Five oximes (K-27, K-48, obidoxime, HI-6 and trimedoxime) in comparison with pralidoxime: survival in rats exposed to methyl-paraoxon.
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 micromol methyl-POX ( approximately LD(50)), the other groups (G2-7) received 2 micromol 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 micromol 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 IC(50)) 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).
Petroianu
G A
GA
UAE University, Faculty of Medicine & Health Sciences, Al Ain - United Arab Emirates. georg.petroianu@uaeu.ac.ae
Nurulain
S M
SM
Nagelkerke
N
N
Shafiullah
M
M
Kassa
J
J
Kuca
K
K
D000818:Animals; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D009768:Obidoxime Chloride / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology*; D010261:Paraoxon / Q000031:analogs & derivatives* / Q000633:toxicity; D011220:Pralidoxime Compounds / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014289:Trimedoxime / Q000494:pharmacology*
C513728:4-(aminocarbonyl)-1-(3-(4-((E)-(hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide; D002801:Cholinesterase Reactivators; C520230:K-48 compound; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D009768:Obidoxime Chloride; D014289:Trimedoxime; C022870:asoxime chloride; C028797:pralidoxime; D010261:Paraoxon; C008480:methylparaoxon