Novel Medical Countermeasures for Nerve Agent and Pharmaceutical Based Agent Poisoning

Year 2024, Volume: 52 Issue: 5, 257 - 266, 12.12.2024

Gülşah Çıkrıkçı Işık , Sermet Sezigen

https://doi.org/10.15671/hjbc.1571796

Abstract

Nerve agents are organophosphorus compounds which inhibit acetylcholinesterase (AChE) enzyme. Existing AChE reactivators (Oximes) have several limitations in mean of reactivation potential, broad action spectrum, and penetration rate through blood-brain barrier. Ongoing studies focus on design and synthesis of novel oximes. Pharmaceutical based agents like fentanyl abuse becomes an important public health threat. Naloxone and naltrexone that are centrally acting opioid receptor antagonists, are used for reversing the effects of the opioid overdose.

Keywords

nerve agent, oxime, fentanyl, naloxone, CBRN

Supporting Institution

none

References

• References C. Voros, J. Dias, C.M. Timperley, F. Nachon, R.C.D. Brown, R. Baati, The risk associated with organophosphorus nerve agents: from their discovery to their unavoidable threat, current medical countermeasures and perspectives, Chem. Biol. Interact., 2 (2024) 110973.
• V. Aroniadou-Anderjaska, J.P. Apland, T.H. Figueiredo, M. De Araujo Furtado, M.F. Braga, Acetylcholinesterase inhibitors (nerve agents) as weapons of mass destruction: History, mechanisms of action, and medical countermeasures, Neuropharmacology., 181 (2020) 108298.
• M.A. Hayoun, M.E. Smith, C. Ausman, S.N.S. Yarrarapu, H.D. Swoboda, Toxicology, V-Series Nerve Agents, In: StatPearls [Internet], StatPearls Publishing, Treasure Island (FL), USA, 2023.
• M. Noga, A. Michalska, K. Jurowski, Review of Possible Therapies in Treatment of Novichoks Poisoning and HAZMAT/CBRNE Approaches: State of the Art, J. Clin. Med., 12 (2023) 2221.
• M. Moshiri, E. Darchini-Maragheh, M. Balali-Mood, Advances in Toxicology and Medical Treatment of Chemical Warfare Nerve Agents, Daru., 20 (2012) 81
• OPCW, [online] https://www.opcw.org/evolution-status-participation-convention [Accessed: 22.04.2024]
• N.M. Hrvat, Z. Kovarik , Counteracting poisoning with chemical warfare nerve agents, Arh. Hig. Rada. Toksikol., 71 (2020) 266-284.
• C.N. Pope, S. Brimijoin, Cholinesterases and the fine line between poison and remedy, Biochem. Pharmacol., 153 (2018) 205-216.
• F. Nachon, Y. Nicolet, P. Masson, Structure tridimensionnelle de la butyrylcholinestérase humaine: hypothèses mécanistiques et ingéniére de mutéines dégradent les composés organophosphorés [Butyrylcholinesterase: 3D structure, catalytic mechanisms], Ann. Pharm. Fr., 63 (2005) 194-206.
• R.T. Delfino, T.S. Ribeiro, J.D. Figueroa-Villar, Organophosphorus compounds as chemical warfare agents: a review, J. Braz. Chem. Soc., 20 (2009) 407–28.
• A.J. Franjesevic, S.B. Sillart, J.M. Beck, S. Vyas, C.S. Callam, C.M. Hadad, Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase, Chemistry., 25 (2019) 5337-5371.
• F. Worek, H. Thiermann, The value of novel oximes for treatment of poisoning by organophosphorus compounds, Pharmacol. Ther., 139 (2013) 249-59.
• S.X. Naughton, A.V. Terry Jr, Neurotoxicity in acute and repeated organophosphate exposure, Toxicology., 408 (2018) 101-112.
