Anti-arrhythmic effects of taurine-magnesium coordination compound on torsades de pointes / 中国应用生理学杂志

OBJECTIVES@#To investigate the effect of taurine magnesium coordination compound (TMCC) on torsades de pointes (TdP) in isolated guinea pig hearts.@*METHODS@#Healthy male guinea pigs weighting 250~300 g were randomly divided into 4 groups:①TdP model group (=7):Isolated hearts were perfused by normal K-H solution 20 minutes, then perfused by slowly activated delayed rectifier potassium current(IKs) blocker 10mol/L Chromanol 293B under hypokalemic solution(1.8 mmol/L) to establish TdP model;②~④ TdP model + TMCC group (=6):Isolated hearts were perfused by normal K-H solution for 20 minutes, then perfused by IKs blocker 10mol/L Chromanol 293B under hypokalemic solution(1.8 mmol/L) for 60 minutes, at the same time TMCC which concentration was 1, 2, 4 mmol/L was administered respectively by Langendorff retrograde aortic perfusion method. Cardiac surface electrocardiogram of guinea pigs was collected and recorded by Biopac electrophysiological recorder. Incidence of TdP, transmural dispersion of repolarization (TDR), instability of QT interval were acquired from Lead Ⅱ electrocardiograph (ECG) wave forms to describe the effect of TMCC on TdP model. Datas were acquired at the time of 20 min and pre-TdP, in case there was no TdP observed, a value of 60 min was entered for calculation purpose.@*RESULTS@#Incidence of TdP in TdP model group was 6/7. TdP incidence could be decreased significantly by 1, 2, 4 mmol/L TMCC, and was 5/6, 1/6, 0/6 respectively. Compared with the pre-drug, Chromanol 293B under hypokalemic solution in TdP model group increased TDR(corrected) evidently(0.05). Compared with the TdP model group, 2, 4 mmol/L TMCC could evidently decrease the instability of QT interval induced by Chromanol 293B under hypokalemic solution(<0.05). During the establishment of TdP model, P waves in more than one cardiac cycle continuously were disappeared in ECG. However, P wave could always be seen independent in ECG acquired from TdP model + TMCC group.@*CONCLUSIONS@#TMCC can play the role against TdP through decreasing TDR and instability of QT interval, and inhibiting early after depolarization(EAD).

Investigations on effect of taurine-magnesium coordination compound against SQT2 in isolated hearts of guinea pig / 中国药理学通报

Aim To investigate the effect of taurine-magnesium coordination compound (TMCC) on elec-trocardiogram of isolated guinea pig hearts, hoping to describe a primary research on its characteristic of anti-short QT syndrome. Methods The isolated guinea pig heart was retrograde perfused using Langendorff tech-nique. In order to determine the effects of TMCC on QT interval, transmural dispersion of repolarization, effective refractory period, instability of RR interval and instability of QT interval in the presence of potassi-um channel opener pinacidil, the electrocardiogram of isolated guinea pig hearts was recorded using Biopac physiological recorder. Results The shortened QT in-terval and the effective refractory period induced by pinacidil could be prolonged by TMCC; the increased transmural dispersion of repolarization induced by pinacidil could be decreased by TMCC; the increased instability of RR and QT interval induced by pinacidil could be decreased by TMCC. Conclusion TMCC has the effects of anti-SQT2 by prolonging the QT inter-val and the effective refractory period, reducing the transmural dispersion of repolarization and instability.

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>

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>

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 Dioscorea septemloba on bone metabolism in ovariectomized rats / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the effects of the decoction of Rhizoma Dioscorea septemlobae (RD) on the bone metabolism in ovariectomized rats.</p><p><b>METHOD</b>Thirty female, 3-month-old Wistar rats without pregnancy and deliver were randomly divided into 6 groups: sham (sham-operation), ovariectomy (OVX), OVX + diethylstilbestrol, OVX + high dose RD (4 g x kg(-1) x d(-1)), OVX + middle dose RD (2 g x kg(-1) x d(-1)) and OVX + low dose RD (1 g x kg(-1) x d(-1)) (n = 5 in every group). After 12-week period of continuous treatment, the urinary samples and blood samples were collected for the determination of serum estrodiol (E2), calcium (Ca), phosphorus (P), bone glaprotein (BGP), alkaline phosphatase (ALP), urinary calcium/creatinine (Ca/Cr), phosphorus/ creatinine (P/Cr) and deoxypyridioline/creatinine (DPD/Cr). The uteri were removed and weighed. The bone mineral density (BMD) and the biomechanical parameters of the femur of the rats in every group were determined, respectively.</p><p><b>RESULT</b>The coefficient of uteri in every dose group of OVX + RD was significantly higher than that in the OVX group (P < 0.01). The concentration of serum ALP, BGP and urinary DPD/Cr, Ca/Cr in the OVX group was significantly higher than that in the sham group (P < 0.05), respectively, However, that in the every dose of OVX + RD was lower than that in the OVX group, respectively. There was no significan difference in the concentration of serum Ca, P and urinary P/Cr in every group, respectively. The bone mineral density (BMD) in the OVX group was (0.032 +/- 0.007) g x cm(-2) and was significantly lower than that in the sham group (P < 0.01). However, the value in the group of every dose OVX + RD was significantly higher than that in the OVX group (P < 0.05, P < 0.01), respectively. The maximum loading, deflection and the maximum strain of the femur in the OVX group were (125.78 +/- 15.48) N, (1.87 +/- 0.22) mm, (9.34 +/- 1.10) % and were significantly lower than those in the sham group (P < 0.05, P < 0.01), respectively. The maximum loading and maximum stress were increased in different extent in the every dose group of OVX + RD, respectively.</p><p><b>CONCLUSION</b>The decoction of RD can inhibit bone absorption, decline bone turnover and improve the loss of bone in ovariectomized rats.</p>

The clinical pharmacokinetics and bioequivalence of benzoylmetronidazole capsules / 中国药理学通报

AIM: To compare the pharmacokinetics and bioequivalence of between capsule and solution of benzoylmetronidazole. METHODS: Ten chinese healthy male volunteers in a randomized 2-way crossover study were given a single oral dose 960 mg capsule(test) and solution (control) respectively. The serum concentrations of metronidazole, one of the metabolites of benzoylmetronidazole, was measured by high performance liquid chromatography. RESULTS: The serum concentration- time curves appeared one-compartment open model. The results of the capsule and the solution of benzoylmetronidazole showed that Tmax(5.10 ± 1.60) h and (3.12 ± 0.90) h; Cmax(5.32 ± 0.87) mg·L-1 and (6.51 ± 1.25) mg·L-1; T1/2(10.56 ± 1.75) h and (10.16 ± 1.65) h; AUC (106.96 ± 19.62) mg·h-1·L-1 and (113.59 ± 19.84) mg·h·L-1. CONCLUTION: No significant difference appears in the pharmacokinetic parameters between the two formulations except of Tmaxand Cmax(P<0.05). The relative bioavailability of benzoylmetronidazole capsule is (95.07 ± 14.70) %. The AUC between the two formulations is bioequivalent, but the Tmax and Cmax are non-bioequivalent.