Standard treatment of organophosphorus compounds (OPs) poisoning includes administration of an anti-muscarinic (atropine), anticonvulsive (diazepam) and acetylcholinesterase reactivator (oxime). From a wide group of newly synthesized oximes, oxime K027 and oxime K203 seem to be perspective compounds in some specific OPs intoxication. The available in vitro and in vivo preclinical data indicate that both oximes may be considered for potential human use. The main aim of this study was to establish plasmatic concentration curves of both oximes after intramuscular (i.m.) and intragastric (i.g.) application with subsequent pharmacokinetic analysis and study distribution after (i.m.) application on a non-rodent animal model (experimental pigs; 1500mg/animal). According to the results, both oximes had similar Cmax (K027: 106±19μg/mL and K203: 111±8μg/mL) in Tmax 19±5min, respectively, in 22±3min. Bioavailability of oxime K027 calculated as AUCtotal (8389±1024minμg/mL) was halved compared to oxime K203 (16938±795minμg/mL). The highest concentration from peripheral tissues was found in the kidney and lung, but the brain concentrations stay very low, the plasma/brain ratio being approximately 1%. The applied doses were derived from the recommendation where it is possible to use three autoinjectors to save human life. The results provide us with knowledge about the pharmacokinetics and distribution of these new oximes and may help us to better estimate the human pharmacokinetic profile.

• Klíčová slova
• Acetylcholinesterase, K027, K203, Nerve agents, Oxime, Pharmacokinetics, Pigs,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• aplikace orální MeSH
• injekce intramuskulární MeSH
• orgánová specificita MeSH
• oximy aplikace a dávkování   krev   farmakokinetika   MeSH
• plocha pod křivkou MeSH
• pyridinové sloučeniny aplikace a dávkování   krev   farmakokinetika   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   krev   farmakokinetika   MeSH
• Sus scrofa MeSH
• tkáňová distribuce MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Prohlížeč
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• acetylcholinesterasa MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH

Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively.

• MeSH
• acetylcholin metabolismus   MeSH
• acetylcholinesterasa metabolismus   MeSH
• adsorpce MeSH
• centrální nervový systém účinky léků   MeSH
• katalytická doména MeSH
• krysa rodu Rattus MeSH
• nervosvalové spojení účinky léků   metabolismus   MeSH
• organofosfáty chemie   metabolismus   MeSH
• potkani Wistar MeSH
• reaktivátory cholinesterázy * krev   metabolismus   farmakokinetika   MeSH
• sérový albumin metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholin MeSH
• acetylcholinesterasa MeSH
• organofosfáty MeSH
• reaktivátory cholinesterázy * MeSH
• sérový albumin MeSH

K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-propane dibromide] is a promising new reactivator of organophosphate- or organophosphonate-inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 ± 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg(-1)) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed-phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R(2) > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1-100 µg ml(-1). Near-identical plasma profiles were obtained for both compounds. No differences were found in the mean ± SD values of C(max) (18.6 ± 2.5 vs 20.0 ± 6.3 µg ml(-1), P = 0.72) and AUC(0-180min) (2290 ± 304 vs 2269 ± 197 min µg ml(-1), P = 0.84). However, the percentage coefficient of variation of the first-order rate constant of absorption (k(a)) was 3-fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution.

• MeSH
• injekce intramuskulární MeSH
• krysa rodu Rattus MeSH
• oximy krev   farmakokinetika   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny krev   farmakokinetika   MeSH
• reaktivátory cholinesterázy krev   farmakokinetika   MeSH
• spektrofotometrie ultrafialová metody   MeSH
• tkáňová distribuce MeSH
• trimedoxim krev   farmakokinetika   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• trimedoxim MeSH

