罗格列酮心血管风险十余年回顾

罗格列酮（Rosiglitazone）是噻唑烷二酮类的代表药物之一,为过氧化物酶PPAR-γ受体的高选择性、强效激动剂,可激活PPAR-γ核受体,对参与葡萄糖生成、     

吡格列酮—水肿与充血性心力衰竭

噻唑烷二酮类药物与体重增加和外周水肿有关。在欧洲，接受胰岛素治疗的糖尿病患者不能再给予格列酮类药物，因为有致充血性心力衰竭（CHF）的可疑风险。在有争议的心血管疾病预防试验PROactive，吡格列酮（PIO）可能增加远期CHF的风险。此Meta分析致力于评估在随机对照研究中PIO与水肿和CHV的风险，并且比较不同治疗方法之间的风险，     

吡格列酮与罗格列酮的药理作用机制有哪些异同？

答吡格列酮和罗格列酮均为噻唑烷二酮类降糖药物,其作用机理均通过激活过氧化物酶体增殖物活化受体-γ（PPAR—γ）,从而增加肝脏以外的组织,如脂肪和肌肉细胞的胰岛素敏感性来降低血糖。由于吡格列酮和罗格列酮的分子结构不同,吡格列酮高选择性地作用于PPAR-γ,因此它们在心血管的安全性方面可能存在差异。     

TZD与老年DM患者的CV不良转归有关

加拿大临床评估科学研究院的研究人员的一项研究发现老年糖尿病（DM）患者接受噻唑烷二酮类药物（TZD）Crosiglitazone（I）（Avandia，Avandamet Avandaryl和吡格列酮（Actos,Duetact）]后更可能发生充血性心力衰竭（CHF）或心肌梗死（MI）和发生死亡。     

罗格列酮的安全性再评价

罗格列酮作为噻唑烷二酮类降糖药,可改善胰岛素的敏感性,击中2型糖尿病的要害——胰岛素抵抗。因其作用新颖、独特,弥补了其他降糖药的不足,自1999年上市以来深受临床医师和患者的青眯,并被广泛使用。但随着罗格列酮的大量使用,临床上对其安全性提出了质疑。早在2003年,临床医师就发现罗格列酮可致患者水钠潴留、体质量增加以及外周水肿,并认为可能与充血性心力衰竭及肺水肿有关[1]。从此,罗格列酮的安全性深受关注。2007     

马来本罗格列酮钠和罗格列酮钠治疗2型糖尿病的疗效及安全性评价

<正>糖尿病是世界范围最常见的流行病之一,已经成为继心血管、肿瘤之后的第三大严重威胁人类健康的非传染病。罗格列酮属于噻唑烷二酮类口服抗糖尿病药,为高选择性过氧化物酶体增殖激活受体(PPAR-γ)激动剂,通过提高脂肪、肌肉和肝脏对胰岛素敏感性(马来酸罗格列酮钠可提高胰岛素敏感性达91%)而控制血糖水平,减少糖尿病并     

格列酮类(glitazones)口服胰岛素增敏剂的研究进展

格列酮类药物是以噻唑烷二酮类化学结构为基础的一系列衍生物，是一类具口服活性的胰岛素增敏剂。研究显示其可选择性地激动过氧化物酶增殖体活化受体－γ（PPAR-γ），通过改善胰岛素抵抗（insulin resistance,IR），不刺激胰岛素分泌，即可减少IR的高血糖、高胰岛素血症及高甘油三酯。临床用于治疗2型糖尿病。可见肝素性。本文概要介绍曲格列酮（troglitazone ,Rezulia)、吡格列酮（pioglitazone,Actos)和罗格列酮（rosiglitazone,Avandia)3种格列酮类药物的化学结构、药理作用、药代动力学及不良反应等的研究进展。     

吡格列酮不良反应国内外研究现状

吡格列酮为噻唑烷二酮类糖尿病治疗药物,具较好的安全性和耐受性,但国内外研究报道其常见的不良反应有低血糖、水肿、骨质疏松;个案报告的不良反应有胸腔积液、贫血、上感、头痛、胃出血、肝功异常等;国外还报道有充血性心力衰竭的发生。本文对该药在国内外研究中出现的不良反应进行系统整理,为国内开展使用该药的不良反应调查提供参考,并同时提醒临床医务工作者关注该药可能发生的不良反应,以保证患者用药安全。     

罗格列酮非降糖作用的研究进展

罗格列酮（Rosiglitazone,RSG）属于噻唑烷二酮类口服降糖药,主要通过结合和活化过氧化物酶体增殖物激活受体γ（PPAR-γ）起作用.其可促进脂肪和其它细胞的分化,增强细胞对胰岛素作用的敏感性,减轻胰岛素抵抗（IR）,系胰岛素增敏药.近年来的研究发现,该药除具有降糖作用外,还具有多方面的药理作用,可用于多种疾病的治疗.     

