Isobolographic characterization of interactions of levetiracetam with the various antiepileptic drugs in the mouse 6 Hz psychomotor seizure model

Epilepsy Res. 2009 Oct;86(2-3):163-74. doi: 10.1016/j.eplepsyres.2009.06.003. Epub 2009 Jul 10.


The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with the various antiepileptic drugs (clonazepam [CZP], oxcarbazepine [OXC], phenobarbital [PB], tiagabine [TGB], and valproate [VPA]), in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3s stimulus duration) delivered via ocular electrodes and isobolographic analysis for parallel and non-parallel dose-response effects was used to characterize the consequent anticonvulsant interactions between the various drug combinations. Potential concurrent adverse-effect profiles of interactions between LEV and CZP, OXC, PB, TGB, and VPA at the fixed-ratio of 1:1 were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip-strength (muscular strength) tests. LEV administered singly was associated with a dose-response relationship curve (DRRC) that was parallel to that for CZP and non-parallel to that for OXC, PB, TGB and VPA. With isobolography for parallel DRRCs, the combination of LEV with CZP at three fixed-ratios of 1:3, 1:1 and 3:1 was additive in nature. With isobolography for non-parallel DRRCs the combinations of LEV with OXC, TGB and VPA at the fixed-ratio of 1:1 were also additive. In contrast, the isobolography for non-parallel DRRCs revealed that the interaction for the combination of LEV with PB at the fixed-ratio of 1:1 was supra-additive (synergistic). None of the combinations were associated with any concurrent adverse effects with regards to motor coordination, long-term memory or muscular strength. LEV is associated with favorable anticonvulsant synergism with PB and is additive with regards to CZP, OXC, TGB and VPA in the mouse 6 Hz psychomotor seizure model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / adverse effects*
  • Anticonvulsants / therapeutic use
  • Clonazepam / adverse effects
  • Clonazepam / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Synergism
  • Drug Therapy, Combination
  • Electroshock
  • Epilepsy / drug therapy*
  • Levetiracetam
  • Male
  • Mice
  • Phenobarbital / adverse effects
  • Phenobarbital / therapeutic use
  • Piracetam / adverse effects
  • Piracetam / analogs & derivatives*
  • Piracetam / therapeutic use
  • Psychomotor Performance
  • Valproic Acid / adverse effects
  • Valproic Acid / therapeutic use


  • Anticonvulsants
  • Levetiracetam
  • Clonazepam
  • Valproic Acid
  • Phenobarbital
  • Piracetam