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Clinical Trials in Acute Ischemic Stroke

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Abstract

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.

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Acknowledgments

The authors thank Yoko Tsurusaki, Sachiko Nakashima, Rumi Ito and Tomoko Matsuo for their invaluable assistance.

Ethics Statement

This manuscript does not contain clinical studies or patient data.

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This study received no external funding.

Disclosures

Kiyoshi Kikuchi, Eiichiro Tanaka, Yoshinaka Murai and Salunya Tancharoen have no potential conflicts of interest with the contents of this review.

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Correspondence to Salunya Tancharoen.

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Kikuchi, K., Tanaka, E., Murai, Y. et al. Clinical Trials in Acute Ischemic Stroke. CNS Drugs 28, 929–938 (2014). https://doi.org/10.1007/s40263-014-0199-6

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