Biomedical subjects
Publications and source records attributed to M Weintraub.
We report an infant with congenital nephrotic syndrome who showed clinical and radiological evidence of cerebral oedema, which resolved during prolonged intravenous albumin therapy. The cerebral oedema in this case can possibly be attributed to the relative immaturity of the blood-brain barrier in early infancy.
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To investigate the value of anorexiant medications as an adjunct to other forms of weight control therapy, we studied 121 people in a 34-week, double-blind clinical trial of 60 mg extended-release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Participants weighed 130% to 180% (154% +/- 1.2%, mean +/- SEM) of ideal body weight (1983 Metropolitan Life tables) and were in good health. By week 34, participants receiving active medication lost an average of 14.2 +/- 0.9 kg, or 15.9% +/- 0.9% of initial weight (n = 58), versus a loss of 4.6 +/- 0.8 kg or 4.9% +/- 0.9% of initial weight by subjects taking placebo (n = 54; p less than 0.001). On visual analog scales, participants rated fenfluramine plus phentermine as more helpful than placebo (50.3 +/- 0.5 versus 20.3 +/- 0.3) and not bothersome (fenfluramine plus phentermine, 17.4 +/- 0.3 versus 13.5 +/- 0.2). Blood pressure decreased and pulse remained unchanged in both groups. Dry mouth was the most common adverse effect in subjects receiving fenfluramine plus phentermine; all adverse effects decreased after 4 weeks. Only nine participants left the study in the first 34 weeks. Two subjects from each group left the study as a result of adverse effects. Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise aided weight loss and continued to be efficacious for 34 weeks.
Between weeks 34 and 104, we explored different schema for administering fenfluramine plus phentermine in open-label fashion. At week 34, the original placebo group participants began taking fenfluramine plus phentermine (placebo-to-active group). Those receiving fenfluramine plus phentermine between weeks 6 and 34 either continued to receive medication or began targeted intermittent therapy. Participants who did not lose 10% of initial weight received an augmented dose (60 mg fenfluramine plus 30 mg phentermine. The placebo-to-active group lost an additional 9.1 +/- 0.8 kg (mean +/- SEM) in the period from week 34 to week 60. At week 60, they were assigned to either continue medication, intermittent therapy, or augmented therapy. More than 68% (83) of the original participants completed up to study week 104. At that point, overall weight loss was 10.8 +/- 0.7 kg (11.6 +/- 0.8% of initial weight); participants who continued to receive fenfluramine plus phentermine lost 11.6 +/- 0.8 kg, participants receiving intermittent therapy lost 11.6 +/- 1.3 kg, and participants receiving augmented therapy lost 6.5 +/- 1.5 kg. Although 41% of the participants complained of dry mouth, neither serious adverse effects nor evidence of medication abuse appeared. There were 29 dropouts in the period from weeks 34 to 104. Sixteen of those were related to medication (adverse effects, lack of efficacy, and fear of medication). Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise continued to be efficacious for up to 2 years.
