Stiripentol

Stiripentol (marketed as Diacomit by Laboratoires Biocodex) 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.

Stiripentol
Clinical data
Trade namesDiacomit
AHFS/Drugs.comInternational Drug Names
License data
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • AU: Unscheduled
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.051.329
Chemical and physical data
FormulaC14H18O3
Molar mass234.295 g·mol−1
3D model (JSmol)
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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.[1][2][3] As of 2017 it was not known whether stiripentol remains useful as children become adolescents nor as they become adults.[4]

Adverse effects

Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.[3]

Common (between 1% and 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.[3]

Interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.[3]

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.[5] It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism.[6] 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.[7]

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.[3]

Chemistry

Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1-[3,4-(methylendioxy)-phenyl]-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.[8]

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years.[8] It was originally developed for adults with focal seizures, but failed a Phase III trial.[4]

In December 2001 the European Medicines Agency (EMA) granted stiripentol orphan drug status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy of infancy (SMEI, also known as Dravet's syndrome) 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.[3] It was approved in Canada for this use in 2012.[9] As of 2017 it was also approved for this use in Japan.[2]

As of 2014 it was not approved in the US, and parents of children with Dravets were paying around $1,000 for a month supply to obtain it from Europe.[10]

References
  1. Brigo, F; Igwe, SC; Bragazzi, NL (18 May 2017). "Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy". The Cochrane Database of Systematic Reviews. 5: CD010483. doi:10.1002/14651858.CD010483.pub4. PMC 6481545. PMID 28521067.
  2. Nickels, KC; Wirrell, EC (May 2017). "Stiripentol in the Management of Epilepsy". CNS Drugs. 31 (5): 405–416. doi:10.1007/s40263-017-0432-1. PMID 28434133.
  3. "Diacomit (stiripentol) SPC" (PDF). EMA. 8 January 2014. Retrieved 1 October 2017. For updates see EMA index page
  4. Nabbout, R; Camfield, CS; Andrade, DM; Arzimanoglou, A; Chiron, C; Cramer, JA; French, JA; Kossoff, E; Mula, M; Camfield, PR (April 2017). "Treatment issues for children with epilepsy transitioning to adult care". Epilepsy & Behavior. 69: 153–160. doi:10.1016/j.yebeh.2016.11.008. PMID 28188045.
  5. Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H (2006). "Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels". Epilepsia. 47 (4): 704–16. doi:10.1111/j.1528-1167.2006.00497.x. PMID 16650136.
  6. Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). "Stiripentol. A novel antiepileptic drug" (PDF). Pharmacological Reports : PR. 57 (2): 154–60. PMID 15886413.
  7. Sada N, Lee S, Katsu T, Otsuki T, Inoue T (2015). "Targeting LDH enzymes with a stiripentol analog to treat epilepsy". Science. 347 (6228): 1362–67. doi:10.1126/science.aaa1299. PMID 25792327.
  8. "Scientific evaluation" (PDF). EMA. 2007.
  9. "Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome)" (PDF). Canadian Agency for Drugs and Technologies in Health. April 2015.
  10. Kossoff, E (January 2014). "Stiripentol for dravet syndrome: is it worth it?". Epilepsy Currents. 14 (1): 22–3. doi:10.5698/1535-7597-14.1.22. PMC 3913306. PMID 24526870.
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