A conjugate of pyridine-4-aldoxime and atropine as a potential antidote against organophosphorus compounds poisoning

• Autorzy: Lovric J. , Berend S. , Vrdoljak A. L. , Radic B. , Katalinic M. , Kovarik Z. , Zeljezic D. , Kopjar N. , Rast S. , Mesic M.
• Języki publikacji: EN

Abstrakty

EN

A conjugate of pyridine-4-aldoxime and atropine (ATR-4-OX) was synthesized and its antidotal efficiency was tested in vitro on tabun- or paraoxon-inhibited acetylcholinesterase (AChE) of human erythrocytes as well as in vivo using soman-, tabun- or paraoxon-poisoned mice. Its genotoxic profile was assessed on human lymphocytes in vitro and was found acceptable for further research. ATR-4-OX showed very weak antidotal activity, inadequate for soman or tabun poisoning. Conversely, it was effective against paraoxon poisoning both in vitro and in vivo. All animals treated with 5 % or 25 % LD50 doses of the new oxime survived after administration of 10.0 or 16.0 LD50 doses of paraoxon, respectively. Based on the persistence of toxicity symptoms in mice, the atropine moiety had questionable effects in attenuating such symptoms. It appears that ATR-4-OX has a therapeutic effect related to the reactivation of phosphylated AChE, but not to receptor antagonization.

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2011
• Tom: 58
• Numer: 2
• Opis fizyczny: p.193-198,fig.,ref.

Twórcy

autor

Lovric J.

• School of Medicine, University of Zagreb, Zagreb, Croatia

autor

Berend S.

autor

Vrdoljak A. L.

autor

Radic B.

autor

Katalinic M.

autor

Kovarik Z.

autor

Zeljezic D.

autor

Kopjar N.

autor

Rast S.

autor

Mesic M.

Bibliografia

• Antonijević B, Stojiljković MP (2007) Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res 5: 71-82. 
• Bošković B, Tadić V, Kušić R (1980) Reactivating and protective effects of Pro-2-PAM in mice poisoned with paraoxon. Toxicol Appl Pharmacol 55: 32-36. 
• Bošković B, Kovačević V, Jovanović D (1984) PAM-2 Cl, HI-6 and HGG-12 in soman and tabun poisoning. Fundam Appl Toxicol 4: 106-115. 
• Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26: 249-261.  
• Čalić M, Lucić Vrdoljak A, Radić B, Jelić D, Jun D, Kuča K, Kovarik Z (2006) In vitro and in vivo evaluation of pyridinium oximes: mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity. Toxicology 219: 85-96. 
• Dawson RM (1994) Review of oximes available for the treatment of nerve agent poisoning. J Appl Toxicol 14: 317-331. 
• De Jong LPA, Verhagen MAA, Langenberg JP, Hagedorn I, Löffler M (1989) The bispyridinium-dioxime HLö-7. A potent reactivator for AChE inhibited by the stereoisomers of tabun and soman. Biochem Pharmacol 38: 633-640. 
• Duke RC, Cohen JJ (1992) Morphological and biochemical assays of apoptosis. In Current Protocols in Immunology. Coligan JE, Kruisbeal AM, eds, pp 1-3. John Willey and Sons, New York.
• Kim TH, Kuča K, Jun D, Jung YS (2005) Design and synthesis of new bis-pyridinium oxime reactivators for acetylcholinesterase inhibited by organophosphorous nerve agents. Bioorg Med Chem Lett 15: 2914-2917. 
• Kopjar N, Želježić D, Lucić Vrdoljak A, Radić B, Ramić S, Milić M, Gamulin M, Pavlica V, Fučić A (2007) Irinotecan toxicity to human blood cells in vitro - relationships between various biomarkers. Basic Clin Pharmacol Toxicol 100: 403-413. 
• Kovarik Z, Čalić M, Šinko G, Bosak A (2007) Structure-activity approach in the reactivation of tabun-phosphorylated human acetylcholinesterase with bispyridinium para-aldoximes. Arh Hig Rada Toksikol 58: 201-209. 
• Kovarik Z, Čalić M, Bosak A, Šinko G, Jelić D (2008) In vitro evaluation of aldoxime interactions with human acetylcholinesterase. Croat Chem Acta 81: 47-57.
• Kovarik Z, Lucić Vrdoljak A, Berend S, Čalić M, Kuča K, Musilek K, Radić B (2009) Evaluation of oxime K203 as antidote in tabun poisoning. Arh Hig Rada Toksikol 60: 19-25. 
• Kovarik Z, Katalinić M, Šinko G, Binder J, Holas O, Jung Y-S, Musilova L, Jun D, Kuča K (2010) Pseudo-catalytic scavenging: searching for a suitable reactivator of phosphorylated butyrylcholinesterase. Chem Biol Interact 187: 167-171. 
• Makarevich I, Gubin Y (2006) Quaternary salts of alkaloids. Chem Na Cmpd 4: 473-476.
• Mladinić M, Berend S, Lucić Vrdoljak A, Kopjar N, Radić B, Želježić D (2009) Evaluation of genome damage and its relation to oxidative stress induced by glyphosate in human lymphocytes in vitro. Environ Mol Mutagen 50: 800-807. 
• Namba T, Nolte CT, Jackrel J, Grob D (1971) Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Am J Med 50: 475-492. 
• Pang YP, Kollmeyer TM, Hong F, Lee JC, Hammond PI, Haugabouk SP, Brimijoin S (2003) Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators. Chem Biol 10: 491-502. 
• Poziomek EJ, Hackley BE, Steinberg GM (1958) Pyridinium aldoximes. J Org Chem 23: 714-717.
• Radić B, Lucić Vrdoljak A, Želježić D, Fuchs N, Berend S, Kopjar N (2007) Evaluation of HI-6 oxime: potential use in protection of human acetylcholinesterase inhibited by antineoplastic drug irinotecan and its cyto/genotoxicity in vitro. Acta Biochim Pol 54: 583-593. 
• Schmeller T, Sporer F, Sauerwein M, Wink M (1995) Binding of tropane alkaloids to nicotinic and muscarinic acetylcholine receptors. Pharmazie 50: 493-495. 
• Singh NP, McCoy MT, Tice RR, Schneider LL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175: 184-191. 
• Smith CC, O'Donovan MR, Martin EA (2006) hOGG1 recognizes oxidative damage using comet assay with greater specificity than FPG or ENDOIII. Mutagenesis 21: 185-190. 
• Sugai S, Kajiwara Y, Kubota K (1985) Pharmacological properties of quaternary atropinium derivatives. Yakugaku Zasshi 105: 183-187. 
• Thompson WR (1947) Use of moving averages and interpolation to estimate median-effective dose. Bacteriol Rev 11: 115-145. 
• Weil CS (1952) Tables for convenient calculation of median-effective dose (LD50 or ED50) and instruction in their use. Biometrics 8: 249-263.
• Wojewódzka M, Grądzka I, Buraczewska I (2002) Modified neutral comet assay for human lymphocytes. Nukleonika 47: 1-5.
• Worek F, Thiermann H, Szinicz L, Eyer P (2004) Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes. Biochem Pharmacol 68: 2237-2248. 

Uwagi

PL

Rekord w opracowaniu.