, Volume 48, Issue 2, pp 153–171 | Cite as

New Anticonvulsant Drugs

Focus on Flunarizine, Fosphenytoin, Midazolam and Stiripentol
  • Martina Bebin
  • Thomas P. Bleck
Review Article


In the past decade, several new antiepileptic drugs have been tested. Most recently, 5 new antiepileptic drugs have been launched onto European and US markets. These include vigabatrin, oxcarbazepine and lamotrigine in Europe, and felbamate and gabapentin in the US. In addition to these, 3 additional drugs are in the clinical investigational stage: flunarizine, fosphenytoin and stiripentol. A fourth agent is midazolam, which was originally introduced in 1986, but recently has shown effectiveness in the treatment of status epilepticus.

Flunarizine is a selective calcium channel blocker that has shown anticonvulsant properties in both animal and human studies. It is a long-acting anticonvulsant that clinical studies have shown to have effects similar to those of phenytoin and carbamazepine in the treatment of partial, complex partial and generalised seizures.

Fosphenytoin was developed to eliminate the poor aqueous solubility and irritant properties of intravenous phenytoin. It is rapidly converted to phenytoin after intravenous or intramuscular administration. In clinical studies, this prodrug showed minimal evidence of adverse events and no serious cardiovascular or respiratory adverse reactions. It may have a clear advantage over the present parenteral formulation of phenytoin.

Midazolam is a benzodiazepine that is more potent than diazepam as a sedative, muscle relaxant and in its influence on electroencephalographic measures. It has been shown to be an effective treatment for refractory seizures in status epilepticus.

Stiripentol has anticonvulsant properties as well as the ability to inhibit the cytochrome P450 system. There are significant metabolic drug interactions between stiripentol and phenytoin, carbamazepine and phenobarbital (phenobarbi-tone). Stiripentol has been studied in patients with partial seizures, refractory epilepsy and refractory absence seizures with some efficacious results.


