肥胖症的药物治疗及其进展

肥胖症是指体内脂肪堆积过多和(或)分布异常,是一种多因素的慢性代谢性疾病。遗传因素、高热量、高脂饮食、体力活动少是肥胖的主要原因。肥胖不仅已成为一种全球性的威胁人类健康的流行病,而且与许多慢性病如高血压、脂质异常、糖尿病、高脂血症、呼吸睡眠暂停等密切相关。因此,肥胖症是众多研究者所关注的问题。食欲抑制药、消化吸收阻滞药、增加能量消耗的药物和中医药等都对肥胖症有治疗作用,本文就近年来肥胖症的药物治疗及其进展作一综述。     

心血管疾病患者肥胖症的药物治疗研究进展

肥胖症与2型糖尿病、高血压、血脂异常及心血管病等多种疾病密切相关。目前,肥胖症药物治疗的研究方向主要是针对身体质量指数(BMI)>30kg/m2或BMI>27kg/m2且患有其他合并症的严重肥胖症患者。但药物的副作用及有关安全性和有效性长期证据的缺乏限制了其使用。本文对治疗肥胖症药物的作用机制、疗效及其对心血管风险的影响作一综述。     

2型糖尿病在研药Trodusquemine完成Ib临床

近日，Genaera生物制药公司对外公布了在研药Trodusquemine的Ib临床试验数据，该药属高选择性PTP1B抑制剂，用于治疗2型糖尿病和肥胖症，是该公司的主要候选药物。在试验中，患有肥胖症和2型糖尿病的患者分别采用8种3mg／m^2剂量的药物进行治疗，用药21天。结果显示，药物在治疗2型糖尿病的4个主要实验终点中效果显著。     

肥胖症的药物治疗及其研究进展

肥胖症的治疗需要综合措施,药物治疗是其中重要的一种手段。目前治疗肥胖症的药物按其不同的作用机制可分为作用于外周的药物（奥利司他）和作用于中枢的药物（西布曲明、芬氟拉明）,本文就其各自的作用机制、作用效果和不良反应等方面作简要综述。     

奥利司他与抗逆转录病毒药物可能存在相互作用

2014年3月13日,英国药品和健康产品管理局（MHRA）发出警告：脂肪酶抑制剂奥利司他可能阻碍亲脂性抗逆转录病毒药物的吸收,影响后者的疗效。奥利司他是长效和强效的特异性胃肠道脂肪酶抑制剂,可配合低热量、低脂饮食治疗肥胖症,在许多国家被列为非处方药。奥利司他阻断脂肪的摄入可以使亲脂性抗逆转录病毒药物在胃肠道滞留或通过时间缩短,     

肥胖症的治疗药物

近期研究表明，每年约有28万人死于“营养过剩”（overnutrition）。因此，目前有关肥胖症的治疗研究日趋增多。本文复习了大量文献，着重阐述了肥胖症的各种治疗药物。1苯丙醇胺（phenylpropanol。xne）研究表明，苯丙醇胺在胃肠道的吸收良好，半减期约4小时。最近的三项安慰剂对照临床试验证实，本品有助于减少肥胖症病人的体重。在其中的一项试验中发现，本丙醇胺具有明显的食欲抑制作用，治疗6周时，苯丙醇胺组的体重较安慰剂组平均多减轻0．9kg。苯丙醇肢的一般耐受性良好。其不良反应如惊厥、头痛、困倦的发生率较低，通常为轻度或中…     

肥胖症的药物治疗

目的：了解肥胖症的药物治疗现状。方法：以近年来国内外有关肥胖症药物治疗在临床上应用的文献报道及上市的药物为材料，按经理作用分类进行介绍。结果：各种减肥药在减轻体重的同时，均会产生一定的不良反应，长期用药的安全性尚未评估。结论：肥胖症的药物治疗必须仔细分析药物疗法的益处和危险性，不宜向肥胖者推荐常规药物疗法。     

新型减肥药Lorcaserin Hydrochloride

肥胖症已影响到全世界数百万人，随着社会经济的发展，物质生活水平的提高，肥胖症的发病率呈明显上升趋势。肥胖不但已经成为一种流行性疾病，还将给患者带来如糖尿病、冠心病、高血压之类的并发症。虽然改变生活方式可以减肥，但药物治疗对某些人群来说也是必不可少的。     

肥胖症治疗的新途径

最近研究发现,ｌｅｐｔｉｎ缺陷与人类肥胖病有关,由此引出了肥胖症治疗药物开发的新方向,如神经肽－Ｙ（ＮＰＹ）拮抗剂在理论上可成为治疗肥胖症的有效药物。另外,一些新的药物已处于开发研制或临床观察阶段,如西布曲明,奥利司他,β３－激动剂和ｂｕｔａｂｉｎｄｉｄｅ。 对人群,家庭,双胞胎等的典型研究发现,肥胖症不仅有后天因素参与,先天性遗传因素也起着重要作用,特别是近年来研究发现ｌｅｐｔｉｎ缺陷与肥胖症有着密切的关系。１Ｌｅｐｔｉｎ系统 Ｔｒａｙｈｕｒｎ对肥胖基因及其所编码的蛋白质ｌｅｐｔｉｎ激素的研究发…     

