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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?
Epilepsia ( IF 6.6 ) Pub Date : 2020-03-01 , DOI: 10.1111/epi.16450
Pavel Klein 1 , Alon Friedman 2, 3 , Mustafa Q Hameed 4 , Rafal M Kaminski 5 , Guy Bar-Klein 6 , Henrik Klitgaard 7 , Mathias Koepp 8 , Sergiusz Jozwiak 9 , David A Prince 10 , Alexander Rotenberg 4 , Roy Twyman 11 , Annamaria Vezzani 12 , Michael Wong 13 , Wolfgang Löscher 14, 15
Affiliation  

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

中文翻译:

重新调整用途的抗癫痫发生分子:错过了预防癫痫的机会?

预防癫痫是一个巨大的未满足的需求。急性中枢神经系统(CNS)损伤,如创伤性脑损伤(TBI)、脑血管意外(CVA)和中枢神经系统感染,占所有癫痫的 15%‐20%。TBI 和 CVA 后,癫痫发作前有数天至数年的潜伏期。这使得治疗能够预防或改变损伤后癫痫。不存在这样的治疗方法。在获得性癫痫的动物模型中,临床上用于不同适应症的许多药物已被证明具有抗癫痫或缓解疾病的作用,包括具有良好副作用的药物。这些药物包括阿托伐他汀、头孢曲松、氯沙坦、异氟醚、N-乙酰半胱氨酸和抗癫痫药物左乙拉西坦、布瓦西坦、托吡酯、加巴喷丁、普加巴林、氨己烯酸和醋酸艾斯利卡西平。此外,还有阿那白滞素、雷帕霉素、芬戈莫德和促红细胞生成素的临床前抗癫痫数据,尽管这些药物可能会产生更严重的副作用。然而,除了氨己烯酸外,几乎没有使用这些潜在“可重新利用”的药物来预防或改变癫痫的转化研究。如果不对这些药物进行临床评估,我们可能会错过开发癫痫预防性治疗的机会。缺乏翻译研究的原因之一是,大多数这些药物的临床前数据在损伤类型、不同损伤类型的模型、剂量、损伤治疗开始潜伏期、治疗持续时间和癫痫结果评估模式方面都不同。期间。这使得很难比较各个分子抗癫痫证据的相对强度,也很难确定哪种药物最适合临床评估。此外,大多数临床前抗癫痫研究缺乏翻译所需的信息,例如剂量-血药浓度关系、脑靶点参与和剂量反应,并且许多使用无法应用于临床的治疗参数,例如治疗开始之前或当时伤害和剂量高于人体等效耐受剂量。在这里,我们回顾了这些药物的动物和人类抗癫痫证据。我们强调了我们对每个分子的知识空白,需要填补这些空白,以便考虑临床转化,并建议建立一个对未来可重新利用的分子或其组合进行临床前抗癫痫发生评估的平台。
更新日期:2020-03-01
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