +/- 0.03 v. 0.03 +/- 0.01 kg.min per mU/l, p < 0.01). In conclusion, glimepiride is a "second-generation" sulfonylurea agent which stimulates pancreatic beta-cell insulin secretion, lowers blood glucose and improves tissue insulin sensitivity in non-insulin-dependent diabetic subjects. Its insulinotropic effect is comparable with that of glibenclamide but may diminish in the presence of normoglycaemia. The magnitude and hence, the clinical relevance of a selective beta-cytotropic action, determined by blood glucose concentration, remains to be demonstrated.

TITLE: Progesterone alone versus progesterone combined with HCG as luteal support in GnRHa/HMG induced IVF cycles: a randomized clinical trial.ABSTRACT: Two different regimens of luteal support in gonadotrophin hormone-releasing hormone (GnRH) analogue/human menopausal gonadotrophin (GnRHa/HMG)-induced in-vitro fertilization cycle (IVF) were compared in a randomized clinical trial. After embryo transfer, either vaginal progesterone alone was administered (n = 89, P group), or a combination of vaginal progesterone and human chorionic gonadotrophin (n = 87, P/HCG group). The primary aim of this study was to assess the effect of the different regimens of luteal support on the pregnancy rate. The secondary aim was to compare oestradiol and progesterone concentrations in the luteal phase between the two groups, and assess their effect on the pregnancy rate. A clinical pregnancy rate of 15% was found in the P/HCG group in comparison with 26% in the P group (odds ratio 0.49; 99% confidence interval: 0.18-1.3). The luteal serum oestradiol and progesterone values in the P/HCG group were significantly higher when compared with the P group on the 6th, 9th and 12th day after oocyte retrieval (Wilcoxon P < 0.001). In accordance with the high oestradiol concentrations, more cases of ovarian hyperstimulation syndrome (OHSS) were found in the P/HCG group. Oestradiol values on the 9th day after oocyte retrieval, presumably the day of implantation, appeared to be higher in women who did not become clinically pregnant. We conclude that vaginal progesterone alone provides sufficient luteal support in GnRHa/HMG induced IVF cycles. The combination of vaginal progesterone and HCG as luteal support leads to significant high luteal oestradiol and progesterone concentrations. But a high concentration of oestradiol seems to have a deleterious effect on the implantation process, resulting in a low pregnancy rate.

TITLE: Effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of cystoid macular edema after cataract surgery.ABSTRACT: To evaluate the effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of angiographic cystoid macular edema (CME) after cataract surgery and intraocular lens (IOL) implantation.Eye Clinic, Institute of Biomedical Sciences, San Paolo Hospital, Milan, Italy.Eighty-eight patients having cataract extraction were enrolled in a randomized clinical trial: 42 were given diclofenac eyedrops and 46, placebo. Postoperative inflammation in both groups was graded for 6 months using a dedicated system.Eight patients (9%) had evidence of angiographic CME approximately 1 month after surgery: seven of these were in the placebo group (P = .039). This difference was not significant 3 and 6 months postoperatively. The signs of ocular inflammation were greater in the eyes receiving placebo; the difference was particularly evident up to 1 week after surgery. There was no significant difference in visual acuity between the two groups at any follow-up point, but the contrast sensitivity of the eyes that received diclofenac improved significantly at 10.5 cycles per degree 1 month postoperatively.Diclofenac eyedrops effectively reduced ocular inflammation and the occurrence of angiographic CME after cataract surgery.

TITLE: Hormonal regulation of lipoprotein(a) levels: effects of estrogen replacement therapy on lipoprotein(a) and acute phase reactants in postmenopausal women.ABSTRACT: Estrogen lowers lipoprotein(a) [Lp(a)] levels, but the mechanisms involved have not been clarified. To address the relationship between estrogenic effects on Lp(a) and serum lipids, and on other plasma proteins of hepatic origin, 15 healthy postmenopausal women participated in a randomized, double-blinded, placebo-controlled, crossover study with 4 weeks of oral conjugated estrogens (0.625 mg/d) and placebo, separated by a 6-week period. Lp(a) levels decreased during estrogen treatment in 14 of the 15 subjects (mean decrease, 23%; P < .001). In response to estrogen, apolipoprotein A-I (apoA-I), HDL cholesterol, and triglyceride levels increased by 12% (P = .001), 11% (P < .001), and 10% (P = .02), respectively. Apolipoprotein B (apoB) and LDL cholesterol levels decreased by 7% (P = .01) and 12% (P = .03), respectively, ApoB, LDL cholesterol, and Lp(a) levels fell within 1 week of treatment, whereas apoA-I and HDL cholesterol levels rose more slowly. Levels of acid alpha 1-glycoprotein (AAG) and haptoglobin (HPT), two hepatically derived acute phase proteins, also decreased during estrogen treatment by 18% (P < .001) and 25% (P = .002), respectively. Although the changes in AAG and HPT in response to estrogen were highly correlated (r = .67, P = .009), we were unable to detect a correlation between change in either acute phase protein and change in Lp(a) (r = -.14 and -.24, P = .64 and .41). The lack of correlation between the changes in two acute phase reactants and Lp(a) suggests different underlying mechanisms for the effects of estrogen on these liver-derived proteins.

TITLE: Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation.ABSTRACT: Whether antiarrhythmic drugs improve the rate of successful resuscitation after out-of-hospital cardiac arrest has not been determined in randomized clinical trials.We conducted a randomized, double-blind, placebo-controlled study of intravenous amiodarone in patients with out-of-hospital cardiac arrest. Patients who had cardiac arrest with ventricular fibrillation (or pulseless ventricular tachycardia) and who had not been resuscitated after receiving three or more precordial shocks were randomly assigned to receive 300 mg of intravenous amiodarone (246 patients) or placebo (258 patients).The treatment groups had similar clinical profiles. There was no significant difference between the amiodarone and placebo groups in the duration of the resuscitation attempt (42+/-16.4 and 43+/-16.3 minutes, respectively), the number of shocks delivered (4+/-3 and 6+/-5), or the proportion of patients who required additional antiarrhythmic drugs after the administration of the study drug (66 percent and 73 percent). More patients in the amiodarone group than in the placebo group had hypotension (59 percent vs. 48 percent, P=0.04) or bradycardia (41 percent vs. 25 percent, P=0.004) after receiving the study drug. Recipients of amiodarone were more likely to survive to be admitted to the hospital (44 percent, vs. 34 percent of the placebo group; P=0.03). The benefit of amiodarone was consistent among all subgroups and at all times of drug administration. The adjusted odds ratio for survival to admission to the hospital in the amiodarone group as compared with the placebo group was 1.6 (95 percent confidence interval, 1.1 to 2.4; P=0.02). The trial did not have sufficient statistical power to detect differences in survival to hospital discharge, which differed only slightly between the two groups.In patients with out-of-hospital cardiac arrest due to refractory ventricular arrhythmias, treatment with amiodarone resulted in a higher rate of survival to hospital admission. Whether this benefit extends to survival to discharge from the hospital merits further investigation.

