Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.
Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.
Neuropharmacology. 2020 May 1;167:107750. doi: 10.1016/j.neuropharm.2019.107750. Epub 2019 Aug 27.
Since 1993, over 20 new anti-seizure drugs (ASDs) have been identified in well-established animal seizure and epilepsy models and subsequently demonstrated to be clinically effective in double-blinded, placebo-controlled clinical trials in patients with focal onset seizures. All clinically-available ASDs on the market today are effective in at least one of only three preclinical seizure and epilepsy models: the acute maximal electroshock (MES), the acute subcutaneous pentylenetetrazol (scPTZ) test, or the kindled rodent with chronic evoked seizures. Thus, it reasons that preclinical ASD discovery does not need significant revision to successfully identify ASDs for the symptomatic treatment of epilepsy. Unfortunately, a significant need still persists for more efficacious and better tolerated ASDs. This is particularly true for those patients whose seizures remain drug resistant. This review will focus on the continued utility of the acute MES and scPTZ tests, as well as the kindled rodent for current and future ASD discovery. These are the only "clinically validated" rodent models to date and been heavily used in the search for novel and more efficacious ASDs. This is to say that promising ASDs have been brought to the clinic on the basis of efficacy in these particular seizure and epilepsy models alone. This review also discusses some of the inherent advantages and limitations of these models relative to existing and emerging preclinical models. It then offers insight into future efforts to develop a preclinical model that will advance a truly transformative therapy for the symptomatic treatment of difficult to treat focal onset epilepsy. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
自 1993 年以来，在成熟的动物癫痫发作和癫痫模型中已经确定了超过 20 种新型抗癫痫药物（ASD），随后在局灶性发作性癫痫患者的双盲、安慰剂对照临床试验中证明了这些 ASD 的临床疗效。目前市场上所有可用的 ASD 在三种临床前癫痫发作和癫痫模型中的至少一种中是有效的：急性最大电休克（MES）、急性皮下戊四氮（scPTZ）试验或慢性诱发癫痫的点燃啮齿动物。因此，有理由认为，临床前 ASD 发现不需要进行重大修订，即可成功鉴定出用于癫痫症状治疗的 ASD。不幸的是，仍然非常需要更有效和更好耐受的 ASD。对于那些癫痫发作仍然耐药的患者来说，这一点尤其如此。本综述将重点讨论急性 MES 和 scPTZ 试验以及点燃的啮齿动物在当前和未来 ASD 发现中的持续应用。这些是迄今为止唯一“临床验证”的啮齿动物模型，并在寻找新型和更有效的 ASD 中被广泛使用。这意味着有前途的 ASD 仅基于这些特定的癫痫发作和癫痫模型的疗效而被推向临床。本文还讨论了这些模型相对于现有和新兴临床前模型的一些固有优势和局限性。然后，它为未来开发一种能够推进治疗难治性局灶性癫痫的真正变革性疗法的临床前模型的努力提供了一些见解。本文是题为“21 世纪的新型癫痫治疗方法 - 从抗癫痫药物到癫痫的预防、治疗和治疗”的特刊的一部分。
