Antiepileptic drug combinations and experimental background: The case of phenobarbital and phenytoin

Summary In view of the trend towards single drug therapy of epilepsy, the experimental background for thr combination of phenobarbital (PB) and phenytoin (PHT) was reassessed. Since potentiation of the anticonvulsant activity is in itself neither sufficient nor necessary to demonstrate the superiority of a drug combination, protection against maximal electroshock seizures as well as neurotoxicity were determined in mice. This allowed one to separate the neurotoxic from the anticonvulsant interaction and to base the analysis on changes in the therapeutic index (TI). Pharmacokinetic interactions were excluded from the analysis by expressing all results in terms of brain concentrations. The anticonvulsant interaction between PB and PHT was found to be additive, whereas the neurotoxic interaction was antagonistic. These results provide experimental documentation of one of the theories behind antiepileptic drug combinations. However, because PB had a markedly lower TI than PHT in this model, the TI of the drug combination was lower than the TI of PHT. Thus, the antagonism with regard to neurotoxicity was not sufficient to raise the TI of the combination above the TI of PHT.