Comparison of glycaemic control over 1 year with pioglitazone or gliclazide in patients with Type 2 diabetes.

AIMS: To compare long-term (1 year) efficacy and safety of pioglitazone and gliclazide in patients with Type 2 diabetes. METHODS: This was a double-blind, multicentre, comparative, parallel group trial in 283 patients with Type 2 diabetes, who were randomized to receive 1-year treatment with pioglitazone 30-45 mg/day or gliclazide 80-320 mg/day. Drug dose was titrated on the basis of self-monitored blood glucose (SMBG) measurements and HbA1c values. The 1-year changes in HbA1c, fasting blood glucose (FBG), insulin, HOMA-S (HOmeostatic Model Assessment) and SMBG were compared. In a subgroup of patients (n = 10), systemic glucose production and utilization were determined by a combination of isotopic (deuterated glucose) and clamp techniques. RESULTS: In both groups, there were similar decreases in HbA1c (pioglitazone: -0.79%; gliclazide: -0.79%) and FBG (pioglitazone: -1.0 mmol/l; gliclazide: -0.7 mmol/l), whereas the slope of the reduction of fasting blood glucose was different between groups (P = 0.004). Insulin levels as well as insulin resistance assessed using HOMA-S decreased significantly only after pioglitazone treatment (-11.94 pmol/l and -1.03, respectively, both P = 0.002 vs. baseline). A significantly greater reduction in systemic glucose production was observed in the pioglitazone group (-2.48 micromol/kg/min, P = 0.042) than in the gliclazide group (-1.02 micromol/kg/min). A few, mild adverse events occurred in both groups. CONCLUSIONS: A comparable decrease in HbA1c and FBG was observed with pioglitazone and gliclazide. However, with pioglitazone there was a continuous decrease in FBG over 1 year, whereas gliclazide failed to maintain a similar trend. This favourable effect of pioglitazone was due to its insulin-sensitizing effect and ability to decrease systemic glucose production.     

格列齐特致畸作用观察

目的观察国产格列齐特的致畸作用。②方法对受孕后第６天Ｗｉｓｔａｒ大鼠分别以８５,１７０,６８０ｍｇ／ｋｇ体质量的国产格列齐特（容积为５ｍＬ／ｋｇ体质量）灌胃给药,每天１次,连用１０ｄ;同步设立生理盐水组和敌枯双（５ｍｇ／ｋｇ体质量）对照组。于妊娠第２０天剖腹,取出胎鼠,观察并记录各组活胎数、死胎数以及活胎鼠生长发育等情况。③结果格列齐特各剂量组胚胎数损失率、活胎生长、发育等指标与生理盐水组相比,差异均无显著性（χ２＝０．３７５～３．０９８,Ｐ＞０．０５;Ｆ＝０．０３２～０．１７８,Ｐ＞０．０５）。④结论国产格列齐特无致畸作用     

Remodelling of zero-stress state of small intestine in streptozotocin-induced diabetic rats. Effect of gliclazide

BACKGROUND: Biomechanical properties in terms of residual strains in diabetic small intestine have not been studied. Furthermore, no data have been reported on affect of gliclazide on gastrointestinal complications of diabetes. AIMS: To determine remodelling of zero-stress state of small intestine in streptozotocin-induced diabetic rats and effect of gliclazide treatment. MATERIALS: Morphological properties and residual strains were studied in duodenum, jejunum and ileum obtained from diabetic rats, gliclazide-treated diabetic rats and normal rats (n = 8 each group). METHODS: Diabetes was induced by single intraperitoneal injection of 65 mg/kg streptozotocin. Gliclazide (10 mg kg(-1) day(-1) was injected directly into stomach lumen by intragastric gavage twice daily. Experimental period was 35 days. To approach no-load state; intestinal segments were surgically excised and cut transversely into short ring-shaped segments. Each ring was cut radially to obtain geometry of zero-stress state. Circumferential length, the wall thickness and opening angle were measured from digital images of each specimen and residual strains were computed. RESULTS: Blood glucose level of diabetic group (approximately 20 mmol/l) was consistently higher than that in normal group (approximately 4 mmol/l) after induction of diabetes (p < 0.001). Gliclazide lowered average blood glucose level to between 10 and 15 mmol/l (p < 0.001). Plasma insulin levels of both diabetic groups (average between 10 and 15 pmol/l) were significantly lower than those in normal group (average approximately 18 pmol/l, p < 0.05). Wet weight per unit length and wall thickness of duodenum, jejunum and ileum were significantly higher in Diabetes group than those in Normal group (p < 0.05). Opening angle and absolute value of residual strain were significantly smaller in duodenum and larger in jejunum and ileum in Diabetes group than in Normal group (p < 0.001). Gliclazide treatment partly restored these changes (p < 0.05). CONCLUSIONS: Diabetes induced morphometric and biomechanical remodelling in intestine. Gliclazide partly restored these changes.     

Population pharmacokinetics of gliclazide in normal and diabetic rabbits

Gliclazide is a second‐generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan‐induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with three doses (4.13, 8.27 and 16.53 mg/kg b.wt) of gliclazide by an oral route. Blood samples were collected up to 24 hr and the gliclazide concentrations in rabbit were determined using the HPLC method. The non‐compartmental and classical compartmental PK analyses were performed using Phoenix WinNonlin. Population PK analysis of gliclazide was performed using nonlinear mixed‐effects model software NONMEM and Phoenix NLME considering the weight, age, sex, health and dose as covariates. The final population values for clearance (CL), volume of distribution (V) and the absorption rate constant (k_a) were 5270 ml/hr, 55700 ml and 0.708 hr^?1, respectively. The inter‐individual variability in gliclazide CL, V and k_a was 16.3%, 14.9% and 26.5%, respectively. There was no significant difference between NONMEM and Phoenix NLME pharmacokinetic results. The visual predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates from this model. This population PK model demonstrated that gliclazide pharmacokinetics is best described by one‐compartment model with first‐order absorption in rabbits. Body weight is a covariate that significantly influences gliclazide kinetic disposition in rabbits.     

Erythroderma secondary to gliclazide: a case report

Erythroderma is generalized exfoliative dermatitis, which involves more than 90% of the patient's skin. The most common cause of erythroderma is exacerbation of an underlying skin disease, malignancies or drug reaction. There is a long list of drugs responsible for erythroderma such as antiepileptics, sulfonamides, antibiotics, and angiotensin converting enzyme (ACE) inhibitors. We herein report a case of erythroderma due to gliclazide usage which is also proved by histopathologic examination and patch test. We could not find any case report of gliclazide, an oral antidiabetic, as a cause erythroderma in the literature.     

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。     

格列齐特缓释片改善糖尿病周围血管病患者血管功能的临床研究

目的研究格列齐特缓释片对2型糖尿病并发周围血管病患者血管功能的作用。方法将70例2型糖尿病周围血管病患者随机分为2组：格列齐特组（格列齐特缓释片,每日30～90mg,早餐前1次服用）和格列吡嗪组（格列吡嗪控释片,每日5～15mg,早餐前1次服用）,均治疗6个月。观察两组患者临床症状、糖化血红蛋白（HbAtc）、经皮氧分压（TcpO2）、踝臂指数（ABI）、足背动脉血流量、血液流变学等指标的变化情况。结果格列齐特组临床总有效率高于格列吡嗪组（94．3％VS80．0％,P〈0．05）;格列齐特组和格列吡嗪组治疗后HbA,C与治疗前比较明显下降（均P〈0．05）,但两组比较差异均无统计学意义;格列齐特组治疗后ABI、足背动脉血流量及TcpO2明显升高（均P〈0．05）,而格列吡嗪组治疗后ABI、足背动脉血流量及TcpO2无明显变化,两组相比差异均有统计学意义,分别为1．02±0．12vs0．92±0．14,（0．69±0．15）m·s^-1·mm^-2 vs（0．60±0．13）m·s^-1mm^-1,（28．79±6．83）mmHgVS（25．50±5．03）mmHg（P〈0．01或〈0．05）;两组治疗后血液流变学指标较治疗前明显下降（均P〈0．01）,而格列齐特组下降程度均优于格列吡嗪组,全血高切还原黏度（4．27±0．56）mPa·s vs（4．67±0．66）mPa·s、全血低切还原黏度（8．52±0．65）mPa·s vs（9．27±0．71）mPa·s、血浆黏度（1．53±0．29）mPa·s vs（1.83±0．33）mPa·s、纤维蛋白原（3．73±0．44）g／L vs（4．09±0．55）g／L、血沉（23．15±4．63）ram／1h vs（25．87±4．72）mm／1h、红细胞聚集指数2．08±0．25 vs 2．21±0．26（P〈0.01或〈0．05）。结论格列齐特缓释片能有效改善2型糖尿病患者周围血管功能,延缓周围血管病变的发展。     

