Zaleska Margaret M, Mercado Mary Lynn T, Chavez Juan, Feuerstein Giora Z, Pangalos Menelas N, Wood Andrew
Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA.
Neuropharmacology. 2009 Feb;56(2):329-41. doi: 10.1016/j.neuropharm.2008.10.006. Epub 2008 Nov 1.
Ischemic stroke is the second most common cause of death worldwide and a major cause of disability. Intravenous thrombolysis with rt-PA remains the only available acute therapy in patients who present within 3h of stroke onset other than the recently approved mechanical MERCI device, substantiating the high unmet need in available stroke therapeutics. The development of successful therapeutic strategies remains challenging, as evidenced by the continued failures of new therapies in clinical trials. However, significant lessons have been learned and this knowledge is currently being incorporated into improved pre-clinical and clinical design. Furthermore, advancements in imaging technologies and continued progress in understanding biological pathways have established a prolonged presence of salvageable penumbral brain tissue and have begun to elucidate the natural repair response initiated by ischemic insult. We review important past and current approaches to drug development with an emphasis on implementing principles of translational research to achieve a rigorous conversion of knowledge from bench to bedside. We highlight current strategies to protect and repair brain tissue with the promise to provide longer therapeutic windows, preservation of multiple tissue compartments and improved clinical success.
缺血性中风是全球第二大常见死因，也是致残的主要原因。除了最近获批的机械取栓装置MERCI外，对于在中风发作3小时内就诊的患者，静脉注射rt-PA溶栓仍然是唯一可用的急性治疗方法，这证实了现有中风治疗方法存在高度未满足的需求。成功治疗策略的开发仍然具有挑战性，临床试验中新疗法的持续失败就是明证。然而，我们已经吸取了重要教训，目前正在将这些知识纳入改进的临床前和临床设计中。此外，成像技术的进步以及对生物途径理解的不断进展，已经证实了可挽救的半暗带脑组织的长期存在，并开始阐明缺血性损伤引发的自然修复反应。我们回顾过去和当前药物开发的重要方法，重点是实施转化研究原则，以实现从实验室到临床的严格知识转化。我们强调当前保护和修复脑组织的策略，有望提供更长的治疗窗口、保留多个组织区域并提高临床成功率。
