Advertisement

Archives of Toxicology

, Volume 66, Issue 9, pp 603–621 | Cite as

HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

  • P. Eyer
  • I. Hagedorn
  • R. Klimmek
  • P. Lippstreu
  • M. Löffler
  • H. Oldiges
  • U. Spöhrer
  • I. Steidl
  • L. Szinicz
  • F. Worek
Original Investigations

Abstract

HLö 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio] methoxy] methyl] -2,4-bis [(hydroxyimino) methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HLö 7 dimethanesulfonate is the first water-soluble salt of HLö 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLö 7 are not very stable (calculated shelf-life 0.2 years when stored at 8°C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of thesyn/syn-isomer, less than 2% of thesyn/anti-isomer and some minor identified by-products. HLö 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLö 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HLö 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLö 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLö 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLö 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HLö 7 (57 min). HLö 7 alone did not prolong the survival. The most impressive effect of HLö 7 was on respiration: 3 min after i.v. injection of HLö 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HLö 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLö 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLö 7 in male beagle dogs are similar to those of HI 6. After i.v. injection: t1/2α = 5 min; t1/2ß = 46 min; VD = 0.24 1/kg; Clp1 = 3.7 ml x min−1 x kg−1; Clren= 3.2 ml x min−1 x kg−1; renal excretion of unchanged HLö 7 = 86%. After i. m. injection: t1/2abs = 14 min; t1/2ß = 48 min; Vd = 0.27 1/kg; Clp1= 3.9 ml x min−1 x kg−1; Clren= 2.7 ml x min−1 x kg−1; renal excretion of unchanged HLö 7 = 76%; bioavailability >95%. Plasma protein binding was <5%; HLö 7 did not permeate into red cells. A dose of 20 μmol/kg was well tolerated both after i.v. and i.m. administration. In anaesthetized dogs (chloralose) HLö 7 i.v. (20 (imol/kg) showed marginal hypotensive effects, whereas 50 μmol/kg resulted in decreased mean blood pressure (−15%) and blood flow (−30%) without reflex tachycardia. One out of four dogs developed a circulatory shock syndrome with anuria. Respiration varied only transiently. Blood gases and pH were not influenced. Similar cardiovascular effects were observed in anaesthetized (urethane) guinea-pigs. In isolated guinea-pig hearts (Langendorff) sinus and ventricular heart rate were not influenced by HLö 7 <500 μM. HLö 7 antagonized both carbachol and nicotine effects. Red cell AChE was inhibited by HLö 7 by up to 50%; C50 about 100 μM. Previously, HLö 7 was shown to block ganglionic transmission (IC50= 500 μM), probably due to ion-channel blockade. These data indicate that HLö 7 combines ganglion blocking, anticholinergic and indirect cholinergic properties like other bispyridinium compounds. The results suggest that HLö 7 may be tolerated by man at a dose of 10 μmol/kg. Vital functions are not expected to be impaired. At such a dose (250–500 mg), which can be injected by an autoinjector, HLö 7 is expected to be superior to HI 6.

