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

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.
 ...
PMID:Dexfenfluramine. An updated review of its therapeutic use in the management of obesity. 911 19

Sibutramine is a noradrenaline and 5-hydroxytryptamine reuptake inhibitor which causes weight loss in laboratory rodents via effects on both food intake and metabolic rate. Sibutramine's effects are predominantly mediated by two pharmacologically-active metabolites (its primary and secondary amines). Sibutramine and its active metabolites do not cause the release of monoamine neurotransmitters and do not have affinity for their receptors. Sibutramine dose-dependently inhibits 24 h food intake in rats by enhancing the natural physiological process of satiety. Sibutramine also stimulates thermogenesis in rats, producing sustained (> 6 h) increases in oxygen consumption of up to 30%. The thermogenic effect of sibutramine results from central activation of efferent sympathetic activity which, in turn, involves activation of beta 3-adrenoceptors. Sympathetic stimulation of brown adipose tissue via beta 3-adrenoceptors is thought to be the cause of the large, 18 fold increase in brown adipose tissue glucose utilization induced by sibutramine. These dual effects of sibutramine on food intake and thermogenesis explain its anti-obesity effect in animals.
 ...
PMID:Sibutramine: a review of the pharmacology of a novel anti-obesity agent. 913 38

1. Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. 2. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. 3. Sibutramine (10 mg kg-1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the alpha 1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg-1, i.p.), and partially antagonized by the beta 1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg-1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg-1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg-1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg-1, p.o.). 4. By contrast, the alpha 2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg-1, i.p.) and the beta 2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg-1, i.p.) did not reduce the decrease in food intake induced by sibutramine. 5. These results demonstrate that beta 1-adrenoceptors, 5-HT2A/2C-receptors and particularly alpha 1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.
 ...
PMID:Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat. 928 94

1. The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine. 2. Sibutramine (3 and 10 mg kg-1, p.o.) and (+)-fenfluramine (1 and 3 mg kg-1, p.o.) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration. 3. Fluoxetine (3, 10 and 30 mg kg-1, p.o.), and nisoxetine (3, 10 and 30 mg kg-1, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg-1, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration. 4. Venlafaxine (100 and 300 mg kg-1, p.o.) and duloxetine (30 mg kg-1, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration. 5. The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity.
 ...
PMID:Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. 928 14

D-Fenfluramine is a serotonin (5-hydroxytryptamine, 5-HT) releaser and reuptake inhibitor. It is used to study the neurochemical control of feeding and has been used to treat obesity. It has also been employed as a pharmacological tool to study changes in serotonergic function in psychiatric patients. Brain sites activated by D-fenfluramine via the release of 5-HT have been mapped via the expression of the immediate early gene c-fos. Studies in our laboratory have indicated that D-fenfluramine induces Fos in the hypothalamus and cortex through 5-HT release. The present study investigated whether 5-HT released by D-fenfluramine induces Fos expression in the brain by activating 5-HT1A or 5-HT2A/2C receptors. Rats were pretreated either with WAY-100635, a 5-HT1A antagonist, or ritanserin, a 5-HT2A/2C antagonist, prior to d-fenfluramine injection. Blockade of either 5-HT1A or 5-HT2A/2C receptors was not sufficient to suppress the Fos response to D-fenfluramine in any region of the brain examined, including the cingulate cortex, frontal cortex, caudate-putamen, paraventricular nucleus of the hypothalamus, amygdala, and brainstem. These results indicate that Fos response elicited by D-fenfluramine may be mediated by other receptors, in addition to the 5-HT1A or 5-HT2A/2C receptors.
 ...
PMID:The 5-HT1A and 5-HT2A/2C receptor antagonists WAY-100635 and ritanserin do not attenuate D-fenfluramine-induced fos expression in the brain. 959 27

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric alpha 7 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 microM, when fluoxetine was coapplied with ACh, and of 1.6 microM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T alpha 7 mutant nAChR. Furthermore, blockage of mutant alpha 7 receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T alpha 7 mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant alpha 7 receptors; and that the Leu-247T mutation in the channel domain renders the blockage of alpha 7 nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on alpha 7 receptors may be clinically important.
 ...
PMID:Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors. 970 46

