Löscher W, Cramer S, Ebert U
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Epilepsy Res. 1998 Aug;31(3):175-86. doi: 10.1016/s0920-1211(98)00029-1.
Studies on the anticonvulsant efficacy of the major antiepileptic drug phenytoin in kindled rats have often reported inconsistent effects. It has been proposed that technical and genetic factors or poor and variable absorption of phenytoin after i.p. or oral administration may be involved in the lack of consistent anticonvulsant activity of phenytoin in this model of temporal lobe epilepsy. We examined if kindling itself changes the anticonvulsant efficacy of phenytoin by testing this drug before and after amygdala kindling in male and female Sprague-Dawley rats. To exclude the possible bias of poor and variable absorption, blood was sampled in all experiments for drug analysis in plasma. The threshold for induction of focal seizures (afterdischarge threshold; ADT) was used for determining phenytoin's anticonvulsant activity. Before kindling, phenytoin, 75 mg/kg i.p., markedly increased ADT in both genders, although the effect was more pronounced in males. Following kindling, the anticonvulsant activity obtained with phenytoin, 75 mg/kg, before kindling was totally lost, and female rats even exhibited a proconvulsant effect upon administration of this dose, indicating that kindling had dramatically altered the anticonvulsant efficacy of phenytoin. Plasma levels of phenytoin were comparable before and after kindling, and were within or near to the 'therapeutic range' known from epileptic patients. When the dose of phenytoin was reduced to 50 or 25 mg/kg i.p., significant anticonvulsant effects on ADT were obtained. When phenytoin, 50 mg/kg, was administered i.p. or i.v. in the same group of fully kindled rats, both anticonvulsant activity and plasma drug levels were comparable with both routes, indicating that the i.p. route is suited for such studies. The data indicate that kindling alters the dose-response of phenytoin in that a high anticonvulsant dose becomes ineffective or proconvulsant after kindling, possibly by an increased sensitivity of the kindled brain to proconvulsant effects of phenytoin which normally only occur at much higher doses. If similar alterations evolve in humans during development of chronic epilepsy, this may be involved in the mechanisms leading to intractability of temporal lobe epilepsy.
关于主要抗癫痫药物苯妥英在点燃大鼠模型中的抗惊厥疗效的研究，常常报道其效果不一致。有人提出，技术和遗传因素，或者腹腔注射或口服给药后苯妥英吸收不佳且存在差异，可能与苯妥英在这种颞叶癫痫模型中缺乏一致的抗惊厥活性有关。我们通过在雄性和雌性Sprague-Dawley大鼠杏仁核点燃前后测试该药物，来研究点燃本身是否会改变苯妥英的抗惊厥疗效。为排除吸收不佳和存在差异可能带来的偏差，在所有实验中均采集血液以分析血浆中的药物。诱发局灶性癫痫发作的阈值（后放电阈值；ADT）用于确定苯妥英的抗惊厥活性。在点燃前，腹腔注射75mg/kg苯妥英可显著提高两性的ADT，尽管在雄性中效果更明显。点燃后，点燃前腹腔注射75mg/kg苯妥英所获得的抗惊厥活性完全丧失，雌性大鼠在给予该剂量后甚至出现促惊厥作用，这表明点燃显著改变了苯妥英的抗惊厥疗效。点燃前后苯妥英的血浆水平相当，且处于或接近癫痫患者已知的“治疗范围”。当苯妥英剂量降至腹腔注射50或25mg/kg时，对ADT有显著的抗惊厥作用。当在同一组完全点燃的大鼠中腹腔注射或静脉注射50mg/kg苯妥英时，两种给药途径的抗惊厥活性和血浆药物水平相当，这表明腹腔注射途径适用于此类研究。数据表明，点燃改变了苯妥英的剂量反应，即高抗惊厥剂量在点燃后变得无效或具有促惊厥作用，这可能是由于点燃的大脑对苯妥英促惊厥作用的敏感性增加，而这种作用通常仅在更高剂量时才会出现。如果在人类慢性癫痫发展过程中出现类似变化，这可能与导致颞叶癫痫难治性的机制有关。
