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]
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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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| ECHA InfoCard | 100.051.329 |
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| Formula | C14H18O3 |
| Molar mass | 234.295 g·mol−1 |
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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
editIn 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
editStiripentol 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
editVery 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
editStiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.[9]
Pharmacology
editAs 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
editStiripentol 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
editStiripentol 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
editEconomics
editPrior 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- ^ a b "Diacomit". Therapeutic Goods Administration (TGA). 13 December 2019. Retrieved 17 September 2021.
- ^ a b "AusPAR: Stiripentol". Therapeutic Goods Administration (TGA). 19 December 2019. Retrieved 17 September 2021.
- ^ "Diacomit 250mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 31 May 2019. Retrieved 8 November 2020.
- ^ a b c "Diacomit- stiripentol capsule Diacomit- stiripentol powder, for suspension". DailyMed. 15 May 2020. Retrieved 8 November 2020.
- ^ a b c d e f "Diacomit EPAR". European Medicines Agency. 17 September 2018. Retrieved 8 November 2020. 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. Retrieved 8 November 2020.
- ^ 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. PMC 6481545. PMID 28521067.
- ^ a b 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.
- ^ a b c d e f Diacomit (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. PMC 9447417. PMID 36066395.
- ^ a b Nabbout 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. PMID 28188045. S2CID 205759047.
- ^ 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. PMID 16650136. S2CID 14199574.[dead link]
- ^ Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). "Stiripentol. A novel antiepileptic drug" (PDF). Pharmacological Reports. 57 (2): 154–160. PMID 15886413.
- ^ 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. PMID 25792327. S2CID 22024222.
- ^ a b "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. Retrieved 8 November 2020.
- ^ "Drug Approval Package: Diacomit (stiripentol)". U.S. Food and Drug Administration (FDA). 7 September 2018. Retrieved 8 November 2020.
- ^ 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. PMC 3913306. PMID 24526870.
