复方醋酸环丙孕酮和罗格列酮序贯用药对氯米芬抵抗的多囊卵巢综合征患者内分泌及生育功能的影响

目的探讨复方醋酸环丙孕酮和罗格列酮序贯用药对改善多囊卵巢综合征（PCOS）患者生育功能的临床疗效。方法30例氯米芬抵抗的PCOS胰岛素抵抗患者，口服复方醋酸环丙孕酮3个月后，罗格列酮联合氯米芬用药6个月，比较用药前后体重指数、月经周期、生殖激素水平、排卵率、妊娠率、血糖和胰岛素水平的变化。结果与用药前相比，服用复方醋酸环丙孕酮后，雄激素水平和LH／FSH值明显降低（P〈0．05），服用罗格列酮后，胰岛素抵抗指数（Homa IR）、胰岛素分泌指数（Homa β）以及β细胞功能评定指数（MBCI）均较用药前降低（P〈0．05）。结论复方醋酸环丙孕酮和罗格列酮序贯用药可有效地抑制氯米芬抵抗的PCOS患者的高雄激素血症，改善胰岛素抵抗及生育功能。     

二甲双胍和罗格列酮对肥胖型PCOS治疗作用的对照性研究

目的观察罗格列酮和二甲双胍联合氯米芬治疗肥胖型多囊卵巢综合征患者的内分泌改善及生殖功能的临床疗效。方法50例肥胖型PCOS患者分别给予罗格列酮4mg/d和二甲双胍1500mg/d联合氯米芬100mg/d,治疗3个月,比较治疗前后体重指数、内分泌参数、腰臀比和Hom a IR的变化。结果用罗格列酮治疗后排卵率为88%,周期排卵率为64.29%,优势卵泡平均个数为1.8±0.8个,妊娠率为56%,而用二甲双胍治疗后分别为72%、54.84%、1.1±0.6个、48%。两者治疗后能使LH、LH/FSH、T的血清浓度明显下降,SHBG的浓度明显上升,Hom a IR明显改善。结论罗格列酮和二甲双胍联合氯米芬治疗肥胖型多囊卵巢综合征疗效可靠。二甲双胍有降低体重作用、价格便宜,适用于肥胖型P-COS伴胰岛素抵抗不严重者;罗格列酮在胰岛素增敏作用优于二甲双胍,适用于胰岛素抵抗较严重的PCOS患者。     

国产罗格列酮胶囊在健康人体的相对生物利用度

目的研究健康受试者口服罗格列酮胶囊的药代动力学。方法20名健康受试者随机服用罗格列酮受试和参比制剂各4mg,用HPLC-MS法测定血浆中罗格列酮的浓度。结果经3P97程序处理,主要药代动力学参数如下。罗格列酮胶囊剂:t1/2为(5.18±0.84)h,AUC0-24h为(2.13±0.21)μg·h·mL-1,Cmax为(305.31±38.21)ng·mL-1,tmax为(1.1±0.4)h;罗格列酮片剂:t1/2为(5.10±0.64)h,AUC0-24h为(2.20±0.20)μg·h·mL-1,Cmax为(318.84±38.38)ng·mL-1,tmax为(1.2±0.3)h。罗格列酮受试和参比制剂的相对生物利用度为(97.6±12.7)%。结论2制剂具有生物等效性。     

罗格列酮增强顺铂抑制人肺腺癌细胞增殖作用

目的　探讨过氧化物酶体增殖因子活化受体γ(PPARγ)配体罗格列酮 (Rosiglitazone,RSG)的体外化疗增敏作用及机制。方法　体外培养人肺腺癌A549细胞,MTT法测定药物的细胞生长抑制率,吖啶橙 /溴化乙啶 (AO/EB)荧光双染,流式细胞仪(Flowcytometry,FCM)检测细胞凋亡,免疫细胞化学检测药物处理前后PPARγ,Bcl 2蛋白表达的改变。结果　RSG(1 25, 2 5μmol·L-1 )分别与CDDP合用,可增加CDDP对A549细胞的抑制率, (q> 1 )。RSG(1 25μmol·L-1 )可增强CDDP诱导A549细胞凋亡作用。RSG(1 25μmol·L-1 )处理后,A549细胞的PPARγ蛋白核内表达上调,Bcl 2蛋白表达下调, (P<0 01)。结论　过氧化物酶体增殖因子活化受体γ配体罗格列酮能增强顺铂抑制A549细胞增殖并诱导凋亡作用。PPARγ蛋白核内表达上调,Bcl 2蛋白表达下调在罗格列酮对A549细胞体外化疗增敏作用中发挥重要的作用。目的　探讨过氧化物酶体增殖因子活化受体γ(PPARγ)配体罗格列酮 (Rosiglitazone,RSG)的体外化疗增敏作用及机制。方法　体外培养人肺腺癌A549细胞,MTT法测定药物的细胞生长抑制率,吖啶橙 /溴化乙啶 (AO/EB)荧光双染,流式细胞仪(Flowcytometry,FCM)检测细胞凋亡,免疫细胞化学检测药物处理前后PPARγ,Bcl 2蛋白表达的改变。结果　RSG(1 25,     

