title: Efficacy of eight experimental bispyridinium oximes against paraoxon-induced mortality: comparison with the conventional oximes pralidoxime and obidoxime.
abstract: Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized that show excellent in vitro efficacy in protecting acetylcholinesterase (AChE) from inhibition by a broad variety of organophosphorus compounds (OPCs). However, oximes themselves are also AChE inhibitors, albeit at higher concentrations, which is a major cause of their toxicity and may be a dose-limiting factor in oxime therapy. To assess the efficacy of the experimental K-oximes in vivo, the extent of oxime-conferred protection from mortality induced by paraoxon was quantified. Rats received paraoxon in a dosage of 1, 5, or 10 mumol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD(01). The relative risk of death (RR) over time was estimated by Cox survival analysis for treatment with experimental K-oximes (K-53, K-74, K-75, K-107, K-108, and K-113), with the clinically available oximes pralidoxime (2-PAM) and obidoxime, and with the well-characterized K-oximes K-27 and K-48, comparing results with the no-treatment group. Best protection was conferred by K-27, reducing the RR to 20% of controls (P </= 0.05), which was significantly (P <or= 0.05) better than all other tested oximes. Marked reduction in mortality was also achieved by K-48 and the three new bispyridinium oximes containing two aldoxime groups, but no xylene linker: K-48 (RR = 0.32), K-53 (RR = 0.36), K-74 (RR = 0.42), K-75 (RR = 0.35). This effect was significantly (P <or= 0.05) superior to that of all other oximes, except K-27. The remaining oximes, i.e., obidoxime (RR = 0.64), 2-PAM (RR = 0.78), K-107 (RR = 0.70), K-108 (RR = 0.77), and K-113 (RR = 0.87) reduced paraoxon-induced mortality only poorly, but significantly (P <or= 0.05). Our data show that K-27, K-48, K-53, K-74, and K-75, due to their far superior in vivo efficacy, are the most promising candidates to eventually replace the established oximes 2-PAM and obidoxime. Further studies in other species exposed to a broader spectrum of OPCs are, however, necessary before considering their use in humans.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17 666, Al Ain, United Arab Emirates.
authors.forename: S M
authors.initials: SM
authors.lastname: Nurulain
authors.forename: D E
authors.initials: DE
authors.lastname: Lorke
authors.forename: M Y
authors.initials: MY
authors.lastname: Hasan
authors.forename: M
authors.initials: M
authors.lastname: Shafiullah
authors.forename: K
authors.initials: K
authors.lastname: Kuca
authors.forename: K
authors.initials: K
authors.lastname: Musilek
authors.forename: G A
authors.initials: GA
authors.lastname: Petroianu
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007928:Lethal Dose 50; D008297:Male; D009768:Obidoxime Chloride / Q000633:toxicity*; D010261:Paraoxon / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000737:chemistry / Q000494:pharmacology*; D016016:Proportional Hazards Models; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D011220:Pralidoxime Compounds; D009768:Obidoxime Chloride; D010261:Paraoxon