Circadian time-dependent differences in murine tolerance to the antihistaminic agent loratadine.
Loratadine is a second-generation histamine H(1)-receptor antagonist used in the treatment of allergic diseases. The aim of the study was to assess whether lethal toxicity and motor incoordination (neurotoxicity) of loratadine is circadian rhythm-dependent. A total of 210 male Swiss mice, aged 10 wk, were synchronized for 3 wk to 12 h light (rest span)/12 h dark (activity span). The drug was administered per os. The choice of the sublethal (TD(50) = 82 mg/kg body weight) and the lethal (LD(50) = 4 g/kg body weight) dosage was based on preliminary studies. Each of these two doses was administered to comparable groups of animals at six different circadian time points (1, 5, 9, 13, 17, and 21 Hours After Light Onset [HALO]). The survival duration was dosing time-dependent (chi(2) = 16.96; p < 0.001). Drug dosing at 17 HALO resulted in best (67%) survival rate; whereas, dosing at 9 HALO resulted in poorest (21%) survival rate. Cosinor analyses (with a trial period tau = 24 h) validated a statistically significant circadian rhythm in survival rate (p < 0.04) with an acrophase (peak time Ø of best tolerance to loratadine) being at 17.5 HALO +/- 4.65 h. Troughs of motor incoordination were located at the administration times of 5 and 17 HALO (60% and 32% of animals affected, respectively), whereas peaks were located at 9 and 21 HALO (87% and 68% of animals affected, respectively). The 24 h mean of the motor incoordination was 61%, the mean proportion of animals affected by the treatment for the six different circadian times studies. The extent of this neurotoxic effect varied as a function of loratadine dosing time (p < 0.001). A statistically significant ultradian component rhythm (p < 0.01) with a trial period tau = 12 h was also validated. The obtained results show that the dosing time of loratadine at the mid-activity (dark) span seems to be optimal, since it corresponds to the longest (21 vs. 12 days) survival span and to least neurotoxicity.
Dridi
Dorra
D
Laboratoire de Pharmacologie, Faculté de Médecine, Monastir, Tunisia.
Boughattas
Naceur A
NA
Aouam
Karim
K
Reinberg
Alain
A
Ben Attia
Mossadok
M
D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D001921:Brain / Q000187:drug effects*; D002940:Circadian Rhythm / Q000502:physiology*; D004361:Drug Tolerance / Q000502:physiology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000378:metabolism / Q000633:toxicity*; D017336:Loratadine / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D051379:Mice; D009498:Neurotoxins / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors
D039563:Histamine H1 Antagonists, Non-Sedating; D009498:Neurotoxins; D017336:Loratadine