Protection by sustained release of physostigmine and procyclidine of soman poisoning in rats.

Abstract

The efficacy of a combinational prophylactic regimen on the lethality, convulsions, and loss of morphological and functional integrities of the brain induced by an organophosphate soman was investigated in rats. The rats were implanted subcutaneously with osmotic minipumps containing the combinational prophylactic regimen composed of physostigmine, a reversible cholinesterase inhibitor, and procyclidine, an N-methyl-D-aspartate antagonist possessing anticholinergic action, for 3 days, and intoxicated subcutaneously with soman (160 microg/kg, 1.3 LD50). The doses of combinational regimen in minipumps were optimized to achieve 30-35% inhibition of blood cholinesterase activity by physostigmine and 50-100 ng/ml of blood concentrations of procyclidine as clinically available doses, respectively. In comparison, 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 125 mg/kg) was administered intraperitoneally 30 min prior to the soman challenge in control groups to reduce mortality of rats without affecting convulsions. Soman induced profound limbic convulsions and 30% mortality, leading to increased blood-brain barrier permeability, neural injuries, learning and memory impairments, and physical incapacitation of survived rats pretreated with HI-6. The combinational regimen, at optimal doses without adverse effects on passive avoidance performances (72 microg/kg/h of physostigmine plus 432 microg/kg/h of procyclidine), exerted full protective effects against lethality, convulsions, blood-brain barrier opening, brain injuries, learning and memory impairments, and physical incapacitation induced by soman. Taken together, it is suggested that the combination of physostigmine and procyclidine, at adequate doses, could be a choice to provide the victims of organophosphate poisoning with chance of intensive care for survival and neuroprotection.

• Authors: Ehn-Kyoung Choi, Dongsun Park, Jung-Min Yon, Gyeung-Haeng Hur, Yeon-Cheol Ha, Jeong-Hwan Che, Jongsun Kim, Sunhee Shin, Ja Young Jang, Seock-Yeon Hwang, Yeon-Hee Seong, Dae Joong Kim, Jong-Choon Kim, Yun-Bae Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 505 Issue 1-3 Pg. 83-91 (Nov 28 2004) ISSN: 0014-2999 [Print] Netherlands
• PMID: 15556140 (Publication Type: Journal Article)

Chemical References

• Cholinesterase Inhibitors
• Delayed-Action Preparations
• Muscarinic Antagonists
• Soman
• Physostigmine
• Procyclidine

Topics

• Animals
• Avoidance Learning (drug effects)
• Blood-Brain Barrier (drug effects, physiology)
• Brain (drug effects, pathology)
• Capillary Permeability (drug effects)
• Cholinesterase Inhibitors (administration & dosage, pharmacology)
• Delayed-Action Preparations
• Dose-Response Relationship, Drug
• Infusion Pumps
• Male
• Memory (drug effects)
• Muscarinic Antagonists (administration & dosage, pharmacology)
• Physostigmine (administration & dosage, pharmacology)
• Procyclidine (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Seizures (chemically induced, physiopathology, prevention & control)
• Soman (poisoning)
• Specific Pathogen-Free Organisms
• Time Factors