Effect Of Sibutramine Research Articles

Tissue and Circulating MicroRNAs 378 and 142 as Biomarkers of Obesity and Its Treatment Response.

Promising approaches to the treatment of obesity include increasing energy expenditure and slowing down fibrogenesis of adipose tissue. The neurotransmitter reuptake inhibitor sibutramine affects appetite and activates lipolysis in a catecholaminergic way. MicroRNAs (miRs) are considered as biomarkers of molecular genetic mechanisms underlying various processes. The profile of a number of miRs is altered in obesity, both in the circulation and in adipose tissue. The aim of this study was to assess the expression levels of miRs (hsa-miR-378a-3p, hsa-miR-142-3p) by real-time polymerase chain reaction in subcutaneous adipose tissue (SAT) and in plasma in patients with different degrees and duration of obesity and during sibutramine therapy. This study included 51 obese patients and 10 healthy subjects with normal weight who formed a control group. The study found that, before treatment, obese patients had no significant difference in the expression level of miR-378 in SAT and plasma compared to the control group, while the expression of miR-142 was significantly decreased in SAT and increased in plasma. A significant elevation in miR-378 expression level was noted in patients with first-degree obesity and duration of less than 10 years, and the decline in miR-142 increased with the duration of obesity. These data indicate a maximal increase in the expression of the adipogenesis inducer miR-378 in the early stages of obesity, a progressive decrease in the expression of the fibrogenesis inhibitor miR-142 in SAT with growth of duration of obesity and the likely presence of antifibrogenic effects of sibutramine realized through miR-142 activation.

English

Obesity is a global problem due to widespread consumption of high fat diet (HFD) with implications to well-being. This study was to investigate the modulatory effect of sibutramine and normal diet on obesity-induced alteration in kidney functions and adipokines in Wistar rats. Hundred rats were divided into four groups of 25 each and fed with either normal rat chow (NRC) (group I, control group, n=25) or HFD (n=75). Obese rats were subjected to treatment with HFD (group II, Obese + HFD, n=25), Sibutramine and NRC (group III, Obese + Sibutramine + NRC, n=25); and NRC (group IV, Obese + NRC, n=25) for another 12 weeks. Five rats from each group were sacrificed, urine and blood samples collected for baseline values after the acclimatization period. Similarly, at post induction, 4, 8 and 12 weeks urine and blood samples were collected from 5 rats per group for investigations. Induction of obesity significantly (p<0.05) increased mean Lee index, urine albumin, urine albumin:creatinine ratio, serum interleukin (IL)-1β, IL-6, tumor necrotic factor (TNF)-α, interferon (IFN)-γ, leptin and decreased urine creatinine and serum adiponectin compared to control. Sibutramine treatment and withdrawal of HFD ameliorated these effects. Obesity induced renal impairment by deranging renal and inflammatory biomarkers investigated in this study. These adverse effects on the kidney were mitigated by sibutramine10 mg/kg/day and NRC by resisting the disturbance, thereby showing nephron-protective effect. The combined treatment of sibutramine with NRC reduced progression of kidney disease to a lesser extent than NRC alone suggesting nonsynergistic effect. Key words: Adipokines, cytokines, diet modification, obesity, renal function, sibutramine, urine albumin creatinine ratio.

Study of the effect of sibutramine on central mechanisms of regulation of eating behavior in patients with obesity by means of fMRI. Preliminary results

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Impact of timing of the anorexigen sibutramine administration on reproductive end-points of male rats.

Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10mg/kg/d) or vehicle for 15days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action.

Effect of Sibutramine on Plasma C-Reactive Protein, Leptin and Adipon ectin Concentrations: A Systematic Review and Meta-Analysis of Randomized Contr olled Trials.

Sibutramine is an anti-obesity medication whose effects on weight loss have been widely explored. Moreover, limited number of studies also evidenced its correlates on adipokines and proinflammatory markers; however, their results have not been conclusive. Hence, a systematic review and meta-analysis of available evidence was conducted in order to calculate the effect size of sibutramine therapy on C-reactive protein (CRP), leptin and adiponectin concentrations. Seven randomized clinical trials with a total of 601 subjects met the eligibility criteria. Random effect meta-analysis evidenced a significant decrease in plasma levels of CRP and leptin (weighted mean difference [WMD] -15.58%, 95% confidence interval [95%CI]: -28.84, -2.33, p=0.021 and WMD -9.25, 95%CI: -15.73, -2.78, p=0.005, respectively) and increase of adiponectin (WMD 9.86%, 95%CI: 1.76, 17.96, p=0.017) following sibutramine therapy. Subgroup analysis showed a greater CRP-lowering effect of sibutramine with doses <15 mg/day (WMD -17.26%, 95%CI: -31.02, -3.5, p=0.014) compared with doses .15 mg/day (WMD 6.01%, 95%CI: -43.38, 55.40, p=0.811). In meta-regression analysis, changes in CRP were found to be independent of baseline or percentage change in body mass index. These results suggest a significant improvement of plasma CRP, leptin and adiponectin levels following treatment with sibutramine. Possible impacts and relevance of these alterations on cardiovascular risk profile remain to be clarified, especially in post-hoc analyses of sibutramine outcome trials among people without pre-existing cardiovascular disease.

