超高效液相色谱-串联质谱法同时测定食蟹猴血浆中地高辛、安非他酮及活性代谢物浓度和药动学评价

目的：建立同时测定食蟹猴体内地高辛、安非他酮及其活性代谢物血浆浓度的方法，并评价药动学特征。方法：以乙腈沉淀蛋白处理血浆样品。色谱柱Agilent Zorbax SB-C8（4.6×100 mm 3.5 μm）；流动相为甲醇-水（含5 mmol·L^-1甲酸铵，pH 3.6），梯度洗脱；质谱条件为电喷雾离子源，正离子模式，扫描方式为多反应离子监测，m/z 798.4→651.3（地高辛）；m/z 240.2→184.0（安非他酮）；m/z 256.3→238.0（羟基安非他酮）；m/z 242.2→168.1（赤式/苏式羟化安非他酮）；m/z 172.2→128.2（甲硝唑，内标）。食蟹猴3只，♂，体质量2~4 kg，0.1 mg·5 mL^-1·kg^-1地高辛和1.5 mg·5 mL^-1·kg^-1盐酸安非他酮静滴给药。给药前后0.08，0.25，0.5，1，1.5，2，4，6，8，12，24，48 h采血。测定地高辛、安非他酮及其活性代谢物浓度。结果：血浆标准曲线在0.25~100 ng·mL^-1（地高辛），0.2~1 000 ng·mL^-1（安非他酮/羟基安非他酮），0.2~50 ng·mL^-1（赤式/苏式羟化安非他酮），定量范围内线性良好（r≥0.995）。批内批间精密度均小于13.7%，绝对回收率为83.8%~104.2%，基质效应小于10.6%。地高辛、安非他酮、羟基安非他酮、赤式、苏式羟化安非他酮药动学参数C_max分别为（29.32±7.31）、（254.00±68.23）、（22.43±7.56）、（1.53±0.27）、（3.96±0.42） ng·mL^-1，T_max分别为（0.14±0.10）、（0.08±0）、（1.50±0.00）、（1.17±0.29）、（4.06±1.46） h，AUC_0-48h分别为（123.87±9.59）、（550.68±17.43）、（160.47±62.92）、（9.26±3.65）、（24.43±5.28） ng·h·mL^-1，半衰期分别为（21.26±3.77）、（5.54±1.76）、（3.96±1.21）、（5.58±2.40）、（4.06±1.46） h。结论：和已报道的方法比较，建立的分析方法灵敏、准确，样品处理简便、快速，适用于药动学研究以及地高辛-安非他酮药物相互作用的评价，也能为临床个体化用药实践提供方法学参考。     

Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study

Objective: Antiepileptic drugs (AEDs) are commonly employed in the treatment of bipolar disorder. The efficacy and tolerability of topiramate, a novel anticonvulsant, and bupropion SR when added to mood stabilizer therapy were compared under single‐blind conditions (rater‐blinded) in patients meeting DSM‐IV criteria for bipolar I/II depression. Methods: A total of 36 out‐patients with Hamilton Depression Rating Scale (HDRS‐17) scores ≥16 were randomized to receive escalating doses of either topiramate (50–300 mg/day) or bupropion SR (100–400 mg/day) for 8 weeks. Data were analyzed on an intent‐to‐treat basis using the last observation carried forward method. Results: The percentage of patients meeting a priori response criteria (≥50% decrease from baseline in mean HDRS‐17 total score) was significant for both topiramate (56%) and bupropion SR (59%) [t(17)=2.542, p=0.04 and t(17)=2.661, p=0.03, respectively]. Baseline demographic and clinical parameters were comparable between the two treatment groups. The mean doses of study medication were 176 mg/day (SD=102 mg/day) for the topiramate‐treated group and 250 mg/day (SD=133 mg/day) for the bupropion SR‐treated group. A significant and comparable reduction in depressive symptoms was observed from baseline to endpoint following topiramate and bupropion SR treatment, according to a ≥ 50% reduction in the HDRS‐17. Total mean HDRS‐17 scores significantly decreased from baseline to endpoint in both groups (p=0.001), however, differences between the topiramate‐treated group and the bupropion SR‐treated group were not significant [t(36)=1.754, p=0.097]. Both topiramate and bupropion SR were generally well tolerated. Thirteen patients discontinued the study: 2 because of lack of efficacy, 1 due to withdrawal of consent and 10 following side‐effects (six in the topiramate and four in the bupropion SR‐treated group). There were no cases of affective switch in either arm. Weight loss was experienced by patients in both groups (mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate) [t(17)=2.325, p=0.061 and t(17)=2.481, p=0.043, respectively]. Conclusions: These preliminary data suggest that adjunctive topiramate may reduce depressive symptom severity in acute bipolar depression. The antidepressant efficacy of this compound requires confirmation via double‐blind placebo controlled investigation.     

Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs

ABSTRACT

Introduction: Obesity poses a significant increase in morbidity and mortality and thus five anti-obesity drugs have been approved currently by US FDA. Several phase 3 trials have shown a significant improvement in cardio-metabolic profile including significant weight reduction with these agents compared to placebo.

Areas covered: We systematically searched the database of PubMed, Embase, The Cochrane Library and The ClinicalTrials.gov up to 30 September 2019 and retrieved all the randomized controlled trials (RCTs) that were conducted with these five drugs for ≥1 year and explicitly reported their efficacy versus placebo. Subsequently, we have conducted the meta-analysis to primarily study the effect of these anti-obesity drugs on weight reduction. We additionally reviewed the effect of these drugs on other cardio-metabolic parameters including key adverse events.

Expert opinion: This meta-analysis finds a significant reduction in body weight with orlistat (N = 10,435; ? ?3.07 Kg, 95% CI, ?3.76 to ?2.37), phentermine plus topiramate (N = 2985; ? ?9.77 Kg; 95% CI, ?11.73 to ?7.81), lorcaserin (N = 16,856; ? ?3.08 Kg; 95% CI, –3.49 to –2.66), naltrexone plus bupropion (N = 3239; ? ?4.39 Kg; 95% CI, ?5.05 to ?3.72) and liraglutide (N = 4978; ? ?5.25 Kg; 95% CI, ?6.17 to ?4.32), compared to placebo (all p < 0.00001).     

安非他酮缓释片治疗抑郁症对照研究

目的探讨安非他酮缓释片治疗抑郁症的临床疗效及安全性。方法将72例抑郁症患者随机分为两组各36例,研究组口服安非他酮治疗,对照组口服氟西汀治疗,观察6w。于治疗前及治疗1w、2w、4w、6w末采用汉密顿抑郁量表、汉密顿焦虑量表、临床总体印象量表、副反应量表评定临床疗效及不良反应。结果研究组有效率83.3%,对照组为86.1%,两组有效率比较差异无显著性(P>0.05)。两组各量表评分,治疗1w起均较治疗前有显著或极显著性下降(P<0.05或0.01),2w末起均有极显著性下降(P均<0.01),但同期两组间比较差异无显著性(P均>0.05)。两组不良反应均较轻微,发生率比较无显著性差异。结论盐酸安非他酮缓释片治疗抑郁症疗效与氟西汀相当,安全性高,依从性好。     

Can we win the war on obesity with pharmacotherapy?

Introduction: Obesity is a major health concern for several countries. The United States (U.S.) has arguably led the world in the percentage of overweight and/or obese per capita for several decades. As a result, numerous FDA-approved pharmacotherapeutic options are available for the long-term treatment of obesity. Although most of these medications have been on the U.S. market for a few years and have demonstrated efficacy for long-term weight loss in clinical trials, the impact of these medications on obesity in the U.S. has yet to be realized.

Areas covered: We will review and evaluate why pharmacotherapy for obesity has not produced a meaningful reduction in the number of overweight and obese adults in the U.S.

Expert commentary: Several obstacles, such as adverse drug effects, poor insurance coverage, not treating obesity as a chronic disease, and availability of other weight loss alternatives, has resulted in poor performance of pharmacotherapy for obesity in the U.S. market.     

Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity

Background: Bupropion and naltrexone are centrally active drugs that have shown potential efficacy – alone and in combination – for the treatment of obesity. Objective: To explore the efficacy and safety of naltrexone and bupropion alone and in a novel combination drug that utilizes sustained-release (SR) formulations of both drugs and to evaluate their efficacy in promoting weight loss. The mechanisms of action of these centrally acting drugs are discussed. Preclinical and clinical studies of bupropion and naltrexone alone and in combination are reviewed. Results/conclusions: Both bupropion and naltrexone have been shown individually to induce weight loss. Bupropion has greater efficacy as monotherapy. Naltrexone SR potentiates the effects of bupropion SR; thus, this synergistic combination has the potential for additional weight loss compared to monotherapy. Current Phase III trials will yield further safety and efficacy information regarding these drugs in combination.     

