| Objective: To study the antiarrhythmic effect of liensinine lyophilization and it's general pharmacology, establish the methods of preparation, extraction , analysis and determination of liensine plasma concentration. Study liensine plasma concentration-time curves and its pharmacokinetic parameters after intravenous administration of dosage of 6.0 mg·'kg-1 in rabbits. Investigate the relationship between liensine plasma concentration and it's effects on cardiac electrophysiology, blood pressure and construct a simultaneous pharmacokinetic-pharmacodynamic model of liensine,then get the PD parameters.Methods: Four arrhythmic animal models were performed respectively: ouabain-induced arrhythmia in guinea pigs to study the relationship of effects an dosage,Cacl2 and aconitine-induced arrhythmia in rats ,trichloromethane-induced arrihythmia in mice used the three selected dosage. The effects of the liensine lyophilized powder for injection on electrocardiogram, blood pressure, breathing, and nervous system were determined by experiments. After intravenous administration of dosage of 6mg·kg-1 of body weight in rabbits, determine the plasma concentration by HPLC of 0,2,5,10,15,30,45min and l,1.5,2,3h after the injection.. At the same time , investigated the drug's effects on cardiac electrophysiology(HR and P-R,QRS,Q-Tc interval), blood pressure(SBP and DBP).The pharmacokinetic parameters were got through 3p97 program. By means of effect compartment theory proposed by Sheiner , the relationship between the effects and compartment concentrations were characterized by the sigmoid-Emax modle, and the PD parameters were got through PK-PD program.Results: With the injective dosage of high, middle and low, liensinine lyophilization could markedly increase the threshold dosage of ventricular extrasystol(VE), ventricular fibrillation(VF) and cardiac arrest(CA) caused by ouabain in guinea pigs or by aconitine in rats; delay the onset time of arrhythythmia and shorten the recovering time of normal heart rate and mortality of CA caused by Cacl2 in rats;Reduce the ratio and delay the onset time of VF caused by trichloromethane in mice. The three dosage of liensinine lyophilization could reduce the level of systolic pressure(SBP) and diastolic pressure(DBP),slow down the heart rate of rats, prolong QRS> QT interval. The influence on respiratory rate and depth of rats and the number of times of free movements of mice was not obvious. Afterintravenous administration of dosage of 6mg?kg"' of body weight in rabbits, the plasma concentration-time curves were best described by a two-compartment open model, the decline in plasma concentration was biexponential with Ti/2a=9.148±2.152min, Ti/2p=132.426±21.044min ,Cl=0.041±0.013L'kg"1?min"\ Vc= 2.599±0.777L'kg-' ,a=0.076±0.016min"] , pMXOOSiO.OOlmin'1. The results showed that the drug could reduced heart rates(HR),prolong P-R,QRS and Q-T intervals. 5-10mins after intravenous administration, the maximum effects were recorded. And the reduction percentages of HR were 33.4±8.1%,The prolongation percentage of P-R,QRS, and Q-Tc intervals were 44.2±11.3%,48.4±10.9%,30.3±9.4%,respetively.In this study, both systolic and diastolic blood pressure declined after intravenous administration, the maximum effects were detected at 5min after administration with reduction percentage of 41.7±10.9% and 52.1±12.5% for SBP and DBP respectively. The results demonstrated that the maximum pharmacological effects were 5-10min later than the maximum plasma concentrations. There were no direct correlation between pharmacological effects and plasma concentrations(Cp),and a counterclockwise hysteresis loop existed between them. By means of effect compartment theory proposed by Sheiner ,the measured pharmacological effects were parallel to the effect compartment concentrations(Ce).The relationship between the effects and Ce were successfully characterized by the sigmoid-Emax model with the PD parameters were 0.072±0.016 0.124±0.029min"1,36.8±9.8 53.8±13.4 , 0.324±0.0170.412±0.032ug?ml"1 , 2.226±0.0153.415±0.026 for Keo,Emax,CE50 and r respectively.Conclusion: Liensinine lyophilization has extensive antiarrhythmic effects, and can reduce blood pressure, moreover, haven't obvious influence on respiration of rats and free movements of mice. The plasma concentration-time curves were best described by atwo-compartment open model in rabbits. The drug spreaded quickly to the tissue and had a wide distribution in body. Keo>a,which showed that the time between the maximum effects and the maximum plasma concentrations was not long. Keo>P,which showed that the lasting time of effects was shorter than the drug existed in plasma. The value of Emax and EC50 demonstrated that the drug had close touch with the receptor. |
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