基于报告基因和PPARγ信号通路的药物筛选模型的建立

目的　建立基于报告基因和PPARγ(peroxisomeprolif erator activatedreceptorγ)信号通路的药物筛选模型,用此模型筛选具有胰岛素增敏活性的小分子化合物。方法　五种细胞分别进行瞬时转染,将含有目的片段PPRE(peroxisomeproliferatorresponseelement)和报告基因荧光素酶(Luc)的质粒及表达PPARγ的质粒共转染到细胞中,通过测定荧光素酶活力来考察马来酸罗格列酮对PPARγ信号通路的影响,选取诱导表达倍数最高的细胞株建立模型。用其他类型核受体激动剂对此模型进行特异性考察。结果　293T细胞中,荧光素酶的表达受马来酸罗格列酮的诱导倍数最高,可达4 9倍,并呈现一定的剂量依赖关系,Z′因子为0 .72。而其他各类核受体激动剂的诱导表达率均在1倍左右。马来酸罗格列酮在转染剂量范围内无促进细胞增殖的作用。结论　马来酸罗格列酮对共转染报告基因质粒和表达PPARγ质粒的293T细胞Luc的表达具有较强的诱导作用,此模型具有较好的特异性和稳定性,适用于建立筛选PPARγ激动剂的高通量筛选模型。     

Rosiglitazone may reduce thyroid cancer risk in patients with type 2 diabetes

Abstract

Background. Whether rosiglitazone use in patients with type 2 diabetes may affect thyroid cancer risk has not been investigated.

Methods. The reimbursement databases of all diabetic patients under oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance of Taiwan. An entry date was set at 1 January 2006, and 887,665 patients with type 2 diabetes were followed for thyroid cancer incidence until the end of 2009 for ever-users, never-users, and subgroups of rosiglitazone exposure using tertile cut-offs for time since starting rosiglitazone, duration of therapy, and cumulative dose. Hazard ratios were estimated by Cox regression.

Results. There were 103,224 ever-users and 784,441 never-users, with respective numbers of incident thyroid cancer of 84 (0.08%) and 764 (0.10%), and respective incidence of 23.12 and 28.09 per 100,000 person-years. The overall multivariable-adjusted hazard ratio was not significant. However, in dose-response analyses, the adjusted hazard ratios (95% confidence intervals) were significant for the third tertile of duration of therapy (≥ 14 months) and cumulative dose (≥ 1,800 mg) for age ≥ 50 years: 0.53 (0.31–0.89) and 0.50 (0.29–0.87), respectively.

Conclusions. This study suggests that rosiglitazone use in patients with type 2 diabetes may reduce the risk of thyroid cancer.     

噻唑烷二酮类药物对氯米芬抵抗型的多囊卵巢综合征不孕患者治疗有效性的Meta分析

目的:系统评价罗格列酮、吡格列酮等噻唑烷二酮类药物(TZD)治疗氯米芬(CC)抵抗型多囊卵巢综合征(PCOS)不孕患者的疗效。方法:计算机检索Pubmed、Embase、Cochrane Library、Web of Science、CNKI、维普、生物医学文献、万方等数据库,检索时间截止至2015年1月。由两名评价者按照纳入与排除标准独立筛选文献、提取资料并评价纳入研究的方法学质量后,采用Rev Man 5.3软件进行Meta分析。结果:最终纳入4个随机对照研究,222例CC抵抗型PCOS不孕患者。Meta分析结果表明,TZD组在排卵率、妊娠率、成熟卵泡数、改善卵泡刺激素(FSH)、黄体生成素(LH)、睾酮(T)方面均优于对照组,其中提高排卵率[MD=2.14;95%CI(1.16,3.95),P=0.02]、妊娠率[MD=2.02;95%CI(1.14,3.58),P=0.02]、增加成熟卵泡数[MD=0.82;95%CI(0.61,1.04),P<0.01]及降低LH值[MD=-1.18;95%CI(-1.76,-0.60),P<0.01]等4个结局指标的两组间差异具有统计学意义。结论:对于生育要求较强、经济条件好且胰岛素抵抗较严重的CC抵抗型PCOS患者,可首选TZD预治疗。     

Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes

Aim: This study assessed the efficacy and safety of two different dosing regimens of fixed‐dose combination (FDC) rosiglitazone (RSG) plus glimepiride (GLIM) compared with RSG or GLIM monotherapy in drug‐naive subjects with type 2 diabetes mellitus (T2DM). Methods: Drug‐naive subjects (n = 901) were enrolled into this 28‐week, double‐blind, parallel‐group study if their glycosylated haemoglobin A_1c (HbA_1c) was >7.5% but ≤12%. Subjects were randomized to receive either GLIM [4 mg once daily (OD) maximal], RSG (8 mg OD maximal) or RSG/GLIM FDC regimen A (4 mg/4 mg OD maximal) or RSG/GLIM FDC regimen B (8 mg/4 mg OD maximal). Patients were assessed for efficacy and safety every 4 weeks for the first 12 weeks of the study, and at weeks 20 and 28. The primary efficacy endpoint was change in HbA_1c from baseline. Key secondary endpoints included the proportion of patients achieving recommended HbA_1c and fasting plasma glucose (FPG) targets; change from baseline in FPG, insulin, C‐reactive protein (CRP), adiponectin, free fatty acids and lipids; and percentage change in homeostasis model assessment‐estimated insulin sensitivity and β‐cell function. Safety evaluations included adverse‐event (AE) monitoring and clinical laboratory evaluations. Results: At week 28, both RSG/GLIM FDC regimens significantly reduced HbA_1c (mean ± s.d.: ?2.4 ± 1.4% FDC regimen A; ?2.5 ± 1.4% FDC regimen B) to a greater extent than RSG (?1.8 ± 1.5%) or GLIM (?1.7 ± 1.4%) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 vs. both RSG and GLIM). Significantly more subjects achieved HbA_1c target levels of ≤6.5 and <7% with either RSG/GLIM FDC regimen compared with RSG or GLIM alone (model‐adjusted odds ratio, p < 0.0001 for both comparisons). Similarly, a significantly greater reduction in FPG levels was observed in subjects treated with the RSG/GLIM FDC [mean ± s.d. (mg/dl): ?69.5 ± 57.5 FDC regimen A; ?79.9 ± 56.8 FDC regimen B) compared with RSG (?56.6 ± 58.1) or GLIM (?42.2 ± 66.1) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 for both comparisons). Improvement in CRP was also observed in subjects who were treated with a RSG/GLIM FDC or RSG monotherapy compared with GLIM monotherapy. RSG/GLIM FDC was generally well tolerated, with no new safety or tolerability issues identified from its monotherapy components, and a similar AE profile was observed across FDC regimens. The most commonly reported AE was hypoglycaemia, and the incidence of confirmed symptomatic hypoglycaemia (3.6–5.5%) was comparable among subjects treated with an RSG/GLIM FDC and GLIM monotherapy. Conclusions: Compared with RSG or GLIM monotherapy, the RSG/GLIM FDC improved glycaemic control with no significant increased risk of hypoglycaemia. RSG/GLIM FDC provides an effective and well‐tolerated treatment option for drug‐naive individuals with T2DM.     

Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone.

AIMS: Peroxisome proliferator-activated receptor gamma (PPARgamma) activators have recently been identified as regulators of cellular proliferation, inflammatory responses and lipid and glucose metabolism. These agents prevent coronary arteriosclerosis and improve left ventricular remodelling and function in heart failure after myocardial infarction. Improvement in myocardial metabolic state may be one of the mechanisms behind these findings. The aim of this study was to investigate the effects of rosiglitazone on myocardial glucose uptake in patients with Type 2 diabetes. Placebo and metformin were used as control treatments. METHODS: Forty-four patients were randomized to treatment with rosiglitazone (4 mg b.i.d.), metformin (1 g b.i.d.) or placebo in a 26-week double-blinded trial. Myocardial glucose uptake was measured using [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and positron emission tomography (PET) during euglycaemic hyperinsulinaemia before and after the treatment. RESULTS: Rosiglitazone increased insulin-stimulated myocardial glucose uptake by 38% (from 38.7 +/- 3.4 to 53.3 +/- 3.6 micromol 100 g(-1) min(-1), P = 0.004) and whole body glucose uptake by 36% (P = 0.01), while metformin treatment had no significant effect on myocardial (40.5 +/- 3.5 vs. 36.6 +/- 5.2, NS) or whole body glucose uptake. Myocardial work as determined by the rate-pressure-product was similar between the groups. Neither treatment had any significant effect on fasting serum free fatty acids (FFA) but the FFA levels during hyperinsulinaemia were more suppressed in the rosiglitazone group (-47%, P = 0.02). Myocardial glucose uptake correlated inversely to FFA concentrations both before (r =-0.54, P = 0.002) and after (r = -0.43, P = 0.01) the treatment period in the pooled data. Furthermore, the increase in myocardial glucose uptake correlated inversely with interleukin-6 (IL-6) concentrations (r = -0.58, P = 0.03). CONCLUSIONS: In addition to the improvement in whole body insulin sensitivity, rosiglitazone treatment enhances insulin stimulated myocardial glucose uptake in patients with Type 2 diabetes, most probably due to its suppression of the serum FFAs.