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PubMed1995

Effects of vagotomy on cholecystokinin- and dexfenfluramine-induced Fos-like immunoreactivity in the rat brain.

This study compared the effects of bilateral subdiaphragmatic vagotomy on the Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat brain induced by two anorectic agents, cholecystokinin (CCK) and the serotonin agonist, dexfenfluramine (DFEN). In the nonvagotomized rats, both CCK (5 micrograms/kg, IP) and DFEN (2 mg/kg, IP) induced FLI in the nucleus of the solitary tract (NST), the external subdivision of the lateral parabrachial nuclei (LPBE), the lateral subdivision of the central amygdaloid nucleus (CeL), and the bed nucleus of the stria terminalis (BST). However, subregional distribution of the FLI induced by the two agents was different in most of these regions. Additionally, the area postrema and the medial subdivision of the hypothalamic paraventricular nucleus were preferentially activated by CCK but not DFEN, while the caudate-putamen was activated by DFEN but not CCK. Bilateral subdiaphragmatic vagotomy completely abolished CCK-induced FLI in all the brain regions but did not attenuate DFEN-induced FLI in any of these regions, including the NST. The results of the present study suggest that DFEN-activation of the NST-LPBE-CeL/BST neuraxis is not mediated by the vagus nerve. On the other hand, and consistent with a variety of other data, activation of various parts of the brain by peripherally administered CCK depends on a vagal pathway. These data are discussed in relation to a previously proposed interaction between CCK and serotonin in mediating satiety.

Animals↗
PubMedDate not supplied

Effect of dexfenfluramine on alcohol intake in alcohol-preferring "P" rats.

The intake of alcohol, in 2-h daily sessions, by the preferring (P) line of rats was reduced in a dose-related manner by acute subcutaneous (SC) administration of dexfenfluramine (DFEN). Ad lib intake of alcohol was reduced by chronic SC administration of DFEN. The effective doses and magnitude of effects of DFEN on alcohol intake are comparable to those previously reported for DFEN anorexia. Because DFEN anorexia is related to increased brain serotonin (5HT) activity, its effect on alcohol consumption may also be via 5HT.

Alcohol Drinking↗
PubMed1997

Neuropharmacological effects of low and high doses of repeated oral dexfenfluramine in rats: a comparison with fluoxetine.

The neuropharmacological effects of repeated oral doses of dexfenfluramine (DF; 1.25-10 mg/kg, twice daily for 21 days) were examined in rats and related to the drug brain levels. Results were compared with fluoxetine (FL) given at similar doses relative to its anorectic ED50. Both drugs dose-dependently slowed body weight gain and reduced brain serotonin (5-HT). However, at 1.25 mg/kg DF caused only a slight and transient decrease in cortical 5-HT. Comparable doses of FL (6.25-12.5 mg/kg) lowered 5-HT more than DF, besides slightly reducing striatal dopamine. At higher doses DF markedly reduced 5-HT in all regions, and to a lesser extent noradrenaline in hippocampus. There was a negative relationship between 5-HT and log total active drug levels and the indole was approximately halved at drug levels about 50 times lower with DF than FL. However, the ratio between drug levels causing marked 5-HT reductions and those considered anorectic was similar for DF and FL because brain levels at the anorectic ED50 were higher with FL than DF. Long-lasting reductions of 5-HT were also observed but recovery was only consistently slow beginning from 5 mg/ kg DF. Comparable doses of FL could not be used because its general toxicity leads to the death of rats after only 2-4 multiples of its anorectic ED50.

Administration, Oral↗
PubMed1989

International trial of long-term dexfenfluramine in obesity.

In a randomised, placebo-controlled, double-blind study, 822 obese patients of both sexes were given either dexfenfluramine (dF), 15 mg twice daily (404), or placebo (418) in addition to a calorie-restricted diet for 1 year. Patients in both groups lost weight significantly in the first 6 months; after 6 months dF patients had a higher cumulative mean weight loss. Dropout rates were lower in dF patients than in placebo patients, mainly because of dissatisfaction with weight loss in the latter group. More than twice as many dF patients as placebo patients achieved a given weight loss; but more dF patients than placebo patients had transient side-effects (tiredness, diarrhoea, dry mouth, polyuria, and drowsiness).

Adult↗
PubMed1986

Effect of dexfenfluramine on body weight set-point: study in the rat with hoarding behaviour.

