Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.,Nature Reviews Rheumatology

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Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.
Nature Reviews Rheumatology ( IF 29.4 ) Pub Date : 2020-02-07 , DOI: 10.1038/s41584-020-0372-x
Eva Schrezenmeier ₁ , Thomas Dörner _{2,

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Affiliation

Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other inflammatory rheumatic diseases, insights into the mechanism of action of these drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a characteristic 'deep' volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. These modes of action, together with the drug's chemical properties, might explain the clinical efficacy and well-known adverse effects (such as retinopathy) of these drugs. The unknown dose-response relationships of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and what doses are toxic pose challenges to clinical practice. Further challenges include patient non-adherence and possible context-dependent variations in blood drug levels. Available mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine and provide the rationale to search for more potent and/or selective inhibitors.

中文翻译：

羟氯喹和氯喹的作用机理：对风湿病的影响。

尽管在临床上广泛使用抗疟药，例如羟氯喹和氯喹，以治疗类风湿关节炎（RA），系统性红斑狼疮（SLE）和其他炎性风湿性疾病，但对这些药物作用机理的见解仍在不断涌现。羟氯喹和氯喹是弱碱，具有特征性的“较深”分布，半衰期约为50天。这些药物干扰溶酶体活性和自噬，与膜稳定性相互作用并改变信号传导途径和转录活性，这可导致抑制细胞因子的产生和某些共刺激分子的调节。这些作用方式以及药物的化学性质可能可以解释这些药物的临床疗效和众所周知的不良反应（例如视网膜病变）。这些药物的未知的剂量反应关系以及缺乏临床疗效所需的最小剂量的定义以及哪些剂量是有毒的，对临床实践提出了挑战。进一步的挑战包括患者的不依从性以及血液中药物水平的可能与背景有关的变化。可获得的机理数据提供了对羟氯喹的免疫调节潜能的见识，并为寻找更有效和/或选择性抑制剂提供了理论依据。进一步的挑战包括患者的不依从性以及血液中药物水平的可能与背景有关的变化。可获得的机理数据提供了对羟氯喹的免疫调节潜能的见识，并为寻找更有效和/或选择性抑制剂提供了理论依据。进一步的挑战包括患者的不依从性以及血液中药物水平的可能与背景有关的变化。可获得的机理数据提供了对羟氯喹的免疫调节潜能的见识，并为寻找更有效和/或选择性抑制剂提供了理论依据。

更新日期：2020-02-07

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