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.

Arsenicals have been widely used in the treatment of cancers such as leukemia and other tumors. However, their side effects limit their clinical application. Stiripentol, a second-line adjunctive treatment for epilepsy with a good safety profile, inhibits microsomal cytochrome-P450-family enzymes to extend the retention time of co-administration. Inspired by the metabolism of stiripentol, the 1,3-benzodioxole responsible for the inhibition and its metabolic derivatives were conjugated with arsenical precursors. The fabricated arsenicals were eliminated much slower in mice and maintained an efficient concentration in the blood for a longer time than that of the arsenical precursors. They also performed better in anti-proliferation by inhibiting the thioredoxin system to induce oxidative stress, and concomitantly to initiate apoptosis in vitro and in vivo. The fabricated arsenicals reversed the hemogram of tumor-bearing mice to normal and eliminated the tumor without causing damage to any organs, exhibiting a good design strategy and pre-clinical application for leukemia and other tumors.

Due to poor solubility and stability in acid conditions, the gastrointestinal administration of stiripentol (STP) is still a significant challenge. This study aimed to explore the applicability of effervescent tablets compressed from STP-loaded enteric solid dispersions to improve the solubility and stability of the insoluble and acid-labile drug. STP-loaded solid dispersions (STP-SDs) and the effervescent tablets (STP-SD-ETs) were prepared using solvent evaporation and dry granulation technology, respectively, and their formulations were optimized. Then, STP-SDs were characterized regarding solid state, in vitro release, stability, etc. Results showed that enteric amorphous STP-SDs were successfully prepared and significantly improved the solubility and stability of STP. Moreover, compared with STP suspensions, the bioavailability of STP-SD-ETs was as high as 138.71%. Concomitantly, STP-SD-ETs significantly increased the intestinal absorption rate of STP. Overall, the oral preparation encompassing enteric solid dispersion combined with effervescent tablet technology possesses excellent performance in enhancing dissolution, anti-acid hydrolysis stability, and absorption of STP. Our work provides a promising method to improve the delivery of drugs with poor solubility and acid-labile stability.

This study aimed to develop a self-nanoemulsifying drug delivery system (SNEDDS) for poorly water-soluble drug stiripentol (STP) with enhanced oral bioavailability. Optimal excipients were selected by constructing pseudo-ternary phase diagrams using determined solubilities of STP, and then the proper composition of SNEDDS was investigated by employing a central composite design method. The optimized SNEDDS was composed of oil (ethyl oleate 39.61%), surfactant (Cremophor® RH 40 43.18%), co-surfactant (1,2-propanediol 17.21%), and STP of 50 mg/mL. The hydrodynamic size, zeta potential, and polydispersity index (PDI) were found to be 45.52 ± 1.99 nm, - 21.67 ± 0.24 mV, and 0.076 ± 0.011, respectively. The optimized STP-SNEDDS showed good stability in accelerated and dilution stability studies. It was also helpful to suppress STP degradation in acidic solution. Compared with STP suspension, STP-SNEDDS presented much faster dissolution rate. STP-SNEDDS successfully resulted in superior levels of Cmax and AUC0 → 6 h (4048.38 ± 704.54 μg/L and 7754.58 ± 1489.37 h μg/L, respectively) to STP suspension (1894.09 ± 1077.64 μg/L and 3556.93 ± 2470.01 h μg/L, respectively). The relative oral bioavailability of STP was 218.01%. The brain biodistribution studies showed that STP-SNEDDS presented significantly higher STP concentrations in the brain at 0.5 h and 1 h than that of STP suspension after administration. These findings indicated that a SNEDDS-based oral formulation of STP would be helpful for increasing its therapeutic potential.

Epilepsy is a serious and common neurological disorder threatening the health of humans. Despite enormous progress in epileptic research, the anti-epileptic drugs present many limitations. These limitations prompted the development of more safer and effective AEDs.
A series of N-substituted (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)- 2-thioxothiazolidin-4- one derivatives and 5-substituted-thioxothiazolidindione derivatives were designed, synthesized and tested for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ). Neurotoxicity was determined by the rotarod test.
Among them, the most potent 4e displayed high protection against MES-induced seizures with an ED50 value of 9.7 mg/kg and TD50 value of 263.3 mg/kg, which provided 4e with a high protective index (TD50/ED50) of 27.1 comparable to reference antiepileptic drugs. 4e clearly inhibits the NaV1.1 channel in vitro. The molecular docking study was conducted to exploit the results.
Stiripentol is a good lead compound for further structural modification. Compound 4e was synthesized, which displayed remarkable anticonvulsant activities, and the NaV1.1 channel inhibition was involved in the mechanism of action of 4e.

Oral administration remains a significant challenge in regards to drugs with serious solubility and stability issues. This article aimed to investigate the suitability of nanoemulsions as oral carriers of stiripentol (STP), an acid-labile drug, for enhancement of stability and bioavailability. STP-loaded nanoemulsions (STP-NEs) were prepared by using a solvent-diffusion/ultrasonication technique. STP-NEs were characterized in a variety of ways such as by particle size, entrapment efficiency, in vitro drug release, and transmission electron microscopy. A bioavailability study was performed in rats after oral administration of either STP-NEs, or commercial formulation (Diacomit). The resultant nanoemulsions were 146.6 nm in particle size with an entrapment efficiency of 99.47%. It was demonstrated that nanoemulsions significantly improved the biochemical stability and bioavailability of STP. The bioavailability of STP-NEs was up to 206.2% relative to Diacomit. Nanoemulsions fabricated from poly(ethylene glycol) monooleate/medium-chain triglycerides exhibited excellent performance in drug stabilization and absorption enhancement. The results suggest that STP-NEs are a promising means to solve the problems associated with stability and solubility of STP.

Oral delivery of many drugs is plagued with limited solubility and/or poor stability. This paper aimed to explore the performance of polymeric mixed micelles on solubilization, stabilization and bioavailability enhancement with stiripentol as model drug. Stiripentol-loaded mixed micelles were prepared by solvent-diffusion method: rapid dispersion of an ethanol solution containing stiripentol, monomethoxy poly(ethylene glycol)-b-poly(ε-caprolactone) and sodium oleate into water. Stiripentol micelles were characterized by the particle size, entrapment efficiency, in vitro drug release, TEM, DSC and FTIR. The pharmacokinetic profile of stiripentol was determined in rats after oral administration of stiripentol micelles. The obtained stiripentol micelles were 44.2 nm in size with an entrapment efficiency over 90%. It was shown that micelles substantially improved the solubility and gastric stability of stiripentol. The oral absorption of stiripentol was also enhanced to a great extent with a relative bioavailability of 157% and 444% to the commercial formulation (Diacomit®) and in-house suspensions. Mixed micelles assembled by di-block copolymer/sodium oleate exhibited a good potential in the improvement of drug stability and bioavailability. It should be a promising carrier for oral delivery of therapeuticals with solubility and stability issues.