Stiripentol

Stiripentol
Clinical data
Trade names Diacomit
AHFS/Drugs.com International Drug Names
Routes of
administration		 Oral
ATC code N03AX17 (WHO)
Legal status
Legal status
  • AU: Unscheduled
Identifiers
CAS Number 49763-96-4 N
PubChem (CID) 5311454
IUPHAR/BPS 5469
ChemSpider 4470940 YesY
UNII R02XOT8V8I YesY
KEGG D05928 YesY
ECHA InfoCard 100.051.329
Chemical and physical data
Formula C14H18O3
Molar mass 234.30 g·mol−1
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

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.

Mechanism of action

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.[1] It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism.[2] 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.[3]

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.

History

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). On 4 January 2007, the EMA granted the drug a marketing authorisation that is valid throughout the European Union.

Indications and usage

It is indicated as an adjunctive therapy with sodium valproate and clobazam for treating Dravet syndrome[4] whose seizures are not adequately controlled with clobazam and valproate. Children with SMEI develop often intractable seizures during their first year of life and developmental delay follows. Small-scale trials have shown remarkably high response rates, with a significant minority of those treated becoming seizure free.

In addition, it may be used to treat refractory childhood epilepsy in conjunction with carbamazepine. It appears to be less effective in adolescents and adults.

Dosing

Stiripentol is available as a gelatine capsule (250 mg, 500 mg) and as a sachet of powder to make a drinkable suspension (250 mg, 500 mg).

Initial dose is 50 mg/kg per day. This may be increased up to 100 mg/kg per day, with a maximum of 4 g/day. The dose is to be divided into two or three and to be taken with meals. The dose of other anticonvulsants may have to be reduced (possibly down to 50%).

Side effects

Side effects are largely due to the increase in plasma concentrations of other anticonvulsants and can be reduced by lowering the dose of those drugs. Nausea and vomiting are particularly noted when used in combination with sodium valproate.

Drug interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines. This is both a strength and weakness. It appears to increase the potency of phenobarbital, primidone, phenytoin, carbamazepine, clobazam and diazepam. For example, blood levels of carbamazepine can be maintained while reducing the dose by 50%.

References

  1. ↑ 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 : PR. 47 (4): 704–16. doi:10.1111/j.1528-1167.2006.00497.x. PMID 16650136.
  2. ↑ Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). "Stiripentol. A novel antiepileptic drug" (PDF). Pharmacological reports : PR. 57 (2): 154–60. PMID 15886413.
  3. ↑ 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.
  4. ↑ Thanh TN, Chiron C, Dellatolas G, et al. (November 2002). "[Long-term efficacy and tolerance of stiripentaol in severe myoclonic epilepsy of infancy (Dravet's syndrome)]". Archives de Pédiatrie (in French). 9 (11): 1120–7. PMID 12503502.

Further reading

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