Download PDF
Aktuelle Neurologie 2007; 34: S245-S248
DOI: 10.1055/s-2006-952022
Originalarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Einführung und Wirkmechanismen

Introduction and Mechanism of ActionB.  J.  Steinhoff1 , B.  N.  Bauer2
  • 1Epilepsieklinik für Erwachsene, Diakonie Kork
  • 2Eisai GmbH, Frankfurt
Further Information

Publication History

Publication Date:
04 March 2008 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Zonisamid (ZNS) ist ein Benzisoxazolderivat, das sich strukturell von bisher zugelassenen antiepileptisch wirksamen Substanzen unterscheidet. Es besitzt multiple Wirkmechanismen, deren Bedeutung für die antikonvulsive Wirkung noch nicht vollständig geklärt ist. So unterbricht Zonisamid die synchronisierte neuronale Entladung durch direkte Effekte auf spannungsabhängige Natriumkanäle und T-Typ-Kalziumkanäle. Dadurch wird die Verbreitung von epileptischen Entladungen reduziert und die epileptische Aktivität unterbunden. Zugleich besitzt Zonisamid eine modulatorische Wirkung auf die GABA-vermittelte neuronale Inhibition und es gibt Hinweise, dass die Substanz sowohl die dopaminerge und serotonerge Neurotransmission erleichtert als auch den Azetylcholinstoffwechsel beeinflusst. Auch eine Inhibition der exzitatorischen glutamatergen Transmission durch Reduktion der präsynaptischen Glutamatfreisetzung wurde beschrieben. Klinisch scheinen diese multiplen Wirkmechanismen mit einer breiten antikonvulsiven Wirksamkeit zu korrelieren.

Abstract

Zonisamide (ZNS) is a benzisoxazole derivate not structurally related to currently licensed antiepileptic drugs. It has multiple modes of action whose impact on the anticonvulsant effect is not yet fully understood: ZNS interrupts the synchronized neuronal firing through direct effects on voltage-dependent sodium and T-type calcium channels. Thus epileptiform propagation and activity are blocked. Furthermore ZNS has a modulating effect on the GABAergic inhibition, and may act on the dopaminergic and serotonergic neurotransmission and on acetylcholine pathways. An inhibition of excitatory glutamatergic transmission by reduction of the presynaptic release of glutamate has been also described. These modes of action suggest a broad anticonvulsant efficacy.

