stiripentol

替利戊醇
  • 文章类型: Journal Article
    Stiripentol(STP,Diacomit©)是一种用于Dravet综合征的抗癫痫药物,一种罕见的以抗药性癫痫发作为特征的发育性和癫痫性脑病,包括癫痫持续状态(SE)。SE是一种危及生命的事件,可能导致发病率和死亡率增加。这里,我们使用全身给药蛋氨酸亚砜胺(MSO)诱导的CBA小鼠模型评估了STP对SE和SE相关死亡率的影响,一种不可逆的谷氨酰胺合成酶抑制剂.MSO诱发抽搐,长时间癫痫发作(SE)和死亡,随着血氨水平的增加。单次急性腹腔内预处理200-300-400mg/kgSTP显著抑制癫痫发作次数,MSO处理的动物中SE的发生和死亡呈剂量依赖性。关于血氨水平,STP可显著降低MSO引起的高氨血症41%。总之,我们的结果显示STP在小鼠中具有降低和/或抑制SE的发生及其相关死亡率的保护作用.
    Stiripentol (STP, Diacomit©) is an antiseizure medication indicated for Dravet syndrome, a rare developmental and epileptic encephalopathy characterized by drug-resistant seizures, including status epilepticus (SE). SE is a life-threatening event that may lead to increased risk of morbidity and mortality. Here, we evaluated the effect of STP on SE and SE-associated mortality using a CBA mouse model induced by systemic administration of methionine sulfoximine (MSO), an irreversible inhibitor of glutamine synthetase. MSO induces convulsions, prolonged seizure (SE) and death, with an increase of blood ammonia level. A single acute intraperitoneal pretreatment with 200-300-400 mg/kg of STP significantly inhibited the number of seizures, SE occurrence and death in MSO-treated animals in a dose-dependent manner. Regarding blood ammonia level, STP significantly reduced by 41 % the hyperammonemia induced by MSO. In conclusion, our results show protective effects of STP to reduce and or suppress the occurrence of SE as well as its associated mortality in mice.
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  • 文章类型: Journal Article
    背景:本报告重点介绍了在华沙母子研究所的照顾下诊断为Dravet综合征(DRVT)的21例患者的治疗史。本文旨在提出耐药癫痫患者的典型治疗方案,以及强调基因诊断对药物治疗管理的影响,并提出住院费用的经济分析。本文还将总结用于DRVT的最新药物的有效性。
    方法:从现有的医疗记录中回顾性收集临床数据。抗惊厥治疗的有效性是根据癫痫发作日记和护理人员和儿科神经科医生的观察进行评估的。
    结果:研究组(n=21)由3-26岁的患者组成。由于基因诊断,所有患者都引入了专门治疗Dravet综合征的孤儿药物,这显著改善了患者的临床状况。突破性药物是替硝普醇(16/21)和芬氟拉明(3/21)。
    结论:近年来,分子遗传学在波兰迅速发展,随着医学界对Dravet综合征的了解稳步增加。早期和精确的诊断提供了用专用于Dravet综合征的药物进行高效靶向治疗的机会。
    BACKGROUND: This report focuses on the treatment histories of 21 patients diagnosed with Dravet syndrome (DRVT) under the care of the Mother and Child Institute in Warsaw. This paper aims to present typical treatment schemes for patients with drug-resistant epilepsy, as well as to highlight the influence of genetic diagnosis on pharmacotherapeutic management and to present an economic analysis of hospitalization costs. This paper will also summarize the effectiveness of the latest drugs used in DRVT.
    METHODS: Clinical data were collected retrospectively from available medical records. The effectiveness of anticonvulsant treatment was assessed based on epileptic seizure diaries and observations by caregivers and pediatric neurologists.
    RESULTS: The study group (n = 21) consisted of patients aged 3-26 years. Orphan drugs dedicated to Dravet syndrome were introduced in all patients due to the genetic diagnosis, which significantly improved the patients\' clinical conditions. The breakthrough drugs were stiripentol (in 16/21) and fenfluramine (in 3/21).
    CONCLUSIONS: In recent years, molecular genetics has rapidly developed in Poland, along with a steady increase in knowledge of Dravet syndrome among the medical profession. Early and precise diagnosis provides the opportunity to target treatment with drugs dedicated to Dravet syndrome with high efficacy.
