One to three day dose intervals during subchronic treatment of epileptic gerbils with gamma-vinyl GABA: anticonvulsant efficacy and alterations in regional brain GABA levels.
gamma-Vinyl GABA (GVG), an irreversible inhibitor of GABA degradation, was administered to seizure-susceptible gerbils at different dosage regimens. After acute i.p. administration, GVG dose dependently protected the animals against air blast-induced seizures with an ED50 of 50 mg/kg. After oral administration, GVG exerted similar anticonvulsant potency. However, during subchronic daily oral dosing of 100 mg/kg GVG, tolerance developed to the anticonvulsant effect of the treatment. No tolerance was observed with daily oral dosing of 50 mg/kg or every other day and every third day dosing of 100 mg/kg GVG. The disadvantage of the two latter dosage regimens was that no sufficient seizure control was obtained on the days between two administrations. Determination of GABA levels in 11 brain regions of gerbils after subchronic treatment with the different dosage regimens of GVG indicated that tolerance during treatment with daily administration of 100 mg/kg GVG could be the consequence of feedback reduction of GABA synthesis. The data suggest that the choice of suitable dosage regimens for chronic treatment is more critical with GVG than with other antiepileptic drugs, because compensatory mechanisms within the GABA system may develop when GVG-induced GABA accumulation is too marked.
Laboratory of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, F.R.G.
W
W
Löscher
H H
HH
Frey
D000614:Aminocaproates / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005849:Gerbillinae; D008297:Male; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000614:Aminocaproates; D000927:Anticonvulsants; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin