Toxicological Reviews

, Volume 25, Issue 4, pp 297–323 | Cite as

The Role of Oximes in the Treatment of Nerve Agent Poisoning in Civilian Casualties

  • Timothy C. Marrs
  • Paul Rice
  • J. Allister Vale
Review Article


There are important differences between on-target military attacks against relatively well protected Armed Forces and nerve agent attacks initiated by terrorists against a civilian population. In contrast to military personnel, civilians are unlikely to be pre-treated with pyridostigmine and protected by personal protective equipment. Furthermore, the time after exposure when specific therapy can first be administered to civilians is likely to be delayed. Even conservative estimates suggest a delay between exposure and the first administration of atropine/oxime of at least 30 minutes.

The organophosphorus nerve agents are related chemically to organophosphorus insecticides and have a similar mechanism of toxicity, but a much higher mammalian acute toxicity, particularly via the dermal route. Nerve agents phosphonylate a serine hydroxyl group in the active site of the enzyme, acetylcholinesterase (AChE), which results in accumulation of acetylcholine and, in turn, causes enhancement and prolongation of cholinergic effects and depolarisation blockade. The rate of spontaneous reactivation of AChE is variable, which partly accounts for differences in acute toxicity between the nerve agents. With soman in particular, an additional reaction occurs known as ‘aging’. This consists of monodealkylation of the dialkylphosphonyl enzyme, which is then resistant to spontaneous hydrolysis and reactivation by oximes. Monodealkylation occurs to some extent with all dialkylphosphonylated AChE complexes; however, in general, is only of clinical importance in relation to the treatment of soman poisoning, where it is a very serious problem. With soman, aging occurs so fast that no clinically relevant spontaneous reactivation of AChE occurs before aging has taken place. Hence, recovery of function depends on resynthesis of AChE. As a result, it is important that an oxime is administered as soon after soman exposure as possible so that some reactivation of AChE occurs before all the enzyme becomes aged. Even though aging occurs more slowly and reactivation occurs relatively rapidly in the case of nerve agents other than soman, early oxime administration is still clinically important in patients poisoned with these agents.

Experimental studies on the treatment of nerve agent poisoning have to be interpreted with caution. Some studies have used prophylactic protocols, whereas the drugs concerned (atropine, oxime, diazepam) would only be given to a civilian population after exposure. The experimental use of pyridostigmine before nerve agent exposure, although rational, is not of relevance in the civilian context. With the possible exception of the treatment of cyclosarin (GF) and soman poisoning, when HI-6 might be preferred, a review of available experimental evidence suggests that there are no clinically important differences between pralidoxime, obidoxime and HI-6 in the treatment of nerve agent poisoning, if studies employing pre-treatment with pyridostigmine are excluded.


  1. 1.
    Wilson BH, Hooper MJ, Hansen ME, et al. Reactivation of organophosphorus inhibited AChE with oximes. In: Chambers JE, Levi PE, editors. Organophosphates: chemistry, fate and effects. San Diego (CA): Academic Press, 1992: 37Google Scholar
  2. 2.
    Harris LW, Heyl WC, Stitcher DL, et al. Effects of 1,1′-oxydimethylene bis-(4-tert-butylpyridinium chloride) (SAD-128) and decamethonium on reactivation of soman- and sarin-inhibited cholinesterase by oximes. Biochem Pharmacol 1978; 27: 757–61PubMedCrossRefGoogle Scholar
  3. 3.
    Davies DR, Green AL. The kinetics of reactivation, by oximes, of cholinesterase inhibited by organophosphorus compounds. Biochem J 1956; 63: 529–35PubMedGoogle Scholar
  4. 4.
    Heilbronn E. In vitro reactivation and ‘aging’ of tabun-inhibited blood cholinesterases: studies with N-methylpyridinium-2-aldoxime methane sulphonate and N,N′-trimethylene bis (pyridinium-4-aldoxime) dibromide. Biochem Pharmacol 1963; 12: 25–36PubMedCrossRefGoogle Scholar
  5. 5.
