Prophylactic administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: Assessment using terbufos sulfone

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.