EFFECTS OF SIBUTRAMINE AND GREEN COFFEE ON THE HISTOLOGICAL AND ULTRASTRUCTURAL ALTERATIONS IN THE TESTES OF RATS INDUCED BY OBESITY

Obesity is a multi-factorial chronic disorder which causes some serious problems. Sibutramine is anti-obesity drug with established efficacy in sustained weight reduction, but it has a side effect on blood pressure and heart rate elevation. The present study aimd to pinpointing the effects of sibutramine and green coffee in ameliorating the histological and ultrastructural disorders in the testes of rats induced by obesity. This study was assessed in male albino rats (120-150 g). The rats were divided into four groups: the 1st group received a normal diet and acted as a control negative, the 2nd high fat diet (HFD) group acted as control positive, the 3rd HFD group treated with sibutramine (10 mg/kg body weight/day), and the 4th HFD group treated with green coffee (100 mg/kg body weight/day). The present histological study revealed that sibutramine caused histopathological changes in the testes of obese rat including vacuolation, maturation arrest and exfoliation of germ cells in the lumina of the seminiferous tubules. Moreover, congestion of the intertubular blood vessels and proliferation of Leydig cells in the interstitial tissue were also observed. Ultrastructurally, the boundary tissue of some tubules showed marked changes; it was folded and thickened. Sertoli cells showed cytoplasmic vacuolation, vacuolated mitochondria, increased number of lysosomes and their nuclei showed signs of pyknosis. Moreover, Leydig cells revealed vacuolation and decrease in the number of lipid droplets. On the other hand, treatment of the obese rats with green coffee induced great recovery of the damaged testicular tissues. This improvement may be due to the antioxidant properties and scavenging abilities of green coffee against active free radicals.

Effect of sibutramine on cardiovascular events when administered in routine clinical practice

Effect of sibutramine on cardiovascular events when administered in routine clinical practice

A descriptive study to provide evidence of the teratogenic and cellular effects of sibutramine and ephedrine on cardiac‐ and liver‐tissue of chick embryos

Exposure to drugs during pregnancy is a major concern, as some teratogenic compounds can influence normal foetal development. Although the use of drugs during pregnancy should generally be avoided, exposure of the developing foetus to teratogens may occur unknowingly since these compounds may be hidden in products that are being marketed as "all natural." The aim of the current study was to investigate the possible teratogenic and cellular effects of sibutramine-a serotonin-norepinephrine reuptake inhibitor used in the treatment of obesity-on the heart and liver tissue of chick embryos. Ephedrine was used as a positive control. The chick embryo model was chosen because it has been used in studying developmental and experimental biology and teratology with great success. The embryos were exposed to three different concentrations of sibutramine and ephedrine respectively. The results obtained revealed that both compounds exhibited embryotoxicity when compared to the control groups. Liver and heart tissue of the exposed embryos was severely affected by these compounds in a dose-related manner. Morphology similar to that of muscle dystrophy was observed in the heart, where the muscle tissue was infiltrated by adipose and connective tissue. Severe liver steatosis was also noted. A more in-depth investigation into the molecular pathways involved might provide more information on the exact mechanism of toxicity of these products influencing embryonic development.

Sibutramine, a serotonin–norepinephrine reuptake inhibitor, causes fibrosis in rats

Sibutramine hydrochloride monohydrate is a weight loss agent indicated for the treatment of obesity. Although it has been banned from most markets, studies are still relevant as it is often a hidden ingredient in herbal and over the counter slimming products. Sibutramine induces liver fibrosis with steatosis in female Sprague-Dawley rats fed a high-energy diet without significant weight gain. In this study, using the same animal model, the effect of Sibutramine on lung morphology was investigated using histological evaluation of the terminal bronchiole and transmission electron microscopy evaluation of the respiratory tissue. From these results Sibutramine was found to induce lung fibrosis in Sprague-Dawley rats as increased collagen synthesis, mast cell accumulation and aggregates of Bronchus Associated Lymphoid Tissue (BALT) in the terminal bronchiole as well as increased collagen deposition in the respiratory tissue was seen.

English

Grapefruit (Citrus Paradise, family Rutaceae) is a citrus fruit that is low in calories and rich in dietary fibers. Sibutramine (Sibutramine hydrochloride monohydrate) is an anti-obesity drug that enhances satiety. The effect of grapefruit juice and sibutramine on body weight and neurotransmitters controlling appetite was investigated in obese rats. &nbsp;Rats were assigned to two dietary groups for 3 weeks; control group (n=6) was fed commercial standard pellets diet and obese group (n=24) was fed cafeteria diet (hypercaloric diet consisting of highly palatable food). The effect of sibutramine and grapefruit juice was studied on obese rats. Statistical difference and interactions were evaluated through one-way analysis of variance test (one-way ANOVA) followed by Dunnett&rsquo;s test was used for means of different groups. For all statistical tests done, a 0.05 level of probability was used as the criterion for significance. Grapefruit juice produced its weight reduction effect after 1 week of administration and lasted till the end of the experiment and did not affect brain neurotransmitters. Sibutramine produced its weight reduction effect after 1 week of administration and lasted for only 2 weeks and produced an increase in brain noradrenaline while grapefruit juice produced its effect from the first week till the end of the study. It can be concluded that grapefruit juice is better than sibutramine since its effect lasted till the end of the experiment and also did not affect brain noradrenaline. &nbsp;Key words: Obesity, sibutramine, grapefruit juice, cafeteria diet.

The Effect of Sibutramine, a Serotonin-Norepinephrine Reuptake Inhibitor, on Platelets and Fibrin Networks of Male Sprague-Dawley Rats: A Descriptive Study

Sibutramine is used in the treatment of obesity due to its ability to influence feelings of hunger and satiety by inhibiting the re-uptake of serotonin and noradrenalin in the central nervous system (CNS). Sibutramine use has been associated with numerous adverse events in particular cardiovascular complications possibly due to the formation of thrombi. This ultrastructural descriptive study investigated the effect of sibutramine on blood coagulation, specifically the effect on morphology of platelets and fibrin networks using scanning electron microscopy. Male Sprague–Dawley rats treated with either a recommended therapeutic dose [low dosage 1.32 mg/kg] or a toxicological higher dose [high dosage 13.2 mg/kg] of sibutramine for 28 days were used and compared to control animals. Blood samples were collected and plasma smears were prepared for platelet evaluation. Following the addition of thrombin to the plasma samples, the morphology of the fibrin clots was evaluated. Platelet evaluation by scanning electron microscopy revealed morphology typical of a prothrombotic state with a characteristic excessive platelet activation in both low-dose (LD) and high-dose (HD) rats. The fibrin clots of sibutramine-treated rats, LD and HD revealed fused thick fibers with thin fibers forming a net-like structure over the thick fibers which differ considerably from the organized structure of the control animals. It can be concluded that sibutramine alters the ultrastructure of platelets and fibrin networks creating a prothrombotic state.

Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet.

The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes.

Monoamine reuptake site occupancy of sibutramine: Relationship to antidepressant-like and thermogenic effects in rats

Sibutramine was formerly marketed as an anti-obesity agent. The current study investigated the relationships between monoamine reuptake site occupancy for sibutramine and both its antidepressant-like efficacy and thermogenic effects. Sibutramine’s effects on locomotor activity (LMA) and food intake were also evaluated. Sibutramine occupied monoamine reuptake binding sites with the rank order of potency of NET>SERT>DAT; at 10mg/kg, po, occupancy was 95% NET, 81% SERT and 73% DAT. Sibutramine produced antidepressant-like behavior in the forced swim test; at the lowest effective dose (3mg/kg, po) occupancy was 61%, 90% and 23% at SERT, NET and DAT sites, respectively. Sibutramine also increased body core temperature in a dose- and time-dependent manner; at the lowest effective dose (30mg/kg) SERT, NET and DAT occupancies were respectively 78%, 86% and 59%. A significant decrease in food consumption was observed at 3 and 10mg/kg, po. LMA was increased at ≥10mg/kg, sc. The relationship between efficacy in the FST and occupancy was also determined for citalopram, fluoxetine and reboxetine. Similarly, the relationship between thermogenesis and target occupancy for several single or double/triple reuptake inhibitors was measured and showed that >40–50% DAT binding was required for thermogenesis. Thermogenesis was blocked by the D1 antagonist SCH39166 (3mg/kg, sc). Our findings indicate that the antidepressant-like effect of sibutramine may result from additive or synergistic actions on the three reuptake binding targets. At higher doses, sibutramine produces thermogenesis; DAT inhibition and activation of dopamine D1 receptors are required for this effect.

