ISSN 1214-0287 (on-line), ISSN 1214-021X (printed)
J Appl Biomed
Volume 9 (2011), No 4, p 225-230
DOI 10.2478/v10136-011-0011-6

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

Jiri Kassa, Jana Zdarova Karasova, Vendula Sepsova, Jiri Bajgar

Address: Jiri Kassa, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
kassa@pmfhk.cz

Received 5th May 2011.
Revised 9th June 2011.
Published online 8th July 2011.

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SUMMARY
This study compares the abilities of the newly developed bispyridinium oxime K203 with currently available oximes (HI-6, obidoxime, and trimedoxime) in the reactivation of sarin-inhibited acetylcholinesterase and the reduction of the acute toxicity of sarin. The percentage of reactivation of sarin-inhibited rat blood and tissue acetylcholinesterase was determined in vivo and it was shown that the potency of bispyridinium oxime K203 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the relatively low reactivating efficacy of obidoxime and trimedoxime except in the diaphragm where K203 was not effective. On the other hand, the oxime HI-6 was found to be a very efficient reactivator of sarin-inhibited acetylcholinesterase in the peripheral as well as central compartment. The oxime HI-6 was able to reduce the acute toxicity of sarin by more than four times, but the other oximes studied, including K203, decreased the acute toxicity of sarin by less than three times. Based on these results, we can conclude that the reactivating and therapeutic efficacy of the oxime K203 is significantly lower compared to the oxime HI-6 and, therefore, it is not a suitable replacement for the oxime HI-6 in the antidotal treatment of acute sarin poisoning.

KEY WORDS
sarin; acetylcholinesterase; K203; HI-6; obidoxime; trimedoxime; rats; mice

REFERENCES
Bajgar J. Organophosphate/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv Clin Chem. 38: 151-216, 2004.

Clement JG, Shiloff JD, Gennings Ch. Efficacy of a combination of acetylcholinesterase reactivators, HI-6 and obidoxime, against tabun and soman poisoning of mice. Arch Toxicol. 61: 70-75, 1987.

Clement JG, Hansen AS, Boulet CA. Efficacy of HLo-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice. Arch Toxicol. 66: 216-219, 1992.

Dawson RM. Review of oximes available for treatment of nerve agent poisoning. J Appl Toxicol. 14: 317-331, 1994.

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

Ellman GL, Courtney DK, Andres V, Jr., Featherstone RM. A new and rapid determination of acetylcholinesterase activity. Biochem Pharmacol. 7: 88-93, 1961.

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.

Jun D, Kuca K, Stodulka P, Koleckar V, Dolezal B, Simon P, Veverka M. HPLC analysis of HI-6 dichloride and dimethanesulfonate - antidotes against nerve agents and organophosphorus pesticides. Anal Lett. 40: 2783-2787, 2007.
[CrossRef]

Kassa J. Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J Toxicol Clin Toxicol. 40: 803-816, 2002.

Kassa J, Cabal J. A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with currently available oximes and H oximes against soman by in vitro and in vivo methods. Toxicology. 132: 111-118, 1999a.

Kassa J, Cabal J. A comparison of the efficacy of acetylcholinesterase reactivators against cyclohexyl methylphosphonofluoridate (GF agent) by in vitro and in vivo methods. Pharmacol Toxicol. 84: 41-45, 1999b.

Kassa J, Kuca K, Bartosova L, Kunesova G. The development of new structural analogues of oximes for the antidotal treatment of poisoning by nerve agents and the comparison of their reactivating and therapeutic efficacy with currently available oximes. Cur Org Chem. 11: 267-283, 2007.
[CrossRef]

Kassa J, Karasova J, Musilek K, Kuca K. An evaluation of therapeutic and reactivating effects of newly developed oximes (K156, K203) and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice. Toxicology. 243: 311-316, 2008.
[CrossRef]

Kovacevic V, Maksimovic M, Deljac V, Binenfeld Z. Protective effects of mixture of oximes in poisoning by nerve chemical warfare agents. Acta Pharm Jugosl. 41: 75-78, 1991.

