Onset Rate and Intensity of Signs of Organophosphate Poisoning Related to Paraoxon Dose and Survival in Rats

  • Žana M Maksimović Dom zdravlja Modriča, Služba hitne medicinske pomoći; Medicinski fakultet Banja Luka, Centar za biomedicinska istraživanja
  • Dajana Duka
  • Nataša Bednarčuk
  • Ranko Škrbić Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srspka, Bosnia and Herzegovina
  • Miloš P Stojiljković Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srspka, Bosnia and Herzegovina
DOI: https://doi.org/10.5937/scriptamed52-31191
Keywords: Organophosphate, Acetylcholinesterase inhibitor, Paraoxon, Insecticide, Poisoning, Atropine

Abstract


Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate it. In the synaptic cleft, undestroyed and accumulated acetylcholine produce the acute cholinergic effects. The aim of this study was to determine the frequency, speed of onset and intensity of certain signs of paraoxon poisoning depending on dose and outcome of poisoning.

Methods: The study was conducted in adult Wistar rats. The median lethal dose (LD50) of paraoxon as well as protective ratio (PR) of atropine (10 mg/kg intramuscularly) was determined. Clinical signs of poisoning were observed: fasciculations, tremor, seizures, ataxia, piloerection, lacrimation, exophthalmos, bizzare/stereotypic behaviour and dyspnoea. The time from paraoxon injection to the first appearance of the sign of poisoning was recorded as well as the intensity of poisoning with evaluation at 10 time intervals throughout the 4 h observational period.

Results: The LD50 of paraoxon was 0.33 mg/kg (subcutaneously) and PR of atropine was 2.73. Dose-dependent, piloerection occurred more often (p = 0.009) and at higher intensity (p = 0.016) at higher doses. Fasciculations, tremor, seizures and ataxia occurred significantly earlier at higher doses of paraoxon (p = 0.015, 0.002, 0.021 and 0.016, respectively), as well as the intensity of seizure, tremor and fasciculation. Piloerection (p = 0.002) and seizures occurred more frequently (p = 0.009) in non-survivors. Fasciculations, tremor, seizures and ataxia occurred significantly earlier and at higher intensity in non-survivors (p < 0.001, for all parameters), as well as dyspnoea (p = 0.009 and p = 0.048). In atropine-protected rats, nicotinic effects persevered, so they were the prognostic parameter of the severity of the poisoning.

Conclusion: Seizures and fasciculations followed by tremor were strong prognostic parameters of the probability of lethal outcome of paraoxon poisoning. Also, the mentioned poisoning signs were with their intensity and speed of occurrence in a clear positive correlation with the administered dose of paraoxon. Even at high doses of paraoxon, atropine blocked the muscarinic (but not nicotinic) effects and somewhat mitigated the CNS toxic effects.

