Eight new bispyridinium oximes in comparison with the conventional oximes pralidoxime and obidoxime: in vivo efficacy to protect from diisopropylfluorophosphate toxicity

Abstract

In search for more efficacious reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus compounds, experimental K-oximes have been synthesized which show good in vitro efficacy. However, AChE inhibition by oximes themselves (as quantified by their intrinsic IC50) is the major cause of oxime toxicity and the dose-limiting factor. To assess K-oxime efficacy in vivo, the extent of protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified by Cox survival analysis and compared with that of the clinically available oximes. Oximes were administered in an equitoxic dosage, i.e. half the LD01. Best protection was conferred by K-27, reducing the relative risk of death (RR) to 16% of control RR (P < or = 0.05), which was statistically significantly better (P < or = 0.05) than all other tested oximes, except obidoxime, K-53 and K-75. The efficacy of obidoxime (RR = 0.19), K-48 (RR = 0.28), K-53 (RR = 0.22), K-74 (RR = 0.38) and K-75 (RR = 0.29) was significantly (P < or = 0.05) better than that of 2-PAM (RR = 0.62) and K-113 (RR = 0.73). No significant protective effect was observed for K-107 and K-108. Our LD50 data show that K-107, K-108 and K-113 (which strongly inhibit AChE in vitro) are in vivo markedly more toxic than all other oximes tested and can therefore only be safely administered at a low dosage which is insufficient to protect from DFP-induced mortality. Dosage calculations based on in vitro IC50 measurements may therefore in future replace in vivo LD50 determinations, thereby reducing the number of animals required.

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.…”

HPLC determination of K027 in the body of pregnant mice

“…The plasma K027 level versus time graphs showed a definite single maximum at 15 min, followed by a constant decline. Lorke et al found that about 0.6% of K027 enters the brain [26][27][28].…”

Reactivation Potency of the Acetylcholinesterase Reactivator Obidoxime Is Limited

“…Obidoxime is the only accessible reactivator available for the civilian sector in the Czech Republic. Its reactivation potency is according to the literature not so good to think that it is a universal antidote [21][22][23][24] . In our in vitro experiment, we confirmed this statement.…”