title: Influence of Ivabradine on the Anticonvulsant Action of Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice.
abstract: Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint.
authors.affiliation: Medical University in Lublin, Lublin, Poland.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Sawicka
authors.affiliation: Medical University in Lublin, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wawryniuk
authors.affiliation: Medical University in Lublin, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zwolak
authors.affiliation: Medical University in Lublin, Lublin, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Daniluk
authors.affiliation: The Jan Kochanowski University in Kielce, Kielce, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Szpringer
authors.affiliation: Institute of Rural Health, Lublin, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Florek-Luszczki
authors.affiliation: Medical University in Lublin, Lublin, Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Drop
authors.affiliation: School of Medicine, University of California-Davis, Sacramento, California, USA.
authors.forename: Dorota
authors.initials: D
authors.lastname: Zolkowska
authors.affiliation: Medical University in Lublin, Lublin, Poland. jluszczki@yahoo.com.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000627:therapeutic use*; D001552:Benzazepines / Q000378:metabolism* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D004597:Electroshock / Q000009:adverse effects*; D000077550:Ivabradine; D008297:Male; D051379:Mice; D011897:Random Allocation; D012640:Seizures / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D001552:Benzazepines; D000077550:Ivabradine
keywords: Antiepileptic drugs; Ivabradine; Maximal electroshock-induced seizures; Pharmacokinetic/pharmacodynamic interaction