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SODIUM VALPROATE

A New Anticonvulsant
Review of a symposium on sodium valproate (epilim) at Nottingham University, 23rd-24th
September, 1975, organised on behalf of Reckitt-Labaz.

by Dr. R. A. C. Hughes

Advances in pharmacology are slowly eroding the hard core of "untreatable"


neurological disease. The past ten years have seen the introduction of levodopa and then
levodopa with dopa decarboxylase inhibitors for Parkinson's Disease, clonazepam for some
forms of myoclonus, tetrabenazine for chorea, and baclofen for spasticity. The control of
epilepsy has been advanced by the introduction of phenobarbitone in 1912, phenytoin in 1938
and ethosuximide in 1958. A succession of other anticonvulsants have been introduced with
relatively little impact on the management of epilepsy. A new compound, sodium valproate,
was demonstrated to have anticonvulsant activity in France in 1963 and was recently released
for use in this country by Reckitt-Labaz under the trade name Epilim. The results presented at
a recent symposium organised on behalf of the manufacturers indicate that sodium valproate
is an effective anticonvulsant whose properties deserve wider attention.
Sodium valproate is a simple molecule unrelated to any of the known anticonvulsants
with the structure

Doses vastly higher than those which are used in clinical practice raise y-amino-
butyric acid (GABA) concentrations in the cerebrum and cerebellum, probably by inhibiting
GABA transaminase or other enzymes involved in the conversion of GABA into succinic
acid. GABA is an inhibitory transmitter and might have an anticonvulsant effect. Since,
however, this rise in GABA only occurs with vast doses, it may not be relevant to the
therapeutic action of sodium valproate. The answer to the pharmacological action of sodium
valproate is unlikely to He in massive changes of GABA in chunks of nervous tissue, but
more likely to involve a subtle change in the distribution of GABA or other compounds at the
synapse. It has been suggested that sodium valproate may block the reuptake of GABA into
the presynaptic terminal.
Sodium valproate, like phenytoin and to a lesser extent phenobarbitone, is very
strongly protein bound. In plasma 90 per cent is bound to albumen. At high doses it competes
for the same binding sites as phenytoin and phenobarbitone. It has a plasma half-life of about
eight hours suggesting the need for thrice-daily dosage, but nevertheless some clinicians have
been satisfied with a twice-daily administration schedule. If the patient is already on
phenobarbitone the addition of sodium valproate causes an increase in the phenobarbitone
blood level of about 25 per cent.
If the patient is on phenytoin there is little change or a slight reduction in phenytoin
blood levels, but prehminary animal studies suggest that there is a paradoxical rise in
phenytoin levels in the brain.
Scientific verification of the anticonvulsant properties of sodium valproate has been
painfully slow appearing. Experimental studies have shown anticonvulsant efi'ects on
electrically and chemically induced seizures in mice. Double-blind controlled trials of
treatment in epilepsy are bedevilled by many factors particularly the characteristic but
enigmatic fluctuations in fit frequency. Nevertheless one well controlled double-blind
crossover trial of sodium valproate versus placebo in a group of institutionalised patients with
severe epilepsy demonstrated a significant reduction in fit frequency. A similar but smaller
study on the continent had been published in 1969.
If all the uncontrolled trials discussed at the symposium are lumped together, rather
less than a third of those with focal attacks (excluding temporal lobe), a third of those with
temporal lobe epilepsy, half of those with primary grand mal epilepsy and more than three
quarters of those with petit mal had a reduction in fit frequency by 75 per cent or more. The
results tended to be better in younger people, but worse in those with generalised brain
damage. The trials were conducted on patients with severe epilepsy resistant to other
anticonvulsants. Nevertheless these results almost certainly over-estimate the usefulness of
the drug because the uncontrolled design makes no allowance for powerful placebo effects
both of the new drug and the intensified medical attendance which accompanies a trial. It
could be cogently argued that all patients with chronic disease should be in therapeutic trials
all the time to take full advantage of this placebo effect! It is not clear from any of the trials to
what extent the improvement in fit control is caused by the anticonvulsant properties of
sodium valproate itself or by the accompanying rise in phenobarbitone levels in the blood and
possible rise in phenytoin in the brain.
As with all new drugs, the incidence of side-effects is said to be small but judgment on
this question and the desperately important and difficult problem of teratogenicity must be
reserved. The drug has been released with the warning that it has been shown to be
teratogenic in animals. Very few women in this country have been taking this drug during
pregnancy, and the data on their offspring are inadequate. Many more women on the
continent have presumably had pregnancies while taking the drug, but unfortunately statistical
data on the incidence of fetal abnormalities are not available. With the memory of
thalidomide, few clinicians will be happy to allow their female patients to take sodium
valproate at a time of pregnancy risk or during pregnancy until this point has been clarified.
Gastrointestinal upsets have been reported in about 10 per cent—and drowsiness in 5 per
cent—of patients on the drug. Temporary partial loss of hair from the head has been reported
in about 1 per cent. Other side-effects including thrombocytopenia have been reported but no
definite causal relationship with sodium valproate has been established.
It is too early to judge the ultimate place of sodium valproate in the neurological
armamentarium. There is sufficient evidence for optimism that the drug will play a significant
part in controlling some forms of epilepsy, particularly petit mal. It would seem wise to wait
for longer experience of its side-effects, clarification of its teratogenic properties and
reduction in price before using it as a front rank anticonvulsant. Where control with existing
anticonvulsants is inadequate despite satisfactory dosage, sodium valproate is well worth a
trial. The arrival of effective new drugs and gas chromatograph techniques for measuring
anticonvulsant blood levels represent real advances in the management of epilepsy and relief
for an extra group of patients who can be better controlled.
Full proceedings of this Symposium will be published by Medical Congresses and
Symposia Consultants and will be available on application to: Reckitt and Colman
Pharmaceutical Division, Dansom Lane, Hull, HU8 7DS.

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