Protection by sustained release of physostigmine and procyclidine of soman poisoning in rats.
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.
Choi
Ehn-Kyoung
EK
College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, San 48, Gaeshin-dong, Cheongju 361-763, Korea.
Park
Dongsun
D
Yon
Jung-Min
JM
Hur
Gyeung-Haeng
GH
Ha
Yeon-Cheol
YC
Che
Jeong-Hwan
JH
Kim
Jongsun
J
Shin
Sunhee
S
Jang
Ja Young
JY
Hwang
Seock-Yeon
SY
Seong
Yeon-Hee
YH
Kim
Dae Joong
DJ
Kim
Jong-Choon
JC
Kim
Yun-Bae
YB
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D007260:Infusion Pumps; D008297:Male; D008568:Memory / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010830:Physostigmine / Q000008:administration & dosage / Q000494:pharmacology*; D011352:Procyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D012999:Soman / Q000506:poisoning*; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists; D012999:Soman; D010830:Physostigmine; D011352:Procyclidine