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  • 文章类型: Journal Article
    背景:在Dravet综合征儿童中使用stiripentol的疗效在两个随机分组中得到证实,双盲,安慰剂对照,第三阶段研究,即STICLO法国(1996年10月至1998年8月)和STICLO意大利(1999年4月至2000年10月),但是当时数据还没有被充分利用。
    方法:此事后分析使用了其他信息,特别是在开放标签扩展(OLE)月份收集的,或由看护者在个别日记中报告,评估新的结果。
    结果:总体而言,纳入64例患者(安慰剂组31例,stiripentol组33人),其中34人(53.1%)为女性。患者的平均和中位年龄(25%;75%)分别为9.2岁(范围3.0-20.7岁)和8.7岁(6.0;12.1)。在双盲治疗期结束时,72%的患者在stiripentol组的广泛性强直阵挛性癫痫发作(GTCS)频率降低≥50%,安慰剂组为7%(P<0.001),与安慰剂组的3%相比,56%的患者有显著下降(≥75%)(P<0.001),38%的人没有GTCS,但安慰剂组无(P<0.001)。stiripentol的起效迅速,从治疗的第四天开始显着。没有GTCS的连续天数的中位最长时间在替他戊醇组中为32天,而在安慰剂组中为8.5天(P<0.001)。进一步切换到第三个月OLE,在先前接受安慰剂的患者中,癫痫发作频率从基线下降了80.2%,而在那些已经服用stiripentol的患者中没有观察到疗效变化。不良事件在stiripentol组中更常见,随着更多的嗜睡发作,厌食症,和体重减轻比安慰剂组。
    结论:总之,这些对STICLO数据的新分析加强了对替利坦在Dravet综合征中具有显著疗效的证据,表现出迅速的行动和持续的反应,进一步的随机后试验也证明了这一点.
    BACKGROUND: The efficacy of stiripentol in Dravet syndrome children was evidenced in two randomized, double-blind, placebo-controlled, phase 3 studies, namely STICLO France (October 1996-August 1998) and STICLO Italy (April 1999-October 2000), but data were not fully exploited at the time.
    METHODS: This post-hoc analysis used additional information, notably collected during the open-label extension (OLE) month, or reported by caregivers in individual diaries, to evaluate new outcomes.
    RESULTS: Overall, 64 patients were included (31 in the placebo group, 33 in the stiripentol group) of whom 34 (53.1%) were female. Patients\' mean and median (25%; 75%) age were 9.2 years (range 3.0-20.7 years) and 8.7 years (6.0; 12.1) respectively. At the end of the double-blind treatment period, 72% of the patients in the stiripentol group had a ≥ 50% decrease in generalized tonic-clonic seizure (GTCS) frequency, versus 7% in the placebo group (P < 0.001), 56% had a profound (≥ 75%) decrease versus 3% in the placebo group (P < 0.001), and 38% were free of GTCS, but none in the placebo group (P < 0.001). The onset of stiripentol efficacy was rapid, significant from the fourth day of treatment onwards. The median longest period of consecutive days with no GTCS was 32 days in the stiripentol group compared to 8.5 days in the placebo group (P < 0.001). Further to the switch to the third month OLE, an 80.2% decrease in seizure frequency from baseline was observed in patients previously receiving placebo, while no change in efficacy was observed in those already on stiripentol. Adverse events were more frequent in the stiripentol group, with significantly more episodes of somnolence, anorexia, and weight decrease than in the placebo group.
    CONCLUSIONS: Altogether these new analyses of the STICLO data reinforce the evidence for a remarkable efficacy of stiripentol in Dravet syndrome, with a demonstrated rapid onset of action and sustained response, as also evidenced in further post-randomized trials.
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  • 文章类型: Journal Article
    Stiripentol(Diacomit®)(STP)是一种口服活性抗癫痫药物(ASM),可作为辅助治疗,用于治疗与Dravet综合征(DS)相关的癫痫发作,一种严重的儿童癫痫,与clobazam一起,在一些地区丙戊酸。自从发现STP以来,已经描述了几种作用机制(MoA),可以解释其对DS相关癫痫发作的特定影响.STP主要被认为是γ-氨基丁酸(GABA)神经传递的增效剂:(i)通过摄取阻断,(ii)抑制降解,而且(iii)作为GABAA受体的正变构调节剂,特别是那些含有α3和δ亚基的。阻断电压门控钠和T型钙通道,这通常与抗惊厥和神经保护特性有关,也证明了STP。最后,研究表明STP具有调节糖能量代谢和抑制乳酸脱氢酶的作用。STP也是参与其他ASM代谢的几种细胞色素P450酶的抑制剂,有助于提高其作为附加疗法的抗惊厥功效。这些参与DS治疗的不同MoA和最近的数据表明STP治疗其他神经性或非神经性疾病的潜力。
    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.
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  • 文章类型: Journal Article
    目标:替利戊醇,芬氟拉明,和大麻二酚是许可的附加疗法,用于治疗Dravet综合征(DS)的癫痫发作。没有直接或间接的比较评估其完全许可剂量方案,在不同的司法管辖区,作为DS的一线附加疗法。
    方法:我们对获得许可的附加DS治疗的随机对照试验(RCT)数据进行了系统评价和频繁网络荟萃分析(NMA)。我们比较了患者的比例:每月惊厥性癫痫发作频率(MCSF)从基线减少≥50%(临床意义),≥75%(深度),100%(无癫痫发作);严重不良事件(SAE);因AE而停药。
    结果:我们从每种药物的两种安慰剂对照随机对照试验中确定了相关数据。50mg/kg/天的Stiripentol和0.7mg/kg/天的芬氟拉明在MCSF中从基线降低≥50%(临床意义)和≥75%(深刻)方面具有相似的疗效(绝对风险差异[RD],相对于1%的芬氟拉明为1%[95%置信区间:-20%至22%;p=0.93]和6%[-15%至27%;p分别),并且两者在统计学上都优于(p<0.05)大麻二酚的许可剂量方案(10或20mg/kg/天,与/不考虑clobazam)对于这些结果。与芬氟拉明(RD=26%[CI:8%至44%;p<0.01])和大麻二酚的许可剂量方案相比,在实现无癫痫发作的间隔方面具有统计学上的优势。经历SAE的患者比例没有显着差异。stibentol因不良事件而停药的风险较低,尽管stiripentol试验较短。
    结论:RCT数据的NMA表明,作为DS的一线附加疗法,至少与芬氟拉明一样有效,并且在减少惊厥性癫痫发作方面都比大麻二酚更有效。观察到三种添加剂之间SAE的发生率没有显着差异,但斯替戊醇可能具有较低的因不良事件导致的停药风险。这些结果可能为临床决策和DS患者治疗指南的持续发展提供信息。
    结论:本研究比较了三种药物(stiripentol,芬氟拉明,和大麻二酚)与其他药物一起使用,用于管理称为DS的严重类型癫痫中的癫痫发作。研究发现,stibentol和fenfluramine在减少癫痫发作方面同样有效,并且两者都比大麻二酚更有效。根据现有的临床试验数据,Stiripentol是完全停止癫痫发作的最佳药物。这三种药物的严重副作用发生率相似,但是stiripentol由于副作用而被停用的机会较低。这些信息可以帮助指导DS患者的治疗选择。
    OBJECTIVE: Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS.
    METHODS: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs.
    RESULTS: We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter.
    CONCLUSIONS: This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS.
    CONCLUSIONS: This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS.
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  • 文章类型: Observational Study
    目的:评估替尼醇(STP)辅助治疗Dravet综合征和非Dravet难治性发育性脑病和癫痫性脑病(DREE)的疗效和耐受性。
    方法:2000年1月至2023年2月在RuberInternacional医院对所有患有DREE和处方辅助STP的儿童和成人进行回顾性观察研究。结果是保留率;应答率(总发作频率相对于基线降低≥50%的患者比例);癫痫发作自由率;癫痫持续状态的应答率;不良事件和个别不良事件的发生率;在3、6和12个月时报告,在最后的访问。癫痫发作结果总体报告,和Dravet和非Dravet子组。
    结果:共有82名患者,(包括55个Dravet综合征和27个非DravetDREE)。中位年龄为5岁(范围1-59岁),Dravet组癫痫发作的中位年龄(4.9[3.6-6]个月)比非Dravet组年轻(17.9[6-42.3],p<0.001)。STP的中位随访时间为24.1个月(2年;范围0.3-164个月),Dravet组(35.9个月;范围0.8-164)比非Dravet组(17个月,范围0.3-62.3,p<0.001)更长。12个月时,保留率,应答率和无癫痫发生率为68.3%(56/82),65%[48-77%]和18%[5.7-29%],分别。在这些癫痫发作结果方面,组间没有统计学上的显著差异。46.3%的患者报告了不良事件(38/82),没有组间差异。
    结论:在患有癫痫和发育性脑病的患者人群中,非DravetDREE患者的辅助STP结局与Dravet综合征患者相似.
