Bioequivalence evaluation of two brands of gliclazide 80 mg tablets (Glyzide & Diamicron)--in healthy human volunteers

A randomized, two-way, crossover, bioequivalence study in 24 fasting, healthy, male volunteers was conducted to compare two brands of gliclazide 80 mg tablets, Glyzide (Julphar, UAE) as test and Diamicron (Servier Industries, France) as reference product. The study was performed at the International Pharmaceutical Research Centre (IPRC), in joint venture with Speciality Hospital, Amman, Jordan. The drug was administered with 240 ml of 20% glucose solution after a 10 h overnight fasting. After dosing, serial blood samples were collected for a period of 48 h. Plasma harvested from blood was analyzed for gliclazide by validated HPLC method. Various pharmacokinetic parameters including AUC(0-t), AUC(0- proportional, variant), C(max), T(max), T(1/2), and elimination rate constant were determined from plasma concentrations of both formulations. Statistical modules (ANOVA and 90% confidence intervals) were applied to AUC(0-t), AUC(0- proportional, variant), and C(max) for bioequivalence evaluation of the two brands which revealed no significant difference between them, and 90% CI fell within US FDA accepted bioequivalence range of 80-125%. Based on these statistical inferences, Glyzide was judged bioequivalent to Diamicron.     

LC-MS/MS快速测定人血浆中格列齐特

 目的建立测定人血浆中格列齐特的液相色谱-质谱/质谱联用法,并应用于人体药代动力学研究。方法0.25 mL血浆样品经液-液萃取后,以乙腈-水-甲酸(90∶10∶0.5)为流动相,采用Zorbax SB C₈柱分离,通过大气压化学电离四极杆串联质谱,以选择离子反应监测(SRM)方式进行检测。用于定量分析的离子反应分别为m/z324～m/z127(格列齐特)和m/z494(m/z369(内标格列本脲)。结果格列齐特血浆质量浓度线性范围为1.0～4 000μg·L^-1,定量下限为1.0μg·L^-1。日内和日间精密度(RSD)均小于4%,准确度(RE)在±5.1%内。每个样品色谱分析仅为2.8 min,应用此法每天可以测试150个样品。结论该法操作简便、快速、灵敏,适用于格列齐特的临床药动学研究及制剂的生物等效性评价。     

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.     

Differential effects of sulphonylureas on the vasodilatory response evoked by K(ATP) channel openers

The potency of three sulphonylureas, glibenclamide, glimepiride and gliclazide in antagonizing the vasorelaxant action of openers of adenosine triphosphate (ATP)-regulated K+ channel (KATP) was studied in vivo and in vitro in micro- and macrovessels, respectively. In the hamster cheek pouch, the vasodilatation and the increase in vascular diameter and blood flow induced by diazoxide were markedly reduced by the addition of either glibenclamide or glimepiride (0.8 microm) while they were not affected by gliclazide up to 12 microm. Similarly, in rat and guinea-pig isolated aortic rings, glibenclamide, glimepiride and gliclazide reduced the vasodilator activity of cromakalim. However, the inhibitory effect of gliclazide was considerably less when compared with either glimepiride or glibenclamide. These results suggest that, in contrast to glibenclamide and glimepiride, therapeutically relevant concentrations of gliclazide do not block the vascular effects produced by KATP channel openers in various in vitro and in vivo animal models.     

Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose

BACKGROUND: Decreased beta-cell mass, mainly due to apoptosis, is crucial for the development and progression of type 2 diabetes. Chronic exposure to high glucose levels is a probable underlying mechanism, whereas the role of oral anti-diabetic agents (sulphonylureas in particular) is still unsettled. METHODS: To directly investigate more on such issues, we prepared isolated human islets, which were then cultured for 5 days in continuous normal glucose concentration (NG, 5.5 mmol/L) or normal and high (HG, 16.7 mmol/L) glucose levels (alternating every 24 h), with or without the addition of therapeutical concentration (10 micromol L) of gliclazide or glibenclamide. RESULTS: Intermittent high glucose caused a significant decrease of glucose-stimulated insulin secretion, which was not further affected by either sulphonylurea. Apoptosis, as assessed by electron microscopy, was also significantly increased by alternating high glucose exposure, which was accompanied by altered mitochondria morphology and density volume, and increased concentrations of nitrotyrosine, a marker of oxidative stress. Gliclazide, but not glibenclamide, was able to significantly reduce high glucose induced apoptosis, mitochondrial alterations, and nitrotyrosine concentration increase. CONCLUSION: Therefore, gliclazide protected human beta-cells from apoptosis induced by intermittent high glucose, and this effect was likely to be due, at least in part, to the anti-oxidant properties of the molecule.     

