title: Effects of combinational prophylactics composed of physostigmine and procyclidine on soman-induced lethality, seizures and brain injuries.
abstract: The antidotal, anticonvulsant and neuroprotective effects of physostigmine (PhS) and procyclidine (PC), the combinational prophylactics for organophosphate poisoning, were evaluated. For the investigation of dose-response relationship in rats and guinea pigs, various doses (0-6 mg/kg) of PC in combination with a fixed dose (0.1 mg/kg) of PhS were pretreated subcutaneously 30 min prior to subcutaneous poisoning with soman. Procyclidine in combination with PhS exhibited remarkable synergistic effects in a dose-dependent manner, leading to 1.92-5.07 folds of protection ratio in rats and 3.00-4.70 folds in guinea pigs. On the other hand, a low effect (1.65 fold) was achieved with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) treated immediately after soman poisoning, compared with a marked protection (5.50 fold) with atropine (17.4 mg/kg) plus HI-6 (125 mg/kg) in unpretreated rats. Noteworthy, the combinational prophylactics greatly potentiated the effect of atropine plus 2-pralidoxime to 6.13 or 12.27 folds and that of atropine plus HI-6 to 12.00 or 21.50 folds with 1.0 or 3.0 mg/kg of PC, respectively. A high dose (100 μg/kg, 1.3×LD(50)) of soman induced severe epileptiform seizures in rats pretreated with HI-6 (125 mg/kg), resulting in brain injuries in discrete brain regions under histopathological examination in 24 h. Interestingly, such seizures and excitotoxic brain injuries were fully prevented by pretreatment with PhS (0.1 mg/kg) and PC (1 mg/kg). Taken together, it is proposed that the prophylactics composed of PhS and PC could be a promising regimen for the prevention of lethality, seizures and brain injuries induced by soman poisoning.
authors.affiliation: Biomedical Assessment Laboratory (GSDC-2-4), Agency for Defense Development, Yuseong, P.O. Box 35-1, Taejon 305-600, South Korea.
authors.forename: Yun-Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Ki-Cheol
authors.initials: KC
authors.lastname: Cheon
authors.forename: Gyeung-Haeng
authors.initials: GH
authors.lastname: Hur
authors.forename: Taek-San
authors.initials: TS
authors.lastname: Phi
authors.forename: Seung-Ju
authors.initials: SJ
authors.lastname: Choi
authors.forename: Deasik
authors.initials: D
authors.lastname: Hong
authors.forename: Jong-Koo
authors.initials: JK
authors.lastname: Kang