AbstractThere 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.