Efficacy of eight experimental bispyridinium oximes against paraoxon-induced mortality: comparison with the conventional oximes pralidoxime and obidoxime.
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
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