ArticlesSafety and efficacy of vigabatrin and carbamazepine in ne wly diagnosed epilepsy: a multicentre randomised double-blind study
Introduction
Vigabatrin (γ-vinyl-aminobutyric acid; 4-aminohex-5-enoic acid) is an irreversible inhibitor of γ-aminobutyric acid (GABA)-transaminase. Vigabatrin increases GABA concentrations in the central nervous system of laboratory animals1 and human beings.2, 3 In various animal seizure models, vigabatrin-induced increases in GABA concentrations have been associated with anticonvulsant activity.4, 5
In double-blind, placebo-controlled, crossover studies, the addition of vigabatrin to standard antiepileptic therapy has decreased seizure frequency and severity in patients with uncontrolled partial seizures.6, 7, 8, 9 In a meta-analysis of double-blind, add-on, parallel-group studies in patients with partial epilepsy, vigabatrin seems to be one of the more potent antiepileptic drugs, particularly at higher doses (3–6 g daily).10
Studies of toxic effects in rodents and dogs revealed microvacuolation in white-matter tracts after 12 months at doses of 30–50 mg/kg daily, increasing in severity within a restricted dose range.11 The results of magnetic resonance imaging studies that show vigabatrin-induced intramyelinic oedema in dogs have been correlated with increased latencies in canine somatosensory and visual evoked potentials.12 There is no electrophysiological, magnetic resonance imaging, or neuropathological evidence for microvacuolation in human beings after vigabatrin treatment.13, 14 Findings are, however, supported by analysis of neuropathological samples from 60 patients exposed to vigabatrin for up to 7 years.15 However, since the end of our study there have been reports of visual-field constriction with longer-term use of vigabatrin.16 Psychiatric complications may also occur, and there have been reports of an increased incidence of depression in placebo-controlled studies17 and rarer reports of psychosis.18
All double-blind controlled studies of vigabatrin in epilepsy have been done with placebo as add-on therapy in uncontrolled epilepsy and have, by necessity, been short. Only two monotherapy studies have been published.19, 20 Both were open, single-centre randomised studies, and used carbamazepine as comparator. Tanganelli and Regesta19 studied 51 patients for 16 weeks in a randomised crossover study; 17 (46%) of 37 patients on vigabatrin and 20 (51%) of 39 on carbamazepine were seizure-free. Kälviäinen and colleagues20 randomised 100 patients; 32 on vigabatrin and 52 on carbamazepine completed 1 year of monotherapy and remained seizure-free. In these two studies, the side-effect profile was in favour of vigabatrin, with significantly more withdrawals because of carbamazepine-related side-effects.
We did a double-blind monotherapy study in untreated, newly diagnosed patients to assess the efficacy and safety of vigabatrin.
Section snippets
Patients
Patients, all of whom had newly diagnosed epilepsy, were aged 12–65 years and had had at least two seizures in the previous 12 months (simple or complex partial seizures with or without secondary generalisation). All patients gave written informed consent. The occurrence of generalised seizure types was one exclusion criterion.
Pãtients were recruited between February, 1993, and January, 1996, in 44 centres in the UK, Denmark, Finland, Sweden, Germany, Belgium, Netherlands, Italy, France,
Patient withdrawal
459 patients were enrolled. Two patients failed to take the study drug and were excluded from safety analysis. Of the 457 patients with safety data, 195 patients withdrew from the study early: 98 in the vigabatrin group, 97 in the carbamazepine group (figure 1). The most common reason for withdrawal was adverse events (104 patients: 43 vigabatrin, 61 carbamazepine). 32 patients withdrew because of absence of therapeutic effect (23 vigabatrin, nine carbamazepine). Of the patients who had adverse
Discussion
Monotherapy studies of antiepileptic drugs are important for several reasons. They are relevant to the 70% of patients with epilepsy who are treated with monotherapy, and allow comparisons without potential pharmacokinetic and pharmacodynamic interactions that can confound the interpretation of add-on studies. These studies allow comparison of newly licensed drugs with standard drugs, thereby helping to define the place of new drugs in the clinical armamentarium.
Over the past 15 years, several
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