Sawicka Katarzyna M, Załuska Katarzyna, Wawryniuk Agnieszka, Załuska-Patel Karolina, Szczyrek Michał, Drop Bartłomiej, Daniluk Jadwiga, Szpringer Monika, Żółkowska Dorota, Łuszczki Jarogniew J
Department of Internal Medicine in Nursing, Medical University of Lublin, Lublin, Poland; Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
Epilepsy Res. 2017 Jul;133:67-70. doi: 10.1016/j.eplepsyres.2017.04.011. Epub 2017 Apr 22.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved not only in synaptic transmission and neuronal excitability under physiological conditions, but also in seizure activity. To determine the influence of ivabradine (an HCN channel inhibitor) on the anticonvulsant potency of four novel antiepileptic drugs (AEDs: lacosamide, lamotrigine, pregabalin and topiramate) in the mouse maximal electroshock-induced seizure (MES) model. Adult male albino Swiss mice were challenged with maximal electroconvulsions (electric current of 25mA delivered via auricular electrodes). Total brain concentrations of AEDs were measured with high-pressure liquid chromatography. Ivabradine (10mg/kg, i.p.) significantly reduced the anticonvulsant potency of lamotrigine by elevating the ED value of the AED from 7.48 (6.15-9.11) to 10.07 (8.85-11.45) mg/kg (P<0.05) in the mouse MES model. In contrast, ivabradine (10mg/kg, i.p.) did not significantly affect the anticonvulsant potency of lacosamide, pregabalin or topiramate in the mouse MES model. Additionally, ivabradine had no impact on total brain concentrations of all the studied AEDs in mice. A special caution is advised when combining ivabradine with lamotrigine in epilepsy patients due to the possible pharmacodynamic reduction of the anticonvulsant action of the later drug. The combinations of ivabradine with lacosamide, pregabalin and topiramate seem to be pharmacodynamic and neutral from a preclinical viewpoint.
超极化激活的环核苷酸门控（HCN）通道不仅参与生理条件下的突触传递和神经元兴奋性，还与癫痫发作活动有关。为了确定伊伐布雷定（一种HCN通道抑制剂）对四种新型抗癫痫药物（AEDs：拉科酰胺、拉莫三嗪、普瑞巴林和托吡酯）在小鼠最大电休克诱导癫痫（MES）模型中抗惊厥效力的影响。成年雄性白化瑞士小鼠接受最大电惊厥刺激（通过耳廓电极施加25mA电流）。用高压液相色谱法测量AEDs的全脑浓度。在小鼠MES模型中，伊伐布雷定（10mg/kg，腹腔注射）通过将AED的ED值从7.48（6.15 - 9.11）提高到10.07（8.85 - 11.45）mg/kg，显著降低了拉莫三嗪的抗惊厥效力（P<0.05）。相比之下，在小鼠MES模型中，伊伐布雷定（10mg/kg，腹腔注射）对拉科酰胺、普瑞巴林或托吡酯的抗惊厥效力没有显著影响。此外，伊伐布雷定对小鼠中所有研究的AEDs的全脑浓度没有影响。由于可能会使拉莫三嗪的抗惊厥作用药效动力学降低，因此建议癫痫患者将伊伐布雷定与拉莫三嗪联合使用时要特别谨慎。从临床前的角度来看，伊伐布雷定与拉科酰胺、普瑞巴林和托吡酯的联合使用似乎在药效动力学上是中性的。
