Seasonal modulation of the 8-and 24-hour rhythms of ondansetron tolerance in mice

摘要

Ondansetron (Zophren((R))) is a serotonin 5HT(3)-receptor antagonist used primarily to control nausea and vomiting caused by cytotoxic chemo- and radio-therapy. Tolerance to this drug shows both 24 and 8 h periodicities. In this framework, this study aimed to determine whether these ondansetron tolerance rhythms are modulated by season. The chronotoxic effect of a fixed dose (3.5 mg/kg, i.p.) of the drug was investigated with reference to both time of the day and year dependencies. Season-related studies were performed on 560 male Swiss mice, 10 to 12 wks old, synchronized with L:D = 12:12 for three weeks. During a 1 yr span (2005), four 24 h studies were performed with a single dosing time at 1, 7, 13, and 19 hours after light onset (HALO), respectively. Tolerance was assessed daily during a 40-day span after acute ondansetron treatment. Both chi(2) test and cosinor methods were used to analyze the time series data. Statistically significant dosing time-dependent changes were validated in both yearly and daily time scales. The 24 h mean survival rate peaked in spring (92%) compared to fall (72%), the 20% difference being statistically significant (chi(2) test with p < 0.05 and cosinor with p < 0.0001 for seasonal rhythm detection and with a peak time, phi, = April 3 +/- 6.6 days). A 24 h rhythm was also detected in each of the seasonal time points. However, the curve pattern was monophasic in fall as well as spring. In fall, a large amplitude (A) circadian rhythm was detected that peaked at 19 HALO, while in the spring, a small circadian rhythm was detected that peaked at 1 HALO. The curve pattern was biphasic in summer (with large A) and in winter (with a small A). The existence of two peaks of equal magnitude in winter (100% survival rate) and in summer (100% and 90%) suggests the presence of both circadian and ultradian rhythms rather than an ultradian component of the 24 h period. The seasonal modulation of ondansetron circadian chronotolerance seems to involve several rhythm parameters: season-related changes in the 24 h mean (M), amplitude (A), acrophase location (phi), as well as bimodal curve patterns including the coexistence of rhythms with respectively 24 and 8 h periods in winter and summer. In conclusion, tolerance to ondansetron varies not only according to the 24 and 8 h periods but also according to seasons, which suggests the complexity of ondansetron toxicity rhythms. Seasonal modulation of ondansetron tolerance may also influence the strategies of chemo- and chrono-therapy, and it is therefore necessary to take it into account in clinical drug-delivery protocols to minimize side effects of cytotoxic anticancer and antiemetic agents. (Author correspondence: naboughattas @yahoo. fr).