Development of Chronotherapy Based on Clock Genes

哺乳动物的昼夜节律起搏器位于成对的视交叉上核（SCN）。时钟基因是控制生理和行为的昼夜节律的基因。许多药物的有效性和毒性取决于在生物钟控制下与生化、生理和行为过程的24小时节律相关的给药时间。然而，许多药物仍然不考虑一天中的时间。确定节律性标记物用于选择给药时间将改善时间药物治疗的进展和扩散。在本研究中，澄清了以下几点。监测节律标志物可能有助于选择一天中最合适的给药时间，从而增加药物的治疗效果和/或减少药物的副作用。此外，我们还展示了干扰素对外周和SCN中运动活动节律、体温和时钟基因mRNA表达的破坏性影响。时钟功能的改变是不良反应的一个新概念，可以通过设计一个使药物对时钟功能的不良影响最小化的给药计划来克服。此外，通过改变进食时间表或几种药物的节律性管理来操纵活体器官的条件，从而产生新的节律性，这可能会导致时间药物治疗的新概念。

Mammal ians 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. In the present study, the following points were clarified. To monitor the rhythmic marker 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. Also, 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, can be 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 maylead to the new concept of chronopharmacotherapy.