减肥药Taranabant

肥胖症可广泛引起一系列并发症，尤其是糖尿病、冠心病及高血压等，严重威胁人类健康。与同龄的正常体重个体相比，相对于各种原因的死亡，肥胖症患者的死亡风险率增加50％-100％。而能长期遵循节食和运动疗法的肥胖症患者却很少，许多患者需要药物治疗以降低体重。     

Drug strategies for the treatment of obesity

There are three major classes of drugs for the treatment of obesity: (i) inhibitors of food intake, which reduce hunger perception and, consequently, food intake; the most representative are centrally acting neurotransmitters and intestinal or neural satiety peptides; (ii) inhibitors of nutrient absorption, which reduce energy disposal through a peripheral gastrointestinal mechanism; and (iii) thermogenic drugs, which increase energy expenditure. At present, there are only two drugs for long-term use: sibutramine, an inhibitor of both serotonin and norepinephrine reuptake, and orlistat, a lipase inhibitor that targets pancreatic lipases and reduces absorption of dietary fat. New treatments and better drugs are expected in the near future because of the rapid expansion of research in body-weight regulation mechanisms.     

Pharmacoeconomics of obesity management in childhood and adolescence

The level of fatness of a child at which morbidity acutely increases is operationally determined by calculating the body mass index (BMI). An increased risk of death from cardiovascular disease in adults has been found in subjects whose BMI had been > 75^th percentile as adolescents. Childhood obesity seems to substantially increase the risk of subsequent morbidity whether or not obesity persists into adulthood. Among the most common sequelae of primary childhood obesity are hypertension, dyslipidaemia, back pain and psychosocial problems. Environmental/exogenous factors largely contribute to the development of body fatness early in life. Therapeutic strategies include psychological and family therapy, lifestyle/behaviour modification and nutrition education. The role of regular exercise and exercise programmes is emphasised. Surgical procedures and drugs used in adult obesity are not generally recommended in children and adolescents. Appetite suppressants and thermogenic drugs have not been approved for use in children. Digestive inhibitors such as lipase inhibitors and fat substitutes have been used in children and adolescents in off-label use and in only a few clinical studies. As obesity is the most common chronic disorder in the industrialised societies, its impact on individual lives, as well as on health economics, has to be recognised more widely. One should aim to increase public awareness of the ever increasing health burden and economic dimension of the childhood obesity epidemic that is present around the globe.     

Pharmacoeconomics of obesity management in childhood and adolescence

The level of fatness of a child at which morbidity acutely increases is operationally determined by calculating the body mass index (BMI). An increased risk of death from cardiovascular disease in adults has been found in subjects whose BMI had been > 75(th) percentile as adolescents. Childhood obesity seems to substantially increase the risk of subsequent morbidity whether or not obesity persists into adulthood. Among the most common sequelae of primary childhood obesity are hypertension, dyslipidaemia, back pain and psychosocial problems. Environmental/exogenous factors largely contribute to the development of body fatness early in life. Therapeutic strategies include psychological and family therapy, lifestyle/behaviour modification and nutrition education. The role of regular exercise and exercise programmes is emphasised. Surgical procedures and drugs used in adult obesity are not generally recommended in children and adolescents. Appetite suppressants and thermogenic drugs have not been approved for use in children. Digestive inhibitors such as lipase inhibitors and fat substitutes have been used in children and adolescents in off-label use and in only a few clinical studies. As obesity is the most common chronic disorder in the industrialised societies, its impact on individual lives, as well as on health economics, has to be recognised more widely. One should aim to increase public awareness of the ever increasing health burden and economic dimension of the childhood obesity epidemic that is present around the globe.     

Pancreatic lipase inhibitors from natural sources: unexplored potential

The prevalence of obesity is increasing at an alarming rate, but, unfortunately, only a few medications are currently on the market. Obesity is primarily regarded as a disorder of lipid metabolism and the enzymes involved in this process could be selectively targeted to develop antiobesity drugs. Recently, newer approaches for the treatment of obesity have involved inhibition of dietary triglyceride absorption via inhibition of pancreatic lipase (PL) as this is the major source of excess calories. Natural products provide a vast pool of PL inhibitors that can possibly be developed into clinical products. This article reviews various extracts and secondary metabolites from plants and microbial origin with PL inhibitory activity that can be focused for drug development programs.     

Natural inhibitors of pancreatic lipase as new players in obesity treatment

Obesity is a multifactorial disease characterized by an excessive weight for height due to an enlarged fat deposition such as adipose tissue, which is attributed to a higher calorie intake than the energy expenditure. The key strategy to combat obesity is to prevent chronic positive impairments in the energy equation. However, it is often difficult to maintain energy balance, because many available foods are high-energy yielding, which is usually accompanied by low levels of physical activity. The pharmaceutical industry has invested many efforts in producing antiobesity drugs; but only a lipid digestion inhibitor obtained from an actinobacterium is currently approved and authorized in Europe for obesity treatment. This compound inhibits the activity of pancreatic lipase, which is one of the enzymes involved in fat digestion. In a similar way, hundreds of extracts are currently being isolated from plants, fungi, algae, or bacteria and screened for their potential inhibition of pancreatic lipase activity. Among them, extracts isolated from common foodstuffs such as tea, soybean, ginseng, yerba mate, peanut, apple, or grapevine have been reported. Some of them are polyphenols and saponins with an inhibitory effect on pancreatic lipase activity, which could be applied in the management of the obesity epidemic.     

