مورد إلكتروني
Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis.
| العنوان: | Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis. |
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| المؤلفون: | Lawitz, Eric J |
| المصدر: | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association; vol 16, iss 12, 1983-1991.e3; 1542-3565 |
| بيانات النشر: | eScholarship, University of California 2018-12-01 |
| تفاصيل مُضافة: | Lawitz, Eric J Coste, Angie Poordad, Fred Alkhouri, Naim Loo, Nicole McColgan, Bryan J Tarrant, Jacqueline M Nguyen, Tuan Han, Ling Chung, Chuhan Ray, Adrian S McHutchison, John G Subramanian, G Mani Myers, Robert P Middleton, Michael S Sirlin, Claude Loomba, Rohit Nyangau, Edna Fitch, Mark Li, Kelvin Hellerstein, Marc |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | BACKGROUND & AIMS:Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH. METHODS:In an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis. RESULTS:The contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF. CONCLUSION:In an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555. |
| مصطلحات الفهرس: | Liver, Humans, Oxazoles, Pyrimidines, Acetyl-CoA Carboxylase, Enzyme Inhibitors, Magnetic Resonance Imaging, Treatment Outcome, Administration, Oral, Prospective Studies, Adolescent, Adult, Aged, Middle Aged, Female, Male, Lipogenesis, Elasticity Imaging Techniques, Young Adult, Isobutyrates, Non-alcoholic Fatty Liver Disease, ALT, Clinical Trial, Drug, Fatty Liver, TIMP1, Treatment, Liver Disease, Hepatitis, Chronic Liver Disease and Cirrhosis, Biomedical Imaging, Digestive Diseases, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Oral and gastrointestinal, Clinical Sciences, Gastroenterology & Hepatology, article |
| URL: | |
| الإتاحة: | Open access content. Open access content public |
| ملاحظة: | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association vol 16, iss 12, 1983-1991.e3 1542-3565 |
| أرقام أخرى: | CDLER oai:escholarship.org:ark:/13030/qt4j57x1h1 qt4j57x1h1 https://escholarship.org/uc/item/4j57x1h1Test https://escholarship.orgTest/ 1367415903 |
| المصدر المساهم: | UC MASS DIGITIZATION From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1367415903 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |