Löscher W, Rundfeldt C
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
J Pharmacol Exp Ther. 1991 Aug;258(2):483-9.
Complex partial seizures comprise the major uncontrolled seizure type in adult patients with epilepsy. Any improvement of our understanding of the mechanisms through which these seizures are often refractory to antiepileptic drugs is therefore of considerable importance. By examining the effects of the anti-epileptic drug phenytoin in a large group of kindled rats, a widely used model of complex partial seizures, animals with different sensitivity to this drug were selected. Using determination of the focal seizure threshold for evaluation of phenytoin's anticonvulsant effect, most animals (about 60%) showed variable effects in response to phenytoin. However, about 20% of the animals ("phenytoin nonresponders") showed no increase in their focal seizure threshold at repeated test trials with phenytoin, and 20% ("phenytoin responders") exhibited reproducible increases in focal seizure threshold after injection of phenytoin. Phenytoin responders and nonresponders thus selected were used for subsequent experiments. The different response of focal seizures to phenytoin was not related to differences in pharmacokinetics or location of the stimulating electrode. Although phenytoin reproducibly increased the threshold for induction of afterdischarges in responders, it did not alter severity or duration of the elicited seizure response. In contrast to phenytoin, carbamazepine induced increases in focal seizure threshold in all kindled rats. Duration of seizures and afterdischarges were significantly reduced by carbamazepine in phenytoin responders, but not in nonresponders, although plasma levels of carbamazepine were the same in both groups. The difference in response of kindled rats to phenytoin was restricted to kindled seizures, because phenytoin induced the same anticonvulsant effect on the threshold for generalized tonic electroconvulsions (determined via transauricular electrodes) in both groups of kindled rats.(ABSTRACT TRUNCATED AT 250 WORDS)
复杂部分性发作是成年癫痫患者中主要的未得到有效控制的发作类型。因此，深入了解这些发作常常对抗癫痫药物难治的机制，对我们而言具有相当重要的意义。通过在一大群点燃大鼠（一种广泛应用的复杂部分性发作模型）中研究抗癫痫药物苯妥英钠的作用，挑选出了对该药物敏感性不同的动物。利用测定局灶性发作阈值来评估苯妥英钠的抗惊厥效果，大多数动物（约60%）对苯妥英钠的反应各不相同。然而，约20%的动物（“苯妥英钠无反应者”）在多次使用苯妥英钠进行测试时，局灶性发作阈值并未升高，另外20%（“苯妥英钠反应者”）在注射苯妥英钠后，局灶性发作阈值出现了可重复的升高。如此挑选出的苯妥英钠反应者和无反应者被用于后续实验。局灶性发作对苯妥英钠的不同反应与药代动力学或刺激电极位置的差异无关。尽管苯妥英钠可重复性地提高反应者的后放电诱发阈值，但它并未改变诱发的癫痫发作反应的严重程度或持续时间。与苯妥英钠不同，卡马西平可使所有点燃大鼠的局灶性发作阈值升高。在苯妥英钠反应者中，卡马西平显著缩短了癫痫发作和后放电的持续时间，但在无反应者中却没有，尽管两组的卡马西平血浆水平相同。点燃大鼠对苯妥英钠反应的差异仅限于点燃性发作，因为苯妥英钠对两组点燃大鼠的全身强直电惊厥阈值（通过经耳电极测定）产生了相同的抗惊厥作用。（摘要截选至250词）
