Kikuchi Kiyoshi, Tanaka Eiichiro, Murai Yoshinaka, Tancharoen Salunya
Department of Pharmacology, Faculty of Dentistry, Mahidol University, 6 Yothe Road, Rajthevee, Bangkok, 10400, Thailand.
CNS Drugs. 2014 Oct;28(10):929-38. doi: 10.1007/s40263-014-0199-6.
Acute ischemic stroke (AIS) is a major cause of mortality and disability and remains a serious and significant global health problem. The development of neurovascular protectants to treat AIS successfully has been beset by disappointments and setbacks. Many promising candidates have lacked significant pleiotropic protective activity for brain tissue and cerebral blood vessels in clinical trials, while those with protective activity have had poor bioavailability or high toxicity. Moreover, the majority of agents did not confer significant neurovascular protection or clinical efficacy, as measured by standard behavioral endpoints in clinical trials of heterogeneous populations of patients with AIS. The recombinant tissue plasminogen activator alteplase is approved in many countries for the treatment of AIS in the first 3 h after symptom onset. Many drug candidates have been subject to clinical trials, including those with anti-excitotoxic, anti-inflammatory, antioxidant, antiapoptotic/regenerative, calcium/adrenergic-modulating/antihypertensive, thrombolytic, nootropic/stimulant, fluid regulatory, or oxygen-delivering mechanisms of action. Some agents, such as tenecteplase, edaravone and minocycline, may be approved for global use in the future. This review evaluates almost all neurovascular protectants subject to clinical trial evaluation for the treatment of AIS, and includes 241 studies conducted between 1978 and 2014. The development of agents that reduce brain injury after AIS will require new and different approaches based on a deeper understanding of the pathophysiology of AIS. Moreover, the future treatment for AIS is likely to lie in combination therapy rather than monotherapy. Additional approaches to the testing and use of neurovascular protectants should be considered.
急性缺血性卒中（AIS）是导致死亡和残疾的主要原因，仍然是一个严重且重大的全球健康问题。成功开发用于治疗AIS的神经血管保护剂一直受到挫折和阻碍。许多有前景的候选药物在临床试验中对脑组织和脑血管缺乏显著的多效性保护活性，而具有保护活性的药物生物利用度差或毒性高。此外，在AIS患者异质群体的临床试验中，以标准行为终点衡量，大多数药物并未提供显著的神经血管保护或临床疗效。重组组织型纤溶酶原激活剂阿替普酶在许多国家被批准用于症状发作后3小时内的AIS治疗。许多候选药物已经进行了临床试验，包括那些具有抗兴奋毒性、抗炎、抗氧化、抗凋亡/再生、钙/肾上腺素能调节/抗高血压、溶栓、益智/刺激、液体调节或氧输送作用机制的药物。一些药物，如替奈普酶、依达拉奉和米诺环素，未来可能被批准全球使用。本综述评估了几乎所有接受临床试验评估用于治疗AIS的神经血管保护剂，包括1978年至2014年间进行的241项研究。开发能够减少AIS后脑损伤的药物将需要基于对AIS病理生理学更深入理解的新的不同方法。此外，AIS的未来治疗可能在于联合治疗而非单一治疗。应该考虑神经血管保护剂测试和使用的其他方法。