    OBJECTIVE: To assess efficacy and tolerability of stiripentol (STP) as adjunctive treatment in Dravet syndrome and non-Dravet refractory developmental and epileptic encephalopathies (DREEs).
    METHODS: Retrospective observational study of all children and adults with DREE and prescribed adjunctive STP at Hospital Ruber Internacional from January 2000 to February 2023. Outcomes were retention rate, responder rate (proportion of patients with ≥50% reduction in total seizure frequency relative to baseline), seizure freedom rate, responder rate for status epilepticus, rate of adverse event and individual adverse events, reported at 3, 6, and 12 months and at final visit. Seizure outcomes are reported overall, and for Dravet and non-Dravet subgroups.
    RESULTS: A total of 82 patients (55 Dravet syndrome and 27 non-Dravet DREE) were included. Median age was 5 years (range 1-59 years), and median age of epilepsy onset was younger in the Dravet group (4.9 [3.6-6] months) than non-Dravet (17.9 [6-42.3], P < 0.001). Median follow-up time STP was 24.1 months (2 years; range 0.3-164 months) and was longer in the Dravet group (35.9 months; range 0.8-164) than non-Dravet (17 months range 0.3-62.3, P < 0.001). At 12 months, retention rate, responder rate and seizure free rate was 68.3% (56/82), 65% [48-77%] and 18% [5.7-29%], respectively. There were no statistically significant differences between groups on these seizure outcomes. Adverse events were reported in 46.3% of patients (38/82), without differences between groups.
    CONCLUSIONS: In this population of patients with epileptic and developmental encephalopathies, outcomes with adjunctive STP were similar in patients with non-Dravet DREE to patients with Dravet syndrome.
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  • 文章类型: Journal Article
    发育性和癫痫性脑病(DEEs)是罕见的神经发育障碍,其特征是早发性和常为难治性癫痫发作和发育延迟/消退。包括Dravet综合征和Lennox-Gastaut综合征(LGS)。Rufinamide,芬氟拉明,stiripentol,大麻二酚和加奈索酮是具有多种作用机制的抗癫痫药物(ASM),已被批准用于治疗特定的DEE。Rufinamide被认为通过阻止电压门控钠通道从失活状态到静息状态的功能再循环来抑制神经元过度兴奋。它被许可用于与LGS相关的癫痫发作的辅助治疗。芬氟拉明会增加细胞外5-羟色胺水平,并可能通过激活特定的5-羟色胺受体和sigma-1受体的正调节来减少癫痫发作。芬氟拉明被许可用于与Dravet综合征和LGS相关的癫痫发作的辅助治疗。Stiripentol是A型γ-氨基丁酸(GABAA)受体的正变构调节剂。作为细胞色素P450酶的广谱抑制剂,它的抗惊厥作用可能是通过与共同给药的ASM的药代动力学相互作用而产生的。在服用氯巴赞和/或丙戊酸钠的患者中,Stiripentol被许可用于治疗与Dravet综合征相关的惊厥。大麻二酚的作用机制仍不清楚,尽管已经提出了多个目标,包括瞬时受体电位香草素1,G蛋白偶联受体55和平衡核苷转运蛋白1。大麻二酚被许可与氯巴赞一起用于与Dravet综合征和LGS相关的癫痫发作的辅助治疗。作为结节性硬化症相关癫痫发作的辅助治疗。像stiripentol一样,加奈索酮是GABAA受体的正变构调节剂。它最近在美国被批准用于治疗与细胞周期蛋白依赖性激酶样5缺乏症相关的癫痫发作。对DEE原因的更多了解推动了对其他新颖和重新利用的药物的潜在用途的研究。目前正在临床开发中用于DEE的推定ASM包括seticlestat,Carisbamate,维拉帕米,radiprodil,Clemizole和Lorcaserin.
    Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox-Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.
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  • 文章类型: Journal Article
    Stiripentol(STP)是仅可用于口服的新一代抗癫痫药。然而,它在酸性环境中非常不稳定,并且经历胃肠道缓慢和不完全溶解。因此,STP鼻内(IN)给药可以克服达到治疗浓度所需的高口服剂量。本文开发了IN微乳液和两种变体:第一种包含更简单的外相(FS6);第二种包含0.25%的壳聚糖(FS6+0.25%CH);和最后的0.25%壳聚糖加1%白蛋白(FS6+0.25%CH+1%BSA)。在IN(12.5mg/kg)后比较小鼠的STP药代动力学曲线,静脉注射(12.5mg/kg),和口服(100mg/kg)给药。所有微乳液均匀地形成平均尺寸≤16nm且pH在5.5和6.2之间的液滴。与口服途径相比,INFS6导致STP血浆和脑最大浓度增加37.4倍和110.6倍,分别。FS6+0.25%CH+1%BSA给药后8小时,观察到第二个STP脑浓度峰值,STP靶向效率为116.9%,直接转运百分比为14.5%,提示白蛋白可能增强STP的直接脑转运。相对全身生物利用度为947%(FS6),893%(FS6+0.25%CH),和1054%(FS6+0.25%CH+1%BSA)。总的来说,使用开发的微乳剂和明显低于口服给药剂量的STPIN给药可能是临床测试的有希望的替代方案。
    Stiripentol (STP) is a new-generation antiepileptic only available for oral administration. However, it is extremely unstable in acidic environments and undergoes gastrointestinal slow and incomplete dissolution. Thus, STP intranasal (IN) administration might overcome the high oral doses required to achieve therapeutic concentrations. An IN microemulsion and two variations were herein developed: the first contained a simpler external phase (FS6); the second one 0.25% of chitosan (FS6 + 0.25%CH); and the last 0.25% chitosan plus 1% albumin (FS6 + 0.25%CH + 1%BSA). STP pharmacokinetic profiles in mice were compared after IN (12.5 mg/kg), intravenous (12.5 mg/kg), and oral (100 mg/kg) administrations. All microemulsions homogeneously formed droplets with mean sizes ≤16 nm and pH between 5.5 and 6.2. Compared with oral route, IN FS6 resulted in a 37.4-fold and 110.6-fold increase of STP plasmatic and brain maximum concentrations, respectively. Eight hours after FS6 + 0.25%CH + 1%BSA administration, a second STP brain concentration peak was observed with STP targeting efficiency being 116.9% and direct-transport percentage 14.5%, suggesting that albumin may potentiate a direct STP brain transport. The relative systemic bioavailability was 947% (FS6), 893% (FS6 + 0.25%CH), and 1054% (FS6 + 0.25%CH + 1%BSA). Overall, STP IN administration using the developed microemulsions and significantly lower doses than those orally administrated might be a promising alternative to be clinically tested.
