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PubMed1998

An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group.

BACKGROUND: The appetite-suppressant drug fenfluramine, usually given in combination with phentermine, has been reported to be associated with cardiac valvular regurgitation. Concern has been raised that the d-enantiomer of fenfluramine, dexfenfluramine, may also cause this problem. We were able to study the question by modifying an ongoing trial comparing dexfenfluramine with regular dexfenfluramine and placebo. METHODS: We modified our randomized, double-blind, placebo-controlled study of dexfenfluramine to include echocardiographic examinations of 1072 overweight patients within a median of one month after the discontinuation of treatment. The patients (approximately 80 percent of whom were women) had been randomly assigned to receive dexfenfluramine (366 patients), investigational sustained-release dexfenfluramine (352 patients), or placebo (354 patients). The average duration of treatment was 71 to 72 days in each of the three groups. Echocardiograms were assessed in a blinded fashion. RESULTS: When all degrees of valvular regurgitation were considered and when the two dexfenfluramine groups were combined, there was a higher prevalence of any degree of aortic regurgitation (17.0 percent vs. 11.8 percent, P=0.03) and any degree of mitral regurgitation (61.4 percent vs. 54.4 percent, P=0.01) in the active-treatment groups than in the placebo group. These differences were primarily due to a higher prevalence of physiologic, trace, or mild regurgitation. Analyses that used the criteria of the Food and Drug Administration for aortic regurgitation of mild or greater severity and mitral regurgitation of moderate or greater severity found no statistically significant difference among the groups (P=0.14 to 0.75). These analyses showed that aortic regurgitation of mild or greater severity occurred in 5.0 percent of the patients in the dexfenfluramine group, 5.8 percent of those in the sustained-release dexfenfluramine group, 5.4 percent of those in the two active-treatment groups combined, and 3.6 percent of those in the placebo group. Mitral regurgitation of moderate or greater severity occurred in 1.7, 1.8, 1.8, and 1.2 percent, respectively. Aortic regurgitation of mild or greater severity, mitral regurgitation of moderate or greater severity, or both occurred in 6.5 percent, 7.3 percent, 6.9 percent, and 4.5 percent, respectively. CONCLUSIONS: The increased prevalence of aortic and mitral regurgitation in patients treated with dexfenfluramine was small, and the degree of regurgitation was usually classified as physiologic, trace, or mild. However, the duration of therapy was short, and whether therapy of longer duration would yield the same or different results is not known.

Adult↗

PubMed1997

[A multicenter open study of dexfenfluramine in Italy. The efficacy and safety of using dexfenfluramine in treating patients with simple or complicated obesity. The DIMOS Group].

415 obese subjects received dexfenfluramine 15 mg twice daily for 3 months. These subjects were suffering from obesity with either no concomitant complications (n = 210) or the following concomitant complications: hypertension (n = 59), non-insulin-dependent diabetes mellitus (NIDDM)[n = 86], eating disorders (n = 60). After 3 months of dexfenfluramine treatment, the mean weight loss in the patients who had completed the study was as follows: simple obesity 5.7(+)-0.3 kg (n = 183); obesity with hypertension: 6.0(+)-0.3 kg (n = 57); obesity with NIDDM: 4.2(+)-0.3 kg (n = 78); obesity with eating disorders: 6.1(+)-0.4 kg (n = 58). In the patients with obesity and hypertension, the mean systolic and diastolic pressures showed highly significant reductions. In the patients with obesity and NIDDM, the fasting and postprandial blood glucose and glycosylated haemoglobin were also highly significantly reduced. In the obese patients with eating disorders, the mean total caloric intake was reduced by 36%, which was highly significant. The mean carbohydrate and fat intake was reduced by 35.4 and 37.9%, respectively, whereas protein intake was only marginally reduced. Adverse events were usually moderate and transient, occurring at the beginning of treatment. In conclusion, dexfenfluramine induced significant weight loss in this group of obese patients, both with and without concomitant complications. A concomitant improvement in diabetes and hypertension was observed in patients initially presenting with these complications.

Adolescent↗

PubMed1994

Dexfenfluramine and serotonin neurotoxicity: further preclinical evidence that clinical caution is indicated.

