Current status of neuroprotection for cerebral ischemia: synoptic overview.
Current status of neuroprotection for cerebral ischemia: synoptic overview.
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DOI：
10.1161/strokeaha.108.528877
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发表时间：
2009-03
期刊：
影响因子：
8.3
通讯作者：
Ginsberg MD
中科院分区：
文献类型：
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作者：
Ginsberg MD
大量的临床前研究已经确定了缺血性脑损伤的多种机制，并提供了原理证明，旨在对抗这些机制的策略可以保护缺血性脑。这篇综述文章强调了这些策略从实验室到临床试验的转化。令人失望的事实是，尽管神经保护功效的临床前证据有限或不一致，但许多药物已进入临床试验。临床前研究需要严格关注可能影响结果的各种变量。广受好评的 STAIR 标准代表了临床前测试的建设性指南，但经验表明，它并没有增加转化成功的可能性。截至 2007 年末，在约 160 项针对缺血性中风进行神经保护的临床试验中，只有 约 40 项代表了已完成的较大阶段试验，其中一半的试验使用了 > 6 小时的治疗窗口，尽管有强有力的临床前证据表明这种延迟超过了急性中风可能的疗效治疗窗口。这些试验的其他缺点包括使用缺乏稳健、一致的临床前疗效的药物；无法在人体中达到足够的剂量；以及次优的临床和统计设计特征。综合起来，这些因素确定了未来试验需要改进的领域。
Abundant preclinical studies have identified multiple mechanisms of ischemic brain injury and have provided proof of principle that strategies designed to counter these mechanisms can protect the ischemic brain. This review article emphasizes the translation of these strategies from the laboratory to clinical trials. It is a disappointing fact that many agents have been brought to clinical trial despite only modest or inconsistent preclinical evidence of neuroprotective efficacy. Preclinical investigations require rigorous attention to a variety of variables that may influence outcome. The widely touted STAIR criteria represent constructive guidelines for preclinical testing but, as experience has shown, do not increase the likelihood of translational success. Of the ≈160 clinical trials of neuroprotection for ischemic stroke conducted as of late 2007, only ≈40 represent larger-phase completed trials, and fully one half of the latter utilized a window to treatment of >6 hours, despite strong preclinical evidence that this delay exceeds the likely therapeutic window of efficacy in acute stroke. Other shortcomings of these trials include the use of agents lacking robust, consistent preclinical efficacy; inability to achieve adequate dosing in humans; and suboptimal clinical and statistical design features. Taken together, these factors identify areas of needed improvement for future trials.