References

1. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. PubChem Compound Summary for CID 9395, Paraoxon. [Cited 2021-Mar-02]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Paraoxon
2. Kaushal J, Khatri M, Arya SK. A treatise on Organophosphate pesticide pollution: Current strategies and advancements in their environmental degradation and elimination. Ecotoxicol Environ Saf 2020 Oct 22;207:111483. doi: 10.1016/j.ecoenv.2020.111483.
3. WHO. Health topics: mental health [Internet]. Geneva. [Cited: 2020-Dec-30]. Available from https://www.who.int/mental_health/prevention/suicide/en/PesticidesHealth2.pdf
4. Stojiljković MP. Nerve agents – a clear and present danger to mankind. Scr Med 2019;50(3):109-11.
5. Adeyinka A, Muco E, Pierre L. Organophosphates. [Updated 2020 Aug 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499860/
6. Pope CN, Brimijoin S. Cholinesterases and the fine line between poison and remedy. Biochem Pharmacol 2018;153:205-16.
7. Eddleston M. Novel clinical toxicology and pharmacology of organophosphorus insecticide self-poisoning. Annu Rev Pharmacol Toxicol 2019 Jan 6;59:341-60.
8. Reddy BS, Skaria TG, Polepalli S, Vidyasagar S, Rao M, Kunhikatta V, Nair S, Thunga G. Factors associated with outcomes in organophosphate and carbamate poisoning: a retrospective study. Toxicol Res 2020 Feb 7;36(3):257-266.
9. Jokanović M, Stojiljković MP, Kovač B, Ristić D. Pyridinium oximes in the treatment of poisoning with organophosphorus compounds. In: Gupta RC. Handbook of Toxicology of Chemical Warfare Agents (Third Edition). Academic Press, 2020; 1145-59.
10. Worek F, Thiermann H, Wille T. Organophosphorus compounds and oximes: a critical review. Arch Toxicol 2020 Jul;94(7):2275-92.
11. Antonijevic B, Stojiljkovic MP. Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res 2007 Mar;5(1):71-82.
12. Vanova N, Pejchal J, Herman D, Dlabkova A, Jun D. Oxidative stress in organophosphate poisoning: role of standard antidotal therapy. J Appl Toxicol 2018 Aug;38(8):1058-70.
13. Henretig FM, Kirk MA, McKay CA Jr. Hazardous chemical emergencies and poisonings. N Engl J Med 2019 Apr 25;380(17):1638-55.
14. Amir A, Raza A, Qureshi T, Mahesar GB, Jafferi S, Haleem F, Ali Khan M. Organophosphate poisoning: demographics, severity scores and outcomes from National Poisoning Control Centre, Karachi. Cureus 2020 May 31;12(5):e8371. doi: 10.7759/cureus.8371.
15. Reddy BS, Skaria TG, Polepalli S, Vidyasagar S, Rao M, Kunhikatta V, Nair S, Thunga G. Factors associated with outcomes in organophosphate and carbamate poisoning: a retrospective study. Toxicol Res 2020 Feb 7;36(3):257-66.
16. Litchfield JT Jr, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther. 1949 Jun;96(2):99-113.
17. Misik J, Pavlikova R, Cabal J, Kuca K. Acute toxicity of some nerve agents and pesticides in rats. Drug Chem Toxicol 2015 Jan;38(1):32-6.
18. Kassa J, Misik J, Hatlapatkova J, Zdarova Karasova J, Sepsova V, Caisberger F, Pejchal J. The Evaluation of the reactivating and neuroprotective efficacy of two newly prepared bispyridinium oximes (K305, K307) in tabun-poisoned rats - a comparison with trimedoxime and the oxime K203. Molecules 2017 Jul 11;22(7):1152. doi: 10.3390/molecules22071152.
19. Holmstedt B. Pharmacology of organophosphorus cholinesterase inhibitors. Pharmacol Rev 1959 Sep;11:567-688.
20. Stojiljković MP, Škrbić R, Jokanović M, Kilibarda V, Bokonjić D, Vulović M. Efficacy of antidotes and their combinations in the treatment of acute carbamate poisoning in rats. Toxicology 2018 Sep 1;408:113-124.
21. Natoff IL, Reiff B. Effect of oximes on the acute toxicity of anticholinesterase carbamates. Toxicol Appl Pharmacol 1973 Aug;25(4):569-75.