Kovarik Z, Vrdoljak AL, Berend S, Katalinic M, Kuca K, Musilek K, Radic B. Evaluation of oxime K203 as antidote in tabun poisoning (In Croatian). Arh Hig Rada Toksikol. 60: 19-26, 2009.
[CrossRef]

Kuca K, Cabal J, Kassa J. A comparison of the efficacy of a bispyridinium oxime - 1,4-bis-(2-hydroxyiminomethylpyridinium) butane dibromide and currently used oximes to reactivate sarin, tabun or cyclosarin-inhibited acetylcholinesterase by in vitro methods. Pharmazie. 59: 795-798, 2004.

Kuca K, Jun D, Musilek K. Structural requirements of acetylcholinesterase reactivators. Mini Rev Med Chem. 6: 269-277, 2006.
[CrossRef]

Kuca K, Racakova V, Jun D, Bajgar J. Structure-activity relationship of acetylcholinesterase reactivators - antidotes against nerve agents. Lett Org Chem. 4: 212-217, 2007.

Kuca K, Musilek K, Jun D, Pohanka M, Zdarova Karasova J, Novotny L, Musilova L. Could oxime HI-6 really be considered as "broad-spectrum" antidote? J Appl Biomed. 7: 143-149, 2009.
[JAB]

Lotti M. Organophosphorus compounds. In Spencer PS, Schaumburg HH (eds.): Experimental and Clinical Neurotoxicology, Oxford University Press, New York, 2000, pp. 898-925.

Lundy PM, Raveh L, Amitai G. Development of the bisquaternary oxime HI-6 toward clinical use in the treatment of organophosphate nerve agent poisoning. Toxicol Rev. 25: 231-243, 2006.

Maksimovic M, Kovacevic V. Protective and reactivating effects of HI-6-toxogonin mixture in rats and guinea-pigs poisoned by nerve agents. Acta Pharm Jugoslav. 39: 27-33, 1989.

Marrs TC. Organophosphate poisoning. Pharmacol Ther. 58: 51-66, 1993.

Marrs TC, Rice P, Vale JA. The role of oximes in the treatment of nerve agent poisoning in civilian casualties. Toxicol Rev. 25: 297-323, 2006.

Musilek K, Kuca K, Jun D, Dolezal M. Synthesis of bispyridinium compounds bearing propane linker and evaluation of their reactivation activity against tabun- and paraoxon-inhibited acetylcholinesterase. Lett Org Chem. 3: 831-835, 2006.

Musilek K, Holas O, Kuca K, Jun D, Dohnal V, Opletalova V, Dolezal M. Synthesis of monooxime-monocarbamoyl bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against tabun- and paraoxon-inhibited acetylcholinesterase. J Enzyme Inhib Med Chem. 23: 70-76, 2008.
[CrossRef]

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]

Szinicz L, Worek F, Thiermann H, Kehe K, Eckert S, Eyer P. Development of antidotes: problems and strategies. Toxicology. 233: 23-30, 2007.
[CrossRef]

Tallarida R, Murray R. Manual of Pharmacological Calculation with Computer Programs. Springer-Verlag, New York, 1987.

Taylor P. Anticholinesterase agents. In Hardman JG, Limbird LE (eds.): The Pharmacological Basis of Therapeutics, McGraw Hill, New York, 2001, pp. 175-191.

Van Helden HPM, Busker RW, Melchers BPC, Bruijnzeel PLB. Pharmacological effects of oximes: how relevant are they? Arch Toxicol. 70: 779-786, 1996.
[CrossRef]

Worek F, Aurbek N, Thiermann H. Reactivation of organophosphate-inhibited human AChE by combinations of obidoxime and HI 6 in vitro. J Appl Toxicol. 27: 582-588, 2007.
[CrossRef]
CITED

Kassa J, Misik J, Zdarova Karasova J. A Comparison of the Potency of a Novel Bispyridinium Oxime K203 and currently available Oximes (Obidoxime, HI-6) to Counteract the Acute Neurotoxicity of Sarin in Rats. Basic Clin Pharmacol Toxicol. 111: 333-338, 2012.

Zdarova Karasova J, Hnidkova Dd Pohanka M, Musilek K, Chilcott RP, Kuca K. Pharmacokinetics of acetylcholinesterase reactivator K203 and consequent evaluation of low molecular weight antioxidants/markers of oxidative stress. J Appl Biomed. 10: 71-78, 2012.

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