J Appl Biomed 15:49-53, 2017 | DOI: 10.1016/j.jab.2016.09.008

A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K305, K307) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice

Jiri Kassa*, Vendula Sepsova, Anna Horova, Kamil Musilek
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czechia

The reactivating and therapeutic efficacy of two newly developed oximes (K305, K307) was compared with the oxime K203 and trimedoxime using in vivo methods The study determining percentage of reactivation of tabun-inhibited acetylcholinesterase in the peripheral as well as central nervous system (diaphragm, brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed oximes is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While the ability of the oxime K305 to reduce acute toxicity of tabun in mice is approaching to the therapeutic efficacy of trimedoxime, the ability of another novel bispyridinium oxime K307 to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and the oxime K203. Thus, the reactivating and therapeutic efficacy of both examined newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.

Keywords: Tabun; Acetylcholinesterase; Oximes; Rats; Mice

Received: May 13, 2016; Accepted: September 1, 2016; Published: January 1, 2017  Show citation

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Kassa J, Sepsova V, Horova A, Musilek K. A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K305, K307) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice. J Appl Biomed. 2017;15(1):49-53. doi: 10.1016/j.jab.2016.09.008.
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    References

    1. Antonijevic, B., Stojiljkovic, P., 2007. Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin. Med. Res. 5, 71-82. Go to original source... Go to PubMed...
    2. Bajgar, J., 2004. Organophosphate/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis and treatment. Adv. Clin. Chem. 38, 151-216. Go to original source... Go to PubMed...
    3. Berend, S., Vrdoljak, A.L., Radic, B., Kuca, K., 2008. New bispyridinium oximes: in vitro and in vivo evaluation of their biological efficiency in soman and tabun poisoning. Chem. Biol. Interact. 175, 413-416. Go to original source... Go to PubMed...
    4. Cabal, J., Kuca, K., Kassa, J., 2004. Specification of the structure of oximes able to reactivate tabun-inhibited acetylcholinesterase. Pharmacol. Toxicol. 95, 81-86. Go to original source... Go to PubMed...
    5. Cabal, J., Bajgar, J., 1999. Tabun Àreappearance 50 years later (in Czech). Chem. Listy 93, 27-31.
    6. Clement, J.G., Hansen, A.S., Boulet, C.A., 1992. Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice. Arch. Toxicol. 66, 216-219. Go to original source... Go to PubMed...
    7. Dawson, R.M., 1994. Review of oximes available for treatment of nerve agent poisoning. J. Appl. Toxicol. 14, 317-331. Go to original source... Go to PubMed...
    8. Delfino, R.T., Ribeiro, T.S., Figueroa-Villar, J.D., 2009. Organophosphorus compounds as chemical warfare agents: a review. J. Braz. Chem. Soc. 20, 407-428. Go to original source...
    9. Ekström, F., Akfur, C., Tunemalm, A.K., Lundberg, S., 2006. Structural changes of phenylalanine 338 and histidine 447 revealed by the crystal structures of tabuninhibited murine acetylcholinesterase. Biochemistry 45, 74-81. Go to original source... Go to PubMed...
    10. Ellman, G.L., Courtney, D.K., Andres V.Jr. Feartherstone, R.M., 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7, 88-93. Go to original source... Go to PubMed...
    11. Jokanovic, M., Prostran, M., 2009. Pyridinium oximes as cholinesterase reactivators: structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. Curr. Med. Chem. 16, 2177-2188. Go to original source... Go to PubMed...
    12. Jokanovic, M., 2012. Structure-activity relationship and efficacy of pyridinium oximes in the treatment of poisoning with organophosphorus compounds: a review of recent data. Curr. Topic. Med. Chem. 12, 1775-1789. Go to original source...
    13. Jun, D., Kuca, K., Stodulka, P., Koleckar, V., Dolezal, B., Simon, P., Veverka, M., 2007. HPLC analysis of HI-6 dichloride and dimethanesulfonate Àantidotes against nerve agents and organophosphorus pesticides. Anal. Lett. 40, 2783-2787. Go to original source...
    14. Kalasz, H., Nurulain, S.M., Veress, G., Antus, S., Darvas, F., Adeghate, E., Adem, A., Hashemi, F., Tekes, K., 2015. Mini review on blood-brain barrier penetration of pyridinium aldoximes. J. Appl. Toxicol. 35, 116-123. Go to original source... Go to PubMed...
    15. Kassa, J., Cabal, J., 1999a. 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. Go to original source... Go to PubMed...
    16. Kassa, J., Cabal, J., 1999b. A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with presently used oximes and H oximes against sarin by in vitro and in vivo methods. Hum. Exp. Toxicol. 18, 560-565. Go to original source... Go to PubMed...
    17. Kassa, J., Cabal, J., 1999c. A comparison of the efficacy of acetylcholinesterase reactivators against cyclohexylmethylphosphonofluoridate (GF agent) by in vitro and in vivomethods. Pharmacol. Toxicol. 84, 41-45. Go to original source... Go to PubMed...
