Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study
Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study
复制标题
DOI：
10.1016/s1474-4422(07)70194-1
复制
发表时间：
2007-09-01
期刊：
影响因子：
48
通讯作者：
Wraith, James E.
中科院分区：
文献类型：
--
作者：
Patterson, Marc C.;Vecchio, Darleen;Wraith, James E.
尼曼-皮克C型病（NPC）是一种遗传性神经退行性疾病，其特征是细胞内脂转运缺陷伴继发性鞘糖脂积累。米卢司他是一种小的亚糖，可可逆地抑制葡萄糖神经酰胺合成酶，该合成酶催化鞘糖脂合成的第一步。米卢司他能够穿过血脑屏障，因此是一种治疗神经系统疾病的潜在药物。我们的目的是确定米卢司他对鼻咽癌严重程度的几个标志的影响。方法将年龄在12岁及以上的鼻咽癌患者（n=29）随机分为两组，一组接受米卢司他200mg，每日3次（n=20），另一组接受标准治疗（n=9），疗程12个月。12名年龄小于12岁的儿童被纳入另一个队列；所有人都接受了根据体表面积调整剂量的米卢司他。在一项扩展研究中，所有参与者都接受了额外一年的米卢司他治疗。主要终点是水平跳眼运动（HSEM）速度，基于其与疾病进展的相关性。本研究已注册为国际标准随机对照试验，编号为ISRCTN26761144。在12个月时，接受米格司他治疗的患者与接受标准治疗的患者相比，hsem速度有所改善；当排除服用苯二氮卓类药物的患者时，结果具有统计学意义（p=0.028）。儿童在12个月时表现出类似大小的HSEM速度的改善。在12岁以上接受治疗的患者中，吞咽能力的改善、听觉的稳定以及活动指数的缓慢恶化也被观察到。米卢司他200mg，每日三次，在研究参与者中的安全性和耐受性与先前的I型戈谢病试验一致，其中使用该剂量的一半。解释米卢司他改善或稳定了一些鼻咽癌的临床相关指标。这是第一个在NPC中研究的药物，有动物和临床数据支持疾病改善的益处。
Background Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity.Methods Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144.Findings At 12 months, H SEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used.Interpretation Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.