Adis International Limited Midazolam Carbamazepine Valproic Acid Status Epilepticus 
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. 1.
    Kälviäinen R, Keränen T, Riekkinen Sr PJ. Place of newer antiepileptic drugs in the treatment of epilepsy. Drugs 1993; 46: 1109–24CrossRefGoogle Scholar
  2. 2.
    Bian K, Toda N. Vasodilator actions of flunarizine in isolated dog cerebral and extracerebral arteries. Jpn J Pharmacol 1989; 49: 83–94PubMedCrossRefGoogle Scholar
  3. 3.
    Todd PA, Benfield P. Flunarizine: a reappraisal of its pharmacological properties and therapeutic use in neurological disorders. Drugs 1989; 38: 481–99PubMedCrossRefGoogle Scholar
  4. 4.
    Homes B, Brogden RN, Heel RC, et al. Flunarizine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs 1984; 27: 6–44CrossRefGoogle Scholar
  5. 5.
    Wauquier A, Ashton D, Clincke GHC. Brain ischemia as a target for Ca++entry blockers. Ann N Y Acad Sei 1988; 522: 478–90CrossRefGoogle Scholar
  6. 6.
    Beck T, Nuglish J, Sauer D, et al. Effects of flunarizine on postischemic blood flow, energy metabolism and neuronal damage in the rat brain. Eur J Pharmacol 1988; 158: 271–4PubMedCrossRefGoogle Scholar
  7. 7.
    Höller M, Dierking H, Dengler K, et al. Effect of flunarizine on extracellular ion concentration in the rat brain under hypoxia and ischemia. In: Battistine N, Firoani P, Courbier R, et al., editors. Acute brain ischemia and medical surgical therapy. New York: Raven Press, 1986: 229–36Google Scholar
  8. 8.
    Desmedt CKC, Niemegeers CJE, Janssen PAJ. Anticonvulsant properties of cinnarizine and flunarizine in rats and mice. Arzneimittelforschung 1975; 25 (9): 1408–13PubMedGoogle Scholar
  9. 9.
    Ashton D, Wauquier A. Behavioral analysis of the effects of 15 anticonvulsants in the amygdaloid kindled rat. Psychophar-macology (Ber) 1979; 65: 7–13CrossRefGoogle Scholar
  10. 10.
    Wauquier A, Ashton D, Melis W. Behavioral analysis of amygdaloid kindling in beagle dogs and the effects of clonazepam, diazepam, phenobarbital, diphenylhydantoin, and flunarizine on the seizure manifestation. Exp Neurol 1979; 64: 579–86PubMedCrossRefGoogle Scholar
  11. 11.
    Ashton D, Wauquier A. Effects of some antiepileptic, neuroleptic and gabaminergic drugs on convulsions induced in rats by injection of D, L-allylglycine. Pharmacol Biochem Behav 1979; 11: 221–6PubMedCrossRefGoogle Scholar
  12. 12.
    Reid KH, Marrannes R, Wauquier A. Effects of flunarizine on rat cerebral cortex. Drug Dev Res 1987; 10: 107–116CrossRefGoogle Scholar
  13. 13.
    Kataoka K, Kanamori N, Oishi M, et al. Determination of flunarizine in serum by high performance liquid chromatography and its clinical application. Yakugaku Zasshi 1988; 108: 226–31PubMedGoogle Scholar
  14. 14.
    Yamaji A, Kataoka K, Oishi M, et al. Simple method for determination of flunarizine in serum by gas chromatography. J Chromatogr 1987; 421: 372–6PubMedCrossRefGoogle Scholar
  15. 15.
    Binnie CD, de Beukelaar F, Meyer JWA, et al. Open dose-ranging trial of flunarizine as add-on therapy in epilepsy. Epilepsia 1985; 26: 424–8PubMedCrossRefGoogle Scholar
  16. 16.
    Kapetanovic FM, Torchin CD, Kupferberg HJ, et al. Pharmacokinetic profile of flunarizine after single and multiple dosing in epileptic patients receiving comedication. Epilepsia 1988; 29 (6): 770–4PubMedCrossRefGoogle Scholar
  17. 17.
    Alvinz J, Kristensen O, Tsiropoulus I, et al. Double-blind placebo-controlled evaluation of flunarizine as adjunct therapy in epilepsy with complex partial seizures. Acta Neurol Scand 1989; 79: 128–32CrossRefGoogle Scholar
  18. 18.
    Strarreveld E, de Beukelaar F, Wilson AF, et al. Double-blind cross-over placebo controlled study of flunarizine in patients with therapy resistant epilepsy. Can J Neurol Sei 1989; 16: 187–90Google Scholar
