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1
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Służały P, Paśko P, Galanty A. Natural Products as Hepatoprotective Agents-A Comprehensive Review of Clinical Trials. PLANTS (BASEL, SWITZERLAND) 2024; 13:1985. [PMID: 39065511 PMCID: PMC11280762 DOI: 10.3390/plants13141985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/18/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024]
Abstract
The hepatoprotective effects of natural products have been a significant focus in recent decades due to the growing demand for the help in the treatment of hepatic impairments. This review specifically delves into the findings of clinical trials involving 13 selected natural products, namely plants and their derived compounds (e.g., artichoke, berberine, and turmeric), algae (e.g., spirulina), probiotics, and other products like phospholipids and vitamin D. A literature search was performed in the Scopus database, PubMed, and Google Scholar, covering all articles found up to June 2024. Artichoke, berberine, chlorella, chicory, green tea, probiotics, phospholipids, schisandra, silymarin, spirulina, and vitamin D caused a decrease in liver enzymes, while for cinnamon and turmeric such an effect was either not observed or not convincing. The presented results indicate that some natural products might satisfactorily improve hepatic outcomes in NAFLD, NASH, and other liver disorders; however, further studies and metanalyses are needed to clearly demonstrate their effectiveness.
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Affiliation(s)
- Piotr Służały
- Department of Pharmacognosy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland;
| | - Paweł Paśko
- Department of Food Chemistry and Nutrition, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland;
| | - Agnieszka Galanty
- Department of Pharmacognosy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland;
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2
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Mohammadi S, Ashtary-Larky D, Asbaghi O, Farrokhi V, Jadidi Y, Mofidi F, Mohammadian M, Afrisham R. Effects of silymarin supplementation on liver and kidney functions: A systematic review and dose-response meta-analysis. Phytother Res 2024; 38:2572-2593. [PMID: 38475999 DOI: 10.1002/ptr.8173] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 01/12/2024] [Accepted: 02/11/2024] [Indexed: 03/14/2024]
Abstract
It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis assessed the impact of SIL administration on certain hepatic, renal, and oxidative stress markers. A systematic search was conducted in various databases to identify relevant trials published until January 2023. Randomized controlled trials (RCTs) that evaluated the effects of SIL on kidney and liver markers were included. A random-effects model was used for the analysis and 41 RCTs were included. The pooled results indicated that SIL supplementation led to a significant reduction in serum levels of alkaline phosphatase, alanine transaminase, creatinine, and aspartate aminotransferase, along with a substantial elevation in serum glutathione in the SIL-treated group compared to their untreated counterparts. In addition, there was a nonsignificant decrease in serum levels of gamma-glutamyl transferase, malondialdehyde (MDA), total bilirubin, albumin (Alb), total antioxidant capacity, and blood urea nitrogen. Sub-group analyses revealed a considerable decline in MDA and Alb serum values among SIL-treated participants with liver disease in trials with a longer duration (≥12 weeks). These findings suggest that SIL may ameliorate certain liver markers with potential hepatoprotective effects, specifically with long-term and high-dose supplementation. However, its nephroprotective effects and impact on oxidative stress markers were not observed. Additional high-quality RCTs with longer durations are required to determine the clinical efficacy of SIL supplementation on renal and oxidative stress markers.
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Affiliation(s)
- Shooka Mohammadi
- Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Damoon Ashtary-Larky
- Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Omid Asbaghi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vida Farrokhi
- Department of Hematology, Faculty of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yasaman Jadidi
- Department of Clinical Laboratory Sciences, Faculty of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mofidi
- Department of Clinical Nutrition and Dietetics, National Nutrition and Food Technology Research Institute, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrnaz Mohammadian
- Department of Exercise Physiology, Islamic Azad University of Ahvaz, Ahvaz, Iran
| | - Reza Afrisham
- Department of Clinical Laboratory Sciences, Faculty of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Calderon Martinez E, Herrera D, Mogan S, Hameed Z, Jangda AA, Khan TJ, Mroke P, Sajid S, Shah YR, Baig I. Impact of Silymarin Supplements on Liver Enzyme Levels: A Systematic Review. Cureus 2023; 15:e47608. [PMID: 38021897 PMCID: PMC10667129 DOI: 10.7759/cureus.47608] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Abstract
Silymarin, extracted from milk thistle (Silybum marianum), is esteemed for its antioxidative, anti-inflammatory, and antifibrotic properties, notably within liver-related contexts. Nevertheless, a comprehensive grasp of its effects on liver enzymes remains elusive. This systematic review aims to scrutinize the influence of silymarin supplements on liver enzyme levels, elucidating its potential for hepatoprotection. Following PRISMA 2020 guidelines, we systematically reviewed pertinent studies in PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online). Our inclusion criteria comprised randomized clinical trials (RCTs) published between 1992 and 2023, accessible in English, with a primary focus on liver enzyme levels. Non-original research, ambiguously defined studies, and those lacking essential data were excluded. Of the 1,707 initially identified articles, 29 RCTs met the inclusion criteria, encompassing 3,846 participants with diverse underlying conditions. Silymarin dosages ranged from 140 mg to 420 mg, administered for various durations. Results revealed that 65.5% of the studies reported reduced liver enzyme levels, 20.7% exhibited no significant change, and 13.8% observed elevated liver enzymes. The systematic review implies a potential advantageous influence of silymarin on liver enzyme levels, indicating its hepatoprotective potential. Nevertheless, outcome disparities may stem from comorbidities, suboptimal doses, and underlying diseases. Notably, silymarin's impact on liver enzymes could be context-dependent, with varying responses among different conditions, with the decrease of liver enzyme levels in patients with non-alcoholic fatty liver disease. Silymarin supplements exhibit potential for hepatoprotection by ameliorating liver enzyme levels across diverse conditions. Further research should ascertain optimal dosages and contexts, accounting for individual patient characteristics and underlying diseases.
