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Kamil Kuca - One of the best experts on this subject based on the ideXlab platform.
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A fieldable, high-throughput, cost-efficient high performance liquid chromatography-ultraviolet absorption detection (HPLC-UV) method for the quantitation of bispyridinium quaternary aldoxime Cholinesterase Reactivators in blood
Acta Chromatographica, 2020Co-Authors: Gellért Karvaly, Kamil Kuca, Kornélia Tekes, Zoltán Szimrók, József FŰrÉsz, Huba KalászAbstract:Abstract Mono- 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.
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SAR study to find optimal Cholinesterase Reactivator against organophosphorous nerve agents and pesticides
Archives of Toxicology, 2016Co-Authors: Lukas Gorecki, Jan Korabecny, Kamil Musilek, David Malinak, Eugenie Nepovimova, Rafael Dolezal, Ondrej Soukup, Kamil KucaAbstract:Irreversible inhibition of acetylCholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylCholinesterase Reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel Reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure–activity relationships and biological activities of recently proposed acetylCholinesterase Reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.
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Modulation of Tularemia Disease Progress by the Bisquaternary Pyridinium Oxime HI-6
University of Veterinary and Pharmaceutical Sciences Brno, 2010Co-Authors: Miroslav Pohanka, Oto Pavliš, Jiří Pikula, František Treml, Kamil KucaAbstract:Cholinesterase Reactivator HI-6 is a drug commonly used to treat individuals exposed to nerve agents. Recent experiments proved HI-6 impact on parasympathetic response and impact on the nervus vagus associated cholinergic anti-inflammatory pathway is hypothesized here. The modulation effect of HI-6 was studied on BALB/c mice infected with Francisella tularensis, the bacteria causing tularemia. Cultivation test in vitro confirmed weak bacteriostatic effects of HI-6. Results in experiments revealed intriguing effect differences resulting from HI-6 administration to mice. While the HI-6 dose of 7 mg per animal (pro toto) had no significant effects on infection progress, lower dose of 8 μg of HI-6 pro toto reduced mice mortality caused by tularemia infection compared to control group of mice infected only with F. tularensis (survival curves were compared by the logrank test, chi square = 4.335, df = 1, P = 0.0373). The effect observed in mice exceeded the effect provided in vitro on bacterial cultures. Though the exact molecular mechanism of HI-6 modulation during infection should be investigated, HI-6 is seems to be suitable as immunomodulans
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amperometric biosensor for evaluation of competitive Cholinesterase inhibition by the Reactivator hi 6
Analytical Letters, 2007Co-Authors: Miroslav Pohanka, Daniel Jun, Kamil KucaAbstract:Abstract Amperometric biosensors containing enzymes butyrylCholinesterase or acetylCholinesterase were prepared. The biosensors were employed for studying of Cholinesterase Reactivator: HI‐6. Competitions between HI‐6 and acetylthiocholine as enzyme substrate were used for determination of IC50 value. Biosensors with butyrylCholinesterase from human serum determined IC50 as (1.00±0.02)×10−6 M; the biosensor with acetylCholinesterase from human erythrocytes performance provided IC50 (3.31±0.13)×10−6 M, the one with human recombinant acetylCholinesterase (2.00±0.06)×10−6 M and finally biosensor with acetylCholinesterase from electric eel (6.17±0.17)×10−6 M when 5 mM acetylthiocholine as substrate was used. We are encouraged to consider presented biosensors as a very useful for evaluation of newly prepared Cholinesterase Reactivators.
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Measurement of K-27, an oxime-type Cholinesterase Reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples.
Journal of chromatography. A, 2007Co-Authors: Melinda Gyenge, Kamil Kuca, Huba Kalász, George A Petroianu, Rudolf Laufer, Kornélia TekesAbstract:K-27 is a bisquaternary asymmetric pyridinium aldoxime-type Cholinesterase Reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 degrees C at E(ox) 0.65 V. The calibration curve was linear through the range of 10-250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 microL of cerebrospinal fluid. The method--with slight modification in the composition of the mobile phase--can be used to measure a wide range of other related pyridinium aldoxime-type Cholinesterase Reactivators.
Huba Kalász - One of the best experts on this subject based on the ideXlab platform.
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A fieldable, high-throughput, cost-efficient high performance liquid chromatography-ultraviolet absorption detection (HPLC-UV) method for the quantitation of bispyridinium quaternary aldoxime Cholinesterase Reactivators in blood
Acta Chromatographica, 2020Co-Authors: Gellért Karvaly, Kamil Kuca, Kornélia Tekes, Zoltán Szimrók, József FŰrÉsz, Huba KalászAbstract:Abstract Mono- 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.
