UMLS:C0028754 - FACTA Search

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Query: UMLS:C0028754 (obesity)
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Individuals with a low activity of the sympathoadrenal system are at high risk of weight gain and obesity, and obese patients with low sympathetic activity lose less weight on dietary reduction programs. Treatment with sibutramine may be particularly efficient in these patients, because sibutramine normalizes sympathoadrenal activity and thereby stimulates thermogenesis. By a combined stimulation of adrenergic and serotoninergic pathways satiety is enhanced and energy intake is suppressed. This dual effect of sibutramine on energy balance seems to be responsible for the efficient weight loss and improved weight maintenance observed in clinical trials with obese patients. In conclusion, sibutramine can contribute to normalization of the disturbed energy balance in obesity by enhancing satiety and by stimulation of energy expenditure, thereby producing weight loss and an important improvement in risk factor profile and comorbid conditions. Meantime sibutramine is on the market in the United States under the trade name Meridia.
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PMID:[Sibutramine, an upcoming drug for weight loss acting on energy consumption and energy expenditure]. 987 91

1. The thermogenic activity of the serotonin and noradrenaline reuptake inhibitor sibutramine (BTS 54524; Reductil) was investigated by measuring oxygen consumption (VO2) in rats treated with sibutramine or its two pharmacologically-active metabolites. 2. Sibutramine caused a dose-dependent rise in VO2, with a dose of 10 mg kg(-1) of sibutramine or its metabolites producing increases of up to 30% that were sustained for at least 6 h, and accompanied by significant increases (0.5-1.0 degrees C) in body temperature. 3. Based on the accumulation in vivo of radiolabelled 2-deoxy-[3H]-glucose, sibutramine had little or no effect on glucose utilization in most tissues, but caused an 18 fold increase in brown adipose tissue (BAT). 4. Combined high, non-selective doses (20 mg kg(-1)) of the beta-adrenoceptor antagonists, atenolol and ICI 118551, inhibited completely the VO2 response to sibutramine, but the response was unaffected by low, beta1-adrenoceptor-selective (atenolol) or beta2-adrenoceptor-selective (ICI 118551) doses (1 mg kg(-1)). 5. The ganglionic blocking agent, chlorisondamine (15 mg kg(-1)), inhibited completely the VO2 response to the metabolites of sibutramine, but had no effect on the thermogenic response to the beta3-adrenoceptor-selective agonist BRL 35135. 6. Similar thermogenic responses were produced by simultaneous injection of nisoxetine and fluoxetine at doses (30 mg kg(-1)) that had no effect on VO2 when injected individually. 7. It is concluded that stimulation of thermogenesis by sibutramine requires central reuptake inhibition of both serotonin and noradrenaline, resulting in increased efferent sympathetic activation of BAT thermogenesis via beta3-adrenoceptor, and that this contributes to the compound's activity as an anti-obesity agent.
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PMID:Thermogenic effects of sibutramine and its metabolites. 1021 44

Physicians have struggled with the pharmacological treatment of obesity. In the past, thyroid hormone was often used inappropriately. Dangerous drugs such as dinitrophenol and amphetamines were prescribed, with serious side effects. In the 1980s, a 3 1/2-year study using antiobesity medications with different mechanisms of action supported the theory that patients treated with combination therapy experienced greater weight loss than the placebo-treated patients and that those who remained on therapy were more likely to keep the weight off. Thus, physicians began prescribing "fen-phen" to their patients in the mid-1990s. In 1997, manufacturers voluntarily withdraw the fenfluramines from the market after study results linked their use with valvular heart disease. Since then, two new drugs with different mechanisms of action have been approved for use by the FDA. Sibutramine (Meridia) is a serotonin-norepinephrine reuptake inhibitor acting on the appetite center in the hypothalamus, and orlistat (Xenical) is a pancreatic lipase inhibitor. Research on antiobesity drugs continues. More than 30 potentially new drugs are in various stages of research. It could be years, however, before any of them are proven useful and safe. Antiobesity pharmacology is meant to be used as a tool to treat the disease. Lifestyle changes in the form of diet and exercise patterns are still the crux of therapy.
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PMID:Pharmacological treatment of obesity. Past, present, and future. 1112 76

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.
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PMID:[Pharma-clinics. Medication of the month. Sibutramine (Reductil)]. 1170 9

