SUMMARY
Trimedoxime is a bisquaternary oxime that is widely used in the treatment of organophosphorous poisoning caused by tabun and paraoxon. We tested its affinity to acetylcholinesterase (AChE), its mechanism of interaction and effect on the cholinergic system of the rat bladder. The half maximal inhibitory concentration (IC50) of trimedoxime to recombinant AChE was found to be 82.0 mM ± 30.1 mM. This represents a weak inhibition. Its interaction with AChE seems to be very similar to obidoxime - one aromatic nucleus interacts with the peripheral anionic site and the other with the residues TYR337 and TYR341 inside the cavity. Also the oxime moiety is moving towards the catalytic triade ready for the reactivation of the inhibited AChE. In the organ bath experiment no significant effect of trimedoxime was observed on the contraction of the detrusor caused by the muscarinic agonist metacholine.
KEY WORDS
acetylcholinesterase; trimedoxime; antidote; muscarinic receptors; reactivation
REFERENCES
Abrams P, Andersson KE, Buccafusco JJ, Chapple C, de Groat WC, Fryer AD, Kay G, Laties A, Nathanson NM, Pasricha PJ, Wein AJ: Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 148:565-578, 2006.
Antonijevic B, Stojiljkovic MP: Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res 5:71-82, 2006.
Bajgar J: Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv Clin Chem 38:151-216, 2004.
Cabal J, Kuca K, Kassa J: Specification of the structure of oximes able to reactivate tabun-inhibited acetylcholinesterase. Basic Clin Pharmacol Toxicol 95:81-86, 2004.
Collins SM, Crankshaw DJ: Dissociation of contraction and muscarinic receptor binding to isolated smooth muscle cells. Am J Physiol 251:G546-552, 1986.
Ekstrom F, Pang YP, Boman M, Artursson E, Akfur C, Borjegren S: Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: Structural basis for differences in the ability to reactivate tabun conjugates. Biochem Pharmacol 72:597-607, 2006.
Ellman GL, Courtney KD, Andres V, Featherstone RM: A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88-95, 1961.
Giglio D, Aronsson P, Eriksson L, Tobin G: In vitro characterization of parasympathetic and sympathetic responses in cyclophosphamide-induced cystitis in the rat. Basic Clin Pharmacol Toxicol 100:96-108, 2007.
Giniatullin RA, Shabunova IA, Nikolskii EN, Bukharaeva EA: Reactivating and cholinolytic action of trimedoxime bromide at the neuromuscular-junction of warm-blooded animals. Neurophysiology 20:256-260, 1988.
Hamilton MG, Lundy PM: HI-6 therapy of soman and tabun poisoning in primates and rodents. Arch Toxicol 63:144-149, 1989.
Jun D, Musilova L, Kuca K, Kassa J, Bajgar J: Potency of several oximes to reactivate human acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon in vitro. Chem Biol Interact 175:421-424, 2008.
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, Kuca K, Cabal J: Comparison of the efficacy of currently available oximes against tabun in rats. Biologia (Bratisl) 60:77-79, 2005.
Kassa J, Kuca K, Cabal J, Paar M: A comparison of the efficacy of new asymmetric bispyridinium oximes (K027, K048) with currently available oximes against tabun by in vivo methods. J Toxicol Environ Health A 69:1875-1882, 2006.
Kassa J, Zdarova Karasova J, Tesarova S: Evaluation of the neuroprotective efficacy of individual oxime (HI-6) and oxime mixtures (HI-6 + trimedoxime, HI-6 + K203) in tabun-poisoned rats. J Appl Biomed 7:189-199, 2009.
Kuca K, Jun D, Bajgar J: Currently used cholinesterase reactivators against nerve agent intoxication: Comparison of their effectivity in vitro. Drug Chem Toxicol 30:31-40, 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.
Marrs TC: Organophosphate poisoning. Pharmacol Ther 58:51-66, 1993.
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ: Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639-1662, 1998.
Ogura H, Kosasa T, Kuriya Y, Yamanishi Y: Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro. Methods Find Exp Clin Pharmacol 22:609-613, 2000.
Soukup O, Pohanka M, Tobin G, Jun D, Fusek J, Musilek K, Marek J, Kassa J, Kuca K: The effect of HI-6 on cholinesterases and on the cholinergic system of the rat bladder. Neuro Endocrinol Lett 29:759-762, 2008.
Tattersall JE: Ion channel blockade by oximes and recovery of diaphragm muscle from soman poisoning in vitro. Br J Pharmacol 108:1006-1015, 1993.
Zdarova Karasova J, Bajgar J, Novotny L, Kuca K: Is a high dose of Huperzine A really suitable for pretreatment against high doses of soman? J Appl Biomed 7:93-99, 2009.
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CITED
Zdarova Karasova Jana, Hnidkova D, 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.
Kassa J, Zdarova Karasova J, 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.
Berger J. The age of biomedicine: current trends in traditional subjects. J Appl Biomed. 9: 57-61, 2011.
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