Current and future pharmacological therapies for NAFLD/NASH.
Current and future pharmacological therapies for NAFLD/NASH.
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DOI：
10.1007/s00535-017-1415-1
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发表时间：
2018-03
影响因子：
6.3
通讯作者：
Yoneda M
中科院分区：
文献类型：
--
作者：
Sumida Y;Yoneda M
非酒精性脂肪性肝病（NAFLD）是全球最常见的肝病，目前尚无批准的药物治疗。已确定维生素E和吡格列酮在非酒精性脂肪性肝炎（NASH）（NAFLD的一种进展形式）中的疗效。目前已批准用于糖尿病的GLP-1 RA和SGLT 2抑制剂已显示出对NASH的早期疗效，并且还具有有益的心血管或肾脏作用。创新的NASH疗法包括四个主要途径。第一种方法是针对肝脏脂肪堆积。该方法中的药物包括调节过氧化物酶体增殖物激活物受体（例如，pemafibrate，elafibranor），靶向法尼醇X受体轴的药物[奥贝胆酸; OCA）]，新生脂肪生成抑制剂（aramchol，ACC抑制剂）和成纤维细胞生长因子-21类似物。第二个目标是氧化应激、炎症和凋亡。这类药物包括凋亡信号激酶1（ASK 1）抑制剂和emricasan（一种不可逆的半胱天冬酶抑制剂）。第三个目标是肠道微生物组和代谢性内毒素血症。几种药物正在进行试验，包括IMMe 124、TLR 4拮抗剂和索利霉素（大环内酯类抗生素）。最终目标是肝纤维化，这与NASH中的全因或肝脏相关死亡率密切相关。抗纤维化剂是半胱氨酸-半胱氨酸基序趋化因子受体-2/5拮抗剂（赛尼克韦罗; CVC）和半乳糖凝集素3拮抗剂。在开发中的各种药物中，OCA、elafibranor、ASK 1抑制剂和CVC等四种药物目前正在一项治疗NASH的国际III期试验中进行评估。在未来几年内，NASH治疗选择的可用性将有望遏制NASH相关疾病的上升趋势。
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine–cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.
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影响因子：
7.6
作者：
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