[Circadian rhythms in the toxic effects of the histamine antagonist cetirizine in mice].
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 cetirizine administration is dosing time-dependent.


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 cetirizine (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 (chi(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 approximately 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 approximately 24 h) rhythmic component in ataxia.


CONCLUSIONS
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.
Dridi
D
D
Laboratoire de pharmacologie, faculté de médecine, Monastir, Tunisie. dadou1us@yahoo.com
Ben Attia
M
M
Reinberg
A
A
Boughattas
N A
NA
D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001831:Body Temperature / Q000187:drug effects; D017332:Cetirizine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D005334:Fever / Q000139:chemically induced; D039563:Histamine H1 Antagonists, Non-Sedating / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007928:Lethal Dose 50; D008027:Light; D008297:Male; D051379:Mice
D039563:Histamine H1 Antagonists, Non-Sedating; D017332:Cetirizine