Ballesta, Annabelle, Innominato, Pasquale F., Dallmann, Robert, Rand, D. A. (David A.) and Lévi, Francis A. (2017) Systems chronotherapeutics. Pharmacological Reviews, 69 (2). pp. 161-199. doi:10.1124/pr.116.013441 ISSN 0031-6997.

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Abstract

Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system–resetting strategies for improving chronic disease control and patient outcomes.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science, Engineering and Medicine > Science > Mathematics Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Chronopharmacology , Circadian rhythms
Journal or Publication Title:	Pharmacological Reviews
Publisher:	American Society for Pharmacology and Experimental Therapeutics
ISSN:	0031-6997
Official Date:	28 March 2017
Dates:	Date Event 28 March 2017 Published 1 March 2017 Accepted
Volume:	69
Number:	2
Page Range:	pp. 161-199
DOI:	10.1124/pr.116.013441
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	8 June 2017
Date of first compliant Open Access:	8 June 2017
Funder:	Seventh Framework Programme (European Commission) (FP7), Cancer Research UK (CRUK)
Grant number:	Grant 305033 (FP7), Grant C53561/A19933 (CRUK)

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