Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs.
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.
Löscher
W
W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
Hönack
D
D
Nolting
B
B
Fassbender
C P
CP
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000379:methods; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000503:physiopathology*; D013237:Stereoisomerism; D013997:Time Factors
D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; C014168:2-propyl-2-pentenoic acid