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Affiliation(s)
| | - Domenica Herrera
- Internal Medicine, Pontificia Universidad Católica del Ecuador, Quito, ECU
| | - Saruveish Mogan
- Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak (UNIMAS), Kuching, MYS
| | - Zainab Hameed
- Internal Medicine, Shifa College of Medicine, Islamabad, PAK
| | | | - Tayyaba J Khan
- Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, PAK
| | - Palvi Mroke
- Internal Medicine, Caribbean Medical University School of Medicine, Willemstad, CUW
| | - Samar Sajid
- Medicine, Dow University of Health Sciences, Karachi, PAK
| | - Yash R Shah
- Medicine, GMERS (Gujarat Medical Education and Research Society) Medical College and Civil Hospital, Sola, Ahmedabad, IND
| | - Imran Baig
- Internal Medicine, Houston Methodist Hospital, Houston, USA
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Mandal A, Hazra B. Medicinal plant molecules against hepatitis C virus: Current status and future prospect. Phytother Res 2023; 37:4353-4374. [PMID: 37439007 DOI: 10.1002/ptr.7936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/16/2023] [Accepted: 06/21/2023] [Indexed: 07/14/2023]
Abstract
Hepatitis C virus (HCV), a global malady, causes acute and chronic hepatitis leading to permanent liver damage, hepatocellular carcinoma, and death. Modern anti-HCV therapies are efficient, but mostly inaccessible for residents of underdeveloped regions. To innovate more effective treatments at affordable cost, medicinal plant-based products need to be explored. The aim of this article is to review plant constituents in the light of putative anti-HCV mechanisms of action, and discuss existing problems, challenges, and future directions for their potential application in therapeutic settings. One hundred sixty literatures were collected by using appropriate search strings via scientific search engines: Google Scholar, PubMed, ScienceDirect, and Scopus. Bibliography was prepared using Mendeley desktop software. We found a substantial number of plants that were reported to inhibit different stages of HCV life cycle. Traditional medicinal plants such as Phyllanthus amarus Schumach. and Thonn., Eclipta alba (L.) Hassk., and Acacia nilotica (L.) Delile exhibited strong anti-HCV activities. Again, several phytochemicals such as epigallocatechin-3-gallate, honokilol, punicalagin, and quercetin have shown broad-spectrum anti-HCV effect. We have presented promising phytochemicals like silymarin, curcumin, glycyrrhizin, and camptothecin for nanoparticle-based hepatocyte-targeted drug delivery. Nevertheless, only a few animal studies have been performed to validate the anti-HCV effect of these plant products. Again, insufficient clinical evaluation of the safety and effectiveness of herbal medications remain a problem. Selected plants products could be developed as novel therapeutics for HCV patients only after scrupulous evaluation of their safety and efficacy in a clinical set-up.
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Affiliation(s)
- Anirban Mandal
- Department of Microbiology, Mrinalini Datta Mahavidyapith, Birati, Kolkata, India
| | - Banasri Hazra
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
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Musazadeh V, Karimi A, Bagheri N, Jafarzadeh J, Sanaie S, Vajdi M, Karimi M, Niazkar HR. The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms. Biomed Pharmacother 2022; 154:113593. [PMID: 36027611 PMCID: PMC9393179 DOI: 10.1016/j.biopha.2022.113593] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/17/2022] [Accepted: 08/19/2022] [Indexed: 11/11/2022] Open
Abstract
The proceeding pandemic of coronavirus disease 2019 is the latest global challenge. Like most other infectious diseases, inflammation, oxidative stress, and immune system dysfunctions play a pivotal role in the pathogenesis of COVID-19. Furthermore, the quest of finding a potential pharmaceutical therapy for preventing and treating COVID-19 is still ongoing. Silymarin, a mixture of flavonolignans extracted from the milk thistle, has exhibited numerous therapeutic benefits. We reviewed the beneficial effects of silymarin on oxidative stress, inflammation, and the immune system, as primary factors involved in the pathogenesis of COVID-19. We searched PubMed/Medline, Web of Science, Scopus, and Science Direct databases up to April 2022 using the relevant keywords. In summary, the current review indicates that silymarin might exert therapeutic effects against COVID-19 by improving the antioxidant system, attenuating inflammatory response and respiratory distress, and enhancing immune system function. Silymarin can also bind to target proteins of SARS-CoV-2, including main protease, spike glycoprotein, and RNA-dependent RNA-polymerase, leading to the inhibition of viral replication. Although multiple lines of evidence suggest the possible promising impacts of silymarin in COVID-19, further clinical trials are encouraged.
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Affiliation(s)
- Vali Musazadeh
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Karimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Nasim Bagheri
- Department of microbiology Islamic Azad University of medical science, Tehran, Iran
| | - Jaber Jafarzadeh
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarvin Sanaie
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Vajdi
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mozhde Karimi
- Department of Immunology, Faculty ofMedical Sciences ,Tarbiat Modares University
| | - Hamid Reza Niazkar
- Breast Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Ghiasian M, Nafisi H, Ranjbar A, Mohammadi Y, Ataei S. Antioxidative effects of silymarin on the reduction of liver complications of fingolimod in patients with relapsing-remitting multiple sclerosis: A clinical trial study. J Biochem Mol Toxicol 2021; 35:e22800. [PMID: 33934443 DOI: 10.1002/jbt.22800] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 04/05/2021] [Accepted: 04/22/2021] [Indexed: 11/06/2022]
Abstract
Multiple sclerosis (MS) is a chronic disease that affects the central nervous system and is characterized by inflammation, demyelination, and degenerative changes. Relapsing-remitting MS (RRMS) is the most common form of MS. Fingolimod (FTY720) is a once-daily disease-modifying agent approved to treat RRMS, and it binds to sphingosine 1-phosphate receptors. Milk thistle (silybum marianum; SM) is an herb generally used to protect the liver with antioxidant and antifibrotic effects. The purpose of this study was to evaluate the effects of silymarin on reducing liver complications of FTY720 in patients with RRMS and decrease the oxidative stress that plays an important role in the pathogenesis of this disease. Forty-eight patients with RRMS were divided into two groups using random assignment: the placebo and drug-treated groups. Participants of intervention and control groups took FTY720 with silymarin and placebo without silymarin per day for six months. Findings showed a significant reduction in the level of ALT and AST, reduction of main pathogenic factors in MS containing malondialdehyde, and also a significant rise in total antioxidant capacity, and total thiol groups in the serum of patients treated with silymarin as compared with the placebo group. Our outcomes propose the practical effects of silymarin in multiple sclerosis and reduction of hepatic side effects of fingolimod.
