VIEWS & REVIEWS

Vigabatrin - generating interest in epilepsy research

-David Jack-

Epilepsy is a difficult disease to treat and is particularly distressing because it often starts in childhood. Following the arrival of valproic acid in the late 1960s there was a gap of almost 20 years until a handful of promising new anticonvulsant compounds were ready for clinical study. Vigabatrin is a "designer drug", developed from the detailed knowledge we now have of how GADA receptors act in epilepsy. In a symposium at the Epilepsy Europe meeting, held in Glasgow in September, the importance of this new anticonvulsant agent was discussed.

Vigabatrin is currently one of the anticonvulsants being most actively studied. Dr M Brodie believes that the steady rise in publications on epilepsy since around 1984 is due largely to this drug, which was launched in the UK in 1989.

'Vigabatrin has given a new lease of life to epileptologists. '

Dr Martin Brodie. Glasgow

Role of GABA important in epilepsy Epileptic seizures are probably caused by an

imbalance developing between excitatory and inhibitory transmission in the brain. The role of GAB A receptors in epilepsy was outlined by Dr Robert McDonald from the University of Michigan Medical Center, USA.

GAB A is one of the major neurotransmitters and there is evidence that its levels are reduced in some patients with epilepsy. In animal models, seizures can be provoked by inhibiting GABA synthesis or blocking the GAB A receptor.

One of the ways to raise GABA levels is by inhibition of its metabolism by blocking the transaminase enzyme responsible, GABA-T. Vigabatrin is a potent selective inhibitor of this enzyme and its effects are long-lasting. The anticipated activity of vigabratin has been confirmed in animals models of epilepsy and the degree of selectivity is high and confined to the S-enantiomer. At 20-times the concentration needed to block GABA-T, no effects are seen on other enzymes, such as aspartate and alanine transaminases and glutamate decarboxylase, which are also present in nerve terminals.

Ten years dinical experience confinns efficacy Vigabatrin has now been studied in Denmark for

over 10 years and Dr Dam from the University Clinic of Neurology, Copenhagen, presented the latest results from his long-term study.

At present, a total of 117 patients ranging in age from 3-73 years (mean 31.9 years) have received vigabatrin as add-on therapy to their existing medication. The majority of patients suffer from partial seizures. Although in almost half (45%), vigabatrin had to be discontinued because of lack of efficacy, the remainder responded well and have

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now been treated for on average 3 years with no loss in efficacy. Side-effects were minor and mainly neurological.

Positive results from the Italian multicentre trial In Italy, 12 centres have participated in a trial of

vigabatrin as add-on therapy. Just over 100 patients were recruited suffering from drug-resistant epilepsy, mostly partial seizures. In this single-blind study, vigabatrin doses up to a maximum of 4g/day have been given. Dr E Perucca, Pavia, described how both partial and generalized tonic-clonic seizures have been reduced, with 60 patients showing a ~ 50% reduction in seizure frequency compared with placebo. Adverse events have been rare.

Moving into first-line in childhood epilepsy As many as 20-30% of childhood epilepsies

prove to be drug-resistant and this is very disconcerting to both the children and their parents. Dr RE Appleton from Liverpool, UK, reviewed the use of vigabatrin in a number of trials involving over 350 children with intractable epilepsy.

Vigabatrin is now being used as a first-line treatment in children

After 6 months' treatment, 30-40% of children have shown a ~ 50% reduction in seizure frequency. There has been no obvious dose-response relationship observed and the optimal dose seems to be around 40-80 mg/kg/day for partial seizures and I OO-150mg/kg/day for spasms. Although the incidence of adverse events has generally been low, a number of children have experienced persistent and severe agitation and in such cases the drug should be withdrawn.

At the Royal Liverpool Childrens' Hospital, vigabatrin is now being used as a first-line treatment in children.

Fears of intramyelinic oedema unfoonded? During the early development of vigabatrin, one

of the concerns was the finding of intramyelinic oedema in the brains of some animals. Dr John Duncan from the Institute of Neurology and Neurosurgery, London, UK, showed how magnetic resonance imaging could be used to detect the development of this condition in animals. The technique is now being applied to study vigabatrin treatment in patients using a double-blind, placebo-controlled design. To date 46 patients have been recruited and, so far, no evidence of intramyelinic oedema has been found.

Advantageous effects on cognitive function The older anticonvulsants, such as phenytoin and

phenobarbital, have always been associated with a high incidence of cognitive impairment. However, 'vigabatrin generally has no detrimental effects on cognitive junction, and in some studies has even been

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6 VIEWS & REVIEWS

shown to improve it' noted Dr M R Trimble, from the Institute of Neurology, London. UK.

Dr Trimble described the results of a number of studies in which vigabatrin perfonned well. including 2 that he himself has carried out in 34 patients. A mean dose of 2.5 g/day was given and a battery of tests perfonned to measure attention, mental and motor speed and a number of other functions dependent on cognition.

First-Hoe agent? Vigabatrin has been studied as a first-line

treatment in Finland since 1988. Dr P Riekkinen, from the University of Kuopio, has compared vigabatrin with carbamazepine as first-line treatment in an open, randomized parallel design trial in 80 adults with previously untreated, newly-diagnosed epilepsy. The patients have now been followed for 3-38 months.

Vigabatrin may well become a valuable alternative to more established first-line

agents

The 2 therapies seemed to be comparable in many respects; vigabatrin has been stopped more often because of unacceptable seizure control while carbamazepine has been stopped more often because of side-effects. Although this is only a small study needing confmnation in a larger patient group, vigabatrin seems to help memory recall.

Dr Riekkinen wonders whether vigabatrin might be a "smart" drug. It certainly appears to counteract the decline in cognitive function in epilepsy and it may well become a valuable alternative to more established first-line agents.

HOOI.57'9M

• Editorial comment: Vigabatrin was developed by Marion Merrell Dow and was launched as Sabri~ in the UK in 1989. Consequently, it has been launched in France and Germany and it is registered in Denmark, Ireland, Portugal and Sweden with registration applications having been submitted in all major European countries. In the US, clinical trials were temporarily suspended because of concerns over the development of brain vascuolisation in monkeys. However, the FDA subsequently voted to allow testing 10 resume.

26 Sep 11192 INPHARMA~ ISSN 0156·270319210926·0061$1 .00" Adlslnternatlonlll Ltd