Prophylaxis against soman inhalation toxicity in guinea pigs by pretreatment alone with human serum butyrylcholinesterase.
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.
Allon
N
N
Israel Institute for Biological Research, Ness-Ziona, Israel.
Raveh
L
L
Gilat
E
E
Cohen
E
E
Grunwald
J
J
Ashani
Y
Y
D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006168:Guinea Pigs; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D011041:Poisoning / Q000517:prevention & control; D011292:Premedication; D012119:Respiration / Q000187:drug effects; D012999:Soman / Q000008:administration & dosage / Q000506:poisoning*
D002800:Cholinesterase Inhibitors; D012999:Soman; D002091:Butyrylcholinesterase