Modern aspects of development of basic therapy and prevention means of organophosphorus compounds acute poisoning (review of literature)

  • Authors: M.L. Zinovieva, N.V. Kurdil, M.G. Prodanchuk, O.P. Kravchuk, P.G. Zhminko
  • UDC: 615.9; 615.917; 615.279
  • DOI: 10.33273/2663-4570-2021-91-2-79-90
Download attachments:

LI Medved’s Research Centre of Preventive Toxicology, Food and Chemical Safety, Ministry of Health, Ukraine (State Enterprise), Kyiv, Ukraine


ABSTRACT. Introduction. Despite large experience in the use of basic therapies for acute poisoning by organophosphorus compounds (OPs)of anticholinesterase action and the results of research conducted in the world, the current methods of treatment of such poisonings are insufficient and do not meet requirements for effective treatment and health.

Purpose. Based on the analysis of scientific publications to outline the main directions of modern developments of drugs for basic therapy and prevention of acute OPs poisoning at the stages of their experimental assessment.

Methods. A systematic content analysis of literature data using the PubMed database was performed.

Results. Modern principles of pharmacotherapy of acute anticholinesterase OPs poisoning are based on the use of anticholinergic drugs (mainly atropine), cholinesterase reactivators and anticonvulsant action. M-cholinolytic therapy remains a mandatory basic component of the treatment of acute OPs poisoning. Today, research is aimed at finding less toxic M-cholinolytics with a wider range of therapeutic effects. A cholinesterase reactivator has not yet been developed that has such a spectrum of action that is able to prevent the central effects of OPs poisoning. The effectiveness of the combined action of AChE reactivators has also been insufficiently studied. One approach to solving the problem of protecting the central nervous system in OPs poisoning may be to find a combination of peripheral cholinesterase reactivators with neuroprotectors capable of overcoming the blood-brain barrier. The development of anticonvulsant therapeutic agents requires further study of the mechanism of status epilepticus in acute OPs poisoning.

Conclusions. There is an intensive search for OPs poisoning treatments around the world. But in time the relevance and importance of finding and implementing a unified methodology for studying the therapeutic efficacy of a wide range of pharmacological agents at the stage of their preclinical evaluation. Efforts to find means of pharmacologically correcting OPs poisoning should be accompanied by the development of a more prudent regulatory policy in the field of pesticide use. It is also necessary to create a clear and consistent policy on information measures that would focus on the dangers of OPs, as well as contribute to the prevention of mental disorders that provoke suicidal consequences.

Key Words: organophosphorus compounds, acute poisoning, means of basic therapy, means of prevention.



1. Watson WA, Litovitz TL, Rodgers GC, Klein-Schwartz W, Youniss J, Rose SR, Borys D, May ME. 2002 annual report of the American association of poison control centers toxic exposure surveillance system 1. The American journal of emergency medicine. 2003;21(5):353-421.

2. Robb EL, Baker MB. Organophosphate toxicity. StatPearls [Internet]. 2020 Jul 27. []

3. Ivashchenko OV, Zozulia IS, Kurdil NV. Suchasni aspekty hostrykh otruien fosfororhanichnymy insektytsydamy. Zbirnyk naukovykh prats spivrobitnykiv NMAPO im. PL Shupyka. 2018(30):683–98.

4. Bertolote JM, Fleischmann A, Eddleston M, Gunnell D. Deaths from pesticide poisoning: a global response. The British Journal of Psychiatry. 2006 Sep;189(3):201–3.

5. Bonvoisin T, Utyasheva L, Knipe D, Gunnell D, Eddleston M. Suicide by pesticide poisoning in India: a review of pesticide regulations and their impact on suicide trends. BMC public health. 2020 Dec;20(1):1–6.

6. Marcus H, De Souza RJ. Risk Factors for Acute Pesticide Poisoning in Developing Countries: A Systematic Review. Global Health: Annual Review. 2020 Jul 4;1(5):4.

7. Prodanchuk NG. Balan GM. Krivenchuk VE. Prodanchuk GN. Kurdil NV. Babich VA. Kharchenko OA. Bubalo NN. O neobkhodimosti sozdaniya proizvodstva reaktivatorov kholinesterazy v Ukraine dlya lecheniya ostrykh otravleniy fosfororganicheskimi soyedineniyami. Suchasni problem toksykolohii, kharchovoi ta khimichnoi bezpeky. 2014;3-4:14-22.

8. Ustinova LA, Seredynska NM, Kurdil NV, Sahlo VI, Barasii MI, Yevtodiev OA. Toksykanty antykholinesteraznoi dii: mekhanizm dii, klinichni oznaky ta aktualni pytannia zabezpechennia zasobamy antydotnoi terapii. Suchasni problem toksykolohii, kharchovoi ta khimichnoi bezpeky. 2017;3:73-82.

9. Harvey SP, McMahon LR, Berg FJ. Hydrolysis and enzymatic degradation of Novichok nerve agents. Heliyon. 2020 Jan 1;6(1):e03153.

10. Vale JA, Marrs TC, Maynard RL. Novichok: a murderous nerve agent attack in the UK. Clinical Toxicology. 2018 Nov 2;56(11):1093–7.

11. Masterson J. OPCW to Investigate Navalny Poisoning. Arms Control Today. 2020 Oct 1;50(8):28–9.

12. Costa LG. Current issues in organophosphate toxicology. Clinica chimica acta. 2006 Apr 1;366(1–2):1–3.

13. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL. Acetylcholinesterase: from 3D structure to function. Chemico-biological interactions. 2010 Sep 6;187(1-3):10–22.

14. Petrov KA. Kharlamova AD. Nikolskiy Eye. Kholinesterazy: vzglyad neyrofiziologa. Geny i kletki. 2014;9(3).

15. McDonough JH Jr, Shih TM. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neuroscience &biobehavioral reviews. 1997 Jan 1;21(5):559–79.

16. Zhuang Q, Young A, Callam CS, McElroy CA, Ekici ÖD, Yoder RJ, Hadad CM. Efforts towards treatments against aging of organophosphorus-inhibited acetylcholinesterase. Annals of the New York Academy of Sciences. 2016 Jun;1374(1):94–104.

17. Buckley NA, Roberts D, Eddleston M. Overcoming apathy in research on organophosphate poisoning. Bmj. 2004 Nov 18;329(7476):1231–3.

18. Peter JV, Moran JL, Graham PL. Advances in the management of organophosphate poisoning. Expert opinion on pharmacotherapy. 2007 Jul 1;8(10):1451–64.

19. Hulse EJ, Haslam JD, Emmett SR, Woolley T. Organophosphorus nerve agent poisoning: managing the poisoned patient. British journal of anaesthesia. 2019 Oct 1;123(4):457–63.

20. Bajgar J, Kuca K, Jun D, Bartosova L, Fusek J. Cholinesterase reactivators: the fate and effects in the organism poisoned with organophosphates/nerve agents. Current drug metabolism. 2007 Dec 1;8(8):803–9.

21. Eddleston M, Chowdhury FR. Pharmacological treatment of organophosphorus insecticide poisoning: the old and the (possible) new. British journal of clinical pharmacology. 2016 Mar;81(3):462–70.

22. Abedin MJ, Sayeed AA, Basher A, Maude RJ, Hoque G, Faiz MA. Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol. 2012; 8: 108–17.

23. Сonnors NJ, Harnett ZH, Hoffman RS. Comparison of current recommended regimens of atropinization in organophosphate poisoning. Journal of Medical Toxicology. 2014 Jun 1;10(2):143–7.

24. Arendse R, Irusen E. An atropine and glycopyrrolate combination reduces mortality in organophosphate poisoning. Human & experimental toxicology. 2009 Nov;28(11):715–20.

25. Kventsel I, Berkovitch M, Reiss A, Bulkowstein M, Kozer E. Scopolamine treatment for severe extra-pyramidal signs following organophosphate (chlorpyrifos) ingestion. Clin Toxicol (Phila). 2005;43(7):877–9.

26. Iyer R, Iken B, Leon A. Developments in alternative treatments for organophosphate poisoning. Toxicology letters. 2015 Mar 4;233(2):200–6.

27. Shemesh I, Bourvin A, Gold D, Kutscherowsky M. Chlorpyrifos poisoning treated with ipratropium and dantrolene: a case report. Journal of Toxicology: Clinical Toxicology. 1988 Jan 1;26(7):495–8.

28. Perrone J, Henretig F, Sims M, Beers M, Grippi MA. A role for ipratropium in chemical terrorism preparedness. Academic Emergency Medicine. 2003 Mar;10(3):290.

29. Eisenkraft A, Falk A. Possible role for anisodamine in organophosphate poisoning. Br J Pharmacol. 2016;173(11):1719–27.

30. Mercey G, Verdelet T, Renou J, Kliachyna M, Baati R, Nachon F, Jean L, Renard PY. Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents. Accounts of chemical research. 2012 May 15;45(5):756–66.

31. Musilek K, Dolezal M, Gunn‐Moore F, Kuca K. Design, evaluation and structure-аctivity relationship studies of the AChE reactivators against organophosphorus pesticides. Medicinal research reviews. 2011 Jul;31(4):548–75.

32. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Current neuropharmacology. 2013 May 1;11(3):315–35.

