第四讲：噻唑烷二酮类治疗2型糖尿病的疗效及安全性

胰岛素抵抗 (ＩＲ)和胰岛素分泌缺陷为 2型糖尿病发病机制的两大要素 ,改善ＩＲ以治疗 2型糖尿病为研制新药的一条主线。 80年代初研制出噻唑烷二酮类化合物 (Ｔｈｉｏｚｏ ｌｉｄｉｎｅｄｉｏｎｅｓ ,ＴＺＤｓ) ,于糖尿病动物可减轻ＩＲ并改善糖代谢 ,第一种为环格列酮 (Ｃｉｇｌｉｔａｚｏｎｅ) ,以后又研制出一系列ＴＺＤｓ。最早进行临床开发研究者为曲格列酮 (Ｔｒｏｇｌｉｔａｚｏｎｅ,ＴＲＧ) ,随后用于临床者有罗格列酮 (Ｒｏｓｉｇｌｉｔａｚｏｎｅ,ＲＳＧ)、吡格列酮 (Ｐｉｏｇｌｉｔａｚｏｎｅ ,ＰＩＯ) ,作为药物 ,统称格列酮类…     

噻唑烷二酮类降糖药物与骨质疏松症

噻唑烷二酮类降糖药物因能改善胰岛素抵抗,临床广泛用于2型糖尿病、多囊卵巢综合征及非酒精性脂肪肝的治疗。最近研究结果提示,噻唑烷二酮类降糖药物在改善胰岛素抵抗降血糖的同时,可提高骨质疏松症及骨质疏松骨折的风险。本文综述了噻唑烷二酮类降糖药物致骨丢失的相关证据和增加骨质疏松症及骨质疏松骨折风险的可能病理机制,并探讨其临床防治策略。     

噻唑烷二酮类降糖药——一把双刃剑

随着我国经济发展和人民生活水平的改善,代谢性疾病的发生呈直线上升的趋势。其中糖尿病,特别是2型糖尿病患病人数在过去的1/4世纪中上升了约60倍。更为严重的是这种上升趋势远未得到控制。目前我国应对糖尿病的策略除了加强糖尿病预防外,迫切的任务是有效控制目前高达6千万的糖尿病患者的血糖,从而最大程度的减少糖尿病并发症的发生。对1型糖尿病而言,其治疗选择以补充外源胰岛素为主;而对2型糖尿病而言,由于其基本病生理过程是胰岛素抵抗,所以长期以来治疗重点在改善患者的胰岛素敏感性方面。其中以罗格列酮(文迪雅)和匹格列酮(艾可拓)为…     

噻唑烷二酮类药物与心脏的安全性

糖尿病是慢性、进行性加重的疾病。随着糖尿病病程的延长，糖尿病患者发生微血管和大血管并发症的危险性明显增加。心血管疾病(CVD)是糖尿病患者死亡的主要原因。多年来的研究显示，2型糖尿病的主要发病原因是胰岛素抵抗和胰岛β细胞功能的缺陷。在胰岛β细胞功能下降的情况下，胰岛素抵抗可导致血糖增高。除此之外，胰岛素抵抗     

噻唑烷二酮类对NASH的作用——系统回顾和荟萃分析

非酒精性脂肪性肝病(NAFLD)被认为是代谢综合征在肝脏的一个表现,普遍认为和胰岛素抵抗(IR)有关,当存在二次(或多次)打击,包括氧化应激、内质网应激、游离脂肪酸的脂毒性、细胞因子和肠道菌群失调等,就会导致细胞脂肪变性、炎症坏死和疾病的进展(综合反应假说),即处于非酒精性脂肪性肝炎(NASH)状态.     

