Skip to main content
NCBI home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2007 Jan;4(1):12–17. doi: 10.1016/j.nurt.2006.11.009

Discovery of antiepileptic drugs

Misty Smith 1, Karen S Wilcox 1, H Steve White 1,✉
PMCID: PMC7479710  PMID: 17199014

Summary

Since 1993, the Anticonvulsant Drug Development Program has contributed to the successful development of nine clinically effective drugs for the symptomatic treatment of epilepsy. These include felbamate (1993), gabapentin (1994), lamotrigine (1994), fosphenytoin (1996), topiramate (1996), tiagabine (1997), levetiracetam (1999), zonisamide (2000), and oxcarbazepine (2000). Despite the apparent success of the current discovery process, a significant need persists for more efficacious and less toxic antiepileptic drugs (AEDs). This is particularly true for patients whose seizures remain refractory to the currently available AEDs. This chapter will review the current process for AED discovery employed by the Anticonvulsant Drug Development Program at the University of Utah and other laboratories working toward the common goal of discovering better therapeutic options for patients living with epilepsy. It will discuss some of the inherent advantages and limitations of the primary animal models employed, while offering insight into potential future directions as we seek to better understand the pathophysiology underlying acquired epilepsy, therapy resistance, and epileptogenesis.

Key words: AED discovery, animal models, seizure, epilepsy

References

  • 1.White HS, Woodhead JH, Wilcox KS, Stables JP, Kupferberg HJ, Wolf HH. Discovery and preclinical development of antiepileptic drugs. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. pp. 36–48. [Google Scholar]
  • 2.White HS, Woodhead JH, Franklin MR, Swinyard EA, Wolf HH. General principles: experimental selection, quantification, and evaluation of antiepileptic drugs. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, Ltd.; 1995. pp. 99–110. [Google Scholar]
  • 3.White HS, Wolf HH, Woodhead JH, Kupferberg HJ. The National Institutes of Health Anticonvulsant Drug Development Program: screening for efficacy. In: French J, Leppik I, Dichter MA, editors. Antiepileptic drug development: advances in neurology. Philadelphia: Lippincott-Raven; 1998. pp. 29–39. [PubMed] [Google Scholar]
  • 4.Kupferberg H. Animal models used in the screening of antiepileptic drugs. Epilepsia. 2001;42(suppl 4):7–12. [PubMed] [Google Scholar]
  • 5.Stables JP, Bertram E, Dudek FE, et al. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the NIH/NINDS/AES models II workshop. Epilepsia. 2003;44:1472–1478. doi: 10.1111/j.0013-9580.2003.32803.x. [DOI] [PubMed] [Google Scholar]
  • 6.Loscher W. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res. 2002;50:105–123. doi: 10.1016/S0920-1211(02)00073-6. [DOI] [PubMed] [Google Scholar]
  • 7.Putnam TJ, Merritt HH. Experimental determination of the anticonvulsant properties of some phenyl derivatives. Science. 1937;85:525–526. doi: 10.1126/science.85.2213.525. [DOI] [PubMed] [Google Scholar]
  • 8.Everett GM, Richards RK. Comparative anticonvulsive action of 3,5,5-trimethyloxazolidine-2,4-dione (Tridione), Dilantin and phenobarbital. J. Pharmacol Exp Ther. 1944;81:402–407. [Google Scholar]
  • 9.Lennox WG. The petit mal epilepsies: their treatment with Tridione. JAMA. 1945;129:1069–1074. doi: 10.1001/jama.1945.02860500001001. [DOI] [PubMed] [Google Scholar]
  • 10.Loscher W, Fassbender CP, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res. 1991;8:79–94. doi: 10.1016/0920-1211(91)90075-Q. [DOI] [PubMed] [Google Scholar]
  • 11.Loscher W, Honack D. Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. Eur J Pharmacol. 1993;232:147–158. doi: 10.1016/0014-2999(93)90768-D. [DOI] [PubMed] [Google Scholar]
  • 12.Gower AJ, Noyer M, Verloes R, Gobert J, Wulfert E. ucb L059, a novel anti-convulsant drug: pharmacological profile in animals. Eur J Pharmacol. 1992;222:193–203. doi: 10.1016/0014-2999(92)90855-X. [DOI] [PubMed] [Google Scholar]
  • 13.Gower AJ, Hirsch E, Boehrer A, Noyer M, Marescaux C. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy. Epilepsy Res. 1995;22:207–213. doi: 10.1016/0920-1211(95)00077-1. [DOI] [PubMed] [Google Scholar]
  • 14.Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol. 1998;353:191–206. doi: 10.1016/S0014-2999(98)00410-5. [DOI] [PubMed] [Google Scholar]
  • 15.Löscher W, Hönack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther. 1998;284:474–479. [PubMed] [Google Scholar]
  • 16.Barton ME, Klein BD, Wolf HH, White HS. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 2001;47:217–227. doi: 10.1016/S0920-1211(01)00302-3. [DOI] [PubMed] [Google Scholar]
