抗肥胖药物发展现状及研究进展

肥胖已成为全球性的重要公共卫生问题之一.不过,尽管肥胖流行且会带来一系列的健康相关疾病风险,但现可供患者选择的抗肥胖药物却仅主要有盐酸芬特明、盐酸安非拉酮和奥利司他这3个,远远不能满足临床的需要.为此,制药公司正在积极致力研究与开发新的抗肥胖药物,以期能够更安全、更有效地治疗肥胖并减少肥胖相关疾病风险.其中,劳卡色林和...     

口服治疗肥胖药物——纳曲酮/安非他酮缓释片

纳曲酮/安非他酮缓释片(naltrexone-bupropion,Contrave)缓释片是由Orexigen Therapeutic公司研发的肥胖治疗药物,它由纳曲酮与安非他酮组成,在2014年9月10日经FDA批准上市。纳曲酮/安非他酮缓释片用于治疗体质指数为30或更大(肥胖)的成人患者,以及体质指数为27或更大(超重)并且患有至少一种体重相关疾病的成人患者,如高血压、2型糖尿病或血脂异常。同时纳曲酮/安非他酮缓释片作为一种结合低热量饮食及体育锻炼治疗肥胖的辅助药物。笔者就纳曲酮/安非他酮缓释片的基本信息、作用机理、药代动力学、药物相互作用、临床研究、药物不良反应以及药物过量、安全警告和警示等研发动态作一概述,以期为医院临床用药起到指导作用。     

美国发布首部《肥胖药物治疗指南》

美国内分泌学会（ TES）发布首部《肥胖药物治疗临床指南》,针对如何处方减肥药物提出建议。
　　截至目前,美国食品药品监督管理局（ FDA）共批准了6种药物用于治疗肥胖。除了奥利司他和非处方型奥利司他外,过去的2年时间里共有4种药物获得批准,包括氯卡色林、芬特明/托吡酯、环丙甲羟二羟吗啡酮/安非他酮、利拉鲁肽。     

复方减肥药物——Qsymia

Qsymia是由美国Vivus公司开发的新型复方减肥药,2012年7月17日,美国FDA批准其作为节食和锻炼疗法的辅助治疗药,适用对象为体质指数(BMI)为30及以上或27及以上且患有与体重相关的疾病(如高血压、高血胆固醇、2型糖尿病等)的成人肥胖者。Qsymia是迄今为止效果最好的减肥药,平均能降低受试者10%的体重,减肥效果是目前市场上其他药物的2倍。Vivus公司已申请Qsymia在中国开展临床试验,其后续进展值得关注。笔者就Qsymia的研发历程、基本性质、作用机制、药动学、药效学、临床试验及应用等研发动态作一概述,以期能为医院临床用药起到指导作用。     

Contrave治疗肥胖的Ⅲ期临床试验达到预期目的

2009年7月2D日，Orexigen Therapeutics公司宣布Contrave（缓释安非他酮＋缓释纳曲酮）治疗肥胖的Ⅲ期临床试验达到预期日的。Contrave为缓释安非他酮纳曲酮构成的复方三层片，在之前的试验中Contrave显示比单独的安非他酮或速释纳曲酮有更强的减肥效果。     

肥胖的药物治疗进展

肥胖已成为一种全球流行病,是导致机体代谢异常的主要诱因,从而引发诸多健康问题,例如心血管疾病、2型糖尿病、卒中等,肥胖甚至与癌症及神经精神疾病的发病风险密切相关.目前治疗肥胖的手段包括生活方式干预以及在此基础上的减肥药物、代谢手术等.本文将对肥胖的药物治疗进展、作用机制和我国肥胖治疗药物的现况进行综述.     

美FDA批准芬特明和托吡酯复合胶囊剂Qsymia长期管理肥胖患者的体重

2012年7月,美国FDA批准了VIVUS有限公司开发的由常释芬特明(phentermine)和控释托吡酯(topiramate)组成的复合胶囊剂Qsymia,用于在低热量饮食和加强运动的基础上长期管理成人体质指数≥30kg/m2(肥胖)或虽体质指数在27～30kg/m2间(超重)、但至少存在1种体重相关疾病(如高血压、2型糖尿病、高脂血症或中心型肥胖)的患者体重。Qsymia有常释芬特明/控释托吡酯7.5/46和15/92mg两种剂量规格,     

