Treatment of Organophosphate Poisoning with Experimental Oximes: A Review

Author(s): Dietrich E. Lorke, Georg A. Petroianu*.

Journal Name: Current Organic Chemistry

Volume 23 , Issue 5 , 2019

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Graphical Abstract:


Standard therapy of Organophosphorus Compound (OPC) poisoning with oxime-type acetylcholinesterase (AChE) reactivators is unsatisfactory. New bispyridinium oximes have therefore been synthesized. This review summarizes in vitro characteristics of established (pralidoxime, obidoxime, trimedoxime, HI-6) and experimental (K-)oximes, and compares their protective efficacy in vivo, when administered shortly after exposure to Diisopropylfluorophosphate (DFP) and three OPC pesticides (ethyl-paraoxon, methylparaoxon, azinphos-methyl) in the same experimental setting.

In addition to reactivating cholinesterase, oximes also inhibit this enzyme; strongest AChE inhibition (IC50 rat blood: 1-9 µM) is observed in vitro for the oximes with a xylene linker (K-107, K-108, K-113). AChE inhibition is weakest for K-27, K-48 and HI-6 (IC50 >500 µM). Intrinsic AChE inhibition of oximes in vitro (IC50, rat) is strongly correlated with their LD50 (rat): oximes with a high IC50 (K-27, K-48, pralidoxime, obidoxime) also show a high LD50, making them relatively non-toxic, whereas oximes K-107, K-108 and K-113 (low IC50 and LD50) are far more toxic.

When given in vivo after OP exposure, best protection is conferred by K-27, reducing the relative risk of death to 16-58% of controls, which is significantly superior to pralidoxime in DFP-, ethyl-paraoxon- and methylparaoxon- exposure, and to obidoxime in ethyl-paraoxon- and methyl-paraoxon-exposure. Marked reduction in mortality is also achieved by K-48, K-53, K-74 and K-75, whereas K-107, K-108 and K-113 have no or only a very weak mortality-reducing effect. K-27 is the most promising K-oxime due to its strong reactivation potency, weak cholinesterase inhibition and high LD50, allowing administration in large, very efficacious dosages.

Keywords: Acetylcholine, azinphos-methyl, cholinesterase, cox analysis, DFP, nerve agent, paraoxon, pesticides, rat.

Gupta, R.C. Classification and uses of organophosphates and carbamates in: Toxicology of Organophosphate and Carbamate Compounds; Gupta, R.C., Ed.; Elsevier Academic Press: Amsterdam, Boston, Heidelberg, 2006, pp. 5-24.
Antonijevic, B.; Stojiljkovic, M.P. Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin. Med. Res., 2007, 5(1), 71-82.
Masson, P.; Nachon, F. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning. J. Neurochem., 2017, 142(Suppl. 2), 26-40.
Myhrer, T.; Aas, P. Pretreatment and prophylaxis against nerve agent poisoning: are undesirable behavioral side effects unavoidable? Neurosci. Biobehav. Rev., 2016, 71, 657-670.
Petroianu, G.A. Pharmacists adolf schall and ernst ratzlaff and the synthesis of tabun-like compounds: A brief history. Pharmazie, 2014, 69(10), 780-784.
Ballinger, E.C.; Ananth, M.; Talmage, D.A.; Role, L.W. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron, 2016, 91(6), 1199-1218.
Lorke, D.; Petroianu, G.; Oz, M. α7-Nicotinic acetylcholine receptors and β- Amyloid Peptides in Alzheimer's Disease In: Nicotinic Acetylcholine Receptor Technologies; Li M, Ed.; Springer Science + Business Media: Berlin, Heidelberg, , 2016; pp. 171-205.
Panchal, M.; Trivedi, D. Clinical profile in patients of organophosphorus poisoning. Int. J. Sci. Res., (Raipur), 2016, 5, 97-99.
Petroianu, G.; Toomes, L.M.; Petroianu, A.; Bergler, W.; Rufer, R. Control of blood pressure, heart rate and haematocrit during high-dose intravenous paraoxon exposure in mini pigs. J. Appl. Toxicol., 1998, 18(4), 293-298.
