ISSN 1214-0287 (on-line), ISSN 1214-021X (printed)
J Appl Biomed
Volume 10 (2012), No 2, p 71-78
DOI 10.2478/v10136-011-0015-2

Pharmacokinetics of acetylcholinesterase reactivator K203 and consequent evaluation of low molecular weight antioxidants/markers of oxidative stress

Jana Zdarova Karasova, Daniela Hnidkova, Miroslav Pohanka, Kamil Musilek, Robert Peter Chilcott, Kamil Kuca

Address: Jana Zdarova Karasova, Department of Public Health, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
karasova@pmfhk.cz

Received 12th July 2011.
Revised 14th September 2011.
Published online 24th October 2011.

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SUMMARY
Oxime K203 is a new compound designed to be used as an acetylcholinesterase reactivator for the treatment of intoxication following exposure to tabun and certain pesticides. After intramuscular administration of a therapeutic (23 mg/kg) dose, the time-course of plasma concentrations of K203 in rats was determined by HPLC. Maximum concentrations were reached between 40 and 60 min (16.5±2.1 microg/ml in 40 min and 16.6±2.0 in 60 min, respectively) with the concentration being relatively constant during this period. There was no significant effect on the plasma concentration of thiobarbituric acid reactive substances (TBARS) during the administration of K203, indicating an absence of oxidative stress. Indeed, administration of K203 led to a significant increase in low molecular weight antioxidants which could tentatively be interpreted as representing a beneficial effect.

KEY WORDS
K203; nerve agent treatment; HPLC; plasma concentration; absorption

REFERENCES
Bartosova L, Kuca K, Kunesova G, Jun D. The acute toxicity of the acetylcholinesterase reactivators in mice in relation to their structure. Neurotoxicity Res. 9: 291-296, 2006.
[CrossRef] [PubMed]

Benschop HP, Konings KA, Kossen SP, Ligtenstein DA. Determination of some pyridinium aldoxime compounds by means of ion-pair reversed-phase high-performance liquid chromatography: application in biological material. J Chromatogr. 225: 107-114, 1981.

Berend S, Vrdoljak AL, Radic B, Kuca K. New bispyridinium oximes: in vitro and in vivo evaluation of their biological efficiency in soman and tabun poisoning. Chem Biol Interact. 25: 413-416, 2008.
[CrossRef] [PubMed]

Brown ND, Hall LL, Steeman HK, Doctor BP, Dewaree DE. Ion-pair high-performance liquid chromatographic separation of a multicomponent anticholinergic drug formulation. J Chromatogr. 148: 453-457, 1978.
[CrossRef]

da Silva AP, Farina M, Franco JL, Dafre AL, Kassa J, Kuca K. Temporal effects of newly developed oximes (K027, K048) on malathion-induced acetylcholinesterase inhibition and lipid peroxidation in mouse prefrontal cortex. Neurotoxicology. 29: 184-189, 2008.
[CrossRef] [PubMed]

Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. Q J Med. 95: 275-283, 2002.

Ekstrom F, Akfur C, Tunemalm AK, Lundberg S. Structural changes of phynylalanine 338 and histidine 447 revealated by the crystal structures of tabun-inhibited murine acetylcholinesterase. Biochemistry. 45: 74-81, 2006.
[CrossRef] [PubMed]

Eyer P, Hagedorn I, Ladstetter B. Study on the stability of the oxime HI 6 in aqueous solution. Arch Toxicol. 62: 224-226, 1998.
[CrossRef] [PubMed]

Guimaraes AP, Franca TCC, Ramalho TC, Renno MN, Ferreira da Cunha EF, Matos KS, Mancini DT, Kuca K. Docking studies and effects of syn-anti isomery of oximes derived from pyridine imidazol bicycled systems as potential human acetylcholinesterase reactivators. J Appl Biomed. 9: 163-171, 2011.
[CrossRef] [JAB]

Guyon F, Tambute A, Caude M, Rosset R. Determination of N-methylpyridinium 2-aldoxime methylsulfate (Contrathion) in rat plasma and urine by high-performance copper(II) - silica ligand-exchange chromatography. J Chromatogr. 229: 475-480, 1982.

Houze P, Borron SW, Scherninski F, Bousquet B, Gourmel B, Baud F. Measurement of serum pralidoxime methylsulfate (Contrathion) by high-performance liquid chromatography with electrochemical detection. J Chromatogr B Analyt Technol Biomed Life Sci. 814: 149-154, 2005.
[CrossRef] [PubMed]

Jokanovic M, Prostran M. Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. Curr Med Chem. 16: 2177-2188, 2009.
[CrossRef] [PubMed]

Kalasz H, Hasan MY, Sheen R, Kuca K, Petroianu G, Ludanyi K, Gergely A, Tekes K. HPLC analysis of K-48 concentration in plasma. Anal Bioanal Chem. 385: 1062-1067, 2006.
[CrossRef] [PubMed]

Kalasz H, Laufer R, Szegi P, Kuca K, Musilek K, Tekesz K. HPLC study of the pharmacokinetics of K203. Acta Chromatogr. 20: 575-584, 2008.
[CrossRef]

Kassa J, Karasova J. The evaluation of the neuroprotective effects of bispyridinium oximes in tabun-poisoned rats. J Toxicol Environ Health A. 70: 1556-1567, 2007.
[CrossRef] [PubMed]

Kassa J, Karasova J, Musilek K, Kuca K, Bajgar J. An evaluation of reactivating and therapeutic efficacy of newly developed oximes (K206, K269) and commonly used oximes (obidoxime, HI-6) in cyclosarin-poisoned rats and mice. Clin Toxicol (Phila). 47: 72-76, 2009.
[CrossRef] [PubMed]

Kassa J, Karasova JZ, Sepsova V, Bajgar J. A comparison of the reactivating and therapeutic efficacy of the newly developed bispyridinium oxime K203 with currently available oximes, in sarin poisoned rats and mice. J Appl Biomed. 9: 225-230, 2011.
[CrossRef] [JAB]

Kovarik Z, Calic M, Sinko G, Bosak A, Berend S, Vrdoljak AL, Radic B. Oximes: Reactivators of phosphorylated acetylcholinesterase and antidotes in therapy against tabun poisoning. Chem Biol Interact. 175: 173-179, 2008.
[CrossRef]

Kovarik Z, Vrdoljak AL, Berend S, Katalinic M, Kuca K, Musilek K, Radic B. Evaluation of oxime K203 as antidote in tabun poisoning. Arh Hig Rada Toksikol. 1: 19-26, 2009.
[CrossRef] [PubMed]

Musilek K, Jun D, Cabal J, Kassa J, Gunn-Moore F, Kuca K. Design of a potent reactivator of tabun-inhibited acetylcholinesterase - synthesis and evaluation of (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). J Med Chem. 50: 5514-5518, 2007.
[CrossRef] [PubMed]

Novotny L, Misik J, Karasova J, Kuca K, Bajgar J. Influence of different ways of euthanasia on the activity of cholinesterases in the rat. J Appl Biomed. 7: 133-136, 2009.
[JAB]

Nurulain SM, Lorke DE, Hasan YM, Shafiullah M, Kuca K, Musilek K, Petroianu GA. Efficacy of eight experimental bispyridinium oximes against paraoxon-induced mortality: comparison with the conventional oximes pralidoxime and obidoxime. Neurotox Res. 16: 60-67, 2009.
[CrossRef] [PubMed]

Pejchal J, Osterreicher J, Kuca K, Jun D, Bajgar J, Kassa J. The influence of acetylcholinesterase reactivators on selected hepatic functions in rats. Basic Clin Pharmacol Toxicol. 103: 119-123, 2008.
[CrossRef]

Petroianu GA, Nurulain SM, Nagelkerke N, Shafiullah M, Kassa J, Kuca K. Five oximes (K-27, K-48, obidoxime, HI-6 and trimedoxime) in comparison with pralidoxime: survival in rats exposed to methyl-paraoxon. J Appl Toxicol. 27: 453-457, 2007.
[CrossRef] [PubMed]

