ABSTRACT
I. Introduction ....................................................................................................................... 176 II. Current Therapy for Nerve Agent Exposure .................................................................... 177 III. Nerve Agent Bioscavengers: An Alternative to Conventional Approaches..................... 177 IV. Stoichiometric Scavengers and the Protection they Offer ................................................ 179 V. Catalytic Bioscavengers .................................................................................................... 185 VI. Behavioral Effects ............................................................................................................. 191 VII. Behavioral Effects of Scavengers Alone .......................................................................... 191 VIII. Summary ........................................................................................................................... 192 References ..................................................................................................................................... 193
Although treatment for intoxication by organophosphorus (OP) poisons exists, the treatment regimen suffers from certain deficiencies. To overcome these disadvantages, the concept of using a bioscavenger has emerged as a new approach to reduce the in vivo toxicity of chemical warfare nerve agents. Bioscavengers fall into two broad categories, stoichiometric, that is, proteins that bind and detoxify a poison in some fixed molecular ratio, and catalytic, that is, 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 over current treatment, a biological scavenger should have minimal or no behavioral or physiological side effects, should provide protection against exposure to as much as five LD50s of one or more nerve agents, and should reduce or eliminate any behavioral or physiological side effects normally associated with the currently fielded therapy. Studies with equine or human butyrylcholinesterase or fetal bovine serum acetylcholinesterase showed that none of these scavengers elicited behavioral side effects
when administered to rats or monkeys. These three scavenger enzymes as well as carboxylesterase were each capable of providing protection against 2-16 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, that is, mouse, rat, or rhesus monkey, pretreated with a bioscavenger, following administration of up to 5 LD50s of GD or VX, either no, or only very minor and transient deficits were reported. These results were in stark contrast to the prolonged, up to 14 days, behavioral incapacitation experienced by animals that were pretreated with pyridostigmine and received the same dose of nerve agent followed by the standard atropine and oxime therapy with or without diazepam. Although several challenges still remain to be met 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.
