Dose-effect study of the reversal by antimuscarinic agents of methomyl-induced respiratory toxicity
Respiratory failure is the primary cause of death in poisonings involving carbamate insecticides. However, the mechanisms of respiratory toxicity induced by carbamates remain unclear. The aims of this study were i) to describe the respiratory effects of methomyl, ii) to assess the peripheral or central origin of those effects, and iii) to study the dose-effect relationship of atropine. A dose of methomyl corresponding to 50% of the median lethal dose was given intraperitoneally to rats. Ventilation at rest was assessed using whole body plethysmography and core body temperature using infra-red telemetry. The central or peripheral origin was assessed comparing the effect of equipotent doses of atropine and methylatropine. The effects of dose of atropine ranging from 1 to 10 mg/kg were assessed. Total cholinesterase activities were determined using a radiometric method. From 5 to 150 minutes post-injection, methomyl induced significant clinical symptoms, including significant decreases in respiratory frequency, which resulted from a significant increase in expiratory time. Methomyl induced a significant inhibition of brain total cholinesterase activities; meanwhile, atropine, but not methylatropine, completely reversed methomyl-induced respiratory toxicity. The dose-effect study showed that the efficient dose of atropine resulting in lowest adverse effects was 3 mg/kg while greater doses were efficient but induced significant adverse effects. Decrease in brain cholinesterase activities accompanied by a positive effect of atropine, but not methylatropine, suggests a central origin of methomylinduced respiratory toxicity. The 3 mg/kg single atropine dose yielded the best compromise between antidotal activity and intrinsic effects.
Pascal Houzé.et al .: Asian Journal of Pharmacology and Toxicology, 05(17), 2017, 01-14.