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Measurement of K-27, an oxime-type Cholinesterase Reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples.
Journal of chromatography. A, 2007Co-Authors: Melinda Gyenge, Kamil Kuca, Huba Kalász, George A Petroianu, Rudolf Laufer, Kornélia TekesAbstract:K-27 is a bisquaternary asymmetric pyridinium aldoxime-type Cholinesterase Reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 degrees C at E(ox) 0.65 V. The calibration curve was linear through the range of 10-250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 microL of cerebrospinal fluid. The method--with slight modification in the composition of the mobile phase--can be used to measure a wide range of other related pyridinium aldoxime-type Cholinesterase Reactivators.
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Measurement of K-27, an oxime-type Cholinesterase Reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples
Journal of Chromatography A, 2007Co-Authors: Melinda Gyenge, Kamil Kuca, Huba Kalász, George A Petroianu, Rudolf Laufer, Kornélia TekesAbstract:Abstract K-27 is a bisquaternary asymmetric pyridinium aldoxime-type Cholinesterase Reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 °C at E ox 0.65 V. The calibration curve was linear through the range of 10–250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 μL of cerebrospinal fluid. The method – with slight modification in the composition of the mobile phase – can be used to measure a wide range of other related pyridinium aldoxime-type Cholinesterase Reactivators.
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high performance liquid chromatographic determination of the plasma concentration of k 27 a novel oxime type Cholinesterase Reactivator
Journal of Chromatography A, 2006Co-Authors: Kornélia Tekes, Kamil Kuca, Huba Kalász, Mohamed Y Hasan, R Sheen, Georg Petroianu, K LudanyiAbstract:Abstract A simple and reliable HPLC method for the determination of the plasma level of K-27, an oxime type antidote of use in organophosphorus poisoning is presented. Separation was carried out by HPLC using an octyl silica stationary phase and a mobile phase consisting of 93% phosphate buffer (pH 2.6) containing octane sulfate sodium salt, and 7% methanol. Quantitative absorbance was monitored at 286 nm. The calibration curve was linear through the range of 1.25–200 μg/mL, that is well beyond the detected plasma level range of K-27. Limit of quantitation was 5 μg/mL. Intra-day and inter-day precisions of the HPLC determinations gave standard deviations as 0.77 and 2.67%, respectively. Following intramuscular administration of 50 μmol (22.31 mg) K-27 in rats, the maximum of K-27 concentration in plasma was reached at about 15 min giving 186 μg/mL and the t1/2 was 85 min. K-27 displays initial (from 15 trough 120 min) zero order elimination kinetics. Similar results have been found after intraperitoneal administration.
Kornélia Tekes - One of the best experts on this subject based on the ideXlab platform.
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A fieldable, high-throughput, cost-efficient high performance liquid chromatography-ultraviolet absorption detection (HPLC-UV) method for the quantitation of bispyridinium quaternary aldoxime Cholinesterase Reactivators in blood
Acta Chromatographica, 2020Co-Authors: Gellért Karvaly, Kamil Kuca, Kornélia Tekes, Zoltán Szimrók, József FŰrÉsz, Huba KalászAbstract:Abstract Mono- 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.
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Measurement of K-27, an oxime-type Cholinesterase Reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples.
Journal of chromatography. A, 2007Co-Authors: Melinda Gyenge, Kamil Kuca, Huba Kalász, George A Petroianu, Rudolf Laufer, Kornélia TekesAbstract:K-27 is a bisquaternary asymmetric pyridinium aldoxime-type Cholinesterase Reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 degrees C at E(ox) 0.65 V. The calibration curve was linear through the range of 10-250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 microL of cerebrospinal fluid. The method--with slight modification in the composition of the mobile phase--can be used to measure a wide range of other related pyridinium aldoxime-type Cholinesterase Reactivators.
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Measurement of K-27, an oxime-type Cholinesterase Reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples
Journal of Chromatography A, 2007Co-Authors: Melinda Gyenge, Kamil Kuca, Huba Kalász, George A Petroianu, Rudolf Laufer, Kornélia TekesAbstract:Abstract K-27 is a bisquaternary asymmetric pyridinium aldoxime-type Cholinesterase Reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 °C at E ox 0.65 V. The calibration curve was linear through the range of 10–250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 μL of cerebrospinal fluid. The method – with slight modification in the composition of the mobile phase – can be used to measure a wide range of other related pyridinium aldoxime-type Cholinesterase Reactivators.
