吡格列酮对脂多糖引起的大鼠海马有丝分裂原激活蛋白激酶p38信号传导通路的影响

<正>吡格列酮(pioglitazone,Pio)能抑制脂多糖诱导的原代培养的星形胶质细胞炎症因子的释放[1],对抗谷氨酸诱导的神经细胞损伤[2],也有研究显示Pio通过抑制p38MAPK信号传导通路抑制LPS诱导的小胶质细胞炎症反应[3]。但关于Pio对大鼠脑内炎症反应的抑制作用是否与p38MAPK信号传导通路有关目前尚未见报道,本研究通过大鼠脑室内注     

吡格列酮或胰岛素治疗对2型糖尿病患者血尿酸的影响

目的:比较吡格列酮或胰岛素治疗对2型糖尿病患者（ type 2 diabetes mellitus T2DM）血糖及血尿酸的影响。方法：133名2型糖尿病合并高尿酸血症的患者随机分为3组,监测12周治疗前后空腹血糖、餐后2h血糖、糖化血红蛋白、血尿酸、肌酐、总胆固醇和甘油三酯。结果：吡格列酮组治疗后空腹血糖、餐后2h血糖、糖化血红蛋白、血尿酸、甘油三酯、总胆固醇等均较治疗前下降（P<0.05）。胰岛素治疗组空腹血糖、餐后2h血糖、HbA1c均较治疗前显著下降（P<0.05）。胰岛素组治疗前后空腹血糖、餐后2h血糖和HbA1c均低于吡咯列酮和常规治疗组（P<0.05）。吡格列酮组降低尿酸的作用显著高于胰岛素治疗组。常规治疗组降低血尿酸作用高于吡咯列酮组和胰岛素组。结论：胰岛素组的降糖作用最强。吡格列酮显著降低血尿酸。对于2型糖尿病合并高尿酸血症,无痛风的患者,宜选用吡格列酮。     

HPLC-MS同时测定人血浆中吡格列酮及其活性代谢产物的浓度

 目的建立高效液相色谱质谱联用测定人血浆中吡格列酮及其活性代谢产物M-Ⅲ(酮类衍生物)和M-Ⅳ(羟化衍生物)的方法。方法采用WatersXTerraTN C₁₈色谱柱(2.1mm×150mm,3.5μm),Phenomenex C₁₈保护柱,柱温50℃,流动相:乙腈-30mmol·L^-1醋酸铵溶液(含0.1%的甲酸和0.05%的三氟醋酸)(35:65),流速0.22mL·min^-1。质谱采用电喷雾电离源正离子模式(ESI⁺),选择性监测质荷比(m/z)357.4(吡格列酮),358.2(内标),371.5(M-Ⅲ),373.2(M-Ⅳ)的准分子分子离子峰;血浆样品经盐酸酸化后,采用叔丁基甲醚-氯仿提取,内标法定量。结果吡格列酮,M-Ⅲ和M-Ⅳ分别在11.16～1748.60,3.33～520.50,5.00～687.50ng·mL^-1内线性良好(r≥0.9997),最低检测浓度分别为2.90,1.10,1.20ng·mL^-1,3个化合物的方法回收率均在90%-110%范围内,日间和日内RSD皆小于15%。结论本方法操作简单,灵敏准确,稳定性好,适用于临床吡格列酮治疗药物监测,药动学及其药物相互作用的研究。     

有限采样法估算口服吡格列酮制剂的生物等效性

目的建立有限采样法模型估算盐酸吡格列酮(PGT)制剂的生物等效性。方法以健康志愿者口服PGT参比制剂后的血药浓度数据建模，有限采样法建立多元回归模型估算C_max和AUC_0-t。模型的内部和外部验证分别以Jackknife法和Monte Carlo法生成的模拟数据进行。选择最佳模型进行生物等效性评价。结果给药后1.5 h和2.5 h血药浓度(C_1.5和C_2.5)估算C_max的准确性较好，C_1.5和C₉估算AUC_0-t的准确性较好，平均预测误差<5%、平均绝对误差<9%，参数预测误差超过±20％的样本数<5%。生物等效性评价结果与经典法一致。结论有限采样法估算口服PGT制剂的生物等效性是可行的，为生物等效性研究提供新的思路和方法。     

吡格列酮对老年糖耐量低减患者内皮功能的影响

目的:探讨吡格列酮对老年糖耐量低减患者（IGT）内皮功能的影响。方法：选取56例老年糖耐量正常者（NGT）及60例老年糖耐量低减患者（IGT），将IGT患者随机分两组进行治疗，每组30例，疗程为6月。非药物干预组，仅改变生活模式；综合治疗组，生活模式改变基础上服吡格列酮（每天30 mg），观察内皮依赖舒张功能（EDD）变化。结果：EDD在IGT患者明显低于NGT个体；在非药物干预组和综合治疗组EDD治疗前无明显差别，6月后EDD在非药物干预组无明显改变，在综合治疗组明显升高（P＜0.05），EDD变化值与糖化血红蛋白（HbA1C）变化值 、胰岛素抵抗指数（HOMA-IR）变化值、高敏感C反应蛋白（HsCRP）变化值呈负相关。结论：在改变生活模式基础上，吡格列酮可进一步改善老年IGT患者内皮功能，其机制可能是通过降低血糖、改善胰岛素抵抗，抑制炎症反应等。     

盐酸吡格列酮的HPLC测定

用HPLC测定盐酸吡格列酮及其有关物质的含量。采用C18色谱柱，以乙腈-水-醋酸(50：50：0．12，用氨试液调至pH6．0)为流动相，流速1．0ml／min，检测波长225nm。盐酸吡格列酮在1-200μg／ml范围内线性良好，平均回收率99．3％(RSD=0．09％)，日内和日间精密度(RSD)分别为0．75％和0．26％。     

A long‐term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized,double‐blind,parallel‐group comparison trial

Aims This study compared the effects of pioglitazone and gliclazide on metabolic control in drug‐naïve patients with Type 2 diabetes mellitus. Methods A total of 1270 patients with Type 2 diabetes were randomized in a parallel‐group, double‐dummy, double‐blind study. Patients with poorly controlled Type 2 diabetes (HbA_1c 7.5–11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA_1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C‐peptide and pro‐insulin levels were measured. Results Mean HbA_1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: ?1.4%; gliclazide: ?1.4%; (90% CI: ?0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference ?0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: ?0.7 to ?0.1)]. Improvements in high‐density lipoprotein cholesterol (HDL‐C) and total cholesterol/HDL‐C were greater with pioglitazone than with gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with pioglitazone than with gliclazide. Conclusions Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA_1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.     

Could thiazolidinediones increase the risk of heart failure in Friedreich's ataxia patients?

Clinical evidence and the recent decisions of the European Medicines Agency and the Food and Drug Administration challenge the safety of thiazolidinediones treatment. Recently, this treatment has been suggested for Friedreich's ataxia because thiazolidinediones improve neurological symptoms. Hypertrophic cardiomyopathy is the most prevalent cardiac feature and the cause of premature death in Friedreich's ataxia patients. We recommend that therapy with peroxisome proliferator‐activated receptor‐gamma agonists like thiazolidinediones be taken with caution, as they cause a decrease in the number of fast fibers and an increase in mitochondrial biogenesis in cardiac muscle because of the induction of peroxisome proliferator‐activated receptor‐gamma coactivator‐1α. Furthermore, the incidence of heart failure may increase when thiazolidinediones are combined with insulin, and moreover, they produce cyclooxygenase 2 inhibition, inducing a thrombotic response. Thus, patients are predisposed to adverse cardiovascular outcomes. In our opinion, the possible fatal consequences must be taken into account when peroxisome proliferator‐activated receptor‐gamma agonist drugs are considered as possible therapeutic agents for Friedreich's ataxia patients. © 2011 Movement Disorder Society     

Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study

BACKGROUND: This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes (HbA1c > or = 7.5% to < or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. RESULTS: There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. CONCLUSIONS: Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.