Gasior M, Kleinrok Z, Czuczwar S J
Department of Pharmacology and Toxicology, Medical School, Lublin, Poland.
Neuropharmacology. 1995 Apr;34(4):433-8. doi: 10.1016/0028-3908(95)00004-p.
BAY k-8644, an agonist at the dihydropyridine binding site of the L-type voltage dependent calcium channel, at the dose of 5 mg/kg (s.c.) did not significantly affect the threshold for electroconvulsions, but impaired the protective efficacy of flunarizine (15 and 20 mg/kg, i.p.) in the electroconvulsive test. Interestingly, the calcium channel agonist (at 1 and 5 mg/kg) distinctly diminished the protection offered by conventional anti-epileptic drugs (carbamazepine, diphenylhydantoin and phenobarbital) against maximal electroshock-induced seizures in mice. A pharmacokinetic interaction does not seem to be involved in the effect of BAY k-8644, since total plasma levels of these anti-epileptics (measured by immunofluorescence) were not affected by the calcium channel agonist. The only anti-epileptic drug resistant to BAY k-8644 (up to 5 mg/kg) was valproate, whose ED50 (in mg/kg) was not changed in the presence of the calcium channel agonist. Further, BAY k-8644 (5 mg/kg) did not influence the flunarizine (a calcium channel blocker)-induced potentiation of the protective action of valproate against maximal electroshock-induced convulsions. The calcium channel agonist (5 mg/kg) reversed the flunarizine-induced augmentation of the anticonvulsive activity of carbamazepine. It may be concluded that carbamazepine, diphenylhydantoin and phenobarbital partially exert their anticonvulsive effects via blockade of calcium influx whilst valproate does not seem to. In this context, the flunarizine-induced potentiation of the anticonvulsive activity of valproate is probably independent of calcium channel blockade.
BAY k - 8644是一种L型电压依赖性钙通道二氢吡啶结合位点的激动剂，5mg/kg（皮下注射）剂量时对电惊厥阈值无显著影响，但会损害氟桂利嗪（15和20mg/kg，腹腔注射）在电惊厥试验中的保护效果。有趣的是，钙通道激动剂（1和5mg/kg）明显削弱了传统抗癫痫药物（卡马西平、苯妥英和苯巴比妥）对小鼠最大电休克诱发惊厥的保护作用。BAY k - 8644的作用似乎不涉及药代动力学相互作用，因为这些抗癫痫药物的总血浆水平（通过免疫荧光测定）不受钙通道激动剂影响。唯一对BAY k - 8644（高达5mg/kg）耐药的抗癫痫药物是丙戊酸盐，在存在钙通道激动剂的情况下其半数有效剂量（mg/kg）未改变。此外，BAY k - 8644（5mg/kg）不影响氟桂利嗪（一种钙通道阻滞剂）诱导的丙戊酸盐对最大电休克诱发惊厥保护作用的增强。钙通道激动剂（5mg/kg）逆转了氟桂利嗪诱导的卡马西平抗惊厥活性增强。可以得出结论，卡马西平、苯妥英和苯巴比妥部分通过阻断钙内流发挥抗惊厥作用，而丙戊酸盐似乎并非如此。在这种情况下，氟桂利嗪诱导的丙戊酸盐抗惊厥活性增强可能与钙通道阻断无关。
