Interactions of stiripentol with clobazam and valproate in the mouse maximal electroshock-induced seizure model

Abstract

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.