Vigabatrin.
The discovery of gamma-aminobutyric acid (GABA) as the first major inhibitory neurotransmitter and a program exploring the use of enzyme inhibition as a therapeutic tool provided the basis for the conception of vigabatrin (VGB, Sabril). This molecule, an analogue of GABA, has a highly specific activity as an enzyme-activated irreversible inhibitor of GABA-transaminase causing several-fold increases in the concentration of brain GABA. In animal models for epilepsy, it was found to have a rather different spectrum of activity than conventional antiepileptic drugs (AEDs). The clinical development of VGB was delayed by the finding of focal areas of reversible microvacuolation in the white matter of the brains of rodents and dogs. An extensive human safety program has confirmed that this finding is species specific and does not occur in humans. Clinically, VGB is well tolerated and has been shown to be specially effective in the management of partial seizures that have failed to respond to other AEDs. In most controlled studies, about 50% of patients with previously uncontrolled seizures have a 50% reduction in frequency and about 4-5% become seizure-free. In children, it also appears to be especially effective in the management of infantile spasms as well as in partial seizures. VGB offers a significant improvement in the management of epilepsy and is now under development as a first-line agent.
Marion Merrell Dow Research Centre, Winnersh, England.
J P
JP
Mumford
D J
DJ
Cannon
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D012377:Rodentia; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin