Archives of Toxicology

, Volume 77, Issue 3, pp 167–172 | Cite as

Nasal midazolam as a novel anticonvulsive treatment against organophosphate-induced seizure activity in the guinea pig

  • E. Gilat
  • M. Goldman
  • E. Lahat
  • A. Levy
  • I. Rabinovitz
  • G. Cohen
  • R. Brandeis
  • G. Amitai
  • D. Alkalai
  • G. Eshel
Organ Toxicity and Mechanisms
First Online:
Received:
Accepted:

Abstract

Seizures and status epilepticus, which may contribute to brain injury, are common consequences of exposure to organophosphorus (OP) cholinesterase inhibitors. Effective management of these seizures is critical. To investigate the efficacy of nasal midazolam as an anticonvulsive treatment for OP exposure, as compared to intramuscular midazolam, guinea pigs were connected to a recording swivel for electrocorticograph (ECoG) monitoring and clinical observation. The experimental paradigm consisted of pyridostigmine pretreatment (0.1 mg/kg i.m.) 20 min prior to sarin exposure (1.2× LD50, 56 µg/kg i.m.). One minute post-exposure, atropine (3 mg/kg i.m.) and TMB-4 (1 mg/kg im) were administered. Within 3–8 min after sarin exposure all animals developed electrographic seizure activity (EGSA), with convulsive behavior. Treatment with midazolam (1 mg/kg i.m.) 10 min after the onset of EGSA abolished EGSA within 389±181 s. The same dose was not effective, in most cases, when given 30 min after onset. However, a higher dose (2 mg/kg) was found efficacious after 30 min (949±466 s). In contrast, nasal application of midazolam (1 mg/kg) was found most effective, with significant advantages, in amelioration of EGSA and convulsive behavior, when given 10 min (216±185 s) or 30 min (308±122 s) following the onset of EGSA (P<0.001). Thus, nasal midazolam could be used as a novel, rapid and convenient route of application against seizure activity induced by nerve agent poisoning.

Keywords

Organophosphate Seizures Midazolam Intranasal EEG 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

Dr. E. Gilat would like to thank Dr. John H. McDonough, from the US Army Medical Research Institute of Chemical Defense, for his excellent advice and inspiration for these studies. The experiments comply with the current laws of the country in which the experiments were performed.

