Effect of pretreatment with human butyrylcholinesterase scavengers on the toxicokinetics and binding of nerve agents in guinea pigs
conference paper
Human butyrylcholinesterase (HuBuChE) is the most promising scavenger for use as a pretreatment drug against nerve agents. Although in animal studies pretreatment with HuBuChE appeared to improve the survival rate following nerve agent challenges and to alleviate post-exposure incapacitation, the information reported so far is insufficient for a thorough and quantitative description of the protective mechanism, which prevents a scientifically sound extrapolation to man. Such an extrapolation is (amongst others) required by regulatory authorities in the registration process of HuBuChE as an antidote against nerve agents.
In order to fill the existing data gaps the following studies are being performed: • influence of pretreatment (i.m.) of guinea pigs and marmosets with HuBuChE on the toxicokinetics of the stereoisomers of C(±)P(±)-soman (i.v. bolus, nose-only exposure), (±)-sarin (i.v. bolus, nose-only exposure) and (±)-VX (i.v. bolus, p.c. exposure); • determination of the rate constants of inhibition of HuBuChE by the stereoisomers of C(±)P(±)-soman, (±)-sarin and (±)-VX; Finally, a physiologically based model for the i.v. toxicokinetics of C(±)P(±)-soman in the guinea pig will be modified and validated on the basis of the results obtained in this study. In this paper the effect of BuChE as scavenger on the toxicokinetics of VX after i.v. administration and soman after nose only exposure will be presented.
In order to fill the existing data gaps the following studies are being performed: • influence of pretreatment (i.m.) of guinea pigs and marmosets with HuBuChE on the toxicokinetics of the stereoisomers of C(±)P(±)-soman (i.v. bolus, nose-only exposure), (±)-sarin (i.v. bolus, nose-only exposure) and (±)-VX (i.v. bolus, p.c. exposure); • determination of the rate constants of inhibition of HuBuChE by the stereoisomers of C(±)P(±)-soman, (±)-sarin and (±)-VX; Finally, a physiologically based model for the i.v. toxicokinetics of C(±)P(±)-soman in the guinea pig will be modified and validated on the basis of the results obtained in this study. In this paper the effect of BuChE as scavenger on the toxicokinetics of VX after i.v. administration and soman after nose only exposure will be presented.
TNO Identifier
526853
Source title
Bioscience 2004 "Medical Chemical Defense Research for the Warfighter and Homeland Defense", US Army Medical Defense Bioscience Review, 18-21 May 2004
Collation
10 p.
Pages
Chapter 24
Files
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