Department of Animal Physiology, Institute of Biology, Maria Curie-Skłodowska University, Lublin, Poland.
Epilepsia. 2010 Aug;51(8):1552-9. doi: 10.1111/j.1528-1167.2009.02485.x. Epub 2010 Jan 7.
The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second-generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated.
Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step-through passive avoidance task, and grip-strength test. Total brain and free plasma concentrations of AEDs were also determined.
Sildenafil raised the threshold for electroconvulsions in a dose-dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long-term memory in mice. Interestingly, sildenafil dose-dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect.
Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long-term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.
本研究旨在评估西地那非对小鼠电诱导癫痫发作阈值的影响。此外，还评估了西地那非与经典和第二代抗癫痫药物（AEDs），即卡马西平（CBZ）、苯巴比妥（PB）、苯妥英（PHT）、丙戊酸钠（VPA）、拉莫三嗪（LTG）、托吡酯（TPM）和奥卡西平（OXC）之间的相互作用。
使用两种电惊厥测试：最大电休克惊厥阈值（MEST）和最大电休克惊厥（MES）测试。在烟囱测试、跨步式被动回避任务和握力测试中研究了组合的急性不良反应。还测定了 AEDs 的总脑和游离血浆浓度。
西地那非以剂量依赖的方式提高了电惊厥的阈值。它还增加了 CBZ、VPA 和 TPM 在 MES 测试中的抗惊厥活性，而其余 AEDs 的活性没有明显改变。西地那非增加了 CBZ 的总脑和游离（未结合蛋白）血浆浓度和 VPA 的总脑浓度。西地那非及其与研究 AEDs 的联合使用均不影响小鼠的运动协调和长期记忆。有趣的是，西地那非剂量依赖性地增强了小鼠的肌肉力量，尽管与 AEDs 的组合在这方面无效。
西地那非显著提高了小鼠的电惊厥阈值，而不会损害运动表现和长期记忆，但会增强肌肉力量。由于药代动力学相互作用，不建议在使用 CBZ 或 VPA 的患者中使用西地那非治疗。西地那非与其他 AEDs 的联合使用，特别是与 TPM 的联合使用，似乎是合理的选择。
