刍议美国罗格列酮的风险评估与减低计划

目的分析美国对罗格列酮的上市后风险管理,以期为我国上市后药品风险管理提供参考和借鉴。方法通过检索FDA和CFDA网站以及相关文献,收集并整理分析罗格列酮相关信息,详细回顾了FDA对罗格列酮采取的风险评估与减低计划（REMS）,同时分析了我国对罗格列酮的上市后监管,并对中美风险干预措施进行比较。结果与结论美国罗格列酮的REMS是罗格列酮上市后风险管理的一项重要举措,严格限制了罗格列酮的使用,对我国上市后药品风险管理具有指导意义。     

罗格列酮与心脏的安全风险

罗格列酮是一种具口服活性的强效胰岛素增敏剂,单独或与二甲双胍联用治疗2型糖尿病的药物。由于可能对血糖和心血管危险因素的有益作用,使它成为对治疗有心血管病高危因素的2型糖尿病患者很有吸引力的药物。近日,FDA发布罗格列酮可能增加心脏病死亡率的安全警示,使用罗格列酮时对心脏的安全性问题引起了广泛关注。本文主要从罗格列酮的心脏风险进行分析,指出在临床使用中应警惕罗格列酮的心血管风险,就药品不良反应监测的薄弱环节,提出医疗单位应谨慎使用新药,全面观察使用药品存在的安全风险,积极上报药品不良反应。药监部门应加强对新药Ⅳ期临床试验的监管,确保用药安全。     

从罗格列酮案例看FDA药品风险管理的实施与应用

目的通过罗格列酮案例分析FDA药品风险管理的实施与应用。方法于2012年12月查阅FDA网站关于罗格列酮风险管理相关信息,运用文献分析的方法进行研究。结果 FDA在药品风险管理的过程中重视药品风险沟通,基于实证理念及REMS的应用。结论学习和运用风险管理和循证理念是我国药品监管的当务之急。     

关于加强罗格列酮及其复方制剂使用管理的通知

各省、自治区、直辖市食品药品监督管理局（药品监督管理局）,卫生厅（局）近年来,国外相关研究机构对罗格列酮使用的安全性进行了研究,结果显示该药品的使用与缺血性心血管疾病的风险增高相关。近期,欧盟、美国等国家的药品管理部门对降糖药物罗格列酮及其复方制剂的上市许可和使用作出严格管理规定。根据相关研究资料,国家食品药品监管局组织相关专家对罗格列酮及其复方制剂在我国临床使用的安全性进行了评估。为保证公众用药安全,现就加强罗格列酮及其复方制剂使用管理的有关事项通知如下：     

大视野

文迪雅在欧洲遭禁 2010—09—23,欧盟药品管理局发布信息,建议暂停文迪雅（罗格列酮）、文达敏（罗格列酮和二甲双胍复方制剂）和Avaglim（罗格列酮和格列美脲复方制剂）的上市许可。同日,美国FDA发布信息,严格限制文迪雅的使用,仅用于那些其他药品不能控制血糖的2型糖尿病患者,但目前正在使用文迪雅并从中受益的患者,如愿意可以继续使用该药品。     

EMEA评估认为罗格列酮和吡格列酮效益大于风险

2007年10月18日，欧洲药品管理局（EMEA）在完成对噻唑烷二酮类药物罗格列酮（商品名：文迪雅）和吡格列酮（商品名：艾可拓）的利弊评估后，认为这些抗糖尿病药物在其适应症范围内仍然效益大干风险。但是，EMEA建议修改罗格列酮产品信息，并建议采取措施进一步提高对罗格列酮和吡格列酮安全性的认识。     

2011年5月美国FDA公布的部分药物警示

1关键词:文迪雅(罗格列酮)心血管事件05/18/2011FDA向公众和医护人员宣布,对处方和使用含罗格列酮的药品增加限制条件。这些药物以Avandia(文迪雅),Avandamet和Avandaryl的名字销售,用于治疗II型糖尿病。对于处方和使用这些药品的医护人员和患者,必     

