1,2,4-三唑-3-硫酮（TP427）的新型衍生物增强丙戊酸的抗惊厥作用，但不增强卡马西平、苯妥英或苯巴比妥在小鼠强直-阵挛性惊厥模型中的作用。
New derivative of 1,2,4-triazole-3-thione (TP427) potentiates the anticonvulsant action of valproate, but not that of carbamazepine, phenytoin or phenobarbital in the mouse tonic-clonic seizure model.
机构信息
Department of Pathophysiology, Medical University, Lublin, Poland; Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
Department of Pathophysiology, Medical University, Lublin, Poland.
出版信息
Pharmacol Rep. 2019 Apr;71(2):299-305. doi: 10.1016/j.pharep.2019.01.003. Epub 2019 Jan 6.
BACKGROUND
To assess the effects of 5-(3-chlorobenzyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP427) on the protective anticonvulsant action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the tonic-clonic seizure model in mice, an isobolographic transformation of data was used.
METHODS
Electrically-induced tonic-clonic seizures were experimentally evoked in adult male albino Swiss mice. The anticonvulsant effects of TP427, when used singly, were determined by the calculation of the threshold increasing the dose by 20% (TID value). The influence of TP427 on the anticonvulsant potency of four various classical antiepileptic drugs was determined with a subthreshold method. Types of interactions between drugs were determined using the isobolographic transformation of data. Additionally, total brain antiepileptic drug concentrations were measured.
RESULTS
TP427, when administered separately, significantly increased the threshold for electroconvulsions. The experimentally determined TID value for TP427 was 11.71 mg/kg. Moreover, TP427 (10 mg/kg) significantly increased the anticonvulsant activity of valproate (p < 0.01), but not that of carbamazepine, phenobarbital or phenytoin in the mouse tonic-clonic seizure model. Isobolographic transformation of data confirmed that the interaction between TP427 and valproate was synergistic. Pharmacokinetic study revealed that TP427 increased total brain valproate concentrations, and had no impact on total brain concentrations of carbamazepine, phenobarbital or phenytoin in mice.
CONCLUSION
The synergistic interaction between TP427 and valproate in the mouse tonic-clonic seizure model might occur favorable for epilepsy patients in future. The combinations of TP427 with carbamazepine, phenobarbital and phenytoin were additive in the mouse tonic-clonic seizure model and also deserves clinical attention.
背景
为了评估 5-(3-氯苄基)-4-己基-2,4-二氢-3H-1,2,4-三唑-3-硫酮 (TP427) 对四种经典抗癫痫药物（卡马西平、苯巴比妥、苯妥英和丙戊酸）在小鼠强直-阵挛性癫痫模型中的保护抗惊厥作用的影响，使用数据的等辐射变换进行了分析。
方法
在成年雄性白化瑞士小鼠中，通过电诱导强直-阵挛性癫痫发作来进行实验性诱发。通过计算增加 20%剂量的阈移 (TID 值) 来确定 TP427 单独使用时的抗惊厥作用。使用亚阈值法确定 TP427 对四种不同经典抗癫痫药物的抗惊厥效力的影响。使用数据的等辐射变换来确定药物之间的相互作用类型。此外，还测量了总脑内抗癫痫药物浓度。
结果
TP427 单独给药时，显著增加了电惊厥的阈值。TP427 的实验测定 TID 值为 11.71mg/kg。此外，TP427(10mg/kg) 显著增加了丙戊酸在小鼠强直-阵挛性癫痫模型中的抗惊厥活性(p<0.01)，但对卡马西平、苯巴比妥或苯妥英没有影响。数据的等辐射变换证实，TP427 和丙戊酸之间的相互作用是协同的。药代动力学研究表明，TP427 增加了丙戊酸的总脑浓度，而对小鼠的总脑卡马西平、苯巴比妥或苯妥英浓度没有影响。
结论
在小鼠强直-阵挛性癫痫模型中，TP427 与丙戊酸之间的协同相互作用可能对未来的癫痫患者有利。在小鼠强直-阵挛性癫痫模型中，TP427 与卡马西平、苯巴比妥和苯妥英的组合是相加的，也值得临床关注。
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