Schoonjans An-Sofie, Marchau Fabienne, Paelinck Bernard P, Lagae Lieven, Gammaitoni Arnold, Pringsheim Milka, Keane Martin G, Ceulemans Berten
a Department of Paediatric Neurology , Antwerp University Hospital, University of Antwerp , Antwerp , Belgium.
b Department of Paediatric Cardiology , Antwerp University Hospital, University of Antwerp , Antwerp , Belgium.
Curr Med Res Opin. 2017 Oct;33(10):1773-1781. doi: 10.1080/03007995.2017.1355781. Epub 2017 Jul 31.
Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS.
Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years.
Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10-20 mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period.
A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.
德雷维特综合征（DS）是一种罕见的、难治性癫痫综合征，目前的治疗方案往往无效。基于20世纪80年代和90年代关于氟苯丙胺在难治性癫痫儿科患者中的抗癫痫活性的报道，氟苯丙胺目前正在研发用于治疗DS。然而，1997年，在有报道称接受肥胖治疗的成年患者中氟苯丙胺与肺动脉高压和心脏瓣膜病有关联后，它从全球市场撤出。进行这项综述是为了评估低剂量使用氟苯丙胺治疗DS时的心脏安全性。
在PubMed上搜索关于氟苯丙胺在报告了心脏瓣膜病发病率的肥胖成年患者中的临床研究。将这些数据与来自比利时接受低剂量氟苯丙胺治疗长达28年的DS患者的已发表结果进行对比审查。
已报道了9项关于氟苯丙胺及相关化合物（右芬氟拉明和/或苯丁胺）的对照研究，这些研究评估了3268例接受治疗的患者和2017例对照受试者中心脏瓣膜病的发病率和严重程度。在接受治疗的患者中，9.6%发现有轻度或更严重的主动脉瓣反流，而对照受试者中这一比例为3.9%；在接受治疗的患者中，3.1%发现有中度或更严重的二尖瓣反流，对照受试者中这一比例为2.5%。19例DS患者接受了每日10 - 20毫克氟苯丙胺治疗长达28年，未出现心脏瓣膜病或肺动脉高压的临床体征或症状。在观察期内的某些时候，5例患者的超声心动图显示瓣膜结构有轻微且临床上无重要意义的变化。
当氟苯丙胺在年轻的DS患者中长期低剂量使用时，似乎出现了不同的效益风险关系。正在进行的3期临床试验期间持续的心脏评估将为这种潜在的新的有效治疗提供更多安全信息。
