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PubMed1992

Body weight evolution during dexfenfluramine treatment after initial weight control.

While very low calorie diets (VLCD) can lead to rapid weight loss, even in patients who have often failed with conventional diets, maintaining this loss remains a clinical challenge. Since dietary re-education or more formal behaviour modification techniques are not easily applicable to large numbers of patients and are not always successful, drugs to maintain and improve upon initial VLCD success would be of clinical benefit. Pharmacological treatment of obesity has evolved in recent years with the development and licensing of potent serotonin agonists, such as dexfenfluramine (D-F). VLCD followed by D-F has been shown to be effective. A double-blind trial randomized 45 patients who had successfully completed eight weeks' VLCD treatment, to either placebo or D-F 15 mg b.d. for 26 weeks. Patients continued on a diet giving 60-75% of daily energy needs. Patients treated with D-F had lost 14.9 +/- 0.9 kg on the Cambridge diet and a further 5.8 +/- 1.8 kg during the drug treatment. In contrast, patients who received placebo regained 2.9 +/- 1.3 kg of the 13.5 +/- 1.0 kg they had lost during VLCD. The total weight loss after 34 weeks in total was thus 21.3 +/- 2.6 versus 11.3 +/- 1.9 kg. Patients were offered the option of continuing on D-F, or switching from placebo, in an open continuation of the trial. Ten patients, regaining weight on placebo, stabilized their weight without further regain over the next 24 weeks when switched to D-F.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of dexfenfluramine on energy expenditure in man.

A short review has been made of the experimental studies performed in man, in which the effect of dexfenfluramine (D-F) on resting energy expenditure has been explored. It appears that the extent to which D-F possesses thermogenic properties (in addition to its anorectic effect) still remains controversial. Some investigators found either no significant increase in energy expenditure in response to the drug or a moderate effect in post-absorptive and/or postprandial state. It may be reasonable to assume that the supplementary weight loss observed with D-F as compared to a placebo can be primarily attributed to its anorectic effect rather than to its putative thermogenic effect.

Adult↗
PubMed1992

Acute and chronic effects of dexfenfluramine on glucose and insulin response to intravenous glucose in diabetic and non-diabetic obese subjects.

Fenfluramine improves glucose tolerance in obese subjects independently of its anorectic effect. Increased insulin action has been reported, but such an effect may be secondary to reduced hyperglycemia following augmented insulin secretion. For this reason, we investigated whether the dextro-enantiomer of fenfluramine (dexfenfluramine, dF) has a direct effect on insulin secretion using the glucose infusion test, a technique that can also be used to indirectly evaluate insulin action. Ten lean controls (BMI 21 +/- 0.4 kg/m2), 9 non-diabetic obese subjects (BMI 32.3 +/- 1.1) and 10 obese mild non-insulin dependent diabetics (BMI 36 +/- 2.6, fasting plasma glucose (FPG) 7.9 +/- 0.9 mmol/l) were studied with a random, double blind cross-over protocol. Each subject received 15 mg dF (or placebo) twice daily for 3 days prior to glucose infusion; 30 mg dF (or placebo) were given 90 min before the test. Obese control and diabetic subjects continued treatment with either dF or placebo for one month after which they were retested. There was no significant change in weight or fasting plasma glucose or insulin in any group. Biphasic insulin secretion was demonstrated in both non-diabetic groups, whereas a complete lack of first-phase and a delayed and reduced second phase insulin response was demonstrated in the diabetic subjects. There was no acute or chronic (obese subjects) effect of dF on insulin secretion in any group. In lean control subjects, plasma glucose curves during glucose infusion were unchanged by dF, whereas in non-diabetic obese subjects the glucose slope was improved after both acute and chronic dF, implying augmented glucose disposal. In diabetic patients, no significant acute or chronic effect of dF on glucose response was registered. When all obese subjects were re-grouped according to fasting plasma insulin levels (FPI) and not glucose tolerance, those with relative fasting hyperinsulinemia (> 100 pmol/l, mean +/- SE = 144 +/- 12 pmol/l) showed significant improvement of insulin action after dF, whereas those with low FPI (< 100 pmol/l, mean +/- SE = 65 +/- 7 pmol/l) did not. These findings, together with previously published results of improved insulin action in diabetics during hyperinsulinemic clamps, suggest that dF-mediated improvement in glucose clearance may require substantial plasma insulin concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

[Efficacy and acceptability of dexfenfluramine in women consulting in gynecology. 336 overweight patients treated for 3 months].

