Development of dosing schedule based on molecular clock mechanisms

点击翻译按钮获取中文摘要

Mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). Clock genes are the genes that control the circadian rhythms in physiology and behavior. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24-hr rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. However, many drugs 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 was useful to choose the most appropriate time of day for administration of drugs that increase their therapeutic effects and/or reduce their side effects. On the other hand, several drugs can cause alterations to the 24-hr rhythms, which leads to illness and altered homeostatic regulation. We showed the disruptive effect of interferon on the rhythm of locomotor activity, body temperature and clock genes mRNA expression in the periphery and SCN. The alteration of the clock function, a new concept of adverse effects, was overcome by devising a dosing schedule that minimizes adverse drug effects on clock function. 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. One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best tolerated. Finally, we developed the vector showing rhythmic gene expression for the intelligent chrono-drug delivery system.