TITLE: Postdural puncture headache is not an age-related symptom in children: a prospective, open-randomized, parallel group study comparing a22-gauge Quincke with a 22-gauge Whitacre needle.ABSTRACT: Many reports have shown a low incidence of postdural puncture headache (PDPH) and other complaints in young children. The objective of this open-randomized, prospective, parallel group study was to compare the use of a cutting point spinal needle (22-G Quincke) with a pencil point spinal needle (22-G Whitacre) in children. We studied the puncture characteristics, success rate and incidence of postpuncture complaints in 57 children, aged 8 months to 15 years, following 98 lumbar punctures (LP). The patient/parents completed a diary at 3 and 7 days after LP. The response rate was 97%. The incidence of PDPH was similar, 15% in the Quincke group and 9% in the Whitacre group (P=0.42). The risk of developing a PDPH was not dependent on the age (r < 0.00, P=0.67). Eight of the 11 PDPHs developed in children younger than 10 years, the youngest being 23-months-old.

TITLE: Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators.ABSTRACT: The clinical use of ambulatory blood pressure (BP) monitoring requires further validation in prospective outcome studies.To compare the prognostic significance of conventional and ambulatory BP measurement in older patients with isolated systolic hypertension.Substudy to the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial, started in October 1988 with follow up to February 1999. The conventional BP at randomization was the mean of 6 readings (2 measurements in the sitting position at 3 visits 1 month apart). The baseline ambulatory BP was recorded with a noninvasive intermittent technique.Family practices and outpatient clinics at primary and secondary referral hospitals.A total of 808 older (aged > or =60 years) patients whose untreated BP level on conventional measurement at baseline was 160 to 219 mm Hg systolic and less than 95 mm Hg diastolic.For the overall study, patients were randomized to nitrendipine (n = 415; 10-40 mg/d) with the possible addition of enalapril (5-20 mg/d) and/or hydrochlorothiazide (12.5-25.0 mg/d) or to matching placebos (n = 393).Total and cardiovascular mortality, all cardiovascular end points, fatal and nonfatal stroke, and fatal and nonfatal cardiac end points.After adjusting for sex, age, previous cardiovascular complications, smoking, and residence in western Europe, a 10-mm Hg higher conventional systolic BP at randomization was not associated with a worse prognosis, whereas in the placebo group, a 10-mm Hg higher 24-hour BP was associated with an increased relative hazard rate (HR) of most outcome measures (eg, HR, 1.23 [95% confidence interval [CI], 1.00-1.50] for total mortality and 1.34 [95% CI, 1.03-1.75] for cardiovascular mortality). In the placebo group, the nighttime systolic BP (12 AM-6 AM) more accurately predicted end points than the daytime level. Cardiovascular risk increased with a higher night-to-day ratio of systolic BP independent of the 24-hour BP (10% increase in night-to-day ratio; HR for all cardiovascular end points, 1.41; 95% CI, 1.03-1.94). At randomization, the cardiovascular risk conferred by a conventional systolic BP of 160 mm Hg was similar to that associated with a 24-hour daytime or nighttime systolic BP of 142 mm Hg (95% CI, 128-156 mm Hg), 145 mm Hg (95% CI, 126-164 mm Hg) or 132 mm Hg (95% CI, 120-145 mm Hg), respectively. In the active treatment group, systolic BP at randomization did not significantly predict cardiovascular risk, regardless of the technique of BP measurement.In untreated older patients with isolated systolic hypertension, ambulatory systolic BP was a significant predictor of cardiovascular risk over and above conventional BP.

TITLE: Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin: evidence for a complex interaction in a multicenter trial. EPILOG Investigators.ABSTRACT: After angioplasty, major complications and ischemic events occur more frequently in diabetic than nondiabetic patients. To determine whether treatment with abciximab is effective in reducing these events in diabetics, we analyzed characteristics and outcomes of diabetic patients enrolled in a large multicenter study (EPILOG).Of 2792 patients enrolled, 638 (23%) were diabetic. Diabetic patients were older, shorter, and heavier; more likely to be female and have three-vessel disease, prior coronary artery bypass graft surgery, a history of hypertension, or a recent myocardial infarction; and less likely to be current smokers than their nondiabetic counterparts. During hospitalization, death, myocardial infarction, or urgent revascularization occurred in 7.1% of diabetics and 7.5% of nondiabetics. By 6 months, the composite of death and myocardial infarction had occurred in 8.8% of diabetic patients and 7.4% of nondiabetics, whereas death, myocardial infarction, or revascularization had occurred in 27.2% and 22.6%, respectively. Abciximab treatment reduced death or myocardial infarction among diabetic and nondiabetic patients (hazard ratios, 0.28 [95% confidence interval (CI), 0.13 to 0.57] and 0.47 [95% CI, 0.33 to 0.70] at 30 days for diabetics and nondiabetics, respectively, and 0.36 [95% CI, 0.21 to 0.61] and 0.60 [95% CI, 0.44 to 0.82] at 6 months for diabetics and nondiabetics, respectively). Abciximab reduced target vessel revascularization among nondiabetic patients (hazard ratio, 0.78 [95% CI, 0.63 to 0.96]) but not among diabetics (hazard ratio, 1.4 [95% CI, 0.94 to 2.08]). When standard- and low-dose heparin adjuncts were compared, diabetics receiving abciximab with standard-dose heparin had marginally greater reductions in the composite of death and myocardial infarction and in target vessel revascularization than diabetics assigned to abciximab with low-dose heparin.Abciximab treatment in diabetic patients led to a reduction in the composite of death and myocardial infarction, which was at least as great as that seen in nondiabetic patients. However, target vessel revascularization was reduced in nondiabetic but not diabetic patients. This effect may be associated in part with lower doses of heparin. These differences may be related to differences in the platelet and coagulation systems between diabetics and nondiabetics, the greater extent of coronary artery disease in diabetics, or patient selection and management factors.