The efficacy on bodyweight and the acceptability of a three month treatment with dexfenfluramine (Isoméride), combined with a prescribed diet, were evaluated in 336 women followed by a gynecologist for overweight. These women were divided into three groups, those in the sexually active age group (80%) and perimenopausal and post-menopausal women (20%) and had the following characteristics: mean bodyweight 80.2 +/- 0.6 kg; excess bodyweight 35.0 +/- 0.5% of theoretical ideal weight, mean bodyweight index = 30.6 +/- 0.2 kg/m2. Simultaneously with the weight loss, a study of the change in gynecological symptoms was carried out at each consultation and for each group. Investigation of the bodyweight showed that 80% of the patient who followed the treatment for three months lost weight, the mean loss being 7.2 kg or 41.9% of the initial excess weight. Simultaneously with this loss of weight, there was an improvement in the gynecological symptoms in all three groups. These symptoms included those seen in the premenstrual phase (sexually active age group) and menopause-related symptoms in the perimenopausal and post menopausal groups. The acceptability and safety of Isomeride were also confirmed in this study.

Adult↗
PubMed1990

The effect of long-term dexfenfluramine treatment on 24-hour energy expenditure in man. A double-blind placebo controlled study.

In order to investigate the effect of long-term treatment with dexfenfluramine (dF) on 24-hour energy expenditure (EE), 10 obese females were studied in a double-blind design. Shortly before and 4 weeks after cessation of a 13 months treatment period with either dF (30 mg/day) or placebo (PL) the 24-hour EE was measured. The measurements were performed using a 24 m3 direct heat sink calorimeter with continuous real time measurements of evaporative and sensible heat losses. The patients performed a standardized program of exercise, rest and meals. The measurements were performed at 24 degrees C and at a humidity between 3 and 11 g/m3. Discontinuation of dF treatment did not change energy expenditure significantly from placebo, neither when expressed in kJ/kg lean body mass nor in kJ/kg body weight. After cessation of treatment total 24-hour EE decreased likewise nonsignificantly by 2.9 percent in the dF group and by 4.0 percent in the PL group. EE measured over 24 hours was subdivided into day and night periods and into resting energy expenditure as well as a measurement of the heat losses over a period of 3 hours after a meal. This subdivision of the EE showed similar nonsignificant differences. The conclusion is therefore that dF possesses no significant thermogenic effect during long-term administration in human obese subjects.

Adult↗
PubMed1988

Human implications of animal experiments--lessons from dexfenfluramine.

Experience with dexfenfluramine and related compounds illustrates some of the potentials and the limitations of studies in experimental animals. Major pharamcological effects of these drugs were identified in animal models, but a variety of behavioral, psychotherapeutic, autonomic, and cardiovascular actions were not predicted from animal experiments, and it is unlikely that satisfactory animal models exist for some of them. An examination of the literature on animal and human studies of drugs on eating behavior, food intake, and body weight leads to the conclusion that the models used, at present, do not truly represent the complexity of the processes being investigated.

Animals↗
PubMed1988

The interaction of metergoline, a 5-HT receptor blocker, and dexfenfluramine in human feeding.

Use of the 5-HT antagonist metergoline (MTG) has shown that dexfenfluramine (d-FF) influences food intake in animals via serotoninergic neurones. This study examined the interaction between d-FF and MTG in humans. Healthy male volunteers reported singly at 8:45 A.M. on four weekly occasions following an overnight fast. At 9:00 A.M. they received 30 mg d-FF or matching placebo and at 11:00 A.M. 4 mg MTG or placebo. Hunger and satiety were assessed hourly using visual analog scales (VAS). Subjects had access to a 4-channel automated food dispenser (AFD) from 1:15 to 3:15 P.M. Delivery and recording of each portion of known energy value was contingent on an appropriate button push. Subjects were offered two nonsweet snacks, plus fruit and a chocolate biscuit chosen to each subject's preference. Results for 13 subjects are reported. d-FF reduced hunger VAS, MTG had no effect on hunger and did not attenuate the effect of d-FF. d-FF reduced total food intake by 1306 kJ (312 kcal p less than 0.01) at 120 min. MTG increased food intake and attenuated the effect of d-FF on food intake but not significantly. d-FF markedly reduced the intake of nonsweet food; this was attenuated by MTG which alone had no effect on nonsweet food. d-FF had no effect on the intake of sweet tasting food during the first hour; by 120 min it had reduced energy intake by 342 kJ (82 kcal, t = 1.34, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Interactions↗
PubMed1988

Correlation between metabolic and behavioral effects of dexfenfluramine treatment.

The consequences of dexfenfluramine (dFF) treatments on food intake (FI), locomotor activity (LA), respiratory quotient (RQ), and on changes in metabolic rate (MR) and in RQ that are induced by LA and FI, were investigated in 12 female Wistar rats fed ad libitum. Reduction of FI induced by dFF was correlated with an overall decrease in RQ that expresses increased lipogenesis. For a given amount of activity, MR and RQ changes were enhanced by dFF. On the other hand, dFF appeared to increase energy expenditure in relation to FI only to the extent that the energetic cost of LA itself was not taken into account. It is concluded that the anorexia induced by dFF may be due to the peripheral consequences of dFF treatments on the peripheral metabolism of glucides and lipids according to a lipostatic, glucostatic, or an ischymetric mechanism, and that the increase in energy expenditure previously reported after feeding, may reflect an increase in the energy produced in relation to LA rather than an increase in the thermic effect of feeding per se.

Animals↗
PubMed1995

The pharmacokinetics of dexfenfluramine in obese and non-obese subjects.

The pharmacokinetics of dexfenfluramine (d-F) and its metabolite dexnorfenfluramine (d-NF) were compared in 10 obese (145 +/- 13 s.d. % of ideal body weight (IBW)) and 10 non-obese healthy volunteers (93 +/- 8% IBW). Each group included five men and five women, aged 28 +/- 8 years. Subjects were given single doses of d-F i.v. (15.5 mg base infused over 3 h) and orally (25.9 mg base in capsules) on separate occasions. After i.v. infusion in obese subjects, the volume of distribution (Vss) of d-F was significantly higher (969.7 +/- 393.3 l; 95% CI 688.6-1250 l) than in controls (668.7 +/- 139.6 l; 95% CI 568.9-768.5 l; P < 0.01). Clearance was not significantly different (43.9 +/- 21.0 l h-1 vs 37.3 +/- 10.6 l h-1) and the terminal half-life tended to be longer (17.8 +/- 9.4 vs 13.5 +/- 3.9 h NS). Combined data from the two groups indicated a positive correlation between Vss and % IBW (r = 0.544; P < 0.02). The oral bioavailability of d-F was 0.61 +/- 0.15 in obese subjects and 0.69 +/- 0.11 in controls. There was no significant difference between obese subjects and controls in Cmax, tmax and t1/2,z (Cmax: 20.1 +/- 6.7 and 27.3 +/- 6.2 micrograms l-1; tmax: 3.5 vs 3.0; t1/2,z: 16.5 +/- 7.1 vs 14.5 +/- 2.6 h respectively). The AUC ratio expressed in molar units for d-F/d-NF was 2.29 +/- 1.78 (i.v.) vs 1.25 +/- 0.64 (oral) in obese subjects and 2.05 +/- 1.26 (i.v.) vs 1.40 +/- 0.87 (oral) in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Effect of dexfenfluramine on energy expenditure in obese patients on a very-low-calorie-diet.

AIM: To investigate the effect of dexfenfluramine (dF) on Energy Expenditure (EE). DESIGN: 20 obese females were studied in a double-blind design. Pre-diet and at 14 and 28 days of VLCD and dF treatment (30 mg/d) or placebo, Resting Metabolic Rate (RMR), 3 h-Thermic Effect of Food (3 h-TEF) and body composition were determined. EE and body composition were measured by indirect calorimetry and bioelectrical impedance, respectively. RESULTS: No differences between groups were observed in relation to weight loss, body composition changes or RMR. At 3 h postprandial, the EE was still elevated in both groups. No changes on TEF were observed in the placebo group during VLCD. In contrast, TEF decreased in dF group during VLCD (P < 0.05). No significant differences in TEF at the end of the study were observed between groups. CONCLUSION: These results suggest that dF modifies 3 h-TEF but not RMR in obese patients during VLCD administration.

Adult↗
PubMed1994

[Voluntary poisoning with dexfenfluramine (Isomeride)].

Dexfenfluramine is one of the most widely prescribed appetite suppressant drugs in Switzerland because of its enhancing effect on certain weight-reducing diets. Nevertheless, the effects of acute intoxication are not well documented. We recently observed a young adolescent girl who ingested large quantities of the drug to achieve a rapid weight loss. She presented with tachycardia, high blood pressure, mydriasis, fever and behavioral disorders. All signs and symptoms cleared after 48 hours. The clinical picture is akin to amphetamine intoxication, in view of the similarity of the two drugs' metabolites.

Adolescent↗
PubMed1994

Energy metabolism and metabolite patterns of rats after application of dexfenfluramine.