噻唑烷二酮类药物对糖尿病肾脏的保护作用

噻唑烷二酮类药物(TZDs)是一类新型的糖尿病治疗药物。大量的研究表明，TZDs通过抑制二脂酰甘油(DAG)—蛋白激酶C(PKC)—细胞外信号调节激酶(ERK)信号转导途径，改善肾小球高滤过状态；调节系膜细胞及肾小管上皮细胞增殖、分化，减轻肾脏损害；减少炎性细胞因子产生，改善胰岛素抵抗；纠正脂代谢紊乱，减轻对肾脏的脂毒性，从而发挥对糖尿病肾脏的保护作用。     

过氧化物酶体增殖物激活受体-Υ与溃疡性结肠炎及其癌变

过氧化物酶体增殖物激活受体(PPARs)是配体激活的核转录因子,属细胞核激素受体超家族成员有PPAR-α、Υ和B/δ三种亚型.近年研究显示PPAR-Υ在维持肠道免疫平衡、抗炎、抗肿瘤等方面发挥重要作用.溃疡性结肠炎(UC)患者存在不同程度的PPAR-Υ表达障碍.本文就PPAR-Υ及其配体在UC结肠炎症和结肠炎癌变中的研究进展作一综述.     

过氧化物酶体增殖物激活受体-γ与溃疡性结肠炎及其癌变

过氧化物酶体增殖物激活受体（PPARs）-γ体激活的核转录因子,属细胞核激素受体超家族成员,有PPAR-γ、1和B,6三种亚型。近年研究显示PPAR-γ在维持肠道免疫平衡、抗炎、抗肿瘤等方面发挥重要作用。溃疡性结肠炎（UC）患者存在不同程度的PPAR-γ表达障碍。本文就PPAR-γ及其配体在UC结肠炎症和结肠炎癌变中的研究进展作一综述。     

噻唑烷二酮类药物对动脉粥样硬化的影响

2型糖尿病(noninsulin-dependent diabetes mellitus,NIDDM)对心血管疾病(CVD)的发病和死亡产生严重影响.动脉粥样硬化(AS)是CVD增加的主要原因.NIDDM患者的AS更广泛、更严重[1].     

英夫利昔治疗溃疡性结肠炎临床疗效的荟萃分析

目的采用荟萃分析的方法,探讨英夫利昔(Infliximab,IFX)治疗溃疡性结肠炎(ulcerative colitis,UC)的疗效。方法全面检索并收集研究IFX治疗UC的临床随机对照试验。纳入7篇文献,共有7个随机对照实验(RCT)。质量评价、独立提取资料后以RevMan 4.2分析。结果荟萃分析显示:比较IFX与安慰剂治疗UC的长期、短期疗效,结果均有显著差异。比较IFX 5 mg、10mg与安慰剂组短期、长期的疗效,结果有显著差异。IFX的短期及长期疗效与激素相比,结果无显著差异。IFX与安慰剂的不良反应结果无显著差异。结论 IFX可以诱导UC的临床缓解及维持,而且对于难治性中重度UC,IFX可以使患者减少结肠切除率,提高生活质量。但是仍然需要大样本多中心的随机对照试验来进一步验证。     

噻唑烷二酮类药物对脂肪细胞增殖与分化的影响及其临床应用

目的研究噻唑烷二酮类代表药物曲格列酮对人大网膜前脂肪细胞增殖和分化的影响及其临床应用意义。方法体外培养人大网膜前脂肪细胞,曲格列酮作用后,四唑盐(MTT)比色法观察细胞增殖;油红O染色抽提法观察细胞分化。结果浓度为1μmol/L,10μmol/L曲格列酮能够明显促进前脂肪细胞的增殖,同时也促进前脂肪细胞向脂肪细胞分化。结论噻唑烷二酮类药物促进前脂肪细胞成熟,发挥脂肪组织完善的储脂和内分泌功能,改善胰岛素抵抗状态。在临床上,对于以胰岛素抵抗为基础的糖尿病和动脉粥样硬化等疾病应作为基础用药。     

噻唑烷二酮类药物抗动脉粥样硬化作用研究进展

过氧化物酶体增殖物激活受体（peroxisomeproliferatorsactivatedreceptor,PPAR）是一类由配体激活的核转录受体,分为PPARα、PPARβ和PPARγ。噻唑烷二酮类药物（thiazolidinediOnes,TZDs）是PPARγ的合成配基,可以激活PPARγ,改善胰岛素抵抗,增加脂肪酸氧化。近年来,越来越多的研究证实,心血管系统是PPARγ的功能靶标,而PPARγ在心血管系统的广泛表达是TZDs作用于心血管系统的基础。现就其抗动脉粥样硬化（atherosclerosis,AS）作用进展作一综述。     

