Double-blind, randomized, multicentre study of the efficacy and safety of gliclazide-modified release in the treatment of Chinese type 2 diabetic patients

BACKGROUND AND AIM: Gliclazide-modified release (gliclazide MR) is a new formulation of the sulfonylurea gliclazide designed for once-daily administration. The hydrophilic matrix of hypromellose-based polymer in the new formulation induces a progressive drug release, which parallels the 24-h glycaemic profile in type 2 diabetic patients. The aim of this study was to compare the efficacy and safety of gliclazide MR (once-daily administration) versus gliclazide (twice-daily administration) in Chinese type 2 diabetic patients. MATERIALS AND METHODS: Sixty-three type 2 diabetic Chinese patients who had been on diet control alone or on treatment with metformin or on low dose of sulfonylurea were randomized to either gliclazide MR taken once daily or gliclazide taken twice daily. Dosage of metformin was maintained throughout the study, and the sulfonylurea was stopped. The dose of gliclazide MR was increased at 1-month intervals from 30 mg to 120 mg, while that of gliclazide from 80 mg to 320 mg until metabolic control was achieved [fasting plasma glucose (FPG) < or = 7.7 mmol/l] or the maximum dose reached. Efficacy was mainly evaluated by levels of haemoglobin A1c (HbA1c) and FPG. RESULTS: The mean baseline characteristics of the full analysis set 1 (FAS1) (HbA1c, n = 58) and the FAS2 (FPG, n = 61) were comparable in both groups. The levels of HbA1c decreased similarly in both groups over the treatment period: -1.6 +/- 1.6% (p < 0.001) on gliclazide MR (n = 31) and -1.6 +/- 1.4% (p < 0.001) on gliclazide (n = 27). Decrease in HbA1c was observed irrespective of pre-existing therapy for diabetes: -2.3 +/- 1.5% for patients on diet alone; -0.6 +/- 1.3% for patients switched from sulfonylurea to study drug and -1.4 +/- 0.8% for patients on metformin in combination with study drug. FPG decreased significantly from 177.5 +/- 63.5 to 136.7 +/- 42.2 (p < 0.001, n = 32) on gliclazide MR and not significant from 188.2 +/- 62.6 to 163.7 +/- 67.9 (p = 0.059, n = 29) on gliclazide. Both treatments were very well tolerated with no major hypoglycaemic episodes requiring external assistance; only three patients experienced mild hypoglycaemic episodes. CONCLUSIONS: Once-daily gliclazide MR showed a better trend in improving blood glucose control in comparison with gliclazide in type 2 diabetic Chinese patients irrespective of the pre-existing anti-diabetic treatment. The safety profiles of gliclazide MR and gliclazide were similar with a small number of patients having reported hypoglycaemic episodes. Once-daily dosing with gliclazide MR should improve patient compliance, an important factor in long-term glycaemic control.     

紫外分光光度法测定格列齐特缓释片含量

目的 采用紫外分光光度法测定格列齐特缓释片的含量.方法 药片研碎后粉末以无水乙醇溶涨2 h后,超声使溶解,过滤,取续滤液一定量,并用水定容至所需浓度,在226 nm波长处测定吸收度.结果 测定的线性范围为4.884～19.536 mg·L-1,相关系数r=0.999 9;缓释片中格列齐特的平均回收率为101.06%,RSD=0.61%;重现性(RSD=0.64%)良好.结论 该法比药典上规定的滴定法操作简便、快速、准确、专属性强,适用于格列齐特缓释片的含量测定.     

Effect of repaglinide and gliclazide on glycaemic control,early-phase insulin secretion and lipid profiles in newly diagnosed type 2 diabetics

Background Both repaglinide and gliclazide are insulin secretagogues widely used in the treatment of type 2 diabetes.They stimulate insulin secretion through distinct mechanisms and may benefit patients from different aspects.The present study was to evaluate the effects of repaglinide or gliclazide on glycaemic control,insulin secretion,and lipid profiles in type 2 diabetes patients.Methods A total of 47 newly diagnosed type 2 diabetes patients were randomized 1:1 to receive a 4-week treatment with repaglinide or gliclazide.The standard mixed meal tolerance test was performed before and after the treatment.Plasma glucose (PG),insulin concentration,and lipid profiles were measured.The area under insulin concentration curve (AUCins) and the early-phase insulin secretion index (△I30/△G3o) were calculated.Results After the trial,fasting and postprandial PG and postprandial insulin improved significantly in both groups (P＜0.05).The maximum insulin concentration occurred earlier in the repaglinide group than that in the gliclazide group.AUCins increased in both groups (P ＜0.05),but no significant difference was found between groups.△I30/△G30 increased in both groups (P ＜0.05),especially in the repaglinide group (P ＜0.05).Triglyceride and total cholesterol decreased significantly in the repaglinide group in some time points,while no significant change was observed in the gliclazide group.Conclusions Repaglinide and gliclazide had similar effects on glycaemic control and total insulin secretion,while repaglinide had more effects on improvements in β-cell function and lipid metabolism.     

