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.