Luszczki Jarogniew J, Mazurkiewicz Lech P, Wroblewska-Luczka Paula, Wlaz Aleksandra, Ossowska Grazyna, Szpringer Monika, Zolkowska Dorota, Florek-Luszczki Magdalena
Department of Pathophysiology, Medical University, Lublin, Poland.
Department of Pathophysiology, Medical University, Lublin, Poland.
Epilepsy Res. 2018 Sep;145:116-122. doi: 10.1016/j.eplepsyres.2018.06.003. Epub 2018 Jun 18.
Despite many antiepileptic drugs (AEDs) are available to treat epilepsy, there is still about 30% of epilepsy patients inadequately treated with these AEDs. For these patients, polytherapy with two or three AEDs to fully control their seizure attacks is recommended. Unfortunately, polytherapy is always associated with drug interactions, whose nature may be beneficial, neutral or unfavorable. To determine a type of interaction for the combination of three AEDs (i.e., phenobarbital [PB], phenytoin [PHT] and pregabalin [PGB]) at the fixed-ratio of 1:1:1, we used a model of tonic-clonic seizures in male albino Swiss mice.
Tonic-clonic seizures in mice were evoked by a current (sine-wave, 25 mA, 500 V, 0.2 s stimulus duration) delivered via auricular electrodes. The anticonvulsant effects of the three-drug combination (PB, PHT and PGB) in terms of suppression of tonic-clonic seizures in mice were assessed with type I isobolographic analysis. Potential acute side effects for the mixture of PB, PHT and PGB along with total brain concentrations of the AEDs were determined to confirm pharmacodynamic nature of observed interaction.
The three-drug combination of PB, PHT and PGB (at the fixed-ratio of 1:1:1) exerted synergistic interaction (at P < 0.01) in the mouse model of tonic-clonic seizures. The combination of PB, PHT and PGB did not produce any side effects in experimental animals, when measuring long-term memory, muscular strength and motor coordination. The measurement of total brain concentrations of PB, PHT and PGB was conducted to confirm that none of the three AEDs significantly influenced total brain concentrations (pharmacokinetic profiles) of the other co-administered AEDs in mice.
The synergistic pharmacodynamic interaction for the combination of PB, PHT and PGB observed in this preclinical study can be translated into clinical settings and this favorable AED combination is worthy of being recommended to some patients with refractory epilepsy.
尽管有多种抗癫痫药物（AEDs）可用于治疗癫痫，但仍有约30%的癫痫患者使用这些AEDs治疗效果不佳。对于这些患者，建议联合使用两种或三种AEDs以完全控制癫痫发作。不幸的是，联合用药总是伴随着药物相互作用，其性质可能是有益的、中性的或不利的。为了确定三种AEDs（即苯巴比妥[PB]、苯妥英[PHT]和普瑞巴林[PGB]）以1:1:1固定比例联合使用时的相互作用类型，我们使用了雄性白化瑞士小鼠的强直阵挛性癫痫模型。
通过耳电极施加电流（正弦波，25 mA，500 V，刺激持续时间0.2 s）诱发小鼠的强直阵挛性癫痫发作。采用I型等效应线图分析法评估三种药物联合使用（PB、PHT和PGB）对小鼠强直阵挛性癫痫发作的抑制作用。测定PB、PHT和PGB混合物的潜在急性副作用以及AEDs的全脑浓度，以确认观察到的相互作用的药效学性质。
PB、PHT和PGB三种药物联合使用（以1:1:1固定比例）在强直阵挛性癫痫小鼠模型中表现出协同相互作用（P < 0.01）。在测量长期记忆、肌肉力量和运动协调性时，PB、PHT和PGB的联合使用在实验动物中未产生任何副作用。测定PB、PHT和PGB的全脑浓度以确认三种AEDs中没有一种会显著影响小鼠体内其他共同给药的AEDs的全脑浓度（药代动力学特征）。
在这项临床前研究中观察到的PB、PHT和PGB联合使用的协同药效学相互作用可转化应用于临床，这种良好的AED联合用药值得推荐给一些难治性癫痫患者。