The food hoarding behaviour paradigm (HB) was used to evaluate the modification of the set-point of body weight (BW) regulation induced by dexfenfluramine (D-FF) in rats fed with chow or previously made obese by a cafeteria diet for 51 days. Daily injections of D-FF at a dose of 7 mg/kg (i.p.) induced a 58.5 g shift-down of the BW set-point in a group of chow fed rats submitted to HB measurement, and induced an equivalent weight reducing effect in a control-BW group always fed with chow ad libitum. In the rats fed ad libitum with the cafeteria diet, the BW reducing effect of D-FF(7 mg/kg/day) was about twice as great as in the lean rats. The HB measurement indicates that the vehicle-injected/cafeteria-obese rats had a BW set-point 54.6 g lower than the BW they reached when fed ad libitum with the cafeteria diet. It was concluded that the hyperphagia induced by the cafeteria diet was above that needed for BW regulation, and that D-FF may suppress this unregulated weight increase. In the cafeteria-obese rats submitted to HB measurement and D-FF injections a BW set-point 110.7 g lower than their initial ad libitum BW was observed. It is concluded that D-FF has induced a double effect in these rats: (1) a shift-down of the BW set-point and (2) the suppression of the unregulated weight increase induced by the cafeteria diet.

Animals↗
PubMed1997

High altitude may be synergistic with pulmonary hazards of appetite control medications fenfluramine and dexfenfluramine.

Clinical observations over the past 15 years incriminated first fenfluramine and recently dexfenfluramine in the provocation of primary pulmonary hypertension. Limited animal toxicology data tend to support this inference. The basis for respiratory pathology of high-altitude pulmonary malfunction, which reaches its maximal level in high-altitude pulmonary edema, evolves from and depends upon the occurrence of pulmonary hypertension. For this reason we hypothesize that high altitude and these two anorexic medications constitute a potentially synergistic combination, of which physicians treating patients for high-altitude illness, as well as those prescribing the drugs, should be aware.

Altitude↗
PubMed1993

Dexfenfluramine, fluoxetine, and weight loss among female carbohydrate cravers.

The consumption of excess calories as carbohydrates (CHO)-rich, protein-poor snacks characterizes the overeating of obese CHO cravers, premenstrual women, patients with Seasonal Affective Disorder, and former smokers. This specific appetite for CHOs may involve brain serotonin, as the synthesis and release of this neurotransmitter can increase following consumption of CHO-rich foods. To examine whether weight loss produced by serotoninergic drugs involves a selective reduction in CHO intake, obese females who consumed at least 30% of their daily calories from CHO-rich snacks were treated with dexfenfluramine ([DF] 15 mg b.i.d.); fluoxetine ([FL] 20 mg t.i.d.); or placebo (PL) for 12 weeks. Weekly weight loss for 25 of 29 PL completers was 0.22 kg +/- 0.06 (mean +/- SEM); for 21 of 28 DF completers, 0.56 +/- 0.08 kg; and for 18 of 30 FL completers, 0.58 +/- 0.09 kg (PL < DF = FL; p = .039). Seven FL subjects, 2 PL subjects, and 1 DF subject withdrew from the study due to side effects; other withdrawals were due to intercurrent illness or personal problems. Prior to treatment, subjects consumed over 40% of their daily CHO intake from snacks. Both of the drugs selectively decreased CHO snack intake (p < 0.05); DF, but not FL, also decreased meal CHO intake (p < .025). These results suggest that weight loss following treatment with serotoninergic drugs may relate to a selective decrease in CHO appetite.

Adult↗
PubMed1995

Modulation of glucagon-induced glucose production by dexfenfluramine in rat hepatocytes.

The mechanism of the antihyperglycaemic action of dexfenfluramine (DEXF) was investigated in isolated rat hepatocytes exposed to glucagon. Preincubation of hepatocytes with DEXF caused a dose-dependent inhibition of cyclic AMP formation by 100 nM glucagon (Ki = 0.29 mM) that was almost complete at 1 mM DEXF. Surprisingly, glucagon-induced phosphorylase activation was not affected by DEXF despite the significant drop in cyclic AMP levels. Glucose production stimulated by glucagon was inhibited by up to 48% by 1 mM DEXF, and the rate of glucose production correlated positively with the steady-state concentration of glucose 6-phosphate. DEXF also partially restored lactate + pyruvate production which was abolished by an optimal concentration of glucagon. Although DEXF was not able to prevent the inactivation of pyruvate kinase by glucagon, the lack of further accumulation of phosphoenolpyruvate in DEXF-treated cells supports the conclusion that the flux through pyruvate kinase is stimulated, probably via the increase in fructose 2,6-bisphosphate, thereby increasing glycolysis. Our results thus indicate that DEXF counteracts the inhibition of glycolysis by glucagon and that this property might contribute to the antihyperglycaemic effect of this drug. Furthermore, this study shows that, in the presence of the drug, glucagon caused phosphorylase activation and pyruvate kinase inactivation without a significant increase in cyclic AMP levels.

