PHARMACODYNAMIC INTERACTIONS BETWEEN PHENYTOIN AND VALPROATE - INDIVIDUAL AND COMBINED ANTIEPILEPTIC AND NEUROTOXIC ACTIONS IN MICE

Although the current trend is to use monotherapy in the treatment of e pilepsy, combination therapy is still employed in patients who have fa iled to respond to monotherapy. There is little clinical or experiment al documentation of evidence against or in favor of anticonvulsant com bination therapy. In this context, anticonvulsant and neurotoxic pharm acodynamic interactions between phenytoin (PHT) and valproate (VPA) we re assessed in an experimental model in mice. All results were express ed in terms of brain drug concentrations for eliminating any pharmacok inetic interaction from the analysis. Both the median neurotoxic and t he median anticonvulsant brain concentrations were determined for each drug used alone and for the combination. The interaction for the comb ination of PHT and VPA was shown to be supraadditive for the anticonvu lsant activity, indicating an antiepileptic potentiation, whereas neur otoxicity was simply additive. These results suggest a potential benef it in terms of overall efficacy versus toxicity for the combination of PHT and VPA, as compared with PHT or VPA used alone.