Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
PLoS One. 2020 Jun 1;15(6):e0234070. doi: 10.1371/journal.pone.0234070. eCollection 2020.
Pharmacotherapy with two antiepileptic drugs in combination is usually prescribed to epilepsy patients with refractory seizures. The choice of antiepileptic drugs in combination should be based on synergistic cooperation of the drugs with respect to suppression of seizures. The selection of synergistic interactions between antiepileptic drugs is challenging issue for physicians, especially, if 25 antiepileptic drugs are currently available and approved to treat epilepsy patients. The aim of this study was to determine all possible interactions among 5 second-generation antiepileptic drugs (gabapentin (GBP), lacosamide (LCM), levetiracetam (LEV), pregabalin (PGB) and retigabine (RTG)) in the 6-Hz corneal stimulation-induced seizure model in adult male albino Swiss mice. The anticonvulsant effects of 10 various two-drug combinations of antiepileptic drugs were evaluated with type I isobolographic analysis associated with graphical presentation of polygonogram to visualize the types of interactions. Isobolographic analysis revealed that 7 two-drug combinations of LEV+RTG, LEV+LCM, GBP+RTG, PGB+LEV, GBP+LEV, PGB+RTG, PGB+LCM were synergistic in the 6-Hz corneal stimulation-induced seizure model in mice. The additive interaction was observed for the combinations of GBP+LCM, GBP+PGB, and RTG+LCM in this seizure model in mice. The most beneficial combination, offering the highest level of synergistic suppression of seizures in mice was that of LEV+RTG, whereas the most additive combination that protected the animals from seizures was that reporting additivity for RTG+LCM. The strength of interaction for two-drug combinations can be arranged from the synergistic to the additive, as follows: LEV+RTG > LEV+LCM > GBP+RTG > PGB+LEV > GBP+LEV > PGB+RTG > PGB+LCM > GBP+LCM > GBP+PGB > RTG+LCM.
对于患有难治性癫痫的患者，通常会开具两种抗癫痫药物的联合药物治疗方案。联合用药中抗癫痫药物的选择应基于药物对癫痫发作的抑制作用的协同合作。选择抗癫痫药物的协同相互作用对医生来说是一个具有挑战性的问题，特别是如果目前有 25 种抗癫痫药物可用于治疗癫痫患者。本研究的目的是确定在成年雄性白化瑞士小鼠的 6-Hz 角膜刺激诱导的癫痫发作模型中，五种第二代抗癫痫药物（加巴喷丁（GBP）、拉科酰胺（LCM）、左乙拉西坦（LEV）、普瑞巴林（PGB）和瑞替加滨（RTG））之间的所有可能相互作用。通过与多边形图的图形表示相关的 I 型等辐射分析评估了 10 种不同的抗癫痫药物的两种药物组合的抗惊厥作用，以可视化相互作用的类型。等辐射分析表明，LEV+RTG、LEV+LCM、GBP+RTG、PGB+LEV、GBP+LEV、PGB+RTG、PGB+LCM 这 7 种两种药物组合在 6-Hz 角膜刺激诱导的癫痫发作模型中具有协同作用。在该模型中，GBP+LCM、GBP+PGB 和 RTG+LCM 的组合观察到相加作用。在小鼠中，LEV+RTG 是提供协同抑制癫痫发作的最高水平的最有利组合，而 RTG+LCM 报告相加性，是保护动物免受癫痫发作的最有利组合。两种药物组合的相互作用强度可以从协同作用排列到相加作用，如下所示：LEV+RTG>LEV+LCM>GBP+RTG>PGB+LEV>GBP+LEV>PGB+RTG>PGB+LCM>GBP+LCM>GBP+PGB>RTG+LCM。