Pohanka M, Karasova JZ, Musilek K, Kuca K, Kassa J. Effect of five acetylcholinesterase reactivators on tabun intoxicated rats: induction of oxidative stress versus reactivation efficacy. J Appl Toxicol. 29: 483-488, 2009.
[CrossRef] [PubMed]

Pohanka M, Bandouchova H, Vlckova K, Karasova JZ, Kuca K, Damkova V, Peckova L, Vitula F, Pikula J. Square wave voltammetry on screen printed electrodes: comparison to ferric reducing antioxidant power in plasma from model laboratory animal (Grey Partridge) and comparison to standard antioxidants. J Appl Biomed. 9: 103-109, 2011.
[CrossRef] [JAB]

Soukup O, Holas O, Binder J, Killy K, Tobin G, Jun D, Fusek J, Kuca K. The effect of trimedoxime on acetylcholinesterase and on the cholinergic system of the rat bladder. J Appl Biomed. 8: 87-92, 2010.
[CrossRef] [JAB]

Spohrer U, Thiermann H, Klimmek R, Eyer P. Pharmacokinetics of the oximes HI-6 and Hlo-7 in dogs after i.m. injection with newly developed dry/wet autoinjectors. Arch Toxicol. 68: 480-489, 1994.
[CrossRef]

Tekes K, Hasan YM, Sheen R, Kuca K, Petroianu G, Ludanyi K. High-performance liquid chromatographic determination of the plasma concentration of K-27, a novel oxime-type cholinesterase reactivator. J Chromatogr A. 1122: 84-87, 2006.
[CrossRef] [PubMed]

Utley D. Analysis of formulations containing pralidoxime mesylate by liquid chromatography. J Chromatogr. 396: 237-250, 1987.
[CrossRef]

Vojvodic VB, Maksimovic M. Absorption and excretion of pralidoxime in man after intramuscular injection of PAM-2Cl and various cholinolytics. Eur J Clin Pharmacol. 5: 58-61, 1972.
[CrossRef]

Wilson IB, Ginsburg S. Reactivation of acetylcholinesterase inhibited by alkylphosphates. Biochim Biophys Acta. 18: 169-171, 1955.
[CrossRef]

Zdarova Karasova J, Kassa J, Musilek K, Pohanka M, Novotny L, Kuca K. Effect of seven newly synthesized and currently available oxime cholinesterase reactivators on cyclosarin-intoxicated rats. Int J Mol Sci. 10: 3065-3075, 2009.
[CrossRef] [PubMed]

Zdarova Karasova J, Novotny L, Antos K, Zivna H, Kuca K. Time-dependent changes in concentration of two clinically used acetylcholinesterase reactivators (HI-6 and obidoxime) in rat plasma determined by HPLC techniques after in vivo administration. Anal Sci. 26: 63-67, 2010.
[CrossRef] [PubMed]

Zdarova Karasova J, Chladek J, Hroch M, Fusek J, Hnidkova D, Kuca K. Pharmacokinetics study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma. J Appl Toxicol. 2011 (in press).
[CrossRef] [PubMed]
CITED

Karasova JZ, Pavlik M, Chladek J, Jun D, Kuca K. Hyaluronidase: Its effects on HI-6 dichloride and dimethanesulphonate pharmacokinetic profile in pigs. Toxicol Lett. 220: 167-171, 2013.

Zemek F, Sepsova V, Drtinova L, Korabecny J, Pohanka M, Karasova JZ, Kuca K. Interaction of acetylcholinesterase reactivators with albumin. Conference: 25th Congress of the European-College-of-Neuropsychopharmacology (ECNP) Location: Vienna, AUSTRIA Date: OCT 13-17, 2012. European Coll Neuropsychopharmacol (ECNP). Eur Neuropsychopharm. 22: S439-S440, 2012.

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