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

✍ Scribed by G. A. Petroianu; S. M. Nurulain; N. Nagelkerke; M. A. H. Al-Sultan; K. Kuča; J. Kassa

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 266 KB
• Volume: 26
• Category: Article
• ISSN: 0260-437X
• DOI: 10.1002/jat.1143

✦ Synopsis

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 broadspectrum 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 µ µ µ µ µM 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 µ µ µ µ µmol POX (≈ ≈ ≈ ≈ ≈ LD 75 ), the other groups (G2-G7) received 1 µ µ µ µ µmol 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 µ µ µ µ µmol 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