Quantification of sibutramine and its two metabolites in human plasma by LC-ESI-MS/MS and its application in a bioequivalence study

Obesity can be considered as a chronic illness of epidemic proportion and its incidents have increased exponentially in recent years.The use of anti-obesity drugs such as sibutramine is somewhat helpful.There is a need to quantify such drugs in biological samples,which is generally quite difficult.In this report,we developed and validated a simple,sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of sibutramine (SB) and its two metabolites N-des methyl sibutramine (DSB) and N-di desmethyl sibutramine (DDSB) in human plasma.Zorbax SBC18 (4.6 mm × 75 mm,3.5 μm,80 (A)) analytical column and 5 mM ammonium formate:acetonitrile (10∶90,v/v) mobile phase were used for chromatographic separation of SB,DSB and DDSB.Multiple reaction monitoring (MRM) in the positive mode was used to detect SB,DSB and DDSB at m/z 280.3/124.9,266.3/125.3 and 252.2/124.9,respectively.Liquid liquid extraction was used for the extraction of analytes and internal standard from human plasma.This method was validated over a linear concentration range of 10.0-10,000.0 pg/mL for SB,DSB and DDSB with correlation coefficients (r) of ≥0.9997.The drug and the two metabolites were stable in plasma samples.The validated method was successfully applied in a bioequivalence and pharmacokinetic study with human volunteers under fasting condition.

Determination of Sibutramine and Its <i>N</i>-Desmethyl Metabolites in Human Plasma Using HPLC Coupled with Tandem Mass Spectroscopy

The following article has been retracted due to the investigation of complaints received against it. The Editorial Board found that there are conflicts of interests between the authors and their organization. The scientific community takes a very strong view on this matter, and the American Journal of Analytical Chemistry treats all unethical behavior seriously. This paper published in Vol. 5 No. 9 589-597, 2014 has been removed from this site. Title: Determination of Sibutramine and Its N-Desmethyl Metabolites in Human Plasma Using HPLC Coupled with Tandem Mass Author: Mohammad

Rise and fall of anti-obesity drugs

Although it is not generally a life-threatening disease,obesity is becoming a major health problem worldwide.It can be controlled by means of drugs,and,consequently,these are required to be safe as well as effective.In this paper,we summarize the fate of various drugs that have been introduced for clinical use in the treatment of obesity.Fenfluramine and dexfenfluramine were withdrawn because of heart valve damage.Sibutramine suppresses appetite and increases heart rate and blood pressure.In the Sibutramine Cardiovascular OUTcomes trial,an increase in major adverse cardiovascular events prompted its withdrawal in Europe and the United States.Rimonabant is an endocannabinoid receptor antagonist that reduces body weight and ameliorates some cardiovascular risk factors.However,adverse psychiatric side effects led to its withdrawal as well.Orlistat is approved in Europe and the United States for the treatment of obesity,but its use is limited by gastrointestinal side-effects.Ephedrine and caffeine are natural ingredients in foods and supplements that may help the person to lose weight.In the light of several failed attempts,there is a clear need to develop drugs that are effective and safe in the long term in order to successfully combat the phenomenon of obesity.

Combination drug treatment in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes simple steatosis, a benign condition, and non-alcoholic steatohepatitis, a condition that beyond TG accumulation also includes necroinflammation and fibrosis. An association between NAFLD and cardiovascular disease (CVD) has been recently suggested. NAFLD patients usually have an increased CVD risk profile. NAFLD is also associated with metabolic syndrome (MetS) and is considered as the hepatic component of MetS by some authors. Currently, the only established treatment of NAFLD is gradual weight loss. However, multifactorial treatment of NAFLD risk factors may be needed to reduce the increased CVD risk of NALFD patients. Drug combinations that include antiobesity drugs (such as orlistat and sibutramine) and target CVD risk factors may be a good approach to NAFLD patients. Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistatezetimibe and sibutramine-antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction and improvement of liver function tests. Small studies give promising results but double-blind, randomized trials examining the effects of such multifactorial treatment in hard CVD endpoints in NAFLD patients are missing.

Combination drug treatment in obese diabetic patients

Drug combinations that include antiobesity drugs(such as orlistat and sibutramine) and target cardiovascular disease(CVD) risk factors may be a good approach to patients with type 2 diabetes and/or metabolic syndrome(MetS).Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistat-ezetimibe and the sibutramine-antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction.In these studies,the combination treatment significantly improved the lipid and lipoprotein profile,the carbohydrate metabolism parameters and many other variables playing a role in the atherosclerotic process.Small studies give pro m ising results but double-blind,randomized trials examining the effects of such multif actorial treatment in hard CVD endpoints in diabet ic or MetS patients are missing.

EFFECT OF ACUPUNCTURE ON HYPERLEPTINAEMIA AND HYPERINSULINEMIA IN OBESITY RATS

Objective: To observe the effect of acupuncture on hyperleptinaemia and hyperinsulinemia for studying its underlying mechanism about anti-obesity and reducing blood lipid in obesity rats. Methods: A total of 80 SD rats were randomized into normal control, model, acupuncture and medication groups, with 20 cases in each group. Hypothalamic obesity model was established by subcutaneous injection of 15% sodium glutamate (0.2 mL/10 g body weight), once daily and continuously for 5 days. “Zusanli” (足三里 ST 36), “Sanyinjiao”(三阴交 SP 6), “Guanyuan”(关元 CV 4) and “Zhongwan”(中脘 CV 12) were punctured and stimulated electrically (100 Hz, dense-sparse waves, and a suitable strength inducing local muscular tremor) for 15 min, once daily. In medication group, rats were fed with Sibutramine 4 mg/kg, once daily. After 4 weeks’ treatment, Lee’s index was detected, and serum leptin and insulin contents were determined by radioimmunoassay (RIA). Results: Compared with normal control group, Lee’s index, serum leptin and insulin contents of model group increased significantly (P<0.01). Comparison between acupuncture and model groups, Lee’s index and serum leptin of acupuncture group decreased significantly (P<0.01), and serum insulin level also lowered. In comparison with model group, Lee’s index, serum leptin and insulin levels of medication group also lowered. Comparison between acupuncture and medication groups showed that Lee’s index and serum leptin level of acupuncture group were significantly lower than those of the later group (P<0.01), displaying that the therapeutic effect of acupuncture is better than that of Sibutramine in lowering Lee’s index and serum leptin. No significant differences were found between acupuncture and medication groups in body weight and length and serum insulin(P>0.05). Conclusion: Acupuncture can effectively reduce Lee’s index, serum leptin and insulin contents in fasting obese rats, which may contribute to its effect in anti-obesity.