The use of bupropion SR in cigarette smoking cessation

Cigarette smoking remains the largest preventable cause of premature death in developed countries. Until recently nicotine replacement therapy (NRT) has been the only recognised form of treatment for smoking cessation. Bupropion, the first non-nicotine based drug for smoking cessation was licensed in the United States of America (US) in 1997 and in the United Kingdom (UK) in 2000 for smoking cessation in people aged 18 years and over. Bupropion exerts its effect primarily through the inhibition of dopamine reuptake into neuronal synaptic vesicles. It is also a weak noradrenalin reuptake inhibitor and has no effect on the serotonin system. Bupropion has proven efficacy for smoking cessation in a number of clinical trials, helping approximately one in five smokers to stop smoking. Up to a half of patients taking bupropion experience side effects, mainly insomnia and a dry mouth, which are closely linked to the nicotine withdrawal syndrome. Bupropion is rarely associated with seizures however care must be taken when co-prescribing with drugs that can lower seizure threshold. Also, bupropion is a potent enzyme inhibitor and can raise plasma levels of some drugs including antidepressants, antiarrhythmics and antipsychotics. Bupropion has been shown to be a safe and cost effective smoking cessation agent. Despite this, NRT remains the dominant pharmacotherapy to aid smoking cessation.     

缓释盐酸安非他酮联合尼古丁替代治疗对烟瘾戒断临床分析

目的:评价缓释盐酸安非他酮联合尼古丁替代治疗对烟瘾戒断临床效果。方法:随机选择68例符合试验要求的吸烟者(平均每天吸烟约24支,Fagerstrom评分平均约7分)。随机分成2组,一组进行单纯尼古丁替代治疗(NRT)(A组),另一组进行缓释盐酸安非他酮联合尼古丁替代治疗戒烟(B组),连续观察12周戒断效果,并随访24周的戒断率。结果:治疗第4周、第12周、第24周自述戒烟率B组均高于A组(分别为48.3%,33.3%;58.6%,37.5%;48.3%,25%),2者间差异均有显著性(P<0.05)。随访期B组烟草依赖自评量表评分均小于A组(P<0.05);B组尼古丁戒断相关症状明显低于A组,且12周体质量增加明显小于A组(P<0.05);2组12周戒烟失败者以伴随哮喘及慢性阻塞性肺疾病(COPD)患者为主;戒烟失败情景诱惑分析前5位为社交、负性情绪、正性情绪、压力及饮酒等。结论:缓释盐酸安非他酮联合尼古丁替代治疗戒烟方式更有效,且戒断相关症状少,对合并慢性疾病的患者更值得推荐,戒烟过程行为心理分析治疗十分重要。     

Bupropion treatment increases epididymal contractility and impairs sperm quality with no effects on the epididymal sperm transit time of male rats

Bupropion is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor used as smoking cessation and antidepressant drug with a lower incidence of male sexual dysfunction. We showed previously that sibutramine, a norepinephrine/serotonine reuptake inhibitor, reduced male rat fertility. As there are no studies evaluating the impact of bupropion treatment on spermatic parameters and male fertility, we evaluated the effects of bupropion treatment (15 and 30 mg kg^?1, 30 days) on sexual behavior, spermatic parameters and fertility of male Wistar rats and on the epididymal duct in vitro contractility. Bupropion 15 mg kg^?1 increased the serum luteinizing hormone level and the epididymal duct contractility, but the sperm quality was not affected. At 30 mg kg^?1 bupropion impaired sperm quality increasing the incidence of non‐progressive sperm. The male sexual behavior and fertility were not modified at both bupropion doses. These results, in rats, suggest the importance of studies evaluating the effects of bupropion on the human male sperm quality. Copyright © 2015 John Wiley & Sons, Ltd.     

Possible involvement of sigma-1 receptors in the anti-immobility action of bupropion, a dopamine reuptake inhibitor

Sigma receptors particularly, sigma-1 subtype is known to modulate the release of catecholamines in the brain and may participate in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the anti-immobility-like effect of bupropion (a dopamine reuptake inhibitor) using the forced swim test (FST) in mice. Bupropion produced dose-dependent (10–40 mg/kg, i.p.) reduction in immobility period and the ED₅₀ value was found to be 18.5 (7.34–46.6) mg/kg, i.p. (+)-Pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergistic response when it was co-administered with a subeffective dose of bupropion (10 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of bupropion (20 mg/kg, i.p.). The various modulators used in the study did not show any effect per se on locomotor activity except bupropion which at a higher dose (15–40 mg/kg, i.p.) significantly increased the locomotor activity. The results for the first time demonstrated the involvement of sigma-1 receptors in the anti-immobility effects of bupropion.