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.

Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review

“…Activation of azinphos‐methyl occurs relatively fast: the conversion of the thion to the oxon form takes less than 10 minutes in an in vitro model using liver slices. In vivo signs and symptoms of cholinergic intoxication are observed 5–10 minutes after oral (Pasquet, Mazuret, Fournel, & Koenig, ) or intraperitoneal (Lorke, Nurulain, Hasan, Kuca, & Petroianu, ; Petroianu et al, ) administration.…”

“…When the OPC azinphos‐methyl is assessed (Petroianu et al, ), all five tested pretreatment compounds again significantly increase survival. K‐27 (RR = 0.15) and physostigmine (RR = 0.21) once more afford best protection, followed by tacrine (RR = 0.29), pyridostigmine (RR = 0.37) and ranitidine (RR = 0.62), the latter being significantly less efficacious than physostigmine, tacrine and K‐27.…”

Oximes as pretreatment before acute exposure to paraoxon

“…It has previously been shown that the experimental oxime K‐27, when given 30 minutes before paraoxon (Petroianu et al, ), methyl‐paraoxon (Lorke et al, ), DFP (Lorke et al, ), terbufos sulfone (Lorke et al, ), azinphos‐methyl (Petroianu et al, ) or dicrotophos (Lorke et al, ) has a significantly better efficacy to reduce organophosphate‐induced mortality than pyridostigmine, the only FDA‐approved compound for prophylaxis in imminent soman exposure (US Food and Drug Administration, ). The present study has therefore been performed to assess the prophylactic efficacy of a group of established (pralidoxime, obidoxime) and experimental (K‐48, K‐53, K‐74, K‐75 and K‐203) oximes, when administered before exposure to the OPC paraoxon.…”

“…Subsequently, gradual dissociation of the reversible AChE inhibitor from the AChE molecule provides a steady supply of fresh uninhibited enzyme (Green, ). It has been shown in various in vitro and in vivo experiments that such a prophylactic application (Lorke et al, ; Lorke et al, ; Lucić Vrdoljak et al, ; Petroianu et al, ; Petroianu, Nurulain, Hasan, Kuča, & Lorke, ; Xia, Wang, & Pei, ) is efficacious (see Dunn et al, ; Lallement et al, ; Lorke & Petroianu, for review). Consequently, the carbamate AChE inhibitor pyridostigmine was handed out to soldiers and civilians to protect from nerve gas attacks during the 1991 Gulf War (Keeler, Hurst, & Dunn, ; McCauley, ; Pope, ).…”

“…In recent years, we have studied several alternative reversible cholinesterase inhibitors (Lorke et al, ; Lorke et al, ; Lorke, Nurulain, Hasan, Kuča, & Petroianu, ; Lorke, Nurulain, Hasan, Kuča, & Petroianu, ; Petroianu et al, ; Petroianu, Hasan, et al, ; Petroianu et al, ; Petroianu et al, ), which are either already in clinical use for other indications (physostigmine, ranitidine, tiapride, tacrine, amiloride, metoclopramide, methylene blue) or which have been developed as potential therapeutics (7‐methoxytacrine; K‐27). We have quantified their AChE inhibitory activity in vitro (Lorke et al, ) and determined their mortality‐reducing efficacy, when administered prophylactically before exposure to a group of chemically diverse OPCs: ethyl‐paraoxon (Petroianu et al, ), methyl‐paraoxon (Lorke et al, ), diisopropylfluorophosphate (DFP) (Lorke et al, ), terbufos (Lorke et al, ), azinphos‐methyl (Petroianu et al, ) and dicrotophos (Lorke et al, ). The common denominator of these experiments was that the most efficacious compounds were physostigmine and K‐27, which showed an efficacy superior to the established compound pyridostigmine (Lorke & Petroianu, ).…”