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Future Considerations for the Medical Management of Nerve-Agent Intoxication

Published online by Cambridge University Press:  28 June 2012

Pål Aas
Pål Aas*
Affiliation:
Professor, Department of Physiology, University of Bergen, Bergen, Norway, Norwegian Defense Research Establishment, Kjeller, Norway
*
Chief Scientist, Norwegian Defense Research Establishment, Postbox 25, NO-2027 Kjeller, Norway, E-mail: [email protected]
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Abstract

The use of chemical warfare agents against civilians and unprotected troops in international conflicts or by terrorists against civilians is considered to be a real threat, particularly following the terrorist attacks on 11 September 2001 against the World Trade Center in New York and against the Pentagon in Washington, DC. Over the past 10 years, terrorists have been planning to use or have used chemical warfare agents on several occasions around the world, and the attacks in 2001 illustrate their willingness to use any means of warfare to cause death and destruction among civilians. In spite of new international treaties with strong verification measures and with an aim to prohibit and prevent the use of weapons of mass destruction, nevertheless, some countries and terrorist groups have been able to develop, produce, and use such weapons, particularly nerve agents, in domestic terrorist attacks or during warfare in international conflicts. This article reviews current medical therapy for nerve-agent intoxication and discusses possible future improvement of medical therapies.

Present medical counter-measures against nerve agents are not sufficiently effective particularly in protecting the brain. Therefore, new and more effective countermeasures must be developed to enable better medical treatment of civilians and military personnel following exposure to nerve agents. Therefore, it is important with an enhanced effort by all countries, to improve and increase research in medical countermeasures, in the development of protective equipment, and in carrying out regular training of medical and emergency personnel as well as of military nuclear, biological, or chemical (NBC) units. Only then will nations be able to reduce the risk from and prevent the use of such weapons of mass destruction (WMD).

Keywords

anticonvulsantschemical warfare agentschemoprophylaxischolinergic antagonistscyclo-sarin (GF)nerve agentsoximessarin (GB)soman (GD)tabun (GA)terrorismtherapyVX
Type
Special Reports
Information
Prehospital and Disaster Medicine , Volume 18 , Issue 3: Terrorism-II: Special Reports , September 2003 , pp. 208 - 216
Copyright
Copyright © World Association for Disaster and Emergency Medicine 2003

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References

1.Zajtchuk, R, Bellamy, RF: Medical aspects of chemical and biological warfare Textbook of Military Medicine. Walter Reed Army Medical Center: Washington DC, USA: The Office of the Surgeon General at TTM Publications, Bordon Institute, 1997.Google Scholar
2.Terrill, WA: The chemical warfare legacy of the Yemen war. Comparative Strategy 1991; 10(2): 109–119.CrossRefGoogle Scholar
3.Waters, L: Chemical weapons in the Iran/Iraq War. Military Review 1990; 70(10): 57–63.Google Scholar
