Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

d-Fenfluramine (dF) (15 mg twice daily) has been studied in controlled trials in human obesity and has been shown to increase adherence to diet, to enhance its efficacy, and most importantly, to prevent weight regain when continued over 1 y. Few side effects, mostly transient, have been observed. A long-term use of dF in the management of some obese patients could be foreseen. Additionally, evidence that dF improves eating symptoms and dysphoric impairments in obese cravers, premenstrual syndrome, seasonal affective disorder, and smoking withdrawal syndrome has been presented.
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PMID:Clinical studies with d-fenfluramine. 172 29

Dextrofenfluramine [+)-fenfluramine) is the dextro-optical isomer of the racemic compound (+/-)-fenfluramine. This compound stimulates the release of serotonin (5-HT) and blocks its re-uptake in serotonergic nerve terminals. (+)-Fenfluramine and its nor metabolite which have been localized in significant amounts in the rat brain are useful anorectic agents in animals. In humans, (+)-fenfluramine is used as an anti-obesity agent when administered orally in doses of 0.25 mg/kg/twice a day. Studies in some animal species (such as the rat and monkey, but not mice) using high doses of (+)-fenfluramine (administered subcutaneously) have shown long-term neurochemical and immunocytochemical effects in selected brain regions. In the present study we used the rat to determine the mechanism underlying the anorectic effect of orally administered (+)-fenfluramine. The rat was selected because long-term effects of (+)-fenfluramine have been previously described in this species. In addition, a variety of other aspects of orally administered (+)-fenfluramine have been addressed in this study. For example, how long does the depletion of 5-HT in the nerve terminals last following cessation of the drug treatment? i.e. is the effect reversible? Is this depletion of 5-HT and the resultant abnormal morphology of 5-HT-immunoreactive nerve terminals seen at high doses dose-dependent? Since some of these questions relate to morphological evaluation of this drug in brain 5-HT systems, we have examined this system as part of our ongoing effort to examine brain monoaminergic systems under perturbed conditions. We have used a morphological (immunocytochemical) approach to answer these questions. The primary function of this study was to evaluate the effects of short-term exposure (4 days) to varying doses of orally administered (+)-fenfluramine on 5-HT-immunoreactive nerve terminals in the frontal cortex of the rat. The frontal cortex was selected because it contains a homogeneous population of nerve fibers and terminals unlike other cortical regions, the hippocampus, striatum and the hypothalamus where a mixed population of coarse and fine fibers has been described. Since the previously reported effect of fenfluramine on 5-HT nerve terminals was the appearance of coarse fibers, the region of cortex selected for this study showed no coarse fibers in the pair-fed control. This essential feature of control regions has not been used in previous studies on this subject. The present study demonstrates that (+)-fenfluramine produces a dose-dependent reduction in 5-HT immunoreactivity of 5-HT nerve terminals in the neocortex of adult rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Reversible, short-lasting, and dose-dependent effect of (+)-fenfluramine on neocortical serotonergic axons. 186 26

Physicians treating adipose patients often hesitate to include drugs. Considering new developments in obesity research and drug-therapy, this attitude should be discussed. Anorectics of the amphetamine-group and analogues (derivates) react with the noradrenergic system and induce appetite-suppression. Fenfluramine in the d-1 configuration and isomeric dextro-rotation influence release of serotonin, reduce intake of food and increase sensation of saturation. In addition, various eating behavior disorders like nibbling and addiction to sweets are discussed. Use of Dextro-fenfluramine for these special situations is discussed as well as its side effects, duration of drug intake and form of application. Importance of concomitant therapeutic means like hypocaloric diet and personal attendance are emphasized.
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PMID:[Judicious use of anorectics]. 200 74

Fenfluramine is an amphetamine derivative that in humans is used primarily as an anorectic agent in the treatment of obesity. In rats, subchronic high-dose d,l-fenfluramine treatment (24 mg/kg subcutaneously, twice daily for 4 days) causes long-lasting decreases in brain serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid, and high-affinity 5HT uptake sites. Moreover, this high-dose treatment regimen causes both selective long-lasting decreases in fine-caliber 5HT-immunoreactive axons and appearance of other 5HT-immunoreactive axons with morphology characteristic of degenerating axons. Determination of the potential neurotoxic effects of fenfluramine treatment using immunohistochemistry is limited from the perspectives that staining is difficult to quantify and that it relies on presence of the antigen (in this case 5HT), and the 5HT-depleting effects of fenfluramine are well known. In the present study, we used quantitative in vitro autoradiography to assess, in detail, the density and regional distribution of [3H]paroxetine-labeled 5HT and [3H]mazindol-labeled catecholamine uptake sites in response to the high-dose fenfluramine treatment described above. Because monoamine uptake sites are concentrated on monoamine-containing nerve terminals, decreases in uptake site density would provide a quantitative assessment of potential neurotoxicity resulting from this fenfluramine treatment regimen. Marked decreases in densities of [3H]paroxetine-labeled 5HT uptake sites occurred in brain regions in which fenfluramine treatment decreased the density of 5HT-like immunostaining when compared to saline-treated control rats. These included cerebral cortex, caudate putamen, hippocampus, thalamus, and medial hypothalamus. Smaller, but nonetheless significant, decreases in density of [3H]paroxetine-labeled 5HT uptake sites were noted in brain regions in which partial sparing of 5HT-like immunoreactive fibers had been reported following fenfluramine treatment, specifically septum, lateral hypothalamus, and amygdala. In contrast, [3H]mazindol autoradiography revealed that total catecholamine (i.e., dopamine and norepinephrine) uptake sites in cerebral cortex, caudate putamen, and locus coeruleus, areas in which [3H]paroxetine-labeled 5HT uptake sites were significantly decreased, were unaffected by this fenfluramine treatment. These data support the hypothesis that subchronic, high-dose fenfluramine treatment causes selective degeneration of 5HT axons in rat brain. Since pharmacokinetic studies show that the dosing regimen used in this study exposes rat brain to concentrations of fenfluramine that are approximately 600 times greater than those resulting from the therapeutic oral dose, caution must be exercised in extrapolating these data to humans.
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PMID:Effects of high-dose fenfluramine treatment on monoamine uptake sites in rat brain: assessment using quantitative autoradiography. 214 64

The position of pharmacotherapy of obesity is still controversial. Different groups of drugs are currently available in Switzerland--none is covered by the health insurances. Apparently the authorities are not convinced of their efficacy. Various groups of drugs have been tried, such as amphetamine derivatives, adrenergic drugs, serotonin agonists or hormones with thermogenic effects, intestinal enzyme inhibitors and dietary fibres. The results of sympathomimetic drugs demonstrate a relatively high incidence of side-effects, and with some preparations there is also the risk of addiction. The serotoninergic drug fenfluramine has been demonstrated in several controlled studies to be an effective weight-reducing agent; however, its effect was relatively modest: It lasted only as long as the drug was taken. Fenfluramine is relatively free of side-effects and is reported to diminish 'carbohydrate craving'.
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PMID:[Drugs against obesity]. 217 Nov 53

Fenfluramine is a widely prescribed anorectic drug as adjuvant therapy for obesity. Pulmonary vascular hypertension after use of fenfluramine is rarely reported. We present a patient with pulmonary hypertension and right heart failure after treatment with fenfluramine. Pulmonary hypertension resolved after withdrawal of the drug.
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PMID:Pulmonary hypertension and fenfluramine. 237 56

In prior studies rats showed a relative shift from self-stimulation to escape (i.e., from reward to aversion) following a large meal, obesity or anorectic doses of insulin. Racemic fenfluramine, on the other hand, decreased both self-stimulation and escape suggesting it had a general behavior suppressant property. To avoid the depressive, antidopaminergic effects of the l-isomer, this study tested the d-isomer which is primarily serotonergic. Rats were screened for stimulation-induced feeding and then trained to self-stimulate with one lever in 5-min periods that alternated with 5-min periods of automatic stimulation from which the animal could escape with a different lever. d-Fenfluramine (1.5-4.5 mg/kg IP) caused a dose-related decrease in self-stimulation. Stimulation-escape was relatively unaffected. This is interpreted as a decrease in feeding reward due to d-fenfluramine.
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PMID:The appetite suppressant, d-fenfluramine, decreases self-stimulation at a feeding site in the lateral hypothalamus. 272 99

