Studies on the mode of action of methyridine

Methyridine [2-(beta-methoxyethyl)pyridine] reached the blood and all regions of the alimentary canal following oral or subcutaneous administration of therapeutic doses of the drug. Concentrations in the lower gut were highest following subcutaneous administration, and there was a close association between blood and intestinal levels suggesting that the drug is excreted into the alimentary canal along its whole length. In vitro experiments with intact nematodes (Ostertagia spp. from sheep; Nematospiroides dubius and Heterakis spumosa from mice; and Nippostrongylus muris from rats) and with preparations of Ascaris sp. have demonstrated that methyridine passes through the cuticle and exerts an "irreversible" paralysing effect on the worms. This action is obtained within 1 hr at concentrations similar to peak levels shown to be present in the alimentary canal following the administration of therapeutic doses. Concentrations of the drug were found to be higher in the abomasum than in the intestine of sheep and yet the anthelmintic activity of methyridine is greatest against intestinal nematodes. No significant differences in the resistance of various nematode species to the drug were demonstrated, but the amount of methyridine entering ascarids was significantly greater at pH 8 than at pH 5 or 3. In addition, the in vitro anthelmintic activity of the compound was greatest in alkaline solutions, which probably accounts for the differences in anthelmintic activity noted in various parts of the alimentary canal. The paralysing effect of methyridine on nematodes is probably due to a neuromuscular block of the decamethonium type, and this can also be produced in the host by over-dosage. It is suggested that nematode tissues are more sensitive to this action than vertebrate tissues.