罗格列酮有心血管风险但现不撤市

2007年7月30日美国FDA顾问委员会就罗格列酮(rosiglitazone,商品名:文迪雅,Avandia)安全性问题举行听证会,认为罗格列酮有心脏风险,但最终还是以22:1的票数通过表决结果,支持在美国市场继续向患者提供罗格列酮。     

关注罗格列酮安全性问题

近日《新英格兰医学杂志》网站刊出的研究报告称，2型糖尿病治疗药物罗格列酮（rosiglitazone）具有潜在的安全性问题。这项对42项临床研究进行的荟萃分析显示，使用罗格列酮治疗2型糖尿病的15500例患者中，心肌梗死及因心血管原因死亡的风险增高。国家食品药品监督管理局（SFDA）目前正对相关数据及资料进行综合分析，并密切关注FDA和欧洲药品评价局（EMEA）的调查结果和该药品在我国临床使用的安全性问题，将及时做出综合性评价。     

罗格列酮心血管风险新证及争议

美国食品药品管理局(FDA)和欧洲药品管理局(EMEA)曾分别评估了罗格列酮的心血管安全性,均认为使用该药的效益大于风险,但加拿大科学家最新发布的一项研究成果再次得出与《新英格兰医学杂志》所发表的荟萃研究相类似的结论,即罗格列酮能够显著增加心血管风险,从而再次引起了对该药安全性的争议。发表于2007年12月12日出版的《美国医学协会杂志》(JAMA)上的这项调查,涉及159026例糖尿病患者(年龄>66岁,服药时间平均为3.8年)。研究人员发现单独服用噻唑烷二酮类药(包括葛兰素史克公司的文迪雅和武田药品公司的艾可拓)的患者发生心肌梗死的…     

Risk communication: the Avandia case, a pilot study

On 21 May 2007, the New England Journal of Medicine published Nissen and Wolski's article entitled 'Effect of rosiglitazone on the risk of myocardial infarcation and death from cardiovascular causes.' The publication of the article had immediate ramifications. The producer of rosiglitazone (under the trademark Avandia(?)); GlaxoSmithKline, saw its share price fall 8% on the day of the publication, and it led to front-page headlines in national newspapers in Europe and North America. This article evaluates the risk-communication strategies of the various actors involved in the Avandia case from the time of the Nissen and Wolski article to the present day. The evaluation is based on a content analysis of a number of USA and UK newspapers from the period January 2007 to May 2008, interviews with GlaxoSmithKline staff, drug regulators (EMEA, Medicines and Healthcare Products Regulatory Agency and US FDA), journalists at the Wall Street Journal and the Financial Times, and advisors to US politicians (Congressional staffers).     

Cardiac ion channel modulation by the hypoglycaemic agent rosiglitazone

The hypoglycaemic thiazolidinedione rosiglitazone is used clinically in the treatment of type 2 diabetes. However, in 2010, information relating to rosiglitazone-associated increased cardiovascular risk led the European Medicines Agency to recommend suspension of marketing authorizations for rosiglitazone-containing anti-diabetes drugs, while the US Food and Drug Administration recommended significant restriction on the agent's use. Two timely studies in this issue of the British Journal of Phrarmacology provide new information regarding modification of cardiac cellular electrophysiology by rosiglitazone. Szentandrássy et al. demonstrate canine ventricular action potential modification and concentration-dependent suppression of L-type Ca current and of transient outward and rapid delayed rectifier K currents. Jeong et al. demonstrate concentration-dependent inhibition of recombinant K(v) 4.3 channels, providing mechanistic insight into the likely molecular basis of transient outward K current inhibition by the compound. Further studies using diabetic models would be of value to determine whether, in a diabetic setting, rosiglitazone modification of these channels could affect the risk of arrhythmia at clinically relevant drug concentrations.     

