Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX

Authors

Ashima Saxena, Walter Reed Army Institute of ResearchFollow
Wei Sun, Walter Reed Army Institute of Research
James M. Fedorko, Walter Reed Army Institute of Research
Irwin Koplovitz, US Army Medical Research Institute of Chemical Defense
Bhupendra P. Doctor, US Army Medical Research Institute of Chemical Defense

Date of this Version

2011

Comments

Published in Biochemical Pharmacology, 81, (2011), 164–169

Abstract

Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200 mg will be required to protect a human against 2 × LD₅₀ of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at ~24 h and had a mean residence time of 78–103 h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5 × LD₅₀ of soman or 8 × LD₅₀ of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents.