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The oxime pro-2-PAM provides minimal protection against the CNS effects of the nerve agents sarin, cyclosarin, and VX in guinea pigs.
Shih, Tsung-Ming; Guarisco, John A; Myers, Todd M; Kan, Robert K; McDonough, John H.
Afiliación
  • Shih TM; Research and Analytical Toxicology Divisions, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
Toxicol Mech Methods ; 21(1): 53-62, 2011 Jan.
Article en En | MEDLINE | ID: mdl-21117832
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Compuestos Organofosforados / Compuestos Organotiofosforados / Compuestos de Pralidoxima / Sarín / Reactivadores de la Colinesterasa Límite: Animals Idioma: En Revista: Toxicol Mech Methods Asunto de la revista: TOXICOLOGIA Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Compuestos Organofosforados / Compuestos Organotiofosforados / Compuestos de Pralidoxima / Sarín / Reactivadores de la Colinesterasa Límite: Animals Idioma: En Revista: Toxicol Mech Methods Asunto de la revista: TOXICOLOGIA Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos