SUBCHRONIC ADMINISTRATION OF PYRIDOSTIGMINE OR HUPERZINE TO PRIMATES: COMPARED EFFICACY AGAINST SOMAN TOXICITY

Abstract

ABSTRACTOrganophosphonate (OP) nerve agents, such as soman, are potent irreversible inhibitors of central and peripheral acetylcholinesterases (AChEs). Pre-treatment of OP poisoning relies on the subchronic administration of a reversible AChE inhibitor. In the present limited study, the protective effects against soman toxicity of such compounds, i.e., the current pre-treatment pyridostigmine and huperzine, a proposed pre-treatment, are compared in primates. This is the first time primates are used to study the potential of pre-treatment with huperzine. Indeed, previous studies with huperzine used nonprimate models which are not the most appropriate for pre-treatment in humans. Each medication is given via a subcutaneous mini-osmotic pump for 6 days at a delivery rate providing about 20% inhibition of red cell AChE activity. In this trial with only four primates, huperzine selectively inhibits red cell AChE activity whereas pyridostigmine also inhibits plasma butyrylcholinesterase (BuChE). This latter may act as endogenous scavenger of OP compounds helping to confer additional protection against OPs. During intoxication, the cumulative dose of soman needed to produce convulsions and epileptic activity is 1.55-fold higher in the animals pre-treated with huperzine compared to those pre-treated with pyridostigmine. Thus, replacing PYR by HUP for a subchronic pre-treatment of primates gives them better tolerance to the epileptic effects of soman.