Disease relevance of C07247

• Currently approved drugs for long-term treatment of obesity include sibutramine, which inhibits food intake, and orlistat, which blocks fat digestion [1].
• Measuring the effect of sibutramine for weight loss [2].
• A randomized, double-blind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder [3].
• RESULTS: There was a significant reduction in the number of days with binge episodes in the sibutramine group compared with the placebo group (t203 = 2.14; P =.03); this was associated with an important and significant weight loss (-7.4 kg) compared with a small weight gain in the placebo group (1.4 kg) (t147 = 4.88; P<.001) [3].
• Dry mouth (P =.01) and constipation (P<.001) were more common adverse reactions with sibutramine than placebo [3].
• The results demonstrate that the benefits associated with sibutramine-induced weight losses are obtained at a reasonable cost in each of the settings explored and suggest that sibutramine treatment could be considered as a viable option for pharmacotherapy treatment alongside diet and exercise [4].
• Open-label sibutramine treatment decreased body weight 4.1 kg (P<0.01) and MSNA 17 bursts per minute (P=0.001), and increased diastolic blood pressure 3 mm Hg (P<0.05) and heart rate 8 bpm (P<0.01) [5].
• This trial demonstrated the efficacy of sibutramine in reducing binge eating, weight, and associated psychopathology [6].
• By comparing the sibutramine and placebo groups with analysis of covariance, our data showed a strong effect of sibutramine on weight reduction (7.4+/-1.4 vs. 3.4+/-1.2 kg; P<0.001) and on body fat percentage loss (4.2+/-0.1 vs. 2.1+/-0.1%; P<0.001) in the combined TT+TC carriers [7].

Psychiatry related information on C07247

• Weight-loss medications including sibutramine facilitate weight control in adults and could be used with obese adolescents in combination with behavior therapy (BT) [8].
• This study examined the effectiveness of sibutramine, an approved weight loss agent, in overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder [9].
• Sibutramine and panic attacks [10].
• Factors included in the analysis were initial body weight, the percentage of initial body weight lost, dietary intake, various components of physical activity (measured with the Baecke questionnaire), the type of treatment (sibutramine or placebo), age, and sex [11].
• The combination therapy group also received 10-15 mg sibutramine daily, low-calorie diets using meal replacement products for 1 week every 2 months, and between low-calorie diet weeks, once daily use of meal replacement product and snack bars to replace one usual meal and snack [12].

High impact information on C07247

• OBJECTIVE: To examine whether increased weight loss in obese adolescents is induced when sibutramine is added to a family-based, behavioral weight control program [8].
• Behavior therapy and sibutramine for the treatment of adolescent obesity: a randomized controlled trial [8].
• RESULTS: In intention-to-treat analysis at month 6, participants in the BT and sibutramine group lost a mean (SD) of 7.8 kg (6.3 kg) and had an 8.5% (6.8%) reduction in BMI, which was significantly more than weight loss of 3.2 kg (6.1 kg) and reduction in BMI of 4.0% (5.4%) in the BT and placebo group [8].
• 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood pressure by 2.3 mm Hg (9.4), and pulse rate by 4.1 beats/min (11.9) [13].
• HDL cholesterol concentrations rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p<0.001) [13].

Chemical compound and disease context of C07247

• The effectiveness of sibutramine hydrochloride in treating obesity has been shown in randomized controlled trials [14].
• Weight loss with sibutramine was associated with modest increases in heart rate and blood pressure, small improvements in high-density lipoprotein cholesterol and triglycerides levels, and, among diabetic patients, small improvements in glycemic control [15].
• BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment [16].
• OBJECTIVE: Sibutramine causes weight loss by suppressing the appetite and by promoting energy expenditure, but it can also increase blood pressure through a norepinephrine effect [17].
• Comparing the two treatments under the conventional null hypothesis of equality as a secondary analysis, weight loss at endpoint in patients receiving sibutramine was significantly greater than that achieved with dexfenfluramine (p<0.05) [18].

