VIGABATRIN
Current
investigations that seek drugs to enhance the effects of GABA include efforts
to find GABA agonists and prodrugs, GABA transaminase inhibitors, and GABA
uptake inhibitors. Vigabatrin is one such drug.
Vigabatrin
is an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme
responsible for the degradation of GABA. It may also inhibit the vesicular GABA
transporter. Vigabatrin produces a sustained increase in the extracellular
concentration of GABA in the brain. This leads to some desensitization of
synaptic GABAA receptors but prolonged activation of nonsynaptic
GABAA receptors that provide tonic inhibition. A decrease in brain
glu-tamine synthetase activity is probably secondary to the increased GABA
concentrations. It is effective in a wide range of seizure models. Vigabatrin
is marketed as a racemate; the S(+)
enantiomer is active and the R(–) enantiomer
appears to be inactive.
Vigabatrin
is useful in the treatment of partial seizures and infantile spasms. The
half-life is approximately 6–8 hours, but considerable evidence suggests that
the pharmacodynamic activity of the drug is more prolonged and not well
correlated with the plasma half-life. In infants, the dosage is 50–150 mg/d. In
adults, vigabatrin should be started at an oral dosage of 500 mg twice daily; a
total of 2–3 g (rarely more) daily may be required for full effectiveness.
Typical
toxicities include drowsiness, dizziness, and weight gain. Less common but more
troublesome adverse reactions are agitation, confusion, and psychosis;
preexisting mental illness is a relative contraindication. The drug was delayed
in its worldwide introduction by the appearance in rats and dogs of a
reversible intramyelinic edema. This phenomenon has now been detected in
infants taking the drug; the clinical significance is unknown. In addition,
long-term therapy with vigabatrin has been associated with development of
peripheral visual field defects in 30–50% of patients. The lesions are located
in the retina, increase with drug exposure, and are usually not reversible.
Newer techniques such as optical coherence tomography may better define the
defect, which has proved difficult to quantify. Vigabatrin is usually reserved
for use in patients with infantile spasms or with complex partial sei-zures
refractory to other treatments.
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