Fenfluramine is an amphetamine derivative which is used primarily as an anorectic agent in the treatment of obesity. High doses of fenfluramine have been reported to cause long-term decreases in brain serotonin (5-HT) levels and density of high-affinity 5-HT uptake sites, actions characteristic of a "neurotoxic" effect of the drug. In view of these neurochemical changes, we used immunocytochemistry to assess, in detail, the effects of fenfluramine treatment on the morphology and density of 5-HT-like immunoreactive neurons in rat brain. Twelve to 18 hr after high dose dl-fenfluramine HCl treatment (24 mg/kg s.c., twice daily for 4 days), there was a profound regional decrease in density of fine-caliber 5-HT-like immunoreactive fibers and terminals in brain. This effect was especially apparent in cerebral cortex, hippocampus, cerebellum and striatum and less striking decreases were noted in septum, locus ceruleus and hypothalamus. On the other hand, 5-HT-like immunoreactive somata in midbrain nuclei and fibers and terminals in spinal cord appeared unaffected after fenfluramine treatment. Remaining 5-HT-like immunoreactive fibers and terminals displayed morphology characteristic of degenerating axons (thickening, swollen varicosities and fragmentation). Two weeks after the 4-day treatment regimen, patterns of 5-HT-like immunostaining appeared similar to those noted immediately (i.e., 18 hr) after drug treatment; however, the presence of grossly deformed fibers and terminals seen shortly after drug treatment was lacking. Tyrosine hydroxylase-like immunoreactivity, used to assess changes in catecholamine-containing neurons, appeared unaffected by drug treatment. These data suggest that, in rats, high s.c. doses of fenfluramine may be neurotoxic to some 5-HT-like immunoreactive axons and terminals. The relevance of these observations to the continued therapeutic use in humans of smaller p.o. doses of fenfluramine remains to be determined.
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PMID:Fenfluramine selectively and differentially decreases the density of serotonergic nerve terminals in rat brain: evidence from immunocytochemical studies. 273 54

Three studies have been undertaken to investigate why there are individual differences in the response to d-fenfluramine with respect to food intake and hunger in the short term and on body weight loss in the long term. Fenfluramine and norfenfluramine plasma levels have been used as probes to help detect and normalize these variances. In a single dose ranging volunteer study (0, 30, 40, and 60 mg), d-fenfluramine levels were significantly related to caloric intake and hunger rating scales when compared individually, and the slopes of the regression lines showed intersubject variation. These slopes, an index of each subject's response to fenfluramine, appear to be related to both the percentage underweight and more weakly to the percentage overweight. Those subjects at the extremes of weight showed a greater response to a given drug level. In two placebo-controlled 3 month studies (30 mg/day), the variances in weight loss were not explained by steady state drug levels, the percentage overweight, initial weight, duration of obesity, or caloric intake even when weight loss was normalized for differences in drug levels. Age, however, was significantly related to weight loss, with each additional 10 years increasing weight loss by approximately 1 kg. If confirmed, the sensitivity of fenfluramine anorexia may be an objective acute test of the central control of food intake. However, in long term clinical studies, drug levels were only weakly related to weight loss and other undefined factors seem to determine which patients responded better to fenfluramine treatment.
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PMID:Factors that may effect the reduction of hunger and body weight following d-fenfluramine administration. 305 14

Obesity is characterized by increased levels of insulin and by subnormal growth hormone (GH) release. Insulin/GH ratio is significantly higher in obese than in lean individuals. Fenfluramine, an anorectic drug, may have some effects on hypothalamic-pituitary function and on insulin secretion, possibly through a serotonergic stimulation. The aim of this work was to study the effects of fenfluramine on the insulin/GH ratio after arginine in obese subjects. Ten volunteer obese females were studied; 10 volunteer women were the normal weight controls. All subjects were given placebo and fenfluramine (60 mg p.o.) in a randomized order and after 120 min underwent arginine infusion (25 g i.v. for 30 min). Blood samples were taken every 30 min until 270 min for GH and insulin radioimmunoassay. In the obese group the GH response to arginine was significantly lower than in controls. Fenfluramine administration restored the subnormal GH response to arginine in obese subjects. Arginine infusion provoked a greater insulin secretion in obese subjects than in lean individuals. Fenfluramine administration diminished the insulin response to arginine. Fenfluramine did not modify the insulin/GH ratio in controls while it significantly lowered the insulin/GH ratio in obese subjects. Because insulin promotes fat and carbohydrate storage while GH stimulates lipolysis, the combination of high insulin and low GH concentrations may worsen the obese condition. A lower insulin/GH ratio can be useful in the treatment of obesity.
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PMID:Effect of fenfluramine on insulin/growth hormone ratio in obese subjects. 328 Nov 73


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