• H.P. van Helden, M.J. Joosen, I.H. Philippens, Non-enzymatic pretreatment of nerve agent (soman) poisoning: a brief state-of-the-art review, Toxicol. Lett. 206(2011) 35-40.
• A.K. Ghosh, M. Brindisi, Organic carbamates in drug design and medicinal chemistry, J. Med. Chem., 58 (2015) 2895-940.
• T. Myhrer, P. Aas, Pretreatment and prophylaxis against nerve agent poisoning: Are undesirable behavioral side effects unavoidable? Neurosci. Biobehav. Rev., 71 (2016) 657-670.
• M. Richtsfeld, S. Yasuhara, H. Fink, M. Blobner, J.A. Martyn, Prolonged administration of pyridostigmine impairs neuromuscular function with and without down-regulation of acetylcholine receptors, Anesthesiology., 119 (2013) 412-21.
• T.M. Shih, J.H. McDonough, Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication, Arch. Toxicol., 74 (2000) 165-72.
• M. Balali-Mood, K. Balali-Mood, Neurotoxic disorders of organophosphorus compounds and their managements, Arch. Iran. Med., 11 (2008) 65-89.
• M. Balali-Mood, H. Saber, Recent advances in the treatment of organophosphorous poisonings, Iran. J. Med. Sci., 37 (2012) 74-91.
• J. Newmark, The birth of nerve agent warfare: lessons from Syed Abbas Foroutan, Neurology., 62 (2004) 1590-1596.
• T. Myhrer, S. Enger, P. Aas, Anticonvulsant efficacy of drugs with cholinergic and/or glutamatergic antagonism microinfused into area tempestas of rats exposed to soman, Neurochem. Res., 33 (2008) 348-54.
• A.A. de Castro, L.C. Assis, F.V. Soares, K. Kuca, D.A. Polisel, E.F.F. da Cunha, T.C. Ramalho, Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016-2019), Biomolecules., 10 (2020) 436.
• T. Zorbaz, D. Malinak, T. Hofmanova, N. Maraković, S. Žunec, N.M. Hrvat, R. Andrys, M. Psotka, A. Zandona, J. Svobodova, L. Prchal, S. Fingler, M. Katalinić, Z. Kovarik, K. Musilek, Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents, Eur. J. Med. Chem., 238 (2022) 114377.
• M.N. Faiz Norrrahim, M.A. Idayu Abdul Razak, N.A. Ahmad Shah, H. Kasim, W.Y. Wan Yusoff, N.A. Halim, S.A. Mohd Nor, S.H. Jamal, K.K. Ong, W.M. Zin Wan Yunus, V.F. Knight, N.A. Mohd Kasim, Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review, RSC. Adv., 10 (2020) 4465-4489.
• I.B. Wilson, S. Ginsburg, C. Quan, Molecular complementariness as basis for reactivation of alkyl phosphate-inhibited enzyme, Arch. Biochem. Biophys., 77 (1958) 286-96.
• M Jokanović, M.P. Stojiljković, Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning, Eur. J. Pharmacol., 553 (2006) 10-17.
• J.G. Clement, Toxicology and pharmacology of bispyridium oximes--insight into the mechanism of action vs Soman poisoning in vivo, Fundam. Appl. Toxicol., 1 (1981) 193-202.
• T.C. Marrs, Toxicology of oximes used in treatment of organophosphate poisoning, Adverse. Drug. React. Toxicol. Rev., 10 (1991) 61-73.
• F. Worek, T. Kirchner, L. Szinicz, Effect of atropine and bispyridinium oximes on respiratory and circulatory function in guinea-pigs poisoned by sarin, Toxicology., 95 (1995) 123-33.
• J.G. Clement, A.S. Hansen, C.A. Boulet, Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice, Arch. Toxicol., 66 (1992) 216-219.
• T.M. Shih, J.W. Skovira, J.C. O'Donnell, J.H. McDonough, Evaluation of nine oximes on in vivo reactivation of blood, brain, and tissue cholinesterase activity inhibited by organophosphorus nerve agents at lethal dose, Toxicol. Mech. Methods., 19 (2009) 386-400.
