The
anticonvulsant potency of the trans isomer of 2-en-valproate (trans-2-en-VPA) was determined in standardized models for different seizure types in rodents and dogs. In mice and rats, adverse effects were quantified by the rotarod and chimney tests. Clinically established
antiepileptic drugs (
valproate,
ethosuximide,
phenobarbital,
carbamazepine,
phenytoin,
diazepam) were used for comparison. Based on time course studies,
drug potencies were determined and compared at the individual time of peak
anticonvulsant effect. Potency comparisons were based on administered dosages and, in the case of
trans-2-en-VPA and
valproate, also on plasma levels determined after administration of
anticonvulsant doses. The data show that
trans-2-en-VPA exerts
anticonvulsant effects against different seizure types, i.e., myoclonic, clonic, and
tonic seizures in rodents and (myo)
clonic seizures in dogs. In most seizure models,
trans-2-en-VPA was more potent than
valproate, when both compounds were compared at their individual times of peak effect. Time course and pharmacokinetic studies showed that duration of action and pharmacokinetic characteristics of
trans-2-en-VPA and
valproate are similar. In the rotarod and chimney tests in mice and rats,
trans-2-en-VPA was more potent than
valproate. However, because of the higher
anticonvulsant potency of
trans-2-en-VPA, protective indices calculated from rodent models were similar to those of
valproate. Similarly, in dogs
trans-2-en-VPA exerted
anticonvulsant effects at doses below those which induced sedation and
ataxia. In view of the previously reported advantages of
trans-2-en-VPA compared to
valproate with respect to teratogenic and hepatotoxic effects, the present data substantiate that
trans-2-en-VPA might be a valuable alternative to
valproate in
antiepileptic therapy.