Animals↗
PubMed1996

Specific stimulation of brain serotonin mediated neurotransmission by dexfenfluramine does not restore growth hormone responsiveness in obese women.

OBJECTIVE: Growth hormone release in response to all known stimuli of GH secretion is blunted in obese subjects. Several studies, using d,l-fenfluramine (d,l-FF) as a serotoninergic tool, suggest that brain serotonin plays a role in the pathogenesis of this phenomenon. However, the effect of d,l-FF appears to be dependent on the stimulus used to induce GH release. Furthermore, d,l-FF has catecholamingergic properties apart from its capacity to stimulate serotonin release and to block its re-uptake. In this study, we investigated whether subchronic treatment with the highly selective serotoninergic drug dexfenfluramine (d-FF) affects the GH response to galanin or GHRH in obese subjects. DESIGN: The study had a randomized, cross-over, placebo controlled design. d-FF was administered in a dose of 15 mg twice daily during 6 days. On days 5 and 6 of treatment (with either d-FF or placebo) an i.v. bolus injection of 100 micrograms hGHRH(1-44) or a continuous infusion of p-galanin (40 pmol/kg/min over 40 minutes) were administered in randomized order. All tests were performed in the follicular phase of two consecutive menstrual cycles. PATIENTS: Eight obese women (body mass index (BMI) 34.5 +/- 3.6 kg/m2); 7 normal weight (BMI 21.9 +/- 1.9 kg/m2) age-matched control women. All women had a regular menstrual cycle. None used oral contraceptive drugs. MEASUREMENTS: GH response to either stimulus was measured both during treatment with d-FF and during treatment with placebo. RESULTS: The GH response to galanin and the response to GHRH were significantly smaller in obese subjects. d-FF significantly reduced the galanin induced GH secretion in obese subjects, but not in normal weight controls. It did not significantly affect GH release in response to GHRH in either group. CONCLUSION: This study confirms that GH secretion in response to stimuli with varying mechanisms of action is blunted in obese subjects. A decrease of central serotonin mediated neurotransmission does not appear to play a role in the pathogenesis of this phenomenon.

Adult↗
PubMed1994

Psychological and metabolic effects of dietary carbohydrates and dexfenfluramine during a low-energy diet in obese women.

Dietary carbohydrates and dexfenfluramine (dF) have been shown to influence serotoninergic neurotransmission. To assess their effect on spontaneous physical activity, mood, sleep quality, and resting metabolic rate (RMR), 32 obese females were studied while consuming diets providing 3970 kJ (950 kcal)/d. They were randomly allocated to either a diet relatively high in carbohydrates (carbohydrate:fat:protein, 49%:22%:29% of energy intake; group 1) or to a diet relatively high in fat (carbohydrate:fat:protein, 12%:59%:29%); subjects receiving the latter diet were treated additionally with either 30 mg dF (group 2) or placebo (group 3) daily in a double-blind fashion. Spontaneous physical activity decreased in the group treated with dF compared with the other two groups (P = 0.0002). Daily self-rated questionnaires indicated that mood and tiredness were negatively affected in two groups after the first week. Subjects treated with dF lost more weight than did those in the other two groups (P = 0.013). This occurred despite a decrease in physical activity and unchanged energy intake and resting energy expenditure.

Adult↗
PubMed1996

Dexfenfluramine and 8-OH-DPAT modulate impulsivity in a delay-of-reward paradigm: implications for a correspondence with alcohol consumption.

Clinical studies identify impulsivity as a defining feature of an alcohol abuse syndrome. We recently reported an animal analogue: impulsivity assessed in a delay-of-reward paradigm strongly predicted magnitude of alcohol consumption. In this study we further explored this relationship. We asked whether serotonergic manipulations previously established to reduce and augment alcohol consumption would have corresponding effects on impulsivity in a delay-of-reward paradigm. This study revealed that two doses (1 and 2mg/kg) of dexfenfluramine, a serotonergic releaser known to reduce alcohol consumption, reduced choice of immediate reward, or impulsivity. We also found that three doses of the 5-HT(1A) agonist, 8-OH-DPAT, caused a biphasic dose effect on impulsivity. There was a clear dose-dependent progression from augmentation (6 and 31µg/kg) to a reduction (62µg/kg) of impulsivity scores. This effect mirrors a biphasic dose effect that has been found for alcohol intake. The findings suggest that impulsivity and alcohol consumption are intimately linked via common serotonergic pathways.

Journal Article↗
PubMed1990

Dexfenfluramine: action with estradiol on food intake and body weight in ovariectomized rats.

Previous work from this laboratory has shown that chronic administration of dexfenfluramine (DF) caused substantial weight loss in rats that were overweight 3-4 mo after ovariectomy (OVX), but not in OVX rats that were of normal weight, as a result of estrogen replacement. The present study was conducted to determine whether the enhanced weight loss in the former group is because of either overweight per se or an inhibitory effect of estrogen on DF. Starting either 0, 6, or 14 wk after OVX, when weight gain was zero, moderate, or near maximal, respectively, rats received a 12-day regimen of either estradiol or the oil vehicle and either DF (3 mg.kg-1.day-1 by osmotic minipump) or no drug. DF had no effect on either food intake or weight gain of groups treated during 0-2 wk after OVX but had significant anorectic and weight loss actions in groups treated 6-8 and 14-16 wk after OVX. Estrogen had a similar effect at all three times and in the 14-wk group produced an effect that was additive with that of DF. Measures of plasma glucose and triglycerides and adipose tissue lipoprotein lipase activity did not correlate with the effectiveness of the drug to promote weight loss.

Adipose Tissue↗
PubMed1993

Turnover and oxidation rates of plasma-free fatty acids in obese patients treated with dexfenfluramine.

In order to assess a possible direct metabolic effect of dexfenfluramine (dF) apart from its action on food intake reduction, 10 obese postmenopausal women and 10 obese men (BMI = 32.19 +/- 1.99 kg/m2) were studied in a single-blind fashion: 4 weeks on placebo (D-28 to D0) and 4 weeks on dF (D0 to D28). A balanced diet, computed on the basis of basal metabolic rate x 1.4, was followed throughout the study. The patients' alimentary diary was checked for compliance. FFA turnover and oxidation rate, using 1-14C palmitate intravenous infusion, was determined basally (D0), after single high-dose (30 mg, D1) and after long-term (15 mg b.i.d., D28) administration. Indirect calorimetric measurements were performed using a mass spectrometer, and the usual metabolic parameters were computed. The isotope method was used in order to assess plasma FFA oxidation rate. Plasma FFA were analyzed by high-performance liquid chromatography (HPLC) and specific activity was determined at 55, 60, 65 and 70 min by counting dpm in HPLC eluates corresponding to the retention time of palmitate. The turnover rate was not significantly modified after single high-dose dF administration when compared to basal values (6.24 +/- 1.62 at D1 vs. 5.63 +/- 2.07 mmol/kg/min at D0), but was significantly increased at D28 compared with D0 (6.35 +/- 1.96 mmol/kg/min; p < 0.05). A significant increase in FFA oxidation rate was observed with respect to basal values after dF administration both at D1 (0.81 +/- 0.33 at D1 vs. 0.61 +/- 0.21 mmol/kg/min at D0; p < 0.01) and at D28 (0.77 +/- 0.34 mmol/kg/min; p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Energy expenditure and substrate oxidation rates of obese rats during a 12-day treatment with dexfenfluramine.

Serotoninergic neuronal networks are included in regulation and modification of eating behavior and energy metabolism. Dexfenfluramine (dF), a serotonin releaser and reuptake inhibitor, was used to investigate changes in food intake, body weight development, energy expenditure, respiratory quotient, and substrate oxidation rates for 12 days. Rats which had been made obese by postnatal overfeeding received an energy-controlled mash diet and water ad libitum and were intraperitoneally injected with either saline or 5 or 10 mg dF/kg. As compared with controls, food intake and energy expenditure were significantly decreased in a dose-dependent manner, especially during the first 6 days. Lipid oxidation was increased, while the oxidation of carbohydrates was decreased. The body weight was only slightly reduced after 2 days of dF treatment. After 4 days, dF-treated rats resumed body weight, but as compared with controls both dF groups exhibited lower body weights at the end of the experiment. After 12 days the plasma glucose concentration was unchanged, whereas plasma free fatty acids were significantly decreased. Plasma insulin levels were unchanged after dF, but 10 mg dF/kg led to increased muscle and, especially liver glycogen contents, indicating an improved nonoxidative glucose disposal. Muscle pyruvate kinase was slightly but not significantly increased after dF treatment but that of the liver was significantly decreased, indicating a reduced glycolytic activity of the liver. Whereas the renal N excretion was rather decreased, the plasma concentrations of urea, citrulline, arginine, and ornithine were increased, and the liver contents of glutamine and arginine were decreased. Possibly, there is a shift of ammonia removal from glutamine synthesis to production of urea. The sum of all large neutral amino acids in muscle was significantly decreased after dF treatment, indicating a diminished proteolysis. Pair-feeding experiments over 2 days revealed that this was not solely a result of diminished food intake, but also an additional metabolic effect of dF, different from its anorectic effect. It is concluded that both increased oxidation of endogenous fat and reduced food intake could mediate the body weight reducing effect of dF.

Amino Acids↗
PubMed1995

Bilateral acute angle-closure glaucoma after dexfenfluramine treatment.

We report the case of a patient with narrow angles who had an attack of bilateral acute angle-closure glaucoma precipitated by dexfenfluramine, a serotoninergic drug developed for appetite suppression. Although the exact mechanism remains uncertain, the pupillary block observed in our case may be the result of the serotoninergic or indirect parasympatholytic properties of the drug on the iris sphincter muscle. Serotonergic psychoactive drugs should be prescribed cautiously in patients with known narrow angles and should be monitored by an ophthalmologist.

Appetite↗
PubMedDate not supplied

Nocturnal eating syndrome: a case report with therapeutic response to dexfenfluramine.

A woman with nocturnal eating syndrome responsive to dexfenfluramine (DXF) is reported. Eating consisted of nightly ingestion of large amounts of high-calorie meals and often sloppy meal consumption or preparation. Amnesia for the episodes was total. Anorexigenic medications produced partial control of her daytime carbohydrate craving and no nocturnal eating change. DXF stopped her eating behavior completely. Nocturnal eating herein meets all 4 DSM-III-R diagnostic criteria for binge eating disorder. 5-HT role in neural process controlling sleep-wakefulness (SW) has been widely shown. A 5-HT agonist like DXF could determine changes in the SW processes producing the therapeutic outcome reported herein. However, a specific DXF effect on the behavioral control of carbohydrate ingestion can not be dismissed.

Adult↗
PubMed1992

Dexfenfluramine as adjuvant to a low-calorie formula diet in the treatment of obesity: a randomized clinical trial.

Dexfenfluramine (dF) was compared to placebo as adjuvant to a very energy-restricted diet (1.6-4.2 MJ/24 h). The diet was continued as long as possible or until a satisfactory weight loss had been achieved, and dietary efforts were continued throughout the study. Of the 37 females and five males included, 71 per cent could be followed up for 12 months. Initial BMI ranged from 28 to 54 kg/m2. The lowest body weight was reached 1 month earlier in the dF group (P = 0.037). Throughout the study, the reduction of excess weight (REW) was greater in dF patients (P less than 0.05 only at 4 and 6 months). At 6 months, excess weight had declined by 15 per cent more in the dF group than in the placebo group (95 per cent confidence limits of the median being 1-31 per cent). Between 6 and 12 months, both groups regained weight significantly, the rates of regain differing only insignificantly. At 12 months, excess weight showed a net decrease of only 8 per cent more in the dF group than in the placebo group (95 per cent confidence limits being -7 to +24 per cent). Therefore, REW showed no significant group difference after 12 months. Type of obesity (android or gynoid) as determined by waist to hip ratio had no significant impact on either weight loss, REW, reductions of waist and hip circumferences, or on waist to hip ratio changes. S-alkaline phosphatases and s-uric acid declined significantly in the dF group only. Side-effects were all mild and their prevalence showed no group difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Strategies to minimize weight gain after smoking cessation: psychological and pharmacological intervention with specific reference to dexfenfluramine.

Cigarette smoking suppresses body weight, discouraging many smokers from trying to quit. Behavioural therapies have so far proved unsuccessful in preventing post-cessation weight gain, and have in fact tended to undercut abstinence from smoking. The mental demands of implementing behavioural weight management strategies may compete with the concentration needed to maintain abstinence from smoking. Consequently, a pharmacological approach offers potential treatment advantages by minimizing the effort needed to achieve weight control. Of the agents found effective in minimizing weight gain, serotoninergic drugs, particularly dexfenfluramine, show special promise because they prevent an increase in caloric intake but do not decrease energy intake below pre-cessation levels.

Behavior↗