Bethmann Kerstin, Brandt Claudia, Löscher Wolfgang
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary, Medicine, Hannover, Germany.
Epilepsia. 2007 Apr;48(4):816-26. doi: 10.1111/j.1528-1167.2007.00980.x. Epub 2007 Feb 23.
Most patients who are resistant to the first antiepileptic drug (AED) treatment are also resistant to a treatment with a second or third AED, indicating that patients who have an inadequate response to initial treatment with AEDs are likely to have refractory epilepsy. Animal models of refractory epilepsy are important tools to study mechanisms of AED resistance and develop new treatment strategies for counteracting resistance. We have recently described a rat model of temporal lobe epilepsy (TLE), in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. Prolonged treatment of epileptic rats with phenobarbital (PB) resulted in two subgroups, PB responders and PB nonresponders.
In the present study we examined if rats with PB-resistant seizures are also resistant to phenytoin (PHT), using continuous EEG/video recording of spontaneous seizures.
First, a new group of 15 epileptic rats was produced and selected by treatment with PB into responders (8 rats) and nonresponders (6 rats), respectively. During subsequent treatment with PHT, the doses of PHT had to be individually adjusted for each rat to avoid toxicity. Treatment with PHT led to complete seizure control in two animals and a >50% reduction of seizure frequency in three other rats, which were considered PHT responders. In nine of the remaining rats, PHT did not exert any clear anticonvulsant effect, so that these rats were considered nonresponders. Plasma levels of PHT did not differ significantly between responders and nonresponders. When comparing the PB and PHT nonresponder groups, five of the six PB-resistant rats (83%) were also resistant to PHT, demonstrating that rats that have an inadequate response to initial treatment with PB are likely to be also resistant to treatment with a second AED.
The AED-resistant rats of our model meet the definition of pharmacoresistance in animal models, that is, persistent seizure activity not responding to at least two AEDs at maximum tolerated doses. This new model of pharmacoresistant TLE may be useful in the targeted development of new therapies for refractory epilepsy.
大多数对第一种抗癫痫药物（AED）治疗耐药的患者对第二种或第三种AED治疗也耐药，这表明对AED初始治疗反应不佳的患者很可能患有难治性癫痫。难治性癫痫的动物模型是研究AED耐药机制和制定对抗耐药性新治疗策略的重要工具。我们最近描述了一种颞叶癫痫（TLE）大鼠模型，在该模型中，通过持续电刺激基底外侧杏仁核诱导癫痫持续状态后会出现自发性反复癫痫发作（SRS）。用苯巴比妥（PB）对癫痫大鼠进行长期治疗产生了两个亚组，PB反应者和PB无反应者。
在本研究中，我们使用连续脑电图/视频记录自发性癫痫发作，检查PB耐药性癫痫大鼠是否也对苯妥英（PHT）耐药。
首先，通过PB治疗产生了一组新的15只癫痫大鼠，并分别选择出反应者（8只大鼠）和无反应者（6只大鼠）。在随后用PHT治疗期间，必须为每只大鼠单独调整PHT剂量以避免毒性。用PHT治疗使两只动物的癫痫发作得到完全控制，另外三只大鼠的癫痫发作频率降低了>50%，这些大鼠被视为PHT反应者。在其余九只大鼠中，PHT没有发挥任何明显的抗惊厥作用，因此这些大鼠被视为无反应者。反应者和无反应者之间的PHT血浆水平没有显著差异。比较PB和PHT无反应者组时，六只PB耐药大鼠中有五只（83%）也对PHT耐药，这表明对PB初始治疗反应不佳的大鼠很可能也对第二种AED治疗耐药。
我们模型中的AED耐药大鼠符合动物模型中药物耐药性的定义，即持续的癫痫发作活动在最大耐受剂量下对至少两种AED无反应。这种新的药物耐药性TLE模型可能有助于难治性癫痫新疗法的靶向开发。
