Stiripentol
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Stiripentol is an antiepileptic agent used in combination with other anticonvulsants to treat seizures associated with Dravet syndrome.
Stiripentol is an antiepileptic agent used in combination with other anticonvulsants to treat seizures associated with Dravet syndrome.
The mechanism by which stiripentol exerts its anticonvulsant effect in humans has not been fully elucidated. Possible mechanisms of action include direct effects mediated through the gamma-aminobutyric acid GABA receptor and indirect effects involving inhibition of cytochrome P450 activity with a resulting increase in blood levels of clobazam and its active metabolite. Stiripentol is a positive allosteric modulator of GABA receptors in the brain that enhances the opening duration of the channel by binding to a site different than the benzodiazepine binding site. It binds to GABA receptors containing any of the α, β, γ, or δ-subunits but displays the most potent potency when bound to receptors containing α3 or δ subunits. Stiripentol also binds to GABA receptor-dependent chloride channels via a barbiturate-like mechanism. Stiripentol potentiates GABA transmission by enhancing the release of GABA, reducing synaptosomal uptake of GABA, and inhibiting GABA transaminase-mediated breakdown of GABA. Stiripentol is an inhibitor of lactate dehydrogenase (LDH), which is involved in the energy metabolism of neurons and regulation of neuronal excitation. The drug binds to the site separate from the enzyme's lactate and pyruvate binding sites, thereby inhibiting both pyruvate-to-lactate conversion and lactate-to-pyruvate conversion. By inhibiting LDH, stiripentol may induce hyperpolarization, thereby reducing neuronal excitability. LDH inhibitors, including stiripentol, mimic a ketogenic diet, where the energy source in the brain is switched from glucose to mainly ketone bodies. The ketone bodies directly regulate neuronal excitation and seizures via ATP-sensitive potassium channels and vesicular glutamate transporters. Stiripentol is also suggested to exhibit neuroprotective properties, which may reduce injury caused by oxygen-glucose deprivation and glutamate excess.
In the US, stiripentol is indicated for the treatment of seizures associated with Dravet syndrome in patients taking clobazam who are 6 months of age and older and weighing 7 kg or more. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome. In Europe and Canada, stiripentol is indicated for use as adjunctive therapy with clobazam and valproate to refractory generalized tonic-clonic seizures in patients with Dravet syndrome in infancy whose seizures are not adequately controlled with clobazam and valproate alone.
每项发明一条，涵盖美国、欧洲、PCT 与中国的同族专利。
