Development of dosing schedule based on molecular clock mechanisms

哺乳动物的昼夜节律起搏器位于成对的视交叉上核（SCN）中。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。监测节律标志物有助于选择一天中最合适的给药时间，以增加其治疗效果和/或减少其副作用。另一方面，一些药物会导致24小时节律的改变，从而导致疾病和体内平衡调节的改变。我们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。时钟功能的改变是一种新的副作用概念，通过设计一种剂量计划来最大限度地减少药物对时钟功能的不良影响，克服了这一问题。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，这似乎导致了时间药物治疗的新概念。提高药物治疗效率的一种方法是在药物耐受性最好的时候给药。最后，我们为智能定时给药系统开发了具有节律性的基因表达载体。

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.