Abstract
Background: The widespread use of organophosphorus compounds in agriculture and their existence in some military arsenals present continuous threats. Quaternary bis-pyridinium aldoximes are potent, highly polar cholinesterase reactivators and the most intensively studied candidate antidotes against poisoning with organophosphorus compounds. Objective: The in vivo experimental pharmacokinetic properties of K-868, a novel bis-chlorinated, bis-pyridinium mono-aldoxime are detailed and put in context with regard to similar compounds described earlier. Methods: Rats received 30 µmol K-868 i.m. and were sacrificed at various time points following treatment. Blood, cerebrospinal fluid and tear were collected, while the brains, eyes, kidneys, livers, lungs and testes were removed, dissected and homogenized. K-868 concentrations were determined using high performance liquid chromatography with ultraviolet absorption detection. Results: K-868 was detected in the eyes, kidneys, lungs and tear within 5 minutes in maximal serum concentrations attained 15 minutes following administration. Elimination was slow for K-868 which remained detectable at 120 minutes in the blood and the kidneys, and at 60 minutes in the eyes, lungs and tear following its administration. Nevertheless, its distribution was overall poor with areas under the 120-minute concentration curves (AUC120) showing close similarity in the blood and the kidneys, while reaching just approximately 5% of serum AUC120 in the eyes and lungs. Conclusion: K-868 is a potent candidate antidote against organophosphate poisoining with a prolonged presence in the circulation.
Highlights
IntroductionAFLOP therapy (the key elements of which are the muscarinic receptor antagonist atropine – competing with acetylcholine for the receptor –, fluids and oxygen to prevent hypotension and respiratory failure, and pyridinium aldoxime cholinesterase reactivators such as pralidoxime or obidoxime) has become the standard treatment for acute intoxication (Table 1) [5, 8]
Cholinesterase reactivators have the unique ability to cleave the covalent bond formed between the organophosphorus toxicant and the serine hydroxyl group located at the active site of the cholinesterase enzyme eventually restoring acetylcholinesterase activity
Clinical evidence suggests that the importance of studying the pharmacodynamic and pharmacokinetic properties of acetylcholinesterase reactivators has not diminished
Summary
AFLOP therapy (the key elements of which are the muscarinic receptor antagonist atropine – competing with acetylcholine for the receptor –, fluids and oxygen to prevent hypotension and respiratory failure, and pyridinium aldoxime cholinesterase reactivators such as pralidoxime or obidoxime) has become the standard treatment for acute intoxication (Table 1) [5, 8]. Cholinesterase reactivators have the unique ability to cleave the covalent bond formed between the organophosphorus toxicant and the serine hydroxyl group located at the active site of the cholinesterase enzyme eventually restoring acetylcholinesterase activity. Kuca et al synthesized several bispyridinium aldoximes that have reactivation potencies similar to those of pralidoxime and obidoxime but show improved pharmacokinetic properties [13 - 18]. Quaternary bis-pyridinium aldoximes are potent, highly polar cholinesterase reactivators and the most intensively studied candidate antidotes against poisoning with organophosphorus compounds
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