Stiripentol

Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder.[5][6]

Stiripentol
Clinical data
Pronunciationstir"i pen' tol
Trade namesDiacomit
AHFS/Drugs.comMonograph
MedlinePlusa618069
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • (RS)-(E)-4,4-dimethyl-1-[3,4(methylenedioxy)-phenyl]-1-penten-3-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.051.329
Chemical and physical data
FormulaC14H18O3
Molar mass234.295 g·mol−1
3D model (JSmol)
SMILES
  • O1c2ccc(cc2OC1)/C=C/C(O)C(C)(C)C
InChI
  • InChI=1S/C14H18O3/c1-14(2,3)13(15)7-5-10-4-6-11-12(8-10)17-9-16-11/h4-8,13,15H,9H2,1-3H3/b7-5+ Y
  • Key:IBLNKMRFIPWSOY-FNORWQNLSA-N Y
 NY (what is this?)  (verify)

The most common side effects include loss of appetite, weight loss, insomnia (difficulty sleeping), drowsiness, ataxia (inability to co‑ordinate muscle movements), hypotonia (low muscle strength) and dystonia (muscle disorders).[5]

Medical uses

In the European Union, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in people with severe myoclonic epilepsy in infancy (SMEI, Dravet's syndrome) whose seizures are not adequately controlled with clobazam and valproate.[5]

In the United States, stiripentol is indicated for the treatment of seizures associated with Dravet syndrome in people two years of age and older taking clobazam.[4] There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.[4]

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.[7][8][9][10] As of 2017, it was not known whether stiripentol remains useful as children become adolescents or adults.[11]

Contraindications

Stiripentol must not be used in people who have had psychosis (a serious mental state with a distorted sense of reality) with attacks of delirium (a mental state with confusion, excitement, restlessness and hallucinations).[5]

Adverse effects

Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.[9]

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.[9]

Interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.[9]

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.[12] It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism.[13] 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.[14]

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.[9]

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 used medically as the racemate. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.[15]

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years.[15] It was originally developed for adults with focal seizures, but failed a Phase III trial.[11]

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 January 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs.[5][9] It was approved in Canada for this use in May 2013.[16][17] As of 2017, it was also approved for this use in Japan.[8]

In August 2018, stiripentol was approved by the US Food and Drug Administration (FDA) as an adjunctive therapy for Dravet Syndrome.[18]

Society and culture

Economics

Prior to approval in the US, parents of children with Dravet Syndrome were paying around $1,000 for a month supply to obtain it from Europe.[19]

References
  1. "Diacomit". Therapeutic Goods Administration (TGA). 13 December 2019. Retrieved 17 September 2021.
  2. "AusPAR: Stiripentol". Therapeutic Goods Administration (TGA). 19 December 2019. Retrieved 17 September 2021.
  3. "Diacomit 250mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 31 May 2019. Retrieved 8 November 2020.
  4. "Diacomit- stiripentol capsule Diacomit- stiripentol powder, for suspension". DailyMed. 15 May 2020. Retrieved 8 November 2020.
  5. "Diacomit EPAR". European Medicines Agency. Retrieved 8 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. "Stiripentol Monograph for Professionals". Drugs.com. 31 August 2020. Retrieved 8 November 2020.
  7. 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.
  8. 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. S2CID 25051912.
  9. Diacomit (stiripentol) SPC (PDF) (Report).
  10. Brigo, Francesco; Igwe, Stanley C.; Bragazzi, Nicola Luigi (2022-09-06). "Stiripentol add-on therapy for drug-resistant focal epilepsy". The Cochrane Database of Systematic Reviews. 9: CD009887. doi:10.1002/14651858.CD009887.pub6. ISSN 1469-493X. PMC 9447417. PMID 36066395.
  11. 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. S2CID 205759047.
  12. 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. S2CID 14199574.
  13. Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). "Stiripentol. A novel antiepileptic drug" (PDF). Pharmacological Reports. 57 (2): 154–60. PMID 15886413.
  14. 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. Bibcode:2015Sci...347.1362S. doi:10.1126/science.aaa1299. PMID 25792327. S2CID 22024222.
  15. "Scientific evaluation" (PDF). EMA. 2007.
  16. Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome) (PDF) (Report). Canadian Agency for Drugs and Technologies in Health. April 2015.
  17. "Diacomit Product information". Health Canada. Retrieved 8 November 2020.
  18. "Drug Approval Package: Diacomit (stiripentol)". U.S. Food and Drug Administration (FDA). 7 September 2018. Retrieved 8 November 2020.
  19. 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.
  • "Stiripentol". Drug Information Portal. U.S. National Library of Medicine.
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