title: In vivo evaluation of cholinesterase activity, oxidative stress markers, cyto- and genotoxicity of K048 oxime–a promising antidote against organophosphate poisoning.
abstract: K048 is a member of K-oximes, a new oxime class that has recently been confirmed effective against poisoning by the nerve agent tabun and several pesticides. The toxicity profile of the K048 oxime has not been fully characterized and its optimal therapeutic dose has not yet been established. Earlier studies report excellent results with K048 in reactivating tabun-phosphorylated AChE and in the therapy of tabun-poisoned mice. It possesses a low acute toxicity and exerts an acceptable toxicity profile on isolated human peripheral blood lymphocytes in vitro. Intraperitoneal administration of K048 in rats resulted in an LD50 of 238.3 mg/kg. In this in vivo study, we investigated cholinesterase (ChE) activity and oxidative stress marker levels (lipid peroxidation and superoxide dismutase activity) in the plasma of exposed rats after administering the compound at 25% of its LD50. Lymphocyte viability was evaluated using an acridine orange/ethidium bromide in situ fluorescent assay. The levels of primary DNA damage in rat white blood cells were measured using the alkaline comet assay. The compound applied at 25% of its LD50 did not significantly affect ChE activity and lipid peroxidation and did not cause significant changes in the SOD activity in plasma. The cytotoxicity profile of K048 in the tested dose was also acceptable, and it did not possess significant DNA-damaging potential. The obtained results are promising for further evaluations of the K048 oxime, which should include tests on a broader concentration range and longer incubation times.
authors.forename: Suzana
authors.initials: S
authors.lastname: Zunec
authors.forename: Nevenka
authors.initials: N
authors.lastname: Kopjar
authors.forename: Davor
authors.initials: D
authors.lastname: Zeljezić
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Ana
authors.initials: A
authors.lastname: Lucić Vrdoljak
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood*; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D007928:Lethal Dose 50; D015227:Lipid Peroxidation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000473:pathology; D010755:Organophosphates / Q000633:toxicity; D018384:Oxidative Stress; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000097:blood; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D023382:Toxicity Tests, Acute
chemical_list: C488676:1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane; D000931:Antidotes; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D017392:Thiobarbituric Acid Reactive Substances; D013482:Superoxide Dismutase; D000110:Acetylcholinesterase; C009374:tabun