The oxime pro-2-PAM provides minimal protection against the CNS effects of the nerve agents sarin, cyclosarin, and VX in guinea pigs.
This study examined whether pro-2-PAM, a pro-drug dihydropyridine derivative of the oxime 2-pralidoxime (2-PAM) that can penetrate the brain, could prevent or reverse the central toxic effects of three nerve agents; sarin, cyclosarin, and VX. The first experiment tested whether pro-2-PAM could reactivate guinea pig cholinesterase (ChE) in vivo in central and peripheral tissues inhibited by these nerve agents. Pro-2-PAM produced a dose-dependent reactivation of sarin- or VX-inhibited ChE in both peripheral and brain tissues, but with substantially greater reactivation in peripheral tissues compared to brain. Pro-2-PAM produced 9-25% reactivation of cyclosarin-inhibited ChE in blood, heart, and spinal cord, but no reactivation in brain or muscle tissues. In a second experiment, the ability of pro-2-PAM to block or terminate nerve agent-induced electroencephalographic seizure activity was evaluated. Pro-2-PAM was able to block sarin- or VX-induced seizures (16-33%) over a dose range of 24-32 mg/kg, but was ineffective against cyclosarin-induced seizures. Animals that were protected from seizures showed significantly less weight loss and greater behavioral function 24 h after exposure than those animals that were not protected. Additionally, brains were free from neuropathology when pro-2-PAM prevented seizures. In summary, pro-2-PAM provided modest reactivation of sarin- and VX-inhibited ChE in the brain and periphery, which was reflected by a limited ability to block or terminate seizures elicited by these agents. Pro-2-PAM was able to reactivate blood, heart, and spinal cord ChE inhibited by cyclosarin, but was not effective against cyclosarin-induced seizures.
Research and Analytical Toxicology Divisions, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
Tsung-Ming
TM
Shih
John A
JA
Guarisco
Todd M
TM
Myers
Robert K
RK
Kan
John H
JH
McDonough
D000818:Animals; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D009943:Organophosphorus Compounds / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology*; D011355:Prodrugs; D012524:Sarin / Q000633:toxicity*; D012640:Seizures / Q000517:prevention & control
D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D011220:Pralidoxime Compounds; D011355:Prodrugs; D012524:Sarin; C011920:1-methyl-1,6-dihydropyridine-2-carbaldoxime; C009680:VX-agent; C053914:cyclohexyl methylphosphonofluoridate