TITLE: Piperacillin/tazobactam versus imipenem: a double-blind, randomized formulary feasibility study at a major teaching hospital.ABSTRACT: With the introduction of piperacillin/tazobactam to the North American market, hospitals have been faced with the task of making a decision regarding its formulary role. In view of its broad spectrum of activity, piperacillin/tazobactam could be considered as a formulary alternative to imipenem. To evaluate the formulary feasibility of substituting piperacillin/tazobactam for imipenem, a comparative assessment of these agents in the empiric treatment of serious bacterial infections was undertaken at this tertiary care hospital. This trial was conducted as a randomized, double-blind, single-center study. Consenting adult patients (>16 years of age) who were prescribed imipenem were randomized to receive either 4 g of i.v. piperacillin/tazobactam or imipenem 500 mg of i.v. Q6H with or without concurrent antibiotics. Doses were adjusted according to renal function. There were no restrictions regarding the use of nonstudy antibiotics before and during the study period. Patients with beta-lactam allergies or meningitis or who had received greater than 72 h of previous imipenem therapy were excluded. Patients were evaluated at the end of treatment, at discharge, and at 30 days postdischarge. Endpoints included both clinical and microbiologic efficacy as well as drug toxicity. Over the 433-day study period, 360 imipenem treatment courses were initiated. Of these, 150 treatment courses (75 piperacillin/tazobactam courses and 75 imipenem courses) met study criteria and were subsequently randomized. The distribution of prescriber services for enrolled patients was similar to that for all patients receiving imipenem during the study period (p = 0.15). Also, there were no statistically significant differences in demographic parameters between enrolled and excluded patients. For those patients enrolled in the study, demographic characteristics, treatment course indication(s), and accompanying antibiotics were similar across treatment arms. The mean duration of study drug therapy was 7.7 days (SD, 6.2) for imipenem and 7.5 days (SD, 6.7)for piperacillin/tazobactam (p = 0.84). In the majority of cases, treatment discontinuation occurred as a result of a favorable treatment course outcome, stepdown to a narrower spectrum parenteral agent, or stepdown to an oral agent and did not differ between study drugs (p = 0.73). Clinical and microbiologic treatment course outcomes were also similar across treatment arms. Clinical outcome was deemed successful or improved for 68% of imipenem and 70% of the piperacillin/tazobactam treatment courses (p = 0.54). Fifty-three percent of treatment courses were microbiologically confirmed. Of the 58 courses that were assessed for microbiological outcome, 93% demonstrated successful eradication of the causative pathogens. There was no difference between study drugs (96% imipenem; 90% piperacillin/tazobactam; p = 0.61). The proportion of treatment courses with at least one adverse event was similar between the study drugs (p = 1.0). Nausea and/or vomiting were/was observed more commonly in the imipenem arm (p = 0.03). Discontinuation of therapy due to drug toxicity occurred in 16% of imipenem and 5% of piperacillin/tazobactam treatment courses (p = 0.06). There was no statistically significant difference between the mean treatment course cost for imipenem ($762; range, $55-$3192) versus piperacillin/tazobactam ($696; range, $79-$2967; p = 0.59). In summary, piperacillin/tazobactam seems to represent a suitable alternative to imipenem for several clinical indications including intraabdominal infections, pneumonia, febrile neutropenia, and skin/soft tissue infections in which the causative pathogens are susceptible. However, in view of the prevalence of multiresistant Gram-negative aerobic pathogens at this institution, we do not believe that imipenem can be removed from the drug formulary. In addition, at the currently studied dosing regimen, there seems to be no evidence of a direct cost advantage associated with

TITLE: Effect of oral antidiabetic agents on plasma amylin level in patients with non-insulin-dependent diabetes mellitus (type 2).ABSTRACT: The purpose of the study was the comparison of the effect of the oral therapy of non-insulin-dependent diabetes mellitus (NIDDM) with either a sulphonylurea or biguanide derivative on plasma amylin level. In 10 healthy individuals the fasting plasma amylin level was 1.56 +/- 0.27 pmol/l (mean +/- SEM) and 6 min after i.v. injection of 1 mg glucagon a fourfold increase was observed. In 10 patients with NIDDM receiving glibenclamide (CAS 10238-21-8) the fasting plasma amylin level was twofold higher than in healthy control (2.72 +/- 0.38 pmol/l; p < 0.025) but following glucagon administration it increased only twofold. In 15 patients treated with metformin (CAS 657-24-9) the fasting plasma amylin level was similar to that in healthy individuals (1.64 +/- 0.25 pmol/l), but after glucagon stimulation the increment of plasma amylin was minimal and the relevant mean value was significantly lower when compared with those in healthy individuals and with NIDDM patients treated with glibenclamide. In 10 untreated obese patients with newly diagnosed NIDDM the administration of glibenclamide (14 days) resulted in the increase of basal (2.47 +/- 0.23 and 3.16 +/- 0.29 pmol/l; p < 0.1), and glucagon stimulated (3.34 +/- 0.39 and 4.56 +/- 0.38; p < 0.05) plasma amylin concentrations, whereas other 10 patients receiving metformin showed a decrease in fasting plasma level of this peptide before (2.64 +/- 0.59 and 1.28 +/- 0.38 pmol/l; p < 0.1), and after glucagon injection (5.02 +/- 0.55 and 2.83 +/- 0.65 pmol/l; p < 0.02). With the respect to the trophic effect of amyloid deposits in the pancreatic islets and to a hypothetic effect of amylin increasing insulin resistance, the present results emphasize the particular usefulness of metformin in the pharmacological treatment of NIDDM. All contraindications and side effects of metformin should be taken into account before drug administration.

TITLE: Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy.ABSTRACT: Teriparatide (rhPTH[1-34]), a bone-forming agent for the treatment of osteoporosis, increases bone mineral density in men and women, and reduces the risk of fractures in women with osteoporosis. However, fracture efficacy has not yet been confirmed in men. Further, there is limited information on the effect of withdrawal of teriparatide. The purpose of this manuscript is to report on bone mineral density and vertebral fracture incidence during a 42-month observation period, from the baseline of the previously reported treatment study in men [1] through 30 months of posttreatment follow-up. Three hundred fifty-five men who were treated with once-daily self-injections of either placebo or 20 or 40 microg of teriparatide participated in the follow-up study. Bone mineral density gradually decreased following discontinuation of teriparatide therapy. However, the lumbar spine and total hip values remained significantly higher than baseline after 30 months of follow-up (p< or =0.001). Antiresorptive treatment prevented the decline and tended to further increase bone mineral density. Lateral thoracic lumbar radiographs obtained at baseline and 18 months after discontinuation of teriparatide were available for 279 men. Of these men, 11.7% assigned to placebo, 5.4% treated with teriparatide 20 microg, and 6.0% treated with teriparatide 40 microg had an incident vertebral fracture. In the combined teriparatide treated groups vs placebo, the risk of vertebral fracture was reduced 51% (nonsignificant, p=0.07). The incidence of moderate or severe fractures was significantly reduced by 83% (p=0.01). In conclusion, men who received teriparatide and who may have received follow-up antiresorptive therapy had a decreased risk of moderate and severe vertebral fractures.

TITLE: Levobupivacaine 0.2% or 0.125% for continuous sciatic nerve block: a prospective, randomized, double-blind comparison with 0.2% ropivacaine.ABSTRACT: In 60 patients receiving elective hallux valgus repair, we compared the efficacy of continuous popliteal sciatic nerve block produced with 0.2% ropivacaine (n = 20), 0.2% levobupivacaine (n = 20), or 0.125% levobupivacaine (n = 20) infused with a patient-controlled system starting 3 h after a 30-mL bolus of the 0.5% concentration of the study drug and for 48 h (baseline infusion rate, 6 mL/h; incremental dose, 2 mL; lockout time, 15 min; maximum incremental doses per hour, 3). No differences were reported in the intraoperative efficacy of the nerve block. The degree of pain was similar in the three groups throughout the study period, both at rest and during motion. Total consumption of local anesthetic solution during the first 24 h was 148 mL (range, 144-228 mL) with 0.2% ropivacaine, 150 mL (range, 144-200 mL) with 0.2% levobupivacaine, and 148 mL (range, 144-164 mL) with 0.125% levobupivacaine (P = 0.59). The volume of local anesthetic consumed during the second postoperative day was 150 mL (range, 144-164 mL) with 0.2% ropivacaine, 154 mL (range, 144-176 mL) with 0.2% levobupivacaine, and 151 mL (range, 144-216 mL) with 0.125% levobupivacaine (P = 0.14). A smaller proportion of patients receiving 0.2% levobupivacaine showed complete recovery of foot motor function as compared with 0.2% ropivacaine and 0.125% levobupivacaine, both at 24 h (35% vs 85% and 95%; P = 0.0005) and at 48 h (60% vs 100% and 100%; P = 0.001). We conclude that sciatic infusion with both 0.125% and 0.2% levobupivacaine provides adequate postoperative analgesia after hallux valgus repair, clinically similar to that provided by 0.2% ropivacaine; however, the 0.125% concentration is preferred if early mobilization of the operated foot is required.