Dexfenfluramine, a drug used as an appetite suppressant in Europe, is currently under evaluation for approval in the United States. Studies in animals indicate that dexfenfluramine damages brain serotonin neurons, but have been challenged by some because of questions regarding their relevance to humans. The present studies were designed to address the three most salient questions regarding the applicability of preclinical dexfenfluramine neurotoxicity data to humans. Specifically, the present studies sought to determine: 1) whether dexfenfluramine's effects on brain serotonin neurons are transient and related to its therapeutic actions; 2) whether the p.o. route of administration affords protection against dexfenfluramine neurotoxicity; and 3) whether the mouse, an animal thought to best approximate the human with regard to dexfenfluramine metabolism, is sensitive to dexfenfluramine's neurotoxic action. Results from the present study indicate that monkeys continue to show large serotonergic deficits as long as 12 to 17 months after dexfenfluramine treatment, suggesting that dexfenfluramine's effects in nonhuman primates are persistent and unlikely to be related to its therapeutic actions. Furthermore, the present results indicate that the p.o. route of administration affords little or no protection against dexfenfluramine neurotoxicity. Finally, mice, like all other animals tested to date, were found to be susceptible to dexfenfluramine neurotoxicity. Taken together, these findings indicate that concern over possible dexfenfluramine neurotoxicity in humans is warranted, and that physicians and patients alike need to be aware of dexfenfluramine's toxic potential toward brain serotonin neurons.

Animals↗

PubMed1996

The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine.

1. To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2. Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post-dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3. Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136 +/- 1509 micrograms vs 1986 +/- 792 micrograms; 95% CI of difference 926-3374; P < 0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753 +/- 411 micrograms vs 1626 +/- 444 micrograms). 4. Dexfenfluramine AUC was higher in PMs (677 +/- 348 micrograms l-1 h) than EMs 359 +/- 250 micrograms l-1 h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6 +/- 42.4 l h-1 vs 45.6 +/- 19.5 l h-1; 95% CI of difference 1.2-94.7; P < 0.05). The renal clearance was similar in both phenotypes (EMs: 5.88 +/- 2.83 l h-1; PMs 6.60 +/- 2.01 l h-1), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5. The apparent nonrenal clearance of dexfenfluramine was substantially lower (P < 0.05; 95% CI of difference 3.0-94.1) in PMs (39.0 +/- 19.5 l h-1) than EMs (87.6 +/- 41.2 l h-1). 6. There was a significant inverse correlation (rs = 0.776 95% CI-0.31-0.94; n = 11; p = 0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7. PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8. In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.

Adult↗

PubMed1997

Dexfenfluramine in obese Chinese NIDDM patients. A placebo-controlled investigation of the effects on body weight, glycemic control, and cardiovascular risk factors.

OBJECTIVE: To investigate the safety, efficacy, and metabolic effects of dexfenfluramine in obese Chinese NIDDM patients. RESEARCH DESIGN AND METHODS: Thirty-two patients, mean (+/- SD) body weight 76.2 +/- 8.5 kg with corresponding BMI 31.1 +/- 2.1 kg/m2, were randomized into a two-phase study, after a 2-week single-blind run-in period on placebo. Phase 1 was a randomized 3-month double-blind placebo-controlled trial during which either dexfenfluramine or placebo was added to the existing treatment regimens of diet plus or minus sulfonylureas without metformin. Phase 2 was a further 3-month single-blind trial during which the placebo group was given dexfenfluramine without patients' knowledge of changing to active medication, while the active group continued with dexfenfluramine. Body weight, glycemic control, blood pressure, lipids, and quality of life were assessed before and at 3 and 6 months after randomization. A total of 27 patients were also followed for an additional period of 6-12 months (215 +/- 53 days) after dexfenfluramine treatment was withdrawn. RESULTS: During the run-in period, both groups were comparable for all parameters measured. At 3 months, mean changes in BMI were -1.2 +/- 1.0 kg/m2 (dexfenfluramine) vs. -0.1 +/- 0.5 kg/m2 (placebo) (P < 0.001). The mean changes in fasting plasma glucose were -1.14 +/- 0.99 vs. 0.51 +/- 1.34 mmol/l (dexfenfluramine vs. placebo, P = 0.004). HbA(1c) also significantly improved in the dexfenfluramine group (-0.80 +/- 0.53 vs. 0.25 +/- 0.64%, P < 0.001). During the 3-month single-blind dexfenfluramine treatment in the ex-placebo group, there were similar improvements in body weight and glycemic indexes. After cessation of dexfenfluramine therapy at 6 months, significant increases in body weight and glycemic indexes, almost back to the baseline, were observed for both groups. CONCLUSIONS: Dexfenfluramine aids weight loss and improves glycemic control in obese Chinese NIDDM patients over a 3- to 6-month period. These effects are emphasized after withdrawal of treatment and further support the longer-term use of dexfenfluramine for chronic complicated obesity.

