Stiripentol
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| Pronunciation | stir "i pen' tol |
| Trade names | Diacomit |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618069 |
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| Routes of administration | By mouth |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.051.329 |
| Chemical and physical data | |
| Formula | C14H18O3 |
| Molar mass | 234.295g·mol−1 |
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Stiripentol,sold under the brand nameDiacomit,is ananticonvulsantmedication used for the treatment ofDravet syndrome- a serious genetic brain disorder.[5][6]
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
[edit]In the European Union, stiripentol isindicatedfor 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 withsodium valproateandclobazamfor treating children withDravet syndromewhose 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
[edit]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
[edit]Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness,ataxia,hypotonia,anddystonia.[9]
Common (between 1% and 10% of people) adverse effects includeneutropenia(sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevatedgamma-glutamyltransferase.[9]
Interactions
[edit]Stiripentol inhibits severalcytochrome P450isoenzymesand so interacts with many anticonvulsants and other medicines.[9]
Pharmacology
[edit]As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.
Stiripentol increasesGABAergicactivity. At clinically relevant concentrations, it enhances central GABA neurotransmission through abarbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices.[12]It has also been shown to increaseGABAlevels in brain tissues by interfering with its reuptake andmetabolism.[13]Specifically, it has been shown to inhibitlactate 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 ofATP-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 increasingblood plasmalevels.[9]
Chemistry
[edit]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
[edit]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, theEuropean Medicines Agency(EMA) granted stiripentolorphan drugstatus (designation number EU/3/01/071) for the treatment ofsevere 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 USFood and Drug Administration(FDA) as an adjunctive therapy for Dravet Syndrome.[18]
Society and culture
[edit]Economics
[edit]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
[edit]- ^ab"Diacomit".Therapeutic Goods Administration (TGA).13 December 2019.Retrieved17 September2021.
- ^ab"AusPAR: Stiripentol".Therapeutic Goods Administration (TGA).19 December 2019.Retrieved17 September2021.
- ^"Diacomit 250mg hard capsules - Summary of Product Characteristics (SmPC)".(emc).31 May 2019.Retrieved8 November2020.
- ^abc"Diacomit- stiripentol capsule Diacomit- stiripentol powder, for suspension".DailyMed.15 May 2020.Retrieved8 November2020.
- ^abcdef"Diacomit EPAR".European Medicines Agency.17 September 2018.Retrieved8 November2020.Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^"Stiripentol Monograph for Professionals".Drugs.com.31 August 2020.Retrieved8 November2020.
- ^Brigo F, Igwe SC, Bragazzi NL (May 2017)."Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy".The Cochrane Database of Systematic Reviews.5(5): CD010483.doi:10.1002/14651858.CD010483.pub4.PMC6481545.PMID28521067.
- ^abNickels KC, Wirrell EC (May 2017). "Stiripentol in the Management of Epilepsy".CNS Drugs.31(5): 405–416.doi:10.1007/s40263-017-0432-1.PMID28434133.S2CID25051912.
- ^abcdefDiacomit (stiripentol) SPC(PDF)(Report).
- ^Brigo F, Igwe SC, Bragazzi NL (September 2022)."Stiripentol add-on therapy for drug-resistant focal epilepsy".The Cochrane Database of Systematic Reviews.2022(9): CD009887.doi:10.1002/14651858.CD009887.pub6.PMC9447417.PMID36066395.
- ^abNabbout R, Camfield CS, Andrade DM, Arzimanoglou A, Chiron C, Cramer JA, et al. (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.PMID28188045.S2CID205759047.
- ^Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H (April 2006)."Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels".Epilepsia.47(4): 704–716.doi:10.1111/j.1528-1167.2006.00497.x.PMID16650136.S2CID14199574.[dead link]
- ^Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005)."Stiripentol. A novel antiepileptic drug"(PDF).Pharmacological Reports.57(2): 154–160.PMID15886413.
- ^Sada N, Lee S, Katsu T, Otsuki T, Inoue T (March 2015). "Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy".Science.347(6228): 1362–1367.Bibcode:2015Sci...347.1362S.doi:10.1126/science.aaa1299.PMID25792327.S2CID22024222.
- ^ab"Scientific evaluation"(PDF).EMA. 2007.
- ^Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome)(PDF)(Report). Canadian Agency for Drugs and Technologies in Health. April 2015.
- ^"Diacomit Product information".Health Canada.Retrieved8 November2020.
- ^"Drug Approval Package: Diacomit (stiripentol)".U.S.Food and Drug Administration(FDA).7 September 2018.Retrieved8 November2020.
- ^Kossoff E (January 2014)."Stiripentol for dravet syndrome: is it worth it?".Epilepsy Currents.14(1): 22–23.doi:10.5698/1535-7597-14.1.22.PMC3913306.PMID24526870.