Sibutramine is an orally administered centrally acting weight management agent apparently devoid of amphetamine-like abuse potential. Its primary (M2; BTS 54,505) and secondary (M1; BTS 54,354) amine metabolites are pharmacologically active and are thought to induce the natural processes leading to enhancement of satiety and thermogenesis by inhibiting serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) reuptake. In clinical trials, once-daily sibutramine was administered at dosages of < or = 30 mg for < or = 24 weeks and 10 or 15 mg for 1 year in conjunction with reduced calorie intake, increased daily exercise and advice on eating behaviour. Dose-related bodyweight loss was greater with sibutramine than with placebo. Clinical effects were most commonly apparent at dosages > or = 10 mg/day. Weight loss of > 1% within the first month of treatment appears indicative of good long term response with sibutramine. Weight loss was maintained during therapy for 1 year; longer term data are lacking. Weight regain occurred after treatment cessation in studies of < or = 24 weeks' duration; data from longer trials are unavailable. Up to 15% of patients in < or = 6-month studies did not respond to treatment irrespective of dose. Obese patients with type 2 (non-insulin-dependent) diabetes or hypertension lost significantly more mean bodyweight with sibutramine than with placebo, although weight loss was less than that in obese patients without comorbidities. The effect of sibutramine on mean fasting blood glucose levels and plasma lipid levels was unclear. Sibutramine, compared with placebo, statistically significantly increased blood pressure and heart rate in obese patients with or without hypertension when given for up to 12 months. However, after 12 weeks' treatment in hypertensive obese patients, diastolic blood pressure was reduced by similar amounts with sibutramine or placebo. Concerns over potential pressor effects with sibutramine are reflected in the manufacturer's dosage and administration recommendations.
 ...
PMID:Sibutramine. A review of its contribution to the management of obesity. 987 96

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.
 ...
PMID:Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover. 991

The hypothalamic serotonergic system is involved in the regulation of food ingestion and energy metabolism. Since disturbances of both energy intake and expenditure can contribute to obesity, the objective of the present study was to evaluate the serotonergic response stimulated by food ingestion in two different models of obesity: the hyperphagic Zucker and the hypophagic and hypometabolic, monosodium glutamate (MSG) obese Wistar rat. For this we used microdialysis to examine the release of 5-hydroxytryptamine (serotonin, 5HT) and 5-hydroxyindoleacetic acid (5HIAA) in the lateral hypothalamus. Daily intake of MSG-obese rats was 40% lower while that of Zucker obese rats was 60% higher than that of the respective lean controls. In overnight-fasted animals, 20-min microdialysate samples were collected before (basal release) and during a 2-h period of access to a balanced palatable food mash. The animals began to eat during the first 20 min of food access, and food consumption was similar among the four groups in all six individual 20-min periods recorded. Ingestion of food increased 5HT release in all groups. In MSG-obese and lean Wistar rats, 5HT levels were similarly elevated during the whole experimental period. In the Zucker strain, 5HT increments of basal release tended to be higher in obese than in lean rats at 20 and 40 min, and a significantly higher increment was observed at 60 min after food access (40 and 135% for lean and obese, respectively). The area under the curve relating serotonin levels to the 120 min of food availability was significantly higher in Zucker obese (246.7 +/- 23.3) than MSG-obese (152.7 +/- 13.4), lean Wistar (151.9 +/- 11.1), and lean Zucker (173.5 +/- 24.0) rats. The present observation, of a food-induced serotonin release in the lateral hypothalamus of lean Wistar and Zucker rats, evidences that 5HT in the lateral hypothalamus is important in the normal response to feeding. In obese animals, the serotonin response was similar to (in the hypophagic-hypometabolic MSG model) or even higher than (in the hyperphagic Zucker model) that seen in the respective lean controls. This result indicates that the energy homeostasis disturbances of both these obesity models may not be ascribed to an impairment of the acute lateral hypothalamic serotonin response to a dietary stimulus.
 ...
PMID:Lateral hypothalamic serotonergic responsiveness to food intake in rat obesity as measured by microdialysis. 1053 77

Sibutramine (Reductil, Abbott-Knoll, 10 mg and 15 mg) is a new appetite regulator recommended in the treatment of obesity. It is a noradrenaline and 5-hydroxytryptamine reuptake inhibitor which exerts its effects in vivo predominantly via its secondary and primary amine metabolites. Sibutramine is indicated as an adjunctive therapy within a weight management programme in patients with obesity (BMI > or = 30 kg/m2) or in overweight subjects (BMI > or = 27 kg/m2) if other eight-related risk factors are present (dyslipidaemias, diabetes mellitus). In those patients with an inadequate response on initial dose of 10 mg per day (suggested as less than 2 kg weight loss in four weeks), the dose may be increased to 15 mg once daily, providing that sibutramine is well tolerated. Several large-scale randomized clinical trials demonstrated the efficacy of long-term (at least one year) treatment with sibutramine in obese subjects with or without type 2 diabetes. Sibutramine was also shown to help in maintaining long-term weight reduction. Most frequent side-effects are dry mouth and constipation, as well as mild increase in heart rate and arterial blood pressure. The impact of sibutramine on cardiovascular morbidity and mortality of obese nondiabetic and diabetic patients will be studied soon in a large international prospective clinical trial.
 ...
PMID:[Pharma-clinics. Medication of the month. Sibutramine (Reductil)]. 1170 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>