Bulletin of Mathematical Biology

, Volume 59, Issue 3, pp 569–579 | Cite as

An indirect method for absorption rate estimation: Flurothyl-induced seizures

  • Petr Lánský
  • Jana Velíšková
  • Libor Velíšek


This paper develops a method to estimate a minimal amount of flurothyl necessary to induce the seizures (the seizure threshold). A simple mathematical model is proposed which permits one to determine the drug absorption rate from the amount which has been administered and from the measured latency to onset of seizure. Experimental animal (rats) were exposed to a continuous intake of flurothyl in two different situations: either being alone in the airtight chamber or sharing it in a pair. In the latter case, we assume that the two rats uniformly share the infused drug. Our calculations estimate that approximately 20 μl of flurothyl is necessary to induced twitches, whereas 25 μl of flurothyl is the dose required for the induction of clonic seizures. The model can be used to estimate the threshold amounts of any drug producing obvious behavioral changes irrespective of the route of administration.


Status Epilepticus Absorption Rate Seizure Type Clonic Seizure Seizure Threshold 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Goddard, G. V. 1967. Development of epileptic seizures through brain stimulation at low intensity.Nature 204, 1020–1021.CrossRefGoogle Scholar
  2. Holmes, G. L. 1991. The long-term effects of seizures on the developing brain: clinical and laboratory issues.Brain Dev. 13, 393–409.Google Scholar
  3. Holmes, G. L., J. L. Thompson, G. F. Carl, B. S. Gallagher, J. Hoy and M. McLaughlin. 1990. Effect of 2-amino-7-phosphonoheptanoic acid (APH) on seizure susceptibility in the prepubescent and mature rat.Epilepsy Res. 5, 125–130.CrossRefGoogle Scholar
  4. Holmes, G. L., S. J. Thurber, Z. Liu, C. E. Stafström, A. Gatt and M. A. Mikati. 1993. Effects of quisqualic acid and glutamate on subsequent learning, emotionality, and seizure susceptibility in the immature and mature animal.Brain Res. 623 325–328.CrossRefGoogle Scholar
  5. Inamura, K., E. Martins, K. Themner, S. Tapper, J. Pallon, G. Lovestam, K. G. Malmqvist and B. K. Siejo. 1990. Accumulation of calcium in substatia nigra lesions induced by status epilepticus. Amicroprobe analysis.Brain Res. 514, 49–54.CrossRefGoogle Scholar
  6. Jacquez, J. A. 1985.Compartmental Analysis in Biology and Medicine, Ann Arbor: University of Michigan Press.MATHGoogle Scholar
  7. Jensen, F. E., I. R. Firkusny and G. D. Mower. 1993. Differences in c-fos immunoreativity due to age and mode of seizure induction.Mol. Brain. Res. 17, 185–193.CrossRefGoogle Scholar
  8. Jensen, F. E., G. L. Holmes, C. T. Lombroso, H. K. Blume and I. R. Firkusny. 1992. Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats.Epilepsia 33, 971–980.CrossRefGoogle Scholar
  9. Lánský, P. 1983. Inference for the diffusion models of neuronal activity.Math. Biosci. 67, 247–260.MATHMathSciNetCrossRefGoogle Scholar
  10. Liu, Z., A. Gatt, S. J. Werner, M. A. Mikati and G. L. Holmes. 1994. Long-term behavioral deficits following pilocarpine seizures in immature rats.Epilepsy Res. 19, 191–204.CrossRefGoogle Scholar
  11. Löscher, W. and D. Schmidt. 1988. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations.Epilepsy Res. 2, 145–181.CrossRefGoogle Scholar
  12. Lowenstein, D. H., R. P. Simon and F. R. Sharp. 1990. The pattern of 72-kDa heat shock protein-like immunoreativity in the rat brain following flurothyl-induced status epilepticus.Brain Res. 531, 173–182.CrossRefGoogle Scholar
  13. Lundgren, J., M. L. Smith, G. Blennow and B. K. Siesio, 1994. Hyperthermia aggravates and hypothermia ameliorates epileptic brain damage.Exp. Brain Res. 99, 43–55.CrossRefGoogle Scholar
  14. Nomikos, G. G., A. P. Zis, G. Damsma an H. C. Fibiger. 1994. Electroconvulsive shock increases interstitial concentrations of uric acid in the rat brain.Brain Res. 660, 50–56.CrossRefGoogle Scholar
  15. Prichard, J. W., B. B. Gallagher and G. H. Glase. 1969 Experimental seizure threshold testing with flurothyl.J. Pharm. Exp. Ther. 166, 170–178.Google Scholar
  16. Ricciardi, L. M. and S. Sato. 1990. Diffusion processes and first-passage-time problems. InLectures in Applied Malthematics and Informatics, L. M. Ricciardi (Ed.) Manchester: Manchester University Press.Google Scholar
