BACKGROUND:Scholars have investigated the differences in drug metabolism and pharmacodynamics between valproate and its sustained-release tablets only from the angle of pharmaceutical sciences or clinical practice.Whether the fact that differences in drug efficacy and time-effect of different doses of valproate and different types of sustained-release valproate tablets at the same concentration can be quantitatively reflected by determining the changes in convulsive threshold pre- and post-administration in rat models of determining the convulsive threshold developed by direct cortical electrical stimulation remains unclear.OBJECTIVE:This study aimed to compare the drug efficacy and time-effect among magnesium valproate,sustained-release magnesium valproate tablet and depakine chrono in the treatment of epilepsy by determining the convulsive threshold of rat models created by direct cortical electrical stimulation,and human serum drug concentration before and after administration.DESIGN:A controlled observational experiment.SETTING:Research Institute of Epilepsy,Shanxi Medical University.MATERIALS:Adult health male SD rats of clean grade,weighing 200 - 220 g,provided by the Laboratory Animal Center of Shanxi Medical University.The protocol was carried out in accordance with requests from Animal Ethics Committees for guidance.Magnesium valproate (Lot No.041004) and sustained-release magnesium valproate tablet (Lot No.050501) were produced in Hunan Xiangzhong Pharmaceutical Co.,Ltd.METHODS:This study was carried out in the Laboratory for Epilepsy,Shanxi Medical University between June and August 2005.①All the SD rats were created into models for determining cortical convulsive threshold.They were randomly divided into 4 groups with 20 rats in each:magnesium valproate tablet group,sustained-release magnesium valproate tablet group,depakine chrono group and control group.After being modeled,the rats in the first 3 groups were intragastrically administrated with magnesium valproate,sustained-release magnesium valproate tablet and depakine chrono,respectively,while the control group were intragastrically administrated with the same volume of normal saline.②Convulsive threshold of each fasting rat was determined 0.5 hour before,and 0.5,1,2,3,4,5,6,7,8,9,10,12,14and24 hours after single administration,separately.③Convulsive threshold was determined repeatedly 2 weeks after single administration.Each rat was administrated two times daily successively.Convulsive threshold was determined 0.5 hour before,and 0.5,2.5,7and12hours after administration,separately.④Hepatic and renal tissues were harvested for pathological examination after 1 month of administration.⑤Nine healthy voluntary medical stuffs were recruited in this study.Written informed consents of experiment were obtained each involved subject.The study was given an approval by the Ethics Committee of Shanxi Medical University.According to the scheme,the 9 volunteers were randomly assigned into 3 groups,in which,volunteers were asked to take magnesium valproate 500 g,sustained-release magnesium valproate tablet 500 g and depakine chrono 500g,respectively,in the morning under the condition of fasting.Serum drug concentration of each drug was determined by fluorescence polarization immunoassay at different time points.MAIN OUTCOME MEASURES:①Rat convulsive threshold after single and repeated administrations.②Hepatic and renal pathological examination results.③Serum drug concentration in vivo.RESULTS:①Rat convulsive threshold after single and repeated administrations:Drug efficacy in the magnesium valproate tablet group reached to a peak level 1 to 2 hours after single administration,and was obviously higher than that in the other groups 1 hour after administration (P＜0.05).Drug efficacy in the sustained-release magnesium valproate tablet group and depakine chrono group both reached to a peak level 7 hours after administration,and was significantly higher than that in the control group (P＜0.05).After repeated administrations,the average peak valley deviation of the convulsive threshold in the magnesium valproate tablet group was 120-150 Μa,which was 2 and 2.5 times as that in the sustained-release magnesium valproate tablet group and depakine chrono group,respectively.After repeated administrations for 10 times,convulsive threshold was increased by 440 Μa in the sustained-release magnesium valproate tablet group,and by 230 μ A in the depakine chrono group in comparison with before administration.② Hepatic and renal pathological examination results:No obvious differences in hepatic and renal impairment were found among the 4 groups after 1 month of administration successively.③ Serum drug concentration in vivo:Serum-drug concentration of magnesium valproate was increased fast and reached to a peak level 0.5-2 hours after administration,remained at a relatively stable level 2-4 hours after administration,and then was slowly decreased.The drug efficacy of sustained-release magnesium valproate tablet and depakine chrono was slowly released 1-6 hours after administration,reached to a peak level at about 7 hours,and could last for about 16 hours.CONCLUSION:Magnesium valproate has a rapid onset and offset of action.Sustained-release magnesium valproate tablet has a slow onset but long duration of drug efficacy.Depakine chrono can be easier to be absorbed than sustained-release agnesium proateet,butng-term effect on improving thect on improving the convulsive threshold is inferior to sustained-release magnesium valproate tablet.