Sibutramine in the treatment of antipsychotic-induced weight gain

Weight gain represents a frequent side effect of antipsychotic drug treatment. The current trial investigated the effect of add-on treatment with sibutramine in schizophrenia outpatients who had gained more than 7% of weight during the course of treatment. This 24-week placebo-controlled study evaluated the effects of sibutramine added to ongoing antipsychotic treatment. Weight, waist-hip ratio, BMI, blood pressure/pulse and ECG were monitored regularly. In addition, several laboratory tests were performed. Psychopathological symptoms and side effects were assessed frequently. Fifteen patients were assigned randomly to add-on treatment with sibutramine 10 mg or placebo. The two groups did not differ in weight, sociodemographic, or clinical data. Eleven patients were considered for statistical analysis. Significant weight loss was observed in the sibutramine group (mean = -6.1 kg), whereas patients on placebo experienced a mean weight gain of 1.9 kg. A reduction in HbA1c was apparent in the sibutramine but not in the placebo group. No significant between-group differences were found in changes in psychopathology or drug safety. This pilot trial suggests that adjunctive treatment with sibutramine may be safe and effective in schizophrenic patients with antipsychotic-induced weight gain.

English

In this study, the effect of sibutramine and carnitine on 5-HIAA and GSH levels in brain regions of malnourished rats was analyzed. Twenty-four rats were fed with a normal protein diet (23%) and another similar group with protein starvation diet (7%). The animals of both groups were re-assigned into four groups of 6 animals per group and treated for 10 days as follows: group 1, saline solution; group 2, sibutramine (10 mg/kg); group 3, carnitine (500 mg/kg); and group 4, sibutramine (10 mg/kg) + carnitine (500 mg/kg). The animals were sacrificed at the end of treatment and their cerebrum, cortex, cerebellum and medulla oblongata were extracted to determine the levels of glucose, glutathione (GSH), lipid peroxidation (TBARS), and 5-hydroxyindole acetic acid (5-HIAA). The corporal weights of animals fed with low protein diet were significantly lower than those on normal diet. The levels of 5-HIAA, TBARS, and GSH showed significant differences due to subitramine and carnitine effects, principally in cortex than in the rest of the brain areas of rats fed with low diet. Sibutramine and carnitine alter serotonergic metabolism in the brain regions of animals subjected to low protein diets. Reduction in oxidative stress may be involved in these effects. Key words: Anorexiant, brain, glutathione, malnutrition, serotonin.

Disparate effects of pharmacotherapy on plasma plasminogen activator inhibitor-1 levels in women with the polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is characterized by obesity and insulin resistance (IR), which result in elevated plasminogen activator inhibitor-1 (PAI-1) levels. We aimed to assess the changes in PAI-1 levels in PCOS during treatment with metformin and during weight loss. Twenty-three normal weight women with PCOS were given metformin 850 mg bid for 6 months. Fifty overweight/obese women with PCOS were prescribed an energy-restricted diet, were instructed to exercise and were randomized to orlistat 120 mg tid or sibutramine 10 mg qd for 6 months. In normal weight women, treatment with metformin reduced the body mass index (BMI) and circulating androgens, improved markers of IR and lowered PAI-1 levels. In overweight/obese women, sibutramine and orlistat yielded comparable reductions in BMI and markers of IR. In contrast, the effects on the free androgen index (FAI) differed (p=0.027): sibutramine reduced the FAI (p=0.005), whereas orlistat had no effect. The effects of sibutramine and orlistat on PAI-1 levels also differed (p=0.042): sibutramine reduced PAI-1 levels (p<0.001), whereas orlistat had no effect. Metformin and sibutramine, but not orlistat, reduce PAI-1 levels in PCOS. The reduction in circulating androgens during metformin and sibutramine treatment might be implicated in this decline.

