PDF(Pubmed)
Abstract：
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.
摘要：
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.
