Patients with drug resistant epilepsy represent about 40% of the whole 
population of epileptic patients. These patients require more than one 
antiepileptic drug. In animal models of epilepsy, it is possible to determine 
which combinations produce supra-additive anticonvulsive effects with minimal or 
even no adverse reactions. The experimental data can be helpful for predicting 
effective drug combinations in patients with refractory epilepsy. Losigamone is 
a new antiepileptic drug with an unknown mechanism of action. The drug belongs 
to the group of beta-methoxy-butenolides, and exists as a racemic mixture of two 
enantiomers (AO-242 and AO-294). The drug is eliminated by oxidation. Cytochrome 
CYP2A6 appears to be the main isoenzyme responsible for the metabolism of 
losigamone. In vitro, losigamone exerts anticonvulsant activity in the 
picrotoxin model in CA1 and CA3 hippocampal areas, the low Ca(2+) model in CA1 
area and the low Mg(2+) model in the entorhinal cortex and hippocampus. In vivo, 
the drug exhibits significant efficacy against maximal electroshock-induced 
seizures in rodents and pentetrazole-induced clonic convulsions in mice. Potency 
of losigamone varies with the respective seizure test, animal species used in 
experiments and route of drug administration. Toxicity studies do not indicate 
any teratogenic risk of the drug, at least in animals. In clinical trial, 
losigamone proved to have satisfactory effectiveness and good tolerance in the 
treatment of partial and secondary generalized seizures. The enantiomer AO-242 
seems to be more potent than AO-294 or racemate.