  17. Sperber, E. F. and S. L. Moshé, 1988. Age-related differences in seizure susceptibility to flurothyl.Dev. Brain Res. 39, 295–297.CrossRefGoogle Scholar
  18. Stafström, C. E., G. L. Holmes and J. L. Thompson. 1993. MK801, pretreatment reduces kainic acid-induced spontaneous seizures in prepubescent rats.Epilepsy Res. 14, 41–48.CrossRefGoogle Scholar
  19. Stafström, C. E., J. L. Thompson and G. L. Holmes. 1992. Kainic acid seizures in the developing brain: status epilepticus and spontaneous recurrent seizures.Dev. Brain Res. 65, 227–236.CrossRefGoogle Scholar
  20. Stein-Behrens, B. A., W. J. Liu and R. M. Sapolsky. 1994. Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus.J. Neurochem. 63, 596–602.CrossRefGoogle Scholar
  21. Terndrup, T., F. Starr and W. E. Fordyce. 1994. A piglet model of status epilepticus: comparison of cardiorespiratory and metabolic changes with two methods of pentylenetetrazol administration.Ann. Emerg. Med. 23, 470–479.Google Scholar
  22. Tortella, F. C., L. Robles, E. Echavarria, J. C. Hunter and J. Hughes. 1990. PD117302, a selective non-peptide opioid kappa agonist, protects against NMDA and maximal electroshock convulsions in rats.Life Sci. 45, PL1–7.CrossRefGoogle Scholar
  23. Tortella, F. C., L. Robles, J. M. Witkin and A. H. Newman. 1994. Novel anticonvulsant analogs of dextromethorphan: improved efficacy, potency, duration and side-effect profile.J. Pharmacol. Exp. ther. 268, 727–733.Google Scholar
  24. Truitt, E. B., E. M. Ebesberg and A. S. G. Ling. 1960. Measurement of brain excitability by use of hexaflurodiethyl ether (Indoclon).J. Pharm. Exp. Ther. 129, 445–453.Google Scholar
  25. van Rossum, J. M., J. G. M. de Bie, G. van Lingen and H. W. A. Teeuwen. 1989. Pharmacokinetics from a dynamical system point of view.J. Pharmacokin Biopharmacol. 17, 365–397.CrossRefGoogle Scholar
  26. Velíšek, L., S. L. Moshé, S.-G. Xu and W. Cammer. 1993. Reduced susceptibility to seizures in carbonic anhydrase II deficient mutant mice.Epilepsy Res.,14, 115–121.CrossRefGoogle Scholar
  27. Velíšek, L., J. Velíšková, Y. Ptachewich, S. Shinnar and S. L. Moshé. 1995 Effects of MK801 and phenytoin on flurothyl-induced seizures during development.Epilepsia 36, 179–185.CrossRefGoogle Scholar
  28. Weiss, M. 1991. Residence time distribution in pharmacokinetics: behavioral and structural models. InAdvanced Methods in Pharmacokinetic and Pharmacodynamic Systems Analysis, D. Z. D'Argenio (Ed), pp. 89–101. New York: Plenum Press.Google Scholar
  29. Xu, S.-G., D. S. Garant, E. F. Sperber and S. L. Moshé. 1992. The proconvulsant effect of nigral infusion of THIP on flurothyl-induced seizures in rat pups.Develop. Brain Res. 68, 275–277.CrossRefGoogle Scholar
  30. Young, R. S., O. A. Petroff, B. Chen, J. C. Gore and W. J. Aquila. 1991. Brain energy state and lactate metabolism during status epilepticus in the neonatal dog: in vivo 31P and 1H nuclear magnetic resonance study.Pediatr. Res. 29, 191–195.Google Scholar
  31. Zhong, J., O. A. Petroff, J. W. Prichard and J. C. Gore. 1995. Barbiturate-reversible reduction of water diffusion coefficient in flurothyl-induced status epilepticus in rats.Magn. Reson. Med. 33, 253–256.Google Scholar
  32. Zis, A. P., G. G. Nomikos, E. E. Brown, G. Damsma and H. C. Fibiger. 1992. Neutrochemical effects of electrically and chemically induced seizures: an in vivo microdialysis study in the rat hippocampus.Neuropsychopharmacology 7, 189–195.Google Scholar
  33. Zis, A. P., G. G. Nomikos, G. Damsma and H. C. Fibiger. 1991. In vivo neurochemical effects of electroconvulsive shock studied by microdialysis in the rat striatum.Psychopharmacology (Berlin)103, 343–350.CrossRefGoogle Scholar

Copyright information

© Society for Mathematical Biology 1997

Authors and Affiliations

  • Petr Lánský
    • 1
  • Jana Velíšková
    • 2
  • Libor Velíšek
    • 1
    • 3
  1. 1.Institute of PhysiologyAcademy of Sciences of the Czech RepublicPraha 4Czech Republic
  2. 2.Department of Neurology, K 316Albert Einstein College of MedicineBronxU.S.A.
  3. 3.Department of Pathological Physiology, Third School of MedicineCharles UniversityPraha 2Czech Republic

Personalised recommendations