曲美布汀分散片健康人体内的药代动力学及生物等效性研究曲美布汀分散片健康人体内的药代动力学及生物等效性研究

目的建立人血浆中曲美布汀的HPLC-ESI-MS测定法,研究曲美布汀在正常人体内的药代动力学行为,评价其两种制剂的生物等效性。方法血浆样品经碱化以环己烷提取,进行HPLC-ESI-MS分析,内标为西布曲明,检测离子为_m/z 388(曲美布汀)、_m/z 280(内标),裂解电压为50 V。20名健康志愿者交叉口服供试片和参比片,剂量均为100 mg。结果受试制剂及参比制剂的曲美布汀消除半衰期分别为(9.2±2.3) h和(9.2±2.8) h,达峰时间分别为(0.9±0.4) h和(1.0±0.3) h,峰浓度分别为(41±20) μg·L^-1和(40±20) μg·L^-1。以AUC_0-24h计算的受试制剂的相对生物利用度为(97±13)%。结论本法灵敏、准确、简便。统计学结果表明两种制剂生物等效。     

减肥类保健食品中非法添加盐酸西布曲明和酚酞的定性定量检测

目的建立准确检测减肥类保健食品中非法添加盐酸西布曲明和酚酞的定性定量方法。方法采用超高效液相色谱-串联质谱(UPLC-MS/MS)法,以0.1%甲酸的甲醇溶液和水溶液为流动相,通过分子离子峰、二级质谱的碎片离子、多反应检测模式的色谱峰等信息,对盐酸西布曲明和酚酞进行定性鉴别和定量测定。结果 4批保健食品中均检出盐酸西布曲明和酚酞。结论该方法准确可靠、专属性强、灵敏度高,可作为检测减肥类保健食品中非法添加盐酸西布曲明和酚酞的有效方法。     

Tesofensine – a novel potent weight loss medicine

Background: The incidence of obesity is increasing; this is of major concern, as obesity is associated with cardiovascular disease, stroke, type 2 diabetes, respiratory tract disease, and cancer. Objectives/methods: This evaluation is of a Phase II clinical trial with tesofensine in obese subjects. Results: After 26 weeks, tesofensine caused a significant weight loss, and may have a higher maximal ability to reduce weight than the presently available anti-obesity agents. However, tesofensine also increased blood pressure and heart rate, and may increase psychiatric disorders. Conclusions: It is encouraging that tesofensine 0.5 mg may cause almost double the weight loss observed with sibutramine or rimonabant. As tesofensine and sibutramine have similar pharmacological profiles, it would be of interest to compare the weight loss with tesofensine in a head-to-head clinical trial with sibutramine, to properly assess their comparative potency. Also, as teso fensine 0.5 mg increases heart rate, as well as increasing the incidence of adverse effects such as nausea, drug mouth, flatulence, insomnia, and depressed mode, its tolerability needs to be further evaluated in large Phase III clinical trials.     

Pharmacotherapy of obesity

The growing recognition of the health risks of obesity coupled with the difficulties in treating it successfully by lifestyle modification predicates a need for effective drug treatment. The history of drug treatment in the second half of the 20th century is, however, one of disappointment and concern over drug toxicity. However, the advances in our understanding of the mechanism of weight control, together with improved ways of evaluating anti-obesity drugs, has resulted in two effective compounds, sibutramine and orlistat, becoming available for clinical use. Sibutramine has actions on both energy intake and expenditure and had been shown to enhance weight loss and weight maintenance achieved by diet, in simple obesity as well as when accompanied by complications of diabetes or hypertension. About 50-80% of patients can achieve a >5% loss, significantly more than if patients receive the same lifestyle intervention with placebo. Orlistat, which acts peripherally to block the absorption of dietary fat, has had similar results in clinical trials; a recent study (XENDOS) has just reported results which show that the enhanced, albeit modest, weight loss achieved with orlistat delays the development of diabetes over a 4-year period. A number of other compounds are expected to complete or enter clinical trials over the next decade. There is considerable optimism that we will soon have the pharmacological tools needed to make the treatment of obesity feasible.     

Effects of sibutramine on abdominal fat mass, insulin resistance and blood pressure in obese hypertensive patients

OBJECTIVE: The objective of this study is to assess the effects of sibutramine on body weight, body fat distribution, insulin resistance, plasma leptin, lipid profile and blood pressure profiles in hypertensive obese patients. METHODS: Eighty-six central obese hypertensive patients (BMI = 39 +/- 5 kg/m(2), 84% of women, 48 +/- 8.5 years old) were placed on a hypocaloric diet and placebo therapy for 4 weeks. They were then randomized to receive sibutramine (10 mg) or placebo for 24 weeks. Both, before therapy and at the end of the study, the waist and hip circumferences were measured and the waist/hip ratio (WHR) was calculated; abdominal ultrasonography was performed in order to estimate the amount of subcutaneous fat (SF) and visceral fat (VF), and the visceral/subcutaneous ratio. Beyond HOMA-r, another insulin resistance index (IRIp) was calculated by means of the formula: peak of blood glucose after oral glucose load x plasma insulin level/10(4). Fasting plasma leptin and lipid levels were also determined. RESULTS: Sibutramine induced greater weight reduction than placebo (6.7 vs. 2.5%, p < 0.001). Reductions in WHR (0.97 +/- 0.08 vs. 0.94 +/- 0.07, p < 0.01), IRIp (0.11 +/- 0.07 vs. 0.09 +/- 0.06 mmol mu/l(2)) and VF (6.4 +/- 2.4-6.0 +/- 2.4 cm, p < 0.01) were observed only with sibutramine. Plasma leptin decreased with placebo (24 +/- 15 vs. 18 +/- 10 UI/l, p < 0.01), but not with sibutramine (18.8 +/- 8.4 vs. 18.2 +/- 13.2 UI/l). No clinically significant change in lipid profile was observed in both groups. Moreover, office and 24-h blood pressure values did not change during placebo or sibutramine therapy, whereas a significant increase in office heart rate, from 78.3 +/- 7.3-82 +/- 7.9 b.p.m., p = 0.02, was observed with sibutramine. CONCLUSIONS: Sibutramine therapy induced greater body weight loss than placebo in hypertensive obese patients. This was associated with WHR reduction, decreases in VF and insulin resistance. The maintenance of leptin levels during sibutramine therapy may be important to avoid weight recovery, although this finding must be confirmed by other prospective studies.     

The effectiveness of pharmaceutical interventions for obesity: weight loss with orlistat and sibutramine in a United Kingdom population-based cohort

Aims

Drug treatments for obesity have proven efficacy from randomized trials, but their effectiveness in routine clinical practice is unknown. We assessed the effects on weight and body mass index (BMI) of orlistat and sibutramine when delivered in routine primary care.

Methods

We used United Kingdom data from the Clinical Practice Research Datalink to estimate the effects of orlistat or sibutramine on weight and BMI over 3 years following treatment initiation. For comparison, we matched each patient with up to five obese patients receiving neither drug. Mixed effects linear regression with splines was used to model change in weight and BMI. Mean change with 95% confidence intervals (CI) was estimated.

Results

We identified 100 701 patients receiving orlistat, 15 355 receiving sibutramine and 508 140 non-intervention patients, with body mass index of 37.2, 36.6 and 33.2 kg m⁻², respectively. Patients receiving orlistat lost, on average, 0.94 kg month⁻¹ (0.93 to 0.95) over the first 4 months. Weight gain then occurred, although weight remained slightly below baseline at 3 years. Patients receiving sibutramine lost, 1.28 kg month⁻¹ (1.26 to 1.30) over the first 4 months, but by 3 years had exceeded baseline weight. Non-intervention patients had slight increases in weight throughout the 3 year period, with gains ranging between 0.01 and 0.06 kg month⁻¹.