  19. 19.
    Keene D, Whiting P, Humphreys P, et al. Flunarizine as a supplementary medication in refractory childhood epilepsy: a double blind crossover study. Can J Neurol Sci 1989; 16: 191–3PubMedGoogle Scholar
  20. 20.
    Fröscher W, Bülau P, Burr W, et al. Double-blind placebo-controlled trial with flunarizine in therapy-resistant epileptic patients. Clin Neuropharmacol 1988; 11 (3): 232–40PubMedCrossRefGoogle Scholar
  21. 21.
    Overwig J, Binnie CD, Meijer JWA, et al. Double-blind placebo controlled trial of flunarizine as add-on therapy in epilepsy. Epilepsia 1984; 25: 217–22CrossRefGoogle Scholar
  22. 22.
    Moglia A, Bergamasco B, Di Perri R, et al. Flunarizine as addon therapy in epilepsy, crossover study versus placebo. Funct Neurol 1986; 1 (4): 547–50PubMedGoogle Scholar
  23. 23.
    DeSarro GB, Nistico G, Meldrum BS. Anticonvulsant properties of flunarizine and reflex and generalized models of epilepsy. Neuropharmacology 1986; 25 (7): 695–701CrossRefGoogle Scholar
  24. 24.
    Smith RD, Brown BS, Maher RW, et al. Pharmacology of ACC-9653 (phenytoin drug). Epilepsia 1989; 30 Suppl. 2: S15–21PubMedCrossRefGoogle Scholar
  25. 25.
    Walton NY, Treiman DM. Efficacy of ACC-9653 (a phenytoin prodrug) in experimental status epilepticus in the rat. Epilepsy Res 1990; 5: 165–8PubMedCrossRefGoogle Scholar
  26. 26.
    Harris S, Kokernot RH. Effects of diphenylhydantoin sodium (dilantin sodium) and phenobarbital sodium upon ectopic ventricular tachycardia in acute myocardial infarction. Am J Physiol 1950; 163: 505–10PubMedGoogle Scholar
  27. 27.
    Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute treatment of seizures. JAMA 1983; 249: 762–5PubMedCrossRefGoogle Scholar
  28. 28.
    Smith RD, Lomas TE. Modifications of cardiovascular responses to intravenous phenytoin by dopamine in dogs. Evidence against an adverse interaction. Toxicol Appl Pharmacol 1973; 45: 665–73CrossRefGoogle Scholar
  29. 29.
    Zoneraich S, Zoneraich O, Siegal J. Sudden death following intravenous sodium diphenylhydantoin. Am Heart J 1976; 91: 375–87PubMedCrossRefGoogle Scholar
  30. 30.
    Unger A, Sklaroff H. Fatalities following intravenous use of sodium diphenylhydantoin for cardiac arrhythmias. JAMA 1976; 200: 1335–6Google Scholar
  31. 31.
    Pang KS, Gillette JR. Sequential first-pass elimination of a metabolite derived from a precursor. J Pharmacokinet Biopharm 1979; 7 (3): 275–90PubMedCrossRefGoogle Scholar
  32. 32.
    Varia SA, Stella VS. Phenytoin prodrugs V: in vivo evaluation of some water soluble phenytoin prodrugs in dogs. J Pharm Sci 1984; 73: 1080–7PubMedCrossRefGoogle Scholar
  33. 33.
    Donn KH, Drissel DA, Quon CY. Systemic availability and pharmacokinetics of phenytoin after intramuscular ACC-9653, a phenytoin prodrug [abstract]. Epilepsia 1987; 28: S87CrossRefGoogle Scholar
  34. 34.
    Browne TR, Davoudi H, Donn KH, et al. Bioavailability of ACC-9653 (phenytoin prodrug). Epilepsia 1989; 30 Suppl. 2: S27–32PubMedCrossRefGoogle Scholar
  35. 35.
    Boucher BA, Bombassaro AM, Rasmussen SN, et al. Phenytoin prodrug 3-fosphoryloxymethyl phenytoin (ACC-9653): pharmacokinetics in patients following intravenous and intramuscular administration. J Pharm Sci 1989; 78 (11): 429–32CrossRefGoogle Scholar
  36. 36.
    Leppik IE, Boucher BA, Wilder BJ, et al. Pharmacokinetics and safety of a phenytoin prodrug given IV or IM in patients. Neurology 1990; 40: 456–60PubMedCrossRefGoogle Scholar
  37. 37.
    Woodbury DM. Phenytoin absorption, distribution, and excretion. In: Levy R, Mattson R, Meddrum B, et al., editors. Antiepileptic drugs, 3rd edition. New York: Raven Press Ltd, 1989: 177–95Google Scholar
  38. 38.
    Leppik IE, Boucher R, Wilder BJ, et al. Phenytoin prodrug: preclinical and clinical studies. Epilepsia 1989; 30 Suppl. 2: S22–6PubMedCrossRefGoogle Scholar
  39. 39.
    Varia SA, Stella VS. Phenytoin prodrugs VI: in vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats. J Pharm Sci 1984; 73: 1087–90PubMedCrossRefGoogle Scholar
  40. 40.
    Amrein R, Hetzel W. Pharmacology of drugs frequently used in ICUs: midazolam and flumazenil. Intensive Care Med 1991; 17: Sl–10CrossRefGoogle Scholar
  41. 41.
    DeJong RH, Bonin JD. Benzodiazepines protect mice from local anesthetic convulsions and deaths. Anesth Analg 1981; 60 (6): 385–9Google Scholar
  42. 42.
    Pieri L. Preclinical pharmacology of midazolam. Br J Clin Pharmacol 1983; 16: 175–275CrossRefGoogle Scholar
  43. 43.
    Kubova H, Mares P. The effect of ontogenetic development of the anticonvulsant activity of midazolam. Life Sci 1992; 50: 1665–72PubMedCrossRefGoogle Scholar
  44. 44.
    Bührer M, Maitre PO, Crevoisier C, et al. Comparative pharmacodynamics of midazolam and diazepam [abstract]. Anesthesiology 1988; 69: A642CrossRefGoogle Scholar
  45. 45.
    Heizmann P, Eckert M, Ziegler WH. Pharmacokinetics and bioavailability of midazolam in man. Br J Clin Pharmacol 1983; 16: 435–95CrossRefGoogle Scholar
  46. 46.
    Jacqz-Aigrain E, Daoud P, Burton P, et al. Pharmacokinetics of midazolam during continuous infusion in critically ill neonates. Eur J Clin Pharmacol 1992; 42: 329–32PubMedCrossRefGoogle Scholar
  47. 47.
    Malacrida R, Fritz M, Suter PM, et al. Pharmacokinetics of midazolam administered by continuous intravenous infusion to intensive care patients. Crit Care Med 1992; 20: 1123–6PubMedCrossRefGoogle Scholar
  48. 48.
    Kanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacotherapy 1985; 5: 138–55PubMedGoogle Scholar
  49. 49.
    Wroblewski B, Joseph AB. The use of intramuscular midazolam for acute seizure cessation on behavioral emergencies in patients with traumatic brain injury. Clin Neuropharmacol 1992; 15 (1): 44–9PubMedCrossRefGoogle Scholar
  50. 50.
    Jawad S, Oxley J, Wilson J, et al. A pharmacodynamic evaluation of midazolam as an antiepileptic compound. J Neurol Neurosurg Psychiatry 1986; 49: 1050–4PubMedCrossRefGoogle Scholar
  51. 51.
    Kumar A, Bleck TP. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care Med 1992; 20: 483–8PubMedCrossRefGoogle Scholar
  52. 52.
    Riveria R, Segnini M, Baltodano A, et al. Midazolam in the treatment of status epilepticus in children. Crit Care Med 1993; 21: 991–4CrossRefGoogle Scholar
  53. 53.
    Bleck TP. Advances in the management of refractory status epilepticus. Crit Care Med 1993; 21 (7): 955–7PubMedCrossRefGoogle Scholar
  54. 54.
    Fee JPH, Collier PD, Howard PJ, et al. Cimetidine and ranitidine increase midazolam bioavailability. Clin Pharmacol Ther 1987; 41: 80–4PubMedCrossRefGoogle Scholar
  55. 55.
    Astoin J, Marwan A, Riveron A, et al. Action de nouveaux alcools alpha-ethyléniques sur le système nerveux central. Eur J Med Chem Ther 1978; 13: 41–7Google Scholar
  56. 56.
    Shen DD, Levy RH, Moon MJ, et al. Efficacy of stiripentol in the intravenous pentylenetetrazol infusion seizure model in the rat. Epilepsy Res 1990; 7: 40–8PubMedCrossRefGoogle Scholar
  57. 57.
    Poisson M, Huguet F, Savatier A, et al. A new type of anticonvulsant stiripentol. Arzneimittelforschung 1984; 34: 199–204PubMedGoogle Scholar
  58. 58.
    Lockard JS, Levy RH, Rhodes PH et al. Stiripentol in acute/chronic efficacy tests in monkey model. Epilepsia 1985; 26 (6): 704–12PubMedCrossRefGoogle Scholar
  59. 59.
    Lockard JS, Levy RH, Rhodes PH, et al. Stiripentol and EEG spike rate in acute/chronic tests in monkey model. Epilepsia 1984; 25: 667Google Scholar