抗肿瘤坏死因子α制剂治疗溃疡性结肠炎的荟萃分析

目的 根据现有临床研究评价抗TNFα制剂治疗溃疡性结肠炎(UC)的疗效与安全性.方法 检索Cochrane图书馆、EMBASE、PubMed、OVID数据库和中国知网、万方数据库、维普数据库中有关抗TNFa制剂[英夫利西单抗、阿达木单抗、塞妥珠单抗、依那西普、奥那西普、CDP571、CNI-1493、沙利度胺]治疗UC的RCT文献,采用Revman 5.0软件进行分析,并绘制漏斗图评定有无发表偏倚.结果 共9项RCT研究符合纳入标准,共包括1226例UC患者,其中806例接受抗TNFα制剂治疗,420例接受安慰剂或其他对照药物治疗.荟萃分析显示,在短期应答、短期缓解、长期应答、长期缓解方面,抗TNFα制剂明显优于对照组,OR值分别为2.36(95%CI 1.34～4.15)、2.42(95%CI 1.22～4.81)、3.22(95%CI 2.28～4.55)、2.82(95%CI 1.91～4.16).与对照组相比,抗TNFα制剂可以降低结肠切除率,OR值为0.31(95%CI 0.20～0.48);但在结肠黏膜愈合方面[OR值为1.59(95%CI 0.91～2.78)]及生活质量方面[炎症性肠病问卷(IBDQ)评分的加权均数差(WMD)为24.00(95%CI为-0.95～48.95)],两组的差异均无统计学意义.在安全性方面,两组不良反应发生率相似,OR值为1.07(95%CI0.55～2.09,P=0.84),但抗TNFα制剂的重度不良反应发生率明显低于对照组,OR值为0.65(95%CI 0.48～0.89).各计数资料观察指标的漏斗图均基本呈现下宽上窄、左右对称的图形,提示无发表偏倚.结论 抗TNFα制剂对于常规药物治疗无效的中、重度UC有较好的疗效,可以诱导UC短期应答,降低结肠切除率,并可维持长期的临床应答与临床缓解,严重不良反应的发生率较低,但抗TNFα制剂未能提高UC患者的生活质量与黏膜愈合率.

Abstract：

Objective To pool the data of studies and evaluate the efficacy and safety of TNFα blocking agents in the treatment of ulcerative colitis(UC).Methods The randomized clinical trials(RCT)that compared the efficacy or safety of TNFα in the treatment of UC were researched from Pubmed. OVID. EMBASE. Cochrane library, CNKI, Wanfang data and VIP Chinese Scientific and Technologic Periodical Database. Statistical heterogeneity between trials was evaluated by Revman 5.0 and was considered to exist when P＜0.1.Heterogeneity of the included articles was tested. which was used to select proper effect model to calculate. Publication bias was investigated through visual inspection of funnel plots. Results Nine RCT including 1226 cases were analyzed. Eight hundred and six cases had received TNFα treatment and 420cases had received placebo or glucocorticoid treatment. Compared with placebo or glucocorticoid groups, TNFα group achieved significantly higher rates of short-term clinical response, short-term clinical remission, long-term clinical response.10ng-term clinical remission and the total OR were 2.36(95%C,1.34-4.15),2.42(95%CI 1.22-4.81).3.22(95%CI2.28-4.55)and 2.82(95%CI1.91-4.16)respectively. TNFα group was less likely to undergo colectomy than placebo group and the total OR was 0.31(95%CI0.20-0.48).TNFα could not improve the mucosal healing and quality of lire. No significant difference was found in adverse effect between TNFα group and placebo or glueoeortieoid group(OR=1.07(95%CI0.55-2.09,P=0.84)).The rate of serious adverse effect in TNFα group was less than placebo or glueoeorticoid groups (OR=0.65,95%CI0.48-0.89,P=0.007).Inspection of the funnel plots for all dichotomous data measures had not revealed evidence of publication bias. Conclusions Patients with moderately to severely active UC treated with TNFαhave effective clinical response and clinical remission and are less likely to undergo colectomy than those receiving placebo or glucocorticoid. TNFα treatment is safe for UC but can not improve the mucosal healing and quality of life. Large-scale, high-quality RCTs ale needed to confirm or refuse the available evidence.     

