In vitro and in vivo genotoxicity assessment of HI-6 dimethanesulfonate/oxime

Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01) the prophylactic efficacy of five experimental (K‐48, K‐53, K‐74, K‐75, K‐203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10‐methylacridine) and after the FDA‐approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon‐induced mortality. Best protection was conferred by the experimental oxime K‐48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K‐203), 0.21 (K‐74), 0.24 (K‐75) and 0.26 (pralidoxime), which were significantly more efficacious than 10‐methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine.

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“…For these reasons, i.p. administration is widely used to test the efficacy of oximes (Lucić Vrdoljak et al, ; Nakab et al, ; Žunec et al, ).…”

Section: Discussionmentioning

confidence: 99%

Oximes as pretreatment before acute exposure to paraoxon

Lorke

Nurulain

Al‐Hasan³

et al. 2019

J of Applied Toxicology

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“…47 Only two oximes, 2-PAM and obidoxime, are commercially available antidotes against CWAs. 48 Most of these oximes are sufficiently effective to reactivate sarin-or VX-inhibited AChE, but their potency to reactivate soman-or tabun-inhibited AChE is generally low. 49,50 2-PAM and obidoxime were also reported to be less effective against soman, cyclosarin, and Russian VX.…”

Section: Organophosphorus Nerve Agentsmentioning

confidence: 99%