SUBCHRONIC ADMINISTRATION OF VARIOUS PRETREATMENTS OF NERVE AGENT POISONING. II. COMPARED EFFICACY AGAINST SOMAN TOXICITY

Abstract

OP nerve agents, such as soman, are potent irreversible inhibitors of central and peripheral acetylcholinesterases. Pretreatment of OP poisoning relies on the subchronic administration of a reversible acetylcholinesterase inhibitor. In the present study, the protective effects against soman toxicity of such compounds i.e. pyridostigmine, physostigmine (alone or associated with scopolamine) or huperzine are compared in guinea-pigs instrumented for EEG recording. Each medication is given via a subcutaneous mini-osmotic pump for 6 days at a delivery rate providing about 30% maximal inhibition of red cell acetylcholinesterase activity. The animals then receive iterative injections of soman (1/3 LD50) every 10 min. With pyridostigmine, reflecting a decreased overall tolerance to the poisoning, the cumulative doses of soman producing either tremors and convulsions or seizures are lower than those found in non-pretreated intoxicated controls. On the other hand, physostigmine does not afford satisfactory protection against the early mortality after intoxication. On this specific point, physostigmine + scopolamine and huperzine, although they do not prevent the appearance of seizures, give best results. The effects of each pretreatment on acetylcholinesterase, butyrylcholinesterase and carboxylesterase (these two latter enzymes may act as endogenous scavengers of OP compounds) are also examined in vitroand in the blood of each animal during subchronic administration. Huperzine appears as a selective inhibitor of red cell acetylcholinesterase activity while pyridostigmine or physostigmine additionally inhibit plasmatic butyrylcholinesterase.Considerations about huperzine or physostigmine + scopolamine as the most appropriate candidate for the pretreatment of OP poisoning are given.