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.

Chronotype and Social Jetlag - a (self-)critical review

“…This concept is referred to as chronotherapy [96,97]. Despite the solid mechanistic basis, the concept is not broadly exploited in ongoing clinical trials [98]. Correctly estimating chronotype using logistically feasible methods is essential for chronotherapy efficacy.…”

Toward Dynamical Systems Medicine: Personalized and Preventive Strategies

“…For example, food components may interact with epigenetic factors with powerful protective and preventive potentials against inflammation in aging and age-related diseases [18]. Moreover, circadian rhythms have profound effects on xenobiotic metabolism and detoxification processes [19]. However, even with strong evidences, chronotherapy including the 'time-of-day' administration still needs more attention for personalized therapeutic regimens to reduce adverse effects and promote the efficacy [3,19].…”

“…Moreover, circadian rhythms have profound effects on xenobiotic metabolism and detoxification processes [19]. However, even with strong evidences, chronotherapy including the 'time-of-day' administration still needs more attention for personalized therapeutic regimens to reduce adverse effects and promote the efficacy [3,19].…”

Timing metabolism in cartilage and bone: links between circadian clocks and tissue homeostasis

“…The numerous connections between the circadian clock and skeletal homeostasis bring about the possibility of targeting circadian rhythms to improve existing therapies and develop new routes. One approach is to adopt the concept of 'chronotherapy', in which the drug regimen is tailored to a patient's circadian rhythm in order to maximise treatment effectiveness and reduce adverse effects (Selfridge et al 2016). Over 40 years ago, it was reported that OA and RA symptoms can be improved by timing the intake of indomethacin and flurbiprofen; and treatment efficiency was correlated with the individual circadian variation of pain (Huskisson et al 1970, Kowanko et al 1981, Levi et al 1985.…”