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Anticonvulsants for soman-induced seizure activity

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

This report describes studies of anticonvulsants for the organophosphorus (OP) nerve agent soman: a basic research effort to understand how different pharmacological classes of compounds influence the expression of seizure produced by soman in rats, and a drug screening effort to determine whether clinically useful antiepileptics can modulate soman-induced seizures in rats. Electroencephalographic (EEG) recordings were used in these studies. Basic studies were conducted in rats pretreated with HI-6 and challenged with 1.6×LD50 soman. Antimuscarinic compounds were extremely effective in blocking (pretreatment) or terminating soman seizures when given 5 min after seizure onset. However, significantly higher doses were required when treatment was delayed for more than 10 min, and some antimuscarinic compounds lost anticonvulsant efficacy when treatment was delayed for more than 40 min. Diazepam blocked seizure onset, yet seizures could recur after an initial period of anticonvulsant effect at doses ≤2.5 mg/kg. Diazepam could terminate ongoing seizures when given 5 min after seizure onset, but doses up to 20 mg/kg were ineffective when treatment was delayed for 40 min. The GABA uptake inhibitor, tiagabine, was ineffective in blocking or terminating soman motor convulsions or seizures. The glutamate receptor antagonists, NBQX, GYKI 52466, and memantine, had weak or minimal antiseizure activity, even at doses that virtually eliminated signs of motor convulsions. The antinicotinic, mecamylamine, was ineffective in blocking or stopping seizure activity. Pretreatment with a narrow range of doses of α2-adrenergic agonist, clonidine, produced variable protection (40–60%) against seizure onset; treatment after seizure onset with clonidine was not effective. Screening studies in rats, using HI-6 pretreatment, showed that benzodiazepines (diazepam, midazolam and lorazepam) were quite effective when given 5 min after seizure onset, but lost their efficacy when given 40 min after onset. The barbiturate, pentobarbital, was modestly effective in terminating seizures when given 5 or 40 min after seizure onset, while other clinically effective antiepileptic drugs, trimethadione and valproic acid, were only slightly effective when given 5 min after onset. In contrast, phenytoin, carbamazepine, ethosuximide, magnesium sulfate, lamotrigine, primidone, felbamate, acetazolamide, and ketamine were ineffective.

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References

  1. Anderson DR, Gennings C, Carter WH, Harris LW, Lennox WJ, Bowersox SL, Solana RP. Efficacy comparison of scopolamine and diazepam against soman-induced debilatation in guinea pigs. Fundam Appl Toxicol 22:588–593;1994.

    Article  PubMed  Google Scholar 

  2. Anderson DR, Harris LW, Bowersox SL, Lennox WJ, Anders JC. Efficacy of injectable anticholinergic drugs against soman-induced convulsive/subconvulsive activity. Drug Chem Toxicol 17:139–148;1994.

    PubMed  Google Scholar 

  3. Berry W, Davis DR. The use of carbamates and atropine in protection of animals against poisoning by 1,2,2-trimethylpropyl methylphosphonofluoridate. Biochem Pharmacol 19:927–934;1970.

    Article  PubMed  Google Scholar 

  4. Bliss CI. The statistics of bioassay with special reference to the vitamins. In: Vitamin methods, vol. II. New York, Academic Press, 1952.

    Google Scholar 

  5. Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol 166:591–592;1989.

    Article  PubMed  Google Scholar 

  6. Boskovic B. The treatment of soman poisoning and its perspectives. Fundam Appl Toxicol 1:203–213;1981.

    PubMed  Google Scholar 

  7. Buccafusco JJ, Graham JH, VanLingen J, Aronstam RS. Protection afforded by clonidine from the acute and chronic behavioral toxicity produced by the cholinesterase inhibitor soman. Neurotoxicol Teratol 11:39–44;1989.

    Article  PubMed  Google Scholar 

  8. Capacio BR, Shih T-M. Anticonvulsant actions of anticholinergic drugs in soman poisoning. Epilepsia 32:604–615;1991.

    PubMed  Google Scholar 

  9. Clement JG, Broxup B. Efficacy of diazepam and avizafone against soman-induced neuropathology in brain of rats. Neuro Toxicology 14:485–504;1993.

    Google Scholar 

  10. Dirnhuber P, French MC, Green DM, Leadbeater L, Stratton JA. The protection of primates against soman poisoning by pretreatment with pyridostigmine. J Pharm Pharmacol 31:295–299;1979.

    PubMed  Google Scholar 

  11. Dixon WJ, Massey FJ. Introduction to statistical analysis. New York, McGraw-Hill, 426–441;1981.

    Google Scholar 

  12. Dunn MA, Sidell FR. Progress in medical defense against nerve agents. J Amer Med Ass 262:649–652;1989.

    Article  Google Scholar 

  13. Gordon JJ, Leadbeater L, Maidment MP. The protection of animals against organophosphate poisoning by pretreatment with a carbamate. Toxicol Appl Pharmacol 43:207–216;1978.

    PubMed  Google Scholar 

  14. Harris LW, Gennings C, Carter WH, Anderson DR, Lennox WJ, Bowersox SL, Solana RP. Efficacy comparison of scopolamine (SCP) and diazepam (DZ) against soman-induced lethality in guinea pigs. Drug Chem Toxicol 17:35–50;1994.

    PubMed  Google Scholar 

  15. Hayward IJ, Wall HG, Jaax NK, Wade JV, Marlow DD, Nold JB. Decreased brain pathology in organophosphate-exposed rhesus monkeys following benzodiazepine therapy. J Neurol Sci 98:99–106;1990.

    Article  PubMed  Google Scholar 

  16. Johnson DD, Lowndes HE. Reduction by diazepam of repetitive electrical activity and toxicity resulting from soman. Eur J Pharmacol 28:245–250;1974.

    Article  PubMed  Google Scholar 

  17. Johnson DD, Wilcox WC. Studies on the mechanism of the protective and antidotal actions of diazepam in organophosphate poisoning. Eur J Pharmacol 34:127–132;1975.

    Article  PubMed  Google Scholar 

  18. Kluwe WM, Chinn JW, Feder JW, Olson C, Joiner R. Efficacy of pyridostigmine pretreatment against acute soman intoxication in a primate model. Proceedings of the Sixth Medical Chemical Defense Bioscience Review, Aberdeen Proving Ground, MD, AD No. B121516:227–234;1987.

  19. Lallement G, Carpentier P, Collet A, Baubichon D, Pernot-Marino I, Blanchet G. Extracellular acetylcholine changes in rat limbic structures during soman-induced seizures. NeuroToxicology 13:557–568;1992.

    PubMed  Google Scholar 

  20. Lallement G, Delamanche 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 an ω3 site ligand. Brain Res 618:227–237;1993.

    Article  PubMed  Google Scholar 

  21. Lallement G, Pernot-Marino I, Baubichon D, Burckhart M-F, Carpentier P, Blanchet G. Modulation of soman-induced neuropathology with an anticonvulsant regimen. NeuroReport 5:2265–2268;1994.

    PubMed  Google Scholar 

  22. Lallement G, Pernot-Marino I, Foquin-Tarricone A, Baubichon D, Piras A, Blanchet G, Carpentier P. Antiepileptic effects of NBQX against soman-induced seizures. NeuroReport 5:425–428;1994.

    PubMed  Google Scholar 

  23. Lallement G, Pernot-Marino I, Foquin-Tarricone A, Baubichon D, Piras A, Blanchet G, Carpentier P. Coadministration of atropine, NBQX and TCP against soman-induced seizures. NeuroReport 5:1113–1117;1994.

    PubMed  Google Scholar 

  24. Leadbeater L, Inns RH, Rylands JM. Treatment of poisoning by soman. Fundam Appl Toxicol 5:S225-S231;1985.

    Article  PubMed  Google Scholar 

  25. Lemercier G, Carpentier P, Sentenac-Roumanou H, Moralis P. Histological and histochemical changes in the central nervous system of the rat poisoned by an irreversible anticholinesterase organophosphorus compound. Acta Neuropathol (Berl.) 61:123–129;1983.

    Article  Google Scholar 

  26. Lipp JA. Effect of diazepam upon soman-induced seizure activity and convulsions. EEG Clin Neurophys 32:557–560;1972.

    Article  Google Scholar 

  27. Lipp JA. Effect of benzodiazepine derivatives on soman-induced seizure activity and convulsions in the monkey. Arch Internat Pharmacodyn Ther 202:244–251;1973.

    Google Scholar 

  28. Martin LJ, Doebler JA, Shih T-M, Anthony A. Protective effect of diazepam pretreatment on soman-induced brain lesion formation. Brain Res 325:287–289;1985.

    Article  PubMed  Google Scholar 

  29. McDonough JH, Jaax NK, Crowley RA, Mays MZ, Modrow HE. Atropine and/or diazepam therapy protects against soman-induced neural and cardiac pathology. Fundam Appl Toxicol 13:256–276;1989.

    Article  PubMed  Google Scholar 

  30. McDonough JH, McLeod CG, Nipwoda MT. Direct micro-injection of soman or VX into the amygdala produces repetitive limbic convulsions and neuropathology. Brain Res 435:123–137;1987.

    Article  PubMed  Google Scholar 

  31. McDonough JH, Shih T-M. Pharmacological modulation of soman-induced seizures. Neurosci Biobehav Rev 17:203–215;1993.

    Article  PubMed  Google Scholar 

  32. McDonough JH, Shih T-M. A study of the N-methyl-d-aspartate antagonistic properties of anticholinergic drugs. Pharmacol Biochem Behav 51:249–253;1995.

    Article  PubMed  Google Scholar 

  33. McDonough JH, Shih T-M. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev 21:559–579;1997.

    Article  PubMed  Google Scholar 

  34. McLean MJ, Gupta RC, Dettbarn W-D, Wamil AW. Prophylactic and therapeutic efficacy of memantine against seizures produced by soman in the rat. Toxicol Appl Pharmacol 112:95–103;1992.

