儿茶酚- o -甲基转移酶及其抑制剂在帕金森病中的作用

Maria João Bonifácio, P. Nuno Palma, Luís Almeida, Patrício Soares-da-Silva
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引用次数: 174

摘要

帕金森病(PD)是一种以多巴胺能神经元退化为特征的神经系统疾病,纹状体多巴胺水平降低导致特征性运动症状。目前最有效的治疗方法仍然是左旋多巴与芳香氨基酸脱羧酶(AADC)抑制剂联合使用多巴胺替代疗法。然而,这种疗法的疗效随着时间的推移而降低,大多数患者出现波动反应和运动障碍。过去十年表明,使用儿茶酚- o -甲基转移酶抑制剂作为左旋多巴/AADC抑制剂治疗的佐剂,显著提高了该治疗的临床疗效。本文的目的是综述目前关于儿茶酚- o -甲基转移酶(COMT)的知识和COMT抑制剂在PD中的作用,COMT抑制剂作为PD的一种新的治疗方法,涉及左旋多巴在大脑靶区转化为多巴胺,并促进该胺在受体位点的持续作用。本文对COMT抑制剂的发现和发展进行了历史回顾,特别强调了目前正在临床开发的内比卡彭,以及已被批准作为PD治疗辅助药物的恩他卡彭和托尔卡彭。本文综述了这些药物的人体药代动力学和药效学特性,以及它们的临床疗效和安全性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Catechol-O-methyltransferase and Its Inhibitors in Parkinson's Disease

Catechol-O-methyltransferase and Its Inhibitors in Parkinson's Disease

Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of dopaminergic neurons, with consequent reduction in striatal dopamine levels leading to characteristic motor symptoms. The most effective treatment for this disease continues to be the dopamine replacement therapy with levodopa together with an inhibitor of aromatic amino acid decarboxylase (AADC). The efficacy of this therapy, however, decreases with time and most patients develop fluctuating responses and dyskinesias. The last decade showed that the use of catechol-O-methyltransferase inhibitors as adjuvants to the levodopa/AADC inhibitor therapy, significantly improves the clinical benefits of this therapy.

The purpose of this article is to review the current knowledge on the enzyme catechol-O-methyltransferase (COMT) and the role of COMT inhibitors in PD as a new therapeutic approach to PD involving conversion of levodopa to dopamine at the target region in the brain and facilitation of the continuous action of this amine at the receptor sites. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on nebicapone, presently under clinical development, as well as entacapone and tolcapone, which are already approved as adjuncts in the therapy of PD. This article reviews human pharmacokinetic and pharmacodynamic properties of these drugs as well as their clinical efficacy and safety.

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