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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sibutramine is a beta-phenethylamine which blocks reuptake of norepinephrine and serotonin. In this clinical study, a group of 173 patients were randomized to treatment with sibutramine at doses of 1, 5, 10, 15, 20 or 30 mg/d and were compared with placebo in a 24-week double-blind trial. There was a dose-dependent reduction in body weight, with doses of 10, 15, 20 and 30 mg being significantly greater than placebo. Weight loss was still continuing in the highest three doses at the end of the study. When drugs were discontinued patients regained weight, as expected. Side effects were generally mild and were most evident in the group treated with the highest dose. These studies suggest that sibutramine may be a valuable new drug for treatment of obesity.
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PMID:A double-blind randomized placebo-controlled trial of sibutramine. 873 60

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.
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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.
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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.
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PMID:Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. 928 14

Sibutramine (SIB), an inhibitor of serotonin and noradrenaline reuptake, has been shown in clinical trials to be associated with a dose-related decrease in bodyweight. This double-blind, placebo-controlled, Latin square crossover study examined whether the effect on bodyweight could be due in part to a reduction in daily food intake. Twelve non-dieting, women with obesity (body mass index of 30.5 to 41.9) received three treatments (0 [matching placebo], 10, or 30 mg SIB/day) for 14 days, with 14-day washout periods in between. On days 7 and 14, participants came to the laboratory to eat breakfast, lunch, and dinner so that daily energy and macronutrient intakes and ratings of hunger and satiety could be measured. Significant reductions occurred in food intake (both grams and energy) over the 14-day study period. On day 7, SIB 30 reduced intake significantly by 1762 kJ (23% reduction from placebo), and on day 14, both SIB 10 and SIB 30 significantly reduced intake compared with placebo (SIB 10, 19% reduction [1490 kJ]; SIB 30, 26% reduction [2079 kJ]). On day 7, the percentage of energy consumed from carbohydrate increased significantly with the 30-mg dose (56.7%) compared with that of placebo (51.4%), with a reciprocal decrease in energy from fat (27.8% to 24%). The results show that SIB reduced energy intake in women with obesity who were not attempting to lose weight.
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PMID:Sibutramine reduces food intake in non-dieting women with obesity. 952 64

Sibutramine (BTS 54 524; N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug. Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline, respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to the actions of the SNRI, sibutramine), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour. Sibutramine reduces food intake by enhancing the physiological response of post-ingestive satiety. This reduction of food intake is a CNS-mediated effect because it is induced by intracerebroventricular injection of sibutramine's potently active secondary and primary amine metabolites (BTS 54 354 and BTS 54 505). Sibutramine increases energy expenditure (thermogenesis) in rats. Once again, whilst fluoxetine and nisoxetine have no thermogenic effect when given alone, the combination of these two selective monoamine reuptake inhibitors profoundly enhances thermogenesis, demonstrating a synergistic interaction of 5-HT and noradrenaline neurotransmission in the regulation of energy expenditure. Sibutramine-induced thermogenesis is abolished by administration of a high non-selective dose of atenolol or ICI 118,551 which blocks beta3-adrenoceptors in addition to beta1- and beta2-adrenoceptors, but not by a low dose of atenolol or ICI 118,551 which blocks beta1- and beta2-adrenoceptors, respectively. Glucose utilization studies demonstrate that sibutramine-induced thermogenesis is mediated via selective sympathetic activation of brown adipose tissue, and it is a centrally mediated effect because it is prevented by pretreating the animals with the ganglionic blocker, chlorisondamine. The SNRI mode of action of sibutramine is clearly differentiated from those of the two major classes of anti-obesity drugs, viz, the 5-HT releasing agents, for example, fenfluramine and dexfenfluramine, and the noradrenaline + dopamine-releasing agents, for example, dexamphetamine. In the case of the 5-HT-releasing agents, this mechanism has been linked in animal studies to profound and prolonged depletion and dysfunction of CNS 5-HT neurons. With noradrenaline + dopamine-releasing agents, it is the enhancement of central dopaminergic function which is believed to be responsible for their stimulant, rewarding and reinforcing properties and it is their releasing mechanism which makes them such powerful psychostimulant drugs of abuse. By utilizing noradrenaline and 5-HT for its anti-obesity effects, sibutramine is differentiated from other weight-reducing drugs which act through either 5-HT alone or noradrenaline + dopamine. In addition, sibutramine is further differentiated because it enhances monoamine function by reuptake inhibition, rather than by monoamine release.
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PMID:Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. 975 40

Obesity develops from a combination of low energy expenditure and increased energy intake. The current treatment strategy aims at reducing energy intake by a low-fat, high-complex-carbohydrate diet and increasing energy expenditure by increased physical activity. In a major proportion of obese patients, however, this treatment is ineffective and does not produce a satisfactory long-term result. Among the risk factors for weight gain and for an unsuccessful diet-induced weight loss in obese patients is a low metabolic rate, which can be attributed in part to a low sympathetic nervous system (SNS) activity. The low SNS activity may also have an adverse effect on appetite control. Pharmacological enhancement of the SNS may have a role in the normalization of the autonomic control of the disturbed energy balance in obesity. In animal studies, sibutramine causes a negative fat balance and weight loss, by a dual mechanism of action. Sibutramine enhances satiety by a combined noradrenergic and serotonergic effect, thus decreasing food intake. In addition, sibutramine stimulates thermogenesis by activating the SNS. Recent studies have demonstrated that sibutramine also enhances satiety, stimulates thermogenesis and diminishes the weight-loss induced decline in energy expenditure in humans, so the dual effect on energy balance seems to be responsible for the efficient fat loss and weight maintenance found in clinical trials on obese patients. In conclusion, sibutramine can contribute to normalization of the disturbed energy balance in obesity, by enhancing satiety and by the stimulation of energy expenditure.
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PMID:Sibutramine and energy balance. 975 41

Visceral adiposity has a strong and independent association with obesity and its related co-morbidities, particularly metabolic complications such as cardiovascular disease and type II diabetes. Waist circumference and waist-to-hip ratio (WHR) are both secondary indicators of visceral obesity. This paper examines the effect of sibutramine, a new serotonin and noradrenaline re-uptake inhibitor, on weight reduction and changes in fat distribution. A meta-analysis of four long-term, placebo-controlled, double-blind studies showed significantly greater mean decreases in waist circumference in sibutramine-treated subjects compared with placebo (P < 0.001). Similar results were seen for WHR, with 15 mg sibutramine daily producing a significant reduction of 0.02 compared with placebo (P < 0.02). Changes in fat distribution have been examined using computerised tomography (CT) scans as part of the Sibutramine Trial of Obesity Reduction and Maintenance (STORM). Preliminary results showed a mean weight loss from baseline of 11.2 +/- 6.3 kg after 6 months of 10 mg sibutramine treatment. Decreases in total abdominal fat (18%), total subcutaneous fat (17%) and total visceral fat (22%) were observed, and there was a significant increase in the subcutaneous-to-visceral fat ratio (P = 0.04). These changes in fat levels and distribution were associated with improvements in related risk factors such as fasting blood glucose and insulin levels, and blood pressure. In conclusion, sibutramine produces statistically and clinically significant decreases in waist circumference and WHR, and preferentially reduces visceral fat levels.
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PMID:Sibutramine and fat distribution: is there a role for pharmacotherapy in abdominal/visceral fat reduction? 975 42

Sibutramine is a serotonin and noradrenaline re-uptake inhibitor (SNRI) which induces weight loss via a dual mode of action: enhancing both satiety and energy expenditure. Sibutramine exerts its in vivo effects predominantly via its secondary and primary amine metabolites. Following oral ingestion, sibutramine is well absorbed and undergoes extensive first pass metabolism. Sibutramine produces statistically and clinically significant, dose-related weight loss over the range 5-30 mg once daily; active weight loss occurs for 6 months. Long-term studies of up to 1 year have found that weight loss is maintained with continued sibutramine therapy. Sibutramine-induced weight loss is associated with beneficial changes in obesity-related risk factors, such as serum lipids, uric acid levels, and glycaemic control (in patients with type 2 diabetes). Subcutaneous/visceral fat ratio was found to increase significantly under sibutramine treatment, indicating that relatively more visceral fat than subcutaneous fat is lost. Sibutramine is well tolerated; side-effects are generally mild, non-treatment limiting, and consistent with the known mechanism of action of the drug. Overall, studies have found sibutramine to be an effective weight loss agent with a good safety profile.
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PMID:Anti-obesity drugs: what does sibutramine offer? An analysis of its potential contribution to obesity treatment. 979 80

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.
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PMID:Sibutramine. A review of its contribution to the management of obesity. 987 96


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