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Affiliation(s)
- Masoud Ghiasian
- Department of Neurology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Nafisi
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Akram Ranjbar
- Department of Toxicology and Pharmacology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Younes Mohammadi
- Department of Epidemiology, School of Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sara Ataei
- Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
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Vairetti M, Di Pasqua LG, Cagna M, Richelmi P, Ferrigno A, Berardo C. Changes in Glutathione Content in Liver Diseases: An Update. Antioxidants (Basel) 2021; 10:364. [PMID: 33670839 PMCID: PMC7997318 DOI: 10.3390/antiox10030364] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Glutathione (GSH), a tripeptide particularly concentrated in the liver, is the most important thiol reducing agent involved in the modulation of redox processes. It has also been demonstrated that GSH cannot be considered only as a mere free radical scavenger but that it takes part in the network governing the choice between survival, necrosis and apoptosis as well as in altering the function of signal transduction and transcription factor molecules. The purpose of the present review is to provide an overview on the molecular biology of the GSH system; therefore, GSH synthesis, metabolism and regulation will be reviewed. The multiple GSH functions will be described, as well as the importance of GSH compartmentalization into distinct subcellular pools and inter-organ transfer. Furthermore, we will highlight the close relationship existing between GSH content and the pathogenesis of liver disease, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), chronic cholestatic injury, ischemia/reperfusion damage, hepatitis C virus (HCV), hepatitis B virus (HBV) and hepatocellular carcinoma. Finally, the potential therapeutic benefits of GSH and GSH-related medications, will be described for each liver disorder taken into account.
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Affiliation(s)
| | - Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
| | | | | | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
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Marmouzi I, Bouyahya A, Ezzat SM, El Jemli M, Kharbach M. The food plant Silybum marianum (L.) Gaertn.: Phytochemistry, Ethnopharmacology and clinical evidence. JOURNAL OF ETHNOPHARMACOLOGY 2021; 265:113303. [PMID: 32877720 DOI: 10.1016/j.jep.2020.113303] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 08/03/2020] [Accepted: 08/21/2020] [Indexed: 05/26/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Silybum marianum (L.) Gaertn. or Milk thistle is a medicinal plant native to Northern Africa, Southern Europe, Southern Russia and Anatolia. It also grows in South Australia, North and South America. In traditional knowledge, people have used S. marianum for liver disorders such as hepatitis, liver cirrhosis and gallbladder diseases. The main active compound of the plant seeds is silymarin, which is the most commonly used herbal supplement in the United States for liver problems. Nowadays, S. marianum products are available as capsules, powders, and extracts. AIM OF STUDY The aim of our study is to draw a more comprehensive overview of the traditional heritage, pharmacological benefits and chemical fingerprint of S. marianum extracts and metabolites; as well as their metabolism and bioavailability. MATERIALS AND METHODS An extensive literature search has been conducted using relavant keywords and papers with rationale methodology and robust data were selected and discussed. Studies involving S. marianum or its main active ingredients with regards to hepatoprotective, antidiabetic, cardiovascular protection, anticancer and antimicrobial activities as well as the clinical trials performed on the plant, were discussed here. RESULTS S. marianum was subjected to thousands of ethnopharmacological, experimental and clinical investigations. Although, the plant is available for use as a dietary supplement, the FDA did not yet approve its use for cancer therapy. Nowadays, clinical investigations are in progress where a global evidence of its real efficiency is needed. CONCLUSION S. marianum is a worldwide used herb with unlimited number of investigations focusing on its benefits and properties, however, little is known about its clinical efficiency. Moreover, few studies have discussed its metabolism, pharmacokinetics and bioavailability, so that all future studies on S. marianum should focus on such areas.
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Affiliation(s)
- Ilias Marmouzi
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, University Mohammed V in Rabat, Rabat, Morocco
| | - Abdelhakim Bouyahya
- Laboratory of Human Pathology Biology, Faculty of Sciences, Department of Biology, Genomic Center of Human Pathology, Mohammed V University in Rabat, Morocco
| | - Shahira M Ezzat
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo, 11562, Egypt; Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, 12451, Egypt.
| | - Meryem El Jemli
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, University Mohammed V in Rabat, Rabat, Morocco
| | - Mourad Kharbach
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, University Mohammed V in Rabat, Rabat, Morocco; Department of Analytical Chemistry, Applied Chemometrics and Molecular Modelling, CePhaR, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090, Brussels, Belgium
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Li H, Huang MH, Jiang JD, Peng ZG. Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy. World J Gastroenterol 2018; 24:5297-5311. [PMID: 30598575 PMCID: PMC6305530 DOI: 10.3748/wjg.v24.i47.5297] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/27/2018] [Accepted: 12/01/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals (DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with anti-inflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanisms of HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection.
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Affiliation(s)
- Hu Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Meng-Hao Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jian-Dong Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zong-Gen Peng
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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10
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Aeginetia indica Decoction Inhibits Hepatitis C Virus Life Cycle. Int J Mol Sci 2018; 19:ijms19010208. [PMID: 29315273 PMCID: PMC5796157 DOI: 10.3390/ijms19010208] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 01/03/2018] [Accepted: 01/05/2018] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is still a global epidemic despite the introduction of several highly effective direct-acting antivirals that are tagged with sky-high prices. The present study aimed to identify an herbal decoction that ameliorates HCV infection. Among six herbal decoctions tested, the Aeginetia indica decoction had the most profound effect on the HCV reporter activity in infected Huh7.5.1 liver cells in a dose- and time-dependent manner. The Aeginetia indica decoction exerted multiple inhibitory effects on the HCV life cycle. Pretreatment of the cells with the Aeginetia indica decoction prior to HCV infection reduced the HCV RNA and non-structural protein 3 (NS3) protein levels in the infected cells. The Aeginetia indica decoction reduced HCV internal ribosome entry site-mediated protein translation activity. It also reduced the HCV RNA level in the infected cells in association with reduced NS5A phosphorylation at serine 235, a predominant phosphorylation event indispensable to HCV replication. Thus, the Aeginetia indica decoction inhibits HCV infection, translation, and replication. Mechanistically, the Aeginetia indica decoction probably reduced HCV replication via reducing NS5A phosphorylation at serine 235.
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11
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Salam OMA, Sleem AA, Omara EA, Hassan NS. Effect of Ribavirin Alone or Combined with Silymarin on Carbon Tetrachloride Induced Hepatic Damage in Rats. Drug Target Insights 2017. [DOI: 10.1177/117739280700200014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Omar M.E. Abdel Salam
- Department of Pharmacology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
| | - Amany A. Sleem
- Department of Pharmacology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
| | - Enayat A. Omara
- Department of Pathology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
| | - Nabila S. Hassan
- Department of Pathology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt
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12
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Fathalah WF, Abdel Aziz MA, Abou el Soud NH, El Raziky MES. High Dose of Silymarin in Patients with Decompensated Liver Disease: A Randomized Controlled Trial. J Interferon Cytokine Res 2017; 37:480-487. [DOI: 10.1089/jir.2017.0051] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Waleed Fouad Fathalah
- Endemic Gastroenterology and Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
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13
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de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World J Gastroenterol 2017; 23:5004-5017. [PMID: 28785154 PMCID: PMC5526770 DOI: 10.3748/wjg.v23.i27.5004] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/06/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of silymarin on the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (γGT) in patients with liver diseases. METHODS A systematic review with meta-analysis of ramdomized and controlled clinical trials was performed, evaluating the effects of sylimarin in patients with hepatic diseases, published by January 31, 2016. Clinical trials were sought on the basis of The Cochrane Central Register of Controlled Trials in the Cochrane Library, PubMed/Medline, Scopus, Web of Science, Lilacs and Clinical Trials. The trials with adult and elderly patients of both sexes, with Liver Diseases who took oral silymarin supplementation, as extract or isolated, as well as Silymarin combined with other nutrients, were included. The trials should provide information about the intervention, such as dosages and detailing of the product used, besides the mean and standard deviation of serum levels of ALT, AST and γGT of the baseline and at the end of the intervention. RESULTS An amount of 10904 publications were identified. From those, only 17 were included in the systematic review and 6 in the meta-analysis, according to the used selection criteria. In this meta-analysis, the results indicated a reduction of 0.26 IU/mL (95%CI: -0.46-0.07, P = 0.007) at the level of ALT and 0.53 IU/mL (95%CI: -0.74-0.32, P = 0.000) at the serum levels of AST after using the silymarin, both, statistically significant, but with no clinical relevance. There was no significant change in the γGT levels. Subgroup analyzes were also performed for the biochemical markers in relation to the type of intervention, whether silymarin isolated or associated with other nutrients and the time of intervention (whether ≥ 6 mo or < 6 mo). Significant differences were not found. The evaluated studies presented a high degree of heterogeneity and low methodological quality in the carried out analysis. CONCLUSION Silymarin minimally reduced, but without clinical relevance, the serum levels of ALT and AST. It is necessary to carry out studies with more appropriate methodological designs.
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Ferenci P. Silymarin in the treatment of liver diseases: What is the clinical evidence? Clin Liver Dis (Hoboken) 2016; 7:8-10. [PMID: 31041017 PMCID: PMC6490246 DOI: 10.1002/cld.522] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Peter Ferenci
- Internal Medicine 3, Department of Gastroenterology and HepatologyMedical University of ViennaViennaAustria
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15
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Evren E, Yurtcu E. In vitro effects on biofilm viability and antibacterial and antiadherent activities of silymarin. Folia Microbiol (Praha) 2015; 60:351-6. [PMID: 25937395 DOI: 10.1007/s12223-015-0399-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 04/27/2015] [Indexed: 12/20/2022]
Abstract
Limited treatment options in infectious diseases caused by resistant microorganisms created the need to search new approaches. Several herbal extracts are studied for their enormous therapeutic potential. Silymarin extract, from Silybum marianum (milk thistle), is an old and a new remedy for this goal. The purpose of this study is to evaluate the antibacterial and antiadherent effects of silymarin besides biofilm viability activity on standard bacterial strains. Minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), antiadherent/antibiofilm activity, and effects on biofilm viability of silymarin were evaluated against standard bacterial strains. MIC values were observed between 60 and >241 μg/mL (0.25->1 mmol/L). Gram-positive bacteria were inhibited at concentrations between 60 and 120 μg/mL. Gram-negative bacteria were not inhibited by the silymarin concentrations included in this study. MBC values for Gram-positive bacteria were greater than 241 μg/mL. Adherence/biofilm formations were decreased to 15 μg/mL silymarin concentration when compared with silymarin-untreated group. Silymarin reduced the biofilm viabilities to 13 and 46 % at 1 and 0.5 mmol/L concentrations, respectively. We demonstrated that silymarin shows antibacterial and antiadherent/antibiofilm activity against certain standard bacterial strains which may be beneficial when used as a dietary supplement or a drug.
