Emory University School of Medicine, Department of Emergency Medicine, 1365 B Clifton Rd NE, Suite 5100, Atlanta, GA, 30322, USA.
Neuropharmacology. 2019 Mar 15;147:66-73. doi: 10.1016/j.neuropharm.2018.04.006. Epub 2018 Apr 6.
The field of neuroprotection after brain injuries has been littered with failed clinical trials. Finding a safe and effective treatment for acute traumatic brain injury remains a serious unmet medical need. Repurposing drugs that have been in use for other disorders is receiving increasing attention as a strategy to move candidate drugs more quickly to trial while reducing the very high cost of new drug development. This paper describes our own serendipitous discovery of progesterone's neuroprotective potential, and the strategies we are using in repurposing and developing this hormone for use in brain injuries-applications very different from its classical uses in treating disorders of the reproductive system. We have been screening and testing a novel analog that maintains progesterone's therapeutic properties while overcoming its physiochemical challenges, and testing progesterone in combination treatment with another pleiotropic hormone, vitamin D. Finally, our paper, in the context of the problems and pitfalls we have encountered, surveys some of the factors we found to be critical in the clinical translation of repurposed drugs. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.
在脑损伤后的神经保护领域，临床试验屡遭失败。寻找一种安全有效的治疗急性创伤性脑损伤的方法仍然是一个严重的未满足的医疗需求。重新利用已经用于治疗其他疾病的药物作为一种策略，正在受到越来越多的关注，目的是更快地将候选药物推向临床试验，同时降低新药开发的极高成本。本文描述了我们偶然发现孕酮具有神经保护潜力的过程，以及我们正在使用的重新利用和开发这种激素治疗脑损伤的策略——这些应用与它在治疗生殖系统疾病方面的经典用途非常不同。我们一直在筛选和测试一种新型类似物，这种类似物保持了孕酮的治疗特性，同时克服了其生理化学挑战，并测试了孕酮与另一种多效性激素维生素 D 的联合治疗。最后，我们的论文在遇到的问题和陷阱的背景下，调查了我们发现对重新利用药物的临床转化至关重要的一些因素。本文是题为“药物再利用：旧分子，快速追踪 CNS 疾病药物发现和开发的新方法”的特刊的一部分。