Design and development of gliclazide-loaded chitosan microparticles for oral sustained drug delivery: in-vitro/in-vivo evaluation

Objectives The objective of this study was to prepare gliclazide–chitosan microparticles with tripolyphosphate by ionic crosslinking. Methods Chitosan microparticles were produced by emulsification and ionotropic gelation. The effects of process variables including chitosan concentration, pH of tripolyphosphate solution, glutaraldehyde volume and release modifier agent such as pectin added to the tripolyphosphate crosslinking solution were evaluated. The microparticles were examined with scanning electron microscopy, infrared spectroscopy and differential scanning colorimetry. The serum glucose lowering effect of gliclazide microparticles was studied in streptozotocin‐diabetic rabbits compared with the effect of pure gliclazide powder and gliclazide commercial tablets. Key findings The particle sizes of tripolyphosphate–chitosan microparticles were over the range 675–887 µm and the loading efficiency of drug was greater than 94.0%. In‐vivo testing of the gliclazide–chitosan microparticles in diabetic rabbits demonstrated a significant antidiabetic effect of gliclazide–chitosan microparticles after 8 h that lasted for 18 h compared with gliclazide powder, which produced a maximum hypoglycaemic effect after 4 h. Conclusions The results suggests that gliclazide–chitosan microparticles are a valuable system for the sustained delivery of gliclazide.     

格列齐特对大鼠局灶性脑缺血再灌注损伤的保护作用及机制研究

目的: 以大脑中动脉栓塞(MCAO)/再灌注模型为研究对象,探讨格列齐特对缺血性脑卒中的保护作用及机制。方法: 雄性Wistar大鼠采用线栓法进行2h左侧MCAO/再灌注,对不同再灌注时间点的梗死核心区样本检测mRNA水平及SUR1蛋白表达水平;不同剂量格列齐特静脉注射到右颈内静脉后灌注12h,采用TUNEL法检测凋亡细胞数量、采用Bederson试验评价神经功能缺损、采用TTC染色法观察脑梗死体积。结果: SUR1mRNA和蛋白水平在MCAO/再灌注组织中显著上调,在缺血后8~12h达到最大水平。格列齐特可减少TUNEL阳性细胞数量,减轻神经功能损伤和脑梗死体积。结论: 研究表明SUR1信号通路可能与MACO/再灌注损伤及梗死相关,静脉注射格列齐特可通过抑制SUR1的表达减轻梗死程度,减少MACO/再灌注造成的梗死面积及脑细胞凋亡程度。     

HPLC分离测定格列齐特片及其有关物质

目的：建立新的HPLC法分离测定格列齐特征及其有关物质。方法：色谱条件为：Shim-Pack VP-ODS(5um,150mm*4.6mm i.d.)色谱柱;甲醇－0．02mol/L磷酸（用三乙胺调节PH至3．5）,（70：30）为流动相;检测波长为229nm。结果：在50－300ug;/ml的浓度范围内线性关系良好。r=0.9999(n=6);平均回收率为100．5％,RSD为0．17％（n=6),重复进样RSD为0．12％（n=6),格列齐特及其有关物质得到基线分离。结论：本法简便,快速,准确,适用于格列齐特及其制剂的质量控制。     

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。     

格列喹酮与格列齐特的临床疗效及不良反应比较

目的回顾性分析对比格列喹酮与格列齐特的临床疗效及不良反应。方法将丽水市中心医院内分泌科用过格列喹酮和格列齐特两种药物3个月以上的门诊和住院患者129例的病历资料及化验单进行统计分析,比较用药后空腹血糖、餐后2 h血糖及肝肾功能等指标。结果两组治疗3个月后空腹血糖均明显下降(P<0.05),格列齐特降空腹血糖效果优于格列喹酮,格列喹酮降餐后2 h血糖作用优于格列齐特;两组肝肾功能各项指标无大的波动,不良反应发生率无显著性差异。结论格列喹酮和格列齐特都有一定的降血糖疗效,格列喹酮不良反应较格列齐特少,且对肾功能具有一定的保护作用。     

3种磺脲类降糖药治疗2型糖尿病的药物经济学分析

目的比较格列美脲、格列吡嗪和格列齐特治疗2型糖尿病的经济效果。方法将85例患者随机分为3组,A组28例,B组29例,C组28例,分别给予格列美脲、格列吡嗪和格列齐特进行治疗,观察疗效,并用最小成本法进行分析。结果A组、B组和C组治疗2型糖尿病有效率分别为8571%、8621%、8571%;不良反应发生率分别为714%、690%、1071%;费用分别为68264元、43624元、46434元。结论格列吡嗪治疗2型糖尿病的经济效果优于格列美脲和格列齐特。     

格列齐特缓释片在比格犬体内的药动学及生物等效性

目的 研究自制格列齐特缓释片在比格犬体内的药动学行为和体内外相关性。方法 取6条比格犬随机分成两组,采用自身对照交叉方式给药,分别灌胃给予自制格列齐特缓释片和参比制剂达美康,给药剂量为30 mg。给药后于不同时间点采血,采用高效液相色谱法测定血药浓度,计算药动学参数,考察自制格列齐特缓释片的药动学特征和相对生物利用度,评价其生物等效性,计算其体内外相关性。结果 达美康的药时曲线下面积（AUC_0-∞）为（101.74±20.29）μg/（mL·h）,自制制剂格列齐特缓释片的AUC_0-∞为（95.40±28.68）μg/（mL·h）,两者间各药动学参数差异均无统计学意义（P>0.05）。自制格列齐特缓释片对达美康的相对生物利用度为93.77%,两者具有生物等效性。将制剂在犬体内的吸收分数与体外累积释药率作线性回归,达美康与自制格列齐特缓释片的相关系数分别为0.912和0.894,均大于临界值（r_0.05,7=0.754）,两者的体外释放速率与犬体内吸收速率均相关。结论 自制格列齐特缓释片在比格犬体内具有缓释特征,其与参比制剂达美康生物等效。本研究建立的体外释放度测定方法可用于预测格列齐特缓释片在体内的吸收行为。