Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption

Mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm. Clock genes are the genes that control the circadian rhythms in physiology and behavior. 24h rhythm is demonstrated for the function of physiology and the pathophysiology of diseases. The effectiveness and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also pharmacokinetics of medications. The underlying mechanisms are associated with 24h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Thus, the knowledge of 24h rhythm in the risk of disease plus evidence of 24h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy. Chronotherapy is especially relevant, when the risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. Morning once-daily administration of corticosteroid tablet medications results in little adrenocortical suppression, while the same daily dose split into four equal administrations to coincide with daily meals and bedtime results in significant hypothalamus-pituitary-adrenal (HPA) axis suppression. However, the drugs for several diseases are still given without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. To monitor the rhythmic marker such as clock genes it may be useful to choose the most appropriate time of day for administration of drugs that may increase their therapeutic effects and/or reduce their side effects. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. Several drugs cause alterations in the 24h rhythms of biochemical, physiological and behavioral processes. The alteration of rhythmicity is sometimes associated with therapeutic effects, or may lead to illness and altered homeostatic regulation. Attention should be paid to the alteration of biological clock and consider it an adverse effect, when it leads to altered regulation of the circadian system which is a serious problem affecting basic functioning of living organisms. One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated. From viewpoints of pharmaceutics, the application of biological rhythm to pharmacotherapy may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and the special drug delivery system to synchronize drug concentrations to rhythms in disease activity. New technology for delivering medications precisely in a time-modulated fashion by bedside or ambulatory pumps is developing to manage human diseases. Therefore, we introduce an overview of the dosing time-dependent alterations in therapeutic outcome and safety of drug. The underlying mechanisms and usefulness are introduced from viewpoint of chronopharmacology and chronotherapy.