TITLE: Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial.ABSTRACT: GnRH agonists decrease bone mineral density and increase fracture risk in men with prostate cancer. Raloxifene increases bone mineral density in postmenopausal women, but its efficacy in hypogonadal men is not known. In a 12-month open-label study, men with nonmetastatic prostate cancer (n = 48) who were receiving a GnRH agonist were assigned randomly to raloxifene (60 mg/d) or no raloxifene. Bone mineral densities of the posteroanterior lumbar spine and proximal femur were measured by dual energy x-ray absorptiometry. Mean (+/-se) bone mineral density of the posteroanterior lumbar spine increased by 1.0 +/- 0.9% in men treated with raloxifene and decreased by 1.0 +/- 0.6% in men who did not receive raloxifene (P = 0.07). Bone mineral density of the total hip increased by 1.1 +/- 0.4% in men treated with raloxifene and decreased by 2.6 +/- 0.7% in men who did not receive raloxifene (P < 0.001). Similar between-group differences were observed in the femoral neck (P = 0.06) and trochanter (P < 0.001). In men receiving a GnRH agonist, raloxifene significantly increases bone mineral density of the hip and tends to increase bone mineral density of the spine.

TITLE: Another way to estimate outcome of advanced nasopharyngeal carcinoma--is concurrent chemoradiotherapy adequate?ABSTRACT: To evaluate a simple risk grouping system and determine whether concurrent chemoradiotherapy (CCRT) is adequate for patients with advanced nasopharyngeal carcinoma (NPC).A total of 284 patients with 1992 American Joint Committee on Cancer (AJCC) Stage III to IV (M0) NPC were analyzed retrospectively. They were treated by either radiotherapy (RT) alone or CCRT. We divided patients into high-risk and low-risk subgroups according to our experience. High-risk patients met at least one of the following criteria: (1) nodal size >6 cm, (2) supraclavicular node metastases, (3) 1992 AJCC stage T4N2, (4) multiple neck node metastases with 1 node >4 cm. The disease extent of each patient was stratified by our risk grouping system, AJCC 1992 and 1997 staging systems. Survival analyses-including nasopharynx disease free (TS), neck disease free (NS), distant metastasis disease free (MS), overall survival (OS), and progression-free (PFS) survival curves-were compared between these three different classifications.According to the 1992 AJCC staging system, 80.3% (228/284) of NPC patients are Stage IV, whereas only 19.7% are Stage III. Most patients are downstaged by the 1997 AJCC staging system with 28.5% (81/284) Stage IV and 71.5% (203/284) Stage III/II. Our risk criteria stratify more even patient distribution, because 119 patients (41.9%) are assigned to the high-risk group and 165 patients (58.1%) to the low-risk group. Log-rank test of Kaplan-Meier survival curves, multivariate comparison of the Cox proportional hazards model, and 3 goodness-of-fit indices validated that our risk grouping system seemed to be at least as efficacious as, or slightly superior to, the 1992 and 1997 AJCC systems. The 5-year TS (95.1% vs. 76.8%, p = 0.0012), NS (100% vs. 95.7%, p = 0.0974), MS (90.5% vs. 78.1%, p = 0.0282), OS (83.2% vs. 59.7%, p = 0.0041), and PFS (87.3% vs. 61.5%, p = 0.0003) were significantly better in patients receiving CCRT than RT alone for the low-risk group. However, the corresponding survival rates between CCRT and RT for high-risk patients were 74.9% vs. 67.6% (p = 0.2545) for TS, 92.1% vs. 86.8% (p = 0.4744) for NS, 59.7% vs. 60.0% (p = 0.5537) for MS, 55.8% vs. 46.3% (p = 0.1761) for OS, and 44.5% vs. 43.1% (p = 0.3911) for PFS, respectively.Concurrent chemoradiotherapy is superior to RT alone for low-risk patients but inadequate for high-risk patients. Adding neoadjuvant and/or adjuvant chemotherapy would be a reasonable approach for high-risk patients. Our risk grouping criteria are a simple and useful guide that will have important implications in the design of future therapeutic trials.

TITLE: Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.ABSTRACT: Oral daily (2.5 mg) and intermittent ibandronate (between-dose interval of >2 months), delivering a similar cumulative exposure, were evaluated in 2946 osteoporotic women with prevalent vertebral fracture. Significant reduction in incident vertebral fracture risk by 62% and 50%, respectively, was shown after 3 years. This is the first study to prospectively show antifracture efficacy for the intermittent administration of a bisphosphonate.Bisphosphonates are important therapeutics in postmenopausal osteoporosis. However, they are currently associated with stringent dosing instructions that may impair patient compliance and hence therapeutic efficacy. Less frequent, intermittent administration may help to overcome these deficiencies. This study assessed the efficacy and safety of oral ibandronate administered either daily or intermittently with a dose-free interval of >2 months.This randomized, double-blind, placebo-controlled, parallel-group study enrolled 2946 postmenopausal women with a BMD T score < or = -2.0 at the lumbar spine in at least one vertebra (L1-L4) and one to four prevalent vertebral fractures (T4-L4). Patients received placebo or oral ibandronate administered either daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months).After 3 years, the rate of new vertebral fractures was significantly reduced in patients receiving oral daily (4.7%) and intermittent ibandronate (4.9%), relative to placebo (9.6%). Thus, daily and intermittent oral ibandronate significantly reduced the risk of new morphometric vertebral fractures by 62% (p = 0.0001) and 50% (p = 0.0006), respectively, versus placebo. Both treatment groups also produced a statistically significant relative risk reduction in clinical vertebral fractures (49% and 48% for daily and intermittent ibandronate, respectively). Significant and progressive increases in lumbar spine (6.5%, 5.7%, and 1.3% for daily ibandronate, intermittent ibandronate, and placebo, respectively, at 3 years) and hip BMD, normalization of bone turnover, and significantly less height loss than in the placebo group were also observed for both ibandronate regimens. The overall population was at low risk for osteoporotic fractures. Consequently, the incidence of nonvertebral fractures was similar between the ibandronate and placebo groups after 3 years (9.1%, 8.9%, and 8.2% in the daily, intermittent, and placebo groups, respectively; difference between arms not significant). However, findings from a posthoc analysis showed that the daily regimen reduces the risk of nonvertebral fractures (69%; p = 0.012) in a higher-risk subgroup (femoral neck BMD T score < -3.0). In addition, oral ibandronate was well tolerated. Oral ibandronate, whether administered daily or intermittently with an extended between-dose interval of >2 months, is highly effective in reducing the incidence of osteoporotic fractures in postmenopausal women. This is the first time that significant fracture efficacy has been prospectively shown with an intermittently administered bisphosphonate in the overall study population of a randomized, controlled clinical trial. Thus, oral ibandronate holds promise as an effective and convenient alternative to current bisphosphonate therapies.

