title: Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy.
abstract: OBJECTIVE
  Anticonvulsive monotherapy fails to be effective in one third of patients with epilepsy resulting in the need for polytherapy regimens. However, with the still limited knowledge, drug choices for polytherapy remain empirical. Here we report experimental data from a chronic epilepsy model for the combination of perampanel and zonisamide, which can render guidance for clinical studies and individual drug choices.
  
  
  METHODS
  The anticonvulsant effects of the combination of perampanel and zonisamide were evaluated in a rat amygdala kindling model. Furthermore, the potential for motor impairment was evaluated. The type of interaction was quantitatively assessed based on isobolographic analysis.
  
  
  RESULTS
  When administered alone, zonisamide dose-dependently increased the afterdischarge threshold in fully kindled rats. Moreover, data confirmed efficacy of perampanel to inhibit seizure initiation and progression with an impact on propagation of activity from the focus. Pronounced threshold increases were observed following administration of a constant zonisamide dosage combined with different doses of perampanel. Isobolographic analysis of drug responses, which is based on individual drug dose-effect data, revealed a synergistic interaction substantiating the high efficacy of the combination. Furthermore, rotarod data indicated that the combination has a favorable tolerability profile when zonisamide is coadministered with low doses of perampanel. Plasma concentration analysis argued against a pharmacokinetic interaction as a basis for the synergism.
  
  
  CONCLUSIONS
  The findings clearly indicate a pronounced synergistic anticonvulsant effect for the combination of the noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel with zonisamide, which modulates voltage-sensitive sodium channels and T-type calcium currents. Consequently, polytherapy using these two antiepileptic drugs might be efficacious for clinical management of partial-onset seizures. The findings indicate that the impact of dose ratios on tolerability needs be taken into account. With regard to conclusions about the extent of the synergism and its implications further antiepileptic drug combinations need to be evaluated allowing direct comparison.
authors: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors: Vera
authors: V
authors: Russmann
authors: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors: Josephine D
authors: JD
authors: Salvamoser
authors: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors: Maruja L
authors: ML
authors: Rettenbeck
authors: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems Eisai Co Ltd, Tsukuba, Ibaraki, Japan.
authors: Takafumi
authors: T
authors: Komori
authors: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors: Heidrun
authors: H
authors: Potschka
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004833:Epilepsy, Temporal Lobe / Q000097:blood / Q000188:drug therapy*; D005260:Female; D007555:Isoxazoles / Q000008:administration & dosage* / Q000097:blood; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles; D011728:Pyridones / Q000008:administration & dosage* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D009570:Nitriles; D011728:Pyridones; D000078305:Zonisamide; C551441:perampanel
keywords: AMPA receptor antagonist; Antiepileptic drug; Chronic epilepsy model; Isobolographic analysis; Rational polytherapy; Sodium channel modulator