    Inns RH, Marrs TC. Prophylaxis against anticholinesterase poisoning. In: Ballantyne B, Marrs TC, editors. Clinical and experimental toxicology of organophosphates and carbamates. Oxford: Butterworth-Heinemann, 1992: 10Google Scholar
  6. 6.
    Wilson IB, Ginsberg S. Reactivation of acetylcholinesterase inhibited by alkylphosphates. Arch Biochem Biophys 1955; 54: 569–71PubMedCrossRefGoogle Scholar
  7. 7.
    Childs AF, Davies DR, Green AL, et al. The reactivation by oximes and hydroxamic acids of cholinesterase inhibited by organo-phosphorus compounds. Br J Pharmacol 1955; 10: 462–5Google Scholar
  8. 8.
    Ligtenstein DA. On the synergism of the cholinesterase reactivating bispyridinium aldoxime HI-6 and atropine in the treatment of organophosphate intoxications in the rat. Pharm Weekblad 1985; 7: 219–21CrossRefGoogle Scholar
  9. 9.
    Alkondon M, Rao KS, Albuquerque EX. Acetylcholinesterase reactivators modify the functional properties of the nicotinic acetylcholine receptor ion channel. J Pharmacol Exp Ther 1988; 245: 543–56PubMedGoogle Scholar
  10. 10.
    Reddy VK, Deshpande SS, Cintra WM, et al. Effectiveness of oximes 2-PAM and HI-6 in recovery of muscle function depressed by organophosphate agents in the rat hemidiaphragm: an in vitro study. Fundam Appl Toxicol 1991; 17: 746–60PubMedCrossRefGoogle Scholar
  11. 11.
    Van Helden HPM, Busker RW, Melchers BPC, et al. Pharmacological effects of oximes: How relevant are they? Arch Toxicol 1996; 70: 779–86PubMedCrossRefGoogle Scholar
  12. 12.
    Van Helden HPM, Van der Wiel HJ, Zijlstra JJ, et al. Comparison of the therapeutic effects and pharmacokinetics of HI-6, HLö-7, HGG-12, HGG-42 and obidoxime following non-reactivatable acetylcholinesterase inhibition in rats. Arch Toxicol 1994; 68: 224–30PubMedCrossRefGoogle Scholar
  13. 13.
    Becker G, Kawan A, Szinicz L. Direct reaction of oximes with sarin, soman, or tabun in vitro. Arch Toxicol 1997; 71: 714–8PubMedCrossRefGoogle Scholar
  14. 14.
    Leader H, Vincze A, Manisterski B, et al. Characterization of O,O-diethylphosphoryl oximes as inhibitors of cholinesterases and substrates of phosphotriesterases. Biochem Pharmacol 1999; 58: 503–15PubMedCrossRefGoogle Scholar
  15. 15.
    Nenner M. Phosphonylated aldoximes. Antagonism of acetylcholinesterase and hydrolytic decomposition [in German]. Biochem Pharmacol 1974; 23: 1255–62PubMedCrossRefGoogle Scholar
  16. 16.
    de Jong LPA, Ceulen DI. Anticholinesterase activity and rate of decomposition of some phosphylated oximes. Biochem Pharmacol 1978; 27: 857–63PubMedCrossRefGoogle Scholar
  17. 17.
    Harvey B, Scott RP, Sellers DJ, et al. In vitro studies on the reactivation by oximes of phosphylated acetylcholinesterase I: on the reactions of P2S with various organophosphates and the properties of the resultant phosphylated oximes. Biochem Pharmacol 1986; 35: 737–44PubMedCrossRefGoogle Scholar
  18. 18.
    Krummer S, Thiermann H, Worek F, et al. Equipotent cholinesterase reactivation in vitro by the nerve agent antidotes HI 6 dichloride and HI 6 dimethanesulfonate. Arch Toxicol 2002; 76: 589–95PubMedCrossRefGoogle Scholar
  19. 19.
    Dawson RM. Review of oximes available for treatment of nerve agent poisoning. J Appl Toxicol 1994; 14: 317–31PubMedCrossRefGoogle Scholar
  20. 20.
    Green DM, Inns RH, Leadbeater L. Technical paper. Porton Down, 1983Google Scholar
  21. 21.
