Jenner Peter, Rocha José-Francisco, Ferreira Joaquim J, Rascol Olivier, Soares-da-Silva Patrício
Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
Department of Research & Development, BIAL - Portela & Ca SA, Portugal.
Expert Rev Neurother. 2021 Sep;21(9):1019-1033. doi: 10.1080/14737175.2021.1968298. Epub 2021 Sep 15.
Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery.
Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment.
This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.
左旋多巴仍然是帕金森病（PD）治疗的金标准，但运动并发症的不可避免发展促使人们积极寻求其最佳给药方式。
长期以来，外周多巴脱羧酶抑制一直被视为左旋多巴治疗在疾病各个阶段的重要组成部分。相比之下，儿茶酚-O-甲基转移酶（COMT）抑制剂直到最近才被用于阻断另一条主要的降解途径，并优化左旋多巴向大脑的输送。第一代和第二代COMT抑制剂存在毒性、药代动力学不理想或作用持续时间短等缺陷。因此，它们仅在“剂末现象”出现后才被使用。然而，第三代COMT抑制剂奥匹卡朋克服了这些困难，表现出持久的酶抑制作用，且没有前代COMT抑制剂所观察到的毒性。在临床试验和真实世界的PD研究中，奥匹卡朋改善了左旋多巴的血浆水平，并使“波动型”疾病的“开”期有显著改善，但它尚未被纳入早期治疗方案。
本综述主张在PD治疗方案中改变奥匹卡朋抑制COMT的定位，并提出一条在早期疾病中证明其有效性的途径。
