Nerve Agent Bioscavengers: Protection With Reduced Behavioral Effects

Abstract

Although treatments for intoxication by organophosphorus nerve agents exist, the treatment regimens suffer from undesirable side effects. To overcome these disadvantages, the use of bioscavengers has emerged as a new approach to reduce the in vivo toxicity of chemical warfare nerve agents. Bioscavengers fall into two broad categories: stoichiometric (i.e., proteins that bind a poison in some fixed ratio) and catalytic (i.e., proteins that can cause the breakdown of a molecule of a poison, regenerate, and then repeat the process until all of the poison molecules have been destroyed). To be an improvement of current treatments, a biological scavenger should have no or minimal behavioral or physiological side effects, should provide protection against one or more nerve agents up to 5 times the median lethal dose (5 LD50), and should reduce or eliminate any behavioral or physiological side effects normally associated with the currently fielded therapy. Studies with equine or human butyryl-cholinesterase or fetal bovine serum acetylcholinesterase show that none of these scavengers exhibit behavioral side effects when administered to rats or monkeys. These three scavengers as well as carboxylesterase are each capable of providing protection against 2 to 16 LD50s of GD, GB, or VX depending on the scavenger and the test species (rat, mouse, rabbit, guinea pig, or rhesus monkey). When behavioral testing was performed on animals pretreated with a bioscavenger and then administered up to 5 LD50s of GD or VX, either no, or only very minor, transient deficits were reported. These results are in stark contrast to the prolonged (1 to 2 week) behavioral in-capacitation experienced by animals pretreated with pyridostigmine and then exposed to the same dose of nerve agent followed by the standard atropine, oxime therapy with or without diazepam. Although several challenges still remain before bioscavengers could augment or replace the current therapeutic regimes for nerve agent intoxication, the results to date offer impressive evidence for the value of this approach as the next generation of pharmaceuticals to afford protection against nerve agent poisoning with a virtual absence of behavioral side effects.