Petroianu, G.A. Organophosphate poisoning: The lesser-known face of a toxidrome. Eur. J. Emerg. Med., 2005, 12(2), 102-103.
Balali-Mood, M.; Balali-Mood, K. Neurotoxic disorders of organophosphorus compounds and their managements. Arch. Iran Med., 2008, 11(1), 65-89.
Hrabetz, H.; Thiermann, H.; Felgenhauer, N.; Zilker, T.; Haller, B.; Nahrig, J.; Saugel, B.; Eyer, F. Organophosphate poisoning in the developed world - a single centre experience from here to the millennium. Chem. Biol. Interact., 2013, 206(3), 561-568.
Blumenberg, A.; Benabbas, R.; deSouza, I.S.; Conigliaro, A.; Paladino, L.; Warman, E.; Sinert, R.; Wiener, S.W. Utility of 2-Pyridine Aldoxime Methyl Chloride (2-Pam) for Acute Organophosphate Poisoning: A systematic review and meta-analysis. J. Med. Toxicol., 2018, 14(1), 91-98.
World Health Organization. Public Health Impact of Pesticides Used in Agriculture., (Accessed March 13, 2019).
Eddleston, M.; Buckley, N.A.; Eyer, P.; Dawson, A.H. Management of acute organophosphorus pesticide poisoning. Lancet, 2008, 371(9612), 597-607.
Lekei, E.; Ngowi, A.V.; London, L. Acute pesticide poisoning in children: Hospital review in selected hospitals of tanzania. J. Toxicol., 2017, 4208405
Sudakin, D.L.; Power, L.E. Organophosphate exposures in the united states: A Longitudinal analysis of incidents reported to poison centers. J. Toxicol. Environ. Health, 2007, 70(2), 141-147.
Buckley, N.A.; Eddleston, M.; Li, Y.; Bevan, M.; Robertson, J. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst. Rev., 2011, (2), CD005085.
Eyer, P. In Memory of Ilse Hagedorn. Toxicology, 2007, 233(1-3), 3-7.
Johnson, M.K.; Jacobsen, D.; Meredith, T.J.; Eyer, P.; Heath, A.J.; Ligtenstein, D.A.; Marrs, T.C.; Szinicz, L.; Vale, J.A.; Haines, J.A. Evaluation of antidotes for poisoning by organophosphourus pesticides. J. Emerg. Med., 2000, 12(1), 22-37.
Lossen, W. Über Das Hydroxylamin. Zeitschrift Chemie, 1865, 8, 551-553.
Petroianu, G.A. The history of cholinesterase reactivation: Hydroxylamine and pyridinium aldoximes. Int. J. Pharm., 2012, 67(10), 874-879.
Stojiljkovic, M.P.; Jokanovic, M. Pyridinium oximes: Rationale for their selection as causal antidotes against organophosphate poisonings and current solutions for auto-injectors. Arh. Hig. Rada Toksikol., 2006, 57(4), 435-443.
Wilson, I.B. Acetylcholinesterase. Xi. Reversibility of tetraethyl pyrophosphate. J. Biol. Chem., 1951, 190(1), 111-117.
Wilson, I.B.; Ginsburg, B. A powerful reactivator of alkylphosphate-inhibited acetylcholinesterase. Biochim. Biophys. Acta, 1955, 18(1), 168-170.
Childs, A.F.; Davies, D.R.; Green, A.L.; Rutland, J.P. The reactivation by oximes and hydroxamic acids of cholinesterase inhibited by organo-phosphorus compounds. Br. J. Pharmacol. Chemother., 1955, 10(4), 462-465.
Poziomek, E.J.; Hackley, B.E.; Seinberg, G.M. Pyridinium aldoximes. J. Org. Chem., 1958, 23, 714-717.
Hobbiger, F.; O’Sullivan, D.G.; Sadler, P.W. New potent reactivators of acetocholinesterase inhibited by tetraethyl pyrophosphate. Nature, 1958, 182(4648), 1498-1499.
Hobbiger, F.; Sadler, P.W. Protection against lethal organophosphate poisoning by quaternary pyridine aldoximes. Br. J. Pharmacol. Chemother., 1959, 14(2), 192-201.
