The oxime pro-2-PAM provides minimal protection against the CNS effects of the nerve agents sarin, cyclosarin, and VX in guinea pigs.

Abstract

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.

• Authors: Tsung-Ming Shih, John A Guarisco, Todd M Myers, Robert K Kan, John H McDonough
• Journal: Toxicology mechanisms and methods (Toxicol Mech Methods) Vol. 21 Issue 1 Pg. 53-62 (Jan 2011) ISSN: 1537-6524 [Electronic] England
• PMID: 21117832 (Publication Type: Journal Article)

Chemical References

• Cholinesterase Reactivators
• Organophosphorus Compounds
• Organothiophosphorus Compounds
• Pralidoxime Compounds
• Prodrugs
• 1-methyl-1,6-dihydropyridine-2-carbaldoxime
• VX
• Sarin
• cyclohexyl methylphosphonofluoridate

Topics

• Animals
• Cholinesterase Reactivators (pharmacology)
• Guinea Pigs
• Male
• Organophosphorus Compounds (toxicity)
• Organothiophosphorus Compounds (toxicity)
• Pralidoxime Compounds (pharmacology)
• Prodrugs
• Sarin (toxicity)
• Seizures (prevention & control)