TITLE: Comprehensive lifestyle modification and blood pressure control: a review of the PREMIER trial.ABSTRACT: The PREMIER trial assessed the aggregate effect on blood pressure (BP) of nationally recommended lifestyle modifications in free-living adults with high-normal (stage 1) hypertension. Participants (N=810) were randomized to the advice-only group; the established group (consisting of weight loss, increased physical activity, and reduced sodium and alcohol intake); or the established plus Dietary Approaches to Stop Hypertension (DASH) diet group (consisting of the established interventions in addition to the DASH dietary pattern). The primary outcome was change in systolic BP at 6 months. Net of advice only, mean systolic BP declined by 3.7 mm Hg for members of the established group (p<0.001) and 4.3 mm Hg for the established plus DASH group (p<0.001). The prevalence of hypertension decreased from a baseline of 38% to 17% in the established group (p=0.01) and to 12% in the established plus DASH group (p<0.001) compared with a decrease to 26% in the advice-only group. The PREMIER trial demonstrated that persons with above-optimal BP and stage 1 hypertension can make multiple lifestyle changes leading to better control of BP.

TITLE: Once-daily insulin glargine compared with twice-daily NPH insulin in patients with type 1 diabetes.ABSTRACT: To present the findings in a randomized, parallel-group study, comparing once-daily insulin glargine with twice-daily NPH insulin in patients with type 1 diabetes previously treated with multiple daily injections of basal and regular insulin.Of 394 patients with type 1 diabetes treated for up to 28 weeks, 195 received insulin glargine and 199 received NPH insulin, in addition to preprandial regular insulin. Glycemic control and hypoglycemic episodes were assessed.A greater mean decrease in fasting blood glucose (FBG) was achieved at endpoint with insulin glargine than with NPH insulin (-21 mg/dL versus -10 mg/dL [-1.17 mmol/L versus -0.56 mmol/L]; P = 0.015), and a greater percentage of patients treated with insulin glargine reached the target FBG (32.6% versus 21.3%; P = 0.015). Similar percentages of patients in both treatment groups achieved glycosylated hemoglobin values of 7.0% or less at endpoint (insulin glargine, 35.8%; NPH insulin, 35.4%). After the 1-month titration phase, the percentage of patients who reported at least one symptomatic hypoglycemic event confirmed by a blood glucose value of less than 50 mg/dL (2.8 mmol/L) was significantly lower with insulin glargine than with NPH insulin (73.3% versus 81.7%; P = 0.021). Furthermore, the percentage of patients who reported at least one symptomatic hypoglycemic event confirmed by a blood glucose value of less than 36 mg/dL (2.0 mmol/L) was significantly lower with insulin glargine than with NPH insulin (36.6% versus 46.2%; P = 0.033).Once-daily insulin glargine was at least as effective as twice-daily NPH insulin in improving fasting glycemic control and resulted in fewer reported symptomatic hypoglycemic events.

TITLE: Low-dose international normalized ratio self-management: a promising tool to achieve low complication rates after mechanical heart valve replacement.ABSTRACT: International normalized ratio (INR) self-management can significantly reduce INR fluctuations, bleeding, and thromboembolic events compared with INR control managed by general practitioners. However, even patients with INR self-management may have an increased risk of bleeding if their INR value is above 3.5. This study evaluated the compliance, clinical complications, and survival of patients after mechanical heart valve replacement with low-dose INR self-management compared with conventional-dose anticoagulation.Group 1 (n = 908) received low-dose anticoagulation with a target INR range of 1.8 to 2.8 for aortic valve replacement and 2.5 to 3.5 for mitral or double valve replacement. Group 2 (n = 910) received conventional-dose anticoagulation with a target INR range of 2.5 to 4.5 for all heart valve prostheses.In groups 1 and 2, 76% and 75% of INR values, respectively, were in the target range. Results did not differ according to schooling and age. The rate of thromboembolic events per patient year was 0.18% in group 1 and 0.40% in group 2 (p = 0.210). The rate of bleeding complications was 0.74% for group 1 and 1.20% for group 2 (p = 0.502). In most patients with clinically relevant bleeding, these complications occurred although their measured INR values were below 3.5. The survival rate did not differ between the study groups (p = 0.495).Low-dose INR self-management is a promising tool to achieve low hemorrhagic complications without increasing the risk of thromboembolic complications. INR self-management is applicable for all patients in whom permanent anticoagulation therapy is indicated. Even INR values below 3.5 can bear the risk of bleeding complications.

TITLE: Rectal paracetamol has a significant morphine-sparing effect after hysterectomy.ABSTRACT: We have evaluated the morphine-sparing effect of rectal paracetamol during the first 24 h after abdominal hysterectomy in a placebo-controlled, double-blind study. We studied 72 patients receiving patient-controlled analgesia (PCA) with i.v. morphine after a standardized anaesthetic, allocated randomly to receive rectal paracetamol 1.3 g, diclofenac 50 mg or placebo, after wound closure and at 8 and 16 h. Suppositories were blinded by the hospital pharmacy. Study violations excluded data from seven patients. Patient data, morphine doses during anaesthesia and recovery, and sedation and nausea scores were comparable. Mean morphine consumption during PCA was 35.0 (SD 20.4) mg, 32.7 (27.4) mg and 54.9 (28.3) mg in the paracetamol (n = 24), diclofenac (n = 20) and placebo (n = 21) groups, respectively (P < 0.05). Morphine sparing during PCA for paracetamol and diclofenac (36% vs 40% over 24 h) was significant from 4 h. Global scores of average pain over 24 h were lower after diclofenac compared with paracetamol (P < 0.01) and placebo (P = 0.08). We conclude that rectal paracetamol was an efficacious adjuvant analgesic after regular dosing.

