Vigabatrin

Abstract

Objective To introduce the reader to the use of a new agent, vigabatrin, in the treatment of refractory complex partial seizures. Clinical trials and pharmacokinetic data are reviewed, as well as neuropathology, adverse effects, drug interactions, and dosage guidelines. Data Sources A MEDLINE search through March 1992 was used to identify pertinent English-language literature, including clinical trials, reviews, abstracts, and conference proceedings. Indexing terms included vigabatrin and anticonvulsants. Study Selection All clinical trials (total of 21) were reviewed, as were all pharmacokinetic studies (total of 8). Selected studies highlighting chemistry, pharmacology, neuropathology, and adverse effects were also reviewed. Data Extraction Performed subjectively by the author. Trials were assessed by design, sample size, types of seizures of the subjects, and clinical response. Data Synthesis Vigabatrin represents the first of a new class of antiepileptic drugs (AEDs)—the gamma-aminobutyric acid transaminase (GABA-T) inhibitors. Vigabatrin works by selective, irreversible inhibition of GABA-T, thus preventing the breakdown of GABA. It has been shown to produce dose-dependent increases in cerebrospinal fluid GABA concentrations, and decreases in GABA-T activity. Vigabatrin may also cause a decrease in excitation-related amino acids. It is well absorbed, is not protein bound, and is eliminated by glomerular filtration. However, even with a short half-life (5–7 h), vigabatrin may be given once or twice daily because of its mechanism of action. Few drug interactions have been reported with this agent, although decreases in phenytoin concentration may reach clinical significance. Concern over neuropathologic findings (microvacuolization of white matter) in animals caused trials of vigabatrin to be halted in 1983, but trials have now resumed as there is no evidence of toxicity in humans. Clinical efficacy of vigabatrin has been evaluated in controlled trials and appears to be most effective in complex partial seizures, producing a 50 percent or greater reduction in seizure frequency in approximately 50 percent of the adult patients studied. Efficacy in children with partial seizures also appears promising, and one uncontrolled study suggests that further study of vigabatrin in infantile spasms may be warranted. Conclusions Vigabatrin appears to be effective in treating refractory complex partial seizures in adults and refractory partial seizures in children. Its relatively benign adverse-effect profile and few known drug interactions may give this agent an advantage over existing anticonvulsants. However, definitive conclusions about the role of vigabatrin in epilepsy treatment should await the completion of ongoing Phase II and Phase III trials.

Advances in pharmacotherapy: recent developments in the treatment of epilepsy

“…The results in adults with complex partial seizures with or without secondary generalization, primary generalized, myodonic and juvenile myodonic epilepsies have been favourable, with up to 3 0 4 0 % of patients showing a 50-100% decrease in seizure frequency (95). Similar results have been seen in children (95,96) with partial, generalized, Lennox-Gastaut and West syndromes and intractable infantile spasms. Vigabatrin is more effective in partial seizures than in ones which have a generalized origin (97).…”

“…Less frequently reported are irritability, nervousness, dizziness, headache or confusion. Psychosis has been reported in at least 30 patients, many of whom had preexisting psychiatric diagnoses (95). Thus, patients with a history of psychosis or behavioural disturbances should probably not receive vigabatrin.…”

“…In clinical trials, vigabatrin has produced very few adverse effects, with up to 75% of patients reporting no sideeffects (95). Some 30-40% of patients complained of drowsiness and fatigue (95). Less frequently reported are irritability, nervousness, dizziness, headache or confusion.…”

“…After repeated high-dose administration, alopecia, reduced weight gain, anorexia and anaemia have been seen in various animal species. In clinical trials, vigabatrin has produced very few adverse effects, with up to 75% of patients reporting no sideeffects (95). Some 30-40% of patients complained of drowsiness and fatigue (95).…”

Rett Syndrome: Reaching for Clinical Trials

“…Selective deletion of Mecp2 in GABAergic neurons caused impaired GABAergic transmission, cortical hyperexcitability, and several neurologic features of RTT and autism spectrum disorders [110]. Vigabatrin is an antiepileptic drug that irreversibly inhibits GABA transaminase, inhibits GABA catabolism, and thereby increases GABA levels [111]. The drug is already FDA-approved for use in epilepsy syndromes.…”