Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.
Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.
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DOI：
10.1186/s12944-015-0006-5
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发表时间：
2015-02-18
影响因子：
4.5
通讯作者：
Gaudet D
中科院分区：
文献类型：
--
作者：
Meyers CD;Tremblay K;Amer A;Chen J;Jiang L;Gaudet D
家族性乳糜微血症综合征（FCS）是由完全脂蛋白脂肪酶（LPL）缺乏引起的一种罕见的脂质疾病，导致空腹乳糜微血症和严重的高甘油三酯血症。抑制介导乳糜微粒甘油三酯（TG）合成的二酰基甘油酰基转移酶1 （DGAT1）是降低FCS中甘油三酯水平的一个有吸引力的策略。在这项研究中，我们评估了DGAT1抑制剂普拉西他在FCS患者中的安全性、耐受性和降低tg的疗效。6名FCS患者参加了一项开放标签临床研究。经过1周的极低脂肪饮食磨合期后，患者接受基线脂质评估，包括低脂肪饮食耐受性测试。然后，患者接受3个连续21天的治疗期（pradigastat分别为20mg、40mg和10mg）。治疗期以≥4周的洗脱期分开。在整个治疗期间，每周评估空腹TG水平。同时监测餐后TGs、ApoB48和脂蛋白脂含量。在每日一次口服给药后，第14天达到稳态暴露。在所研究的剂量下，普拉西他暴露量大约呈剂量正比增加。在21天的治疗中，Pradigastat与空腹甘油三酯降低41% （20mg）和70% （40mg）相关。空腹TG的减少几乎完全是由乳糜微粒TG的减少引起的。普拉西他治疗也导致餐后TG和apo48（空腹和餐后）的显著降低。Pradigastat是安全且耐受性良好的，只有轻微的、短暂的胃肠道不良事件。新型DGAT1抑制剂pradigastat可显著降低FCS患者血浆TG水平，可能是一种有希望的治疗这种孤儿疾病的新方法。ClinicalTrials.gov识别码NCT01146522。
Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS. Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored. Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events. The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease. ClinicalTrials.gov identifier NCT01146522.
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影响因子：
16.2
作者：
CHAIT, A;ROBERTSON, HT;BRUNZELL, JD
通讯作者：
BRUNZELL, JD
影响因子：
37.8
作者：
Zee, RYL;Cook, NR;Ridker, PM
通讯作者：
Ridker, PM
影响因子：
2.6
作者：
Brisson, Diane;Methot, Julie;Gaudet, Daniel
通讯作者：
Gaudet, Daniel
影响因子：
4.8
作者：
Buhman, KK;Smith, SJ;Farese, RV
通讯作者：
Farese, RV
影响因子：
5.8
作者：
Carpentier, Andre C.;Frisch, Frederique;Gaudet, Daniel
通讯作者：
Gaudet, Daniel