4.US Department of State: Chemical Warfare in Southeast Asia and Afghanistan. Report to the Congress from Secretary of State Alexander Haig, Jr, Special Report No 98 (Washington, D.C.US Department of State), 1982.Google Scholar
5.Human Rights Watch: Chemical warfare in Bosnia? The strange experiences of Srebrenica survivors. Human Rights Watch 1998; 10: 9(D).Google Scholar
6. United Nations Security Council Resolution 687, 1991.Google Scholar
7.United Nations: The United Nations and the Iraq-Kuwait Conflict, 1990–1996. The United Nations Blue Book Series, Volume IX, United Nations: New York, USA, Department of public information, 1996.Google Scholar
8.Aas, P: UNSCOM's and IAEA's disarmament of Iraq's weapons of mass destruction. International Politikk 1997; 55(1): 41–60.Google Scholar
9.Pearson, G: The UNSCOM Saga: Chemical and Biological Weapons Non-Proliferation. London, England: MacMillan Press Ltd., 1999.CrossRefGoogle Scholar
10.Lia, B, Hegghammer, T, Andersen, RIV, Kjøk, Å, Bokhari, L: Nuclear materials, gas and microbes as terrorist weapons? Groups interest in, and actual use of non-conventional weapons. FFI/Rapport 2001; 29–30.Google Scholar
11.Morita, H, Yanagisawa, N, Nakajima, T, Shimizu, M, Hirabayashi, H, Okudera, H, Nohara, M, Midorikawa, Y, Mimura, S: Sarin poisoning in Matsumoto, Japan. Lancet 1995; 346: 290–293.Google ScholarPubMed
12.Otomi, S, Takase, M, Kumagai, F: Sarin poisoning in Japan: A clinical experience in Japan Self Defence Force (JSDF) Central Hospital. Int Review of Armed Forces Medical Services 1996; 4–6: 97–102.Google Scholar
13.Okudera, H, Morita, H, Iwashita, T, Shibata, T, Odagir, T, Kobayashi, S, Yanagisawa, N: Unexpected nerve gas exposure in the city of Matsumoto: Report of rescue activity in the first sarin gas terrorism. Am J Emerg Med 1997; 15(5) 527–528.CrossRefGoogle ScholarPubMed
14.Mirzayanov, V, Fedorov, L: A poisoned policy, Moscow News 1992; 27 September -04 October:9.Google Scholar
15.Stock, T: Chemical and biological weapons: Developments and proliferation. SIPRI Yearbook 1993: World Armaments and Disarmaments, Oxford, UK: Oxford University Press, 1993; 7: 259–292.Google Scholar
16.Stock, T, De Geer, A: Chemical weapons developments. SIPRI Yearbook 1994, Oxford, UK: Oxford University Press, 1994. pp 9:315–342.Google Scholar
17.Mirzaynov, S: Dismantling the Soviet/Russian chemical weapons complex: An insider's view. In: Chemical Weapons Disarmanent in Russia: Problems and Prospectis. Report No. 17, October 1995, the Henry L. Stimson Center. Eds: Smithson, AE, Mirzayanov, S, Lajoie, R, Krepon, M.Google Scholar
18.Leadbeater, L, Inns, RH, Rylands, JM: Treatment of poisoning by soman. Fund App Toxicol 1985; 5: S225–S231.CrossRefGoogle ScholarPubMed
19.Friedman, A, Kaufner, D, Shemer, J, Hendler, I, Soreq, H, Tur-Kaspa, I: Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nature Medicine 1996; 2: 1382–1385.CrossRefGoogle ScholarPubMed
20.Taylor, P: Anticholinesterase agents. In: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed.Hardman, JG, Limbird, LE, Molinoff, PB, Ruddon, RW, Gilman, AG (eds), New York, NY: McGraw-Hill, 1996. pp 161–176.Google Scholar
21.McDonough, JH, Shih, T-M: Pharmacological modulation of soman-induced seizures, Neurosci Biobehav Rev 1993; 17: 203–215.CrossRefGoogle ScholarPubMed
22.Lallement, G, Dorandeu, F, Filliat, P, Carpentier, P, Baille, V, Blanchet, G: Medical management of organophosphate-induced seizures. J Physiol (Paris) 1998; 92: 369–373.CrossRefGoogle ScholarPubMed
