Butyrylcholinesterase as a therapeutic drug for protection against percutaneous VX.
The administration of purified human plasma-derived butyrylcholinesterase (HuBuChE) as a pretreatment has been demonstrated to enhance survival and protect against decreased cognitive function after exposure to organophosphorus poisons (OPs). Based on efficacy data obtained with guinea pigs and non-human primates and the lack of behavioral side effects, plasma-derived HuBuChE has been granted investigational new drug status by the US Food and Drug Administration. The recent availability of a recombinant form of HuBuChE (rHuBuChE) from the milk of transgenic goats has now allowed us to determine the pharmacokinetics of that material in guinea pigs and use it as a therapy following exposure to the VX. The rHuBuChE was expressed as a dimer and following intramuscular (i.m.) administration had more a rapid adsorption and clearance profile in guinea pigs than the plasma-derived material. Based on those data, we administered rHuBuChE i.m. 1h after a percutaneous exposure of guinea pigs to either 2xLD(50) or 5xLD(50) of VX. Post-exposure therapy with rHuBuChE provided improved survival at both challenge levels, 90% and 33% respectively versus 20% or 0% respectively for animals that did not receive therapy. These studies showed that BuChE can be efficacious as a therapy against percutaneous exposure to VX.
US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, United States of America. david.lenz@us.army.mil
David E
DE
Lenz
Edward D
ED
Clarkson
Susan M
SM
Schulz
Douglas M
DM
Cerasoli
D000279:Administration, Cutaneous; D000818:Animals; D002091:Butyrylcholinesterase / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis
D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D009946:Organothiophosphorus Compounds; D011994:Recombinant Proteins; C009680:VX-agent