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.