Prophylaxis against Soman Inhalation Toxicity in Guinea Pigs by Pretreatment Alone with Human Serum Butyrylcholinesterase

Abstract

Human butyrylcholinesterase (HuBChE) has previously been shown to protect mice, rats, and monkeys against multiple lethal toxic doses of organophosphorus (OP) anticholinesterases that were challenged by i.v. bolus injections. This study examines the concept of using a cholinesterase scavenger as a prophylactic measure against inhalation toxicity, which is the more realistic simulation of exposure to volatile OPs. HuBChE-treated awake guinea pigs were exposed to controlled concentration of soman vapors ranging from 417 to 430 micrograms/liter, for 45 to 70 s. The correlation between the inhibition of circulating HuBChE and the dose of soman administered by sequential i.v. injections and by respiratory exposure indicated that the fraction of the inhaled dose of soman that reached the blood was 0.29. HuBChE to soman molar ratio of 0.11 was sufficient to prevent the manifestation of toxic signs in guinea pigs following exposure to 2.17x the inhaled LD50 dose of soman (ILD50, 101 micrograms/kg). A slight increase in HuBChE:soman ratio (0.15) produced sign-free animals after two sequential respiratory exposures with a cumulative dose of 4.5x ILD50. Protection was exceptionally high and far superior to the currently used traditional approach that consisted of pretreatment with pyridostigmine and postexposure combined administration of atropine, benactyzine, and an oxime reactivator. Quantitative analysis of the results suggests that in vivo sequestration of soman, and presumably other OPs, by exogenously administered HuBChE, is independent of the species used or the route of challenge entry. This assuring conclusion significantly expands the database of the bioscavenger strategy that now offers a dependable extrapolation from animals to human.

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

“…Indeed, doses of 3-60 mg (36-720 nmol)/kg of Hu BChE administered into guinea pigs by i.m. injection displayed a pharmacokinetic profile similar to that observed previously in rats and mice [14,20], guinea pigs [18,21], and rhesus monkeys [22,23]. The prolonged circulatory stability of the enzyme observed in guinea pigs (MRT = 78-110 h) is consistent with that observed in mice (MRT = 48 h) and monkeys (MRT = 72-74 h) [24].…”

Adenovirus-Transduced Human Butyrylcholinesterase in Mouse Blood Functions as a Bioscavenger of Chemical Warfare Nerve Agents

“…Among these, plasma-derived human butyrylcholinesterase (Hu BChE; EC 3.8.1.1; accession no. M16541) is the most viable candidate for human use (Ashani et al, 1991;Raveh et al, 1993;Raveh et al, 1997;Allon et al, 1998;Doctor and Saxena, 2005;Lenz et al, 2005). Hu BChE is a stoichiometric scavenger in that 1 mol of the enzyme binds and inactivates 1 mol of OP nerve agent Lenz et al, 2005).…”

Development of a Guinea Pig Lung Deposition Model

“…Guinea pigs have been used as a surrogate for humans in a number of inhalation toxicology studies by exposing the animals to airborne viruses, biological agents, and other chemicals (Allon et al, 1998;Botham et al, 1988;Chen et al, 1992;Conner et al, 1988;Fryer et al, 1990;and many others). Findings from these studies can be extrapolated to humans based on a particular dose-metric of interest to determine potential health effects in humans.…”