Adult↗

PubMed1995

Dexfenfluramine treatment of obesity: a double blind trial with post trial follow up.

OBJECTIVE: As successful weight management demands a long term approach, a better understanding of weight changes during and for significant periods after cessation of dexfenfluramine therapy is essential to the evaluation of the drug's effectiveness in clinical practice. This study aimed to investigate additional benefits to weight loss during 6 months treatment with dexfenfluramine in 60 patients enrolled in a weight loss programme. DESIGN: Sixty obese subjects (21 males; 39 females) were randomised to dexfenfluramine (15 mg twice daily) or placebo for six months. Fifty one (27 dexfenfluramine; 24 placebo) subjects completed the double blind, randomised, placebo controlled clinical trial. RESULTS: After a one month 'run in' phase and six months treatment, weight loss in the dexfenfluramine group was significantly greater than placebo, 9.7 +/- 1.1 kg vs 4.9 +/- 0.9 kg (mean +/- s.e.m.); P = 0.002. Reduction in body fat, 5.0 +/- 0.7 kg vs 1.0 +/- 0.9 kg; P = 0.002 and waist circumference, 10.5 +/- 1.9 cm vs 5.7 +/- 1.1 cm; P = 0.04 was also greater in the dexfenfluramine group. Despite significant weight loss, waist to hip ratio (WHR) did not change in either group. The dexfenfluramine group reported a significantly greater incidence of nausea, dry mouth and dizziness which tended to decrease as treatment progressed. No subjects withdrew due to drug induced side effects. Reduction in serum triglyceride levels and an increase in HDL cholesterol (in female subjects) in conjunction with a reduction in fasting insulin, collectively support an improved cardiovascular risk profile in the dexfenfluramine group. Despite significant weight loss, these risk factor measurements worsened in the placebo group. After cessation of dexfenfluramine therapy, there was a significantly greater weight regain indicating a loss of treatment effect. By 5 months after cessation of dexfenfluramine, the treatment effect was negated with weight loss in the dexfenfluramine (6.0 +/- 1.6 kg) and placebo (6.2 +/- 1.3 kg) group, similar. CONCLUSION: The results of this study support the longer term use of dexfenfluramine therapy for patients with chronic obesity.

Adolescent↗

PubMed1998

Metabolism of dexfenfluramine in human liver microsomes and by recombinant enzymes: role of CYP2D6 and 1A2.

Dexfenfluramine has been widely used as an appetite suppressant in the treatment of obesity. It was recently shown that the apparent non-renal clearance of dexfenfluramine was significantly lower in poor metabolizers than in extensive metabolisers of debrisoquine which suggested the involvement of the polymorphically expressed enzyme, CYP2D6, in dexfenfluramine metabolism. In this study, human liver microsomes and yeast-expressed recombinant enzymes were used to examine dexfenfluramine metabolism in vitro. In human liver microsomes, the major product of dexfenfluramine was nordexfenfluramine with lesser amounts of a novel metabolite, N-hydroxynordexfenfluramine, and ketone and alcohol derivatives being formed. Eadie-Hofstee plots (v against v/[s]) of nordexfenfluramine formation between 1 and 1000 microM substrate concentration were biphasic in three of four liver microsome samples examined, with mean Km values of 3 and 569 microM for the high and low affinity enzymes, respectively. At a substrate concentration (0.5 microM) around the known therapeutic plasma concentration, there was negligible inhibition of microsomal dexfenfluramine N-dealkylation by sulphaphenazole and ketoconazole, but between 33 and 100% inhibition by quinidine, and 0-58% inhibition by 7,8-naphthoflavone in seven liver samples. In human liver microsomes, there was also a significant correlation (rs= 0.79, n = 10, P < 0.01) between dextromethorphan O-demethylation and dexfenfluramine (at 1 microM) N-dealkylation activities. Dexfenfluramine was a specific inhibitor (IC50 46 microM) of CYP2D6-mediated dextromethorphan O-demethylation in human liver microsomes but did not appreciably inhibit six other cytochrome P450 isoform-selective activities for CYP1A2, 2A6, 2C9, 2C19, 2E1 and 3A activities in human liver microsomes. Yeast-expressed recombinant human CYP2D6 metabolized dexfenfluramine with high affinity (Km 1.6 microM, Vmax 0.18 nmol min(-1) nmol P450(-1)) to nordexfenfluramine which was the sole product observed. Recombinant CYP1A2 was a lower affinity enzyme (Km 301 microM, Vmax 1.12 nmol min(-1) nmol P450(-1)) and produced nordexfenfluramine with small amounts of N-hydroxynordexfenfluramine. This is the first detailed study to examine the in-vitro metabolism of dexfenfluramine in human liver microsomes and by recombinant human P450s. We were able to identify CYP2D6 (high affinity) and CYP1A2 (low affinity) as the major enzymes catalysing the N-dealkylation of dexfenfluramine in human liver microsomes.