Lorke, D.E.; Hasan, M.Y.; Arafat, K.; Kuca, K.; Musilek, K.; Schmitt, A.; Petroianu, G.A. In vitro oxime protection of human red blood cell acetylcholinesterase inhibited by diisopropyl-fluorophosphate. J. Appl. Toxicol., 2008, 28(4), 422-429.
Lorke, D.E.; Petroianu, G.A. Minireview: Does in vitro testing of oximes help predict their in vivo action after paraoxon exposure? J. Appl. Toxicol., 2009, 29(6), 459-469.
Petroianu, G.A.; Lorke, D.E.; Kalasz, H. Comparison of the ability of pyridinium aldoximes to reactivate human red blood cell acetylcholinesterases inhibited by ethyl- and methyl-paraoxon. Curr. Org. Chem., 2012, 16(10), 1359-1369.
Marrs, T.C. Toxicology of oximes used in treatment of organophosphate poisoning. Adverse Drug React. Toxicol. Rev., 1991, 10(1), 61-73.
Lüttringhaus, A.; Hagedorn, I. Quartӓre Hydroxyiminomethyl-Pyridiniumsalze. Das Dichlorid Des Bis-(4-Hydroxyiminomethyl-1-Pyridinium-Methyl)-Ethers (Lueh6).[Quaternary Hydroxyiminomethylpyridinium Salts. The Dischloride of Bis-(4-Hydroxyiminomethyl-1-Pyridinium-Methyl)-Ether (Lueh6), A New Reactivator of Acetylcholinesterase inhibited by organic phosphoric acid esters]. Arzneimittelforschung, 1964, 14, 1-5.
Erdmann, W.D.; Von Clarmann, M. Ein Neuer Esterase-Reaktivator Für Die Behandlung Von Vergiftungen Mit Alkylphosphaten.[A new esterase reactivator for the treatment of Alkylphosphate Poisonings]. Dtsch. Med. Wochenschr., 1963, 88, 2201-2206.
Inns, R.H.; Leadbeater, L. The efficacy of bispyridinium derivatives in the treatment of organophosphonate poisoning in the guinea-pig. J. Pharm. Pharmacol., 1983, 35(7), 427-433.
Clement, J.G. Hi-6: Reactivation of central and peripheral acetylcholinesterase following inhibition by soman, Sarin and tabun in vivo in the rat. Biochem. Pharmacol., 1982, 31(7), 1283-1287.
Wetherell, J.; Price, M.; Mumford, H.; Armstrong, S.; Scott, L. Development of next generation medical countermeasures to nerve agent poisoning. Toxicology, 2007, 233(1-3), 120-127.
Lorke, D.E.; Petroianu, G.A. Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. J. Appl. Toxicol., 2019, 39(1), 101-116.
Worek, F.; Thiermann, H. The value of novel oximes for treatment of poisoning by organophosphorus compounds. Pharmacol. Ther., 2013, 139(2), 249-259.
Kuca, K.; Bielavsky, J.; Cabal, J.; Bielavska, M. Synthesis of a potential reactivator of Acetylcholinesterase—1-(4-Hydroxyiminomethylpyridinium)-3-(Carbamoylpyridinium)Propane Dibromide. Tetrahedron Lett., 2003, 44(15), 3123-3125.
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, 2006, 69(20), 1875-1882.
Kuca, K.; Jun, D. Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes. J. Med. Toxicol., 2006, 2(4), 141-146.
Musilek, K.; Komloova, M.; Holas, O.; Horova, A.; Pohanka, M.; Gunn-Moore, F.; Dohnal, V.; Dolezal, M.; Kuca, K. Mono-Oxime bisquaternary acetylcholinesterase reactivators with Prop-1,3-Diyl Linkage-Preparation, in vitro screening and molecular docking. Bioorg. Med. Chem., 2011, 19(2), 754-762.
Berend, S.; Vrdoljak, A.L.; 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., 2008, 175(1-3), 413-416.
Kuca, K.; Musilova, L.; Palecek, J.; Cirkva, V.; Paar, M.; Musilek, K.; Hrabinova, M.; Pohanka, M.; Karasova, J.Z.; Jun, D. Novel Bisquaternary Oximes--Reactivation of Acetylcholinesterase and Butyrylcholinesterase inhibited by paraoxon. Molecules, 2009, 14(12), 4915-4921.
Musilek, K.; Kuca, K.; Dohnal, V.; Jun, D.; Marek, J.; Koleckar, V. Two step synthesis of a non-symmetric acetylcholinesterase reactivator. Molecules, 2007, 12(8), 1755-1761.
Worek, F.; Von der Wellen, J.; Musilek, K.; Kuca, K.; Thiermann, H. Reactivation kinetics of a homologous series of Bispyridinium Bis-Oximes with nerve Agent-Inhibited human acetylcholinesterase. Arch. Toxicol., 2012, 86(9), 1379-1386.
Kassa, J.; Humlicek, V. A comparison of the potency of newly developed oximes (K074, K075) and currently available oximes (Obidoxime, Trimedoxime, Hi-6) to counteract acute toxic effects of tabun and cyclosarin in mice. Drug Chem. Toxicol., 2008, 31(1), 127-135.
Musilek, K.; Holas, O.; Kuca, K.; Jun, D.; Dohnal, V.; Dolezal, M. Synthesis of a novel series of non-symmetrical bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase. J. Enzyme Inhib. Med. Chem., 2007, 22(4), 425-432.
Bajgar, J. Organophosphates/Nerve agent poisoning: Mechanism of action, diagnosis, prophylaxis, and treatment. Adv. Clin. Chem., 2004, 38, 151-216.
Jokanovic, M.; Stojiljkovic, M.P. Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning. Eur. J. Pharmacol., 2006, 553(1-3), 10-17.
Worek, F.; Eyer, P.; Aurbek, N.; Szinicz, L.; Thiermann, H. Recent advances in evaluation of oxime efficacy in nerve agent poisoning by in vitro analysis. Toxicol. Appl. Pharmacol., 2007, 219(2-3), 226-234.
McCombie, H.; Saunders, B.C. Alkyl fluorophosphonates: Preparation and physiological properties. Nature, 1946, 157, 287-289.
Lorke, D.E.; Nurulain, S.M.; Hasan, M.Y.; Kuca, K.; Musilek, K.; Petroianu, G.A. Eight new bispyridinium oximes in comparison with the conventional oximes pralidoxime and obidoxime: in vivo efficacy to protect from diisopropylfluorophosphate toxicity. J. Appl. Toxicol., 2008, 28(7), 920-928.
Sanchez-Fortun, S.; Barahona, M.V. Toxicity and characterization of cholinesterase-inhibition induced by diisopropyl fluorophosphate in artemia salina larvae. Ecotoxicol. Environ. Saf., 2009, 72(3), 775-780.
Koelle, G.B. Protection of cholinesterase against irreversible inactivation by Di-Isopropyl Fluorophosphate in vitro. J. Pharmacol. Exp. Ther., 1946, 88(3), 232-237.
Galli, A.; Mori, F. Effectiveness of 1,2,3,4-Tetrahydro-9-Aminoacridine (Tha) as a pretreatment drug for protection of mice from acute Diisopropylfluorophosphate (Dfp) intoxication. Arch. Toxicol., 1991, 65(4), 330-334.
Koster, R. Synergisms and antagonisms between physostigmine and di-isopropyl fluorophosphate in cats. J. Pharmacol. Exp. Ther., 1946, 88(1), 39-46.
Modell, W.; Krop, S. Antidotes to poisoning by di-isopropyl fluorophosphate in cats. J. Pharmacol. Exp. Ther., 1946, 88(1), 34-38.
Meshorer, E.; Erb, C.; Gazit, R.; Pavlovsky, L.; Kaufer, D.; Friedman, A.; Glick, D.; Ben-Arie, N.; Soreq, H. Alternative splicing and neuritic mrna translocation under long-term neuronal hypersensitivity. Science, 2002, 295(5554), 508-512.
McBain, E.H. Diagnosis and treatment of glaucoma; A review of recent developments. Calif. Med., 1954, 81(3), 231-234.
Schrader, G. The Development of new insecticides, in: British Intelligence. Stationery Office. Objectives SubCommittee Final Report 714 (revised). Item No.8.: London-H.1\I.:. 1947.
Gupta, R.C. Introduction. In: Toxicology of Organophosphate and Carbamate Compounds; Gupta, R.C., Ed.; Elsevier Academic Press: Amsterdam, Boston, Heidelberg, 2006; pp. 3-4.