    Worek F, Bäcker M, Thiermann H, et al. Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning. Hum Exp Toxicol 1997; 16: 466–72PubMedCrossRefGoogle Scholar
  22. 22.
    Worek F, Eyer P, Szinicz L. Inhibition, reactivation and aging kinetics of cyclohexylmethylphosphonofluoridate-inhibited human cholinesterases. Arch Toxicol 1998; 72: 580–7PubMedCrossRefGoogle Scholar
  23. 23.
    Worek F, Widmann R, Knopff O, et al. Reactivating potency of obidoxime, pralidoxime, HI 6 and HLö 7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compounds. Arch Toxicol 1998; 72: 237–43PubMedCrossRefGoogle Scholar
  24. 24.
    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: 111–8PubMedCrossRefGoogle Scholar
  25. 25.
    Wallace KB. Species-selective toxicity of organophosphorus insecticides: a pharmacodynamic phenomenon. In: Chambers JE, Levi PE, editors. Organophosphates: chemistry, fate and effects. San Diego (CA): Academic Press, 1992, 105Google Scholar
  26. 26.
    Inns RH, Leadbeater L. The efficacy of bispyridinium derivatives in the treatment of organophosphonate poisoning in the guinea-pig. J Pharm Pharmacol 1983; 35: 427–33PubMedCrossRefGoogle Scholar
  27. 27.
    Leadbeater L, Inns RH, Rylands JM. Treatment of poisoning by soman. Fundam Appl Toxicol 1985; 5: S225–31PubMedCrossRefGoogle Scholar
  28. 28.
    Talbot BG, Anderson DR, Harris LW, et al. A comparison of in vivo and in vitro rates of aging of soman-inhibited erythrocyte acetylcholinesterase in different animal species. Drug Chem Toxicol 1988; 11: 289–305PubMedCrossRefGoogle Scholar
  29. 29.
    Worek F, Reiter G, Eyer P, et al. Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch Toxicol 2002; 76: 523–9PubMedCrossRefGoogle Scholar
  30. 30.
    Davies DR, Green AL. The chemotherapy of poisoning by organophosphate anticholinesterases. Br J Ind Med 1959; 16: 128–34PubMedGoogle Scholar
  31. 31.
    Johnson DD, Stewart WC. The effects of atropine, pralidoxime, and lidocaine on nerve-muscle and respiratory function in organophosphate-treated rabbits. Can J Physiol Pharmacol 1970; 48: 625–30PubMedCrossRefGoogle Scholar
  32. 32.
    Harris LW, Stitcher DL. Reactivation of VX-inhibited cholinesterase by 2-PAM and HS-6 in rats. Drug Chem Toxicol 1983; 6: 235–40PubMedCrossRefGoogle Scholar
  33. 33.
    Bevandic Z, Deljac A, Maksimovic M, et al. Methylthio analogues of PAM-2,TMB-4 and obidoxime as antidotes in organophosphate poisoning. Acta Pharm Jugosl 1985; 35: 213–8Google Scholar
  34. 34.
    Koplovitz I, Harris LW, Anderson DR, et al. Reduction by pyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents. Fundam Appl Toxicol 1992; 18: 102–6PubMedCrossRefGoogle Scholar
  35. 35.
    Anderson DR, Harris LW, Woodard CL, et al. The effect of pyridostigmine pretreatment on oxime efficacy against intoxication by soman or VX in rats. Drug Chem Toxicol 1992; 15: 285–94PubMedCrossRefGoogle Scholar
  36. 36.
    Lüttringhaus A, Hagedorn I. Quatäre Hydroxyiminomethyl-pyridinium-salze. Das Dichlorid des Bis-[4-hydroxyiminomethyl-pyridinium-(l)-methyl]-äthers] (“LüH 6”), ein neuer Reaktivator der durch organische Phosphorsäureester gehemmten Acetylcholin-Esterase. Arzneimittelforschung 1964; 14: 1–5Google Scholar
  37. 37.
    Borbely AA, Tunod U, Hopft W. Studies on the protective action of atropine and obidoxime against sarin poisoning in mice. In: Waser PG, editor. Cholinergic mechanisms. New York: Raven Press, 1975: 32Google Scholar
  38. 38.