Between weeks 104 and 156 we attempted to optimize response by adjusting the doses of fenfluramine and phentermine. Dosing changes were based on an algorithm that aimed to achieve 120% of ideal body weight (IBW) while minimizing adverse effects. The dose groups were as follows: stage I, 30 mg fenfluramine plus 15 mg phentermine in the morning; stage II--continuous or targeted intermittent, 60 mg fenfluramine plus 15 mg phentermine in the morning; stage III, 60 mg fenfluramine plus 30 mg phentermine in the morning; stage IV, 60 mg fenfluramine plus 30 mg phentermine in the morning and 30 mg fenfluramine in the evening; and stage V, 60 mg fenfluramine plus 30 mg phentermine in the morning and 60 mg fenfluramine in the evening. Seventy-seven participants began this segment of the study and 59 completed to week 156. Completers of this segment of the study gained an average of 2.7 +/- 0.5 kg between weeks 104 and 156 but remained 9.4 +/- 0.8 kg (10.5%) below baseline. On average, weight loss from baseline by group was as follows: for stage I (n = 2), 14.1 +/- 6.8 kg; for stage II continuous (n = 14), 10.9 +/- 0.7 kg; for stage II targeted intermittent (n = 7), 8.8 +/- 2.4 kg; for stage III (n = 9), 7.7 +/- 2.6 kg; for stage IV (n = 8), 10.5 +/- 2.6 kg; and for stage V (n = 19), 8.4 +/- 2.4 kg. Upward dose adjustment (n = 36) resulted in further weight loss in 11 and no gain in six participants.(ABSTRACT TRUNCATED AT 250 WORDS)
To assess continued efficacy of anorexiants after 3 years of use, 52 participants (43% of those starting) entered a second double-blind trial to compare 60 mg sustained-release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Although participants in both the active medication and placebo groups gained weight, participants receiving fenfluramine plus phentermine (n = 27) gained significantly (p less than 0.01) less (4.4 +/- 0.5 kg or 5.3% +/- 0.5% of initial weight) than participants receiving placebo (n = 24) (6.9 +/- 0.8 kg or 8.5% +/- 1.1% of initial weight). At week 190, both groups were still below their initial weight (fenfluramine plus phentermine group, 5.0 +/- 1.4 kg; placebo group, 2.1 +/- 1.2 kg; p less than 0.01). Overall, 12 participants (23.5% of those still in the study) were greater than or equal to 10% below initial weight. One participant dropped out during this phase because of personal reasons and loss of medication efficacy. During the 30 weeks, participants receiving fenfluramine plus phentermine had 26 moderate or severe complaints versus eight participants receiving placebo. Fenfluramine plus phentermine provided better appetite control and only slightly more bother. Analysis of participant response in this phase by treatment assignment in the first double-blind phase (weeks 6 to 34) indicated that initial receipt of medication did not have negative learning effects. Eleven participants receiving active medication between weeks 6 and 34 and receiving placebo between weeks 160 to 190 gained 5.1 +/- 1.0 kg. In contrast, 13 participants originally taking placebo gained 8.3 +/- 9 kg in this second double-blind phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Participants who completed up to week 190 in the long-term weight control study were monitored after cessation of medication between weeks 190 and 210. Caloric restriction, behavior modification sessions, exercise reinforcement, and physician visits continued. We assessed whether or not participants had reset their weight control mechanisms and compared the effect of stopping medication under open-label conditions (weeks 190 to 210) with the results of stopping anorexiants under double-blind conditions (weeks 160 to 190). At week 210, participants were, on average, 1.4 +/- 1.0 kg (mean +/- SEM, 1.5% +/- 1.1%) below their weights at baseline (week 0). Of the 48 participants who remained in the study, 13 were still 5% or more and seven were 10% or more below their initial weights. On average, participants gained 2.7 +/- 0.5 kg (3.2%) in the period from weeks 190 to 210. Those who had been taking medication in the period from weeks 160 to 190 gained weight at a somewhat faster rate than those who had been taking placebo. However, participants who had transferred from fenfluramine plus phentermine to no medication in this phase gained at a slower rate than participants who had changed from fenfluramine plus phentermine to placebo under double-blind conditions at week 160 (0.195 kg per week versus 0.277 kg per week). The findings indicate that participants had difficulty maintaining weight loss without anorexiant medications. Despite long periods of time at weights much lower than baseline, permanent resetting of weight control mechanisms could not be shown for most participants.
