Löscher W, Rundfeldt C, Hönack D
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Epilepsy Res. 1993 Jul;15(3):207-19. doi: 10.1016/0920-1211(93)90058-f.
By repeated treatment with phenytoin, subgroups of animals with different response to phenytoin were selected from a large group of amygdala-kindled rats. In one subgroup ('phenytoin responders') phenytoin induced reproducible increases in focal seizure threshold, while in another subgroup ('phenytoin nonresponders') animals were resistant to phenytoin. These phenytoin nonresponders, which comprised about 12% of the kindled animals tested, did not differ from phenytoin responders in drug levels, drug adverse effects or location of the stimulation electrode in the amygdala. Treatment of phenytoin responders and nonresponders with other primary antiepileptic drugs showed that valproate and phenobarbital induced much smaller increases in focal seizure threshold in phenytoin nonresponders than in responders, whereas carbamazepine induced about the same threshold increase in both groups. The novel antiepileptic drug vigabatrin, which acts by increasing GABA levels, exerted anticonvulsant effects in phenytoin responders but was inactive in nonresponders. Determination of plasma amino acids before and after vigabatrin treatment demonstrated marked differences in biochemical responses to vigabatrin although drug levels were about the same in both groups. The data demonstrate that amygdala-kindled rats with phenytoin resistance offer a basic approach to the investigation of mechanisms of drug resistance in epilepsy. Furthermore, these animals may be used in the evaluation of new anticonvulsant drugs for treatment of partial seizures which do not respond to the currently available therapies.
通过用苯妥英反复治疗，从一大群杏仁核点燃大鼠中选出了对苯妥英有不同反应的动物亚组。在一个亚组（“苯妥英反应者”）中，苯妥英可使局灶性癫痫发作阈值产生可重复的升高，而在另一个亚组（“苯妥英无反应者”）中，动物对苯妥英有抗性。这些苯妥英无反应者约占所测试的点燃动物的12%，在药物水平、药物不良反应或杏仁核中刺激电极的位置方面与苯妥英反应者并无差异。用其他一线抗癫痫药物治疗苯妥英反应者和无反应者发现，丙戊酸盐和苯巴比妥在苯妥英无反应者中引起的局灶性癫痫发作阈值升高比在反应者中要小得多，而卡马西平在两组中引起的阈值升高大致相同。新型抗癫痫药物氨己烯酸通过提高γ-氨基丁酸（GABA）水平发挥作用，在苯妥英反应者中具有抗惊厥作用，但在无反应者中无活性。氨己烯酸治疗前后血浆氨基酸的测定表明，尽管两组药物水平大致相同，但对氨己烯酸的生化反应存在显著差异。数据表明，对苯妥英有抗性的杏仁核点燃大鼠为研究癫痫耐药机制提供了一种基本方法。此外，这些动物可用于评估治疗对现有疗法无反应的部分性癫痫发作的新型抗惊厥药物。