• C.M. Timperley, J.E. Forman, M. Abdollahi, A.S. Al-Amri, A. Baulig, D. Benachour, V. Borrett, F.A. Cariño, M. Geist, D. Gonzalez, W. Kane, Z. Kovarik, R. Martínez-Álvarez, N.M.F. Mourão, S. Neffe, S.K. Raza, V. Rubaylo, A.G. Suárez, K. Takeuchi, C. Tang, F. Trifirò, F.M. van Straten, P.S. Vanninen, S. Vučinić, V. Zaitsev, M. Zafar-Uz-Zaman, M.S. Zina, S. Holen, Advice on assistance and protection provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 1. On medical care and treatment of injuries from nerve agents, Toxicology., 415 (2019) 56-69.
• T. Rebmann, B.W. Clements, J.A. Bailey, R.G. Evans, Organophosphate antidote auto-injectors vs. traditional administration: a time motion study, J. Emerg. Med., 37 (2009) 139-143.
• T.C. Marrs, P. Rice, J.A. Vale, The role of oximes in the treatment of nerve agent poisoning in civilian casualties, Toxicol. Rev., 25 (2006) 297-323.
• J.M. Rousseau, I. Besse Bardot, L. Franck, N. Libert, G. Lallement, P. Clair, Intérêt de la seringue Ineurope devant une intoxication par neurotoxique de guerre [Interest of Ineurope syringe for nerve agent intoxication], Ann. Fr. Anesth. Reanim., 28 (2009) 482- 488.
• S. Habiballah, J. Chambers, E. Meek, B. Reisfeld, The in silico identification of novel broad-spectrum antidotes for poisoning by organophosphate anticholinesterases, J. Comput. Aided. Mol. Des., 37 (2023) 755-764.
• I. Primozic, R. Odzak, S. Tomic, V. Simeon-Rudolf, E. Reiner, Pyridinium, imidazolium, and quinucludinium oximes: synthesis, interaction with native and phosphylated cholinesterases, and antidotes against organophosphorus compounds, J. Med. Chem. Def., 2 (2004) 1–30.
• P.I. Hammond, C. Kern, F. Hong, T.M. Kollmeyer, Y.P. Pang, S. Brimijoin, Cholinesterase reactivation in vivo with a novel bis-oxime optimized by computer-aided design, J. Pharmacol. Exp. Ther., 307 (2003) 190-196.
• T. Wille, F. Ekström, J.C. Lee, Y.P. Pang, H. Thiermann, F. Worek, Kinetic analysis of interactions between alkylene-linked bis-pyridiniumaldoximes and human acetylcholinesterases inhibited by various organophosphorus compounds, Biochem. Pharmacol., 80 (2010) 941-946.
• K. Kuca, J. Cabal, D. Jun, J. Bajgar, M. Hrabinova, Potency of new structurally different oximes to reactivate cyclosarin-inhibited human brain acetylcholinesterases, J. Enzyme. Inhib. Med. Chem., 21 (2006) 663-666.
• P. Eyer, In memory of Ilse Hagedorn, Toxicology., 233 (2007) 3-7.
• F. Worek, H. Thiermann, L. Szinicz, P. Eyer, Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes, Biochem. Pharmacol., 68 (2004) 2237-2248.
• G.E. Garcia, A.J. Campbell, J. Olson, D. Moorad-Doctor, V.I. Morthole, Novel oximes as blood-brain barrier penetrating cholinesterase reactivators, Chem. Biol. Interact., 187 (2010) 199-206.
• J. Kalisiak, E.C. Ralph, J.R. Cashman, Nonquaternary reactivators for organophosphate-inhibited cholinesterases, J. Med. Chem., 55 (2012) 465-474.
• J. Kalisiak, E.C. Ralph, J. Zhang, J.R. Cashman, Amidine-oximes: reactivators for organophosphate exposure, J. Med. Chem., 54 (2011) 3319-30.
