title: Prophylactic administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using terbufos sulfone.
abstract: Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)-approved substance for such pre-treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad-spectrum alternatives, we have assessed in vivo the mortality-reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K-27), when given in equitoxic dosage (25% of LD01 ) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre-treatment. All tested AChE inhibitors reduced terbufos sulfone-induced mortality significantly (p ≤ 0.05) as compared with the non-treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone-induced mortality was achieved, when K-27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly (P ≤ 0.05) superior to the pre-treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K-27) in case of imminent OPC exposure may be a viable option.
authors.affiliation: Department of Cellular Biology & Pharmacology, Florida International University, Miami, Florida, USA; Department of Anatomy, FMHS, UAE University, Al Ain, United Arab Emirates.
authors.forename: Dietrich E
authors.initials: DE
authors.lastname: Lorke
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: Georg A
authors.initials: GA
authors.lastname: Petroianu
mesh_terms: D000208:Acute Disease; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D007928:Lethal Dose 50; D008297:Male; D062025:Organophosphate Poisoning / Q000517:prevention & control*; D010755:Organophosphates / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis
chemical_list: D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D009946:Organothiophosphorus Compounds; C036515:terbufos sulfone
keywords: Cox analysis; carbamates; cholinesterase; organophosphate; oximes; pre-treatment; rat; terbufos sulfone