Department of Pathophysiology, Medical University, Jaczewskiego 8b, 20-090, Lublin, Poland.
Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
Pharmacol Rep. 2020 Oct;72(5):1288-1296. doi: 10.1007/s43440-020-00117-y. Epub 2020 Jun 7.
Launching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians' experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug-drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice.
The seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1.
The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography.
The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.
在癫痫患者中启动两种或三种抗癫痫药物（ASD）的联合治疗仍然存在问题。选择联合使用的 ASD 通常基于临床医生的经验，并且需要了解研究 ASD 的作用机制及其药物相互作用，其性质可能是有利、中性或不利的。为了描述拉科酰胺（LCM）、拉莫三嗪（LTG）和丙戊酸（VPA）之间的三药相互作用，使用了 I 型等剂量协同作用分析。在白化瑞士小鼠最大电休克诱导癫痫发作（MES）模型中分析了三药组合的抗癫痫作用。
通过交流电刺激（25 mA、500 V、50 Hz、0.2 s）诱发小鼠的癫痫发作活动。使用 I 型等剂量协同作用分析和 ASD 剂量反应效应的平行性检验，以便正确分类以固定比例（1:1:1）联合使用的三种 ASD 之间的相互作用。
LCM、LTG 和 VPA 的三药混合物以 1:1:1 的固定比例保护实验小鼠免受 MES 诱导的癫痫发作；然而，报道的相互作用是相加作用（拮抗作用；p < 0.01），与等剂量协同作用一致。
在 MES 试验中，LCM、LTG 和 VPA 之间的拮抗药效学相互作用不能转化为临床环境，这种不利的组合不应推荐给癫痫患者。
