Chronobiology, drug delivery, and chronotherapeutics.

Biological processes and functions are organized in space, as a physical anatomy, and time, as a biological time structure. The latter is expressed by short-, intermediate-, and long-period oscillations, i.e., biological rhythms. The circadian (24-h) time structure has been most studied and shows great importance to the practice of medicine and pharmacotherapy of patients. The phase and amplitude of key physiological and biochemical circadian rhythms contribute to the known predictable-in-time patterns in the occurrence of serious and life-threatening medical events, like myocardial infraction and stroke, and the manifestation and severity of symptoms of chronic diseases, like allergic rhinitis, asthma, and arthritis. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and, most important to the theme of this special issue, medications. Rhythmicity in the pathophysiology of disease is one basis for chronotherapeutics--purposeful variation in time of the concentration of medicines in synchrony with biological rhythm determinants of disease activity--to optimize treatment outcomes. A second basis is the control of undesired effects of medications, especially when the therapeutic range is narrow and the potential for adverse effects high, which is the case for cancer drugs. A third basis is to meet the biological requirements for frequency-modulated drug delivery, which is the case for certain neuroendocrine peptide analogues. Great progress has been realized with hydrogels, and they offer many advantages and opportunities in the design of chronotherapeutic systems for drug delivery via the oral, buccal, nasal, subcutaneous, transdermal, rectal, and vaginal routes. Nonetheless, innovative delivery systems will be necessary to ensure optimal application of chronotherapeutic interventions. Next generation drug-delivery systems must be configurable so they (i) require minimal volitional adherence, (ii) respond to sensitive biomarkers of disease activity that often vary in time as periodic (circadian rhythmic) and non-periodic (random) patterns to release medication to targeted tissue(s) on a real time as needed basis, and (iii) are cost-effective.