    Worek F, Kirchner T, Szinicz L. Treatment of tabun poisoned guinea-pigs with atropine, HLö 7 or HI 6: effect on respiratory and circulatory function. Arch Toxicol 1994; 68: 231–9PubMedCrossRefGoogle Scholar
  39. 39.
    Bisa K, Fischer G, Müller O, et al. Die Antidotwirkung von Bis-[4-hydroxyimi-nomethyl-pyridinium-(l)-methyl]-äther-dichlorid bei mit Alkylphosphat vergifteten Ratten. Arzneimittelforschung 1964; 14: 85–8PubMedGoogle Scholar
  40. 40.
    Wirth W. Schädigungsmöglichkeiten durch Antidote. Arch Toxikol 1968; 24: 71–82PubMedCrossRefGoogle Scholar
  41. 41.
    Marrs TC. Toxicology of oximes used in the treatment of organophosphate poisoning. Adverse Drug React Toxicol Rev 1991; 10: 61–72PubMedGoogle Scholar
  42. 42.
    Loftier M. Quatäre Salze von Pyridin-2,4-dialdoxim als Gegenmittel für Organophosphat-Vergiftungen [dissertation]. Freiburg: University of Freiberg, 1986Google Scholar
  43. 43.
    Kassa J, Cabal J. A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with presently used oximes and H oximes against sarin by in vitro and in vivo methods. Hum Exp Toxicol 1999; 18: 560–5PubMedCrossRefGoogle Scholar
  44. 44.
    Ekstrom F, Akfur C, Tunemalm AK, et al. Structural changes of phenylalanine 338 and histidine 447 revealed by the crystal structures of tabun-inhibited murine acetylcholinesterase. Biochemistry 2006; 45: 74–81PubMedCrossRefGoogle Scholar
  45. 45.
    Hamilton MG, Lundy PM. HI-6 therapy of soman and tabun poisoning in primates and rodents. Arch Toxicol 1989; 63: 144–9PubMedCrossRefGoogle Scholar
  46. 46.
    Wolthuis OL, Cohen EM. The effects of P2S, TMB4 and LüH6 on the rat phrenic nerve diaphragm preparation treated with soman or tabun. Biochem Pharmacol 1967; 16: 361–7PubMedCrossRefGoogle Scholar
  47. 47.
    Cohen EM, Wiersinga H. Oximes in the treatment of nerve gas poisoning. Acta Physiol Pharmacol Neerland 1959; 8: 40–51Google Scholar
  48. 48.
    Cetkovic S, Cvetkovic M, Jandric D, et al. Effect of PAM-2 Cl, HI-6, and HGG-12 in poisoning by tabun and its thiocholine-like analog in the rat. Fundam Appl Toxicol 1984; 4: S116–23PubMedCrossRefGoogle Scholar
  49. 49.
    Boskovic B, Kovacevic V, Jovanovic D. PAM-2 Cl, HI-6, and HGG-12 in soman and tabun poisoning. Fundam Appl Toxicol 1984; 4: S106–15PubMedCrossRefGoogle Scholar
  50. 50.
    Fleisher JH, Michel HO, Yates L, et al. l,l′-trimethylene bis(4-formylpyridinium bromide) dioxime (TMB-4) and 2-pyridine aldoxime methiodide (2-PAM) as adjuvants to atropine in the treatment of anticholinesterase poisoning. J Pharmacol Exp Ther 1960; 129: 31–5PubMedGoogle Scholar
  51. 51.
    Hildebrandt HJ. Zur kombinierten Antidottherapie der tierexperimentellen Vergiftung mit Tabun, Sarin und Soman. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1969; 263: 222–3PubMedGoogle Scholar
  52. 52.
    Maksimovic M, Boskovic B, Radovic L, et al. Antidotal effects of bis-pyridinium-2-mono oxime carbonyl derivatives in intoxications with highly toxic organophosphorus compounds. Acta Pharm Jugosl 1980; 30: 151–60Google Scholar
  53. 53.
    Eyer P, Hagedorn I, Klimmek R, et al. HLö7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases. Arch Toxicol 1992; 66: 603–21PubMedCrossRefGoogle Scholar
  54. 54.
