Five oximes (K‐27, K‐48, obidoxime, HI‐6 and trimedoxime) in comparison with pralidoxime: survival in rats exposed to methyl‐paraoxon

Abstract

There is a clear need for broad-spectrum cholinesterase reactivators (active against a multitude of organophosphorus ester enzyme inhibitors) with a higher efficacy than pralidoxime. The purpose of the study was to quantify in vivo the extent of oxime-conferred protection, using methyl-paraoxon [dimethyl p-nitrophenyl phosphate; (methyl-POX)] as a cholinesterase inhibitor. There were seven groups of six rats in each cycle of the experiment. Group 1 (G1) received 2 micromol methyl-POX ( approximately LD(50)), the other groups (G2-7) received 2 micromol methyl-POX + one of the six reactivators. The animals were monitored for 48 h and the time of mortality was recorded. The procedure was repeated six times. All substances were applied i.p. The experiments were repeated using 3 and 5 micromol methyl-POX. Mortality data were compared and hazards ratios (relative risks) ranked using the Cox proportional hazards model with methyl-POX dose and group (reactivator) as time-independent covariables. The relative risk of death estimated by Cox analysis (95% CI) in oxime-treated animals when compared with untreated animals, adjusted for methyl-POX dose (high/low) was K-27, 0.58 (0.42-0.80); K-48, 0.60 (0.43-0.83); trimedoxime, 0.76 (0.55-1.04); pralidoxime, 0.88 (0.65-1.20); obidoxime, 0.93 (0.68-1.26); HI-6, 0.96 (0.71-1.31). Only K-27 and K-48 provided statistically significant protection in rats exposed to methyl-POX. Despite the lower inhibitory potency (higher IC(50)) of methyl-POX compared with POX (ratio 4:1), the ability of oxime reactivators to protect from methyl-POX induced mortality was reduced compared with protection from POX (ethyl-analog).

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.…”

Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

“…These findings were confirmed for e.g. paraoxon (Petroianu 2006a), methylparaoxon (Petroianu 2007a) or dichlorvos (Khan 1988). The pralidoxime was also determined with intermediate acute toxicity among standard five reactivators for mice and rats (Table 2; Musilek 2007a, Musilek 2010).…”

“…The methoxime was suggested to be better AChE reactivator than pralidoxime for rats intoxicated by paraoxon (Petroianu 2006a). For methylparaoxon intoxicated rats, methoxime resulted as better reactivator than pralidoxime or obidoxime, but worse reactivator than trimedoxime (Petroianu 2007a). The asoxime use for in vivo animal model intoxicated by OPP was not found.…”

Reactivation Potency of the Acetylcholinesterase Reactivator Obidoxime Is Limited

“…1). However in the current literature, the data discussing obidoxime antidotal potency are controversial [7][8][9][10][11] . Owing to the above mentioned factors, summarization of the reactivation activities of obidoxime are shown in this article.…”