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Affiliation(s)
- Ebru Evren
- Department of Medical Microbiology, Faculty of Medicine, Baskent University, Eskisehir yolu 20.km Baglica, Ankara, Turkey,
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16
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Yang Z, Zhuang L, Lu Y, Xu Q, Chen X. Effects and tolerance of silymarin (milk thistle) in chronic hepatitis C virus infection patients: a meta-analysis of randomized controlled trials. BIOMED RESEARCH INTERNATIONAL 2014; 2014:941085. [PMID: 25247194 PMCID: PMC4163440 DOI: 10.1155/2014/941085] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 08/06/2014] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This study aimed to evaluate the efficacy and safety of silymarin on chronic hepatitis C virus- (HCV-) infected patients. METHODS Randomized controlled trials (RCTs) of silymarin in chronic HCV-infected patients up to April 1, 2014 were systematically identified in PubMed, Ovid, Web of Science, and Cochrane Library databases. RESULTS A total of 222 and 167 patients in five RCTs were randomly treated with silymarin (or intravenous silibinin) and placebo, respectively. Serum HCV RNA relatively decreased in patients treated with silymarin compared with those administered with placebo, but no significance was found (P = 0.09). Meta-analysis of patients orally treated with silymarin indicated that the changes of HCV RNA are similar in the two groups (P = 0.19). The effect on alanine aminotransferase (ALT) of oral silymarin is not different from that of placebo (P = 0.45). Improvements in quality-of-life (Short Form-36) in both silymarin and placebo recipients were impressive but relatively identical (P = 0.09). CONCLUSION Silymarin is well tolerated in chronic HCV-infected patients. However, no evidence of salutary effects of oral silymarin has yet been reported based on intermediate endpoints (ALT and HCV RNA) in this population. Moreover, intravenous administration of silymarin should be further studied.
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Affiliation(s)
- Zongguo Yang
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
| | - Liping Zhuang
- Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yunfei Lu
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
| | - Qingnian Xu
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
| | - Xiaorong Chen
- Shanghai Public Health Clinical Center Affiliated to Fudan University, No. 2901, Caolang Road, Jinshan District, Shanghai 201508, China
- Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (Clinical Base), Shanghai 201508, China
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17
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Kazazis CE, Evangelopoulos AA, Kollas A, Vallianou NG. The therapeutic potential of milk thistle in diabetes. Rev Diabet Stud 2014; 11:167-74. [PMID: 25396404 PMCID: PMC4310066 DOI: 10.1900/rds.2014.11.167] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 08/07/2014] [Accepted: 08/08/2014] [Indexed: 01/11/2023] Open
Abstract
Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed.
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Affiliation(s)
- Christos E. Kazazis
- School of Medicine, University of Leicester, University Rd, Leicester, LE1 9HN, UK
| | | | - Aris Kollas
- First Department of Internal Medicine, Evangelismos General Hospital, 10676 Athens, Greece
| | - Natalia G. Vallianou
- First Department of Internal Medicine, Evangelismos General Hospital, 10676 Athens, Greece
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18
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Brantley SJ, Argikar AA, Lin YS, Nagar S, Paine MF. Herb-drug interactions: challenges and opportunities for improved predictions. Drug Metab Dispos 2014; 42:301-17. [PMID: 24335390 PMCID: PMC3935140 DOI: 10.1124/dmd.113.055236] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 12/11/2013] [Indexed: 01/23/2023] Open
Abstract
Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.
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Affiliation(s)
- Scott J Brantley
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (S.J.B.); Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania (A.A.A., S.N.); Department of Pharmaceutics, University of Washington, Seattle, Washington (Y.S.L.); and College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.)
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19
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Carreño V. Review article: management of chronic hepatitis C in patients with contraindications to anti-viral therapy. Aliment Pharmacol Ther 2014; 39:148-62. [PMID: 24279580 DOI: 10.1111/apt.12562] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 08/13/2013] [Accepted: 11/05/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND There are patients with chronic hepatitis C who are not eligible for the current interferon-based therapies or refuse to be treated due to secondary effects. AIM To provide information on alternative treatments for the management of these patients. METHODS A PubMed search was performed to identify relevant literature. Search terms included hepatitis C virus, anti-inflammatory treatment, antioxidant, natural products and alternative treatment, alone or in combination. Additional publications were identified using the references cited by primary and review articles. RESULTS Several approaches, such as iron depletion (phlebotomy), treatment with ursodeoxycholic acid or glycyrrhizin, have anti-inflammatory and/or anti-fibrotic effects. Life interventions like weight loss, exercise and coffee consumption are associated with a biochemical improvement. Other alternatives (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) do not have any beneficial effect or need to be tested in larger clinical studies. CONCLUSION There are therapeutic strategies and lifestyle interventions that can be used to improve liver damage in patients with chronic hepatitis C who cannot receive or refuse interferon-based treatments.
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Affiliation(s)
- V Carreño
- Fundación Estudio Hepatitis Virales, Madrid, Spain
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20
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Polyak SJ, Ferenci P, Pawlotsky JM. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology 2013; 57:1262-1271. [PMID: 23213025 PMCID: PMC3594650 DOI: 10.1002/hep.26179] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 09/05/2012] [Indexed: 12/21/2022]
Affiliation(s)
- Stephen J Polyak
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98104, USA.
