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Seasonal modulation of the 8-and 24-hour rhythms of ondansetron tolerance in mice.
Chronobiol Int. 2007; 24(6):1199-212.CI

Abstract

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, Ø,=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 (Ø), 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.

Authors+Show Affiliations

Khedhaier A
Faculté de Médecine, Laboratoire d'Immuno-Oncologie Moléculaire, Monastir, Tunisia.
Ben-Attia M
No affiliation info available
Gadacha W
No affiliation info available
Sani M
No affiliation info available
Reinberg A
No affiliation info available
Boughattas NA
No affiliation info available

MeSH

AnimalsCircadian RhythmDrug ToleranceMaleMiceOndansetronPeriodicitySeasonsSerotonin AntagonistsSurvival Analysis

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18075807

Citation

Khedhaier, Achraf, et al. "Seasonal Modulation of the 8-and 24-hour Rhythms of Ondansetron Tolerance in Mice." Chronobiology International, vol. 24, no. 6, 2007, pp. 1199-212.
Khedhaier A, Ben-Attia M, Gadacha W, et al. Seasonal modulation of the 8-and 24-hour rhythms of ondansetron tolerance in mice. Chronobiol Int. 2007;24(6):1199-212.
Khedhaier, A., Ben-Attia, M., Gadacha, W., Sani, M., Reinberg, A., & Boughattas, N. A. (2007). Seasonal modulation of the 8-and 24-hour rhythms of ondansetron tolerance in mice. Chronobiology International, 24(6), 1199-212.
Khedhaier A, et al. Seasonal Modulation of the 8-and 24-hour Rhythms of Ondansetron Tolerance in Mice. Chronobiol Int. 2007;24(6):1199-212. PubMed PMID: 18075807.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Seasonal modulation of the 8-and 24-hour rhythms of ondansetron tolerance in mice. AU - Khedhaier,Achraf, AU - Ben-Attia,Mossadok, AU - Gadacha,Wafa, AU - Sani,Mamane, AU - Reinberg,Alain, AU - Boughattas,Naceur A, PY - 2007/12/14/pubmed PY - 2008/4/2/medline PY - 2007/12/14/entrez SP - 1199 EP - 212 JF - Chronobiology international JO - Chronobiol Int VL - 24 IS - 6 N2 - 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, Ø,=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 (Ø), 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. SN - 0742-0528 UR - https://www.unboundmedicine.com/medline/citation/18075807/Seasonal_modulation_of_the_8_and_24_hour_rhythms_of_ondansetron_tolerance_in_mice_ DB - PRIME DP - Unbound Medicine ER -