Konst, H.; Plummer, P.J. Acute and chrone toxicity of parathion to warm-blooded animals. Can. J. Comp. Med. Vet. Sci., 1950, 14(3), 90-108.
Jan, Y.H.; Richardson, J.R.; Baker, A.A.; Mishin, V.; Heck, D.E.; Laskin, D.L.; Laskin, J.D. Vitamin K3 (Menadione) redox cycling inhibits cytochrome P450-Mediated metabolism and inhibits parathion intoxication. Toxicol. Appl. Pharmacol., 2015, 288(1), 114-120.
Garcia, S.J.; Abu-Qare, A.W.; Meeker-O’Connell, W.A.; Borton, A.J.; Abou-Donia, M.B. Methyl Parathion: A review of health effects. J. Toxicol. Environ. Health B Crit. Rev., 2003, 6(2), 185-210.
Isbister, G.K.; Mills, K.; Friberg, L.E.; Hodge, M.; O'Connor, E.; Patel, R.; Abeyewardene, M.; Eddleston, M. Human methyl parathion poisoning., Clin., Toxicol, (Phila), . 2007, 45(8), 956-960.
Ruckart, P.Z.; Kakolewski, K.; Bove, F.J.; Kaye, W.E. Long-Term neurobehavioral health effects of methyl parathion exposure in children in mississippi and ohio. Environ. Health Perspect., 2004, 112(1), 46-51.
Imtiaz, R.; Haugh, G. Analysis of environmental and biologic methyl parathion data to improve future data collection. Environ. Health Perspect., 2002, 6, 1071-1074.
Belenguer, V.; Martinez-Capel, F.; Masia, A.; Pico, Y. Patterns of presence and concentration of pesticides in fish and waters of the jucar river (Eastern Spain). J. Hazard. Mater., 2014, 265, 271-279.
Schulz, R. Field studies on exposure, effects, and risk mitigation of aquatic nonpoint-source insecticide pollution: A review. J. Environ. Qual., 2004, 33(2), 419-448.
Stoner, K.A.; Eitzer, B.D. Using a hazard quotient to evaluate pesticide residues detected in pollen trapped from honey bees (Apis Mellifera) in connecticut. PLoS One, 2013, 8(10), e77550.
Lewis, C.M. Azinphos-Methyl (Guthion) Risk Characterization Document (Revision No. 1). (Accessed March 13, 2019).
Schrader, G. Gusathion. In: Die Entwicklung Neuer Insektizider Phosphosäure-Ester; Ed.; Verlag Chemie: Weinheim. , 1963; pp. 176-186.
Buratti, F.M.; Volpe, M.T.; Fabrizi, L.; Meneguz, A.; Vittozzi, L.; Testai, E. Kinetic parameters of Opt Pesticide Desulfuration by C-DNA Expressed Human Cyps. Environ. Toxicol. Pharmacol., 2002, 11(3-4), 181-190.
Pasquet, J.; Mazuret, A.; Fournel, J.; Koenig, F.H. Acute oral and percutaneous toxicity of phosalone in the rat, in comparison with azinphosmethyl and parathion. Toxicol. Appl. Pharmacol., 1976, 37(1), 85-92.
Lorke, D.E.; Nurulain, S.M.; Hasan, M.Y.; Kuca, K.; Petroianu, G.A. Five experimental bispyridinium oximes in comparison with the conventional oximes pralidoxime and obidoxime: In vivo efficacy to protect from Azinphos-Methyl-Induced Toxicity. J. Environ. Immunol. Toxicol., 2013, 1(1), 44-50.
Petroianu, G.A.; Nurulain, S.M.; Hasan, M.Y.; Kuca, K.; Lorke, D.E. Reversible cholinesterase inhibitors as Pre-Treatment for Exposure to Organophosphates: Assessment Using Azinphos-Methyl. J. Appl. Toxicol., 2015, 35(5), 493-499.
Holmes, R.; Robins, E.L. The reversal by oximes of neuromuscular block produced by Anticholinesterases. Br. J. Pharmacol. Chemother., 1955, 10(4), 490-495.