    Lundy PM, Goulet JC, Hand BT. Hormone- and dose schedule-dependent protection by HI-6 against soman and tabun poisoning. Fundam Appl Toxicol 1989; 12: 595–603PubMedCrossRefGoogle Scholar
  55. 55.
    Das Gupta S, Bhattacharya R, Purnanand B, et al. Protection studies on anticholinesterase agents in rats. Pharmazie 1990; 45: 801–2PubMedGoogle Scholar
  56. 56.
    Schoene K, Oldiges H. Die Wirkungen von Pyridiniumsalzen gegenüber Tabun- und Sarinvergiftungen in vivo und in vitro. Arch Int Pharmacodyn 1973; 204: 110–23PubMedGoogle Scholar
  57. 57.
    Askew BM. Oximes and atropine in sarin poisoning. Br J Pharmacol 1957; 12: 340–3Google Scholar
  58. 58.
    Bhattacharya R, Kumar P, Jeevaratnam K, et al. Therapeutic evaluation of brochodilators as an adjunct against organophosphorus intoxication in mice. Asia Pac J Pharmacol 1991; 6: 75–80Google Scholar
  59. 59.
    Kaliste-Korhonen E, Ryhänen R, Ylitalo P, et al. Cold exposure decreases the effectiveness of atropine-oxime treatment in organophosphate intoxication in rats and mice. Gen Pharmacol 1989; 20: 805–9PubMedCrossRefGoogle Scholar
  60. 60.
    Wang P-H, Ma C, Liu R-F, et al. Design, synthesis and testing of new oximes as potential antidotes against organophosphate poisoning. J Taiwan Pharm Assoc 1985; 37: 44–51Google Scholar
  61. 61.
    Fleisher JH, Harris LW, Miller GR, et al. Antagonism of sarin poisoning in rats and guinea pigs by atropine, oximes, and mecamylamine. Toxicol Appl Pharmacol 1970; 16: 40–7PubMedCrossRefGoogle Scholar
  62. 62.
    Urbanski R. Ocena skutecznosci leczniczej optimalnych dawek siarczanu atropiny, obidoksymu i diazepamu w ostrym zatruciu somanem, sarinem i VX. Lek Wojsk 1988; 64: 486–90Google Scholar
  63. 63.
    Gordon JJ, Leadbeater L. The prophylactic use of l-methyl,2-hydroxyimi-nomethylpyridinium methanesulfonate (P2S) in the treatment of organophosphate poisoning. Toxicol Appl Pharmacol 1977; 40: 109–14PubMedCrossRefGoogle Scholar
  64. 64.
    O’Leary JF, Kunkel AM, Jones AH. Efficacy and limitations of oxime-atropine treatment of organophosphorus anticholinesterase poisoning. J Pharmacol Exp Ther 1961; 132: 50–7PubMedGoogle Scholar
  65. 65.
    Wills JH, Kunkel AM, Brown RV, et al. Pyridine-2-aldoxime methiodide and poisoning by anticholinesterases. Science 1957; 125: 743–4PubMedCrossRefGoogle Scholar
  66. 66.
    Bismuth C, Inns RH, Marrs TC. Efficacy, toxicity and clinical use of oximes in anticholinesterase poisoning. In: Ballantyne B, Marrs TC, editors. Clinical and experimental toxicology of organophosphates and carbamates. Oxford: Butterworth-Heinemann, 1992: 77Google Scholar
  67. 67.
    Clement JG, Lockwood PA. HI-6, an oxime which is an effective antidote of soman poisoning: a structure-activity study. Toxicol Appl Pharmacol 1982; 64: 140–6PubMedCrossRefGoogle Scholar
  68. 68.
    Shih T-M, Whalley CE, Valdes JJ. A comparison of cholinergic effects of HI-6 and pralidoxime-2-chloride (2-PAM) in soman poisoning. Toxicol Lett 1991; 55: 131–47PubMedCrossRefGoogle Scholar
  69. 69.
    Shih T-M. Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats. Arch Toxicol 1993; 67: 637–46PubMedCrossRefGoogle Scholar
  70. 70.
