Abstract
Treatment of serious poisoning by phosphate and phosphonate esters of the “nerve gas” and insecticide type relies principally on prevention and control of the actions of acetylcholine (1,2,3). Long-lasting “irreversible” inhibition of body cholinesterase by these esters in small amounts is believed to account for their great toxicity(4,5) and control of their actions has centered on liberal use of atropine, long known for its capacity to block the actions of acetylcholine in many of its loci of action, including the central nervous system(1,2,6,7). Although the symptom-relieving and life-saving capacity of atropine is considerable when given in large amounts early in poisoning coupled with artificial respiration(8), its use is nevertheless limited. No other compounds with atropine-like properties, offering substantial improvement, have been found(8).
Repair of the biochemical lesion produced by nerve gas and similarly-acting phosphate esters (e.g. certain insecticides) has been a more recent approach to the problem(5). Restoration of cholinesterase activity to physiologically adequate levels with sufficient rapidity to avert or halt progress of poisoning serious enough to be beyond the control of atropine has been the object of this approach. The approach attempts to “cure the disease” by restoring the body mechanisms for dealing with its acetylcholine competently, rather than by treating symptomatically with a drug such as atropine. Suggestions that such an approach might be feasible appeared when it was demonstrated that certain oximes and hydroxamic acids may catalyze breakdown of such phosphate esters to innocuous products, may restore cholinesterase activity, or perform both functions in vitro(5,10). Limited in vivo data appear to demonstrate chemotherapeutic effectiveness of 2-pyridine aldoxime methiodide (2-PAM) and other oximes against some phosphate esters(10,11). However, other investigators pointed out that in the absence of atropine the effectiveness of 2-PAM was negligible against phosphate esters(12).
It reactivates GB-inhibited cholinesterases in vitro at a higher rate than does 2-PAM (13).
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