Effects of the combination of valproate and ethosuximide on spike wave discharges in WAG/Rij rats

Objective: We studied the interaction between valproate (VPA) and ethosuximide (ESM) in diminishing the incidence of absence-like spike-wave discharges (SWDs) in the EEG of WAG/Rij rats. Methods: VPA, ESM, their combination and saline were evaluated in 16 rats. The doses of VPA ranged from 0 to 280 mg/kg and the doses of ESM ranged from 0 to 40 mg/kg. For the drug combination, a fixed weight ratio of 7/1 VPA/ESM was used. The incidence of SWDs in the EEG was determined for the period of 15-75 min after injection and compared to the incidence of SWDs prior to injection. The sigmoid-E-max equation was fitted to the data. Isobolic analysis, on 50% effect, was used to assess the character of the drug interaction. Results: The parameters for diminishing the incidence of the SWDs were: VPA: ED50: 121 mg/kg; ESM: ED50: 21.5 mg/kg; VPA/ESM: ED50: 112/16 mg/kg. Isobolic analysis showed that a higher drug load was needed of the combination than of the individual drugs to achieve a 50% reduction of SWDs: factor 1.67; P = 0.012. Conclusion: The interaction between valproate and ethosuximide was shown to be infra-additive in diminishing the incidence of SWDs in WAG/Rij rats. (C) 2004 Elsevier B.V. All rights reserved.