Circadian Mechanisms in Medicine- A Comprehensive Review By
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In addition to the sleep–wake cycle and cognitive functions such as learning and memory, intrinsic clocks determine nearly all circadian cycles in physiology, such as daily variation in blood pressure, heart rate, hormone levels, respiratory and exercise capacity, and coagulation. Many pathologic events occur at specific times of day, indicating that circadian processes contribute to disease. A central function of the clock system is to drive periods of energy acquisition and use in anticipation of the cycling of day and night. A molecular understanding of circadian time opens therapeutic insights that can help prevent and treat disease.

Beyond the potential pathophysiological role of circadian pathways, emerging evidence indicates that synchronizing drug delivery with endogenous physiological rhythms may be used to optimize treatment efficacy. For example, adjusting the administration of oxaliplatin, a cis-platinum derivative, to the time of day reduces off-target side effects in patients with colorectal cancer.

More recent evidence has revealed significant diurnal variation in the metabolism of a small molecule receptor tyrosine kinase inhibitor, suggesting that consideration of endogenous clock time may enhance the efficacy of this and perhaps other chemotherapeutic agents. Rhythmic expression of central mitochondrial enzymes in the liver that are important in the activation or catabolism of lipid-soluble drugs may influence pharmacokinetics at different times of the day.

Alternatively, drug targets themselves may peak at different times. An example is the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase, which peaks at night in humans. This observation led to the recommendation that short-acting statins be administered in the evening. Many agents with a half-life shorter than 12 hours are most effective when delivery is adjusted for intrinsic circadian time.