STIRIPENTOL Stiripentol is an aromatic allylic alcohol that has activity in the treatment of Dravet’s syndrome. Clinical studies indicate that it reduces the frequency of prolonged seizures in children with this condition. Stiripentol is often used in conjunction with HHOONH2NH2 clobazam or valproate; whether it has activity by itself has not been studied in clinical trials. The drug has various actions on GABA-mediated neurotransmission including acting as a positive allosteric modulator of GABAA receptors. It is a potent inhibitor of CYP3A4, CYP1A2, and CYP2C19 and dramatically increases the levels of clobazam and its active metabolite norclobazam; it also inhibits valproate metabolism. These drug-drug interactions have been proposed as the basis for the clinical effectiveness of stiripentol, and elevations in concomitant drugs likely contribute to some extent to efficacy. However, stiripentol has activity in various animal seizure models, indicating that it has antiseizure activity in its own right. Dosing is complex, typically beginning with a reduction in concomitant medications. Stiripentol is then started at 10 mg/kg/d and is increased gradually as tolerated. The most frequent adverse effects are sedation/drowsiness, reduced appetite, slowing of mental function, ataxia, diplopia, nausea, and abdominal pain. Stiripentol exhibits nonlinear pharmacokinetics, decreasing in clearance as the dose increases.
Infantile spasms are treated with adrenocorticotropic hormone (ACTH) by intramuscular injection or oral corticosteroids such as prednisone or hydrocortisone. Vigabatrin is also often used and is particularly effective in cases associated with tuberous sclerosis. Other antiseizure medications that may be helpful are valproate, topiramate, zonisamide, or a benzodiazepine such as clonazepam or nitrazepam. ACTH and corticosteroids are associated with substantial morbidity, and vigabatrin, as discussed below, has a risk of permanent loss of vision. The goal of treatment is cessation of seizures, and this generally requires ACTH, corticosteroids, or vigabatrin and is not generally achieved with the safer antiseizure agents. The mechanism of action of ACTH and corticosteroids in the treatment of infantile spasms is unknown.
Vigabatrin is an analog of GABA, designed as an inhibitor of GABA transaminase (GABA-T), the enzyme responsible for the metabolism of synaptically released GABA. Vigabatrin is effective in the treatment of focal seizures (but not generalized seizures) and in the treatment of infantile spasms. Because it may cause irreversible visual loss, it is usually reserved for patients with seizures refractory to other treatments.
Mechanism of Action
Vigabatrin is a specific, irreversible inhibitor of GABA-T, producing a sustained increase in the extracellular concentrations of GABA in the brain. This paradoxically leads to inhibition of synaptic GABAA receptor responses, but also prolongs the activation of extrasynaptic GABAA receptors that mediate tonic inhibition. Vigabatrin is effective in a wide range of animal seizure models. Vigabatrin is marketed as a racemate; the S(+) enantiomer is active and the R(−) enantiomer appears to be inactive.