Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial


Autoři: Victor J. Navarro aff001;  Steven H. Belle aff002;  Massimo D’Amato aff003;  Nezam Adfhal aff004;  Elizabeth M. Brunt aff005;  Michael W. Fried aff006;  K. Rajender Reddy aff007;  Abdus S. Wahed aff002;  Stephen Harrison aff008
Působiště autorů: Department of Digestive Disease and Transplantation, Einstein Medical Center and Sidney Kimmel Medical College, Philadlephia, Pennsylvania, United States of America aff001;  Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America aff002;  Clinical Research, Rottapharm Biotech, Monza MB, Italy aff003;  Division of Hepatology, Department of Medicine, Beth-Israel Deaconess Medical Center, Boston, Massachusetts, United States of America aff004;  Department of Pathology and Immunology, Washington University School of Medicine, CB 8118, St. Louis, Missouri, United States of America aff005;  Department of Medicine, Division of Gastroenterology and Hepatology, Liver Center, University of North Carolina, Chapel Hill, North Carolina, United States of America aff006;  Department of Medicine, Division of Gastroenterology University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff007;  Department of Medicine, Division of Gastroenterology, Brooke Army Medical Center, Fort Sam Houston, Texas, United States of America aff008
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221683

Souhrn

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist’s assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48–50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials.

Trial Registration: clinicaltrials.gov, Identifier: NCT00680407.

Klíčová slova:

Medicine and health sciences – Surgical and invasive medical procedures – Biopsy – Health care – Health care providers – Medical doctors – Pathologists – Gastroenterology and hepatology – Liver diseases – Fatty liver – Cirrhosis – Pathology and laboratory medicine – Anatomical pathology – Cytopathology – Steatosis – Biology and life sciences – Anatomy – Histology – Developmental biology – Fibrosis – People and places – Population groupings – Professions – Medical personnel – Research and analysis methods – Research design – Clinical research design – Adverse events


Zdroje

1. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:3–20.

2. Kleiner DE. Brunt EM. Van Natta M. Behling C. Contos MJ. Cummings OW. Et al. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21. doi: 10.1002/hep.20701 15915461

3. Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phyto- ther Res. 2010;24(10):1423–1432.

4. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs 2001;61:2035–2061. doi: 10.2165/00003495-200161140-00003 11735632

5. Bosisio E, Benelli C, Pirola O. Effect of flavanolignans of silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. Pharmacol Res 1992;25:147–54. 1635893

6. Carini R, Comoglio A, Albano E, Poli G. Lipid peroxidation and irreversible damage in the rat hepatocyte model: protection by the silybin-phospholipid complex IdB 1016. Biochemical Pharmacology 1992;43:2111–2115. doi: 10.1016/0006-2952(92)90168-i 1599497

7. Mira L, Silva M, Manso CF. Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharamacol 1994;42:964–8.

8. Kheong CW, Mustapha NRN, Mahadeva S. A randomized trial of silymarin for the treatment of nonalcoholic steatohepatitis. Clin Gastro Hepatol 2017;15:1940–1949.

9. Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy ER et al; SyNCH Trial Group. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol. 2010;50 (4):434–449. doi: 10.1177/0091270009347475 19841158

10. Fried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled tiral. JAMA 2012;308:274–282. doi: 10.1001/jama.2012.8265 22797645

11. Brunt E, Janney C, Di Bisceglie A, Neuschwander-Tetri B, Bacon B. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. The American Journal of Gastroenterology 1999;94:2467–2474 10484010

12. Zhong S, Fan Y, Yan Q, Fan X, Wu B, Han Y, et al. The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: A meta-analysis (PRISMA) of randomized control trials. Medicine 2017;96:e9061. doi: 10.1097/MD.0000000000009061 29245314

13. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al.; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015 Mar 14;385(9972):956–65. doi: 10.1016/S0140-6736(14)61933-4 25468160


Článek vyšel v časopise

PLOS One


2019 Číslo 9

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