Bergner, A.D.; O’Neill, J.J. A modification of the koelle technique for use with oximes. the journal of histochemistry and cytochemistry. J. Histochem. Cytochem., 1958, 6(1), 72-74.
Petroianu, G.A.; Missler, A.; Zuleger, K.; Thyes, C.; Ewald, V.; Maleck, W.H. Enzyme reactivator treatment in organophosphate exposure: Clinical relevance of thiocholinesteratic activity of pralidoxime. J. Appl. Toxicol., 2004, 24(6), 429-435.
Worek, F.; Mast, U.; Kiderlen, D.; Diepold, C.; Eyer, P. Improved determination of acetylcholinesterase activity in human whole blood. clinica chimica acta. Int. J. Clin. Chem., 1999, 288(1-2), 73-90.
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. A new and rapid Colorimetric Determination of Acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7, 88-95.
Winter, M.; Wille, T.; Musilek, K.; Kuca, K.; Thiermann, H.; Worek, F. Investigation of the reactivation kinetics of a large series of Bispyridinium Oximes with Organophosphate-Inhibited Human Acetylcholinesterase. Toxicol. Lett., 2016, 244, 136-142.
Petroianu, G.A.; Arafat, K.; Kuca, K.; Kassa, J. Five Oximes (K-27, K-33, K-48, Bi-6 and Methoxime) in comparison with pralidoxime: in vitro reactivation of red blood cell Acetylcholinesterase inhibited by Paraoxon. J. Appl. Toxicol., 2006, 26(1), 64-71.
Petroianu, G.A.; Arafat, K.; Nurulain, S.M.; Kuca, K.; Kassa, J. In vitro Oxime reactivation of red blood cell Acetylcholinesterase inhibited by Methyl-Paraoxon. J. Appl. Toxicol., 2007, 27(2), 168-175.
Kuca, K.; Musilek, K.; Jun, D.; Pohanka, M.; Ghosh, K.K.; Hrabinova, M. Oxime K027: novel low-toxic candidate for the universal reactivator of nerve agent- and Pesticide-Inhibited Acetylcholinesterase. J. Enzyme Inhib. Med. Chem., 2010, 25(4), 509-512.
Gupta, B.; Singh, N.; Sharma, R.; Foretic, B.; Musilek, K.; Kuca, K.; Acharya, J.; Satnami, M.L.; Ghosh, K.K. Assessment of antidotal efficacy of cholinesterase reactivators against paraoxon: In vitro reactivation kinetics and physicochemical properties. Bioorg. Med. Chem. Lett., 2014, 24(19), 4743-4748.
Cox, D.R. Regression models and life tables. J. R. Stat. Soc. , 1972, 34, 189-220.
Nurulain, S.M.; Lorke, D.E.; Hasan, M.Y.; Shafiullah, M.; Kuca, K.; Musilek, K.; Petroianu, G.A. Efficacy of eight experimental bispyridinium oximes against paraoxon-induced mortality: Comparison with the conventional oximes pralidoxime and obidoxime. Neurotox. Res., 2009, 16(1), 60-67.
Petroianu, G.A.; Lorke, D.E. Pyridinium oxime reactivators of cholinesterase inhibited by Diisopropyl-Fluorophosphate (Dfp): Predictive value of in vitro testing for in vivo efficacy. Mini Rev. Med. Chem., 2008, 8(13), 1328-1342.
Becker, C.; Worek, F.; John, H. Chromatographic analysis of toxic phosphylated oximes (Pox): A brief overview. Drug Test. Anal., 2010, 2(10), 460-468.
Kiderlen, D.; Eyer, P.; Worek, F. Formation and Disposition of Diethylphosphoryl-Obidoxime, a Potent Anticholinesterase That Is Hydrolyzed by Human Paraoxonase (Pon1). Biochem. Pharmacol., 2005, 69(12), 1853-1867.
Stenzel, J.; Worek, F.; Eyer, P. Preparation and characterization of Dialkylphosphoryl-Obidoxime conjugates, potent anticholinesterase derivatives that are quickly hydrolyzed by human paraoxonase (Pon1192q). Biochem. Pharmacol., 2007, 74(9), 1390-1400.