We analyzed the individual response patterns of all 121 participants who entered the study. Fifty-one participants completed up to week 190. In 26 completers, the response pattern consisted of an initial beneficial effect (greater than or equal to 6 months of weight loss greater than or equal to 10% from baseline) and later success (weight loss of greater than or equal to 10% from baseline at week 160). These successful participants had lost 14.1 +/- 1.0 kg (mean +/- SEM); 15.9% +/- 0.9% of initial weight) at week 160 and 8.1 +/- 1.2 kg (9.1% +/- 1.3% of initial weight) at week 190. A second pattern observed in 16 completers consisted of initial benefit and later partial success (loss of 0.1% to 9.9% at week 160). Other response patterns observed in completers included showing initial benefit only (n = 3) and no success (n = 6). Seventy of the 121 participants left the study before week 190. There were 22 "dropout successes" who had consistent weight loss for 1 year or more and were greater than or equal to 10% below their initial weights at time of dropout. Fifteen "dropouts with initial benefit" stayed in the study for greater than or equal to 1 year with initial benefit (weight loss greater than or equal to 10% from baseline maintained for greater than or equal to 6 months). Medication-related reasons accounted for only 10 of the 37 dropouts in the group with initial or later benefit. Minimal benefit was seen in 17 dropouts. Another 16 were in the study less than 1 year. Analysis of individual participant responses made some other generalizations possible. Participants receiving continuous medication lost more weight and had fewer adverse effects than those receiving targeted intermittent medication. Upward dose adjustment appeared to help 24 participants achieve the criteria for late or partial success. Analyses of individual participant responses can suggest ways to optimize anorectic medication use for individual patients.
We analyzed serum total cholesterol, triglycerides, and lipoprotein profile changes occurring in the participants (N = 121) through 210 weeks of the study. On average, baseline lipid levels were within normal limits. The most consistent changes occurred in the high-density lipoprotein cholesterol (HDL-C), serum total cholesterol/HDL-C ratios, and triglyceride levels. HDL-C increased significantly (p less than 0.01), compared with baseline, by 10% at week 34, 15% at week 54, 19% at week 104, and 27% at week 139. At week 210, 20 weeks after treatment had ended, HDL-C was 15% higher than baseline. At weeks 34, 54, 104, and 139, the serum total cholesterol/HDL-C ratio was significantly decreased, compared with baseline, by 9%, 19%, 17%, and 25%, respectively. At week 210, serum total cholesterol/HDL-C ratio was 8% less than week 0. Compared with baseline, triglyceride levels decreased significantly by 21%, 31%, 29%, and 29% at weeks 34, 54, 104, and 139, respectively. At week 210, triglyceride levels were 16% below baseline. Total cholesterol levels and low-density lipoprotein cholesterol (LDL-C) showed less dramatic changes. Patterns of lipid and lipoprotein changes were qualitatively similar between men and women. However, greater decreases in serum total cholesterol, LDL-C, and triglyceride levels were observed in participants with high (n = 10) compared with low (n = 10) baseline lipid levels. Cholesterol changes were not affected by anorexiant medications. However, triglyceride levels at week 34 were significantly (p less than 0.025) less in the participants treated with anorexiants.(ABSTRACT TRUNCATED AT 250 WORDS)
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Lipid abnormalities have been suggested as a major cause of the accelerated atherosclerosis and the high incidence of coronary heart disease in chronic renal failure patients. In the present work the postprandial lipoprotein metabolism was studied in chronic dialysis patients with or without fasting hypertriglyceridemia using the vitamin A loading test. This method investigates specifically postprandial lipoprotein metabolism. The determination of vitamin A ester level retinyl palmitate (RP) differentiates the circulating plasma chylomicron and chylomicron remnant fractions from the endogenous VLDL and IDL. Subjects with normal renal function with or without fasting hypertriglyceridemia served as control groups. Dialysis patients have significantly higher level of chylomicron remnants for a more prolonged period of time than controls, irrespective of their fasting triglyceride levels. The area below retinyl palmitate chylomicron remnants curve was 26308 +/- 12422 micrograms/liter.hr in the normolipidemic dialysis patients, significantly higher than (6393 +/- 2098 micrograms/liter.hr; P < 0.0001) in the normolipidemic controls. The retinyl palmitate chylomicron remnants curve of the hypertriglyceridemic dialysis patients was 21021 +/- 4560 micrograms/liter.hr, which was higher than 12969 +/- 2215 micrograms/liter.hr (P < 0.0001) in the hypertriglyceridemic controls. Moreover, the hypertriglyceridemic dialysis patients had an additional defect in the lipolysis metabolic step, that is, accumulation of chylomicrons in circulation. These findings show a severe defect in postprandial lipoprotein metabolism in chronic renal failure patients. The prolonged exposure of the vascular wall to high chylomicron remnant concentrations might be an important pathogenetic factor in the accelerated atherosclerosis seen in chronic dialysis patients.
