Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland.
Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
Neurotox Res. 2018 Oct;34(3):333-346. doi: 10.1007/s12640-018-9876-4. Epub 2018 Feb 9.
Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first- and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20 mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with epilepsy.
他达拉非是一种选择性磷酸二酯酶 5 抑制剂，是一种用于治疗多种病因勃起功能障碍的长效口服药物。尽管在服用他达拉非后，一名健康男性出现了全身性强直阵挛性癫痫发作，但目前尚未研究他达拉非对癫痫易感性的影响。因此，本研究旨在研究他达拉非对三种急性癫痫发作试验中小鼠癫痫发作阈值以及第一代和第二代一些抗癫痫药物活性的影响。研究结果表明，他达拉非在测试的最高剂量（20mg/kg）下，显著降低了静脉注射戊四氮（i.v. PTZ）癫痫发作试验中首次肌阵挛抽搐的阈值。它不影响 i.v. PTZ 中全身性强直阵挛和前肢张力、最大电休克癫痫发作阈值试验中的强直后肢伸展以及 6-Hz 诱导的癫痫发作阈值试验中的精神运动性癫痫发作的阈值。他达拉非在电诱导的癫痫发作试验中没有改变任何研究抗癫痫药物的抗惊厥活性。有趣的是，他达拉非增强了氯硝西泮的抗惊厥活性，降低了 i.v. PTZ 试验中奥卡西平的抗惊厥活性。这些相互作用在性质上是药效学的，因为他达拉非既没有改变氯硝西泮和奥卡西平在血清和脑组织中的浓度。此外，他达拉非单独或与研究中的抗癫痫药物联合使用均不会导致运动协调（在烟囱试验中评估）、肌肉力量（在握力试验中研究）和长期记忆（在被动回避任务中评估）出现任何显著损害。总之，他达拉非可能会增加肌阵挛性癫痫发作的风险，并降低奥卡西平的抗惊厥作用。需要进一步研究以评估癫痫患者使用他达拉非的安全性。