肥胖和代谢综合征的药物治疗与研究进展

肥胖与IR被公认为是代谢综合征的重要致病因素,本文通过讨论肥胖和脂肪组织的关系综述了目前食欲抑制剂、消化吸收阻滞剂、降糖药物(双胍类、α-糖苷酶抑制剂、GLP-1和DPP-4抑制剂)和代谢刺激剂在肥胖药物治疗中的研究进展;同时又从脂代谢异常角度讨论了胰岛素增敏剂和调脂药物(他汀类、贝特类和烟酸)在代谢综合征的药物治疗中研究进展。最后结论为调脂药物的研究已获得广泛成效,但新的减肥药物的研发仍有待进一步突破。     

抗晕动病缓控释药物的研究进展

目的:了解抗晕动病药物缓控释制剂的研究进展,以期为该类药物的新剂型研发提供参考。方法:以"晕动病""运动病""东莨菪碱""盐酸苯环壬酯""茶苯海明""Motion sickness""Scopolamine""Phencynonate hydrochloride""Dimenhydrinate"等为关键词,在中国知网、万方数据、Pub Med、Soo PAT等国内外数据库中查询自建库起至2020年11月收录的相关文献和专利,对抗晕动病缓控释制剂的研究进展进行综述。结果与结论:共检索到相关文献和专利143篇,其中有效文献和专利64篇。目前我国市售的抗晕动药物缓控释制剂尚少见。关于抗晕动病药物的缓控释制剂的研究主要围绕着可避免胃肠道首关效应的透皮给药制剂(如贴剂、膜剂、微乳剂、脉冲给药制剂)及鼻用制剂、可实现特定部位高效吸收的新型纳米粒-微球给药系统、工艺稳定且易实现产业化生产的口服缓释制剂以及具有零级释药特征的口服渗透泵控释制剂等开展。军队防治晕动病常常联合使用两种及以上的药物,提示可采用军民融合新药创制思路,通过新制剂技术研制复合型的抗晕动病缓控释药物。此外,将速释和缓控释相结合,研制...     

美国FDA批准体重控制药物芬特明-托吡酯上市

美国FDA于2012年7月17日批准美国VIVUS公司的芬特明-托吡酯(通用名:Phentermine-Top-iramate;商品名:Qsymia)缓释片上市,作为降低饮食热量及增加身体锻炼以外的辅助治疗,用于以下患者:初始体质量指数(BMI)大于或等于30kg/m2(肥胖)的患者;初始BMI大于或等于27kg/m2(超重)且伴有1种或多种与体质量相关并发     

Overview of new antiobesity drugs

A short overview of new drugs approved for the treatment of obesity (lorcaserin, phentermine/topiramate combination) as well as those with a perspective for approval as antiobesity drugs (cetilistat, naltrexone/bupropion combination, liraglutide) is presented. All these drugs produce significant weight loss accompanied by reductions in cardiometabolic health risks. Although the adverse events were rather rare and tended to decrease with the duration of treatment with most of these medications, the drug-specific safety concerns should be seriously considered. In order to ensure an appropriate, efficient and safe implementation of novel antiobesity drugs into the comprehensive treatment of obesity, it will be necessary to establish a network of physicians and other health-care providers well educated in obesity management.     

Current pharmacotherapy for obesity: extrapolation of clinical trials data to practice

Introduction: When used prudently and in combination with lifestyle modification, pharmacotherapy has an important role in the management of obesity.

Areas covered: This review covers targets for antiobesity drugs, challenges and limitations, failed translation of basic science to clinical practice, methodological and regulatory issues in clinical trials of pharmacotherapy, efficacy and risks of drugs currently approved for obesity, and clinical practice issues when using antiobesity drugs with emphasis on recently approved drugs.

Expert opinion: Drugs currently approved for long-term therapy of obesity offer modest benefits for most patients, substantial benefits for some and no benefits for others. Numerous methodological problems including exclusion of the type of patients who are most often seen in clinical practices, inadequate enrollment of men and minorities, exclusion of patients taking antidepressants, high dropout rates, lack of follow-up after treatment discontinuation, and less than ideal imputation methods in data analysis limit the interpretation of clinical trials data and generalizability. Single-drug therapies offer small to moderate weight-loss benefits, but are generally better tolerated. Efficacy is enhanced with combination drug therapies, but so are the hazards. Clinicians should base their decisions on the expected and observed benefit-to-risk balance.     

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).     

Emerging drugs for the treatment of obesity

Introduction: The increasing prevalence of obesity represents a huge threat to public health and the current pharmacological treatment options are limited. Bariatric surgery is by far the most effective treatment for severe obesity, highlighting the urgent need for new and improved drug therapies.

Areas covered: Based on the physiological regulation of energy homeostasis, pharmacological strategies to treat obesity are evaluated with focus on drugs in phase 2 and 3 clinical development. The potential impact of these drugs on current treatment standards and the barriers for development are discussed and set in a historical perspective of previous antiobesity medications.

Expert opinion: The radical effects of bariatric surgery have extended our understanding of the mechanisms controlling appetite and boosted the search for new drug targets in obesity treatment. Accordingly, several compounds targeting the central nervous system and/or periphery are in pipeline for obesity. These drugs should be evaluated over a wide array of end-points; in particular, long-term safety monitoring is necessary as serious adverse events may appear. Combination therapy targeting more than one pathway controlling energy balance might be necessary to achieve substantial weight loss while minimising side effects.     

The limits and challenges of antiobesity pharmacotherapy

ABSTRACT

Introduction

Pharmacotherapy is a useful adjunct when patients with obesity are unable to achieve adequate benefit from lifestyle interventions.     

Carbonic anhydrase inhibitors as emerging drugs for the treatment of obesity

Background: Obesity is a widespread disease in both the developed and developing world. Few pharmacological approaches for its treatment exist at this time. Objective: This review summarises the currently approved obesity therapies and describes a possible new approach for the treatment and prophylaxis of this disease, based on the inhibition of carbonic anhydrases (CAs, EC 4.2.1.1), enzymes involved in several steps of de novo lipogenesis, both in the mitochondria and the cytosol of cells. Methods: Topiramate and zonisamide, two antiepileptic drugs showing strong CA inhibitory properties, have been reported as an example of this approach, as clinical data have shown that these compounds induce persistent weight loss in obese patients. Conclusions: The use of topiramate and zonisamide as lead molecules for the design of CA inhibitors targeting isozymes involved in lipogenesis could represent the beginning of a very promising new approach for the treatment of obesity.     

盐酸绿卡色林的工艺研究

目的 研究减肥药盐酸绿卡色林（1）的合成工艺。方法 以N-烯丙基-N-[2-（4-氯苯基）乙基]氨基甲酸叔丁酯（3）为原料,经一步反应同时实现分子内的傅-克烷基化反应和脱Boc保护基反应,再经L-（+）-酒石酸手性拆分和成盐制备得到1。结果 合成工艺总收率为24.7%,化学纯度为99.9%,光学纯度ee值>99.8%。各中间体和目标产物经¹H NMR、¹³C NMR、ESI-MS表征。结论 所研制的合成工艺路线操作简便、经济实用,适合工业化生产。     

Combination pharmaceutical therapies for obesity

The anti-obesity medications available at present achieve a rather modest degree of weight loss that falls below the expectations of clinicians as well as consumers. Several combination drug therapies are in development with the aim of achieving better results that would be clinically more meaningful in the reduction of obesity-related health risks. This paper discusses the pros and cons of combination therapies, and the ongoing research in this area.     

Lorcaserin Hcl for the treatment of obesity

Introduction: Obesity is a major health priority necessitating safe and effective strategies to address the obesity epidemic. Lorcaserin is a serotonergic agonist specific to the 5HT­ 2C receptor approved for chronic management of obesity in patients with a BMI ≥ 30 kg/m² or a BMI ≥ 27 kg/m² with comorbidities related to obesity.

Areas covered: In this paper, the pharmacodynamic and pharmacokinetic properties of lorcaserin are reviewed followed by a discussion of efficacy and safety data from major clinical trials.

Expert opinion: Lorcaserin is a unique highly selective serotonergic agonist designed to mitigate the risks associated with previous agents in this class. At therapeutic doses, it is well tolerated and produces modest but clinically meaningful weight loss with significant improvement in cardiometabolic parameters. Therapeutic efficacy should be assessed at 12 weeks (≥ 5% weight loss) to identify responders who will derive maximum weight loss and metabolic benefit from long-term therapy. The results of the ongoing cardiovascular outcomes trial (CAMELLIA TIMI 61) will determine the role of lorcaserin in primary prevention of diabetes in overweight/obese individuals and its use in the high-risk population of patients with established cardiovascular disease or multiple cardiovascular risk factors.