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.

Terbufos-sulfone exacerbates cardiac lesions in diabetic rats: a sub-acute toxicity study

“…Terbufos sulfone (TS) was administered i.p. at a dose of 100 nmol per rat (1/20 of LD 50 ) following our previous laboratory studies (13). The animals were treated daily for two weeks.…”

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

“…This is followed by RR = 0.29 for tacrine, RR = 0.37 for pyridostigmine and RR = 0.62 for ranitidine. A comparison of these data with the results of previous studies during which the same AChE inhibitors were tested as prophylactic agents in the same experimental setting, but before exposure to chemically dissimilar OPCs (DFP, ethyl‐paraoxon, methyl‐paraoxon, terbufos sulfone) corroborates the assumption that the prophylactic efficacy varies, when different OPCs are administered (Lorke et al , ; Petroianu et al , ; Tuovinen et al , ). Reductions in RR observed for DFP exposure were, in ascending order: RR = 0.02 for physostigmine, RR = 0.05 for tacrine, RR = 0.18 for K‐27, RR = 0.28 for pyridostigmine and RR = 0.41 for ranitidine pre‐treatment (Lorke et al , ).…”

“…Given before methyl‐paraoxon (Lorke et al , ), only physostigmine (RR = 0.39), K‐27 (RR = 0.40) and tacrine (RR = 0.48) significantly reduced mortality; pyridostigmine and ranitidine had no significant effect. Terbufos sulfone‐induced mortality (Lorke et al , ) was reduced to RR = 0.06 by K‐27, to RR = 0.21 by tacrine, to RR = 0.28 by pyridostigmine, to RR = 0.29 by physostigmine and to RR = 0.33 by ranitidine. In spite of the variations in RR values and rankings observed for different AChE inhibitors, depending on the OPC administered, all these studies have in common that K‐27, physostigmine and tacrine are generally the three most efficacious prophylactic agents.…”

Enzymatic detoxification of organophosphorus pesticides and related toxicants

“…The most promising compound in this matter is the experimental oxime K-27, which is significantly more efficient than other tested cholinesterase inhibitors. 18) In the search of an AChE reversible inhibitor of the central nervous system, Huperzine A, a natural alkaloid, appears to have the greatest potential. However, this alkaloid is toxic at doses required for protection.…”