Limited sampling strategy to estimate pharmacokinetic parameters of orally administered metformin hydrochloride / 药学学报

The present study was to estimate pharmacokinetic parameters of metformin hydrochloride in 20 Chinese healthy volunteers with a limited sampling strategy (LSS), which will provide scientific data for bioequivalence and clinical application. A single dose of metformin was administrated to 20 healthy volunteers. The concentration of metformin in whole blood was determined by validated high performance liquid chromatography (HPLC) method. Multi-linear regression analysis was performed to establish a model to estimate AUC(0-24 h) and Cmax of metformin by LSS method. The LSS models were validated by the Jackknife method. The result indicated: the linearity relationship between AUC(0-24 h) or Cmax and single concentration point was poor. Several models for metformin AUC(0-24 h) or Cmax, estimation were better (r2 > 0.9, P < 0.05). Validation tests indicated that most informative sampling points (C2, C6 for AUC(0-24 h), C1.5, C2 for Cmax) provided accurate estimations of these parameters. So, a multi-linear regression model for estimation pharmacokinetic parameters of metformin by using LSS method is feasible.

Study on ultrastructure of cardioprotection of ramipril against ischemia/reperfusion injury in diabetic rats / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effects of ramipril on myocardial ischemia/reperfusion injury in diabetic rats, and to explore its mechanism according to the observation on myocardial ultrastructure.</p><p><b>METHODS</b>Streptozotocin induced diabetic rats were divided randomly into three groups (n = 16): ischemia/reperfusion (I/R), ischemic preconditioning (IPC) and ramipril (RAM) group. Rats in RAM group were administered by RAM(1 mg x kg(-1) x d(-1)) orally for 4 weeks, the others were administered by normal saline. Then all rats were subjected to myocardial ischemia/ reperfusion injury. Rats in IPC group were preconditioned before ischemia. The ECG and the infarct size were examined. The changes of myocardial morphology were examined by light and electron microscopes.</p><p><b>RESULTS</b>Compared with I/R group, the elevation of ST segment and the incidence of ventricular tachycardia and ventricular fibrillation during ischemia were significantly decreased, the infarct size at the end of reperfusion was remarkably reduced, the myocardial morphology were significantly improved, special structure of myofilaments and mitochondria remained clearly, blood vessels were unobstructed, injury of endothelium were decreased in PC and RAM groups.</p><p><b>CONCLUSION</b>Ramipril administered for 4 weeks induces myocardial protection in diabetic rats, which is similar to that of IPC. The mechanism may be involved in protection of cardiocytes and mitochondria, and improvement of endothelial function.</p>

A limited sampling strategy of phenotyping probe midazolam to predict inhibited activities of hepatic CYP3A in rats / 药学学报

The present study was to evaluate feasibility of a limited sampling strategy (LSS) in the prediction of inhibited hepatic CYP3A activity with systemic clearance of midazolam (MDZ), a hepatic CYP3A activity phenotyping probe. Rats were pretreated with a serial doses of ketoconazole, a selective inhibitor on CYP3A. Blood samples were collected and detected for MDZ at specified time points after intravenous injection of MDZ. Stepwise regression analysis and a Jack-knife validation procedures were performed in one group of rats as training set to establish the most informative LSS model for accurately estimating the clearance of MDZ. Another group of rats with same treatment was used as validation set to estimate the individual clearance based on predictive equations derived from the training set. Bland-Altman plots showed a good agreement between the systemic clearance calculated from DAS (CLobs) and corresponding parameter that was derived from three LSS models (CLest). LSS models derived from two or three sampling time points, including 60, 90 min, 30, 60, 90 min and 30, 60, 120 min, exhibited a good accuracy and acceptable error for estimating the CLobs of MDZ to evaluate hepatic CYP3A activity, especially the 60, 90 min LSS model is most accurate and convenient. The results supported that limited plasma sampling to predict the systemic clearance of MDZ is easier than the usual method for estimating CYP3A phenotyping when the hepatic activity of CYP3A is reduced in the rat. The present study provided theoretical basis and laboratory evidence for LSS to clinically evaluate metabolizing function of liver and

Effects of noninvasive limb ischemic preconditioning on anti-stress ability in mice / 中国应用生理学杂志

<p><b>AIM</b>To explore the effects of noninvasive limb ischemic preconditioning on the anti-stress ability in mice.</p><p><b>METHODS</b>Mice were divided into: normal group, control group, preconditioning group and drug group. Hypoxia tolerance test, swimming with weight loading, cold tolerance test and thermostable test were performed, and tolerance time in all the stringent state were observed. SOD activity of serum in hypoxia tolerance test and lactic acid of serum in swimming with weight loading test were determined.</p><p><b>RESULTS</b>The time of hypoxia tolerance in preconditioning group was markedly increased, and SOD activity of preconditioning group mice was significantly higher than those of control group, while they were both shorter than drug group. The average time of swimming in preconditioning group was markedly increased and the level of increasing the swimming time of preconditioning was the same as caffeine. Preconditioning could increase the survival time on high temperature markedly, and there was no significantly difference in the level of increasing the survival time between preconditioning group and chlorpromazine group. Preconditioning could increase the time of cold tolerance markedly compared with normal group.</p><p><b>CONCLUSION</b>Noninvasive limb ischemic preconditioning can improve the ability of anti-hypoxia, anti-fatigue, thermoresistance and cold-resistance in mice.</p>