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.