Acta Med. 2010, 53: 207-211

Optimal Choice of Acetylcholinesterase Reactivators for Antidoral Treatment of Nerve Agent Intoxication

Jiří Bajgar

University of Defence in Brno, Faculty of Military Health Sciences in Hradec Králové, Department of Toxicology, Czech Republic

Received June 14, 2010
Accepted July 2, 2010


1. Bajgar J. Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis and treatment. Adv.Clin.Chem. 2004; 38: 151–216. <>
2. Bajgar J, Fusek J, Kuca K, Bartosova L, Jun D. Treatment of organophosphate intoxication using cholinesterase reactivators: facts and fiction. Mini-Rev. Med. Chem. 2007; 7: 461–466. <>
3. Bajgar J, Kuca K, Jun D, Bartosova L, Fusek J. Cholinesterase reactivators: the fate and effects in the organism poisoned with organophosphates/nerve agents. Curr. Drug Metab. 2007; 8: 803–809. <>
4. Bajgar J, Hajek P, Karasova J, Slizova D, Krs O, Kuca K, Jun D, Fusek J, Capek L. Inhibition of acetylcholinesterase in different structures of the rat brain following soman intoxication pretreated with Huperzine A. Int. J. Mol. Sci. 2007; 8: 1165–1176. <>
5. Bajgar J. Treament and prophylaxis of nerve agent/organophosphates intoxication. Therap. Pharmacol. Clin. Toxicol. 2009; 13: 247–253.
6. Bajgar J, Fusek J, Kassa J, Kuca K, Jun D. Pharmacological prophylaxis against nerve agent poisoning: experimental studies and practical implications, Chapter 64. In: Handbook of Toxicology of Chemical Warfare Agents (R.C. Gupta, Ed.), Elsevier – Academic Press, 2009, pp. 877–885.
7. Bajgar J. Development of antidotes against nerve agents in the Czech Republic. ASA Newslett. 2009; 09–8: 7–9.
8. Bajgar J, Zdarova Karasova J, Kassa J, Cabal J, Fusek J, Blaha V, Tesarova V. Tabun-inhibited rat tissue and blood cholinesterases and their reactivation with the combination of trimedoxime and HI-6 in vivo. Chem.-Biol. Interact. 2010; 187:287–290. <>
9. Cabal J, Kuca K, Kassa J. Specification of the structure of oximes able to reactivate tabun-inhibited acetylcholinesterase. Basic Clin. Pharmacol. Toxicol. 2004; 95: 81–86. <>
10. Calic M, Lucic-Vrdoljak A, Radic B, Jelic D, Jun D, Kuca K, Kovarik Z. 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 2006; 219: 85–96. <>
11. Clement JG, Hansen AS, Boulet CA. Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice. Arch. Toxicol. 1992; 66: 216–219. <>
12. Clement JG, Bailey DG, Madill HD, Tran LT, Spence JD. The acetylcholinesterase oxime reactivator in man: pharmacokinetics and tolerability in combination with atropine. Biopharm. Drug Dispos. 1995; 6: 415–425. <>
13. Delfino RT, Ribeiro TS, Figueroa-Villar JD. Organophosphorus compounds as chemical warfare agents: a review. J. Braz. Chem. Soc., 2009; 20: 407–428. <>
14. Eddleston M, Eyer P, Worek F, Mohamed F, Senarathna L, von Mayer L, Juszczak E, Hittarage A, Azhar S, Dissanayake W, Rezvi Sheriff MH, Szinicz L, Dawson AH, Buckley NA. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005; 366: 1452–1459. <>
15. Eyer P. The role of oximes in the menagement of organophosphorus pesticide poisoning. Toxicol. Rev. 2003; 22: 165–190. <>
16. Fusek J, Bajgar J, Kassa J, Hajek P, Slizova D, Krs O. Differences in the action of G- and V-agents, Chapter 2. In: Central and peripheral nervous system: effects of highly toxic organophosphates and their antidotes (J. Bajgar, Ed.), Research Signpost, Kerala, 2009, pp. 9–17.
17. 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. 2009; 16: 2177–2188. <>
18. Jovanovic D, Randelovic S, Joksovic D, Todorovic V. Farmakokinetika oksima HI-6 u bolesnika sa akutním trovanijem organofosfornim insekticidina. Vojnosanit. Pregl. 1993; 50: 27–31.
19. Kalasz HJ, Furész J, Tekes K. Monitoring the pharmacokinetics of pyridinium aldoximes in the body. Mini-Rev. Med. Chem. 2009; 9: 448–446. <>
20. Kassa J, Frankova K, Hoder P, Patocka J. A comparison of the efficacy ofcholinolytics atropine and biperiden (Akineton) in combination with HI-6 on cholinergic and stressogenic effects of soman in rats. Homeostasis 1996; 37: 135–136.
21. 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 1999; 132: 111–118. <>
22. Kassa J, Vachek J, Bajgar J, Fusek J. A combination of pyridostigmine with anticholinergic drugs: effective pharmacological pretreatment of soman-poisoned mice. ASA Newslett. 2001; 84: 16–19.
23. Kassa J, Vachek J, Bajgar J, Fusek J. A comparison of the efficacy of pharmacological pretreatments against soman in mice. Voj. Zdrav. Listy 2001; 70 (Suppl): 22–25.
24. Kassa J. Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J. Toxicol. Clin. Toxicol. 2002; 40: 803–816. <>
