Changing the dosing schedule minimizes the disruptive effects of interferon on clock function

The effectiveness and toxicity of many drugs vary depending on the relation ship between the dosing schedule and the 24-hour rhythms of biochemical, ph ysiological and behavioral processes. In addition, several drugs can cause alterations to the 24-hour rhythms leading to illness and altered homeostat ic regulation. However, the mechanisms of this drug-based disruption of cir cadian 'clock' genes remain unclear. Here, we show the disruptive effect of interferon-alpha on the rhythm of locomotor activity, body temperature and clock-gene mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the Per gene in suprachiasmatic nuclei were disturbed by the r epetitive administration of interferon-alpha. Moreover, alteration of clock function, a new concept of adverse effects, can be overcome by optimizing the dosing schedule to minimize adverse drug effects.