Abstract

Nikethamide offered some protection against EPN poisoning in mice, guinea pigs and rats. A latent period was seen in the action of nikethamide against EPN in rats. Nikethamide either decreased the survival time or did not alter the toxicity of Parathion, OMPA, TEPP or DFP in rats or mice.

Nicotinamide decreased the toxicity of simultaneously injected EPN in rats and mice, but not in guinea pigs. It prolonged the survival time of rats treated with Parathion or TEPP. There was no latency in the protective action of nicotinamide in rats poisoned by EPN. Nicotinamide decreased the toxicity of acetylcholine in rats, whil nikethamide did not.

Tryptophan and nicotinic acid gave some protection against EPN in rats, but not in guinea pigs. Neither dimethylethanolamine nor methionine altered the toxicity of EPN in rats and methionine did not overcome the protection by nicotinamide. N1-methyl nicotinamide, a metabolite of nicotinamide, did not alter the toxicity of EPN in rats. A metabolic antagonist of nitotinamide, 6-aminonicotinamide, increase the survival time of mice treated with EPN, and enhanced the protection by nicotinamide.

Injected nikethamide and nicotinamide protected the cholinesterase activity of several rat tissues against inhibition by EPN. Both Compounds in vitro, in concentrations theoretically attainable in vivo, did not markedly reactivate rat brain cholinesterase inhibited in vivo or in vitro by EPN. Protection against in vitro but not in vivo EPN inhibition of brain cholinesterase by nikethamide and nicotinamide preincubated with rat liver slices appeared greater than with the unincubated compounds.

The decrease in mortality produced in EPN-poisoned rats by nikethamide and nicotinamide is most likely due to the observed protection of tissue cholinesterase activity. Whether these compounds prevent the formation of the EPN cholinesterase complex, or reactivate the inhibited enzyme is unknown. From our knowledge of nicotinamide metabolism and from the present results it appears that nicotinamide is the effective antagonist in EPN poisoning when nicoptinamide, nikethamide, nicotinic acid or tryptophan are injected into rats.