Fenfluramine for the Treatment of Dravet Syndrome and Lennox-Gastaut Syndrome
Fenfluramine for the Treatment of Dravet Syndrome and Lennox-Gastaut Syndrome
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DOI：
10.1007/s40263-020-00755-z
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发表时间：
2020-09-01
期刊：
影响因子：
6
通讯作者：
Verrotti, Alberto
中科院分区：
文献类型：
--
作者：
Balagura, Ganna;Cacciatore, Marta;Verrotti, Alberto
近50年来，大量抗癫痫药物问世，减轻了许多患者的癫痫发作负担。然而，某些病症对癫痫学家来说仍然是一个挑战，特别是 Dravet 综合征和 Lennox-Gastaut 综合征，它们是严重的癫痫和发育性脑病，其特征是多种癫痫发作类型和脑电图异常，通常对抗癫痫药物组合无反应。芬氟拉明等旧药的重新利用可以为临床医生提供不可或缺的工具，特别是因为只有少数药物在相对同质的人群中进行了测试，例如 Dravet 综合征。它还可以为治疗癫痫综合征的精准医学方法提供见解。我们在 MEDLINE、EMBASE 和临床试验数据库中搜索了相关论文，考虑了截至 2020 年 7 月的出版物。临床前研究表明，芬氟拉明的作用机制超出了其促血清素活性，并且位于涉及兴奋/抑制平衡的多个途径的交叉点。从正在进行的临床试验数据可以明显看出，芬氟拉明被证明是一种有前途的抗癫痫药物，具有非常有利的药代动力学，并且在较低剂量（0.2-0.7 mg/kg/天）使用时具有良好的总体安全性，尽管它之前与导致其于 1997 年退出市场的主要心脏不良事件有关。在这里，我们回顾了芬氟拉明功效的实验和临床证据，包括正在进行的临床试验的最新结果，并严格审查讨论芬氟拉明在安全性和精准医学方面的未来潜力。文献中的现有数据表明，对于两种癫痫综合征均具有良好的疗效，可减少癫痫发作负担并延长无癫痫发作间隔。我们注意到 Dravet 综合征患者的证据患病率较高。芬氟拉明已与一线和二线药物联合使用，但其在单一疗法中的使用仍需评估。
The last 50 years has seen the introduction of a great number of antiepileptic drugs, relieving the burden of seizures for many patients. However, some conditions remain a challenge for epileptologists, especially Dravet syndrome and Lennox-Gastaut syndrome, which are severe epileptic and developmental encephalopathies characterized by multiple seizure types and electroencephalographic abnormalities that are often unresponsive to combinations of antiepileptic drugs. The re-purposing of an old drug such as fenfluramine could provide an indispensable tool for clinicians, especially because only a few drugs have been tested in relatively homogeneous populations, like Dravet syndrome. It could also provide insights into precision medicine approaches to the treatment of epileptic syndromes. We searched for relevant papers within MEDLINE, EMBASE, and the Clinical Trial Database, considering publications through July 2020. Pre-clinical studies show a mechanism of action for fenfluramine that goes beyond its pro-serotoninergic activity and that is at the intersection of several pathways involved in excitation/inhibition balance. From the ongoing clinical trial data, it is evident that fenfluramine is proving to be a promising antiepileptic drug with very favorable pharmacokinetics and with a good overall safety profile when used at a lower dosage (0.2-0.7 mg/kg/day), despite its previously link to major cardiac adverse events that prompted its withdrawal from the market in 1997. Here, we review the experimental and clinical evidence of the efficacy of fenfluramine, including the latest results from ongoing clinical trials, and critically discuss the future potential of fenfluramine in terms of safety and precision medicine. Available data from the literature suggest a very good efficacy for both epileptic syndromes with a reduction in seizure burden and a longer seizure-free interval. We note the higher prevalence of evidence in patients with Dravet syndrome. Fenfluramine has been used in association with both first- and second-line medications, while its use in monotherapy still needs to be assessed.