    Kassa J. Srpvnání effectu vybranych reaktivátoru cholinesteráz v kombinaci s atropinem na toxicitu somanu a fosdrinu mysí. Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl 1995; 38: 63–6PubMedGoogle Scholar
  71. 71.
    Kassa J, Bajgar J. Changes of acetylcholinesterase activity in various parts of brain following nontreated and treated soman poisoning in rats. Mol Chem Neuropathol 1998; 33: 175–84PubMedCrossRefGoogle Scholar
  72. 72.
    Tušarová I, Halámek E, Kobliha Z. Study on reactivation of enzyme-inhibitor complexes by oximes using acetylcholine esterase inhibited by organophosphate chemical warfare agents. Enzyme Microb Technol 1999; 25: 400–3CrossRefGoogle Scholar
  73. 73.
    Kassa J, Cabal J. A comparison of the efficacy of acetylcholinesterase reactivators against cyclohexyl methylphosphonofluoridate (GF agent) by in vitro and in vivo methods. Pharmacol Toxicol 1999; 84: 41–5PubMedGoogle Scholar
  74. 74.
    Luo C, Liang J. Evaluation of combined toxic effects of GB/GF and efficacy of jielin injection against combined poisoning in mice. Toxicol Lett 1997; 92: 195–200PubMedCrossRefGoogle Scholar
  75. 75.
    Koplovitz I, Gresham VC, Dochterman LW, et al. Evaluation of the toxicity, pathology, and treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rhesus monkeys. Arch Toxicol 1992; 66: 622–8PubMedCrossRefGoogle Scholar
  76. 76.
    Lundy PM, Hansen AS, Hand BT, et al. Comparison of several oximes against poisoning by soman, tabun and GF. Toxicology 1992; 72: 99–105PubMedCrossRefGoogle Scholar
  77. 77.
    Kassa J, Bajgar J. Therapeutic efficacy of obidoxime or HI-6 with atropine against intoxication with some nerve agents in mice. Acta Med Hradec Kralove 1996; 39: 27–30Google Scholar
  78. 78.
    Clement JG. Efficacy of various oximes against GF (cyclohexyl methylphosphonofluoridate) poisoning in mice. Arch Toxicol 1992; 66: 143–4PubMedCrossRefGoogle Scholar
  79. 79.
    Clement JG, Hansen AS, Boulet CA. Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice. Arch Toxicol 1992; 66: 216–9PubMedCrossRefGoogle Scholar
  80. 80.
    Kassa J, Bajgar J. Comparison of the efficacy of HI-6 and obidoxime against cyclohexyl methyl-phosphonofluoridate (GF) in rats. Hum Exp Toxicol 1995; 14: 923–8PubMedCrossRefGoogle Scholar
  81. 81.
    Simeon V, Wilhelm K, Granov A, et al. 1,3-Bispyridinium-dimethylether mono- and dioximes: synthesis, reactivating potency and therapeutic effect in experimental poisoning by organophosphorus compounds. Arch Toxicol 1979; 41: 301–6PubMedCrossRefGoogle Scholar
  82. 82.
    Maksimovic M, Kovacevic V, Binenfeld Z. Protective and reactivating effects of HI-6-toxogonin mixture in rats and guinea-pigs poisoned by nerve agents. Acta Pharm Jugosl 1989; 39: 27–33Google Scholar
  83. 83.
    Wilhelm K, Fajdetic A, Deljac V, et al. Protective effect of dexetimide and HI-6 in poisoning with highly toxic organophosphorus compounds. Arh Hig Rada Toksikol 1979; 30: 147–51PubMedGoogle Scholar
  84. 84.
    Kovacevic V, Maksimovic M, Pantelic D, et al. Protective and reactivating effects of HI-6 PAM-2 mixture in rats poisoned with nerve chemical warfare agents (nerve CWA). Acta Pharm Jugosl 1989; 39: 161–5Google Scholar
  85. 85.
    Worek F, Kirchner T, Szinicz L. Effect of atropine, HLö 7 and HI 6 on respiratory and circulatory function in guinea-pigs poisoned by O-ethyl S-[2-(diisopropy-lamino) ethyl] methylphosponothioate (VX). Pharmacol Toxicol 1994; 75: 302–9PubMedCrossRefGoogle Scholar
  86. 86.