TITLE: Randomised controlled trial of thiopental for intubation in neonates.ABSTRACT: To determine the effects of premedication with thiopental on heart rate, blood pressure, and oxygen saturation during semi-elective nasotracheal intubation in neonates.A randomised, placebo controlled, non-blinded study design was used to study 30 neonates (mean birthweight 3.27 kg) requiring semi-elective nasotracheal intubation. The babies were randomly allocated to receive either 6 mg/kg of thiopental (study group) or an equivalent volume of physiological saline (control group) one minute before the start of the procedure. Six infants were intubated primarily and 24 were changed from orotracheal to a nasotracheal tube. The electrocardiogram, arterial pressure wave, and transcutaneous oxygen saturation were recorded continuously 10 minutes before, during, and 20 minutes after intubation. Minute by minute measurements of heart rate, heart rate variability, mean blood pressure (MBP) and transcutaneous oxygen saturation (SpO(2)) were computed. The differences for all of these between the baseline measurements and those made during and after intubation were determined. Differences in the measurements made in the study and the control groups were compared using Student's t test.During intubation, heart rate increased to a greater degree (12.0 vs -0.5 beats per minute, p < 0.03) and MBP increased to a lesser degree (-2.9 vs 4.4 mm Hg; p < 0.002) in the infants who were premedicated with thiopental. After intubation only the changes in MBP differed significantly between the two groups (-3.8 vs 4.6 mm Hg; p < 0.001). There were no significant changes in the oxygen saturation between the two groups during or after intubation. The time taken for intubation was significantly shorter in the study group (p < 0.04).The heart rate and blood pressure of infants who are premedicated with thiopental are maintained nearer to baseline values than those of similar infants who receive no premedication. Whether this lessening of the acute drop in the heart rate and increase in blood pressure typically seen during intubation of unmedicated infants is associated with long term advantages to the infants remains to be determined.

TITLE: The misoprostol third stage of labour study: a randomised controlled comparison between orally administered misoprostol and standard management.ABSTRACT: To compare misoprostol with standard oxytocic regimens in the prevention of postpartum haemorrhage.Randomised controlled trial.Obstetric unit in a large teaching hospital.One thousand women randomised to 500 microg misoprostol given orally or to standard oxytocic regimens of oxytocin, oxytocin with ergometrine, or ergometrine.Incidence of postpartum haemorrhage and the incidence and severity of side effects.Postpartum haemorrhage occurred in 12% of women given misoprostol and in 11% of women given standard oxytocic drugs (relative risk (RR) 1.10, 95% confidence interval (CI) 0.79, 1.55). Blood loss of 1000 mL or more occurred in 2% of women in each group. Nausea, headache, dizziness and tiredness were less frequent with misoprostol (RR (95% CI) 0.71 (0.59, 0.84); 0.53 (0.38, 0.74); 0.73 (0.61, 0.87) and 0.88 (0.83, 0.94) respectively). The main side effects of misoprostol were shivering (RR 1.95, 95% CI 1.69, 2.25) and a rise in temperature (difference in mean rise 0.34 degrees C, 95% CI 0.26, 0.42).Oral misoprostol for the prevention of postpartum haemorrhage was comparable to standard oxytocics. Many side effects were less common with misoprostol but shivering and pyrexia were more common. Larger randomised trials are needed before establishing the equivalence between misoprostol and standard oxytocic drugs in the prevention of postpartum haemorrhage.

TITLE: Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: an interim analysis.ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is an early-onset neuropsychiatric disorder that affects 3% to 7% of school-age children and 4% of adults. Its pathophysiology is thought to involve the dopaminergic and nor-adrenergic pathways associated with attention control and impulsivity. These symptoms have largely been defined in the childhood population, but the course of the condition and expression in the adult population are not as well characterized.This is an ongoing, 3-year, open-label study consisting of adults with DSM-IV ADHD who were previously enrolled in 1 of 2 double-blind, acute-treatment studies of atomoxetine. The results of the interim analysis reported here were derived from the study of 384 patients at 31 sites who had been studied for a period of up to 97 weeks. The primary efficacy measure was the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) total ADHD symptom score. In addition, safety, adverse events, and vital sign measurements were assessed.Significant improvement was noted with atomoxetine therapy, with mean CAARS-Inv:SV total ADHD symptom scores decreasing 33.2% from 29.2 (baseline of open-label therapy) to 19.5 (endpoint of open-label therapy) (p < .001). Similar and significant decreases were noted for the secondary efficacy measures. Adverse events consisted primarily of pharmacologically (noradrenergic) expected effects, such as increases in heart rate and blood pressure and a slight decrease in weight.The results of this interim analysis of an ongoing, open-label study of adults with ADHD support the long-term efficacy, safety, and tolerability of atomoxetine for the treatment of adult ADHD.

TITLE: Add-on melatonin improves sleep behavior in children with epilepsy: randomized, double-blind, placebo-controlled trial.ABSTRACT: This double-blind, randomized, placebo-controlled study in epileptic children, aged 3 to 12 years, evaluated the effect of add-on melatonin on the sleep behavior of these children on sodium valproate monotherapy using a parental questionnaire. Of the 31 patients, 16 randomly received add-on melatonin, whereas 15 received add-on placebo. The questionnaire showed good internal consistency in our patient population (Cronbach's alpha = .83). The percentage decrease in the median total sleep score was 24.4 (range 0.0-34.9) in the valproate + melatonin group compared with 14.0 (range -2.2-18.8) in the valproate + placebo group, the difference being statistically significant (P < .05). The median percentage decrease in the parasomnias score was 60 (range 0.0-70.8) in the valproate + melatonin group compared with 36.4 (range 0.0-63.2) in the valproate + placebo group, the difference being statistically significant (P < .05). There was no significant difference between the percentage decrease in the daytime drowsiness scores and sleep fragmentation scores. Parent-child interaction subscale scores were not significantly different between age groups. The age at onset of seizures and the type of seizures did not correlate significantly to the total sleep scores. Given that sleep problems are known to complicate epilepsy, add-on melatonin, which has a wide safety window, can be of promise in the pharmacotherapy of pediatric epilepsy.

TITLE: A randomized trial of electronic clinical reminders to improve quality of care for diabetes and coronary artery disease.ABSTRACT: The aim of this study was to evaluate the impact of an integrated patient-specific electronic clinical reminder system on diabetes and coronary artery disease (CAD) care and to assess physician attitudes toward this reminder system.We enrolled 194 primary care physicians caring for 4549 patients with diabetes and 2199 patients with CAD at 20 ambulatory clinics. Clinics were randomized so that physicians received either evidence-based electronic reminders within their patients' electronic medical record or usual care. There were five reminders for diabetes care and four reminders for CAD care.The primary outcome was receipt of recommended care for diabetes and CAD. We created a summary outcome to assess the odds of increased compliance with overall diabetes care (based on five measures) and overall CAD care (based on four measures). We surveyed physicians to assess attitudes toward the reminder system.Baseline adherence rates to all quality measures were low. While electronic reminders increased the odds of recommended diabetes care (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.01-1.67) and CAD (OR 1.25, 95% CI 1.01-1.55), the impact of individual reminders was variable. A total of three of nine reminders effectively increased rates of recommended care for diabetes or CAD. The majority of physicians (76%) thought that reminders improved quality of care.An integrated electronic reminder system resulted in variable improvement in care for diabetes and CAD. These improvements were often limited and quality gaps persist.