Serotoninergic neuronal networks are important for food intake and body weight regulation. However, the mechanisms by which some metabolic pathways are influenced are rather unclear. Dexfenfluramine (DF), a serotonin releaser and re-uptake inhibitor, was used to investigate changes in food intake, body weight development, energy expenditure, respiratory quotient and substrate oxidation rates for 12 days. Normal rats, receiving an energy-controlled mash diet and water ad libitum were intraperitoneally injected daily with either saline, 1, 2.5, 5 or 10 mg DF/kg. Compared to controls, food intake, body weight development and energy expenditure were decreased in a dose-dependent manner, especially during the first six days. Lipid oxidation was increased while oxidation of carbohydrates was decreased. Pair-feeding experiments over three days revealed that this was a clear pharmacological effect and not simply a result of diminished food intake. At the end of these experiments, plasma glucose and liver and muscle glycogen were unchanged after DF, but isoleucine, leucine and lysine were significantly decreased in plasma and liver. Therefore, the plasma tryptophan/large neutral amino acids ratio was slightly increased. Protein oxidation was unchanged after DF. It is concluded that a prompt decline in energy expenditure with increased fat oxidation rates could mediate the body weight reducing effect of DF.

Amino Acids↗
PubMed1994

Long-term changes of body weight and cardiovascular risk factors after weight reduction with group therapy and dexfenfluramine.

The aim of this work was to investigate the long-term changes of body weight and cardiovascular risk factors after weight reduction with dexfenfluramine (dF) compared to placebo (pI) and additional group therapy. There was a 3 year follow-up of obese patients after 1 year double-blind, randomized treatment with 30mg dF or pI and group therapy. The work was carried out at the outpatient clinic of University Hospital, Tübingen. Forty-eight (24 dF, 24 pI) patients were investigated with more than 120% of ideal body weight. Body weight, blood pressure, blood glucose, serum cholesterol and triglycerides were measured. During 1 year of treatment body weight fell by 11.2% (dF) and 9.1% (pI) (P < 0.001 for time, n.s. for dF/pI), systolic blood pressure by 7.3 and 9.9 mm Hg (P = 0.044/n.s.). There were no significant changes of serum cholesterol, triglycerides, and blood glucose. At the follow-up of 22 (11/11) patients 3 years later, the dF group had regained more than the lost weight; the placebo group had lost 2.4% of the initial body weight. Serum cholesterol (dF + 0.64/pI + 0.65 mmol/l, P = 0.010/n.s.), triglycerides (+0.74/+0.59 mmol/l, P = 0.002/n.s.), and blood glucose (+0.56/+0.81mmol/l, P < 0.001/n.s.) increased significantly. Systolic blood pressure increased slightly, diastolic blood pressure did not change significantly. Without appropriate prevention of weight regain even combined weight reduction therapy over a period of one year results in weight regain and deterioration of cardiovascular risk factors.

Adult↗
PubMed1994

Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice.

In previous separate studies, dexfenfluramine (DF) and ephedrine/caffeine (EC) have been shown to promote weight loss in obese patients as compared with placebo. In order to compare the efficacy and safety of these two anorectic drugs, 103 patients with 20-80% overweight were included in a 15-week double-blind study in general practice. Patients were randomized to either 15 mg DF twice daily (n = 53), or 20 mg/200 mg ephedrine/caffeine three times a day (n = 50), supplementary to a 5 MJ/day diet. Forty-three patients from the DF group and 38 from the EC group completed the study. After 15 weeks of treatment, the DF group (n = 43) had lost 6.9 +/- 4.3 kg and the EC group (n = 38) had lost 8.3 +/- 5.2 kg (mean +/- s.d., P = 0.12). In the subgroup of patients with BMI > or = 30 kg/m2 (n = 59), the mean weight loss was 7.0 +/- 4.2 kg in the DF group (n = 29) and 9.0 +/- 5.3 kg in the EC group (n = 30), P < 0.05. Both systolic and diastolic blood pressures were reduced similarly during both treatments. Twenty-three patients in the DF group (43%) and 27 in the EC group (54%) complained of side-effects. Central nervous system side-effects, especially agitation, were more pronounced in the EC group (P < 0.05), whereas gastro-intestinal symptoms were more frequent in the DF group (P < 0.05). The side-effects declined markedly during the first month of treatment in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Dexfenfluramine influences dietary compliance and eating behaviors of obese subjects.

Results of a 14-month Dutch study using dexfenfluramine as an appetite suppressant show that although weight loss was not enhanced, subjects showed greater dietary compliance and were less anxious about eating behaviors than placebo-treated counterparts. Adjunctive dietary drug therapy may be useful for clinicians working with obese patients in long-term weight loss trials, and may show promise in the treatment of bulimia.

