Toxicokinetics and binding of nerve agents in the presence of scavengers

Traditional multidrug therapy of organophosphorus nerve agent poisoning has several drawbacks such as postexposure incapacitation while optimal timing of administration of the drugs is also crucial. A priori, sequestration of the agent before it can reach its physiological targets would provide optimal protection. Within this context, a plethora of bioscavengers has been developed and tested over the last half century including enzymes that hydrolyze phosphofluoride agents, e.g., phosphorylphosphatases and catalytic antibodies, reversibly binding antibodies, and covalently binding enzymes, e.g. carboxylesterases and cholinesterases from various sources. In view of its competing reaction rates with nerve agents, reasonable availability and long in vivo half life, human butyrylcholinesterase is presently considered as the most promising bioscavenger. This enzyme proved to protect several species fully against multiple lethal dosages of soman and other nerve agents, albeit mostly after rather impractical i.v.-administration of the scavenger. A quantitative description of the observed protection is not available, which hampers optimization of the treatment as well as extrapolation to humans. Therefore, we have embarked upon investigations that involve (i) pretreatment of (hairless) guinea pigs with i.m.-administered HuBuChE , (ii) toxicokinetics of the nerve agents sarin, soman and VX in the pretreated animals after i.v., respiratory or percutaneous administration , and (iii) binding experiments in extravascular compartments. The results obtained sofar, in combination with modelling experiments will indicate potential (dis)advantages of scavengers and perhaps some indications for future research.