Literatur

  • 1 National Institute for Clinical Excellence .Clinical Guideline 20. The Epilepsies: the Diagnosis and Management of Epilepsies in Adults and Children in primary and secondary Care. October 2004 http://www.nice.org.uk/CG020NICEguideline
    Google Scholar
  • 2 Brodie M J, Mumford J P. Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy.  Epilepsy Res. 1999;  34 199-205
    CrossrefPubMedGoogle Scholar
  • 3 Perucca E, Levy R. Combination therapy and drug interactions. In: Levy R, Mattson R, Meldrim B, Perucca E (eds) Antiepileptic Drugs, 5th ed. Philadelphia, USA; Lippincott, Williams & Wilkins 2002: 96-102
    Google Scholar
  • 4 Wallace S J. Newer antiepileptic drugs: advantages and disadvantages.  Brain & Development. 2001;  23 277-283
    PubMedGoogle Scholar
  • 5 Kanner A M. The complex epilepsy patient: intricacies of assessment and treatment.  Epilepsia. 2003;  44, Suppl 5 3-8
    PubMedGoogle Scholar
  • 6 Anderson G D, Miller J W. Newer antiepileptic drugs: Their collective role and defining characteristics.  Formulary. 2001;  36 114-135
    PubMedGoogle Scholar
  • 7 Schauf C L. Zonisamide enhance slow sodium activation in Myxicola.  Brain Res. 1987;  413 185-188
    CrossrefPubMedGoogle Scholar
  • 8 Rock D M, Macdonald R L, Taylor C P. Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD-810, CI-912), a novel anticonvulsant.  Epilepsy Res. 1989;  3 138-143
    CrossrefPubMedGoogle Scholar
  • 9 McLean M J, Macdonald R L, Taylor C P. Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD 810, CI 912), a novel anticonvulsant.  Epilepsy Res. 1989;  3 138-143
    CrossrefPubMedGoogle Scholar
  • 10 Suzuki N, Seki T, Yamawake H. Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex.  Epilepsy Res. 1992;  12 21-27
    CrossrefPubMedGoogle Scholar
  • 11 Kito M, Maehara M, Wantanabe K. Mechanism of T-type calcium channel blockade by zonisamide.  Seizure. 1996;  5 115-119
    PubMedGoogle Scholar
  • 12 Coulter D A, Hugenard J R, Prince D A. Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons.  Neurosci Lett. 1989;  98 74-78
    CrossrefPubMedGoogle Scholar
  • 13 Coulter D A, Hugenard J R, Prince D A. Characterization of ethosuximide reduction of low-threshold calcium currents in thalamic neurons.  Neurosci Lett. 1989;  25 582-593
    PubMedGoogle Scholar
  • 14 Kelly K M, Gross R A, Macdonald R L. Valproic acid selectively reduces the low-threshold (T) calcium in rat nodose neurons.  Neurosci Lett. 1990;  116 233-238
    CrossrefPubMedGoogle Scholar
  • 15 Kawai M, Hiramatsu M, Endo A. et al . Effect of zonisamid on the release of aspartic acid and gamma-aminobutyric acid from the hippocampal slices of E1 mice.  Neurosciences. 1994;  20 115-119
    PubMedGoogle Scholar
  • 16 Okada M, Kaneko S, Hirano T. et al . Effects of zonisamide on dopaminergic system.  Epilepsy Res. 1995;  22 193-205
    CrossrefPubMedGoogle Scholar
  • 17 Kaneko S, Okada M, Hirano T. et al . Carbamazepine and zonisamide increase extracellular dopamine and serotonin levels in vivo, and carbamazepine does not antagonize adenosic effect in vitro: mechanisms of blockade of seizure spread.  Jpn J Psychiatry Neurol. 1993;  47 371-373
    PubMedGoogle Scholar
  • 18 Okada M, Kaneko S, Hirato T. et al . Effets of zonisamide on extracellular levels of monoamine and its metabolites, and on Ca2+ dependent dopamine release.  Epilepsy Res. 1992;  13 113-119
    CrossrefPubMedGoogle Scholar
  • 19 Okada M. Effects of carbamazepine and Zonisamid on monoaminergic system in rat striatum and hippocampus.  J Psychopharmacol. 1994;  14 337-354
    PubMedGoogle Scholar
  • 20 Okada M, Hirano T, Kawata Y. et al . Biphasic effects of zonisamide on serotonergic system in rat hippocampus.  Epilepsy Res. 1999;  34 187-197
    CrossrefPubMedGoogle Scholar
  • 21 Mizuno K. Effects of carbamazepin and zonisamide on acetylcholin levels in rat striatum.  Nihon Shinkei Seisin Yakurigaku Zasshi. 1997;  17 17-23
    PubMedGoogle Scholar
  • 22 Zhu W, Rogawski M A. Zonisamide depresses excitatory synaptic transmission by a presynaptic action.  Epilepsia. 1999;  40 (Suppl 7) 245
    PubMedGoogle Scholar
  • 23 Okada M, Kawata Y, Mizuno K. et al . Interaction between Ca2+, K+, carbamazepine and zonisamide on hippocampal extracellular glutamate monitored with microdialysis electrode.  Br J Pharmacol. 1998;  124 1277-1285
    CrossrefPubMedGoogle Scholar
  • 24 Masuda Y, Karasawa T. Inhibitory effect on zonisamide on human carbonic anhydrase in vitro.  Arzneimittelforschung. 1993;  43 416-418
    PubMedGoogle Scholar
  • 25 Masuda Y, Noguchi H, Karasawa T. Evidence against a significant implication of carbonic anhydrase inhibitory activity of zonisamide in its anticonvulsive effects.  Arzneimittelforschung. 1994;  44 267-269
    PubMedGoogle Scholar
  • 26 MacDonald R L. Zonisamide mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, Perucca E Antiepileptic Drugs, 5th ed. Philadelphia, USA; Lippincott, Williams & Wilkins 2002: 867-872
    Google Scholar
  • 27 Wada Y, Hasegawa H, Okuda A. et al . Anticonvulsant effects of zonisamide and phenytoin on seizure activity of the feline visual cortex.  Brain Dev. 1990;  12 206-210
    PubMedGoogle Scholar
  • 28 Takano K, Tanaka T, Fujita T. et al . Zonisamide. Electrophysiological and metabolic changes in kainic acid-induced limbic seizures in rats.  Epilepsia. 1995;  36 644-648
    CrossrefPubMedGoogle Scholar
  • 29 Ito T, Hori M, Masuda Y. et al . 3-Sulfamyolmethyl-1,2-benzisoxazole, a new type of anticonvulsant drug: electroencephalographic profile.  Arzneimittelforschung. 1980;  30 603-609
    PubMedGoogle Scholar
  • 30 Ito T, Hori M, Kadokawa T. Effects of zonisamide (AD-810) on tungstic acid gel-induced thalamic generalized seizures and conjugated estrogen-induced cortical spikewave discharges in cats.  Epilepsia. 1986;  27 367-374
    PubMedGoogle Scholar
  • 31 Kamei C, Oka M, Masuda Y. et al . Effects of 3-sulfamoylmethyl1,2-benzisoazole and some antiepileptics on the kindled seizures in the neocortex, hippocampus and amygdala in rats.  Arch Int Pharmacodyn. 1981;  249 164-176
    PubMedGoogle Scholar
  • 32 Hamada K, Ishida S, Yagi K, Seino M. Anti-convulsant effects of zonisamide on amygdaloid kindling in rats.  Neurosciences. 1990;  16 407-412
    PubMedGoogle Scholar
  • 33 Kakegawa N. An experimental study on the modes of appearance and disappearance of suppressive effect of antiepileptic drugs on kindled seizure.  Psychiatr Neurol Jpn. 1986;  88 81-98
    PubMedGoogle Scholar
  • 34 Bartoszyk G D, Hamer M. The genetic animal model of reflex epilepsy in the Mongolian gerbil: differential efficacy of new anticonvulsive drugs and prototype antiepileptics.  Pharmacol Res Comun. 1987;  19 429-440
    PubMedGoogle Scholar
  • 35 Nakamura J, Tamura S, kandra T. et al . Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice.  Eur J Pharmacol. 1994;  254 83-89
    CrossrefPubMedGoogle Scholar
  • 36 Hosford D A, Wang Y. Utility of lethargic (lh/lh) mouse model for absence seizures in predicting the effects of lamotrigine, vigabatrin, tiagabin, gabapentin and topiramate against human absence seizures.  Epilepsia. 1997;  38 408-414
    PubMedGoogle Scholar
  • 37 Masuda Y, Karasawa T, Shiraishi Y. et al . 3-Sulfamoylmethyl-1,2-benz-isoazole, a new type of anticonvulsant drug: pharmacological profile.  Arzneimittelforschung. 1980;  30 477-483
    PubMedGoogle Scholar
  • 38 Mertz T, Kaplin H. Cardiovascular effects of AD-810 (CI-912): and the reference anticonvulsant agent phenytoin in a variety of animal models and species. RR 740-00909, 02/18/82. 
    Google Scholar
  • 39 McLean J R. Comprehensive summary of the pharmacology of CI-912, a new anticonvulsant drug. RRR 740-00910, 02/19/82. 
    Google Scholar
  • 40 Sackellares J C, Ramsay R E, Wilder B J. et al . Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures.  Epilepsia. 2004;  45 610-617
    CrossrefPubMedGoogle Scholar

Prof. Dr. Bernhard J. Steinhoff

Epilepsieklinik für Erwachsene, Diakonie Kork

Landstraße 1

77694 Kehl-Kork

Email: BSteinhoff@epilepsiezentrum.de

      >