Interaction between lamotrigine and felbamate in the maximal electroshock-induced seizures in mice: an isobolographic analysis.
Isobolographic profile of interactions between lamotrigine (LTG) and felbamate (FBM), two second-generation antiepileptic drugs, against maximal electroshock (MES)-induced seizures, and neurotoxic adverse effects in the chimney test in mice were determined. LTG combined with FBM at the fixed ratios of 1:3, 1:1, and 3:1 exerted merely additive interactions against MES-induced seizures. In the chimney test, isobolography revealed that LTG coadministered with FBM at the fixed ratio of 1:1 displayed subadditivity (antagonism), whereas the remaining combinations tested (1:3 and 3:1) exerted additivity in terms of their neurotoxic side effects. LTG (at the dose of 2.3 mg/kg) coadministered with FBM (25.7 mg/kg) at the fixed ratio of 1:1 from the MES test did not impair long-term memory of mice challenged with the passive avoidance task. Furthermore, FBM (25.7 mg/kg) altered neither the free plasma nor brain concentration of LTG, hence pharmacokinetic events, which might affect the observed interactions in the MES test, are unlikely. Considering benefit indices for the respective fixed ratio combinations, it may be concluded that the combination of LTG with FBM at the fixed ratio of 1:1 is advantageous from a preclinical point of view, offering the highest benefit index reaching the value of 1.46. Likewise, the two-drug combination of 1:3 was also beneficial and is worth recommendation with benefit index amounting to 1.36. Only the combination of 3:1 was neutral with a benefit index of 1.08. Protection offered by LTG in combination with FBM against maximal electroconvulsions and its favorable neurotoxic side effect profile might provide the patients with intractable seizures with an efficacious treatment, as the rational polytherapy however, it requires to be clinically confirmed and verified.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Skubiszewski Medical University, Jaczewskiego 8, PL-20-090 Lublin, Poland. jluszczki@yahoo.com
Czuczwar
Stanislaw J
SJ
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004597:Electroshock / Q000379:methods*; D000078328:Felbamate; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012640:Seizures / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D014227:Triazines / Q000493:pharmacokinetics / Q000627:therapeutic use*
D048448:Phenylcarbamates; D011409:Propylene Glycols; D014227:Triazines; D000077213:Lamotrigine; D000078328:Felbamate