Key words

Oximes HLö 7 [CAS reg. No. 120 103-35-7] HI 6 [CAS reg. No. 34433-31-31] Obidoxime [CAS reg. No. 114-90-9] Syntheses Organophosphates Therapy Reactivation Acetylcholinesterase 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adolph EF (1949) Quantitative relations in the physiological constitutions of mammals. Science 109: 579–585Google Scholar
  2. Alberts P (1990) A new H-oxime restores rat diaphragm contractility after esterase inhibition in vitro. Eur J Pharmacol 184: 191–194CrossRefPubMedGoogle Scholar
  3. Alkondon M, Rao KS, Albuquerque EX (1988) Acetylcholinesterase reactivators modify the functional properties of the nicotinic acetylcholine receptor ion channel. J Pharmacol Exp Ther 245: 543–556PubMedGoogle Scholar
  4. Benschop HP, Keijer JH (1966) On the mechanism of ageing of phosphonylated cholinesterases. Biochim Biophys Acta 128: 586–588Google Scholar
  5. Bisa K, Fischer G, Müller O, Oldiges H, Zoche E (1964) Die Antidotwirkung von Bis-[4-hydroxyiminomethyl-pyridinium-(1)-methyl]-äther-dichlorid bei mit Alkylphosphat vergifteten Ratten. Arzneimittelforschung 14: 85–88PubMedGoogle Scholar
  6. Boskovic B, Kovacevic V, Jovanovic D (1984) PAM-2 Cl, HI 6 and HGG 12 in soman and tabun poisoning. Fundam Appl Toxicol 4: S106-S115CrossRefPubMedGoogle Scholar
  7. Burness DM, Wright CJ, Perkins WC (1977) Bis(methylsulfonoxymethyl)-ether. J Org Chem 42: 2910–2913CrossRefGoogle Scholar
  8. Cetkovic S, Cvetkovic M, Jandric D, Cosic M, Boskovic B (1984) Effect of 2-PAM Cl, HI 6, and HGG 12 in poisoning by tabun and its thiocholine-like analog in the rat. Fundam Appl Toxicol 4: S116-S123CrossRefPubMedGoogle Scholar
  9. Clement JG (1981) Toxicology and pharmacology ofbis-pyridinium oximes. Insight into the mechanism of action vs soman poisoning in vivo. Fundam Appl Toxicol 1: 193–202PubMedGoogle Scholar
  10. Clement JG (1982) HI 6: Reactivation of central and peripheral acetylcholinesterase following inhibition by soman, sarin and tabun in vivo in the rat. Biochem Pharmacol 31: 1283–1287CrossRefPubMedGoogle Scholar
  11. Clement JG (1983) Efficacy ofmono-, andbis-pyridinium oximes versus soman and tabun poisoning in mice. Fundam Appl Toxicol 3: 533–535PubMedGoogle Scholar
  12. Clement JG (1984) Role of aliesterase in organophosphate poisoning. Fundam Appl Toxicol 4: S96-S105CrossRefPubMedGoogle Scholar
  13. Clement JG (1991 a) Variability of sarin-induced hypothermia in mice: investigation into incidence and mechanism. Biochem Pharmacol 42: 1316–1318CrossRefPubMedGoogle Scholar
  14. Clement J (1991 b) Central actions of acetylcholinesterase oxime reactivators. Fundam Appl Toxicol (submitted)Google Scholar
  15. Clement JG, Lockwood PA (1982) HI 6, an oxime which is an effective antidote of soman poisoning: a structure-activity study. Toxicol Appl Pharmacol 64: 140–146CrossRefPubMedGoogle Scholar
  16. Clement JG, Hansen AS, Boulet CA (1992) Efficacy of HLö 7 and pyrimidoxime as antidotes of nerve agent poisoning in mice. Arch Toxicol 66: 216–219PubMedGoogle Scholar
  17. DFG Deutsche Forschungsgemeinschaft (1987) Maximum concentrations at the workplace and biological tolerance values for working material. VCH Verlagsgesellschaft mbH, Weinheim, p 57Google Scholar
  18. van Dongen CJ, Elskamp RM, de Jong LPA (1987) Influence of atropine upon reactivation and ageing of rat and human erythrocyte acetylcholinesterase inhibited by soman. Biochem Pharmacol 36: 1167–1169CrossRefPubMedGoogle Scholar