罗格列酮对大鼠冠状动脉平滑肌外向钾电流的影响

<正>噻唑烷二酮类(TZDs)药物,是合成的过氧化物酶体增殖物激活受体γ(PPAR-γ)选择性激动剂,作为治疗2型糖尿病的药物,通过与存在于胰岛素的主要靶组织如肝脏、脂肪和肌     

Selective peroxisome proliferator-activated receptor-γ modulation to reduce cardiovascular risk in patients with insulin resistance

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone improve glucose homeostasis through activation of peroxisome proliferator-activated receptor (PPAR)-γ. Their use, however, has been limited due to adverse effects that include body weight gain and edema leading to congestive heart failure. Selective PPAR-γ modulators (SPPARMs) are second generation PPAR-γ ligands designed to improve insulin sensitivity with minimal undesirable effects associated with first generation PPAR-γ agonists. INT131 is one of the first SPPARMs to reach human trials. Early phase human studies with INT131 look promising with changes in plasma lipids and glucose being equal or better than what is seen with rosiglitazone and pioglitazone treatment but without evidence of edema. This profile of improved glucose homeostasis, improved plasma lipids, and reduced inflammation in the absence of edema would be expected to reduce cardiovascular risk in patients with Type 2 diabetes mellitus. Recent patents of novel approaches for the use of PPAR-γ related compounds with the potential for this improved risk-benefit ratio are discussed.     

Clinical Trials Reports: Ongoing and planned clinical trials of antiarrhythmic drugs:Cardiovascular & Renal

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-γ (PPARγ) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-γ may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-γ agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-γ agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-γ-modulating activity. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent. The potential utility of the currently available TZDs rosiglitazone and pioglitazone and PPAR-γ-modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular, metabolic and inflammatory diseases in insulin resistant and euglycaemic states is of immense clinical potential and should be investigated.     

Pharmacokinetics, efficacy and safety of aleglitazar for the treatment of type 2 diabetes with high cardiovascular risk

INTRODUCTION: In preliminary clinical studies, aleglitazar, a new dual PPAR-α-γ agonist, has been demonstrated to improve hyperglycemia and dyslipidemia in patients with type 2 diabetes mellitus. This review will provide up-to-date information on the clinical safety and efficacy of aleglitazar, which is currently under Phase III clinical investigation for reduction of cardiovascular events in patients with type 2 diabetes and recent acute coronary syndrome. AREAS COVERED: A PubMed literature search (January 1950 to February 2011) was conducted using the following search terms: aleglitazar, PPAR, PPAR α agonist, PPAR γ agonist and PPAR α/γ agonist. Additional articles were gathered using reference lists from sources obtained from the original literature search. This review summarizes available information pertaining to pharmacodynamics, pharmacokinetics, clinical studies and safety/tolerability of aleglitazar. The effects of this new drug are compared and contrasted with those of fibrates (PPAR-α agonists), thiazolidinediones (PPAR-γ agonists) and other dual PPAR-α-γ agonists. EXPERT OPINION: Preliminary evidence from clinical studies with aleglitazar is promising, with reported improvements in glycemia, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein B and blood pressure. However, PPAR-α- and -γ-associated side effects have been observed and additional large-scale, long-term clinical studies are necessary to better understand the clinical implications of these effects.     

Peroxisome proliferator-activated receptor ligands in atherosclerosis

In this review, the effect of peroxisome proliferator-activated receptor (PPAR) ligands on atherosclerosis is examined. The PPAR-γ agonist thiazolidinediones are currently indicated for the management of Type 2 diabetes mellitus, and the PPAR-α agonist fibrates are used in dyslipidaemia. Here their mechanism of action and the pre-clinical and clinical evidence for the use of these medications for the prevention and treatment of atherosclerotic disease is explored. In addition, the role of PPAR-δ and the possibilities for the role of dual-binding agonists are examined.     

选择性PPARγ调节剂治疗二型糖尿病的分子机制研究进展

第一类胰岛素增敏剂——过氧化物酶体增殖体激活受体γ(PPARγ)激动剂噻唑烷二酮类药物(TZDs)曾在二型糖尿病(T2DM)治疗中具有不可替代的作用。但由于TZDs类药物存在增重、水肿、骨折、充血性心力衰竭等严重副作用,保留TZDs类药物的胰岛素增敏效果而无其副作用的选择性PPARγ调节剂(SPPARγM)是新型胰岛素增敏剂的发展方向。现有实验主要对SPPARγM候选分子影响PPARγ受体构象改变、受体磷酸化、受体对共调节因子的选择性募集和PPARγ下游靶基因选择性开启等几个层次的分子作用机制作了初步探讨。该文综述了SPPARγM治疗二型糖尿病的分子机制研究进展。     

