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

Georg A. Petroianu, S. M. Nurulain, N. Nagelkerke, M. Shafiullah, J. Kassa, K. Kuča

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

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 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).

Original languageEnglish
Pages (from-to)453-457
Number of pages5
JournalJournal of Applied Toxicology
Volume27
Issue number5
DOIs
Publication statusPublished - Sep 2007
Externally publishedYes

Keywords

  • Cholinesterase
  • Methyl-paraoxon
  • Organophosphate
  • Oxime

ASJC Scopus subject areas

  • Toxicology

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