格列齐特缓释片治疗2型糖尿病的疗效及安全性

目的：比较口服格列齐特缓释片和普通片治疗2型糖尿病患者的疗效和安全性。方法：在随机、双盲、双模拟、平行对照临床试验中，72例2型糖尿病患者分为两组，格列齐特片组36例，80mg／次，2次／d；格列齐特缓释片组36例，60mg／次，1次／d，疗程均为12周。结果：与基线值比较；格列齐特缓释片组中，HbA1c平均下降1．19％，空腹和餐后血糖值分别下降2．16、2．06mmol／L；而格列齐特片组中，HbA1c平均下降1．08％，空腹和餐后血糖值分别下降1．87、2．28mmol／L。两组间空腹和餐后血糖水平下降率比较没有统计学差异。未见严重不良反应及实验室证实的低血糖（血糖≤2．78mmol／L）。结论：格列齐特缓释片能有效改善2型糖尿病患者的全天血糖及HbA1c水平。     

罗格列酮对高脂血症大鼠的胰岛素抵抗作用及其机制研究

目的 :研究罗格列酮及格列齐特对高脂血症大鼠胰岛素抵抗的改善作用及其机制。方法 :建立高脂血症大鼠胰岛素抵抗模型 ,并将其分为模型组、罗格列酮组和格列齐特组 ,观察罗格列酮和格列齐特对其糖耐量减退、血清血糖血脂、TNF α、Fins含量、肝细胞TG含量、脂质过氧化和肝肾功能等的影响。结果 :罗格列酮和格列齐特均有可能改善高脂血症致胰岛素抵抗模型病鼠的IGT状态 ,给药 2h后不同程度地降低病鼠FSG及TNF α浓度 (P <0 .0 5 ) ,显著降低病鼠肝组织中TG含量 (P <0 .0 1) ,明显抑制MDA产生 (P <0 .0 1)及增强GSH贮量作用 (P <0 .0 1)。罗格列酮还可降低病鼠高胰岛素水平及Fins浓度 (P <0 .0 1) ,明显降低病鼠BUN和Cr含量 (P <0 .0 5 ) ,提高ISI(P <0 .0 1)及增强SOD活性 (P <0 .0 5 )。结论 :罗格列酮能改善高脂饲养引发的胰岛素抵抗。     

格列齐特3种片剂的溶出度比较

目的 :对市售 3种格列齐特片剂进行溶出度比较。方法 :按中国药典 2 0 0 0版溶出度方法 ,用紫外分光光度法测定其含量 ,测定波长为 2 2 6nm。结果 :A ,B ,C 3个厂家的片剂标示百分含量分别为98.5 % ,10 0 .0 %和 99.0 % ;6 0min时的平均溶出度分别为 4 8.4 % ,89.6 %和 86 .9% ;180min时的平均溶出度分别为 90 .7% ,90 .9%和 90 .7%。根据统计学分析A厂与B ,C厂的片剂在 6 0min时溶出度差异有非常显著意义 (P <0 .0 1) ,B厂和C厂的片剂差异有显著意义 (P <0 .0 5 ) ;在 180min时A ,B ,C厂 3种片剂的溶出度差异无显著意义 (P >0 .0 5 )。结论 :A厂产品的溶出度符合中国药典2 0 0 0版的要求     

格列齐特缓释片的制备及体外释放度

选用两种黏度的羟丙甲纤维素为骨架材料和粘合剂,采用湿法制粒制备格列齐特缓释片;并与参比制剂比较体外释放行为.结果表明,所得片剂的体外释放符合一级动力学规律,释放曲线经f2(相似因子)判断,与参比制剂相似.     

格列齐特缓释片的人体药物动力学及相对生物利用度

目的研究2种格列齐特缓释片的人体药物动力学及相对生物利用度。方法40例健康受试者采用随机交叉给药方案,单次或多次口服60 mg供试或参比格列齐特缓释片后,采用HPLC测定人体血浆中格列齐特的浓度,计算其药物动力学参数和相对生物利用度,评价两制剂的生物等效性。结果单次口服格列齐特缓释片供试制剂和参比制剂主要药物动力学参数Cmax分别为（2.92±1.29）和（2.73±1.39）μg.mL^-1,tmax分别为（6.9±2.1）和（6.3±2.0）h,t1/2分别为（14.63±3.06）和（15.89±3.46）h,AUC0-60分别为（53.82±17.58）和（57.11±22.67）μg.h.mL^-1。多次口服格列齐特缓释片达稳态后供试和参比制剂主要药物动力学参数Cssmax分别为（3.33±1.07）、（3.11±1.22）μg.mL^-1,Tsmsax分别为（54.3±1.9）和（54.5±2.5）h,Cmin分别为（0.20±0.19）和（0.19±0.20）μg.mL^-1,Cav分别为（1.11±0.64）和（1.10±0.63）μg.mL^-1,AUCSS分别为（119.92±68.94）和（119.10±68.20）μg.h.mL^-1。结论建立的格列齐特分析方法简单、快速、准确。2种制剂具有生物等效性。     

