Stiripentol (Diacomit®) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet syndrome (DS), a severe form of childhood epilepsy, in conjunction with clobazam and, in some regions valproic acid. Since the discovery of STP, several mechanisms of action (MoA) have been described that may explain its specific effect on seizures associated with DS. STP is mainly considered as a potentiator of gamma-aminobutyric acid (GABA) neurotransmission: (i) via uptake blockade, (ii) inhibition of degradation, but also (iii) as a positive allosteric modulator of GABAA receptors, especially those containing α3 and δ subunits. Blockade of voltage-gated sodium and T-type calcium channels, which is classically associated with anticonvulsant and neuroprotective properties, has also been demonstrated for STP. Finally, several studies indicate that STP could regulate glucose energy metabolism and inhibit lactate dehydrogenase. STP is also an inhibitor of several cytochrome P450 enzymes involved in the metabolism of other ASMs, contributing to boost their anticonvulsant efficacy as add-on therapy. These different MoAs involved in treatment of DS and recent data suggest a potential for STP to treat other neurological or non-neurological diseases.

BACKGROUND: Numerous anti-seizure medications (ASMs) have been developed to treat Dravet syndrome (DS). This network meta-analysis aimed to comprehensively analyse the efficacy of ASMs in DS patients, especially in non-seizure-free patients after treatment.
METHODS: PubMed, EMBASE, Cochrane Library, and Chinese National Knowledge Infrastructure databases were searched. The treatment efficacy was assessed by the percentage reduction in monthly convulsive seizure frequency (MCSF) from baseline or individuals who achieved at least a 50 % or 75 % reduction from baseline in convulsive seizure frequency (CSF).
RESULTS: Six randomised controlled trials with 633 participants and seven regimens based on four add-on ASMs-fenfluramine (FFA), stiripentol (STP), cannabidiol (CBD), and soticlestat-were included. All drug regimens were superior to the placebo at achieving at least 50 % and 75 % reductions in CSF, but only STP, 0.4 mg/kg/d FFA (FFA0.4), and 0.7 mg/kg/d FFA (FFA0.7) reduced MCSF. STP (50 mg/kg/d) had the highest correlation with reducing MCSF and achieving at least a 50 % reduction from baseline in CSF, followed by FFA0.4 and FFA0.7. Soticlestat and CBD may also be effective in reducing seizures in DS patients.
CONCLUSIONS: STP can be recommended as the first choice among the included drug regimens for reducing seizures in DS patients, while FFA0.4 may be considered the second choice. Other drug regimens can be used as alternative treatments. STP, FFA0.4, and FFA0.7 may consistently present favourable efficacy in most DS patients, while other regimens may present prominent inter-individual variability. Appropriate dose selection and intense monitoring are necessary when treating DS using these drugs.

Purpose: Recently, the U.S. Food and Drug Administration (FDA) approved stiripentol, cannabidiol, and fenfluramine to treat patients with Dravet syndrome (DS). Moreover, soticlestat was determined as a promising new drug for the treatment of DS as it has good efficacy and safety. However, the efficacy and safety of these drugs have not yet been evaluated in \"head-to-head\" trials. This study aimed to compare and evaluate the efficacy and safety of these adjunctive antiseizure medications in the treatment of DS. Methods: We searched in PubMed, Embase, Cochrane Library, and Web of Science databases for randomized controlled trials (RCTs) and open-label extension (OLE) studies in patients with DS. We performed a random-effect meta-analysis of OLE studies and a network meta-analysis for RCTs to evaluate the efficacy and safety of antiseizure medications in the treatment of DS. Primary efficacy outcomes were defined as a ≥50% reduction in seizure frequency compared with baseline. Furthermore, safety evaluation indicators were defined as the incidence of adverse events (AEs) and serious adverse events (SAEs) during treatment. Relative ranking was assessed using the surface under the cumulative ranking curve (SUCRA) probabilities. Results: Seven RCTs involving four antiseizure medications (stiripentol, cannabidiol, fenfluramine, and soticlestat) and a total of 634 patients were included in the analysis. According to the SUCRA results, all four drugs significantly reduced the frequency of seizures compared with the placebo. Soticlestat was the most likely to reduce seizure frequency by ≥50% compared to the baseline [risk ratio (RR): 19.32; 95% confidence interval (CI): 1.20-311.40], followed by stiripentol and fenfluramine. Stiripentol was ranked highest for the near percentage reduction in the seizure rate from baseline [RR: 12.33; 95% CI: 1.71-89.17] and the occurrence of any treatment-emergent adverse events [RR: 3.73; 95% CI: 1.65-8.43] and serious adverse events [RR: 4.76; 95% CI: 0.61-37.28]. A total of ten OLE studies containing 1,121 patients were included in our study. According to the results of the meta-analysis, the order of probability of reducing seizure frequency by ≥50% was fenfluramine (0.715, 95% CI: 0.621-0.808), stiripentol (0.604, 95% CI: 0.502-0.706), cannabidiol (0.448, 95% CI: 0.403-0.493). And the probability of occurrence of AEs is ranked as fenfluramine(0.832, 95% CI: 0.795-0.869), cannabidiol (0.825, 95% CI:0.701-0.950), stiripentol (0.823, 95% CI: 0.707-0.938), soticlestat (0.688, 95% CI: 0.413-0.890). Conclusion: According to the results of indirect comparison of efficacy and safety, cannabidiol is slightly inferior to the other three antiseizure medications in terms of efficacy and safety. Soticlestat, fenfluramine, and stripentol may have little difference in efficacy, but soticlestat and fenfluramine are safer. Soticlestat is probably the best adjunctive antiseizure medication, followed by fenfluramine. This conclusion is consistent with the comparison of long-term efficacy and safety.

The new antiepileptic drugs perampanel, retigabine, rufinamide and stiripentol have been recently approved for different epilepsy types. Being them an innovation in the antiepileptics armamentarium, a lot of investigations regarding their pharmacological properties are yet to be performed. Besides, considering their broad anticonvulsant activities, an extension of their therapeutic indications may be worthy of investigation, especially regarding other seizure types as well as other central nervous system disorders. Although different liquid chromatographic (LC) methods coupled with ultraviolet, fluorescence, mass or tandem-mass spectrometry detection have already been developed for the determination of perampanel, retigabine, rufinamide and stiripentol, new and more cost-effective methods are yet required. Therefore, this review summarizes the main analytical aspects regarding the liquid chromatographic methods developed for the analysis of perampanel, retigabine (and its main active metabolite), rufinamide and stiripentol in biological samples and pharmaceutical dosage forms. Furthermore, the physicochemical and stability properties of the target compounds will also be addressed. Thus, this review gathers, for the first time, important background information on LC methods that have been developed and applied for the determination of perampanel, retigabine, rufinamide and stiripentol, which should be considered as a starting point if new (bio)analytical techniques are aimed to be implemented for these drugs.

Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments.
This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies.
Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.