Novel substituted heteroaromatic compounds as inhibitors of stearoyl-CoA desaturase

Stearoyl-CoA desaturase 1 (SCD1) has been implicated as a novel therapeutic target for the treatment of a variety of metabolic diseases, including diabetes, obesity, hepatic steatosis, atherosclerosis and cardiovascular disease. The application WO2009129625 from Merck Frosst Canada claims novel substituted heteroaromatic compounds as inhibitors of SCD and potential drugs for the pharmacological treatment of metabolic disorders, when used alone or in combination with other drugs. Based on in vitro activity of the patented compounds, these molecules may be considered as potential SCD inhibitors and could be of therapeutic value. However, further preclinical studies are needed to evaluate their curative potential and safety before clinical development.     

Linagliptin and newer DPP-4 inhibitors: newer uses and newer indications

The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin, saxagliptin, vildagliptin and alogliptin are being developed and have been approved for the treatment of type-2 diabetes. These agents may be used either as monotherapy for the treatment of type-2 diabetes or in combination with other anti-diabetic drugs. The present review highlights the use of linagliptin and other new (DPP-4) inhibitors in the management of type-2 diabetes. The review also highlights advantages, comparative pharmacokinetic, safety profile and other potential uses including potential newer indications of DPP-4 inhibitors and relevant patents. The other potential uses that are not restricted to diabetes include obesity, cardiovascular disease, neurological disease, hepatobiliary disease, wound healing, and other inflammatory illnesses.     

二肽基肽酶Ⅳ抑制剂与急性胰腺炎

二肽基肽酶IV（DPP-4）抑制剂是新型口服降糖药物,该类药物能有效降低糖化血红蛋白,耐受性与安全性较好,急性胰腺炎是其少见而严重的不良反应。DPP-4抑制剂致急性胰腺炎潜伏期为14～515d,临床表现为上腹部疼痛,实验室检查可见血清淀粉酶、脂肪酶和弹性蛋白酶水平显著升高。病理学检查可见胰腺和胰周组织水肿和坏死。DPP-4抑制剂致急性胰腺炎的机制主要涉及变态反应和药物或代谢产物对胰腺的直接毒性。有胰腺炎病史者应慎用DPP-4抑制剂。密切注意患者用药情况并监测血清淀粉酶、脂肪酶和弹性蛋白酶水平,是预防DPP-4抑制剂致急性胰腺炎发生和发展的有效措施。     

Antiobesity carbonic anhydrase inhibitors

Few pharmacological approaches for the treatment of obesity exist at this time, and most of them are unsatisfactory, whereas this disease is widespread both in the developed and developing world. Novel effective approaches are needed for the development of antiobesity agents possessing different mechanisms of action. A possible new approach for the treatment and prophylaxis of obesity is 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. Topiramate and zonisamide are two antiepileptic drugs that were shown to induce persistent weight loss in obese patients, but their mechanism of action is largely unknown. We demonstrated strong CA inhibitory properties for these two drugs, by means of kinetic studies in solution and X-ray crystallography, against several physiologically relevant isoforms, such as CA II, VA and VB. It has been proved that topiramate also inhibits lipogenesis in adipocytes, similarly to other sulfonamide CA inhibitors investigated earlier. A large number of new sulfonamides have been synthesized and assayed as possible inhibitors of CA isoforms involved in lipogenesis. This is the beginning of a very new and promising approach for the treatment of obesity, with the hope that new compounds showing this property will be soon developed and available for clinical use.     

Are carbonic anhydrase inhibitors suitable for obtaining antiobesity drugs?

Obesity is widespread disease both in the developed and developing world, which currently affects over 300 million individuals worldwide and is associated with premature mortality and chronic morbidity. Although diet, physical activity and behavioral modifications should theoretically help in controlling this condition, very often these strategies are insufficient to normalize the multiple risks associated with this condition. Thus, pharmacological interventions for the treatment of this disease are essential. Paradoxically, the currently available drugs for the treatment of obesity are very few, their mechanism of action is hardly understood and their side effects are generally quite serious. Therefore, novel effective anti-obesity drugs possessing different mechanisms of action are needed. In this review we describe in detail 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. In particular, we summarize here a series of kinetic and structural studies recently reported on Topiramate (TPM) and Zonisamide (ZNS), two antiepileptic drugs showing strong CA inhibitory properties, that were shown to induce persistent weight loss in obese patients. On the basis of the reviewed studies we suggest that the use of TPM and ZNS as lead molecules for the design of CA inhibitors targeting isozymes involved in lipogenesis could represent the beginning of a very promising approach for the treatment of obesity.