  19. Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7: 88–95CrossRefPubMedGoogle Scholar
  20. Endres W, Spuhler A, ten Bruggencate G (1989) Acetylcholinesterase reactivators antagonize epileptiform bursting induced by paraoxon in guinea-pig hippocampal slices. J Pharmacol Exp Ther 251: 1181–1186PubMedGoogle Scholar
  21. Engelhard H, Erdmann WD (1963) Ein neuer Reaktivator für durch Alkylphosphat gehemmte Acetylcholinesterase Klin Wochenschr 41: 225–227CrossRefGoogle Scholar
  22. Engelhard N, Erdmann WD (1964) Beziehungen zwischen chemischer Struktur und Cholinesterase reaktivierender Wirksamkeit bei einer Reihe neuer bis-quartärer Pyridin-4-aldoxime. Arzneimittelforschung 14: 870–875PubMedGoogle Scholar
  23. Erdmann WD, Engelhard H (1964) Pharmakologisch-toxikologische Untersuchungen mit dem Dichlorid des Bis-[4-hydroxyiminomethyl-pyridinium-(1)-methyl]-äthers, einem neuen Esterase-Reaktivator. Arzneimittelforschung 14: 5–11PubMedGoogle Scholar
  24. Eyer P, Lierheimer E, Schneller M (1984) Reactions of nitrosochloramphenicol in blood. Biochem Pharmacol 33: 2299–2308CrossRefPubMedGoogle Scholar
  25. Eyer P, Hell W, Kawan A, Klehr H (1986) Studies on the decomposition of the oxime HI 6 in aqueous solution. Arch Toxicol 59: 266–271CrossRefPubMedGoogle Scholar
  26. Eyer P, Hagedorn I, Ladstetter B (1988) Study on the stability of the oxime HI 6 in aqueous solution. Arch Toxicol 62: 224–226CrossRefPubMedGoogle Scholar
  27. Eyer P, Ladstetter B, Schäfer W, Sonnenbichler J (1989) Studies on the stability and decomposition of the Hagedorn-oxime HLö 7 in aqueous solution. Arch Toxicol 63: 59–67CrossRefPubMedGoogle Scholar
  28. Fonnum F, Sterri SH (1981) Factors modifying the toxicity of organophosphorus compounds including soman and sarin. Fundam Appl Toxicol 1: 143–147PubMedGoogle Scholar
  29. Fonnum F, Sterri SH, Aas P, Johnsen H (1985) Carboxylesterases, importance for detoxification of organophosphorus anticholinesterases and trichothecenes. Fundam Appl Toxicol 5: S29-S38CrossRefPubMedGoogle Scholar
  30. Gaustad R, Johnsen H, Fonnum F (1991) Carboxylesterases in guineapig. A comparison of the different isoenzymes with regard to inhibition by organophosphorus compounds in vivo and in vitro. Biochem Pharmacol 42: 1335–1343CrossRefPubMedGoogle Scholar
  31. Glick D (1937) Properties of choline esterase in human serum. Biochem J 31: 521–525Google Scholar
  32. Gramstad T, Haszeldine RN (1956) Perfluoroalkyl derivatives of sulphur. Part IV. Perfluoroalkanesulphonic acids. J Chem Soc 173–180Google Scholar
  33. Hackley BE, Steinberg GM, Lamb JC (1959) Formation of potent inhibitors of AChE by reaction of pyridinaldoximes with isopropyl methylphosphonofluoridate (GB). Arch Biochem Biophys 80: 211–214CrossRefGoogle Scholar
  34. Hagedorn I, Gündel WH, Schoene K (1969) Reaktivierung phosphorylierter Acetylcholinesterase mit Oximen: Beitrag zum Studium des Reaktionsablaufes. Arzneimittelforschung 19: 603–606PubMedGoogle Scholar
  35. Hagedorn I, Stark I, Lorenz P (1972) Reaktivierung phosphorylierter Acetylcholinesterase — Abhängigkeit von der Aktivator-Acidität. Angew Chem 84: 354–356Google Scholar
  36. Hagedorn I, Stark I, Schoene K, Schenkel H (1978) Reaktivierung phosphorylierter Acetylcholinesterase. Isomere bisquartäre Salze von Pyridinaldoximen. Arzneimittelforschung 28: 2055–2057PubMedGoogle Scholar
