Abstract
AbstractMono- and bis-pyridinium quaternary aldoximes (K-oximes) have long been employed as cholinesterase reactivator components of antidotes against lethal cholinesterase-inhibiting organophosphorous chemicals. Their positive charge poses difficulties in their chromatographic analysis, resulting in the publication of different approaches for each K-oxime. A multiplexed method is presented for the rapid quantitation of 10 K-oximes in blood with its utility demonstrated in vivo. Liquid chromatography with absorbance detection was employed. Reversed-phase separation was achieved on a highly nonpolar stationary phase. Method validation was based on the respective guideline of the European Medicines Agency. Times to peak concentrations and 120-min areas under the time–concentration curves were determined in rats following intraperitoneal administration. Adequate retention and separation of K-oximes with acceptable peak shapes in short isocratic runs was achieved by adjusting ionic strength, organic content and the concentration of the ion-pairing agent of the mobile phase. Chromatographic properties were governed by optimizing the concentration of dissolved ions. Accurate adjustment of the organic content was indispensable for avoiding peak drifting and splitting. Dose-adjusted exposure to K-347 and K-868 was exceptionally low, while exposure to K-48 was the highest. The method is suitable for screening systemic exposure to various K-oximes and can be extended.
Highlights
Organophosphate pesticides and organophosphonate chemical warfare agents, belonging to the class of nerve agents, are irreversible inhibitors of acetylcholinesterases on account that the amount of acetylcholine increases dramatically at nerve endings, leading to severe clinical symptoms or even death
Acetylcholinesterases can be reactivated for a limited time, depending on the nerve agent used, before the toxicant is covalently bound and a subsequent and irreversible structural alteration, called aging, of the product takes place
As part of the investigation of the pharmacokinetics of several novel K-oximes, our aim is to present a high-throughput, cost-efficient, multiplexed approach relying on high performance liquid chromatography (HPLC) and ultraviolet (UV) detection for the quantitation of an extendable set of analytes in serum, and to demonstrate its utility in pharmacokinetic experiments
Summary
Organophosphate pesticides and organophosphonate chemical warfare agents, belonging to the class of nerve agents, are irreversible inhibitors of acetylcholinesterases on account that the amount of acetylcholine increases dramatically at nerve endings, leading to severe clinical symptoms or even death. The most accepted combination treatment protocols of organophosphate and organophosphonate intoxication employ atropine to protect acetylcholine receptors against the overwhelming quantities of acetylcholine, diazepam or midazolam to prevent or decrease the severity of seizures, and an oxime reactivator [currently pralidoxime, trimedoxime, obidoxime or asoxime (HI-6)] to alleviate acetylcholinesterase blockade [3]. The effectiveness of current treatment protocols is unpredictable due to the weak effect of atropine on the central nervous system and the poor pharmacokinetic properties of the available acetylcholinesterase reactivators. The antidote could be a single active agent, a precursor undergoing transformation and giving rise to the effective substance in the central nervous system, or a mixture of molecules
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