Stiripentol

Structural formula
( R ) -Stiripentol (top) and ( S ) -Stiripentol (bottom), 1: 1 stereoisomeric mixture
General
Non-proprietary name	Stiripentol
other names	( RS ) - ( E ) -1- (1,3-Benzodioxol-5-yl) -4,4-dimethylpent-1-en-3-ol ( IUPAC )
Molecular formula	C 14 H 18 O 3
External identifiers / databases
CAS number 49763-96-4 EC number 256-480-9 ECHA InfoCard 100.051.329 PubChem 5311454 ChemSpider 4470940 DrugBank DB09118 Wikidata Q412182
Drug information
ATC code	N03 AX17
Drug class	Anticonvulsant
properties
Molar mass	234.29 g mol −1
Physical state	firmly
Melting point	74 ° C
solubility	Easily soluble in acetone and ethanol , moderately soluble in chloroform , almost insoluble in water
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302 P: ?
Toxicological data	72 mg kg −1 ( LD 50 ,  mouse ,  iv ) > 5 g kg −1 ( LD 50 ,  mouse ,  oral ) > 3 g kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Stiripentol ( Europe-wide trade name Diacomit ^® ; manufacturer: Biocodex ; distribution in Germany: Desitin ) is a drug that is used in the treatment of severe myoclonic epilepsy in childhood (SMEI, Dravet syndrome).

Clinical information

application areas

Stiripentol has only a very limited approval . It can be used in conjunction with clobazam and valproic acid as add-on therapy for difficult-to-treat generalized tonic-clonic seizures in children with severe myoclonic epilepsy (Dravet's syndrome) whose seizures can not be adequately treated with clobazam and valproate .

Alternations and side effects

Stiripentol inhibits several enzymes in the liver metabolism , in particular CYP450 3A4 and 2C19, which are also involved in the breakdown of other anti-epileptic drugs.

The following undesirable effects are very common: loss of appetite, ataxia , drowsiness, dystonia , weight loss (especially in combination with valproic acid ), muscle weakness or difficulty sleeping.

Negative behavior, aggressiveness, nausea, vomiting, elevated liver values (especially in combination with carbamazepine and valproic acid), states of excitement, hyperkinesis , irritability, reversible neutropenia , behavioral disorders or nausea occur.

Pharmacological properties

Mechanism of action

Stiripentol acts as a positive allosteric modulator at the GABA _A receptor . At this receptor, which is composed of subunits, stiripentol binds more intensely to the subunits α3 and δ. In contrast to the benzodiazepines , this bond does not require a γ subunit. The physiological occurrence of GABA _A receptors with α3 subunits is development-dependent and is highest in the young, immature brain of mammals. The dextrorotatory active ingredient (see info box, formula I) shows a more pronounced anticonvulsant effectiveness than the levorotatory stereoisomer.

Stiripentol is also attributed to increasing the concentration of γ-aminobutyric acid (GABA) - the most important inhibitory messenger substance in the nervous system . The reasons for this could be an inhibition of the reuptake of GABA in the synapses or an inhibition of the breakdown of GABA. Another mode of action could be an enhancement of the effect of GABA by means of a barbiturate- like mechanism.

In addition, stiripentol increases the plasma concentration of other anticonvulsants such as carbamazepine , valproic acid, phenytoin , phenobarbital and many benzodiazepines by inhibiting the enzymes involved in breaking down these anticonvulsants.

In animal models , stiripentol inhibits seizures caused by electric shocks or chemicals .

Absorption and distribution in the body

Stiripentol shows an atypical, non-linear pharmacokinetic behavior. The plasma half-life is 4.5 to 13 hours, with the dextrorotatory eutomer being eliminated more quickly. The enantiomers influence each other in their kinetics. The plasma protein binding is approx. 99%.

Five metabolic pathways have been identified: (i) conjugation of the alcohol with glucuronic acid , (ii) cleavage of the methylenedioxy ring, (iii) O -methylation of the catechol metabolite, (iv) hydroxylation of the t - butyl group , (v) conversion of the allyl alcoholic Side chain into an isomeric 3-pentanone structure. By 2005, thirteen metabolites were known.

Development and marketing

Stiripentol was first described in the literature in 1979. The development was carried out under the conditions of the European regulations for medicinal products for orphan diseases (status granted on December 4, 2001 under number EU / 3/01/071). On January 4, 2007, Stiripentol received the o. EU approval.

Individual evidence

1. ^ ^{A b} The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th edition. (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006, ISBN 0-911910-00-X .
2. ↑ There is not yet a harmonized classification for this substance . A labeling of stiripentol in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), retrieved on July 12, 2020, is reproduced from a self-classification by the distributor .
3. ↑ ^{a b c} M. Poisson, F. Huguet, A. Savattier et al: A new type of anticonvulsant, stiripentol. Pharmacological profile and neurochemical study . In: drug research. 34, 1984, pp. 199-204. PMID 6326778 .
4. ↑ ^{a b c d} Desitin: Specialist information Diacomit. (As of 10/2007).
5. ↑ drug telegram. Drug database. Stiripentol. ( Memento of the original from December 5, 2008 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Accessed December 16, 2008. 
6. ↑ JL Fisher: The anti-convulsant stiripentol acts directly on the GABA (A) receptor as a positive allosteric modulator . In: Neuropharmacology . tape 56 , no. 1 , 2009, p. 190–197 , doi : 10.1016 / j.neuropharm.2008.06.004 , PMID 18585399 , PMC 2665930 (free full text).
7. ↑ JL Fisher: The effects of stiripentol on GABA (A) receptors . In: Epilepsia . 52 Suppl 2, 2011, p. 76-78 , doi : 10.1111 / j.1528-1167.2011.03008.x , PMID 21463286 .
8. ↑ MK Trojnar, K. Wojtal, MP Trojnar, SJ Czuczwar: stiripentol. A novel antiepileptic drug . In: Pharmacol Rep . tape 57 , no. 2 , 2005, p. 154-160 , PMID 15886413 .
9. ^ R. Wegmann, A. Ilies, M. Aurousseau, F. Patte: Pharmaco-cellular enzymology of the mode of action of stiripentol during cardiazolic epilepsia. In: Cell Mol Biol Incl Cyto Enzymol. 24, 1979, pp. 51-60. PMID 476759 .

Web links

• Regulation (EG 141/2000) on orphan medicinal products (PDF file; 119 kB)
• EU Community Register of Orphan Medicinal Products ( Community Register of orphan medicinal products for human use )

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !