Poisoning with organophosphorus compounds (OPCs) represents an ongoing threat to civilians and rescue personal. We have previously shown that oximes, when administered prophylactically before exposure to the OPC paraoxon, are able to protect from its toxic effects. In the present study, we have assessed to what degree experimental (K-27; K-48; K-53; K-74; K-75) or established oximes (pralidoxime, obidoxime), when given as pretreatment at an equitoxic dosage of 25% of LD01, are able to reduce mortality induced by the OPC azinphos-methyl. Their efficacy was compared with that of pyridostigmine, the only FDA-approved substance for such prophylaxis. Efficacy was quantified in rats by Cox analysis, calculating the relative risk of death (RR), with RR=1 for the reference group given only azinphos-methyl, but no prophylaxis. All tested compounds significantly (p ≤ 0.05) reduced azinphos-methyl-induced mortality. In addition, the efficacy of all tested experimental and established oximes except K-53 was significantly superior to the FDA-approved compound pyridostigmine. Best protection was observed for the oximes K-48 (RR = 0.20), K-27 (RR = 0.23), and obidoxime (RR = 0.21), which were significantly more efficacious than pralidoxime and pyridostigmine. The second-best group of prophylactic compounds consisted of K-74 (RR = 0.26), K-75 (RR = 0.35) and pralidoxime (RR = 0.37), which were significantly more efficacious than pyridostigmine. Pretreatment with K-53 (RR = 0.37) and pyridostigmine (RR = 0.52) was the least efficacious. Our present data, together with previous results on other OPCs, indicate that the experimental oximes K-27 and K-48 are very promising pretreatment compounds. When penetration into the brain is undesirable, obidoxime is the most efficacious prophylactic agent already approved for clinical use.

• Klíčová slova
• Cox analysis, acetylcholine, azinphos-methyl, carbamates, cholinesterase, obidoxime, organophosphate, pesticide, pralidoxime, prophylaxis, rat,
• MeSH
• analýza přežití MeSH
• azinfos-methyl chemie   toxicita   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• krysa rodu Rattus MeSH
• molekulová hmotnost MeSH
• organofosforové sloučeniny chemie   toxicita   MeSH
• oximy farmakologie   MeSH
• pesticidy chemie   toxicita   MeSH
• potkani Wistar MeSH
• proporcionální rizikové modely MeSH
• riziko MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• azinfos-methyl MeSH
• cholinesterasové inhibitory MeSH
• organofosforové sloučeniny MeSH
• oximy MeSH
• pesticidy MeSH

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.

• Klíčová slova
• carbamates, cholinesterase, cox analysis, organophosphate, oximes, paraoxon, pretreatment, prophylaxis, rat,
• MeSH
• analýza přežití MeSH
• cholinesterasové inhibitory aplikace a dávkování   toxicita   MeSH
• fysostigmin aplikace a dávkování   chemie   MeSH
• krysa rodu Rattus MeSH
• organofosfáty toxicita   MeSH
• oximy aplikace a dávkování   chemie   MeSH
• paraoxon chemie   toxicita   MeSH
• postexpoziční profylaxe MeSH
• potkani Wistar MeSH
• preexpoziční profylaxe MeSH
• proporcionální rizikové modely MeSH
• pyridostigmin-bromid aplikace a dávkování   chemie   MeSH
• ranitidin chemie   farmakologie   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• takrin aplikace a dávkování   chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• fysostigmin MeSH
• organofosfáty MeSH
• oximy MeSH
• paraoxon MeSH
• pyridostigmin-bromid MeSH
• ranitidin MeSH
• reaktivátory cholinesterasy MeSH
• takrin MeSH