    Article  PubMed  Google Scholar 

  35. McLeod CG. Pathology of nerve agents: perspectives on medical management. Fundam Appl Toxicol 5:S10-S16;1985.

    Article  PubMed  Google Scholar 

  36. McLeod CG, Singer AW, Harrington DG. Acute neuropathology in soman poisoned rats. NeuroToxicology 5:53–58;1984.

    Google Scholar 

  37. Morre DH, Clifford CB, Crawford IT, Cole GM, Baggett JM. Review of nerve agent inhibitors and reactivators of acetylcholinesterase. In: DM Quinn, AS Balasubramanian, BP Doctor, P Taylor, eds. Enzymes of the Cholinesterase Family. New York, Plenum Press, 297–304;1995.

    Google Scholar 

  38. Petras JM. Soman neurotoxicity. Fundam Appl Toxicol 1:242;1981.

    PubMed  Google Scholar 

  39. Petras JM. Neurology and neuropathology of soman-induced brain injury: an overview. J Exp Anal Behav 61:319–329;1994.

    PubMed  Google Scholar 

  40. Philippens IHCHM, Melchers BPC, DeGroot DMG, Wolthius OL. Behavioral performance, brain histology, and EEG sequela after immediate combined atropine/diazepam treatment of soman-intoxicated rats. Pharmacol Biochem Behav 42:711–719;1992.

    Article  PubMed  Google Scholar 

  41. Rump S, Grudzinska E, Edelwein Z. Effects of diazepam on abnormalities of bioelectrical activity of the rabbit's brain due to fluostigmine. Acta Nervousa Superior (Praque) 14:176–177;1972.

    Google Scholar 

  42. Rump S, Grudzinska E, Edelwein Z. Effects of diazepam on epileptiform patterns of bioelectrical activity of the rabbit's brain induced by fluostigmine. Neuropharmacology 12:813–817;1973.

    Article  PubMed  Google Scholar 

  43. Shih T-M. Anticonvulsant effects of diazepam and MK-801 in soman poisoning. Epilepsy Res 7:105–116;1990.

    Article  PubMed  Google Scholar 

  44. Shih T-M, Koviak TA, Capacio BR. Anticonvulsants for poisoning by the organophosphorus compound soman: pharmacological mechanisms. Neurosci Biobehav Rev 15:349–362;1991.

    Article  PubMed  Google Scholar 

  45. Shih T-M, McDonough JH. Neurochemical mechanisms and pharmacological control of soman-induced seizures and pathology. Can J Physiol Pharmacol 72(suppl. 1):396;1994.

    Google Scholar 

  46. Shih T-M, McDonough JH. Neurochemical mechanisms in soman-induced seizures. J Appl Toxicol 17:255–264;1997.

    Article  PubMed  Google Scholar 

  47. Smith SE, Durmuller N, Meldrum BS. The non-N-methyl-d-aspartate receptor antagonists, GYKI 52466 and NBQX are anticonvulsant in two animal models of reflex epilepsy. Eur J Pharmacol 201:179–183;1991.

    Article  PubMed  Google Scholar 

  48. Sparenborg S, Brennecke LH, Beers ET. Pharmacological dissociation of the motor and electrical aspects of convulsive status epilepticus induced by the cholinesterase inhibitor soman. Epilepsy Res 14:95–103;1993.

    Article  PubMed  Google Scholar 

  49. Szdak PD, Jansen JA. A review of the preclinical pharmacology of tiagabine: A potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 36:612–626;1995.

    Article  PubMed  Google Scholar 

  50. Taylor PD. Anticholinesterase agents. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds. The Pharmacological Basis of Therapeutics, 6th ed. New York, Macmillan, 110–129;1985.

    Google Scholar 

  51. Vale JA, Scott GW. Organophosphorus poisoning. Guy's Hosp Rep 123:13–25;1974.

    Google Scholar 

  52. Wills JH. Pharmacological antagonists of the anticholinesterase agents. In: Koelle GB, ed. Cholinesterases and Anticholinesterase Agents. Handbuch der Experimentellen Pharmakologie. Berlin, Springer-Verlag, 883–920;1963.

    Google Scholar 

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Authors and Affiliations

  1. Pharmacology and Drug Assessment Divisions, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Md., USA

    Tsung-Ming Shih (Commander), John H. McDonough Jr. & Irwin Koplovitz

  2. US Army Medical Research Institute of Chemical Defense ATTN:MCMR-UV-PN, 3100 Ricketts Point Rd., 21010-5400, Aberdeen Proving Ground, MD, USA

    Tsung-Ming Shih (Commander)

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  1. Tsung-Ming Shih
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  2. John H. McDonough Jr.
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The animals used in studies performed in, or sponsored by, this Institute were handled in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals, proposed by the Committee to Revise the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, and published by National Academy Press, 1996, and the Animal Welfare Act of 1966, as amended. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.

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Shih, TM., McDonough, J.H. & Koplovitz, I. Anticonvulsants for soman-induced seizure activity. J Biomed Sci 6, 86–96 (1999). https://doi.org/10.1007/BF02256439

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  • DOI: https://doi.org/10.1007/BF02256439

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