结肠炎丸治疗老年溃疡性结肠炎疗效观察

溃疡性结肠炎病因比较复杂 ,病程迁延 ,易复发 ,目前尚无特效治疗方法。我们近年内使用结肠炎丸治疗老年性溃疡性结肠炎 34例 ,并与柳氮磺胺吡啶 (ＳＡＳＰ)进行对照观察 ,现将结果报道如下。1　对象与方法1 1　病例选择　本组病例为我院 1995～1999年收治溃疡性结肠炎 12 6例 ,其中老年溃疡性结肠炎 6 4例。溃疡性结肠炎诊断符合 1993年太原全国慢性非感染性肠道疾病学术研讨会所规定的溃疡性结肠炎诊断标准。 6 4例中男 42例 ,女 2 2例 ,年龄 6 0～ 74岁 ,平均 ( 6 4 5± 0 6 )岁。初发型 15例 ,慢性复发型 19例 ,慢性持续型 30例。病程 …     

噻唑烷二酮类药物在治疗心血管疾病中的研究现状

噻唑烷二酮类化合物(thiazolidinediones,TZDs)在Ⅱ型糖尿病治疗中已有10年的历史。经分析发现,TZDs不但可以控制血糖、改善胰岛素敏感性,而且可以改善糖尿病患者的心血管参数。过氧化物酶体增殖物激活受体γ(PPAR-γ)是TZDs的主要作用靶点,探讨TZDs/PPAR-γ的作用机制及与心血管疾病的关系具有重要意义。本文将就TZDs在心血管疾病中的研究现状进行综述。     

抗肿瘤坏死因子α制剂治疗溃疡性结肠炎的荟萃分析

Objective To pool the data of studies and evaluate the efficacy and safety of TNFα blocking agents in the treatment of ulcerative colitis(UC).Methods The randomized clinical trials(RCT)that compared the efficacy or safety of TNFα in the treatment of UC were researched from Pubmed. OVID. EMBASE. Cochrane library, CNKI, Wanfang data and VIP Chinese Scientific and Technologic Periodical Database. Statistical heterogeneity between trials was evaluated by Revman 5.0 and was considered to exist when P＜0.1.Heterogeneity of the included articles was tested. which was used to select proper effect model to calculate. Publication bias was investigated through visual inspection of funnel plots. Results Nine RCT including 1226 cases were analyzed. Eight hundred and six cases had received TNFα treatment and 420cases had received placebo or glucocorticoid treatment. Compared with placebo or glucocorticoid groups, TNFα group achieved significantly higher rates of short-term clinical response, short-term clinical remission, long-term clinical response.10ng-term clinical remission and the total OR were 2.36(95%C,1.34-4.15),2.42(95%CI 1.22-4.81).3.22(95%CI2.28-4.55)and 2.82(95%CI1.91-4.16)respectively. TNFα group was less likely to undergo colectomy than placebo group and the total OR was 0.31(95%CI0.20-0.48).TNFα could not improve the mucosal healing and quality of lire. No significant difference was found in adverse effect between TNFα group and placebo or glueoeortieoid group(OR=1.07(95%CI0.55-2.09,P=0.84)).The rate of serious adverse effect in TNFα group was less than placebo or glueoeorticoid groups (OR=0.65,95%CI0.48-0.89,P=0.007).Inspection of the funnel plots for all dichotomous data measures had not revealed evidence of publication bias. Conclusions Patients with moderately to severely active UC treated with TNFαhave effective clinical response and clinical remission and are less likely to undergo colectomy than those receiving placebo or glucocorticoid. TNFα treatment is safe for UC but can not improve the mucosal healing and quality of life. Large-scale, high-quality RCTs ale needed to confirm or refuse the available evidence.     

