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Circadian time-dependent differences in murine tolerance to the antihistaminic agent loratadine
Dorra Dridi1, Naceur A Boughattas, Karim Aouam
1Laboratoire de Pharmacologie, Faculté de Médecine, Monastir, Tunisia.
Abstract:
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.
Insights
Loratadine
Area of Science:
- Pharmacology
- Chronobiology
Background:
- Loratadine is a widely used antihistamine for allergic conditions.
- Understanding the impact of drug administration timing on efficacy and toxicity is crucial.
Purpose of the Study:
- To investigate if the lethal toxicity and neurotoxicity of loratadine are influenced by circadian rhythms.
- To determine optimal dosing times for loratadine to maximize survival and minimize side effects.
Main Methods:
- 210 male Swiss mice were synchronized to a 12h light/12h dark cycle for 3 weeks.
- Mice received either a sublethal (82 mg/kg) or lethal (4 g/kg) dose of loratadine at six different time points (1, 5, 9, 13, 17, 21 HALO).
- Survival rates and motor incoordination (neurotoxicity) were assessed, and data were analyzed using cosinor and chi-squared tests.
Main Results:
- Survival duration and neurotoxicity of loratadine were significantly dependent on the dosing time (p < 0.001).
- The highest survival rate (67%) and best tolerance (acrophase at 17.5 HALO) occurred when loratadine was administered at 17 HALO.
- Motor incoordination peaked at 9 HALO (87%) and 21 HALO (68%), with troughs at 5 HALO (60%) and 17 HALO (32%).
- An ultradian rhythm (12h) component was also observed in neurotoxicity.
Conclusions:
- Dosing loratadine during the mid-activity (dark) span appears optimal for maximizing survival and minimizing neurotoxicity.
- Circadian-dependent variations in loratadine's toxicity highlight the importance of chronopharmacology in drug administration.
- Optimal dosing at 17 HALO resulted in a longer survival span (21 days vs. 12 days) and reduced neurotoxic effects.