Petroianu, G.A.; Lorke, D.E.; Athauda, G.; Kalasz, H. Pralidoxime and obidoxime: phosphylationinduced changes in logp (Partition Coefficient). J. Environ. Immunol. Toxicol., 2013, 1(1), 35-40.
Eyer, P.; Hell, W.; Kawan, A.; Klehr, H. Studies on the decomposition of the Oxime Hi 6 in aqueous solution. Arch. Toxicol., 1986, 59(4), 266-271.
Liu, W.F.; Hu, N.W.; Beaton, J.M. Behavioral toxicological assessment of oral Pralidoxime Methanesulfonate in the rat. Neurotoxicol. Teratol., 1984, 6(2), 121-127.
Von, B. K.; Fischer, G.; Mueller, O.; Oldiges, H.; Zoch, E. Die Antidotwirkung Von Bis-(4-Hydroxyiminomethyl-1-Pyridiniummethyl)-Ether-Dichlorid Bei Mit Alkylphosphat Vergifteten Ratten.[the antidote effect of Bis-(4-Hydroxyiminomethyl-1-Pyridiniummethyl)-Ether Dichloride in Alkylphosphate-Poisoned Rats]. Arzneimittelforschung, 1964, 14, 85-88.
Boelcke, G.; Gaaz, J.W. Zur Frage Der Lebertoxicitaet Von Nitrostigmin (E 605 Forte) Und Obidoxim (Toxogonin) an Hunden.[Hepatotoxicity of Nitrostigmine (E 605 Forte) and Obidoxime (Toxogonin) in Dogs]. Arch. Toxikol., 1970, 26(2), 93-101.
Boelcke, G.; Feise, G.; de Cassan, K.; Keyser, E. Der Einfluss Der Vergiftung Durch Alkylphosphate Und Der Spezifischen Antidot Therapie Auf Die Leberfunktion Von Raten Und Kaninchen.[Effect of Alkylphosphate Poisoning and Specific Antidote Therapy on the liver function in rats and rabbits]. Arzneimittelforschung, 1970, 20(6), 770-774.
Calesnick, B. Christensen; Richter, M. Human toxicity of various Oximes. 2-Pyridine Aldoxime Methyl Chloride, Its methane sulfonate salt, and 1,1′-Trimethylenebis-(4-Formylpyridinium Chloride). Arch. Environ. Occup. Health, 1967, 15(5), 599-608.
Clement, J.G. Toxicology and pharmacology of Bispyridium Oximes--Insight into the mechanism of action vs soman poisoning in vivo. Fundamental and applied toxicology. Toxicol. Sci., 1981, 1(2), 193-202.
Muckova, L.; Pejchal, J.; Jost, P.; Vanova, N.; Herman, D.; Jun, D. Cytotoxicity of acetylcholinesterase reactivators evaluated in vitro and its relation to their structure. Drug Chem. Toxicol., 2018, 1-5.
Prado, A.; Petroianu, G.A.; Lorke, D.E.; Chambers, J.W. A trivalent approach for determining in vitro toxicology: Examination of oxime K027. J. Appl. Toxicol., 2015, 35(2), 219-227.
Spicakova, A.; Anzenbacher, P.; Liskova, B.; Kuca, K.; Fusek, J.; Anzenbacherova, E. Evaluation of possible inhibition of human liver drug metabolizing Cytochromes P450 by two new Acetylcholinesterase Oxime-Type reactivators. food and chemical toxicology. Food Chem. Toxicol., 2016, 88, 100-104.
Janockova, J.; Gulasova, Z.; Plsikova, J.; Musilek, K.; Kuca, K.; Mikes, J.; Culka, L.; Fedorocko, P.; Kozurkova, M. Interaction of cholinesterase modulators with DNA and their cytotoxic activity. Int. J. Biol. Macromol., 2014, 64, 53-62.
Zunec, S.; Radic, B.; Kuca, K.; Musilek, K.; Lucic Vrdoljak, A. Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning. Arh. Hig. Rada Toksikol., 2015, 66(2), 129-134.
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., 2008, 103(2), 119-123.
Worek, F.; Thiermann, H.; Wille, T. Oximes in organophosphate poisoning: 60 Years of hope and despair. Chem. Biol. Interact., 2016, 259, 93-98.

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DOI: 10.2174/1385272823666190408114001
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