1999;7: 189-198. Objective: Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. Research Methods and Procedures: Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia. Discussion: Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.
Results
We tested the safety and efficacy of sibutramine, 5 and 20 mg, and placebo on weight loss. Medication was added to caloric restriction, behavior modification, and exercise in a parallel-group, double-blind clinical trial. Participants were 130% to 180% of ideal body weight and in good health. The study lasted 12 weeks over Thanksgiving, Christmas, and New Year's Day. Weight loss during 8 weeks of study medication was: placebo, 1.4 +/- 2.1 kg (n = 19); 5 mg sibutramine, 2.9 +/- 2.3 kg (n = 18); and 20 mg sibutramine, 5.0 +/- 2.7 kg (n = 18) (p less than 0.05 sibutramine, 5 and 20 mg, versus placebo; p less than 0.05 sibutramine, 20 mg versus 5 mg). There is a significant dose-effect relationship. Five participants left the study before completion, all because of adverse events; placebo (one patient), 5 mg sibutramine (one patient), and 20 mg sibutramine (three patients). Sleep difficulties were noted by eight participants (20 mg sibutramine, seven patients; 5 mg, one patient; and placebo, no patients). Six of 21 participants receiving 20 mg complained of irritability, unusual impatience, or "excitation." Sibutramine, 5 and 20 mg, added to a multimodal program assisted participants in losing weight.
Sibutramine HCl, a monoamine reuptake inhibitor type of antidepressant, was administered to healthy male volunteers as either a single dose (12.5 or 50 mg) or repeated treatment (5-20 mg once daily or 15 mg twice daily). Plasma, obtained at regular intervals during and after sibutramine HCl or placebo treatment, was assayed in vitro for its ability to inhibit the uptake of [3H]-noradrenaline (NA) by rat cortical synaptosomes, [3H]-5-hydroxytryptamine (5HT) by human platelets and [14C]-dopamine (DA) by rat striatal synaptosomes. After both single and repeated sibutramine HCl administration, the rank order of uptake inhibition was [3H]-NA greater than [3H]-5HT greater than [14C]-DA. The level of monoamine uptake inhibition increased on daily administration to a plateau 4-6 days after initiation of treatment, for example, approximately 60% and 40% inhibition of [3H]-NA and [3H]-5HT, respectively, following 15 mg sibutramine HCl twice daily. The pattern of monoamine uptake inhibition following sibutramine HCl administration to man is similar to that observed in sibutramine HCl-treated rats, and probably at least partly reflects inhibition of uptake by drug metabolites in both species. The inhibition of monoamine uptake following sibutramine HCl administration to man is consistent with an antidepressant effect.
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