Donnan Geoffrey A
National Stroke Research Institute, Austin Health, University of Melbourne, Waterdale Road, Heidelberg Heights, 3081, Australia.
Stroke. 2008 Jan;39(1):242. doi: 10.1161/STROKEAHA.107.493296. Epub 2007 Nov 29.
There have now been numerous phase III trials of neuroprotection that have failed to live up to the expectations created by preclinical testing in animal models, the most recent of which was the second pivotal trial of the spin trap agent NXY-059. We have reached a stage at which research in this area should stop altogether or radical new approaches adopted. The purpose of this article is to review how we reached this stage and make recommendations for a new approach to neuroprotection research.
The background to neuroprotection research is reviewed and its problems are highlighted based on the research of others and of our own research group. From this, a series of questions are posed that require answers if the field is to progress. A road map for future research is then proposed.
The road map involves the following steps for putative neuroprotectants: (1) better proof of efficacy in animal models; (2) in vivo evidence of efficacy in human tissue using cell cultures or brain slices; (3) in vivo studies of their distribution in the normal and ischemic human brain, particularly focusing on the ischemic penumbra; (4) demonstration of efficacy in novel human models of cerebral ischemia; and (5) phase II and III clinical trails with penumbral selection using imaging techniques.
The accumulated evidence suggests that neuroprotection failure in clinical trial is due to identifiable preclinical and clinical factors. Neuroprotection research should be pursued but with a very different and more rigorous approach.
目前已有众多神经保护的III期试验，但均未达到动物模型临床前试验所带来的预期效果，其中最近的一次是自旋捕捉剂NXY - 059的第二项关键试验。我们已到了该领域研究要么彻底停止，要么采用全新方法的阶段。本文旨在回顾我们是如何走到这一阶段的，并为神经保护研究的新方法提出建议。
基于他人及我们自己研究团队的研究，回顾神经保护研究的背景并突出其问题。由此提出一系列问题，若该领域要取得进展则需要找到答案。随后提出未来研究的路线图。
该路线图对假定的神经保护剂涉及以下步骤：（1）在动物模型中更好地证明疗效；（2）使用细胞培养或脑片在人体组织中获得体内疗效证据；（3）对其在正常和缺血人脑，特别是缺血半暗带中的分布进行体内研究；（4）在新型脑缺血人体模型中证明疗效；（5）使用成像技术进行半暗带选择的II期和III期临床试验。
累积证据表明，临床试验中神经保护失败是由于可识别的临床前和临床因素。应继续进行神经保护研究，但要采用截然不同且更为严格的方法。
