Five oximes (K-27, K-48, obidoxime, HI-6 and trimedoxime) in comparison with pralidoxime: survival in rats exposed to methyl-paraoxon
Article first published online: 16 FEB 2007
Copyright © 2007 John Wiley & Sons, Ltd.
Journal of Applied Toxicology
Volume 27, Issue 5, pages 453–457, September/October 2007
How to Cite
Petroianu, G. A., Nurulain, S. M., Nagelkerke, N., Shafiullah, M., Kassa, J. and Kuča, K. (2007), Five oximes (K-27, K-48, obidoxime, HI-6 and trimedoxime) in comparison with pralidoxime: survival in rats exposed to methyl-paraoxon. J. Appl. Toxicol., 27: 453–457. doi: 10.1002/jat.1224
- Issue published online: 20 JUL 2007
- Article first published online: 16 FEB 2007
- Manuscript Revised: 18 DEC 2006
- Manuscript Accepted: 18 DEC 2006
- Manuscript Received: 7 OCT 2006
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 µmol methyl-POX (≈ LD50), the other groups (G2-7) received 2 µmol 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 µmol 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 IC50) 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). Copyright © 2007 John Wiley & Sons, Ltd.