References

  1. Dunn MA, Sidell FR (1989) Progress in medical defense against nerve agents. JAMA 262:649–652PubMedGoogle Scholar
  2. Einer-Jensen N, Khorooshi MH (2000) Cooling of the brain through oxygen flushing of the nasal cavities in intubated rats: an alternative model for treatment of brain injury. Exp Brain Res 130:244–247CrossRefPubMedGoogle Scholar
  3. Einer-Jensen N, Larsen L (2000a) Transfer of tritiated water, tyrosine, and propanol from the nasal cavity to cranial arterial blood in rats. Exp Brain Res 130:216–220CrossRefPubMedGoogle Scholar
  4. Einer-Jensen N, Larsen L (2000b) Local transfer of diazepam but not of cocaine from the nasal cavities to the brain arterial blood in rats. Pharmacol Toxicol 87:276–278PubMedGoogle Scholar
  5. Giorgetti M, Bacciottini L, Giovannini MG, Colivicchi MA, Goldfarb J, Blandina P (2000) Local GABAergic modulation of acetylcholine release from the cortex of freely moving rats. Eur J Neurosci 12:1941–1948CrossRefPubMedGoogle Scholar
  6. Glenn JF, Hinman DJ, McMaster SB (1987) Electroencephalographic correlates of nerve agent poisoning. In: Dun NJ, Perlman RL (eds) Neurobiology of acetylcholine. Plenum Press, New York, pp 503–534Google Scholar
  7. Koplovitz I, Skvorak JP (1998) Electrocorticographic changes during generalized convulsive status epilepticus in soman intoxicated rats. Epilepsy Res 30:159–164CrossRefPubMedGoogle Scholar
  8. Lahat E, Aladjem M, Eshel G, Bistritzer T, Katz Y (1992) Midazolam in treatment of epileptic seizures. Pediatr Neurol 8:215–216PubMedGoogle Scholar
  9. Lahat E, Goldman M, Barr J, Eshel G, Berkovitch M (1998) Intranasal midazolam for childhood seizures. Lancet 352:620Google Scholar
  10. Lemercier G, Carpentier P, Sentenac-Roumanou H, Morelis P (1983) Histological and histochemical changes in the central nervous system of the rat poisoned by an irreversible anticholinesterase organophosphorus compound. Acta Neuropathol 61:123–129PubMedGoogle Scholar
  11. Lipp JA (1968) Cerebral electrical activity following soman administration. Arch Int Pharmacodyn Ther 175:161–169PubMedGoogle Scholar
  12. McDonough JH, Shih TM (1993) Pharmacological modulation of soman-induced seizures. Neurosci Biobehav Rev 17:203–215PubMedGoogle Scholar
  13. McDonough JH, Shih TM (1997) Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev 21:559–579CrossRefPubMedGoogle Scholar
  14. McDonough JH, McMonagle J, Copeland T, Zoeffel D, Shih TM (1999) Comparative evaluation of benzodiazepines for control of soman-induced seizures. Arch Toxicol 73:473–478CrossRefPubMedGoogle Scholar
  15. McLeod CG (1985) Pathology of nerve agents: perspectives on medical management. Fundam Appl Toxicol 5:S10–S16PubMedGoogle Scholar
  16. Mcleod CG, Singer AW, Harrington DG (1984) Acute neuropathology in soman poisoned rats. Neurotoxicology 5:53–58Google Scholar
  17. Moore DH, Clifford CB, Crawford IT, Cole GM, Baggett JM (1995) Review of nerve agent inhibitors and reactivators of acetylcholinesterase. In: Quinn DM, Balasubramanian AS, Doctor BP, Taylor P (eds) Enzymes of the cholinesterase family. Plenum Press, New York, pp 297–304Google Scholar
  18. Parent JM, Lowenstein DH (1994) Treatment of refractory generalized status epilepticus with continuous midazolam infusion. Neurology 44:1837–1840PubMedGoogle Scholar
  19. Pellock JM (1998) Use of midazolam for refractory status epilepticus in pediatric patients. J Child Neurol 13:581–587PubMedGoogle Scholar
  20. Petras JM (1981) Soman neurotoxicity. Fundam Appl Toxicol 1:242PubMedGoogle Scholar
  21. Philippens IHCHM, Melchers BPC, DeGroot DMG, Wolthius OL (1992) Behavioral performance, brain histology, and EEG sequela after immediate combined atropine/diazepam treatment of soman-intoxicated rats. Pharmacol Biochem Behav 42:711–719PubMedGoogle Scholar
  22. Quadi M, Zia H, Needham TE (1999) Toxicological implications of nasal formulations. Drug Delivery 6:227–242CrossRefGoogle Scholar
  23. Rivera R, Segnini M, Battodumo A, Perez V (1993) Midazolam in the treatment of status epilepticus in children. Crit Care Med 21:991–994PubMedGoogle Scholar
  24. Shih TM, Koviak TA, Capacio BR (1991) Anticonvulsants for poisoning by the organophosphorus compound soman: pharmacological mechanisms. Neurosci Biobehav Rev 15:349–362PubMedGoogle Scholar
  25. Singer A, Jaax NK, Graham J (1987) Acute neuropathology and cardiomyopathy in soman and sarin intoxicated rats. Toxicol Lett 36:243–249PubMedGoogle Scholar
  26. Tryphonas L, Clement JG (1995) Histomorphogenesis of soman-induced encephalocardiomiopathy in Sprauge-Dawley rats. Toxicol Pathol 23:393–409PubMedGoogle Scholar
  27. Tryphonas L, Veinot JP, Clement JG (1996) Early histopathologic and ultrastructural changes in the heart of Sprauge-Dawley rats following administration of soman. Toxicol Pathol 243:190–198Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • E. Gilat
    • 1
  • M. Goldman
    • 2
  • E. Lahat
    • 2
  • A. Levy
    • 1
  • I. Rabinovitz
    • 1
  • G. Cohen
    • 1
  • R. Brandeis
    • 1
  • G. Amitai
    • 1
  • D. Alkalai
    • 1
  • G. Eshel
    • 2
  1. 1.Department of PharmacologyIsrael Institute for Biological ResearchNess ZionaIsrael
  2. 2.Pediatric DivisionAssaf Harofeh Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv UniversityZerifinIsrael

Personalised recommendations