23.McDonough, JH, Zoeffel, LD, McMonagle, J, Copeland, TL, Smith, CD, Shih, TM: Anticonvulsant treatment of nerve agent seizures: Anticholinergics versus diazepam in soman-intoxicated guinea pigs. Epilepsy Res 2000; 38: 1–14.CrossRefGoogle ScholarPubMed
24.Anderson, DR, Harris, LW, Chang, FT, Baze, WB, Capacio, BR, Byers, SL, Lennox, WJ: Antagonism of soman-induced convulsions by midazolam, diazepam and scopolamine. Drug Chem Toxico. 1997; 20: 115–131.CrossRefGoogle ScholarPubMed
25.Shih, T-M, McDonough, JH, Koplovitz, I: Evaluation of anticonvulsant drugs for soman-induced seizure activity. J Am Coll Toxicol 1997; 15: 2: S43–S60.CrossRefGoogle Scholar
26.Sidell, FR: Nerve agents. In: Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare, Zajtchuk, R, Bellamy, RF (eds), Walter Reed Army Medical Center, Washington DC, USA: The Office of The Surgeon General at TTM Publications, Bordon Institute, 1997. pp 129–179.Google Scholar
27.Dawson, RM: Review of oximes available for treatment of nerve agent poisoning. J Appl Toxicol 1994; 14: 5: 317–331.CrossRefGoogle ScholarPubMed
28.Lundy, PM, Hand, BT, Broxup, BR, Yipchuk, G, Hamilton, MG: Distribution of the bispyridinium oxime (14C)HI-6 in male and female rats. Arch To xicol 1990; 64: 377–382.CrossRefGoogle ScholarPubMed
29.Clement, JG: Central activity of acetylcholinesterase oxime reactivators. Appl Pharmacol Toxicol 1992; 112: 104–109.CrossRefGoogle ScholarPubMed
30.Cassel, G, Fosbraey, P: Measurement of oxime HI-6 after peripheral administration in tandem with neurotransmitter levels in striatal dialysates: Effects of soman intoxication. J Pharmacol Toxicol Methods 1996; 35: 159–166.CrossRefGoogle ScholarPubMed
31.Cassel, G, Karlsson, L, Waara, L, Ang, KW, Göransson-Nyberg, A: Pharmacokinetics and effects of HI-6 in blood and brain of soman-intoxi-cated rats: A microdialysis study. Eur J Pharmacol 1997; 332: 43–52.CrossRefGoogle ScholarPubMed
32.McDonough, JH, McMonagle, J, Copeland, T, Zoeffel, D, Shih, FM: Comparative evaluation of bezodiazepines for control of soman-induced seizures. Arch To xicol 1999; 73: 473–478.CrossRefGoogle Scholar
33.Wolthuis, OL, van Helden, HPM, Melchers, BPC, Busker, RW, de Groot, DMG: Search for a therapy against soman-intoxication. Neurosci Behav Reviews 1994; 18: 4: 469–486.CrossRefGoogle ScholarPubMed
34.Harris, LW, McDonough, JH, Sticher, DL, Lennox, WJ: Protection against both lethal and behavioural effects of soman. Drug Chem Toxicol 1984; 7: 605–624.CrossRefGoogle ScholarPubMed
35.Solana, RP, Gennings, C, Carter, WH, Anderson, D, Lennox, WJ, Carchman, RA, Harris, LW: Evaluation of the efficacy of two carbamates, physostigmine and pyridostigmine, when used in conjunction for protection against organophosphate exposure. Fundam Appl Toxicol 1990; 15: 814–819.CrossRefGoogle ScholarPubMed
36.Walday, P, Aas, P, Haider, T, Fonnum, F: Effect of pyridostigmine pre-treatment, HI-6 and toxogonin treatment on rat tracheal smooth muscle response to cholinergic stimulation after organophosphorus inhalation exposure. Arch To xicol 1993; 67: 212–219.CrossRefGoogle Scholar
37.Wetherell, J: Continuous administration of low dose rates of physostigmine and hyoscine to guinea-pigs prevents the toxicity and reduces the incapaci-tation produced by soman poisoning. J Pharm Pharmacol 1994; 46: 1023–1028.CrossRefGoogle ScholarPubMed
38.Kim, Y-B, Shin, S, Sok, D-E, Kang, J-K: Effectiveness of procyclidine in combination with carbamate prophylactics against diisopropylfluorophosphate. Environ Toxicol Pharmacol 1998; 5: 43–49.CrossRefGoogle ScholarPubMed
39.Philippens, IHCHM, Melchers, BPC, Olivier, B, Bruijnzeel, PLB: Scopolamine augments the efficacy of physostigmine against soman poisoning in guinea pigs. Pharmacol Biochem Behaviour 2000; 65(1): 175–182.CrossRefGoogle ScholarPubMed
40.Meshulam, Y, Davidovici, R, Wengier, A, Levy, A: Prophylactic transdermal treatment with physostigmine and scopolamine against soman intoxication in guinea-pigs. J Appl Toxicol 1995; 15: 4: 263–266.CrossRefGoogle ScholarPubMed
41.Lallement, G, Baille, V, Baubichon, D, Carpentier, P, Collombet, J-M, Filliat, P, Foquin, A, Four, E, Masqueliez, C, Testylier, G, Tonduli, L, Dorandeu, F: Review of the value of huperzine as pre-treatment of organophosphate poisoning. Neurotoxicol 2002; 23: 1–5.CrossRefGoogle Scholar
42.Weinstock, M: Selectivity of cholinesterase inhibition. CNS Drugs 1999; 12: 4: 307–323.CrossRefGoogle Scholar
43.Lahiri, DK, Farlow, MR, Greig, NH, Sambamurti, K: Current drug targets for Alzheimer's disease treatment. Drug Development Res 2002; 56: 267–281.CrossRefGoogle Scholar
44.McDonough, JH, Jaax, NK, Crowley, RA, Mays, MZ, Modrow, HE: Atropine and/or diazepam therapy protects against soman-induced neural and cardiac pathology. Fund Appl Toxicol 1989; 13: 256–276.CrossRefGoogle ScholarPubMed
45.Capacio, BR, Shih, T-M: Anticonvulsant actions of anticholinergic drugs in soman poisoning. Epilepsia 1991; 32: 604–615.CrossRefGoogle ScholarPubMed
46.Shih, T-M, Koviak, TA, Capacio, BR: Anticonvulsants for poisoning by the organophosphorus compound soman: Pharmacological mechanisms. Neurosci Biobehav Rev 1991; 15: 349–362.Google ScholarPubMed
47.Shih, T-M, McDonough, JH, Koplovitz, I: Anticonvulsants for soman-induced seizure activity. J Biomed Sci 1999; 6: 86–96.Google ScholarPubMed
48.Kim, Y-B, Cheon, K-C, Hur, G-H, Phi, T-S, Choi, S-J, Hong, D, Kang, J-K: Effects of combinational prophylactics composed of physostigmine and pro-cyclidine on soman-induced lethality, seizures and brain injuries. Envir To xicol Pharmacol 2002; 11: 15–21.CrossRefGoogle ScholarPubMed
49.Myhrer, T, Skymoen, LR, Aas, P: Pharmacological agents, hippocampal EEG and anticonvulsant effects on soman-induced seizures in rats. Neurotoxicol 2003 (in press).CrossRefGoogle Scholar
50.Sparenborg, S, Brennecke, LH, Jaax, NK, Braitman, DJ: Dizocilpine (MK-801) arrests status-epilepticus and prevents brain-damage induced by soman. Neuropharm 1992; 31: 4: 357–368.CrossRefGoogle ScholarPubMed
51.Carpentier, P, Foquin-Tarricone, A, Bodjarian, N, Rondouin, G, Lerner-Natoli, M, Kamenka, JM, Blanchet, G, Denoyer, M, Lallement, G: Anticonvulsant and antilethal effects of the phencyclidine derivative TCP in soman poisoning. Neurotoxicol 1994; 15: 4: 837–852.Google ScholarPubMed
52.Lallement, G, Pernot-Marino, I, Baubichon, D, Burckhart, MF, Carpentier, P, Blanchet, G: Modulation of soman-induced neuropathology with an anti-convulsant regimen. NeuroReport 1994; 5: 2265–2268.CrossRefGoogle Scholar
53.Solberg, Y, Belkin, M: The role of excitotoxicity in organophosphorus nerve agents central poisoning. Trends Pharmacol Sci 1997; 18: 183–185.CrossRefGoogle Scholar
54.Phillis, JW: Adenosine in the control of the cerebral circulation. Cerebrovascular and Brain Metabolism Rev 1989; 1: 26–54.Google ScholarPubMed
