Top Priorities for Cerebroprotective Studies-A Paradigm Shift: Report From STAIR XI.
Top Priorities for Cerebroprotective Studies-A Paradigm Shift: Report From STAIR XI.
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DOI：
10.1161/strokeaha.121.034947
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发表时间：
2021-08
期刊：
影响因子：
8.3
通讯作者：
STAIR XI Consortium*
中科院分区：
文献类型：
--
作者：
Lyden P;Buchan A;Boltze J;Fisher M;STAIR XI Consortium*
尽管进行了多年的基础研究和开创性的临床工作，缺血性中风仍然是一个主要的公共卫生问题。之前的 STAIR 会议指出了开发假定的缺血性中风治疗的临床试验设计和临床前评估的失败。在 STAIR XI 上，研讨会#1“神经保护的首要任务”的参与者试图重新定义“神经保护范式”，并考虑到临床前评估证据的缺乏，提出基于共识的建议。当研究的目的是证明新的候选治疗方法有益于整个大脑时，STAIR 提出用“脑细胞保护”或“脑保护”一词来代替“神经保护”一词。尽管“时间仍然是大脑”，但组织成像技术已经开发出来，可以识别出预测有核心损伤和半暗可挽救脑组织的患者，无论中风症状发作后的时间如何。 STAIR XI 研讨会参与者将这种成像方法称为“组织窗口”，用于选择患者进行再通。神经血管单元的元素在不同的大脑区域在不同的时间尺度上表现出不同的脆弱性。 STAIR 提出了“目标窗口”这一术语，以建议在不同时间针对 NVU 不同元素的治疗方法。基于当代严谨和透明的原则，研讨会更新、修订和增强了 STAIR 临床前建议，分两个阶段开发新疗法：探索性“资格阶段”和明确的“验证阶段”。对于新的、假定的治疗方法，研究人员应仔细描述作用机制、药代动力学/药效学、证明靶点参与并确认穿过血脑屏障。在临床试验之前，可以使用两种性别的动物以全面的方式对中风模型中的候选分子进行测试，并包括年龄和合并症等重要变量。全面的临床前评估可能包括多中心协作测试，例如网络试验。然而，在缺乏经过验证的脑保护剂作为“金标准”的情况下，这种全面的临床前评估是否能够有效预测临床结果仍然值得怀疑。
Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR conferences identified both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in Workshop #1 “Top Priorities for Neuroprotection” sought to redefine the “neuroprotection paradigm” and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term “brain cytoprotection” or “cerebroprotection” to replace the term ‘neuroprotection’ when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although “time is still brain,” tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a ‘tissue window’ to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term “target window”, to suggest therapies that target the different elements of the NVU at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised and enhanced the STAIR preclinical recommendations for developing new treatments in two phases: an exploratory ‘qualification phase’ and a definitive ‘validation phase’. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood brain barrier. Prior to clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multi-center, collaborative testing, e.g., network trials. In the absence of a proven cerebroprotective agent to use as a ‘gold standard’ however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.