Cytochrome P-450 CYP1A2↗

PubMed1996

Dexfenfluramine. An updated review of its therapeutic use in the management of obesity.

Dexfenfluramine increases serotonergic activity by stimulating serotonin (5-hydroxytryptamine; 5-HT) release into brain synapses, inhibiting its reuptake into presynaptic neurons and by directly stimulating postsynaptic serotonin receptors. On the basis of the serotonin hypothesis of appetite control, these actions would be expected to reduce appetite and, consequently, bodyweight. Studies conducted in animals and in overweight patients with and without associated disorders have confirmed the weight-reducing efficacy and good tolerability of dexfenfluramine. In 3-month clinical studies in obese patients, weight reductions with dexfenfluramine 15mg twice daily combined with dietary support were significantly higher than those achieved with placebo and similar to those with ephedrine/caffeine 20/20mg 3 times daily, sibutramine 10mg once daily and fluoxetine 60 mg/day. Furthermore, dexfenfluramine recipients with non-insulin-dependent diabetes mellitus, hyperlipidaemia or hypertension consistently show improvements in glycaemic control, blood lipid profiles and blood pressure. 12-month trial results indicate that most weight loss occurs in the initial 6 months and appears to be maintained for a further 6 months. Weight regain after withdrawal of treatment in 12-month studies demonstrates that dexfenfluramine is effective in maintaining a stable bodyweight at a lower level than placebo and in limiting food intake over this time period. Commonly reported adverse events with dexfenfluramine include diarrhoea, tiredness, dry mouth and somnolence; these symptoms are generally mild and transient. Approximately 7 and 10% of dexfenfluramine recipients in short and long term studies withdrew because of adverse events. Dexfenfluramine was better tolerated than ephedrine/caffeine and fluoxetine in short term studies. Obesity is a chronic condition that is accompanied by a number of metabolic complications. It is a significant health problem in developed countries, and as a major risk factor for many chronic diseases, including diabetes and cardiovascular disease, the economic burden of this condition is considerable. As with other chronic conditions, there is a role for pharmacological intervention in patients with severe obesity. However, drugs should be considered as only one component of a weight-control programme, since additional lifestyle modification is required to maintain weight loss. The promising data on the long term efficacy and tolerability of dexfenfluramine as well as its favourable effects on risk factors associated with obesity requires confirmation in long term studies. In the meantime, dexfenfluramine should be considered a valuable adjunct to a reduced-calorie diet in the management of severe obesity, particularly in patients with associated disorders and those unsuccessful with conventional weight loss measures. Available data support the use of the drug for up to 1 year to maintain weight loss and thus dexfenfluramine should be considered for long term administration.

Animals↗

PubMed1998

Blood pressure and plasma norepinephrine responses to dexfenfluramine in obese postmenopausal women.

Dexfenfluramine has been shown to reduce body weight and lower blood pressure in obese individuals. However. it is not clear whether the blood pressure-lowering effect is due to dexfenfluramine or to the loss of weight. This project was designed to study the effect of a 5-d treatment of dexfenfluramine on blood pressure changes in obese postmenopausal women. Twenty women aged 51-60 y matched for body mass index [BMI (in kg/m2) of 34.5-50.1] were assigned to either the dexfenfluramine group (15 mg orally twice a day for 5 d) or the control group. All subjects were instructed about an isoenergetic diet. Twenty-four-hour ambulatory blood pressure, plasma catecholamines, glucose, insulin, and lipids were measured at the beginning and repeated at the conclusion of the study. On day 5 the mean systolic (SBP) and mean diastolic blood pressures (DBP) in the dexfenfluramine group were lower than those of the control group (SBP: 114+/-7 mm Hg in the dexfenfluramine group compared with 124+/-12 mm Hg in the control group, P < 0.05; DBP: 70+/-9 mm Hg in the dexfenfluramine group compared with 76+/-10 mm Hg in the control group, P < 0.05). The mean plasma norepinephrine concentration was lower in the dexfenfluramine group than in the control group (1.60+/-0.5 compared with 2.41+/-0.5 nmol/L, respectively, P < 0.05). No differences were noted in epinephrine, glucose, insulin. and lipid concentrations between the two groups. We showed that a 5-d treatment of dexfenfluramine decreases blood pressure and reduces heart rate in obese postmenopausal women. Our data suggest that these effects are results of the direct action of dexfenfluramine.

Adult↗

PubMed1996

The effects of dexfenfluramine on weight loss and cardiovascular risk factors in female patients with upper and lower body obesity.

BACKGROUND: Obesity has been identified as a risk factor for atherosclerosis, and fat distribution has proved to be a critical variable. Weight loss improves health, but failure rates in dietary treatment are high. The effects of dexfenfluramine, which is useful in many patients, were studied on cardiovascular risk factors in obese female patients with upper and lower body obesity. METHODS: In a placebo-controlled, double-blind trial, which was part of a multicentre study, 52 obese female patients (body mass index 35.1 +/- 7.8 kg/m2, age 43.3 +/- 6.4 years) were given either 15 mg dexfenfluramine twice daily, or placebo in addition to a calorie-restricted diet (1500 kcal/day) for 12 months. Forty-two patients (20 with upper body obesity, 12 dexfenfluramine and 10 placebo; 22 with lower body obesity, 16 dexfenfluramine and six placebo) completed the 14-month study. RESULTS: Patients with upper body obesity lost 14.2 +/- 2.20 kg with dexfenfluramine, and 4.92 +/- 2.99 kg with placebo (P < or = 0.05). In contrast, patients with lower body obesity lost 11.1 +/- 2.89 kg with dexfenfluramine and 2.6 +/- 2.32 kg with placebo (P < 0.05). With dexfenfluramine, patients with upper body obesity lost more weight than patients with lower body obesity (P < 0.05). After 1 year of dexfenfluramine treatment, reduction of systolic blood pressure in patients with upper body obesity (157 +/- 10 versus 133 +/- 8 mmHg, P < 0.05) was significantly (P < 0.05) greater than in patients with lower body obesity (136 +/- 14 versus 127 +/- 12 mmHg). During dexfenfluramine treatment cardiovascular risk factors improved. In upper body obesity blood glucose (5.18 +/- 0.28 versus 4.40 +/- 0.34 mmol/l, P < 0.05), serum insulin (23.4 +/- 8.9 versus 13.2 +/- 4.2 microU/ml, P < 0.05) and triglycerides (1.96 +/- 0.45 versus 1.23 +/- 0.54 mmol/l, P < 0.05) decreased, and high-density lipoprotein cholesterol increased (1.0 +/- 0.14 versus 1.21 +/- 0.14 mmol/l P < 0.05). In lower-body obesity, cardiovascular risk factors were in the normal range and did not change significantly during the study. CONCLUSIONS: Dexfenfluramine lowers body weight in obese patients with upper and lower body obesity and reduces the cardiovascular risk factors clustering in upper body obesity.

Adult↗

PubMed1994

Dexfenfluramine reduces cardiovascular risk factors.

This study investigated the potential for dexfenfluramine to improve biochemical and clinical risk factors for cardiovascular disease, in obese dyslipidaemic individuals. Dexfenfluramine, the dextro isomer of fenfluramine, has been shown to aid weight reduction and lower blood lipids in normal subjects, and to improve glucose tolerance and insulin sensitivity in subjects with diabetes mellitus. Twenty-nine overweight (mean weight 83.3 +/- 11.3 kg), hyperlipidaemic (mean total cholesterol 7.3 +/- 1.2 mol/l) subjects participated in a 12-week randomized double-blind parallel study of dexfenfluramine versus placebo. After an eight-week dietary run-in phase, subjects were randomised to treatment with either dexfenfluramine or placebo for 12 weeks. During the run-in, energy intakes fell in both groups (5.5% for dexfenfluramine, 5% for placebo, no significant difference between groups). Dietary composition improved, fat as a percentage of energy decreased (14%, P < 0.001, for dexfenfluramine; 11.7%, P < 0.05, for placebo), and carbohydrate increased (8.5%, P < 0.05, for dexfenfluramine; 5.6%, not significant, for placebo). During the treatment period, energy intakes in the dexfenfluramine group were further reduced by 7.5%, whereas there was no change in the placebo group (P = 0.02 between dexfenfluramine and placebo groups); however, nutrient composition remained constant for both groups. Side-effects were formally reported by 40% of subjects during the initial four weeks' treatment with dexfenfluramine with three subjects withdrawing from the study. Side-effects were largely resolved by week 4. Both groups lost weight similarly during the run-in but there were no significant changes in any biochemical parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins B↗

PubMed2000

Sibutramine does not decrease the number of 5-HT re-uptake sites in rat brain and, like fluoxetine, protects against the deficits produced by dexfenfluramine.