  37. Hamilton MG, Lundy PM (1989) HI 6 therapy of soman and tabun poisoning in primates and rodents. Arch Toxicol 63: 144–149CrossRefPubMedGoogle Scholar
  38. Heilbronn E, Tolagen B (1965) Toxogonin in sarin, soman and tabun poisoning. Biochem Pharmacol 14: 73–77CrossRefPubMedGoogle Scholar
  39. van Helden HPM, de Lange J, Busker RW, Melchers BPC (1991) Therapy of organophosphate poisoning in the rat by direct effects of oximes unrelated to ChE reactivation. Arch Toxicol 65: 586–593PubMedGoogle Scholar
  40. Irwin S (1968) Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioural and physiologic state of the mouse. Psychopharmacology 13: 222–257CrossRefGoogle Scholar
  41. de Jong LPA, Ceulen DI (1978) Anticholinesterase activity and rate of decomposition of some phosphylated oximes. Biochem Pharmacol 27: 857–863CrossRefPubMedGoogle Scholar
  42. de Jong LPA, Wolring GZ (1980) Reactivation of acetylcholinesterase inhibited by 1,2,2′-trimethylpropyl methylphosphonofluoridate (soman) with HI 6 and related oximes. Biochem Pharmacol 29: 2379–2387CrossRefPubMedGoogle Scholar
  43. de Jong LPA, Wolring GZ (1984) Stereospecific reactivation by some Hagedorn-oximes of acetylcholinesterases from various species including man, inhibited by soman. Biochem Pharmacol 33: 1119–1125CrossRefPubMedGoogle Scholar
  44. de Jong LPA, Wolring GZ (1985) Aging and stereospecific reactivation of mouse erythrocyte and brain acetylcholinesterase inhibited by soman. Biochem Pharmacol 34: 142–145CrossRefPubMedGoogle Scholar
  45. de Jong LPA, Verhagen MAA, Langenberg JP, Hagedorn I, Löffler M (1989) The bispyridinium-dioxime HLö 7. A potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman. Biochem Pharmacol 38: 633–640CrossRefPubMedGoogle Scholar
  46. Josselson J, Sidell FR (1978) Effects of intravenous thiamine on pralidoxime kinetics. Clin Pharmacol Ther 24: 95–100PubMedGoogle Scholar
  47. Karger MH, Mazur Y (1971) Mixed sulfonic-carboxylic anhydrides. I. Synthesis and thermal stability. New syntheses of sulfonic anhydrides. J Org Chem 36: 528–531CrossRefGoogle Scholar
  48. Kirsch DM, Weger N (1981) Effects of the bispyridinium compounds HGG 12, HGG 42, and obidoxime on synaptic transmission and NAD(P)H-fluorescence in the superior cervical ganglion of the rat in vitro. Arch Toxicol 47: 217–232CrossRefPubMedGoogle Scholar
  49. Klimmek R, Eyer P (1985) Pharmacokinetics and toxicity of the oxime HGG 12 in dogs. Arch Toxicol 57: 237–242CrossRefPubMedGoogle Scholar
  50. Klimmek R, Eyer P (1986) Pharmacokinetics and pharmacodynamics of the oxime HI 6 in dogs. Arch Toxicol 59: 272–278CrossRefPubMedGoogle Scholar
  51. Kusic R, Boskovic B, Vojvodic V, Jovanovic D (1985) HI 6 in man: blood levels, urinary excretion, and tolerance after intramuscular administration of the oxime to healthy volunteers. Fundam Appl Toxicol 5: S89-S97CrossRefPubMedGoogle Scholar
  52. Kusic R, Jovanovic D, Randjelovic S, Joksovic D, Todorovic V, Boskovic B, Jokanovic M, Vojvodic V (1991) HI 6 in man: Efficacy of the oxime in poisoning by organophosphorus insecticides. Hum Exp Toxicol 10: 113–118PubMedGoogle Scholar
  53. Ladstetter B (1990) Stabilität und metabolisches Schicksal neuer Antidote gegen Organophosphate. Thesis, Univ. MünchenGoogle Scholar
  54. Ligtenstein DA, Kossen SP (1983) Kinetic profile in blood and brain of the cholinesterase reactivating oxime HI 6 after intravenous administration to the rat. Toxicol Appl Pharmacol 71: 177–183CrossRefPubMedGoogle Scholar
