Neurology Clinical Trial Unit, Bldg 149, Room 2274, Charlestown, MA 02129, USA.
Expert Opin Investig Drugs. 2009 Dec;18(12):1907-18. doi: 10.1517/13543780903357486.
Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.
近年来,参与细胞应激反应的热休克蛋白表达调节剂氨氯可来(arimoclomol)作为一种潜在的治疗候选药物,在肌萎缩侧索硬化症(ALS)中受到关注。在运动神经元疾病的小鼠模型中,氨氯可来治疗被报道可改善生存和肌肉功能。已在健康对照受试者中完成了几项单剂量和多剂量安全性研究。一项在 ALS 患者中进行的为期 3 个月的 2a 期研究表明,高达 300mg/天的剂量是安全的,另一项研究目前正在招募由超氧化物歧化酶基因突变引起的家族性 ALS 患者。我们根据现有的安全性和药代动力学数据,综述了在散发性和家族性 ALS 中测试氨氯可来的原理。讨论了过去二十年来与该药物相关的已发表和未发表的文献。本综述试图将我们对氨氯可来作用的现有认识与 ALS 的疾病特征结合起来。氨氯可来的药理学特征和现有的临床前数据使其成为 ALS 中一种很有前途的治疗可能性。