Clinical Investigation Center CIC1436, Department of Clinical Pharmacology and Neurosciences, Parkinson Expert Centre and NeuroToul Center of Excellence in Neurodegeneration (COEN) of Toulouse; INSERM, University of Toulouse 3, CHU of Toulouse , Toulouse, France.
Center for Health Sciences Research, National Research Council (ININCA-UAI-CONICET) , Buenos Aires, Argentina.
Expert Opin Investig Drugs. 2020 Nov;29(11):1249-1267. doi: 10.1080/13543784.2020.1814252. Epub 2020 Sep 2.
To date, no drug has demonstrated clinically indisputable neuroprotective efficacy in Parkinson's disease (PD). We also have no effective symptomatic treatment for disabling symptoms such as balance problems, and dementia, and we need to improve the efficacy and safety profile of drugs currently used in the management of motor complications.
We examine the agents which appear to have most therapeutic promise based on concepts, feasibility in a reasonable time frame, and available clinical data and place an emphasis on disease-modifying treatments. PUBMED and Clinicaltrials.gov databases were searched for Phase I and II randomized trials for symptomatic or disease-modifying treatments considering only studies that began since 2010 or that were completed after 2015, up to 30 April 2020.
Encouraging progress has been made in our understanding of molecular pathways. We find passive immunization approaches against α-synuclein, LRRK2 kinase inhibitors, and treatment that can increase GCase activity, which have shown some efficacy on both GBA-mutated and non-mutated PD patients. The recognition of non-dopaminergic impairment and the prominent role of non-motor symptoms have prompted the development of trials on compounds that could tackle different neurotransmitter systems. Future approaches will encompass more personalized medicine strategies based on molecular signatures and non-motor phenotypes.
迄今为止，尚无药物在帕金森病 (PD) 中表现出临床无可争议的神经保护疗效。我们也没有针对平衡问题和痴呆等致残症状的有效对症治疗方法，我们需要提高目前用于治疗运动并发症的药物的疗效和安全性。
我们根据概念、在合理时间内的可行性以及现有临床数据，检查了那些在治疗方面最有希望的药物，重点是疾病修饰治疗。我们在 PUBMED 和 Clinicaltrials.gov 数据库中搜索了针对症状或疾病修饰治疗的 I 期和 II 期随机试验，仅考虑自 2010 年以来开始或在 2015 年后完成的研究，截至 2020 年 4 月 30 日。
我们在分子途径的理解方面取得了令人鼓舞的进展。我们发现针对α-突触核蛋白的被动免疫方法、LRRK2 激酶抑制剂以及可以增加 GCase 活性的治疗方法，对 GBA 突变和非突变 PD 患者都显示出一定的疗效。对非多巴胺能损伤的认识以及非运动症状的突出作用促使人们开发了针对不同神经递质系统的化合物试验。未来的方法将包括更多基于分子特征和非运动表型的个性化医学策略。