苯溴马隆对罗格列酮在小鼠体内药动学的影响

目的:探讨罗格列酮在小鼠体内的药动学特征,并考察苯溴马隆对罗格列酮药动学的影响。方法:取小鼠随机分为单用组(罗格列酮0.2mg.kg-1)和联用组(罗格列酮0.2mg.kg-1+苯溴马隆5mg.kg-1)组,每组55只,灌胃给予相应药物,采用高效液相色谱-荧光法,检测给药后0.17、0.33、0.75、1.5、2.0、2.5、4.0、6.0、8.0、12.0、24.0h各组小鼠的罗格列酮血药浓度,采用3p97软件拟合药动学参数。结果:罗格列酮在单用组和联用组小鼠体内的药动学参数分别为cmax:253.1、649.5ng.mL-1,t1/2Ke:0.94、0.74h,AUC0～24h:511.3、1150.9ng.h.mL-1。其中联用组cmax、AUC0～24h与单用组比较明显升高(P<0.05)。结论:苯溴马隆可增强罗格列酮在小鼠体内的吸收。     

Economic model of first-line drug strategies to achieve recommended glycaemic control in newly diagnosed type 2 diabetes mellitus

OBJECTIVE: To assess the short-term direct medical costs and effectiveness associated with achieving recommended glycaemic goals using commonly prescribed first-line oral antihyperglycaemic medications in type 2 diabetes mellitus. MATERIALS AND METHODS: A literature-based, decision-tree model was developed to project the number of patients achieving glycosylated haemoglobin values of <7% on oral therapies and the associated costs over a 3-year timeframe. For each first-line strategy, patients could progress to combination therapy using two or more agents prior to the introduction of insulin. The overall cost of treatment included costs (2001/2002 values; US dollars) of comprehensive medical care, laboratory tests, patient education, drug therapy, home glucose monitoring and adverse events. RESULTS: At 3 years, the overall cost of treatment for the various first-line strategies was 6,106 US dollars for glipizide gastrointestinal therapeutic system, 6,727 US dollars for metformin immediate release, 6,826 US dollars for metformin extended release, 7,141 US dollars for glibenclamide (glyburide)/metformin, 7,759 US dollars for rosiglitazone and 9,298 US dollars for repaglinide. Costs of comprehensive routine medical care ranged from approximately 1,538-2,128 US dollars in year 1 and from approximately 952-1,543 US dollars in subsequent years, for controlled and uncontrolled patients, respectively. Adverse events represented <1%, and drug therapies represented approximately 50%, of the overall cost, respectively. Substantial cost differences between the strategies were seen within the first year. Regardless of first-line therapy, patients progressed quickly to combination therapies, with effectiveness among the agents being similar. CONCLUSIONS: Short-term costs required to provide comprehensive diabetes care and achieve glycemic goals can be substantial. The model suggests a sulphonylurea strategy may provide similar effectiveness with cost savings over other agents and should be considered when selecting an initial drug therapy in newly diagnosed patients with type 2 diabetes mellitus.     

罗格列酮治疗2型糖尿病的研究进展

噻唑烷二酮类药物为治疗2型糖尿病开辟了新途径，本文综述了罗格列酮治疗2型糖尿病的研究进展，分别就其作用机制、药理作用、药动学特性、药物相互作用和不良反应作一概述，为临床用药提供参考。     

Spectrophotometric Determination of Poorly Water Soluble Drug Rosiglitazone Using Hydrotropic Solubilization technique

In the present investigation, hydrotropic solution of urea was employed as a solubilizing agent for spectrophotometric determination of poorly water-soluble drug rosiglitazone maleate. In solubility determination study, it was found that there was more than 14-folds enhancement in solubility of rosiglitazone maleate in a 6M solution of urea. Rosiglitazone maleate obeys Beer's law in concentration range of 5-300 μg/ml. Linearity of rosiglitazone maleate was found in the range of 80-120% of the label claim. The proposed method has been applied successfully to the analysis of the cited drug in pharmaceutical formulations with good accuracy and precision. The method herein described is new, simple, eco-friendly, economic, and accurate and can be utilized in routine analysis of rosiglitazone maleate in bulk drug and tablet dosage form.     

