Labiche Lise A, Grotta James C
Stroke Program, University of Texas at Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA.
NeuroRx. 2004 Jan;1(1):46-70. doi: 10.1602/neurorx.1.1.46.
To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-to-treat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.
迄今为止，许多细胞保护药物已进入急性中风患者关键的3期疗效试验阶段。（表1）不幸的是，在整个神经保护文献中，“未能证明疗效”这句话在众多中性或阴性试验中普遍存在，尽管临床前研究取得了很大程度上令人鼓舞的结果。这种差异的原因是多方面的，齐文博士在他的综述中已经讨论过。最近的许多试验通过更严格的试验设计解决了先前试验的不足之处，包括更具体的患者选择标准（确保中风部位和严重程度的同质性）、分层随机化算法（治疗时间）、缩小治疗时间窗和药代动力学监测。当前的试验还纳入了毒性和预后的生物学替代标志物，如药物水平和神经影像学。最后，正在研究多模式疗法以及联合细胞保护/再灌注策略以优化组织挽救。本综述将聚焦于个体治疗策略，并且我们将强调我们从这些试验中学到的关于试验设计以及这些药物的生物学效应（或缺乏生物学效应）的内容。
