【作者】 孙春艳；

【导师】 罗顺德；

【作者基本信息】 武汉大学 ， 药剂学， 2005， 硕士

【摘要】 目的:研究莲心碱冻干粉针抗心律失常作用的药效学及其一般药理学,建立其血浆样品的制备、提取及HPLC分析方法,探讨其在家兔体内的药动学和药效学过程,并建立药动学一药效学模型,计算其药代动力学和药效动力学参数,完善莲心碱冻干粉针临床前药学研究内容,为本品的临床研究提供依据。 方法:先采用哇巴因致心律失常模型探讨莲心碱冻干粉针的药效与剂量的关系,然后选择高、中、低三个剂量组,用氯化钙、乌头碱、氯仿致心律失常模型,分别考察不同剂量组的莲心碱冻干粉针的抗心律失常作用;通过实验考察其对大鼠血压、心电、呼吸和小鼠自主活动次数的影响;以家兔为研究对象,以6mg·kg^-1的剂量静脉注射莲心碱冻干粉针,分别于0、2、5、10、15、30、45min和1、1.5、2、3h取血,用HPLC法测定血药浓度,并同时连续监测心电和血压,以HR、P-R间期、QRS间期、Q—Tc间期、SBP、DBP的延长或抑制率为效应指标,用3P97药动学程序计算药动学参数,根据Sheiner提出的效应室理论,效应一时间数据采用PK—PD程序进行拟合,即可得到PD参数。 结果:不同剂量组的莲心碱冻干粉针均能显著提高哇巴因致豚鼠和乌头碱致大鼠室性早博（VE）、室性纤颤（VF）及心脏停搏（CA）时的用量,延长氯化钙诱发大鼠心律失常出现的时间,缩短生存大鼠的窦性心律恢复时间,减少死亡率,降低氯仿所致小鼠室颤发生率,延长小鼠室颤出现的时间;三个剂量组的莲心碱冻干粉针均能减慢大鼠心率、延长P—R、ORS、Q-Tc间期,而对大鼠的呼吸频率及深度和小鼠的自主活动次数无显著影响。静脉注射莲心碱冻干粉针后,血药浓度呈双指数衰减,符合二室开放模型,药动学参数T-（1/2α）=9.148±2.152min,T₁/2β=132.426±21.044min,Cl=0.041±0.013L·kg^-1·min^-1,Vc=2.599±0.777L·kg^-1α=0.076±0.016min^-1,β=0.005±0.001min^-1。给药后,HR明显减慢,P-R、QRS、Q—Tc间期均明显延长,在给药后5-10min达到最大效应,减慢或延长的最大百分率分别为33.4±8.1%,44.2±11.3%,48.4±10.9%,30.3±9.4%;SBP和DBP的降低百分率在5min达到最大值,降低百分率分别为41.7±10.9%,52.1±12.5%;药物效应与血药浓度之间存在明显的滞后现象,即药物效应与血药浓度之间存在逆时针滞后环,效应并不与浓度直接相关。运用Sheiner提出的效应室更多还原

【Abstract】 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-E_max 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.更多还原