Formulation parameters influencing the physicochemical characteristics of rosiglitazone-loaded cationic lipid emulsion

To enhance the solubility of rosiglitazone, rosiglitazone-loaded cationic lipid emulsion was formulated using cationic lipid DOTAP, DOPE, castor oil, tween 20, and tween 80. The formulation parameters in terms of droplet size were optimized focused on the effect of the cationic lipid emulsion composition ratio on drug encapsulating efficiency, in vitro drug release, and cellular uptake of the rosiglitazone-loaded emulsion. Droplet sizes of a blank cationic emulsion and a rosiglitazone-loaded cationic emulsion ranged between 195-230 nm and 210-290 nm, respectively. The encapsulation efficiency of the rosiglitazone-loaded emulsion was more than 90%. The rosiglitazone-loaded cationic emulsion improved in vitro drug release over the drug alone and showed a much higher cellular uptake than rosiglitazone alone. Moreover, drug loading in cationic emulsions increased cellular uptake of rosiglitazone in insulin-resistant HepG2 cells more than the normal HepG2 cells. Taken together, these results indicate that cationic lipid emulsions could be a potential delivery system for rosiglitazone and could enhance its cellular uptake efficiency into target cells.     

马来酸罗格列酮固体分散体及其溶出速率

目的提高难溶性药物马来酸罗格列酮的体外溶出速率 ,满足脉冲制剂的设计要求。方法选用PVPK3 0为载体 ,用溶剂法制备了马来酸罗格列酮固体分散体 ,比较考察了原料药及其物理混合物和固体分散体的溶出差别 ,并通过红外光谱及X 射线粉末衍射对固体分散体进行了鉴定。结果体外溶出结果表明固体分散体能显著增加药物在水中及人工肠液中的溶出速率 ;红外光谱分析结果表明药物与载体之间没有发生化学反应 ;X 射线粉末衍射图谱表明药物以无定形状态分散于载体PVPK3 0中。结论固体分散体体外溶出速率的提高可以满足脉冲制剂的设计要求。     

Behind the rosiglitazone controversy

On 23 September 2010, the US FDA and the EMA issued statements announcing their response to data implicating the use of the antidiabetes drug rosiglitazone (Avandia(?), GlaxoSmithKline plc, London, UK) with an increased risk of cardiovascular events, including acute myocardial infarction and stroke. The EMA has implemented an immediate suspension of the drug, meaning that it will no longer be available in Europe. The FDA stopped short of a total suspension, but has stated that use of the drug should be restricted to patients with Type 2 diabetes who cannot control their diabetes with other medications. In this article, Bernard Cheung of the Expert Review of Clinical Pharmacology Editorial Advisory Board gives his insight into the matter. Cheung graduated from the University of Cambridge (UK) and received a PhD in Clinical Pharmacology in 1995. He then joined the University of Hong Kong as the Lecturer in Clinical Pharmacology and later became Professor. He held the Chair in Clinical Pharmacology and Therapeutics at the University of Birmingham (UK) in 2007-2009. Cheung's main research interest is in cardiovascular diseases and risk factors, including hypertension and the metabolic syndrome. He works on vasoactive peptides, such as adrenomedullin and urotensin II. He is also interested in clinical trials, meta-analyses, drug utilization and medication safety and is the Chief Editor of the Open Diabetes Journal, and an Executive Editor of the British Journal of Clinical Pharmacology.     

The antidiabetic drug rosiglitazone blocks Kv1.5 potassium channels in an open state

An antidiabetic drug, rosiglitazone is a member of the drug class of thiazolidinedione. Although restrictions on use due to the possibility of heart toxicity have been removed, it is still a drug that is concerned about side effects on the heart. We here examined, using Chinese hamster ovary cells, the action of rosiglitazone on Kv1.5 channels, which is a major determinant of the duration of cardiac action potential. Rosiglitazone rapidly and reversibly inhibited Kv1.5 currents in a concentration-dependent manner (IC₅₀ = 18.9 µM) and accelerated the decay of Kv1.5 currents without modifying the activation kinetics. In addition, the deactivation of Kv1.5 current, assayed with tail current, was slowed by the drug. All of the results as well as the use-dependence of the rosiglitazone-mediated blockade indicate that rosiglitazone acts on Kv1.5 channels as an open channel blocker. This study suggests that the cardiac side effects of rosiglitazone might be mediated in part by suppression of Kv1.5 channels, and therefore, raises a concern of using the drug for diabetic therapeutics.