title: Isobolographic characterization of the anticonvulsant interaction profiles of levetiracetam in combination with clonazepam, ethosuximide, phenobarbital and valproate in the mouse pentylenetetrazole-induced seizure model.
abstract: This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Dudra-Jastrzebska
authors.forename: Marta M
authors.initials: MM
authors.lastname: Andres-Mach
authors.forename: Neville
authors.initials: N
authors.lastname: Ratnaraj
authors.forename: Philip N
authors.initials: PN
authors.lastname: Patsalos
authors.forename: Stanislaw J
authors.initials: SJ
authors.lastname: Czuczwar
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005013:Ethosuximide / Q000494:pharmacology; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000633:toxicity; D010634:Phenobarbital / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D000077287:Levetiracetam; D002998:Clonazepam; D005013:Ethosuximide; D014635:Valproic Acid; D010433:Pentylenetetrazole; D010634:Phenobarbital; D010889:Piracetam