  55. Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. Pharmacol Exp Ther 96: 99–113Google Scholar
  56. Löffler M (1986) Quartäre Salze von Pyridin-2,4-dialdoxim als Gegenmittel für Organophosphat-Vergiftungen. Thesis, Univ. FreiburgGoogle Scholar
  57. Lorenz HP (1974) Syn- und anti-Aldoxime N-heteroaromatischer Aldoxime: Darstellung, Ermittlung ihrer Konfiguration und Stabilität sowie Studium der Isomerisierungsreaktion. Thesis, Univ. FreiburgGoogle Scholar
  58. Lundy PM, Tremblay KP (1979) Ganglion blocking properties of some bispyridinium soman antagonists. Eur J Pharmacol 60: 47–53CrossRefPubMedGoogle Scholar
  59. Lundy PM, Hansen AS, Hand BT, Boulet CA (1992) Comparison of several oximes against poisoning by soman, tabun and GF. Toxicology 72: 99–105CrossRefPubMedGoogle Scholar
  60. Lüttringhaus A, Hagedorn I (1964) Quartäre Hydroxyiminomethyl-pyridinium-salze. Das Dichlorid des Bis-[4-hydroxyiminomethyl-pyridinium-(1)-methylläthers] (“LüH 6”), ein neuer Reaktivator der durch organische Phosphorsäureester gehemmten Acetylcholinesterase. Arzneimittelforschung 14: 1–5PubMedGoogle Scholar
  61. Marquardt DW (1963) An algorithm for least-square estimation on nonlinear parameters. J Soc Industr Appl Math 11: 431–441CrossRefGoogle Scholar
  62. Moncada S, Palmer MJ, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109–142PubMedGoogle Scholar
  63. de la Motte S, Szinicz L (1991) Effects of pyridinium, 1-[[[4-(carbamoyl)-pyridinio]methoxy]methyl]-2-(hydroxyiminomethyl) dichloride monohydrate (HI 6) and atropine on the circulation and respiration of anaesthetized guinea-pigs. Arch Toxicol Suppl 14: 266–268PubMedGoogle Scholar
  64. Nenner M (1970) Gleichzeitige Bestimmung der Aktivität von Acetylcholinesterase in Vollblut, Plasma und Erythrozyten mit dem automatischen Titrator. Z Klin Chem Klin Biochem 8: 537–540PubMedGoogle Scholar
  65. Nenner M (1974) Phosphonylierte Aldoxime. Hemmwirkung auf Acetylcholinesterase und hydrolytischer Abbau. Biochem Pharmacol 23: 1255–1262CrossRefPubMedGoogle Scholar
  66. Oldiges H, Schoene K (1970) Pyridinium- und Imidazoliniumsalze als Antidote gegenüber Soman- und Paraoxonvergiftungen bei Mäusen. Arch Toxicol 26: 293–305CrossRefGoogle Scholar
  67. Queguiner G, Pastour P (1964) Preparation of pyridinedicarboxaldehydes. Compt Rend 258: 5903–5906Google Scholar
  68. Queguiner G, Pastour P (1969) Synthesis in the pyridine series. V. Study of the reduction of ethyl pyridinedicarboxylates. Bull Soc Chim Fr 10: 3678–3683Google Scholar
  69. Rand MJ, McCulloch MW, Story DT (1980) Catecholamine receptors on nerve terminals. In: Szekeris L (ed) Adrenergic activators and inhibitors. Part I. Handbook of experimental pharmacology, vol 54/I. Springer Berlin Heidelberg New York, pp 223–266Google Scholar
  70. Reddy VK, Deshpande SS, Cintra WM, Scoble GT, Albuquerque EX (1991) 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 17: 746–760CrossRefPubMedGoogle Scholar
  71. Reithmann C, Arbogast H, Hallek M, Auburger G, Szinicz L (1988) Studies on the role of central catecholaminergic mechanisms in the antidotal effect of the oxime HI 6 in soman poisoned mice. Arch Toxicol 62: 41–44CrossRefPubMedGoogle Scholar
