期刊
JOURNAL OF HEPATOLOGY
卷 76, 期 5, 页码 1215-1224出版社
ELSEVIER
DOI: 10.1016/j.jhep.2021.12.039
关键词
Non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; circadian; chronopharmacology
资金
- Wellcome Trust Clinical Research Training Fellowship [102176/B/13/Z]
- Medical Research Council [MR/P011462/1]
Liver homeostasis is influenced by the circadian clock. Disruption of the clock has been implicated in metabolic dysfunction like NAFL and NASH. Although current NASH drug candidates target pathways under circadian control, little consideration has been given to chronopharmacology in NASH.
Liver homeostasis is strongly influenced by the circadian clock, an evolutionarily conserved mechanism synchronising physiology and behaviour across a 24-hour cycle. Disruption of the clock has been heavily implicated in the pathogenesis of metabolic dysfunction including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Furthermore, many of the current NASH drug candidates specifically target pathways known to be under circadian control including fatty acid synthesis and signalling via the farnesoid X receptor, fibroblast growth factor 19 and 21, peroxisome proliferator-activated receptor a and c, glucagon-like peptide 1, and the thyroid hormone receptor. Despite this, there has been little consideration of the application of chronopharmacology in NASH, a strategy whereby the timing of drug delivery is informed by biological rhythms in order to maximise efficacy and tolerability. Chronopharmacology has been shown to have significant clinical benefits in a variety of settings including cardiovascular disease and cancer therapy. The rationale for its application in NASH is therefore compelling. However, no clinical trials in NASH have specifically explored the impact of drug timing on disease progression and patient outcomes. This may contribute to the wide variability in reported outcomes of NASH trials and partly explain why even late-phase trials have stalled because of a lack of efficacy or safety concerns. In this opinion piece, we describe the potential for chronopharmacology in NASH, discuss how the major NASH drug candidates are influenced by circadian biology, and encourage greater consideration of the timing of drug administration in the design of future clinical trials. (C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据