Journal Mobile Options
Table of Contents
Vol. 6, No. 2, 1999
Issue release date: March–April 1999
J Biomed Sci 1999;6:86–96

Anticonvulsants for Soman-Induced Seizure Activity1

Shih T.-M. · McDonough Jr. J.H. · Koplovitz I.
Pharmacology and Drug Assessment Divisions, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Md., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


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.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  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.
  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.
  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.
  4. Bliss CI. The statistics of bioassay with special reference to the vitamins. In: Vitamin methods, vol. II. New York, Academic Press, 1952.
  5. Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol 166:591–592;1989.
  6. Boskovic B. The treatment of soman poisoning and its perspectives. Fundam Appl Toxicol 1:203–213;1981.
  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.
  8. Capacio BR, Shih T-M. Anticonvulsant actions of anticholinergic drugs in soman poisoning. Epilepsia 32:604–615;1991.
  9. Clement JG, Broxup B. Efficacy of diazepam and avizafone against soman-induced neuropathology in brain of rats. NeuroToxicology 14:485–504;1993.
  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.
  11. Dixon WJ, Massey FJ. Introduction to statistical analysis. New York, McGraw-Hill, 426–441;1981.
  12. Dunn MA, Sidell FR. Progress in medical defense against nerve agents. J Amer Med Ass 262:649–652;1989.
  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.
  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.
  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.
  16. Johnson DD, Lowndes HE. Reduction by diazepam of repetitive electrical activity and toxicity resulting from soman. Eur J Pharmacol 28:245–250;1974.
  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.
  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.
  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.
  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.
  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.
  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.
  24. Leadbeater L, Inns RH, Rylands JM. Treatment of poisoning by soman. Fundam Appl Toxicol 5:S225–S231;1985.
  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.
  26. Lipp JA. Effect of diazepam upon soman-induced seizure activity and convulsions. EEG Clin Neurophys 32:557–560;1972.
  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.
  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.
  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.
  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.
  31. McDonough JH, Shih T-M. Pharmacological modulation of soman-induced seizures. Neurosci Biobehav Rev 17:203–215;1993.
  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.
  33. McDonough JH, Shih T-M. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev 21:559–579;1997.
  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.
  35. McLeod CG. Pathology of nerve agents: perspectives on medical management. Fundam Appl Toxicol 5:S10–S16;1985.
  36. McLeod CG, Singer AW, Harrington DG. Acute neuropathology in soman poisoned rats. NeuroToxicology 5:53–58;1984.
  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.
  38. Petras JM. Soman neurotoxicity. Fundam Appl Toxicol 1:242;1981.
  39. Petras JM. Neurology and neuropathology of soman-induced brain injury: an overview. J Exp Anal Behav 61:319–329;1994.
  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.
  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.
  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.
  43. Shih T-M. Anticonvulsant effects of diazepam and MK-801 in soman poisoning. Epilepsy Res 7:105–116;1990.
  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.
  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.
  46. Shih T-M, McDonough JH. Neurochemical mechanisms in soman-induced seizures. J Appl Toxicol 17:255–264;1997.
  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.
  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.
  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.
  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.
  51. Vale JA, Scott GW. Organophosphorus poisoning. Guy’s Hosp Rep 123:13–25;1974.
  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.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50