Stiripentol
Encyclopedia
Stiripentol is an anticonvulsant
drug used in the treatment of epilepsy
. It is unrelated to other anticonvulsants and belongs to the group of aromatic allyl
ic alcohols.
It increases GABA
transmission. At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate
-like effect, since it increases the duration of opening of GABA-A receptors channels in hippocampal slices. It has also been shown that STP may increase the GABA
levels in brain tissues and by interfering with its uptake and its metabolism
.
It also improves the effectiveness of many other anticonvulsants, possibly due to it inhibiting certain enzymes. This slows the drug's metabolism, increasing blood plasma
levels.
(EMA) granted stiripentol orphan drug
status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy in 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.
and clobazam
for treating severe myoclonic epilepsy in infancy (SMEI) whose seizures are not adequately controlled with clobazam and valproate. Children with SMEI develop often intractable seizures during their first year of life and mental retardation
follows. Small-scale trials have show 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.
Initial dose is 50 mg/kg per day. This may be increased up to 100 mg/kg per day, with a maximum of 4g. The dose to be divided into two or three with meals. The does of other anticonvulsants may have to be reduced (possibly up to 50%).
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%.
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
drug used in the treatment of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. It is unrelated to other anticonvulsants and belongs to the group of aromatic allyl
Allyl
An allyl group is a substituent with the structural formula H2C=CH-CH2R, where R is the connection to the rest of the molecule. It is made up of a methylene , attached to a vinyl group . The name is derived from the Latin word for garlic, Allium sativum. Theodor Wertheim isolated an allyl...
ic alcohols.
Mechanism of action
As with most anticonvulsants, the precise mechanism is unknown. It has been shown to have anticonvulsant effects on its own.It increases GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
transmission. At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
-like effect, since it increases the duration of opening of GABA-A receptors channels in hippocampal slices. It has also been shown that STP may increase the GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
levels in brain tissues and by interfering with its uptake and its metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
.
It also improves the effectiveness of many other anticonvulsants, possibly due to it inhibiting certain enzymes. This slows the drug's metabolism, increasing blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
levels.
History
In December 2001 the European Medicines AgencyEuropean Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMA) granted stiripentol orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy in 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 valproateSodium valproate
Sodium valproate or valproate sodium is the sodium salt of valproic acid and is an anticonvulsant used in the treatment of epilepsy, anorexia nervosa, panic attack, anxiety disorder, posttraumatic stress disorder, migraine and bipolar disorder, as well as other psychiatric conditions requiring...
and clobazam
Clobazam
Clobazam , is a drug which is a benzodiazepine derivative. It has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984...
for treating severe myoclonic epilepsy in infancy (SMEI) whose seizures are not adequately controlled with clobazam and valproate. Children with SMEI develop often intractable seizures during their first year of life and mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
follows. Small-scale trials have show 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 4g. The dose to be divided into two or three with meals. The does of other anticonvulsants may have to be reduced (possibly up 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 isoenzymesIsozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
and so interacts with many anticonvulsants and other medicines. This is both a strength and weakness. It appears to increase the potency of phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, primidone
Primidone
Primidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
, carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, clobazam
Clobazam
Clobazam , is a drug which is a benzodiazepine derivative. It has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984...
and diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
. For example, blood levels of carbamazepine can be maintained while reducing the dose by 50%.
Further reading
- Diacomit: Summary of Product Characteristics (Article in French).
- The Comparative Toxicogenomics Database: Stiripentol