Two metabolites, isolated from the urine of rats given the cholinesterase reactivator HI-6 intravenously, still contained quaternary nitrogen atoms and therefore could not be extracted from aqueous solutions by organic solvents. Both metabolites were isolated by preparative high performance liquid chromatography and were identified using mass spectrometry, gas chromatography, infrared spectrometry, ultraviolet spectrometry and proton nuclear magnetic resonance spectrometry. The structures were confirmed by in-vitro preparation of the compounds. both metabolites contained 2-pyridone moieties. One had an intact pyridinium-aldoxime moiety, and therefore could still be therapeutically active. The excretion of unchanged HI-6 together with the two identified metabolites does not provide for a 100% mass balance, indicating that in the rat, other, as yet unidentified, metabolites must be formed.
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Drug Chem Toxicol
January 2025
Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina.
The aim of this study was to determine the antidotal potential of the chlorinated oxime K870 compared to obidoxime, as a monotherapy and in combination with atropine, in paraoxon (POX)-poisoned rats. The treatment doses of oximes were chosen as 20% of their LD values. The protective ratio (PR) of oxime K870 with atropine was significantly higher than that of obidoxime with atropine (68.
View Article and Find Full Text PDFChem Biol Interact
February 2025
Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, Hradec Kralove, Czech Republic. Electronic address:
The current pharmacological pretreatment and medical treatment of nerve agent poisoning is an insufficiently addressed medical task. The prophylactic efficacy of a novel compound acting dually as an acetylcholinesterase inhibitor and NMDA receptor antagonist (K1959) and the therapeutic efficacy of a novel NMDA receptor antagonist (K2060) were evaluated in the NMRI mice model of nerve agent poisoning by tabun, soman and sarin. Their added value to the standard antidotal treatment (a combination of oxime reactivator and atropine) was also analyzed.
View Article and Find Full Text PDFJ Chromatogr B Analyt Technol Biomed Life Sci
January 2025
United States Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010, USA. Electronic address:
Chemical warfare nerve agents (CWNAs) are potent and irreversible inhibitors of acetylcholinesterase (AChE). Oxime reactivators are an important part of the standard treatment for CWNA exposure as they can reactivate inhibited AChE. Evaluating the oxime candidates of interest in biological samples requires analytical detection methods and oxime reactivators as a class of compounds have historically been notoriously difficult to isolate, detect and analyze in an analytical laboratory, and there are currently no sensitive or robust analytical detection methods in the literature.
View Article and Find Full Text PDFACS Med Chem Lett
December 2024
University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
Organophosphorus compounds are highly toxic irreversible inhibitors of cholinesterases, causing the disruption of cholinergic functions. Treatment of poisoning includes causal antidotes (oximes) used as reactivators of inhibited cholinesterases, such as pralidoxime. In this work, new halogenated oxime reactivators derived from pralidoxime were developed.
View Article and Find Full Text PDFAntibiotics (Basel)
October 2024
Infectious Diseases Unit, Pescara General Hospital, 65100 Pescara, Italy.
Multidrug-resistant (CRAB) infections are a serious problem in critical care. This study aims to develop an early prognostic score for immune paralysis, using practical and cost-effective parameters, to predict ICU mortality in patients with CRAB infections being treated with Cefiderocol. We carried out an observational pilot study on consecutive patients hospitalized in the ICU with ensuing septic infections treated with Cefiderocol monotherapy or Cefiderocol including combinations.
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