Postprandial lipoprotein metabolism may play an important role in the development of atherosclerosis. It is widely believed that in healthy octogenarians, the atherogenic process occurs very slowly. In the present study, postprandial lipoprotein metabolism was examined in 14 octogenarian subjects (mean age, 84 +/- 4.2 years) and 19 younger controls (mean age, 50 +/- 4.8 years) using the vitamin A-fat loading test, in which intestinally derived lipoproteins are specifically labeled with retinyl palmitate (RP). Results indicated that mean peak chylomicron remnant RP levels and the areas below the chylomicron remnant RP curve were significantly lower in the octogenarian group than in the controls (625 +/- 329 vs 1321 +/- 688 micrograms/L and 3740 +/- 1078 vs 6162 +/- 1063 micrograms/L.h, respectively; p < .0001). No differences were found between the two groups in chylomicron RP levels or in lipolytic activity. The study suggests that octogenarians do not exhibit the decrease in chylomicron lipolysis that usually accompanies aging. In addition, these subjects have significantly lower levels of chylomicron remnants in the circulation. Since accumulation of these particles has been implicated in the development of atherogenesis, our findings may indicate a major mechanism of atherosclerosis prevention in healthy octogenarians.
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This analysis illustrates the importance of compliance in understanding intrapatient variation in plasma drug concentrations during 2 weeks of repeated (4 times daily) administration. Plasma concentration data are presented from 4 illustrative patients enrolled in a dose-ranging randomised clinical trial comparing diltiazem with placebo for the prevention of painful vaso-occlusive crises in sickle cell disease. Nonlinear regression was used to fit a 1-compartment model (using 1 elimination constant for the first dose and another for subsequent doses) to the observed diltiazem concentration curves for individual patients, taking into account the time of administration of each dose. Actual dosage intervals were obtained from an electronic device (the Medication Event Monitoring System). The parameters estimated from fitting the actual compliance curves were then used to predict the curves obtained if compliance had been as prescribed (perfect compliance curves). Comparison of the actual and perfect compliance curves shows that within-patient variation in plasma diltiazem concentrations over time can only be understood when the timing of drug administration is included in the analysis. We conclude that dynamic compliance data are important in those situations where close monitoring of treatment is required and may be important in population pharmacokinetic modelling when limited data are available from each patient.
To study post-prandial lipoprotein metabolism in normolipidemic and hypertriglyceridemic subjects, a vitamin A fat loading test was used. This method specifically labels dietary fat particles with retinyl palmitate (RP). Following RP concentrations, metabolic behavior of chylomicrons and chylomicron remnants were studied. In normal subjects, post-prandial lipoproteins were present for more than 10 h. Total RP increased rapidly between 1 and 4 h, peaked at 6 h and declined rapidly between 6 and 10 h. The chylomicron and chylomicron remnant fractions behaved differently, showing precursor product relationship. The hypertriglyceridemic patients demonstrated a very severe defect in chylomicron clearance. This fraction was 2.8-fold higher than in normal subjects, which was 7,260 vs. 2,600 micrograms/l, respectively. The large magnitude and long duration of post-prandial lipemia in normal and hypertriglyceridemic patients support the hypothesis that these atherogenic particles may play a role in the development of coronary heart disease.