The effect of sibutramine and dexfenfluramine on 5-HT re-uptake sites, labelled with [(3)H]paroxetine, have been determined in various rat brain regions. In addition, the ability of fluoxetine and sibutramine to protect against the changes in [(3)H]paroxetine binding produced by dexfenfluramine was examined. Sibutramine (9 mg/kg, p.o.) and dexfenfluramine (1, 3 and 10 mg/kg, p.o.) were administered twice daily (before 09.00 h and after 16.00 h) for four days, followed by a 14 day drug-free period. In the protection studies, fluoxetine (10 mg/kg, i.p.) and sibutramine (9 mg/kg, p.o.) were given 1 h prior to dexfenfluramine (10 mg/kg, p.o.) using the same dosing regimen as described above. Sibutramine (9 mg/kg, p.o.; three times its ED(50) to inhibit food intake at 2 h) had no significant effect on the number or affinity of 5-HT re-uptake sites the brain regions studied. In contrast, dexfenfluramine at an equivalent dose (3 mg/kg, p.o.) significantly decreased the number of 5-HT re-uptake sites in frontal cortex (by 35%), hippocampus (by 47%) and hypothalamus (by 27%). This effect was dose-dependent with marked decreases (by 58-84%) in the number of sites following 10 mg/kg, p.o. These effects were not associated with changes in binding affinity. Fluoxetine (10 mg/kg, i.p.) completely blocked the effect of dexfenfluramine (10 mg/kg, p.o.) without having any significant effect alone. Sibutramine (9 mg/kg, p.o.) also blocked the effects of dexfenfluramine, although the reversal was only partial in frontal cortex, hippocampus and hypothalamus. Thus sibutramine, unlike dexfenfluramine, does not alter brain 5-HT re-uptake sites. Furthermore, sibutramine and fluoxetine protect against the deficits in 5-HT re-uptake sites produced by dexfenfluramine. These data provide further evidence that sibutramine is a 5-HT re-uptake inhibitor and it does not have neurotoxic potential.

Animals↗

PubMed1997

Dexfenfluramine hydrochloride: an anorexigenic agent.

The pharmacology, pharmacokinetics, efficacy, and adverse effects of dexfenfluramine hydrochloride are reviewed. Dexfenfluramine, the dextrorotatory isomer of fenfluramine, is indicated for use in the management of obesity in patients with a body mass index of > or = 30 kg/m2, or > or = 27 kg/m2 in the presence of other risk factors. Unlike fenfluramine, dexfenfluramine is a pure serotonin agonist. Dexfenfluramine may mimic the effect of carbohydrate intake. Systemic bioavailability is about 68%, and the drug is metabolized in the liver. In randomized, placebo-controlled trials, dexfenfluramine was effective in reducing weight in obese patients given the drug for three or six months. In trials lasting one year, the statistically significant weight loss occurred during months 4 to 6. Dexfenfluramine reduces blood pressure, percent glycosylated hemoglobin, and concentrations of blood glucose and blood lipids, but these benefits may be indirect. Dexfenfluramine may also be of some value in controlling eating habits in diabetic patients, preventing weight gain after smoking cessation, and treating bulimia, seasonal affective disorder, neuroleptic-induced obesity, and premenstrual syndrome. Dexfenfluramine's most frequent adverse effects are insomnia, diarrhea, and headache; it has also been associated with primary pulmonary hypertension. The drug should not be combined with other serotonergic agonists because of the risk of serotonin syndrome. The recommended dosage is 15 mg twice daily. Dexfenfluramine is effective in the treatment of obesity in selected patients. Because its efficacy is lost after six months of continuous treatment, it should be viewed primarily as an adjunct to diet and exercise.

Animals↗

PubMed2000

Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine.