  60. 60.
    Oieri F, Wegmann R, Astoin J. Etude pharmacocinétique du 3H-stiripentol chez le rat. Eur J Drug Metab Pharmacokinet 1982; 7: 5–10CrossRefGoogle Scholar
  61. 61.
    Lin HS, Levy RH, Blehart H, et al. Pharmacokinetic properties and metabolic profile of stiripentol in primates. In: Levy RH, Pitlek WH, Eichelbaum M, et al., editors. Metabolism of antiepileptic drugs. New York: Raven Press Ltd, 1984: 199–207Google Scholar
  62. 62.
    Levy RH, Lin HS, Blehart H, et al. Pharmacokinetics of stiripentol in normal man: evidence of nonlinearity. J Clin Pharmacol 1983; 23: 523–33PubMedGoogle Scholar
  63. 63.
    Levy RH, Loiseau P, Guyot M, et al. Michaelis-Menten kinetics of stiripentol in normal humans. Epilepsia 1984; 25 (4): 486–91PubMedCrossRefGoogle Scholar
  64. 64.
    Moreland TA, Astoin J, Lepage F, et al. The metabolic fate of stiripentol in man. Drug Metab Dispos 1986; 14: 654–62PubMedGoogle Scholar
  65. 65.
    Levy RH, Loiseau P, Guyot M, et al. Stiripentol kinetics in epilepsy: nonlinearity and interactions. Clin Pharmacol Ther 1984; 36: 661–9PubMedCrossRefGoogle Scholar
  66. 66.
    Loiseau P, Tor J. Stiripentol in absence seizures. Epilepsia 1987; 28: 579CrossRefGoogle Scholar
  67. 67.
    Levy RH, Martinez-Lange M, Kern BM, et al. Effect of stiripentol on the formation and elimination of carbamaze-pine-epoxide [abstract]. Abstracts of the 17th Epilepsy International Congress; 1987 Sept 6–11; Jerusalem, Israel, 1987: 71Google Scholar
  68. 68.
    Kerr BM, Martinez-Lange JM, Viteri C, et al. Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome P-450 inhibition by stiripentol. Epilepsia 1991; 32 (2): 267–74PubMedCrossRefGoogle Scholar
  69. 69.
    Loiseau P, Strube E, Tor J, et al. Evaluation neuropsychologique et thérapeutique du stiripentol dans léepilepsie. Résultats préliminaires. Rev Neurol (Paris) 1988; 144: 165–72Google Scholar
  70. 70.
    Levy RH, Loiseau P, Guyot M, et al. Effects of stiripentol on valproate plasma level and metabolism. Epilepsia 1987; 28: 605Google Scholar
  71. 71.
    Rascol O, Squalli A, Montastruc JL, et al. A pilot study of stiripentol, a new anticonvulsant drug, in complex partial seizures uncontrolled by carbamazepine. Clin Neuropharmacol 1989; 12 (2): 119–23PubMedCrossRefGoogle Scholar
  72. 72.
    Martinez-Lange M, Loiseau P, Levy RH, et al. Clinical antiepileptic efficacy of stiripentol in resistant partial epilepsies. Epilepsia 1984; 25: 673Google Scholar
  73. 73.
    Martinez-Lange M, Levy RH, Gonzalez I, et al. Stiripentol in therapy-resistive and severe epileptic patients: a long-term open trial in bitherapy. In: Wolf P, Dam M, Janz D, et al., editors. Advances in epileptology. Vol. 16. New York: Raven Press Ltd, 1987: 541–6Google Scholar
  74. 74.
    Farwell JR, Anderson GD, Kerr BM, et al. Stiripentol in atypical absence seizures in children: an open trial. Epilepsia 1993; 34 (2): 305–11PubMedCrossRefGoogle Scholar
  75. 75.
    Loiseau P, Duché B. Stiripentol. In: Levy R, Mattson R, Meldrum B, et al., editors. Potential antiepileptic drugs, 3rd edition. New York: Raven Press Ltd, 1989: 955–69Google Scholar
  76. 76.
    Loiseau P, Tor J. Stiripentol in absence seizures. Epilepsia 1987; 28: 579CrossRefGoogle Scholar
  77. 77.
    Martinez-Lange M, Loiseau P, Levy RH, et al. Clinical antiepileptic efficacy of stiripentol in resistant partial epilepsies. Epilepsia 1984; 26: 673Google Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Martina Bebin
    • 1
  • Thomas P. Bleck
    • 1
  1. 1.Departments of Neurology and Neurological SurgeryUniversity of Virginia Health Sciences CenterCharlottesvilleUSA

Personalised recommendations