Efficacy of two new asymmetric bispyridinium oximes (K-27 and K-48) in rats exposed to diisopropylfluorophosphate: comparison with pralidoxime, obidoxime, trimedoxime, methoxime, and HI-6

Abstract

Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) propane dibromide] and K-48 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], show good in vitro efficacy in protecting acetylcholinesterase from inhibition by different organophosphorus compounds (OPCs), including nerve agents. To assess their efficacy in vivo, the extent of oxime-conferred protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified and compared with that of five established oximes. Materials and Methods. Rats received DFP intraperitoneally in a dosage of 6, 8, or 10 μmol/rat and immediately thereafter intraperitoneal injections of K-27, K-48, pralidoxime, obidoxime, trimedoxime, methoxime, or HI-6. The relative risk (RR) of death over time (48 h) was estimated by Cox survival analysis, comparing results with the no-treatment group. Results. Best protection was observed when K-27 was used, reducing the RR of death to 19% of control RR (p ≤ 0.005), whereas obidoxime (RR = 26%, p ≤ 0.01), K-48 (RR = 29%, p ≤ 0.005) and methoxime (RR = 26%, p ≤ 0.005) were comparable. The RR of death was reduced only to about 35% of control by HI-6, to 45% by trimedoxime, and to 59% by 2-PAM (p ≤ 0.005). Whereas the differences between the best oximes (K-27, obidoxime, methoxime, and K-48) were not statistically significant; these four oximes were significantly more effective than 2-PAM (p ≤ 0.05). The efficacy of K-27 was also significantly higher than that of HI-6, trimedoxime, and 2-PAM (p ≤ 0.05). Conclusion. Our data provide further evidence that K-27 is a very promising candidate for the treatment of intoxication with a broad spectrum of OPCs.

Keywords::

• Cox analysis
• DFP
• rat
• k-oxime
• organophosphate
• oxime

Acknowledgements

The authors thank Shobha Duncan for assistance in preparing the manuscript. The study was supported by the Ministry of Defense of the Czech Republic (project number: FVZ0000604).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.