title: Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl.
abstract: Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01) 30 min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR = 1). The most efficacious prophylactic agents were K-27 (RR = 0.15) and physostigmine (RR = 0.21), being significantly more efficacious than ranitidine (RR = 0.62) and pyridostigmine (RR = 0.37). Pre-treatment with tacrine (RR = 0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure.
authors.affiliation: Department of Cellular Biology & Pharmacology, Herbert Wertheim College of Medicine, Florida International University, University Park GL 495 D, 11200 SW 8th St, Miami, FL 33199, Florida, USA; Department of Pharmacology & Therapeutics, FMHS, UAE University, Al Ain, United Arab Emirates.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Petroianu
authors.forename: Syed M
authors.initials: SM
authors.lastname: Nurulain
authors.forename: Mohamed Y
authors.initials: MY
authors.lastname: Hasan
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuča
authors.forename: Dietrich E
authors.initials: DE
authors.lastname: Lorke
mesh_terms: D000818:Animals; D001387:Azinphosmethyl / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010091:Oximes / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D016016:Proportional Hazards Models; D011726:Pyridinium Compounds / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000494:pharmacology
chemical_list: C513728:4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide; D002800:Cholinesterase Inhibitors; D010091:Oximes; D011726:Pyridinium Compounds; D001387:Azinphosmethyl; D013619:Tacrine; D011899:Ranitidine; D010830:Physostigmine; D011729:Pyridostigmine Bromide
keywords: Cox analysis; acetylcholine; azinphos-methyl; carbamates; cholinesterase; organophosphate; oximes; prophylaxis; rat