Stiripentol

Abstract

Summary: Stiripentol (STP) is a new antiepileptic compound made by Biocodex. It recently proved to increase the GABAergic transmission in vitro in an experimental model of immature rat. Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2, and CYP2C19 in vivo in epileptic patients. Whereas the studies in adult patients were disappointing, the trials conducted in pediatric populations demonstrated a specific efficacy of STP in severe myoclonic epilepsy in infancy, Dravet syndrome, when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in pediatric patients with pharmacoresistant partial epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account, with doses of the combined antiepileptic drugs adjusted to improve the tolerability of the therapeutic association.

SB-205384 Is a Positive Allosteric Modulator of Recombinant GABAA Receptors Containing Rat α3, α5, or α6 Subunit Subtypes Coexpressed with β3 and γ2 Subunits

“…Several studies have suggested that receptors containing these subunits mediate at least part of the anxiolytic, analgesic, myorelaxant, and anesthetic effects of GABA-modulating drugs (Rudolph and Mohler, 2004;Dias et al, 2005;Knabl et al, 2008;Straub et al, 2013), and deficits in signaling through a3-containing receptors have been linked to disruption of sensorimotor gating (Yee et al, 2005). The anticonvulsant drug stiripentol preferentially enhances activity of a3-containing receptors (Fisher, 2009) and has been found to be effective in treatment of some childhood seizure disorders (Chiron, 2007). Modulation of a3-containing receptors by SB-205384 suggests that it may have anxiolytic effects and could have an age-dependent modulatory effect in reducing neuronal excitability.…”

A Case of Dravet Syndrome Who Developed Acute Reversible Encephalopathy That May Have Been Caused by Hyperamonnemia Due to Pharmacokinetic Interaction Between Valproate and Stiripentol

“…[8] GABA'nın salınımını arttırır, GABA-A reseptörlerindeki alfa-3 ve beta subünitleri üzerine direkt allosterik modülasyon ile GABA-A reseptörlerinin aktivasyon süresini arttırır. [9,10] STP oral olarak alındıktan sonra 1.5 saatte plazma pik konsantrasyonuna ulaşır. [11] Suda iyi çözünür, karaciğerde ilk geçiş etkisine maruz kalır, biyoyararlanımı rölatif olarak düşüktür.…”

Stiripentol (Diacomit®) – eine neue Therapieoption zur Behandlung des Dravet-Syndroms (SMEI)

“…Lebensmonat) mit rezidivierenden, fieberassoziierten generalisierten oder halbseitig betonten Krampfanfällen. Im weiteren Verlauf der Erkrankung kommen weitere Anfallstypen wie myoklonische, partielle und Absence-ähnliche Anfälle in wechselnd starker Ausprägung hinzu [1,2,4,[7][8][9]. Mit Beginn der Epilepsie erfahren die bis zu diesem Zeitpunkt in der Regel normal entwickelten Kinder einen Entwicklungsstillstand, nicht selten kommt es sogar zu einem Entwicklungsrückstand.…”

“…Insgesamt konnten bislang 13 Metabolite identifiziert werden [15]. 13 [4,12]. Um diese initialen Studienergebnisse zu untermauern bzw.…”

“…Zeigte ein Patient im Vergleich zur Baseline eine Zunahme der Anfallshäufigkeit um mehr als 50%, so wurde er aus ethischen Gründen aus der laufenden Untersuchung herausgenommen. Die Datenauswertung nach Studienende ergab zwar eine Verringerung der Anfallsfrequenz in der Stiripentolgruppe um etwa 75% gegenüber 22% in der Plazebogruppe, eine statistische Relevanz konnte jedoch aufgrund der zu niedrigen Fallzahl gegen Ende der Studie nicht erreicht werden [3,4]. Weitere kontrollierte Studien bei fokalen Epilepsien liegen nicht vor.…”