Evaluation of the Effect of Acute Sibutramine in Female Rats in the Elevated T-Maze and Elevated Plus-Maze Tests

Sibutramine is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of obesity. A pre-clinical study showed that acute administration of sibutramine promoted anxiolytic- and panicolytic-like effects in male rats. However, in clinical reports, sibutramine favoured the onset of panic attacks in women. In this study, the effect of sibutramine on experimental anxiety in females and the relevance of different oestrous cycle phases for this effect were analysed. In experiment 1, both male and female rats were submitted to acute intraperitoneal injection of sibutramine or vehicle 30 min. before testing in the elevated T-maze (ETM) and in the open-field test (OF). Females in the pro-oestrus (P), oestrus (E), early dioestrus (ED) and late dioestrus (LD) phases were tested in the ETM and OF (experiment 2) or in the elevated plus-maze (EPM) 30 min. after the injection of sibutramine. Sibutramine impaired the escape response in the ETM in both males and females. This effect was observed for P, E and ED, but not for LD females. Sibutramine altered neither the inhibitory avoidance in the ETM nor the behaviour of females in the EPM. Thus, sibutramine promoted a panicolytic-like effect in female rats cycling at P, E and ED, but not in the LD phase and did not alter behaviours related to anxiety in both ETM and EPM. Considering that pre-clinical studies aiming the screening of anxiolytic drugs employ male rodents, data here obtained reinforce the importance of better understanding the effects of drugs in females.

Potent inhibition of cytochrome P450 2B6 by sibutramine in human liver microsomes

The present study was performed to evaluate the potency and specificity of sibutramine as an inhibitor of the activities of nine human CYP isoforms in liver microsomes. Using a cocktail assay, the effects of sibutramine on specific marker reactions of the nine CYP isoforms were measured in human liver microsomes. Sibutramine showed potent inhibition of CYP2B6-mediated bupropion 6-hydroxylation with an IC50 value of 1.61μM and Ki value of 0.466μM in a competitive manner at microsomal protein concentrations of 0.25mg/ml; this was 3.49-fold more potent than the typical CYP2B6 inhibitor thio-TEPA (Ki=1.59μM). In addition, sibutramine slightly inhibited CYP2C19 activity (Ki=16.6μM, noncompetitive inhibition) and CYP2D6 activity (Ki=15.7μM, noncompetitive inhibition). These observations indicated 35.6- and 33.7-fold decreases in inhibition potency, respectively, compared with that of CYP2B6 by sibutramine. However, no inhibition of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, or CYP2E1 activities was observed. In addition, the CYP2B6 inhibitory potential of sibutramine was enhanced at a lower microsomal protein concentration of 0.05mg/ml. After 30min preincubation of human liver microsomes with sibutramine in the presence of NADPH, no shift in IC50 was observed in terms of inhibition of the activities of the nine CYPs, suggesting that sibutramine is not a time-dependent inactivator. These observations suggest that sibutramine is a selective and potent inhibitor of CYP2B6 in vitro, whereas inhibition of other CYPs is substantially lower. These in vitro data support the use of sibutramine as a well-known inhibitor of CYP2B6 for routine screening of P450 reversible inhibition when human liver microsomes are used as the enzyme source.

The effect of sibutramine on platelet morphology of Spraque‐Dawley rats fed a high energy diet

The aim of this study was to investigate the effect of Sibutramine on platelet ultrastructure and discuss the morphological observations in relation to known physiological effects of the compound. Six-week-old, female Spraque-Dawley rats were used in this study. The animals were placed on a high energy diet after which sibutramine administration followed. Blood was drawn on the day of termination and platelet rich plasma was obtained to prepare plasma smears for analysis. Scanning electron microscopy was used to investigate the ultrastructure of the platelets. Platelets of the Sibutramine-treated animals showed smooth surface with limited pseudopodia formation when compared with that of the control animals. Higher magnification of the platelet surface showed membrane tears and swelling, typically seen in necrotic cells. It can therefore be concluded from these results that Sibutramine alters the membrane morphology of platelets to that typical of necrotic cells.

The effect of sibutramine on weight loss in obese adolescents

To evaluate the effect of sibutramine on weight loss in obese adolescents. A double-blind controlled study lasting 13 months. The study included 73 obese adolescents of both sexes aged between 10 and 18 years. Laboratory tests and imaging studies were performed before, during wash-out, and at the end of 13 months. The percentage of patients who lost 10% of their initial weight in the placebo group was 46%, and in the sibutramine group was 75%. When placebo was used, average weight rose by 1.61 kg, and BMI decreased by 0.24 kg/m(2) whereas with the use of sibutramine, weight decreased by 4.47 kg, and average BMI decreased, 2.38 kg/m(2), with p < 0.001. Sibutramine induced significantly more weight loss in obese adolescents compared with placebo, without significant side effects. The weight loss curve was different depending on the moment sibutramine was introduced. This finding indicates that the best time to start sibutramine is when adhesion begins to fail.