• R.K. Sit, Z. Radić, V. Gerardi, L. Zhang, E. Garcia, M. Katalinić, G. Amitai, Z. Kovarik, V.V. Fokin, K.B. Sharpless, P. Taylor, New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases, J. Biol. Chem., 286 (2011) 19422-19430.
• M.C. de Koning, M. van Grol, D. Noort, Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase, Toxicol. Lett., 206 (2011) 54-59.
• F. Worek, H. Thiermann, T. Wille, Organophosphorus compounds and oximes: a critical review, Arch. Toxicol., 94 (2020) 2275-2292.
• F.S. Katz, S. Pecic, T.H. Tran, I. Trakht, L. Schneider, Z. Zhu, L. Ton-That, M. Luzac, V. Zlatanic, S. Damera, J. Macdonald, D.W. Landry, L. Tong, M.N. Stojanovic, Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates, Chembiochem., 16 (2015) 2205-2215.
• M.C. de Koning, G. Horn, F. Worek, M. van Grol, Discovery of a potent non-oxime reactivator of nerve agent inhibited human acetylcholinesterase, Eur. J. Med. Chem., 157 (2018) 151-160.
• T. Seeger, M. Eichhorn, M. Lindner, K.V. Niessen, J.E. Tattersall, C.M. Timperley, M. Bird, A.C. Green, H. Thiermann, F. Worek, Restoration of soman-blocked neuromuscular transmission in human and rat muscle by the bispyridinium non-oxime MB327 in vitro, Toxicology., 294 (2012) 80-84.
• K.V. Niessen, T. Seeger, S. Rappenglück, T. Wein, G. Höfner, K.T. Wanner, H. Thiermann, F. Worek, In vitro pharmacological characterization of the bispyridinium non-oxime compound MB327 and its 2- and 3-regioisomers, Toxicol. Lett., 293 (2018) 190-197.
• Q. Zhuang, A.J. Franjesevic, T.S. Corrigan, W.H. Coldren, R. Dicken, S. Sillart, A. DeYong, N. Yoshino, J. Smith, S. Fabry, K. Fitzpatrick, T.G. Blanton, J. Joseph, R.J. Yoder, C.A. McElroy, Ö.D. Ekici, C.S. Callam, C.M. Hadad, Demonstration of In Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents, J. Med. Chem., 61 (2018) 7034-7042.
• M. de Araujo Furtado, F. Rossetti, S. Chanda, D. Yourick, Exposure to nerve agents: from status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy, Neurotoxicology., 33 (2012) 1476-1490.
• J.M. Collombet, Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects, Toxicol. Appl. Pharmacol., 255 (2011) 229-241.
• F.R. Sidell, J. Newmark, J.H. McDonough, In Textbooks of military medicine, medical aspects of chemical warfare, Washington D.C: Department of the Army, USA, 2008.
• ATSDR, [online] http://www.atsdr.cdc.gov/MHMI/mmg166.pdf [Accessed 03.05.2024]
• CHEMM, [online] https://chemm.hhs.gov/antidote_nerveagents.htm [Accessed 03.05.2024]
• J.H. Jr McDonough, J. McMonagle, T. Copeland, D. Zoeffel, T.M. Shih, Comparative evaluation of benzodiazepines for control of soman-induced seizures, Arch. Toxicol., 73 (1999) 473-478.
• X. Wu, R. Kuruba, D.S. Reddy, Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents, J. Pharmacol. Exp. Ther., 367 (2018) 302-321.
• J.H. Jr McDonough, L.D. Zoeffel, J. McMonagle, T.L. Copeland, C.D. Smith, T.M. Shih, Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea pigs, Epilepsy. Res., 38 (2000) 1-14.
• T.H. Figueiredo, F. Qashu, J.P. Apland, V. Aroniadou-Anderjaska, A.P. Souza, M.F. Braga, The GluK1 (GluR5) Kainate/{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 reduces soman-induced seizures and neuropathology, J. Pharmacol. Exp. Ther., 336 (2011) 303-312.
