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The pharmacology of chlormethiazole: a potential neuroprotective agent?

机译：氯甲唑的药理作用：潜在的神经保护剂？

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Chlormethiazole is a thiazole derivative with a long history of use as a sedative agent. The mode of action of the drug has been partly worked out and has been established with recognition that its mechanism of action involves potentiation of GABA activity, the major intrinsic inhibitory neurotransmitter. Animal models of stroke ranging from rodents to primates have suggested an optimistic role for chlormethiazole in preventing both anatomical and functional deleterious effects of stroke. Phase III clinical trials, therefore, proceeded but unfortunately with very little success. Recently, the animal models have been revisited in an attempt to identify causes for this discrepancy between the results from preclinical and clinical studies. This review studies the pharmacological roots of chlormethiazole from its origin through to its licensed and novel applications. Emphasis is placed on discussing the animal experiments which led to its grooming as a neuroprotective agent and also on the human trials. The review seeks to explain the discrepancies between animal and human studies, which include short survival times of experimental subjects, speed of drug administration and fundamental differences between species. The primate model of stroke perhaps offers the nearest alternative to phase III trials and has recently been used to compare a number of newer neuroprotective agents with greater efficacy than chlormethiazole. In addition, novel approaches involving human neurochemical analyses in vivo are described which may help bridge the gap between animal models and future phase III trials.
机译：氯甲唑是噻唑衍生物，具有用作镇静剂的悠久历史。该药物的作用方式已经部分制定出来，并且已经认识到该药物的作用机制涉及增强GABA活性（主要的内在抑制性神经递质）。从啮齿动物到灵长类动物的中风动物模型都表明，氯咪唑在预防中风的解剖学和功能性有害作用方面具有乐观作用。因此，进行了III期临床试验，但不幸的是，收效甚微。最近，已经对动物模型进行了重新研究，以找出导致临床前和临床研究结果之间存在差异的原因。这篇综述研究了氯甲基咪唑从其起源一直到其许可的和新颖的应用的药理根源。重点放在讨论动物实验，该实验导致了其作为神经保护剂的修饰，同时也放在了人类试验中。该综述旨在解释动物与人类研究之间的差异，其中包括实验对象的生存时间短，药物施用的速度以及物种之间的根本差异。灵长类动物的中风模型也许提供了最接近III期试验的替代方法，并且最近被用于比较许多比氯甲唑效果更好的新型神经保护剂。此外，描述了涉及体内人类神经化学分析的新方法，这可能有助于弥合动物模型与未来III期临床试验之间的差距。

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