The stoichiometry of protection against soman and VX toxicity in monkeys pretreated with human butyrylcholinesterase.
Bioscavengers of organophophates (OP) have been examined as potential substitutes for the currently approved drug treatment against OP toxicity. The present work was designed to assess the ability of butyrylcholinesterase, purified from human serum (HuBChE), to prevent the toxicity induced by soman and VX in rhesus monkeys. The consistency of the data across species was then evaluated as the basis for the extrapolation of the data to humans. The average mean residence time of the enzyme in the circulation of monkeys following an intravenous loading was 34 hr. High bioavailability of HuBChE in blood (>80%) was demonstrated after intramuscular injection. A molar ratio of HuBChE:OP approximately 1.2 protected against an i.v. bolus injection of 2.1 x LD50 VX, while a ratio of 0.62 was sufficient to protect monkeys against an i.v. dose of 3.3 x LD50 of soman, with no additional postexposure therapy. A remarkable protection was also seen against soman-induced behavioral deficits detected in the performance of a spatial discrimination task. The consistency of the results across several species offers a reliable prediction of both the stoichiometry of the scavenging and the extent of prophylaxis with HuBChE against nerve agent toxicity in humans.
Raveh
L
L
Israel Institute for Biological Research, Ness-Ziona.
Grauer
E
E
Grunwald
J
J
Cohen
E
E
Ashani
Y
Y
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000378:metabolism / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008253:Macaca mulatta; D008954:Models, Biological; D009946:Organothiophosphorus Compounds / Q000378:metabolism / Q000633:toxicity*; D011041:Poisoning / Q000517:prevention & control; D011897:Random Allocation; D012999:Soman / Q000378:metabolism / Q000633:toxicity*; D013037:Spatial Behavior / Q000187:drug effects; D013223:Statistics as Topic
D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D012999:Soman; C009680:VX-agent