CONTEXT: Fenfluramine and dexfenfluramine were voluntarily withdrawn from the market in September 1997 because of reports of an association with heart valve abnormalities. Studies have been limited by lack of comparison with untreated controls. OBJECTIVE: To evaluate cardiovascular status and the prevalence of valvular abnormalities, as assessed by clinical cardiovascular parameters and echocardiography, in patients treated for obesity with dexfenfluramine or phentermine/fenfluramine. DESIGN: Reader-blinded controlled study completed in February 1998. SETTING AND PARTICIPANTS: Twenty-five clinical centers in the United States. Of 1640 enrolled subjects, 1473 were eligible (479 and 455 had taken dexfenfluramine and phentermine/fenfluramine, respectively, continuously for 30 days or more in the previous 14 months, and 539 were untreated matched controls) and provided clinical and echocardiographic data. Mean (SD) age was 47.4 (11.4) years, mean body mass index was 35.0 (7.4) kg/m2, and 74% were women. Mean (SD) duration of therapy was 6.0 (3.3) months (range, 1-18.4 months) in the dexfenfluramine group, and 11.9 (10.4) months (range, 1.4-63 months) in the phentermine/fenfluramine group, while the untreated group had no anorexigen use during the previous 5 years. MAIN OUTCOME MEASURES: Cardiovascular signs and symptoms; echocardiographic evidence of aortic (AR) or mitral (MR) regurgitation according to US Food and Drug Administration (FDA) criteria (AR > or = mild or MR > or = moderate) and by grade; tricuspid and pulmonic valve regurgitation; and aortic, mitral, and tricuspid valve leaflet mobility and thickness, for treated vs untreated subjects. RESULTS: Cardiovascular signs and symptoms were similar among anorexigen-treated and untreated subjects. Prevalence rates and relative risk (RR) of AR were significantly increased in anorexigen-treated patients and were 8.9% in the dexfenfluramine group (RR, 2.18; 95% confidence interval [CI], 1.32-3.59), 13.7% in the phentermine/fenfluramine group (RR, 3.34; 95% CI, 2.09-5.35), and 4.1% in the untreated group (P<.001). No statistically significant differences in prevalence were observed for MR, thickening or decreased mobility of any valve leaflet, calculated pulmonary artery systolic pressure, or left ventricular ejection fraction. Serious cardiac events (including myocardial infarction, congestive heart failure, or ventricular arrhythmia) occurring at any time were not statistically different in treated and untreated subjects (dexfenfluramine, 9.0%; phentermine/fenfluramine, 4.0%; and untreated, 8.4%); and following anorexigen treatment were uncommon (dexfenfluramine, 2.3%; phentermine/fenfluramine, 2.4%, and untreated, 3.3%, when adjusted for the median start date of anorexigen use). CONCLUSIONS: Our data indicate that use of dexfenfluramine and phentermine/fenfluramine is associated with an increase in the prevalence of AR using FDA echocardiographic criteria, but was not associated with an increase in the prevalence of MR using FDA criteria or with serious cardiac events.

Aortic Valve Insufficiency↗

PubMed2001

Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Previous studies have reported small increases in the prevalence of low-grade aortic and mitral regurgitation in patients treated with dexfenfluramine compared with placebo. However, whether valvular abnormalities develop or progress 1 year after discontinuation of dexfenfluramine therapy has not been determined. OBJECTIVE: To assess change in valvular regurgitation and morphologic characteristics 1 year after discontinuation of dexfenfluramine therapy. DESIGN: Randomized, double-blind, placebo-controlled, multicenter study. SETTING: Outpatient obesity centers. PATIENTS: Obese persons who had been treated for 2 to 3 months with dexfenfluramine, sustained-release dexfenfluramine, or placebo. Blinding was maintained, and patients returned for repeated echocardiography at 1 year. MEASUREMENTS: Pairs of echocardiograms were evaluated with a side-by-side reading method for change in grade of valvular regurgitation, structure, and function. A standardized acquisition and reading protocol was followed, and a core laboratory was used. RESULTS: 914 patients who had initial echocardiography returned for repeated echocardiography 11.4 +/- 1.0 months (mean +/- SD) after discontinuing study medication (10.0 +/- 1.0 months after initial echocardiography). Compared with the placebo group, a greater proportion of patients in both dexfenfluramine groups had decreased aortic regurgitation (P = 0.003 for the dexfenfluramine group, P = 0.02 for the sustained-release group). No change in mitral regurgitation or any other measure of valvular structure or function was seen in any treatment group. CONCLUSIONS: After dexfenfluramine therapy is taken for 2 to 3 months and discontinued, development or progression of any valvular regurgitation over the following year is unlikely. Echocardiographic evidence suggests that aortic regurgitation regresses in some previously treated patients.

Adult↗

PubMed2001

Dexfenfluramine-associated changes in 5-hydroxytryptamine transporter expression and development of hypoxic pulmonary hypertension in rats.

