The chemotherapy of poisoning by organophosphate anticholinesterases.

Oximes (with or without atropine as an adjunct) have recently been used successfully in the treatment of humans poisoned by organophosphate anticholinesterases. The discovery of the nature of the biochemical lesion in organophosphate poisoning has permitted the design of drugs to repair specifically this particular lesion. This paper reviews historically the researches which led to the development of pyridine-2-aldoxime methiodide (PAM) and its corresponding methanesulphonate (P2S), the two most successful oximes yet tried, and summarizes the theoretical background to their rational use. Organophosphates are lethal because they inactivate cholinesterase due to phosphorylation of the enzyme's active centre. Consequently two rational lines of treatment are: (a) To find some compound which could be phosphorylated as rapidly as the enzyme and which, if introduced into the body, would protect the enzyme from inhibition by competing with it for the organophosphate, or (b) to find a compound which would restore the activity of the inhibited enzyme by dephosphorylating it. In both cases essentially the same type of compound is needed, namely one with a high intrinsic reactivity with organophosphoryl compounds, in (a) with the inhibitor itself or in (b) with the phosphorylated enzyme. Types of compounds with either or both of these properties are o-dihydroxybenzene derivatives, metal chelates, hydroxylamine, hydroxamic acids, and oximes. Pyridine-2-aldoxime methiodide and methanesulphonate have been by far the most successful as reactivators and in the treatment of poisoned animals. A brief account is given of the range of compounds for which PAM has been shown to be a successful antidote in intact animals and of the ability ofPAM to overcome the signs and symptoms of poisoning both in animals and in man. Possible lines of future investigations are indicated.