    18. Kassa, J., Karasova, J., Musilek, K., Kuca, K., 2008. An evaluation of therapeutic and reactivating effects of newly developed oximes (K156 K203) with commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice. Toxicology 243, 311-316. Go to original source... Go to PubMed...
    19. Kassa, J., Musilek, K., Karasova, J.Z., Kuca, K., Bajgar, J., 2012. Two possibilities how to increase the efficacy of antidotal treatment of nerve agent poisonings. Mini Rev. Med. Chem. 12, 24-34. Go to original source... Go to PubMed...
    20. Kassa, J., 2002. Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J. Toxicol. Clin. Toxicol. 40, 803-816. Go to original source... Go to PubMed...
    21. Kim, T.-H., Kuca, K., Jun, D., Jung, Y.-S., 2005. Design and synthesis of new bispyridinium oxime reactivators for acetylcholinesterase inhibited by organophosphorous nerve agents. Bioorg. Med. Chem. Lett. 15, 2914-2917. Go to original source... Go to PubMed...
    22. Kovarik, Z., Macek, N., Sit, R.K., Radic, Z., Fokin, V.V., Sharpless, K.B., Taylor, P., 2013. Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. Chem. Biol. Interact. 203, 77-80. Go to original source... Go to PubMed...
    23. Kuca, K., Cabal, J., Kassa, J., 2004. A comparison of the efficacy of a bispyridinium oxime À 1,4-bis-(2-hydroxyiminomethylpyridinium) butane dibromide and currently used oximes to reactivate sarin, tabun or cyclosarin-inhibited acetylcholinesterase byin vitro methods. Pharmazie 59, 795-798. Go to PubMed...
    24. Kuca, K., Cabal, J., Jun, D., Bajgar, J., Hrabinova, M., 2006a. Potency of new structurally different oximes to reactivate cyclosarin-inhibited human brain acetylcholinesterase. J. Enzyme Inhib. Med. Chem. 21, 663-666. Go to original source... Go to PubMed...
    25. Kuca, K., Jun, D., Musilek, K., 2006b. Structural requirements of acetylcholinesterase reactivators. Mini Rev. Med. Chem. 6, 269-277. Go to original source... Go to PubMed...
    26. Lorke, D.E., Kalasz, H., Petroianu, G.A., Tekes, K., 2008. Entry of oximes into the brain. Rev. Curr. Med. Chem. 15, 743-753. Go to original source... Go to PubMed...
    27. Musilek, K., Kuca, K., Jun, D., Dohnal, V., Kim, T.-H., Jung, Y.-S., Dolezal, M., 2006. Synthesis of reactivators of phosphorylated acetylcholinestrerase of bispyridiniumdialdoxime type with a 3-oxapentane connecting chain and their testing in vitro on a model of the enzyme inhibited by chlorpyrifos and methylchlorpyrifos. In Czech) Ceska. Slov. Farm. 55, 115-119. Go to PubMed...
    28. Musilek, K., Jun, D., Cabal, J., Kassa, J., Gunn-Moore, F., Kuca, K., 2007. Design of a potent reactivator of tabun-inhibited acetylcholinesterase Àsynthesis and evaluation of (E)-1-(4-carbamoylpyridinium)-4-(4hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). J. Med. Chem. 50, 5514-5518. Go to original source... Go to PubMed...
    29. Musilek, K., Dolezal, M., Gunn-Moore, F., Kuca, K., 2011. Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides. Med. Res. Rev. 31, 548-575. Go to original source... Go to PubMed...
    30. Nurulain, S.M., 2011. Efficacious oxime for organophosphorus poisoning: a minireview. Trop. J. Pharm. Res. 10, 341-349. Go to original source...
    31. Sharma, R., Gupra, B., Singh, N., Acharya, J.R., Musilek, K., Kuca, K., Ghosh, K.K., 2015. Development and structural modifications of cholinesterase reactivators against chemical warfare agents in last decade: a review. Mini Rev. Med. Chem. 15, 58-72. Go to original source... Go to PubMed...
    32. Tallarida, R., Murray, R., 1987. Manual of Pharmacological Calculation with Computer Programs. Springer-Verlag, New York.
    33. Taylor, P., 1996. Anticholinesterase agents, In: Hardman, J.G., Limbird, L.E. (Eds.), The Pharmacological Basis of Therapeutics. 9th ed. McGraw Hill, New York, pp. 161- 176.
    34. Voicu, V., Bajgar, J., Medvedovici, A., Radulescu, F.S., Miron, D.S., 2010. Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review. J. Appl. Toxicol. 30, 719-729. Go to original source... Go to PubMed...
    35. Voicu, V., Radulescu, F.S., Medvedovici, A., 2015. Relationships between the antidotal efficacy and structure: PK/PD parameters and bio-relevant molecular descriptors of AChE reactivating oximes: inclusion and integration to biopharmaceutical classification systems. Expert Opin. Drug Metab. Toxicol. 11, 95-109. Go to original source... Go to PubMed...
    36. Wilhelm, C.M., Snider, T.H., Babin, M.C., Jett, D.A., Platoff G.E.Jr. Yeung, D.T., 2014. A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides. Toxicol. Appl. Pharmacol. 281, 254-265. Go to original source... Go to PubMed...
    37. Winter, M., Wille, T., Musilek, K., Kuca, K., Thiermann, H., Worek, F., 2016. Investigation of the reactivation kinetics of a large series of bispyridinium oximes with organophosphate-inhibited human acetylcholinesterase. Toxicol. Lett. 244, 136-142. Go to original source... Go to PubMed...
    38. Worek, F., Widmann, R., Knopff, O., Szinicz, L., 1998. Reactivating potency of obidoxime, pralidoxime, HI-6 and HLö-7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compounds. Arch. Toxicol. 72, 237-243. Go to original source... Go to PubMed...
    39. Zdarova Karasova, J., Stodulka, P., Kuca, K., 2010. In vitro screening of blood-brain barrier penetration of clinically used acetylcholinesterase reactivators. J. Appl. Biomed. 8, 35-40. Go to original source...

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