Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl

J Appl Toxicol. 2015 May;35(5):493-9. doi: 10.1002/jat.3052. Epub 2014 Sep 3.

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.

Keywords: Cox analysis; acetylcholine; azinphos-methyl; carbamates; cholinesterase; organophosphate; oximes; prophylaxis; rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azinphosmethyl / toxicity*
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Male
  • Oximes / pharmacology
  • Physostigmine / pharmacology
  • Proportional Hazards Models
  • Pyridinium Compounds / pharmacology
  • Pyridostigmine Bromide / pharmacology
  • Ranitidine / pharmacology
  • Rats
  • Rats, Wistar
  • Tacrine / pharmacology

Substances

  • 4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide
  • Cholinesterase Inhibitors
  • Oximes
  • Pyridinium Compounds
  • Azinphosmethyl
  • Tacrine
  • Ranitidine
  • Physostigmine
  • Pyridostigmine Bromide