Chronopharmacological strategies focused on chrono-drug discovery.

Abstract

In mammals, the circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbation of these rhythms is associated with pathogenic conditions such as cancer, metabolic syndrome, cardiovascular disease, sleep disorder and depression. Clock genes ultimately control a vast array of circadian rhythms involved in physiology and behavior. They regulate several diseases described above. Chronotherapy is especially relevant when the risk and/or intensity of symptoms of a disease vary predictably over time. The effectiveness and toxicity of several drugs vary depending on the dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also the pharmacokinetics of a medication. The underlying mechanisms are associated with the 24-h rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. Identifying a rhythmic marker based on the molecular clock for choosing dosing time can lead to the progress and diffusion of chronopharmacotherapy. To monitor the rhythmic markers such as clock genes, it might be useful to choose the most appropriate time of a day for the administration of a drug, to increase its therapeutic effects and/or reduce its side effects. On the contrary, several drugs affect the molecular clock and alter the 24-h rhythms of various processes. Alterations in rhythmicity are sometimes associated with therapeutic effects, or it might lead to illness and altered homeostatic regulation. Furthermore, to produce new rhythmicity by manipulating the molecular clock of organs by rhythmic administration of drugs at altered feeding schedules appears to lead to a new concept of chronopharmacotherapy. An approach to increase the efficiency of pharmacotherapy is administering drugs at times when they are best tolerated. From the perspective of pharmaceutics, the application of biological rhythm to pharmacotherapy can be accomplished by the appropriate timing of administration of conventionally formulated tablets and capsules, and also by the use of special drug-delivery system to synchronize drug concentrations to the rhythms in disease activity. New drugs targeting the molecular clock are being developed to manage diseases in human. For instance, novel molecular mechanisms that mediate renal dysfunction in mice with chronic kidney disease (CKD) have been identified by examining the relationship between the circadian clock and CKD aggravation. The inhibition of cell cycle regulatory factor ameliorated renal inflammation in a mouse model of CKD. A novel inhibitor of cell cycle regulatory factor has been identified, supporting the potential utility of cell cycle regulatory factor inhibition in the treatment of CKD. Although malignant phenotypes of triple-negative breast cancer are subject to circadian alterations, the role of cancer stem cells (CSCs) in defining this circadian change remains unclear. The effectiveness of anticancer drugs varies with the circadian dynamics of CSCs, which are regulated by the tumor microenvironmental factors. The finding reveals that the circadian dynamics of CSCs are regulated by the tumor microenvironment and provides a proof of principle of its implication for chronotherapy against triple-negative breast cancer. Therefore, we present an overview of the dosing-time-dependent alterations in therapeutic outcome and safety of a drug and the regulatory system of biological rhythm from the perspective of clock genes and the possibility of pharmacotherapy based on the molecular clock.