Stiripentol


Stiripentol is an anticonvulsant drug used in the treatment of epilepsy. It is approved for the treatment of Dravet syndrome, an epilepsy syndrome. It is unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.

Medical use

It is used in some countries as an add-on therapy with sodium valproate and clobazam for treating children with Dravet syndrome whose seizures are not adequately controlled. As of 2017 it was not known whether stiripentol remains useful as children become adolescents nor as they become adults.

Adverse effects

Very common adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.
Common adverse effects include neutropenia, aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.

Interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.

Pharmacology

As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.
Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices. It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism. Specifically, it has been shown to inhibit lactate dehydrogenase, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely through activation of ATP-sensitive potassium channels.
Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs' metabolism and increasing blood plasma levels.

Chemistry

Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1--1penten-3-ol. It is chiral and is marketed as an equimolar racemic mixture. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years. It was originally developed for adults with focal seizures, but failed a Phase III trial.
In December 2001 the European Medicines Agency granted stiripentol orphan drug status for the treatment of severe myoclonic epilepsy of infancy in children and in 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs. It was approved in Canada for this use in 2012. As of 2017 it was also approved for this use in Japan.
In 2018, stiripentol was approved by the United States Food & Drug Administration as an adjunctive therapy for Dravet Syndrome. Prior to approval, parents of children with Dravet were paying around $1,000 for a month supply to obtain it from Europe.