格列齐特对2型糖尿病大鼠心肌缺血预适应保护作用的影响

目的：探讨格列齐特对2型糖尿病大鼠离体心脏缺血预适应保护作用的影响。方法将造模成功的2型糖尿病大鼠随机分为糖尿病缺血预处理组、糖尿病再灌注损伤组、糖尿病缺血预处理＋格列齐特组、糖尿病再灌注损伤＋格列齐特组。将对照组大鼠随机分为缺血预处理组、再灌注损伤组。分别于平衡灌注后、缺血再灌注开始及再灌注60 min末3个时间点分别收集冠脉流出液,测定乳酸脱氢酶（LDH）、肌酸激酶（CK）、肌酸激酶同工酶（CK-MB）的释放量;在再灌注末,取左心室游离壁心肌组织,进行荧光定量PCR检测心肌ATP敏感性钾离子（KATP）通道组成亚基Kir6.2和SUR2A mRNA的表达;免疫组织化学技术检测其蛋白的表达水平。结果对于糖尿病非药物治疗大鼠,糖尿病缺血预处理组与糖尿病再灌注损伤组比较,冠脉流出液中LDH、CK、CK-MB无明显差异;Kir6.2和SUR2A mRNA及蛋白表达也均无明显差异。而与糖尿病缺血预处理组、糖尿病再灌注损伤＋格列齐特组比较,糖尿病缺血预处理＋格列齐特组均降低了糖尿病大鼠心肌缺血预处理后缺血再灌注损伤冠脉流出液中LDH、CK、CK-MB释放量（P＜0.05）;也使Kir6.2 mRNA及蛋白表达明显增加（P＜0.05）;但SUR2A mRNA表达差异无统计学意义。与糖尿病再灌注损伤＋格列齐特组比较,糖尿病缺血预处理＋格列齐特组SUR2A蛋白表达水平也增加明显（P＜0.05）。结论格列齐特对心肌缺血预处理的保护作用无不利影响,反而能改善2型糖尿病大鼠心肌缺血预适应的保护作用。     

Gliclazide improves anti-oxidant status and nitric oxide-mediated vasodilation in Type 2 diabetes.

AIMS: To evaluate the effects of gliclazide on oxidative status and vascular response to systemic administration of L-arginine, the natural precursor of nitric oxide (NO), in Type 2 diabetic patients. METHODS: Thirty Type 2 diabetic patients received glibenclamide (n = 15) or gliclazide (n = 15) in a 12-week, randomized, observer-blinded, parallel study. Plasma lipid peroxides, total radical-trapping anti-oxidant parameter (TRAP), and blood pressure responses to an intravenous bolus of L-arginine were measured pre- and post-treatment. RESULTS: At 12 weeks, gliclazide patients had lower plasma lipid peroxides (13.3 +/- 3.8 micro mol/l vs. 19.2 +/- 4.3 micro mol/l; P = 0.0001) and higher plasma TRAP (1155.6 +/- 143.0 micro mol/l vs. 957.7 +/- 104.3 micro mol/l; P = 0.0001) than the glibenclamide patients. Gliclazide but not glibenclamide significantly reduced systolic and diastolic blood pressure (P = 0.0199 and P = 0.00199, respectively, two-way repeated measures analysis of variance) in response to intravenous L-arginine. CONCLUSIONS: Gliclazide reduces oxidative stress in Type 2 diabetic patients by improving plasma anti-oxidant status. This effect is associated with enhanced NO-mediated vasodilation.     

Changes in liver tests during 1-year treatment of patients with Type 2 diabetes with pioglitazone, metformin or gliclazide.

AIMS: Patients with Type 2 diabetes are at increased risk of liver damage. Therefore, it is of particular importance to investigate the hepatic effects of drugs used to treat such patients. METHODS: Liver testing results performed in four 1-year, randomized, double-blind studies comparing effects of pioglitazone, metformin or a sulphonylurea, gliclazide, in the treatment of over 3700 patients with Type 2 diabetes have been analysed. RESULTS: Pioglitazone caused reductions in mean levels of hepatic enzymes of between 3 and 18%, whilst gliclazide caused small increases of between 3 and 13%. Metformin treatment showed either small mean increases or decreases. More patients receiving pioglitazone had liver tests within the normal range at the end of treatment (> or = 87%) compared with patients receiving metformin (> or= 80%) or gliclazide (> or = 75%). Slightly fewer patients with pioglitazone than with comparators showed a large increase (> 3 upper limit of normal) in alanine aminotransferase levels at any time during treatment (pioglitazone 0.9%, metformin 1.9%, gliclazide 1.9%). CONCLUSIONS: During pioglitazone treatment there is a reduction in liver enzyme levels. Although the mechanism of this effect is not clear, the results demonstrate potential beneficial effects on the liver during treatment of patients with Type 2 diabetes with pioglitazone.     

