U.S. Army Medical Research, Frederick, MD

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U.S. Army Medical Research, Frederick, MD

DOD Funding of Animal Cruelty 2005:
M3: Medical Chemical Defense - 1

Title: Effect of pretreatment with human butyrylcholinesterase scavengers on the toxicokinetics and binding of nerve agents in guinea pigs and marmosets

Research Category: M3: Medical Chemical Defense

FY: 2005 Funding (in dollars):  $1,632,025


Primary Contact:
TNO Prins Maurits Laboratory
City: Fort Detrick
State: MD
Zip: 21702-5102

Keywords: Laboratory animals ra iv volunteers toxicokinetics physiologically based models respiratory intoxication nerve agents human butyrylcholinesterase scavengers

Human butyrylcholinesterase (hubuche) is the most promising scavenger for use as a pretreatment drug against nerve agent intoxication. Although the results obtained in laboratory animals indicate the possible usefulness of hubuche as a scavenger, the information reported so far is insufficient for a thorough and quantitative description of the protective mechanism, which prevents a reliable extrapolation to humans. The goal of the research is to determine the toxicokinetics of nerve agents and hubuche in guinea pigs and marmosets. This is part of a larger goal to determine whether hubuche can be an effective pretreatment in humans for exposure to nerve agent.

The investigators will determine the blood concentrations of the stereoisomers of C(+/-)P(+/-)-SOMAN, (+/-)-SARIN, and (+/-)-VX in guinea pigs pretreated with hubuche subsequent to exposure to nerve agent. They also will determine the blood concentrations to the stereoisomers of C(+/-)P(+/-)-SOMAN in marmosets pretreated with hubuche subsequent to exposure to this agent. Rate constants will be determined from inhibition of hubuche by the stereoisomers of C(+/-)P(+/-)-SOMAN,(+/-)-SARIN, and (+/-)-VX. The fate of hubuche in extravascular compartments will be determined, as will the relative importance of binding sites in these compartments. Finally, a physiologicially based model for the intravenous toxicokinetics of C(+/-)P(+/-)-SOMAN in the guinea pig will be modified and validated on the basis of the results obtained.

Research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to the use of animals in research and was reviewed and approved by the Institute's Animal Care and Use Committee.

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.

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