安全性、耐受性和药效学的顶端sodium-dependent胆汁酸转运体抑制volixibat健康成人和2型糖尿病患者:一项随机安慰剂对照试验。

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Tiessen RG,肯尼迪CA,凯勒BT,莱文N, Acevedo L, Gedulin B, van Vliet AA, Dorenbaum,帕默M

安全性、耐受性和药效学的顶端sodium-dependent胆汁酸转运体抑制volixibat健康成人和2型糖尿病患者:一项随机安慰剂对照试验。

BMC杂志。2018年1月5日,18 (1):3。doi: 10.1186 / s12876 - 017 - 0736 - 0。

PubMed ID
29304731 (在PubMed
]
文摘

背景:在非酒精性脂肪肝(NASH)的发病机制涉及胆固醇代谢异常和肝积累有毒自由胆固醇。顶端sodium-dependent胆汁酸转运体(ASBT)抑制自由胆固醇的回肠末端可能促进去除肝脏通过减少循环的胆汁酸(BAs)肝脏,从而刺激新英航合成胆固醇。这第一阶段研究的目的在成人健康志愿者(HVs)和2型糖尿病(T2DM)病人体内患者评估安全,耐受性,ASBT抑制的药代学和药效学volixibat (SHP626;以前LUM002)。方法:受试者随机3:1获得每日一次口服volixibat(0.5毫克,1毫克,5毫克或10毫克)或安慰剂的28天两组(高压和2型糖尿病)。评估包括安全、粪便英航和血清7 alpha-hydroxy-4-cholesten-3-one (C4;英航合成生物标记)。结果:六十一人随机(HVs:安慰剂,n = 12;volixibat n = 38;2型糖尿病:安慰剂,n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6-3.2 times higher in HVs (643.73-1239.3 mumol/24 h) and ~8 times higher in T2DM (1786.0 mumol/24 h) than with placebo (HVs: 386.93 mumol/24 h; T2DM: 220.00 mumol/24 h). With volixibat, mean C4 concentrations increased by ~1.3-5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. CONCLUSIONS: Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).

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药物
药物靶点
药物 目标 类 生物 药理作用 行动
Volixibat 钠/回肠胆汁酸转运蛋白 蛋白质 人类
是的
抑制剂
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