  72. Remien J, Mellinghoff A, Reithmeier I (1991) Muscarinic and nicotinic actions of oximes. Akademie Symposium: Role of oximes in the treatment of anticholinesterase agent poisoning, Munich, Oct 7Google Scholar
  73. Rowland M, Tozer TN (1989) Clinical pharmacokinetics 2nd edn. Lea and Febiger, PhiladelphiaGoogle Scholar
  74. Sachs L (1978) Angewandte Statistik 5. Aufl. Springer-Verlag Berlin Heidelberg New YorkGoogle Scholar
  75. Schlagmann C, Ulbrich H, Remien J (1990) Bispyridinium (oxime) compounds antagonize the “ganglion blocking” effect of pyridostigmine in isolated superior cervical ganglia of the rat. Arch Toxicol 64: 482–489CrossRefPubMedGoogle Scholar
  76. Schoene K (1973) Phosphonyloxime aus Soman; Bildung und Reaktion mit Acetylcholinesterase in vitro. Biochem Pharmacol 22: 2997–3003CrossRefPubMedGoogle Scholar
  77. Schoene K, Oldiges H (1973) Die Wirkungen von Pyridiniumsalzen gegenüber Tabun- und Somanvergiftungen in vivo und in vitro. Arch Int Pharmacodyn 204: 110–123PubMedGoogle Scholar
  78. Schoene K, Strake EM (1971) Reaktivierung von Diäthylphosphoryl-Acetylcholinesterase. Affinität und Reaktivität einiger Pyridiniumoxime. Biochem Pharmacol 20: 1041–1051CrossRefPubMedGoogle Scholar
  79. Sidell FR, Groff WA, Kaminskis A (1972) Toxogonin and pralidoxime: kinetic comparison after intravenous administration to man. J Pharm Sci 60: 860–863Google Scholar
  80. Simons KJ, Briggs CJ (1983) The pharmacokinetics of HI 6 in beagle dogs. Biopharm Drug Dispos 4: 375–388PubMedGoogle Scholar
  81. Stark I (1968) Versuche zur Darstellung eines LüH6 (Toxogonin) überlegenen Acetylcholinesterase-Reaktivators. Dipl. Arbeit, Univ. FreiburgGoogle Scholar
  82. Stark I (1971) Reaktivierung phosphorylierter Acetylcholinesterase mit quaternierten Pyridinaldoximen. Ermittlung des Zusammenhangs zwischen Oximacidität und Reaktivierungsvermögen. Thesis, Univ. FreiburgGoogle Scholar
  83. Steinberg GM, Solomon S (1966) Decomposition of a phosphonylated pyridinium aldoxime in aqueous solution. Biochemistry 5: 3142–3150CrossRefPubMedGoogle Scholar
  84. Weger N, Szinicz L (1981) Therapeutic effects of new oximes, benactyzine and atropin in soman poisoning: Part I. Effects of various oximes in soman, sarin, and Vx poisoning in dogs. Fundam AppI Toxicol 1: 161–163Google Scholar
  85. Wolthuis OL, Cohen EM (1967) The effects of P2S, TMB-4, and LüH 6 on the rat phrenic nerve diaphragm preparation treated with soman or tabun. Biochem Pharmacol 16: 361–367CrossRefPubMedGoogle Scholar
  86. Wolthuis OL, Vanwersch RAP, van der Wiel HJ (1981) The efficacy of somebis-pyridinium oximes as antidotes to soman in isolated muscles of several species including man. Eur J Pharmacol 70: 355–369CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • P. Eyer
    • 1
  • I. Hagedorn
    • 2
  • R. Klimmek
    • 1
  • P. Lippstreu
    • 1
  • M. Löffler
    • 3
  • H. Oldiges
    • 4
  • U. Spöhrer
    • 1
  • I. Steidl
    • 5
  • L. Szinicz
    • 5
  • F. Worek
    • 5
  1. 1.Walther-Straub-Institut für Pharmakologie und Toxikologie der Ludwig-Maximilians-Universität MünchenMünchen 2Federal Republic of Germany
  2. 2.FreiburgFederal Republic of Germany
  3. 3.FreiburgFederal Republic of Germany
  4. 4.Fraunhofer-Institut für Umweltchemie und ÖkotoxikologieGrafschaftFederal Republic of Germany
  5. 5.Institut für Pharmakologie und ToxikologieAkademie des Sanitäts- und Gesundheitswesens der Bundeswehr, BSWGarchingFederal Republic of Germany

Personalised recommendations