Abstract

Although monotherapy in epilepsy treatment is frequently advocated, this is not based on studies with equal drug loads. This study was performed to investigate the experimental background of polytherapy with standardized drug loads. Dose-dependent effects on grip strength, accelerod performance, and spontaneous behavior of rats was used to study the effect of combining valproate and ethosuximide. The potency of the drugs (combination) was obtained by fitting the sigmoid E_max equation to the data. Drug interaction was assessed using the isobologram method and quantified by comparing equivalent drug loads with their 95% confidence intervals. We found that the effects of valproate and ethosuximide combine in a simple additive way in the grip strength experiment as well as in the accelerod experiment. In the behavioral studies, however, a higher drug load of the combination was needed to obtain the same amount of sedation, signifying infra-additivity. Infra-additivity of sedative effects is an important finding because this is by far the most frequent side effect mentioned in human studies. However, assessment of the therapeutic effect of the combination will have to be completed before a preference for mono- or polytherapy, based on the balance of adverse effects and efficacy, can be expressed.