Interactions of stiripentol with clobazam and valproate in the mouse maximal electroshock-induced seizure model.
The aim of this study was to characterize the anticonvulsant effects of stiripentol (STP) in combination with clobazam [CLB], and valproate [VPA]) in the mouse maximal electroshock (MES)-induced seizure model using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of STP with CLB and VPA at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. In the mouse MES model, STP administered singly had its DRRC non-parallel to that for CLB and, simultaneously, parallel to that for VPA. With type I isobolography for parallel DRRCs, the combinations of STP with VPA at three fixed-ratios of 1:3, 1:1 and 3:1 exerted sub-additive (antagonistic) interaction. Isobolography for non-parallel DRRCs revealed that the combination of STP with CLB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength was affected. Total brain antiepileptic drug concentrations revealed bi-direction changes with the most profound being an 18.6-fold increase in CLB by STP and a 2.3-fold increase in STP by VPA. In conclusion, the additive interaction between STP and CLB was associated with a concurrent pharmacokinetic interaction and these data may explain the clinical efficacy seen with this combination. In contrast, the antagonism between STP and VPA was surprising since synergism is observed clinically.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, Lublin, Poland. jluszczki@yahoo.com
Trojnar
Michal K
MK
Ratnaraj
Neville
N
Patsalos
Philip N
PN
Czuczwar
Stanislaw J
SJ
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D001923:Brain Chemistry / Q000187:drug effects; D000078306:Clobazam; D004148:Dioxolanes / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004597:Electroshock; D018737:Hand Strength; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D004148:Dioxolanes; D001569:Benzodiazepines; D000078306:Clobazam; D014635:Valproic Acid; C021092:stiripentol