Preclinical development of antiepileptic drugs: Past, present, and future directions
Preclinical development of antiepileptic drugs: Past, present, and future directions
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DOI：
10.1046/j.1528-1157.44.s7.10.x
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发表时间：
2003-01-01
期刊：
影响因子：
5.6
通讯作者：
White, HS
中科院分区：
文献类型：
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作者：
White, HS
自1993年以来，9种新的抗癫痫药物（AED）已被引入美国市场，用于部分癫痫的对症治疗。他们的抗癫痫活性，在很大程度上，定义了急性癫痫发作模型，如最大电休克（MES）和皮下戊四氮（scPTZ）癫痫发作试验和点燃大鼠。不幸的是，迄今为止的临床证据表明，这些模型虽然有用，但都不太可能确定有效管理难治性癫痫发作患者的治疗方法。近年来，已经开发了许多体内和体外模型，显示出不同程度的药物抗性。因此，它们可以为识别真正新颖的AED提供独特的机会。通过在分子和遗传水平上更好地了解获得性癫痫的病理生理学，有可能确定一种新的治疗方法，超越癫痫的对症治疗，以改变进展，或者，我们大胆建议，预防易感患者癫痫的发展。实现这种可能性将需要改变我们目前的AED发现方法。本文综述了目前用于寻找新的抗癫痫药物的方法，并对未来的方向提供了一些见解，包括新的和新兴的治疗抵抗和癫痫发生模型。
Since 1993, nine new antiepileptic drugs (AEDs) have been introduced into the U.S. market for the symptomatic treatment of partial epilepsy. Their antiepileptic activity was, for the most part, defined by acute seizure models such as the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) seizure tests and the kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage the patient with refractory seizures. In recent years, a number of in vivo and in vitro models have been developed that display varying degrees of pharmacoresistance. As such, they may provide a unique opportunity for identifying the truly novel AED. Through a greater understanding of the patho-physiology of acquired epilepsy at the molecular and genetic level, it may be possible to identify a new therapeutic approach that reaches beyond the symptomatic treatment of epilepsy to modify the progression, or, dare we suggest, prevent the development of epilepsy in the susceptible patient. The realization of such a possibility will necessitate a change in our current AED discovery approach. The present review describes the current approach used in the search for new AEDs and offers some insight into future directions incorporating new and emerging models of therapy resistance and epileptogenesis.