Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: survival in rats exposed to the organophosphate paraoxon

Abstract

Oximes are cholinesterase reactivators used in organophosphorus poisoning. Clinical experience with pralidoxime (PRX) and other oximes is disappointing and their routine use has been questioned. In addition it is known that not all oximes are equally effective against all existing organophosphorus compounds. There is a demand for broad-spectrum reactivators with a higher efficacy than PRX. Based on our previous in vitro work the protection conferred by the various new oximes against inhibition by paraoxon as quantified by the IC(50) shift (nM increase in the IC(50) of the inhibitor per microM oxime present) is: 0.3 (PRX), 0.4 (methoxime; MMC-4), 1 (K-33), 1.2 (BI-6), 1.5 (K-48) and 3.7 (K-27). The purpose of the study was to quantify in vivo the extent of oxime-conferred protection, using paraoxon (POX) as a cholinesterase inhibitor and to test whether in vitro efficacy translates to protection from mortality. There were seven groups of six rats in each cycle of the experiment. Group 1 (G1) received 1 micromol POX (approximately LD(75)), the other groups (G2-G7) received 1 micromol POX + of one the six reactivators. The animals were monitored for 48 h and the time of mortality was recorded. The procedure was repeated five times (cycles). All substances were applied i.p. The experiments were repeated using 2, 3, 5 and 10 micromol POX. Mortality data were compared and hazards ratios (relative risks) ranked using the Cox proportional hazards model using 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 POX dose (high/low) was K-27: 0.26 (0.19-0.35); K-48: 0.34 (0.25-0.45); methoxime: 0.38 (0.29-0.50); BI-6: 0.53 (0.41-0.69); PRX: 0.70 (0.54-0.91); K-33: 0.82 (0.63-1.07). It is concluded that K-27 and K-48 are the most promising new oximes. The compounds with the best results in vitro also confer the best protection in vivo. Further testing using methyl- and propyl-organophosphates are needed.

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).…”

“…Though some of them were originally developed for nerve agent poisoning, they showed increased reactivation ability against various types of OPPs. Notably, compound K027 showed an increased reactivation capability (dimethoxy-and diethoxy-OPPs) with decreased toxicity, as compared to commercial compounds both using in vitro and in vivo animal models (Petroianu 2006a-b, Petroianu 2007a. These findings make compound K027 the lead compound for further studies and development.…”

“…Their acute toxicity for mice and rats was found very low among commercially available reactivators (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).…”

Two Step Synthesis of a Non-symmetric Acetylcholinesterase Reactivator

“…A similar approach for reactivator K027 was previously published by our group [9]. This compound is currently under consideration as a very promising AChE reactivator with a broad reactivation potency and relatively low toxicity [10][11][12][13][14][15][16]. However, it was not applicable for our current synthesis of the new reactivator K053 (3) because of different connection chains between both the substituted pyridinium rings in each compound (a trimethylene linker in K027 versus an (E)-but-2-ene in K053).…”

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

“…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.…”