TITLE: Losartan benefits over atenolol in non-smoking hypertensive patients with left ventricular hypertrophy: the LIFE study.ABSTRACT: We studied the impact of smoking in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios in 4656 never-smokers, and 3033 previous and 1499 current smokers, adjusting for gender, age, alcohol intake, exercise and race. Composite endpoint rate was higher in previous (28/1000 years), as well as current (39/1000 years) smokers than in never-smokers (21/1000 years). Composite (hazard ratio 0.78, 95% CI 0.65-0.94, p < 0.01) and stroke (hazard ratio 0.61, 95% CI 0.47-0.80], p < 0.001) risks were lower with losartan than atenolol in never-smokers, but not significantly in previous smokers. Drug regimens did not differ in current smokers (composite hazard ratio 0.99, stroke hazard ratio 0.94). Smoking-treatment interactions were non-significant, but a borderline significant trend (p = 0.05) suggested decreasing benefit of losartan vs atenolol for stroke prevention from never- to previous to current smoking status. Smoking increased cardiovascular risk markedly in the LIFE study. The benefit of losartan vs atenolol is consistent with the overall conclusion of the LIFE study, although the treatment effect appeared largest in non-smokers.

TITLE: Analysis of morbidity in patients with endometrial cancer: is there a commitment to offer laparoscopy?ABSTRACT: Benefits of laparoscopy over laparotomy in patients with endometrial cancer (EC) are well known. As many patients with EC carry co-morbid conditions, surgery is exposing them to increased risk of complications. A review of the patients with EC recruited so far in a clinical trial comparing laparoscopy to laparotomy was performed. The goal was to identify patients carrying specific risk factors for complications, who would most benefit of laparoscopy and be the ideal candidates for this surgical approach.Between July 1995 and December 2002, 122 patients with uterine cancer entered the study. Sixty-three patients were allocated to the laparoscopy (LPS) arm (group A), while 59 were allocated to the laparotomy (LPT) arm (group B). Rate and type of intra-, early and late post-operative complications were prospectively recorded. Risk factors for complications are analyzed to define a group of patients truly benefiting from laparoscopy.Overall, 12 patients out of 122 (9.8%) have experienced intra-operative, 43 patients out of 122 (35.2%) early post-operative and 25 patients out of 122 (20.4%) late post-operative complications. Rate of intra-operative complications was 4.7% in group A (3 patients out of 63) vs. 15.2% in group B (9 patients out of 59), P = 0.082. Early post-operative complications rate was 23.8% in group A (15 out of 63) and 47.4% in group B (28 out of 59), P = 0.011. Rate of late post-operative complications was 7.9% (5 out of 63) in group A vs. 35.5% (21 out of 59), P = 0.001. Univariate analysis shows co-morbid medical conditions, weight >80 kg, Quetelet index >30 and age >65 years to be predictive of complications and, in fact, a subgroup of patients presenting with these characteristics (n = 57, 30 in group A and 27 in group B) has been recognized to accumulate 60% of the overall complications. In these patients, multivariate analysis identifies the surgical technique (LPS vs. LPT) to be the only significant risk factor for complications.At least one third of the patients with EC carry serious co-morbidities with an increased surgical risk for complications. For this subgroup of patients, a laparoscopic-vaginal approach significantly reduces the rate of complications and should be the standard of surgical treatment.

TITLE: Impact of an adherence clinic on behavioral outcomes and virologic response in treatment of HIV infection: a prospective, randomized, controlled pilot study.ABSTRACT: The aim of this randomized, controlled pilot study was to examine the impact of a pharmacist operated adherence clinic on adherence to highly active antiretroviral therapy (HAART) and viral suppression in patients with HIV over 28 weeks.Consecutive eligible patients initiating HAART at an indigent-care clinic were randomized to an adherence clinic or to standard care (information provided by physician or nurse practitioner) for education and monitoring. Group assignment was stratified before randomization according to regimen complexity and potential tolerability. Adherence (electronic monitoring and patient self-report) and viral load (reverse-transcription polymerase chain reaction) were assessed at weeks 4, 16, and 28.Thirty-three randomized patients (adherence clinic, n = 16; standard care, n = 17) comprised the intent-to-treat population. The groups were well-matched for demographics and antiretroviral regimen. The median age was 38.0 years in both groups. Most patients were male (85%), had previously used HAART (78%), and had an AIDS diagnosis (79%). Mean (SD) adherence at weeks 4, 16, and 28 was 86% (27%), 77% (28%), and 74% (31%) in the adherence clinic group versus 73% (32%), 56% (39%), and 51% (41%) in the standard care group (week-16 difference, 21% [90% CI, 1%-42%]; week-28 difference, 23% [90% CI, 1%-44%]). Sixty-nine percent of patients in the adherence clinic group took their medication on schedule versus 42% in the standard care group (P = 0.025); mean decline in adherence from weeks 4 to 28 was 12% in the adherence clinic group (P = 0.15) versus 22% in the standard care group (P = 0.002). HIV-1 RNA levels were <400 copies/mL at weeks 4, 16, and 28 in 63%, 100%, and 94% of the adherence clinic group and 29% (P = NS), 71% (P = 0.04), and 65% (P = NS) of the standard care group.In this preliminary trial, an adherence clinic model improved adherence to HAART and virologic response over 28 weeks in the patients studied.

TITLE: Comparative trial of short-course ofloxacin for uncomplicated typhoid fever in Vietnamese children.ABSTRACT: An open, randomised comparison of 2 or 3 days of oral ofloxacin (10 mg/kg/day) for uncomplicated typhoid fever was conducted in 235 Vietnamese children. Multi-drug-resistant Salmonella typhi was isolated from 182/202 (90%) children and 5/166 (3%) tested isolates were nalidixic acid-resistant (Na(R)). Eighty-nine of 116 children randomised to 2 days and 107/119 randomised to 3 days were blood culture-positive and eligible for analysis. There were 12 (13.5%) failures in the 2-day group (six clinical failures, four blood culture-positive post treatment, two relapses) compared with eight (7.5%) failures in the 3-day group (four clinical failures, one blood culture-positive post treatment, three relapses) (OR 1.9, 95% CI 0.7-5.5,p = 0.17). There were no significant differences in the mean (95% confidence interval) fever clearance times (h) [92 (82-102) vs 101 (93-110), p = 0.18] or duration of hospitalisation (d) [7.6 (7.2-8.1) vs 8.0 (7.6-8.4), p = 0.19] between the two groups. There was one failure in the four eligible children infected with an Na(R) isolate of S. typhi. No adverse events were attributable to the ofloxacin. These results extend previous observations on the efficacy of short courses of ofloxacin for children with uncomplicated multi-drug-resistant typhoid fever.

TITLE: Twenty-four-hour diurnal curve comparison of commercially available latanoprost 0.005% versus the timolol and dorzolamide fixed combination.ABSTRACT: To evaluate the efficacy and safety of commercially available latanoprost 0.005% given every evening versus timolol 0.5% and dorzolamide 2% fixed combination (TDFC) given twice daily to white Greeks with primary open-angle glaucoma and ocular hypertensive patients.A single-masked, two-center, crossover comparison with two 6-week treatment periods occurring after at least a 3-week medicine-free period. Diurnal curve intraocular pressures were taken at 2:00 AM, 6:00 AM, 10:00 AM, 2:00 PM, 6:00 PM, and 10:00 PM.Thirty-four subjects with primary open-angle glaucoma or ocular hypertension were enrolled.Latanoprost 0.005% given every evening and TDFC twice daily.The primary efficacy variable was diurnal intraocular pressure.Thirty-three patients completed the study. On the last day of treatment, the mean diurnal intraocular pressure for latanoprost was 15.9 +/- 2.3 mmHg and for TDFC was 15.3 +/- 2.0 mmHg (P = 0.05). Individual time points for intraocular pressure were not statistically different between groups except at the 10:00 PM time point, when the mean for TDFC was 14.6 +/- 2.7 mmHg and for latanoprost was 16.6 +/- 3.1 mmHg (P < 0.006). Eighteen patients overall preferred latanoprost versus 2 patients for the fixed combination, generally because of the greater convenience of once daily dosing. Adverse events were not significantly different between groups except that a bitter taste was found more frequently with TDFC (n = 9) than with latanoprost (n = 0; P = 0.009). Despite screening to exclude intolerance to beta-blockers, a single patient had to discontinue the TDFC because of new-onset asthma.This study indicates that the 24-hour diurnal intraocular pressure is lowered more, by a small but statistically significant amount, with TDFC compared with latanoprost in primary open-angle glaucoma and ocular hypertensive patients.

TITLE: Oral choline decreases brain purine levels in lithium-treated subjects with rapid-cycling bipolar disorder: a double-blind trial using proton and lithium magnetic resonance spectroscopy.ABSTRACT: Oral choline administration has been reported to increase brain phosphatidylcholine levels. As phospholipid synthesis for maintaining membrane integrity in mammalian brain cells consumes approximately 10-15% of the total adenosine triphosphate (ATP) pool, an increased availability of brain choline may lead to an increase in ATP consumption. Given reports of genetic studies, which suggest mitochondrial dysfunction, and phosphorus (31P) magnetic resonance spectroscopy (MRS) studies, which report dysfunction in high-energy phosphate metabolism in patients with bipolar disorder, the current study is designed to evaluate the role of oral choline supplementation in modifying high-energy phosphate metabolism in subjects with bipolar disorder.Eight lithium-treated patients with DSM-IV bipolar disorder, rapid cycling type were randomly assigned to 50 mg/kg/day of choline bitartrate or placebo for 12 weeks. Brain purine, choline and lithium levels were assessed using 1H- and 7Li-MRS. Patients received four to six MRS scans, at baseline and weeks 2, 3, 5, 8, 10 and 12 of treatment (n = 40 scans). Patients were assessed using the Clinical Global Impression Scale (CGIS), the Young Mania Rating Scale (YRMS) and the Hamilton Depression Rating Scale (HDRS) at each MRS scan.There were no significant differences in change-from-baseline measures of CGIS, YMRS, and HDRS, brain choline/creatine ratios, and brain lithium levels over a 12-week assessment period between the choline and placebo groups or within each group. However, the choline treatment group showed a significant decrease in purine metabolite ratios from baseline (purine/n-acetyl aspartate: coef = -0.08, z = -2.17, df = 22, p = 0.030; purine/choline: coef = -0.12, z = -1.97, df = 22, p = 0.049) compared to the placebo group, controlling for brain lithium level changes. Brain lithium level change was not a significant predictor of purine ratios.The current study reports that oral choline supplementation resulted in a significant decrease in brain purine levels over a 12-week treatment period in lithium-treated patients with DSM-IV bipolar disorder, rapid-cycling type, which may be related to the anti-manic effects of adjuvant choline. This result is consistent with mitochondrial dysfunction in bipolar disorder inadequately meeting the demand for increased ATP production as exogenous oral choline administration increases membrane phospholipid synthesis.

TITLE: Effects of iron(II) salts and iron(III) complexes on trace element status in children with iron-deficiency anemia.ABSTRACT: Iron-deficiency anemia (IDA) is the most common nutritional deficiency in childhood throughout the world. Although it has been shown that IRA is associated with elevated plasma copper and depleted zinc levels in children, there are conflicting results on the effect of iron supplementation on the absorption of these elements. The aim of this study was to investigate the effects of ferrous and ferric iron supplementation on the trace element status in children (n=25, aged 8-168 mo) with IDA. Fourteen of them were treated with ferric hydroxide-polymaltose complex (Ferrum, Vifor, Switzerland) (6 mg/d in the first 3 mo for initial therapy and 3 mg/kg for 3 mo as maintenance); the others were treated with a ferrous sulfate complex (FerroSanol, Schwarz, Germany) (6 mg/d in the first 3 mo for initial therapy and 3 mg/kg for 3 mo as maintenance). Plasma copper, zinc, and ceruloplasmin levels as well as hematological parameters were determined at baseline and the first, third, and sixth month of the treatment period. The hemoglobin and iron levels of patients in both groups were higher in the first and sixth months compared to baseline. Although the ceruloplasmin levels were depleted (48.9 mg/dL vs 41.4 mg/dL, p=0.035) during ferrous iron treatment, the copper and zinc levels remained unchanged. On the other hand, ferric iron supplementation led to an increase in zinc levels in the sixth month of treatment (0.77 mg/L vs 1.0 mg/L, p=0.021). The plasma copper levels were lower in the ferrous iron-treated group at the end of the first month of treatment than in the ferric irontreated group (1.06 mg/L vs 1.29 mg/L, p=0.008). In conclusion, our data showed that copper and ceruloplasmin metabolisms were affected by ferrous iron supplementation, whereas ferric iron kept them to normal levels of zinc, possibly by affecting their absorption. We conclude that the copper and zinc status of patients with IDA should be taken into consideration before and after iron therapy.

TITLE: The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients.ABSTRACT: We recently determined that in hemodialysis patients, the use of calcium salts to correct hyperphosphatemia led to progressive coronary artery and aortic calcification as determined by sequential electron beam tomography (EBT) while the use of the non-calcium-containing binder sevelamer did not. Whether the specific calcium preparation (acetate vs. carbonate) might influence the likelihood of progressive calcification was debated.To determine whether treatment with calcium acetate was specifically associated with hypercalcemia and progressive vascular calcification, we conducted an analysis restricted to 108 hemodialysis patients randomized to calcium acetate or sevelamer and followed for one year.The reduction in serum phosphorus was roughly equivalent with both agents (calcium acetate -2.5 +/- 1.8 mg/dl vs. sevelamer -2.8 +/- 2.0 mg/dl, p = 0.53). Subjects given calcium acetate were more likely to develop hypercalcemia (defined as an albumin-corrected serum calcium > or =10.5 mg/dl) (36 vs. 13%, p = 0.015). Treatment with calcium acetate (mean 4.6 +/- 2.1 g/day - equivalent to 1.2 +/- 0.5 g of elemental calcium) led to a significant increase in EBT-determined calcification of the coronary arteries (mean change 182 +/- 350, median change +20, p = 0.002) and aorta (mean change 181 +/- 855, median change +73, p < 0.0001). These changes were similar in magnitude to those seen with calcium carbonate. There were no significant changes in calcification among sevelamer-treated subjects.Despite purported differences in safety and efficacy relative to calcium carbonate, calcium acetate led to hypercalcemia and progressive vascular calcification in hemodialysis patients.