    Davies DR, Willey GL. The toxicity of 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate (P2S). Br J Pharmacol 1958; 13: 202–6Google Scholar
  87. 87.
    Enander I, Sundwall A, Sörbo B. Metabolic studies on N-methylpyridinium-2-aldoxime: I. The conversion to thiocyanate. Biochem Pharmacol 1961; 7: 226–31PubMedCrossRefGoogle Scholar
  88. 88.
    Ballantyne B, Gazzard MF, Robson DC, et al. Concentrations of 2-hydroxyiminomethyl-N-methylpyridinium ion in plasma and aqueous humor as indices of the toxicity of pralidoxime mesylate (P2S) for the rabbit. Toxicol Appl Pharmacol 1975; 33: 559–67PubMedCrossRefGoogle Scholar
  89. 89.
    Putman D, San RHC, Bigger CA, et al. Genetic toxicology assessment of HI-6 dichloride. Environ Mol Mutagen 1996; 27: 152–61PubMedCrossRefGoogle Scholar
  90. 90.
    Boelcke G, Gaaz J-W. Zur Frage der Lebertoxicität von Nitrostigmin (E 605 forte) und Obidoxim (Toxogonin) an Hunden. Arch Toxikol 1970; 26: 93–101PubMedCrossRefGoogle Scholar
  91. 91.
    Boelcke G, Kamphenkel L. Der Einfluß der Nitrostigmin-Vergiftung und der spezifischen Antidote-Therapie mit Obidoxim auf die Bilirubin-Clearance und den Gallefluß der Ratte. Arch Toxikol 1970; 26: 210–9PubMedCrossRefGoogle Scholar
  92. 92.
    Sidell FR. Soman and sarin: clinical manifestations and treatment of accidental poisoning by organophosphates. J Toxicol Clin Toxicol 1974; 7: 1–17CrossRefGoogle Scholar
  93. 93.
    Sidell FR. Nerve agents. In: Zajtchuk R, Bellamy RF, editors. Textbook of military medicine. Part I. Warfare, weaponry and the casualty: medical aspects of chemical and biological warfare. 1st ed. Washington, DC: Borden Institute, Walter Reed Medical Center, 1997, 79Google Scholar
  94. 94.
    Sidell FR. Clinical considerations in nerve agent intoxication. In: Somani SM, editor. Chemical warfare agents. San Diego (CA): Academic Press, 1992, 94Google Scholar
  95. 95.
    Nozaki H, Hori S, Shinozawa Y, et al. Relationship between pupil size and acetylcholinesterase activity in patients exposed to sarin vapor. Intensive Care Med 1997; 23: 1005–7PubMedCrossRefGoogle Scholar
  96. 96.
    Murata K, Araki S, Yokoyama K, et al. Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack. J Neurol 1997; 244: 601–6PubMedCrossRefGoogle Scholar
  97. 97.
    Sekijima Y, Morita H, Yanagisawa N. Follow-up of sarin poisoning in Matsumoto. Ann Intern Med 1997; 127: 1042PubMedGoogle Scholar
  98. 98.
    Marrs TC. The role of diazepam in the treatment of nerve agent poisoning in a civilian population. Toxicol Rev 2004; 23: 145–57PubMedCrossRefGoogle Scholar
  99. 99.
    Nozaki H, Aikawa N. Sarin poisoning in Tokyo subway. Lancet 1995; 345: 1446–7PubMedCrossRefGoogle Scholar
  100. 100.
    Nozaki H, Aikawa N, Shinozawa Y, et al. Sarin poisoning in Tokyo subway. Lancet 1995; 345: 980–1PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Timothy C. Marrs
    • 1
    • 2
  • Paul Rice
    • 3
  • J. Allister Vale
    • 1
    • 4
  1. 1.National Poisons Information Service, (Birmingham Unit)City HospitalBirminghamUK
  2. 2.University of Central LancashirePrestonUK
  3. 3.Dstl Porton DownSalisburyUK
  4. 4.West Midlands Poisons UnitCity HospitalBirminghamUK

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