55.Rudolphi, K, Schubert, P, Parkinson, FE, Fredholm, BB: Neuroprotective role of adenosine in cerebral ischaemia. Trends in Pharmacol Sci 1992; 13: 439–445.CrossRefGoogle ScholarPubMed
56.Aas, P, Fonnum, F: Presynaptic inhibition of acetylcholine release. Acta Physiol Scand 1982; 127: 335–342.CrossRefGoogle Scholar
57.Van Helden, HPM, Beuters, TJH: Protective activity of adenosine receptor agonists in the treatment of organophosphate poisoning. Trends Pharmacol. Sci 1999; 20: 438–441.CrossRefGoogle ScholarPubMed
58.Aas, P, Fonnum, F: The effect of soman on potassium evoked 3H-acetyl-choline release in the isolated rat bronchi. Pharmacol and Toxicol 1987; 60: 206–209.CrossRefGoogle Scholar
59.Aas, P, Maclagan, J: Evidence for prejunctional M2 muscarinic receptors in pulmonary cholinergic nerves in the rat. Br J Pharmacol 1990; 101: 73–76.CrossRefGoogle ScholarPubMed
60.Junien, JL, Leonard, BE: Drugs acting on sigma and phencyclidine receptors: A review of their nature, function and possible therapeutic importance. Clin Neuropharmacol 1989; 12: 353–374.CrossRefGoogle ScholarPubMed
61.Lallement, G, Delmanche, IS, Pernot-Marino, I, Baubichon, D, Denoyer, M, Carpentier, P, Blanchet, G: Neuroprotective activity of glutamate receptor antagonists against soman-induced hippocampal damage: Quantification with a w3 site ligand. Brain Res 1993; 618: 227–237.CrossRefGoogle Scholar
62.Dematteis, M, Mallaret, M, Baubichon, D, Pernot-Marino, I, Lallement, G: Evaluation of dextromethorphan and dextrorphan as preventive treatment of soman toxicity in mice. Neurosci Lett 1997; 234: 91–94.CrossRefGoogle ScholarPubMed
63.Dretchen, KL, Bowles, AM, Raines, A: Protection by phenytoin and calcium channel blocking agents against the toxicity of diisopropylfluorophosphate. To xicol Appl Pharmacol 1986; 83: 584–589.CrossRefGoogle ScholarPubMed
64.Sterri, SH, Lyngaas, S, Fonnum, F: Toxicity of soman after repetitive injection of sublethal doses in guinea-pig and mouse. Acta Pharm et Toxicol 1991; 49: 8–13.CrossRefGoogle Scholar
65.Wolfe, AD, Rush, RS, Doctor, BP, Koplovitz, I, Jones, D: Acetylcholinesterase prophylaxis against organophosphate toxicity. Fund ApplToxicol 1987; 9: 266–270.CrossRefGoogle ScholarPubMed
66.Doctor, BP, Maxwell, DM, Ashani, Y, Saxena, A, Gordon, RK: New approaches to medical protection against chemical warfare nerve agents. In: Chemical Wa r fare Agents: Toxicity at Low Levels. Somani, SM, Romano, JA (eds), 2001. pp 191–214.Google Scholar
67.Filbert, MG, Forster, JS, Smith, CD, Ballough, GPH: Neuroprotective effects of HU-211 on brain damage resulting from soman-induced seizures. Ann NY Acad Sci 1999; 890: 505–514.CrossRefGoogle ScholarPubMed
68.Bouchaud, C, Chollat-Namy, A, Duserre, S, Delamanche, IS: The role of nitric oxide in the neuropathology in soman intoxication. Brain Res 1994; 660: 249–254.CrossRefGoogle ScholarPubMed
69.Jacobsson, SOP, Cassel, G, Persson, SÅ: Increased levels of nitrogen oxides and lipid peroxidation in the rat brain after soman-induced seizures. Arch To xicol 1999; 73: 269–273.CrossRefGoogle ScholarPubMed
70.Svensson, I, Waara, L, Johansson, L, Bucht, A, Cassel, G: Soman-induced interleukin-1 beta mRNA and protein in rat brain. Neurotoxicol 2001; 22: 3: 355–362.CrossRefGoogle ScholarPubMed
71. Review of acute human-toxicity estimates for selected chemical-warfare agents. Washington DC: National Academy Press, 1997.Google Scholar