Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland.
Eur J Pharmacol. 2012 Sep 5;690(1-3):99-106. doi: 10.1016/j.ejphar.2012.06.023. Epub 2012 Jun 23.
The aim of this study was to determine the effects of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP4-a new S-triazole derivative possessing anticonvulsant properties in preclinical studies) on the protective action of four different classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Results indicate that TP4 administered intraperitoneally at doses of 75 and 100 mg/kg significantly elevated the threshold for electroconvulsions in mice. TP4 at doses of 12.5, 25, 37.5 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP4 (50 mg/kg) significantly enhanced the anticonvulsant activity of carbamazepine, phenobarbital and valproate, but not that of phenytoin in the maximal electroshock seizure test in mice. TP4 at 25 mg/kg significantly potentiated the anticonvulsant action of carbamazepine, but not that of phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that TP4 significantly elevated total brain concentrations of carbamazepine and valproate, having no impact on total brain concentrations of phenobarbital in mice. In conclusion, the enhanced anticonvulsant action of phenobarbital by TP4 was probably pharmacodynamic in nature and, therefore, the combination of TP4 with phenobarbital is worthy of consideration while extrapolating the results from this study into clinical settings. The enhanced anticonvulsant action of carbamazepine and valproate by TP4 in the mouse maximal electroshock-induced seizure model was associated with pharmacokinetic increases in total brain concentrations of the antiepileptic drugs in mice. The combination of TP4 with phenytoin was neutral from a preclinical point of view.
本研究旨在确定 4-(4-溴苯基)-5-(3-氯苯基)-2,4-二氢-3H-1,2,4-三唑-3-硫酮（TP4-一种具有临床前研究抗惊厥特性的新型 S-三唑衍生物）对四种不同经典抗癫痫药物（卡马西平、苯巴比妥、苯妥英和丙戊酸钠）对小鼠最大电休克诱导癫痫发作的保护作用的影响。结果表明，TP4 以 75 和 100mg/kg 的剂量腹腔给药可显著提高小鼠电惊厥的阈值。TP4 以 12.5、25、37.5 和 50mg/kg 的剂量对小鼠电惊厥的阈值没有影响。此外，TP4（50mg/kg）显著增强了卡马西平、苯巴比妥和丙戊酸钠在小鼠最大电休克惊厥试验中的抗惊厥活性，但对苯妥英钠没有影响。TP4 以 25mg/kg 显著增强了卡马西平的抗惊厥作用，但对苯巴比妥、苯妥英钠和丙戊酸钠没有影响。药代动力学实验表明，TP4 显著提高了卡马西平和丙戊酸钠在小鼠脑中的总浓度，对苯巴比妥在小鼠脑中的总浓度没有影响。综上所述，TP4 增强苯巴比妥的抗惊厥作用可能是药效学性质的，因此，在将本研究结果外推到临床环境时，应考虑将 TP4 与苯巴比妥联合使用。TP4 在小鼠最大电休克诱导的癫痫发作模型中增强卡马西平和丙戊酸钠的抗惊厥作用与抗癫痫药物在小鼠脑中总浓度的药代动力学增加有关。从临床前角度来看，TP4 与苯妥英钠联合使用是中性的。
