Isobolographic characterization of interactions of levetiracetam with the various antiepileptic drugs in the mouse 6 Hz psychomotor seizure model.
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.
Wojda
Ewa
E
Department of Pathophysiology, Medical University, Jaczewskiego 8, PL 20-090 Lublin, Poland.
Wlaz
Aleksandra
A
Patsalos
Philip N
PN
Luszczki
Jarogniew J
JJ
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D002998:Clonazepam / Q000009:adverse effects / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy*; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D010634:Phenobarbital / Q000009:adverse effects / Q000627:therapeutic use; D010889:Piracetam / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011597:Psychomotor Performance; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use
D000927:Anticonvulsants; D000077287:Levetiracetam; D002998:Clonazepam; D014635:Valproic Acid; D010634:Phenobarbital; D010889:Piracetam