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21
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Abdel-Salam OME, Sleem AA, Shafee N. Hepatoprotective effects of Cynara extract and silymarin on carbon tetrachloride-induced hepatic damage in rats. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/s00580-012-1675-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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22
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Hackett ES, Twedt DC, Gustafson DL. Milk thistle and its derivative compounds: a review of opportunities for treatment of liver disease. J Vet Intern Med 2013; 27:10-6. [PMID: 23140176 DOI: 10.1111/jvim.12002] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 08/18/2012] [Accepted: 09/18/2012] [Indexed: 02/06/2023] Open
Abstract
Milk thistle extracts have been used as a "liver tonic" for centuries. In recent years, silibinin, the active ingredient in milk thistle extracts, has been studied both in vitro and in vivo to evaluate the beneficial effects in hepatic disease. Silibinin increases antioxidant concentrations and improves outcomes in hepatic diseases resulting from oxidant injury. Silibinin treatment has been associated with protection against hepatic toxins, and also has resulted in decreased hepatic inflammation and fibrosis. Limited information currently is available regarding silibinin use in veterinary medicine. Future study is justified to evaluate dose, kinetics, and treatment effects in domestic animals.
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Affiliation(s)
- E S Hackett
- Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
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23
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Abdel-Salam OME, Sleem AA, Shaffie N. Hypericum perforatum protects against hepatic injury induced by carbon tetrachloride. COMPARATIVE CLINICAL PATHOLOGY 2012; 21:1149-1157. [DOI: 10.1007/s00580-011-1252-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2025]
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Calland N, Dubuisson J, Rouillé Y, Séron K. Hepatitis C virus and natural compounds: a new antiviral approach? Viruses 2012; 4:2197-217. [PMID: 23202460 PMCID: PMC3497048 DOI: 10.3390/v4102197] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 10/02/2012] [Accepted: 10/10/2012] [Indexed: 12/18/2022] Open
Abstract
Hepatitis C is a major global health burden with an estimated 160 million infected individuals worldwide. This long-term disease evolves slowly, often leading to chronicity and potentially to liver failure. There is no anti-HCV vaccine, and, until recently, the only treatment available, based on pegylated interferon and ribavirin, was partially effective, and had considerable side effects. With recent advances in the understanding of the HCV life cycle, the development of promising direct acting antivirals (DAAs) has been achieved. Their use in combination with the current treatment has led to encouraging results for HCV genotype 1 patients. However, this therapy is quite expensive and will probably not be accessible for all patients worldwide. For this reason, constant efforts are being made to identify new antiviral molecules. Recent reports about natural compounds highlight their antiviral activity against HCV. Here, we aim to review the natural molecules that interfere with the HCV life cycle and discuss their potential use in HCV therapy.
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Affiliation(s)
- Noémie Calland
- Inserm U1019, CNRS UMR8204, Center for Infection & Immunity of Lille, Institut Pasteur de Lille, Université Lille Nord de France, Lille, France.
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25
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Polyak SJ, Oberlies NH, Pécheur EI, Dahari H, Ferenci P, Pawlotsky JM. Silymarin for HCV infection. Antivir Ther 2012; 18:141-147. [PMID: 23011959 PMCID: PMC4076489 DOI: 10.3851/imp2402] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2012] [Indexed: 12/11/2022]
Abstract
Silymarin, an extract of milk thistle seeds, and silymarin-derived compounds have been considered hepatoprotective since the plant was first described in ancient times. Hepatoprotection is defined as several non-mutually exclusive biological activities including antiviral, antioxidant, anti-inflammatory and immunomodulatory functions. Despite clear evidence for silymarin-induced hepatoprotection in cell culture and animal models, evidence for beneficial effects in humans has been equivocal. This review will summarize the current state of knowledge on silymarin in the context of HCV infection. The information was collated from a recent workshop on silibinin in Germany.
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Affiliation(s)
- Stephen J Polyak
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
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26
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Omar AA, Hadad GM, Badr JM. First detailed quantification of silymarin components in the leaves ofSilybum marianumcultivated in egypt during different growth stages. ACTA CHROMATOGR 2012. [DOI: 10.1556/achrom.24.2012.3.9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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27
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Biermer M, Schlosser B, Fülöp B, van Bömmel F, Brodzinski A, Heyne R, Keller K, Sarrazin C, Berg T. High-dose silibinin rescue treatment for HCV-infected patients showing suboptimal virologic response to standard combination therapy. J Viral Hepat 2012; 19:547-53. [PMID: 22762138 DOI: 10.1111/j.1365-2893.2011.01572.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Incomplete suppression of hepatitis C virus (HCV) replication with persistence of minimal viremia (partial virologic response) leading to treatment failure can be observed in a significant proportion of HCV type 1-infected patients during antiviral therapy. Recently, high-dose intravenous silibinin has demonstrated strong antiviral activity against HCV. We were therefore interested in whether patients with partial virologic response can be rescued by the on-treatment addition of a short-term course of high-dose intravenous silibinin infusions. Twenty patients who failed to achieve a complete virologic response to different interferon-based regimens qualified for the rescue strategy and received 1400 mg/day silibinin infusions on two consecutive days. Complete viral suppression (below the limit of detection <6 IU/mL, TMA assay) could be induced in 13 of 20 patients within the first week after the short-term silibinin infusion, and all but one of them also remained HCV RNA negative during the subsequent follow-up period on continued peginterferon plus ribavirin treatment. In the remaining seven patients, no complete suppression could be achieved although four showed a significant HCV RNA reduction in response to silibinin. Silibinin infusions were generally well tolerated, and activation of abdominal peristalsis with nausea, diarrhoea and vomiting were the most prominent side effects. Of the twelve patients who exhibited a durable response to peginterferon and ribavirin treatment, three achieved an SVR, two achieved a week 12 SVR and four suffered a viral relapse. Three patients could not complete the assigned antiviral treatment with peginterferon alpha and ribavirin for nonvirological reasons. Short-term administration of high-dose intravenous silibinin might be an interesting approach to rescue patients with ongoing minimal residual viremia while on interferon-based therapy. These preliminary findings may stimulate further studies to evaluate more refined therapeutic strategies.