国产和进口格列齐特体外溶出度测定及其药动学特性比较

正常人体内药物动力学测定结果,国产格列齐特和进口达美康片的T_(1/2k)分别为10.16和11.41h;T_(max)分别为3.28和8.18h;C_(max)分别为5.58和1.12μg/ml;AUC分别为101.47和30.13μg·h~(-1)·ml~(-1)。若以po国产格列齐特片80mg的生物利用度为100％,则进口达美康相对生物利用度仅为29.7％。     

格列齐特片健康人体药物动力学及相对生物利用度

目的　研究格列齐特片的健康人体药物动力学及相对生物利用度。方法　 8例健康受试者单剂量交叉口服格列齐特片标准参比制剂和被试制剂 80mg后 ,用高效液色谱法测定血浆中格列齐特片浓度。结果　两药体内过程均符合一房室开放模型 ,Tmax分别为 (5 5 0± 0 5 3)h和 (5 0 0± 0 5 3)h ,Cmax为 (2 95± 0 4 1)mg·L-1和 (3 0 2± 0 31)mg·L-1,AUC为 (45 79± 5 99)mg·h·L-1和 (42 99± 6 93)mg·h·L-1,被试制剂的相对生物利用度为 (10 2 9± 8 2 ) %。两种制剂的药动学参数无显著性差异。结论　两种制剂具有生物等效性。     

格列齐特治疗非胰岛素依赖性糖尿病的疗效

本文对国产和进口格列齐特各治疗８１和７６例非胰岛素依赖性糖尿病进行为期３－４ｍｏ的疗效对比。结果：２组的空腹和餐后血糖、ＨｂＡ１及血清三酰甘油（甘油三酯）明显降低，但空腹和餐后血清胰岛素和血清胆固醇没有明显变化。国产格列齐特的有效剂量明显低于进口格列齐特（Ｐ＜０．０５）。本文证明两者的疗效没有明显差别。     

Is it time to re‐assess the role of gliclazide? Targeting insulin resistance in type 2 diabetes patients suboptimally controlled with insulin

Background

Adult patients with type 2 diabetes controlled with insulin frequently require the addition of insulin sensitising drugs such as metformin and sometimes glitazones to achieve optimum glycaemic control. Five of a group of eight people with suboptimal diabetes control who were treated by the introduction of gliclazide are reported on. Three patients were excluded. One with type 1 diabetes and two others who had dietary or other therapeutic interventions coinciding with re‐introduction gliclazide. Does the re‐introduction of gliclazide effect a clinically significant improvement in glycaemic control in type 2 diabetes patients with suboptimal control taking combinations of short and long acting insulin plus metformin?

Method

Five adult patients with type 2 diabetes with suboptimal control using combinations of short and long acting insulin plus metformin who were adherent to their dietary regimen were treated by the addition of gliclazide at different doses. Two of the patients were taking pioglitazone in addition to metformin and insulin. Their glycaemic control was monitored over the following six months.

Results

All five showed significant improvement in glycaemic control after three months. Mean reduction in HbA1c was 1.4% (range 0.9% to 2.5%). Six months after the introduction of gliclazide four patients had HbA1c below base line figure and in two patients clinically significant improvement had been maintained.

Conclusion

A double blind randomised placebo control study is necessary to evaluate a possible role for gliclazide in type 2 diabetes patients who have suboptimal glycaemic control using combinations of short and long acting insulin plus metformin.