Conclusions

Orlistat and sibutramine had early effects on weight loss, not sustained over 3 years. As new treatments for obesity are approved, their effectiveness should be measured in routine clinical practice, as effectiveness may be considerably less than seen in randomized trials.     

Short-term Evidence in Adults of Anorexigenic Drugs Acting in the Central Nervous System: A Meta-Analysis

PurposeObesity is a chronic clinical condition that is considered one of the most serious health problems in the world because it can cause other chronic metabolic disorders. A meta-analysis was conducted to evaluate the safety and efficacy of 4 central-acting drugs, all approved in Brazil's market for weight loss.MethodsPubMed, EMBASE, and Cochrane library databases were searched from inception until January 2018 to retrieve randomized controlled trials comparing sibutramine, diethylpropion, mazindol, and fenproporex versus placebo in overweight or obese patients. Language was not a restriction for the database searches. We extracted and combined data from studies that reported adverse drug events and weight change. A random effects meta-analytic model was applied in all calculations. The Cochrane Collaboration tool was used to assess the quality and bias of all included studies. Quality of evidence was assessed by using the Grading of Recommendations, Assessment, Development, and Evaluation criteria.FindingsFifty-three studies were included, with a total of 16,903 patients with a median follow-up of 12 weeks (2–260 weeks). The appetite suppressants showed a significant weight loss compared with placebo (mean difference [MD], −4.70 kg; 95% CI, −5.25 to −4.15; I² = 100%; 43 studies). There was an increased total number of adverse events, dry mouth, constipation, insomnia, dizziness, and tachycardia reported in the intervention group (risk ratio [RR], 1.06; 95% CI, 1.01 to 1.10; I² = 20% [22 studies]; RR, 2.08; 95% CI, 1.76 to 2.47; I² = 34% [25 studies]; RR, 2.31; 95% CI, 1.88 to 2.84; I² = 0% [25 studies]; RR, 1.84; 95% CI, 1.40 to 2.39; I² = 0% [17 studies]; RR, 1.78; 95% CI, 1.24 to 2.58; I² = 0% [13 studies]; and RR, 2.01; 95% CI, 1.42 to 2.86; I² = 0% [10 studies], respectively). Sibutramine showed a significant increase in heart rate and mean diastolic pressure compared with placebo (MD, 4.17 beats/min [95% CI, 3.60 to 4.74; I² = 99%; 23 studies]; MD, 1.68 mm Hg [95% CI, 1.29 to 2.07; I² = 98%; 22 studies]).ImplicationsThese drugs are effective for weight loss in overweight and obese patients; however, they increase the risk of adverse events. In fact, the evidence is of low quality, the data availability of studied agents (especially for cardiovascular outcomes) are limited, and the studies are of short duration. PROSPERO identifier: CRD42018091083.     

西布曲明片在健康人体中的药代动力学与相对生物利用度

目的研究国产盐酸西布曲明片（减肥药）在健康人体的药代动力学，并评价2种制剂的生物等效性。方法用双交叉试验设计，20名健康志愿者口服国产西布曲明片剂和参比胶囊15mg，服药后0～72h内，按规定时间取血。用高效液相色谱-质谱法测定血浆中西布曲明主要代谢物N-双脱甲基西布曲明的浓度。计算主要药代动力学参数，判断其生物等效性。结果单次口服国产西布曲明片和参比胶囊后的主要药代动力学参数：AUC0-∞分别为（146．44±36．19），（155．08±46．22）h·ng·mL^-1；AUC0-71分别为（130．32±32．75），（139．41±43．50）h·ng·mL^-1；tmax分别为（3．08±1．36），（3．18±1．15）h；Cmax分别为（6．38±2．07），（6．92±2．48）ng·mL^-1；t1／2分另0为（23．15±4．68），（22．17±3．70）h；西布曲明片剂的相对生物利用度F0-n为（96．24±16．74）％。结论国产西布曲明片剂与参比胶囊具有生物等效性。