Asoxime (HI-6) is a well known oxime reactivator used for counteracting intoxication by nerve agents. It is able to reactivate acetylcholinesterase (AChE) inhibited even by sarin or soman. The present experiment was aimed to determine markers of oxidative stress represented by thiobarbituric acid reactive substances and antioxidants represented by ferric reducing antioxidant power, reduced and oxidized glutathione in a Beagle dog model. Two groups of dogs were intramuscularly exposed to single (11.4 mg/kg.b.wt.) or tenfold (114 mg/kg.b.wt.) human therapeutically doses of HI-6. HI-6 affinity for AChE in vitro was evaluated in a separate experiment. Complete serum biochemistry and pharmacokinetics were also performed with significant alteration in blood urea nitrogen, creatine phosphokinase, glucose and triglycerides. Blood samples were collected before HI-6 application and after 30, 60, and 120 min. The overall HI-6 impact on organism is discussed.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• dusík močoviny v krvi MeSH
• glutathion krev   MeSH
• glutathiondisulfid krev   MeSH
• hyperglykemie krev   chemicky indukované   MeSH
• kreatinkinasa krev   MeSH
• krevní glukóza analýza   MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• oxidační stres * MeSH
• oximy aplikace a dávkování   krev   farmakokinetika   MeSH
• psi MeSH
• pyridinové sloučeniny aplikace a dávkování   krev   farmakokinetika   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   krev   farmakokinetika   MeSH
• sulfhydrylové sloučeniny krev   MeSH
• triglyceridy krev   MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• asoxime chloride MeSH Prohlížeč
• glutathion MeSH
• glutathiondisulfid MeSH
• kreatinkinasa MeSH
• krevní glukóza MeSH
• látky reagující s kyselinou thiobarbiturovou MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• sulfhydrylové sloučeniny MeSH
• triglyceridy MeSH

The penetration of acetylcholinesterase reactivators (oximes) into the central nervous system is typically restricted by the blood-brain barrier. Although oximes are highly hydrophilic compounds, some contradictory results confirming permeation into the brain exist. The aim of this study is to verify the penetration of oximes through the blood-brain barrier and to detect their levels achieved in different brain regions 60 min after the administration. It was confirmed that oximes are able to penetrate into the brain after injection of therapeutic doses corresponding with 5% of LD(50). The level in whole brain was 0.58% for trimedoxime and 0.85% for the experimental drug oxime K074 as the percentage of their plasma concentration. The highest concentration was found in frontal cortex (trimedoxime 2.27%; oxime K074 0.95%) and lowest in basal ganglia (trimedoxime 0.86%; oxime K074 0.42%). Entry of oximes into the brain is minimal, but some low reactivation effect should be expected. The reactivation potency of oximes might be higher or lower, depending on the real oxime concentration in a given area.

• MeSH
• butany aplikace a dávkování   krev   izolace a purifikace   farmakokinetika   farmakologie   MeSH
• injekce intramuskulární MeSH
• kalibrace MeSH
• krysa rodu Rattus MeSH
• limita detekce MeSH
• molekulární struktura MeSH
• mozek metabolismus   MeSH
• oximy aplikace a dávkování   krev   izolace a purifikace   farmakokinetika   farmakologie   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   krev   izolace a purifikace   farmakokinetika   farmakologie   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   krev   izolace a purifikace   farmakokinetika   farmakologie   MeSH
• referenční standardy MeSH
• regresní analýza MeSH
• reprodukovatelnost výsledků MeSH
• tkáňová distribuce MeSH
• trimedoxim aplikace a dávkování   krev   izolace a purifikace   farmakokinetika   farmakologie   MeSH
• vysokoúčinná kapalinová chromatografie přístrojové vybavení   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide MeSH Prohlížeč
• butany MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• trimedoxim MeSH

A simple and reliable HPLC method for determination of rat plasma levels of clinically used acetylcholinesterase (AChE) reactivators (HI-6 and obidoxime) is presented in our study. Separation was carried out by HPLC using an octadecyl silica stationary phase and a mobile phase consisting of 24% acetonitrile and containing 5 mM sodium octanesulfonate and 5 mM tetramethylammonium chloride (pH 2.3). Following intramuscular administration of equimolar doses of both oximes (22.23 mg/kg), the maximum of HI-6 concentration in rat plasma was reached in about 20 min giving 15.26 +/- 1.71 microg/mL. The distribution of obidoxime was fast; the single maximum 23.62 +/- 3.563 microg/mL was recorded at about 10 min. HPLC with UV detection presented in our study is a general method which could be applied for quick measurements of bisquaternary AChE reactivators in rat plasma.

• MeSH
• indikátory a reagencie MeSH
• injekce intramuskulární MeSH
• kalibrace MeSH
• krevní proteiny chemie   MeSH
• krysa rodu Rattus MeSH
• kyselina trichloroctová chemie   MeSH
• obidoxim chlorid krev   farmakokinetika   MeSH
• oximy krev   farmakokinetika   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny krev   farmakokinetika   MeSH
• reaktivátory cholinesterázy krev   farmakokinetika   MeSH
• reprodukovatelnost výsledků MeSH
• spektrofotometrie ultrafialová MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• asoxime chloride MeSH Prohlížeč
• indikátory a reagencie MeSH
• krevní proteiny MeSH
• kyselina trichloroctová MeSH
• obidoxim chlorid MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH