Basic Science

Jarogniew J. Luszczki , Marta M. Andres , Piotr Czuczwar , Anna Cioczek-Czuczwar , Neville Ratnaraj , Philip N. Patsalos , and Stanislaw J. Czuczwar
Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with current front-line antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV), recently introduced as an effective AED for refractory partial seizures. The mouse maximal electroshock (MES)-induced seizure model was investigated with regard to the anticonvulsant effects of carbamazepine (CBZ), phenytoin, phenobarbital (PB), valproate, lamotrigine, topiramate (TPM), and oxcarbazepine (OXC), administered singly and in combination with LEV. Acute adverse effects were ascertained by use of the chimney test, evaluating motor performance, and the passive avoidance task, assessing long-term memory. Brain AED concentrations were determined to ascertain any pharmacokinetic contribution to the observed antiseizure effect. LEV in combination with TPM exerted supraadditive (synergistic) interactions in the MES test. Likewise, the combinations of LEV with CBZ and OXC were supraadditive in this test. In contrast, all other LEV/AED combinations displayed additivity. Furthermore, none of the investigated combinations altered motor performance and long-term memory. LEV brain concentrations were unaffected by concomitant AED administration, and LEV had no significant effect on brain concentrations of concomitant AEDs. These preclinical data would suggest that LEV in combination with TPM is associated with beneficial anticonvulsant pharmacodynamic interactions. Similar, but less profound effects were seen with OXC and CBZ.