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  • 文章类型: Systematic Review
    目的:最近,美国食品和药物管理局(FDA)批准了替他,大麻二酚,和芬氟拉明治疗Dravet综合征(DS)患者。此外,seticlestat被确定为治疗DS的有希望的新药,因为它具有良好的疗效和安全性。然而,这些药物的疗效和安全性尚未在"头对头"试验中进行评估.本研究旨在比较和评估这些辅助抗癫痫药物治疗DS的疗效和安全性。方法:我们在PubMed中搜索,Embase,科克伦图书馆,和WebofScience数据库用于DS患者的随机对照试验(RCTs)和开放标签扩展(OLE)研究。我们对OLE研究进行了随机效应荟萃分析,并对RCT进行了网络荟萃分析,以评估抗癫痫药物治疗DS的有效性和安全性。主要疗效结果定义为与基线相比癫痫发作频率降低≥50%。此外,安全性评价指标定义为治疗期间不良事件(AEs)和严重不良事件(SAEs)的发生率.使用累积排名曲线(SUCRA)概率下的表面评估相对排名。结果:七个RCT涉及四种抗癫痫药物(stiripentol,大麻二酚,芬氟拉明,和seticlestat),总共634例患者被纳入分析。根据SUCRA的结果,与安慰剂组相比,4种药物均显著降低了癫痫发作频率.与基线相比,Soticlestat最有可能将癫痫发作频率降低≥50%[风险比(RR):19.32;95%置信区间(CI):1.20-311.40],其次是stiripentol和fenfluramine。在癫痫发作率相对于基线[RR:12.33;95%CI:1.71-89.17]和任何治疗引起的不良事件[RR:3.73;95%CI:1.65-8.43]和严重不良事件[RR:4.76;95%CI:0.61-37.28]的降低百分比中,Stiripentol排名最高。我们的研究共纳入了10项OLE研究,包含1,121名患者。根据荟萃分析的结果,癫痫发作频率减少≥50%的概率顺序是芬氟拉明(0.715,95%CI:0.621-0.808),stiripentol(0.604,95%CI:0.502-0.706),大麻二酚(0.448,95%CI:0.403-0.493)。AE的发生概率排序为芬氟拉明(0.832,95%CI:0.795-0.869),大麻二酚(0.825,95%CI:0.701-0.950),stiripentol(0.823,95%CI:0.707-0.938),seticlestat(0.688,95%CI:0.413-0.890)。结论:根据疗效和安全性的间接比较结果,大麻二酚在疗效和安全性方面略低于其他三种抗癫痫药物。Soticlestat,芬氟拉明,而曲戊醇在疗效上可能差别不大,但seticlestat和芬氟拉明更安全.Soticlestat可能是最好的辅助抗癫痫药物,其次是芬氟拉明。这一结论与长期疗效和安全性的比较一致。
    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.
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  • 文章类型: Journal Article
    原钙粘蛋白19(PCDH19)综合征以X连锁模式遗传,主要影响女性。该综合征是由编码原钙粘蛋白的PCDH19基因突变引起的。它的特征是在发热发作期间顽固性癫痫发作,并伴有神经精神表现。对PCDH19的治疗尚无共识。我们进行了文献综述,以调查用于该综合征的主要药物,并评估这些患者的最佳辅助治疗方案。我们使用了先进的PubMed搜索策略,包含以下标准:a)全文论文,b)英语语言,和c)在人类中进行的研究。排除标准:a)文献综述,b)系统审查,和c)元分析。我们收集了26篇观察性论文,对氯巴赞和溴化物进行了文献综述,这些文献已被证明可将癫痫发作减少50%。皮质类固醇在少数患者的发作期间改善了神经系统症状。然而,几个月后又复发了.加奈索酮的初步结果,仍在研究中,癫痫发作减少了60%。已经研究了生酮饮食来治疗几种难治性癫痫,包括PCDH19;它作为解决癫痫持续状态的有效辅助治疗,这表明它可以作为儿童早期治疗的一部分。在PCDH19癫痫患者中给予Stiripentol作为辅助治疗,导致无癫痫发作的持续时间最长。但必须进行更多的研究来评估其疗效.
    Protocadherin 19 (PCDH19) syndrome is inherited as an X-linked pattern and affects mainly females. This syndrome is caused by a mutation in the PCDH19 gene encoding for the protocadherin protein. It is characterized by refractory seizures during febrile episodes with neuropsychiatric manifestations. There is no consensus on the treatment of PCDH19. We conducted a literature review to investigate the main drugs used for this syndrome, and to evaluate the best possible course of adjuvant treatment for these patients. We used an advanced PubMed search strategy with the following inclusion criteria: a) full-text papers, b) English Language, and c) studies conducted in humans. Exclusion criteria: a) literature reviews, b) systematic reviews, and c) metanalysis. We gathered 26 observational papers to conduct this literature review on clobazam and bromide which have been shown to reduce seizures by 50%. Corticosteroids improved neurological symptoms during the episodes in a few patients. Nevertheless, they recurred after a few months. Preliminary results of ganaxolone, which is still under study, demonstrated a reduction of 60% in seizure episodes. A ketogenic diet has been studied to treat several refractory epilepsies, including PCDH19; it has promising results as effective adjuvant therapy in the resolution of status epilepticus, suggesting it could be used as part of the treatment in early childhood. Stiripentol was given as adjuvant therapy in a patient with PCDH19 epilepsy resulting in the most extended period of seizure-free episodes, but more studies must be performed to assess its efficacy.
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