格列齐特缓释片的研制

目的 :研究格列齐特缓释片的制备方法 ,筛选最佳制备工艺条件。方法 :采用正交试验设计 ,以处方工艺中羟丙基甲基纤维素、微晶纤维素的用量及缓释片的硬度为试验因素 ,每个因素取三个水平 ,按正交试验表的安排进行实验 ,并确定其最佳制备工艺条件 ,按优化后的结果选择实验条件 ,进行重复实验 ,用体外溶出实验考察其缓释释放效果。结果 :制备的缓释片在 2、6、12h的累积释放率分别为 2 9.91%± 1.3 8%、61.77%± 1.13 %和 95 .89%± 0 .81%。结论 :按优化结果选择的制备工艺所制备的格列齐特缓释片其缓释效果与预测值基本吻合 ,工艺的重复性较好 ,体外累积释放率符合要求     

SBA-15与SBA-16作为药物载体的性能研究

目的:通过建立SD大鼠2型糖尿病模型的方法,研究不同的介孔材料SAB-15与SAB-16分别载药格列齐特(GLZ),释放速率的作用,以筛选出最佳的载药系统,为临床制剂提供参考。方法:考察SAB-15/GLZ、SAB-16/GLZ的载药、释药性能,建立大鼠糖尿病模型,分别检测灌胃给药前(0h)和给药后各时间点(3 h,6 h,9 h,12 h,24 h,27 h,30 h,48 h)各组大鼠血糖浓度的变化。结果:1载药系统的热重分析,SBA-15/GLZ、SBA-16/GLZ在200~700℃均有显著的失重,分别是14.3%和15.4%,且SBA-16/GLZ失重高于SBA-15/GLZ;2FTIR分析中,在红外光谱中500 cm-1~2000 cm-1波数范围内两种材料载药均出现了4个吸收强度较大的特征峰,二者波数范围相同,波峰相似,且与GLZ的分布趋势大致一致,且SBA-16/GLZ的吸收强度略高于SBA-15/GLZ;3载药系统的结构性质,与SBA-15比较,SBA-15/GLZ在比表面积、孔隙容积上均减小(P0.01),与SBA-16比较,SBA-16/GLZ比表面积、孔隙容积上均减小,且SBA-16/GLZ的比表面积、孔隙容积均显著小于SBA-15/GLZ(P0.01);4释放速率:SBA-15/GLZ内格列齐特有一个迅速的释放过程,12 h即达90%以上,24 h后缓释量逐渐趋于平缓,48 h释放量即达到95%以上,最终缓释量约在97%水平;而SBA-16/GLZ内格列齐特的缓释相对平缓,12 h之内释放了80%左右,显著低于同等时间点SBA-15对格列齐特释放(P0.05),48 h最终缓释量约在90%的水平;5血糖变化,在0 h测得的血糖结果中,模型组及各给药组的血糖均显著升高,且≥13.8 mmo L/L,说明造模成功;12 h的血糖值最低,随着时间的推移,GLZ组的血糖变化梯度最大,SBA-15/GLZ次之,SBA-16/GLZ血糖值的变化曲线较平坦,说明介孔材料能有效载药、平稳缓释、在动物模型体内平稳持续释药并发挥作用,避免血糖浓度忽高忽低,SBA-16/GLZ缓释效果显著优于SBA-15/GLZ。结论:SAB-16介孔材料的载药量高于SAB-15,缓释持续时间长。     

固相萃取法对格列齐特血药浓度HPLC测定的优化

目的建立一种简便的格列齐特血药浓度HPLC测定和生物等效性研究测定方法,并使此方法达最佳优化状态。方法18名健康受试者单剂量交叉口服格列齐特供试制剂和参比制剂80 mg后,用固相萃取高效液相色谱法测定血浆中格列齐特的浓度。结果本方法在0.125~8.0 mg/L浓度范围内线性关系良好。最低可定量浓度为0.02 mg/L(信噪比>3),两制剂间AUC、Cmax、Tmax、t1/2β药动学参数经统计学检验无显著性差异(P>0.05)。供试制剂的相对生物利用度为(99.95±12.57)%。结论本HPLC方法简单、快速、准确,很好的评价了两种制剂的生物等效性。     

The direct effect of hypoglycaemic sulphonylureas on myocardial contractile force and arterial blood pressure

Summary The cardiovascular effects of glibenclamide, gliclazide and carbutamide were studied on myocardial contractile force, cardiac output, mean arterial pressure and heart rate in 43 intact, 14 pancreatectomized and 18 adrenalectomized dogs. It is shown that a positive inotropic and hypertensive effect of hypoglycaemic sulphonylureas develops without the mediation of glucagon, insulin or adrenaline. Contrary to the other investigated sulphonylureas, glibenclamide reduced myocardial contractile force and arterial blood pressure.     

格列齐特治疗非胰岛素依赖型糖尿病106例的近期疗效

应用国产格列齐特治疗非胰岛素依赖型糖尿病106例,并以格列本脲(优降糖)作对照药物。治疗3mo后,初诊断27例均有效(100％);已用其他磺酰脲药物79例(包括失效33例),改用格列齐特后有效68例(86％)。有效病例的空腹和餐后2h血糖、24h尿糖、糖基化血红蛋白(HbA_1)均明显降低。初诊断组经治疗后甘油三酯也明显降低。格列齐特不良反应轻微,是一种安全、可靠的药物。     

The stimulus-secretion coupling of glucose-induced insulin release XII. Effects of diazoxide and gliclazide upon45calcium efflux from perifused islets

Summary The effect of diazoxide and gliclazide upon⁴⁵calcium efflux from perifused islets was investigated. In the absence of extracellular calcium and presence of glucose, diazoxide caused an immediate and sustained increase in⁴⁵calcium efflux. This facilitation of the outward transport of calcium might explain why diazoxide inhibits the stimulant action of glucose upon calcium accumulation in the beta cell. Under conditions known to abolish insulin release and the concomitant release of⁴⁵calcium, namely in the absence of extracellular calcium or in the presence of deuterium oxide, gliclazide caused an immediate but transient decrease in⁴⁵calcium efflux, this inhibition of the outward transport of calcium being observed both in the absence and presence of glucose and being followed by a significant rebound in⁴⁵calcium efflux. It is suggested that this biphasic change in⁴⁵calcium efflux could be due to a dual effect of gliclazide upon calcium handling by the beta cell, similar to that evoked by glucose and theophylline respectively.