Abstract
Aims: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome. Methods: Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure. Results: Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens. Conclusions: Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.
Highlights
Poisonings with organophosphorus compounds (OPCs) are amongst the most frequent intoxications worldwide, a fact that is related to their extensive use for diverse purposes and their easy availability
Survival of the experimental animals depended both upon the substance used for pretreatment and upon the paraoxon dosage (Table 1)
Only 13% of rats pretreated with K-27 before the same paraoxon exposure died after this time period (Table 1, first column)
Summary
Poisonings with organophosphorus compounds (OPCs) are amongst the most frequent intoxications worldwide, a fact that is related to their extensive use for diverse purposes and their easy availability (see [1] for review). Whereas many of these compounds (hydrolic fluids, lubricants, or plasticisers) do not inhibit cholinesterases and are of little acute toxicological concern, insecticides and acaricides are highly toxic. There are numerous examples of OPCs being misused in criminal poisonings, terrorist attacks, and chemical warfare [4,5]. Reports of suspected and confirmed gas attacks in the Syrian Civil War [12,13,14] and allegations that the terrorist group ISIS may have stolen and employed sarin in Libya [15] document the ongoing serious threat to civilians and to rescue personnel
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