33. Petroianu GA. The history of cholinesterase reactivation: hydroxylamine and pyridinium aldoximes. Die PharmazieAn International Journal of Pharmaceutical Sciences. 2012 Oct 1;67(10):874–9.

34. Musilek K, Kuca K, Ghosh KK. Development and Structural Modifications of Cholinesterase Reactivators against Chemical Warfare Agents in Last Decade: A Review. Mini Rev Med Chem. 2015;15(1):58–72.

35. Wilson IB, Ginsburg S. Reactivation of acetylcholinesterase inhibited by alkylphosphates. Arch Biochem Biophys. 1955 Feb;54(2):569–71.

36. Lüttringhaus A, Hagedorn I. 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. Arzneimittel-Forschung. 1964 Jan;14:1–5.

37. Stojiljković MP, Pantelić D, Maksimović M. Tabun, sarin, soman and VX poisoning in rats: kinetics of inhibition of central and peripheral acetylcholinesterase, ageing, spontaneous and oxime-facilitated reactivation, Proceedings of VII International Symposium on Protection against Chemical and Biological Agents, Stockholm, Sweden, 2001:1–12.

38. de Jong LP, Verhagen MA, Langenberg JP, Hagedorn I, Löffler M. The bispyridinium-dioxime HLö-7: a potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman. Biochemical pharmacology. 1989 Feb 15;38(4):633–40.

39. Antonijevic B, Stojiljkovic MP. Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res. 2007;5(1):71–82.

40. Kokshareva NV, Kovtun SD, Kagan YuS, Mizyukova IG, Medvedev BM. Effect of a new cholinesterase reactivator, diethyxime, on the central nervous system. Byull. Eksp. Biol. Med.1977;83:29–32 (Abs. іn English).

41. Kenley RA, Howd RA, Mosher CW, Winterle JS. Nonquaternary cholinesterase reactivators. Dialkylaminoalkyl thioesters of alpha-ketothiohydroximic acids as reactivators of diisopropylphosphorofluoridate inhibited acetylcholinesterase. J Med Chem. 1981 Oct;24(10):1124–33.

42. Dube SN, Ghosh AK, Jeevarathinam K, Kumar D, Gupta SD, Pant BP, et al. Studies on the efficacy of diethyxime as an antidote against organophosphorus intoxication in rats. The Japanese Journal of Pharmacology.1986;41(3):267–71.

43. Shih TM, Koplovitz I, Kan RK, McDonough JH. In search of an effective in vivo reactivator for organophosphorus nerve agent-inhibited acetylcholinesterase in the central nervous system. Advanced Studies in Biology 2012;4(10):451–78.

44. Prozorovskiy VB. Skopichev VG. Panchenkova OA. Otsenka reaktivatora kholinesterazy karboksima kak sredstva profilaktiki otravleniy fosfororganicheskimi ingibitorami kholinesteraz. Psikhofarmakologiya I biologicheskaya narkologiya. 2008: 8(3-4): 2457–62.

45. Petroianu GA, Hasan MY, Nurulain SM, Nagelkerke N, Kassa J, Kuca K. New K-Oximes (K-27 and K-48) in Comparison with Obidoxime (LuH-6), HI-6, Trimedoxime (TMB-4), and Pralidoxime (2-PAM): Survival in Rats Exposed IP to the Organophosphate Paraoxon. Toxicol Mech Methods. 2007;17(7):401–8.

46. Petroianu GA, Nurulain SM, Nagelkerke N, Shafiullah M, Kassa J, Kuca K. Five oximes (K-27, K-48, obidoxime, HI-6 and trimedoxime) in comparison with pralidoxime: survival in rats exposed to methyl-paraoxon. J Appl Toxicol. 2007 Sep-Oct;27(5):453–7.

47. Atanasov VN, Petrova I, Dishovsky C. In vitro investigation of efficacy of new reactivators on OPC inhibited rat brain acetylcholinesterase. Chem Biol Interact. 2013 25;203(1):139–43.

48. Kalisiak J, Ralph EC, Cashman JR. Nonquaternary reactivators for organophosphate-inhibited cholinesterases. Journal of medicinal chemistry. 2012 Jan 12;55(1):465–74.

49. Taylor P, Yan-Jye S, Momper J, Hou W, CamachoHernandez GA, Rosenberg Y, Kovarik Z, Sit R, Sharpless KB. Assessment of ionizable, zwitterionic oximes as reactivating antidotal agents for organophosphate exposure. Chemico-biological interactions. 2019 Aug 1;308:194–7.

50. Chambers JE, Meek EC. Novel centrally active oxime reactivators of acetylcholinesterase inhibited by surrogates of sarin and VX. Neurobiology of disease. 2020 Jan 1;133:104487.

51. Dail MB, Leach CA, Meek EC, Olivier AK, Pringle RB, Green CE, Chambers JE. Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators Attenuate Organophosphate-Induced Neuropathology in the Rat Hippocampus. Toxicol Sci. 2019;169(2):465–74.

52. Shih TM, Skovira JW, O'Donnell JC, McDonough JH. Treatment with tertiary oximes prevents seizures and improves survival following sarin intoxication. J Mol Neurosci. 2010 Jan;40(1-2):63–9.

53. Malinak D, Nepovimova E, Jun D, Musilek K, Kuca K. Novel Group of AChE Reactivators-Synthesis, In Vitro Reactivation and Molecular Docking Study. Molecules. 2018 Sep 7;23(9):2291.

54. Sit RK, Fokin VV, Amitai G, Sharpless KB, Taylor P, Radić Z. Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification. J Med Chem. 2014;57(4):1378–89.

55. Worek F, Thiermann H, Wille T. Organophosphorus compounds and oximes: a critical review. Arch Toxicol. 2020;94(7):2275–2292.

56. Kassa J, Karasová JZ, Pavlíková R, Caisberger F, Bajgar J. The ability of oxime mixtures to increase the reactivating and therapeutic efficacy of antidotal treatment of cyclosarin poisoning in rats and mice. ActaMedica (Hradec Kralove). 2012;55(1):27–31.

57. Katz FS, Pecic S, Tran TH, Trakht I, Schneider L, Zhu Z, Ton-That L, Luzac M, Zlatanic V, Damera S, Macdonald J, Landry DW, Tong L, Stojanovic MN. Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates. Chembiochem. 2015;16(15):2205–15.

58. Bierwisch A, Wille T, Thiermann H, Worek F. Kinetic analysis of interactions of amodiaquine with human cholinesterases and organophosphorus compounds. Toxicol Lett. 2016;246:49–56.

59. Kobrlova T, Korabecny J, Soukup O. Current approaches to enhancing oxime reactivator delivery into the brain. Toxicology. 2019;423:75–83.

60. Okumura T, Takasu N, Ishimatsu S, Miyanoki S, Mitsuhashi A, Kumada K, et al. Report on 640 victims of the Tokyo subway Sarin attack. Ann Emerg Med 1996;28:129–35

61. 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(5):461–6.

62. Trinka E, Kälviäinen R. 25 years of advances in the definition, classification and treatment of status epilepticus. Seizure. 2017 Jan 1;44:65-73.

63. Aroniadou-Anderjaska V, Figueiredo TH, Apland JP, Braga MF. Targeting the glutamatergic system to counteract organophosphate poisoning: A novel therapeutic strategy. Neurobiology of disease. 2020 Jan 1;133:104406.

64. McCarren HS, McDonough JH Jr. Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides. Ann N Y Acad Sci. 2016 Jun;1374(1):144-50.

65. Masson P, Nachon F. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning. Journal of neurochemistry. 2017 Aug;142:26–40.

66. Philippens I, Jongsma M, Joosen M, Bouwman G, Vanwersch R. Prophylaxis against nerve agent toxicity: Physiological, behavioral, and neuroprotection of current and novel treatments. InHFM-149 Symposium'Defense against the Effects of Chemical Hazards: Toxicology, Diagnosis and Medical Countermeasures', Edinburgh, Scotland (GBR), 8-10 October 2007 2007 Jan 1.

67. Dunn MA, Sidell FR. Progress in medical defense against nerve agents. JAMA. 1989 Aug 4;262(5):649–52.

68. Wessler I, Kirkpatrick CJ. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol. 2008;154(8):1558–71.

69. Pohanka M. Cholinesterases, a target of pharmacology and toxicology. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011 Sep;155(3):219–29.

70. Wang T, Wang Y, Zhang L, Han B, Wang H, Li Y, Fu F. A novel approach to medical countermeasures against organophosphorus compound toxicity. Biomed Rep. 2013;1(6):901–906.

71. Bajaj P, Tripathy RK, Aggarwal G, Datusalia AK, Sharma SS, Pande AH. Refolded Recombinant Human Paraoxonase 1 Variant Exhibits Prophylactic Activity Against Organophosphate Poisoning. Appl Biochem Biotechnol. 2016 Sep;180(1):165–76.

72. Doctor BP, Saxena A. Bioscavengers for the protection of humans against organophosphate toxicity. Chem Biol Interact. 2005 Dec 15;157–158:167–71.

73. Worek F, Thiermann H, Wille T. Oximes in organophosphate poisoning: 60 years of hope and despair. Chem Biol Interact. 2016 Nov 25;259(Pt B):93–8.


Received 04/27/2021