Feeding Behavior↗
PubMed1993

The acute effect of dexfenfluramine on resting metabolic rate and postprandial thermogenesis in obese subjects: a double-blind placebo-controlled study.

The effects of dexfenfluramine (dFE: 30 mg per os) on energy expenditure were evaluated in seven young obese male subjects (mean +/- s.d.: age 30.9 +/- 6.1 years; BMI 39.8 +/- 4.4 kg/m2). Each subject was submitted, on a double-blind protocol and by random order, to four tests in which dFE or placebo (Pla) were administered either in the fasting state or in combination with a mixed test meal. Energy expenditure was measured by indirect calorimetry for 60 min before (BMR) and from 90 to 330 min after dFE or Pla. In those cases where the protocol required it, a mixed test meal (5 MJ, 1200 kcal; percentage of protein, carbohydrate and fat: 15, 55, and 30 respectively) was eaten 120 min after dFE or Pla. In the fasting state resting metabolic rate increased after dFE (mean +/- s.d.: 0.49 +/- 0.20 kJ/min) but not after Pla (-0.04 +/- 0.16 kJ/min) in comparison to BMR, the difference between the two tests being highly significant (P < 0.01). Post-prandial thermogenesis (over 3h) was also significantly higher after dFE than after Pla (232 +/- 85 kJ vs. 181 +/- 73 kJ; P < 0.025). On the other hand, dFE did not affect respiratory quotient (RQ), either in the fasting state or in the fed state. These results show that in obese subjects dFE increases energy expenditure in the post-absorptive state, as well as after the ingestion of food.

Adult↗
PubMed1995

Dexfenfluramine inhibits catecholamine stimulated in vitro lipolysis in human fat cells.

OBJECTIVE: To investigate the effect of dexfenfluramine (d-F) on basal and isoproterenol stimulated lipolysis in human fat cells in vitro. DESIGN: Adipocytes were incubated in Krebs-Ringer-Hepes buffer either with 10(-6) M or 10(-7) M isoproterenol alone, with 0.02-200 micrograms/ml (74.7 nmol/l-747 mumol/l) of d-F or both. MEASUREMENTS: Glycerol release at 2 h incubation time was measured as an estimate for lipolysis. RESULTS: The addition of d-F did not significantly influence basal lipolysis of 58.6 nmol/2 h. Stimulation by 10(-6) M and 10(-7) M isoproterenol increased glycerol release to 92.5 nmol/2 h and 83.4 nmol/2 h, respectively. Adding increasing doses of d-F and 10(-6) M isoproterenol caused a dose-dependent inhibition of isoproterenol stimulated lipolysis. Glycerol release was significantly decreased to 84.1 nmol/2 h at 20 micrograms/ml, to 77.8 nmol/2 h at 60 micrograms/ml and to 61.9 nmol/2 h at 200 micrograms/dl d-F. Glycerol release induced by 10(-7) M isoproterenol was significantly inhibited to 69.7 nmol/2 h at 20 micrograms/ml, to 61.5 nmol/2 h at 60 micrograms/ml and to 51.9 nmol/2 h at 200 micrograms/ml d-F. 50% inhibition occurred at 80 micrograms/ml d-F with 10(-6) M isoproterenol and at 28 micrograms/ml with 10(-7) M isoproterenol. CONCLUSION: d-F may decrease the release of free fatty acids from adipose tissue. This would lead to a reduced flux to the liver and may partly account for the triglyceride lowering effect of d-F in obese subjects.

Adipocytes↗
PubMed1996

The effect of withdrawal and re-introduction of dexfenfluramine in the treatment of obesity.

In this study 25 patients, who had completed the INDEX trial (Guy-Grand et al. Lancet 1989; 2: 1142-1145) were reexamined 2 months after withdrawal of the study medication. The patients then in an open trial received dexfenfluramine (dF) for 6 months. The observed weight gain after withdrawal of study medication was higher in patients treated beforehand with dF (2.6 +/- 1.2 kg) than in patients who had received placebo (0.8 +/- 1.0 kg). In the open dF trial rate of weight loss was lower than it had initially been in the patients receiving dF from the outset of the INDEX trial (13.1 +/- 4.6 kg within 6 months). In the previous dF treated patients weight loss after re-introduction of dF was 3.7 +/- 2.7 kg. The previous placebo-treated patients, now receiving dF for the first time, lost 4.8 +/- 1.1 kg. Thus, after withdrawal of dF, patients experience weight gain, but after re-introduction of dF, renewed weight loss is achieved. However, the rate of weight loss declines with time.

Adult↗