国产和进口格列吡嗪片在健康人体内的药动学比较

目的:比较国产和进口格列吡嗪片在健康志愿者体内的吸收、分布、代谢和排泄. 方法:健康男性志愿受试者12例,单剂量口服国产和进口格列吡嗪片10 mg,用标准二阶段交叉设计自身对照实验方法,以高效液相色谱法测定血浆中格列吡嗪的经时浓度,计算药动学参数. 结果:国产和进口格列吡嗪片在健康志愿者体内的药-时曲线均符合一级吸收的单室模型,两种格列吡嗪片的主要药动学参数Tmax, Cmax和 AUC(0-17)分别为(2.6±0.5) h和(2.6±0.5) h; (609.7±112.9) ng/mL和(568.8±101.9) ng/mL;(4499.8±969.0)ng/mL和(4108.3±724.9) ng/mL. 结论:国产和进口格列吡嗪片的药代动力学参数无差异.     

格列吡嗪控释片体外药物释放特征和体内外相关性研究

目的 考察格列吡嗪控释片体外药物释放特征和体内外相关性。 方法 分别采用3种不同pH值的缓冲溶液作为释放介质,并对pH 6.8的释放介质分别采用3种不同的转速来测定格列吡嗪控释片的体外药物释放度,考察释放介质pH值和转速对释放度的影响。用Loo-Riegelman法计算格列吡嗪控释片在健康男性受试者体内吸收百分数,并与相应时间体外累积释放度线性回归,进行体内外相关性考察。结果 格列吡嗪控释片在不同pH值释放介质中的释放度一致,均符合零级动力学,且不受转速影响。将体内累积吸收百分数y与相应时间在pH 6.8释放介质中的体外释放百分数x进行线性回归（n=7）,回归方程为y=0.690 4x+22.941,r=0.952 8。结论 格列吡嗪控释片的释放度不受释放介质pH值和转速的影响,释药恒速。体外释放累积百分数与体内吸收百分数呈A级相关,具有良好的体内外相关性。     

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。     

Pinacidil抑制线粒体和死亡受体通路减少大鼠脑缺血再灌注后神经元凋亡(英文)

目的探讨ATP敏感性钾通道开放剂pinacidil对大鼠脑缺血再灌注后神经元凋亡的保护作用及信号转导机制。方法 100 只Wistar 雄性大鼠随机分为四组:A 组(假手术组)、B组 (缺血组)、C 组 (KATP开放剂处理组)及D组 (KATP开放剂和阻断剂处理组)。用线栓法制备大鼠大脑中动脉缺血(middle cerebral artery occlusion,MCAO)模型,用DNA断端末端标记法(terminal-deoxynucleotidytransferase-mediated dUTP-biotin nick end labeling,TUNEL)检测神经元凋亡,用原位杂交方法检测caspase-3、caspase-8及caspase-9 mRNA的表达。结果 (1) C组12 h、24 h、48 h、72 h 时间点的凋亡细胞数较 B、D 组显著减少(P<0.05 或 P<0.01) ;B 组和 D组之间无显著性差异(P>0.05)。(2) C 组 caspase-3 mRNA 和 caspase-8 mRNA 在各时间点及 caspase-9 mRNA 在 12 h、24 h、48 h、72h 时间点的表达显著少于B组和D组(P<0.01或P<0.05),B组和D组之间无显著性差异(P>0.05)。结论 KATP通道开放剂能显著减少大鼠脑缺血再灌注后的细胞凋亡及caspase-3、caspase-8及caspase-9 mRNA的表达。KATP通道开放剂可能通过抑制线粒体通路和死亡受体通路降低神经元凋亡,保护缺血再灌注损伤后的脑组织。     

Glipizide increases plasma insulin but not C-peptide level after a standardized breakfast in type 2 diabetic patients

Summary Peripheral blood glucose, plasma insulin and C-peptide levels were investigated after giving a standardized breakfast (500 kcal, 60g carbohydrates) to 10 nonobese Type 2 diabetic patients previously treated by diet alone. Each patient received at random, at 1 week intervals, either 5 mg glipizide (meal + glipizide) or a placebo (meal alone) 30 min before breakfast. Basal values of blood glucose, plasma insulin and C-peptide were similar on both occasions. After meal + glipizide, the blood glucose increase was sharply limited whereas the rise in plasma insulin was steeper and reached twice as high a level. In contrast, the rise in plasma C-peptide was similar in both conditions. Consequently, the areas under the curves (0–300 min) showed a marked reduction in blood glucose after meal + glipizide (2289±149 versus 3101±169 mmol·min/l; 2p<0.001), associated with a significant increase in plasma insulin (14219±3261 versus 7591±1173 µU·min/ml; 2p<0.025) but no significant change in plasma C-peptide (342±45 versus 326±34 pmol·min/ml; N.S.). The insulin/C-peptide molar ratio was thus significantly increased after meal + glipizide (0.41±0.06 versus 0.23±0.04 at the 60th min; 2p<0.02). The dissociation between the responses of insulin and C-peptide suggests that a single dose of 5 mg glipizide in Type 2 diabetic subjects may enhance availability of peripheral insulin by extrapancreatic mechanism(s). This phenomenon may result in a higher circulating level of the hormone and therefore represent a further mode of action of sulphonylureas. Finally, the usual concept that peripheral insulin levels reflect true insulin secretion may be misleading in studies dealing with sulphonylureas.     

液相色谱-串联质谱法同时测定人血浆中二甲双胍和格列吡嗪

建立了快速、灵敏的液相色谱-串联质谱法测定人血浆中的二甲双胍和格列吡嗪。血浆样品经0.3%甲酸-乙腈(v/v)沉淀蛋白后，以乙腈-水-甲酸(70∶30∶0.3，v/v/v)为流动相，流速为0.50 mL·min^-1。Zorbax Extend C₁₈柱分离，采用大气压化学电离源；以选择反应监测(SRM)方式进行正离子检测。用于定量分析的离子反应分别为m/z 130→m/z 60(二甲双胍)，m/z 446→m/z 321(格列吡嗪)和m/z 256→m/z 167(内标，苯海拉明)。测定血浆中二甲双胍的线性范围为2.00～2 000 ng·mL^-1， 定量下限为2.00 ng·mL^-1； 格列吡嗪的线性范围为1.00～1 000 ng·mL^-1， 定量下限为1.00 ng·mL^-1。该方法专属性好，灵敏度高，准确快捷，适用于二甲双胍和格列吡嗪的临床药代动力学研究。     

复方盐酸二甲双胍格列吡嗪片在健康人体的药动学

目的:研究复方盐酸二甲双胍格列吡嗪片在健康中国人体内的药动学特征。方法:12位受试者(男女各半)在不同试验周期分别口服不同盐酸二甲双胍、格列吡嗪制剂。用HPLC-UV方法测定血浆中盐酸二甲双胍及格列吡嗪浓度。结果:试验所得各药动学参数与文献报道基本一致。经过统计学分析,复方盐酸二甲双胍格列吡嗪片中二成分与单独服用盐酸二甲双胍片及格列吡嗪片相比主要药动学参数差异无显著性,多剂量服药与单次服药相比主要药动学参数差异无显著性。结论:复方盐酸二甲双胍格列吡嗪片中两组分之间在体内不存在相互作用,多剂量服药与单次服药相比其体内药物动力学过程不发生改变。     

铁皮枫斗胶囊合用格列吡嗪降血糖作用的实验研究

目的 研究铁皮枫斗胶囊合用格列吡嗪的降血糖作用,与两药单用进行比较。方法 采用正常小鼠,葡萄糖致高血糖小鼠,链脲霉素(STZ)诱发的糖尿病小鼠,用葡萄糖氧化酶法测定血糖值。结果 对葡萄糖致高血糖小鼠与STZ诱发的糖尿病小鼠,两药合用均比两药单用有更显著的降血糖作用。结论 铁皮枫斗胶囊合用格列吡嗪的降血糖作用比两药单用的效果为好。     

The Sulfonylurea Glipizide Does Not Inhibit Ischemic Preconditioning in Anesthetized Rabbits

The K(ATP) channel blocker glibenclamide inhibits cardioprotection afforded by ischemic preconditioning (IPC), raising concern about sulfonylurea use by patients with cardiovascular disease. We examined the effects of the widely prescribed sulfonylurea glipizide (Glucotrol XL(R) ) on IPC in anesthetized rabbits. Initially, in parallel studies in pentobarbital-anesthetized rabbits, we identified doses of glipizide (GLIP, 0.17 mg/kg + 0.12 mg/kg/h, IV) and glibenclamide (GLIB, 0.05 mg/kg + 0.03 mg/kg/h, IV) that produced steady-state, clinically relevant plasma levels of both drugs; these doses also significantly increased plasma insulin by 51 +/- 17% (GLIP) and by 57 +/- 17% (GLIB, both p < 0.05 vs. their respective baseline levels). Subsequent parallel studies in ketamine-xylazine-anesthetized rabbits examined the effects of these doses of GLIP and GLIB on IPC. Myocardial injury (30 min coronary occlusion/120 min reperfusion), either with or without IPC (5 min occlusion/10 min reperfusion) was induced midway during a 2 h infusion of vehicle (VEH), GLIP or GLIB (n = 10-11 each). Infarct area (IA) normalized to area-at-risk (%IA/AAR) was 62 +/- 3% in the VEH group, and was significantly reduced to 39 +/- 5% by IPC (p < 0.05 vs. VEH). Neither GLIP nor GLIB treatment had any effect on %IA/AAR in the absence of IPC (p > 0.05). IPC-induced cardioprotection was preserved in the GLIP + IPC treatment group (45 +/- 4%) when compared to VEH alone (p < 0.05), but was attenuated in the presence of GLIB (GLIB+IPC: 53 +/- 4% IA/AAR, p > 0.05 vs. VEH). Thus, at a clinically relevant plasma concentration, glipizide did not limit the cardioprotective effects of IPC, and is unlikely to increase the severity of cardiac ischemic injury.     

Pharmacokinetics and metabolic effects of glibenclamide and glipizide in type 2 diabetics

Summary Fifteen Type 2 diabetics were treated for 4-week periods with once daily (10 mg) glibenclamide, glipizide and placebo according to a double-blind cross-over protocol. Post-dose glipizide concentrations were three times higher than those of glibenclamide, due to the incomplete bioavailability of the latter. On the other hand, pre-dose drug levels were similar, as an expression of the slower absorption and/or elimination of glibenclamide. Both active treatments reduced postprandial blood glucose concentrations and 24-hour urinary glucose excretion to a similar degree, but fasting blood glucose concentrations were slightly lower during glibenclamide treatment. Both active treatments enhanced fasting and postprandial insulin and C-peptide concentrations, the C-peptide response being greater after glipizide than after glibenclamide. Plasma glucagon and GIP concentrations were not significantly affected. Insulin sensitivity was increased by glibenclamide but not by glipizide. Neither therapy affected insulin binding to erythrocytes. It appears that both glibenclamide and glipizide improved glucose metabolism by sustained stimulation of insulin secretion, which was most pronounced with glipizide. Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels. The differences may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded.