中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

胆汁淤积性肝病的治疗靶点及药物应用前景

郭濛濛 谢雯

引用本文:
Citation:

胆汁淤积性肝病的治疗靶点及药物应用前景

DOI: 10.3969/j.issn.1001-5256.2019.02.005
基金项目: 

北京市科委科技计划重大项目(D171100003117005); 北京市医院管理局消化内科学科协同发展中心消化专项重点项目(XXZ0402);北京市医院管理局重点医学专业发展计划(ZYLX201808); 

详细信息
  • 中图分类号: R575

New therapeutic targets and drugs for cholestatic liver disease

Research funding: 

 

  • 摘要:

    胆汁淤积性肝病是由胆管的破坏、胆汁酸的积聚和炎症过程的持续导致胆管细胞及肝细胞的损伤而引起。若不及时治疗,胆汁淤积会导致肝纤维化、肝硬化甚至出现终末期肝病。原发性胆汁性胆管炎(PBC)和原发性硬化性胆管炎(PSC)是成人中最常见的2种胆汁淤积性肝病,其病因目前尚不明确。虽然熊去氧胆酸(UDCA)可以较好地改善PBC患者的预后,延长患者肝移植的存活率,但存在部分患者对UDCA治疗无应答的现象。此外,目前尚无有效药物治疗PSC。随着近年来胆汁酸调节分子机制的研究进展及免疫途径的理解加深,涌现了越来越多新的药物。介绍了近年来PBC及PSC新兴治疗靶点及相关药物方面的研究进展。

     

  • [1]Chinese Society of Hepatology, Chinese Medical Association;Chinese Society of Gastroenterology, Chinese Medical Association;Chinese Society of Infectious Diseases, Chinese Medical Association.Consensus on the diagnosis and treatment of cholestasis liver diseases (2015) [J].J Clin Hepatol, 2015, 31 (12) :1989-1999. (in Chinese) 中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会.胆汁淤积性肝病诊断和治疗共识 (2015) [J].临床肝胆病杂志, 2015, 31 (12) :1989-1999.
    [2]BORTOLINI M, ALMASIO P, BRAY G, et al.Multicentre survey of the prevalence of intrahepatic cholestasis in 2520 consecutive patients with newly diagnosed chronic liver disease[J].Drug Investigation, 1992, 4 (Suppl 4) :83-89.
    [3]BEUERS U, TRAUNER M, JANSEN P, et al.New paradigms in the treatment of hepatic cholestasis:From UDCA to FXR, PXRand beyond[J].J Hepatol, 2015, 62 (1 Suppl) :s25-s37.
    [4]SANTIAGO P, SCHEINBERG AR, LEVY C.Cholestatic liver diseases:New targets, new therapies[J].Therap Adv Gastroenterol, 2018, 11:1756284818787400.
    [5]HARMS MH, LAMMERS WJ, THORBURN D, et al.Major hepatic complications in ursodeoxycholic acid-treated patients with primary biliary cholangitis:Risk factors and time trends in incidence and outcome[J].Am J Gastroenterol, 2018, 113 (2) :254-264.
    [6]KARLSEN TH, FOLSERAAS T, THORBURN D, et al.Primary sclerosing cholangitis-a comprehensive review[J].J Hepatol, 2017, 67 (6) :1298-1323.
    [7]LAZARIDIS KN, LARUSSO NF.Primary sclerosing cholangitis[J].N Engl J Med, 2016, 375 (12) :1161-1170.
    [8]OLSSON R, BOBERG KM, de MUCKADELL OS, et al.Highdose ursodeoxycholic acid in primary sclerosing cholangitis:A5-year multicenter, randomized, controlled study[J].Gastroenterology, 2005, 129 (5) :1464-1472.
    [9]LINDOR KD, KOWDLEY KV, LUKETIC VA, et al.High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis[J].Hepatology, 2009, 50 (3) :808-814.
    [10]SHI J, LI Z, ZENG X, et al.Ursodeoxycholic acid in primary sclerosing cholangitis:Meta-analysis of randomized controlled trials[J].Hepatol Res, 2009, 39 (9) :865-873.
    [11]OTHMAN MO, DUNKELBERG J, ROY PK.Urosdeoxycholic acid in primary sclerosing cholangitis:A meta-analysis and systematic review[J].Arab J Gastroenterol, 2012, 13 (3) :103-110.
    [12] TRAUNER M, FUCHS CD, HALILBASIC E, et al.New therapeutic concepts in bile acid transport and signaling for management of cholestasis[J].Hepatology, 2017, 65 (4) :1393-1404.
    [13]de VRIES E, BEUERS U.Management of cholestatic disease in 2017[J].Liver Int, 2017, 37 (Suppl 1) :123-129.
    [14]STEDMAN CA, LIDDLE C, COULTER SA, et al.Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury[J].Proc Natl Acad Sci U S A, 2005, 102 (6) :2063-2068.
    [15]TENG S, PIQUETTE-MILLER M.Hepatoprotective role of PXRactivation and MRP3 in cholic acid-induced cholestasis[J].Br JPharmacol, 2007, 151 (3) :367-376.
    [16]HIRSCHFIELD GM, GERSHWIN ME, STRAUSS R, et al.Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid:A proof-of-concept study[J].Hepatology, 2016, 64 (1) :189-199.
    [17]DYSON JK, HIRSCHFIELD GM, ADAMS DH, et al.Novel therapeutic targets in primary biliary cirrhosis[J].Nat Rev Gastroenterol Hepatol, 2015, 12 (3) :147-158.
    [18]NEVENS F, ANDREONE P, MAZZELLA G, et al.A placebocontrolled trial of obeticholic acid in primary biliary cholangitis[J].N Engl J Med, 2016, 375 (7) :631-643.
    [19]KOWDLEY KV, LUKETIC V, CHAPMAN R, et al.A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis[J].Hepatology, 2018, 67 (5) :1890-1902.
    [20]LARUSSO NF, BOWLUS CL, LEVY C, et al.PC.01.8 The AESOP trial:A randomized, double-blind, placebo-controlled, phase 2 study of obeticholic acid in patients with primary sclerosing cholangitis[J].Digest Liver Dis, 2018, 50 (2) :e67.
    [21]SAMUR S, KLEBANOFF M, BANKEN R, et al.Long-term clinical impact and cost-effectiveness of obeticholic acid for the treatment of primary biliary cholangitis[J].Hepatology, 2017, 65 (3) :920-928.
    [22]MAYO MJ, WIGG AJ, LEGGETT BA, et al.NGM282 for treatment of patients with primary biliary cholangitis:A multicenter, randomized, double-blind, placebo-controlled trial[J].Hepatol Commun, 2018, 2 (9) :1037-1050.
    [23]CORPECHOT C, CHAZOUILLRES O, ROUSSEAU A, et al.A placebo-controlled trial of bezafibrate in primary biliary cholangitis[J].N Engl J Med, 2018, 378 (23) :2171-2181.
    [24]YIN Q, LI J, XIA Y, et al.Systematic review and meta-analysis:Bezafibrate in patients with primary biliary cirrhosis[J].Drug Des Devel Ther, 2015, 9:5407-5419.
    [25]JONES D, BOUDES PF, SWAIN MG, et al.Seladelpar (MBX-8025) , a selective PPAR-δagonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid:A double-blind, randomised, placebo-controlled, phase2, proof-of-concept study[J].Lancet Gastroenterol Hepatol, 2017, 2 (10) :716-726.
    [26]BOUDES P, MICHAEL G, BOWLUS C, et al.Pharmacokinetics and pharmacodynamics of seladelpar, a potent and selective PPAR-delta, in patients with primary biliary cholangitis[J].J Hepatol, 2018, 68:s105-s364.
    [27]TSUDA M, MORITOKI Y, LIAN ZX, et al.Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid[J].Hepatology, 2012, 55 (2) :512-521.
    [28]MYERS RP, SWAIN MG, LEE SS, et al.B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid[J].Am J Gastroenterol, 2013, 108 (6) :933-941.
    [29]HOMMES DW, ERKELENS W, PONSIOEN C, et al.A doubleblind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis[J].J Clin Gastroenterol, 2008, 42 (5) :522-526.
  • 加载中
计量
  • 文章访问数:  1834
  • HTML全文浏览量:  19
  • PDF下载量:  506
  • 被引次数: 0
出版历程
  • 出版日期:  2019-02-20
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回