Efficacy of Eight Experimental Bispyridinium Oximes Against Paraoxon-Induced Mortality: Comparison with the Conventional Oximes Pralidoxime and Obidoxime

Abstract

Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized that show excellent in vitro efficacy in protecting acetylcholinesterase (AChE) from inhibition by a broad variety of organophosphorus compounds (OPCs). However, oximes themselves are also AChE inhibitors, albeit at higher concentrations, which is a major cause of their toxicity and may be a dose-limiting factor in oxime therapy. To assess the efficacy of the experimental K-oximes in vivo, the extent of oxime-conferred protection from mortality induced by paraoxon was quantified. Rats received paraoxon in a dosage of 1, 5, or 10 mumol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD(01). The relative risk of death (RR) over time was estimated by Cox survival analysis for treatment with experimental K-oximes (K-53, K-74, K-75, K-107, K-108, and K-113), with the clinically available oximes pralidoxime (2-PAM) and obidoxime, and with the well-characterized K-oximes K-27 and K-48, comparing results with the no-treatment group. Best protection was conferred by K-27, reducing the RR to 20% of controls (P </= 0.05), which was significantly (P <or= 0.05) better than all other tested oximes. Marked reduction in mortality was also achieved by K-48 and the three new bispyridinium oximes containing two aldoxime groups, but no xylene linker: K-48 (RR = 0.32), K-53 (RR = 0.36), K-74 (RR = 0.42), K-75 (RR = 0.35). This effect was significantly (P <or= 0.05) superior to that of all other oximes, except K-27. The remaining oximes, i.e., obidoxime (RR = 0.64), 2-PAM (RR = 0.78), K-107 (RR = 0.70), K-108 (RR = 0.77), and K-113 (RR = 0.87) reduced paraoxon-induced mortality only poorly, but significantly (P <or= 0.05). Our data show that K-27, K-48, K-53, K-74, and K-75, due to their far superior in vivo efficacy, are the most promising candidates to eventually replace the established oximes 2-PAM and obidoxime. Further studies in other species exposed to a broader spectrum of OPCs are, however, necessary before considering their use in humans.

Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and pesticide-inhibited acetylcholinesterase

“…In the case of pesticides, it was able to reactivate AChE inhibited by all tested members of this family. This is in very good agreement with results shown in former studies [24][25][26][27][28][29][30][31][32][33][34][35][36] . Oxime K027 was tested at two different concentrations, which had already been selected earlier in the study of Kuca and Cabal to capture the promising compounds 7,40 .…”

“…Subsequently, they confirmed their in vitro results using in vivo studies. According to this group, oxime K027 seems to be, at present, the most promising candidate to replace obidoxime ( Figure 1) in the treatment of organophosphorus pesticide poisonings [24][25][26][27][28][29][30][31][32][33][34][35][36] . As mentioned above, in the case of nerve-agent reactivation, the obtained results were not so promising.…”

Design, evaluation and structure—Activity relationship studies of the AChE reactivators against organophosphorus pesticides

“…69,70,72,73,75 Whereas the presence of a double bond displayed only a slightly higher toxicity compared with methylene or xylene linkages. 76,101 Concerning the non-oxime part of the molecule, various functional groups may be introduced to increase the reactivation ability, as was found beneficially with the use of 3-or 4-carbamoyl, methylcarbonyl or isoquinolinium (253, 260, 265, 266, 274) moieties. 75,76,[78][79][80] Indeed, from a toxicity point of view, the carbamoyl, carboxyl, and methylcarbonyl moieties (259-260, 265) were found to be very promising candidates.…”

Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

“…On the other hand, the less toxic obidoxime was several times used for animals exposed to OPPs. The in vivo efficacy of obidoxime in rats exposed to paraoxon was found superior to pralidoxime (Nurulain 2009). The older study in parathion poisoned dogs suggested that obidoxime is able to reverse parathion inhibited AChE in blood and some brain areas (Kewitz 1980).…”