  • 17.Barton ME, Peters SC, Shannon HE. Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electro-shock seizure models. Epilepsy Res. 2003;56:17–26. doi: 10.1016/j.eplepsyres.2003.08.001. [DOI] [PubMed] [Google Scholar]
  • 18.Brown WC, Schiffman DO, Swinyard EA, Goodman LS. Comparative assay of antiepileptic drugs by ‘psychomotor’ seizure test and minimal electroshock threshold test. J Pharmacol Exp Ther. 1953;107:273–283. [PubMed] [Google Scholar]
  • 19.Loscher W, Honack D. Responses to NMDA receptor antagonists altered by epileptogenesis. Trends Pharmacol Sci. 1991;12:52–52. doi: 10.1016/0165-6147(91)90496-F. [DOI] [PubMed] [Google Scholar]
  • 20.Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev. 1990;42:223–286. [PubMed] [Google Scholar]
  • 21.Suzdak PD, Jansen JA. A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia. 1995;36:612–626. doi: 10.1111/j.1528-1157.1995.tb02576.x. [DOI] [PubMed] [Google Scholar]
  • 22.Hosford DA, Wang Y. Utility of the lethargic (lh/lh) mouse model of absence seizures in predicting the effects of lamotrigine, vigabatrin, tiagabine, gabapentin, and topiramate against human absence seizures. Epilepsia. 1997;38:408–414. doi: 10.1111/j.1528-1157.1997.tb01729.x. [DOI] [PubMed] [Google Scholar]
  • 23.Loscher W. Animal models of drug-refractory epilepsy. In: Pitkanen A, Schwartzkroin PA, Moshe SL, editors. Models of Scizures and Epilepsy. New York: Elsevier Academic Press; 2006. pp. 551–567. [Google Scholar]
  • 24.Loscher W, Rundfeldt C, Honack D. Pharmacological characterization of phenytoin-resistant amygdala-kindled rats, a new model of drug-resistant partial epilepsy. Epilepsy Res. 1993;15:207–219. doi: 10.1016/0920-1211(93)90058-F. [DOI] [PubMed] [Google Scholar]
  • 25.Rundfeldt C, Loscher W. Anticonvulsant efficacy and adverse effects of phenytoin during chronic treatment in amygdala-kindled rats. J Pharmacol Exp Ther. 1993;266:216–223. [PubMed] [Google Scholar]
  • 26.Postma T, Krupp E, Li XL, Post RM, Weiss SR. Lamotrigine treatment during amygdala-kindled seizure development fails to inhibit seizures and diminishes subsequent anticonvulsant efficacy. Epilepsia. 2000;41:1514–1521. doi: 10.1111/j.1499-1654.2000.001514.x. [DOI] [PubMed] [Google Scholar]
  • 27.Srivastava A, Woodhead JH, White HS. Effect of lamotrigine, carbamazepine and sodium valproate on lamotrigine-resistant kindled rats. Epilepsia. 2003;44(suppl 9):42–42. [Google Scholar]
  • 28.Srivastava A, Franklin MR, Palmer BS, White HS. Carbamazepine, but not valproate, displays pharmaco-resistance in lamotrigine-resistant amygdala kindled rats. Epilepsia. 2004;45(suppl 7):12–12. [Google Scholar]
  • 29.Srivastava A, White HS. Retigabine decreases behavioral and electrographic seizures in the lamotrigine-resistant amygdala kindled rat model of pharmacoresistant epilepsy. Epilepsia. 2005;46(suppl 8):217–218. [Google Scholar]
  • 30.Brandt C, Volk HA, Loscher W. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia. 2004;45:1488–1497. doi: 10.1111/j.0013-9580.2004.16904.x. [DOI] [PubMed] [Google Scholar]
  • 31.Glien M, Brandt C, Potschka H, Loscher W. Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Epilepsia. 2002;43:350–357. doi: 10.1046/j.1528-1157.2002.18101.x. [DOI] [PubMed] [Google Scholar]
  • 32.Leite JP, Cavalheiro EA. Effects of conventional antiepileptic drugs in a model of spontaneous recurrent seizures in rats. Epilepsy Res. 1995;20:93–104. doi: 10.1016/0920-1211(94)00070-D. [DOI] [PubMed] [Google Scholar]
  • 33.Grabenstatter HL, Ferraro DJ, Williams PA, Chapman PL, Dudek FE. Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy. Epilepsia. 2005;46:8–14. doi: 10.1111/j.0013-9580.2005.13404.x. [DOI] [PubMed] [Google Scholar]
  • 34.Grabenstatter HL, Dudek FE. The effect of carbamazepine on spontaneous seizures in freely-behaving rats with kainate-induced epilepsy. Epilepsia. 2005;46(suppl 8):287–287. [Google Scholar]
  • 35.Smyth MD, Barbara NM, Baraban SC. Effects of antiepileptic drugs on induced epileptiform activity in a rat model of dysplasia. Epilepsy Res 50:251–264. [DOI] [PubMed]
  • 36.Snead OC. Pharmacological models of generalized absence seizures in rodents. J Neural Transm. 1992;35:7–19. doi: 10.1007/978-3-7091-9206-1_2. [DOI] [PubMed] [Google Scholar]
  • 37.Marescaux C, Vergnes M. Genetic absence epilepsy in rats from Strasbourg (GAERS) Ital J Neural Sci. 1995;16:113–118. doi: 10.1007/BF02229083. [DOI] [PubMed] [Google Scholar]
  • 38.Hosford DA, Wang Y, Cao Z. Differential effects mediated by GABAA receptors in thalamic nuclei in lh/lh model of absence seizures. Epilepsy Res. 1997;27:55–65. doi: 10.1016/S0920-1211(97)01023-1. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES