Advances in human chronopharmacology.

Regular and thus predictable changes in biologic susceptibility and response to a large variety of physical as well as chemical agents can now be viewed as rather common phenomena. Chronopharmacology involves both the investigation of drug effects as a function of biologic timing and the investigation of drug effects upon rhythm characteristics (the period, tau, the acrophase, phi, the amplitude, A, and the mesor, M). Illustrative examples of circadian (tau congruent to 24 hrs) chronopharmacology in man are summarized in up-dated tables, keeping in mind that the objective demonstration of chronopharmacologic facts demands the use of an appropriate methodology. Circadian changes in the effects of various chemical agents have been documented: histamine, sodium salicylate, acetylcholine, halothane, prostaglandin F2alpha, reserpine, cyproheptadine, ethanol, insulin, chlorothiazide, oxymetholone, orcinprenaline and SCH 1000 (the latter being bronchodilators), Indomethacin, lignocaine, ACTH, cortisol and various synthetic corticosteroids. Despite that pharmacological facts are well documented in man for circadian rhythms, studies are not only restricted to the 24-h period but have been already extended to rhythms of periods of e.g. approximately 30 days as well as approximately 1 year. For a better understanding of chronopharmacologic findings, three new concepts must be considered: a) the chronokinetics of a drug, defined as both rhythmic (circadian) changes in the drug bioavailability (and/or pharmacokinetic effects) and its excretion (urinary, among others); b) the chronesthesy of a biosystem to a drug, or the circadian change in the susceptibility of any biosystem to a drug (including organ systems, tumors, parasites, etc.); and c) The chronergy of a drug, or the rhythmic change in the overall effects and the effectiveness of a drug. This term takes into consideration the chronokinetics and the chronesthesies of the organismic biosystems involved. Presently, one of the aims of chronopharmacology is to solve problems of drug optimization, i.e. to enhance the desired efficiency of a corticosteroid or other medications, while reducing undesired effects. In the human organism, among other animal species, the metabolic fate of a pharmacologic agent (as well as that of a nutrient) is not constant as a function of biological time. The metabolic pathways are neither open permanently, nor open with a constant patency along the 24-h scale, among other bioperiodic domains. Thus, the chronobiologic approach concerning pharmacologic phenomena involves a lesser risk of errors and/or false information than the conventional homeostatic approach.