磺脲受体1基因外显子16-3c/t多态性与格列齐特降血糖的关系

目的研究磺脲类药物受体1(SUR1)基因多态性与格列齐特降糖疗效的关系。方法用Taqman-PCR技术检测119例2型糖尿病患者SUR1基因型,分析基因型与血糖变化的关系。结果SUR1基因16外显子-3c/t位点的突变纯合子tt基因型患者,其基线空腹胰岛素水平高于野生纯合子cc基因型患者(P<0.05)。格列齐特治疗后,各基因型空腹血糖、餐后2h血糖、糖化血红蛋白、空腹胰岛素及胰岛素抵抗指数下降幅度均无显著性差异。结论16外显子-3c/t多态性与格列齐特降糖疗效无关。     

格列齐特混悬剂的制备及物理稳定性的研究

目的制备格列齐特混悬剂并对其物理稳定性进行考察。方法考察助悬剂的性质(密度,流变特性),以沉降体积比和再分散性为评价指标对制得的混悬剂进行评价。结果聚丙烯酸树脂(carbopol)和微晶纤维素(avicel)助悬效果较好。结论选取合适的助悬剂可制得物理稳定性良好的格列齐特混悬剂。     

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with Type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin

Summary Neonatal rats treated with streptozotocin on the day of birth (n0-STZ) or on day 5 (n5-STZ) exhibited when fully grown a very mild or frank basal hyperglycaemia respectively and a specific failure of insulin release in response to glucose. To determine whether short (1 day) or long-term (30 days) gliclazide treatment modifies the pancreatic insulin content and the B-cell response to secretagogues, diabetic rats were given oral gliclazide (10 mg/kg per day) and compared to control diabetic and non-diabetic rats. Insulin secretion in the isolated perfused pancreas was studied the day after the last gliclazide administration. In severely hyperglycaemic n5-STZ rats (plasma glucose levels >16 mmol/l) long-term gliclazide treatment did not lower the plasma glucose values, did not affect the pancreatic insulin stores, nor did it significantly modify the insulin release in vitro in response to glucose or arginine. In moderately hyperglycaemic n5-STZ rats (plasma glucose levels <16 mmol/l) the plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of the gliclazide therapy. In the n5-STZ rats responsive to gliclazide the pancreatic insulin stores were increased twofold as compared to values in untreated n5-STZ rats, however, this difference did not reached significance and the pancreatic in sulin stores in the responsive gliclazide treated rats remained depleted by 76% compared to normal insulin stores. In the n0-STZ rats (very mild hyperglycaemia) the long-term gliclazide treatment did not significantly modify the plasma glucose levels or the pancreatic insulin stores. After the 30-day gliclazide therapy in both the n5-STZ gliclazide responder group and the n0-STZ group: (1) the in vitro glucose-induced insulin secretion was increased three to fivefold, (2) the response to arginine which was basically increased in the untreated diabetic rats was again amplified two to threefold, (3) the insulin release in response to gliclazide was unchanged. In conclusion, long-term gliclazide therapy augments stimulated insulin secretion in these two rat models of Type 2 (non-insulin-dependent) diabetes and does not induce any refractoriness to acute sulfonylurea stimulation. The improvement of B-cell function observed here was not related to the concomitant variations of hyperglycaemia and/or pancreatic insulin contentThis work was presented in part at the 24th Annual Meeting of the European Association of the Study of Diabetes, Paris, France, 5–8 September 1988     

Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide

Aim:  We have previously demonstrated that advanced glycation end products (AGEs) stimulate bovine retinal endothelial cell (BREC) proliferation through induction of vascular endothelial growth factor (VEGF) production by these cells. We have also shown that gliclazide, a sulfonylurea which decreases oxidative stress, inhibits this effect. The aim of the present study was to characterize the signalling pathways involved in AGE-induced BREC proliferation and VEGF production and mediating the inhibitory effect of gliclazide on these biological events.
Methods:  BRECs were treated or not treated with AGEs in the presence or absence of gliclazide, antioxidants, protein kinase C (PKC), mitogen-activated protein kinase (MAPK) or nuclear factor-κB (NF-κB) inhibitors. BREC proliferation was assessed by measuring [³H]-thymidine incorporation into DNA. Activation of PKC, MAPK and NF-κB signal transduction pathways and determination of VEGF expression were assessed by Western blot analysis using specific antibodies. MAPK activity was also determined by an in vitro kinase assay.
Results:  Treatment of BRECs with AGEs significantly increased cell proliferation and VEGF expression. AGEs induced PKC-β translocation, extracellular signal-regulated protein kinase 1/2 and NF-κB activation in these cells. Pharmacological inhibition of these signalling pathways abolished AGE effects on cell proliferation and VEGF expression. Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N -acetyl- l -cysteine resulted in a significant decrease in AGE-induced activation of PKC-, MAPK- and NF-κB-signalling pathways.
Conclusions:  Our results demonstrate the involvement of PKC, MAPK and NF-κB in AGE-induced BREC proliferation and VEGF expression. Gliclazide inhibits BREC proliferation by interfering with these intracellular signal transduction pathways.     

国产格列齐特片剂的相对生物利用度研究

改进了测定人血清中格列齐特（１）的ＨＰＬＣ方法；在１０名健康志愿者体内，研究了两种国产１片剂的相对生物利用度。结果表明两者的各药物动力学参数均无明显差异。