The appetite suppressant dexfenfluramine, which inhibits neuronal 5-HT uptake and elevates plasma 5-HT levels, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PA-SMCs), an effect that depends upon activity of the 5-HT transporter (5-HTT). To investigate the relationship between dexfenfluramine and pulmonary hypertension, we examined 1) the effect of dexfenfluramine on 5-HT uptake by PA-SMCs and the mitogenic response of these cells to 5-HT, and 2) 5-HTT mRNA in lung tissue from normoxic and chronically hypoxic rats during and at discontinuation of a 4-week dexfenfluramine treatment (2 mg/kg/day). In cultured PA-SMCs, dexfenfluramine (10(-6) M) markedly reduced [3H]5-HT uptake and [3H]thymidine incorporation in response to 5-HT (10(-6) M). In lungs from rats exposed to 4-week hypoxia (10% O(2)), 5-HTT mRNA levels were higher than in normoxic rats (233.5 +/- 22.5 versus 121.8 +/- 4.8 amol/mg of RNA, P < 0.05), but were not affected by concomitant treatment with dexfenfluramine. One week after discontinuation of dexfenfluramine, 5-HTT mRNA levels increased substantially, this effect being additive with that of hypoxia (364.0 +/- 13.1 in hypoxic versus 164.2 +/- 10 amol/mg of RNA in normoxic rats). When exposure to 2 weeks of hypoxia followed discontinuation of a 4-week treatment, right ventricular hypertrophy was more severe and muscularization of distal pulmonary arteries more marked (P < 0.01) than in rats pretreated with the vehicle. These data show that, in rats, the increased 5-HTT expression that follows dexfenfluramine discontinuation promotes the development of hypoxic pulmonary hypertension.

Animals↗

PubMed1996

Evaluation of dexfenfluramine in a weight loss program for obese infertile women.

OBJECTIVE: To evaluate the usefulness of dexfenfluramine as an adjunct to a group treatment program for obese infertile women. METHOD: Twenty-one obese infertile women were referred by the Reproductive Medicine Unit. They attended a 24-week group program which included exercise and educational sessions. Dexfenfluramine and placebo were given, each for 12 weeks, in a double-blind crossover design. RESULTS: Dexfenfluramine treatment was not associated with greater loss of weight. The mean weight loss during dexfenfluramine treatment was 3.21 kg (SD 3.09) and during placebo was 3.31 kg (SD 3.15). Self-esteem, anxiety, and depression ratings all improved significantly over the 24 weeks. DISCUSSION: The group treatment program appeared to be equally effective with or without dexfenfluramine. Previous studies have found dexfenfluramine to be effective in combination with individual treatment, but it has not previously been evaluated as an adjunct to group treatment. It is unclear whether dexfenfluramine may be less effective in combination with group treatment programs, or whether its usefulness is restricted in this particular population of obese patients. No differences were found associated with the order in which active and placebo treatments were given. Patients showed improvement in self-esteem and reduction in depression and anxiety, but dexfenfluramine treatment was not associated with any difference in these measures, compared to placebo.

Adult↗

PubMed1994

Dexfenfluramine-induced prolactin release as an index of central synaptosomal 5-hydroxytryptamine during treatment with fluoxetine.

Serotonin (5-HT) stimulates prolactin release. In the present study the ability of dexfenfluramine to increase serum prolactin was used as an index of central 5-HT function after acute and chronic pretreatment of volunteers with fluoxetine. Following a single-blind, random design, on each experimental day each volunteer received 60 mg dexfenfluramine taken with 250 ml water at zero time and no other treatment, or pretreatment with 40 mg fluoxetine at -8 h, or pretreatment with 20 mg fluoxetine daily for 14 days, or the dexfenfluramine alone 14 days after cessation of 14 days of fluoxetine treatment. There were no significant differences between the prolactin levels found after dexfenfluramine only, dexfenfluramine after a single dose of fluoxetine, and dexfenfluramine 14 days after cessation of fluoxetine treatment. However, baseline levels and those 3 and 4 h after dexfenfluramine administration were significantly lower after pretreatment for 14 days with fluoxetine compared to the other three regimens. At 5 h the levels were still lower, but not significantly so, as the prolactin level rose approximately 110% compared to the baseline and 4 h values. The reduction in the median basal serum prolactin level by almost two-thirds after 14 days of fluoxetine treatment suggests a decrease in 5-HT turnover. Furthermore, the delayed surge in prolactin release produced by dexfenfluramine with this regimen suggests 5-HT release from a less accessible pool or accumulation of fluoxetine in the neuronal cytosol and consequent competitive inhibition of 5-HT transport out of the nerve terminal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