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high performance liquid chromatographic determination of the plasma concentration of k 27 a novel oxime type Cholinesterase Reactivator
Journal of Chromatography A, 2006Co-Authors: Kornélia Tekes, Kamil Kuca, Huba Kalász, Mohamed Y Hasan, R Sheen, Georg Petroianu, K LudanyiAbstract:Abstract A simple and reliable HPLC method for the determination of the plasma level of K-27, an oxime type antidote of use in organophosphorus poisoning is presented. Separation was carried out by HPLC using an octyl silica stationary phase and a mobile phase consisting of 93% phosphate buffer (pH 2.6) containing octane sulfate sodium salt, and 7% methanol. Quantitative absorbance was monitored at 286 nm. The calibration curve was linear through the range of 1.25–200 μg/mL, that is well beyond the detected plasma level range of K-27. Limit of quantitation was 5 μg/mL. Intra-day and inter-day precisions of the HPLC determinations gave standard deviations as 0.77 and 2.67%, respectively. Following intramuscular administration of 50 μmol (22.31 mg) K-27 in rats, the maximum of K-27 concentration in plasma was reached at about 15 min giving 186 μg/mL and the t1/2 was 85 min. K-27 displays initial (from 15 trough 120 min) zero order elimination kinetics. Similar results have been found after intraperitoneal administration.
Patrick Masson - One of the best experts on this subject based on the ideXlab platform.
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mixed cationic liposomes for brain delivery of drugs by the intranasal route the acetylCholinesterase Reactivator 2 pam as encapsulated drug model
Colloids and Surfaces B: Biointerfaces, 2018Co-Authors: T N Pashirova, Irina V Zueva, Konstantin A Petrov, S S Lukashenko, Irek R Nizameev, Natalya V Kulik, A D Voloshina, Laszlo Almasy, Marsil K Kadirov, Patrick MassonAbstract:Abstract New mixed cationic liposomes based on L-α-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 μg mL–1) and Bacillus cereus (MIC=7.8 μg mL–1), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicles and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The Cholinesterase Reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency (∼ 90%) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylCholinesterase inhibition in the brain. 2-PAM−loaded liposomes reactivated 12 ± 1% of brain acetylCholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylCholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.
Melinda Gyenge - One of the best experts on this subject based on the ideXlab platform.
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Measurement of K-27, an oxime-type Cholinesterase Reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples.
Journal of chromatography. A, 2007Co-Authors: Melinda Gyenge, Kamil Kuca, Huba Kalász, George A Petroianu, Rudolf Laufer, Kornélia TekesAbstract:K-27 is a bisquaternary asymmetric pyridinium aldoxime-type Cholinesterase Reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 degrees C at E(ox) 0.65 V. The calibration curve was linear through the range of 10-250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 microL of cerebrospinal fluid. The method--with slight modification in the composition of the mobile phase--can be used to measure a wide range of other related pyridinium aldoxime-type Cholinesterase Reactivators.
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Measurement of K-27, an oxime-type Cholinesterase Reactivator by high-performance liquid chromatography with electrochemical detection from different biological samples
Journal of Chromatography A, 2007Co-Authors: Melinda Gyenge, Kamil Kuca, Huba Kalász, George A Petroianu, Rudolf Laufer, Kornélia TekesAbstract:Abstract K-27 is a bisquaternary asymmetric pyridinium aldoxime-type Cholinesterase Reactivator of use in the treatment of poisoning with organophosphorous esterase inhibitors. A sensitive, simple and reliable reverse-phase high-performance liquid chromatographic method with electrochemical detection was developed for the measurement of K-27 concentrations in rat brain, cerebrospinal fluid, serum and urine samples. Male Wistar rats were treated intramuscularly with K-27 and the samples were collected 60 min later. Separation was carried out on an octadecyl silica stationary phase and a disodium phosphate solution (pH 3.7) containing citric acid, octane sulphonic acid and acetonitrile served as mobile phase. Measurements were carried out at 30 °C at E ox 0.65 V. The calibration curve was linear through the range of 10–250 ng/mL. Accuracy, precision and the limit of detection calculated were satisfactory according to internationally accepted criteria. Limit of quantitation was 10 ng/mL. The method developed is reliable and sensitive enough for monitoring K-27 levels from different biological samples including as little as 10 μL of cerebrospinal fluid. The method – with slight modification in the composition of the mobile phase – can be used to measure a wide range of other related pyridinium aldoxime-type Cholinesterase Reactivators.