Rythmes circadiens des effets toxiques d'un antihistaminique H 1 : la cétirizine chez la souris

Abstract

Cetirizine is a second generation histamine H 1 receptor antagonist used to provide symptomatic relief of allergic signs caused by histamine release. The aim of the study was to learn whether the survival and the motor incoordination (ataxia) side effect of cétirizine administration is dosing time-dependent. Materials and methods. – A total of 240 male Swiss mice, 10 weeks of age were synchronized for 3 weeks by 12 h light (rest span)/12 h dark (activity span). Different doses of cetirizine were administered orally at fixed times during the day to determine both the sublethal (TD 50) and lethal (LD 50) doses, which were, respectively, 55 ± 0.35 and 750 ± 0.40 mg/kg. In the chronotoxicologic study a single dose of cétirizine (DL 50) was administered to comparable groups of animals at six different circadian stages [1, 5, 9, 13, 17, 21 h after light onset (HALO)]. Results. – The survival was statistically significant dosing time-dependent ( χ 2 = 16.73; P < 0.001). Drug dosing at 17 HALO resulted in 83.3% survival rate whereas drug dosing at 5 HALO was only 23.25%. Cosinor analysis revealed a statistically significant circadian (period ≈ 24 h) rhythmic component in survival. Lowest (20%) and highest (88%) ataxia occurred when cetirizine was administered, respectively, at 17 and 5 HALO. Cosinor analysis revealed a statistically significant circadian (period ≈ 24 h) rhythmic component in ataxia. Conclusion. – Our results reveal that the best safety is shown when cetirizine is administered in the middle of the dark (activity) span of the mice, since it produces some side effects: ataxia and hyperthermia. Taking into account of the hour administration of cetirizine, improves treatment efficacy and permit the best control of allergic diseases.