Synergistic interaction of gabapentin and oxcarbazepine in the mouse maximal electroshock seizure model--an isobolographic analysis.
The anticonvulsant effects produced by mixtures of oxcarbazepine and gabapentin (two second-generation antiepileptic drugs) in numerous fixed-ratio combinations of 1:1, 1:2, 1:5, 1:10, 1:15, and 1:20 were examined isobolographically in the mouse maximal electroshock seizure model. Results displayed that mixtures of both drugs at the fixed-ratios of 1:2, 1:5, 1:10, 1:15, and 1:20 exerted supra-additive (synergistic) interactions against electroconvulsions. Only a fixed-ratio of 1:1 was indifferent with isobolography, although the combination displayed the trend towards supra-additivity. Furthermore, the combinations of oxcarbazepine with gabapentin, administered at their median effective doses (ED(50 mix)s), did not alter motor performance of animals challenged with the chimney test. Additionally, neither gabapentin nor oxcarbazepine affected total brain concentrations of co-administered drug, indicating a pharmacodynamic nature of interaction between these antiepileptics. Finally, based on preclinical data presented here the combination of oxcarbazepine and gabapentin is of particular importance for further therapy in patients with refractory partial seizures.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL-20-090 Lublin, Poland. jluszczki@yahoo.com
Andres
Marta M
MM
Czuczwar
Stanislaw J
SJ
D000588:Amines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004597:Electroshock / Q000009:adverse effects; D000077206:Gabapentin; D008297:Male; D051379:Mice; D000078330:Oxcarbazepine; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000078330:Oxcarbazepine