25. Kassa J, Kuca K, Cabal J. Comparison of the efficacy of currently available oximes against tabun in rats. Biologia 2005; 60/Suppl.: 77–79.
26. 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. Environm. Hlth. 2006, part A; 69: 1875–1882. <>
27. Kassa J, Kuca K, Karasova J, Musilek K, Jun D, Bajgar J, Cabal J, Stetina R, Fusek J. Development of new reactivators of tabun inhibited acetylcholinesterase and the evaluation of thein efficacy by in vitro and in vivo methods. HFM-149 Symposium on “Defense against the effects of chemical toxic hazards: Toxicology, diagnosis and medical Countermeasures”. Edinburgh, Scotland (GBR), 8–10 October 2007. Session 4, OP Medical Countermeasures, No 17.
28. Kassa J, Jun D, Kuca K, Bajgar J. Comparison of reactivating and therapeutic efficacy of two salts of the oxime HI-6 against tabun, soman and cyclosarin in rats. Bas. Clin. Pharmacol. Toxicol. 2007; 101: 328–332. <>
29. Kassa J, Bajgar J, Fusek J. Efects of nerve agents, Chapter 1. In: Central and peripheral nervous system: effects of highly toxic organophosphates and their antidotes (J. Bajgar, Ed.), Research Signpost, Kerala, 2009, pp. 1–8.
30. Kuca K, Cabal J, Kassa J. In vitro reactivation of sarin-inhibited brain acetylcholinesterase from various species by various oximes. J. Enz. Inh. Med. Chem. 2005; 20: 227–232. <>
31. Kuca K, Jun D, Bajgar J. Structural factors influencing potency of currently used acetylcholinesterase reactivators for treatment of cyclosarin intoxications. Curr. Pharm. Design 2007; 13: 3445–3452. <>
32. Kuca K, Musilek K, Stodulka P, Marek J, Hanusova P, Jun D, Hrabinova M, Kassa J, Dolezal B. Twelve different HI-6 salts and their potency to reactivate cyclosarin inhibited AChE in vitro. Lett. Drug Des. Discov. 2007; 4: 510–512. <>
33. Kuca K, Musilek K, Jun D, Bajgar J, Kassa J. Novel oximes, Chapter 66. In: Handbook of Toxicology of Chemical Warfare Agents (R.C. Gupta, Ed.), Elsevier – Academic Press, 2009, pp. 997–1021.
34. Kuca K, Jun D, Kassa J, Marek J, Stodulka P, Musilek K, Dolezal B, Povraznik J. Development of new Czech autoinjector with oxime HI-6 DMS. CBMTS – Industry, Dubrovnik (Croatia), 5–10 April 2009.
35. Kusic R, Boskovic B, Vojvodic V, Jovanovic D. HI-6 in man: blood levels, urinary excretion, and tolerance after intramuscular administration of the oxime to healthy volunteers. Fund. Appl. Toxicol. 1985; 5: S89–S97.
36. 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. 2006; 25: 231–243. <>
37. Marrs T, Maynard RL, Sidell FR. Chemical warfare agents – toxicology and treatment, John Wiley and Sons, 1996, pp. 83–113.
38. Mesa M. From battlefield to backpack: evolution of the Auto-injector. ASA Newslett. 2010; 10–1: 15–18.
39. Milatovic D, Jokanovic M. Pyridinium oximes as cholinesterase reactivators in the treatment of OP poisoning, Chapter 65. In: Handbook of Toxicology of Chemical Warfare Agents (R.C. Gupta, Ed.), Elsevier – Academic Press, 2009, pp. 985–996.
40. Musilek K, Kuca K, Jun D, Dohnal V, Dolezal M. Synthesis of a novel series of bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase J. Enzyme Inhib. Med. Chem. 2005; 20: 409–415. <>
41. Musilek K, Jun D, Cabal J. Kassa J, Gunn-More F, Kuca K. Design of a potent reactivator of tabun-inhibited acetylcholinesterase – synthesis and evaluation of (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). J. Med. Chem. 2007; 50: 5514–5518. <>
42. Myhrer T. Prophylactic and therapeutic measures in nerve agent poisoning, Chapter 63. In: Handbook of Toxicology of Chemical Warfare Agents (R.C. Gupta, Ed.), Elsevier – Academic Press, 2009, pp. 965–973.
43. Petroianu GA, Arafat K, Nurulain SM, Kuca K, Kassa J. In vitro oxime reactivation of red blood cell acetylcholinesterase inhibited by methyl-paraoxon. J. Appl. Toxicol. 2007; 27: 168–175. <>
44. Thiermann H, Mast U, Klimmek R, Eyer P, Hibler A, Pfab R, Felgenhauer N, Zilker T. Cholinesterase status, pharmacokinetics and laboratory findings during obidoxime therapy in organophosphate poisoned patients. Hum. Exp. Toxicol. 1997; 16: 473–480. <>
45. Worek F, Diepold C, Eyer P. Dimethylphosphoryl-inhibited human cholinesterases: inhibition, reactivation, and aging kinetics Arch. Toxicol. 1999; 73: 7–14. <>
46. Worek F, Aurbek N, Thiermann H. Reactivation of organophosphate-inhibited human AChE by combinations of obidoxime and HI-6 in vitro. J. Appl. Toxicol. 2007; 27: 582–588. <>
47. Wright L, Pope C, Liu J. The nervous system, as a target for chemical warfare agents, Chapter 32. In: Handbook of Toxicology of Chemical Warfare Agents (R.C. Gupta, Ed.), Elsevier – Academic Press, 2009, pp. 463–480.
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