Stiripentol

Stiripentol
Names
Pronunciationstir"i pen' tol
Trade namesDiacomit
IUPAC name
  • (RS)-(E)-4,4-dimethyl-1-[3,4(methylenedioxy)-phenyl]-1-penten-3-ol
Clinical data
Drug classAnticonvulsant[1]
Main usesSevere myoclonic epilepsy in infancy (Dravet syndrome)[2]
Side effectsLoss of appetite, weight loss, trouble sleeping, sleepiness, poor coordination[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3
  • US: N (Not classified yet)
    Routes of
    use    		By mouth
    Typical dose25 mg/kg BID[3]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa618069
    Legal
    License data
    Legal status
    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+ checkY
    • Key:IBLNKMRFIPWSOY-FNORWQNLSA-N checkY

    Stiripentol, sold under the brand name Diacomit, is a medication used to treat a form of epilepsy known as severe myoclonic epilepsy in infancy (SMEI, Dravet syndrome).[2][1] It is taken by mouth.[1] It is taken with clobazam in children over the age of 2 years.[1]

    Common side effects include loss of appetite, weight loss, trouble sleeping, sleepiness, and poor coordination.[2] Other side effects may include low neutrophils, low platelets, and suicide.[1] Use during pregnancy may harm the baby.[1] It is a anticonvulsant with the chemical structure of an aromatic allylic alcohol.[1]

    Stiripentol was approved for medical use in Europe in 2007 and the United States in 2018.[2][1] In the United Kingdom 250 mg twice per day for a month costs the NHS about £280 as of 2021.[3] In the United States this amount costs about 1,600 USD.[6]

    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.[2]

    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.[5] There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.[5]

    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]

    Dosage

    It is used at a dose of 25 mg/kg twice per day.[3]

    Contraindications

    Stiripentol must not be used in people who have had psychoses (a serious mental state with a distorted sense of reality) with attacks of delirium (a mental state with confusion, excitement, restlessness and hallucinations).[2]

    Side 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 is marketed as an equimolar racemic mixture. 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.[2][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. 1 2 3 4 5 6 7 8 "Stiripentol Monograph for Professionals". Drugs.com. 31 August 2020. Archived from the original on 11 October 2020. Retrieved 8 November 2020.
    2. 1 2 3 4 5 6 7 8 9 "Diacomit EPAR". European Medicines Agency. Archived from the original on 12 November 2020. Retrieved 8 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    3. 1 2 3 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 347. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    4. ↑ "Diacomit 250mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 31 May 2019. Archived from the original on 13 November 2020. Retrieved 8 November 2020.
    5. 1 2 3 "Diacomit- stiripentol capsule Diacomit- stiripentol powder, for suspension". DailyMed. 15 May 2020. Archived from the original on 6 August 2020. Retrieved 8 November 2020.
    6. ↑ "Diacomit Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 20 April 2021. Retrieved 14 October 2021.
    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. 1 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. S2CID 25051912.
    9. 1 2 3 4 5 6 Diacomit (stiripentol) SPC (PDF) (Report). Archived (PDF) from the original on 2021-07-09. Retrieved 2021-05-17.
    10. ↑ Brigo, Francesco; Igwe, Stanley C.; Bragazzi, Nicola Luigi (26 May 2020). "Stiripentol add-on therapy for drug-resistant focal epilepsy". The Cochrane Database of Systematic Reviews. 5: CD009887. doi:10.1002/14651858.CD009887.pub5. ISSN 1469-493X. PMC 7386790. PMID 32468572. Archived from the original on 29 August 2021. Retrieved 17 May 2021.
    11. 1 2 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. Archived (PDF) from the original on 2015-09-24. Retrieved 2021-05-17.
    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. 1 2 "Scientific evaluation" (PDF). EMA. 2007. Archived (PDF) from the original on 2017-12-21. Retrieved 2021-05-17.
    16. ↑ Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome) (PDF) (Report). Canadian Agency for Drugs and Technologies in Health. April 2015. Archived (PDF) from the original on 2020-10-23. Retrieved 2021-05-17.
    17. ↑ "Diacomit Product information". Health Canada. Archived from the original on 29 August 2021. Retrieved 8 November 2020.
    18. ↑ "Drug Approval Package: Diacomit (stiripentol)". U.S. Food and Drug Administration (FDA). 7 September 2018. Archived from the original on 22 November 2019. 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.
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