TY - JOUR
T1 - Efficacy of eight experimental bispyridinium oximes against paraoxon-induced mortality
T2 - Comparison with the conventional oximes pralidoxime and obidoxime
AU - Nurulain, S. M.
AU - Lorke, D. E.
AU - Hasan, M. Y.
AU - Shafiullah, M.
AU - Kuča, K.
AU - Musilek, K.
AU - Petroianu, Georg A.
N1 - Funding Information:
Acknowledgments The authors wish to thank Shobha Duncan for her assistance in preparing the manuscript. The study was supported by the Ministry of Defense of the Czech Republic (project number: FVZ0000604).
PY - 2009
Y1 - 2009
N2 - 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 μmol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD01. 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 ≤ 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 ≤ 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 ≤ 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.
AB - 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 μmol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD01. 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 ≤ 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 ≤ 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 ≤ 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.
KW - Aldoxime
KW - Cox analysis
KW - K-oxime
KW - Organophosphate
KW - Paraoxon
KW - Rat
UR - http://www.scopus.com/inward/record.url?scp=70349733145&partnerID=8YFLogxK
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U2 - 10.1007/s12640-009-9048-7
DO - 10.1007/s12640-009-9048-7
M3 - Article
C2 - 19526299
AN - SCOPUS:70349733145
SN - 1029-8428
VL - 16
SP - 60
EP - 67
JO - Neurotoxicity Research
JF - Neurotoxicity Research
IS - 1
ER -