丙戊酸镁、丙戊酸镁缓释片与德巴金缓释片药效时效关系的比较研究

Comparisons of the drug efficacy and timeeffect among Magnesium Valproate, Sustained-release Magnesium Valproate tablet and Depakine Chrono

目的探讨丙戊酸镁片、丙戊酸镁缓释片与德巴金缓释片在药效、时效、副反应方面的差异。方法利用大鼠抗电刺激皮层惊厥阈值模型，观察三种药物组及假阳性对照组单次及重复给药后大鼠惊厥阈值动态变化趋势，连续给药一个月后取其肝肾做病理学检查。并监测人单次口服三种药物后体内血药浓度变化趋势。结果对照组24h内惊厥阈值稳定在860±40μA，丙戊酸镁单次给药后1～2h达药效高峰，大鼠惊厥阈值升高至1100μA，较其它三组明显升高（P〈0．05），给药后3h其药效开始下降，至12h其惊厥阈值下降至950μA。丙戊酸镁缓释片及德巴金给药后7h左右达峰，惊厥阈值分别升高至1085μA及1000μA，显著高于对照组（P〈0.05），给药后12h两组惊厥阈值均保持在1023μA左右。三种药物药效变化趋势与人体单次服药后体内血药浓度变化相吻合。重复给药过程中丙戊酸镁组的惊厥阈值的峰谷平均差值为120～150μA，是丙戊酸镁缓释片和德巴金峰谷差值的2倍和2．5倍。重复给药10次后，丙戊酸镁缓释片组惊厥阈值较给药前升高430μA，德巴金缓释片组升高230μA。连续给药一个月后，三者肝肾损害较对照组无明显差异。结论丙戊酸镁片起效快、持续时间短，波动大。丙戊酸镁缓释片起效慢，作用力维持时间比丙戊酸镁片长。德巴金吸收较好，药效更平稳，但长时程的抗惊厥效果不如丙戊酸镁缓释片显著。

Objective To compare the differences of drug efficacy, timeeffect and side effects among Magnesium Valproate （MV）, Sustained-release Magnesium Valproate （ SMV ） and Depakine Chrono （ DC ）. Methods The model of determining the convulsive threshold was prepared by direct cortical stimulation. Eighty model rats were randomly received intragastric administration of MV, SMV, DC or normal saline （controls）. The convulsive threshold was detected after single and repeated administrations. After one month of repeated administration, the kidney and the liver of the rats were removed for pathological examinations. Results the convulsive threshold of the MV group reached to a peak （ 1100 μA） at 1-2 hrs after single administration, which were significantly higher than that of the other three groups （P 〈 0.05 ）, and began to decrease 3 hrs after administration. It was reduced to 950 μA at 12 hrs after administration. The convulsive threshold of the SMV and the DC groups peaked at 7 hrs after single administration （ 1085 and 1023 μA respectively ）, which were noticeably higher than that of the controls （ P 〈 0.05 ）. Until to 12 hrs after administration the convulsive threshold of the two groups remained at about 1000 μA. After repeated administration for 10 times, the convulsive threshold of the SMV group increased by 430 μA and that of the DC group increased by 230 μA. The average peak valley deviation of the convulsive threshold in the MV group was 120-150 μA, which was two times as the SMV group and 2.5 times as the DC group after repeated administration. There were no significant differences in the pathological examination of the kidney and the liver among the four groups. Conclusions MV had a rapid onset and offset of action. SMV had a slow onset but long duration of drug efficacy. DC could be easier absorbed than SMV, but its long-term effect on improving the convulsive threshold was lower than SMV.