title: Chronotherapy: Intuitive, Sound, Founded…But Not Broadly Applied.
abstract: Circadian rhythms are a collection of endogenously driven biochemical, physiological, and behavioral processes that oscillate in a 24-h cycle and can be entrained by external cues. Circadian clock molecules are responsible for the expression of regulatory components that modulate, among others, the cell's metabolism and energy consumption. In clinical practice, the regulation of clock mechanisms is relevant to biotransformation of therapeutics. Accordingly, xenobiotic metabolism and detoxification, the two processes that directly influence drug effectiveness and toxicity, are direct manifestations of the daily oscillations of the cellular and biochemical processes taking place within the gastrointestinal, hepatic/biliary, and renal/urologic systems. Consequently, the impact of circadian timing should be factored in when developing therapeutic regimens aimed at achieving maximum efficacy, minimum toxicity, and decreased adverse effects in a patient. However, and despite a strong mechanistic foundation, only 0.16 % of ongoing clinical trials worldwide exploit the concept of 'time-of-day' administration to develop safer and more effective therapies. In this article, we (1) emphasize points of control at which circadian biology intersects critical processes governing treatment interventions; (2) explore the extent to which chronotherapeutics are incorporated into clinical trials; (3) recognize roadblocks; and (4) recommend approaches to precipitate the integration of chronobiological concepts into clinical practice.
authors.affiliation: Virginia Tech Carilion School of Medicine and Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA.|Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Selfridge
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Gotoh
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Schiffhauer
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA.
authors.forename: JingJing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stauffer
authors.affiliation: Virginia Tech Carilion School of Medicine and Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA.|Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Li
authors.affiliation: Protein Signaling Domains Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA.|Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA, 24061, USA.
authors.forename: Daniel G S
authors.initials: DG
authors.lastname: Capelluto
authors.affiliation: Virginia Tech Carilion School of Medicine and Research Institute, 2 Riverside Circle, Roanoke, VA, 24016, USA. finkielc@vt.edu.|Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, 1015 Life Science Circle, Virginia Tech, Blacksburg, VA, 24061, USA. finkielc@vt.edu.
authors.forename: Carla V
authors.identifier: http://orcid.org/0000-0002-8417-4643
authors.initials: CV
authors.lastname: Finkielstein
mesh_terms: D019454:Chronotherapy; D002940:Circadian Rhythm / Q000502:physiology*; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*