慢性心力衰竭外周血单核细胞PPARγ的表达及与血浆HsCRP的相关性研究

目的：观察慢性心力衰竭（CHF）患者外周血单核细胞中过氧化物酶体增殖物激活受体γ（PPARγ）的表达及其与血浆HsCRP的相关性。方法选取2013年1月-2013年6月在我院心内科住院的CHF患者65例（心功能Ⅱ级22例,心功能Ⅲ级25例,心功能Ⅳ级18例）,正常对照组20例。采用免疫比浊法测定血浆Hs-CRP水平,酶联免疫吸附测定法测定细胞培养上清液TNF-α、IL-6浓度,qRT-PCR方法测定单核细胞中PPARγ表达,并对单核细胞中PPARγ表达和血浆Hs-CRP水平进行相关分析。结果 CHF患者血浆中Hs-CRP水平较对照组升高（P＜0.05）;CHF患者单核细胞培养上清液TNF-α、IL-6较对照组升高（P＜0.05）;CHF患者单核细胞中PPARγ表达较对照组下降（P＜0.05）,并且与血浆中Hs-CRP水平呈负相关（r＝-0.641,P＜0.01）。结论 CHF患者单核细胞中PPARγ表达下降,其可能参与了CHF的炎症与抗炎失衡进程。     

Improvement in long term and visuo-spatial memory following chronic pioglitazone in mouse model of Alzheimer's disease

Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists (thiazolidinediones) are widely prescribed for the treatment of type-II diabetes mellitus. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. The current study was carried out to investigate the effects of chronic administration of pioglitazone, a PPAR-γ agonist, on cognitive impairment in a mouse model of Alzheimer's disease induced by scopolamine. Scopolamine was administered in a dose of 1 mg/kg intraperitoneally (i.p.). Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and escape latency in Morris water maze test. Pioglitazone was also investigated for its effects on parameters of oxidative stress by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels in the brain. Scopolamine produced significant reduction in SDL and prolongation of escape latency indicating cognitive impairment in mice. Pioglitazone (20 and 40 mg/kg, i.p.), administered for 21 days, showed significant dose-dependent improvement in scopolamine-induced dysfunctions in long-term and visuo-spatial memory in passive avoidance and Morris water maze tests, respectively. Furthermore, pioglitazone significantly prevented the fall in GSH levels and elevation in brain MDA levels induced by scopolamine. These results demonstrate that pioglitazone offers protection against scopolamine-induced dysfunctions in long-term and visuo-spatial memory, possibly due to its antioxidant action, and therefore, could have a therapeutic potential in Alzheimer's disease.     

循环利钠肽胶原水平与慢性心力衰竭的关系

目的：探讨慢性心力衰竭（CHF）患者循环利钠肽、胶原水平与心功能的关系。方法：采用放射性免疫法和酶联免疫吸附法检测63例CHF（CHF组：其中NYHAⅡ级17例,Ⅲ级27例,Ⅳ级19例）及17例健康者（对照组）血浆心纳素（ANP）、脑纳素（BNP）、C型利钠肽（CNP）、Ⅰ型前胶原羧基端肽（PICP）、Ⅲ型前胶原端肽（PCⅢ）的浓度,同时用多谱勒超声心动要测定左室射血分数（LVEF）。结果：（1）与对照组比较,心力衰竭患者血浆ANP、BNP、CNP、PICP、PCⅢ浓度显著升高（．P〈0．01）。（2）CHF患者血浆ANP、BNP、PICP、PCⅢ浓度随心功能的恶化逐渐升高（均P〈0．01）,血浆CNP浓度在NYHAⅡ级患者显著升高（P〈0．01）,而NYHAⅢ-Ⅳ级患者血浆CNP浓度无明显改变（P〉0．05）。（3）ANP、BNP、PICP、PCⅢ浓度与LVEF之间呈明显的负相关,BNP的相关性更为显著（P〈0．05。P〈0．01。P〈0．05。P〈0．05）,CNP浓度与LVEF之间无明显相关性（P〉0．05）。结论：血浆利钠肽可反映CHF的发生发展,BNP可评价CHF的严重程度．PICP、PCⅢ可作为CHF时心脏胶原重塑严重程度的检测指标．     

持续静脉微量注射呋塞米对严重充血性心力衰竭患者治疗效果

目的观察对比持续静脉微量注射呋塞米对严重充血性心力衰竭（CHF）患者疗效是否优于传统的间断注射疗效。方法在常规防重构、强心、扩血管的基础上,观察分析72例NYHA心功能Ⅲ-Ⅳ级患者,分为持续静脉微量注射呋塞米组（观察组）35例和间断注射呋塞米组（对照组）37例,两组使用呋塞米剂量大致相同,比较两组治疗前后尿量、血压波动、血液电解质浓度、超声心动图心功能指标、症状缓解时间和水肿消退时间的差别。结果观察组治疗后尿量多于对照组,心功能指标FS和LVEF改善显著优于对照组,症状缓解时间和水肿消退时间短于对照组（P〈0.01或0.05）;血压和血液电解质浓度无显著差异（P〉0.05）。结论持续静脉微量注射呋塞米治疗严重CHF,疗效明显优于传统的间断静脉注射法。