A growing number of obese people throughout the world have become a health-economic problem. Obesity and overweight are significant risk factors causing increased morbidity and mortality in obese people. Nevertheless, a marked improvement in the prognosis is achieved by a 5-10% decrease in body weight. Since 1 July 2002, two preparations for long-term therapy of obesity have been registered in the Czech Republic: Xenical (orlistat) and Meridia (sibutramin). Long-term randomized double-blind studies have shown that a decrease of 4.4 kg in weight within a year is achieved by 10 mg sibutramin administration, a decrease of 3.2-6.4 kg in weight within a year is achieved by 15 mg sibutramin administration, a decrease of 7.4-9.1 kg in weight within a year is achieved by orlistat administration, and placebo administration causes changes in weight ranging from -6.5 kg to +0.94 kg. A cost-to-effectiveness comparison has revealed that in one year the direct costs (ORC) of a decrease in body weight by 1 kg after deduction of the placebo effect make 9,817 CZK to 22,078 CZK (the supplementary payment of the patient being 2698 CZK to 7722 CZK) in sibutramin treatment, and 9101 CZK to 13,085 CZK (the supplementary payment of the patient being 632 CZK to 909 CZK) in orlistat treatment.
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PMID:[Long-term drug therapy of obesity in 2002--pharmacoeconomic aspects]. 1461 5

We related the effect of the satiety enhancing drug sibutramine (Meridia, Reductil) on food intake to Rorschach Comprehensive System (Exner, 1991, 1993) personality factors. A placebo-controlled crossover, within-subjects design (n = 36) was used. Food intake after 2 weeks in the sibutramine and placebo conditions was assessed with a test meal using the VIKTOR (Cabmek, Stockholm, Sweden) setup, a computerized eating monitor. Building on baseline VIKTOR measurements, we had earlier studied the microstructure of eating (Elfhag, Barkeling, Carlsson, & Rossner, 2003). In this study, a model including Afr, MOR, and Populars could explain the variance in the effect of sibutramine. Sibutramine may reduce food intake in single test meals for participants whose appetite is prompted by external stimuli including food cues, suggested by the Affective ratio. Distress related to the body in obesity seen in damaged self-imagery (MOR) and adjustment to social expectations (Populars) could also have a moderating effect on the participants' consumption of test meals in an experimental design. Bodily concern (An + Xy) was also related to sibutramine response in univariate analyses.
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PMID:Food intake with an antiobesity drug (sibutramine) versus placebo and rorschach data: a crossover within-subjects study. 1504 22

In the normal population, the prevalence of obesity is almost 20%. It is a condition influenced by genetic factors, so that individual behavior cannot be regarded as its sole cause. The amount of food is essentially determined by the hormone leptin, the feedback regulation of which can be disturbed by a modification of the molecule or a mutation of the receptor. A further important determinant is energy consumption, which is subject to large individual variations, which partly result from thermogenesis. With regard to the fat distribution, it is concentrated on the trunk in the android form as compared to the hips in the gynecoid form. The android form is subject to a higher incidence of cardiovascular morbidity and mortality. The indirect determination of body fat by measuring the body mass index (weight [kg]/body weight [m(2)]) is hence less reliable than measuring the waist (women > 80 cm, men > 94 cm). The effects of generalized obesity on cardiovascular function are chiefly an increase of blood volume and an eccentric left ventricular hypertrophy. This first of all results in diastolic dysfunction, which can give rise to a disturbance of systolic function in left ventricular dilatation. Concentric hypertrophy develops in the presence of arterial hypertension. This is twice as frequent in obese patients than in the normal population, which is due to increased activity of the sympathetic nervous system and stimulation of the renin-angiotensin system. A disturbance of lipid metabolism is observed four to six times more frequently. The qualitative change in LDL fraction with a raised concentration of low density LDL particles appears to be of crucial importance. With increasing fat mass, the sensitivity to insulin is lowered, so that in obesity the risk of developing diabetes mellitus type 2 is tripled. Since there has been a dramatic increase in the numbers of overweight children and adolescents (from 10.5% to 15.5% within the past five years), prevention programs should be started in good time. A reduction in calorie intake and an altered dietary composition (55% complex carbohydrates, 30% fat and 15% to 20% protein) on the one hand, and increased physical activity on the other hand continue to be the central components. The latter is especially effective when it regularly gives rise to an increased turnover of fatty acids as a result of an increased energy metabolism at moderate intensity. This leads to adaptation, i. e. an increase in the activity of lipoprotein lipase. If prevention programs and/or changes in lifestyle do not give rise to the desired weight reduction, medication is indicated in some adults. Sibutramine (Reductil and orlistate (Xenical) lead to an additional weight loss of up to 10%. However, consistent treatment of any cardiovascular risk factors present is more important. Treatment of arterial hypertension is of greatest prognostic significance, especially in concomitant diabetes mellitus. In individual cases and after thorough discussion of indication surgical options should be considered.
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PMID:[Obesity and cardiovascular diseases-theoretical background and therapeutic consequences]. 1524 61