• F. Dhote, P. Carpentier, L. Barbier, A. Peinnequin, V. Baille, F. Pernot, G. Testylier, C. Beaup, A. Foquin, F. Dorandeu, Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice, Toxicol. Appl. Pharmacol., 259 (2012) 195-209.
• G.E. Garcia, A. Vernon, D. Moorad-Doctor, R.H. Ratcliffe, (−)Huperzine A, replacement for pyridostigmine bromide as nerve agent pretreatment measured in Guinea Pig plasma by a new ultrahigh-pressure liquid chromatography (UHPLC)-MS method. FASEBJ, 2009.
• H. Hirbec, M. Gaviria, J. Vignon, Gacyclidine: a new neuroprotective agent acting at the N-methyl-D-aspartate receptor, CNS. Drug. Rev., 7 (2001) 172-198.
• OPCW, [online] https://www.opcw.org/about-us/opcw-basics [Accessed 01.07.2024]
• CDC, [online] https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750022.html [Accesed 01.07.2024]
• P.K. Kerr, R.W. Rosen, Illicit fentanyl and weapons of mass destruction: international controls and policy options, https://crsreports.congress.gov/product/pdf/IN/IN11902 [Accessed 01.07.2024]
• OPCW, [online] https://www.opcw.org/sites/default/files/documents/CSP/C-14/open-forum/Dangerous-Ambiguities-Regulation-of-Riot-Control-Agents-and-Incapacitants-under-the-Chemical-Weapons-Convention_Rev.1.pdf [Accessed 01.07.2024]
• National Defense University [online] https://wmdcenter.ndu.edu/Publications/Publication-View/Article/2031503/fentanyl-as-a-chemical-weapon/ [Accessed 01.07.2024]
• C.D. Lindsaya, J.R. Richesa, N. Roughleya, C.M, Timperley, Chemical defence against Fentanyls, Chemical warfare toxicology, volume 2: management of poisoning, The Royal Society of Chemistry, Croydon, UK, 2016.
• R.S. Vardanyan, V.J. Hruby, Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications, Future. Med. Chem., 6, (2014) 385–412
• F. Wu, M.H. Slawson, K.L. Johnson-Davis, Metabolic patterns of fentanyl, meperidine, methylphenidate, tapentadol and tramadol observed in urine, serum or plasma, J. Anal. Toxicol., 41 (2017) 289-299.
• J.P. Danaceau, M. Wood, M. Ehlers, T.G. Rosano, Analysis of 17 fentanyls in plasma and blood by UPLC-MS/MS with interpretation of findings in surgical and postmortem casework, Clin. Mass. Spectrom., 18 (2020) 38-47.
• M.A. Smith, S.L. Biancorosso, J.D. Camp, S.H. Hailu, A.N. Johansen, M.H. Morris, H.N. Carlson, “Tranq-dope” overdose and mortality: lethality induced by fentanyl and xylazine, Front. Pharmacol., 14 (2020) 1280289.
• T. Mai, Y. Zhang, S. Zhao, Xylazine poisoning in clinical and forensic practice: analysis method, characteristics, mechanism and future challenges, Toxics., 11 (2023) 1012.
• R. Gupta, D.R. Holtgrave, M.A. Ashburn, Xylazine-medical and public health imperatives, N. Engl. J. Med., 388 (2023) 2209-2212.
• M. Cano, R. Daniulaityte, F. Marsiglia, Xylazine in overdose deaths and forensic drug reports in US states, 2019-2022, JAMA. Netw. Open., 7 (2024) e2350630.
• M. van Lemmen, J. Florian, Z. Li, M. van Velzen, E. van Dorp, M. Niesters, E. Sarton, E. Olofsen, R. van der Schrier, D.G. Strauss, A. Dahan, Opioid overdose: limitations in naloxone reversal of respiratory depression and prevention of cardiac arrest, Anesthesiology., 139 (2023) 342–353.
• J. Theriot, S. Sabir, M. Azadfard, Opioid antagonists. In: StatPearls [Internet], StatPearls Publishing, Treasure Island (FL), USA, 2024.