抗肿瘤坏死因子α制剂治疗溃疡性结肠炎的荟萃分析

Objective To pool the data of studies and evaluate the efficacy and safety of TNFα blocking agents in the treatment of ulcerative colitis(UC).Methods The randomized clinical trials(RCT)that compared the efficacy or safety of TNFα in the treatment of UC were researched from Pubmed. OVID. EMBASE. Cochrane library, CNKI, Wanfang data and VIP Chinese Scientific and Technologic Periodical Database. Statistical heterogeneity between trials was evaluated by Revman 5.0 and was considered to exist when P＜0.1.Heterogeneity of the included articles was tested. which was used to select proper effect model to calculate. Publication bias was investigated through visual inspection of funnel plots. Results Nine RCT including 1226 cases were analyzed. Eight hundred and six cases had received TNFα treatment and 420cases had received placebo or glucocorticoid treatment. Compared with placebo or glucocorticoid groups, TNFα group achieved significantly higher rates of short-term clinical response, short-term clinical remission, long-term clinical response.10ng-term clinical remission and the total OR were 2.36(95%C,1.34-4.15),2.42(95%CI 1.22-4.81).3.22(95%CI2.28-4.55)and 2.82(95%CI1.91-4.16)respectively. TNFα group was less likely to undergo colectomy than placebo group and the total OR was 0.31(95%CI0.20-0.48).TNFα could not improve the mucosal healing and quality of lire. No significant difference was found in adverse effect between TNFα group and placebo or glueoeortieoid group(OR=1.07(95%CI0.55-2.09,P=0.84)).The rate of serious adverse effect in TNFα group was less than placebo or glueoeorticoid groups (OR=0.65,95%CI0.48-0.89,P=0.007).Inspection of the funnel plots for all dichotomous data measures had not revealed evidence of publication bias. Conclusions Patients with moderately to severely active UC treated with TNFαhave effective clinical response and clinical remission and are less likely to undergo colectomy than those receiving placebo or glucocorticoid. TNFα treatment is safe for UC but can not improve the mucosal healing and quality of life. Large-scale, high-quality RCTs ale needed to confirm or refuse the available evidence.     

噻唑烷二酮：一类新的糖尿病治疗药物

２型糖尿病是一种严重危害人类健康的常见内分泌代谢疾病。尽管其发病机制尚未完全阐明，但多数学者认为胰岛素抵抗可能是其原发病因，故消除或减轻胰岛素抵抗对于其治疗具有重要意义。遗憾的是，目前对胰岛素抵抗这一发病环节尚缺乏很有效的干预手段。八十年代初，一些...     

抗肿瘤坏死因子α制剂治疗溃疡性结肠炎的荟萃分析

Objective To pool the data of studies and evaluate the efficacy and safety of TNFα blocking agents in the treatment of ulcerative colitis(UC).Methods The randomized clinical trials(RCT)that compared the efficacy or safety of TNFα in the treatment of UC were researched from Pubmed. OVID. EMBASE. Cochrane library, CNKI, Wanfang data and VIP Chinese Scientific and Technologic Periodical Database. Statistical heterogeneity between trials was evaluated by Revman 5.0 and was considered to exist when P＜0.1.Heterogeneity of the included articles was tested. which was used to select proper effect model to calculate. Publication bias was investigated through visual inspection of funnel plots. Results Nine RCT including 1226 cases were analyzed. Eight hundred and six cases had received TNFα treatment and 420cases had received placebo or glucocorticoid treatment. Compared with placebo or glucocorticoid groups, TNFα group achieved significantly higher rates of short-term clinical response, short-term clinical remission, long-term clinical response.10ng-term clinical remission and the total OR were 2.36(95%C,1.34-4.15),2.42(95%CI 1.22-4.81).3.22(95%CI2.28-4.55)and 2.82(95%CI1.91-4.16)respectively. TNFα group was less likely to undergo colectomy than placebo group and the total OR was 0.31(95%CI0.20-0.48).TNFα could not improve the mucosal healing and quality of lire. No significant difference was found in adverse effect between TNFα group and placebo or glueoeortieoid group(OR=1.07(95%CI0.55-2.09,P=0.84)).The rate of serious adverse effect in TNFα group was less than placebo or glueoeorticoid groups (OR=0.65,95%CI0.48-0.89,P=0.007).Inspection of the funnel plots for all dichotomous data measures had not revealed evidence of publication bias. Conclusions Patients with moderately to severely active UC treated with TNFαhave effective clinical response and clinical remission and are less likely to undergo colectomy than those receiving placebo or glucocorticoid. TNFα treatment is safe for UC but can not improve the mucosal healing and quality of life. Large-scale, high-quality RCTs ale needed to confirm or refuse the available evidence.