OBJECTIVE: Comparison of psychoactive medication prescribing and Medicaid expenditures before (1987 through 1988) and after (1989 through 1990) institution of the New York State triplicate benzodiazepine regulations. DATA SOURCES: The National Prescription Audit (IMS America, Plymouth Meeting, Pa), New York State Medicaid, and Blue Cross/Blue Shield fo the Rochester (NY) Area. RESULTS: From 1988 to 1989, New York State benzodiazepine prescribing decreased by 44%, 60%, and 30% as assessed by IMS America, Medicaid, and Blue Cross/Blue Shield, respectively. Prescribing of the following alternative sedative-hypnotics increased in New York State compared with decreases nationally (IMS America data): meprobamate, +125% vs -9%; methyprylon, +84% vs -15%; ethchlorvynol, +29% vs -18%; butabarbital, +31% vs -15%; hydroxyzine, +15% vs -1.1%; and chloralhydrate, +136% vs -0.4%. Increased prescribing of alternatives was also seen in the Medicaid and Blue Cross/Blue Shield data. Medicaid benzodiazepine expenditures decreased 52% from 1988 to 1989 ($21.7 million to $10.4 million). Alternative sedative expenditures increased 115% ($3.9 million to $8.4 million). Total Medicaid psychoactive medication expenditures remained nearly constant ($46.7 million to $45.6 million). CONCLUSION: Although the triplicate regulations have decreased benzodiazepine prescribing, an undesirable increase has occurred in the prescribing of less acceptable medications. The wider public health, patient care, and financial implications of triplicate benzodiazepine regulations are of concern and require further study before other jurisdictions undertake similar programs.
This is a qualitative and quantitative study of dog bundle branch and Purkinje cell development from day 0 to week 12 of life; we correlate the morphologic data with changes observed in the functional properties of developing dog Purkinje tissue. The bundle branch itself has a roughly cylindrical shape and is surrounded by a collagen sheath covered with endocardium. Within the bundle, Purkinje cells are packed closely together in fascicles distributed evenly around a central artery. Cross-sectional area doubles in the right bundle and increases 5-fold in the left bundle system between day 0 and week 12 of life. About one third of the bundle by volume is Purkinje tissue; the rest is extracellular space containing an increasing amount of collagen as the animal ages. Purkinje cell cross-sectional area is constant during the first week of life, but its length doubles and the cell changes from a relatively round to a more cylindrical shape. Between day 7 and week 12, cell diameter doubles; Purkinje cell surface area increases 5-fold and its volume almost 10-fold. As a consequence, the surface to volume ratio halves and approaches the value reported for adult dogs by week 12 of life. The percent of the intercalated disc occupied by nexal junctions virtually doubles by week 12, the same period over which Purkinje fiber conduction velocity increases. The disc itself becomes less dominant as the cell enlarges; the total percent of sarcolemma involved in its formation decreases by a fourth and has achieved the adult value by week 12 of life. As this happens, the percent of cell membrane facing on clefts increases almost 6-fold, so that the total percent of sarcolemma facing on small spaces (approximately 340A wide) is constant over the age period studied. The paucity of clefts in newborn tissue compared with the value reported for the adult dog may help explain the relative lack of responsiveness to extracellular potassium concentration of the resting membrane potential described for fetal Purkinje tissue. Within the Purkinje cell itself, the percent by volume occupied by mitochondria remains relatively constant over the age span studied, while sarcomeric mass increases 3-fold over the same period of time; these data are consonant with the relative resistance of this tissue to hypoxia.
We tested the safety and efficacy of sibutramine, 5 and 20 mg, and placebo on weight loss. Medication was added to caloric restriction, behavior modification, and exercise in a parallel-group, double-blind clinical trial. Participants were 130% to 180% of ideal body weight and in good health. The study lasted 12 weeks over Thanksgiving, Christmas, and New Year's Day. Weight loss during 8 weeks of study medication was: placebo, 1.4 +/- 2.1 kg (n = 19); 5 mg sibutramine, 2.9 +/- 2.3 kg (n = 18); and 20 mg sibutramine, 5.0 +/- 2.7 kg (n = 18) (p less than 0.05 sibutramine, 5 and 20 mg, versus placebo; p less than 0.05 sibutramine, 20 mg versus 5 mg). There is a significant dose-effect relationship. Five participants left the study before completion, all because of adverse events; placebo (one patient), 5 mg sibutramine (one patient), and 20 mg sibutramine (three patients). Sleep difficulties were noted by eight participants (20 mg sibutramine, seven patients; 5 mg, one patient; and placebo, no patients). Six of 21 participants receiving 20 mg complained of irritability, unusual impatience, or "excitation." Sibutramine, 5 and 20 mg, added to a multimodal program assisted participants in losing weight.