Cerebroprotection for Acute Ischemic Stroke: Looking Ahead.
Cerebroprotection for Acute Ischemic Stroke: Looking Ahead.
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DOI：
10.1161/strokeaha.121.032241
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发表时间：
2021-08
期刊：
影响因子：
8.3
通讯作者：
Lyden PD
中科院分区：
文献类型：
--
作者：
Lyden PD
我们寻找缺血性中风的治疗方法，知道我们已经失败了-强烈和经常-将机械知识转化为治疗，减轻我们的病人的功能障碍。我们可以从共同的失败中汲取教训，指出新的方向和新的战略。首先，总结了临床前和临床评估的原则性批评。接下来，以前的努力，发展单一机制的治疗方法进行审查。最后，新的定义，新的方法，和不同的方向。在以前的开发工作中，候选治疗的基础科学和临床前评估往往缺乏严谨性和充分性;临床试验可能缺乏力量，严谨性或正直性;或者很可能临床前和临床研究都有缺陷。针对特定分子机制的单靶点药物被证明是不成功的。神经保护一词应该被替换，因为它已经变得含糊不清：保护整个神经血管单位可以被称为脑细胞保护或脑保护。无论是作为再通的辅助治疗还是作为独立治疗，成功地开发血管保护都需要新的定义，认识到神经血管单位不同脆弱性的重要性。最近关注的多效多靶点药物，通过多种作用机制，中断缺血在多个步骤可能是更富有成效的。多效性治疗的实例包括治疗性低温和3 K3 A-APC。或者，单靶标药物NA-1触发多个下游信号传导事件。对科学严谨性的重新承诺至关重要，资助机构和期刊可能会在临床前科学中实施严格的质量原则。应选择适合研究目的的适当动物模型。在临床试验之前，临床前评估可能包括老年受试者，包括男性和女性，以及患有糖尿病或高血压等合并症的受试者。有了这些新的定义、新的方法和对严格性的重新关注，成功的脑保护性治疗的前景应该会有所改善。
We search for ischemic stroke treatment knowing we have failed—intensely and often—to translate mechanistic knowledge into treatments that alleviate our patients’ functional impairments. Lessons can be derived from our shared failures that may point to new directions and new strategies. First, the principle criticisms of both preclinical and clinical assessments are summarized. Next, previous efforts to develop single-mechanism treatments are reviewed. Finally, new definitions, novel approaches, and different directions are presented. In previous development efforts, the basic science and preclinical assessment of candidate treatments often lacked rigor and sufficiency; the clinical trials may have lacked power, rigor, or rectitude; or most likely both preclinical and clinical investigations were flawed. Single-target agents directed against specific molecular mechanisms proved unsuccessful. The term neuroprotection should be replaced as it has become ambiguous: protection of the entire neurovascular unit may be called cerebral cytoprotection or cerebroprotection. Success in developing cerebroprotection—either as an adjunct to recanalization or as stand-alone treatment—will require new definitions that recognize the importance of differential vulnerability in the neurovascular unit. Recent focus on pleiotropic multi-target agents that act via multiple mechanisms of action to interrupt ischemia at multiple steps may be more fruitful. Examples of pleiotropic treatments include therapeutic hypothermia and 3K3A-APC. Alternatively, the single-target drug NA-1 triggers multiple downstream signaling events. Renewed commitment to scientific rigor is essential, and funding agencies and journals may enforce quality principles of rigor in preclinical science. Appropriate animal models should be selected that are suited to the purpose of the investigation. Prior to clinical trials, preclinical assessment could include subjects that are aged, of both sexes, and harbor co-morbid conditions such as diabetes or hypertension. With these new definitions, novel approaches, and renewed attention to rigor, the prospect for successful cerebroprotective therapy should improve.