液质联用检查降糖中药制剂中掺入的7种化学药品

采用高效液相色谱质谱法对市售7种降糖中药制剂掺入化学药品进行定性筛检。色谱条件:采用Agilent ZORBAX SB-C18柱,以甲醇-甲酸盐缓冲溶液(用冰醋酸调节pH值至3.8)(55∶45)为流动相,检测波长240nm,柱温30℃,流速1mL.min-1;质谱条件:电喷雾离子化,正离子模式,雾化气压力30psi,干燥气温度300℃,流速10L.min-1,毛细管电压4000V,扫描范围100~600,对42批抽验样品进行分析。结果2批样品分别有化学药品盐酸吡格列酮和格列本脲检出。本文建立的HPLC-MS/MS方法可用于同时鉴定中药制剂中掺入的盐酸二甲双胍、盐酸苯乙双胍、格列吡嗪、盐酸吡格列酮、格列齐特、格列本脲、格列美脲7种化学药品。     

气相色谱法测定格列齐特中残留乙醇和N,N-二甲基甲酰胺的量

目的建立格列齐特中残留乙醇和N,N-二甲基甲酰胺的测定方法。方法应用气相色谱法,氢火焰离子化检测器,检测器温度为250℃。结果乙醇的线性范围为0.128～1.02mg.ml-1,r=0.9997,回收率为98.9%,RSD=0.63%(n=6)。N,N-二甲基甲酰胺的线性范围为43.8～175.2μg.ml-1,r=0.9998,回收率为98.2%,RSD=1.12%(n=6)。样品中只检出乙醇。结论该方法简单、准确。     

格列齐特缓释片对2型糖尿病患者血管功能的影响

目的观察格列齐特缓释片对2型糖尿病(T2DM)患者血管功能的影响。方法72例T2DM患者随机均分为对照组(口服格列齐特片,80 mg／次,每日2次)和试验组(口服格列齐特缓释片,60 mg／次,每日1次),疗程为12周。采用高分辨率超声测定肱动脉内皮依赖性血管舒张功能(FMD)和硝酸甘油介导的非内皮依赖性血管舒张功能(GNTMD)的变化,并测定血清一氧化氮(NO)及内皮素-1(ET-1)的水平。同时选择40名年龄和性别相匹配的健康志愿者(正常组)作为基线对照。结果与正常组比较,治疗前试验组和对照组的血清ET-1水平显著升高(P值均<0.01),血清NO水平及GNTMD、FMD值显著下降(P值均<0．01)。与治疗前比较,治疗12周后试验组和对照组血清ET-1水平显著降低(P值均<0．01),NO水平和GNTMD、FMD值显著上升(P值均<0．01)。试验组和对照组均能有效降低空腹和餐后2 h血糖及糖化血红蛋白水平,差异均有统计学意义(P值分别<0．05、0．01)。结论格列齐特缓释片和普通片可在有效降低T2DM患者血糖的同时,改善血管内皮功能。