Biological context of C07247

• The cortical locations of neurons responding to stimulation along the vertical or horizontal visual field meridia were charted on three-dimensional models of the cortex and on unfolded maps of the cortical surface [19].
• Sibutramine-treated patients had small but statistically significant mean increases in diastolic blood pressure (2.0 mm Hg) and pulse rate (4.9 beats/min) compared with placebo-treated patients (-1.3 mm Hg and 0.0 beats/min; P<.05); these changes were similar among African Americans and whites [20].
• OBJECTIVE: We tried to compare the acute thermogenic effect of a single 30-mg dose of sibutramine with placebo on basal energy expenditure (EE) and diet-induced thermogenesis [21].
• Animal studies have shown that sibutramine exerts its effect by enhancing satiety as well as by increasing thermogenesis [21].
• Baroreflex heart rate control was similar with sibutramine and with placebo [16].

Anatomical context of C07247

• RESEARCH METHODS AND PROCEDURES: A total of 15 premenopausal, African American women (age, 29 +/- 5 years; body fat, 38 +/- 7%) completed a randomized, double-blind cross-over design with a 30-mg ingestion of sibutramine or a placebo [22].
• Absence of cardiac valve dysfunction in obese patients treated with sibutramine [23].
• In vitro, sibutramine blocked [(3)H]-dopamine uptake into striatal synaptosomes, with an IC(50) value of 3.8 microM [24].
• RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus [25].
• The parallel findings of a high level of brown adipocyte activation and low parenchymal noradrenergic innervation are discussed and a possible direct effect of sibutramine and/or its active metabolites on peripheral BAT sympathetic nerve terminals is hypothesized [26].

Associations of C07247 with other chemical compounds

• METHODS: After a 2-week run-in period, 60 obese outpatients (body mass index [calculated as weight in kilograms divided by the square of height in meters] 30-45), who met DSM-IV criteria for BED were randomly assigned to receive sibutramine hydrochloride (n = 30), 15 mg/d, or placebo (n = 30) in a 12-week double-blind study at 2 centers [3].
• RESULTS: Sufficient data for the meta-analysis were available for fluoxetine, orlistat, and sibutramine [27].
• OBJECTIVE: To evaluate the effects of sibutramine (15 and 20 mg/day) on weight, metabolic control, and blood pressure in metformin-treated obese subjects with type 2 diabetes [28].
• Additionally, sibutramine, dexfenfluramine, fluoxetine and the 5-HT(2C) receptor agonist chlorophenylpiperazine (mCPP) have all been shown to modify appetite in both lean and obese humans, resulting in reduced caloric intake [29].
• The secondary and primary amines are, however, considerably more active than sibutramine HCl as inhibitors of the uptake of noradrenaline, dopamine and 5-hydroxytryptamine in vitro [30].

Gene context of C07247

• DISCUSSION: The homozygosity/heterozygosity of the PNMT gene was highly predictive of significant weight loss with sibutramine during the first 3 months, which highlights the need for specific pharmacotherapy [31].
• Sibutramine treatment increased sympathetic activity, attenuated the increased ARC NPY, and decreased POMC mRNA levels induced by energy restriction in RV rats [32].
• If also observed in humans, the pharmacological profile of MC4-R agonists would not offer a significant therapeutic advantage over currently used appetite suppressants such as sibutramine [33].
• Sibutramine improves fat distribution and insulin resistance, and increases serum adiponectin levels in Korean obese nondiabetic premenopausal women [34].
• Prediction of successful weight reduction under sibutramine therapy through genotyping of the G-protein beta3 subunit gene (GNB3) C825T polymorphism [35].

Analytical, diagnostic and therapeutic context of C07247

• METHODS: Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates [13].
• EE was measured by indirect calorimetry before and for 5.5 h after sibutramine or placebo administration with or without a 2.1-MJ breakfast [21].
• RESEARCH DESIGN AND METHODS: Controlled clinical trials assessing the effect sizes of sibutramine on weight loss effects on glycemia in obese subjects with type 2 diabetes were identified and reviewed using the Cochrane Library, Medline, EMBASE, and a manual search [36].
• 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 [37].
• Drug therapy for weight loss is available (at present, sibutramine is the only approved appetite suppressant in the United States); however, for most patients already being treated with a psychotropic agent, the risks (such as drug interactions, adverse events, compliance problems) of adding an antiobesity agent probably outweigh the benefits [38].

References