The conventional cardiovascular risk factors such as smoking, hyperlipoproteinemia, arterial hypertension and diabetes are responsible for nearly 75% of myocardial infarction events. Since obesity is associated with a two- or threefold increased risk for arterial hypertension and diabetes, the reduction of body weight presents a basic and causal approach. Indeed 60% of the German population is overweight, and every fifth person has obesity. A low-calorie diet and higher quality nutrition as well as increased physical activity is the main therapeutic strategy. The maximum fat supply in a 1200 kcal/d diet should be less than 70 g. Training should be of low intensity, below the anaerobic threshold (50-70% of VO2max), in order to obtain optimal metabolic effect in combination with maximal fat reduction. Should the newly adopted lifestyle not result in a satisfactory loss of weight, medication can be applied in addition. Sibutramin (Reductil) or Orlistat (Xenical) can in individual cases be of help and lead to a further weight loss of up to 10%. It has been demonstrated that such weight loss can evoke the same positive effects of glucose metabolism in patients with impaired glucose tolerance as can metformin. Nevertheless, from a prognostic point of view, in patients with coronary artery disease and manifest diabetes, insulin therapy is required. Although arterial hypertension carries with it four times the risk of stroke and twice that of myocardial infarction, the majority of the population does not receive adequate treatment. Even after an acute cardiac event, in every second patient, an elevated blood pressure of > 140/90 mm Hg at the beginning of the rehabilitation period is found. In approximately 80% of the patients, a guideline-based therapy can be achieved during the follow-up phase. Comparable results apply to LDL-cholesterol patients as well. For patients with chronic coronary artery disease, it is highly important that medication and change in lifestyle be continued. Patients need to receive standardized information and ongoing medical care.
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PMID:[Modification of conventional risk factors in coronary artery disease]. 1528 4

The aim of the study was to study the role of initial eating behaviour for subsequent weight loss in treatment with sibutramine (Reductil, Meridia) an anti-obesity drug enhancing satiety, and also to assess changes in mood during the treatment. The participants were 36 obese patients with a mean BMI of 39 kg m(-2). Eating behaviour was assessed with the three factor eating questionnaire (TFEQ), and depressive features with the comprehensive psychopathological rating scale (CPRS). Sibutramine (15 mg) was administered daily. The TFEQ restraint scale was negatively related to 6 months weight loss. In particular, strategic dieting behaviour and a more controlled attitude towards self-regulation were negatively related to weight loss. A positive non-placebo controlled change in mood was found already after 2 months treatment. The changes in mood were not related to the weight loss. Patients with more unrestrained eating seem to have reduced their amount of food intake more radically with enhanced satiety, manifested by greater weight loss. Physiologically enhanced satiety could have the greatest weight loss effect for patients whose eating is more governed by hunger drives and appetite rather that by conscious efforts and cognitive control.
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PMID:Sibutramine treatment in obesity: initial eating behaviour in relation to weight loss results and changes in mood. 1562 62

Sibutramine is an anti-obesity drug sold as a racemic mixture under the trademark Meridia or Reductil. With the aim of evaluating the stereoselectivity in phase I of sibutramine biotransformation, the formation of the main metabolites from R -sibutramine, S -sibutramine and rac-sibutramine was studied in rat microsomes and primary cultures of hepatocytes. A novel analytical method for the determination of sibutramine and its phase I metabolites in culture medium and microsomal incubates using isocratic reversed-phase liquid chromatography with UV detection was developed. Only two metabolites, mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2), were found in the rat microsomes incubated with sibutramine and NADPH. The kinetics of M1 and M2 formation slightly differed depending on the enantiomeric form of the sibutramine used. The stereoselectivity in sibutramine biotransformation was much more evident in primary cultures of rat hepatocytes. While R-sibutramine incubation led to the formation of M1 and M2 metabolites only, the incubation of S-sibutramine or rac-sibutramine (to a lesser extent) resulted in four major metabolites (M1, M2, M3 and M4) and 2 or 3 minor metabolites. On the basis of our results, R-sibutramine might represent the more advantageous sibutramine enantiomer from the pharmacokinetic standpoint.
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PMID:The stereoselective biotransformation of the anti-obesity drug sibutramine in rat liver microsomes and in primary cultures of rat hepatocytes. 1580 98

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