22. Kords H, Lüllmann H, Ohnesorge FK, Wassermann O. Action of atropine and some hexane-1.6-bis-ammonium derivatives upon the toxicity of DFP im mice. Eur J Pharmacol 1968 Jul;3(4):341-6.
23. Albuquerque EX, Pereira EF, Aracava Y, Fawcett WP, Oliveira M, Randall WR, et al. Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci U S A 2006 Aug 29;103(35):13220-5.
24. Parkes MW, Sacra P. Protection against the toxicity of cholinesterase inhibitors by acetylcholine antagonists. Br J Pharmacol Chemother. 1954 Sep;9(3):299-305.
25. Krutak-Krol H, Domino EF. Comparative effects of diazepam and midazolam on paraoxon toxicity in rats. Toxicol Appl Pharmacol 1985 Dec;81(3 Pt 1):545-50.
26. Rump S, Faff J, Szymańska T, Bak W, Borkowska G. Efficacy of repeated pharmacotherapy in experimental acute poisonings with fluostigmine. Arch Toxicol 1976 Aug 18;35(4):275-80.
27. Eddleston M, Eyer P, Worek F, Mohamed F, Senarathna L, von Meyer L, et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005 Oct 22-28;366(9495):1452-9.
28. Namba T, Nolte CT, Jackrel J, Grob D. Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Am J Med 1971;50(4):475–492
29. Ballantyne B, Marrs TC. Overview of the biological and clinical aspects of organophosphates and carbamates. In: Ballantyne B, Marrs TC, eds. Clinical and experimental toxicology of
organophosphates and carbamates. Butterworth-Heinemann: Oxford Press; 1992; 3–14.
30. Houze P, Pronzola L, Kayouka M, Villa A, Debray M, Baud FJ. Ventilatory effects of low-dose paraoxon result from central muscarinic effects. Toxicol Appl Pharmacol 2008 Dec 1;233(2):186-92.
31. Villa AF, Houze P, Monier C, Risède P, Sarhan H, Borron SW, et al. Toxic doses of paraoxon alter the respiratory pattern without causing respiratory failure in rats. Toxicology 2007 Mar 22;232(1-2):37-49.
32. Persson HE, Sjöberg GK, Haines JA, Pronczuk de Garbino J. Poisoning severity score. Grading of acute poisoning. J Toxicol Clin Toxicol 1998;36(3):205-13.
33. Sheridan RD, Smith AP, Turner SR, Tattersall JE. Nicotinic antagonists in the treatment of nerve agent intoxication. J R Soc Med 2005 Mar;98(3):114-5.
34. Turner SR, Chad JE, Price M, Timperley CM, Bird M, Green AC, Tattersall JE. Protection against nerve agent poisoning by a noncompetitive nicotinic antagonist. Toxicol Lett 2011 Sep 25;206(1):105-11.
35. Reji KK, Mathew V, Zachariah A, Patil AK, Hansdak SG, Ralph R, Peter JV. Extrapyramidal effects of acute organophosphate poisoning. Clin Toxicol (Phila) 2016 Mar;54(3):259-65.
36. Dhanarisi J, Shihana F, Harju K, Mohamed F, Verma V, Shahmy S, et al. A pilot clinical study of the neuromuscular blocker rocuronium to reduce the duration of ventilation after organophosphorus insecticide poisoning. Clin Toxicol (Phila) 2020 Apr;58(4):254-261.
37. Saadeh AM, Farsakh NA, al-Ali MK. Cardiac manifestations of acute carbamate and organophosphate poisoning. Heart 1997;77(5):461–464.
38. Kikuchi-Utsumi K, Ishizaka M, Matsumura N, Nakaki T. Alpha(1A)-adrenergic control of piloerection and palpebral fissure width in rats. Auton Neurosci 2013 Dec;179(1-2):148-50.
39. Rusyniak DE, Nañagas KA. Organophosphate poisoning. Semin Neurol 2004 Jun;24(2):197-204.
40. Stojiljković MP, Škrbić R, Jokanović M, Bokonjić D, Kilibarda V, Vulović M. Prophylactic potential of memantine against soman poisoning in rats. Toxicology 2019 Mar 15;416:62-74.
41. Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphate insecticide poisoning. J Neurol Neurosurg Psychiatry 1974; 37: 841–7.
42. Peter JV, Sudarsan TI, Moran JL. Clinical features of organophosphate poisoning: A review of different classification systems and approaches. Indian J Crit Care Med 2014 Nov;18(11):735-45.
Published
2021/03/26
Issue
Vol. 52 No. 1 (2021): Q1/March
Section
Original article
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