Influence of vigabatrin, a novel antiepileptic drug, on the anticonvulsant activity of conventional antiepileptics in pentetrazole-induced seizures in mice.
Vigabatrin is a novel antiepileptic drug, which increases GABA levels by irreversible inhibition of GABA-aminotransferase. The aim of this study was to evaluate the effects of vigabatrin on the anticonvulsant activity of valproate, ethosuximide and clonazepam against pentetrazole-induced seizures in mice. In addition, the effects of antiepileptic drugs alone or in combination with vigabatrin were studied on motor performance and long-term memory. Chemical seizures were induced by subcutaneous injection of pentetrazole at its CD(97) and defined as a clonus of the whole body with an accompanying loss of righting reflex, lasting for over 3 s. Vigabatrin inhibited the clonic pentetrazole-induced seizures and ED(30) of the drug was 879 mg/kg. Vigabatrin (at the subthreshold dose of 250 mg/kg) potentiated the protective activity of ethosuximide, reducing its ED(30) from 142 to 95 mg/kg against clonic seizures induced by pentetrazole, but simultaneously elevated its plasma level. The protective activity of valproate and clonazepam remained almost unchanged. However, vigabatrin (250 mg/kg) decreased TD(30) (50% toxic dose - corresponding to the impairment of motor coordination in 50% of the animals) of ethosuximide and clonazepam from 549 and 3.84 to 460 and 1.1 mg/kg, respectively, in the chimney test. Vigabatrin (250 mg/kg) did not influence TD(30) value of valproate in this test. Vigabatrin (at the dose of 250 mg/kg) did not impair long-term memory in combination with antiepileptics. Potentiation of the ethosuximide's protective activity was apparently due to a pharmacokinetic interaction. Consequently, no pharmacodynamic interactions between vigabatrin and the studied conventional antiepileptic drugs were evident.
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D002998:Clonazepam / Q000097:blood / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D005013:Ethosuximide / Q000097:blood / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D012640:Seizures / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D014635:Valproic Acid / Q000097:blood / Q000627:therapeutic use; D020888:Vigabatrin / Q000097:blood / Q000627:therapeutic use*
D000927:Anticonvulsants; D002998:Clonazepam; D005013:Ethosuximide; D014635:Valproic Acid; D020888:Vigabatrin; D010433:Pentylenetetrazole