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Affiliation(s)
- M Biermer
- Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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Ward J, Kapadia K, Brush E, Salhanick SD. Amatoxin poisoning: case reports and review of current therapies. J Emerg Med 2012; 44:116-21. [PMID: 22555054 DOI: 10.1016/j.jemermed.2012.02.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2011] [Revised: 09/15/2011] [Accepted: 02/12/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND Diagnosis and management of Amanita mushroom poisoning is a challenging problem for physicians across the United States. With 5902 mushroom exposures and two resultant deaths directly linked to Amanita ingestion in 2009, it is difficult for physicians to determine which patients are at risk for lethal toxicity. Identification of amatoxin poisoning can prove to be difficult due to delay in onset of symptoms and difficulty with identification of mushrooms. Consequently, it is difficult for the Emergency Physician to determine proper disposition. Further, treatment options are controversial. OBJECTIVES To review current data to help health care providers effectively identify and treat potentially deadly Amanita mushroom ingestions. CASE REPORTS We present two cases of Amanita mushroom ingestion in the northeastern United States treated with N-acetylcysteine, high-dose penicillin, cimetidine, and silibinin, a semi-purified fraction of milk thistle-derived silymarin, as part of their treatment regimen. The mushroom species was identified by a consultant as Amanita Ocreata. CONCLUSIONS We present the successful treatment of 2 patients who ingested what we believe to be an Amanita species never before identified in the northeastern United States.
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Affiliation(s)
- Jeanine Ward
- University of Massachusetts Medical School, Worcester Massachusetts 01655, USA
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Singal AK, Jampana SC, Weinman SA. Antioxidants as therapeutic agents for liver disease. Liver Int 2011; 31:1432-48. [PMID: 22093324 PMCID: PMC3228367 DOI: 10.1111/j.1478-3231.2011.02604.x] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2010] [Accepted: 06/15/2011] [Indexed: 12/12/2022]
Abstract
Oxidative stress is commonly associated with a number of liver diseases and is thought to play a role in the pathogenesis of chronic hepatitis C, alcoholic liver disease, non-alcoholic steatohepatitis (NASH), haemochromatosis and Wilson's disease. Antioxidant therapy has thus been considered to have the possibility of beneficial effects in the management of these liver diseases. Despite this promise, antioxidants have produced mixed results in a number of clinical trials of efficacy. This review summarizes the results of clinical trials of antioxidants as sole or adjuvant therapy of chronic hepatitis C, alcoholic liver disease and non-alcoholic steatohepatitis (NASH). Overall, the most promising results to date are for vitamin E therapy of NASH but some encouraging results have been obtained with antioxidant therapy of acute alcoholic hepatitis as well. Despite evidence for small reductions of serum alanine aminotransferase, there is as yet no convincing evidence that antioxidant therapy itself is beneficial to patients with chronic hepatitis C. Problems such as small sample size, short follow up duration, inadequate endpoints, failure to demonstrate tissue delivery and antioxidant efficacy, and heterogeneous nature of the 'antioxidant' compounds used have complicated interpretation of results of the clinical studies. These limitations and their implications for future trial design are discussed.
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Affiliation(s)
- Ashwani K. Singal
- Department of Internal Medicine, University of Texas Medical Branch; Galveston, TX
| | - Sarat C. Jampana
- Department of Internal Medicine, University of Texas Medical Branch; Galveston, TX
| | - Steven A. Weinman
- Department of Internal Medicine; University of Kansas Medical Center; Kansas City, KS
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Synergistic antibacterial effect between silibinin and antibiotics in oral bacteria. J Biomed Biotechnol 2011; 2012:618081. [PMID: 21941436 PMCID: PMC3173953 DOI: 10.1155/2012/618081] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2011] [Revised: 07/04/2011] [Accepted: 07/14/2011] [Indexed: 01/09/2023] Open
Abstract
Silibinin is a composition of the silymarin group as a hepatoprotective agent, and it exhibits various biological activities, including antibacterial activity. In this study, the antibacterial activities of silibinin were investigated in combination with two antimicrobial agents against oral bacteria. Silibinin was determined with MIC and MBC values ranging from 0.1 to 3.2 and 0.2 to 6.4 μg/mL, ampicillin from 0.125 to 64 and 0.5 to 64 μg/mL, gentamicin from 2 to 256 and 4 to 512 μg/mL, respectively. The ranges of MIC50 and MIC90 were 0.025–0.8 μg/mL and 0.1–3.2 μg/mL, respectively. The antibacterial activities of silibinin against oral bacteria were assessed using the checkerboard and time-kill methods to evaluate the synergistic effects of treatment with ampicillin or gentamicin. The results were evaluated showing that the combination effects of silibinin with antibiotics were synergistic (FIC index <0.5) against all tested oral bacteria. Furthermore, a time-kill study showed that the growth of the tested bacteria was completely attenuated after 2–6 h of treatment with the MBC of silibinin, regardless of whether it was administered alone or with ampicillin or gentamicin. These results suggest that silibinin combined with other antibiotics may be microbiologically beneficial and not antagonistic.
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Loguercio C, Festi D. Silybin and the liver: From basic research to clinical practice. World J Gastroenterol 2011; 17:2288-301. [PMID: 21633595 PMCID: PMC3098397 DOI: 10.3748/wjg.v17.i18.2288] [Citation(s) in RCA: 244] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2010] [Revised: 12/23/2010] [Accepted: 12/30/2010] [Indexed: 02/06/2023] Open
Abstract
Herbal products are increasingly used, mainly in chronic liver disease. Extracts of milk thistle, Silymarin and silybin, are the most prescribed natural compounds, with different indications, but with no definitive results in terms of clinical efficacy. This review analyzes the available studies on the effects of the purified product silybin, both as a free and a conjugated molecule, on liver cells or on experimentally induced liver damage, and in patients with liver disease. We searched PUBMED for articles pertaining to the in vitro and in vivo effects of silybin, its antifibrotic, anti-inflammatory, and antioxidant properties, as well as its metabolic effects, combined with the authors’ own knowledge of the literature. Results indicate that the bioavailability of silybin phytosome is higher than that of silymarin and is less influenced by liver damage; silybin does not show significant interactions with other drugs and at doses < 10 g/d has no significant side effects. Experimental studies have clearly demonstrated the antifibrotic, antioxidant and metabolic effects of silybin; previous human studies were insufficient for confirming the clinical efficacy in chronic liver disease, while ongoing clinical trials are promising. On the basis of literature data, silybin seems a promising drug for chronic liver disease.
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Mehrab-Mohseni M, Sendi H, Steuerwald N, Ghosh S, Schrum LW, Bonkovsky HL. Legalon-SIL downregulates HCV core and NS5A in human hepatocytes expressing full-length HCV. World J Gastroenterol 2011; 17:1694-700. [PMID: 21483629 PMCID: PMC3072633 DOI: 10.3748/wjg.v17.i13.1694] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Revised: 12/22/2010] [Accepted: 12/29/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the effect of Legalon-SIL (LS) on hepatitis C virus (HCV) core and NS5A expression and on heme oxygenase-1 (HMOX-1) and its transcriptional regulators in human hepatoma cells expressing full length HCV genotype 1b. METHODS CON1 cells were treated with 50 μmol/L or 200 μmol/L LS. Cells were harvested after 2, 6 and 24 h. HCV RNA and protein levels were determined by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESULTS HCV RNA (core and NS5A regions) was decreased after 6 h with LS 200 μmol/L (P < 0.05). Both 50 and 200 μmol/L LS decreased HCV RNA levels [core region (by 55% and 88%, respectively) and NS5A region (by 62% and 87%, respectively) after 24 h compared with vehicle (dimethyl sulphoxide) control (P < 0.01). Similarly HCV core and NS5A protein were decreased (by 85%, P < 0.01 and by 65%, P < 0.05, respectively) by LS 200 μmol/L. Bach1 and HMOX-1 RNA were also downregulated by LS treatment (P < 0.01), while Nrf2 protein was increased (P < 0.05). CONCLUSION Our results demonstrate that treatment with LS downregulates HCV core and NS5A expression in CON1 cells which express full length HCV genotype 1b, and suggests that LS may prove to be a valuable alternative or adjunctive therapy for the treatment of HCV infection.
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Eurich D, Boas-Knoop S, Ruehl M, Schulz M, Carrillo ED, Berg T, Neuhaus R, Neuhaus P, Neumann UP, Bahra M. Relationship between the interleukin-28b gene polymorphism and the histological severity of hepatitis C virus-induced graft inflammation and the response to antiviral therapy after liver transplantation. Liver Transpl 2011; 17:289-98. [PMID: 21384511 DOI: 10.1002/lt.22235] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Up to 30% of liver transplants will develop graft cirrhosis within 5 years after liver transplantation (LT) due to recurrent HCV-infection forwarding accelerated graft damage. Genetic variants of cytokines involved in the immune response may contribute to the degree of graft inflammation, fibrosis progression, and antiviral therapy outcome. The aim of our study was to analyze biochemical and histological inflammation extent based on protocol liver biopsies and to evaluate the role of genetic variants of IL-28b in HCV-related graft disease and antiviral treatment response. 183 patients, who underwent liver transplantation for HCV-induced liver disease, were genotyped for IL-28b (rs8099917, G ≥ T) by TaqMan Genotyping Assay. 56 of 159 patients have been successfully treated with interferon-based antiviral therapy. 605 protocol liver biopsies performed 0.5 to 10 and more than 10 years after transplantation were evaluated according to Desmet and Scheuer classification of inflammation and fibrosis. Prevalence of IL-28b-genotypes was correlated with histological severity of graft damage, levels of aminotransferases, occurrence of acute cellular rejection, pre-treatment viremia, and antiviral therapy outcome. Significant association of IL-28b-genotype distribution was observed to the median grade of inflammation (p < 0.001), mean levels of aminotransferases (ALT: p = 0.001, AST: p = 0.003), median pre-treatment viremia level within 1 year after LT (p = 0.046) and interferon-based antiviral therapy failure (p < 0.001). Among successfully treated patients, G-allele was significantly less frequent, and the genotype GG was not present at all. No differences were observed regarding acute cellular rejection (p = 0.798) and fibrosis stages (p = 0.586). IL-28b polymorphism seems to influence the degree of graft inflammation at biochemical and histological levels. G-allele might serve as a marker for graft inflammation and as a predictor for unfavorable antiviral therapy outcome in HCV-re-infected LT-population.
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Affiliation(s)
- Dennis Eurich
- Department of General, Visceral, and Transplant Surgery, Charité, Campus Virchow, Berlin, Germany.
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Freedman ND, Curto TM, Morishima C, Seeff LB, Goodman ZD, Wright EC, Sinha R, Everhart JE, HALT-C Trial Group. Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther 2011; 33:127-37. [PMID: 21083592 PMCID: PMC3490214 DOI: 10.1111/j.1365-2036.2010.04503.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear. AIM To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment. METHODS Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes. RESULTS At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33-1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes. CONCLUSIONS Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
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Affiliation(s)
- N D Freedman
- Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852, USA.
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Delang L, Coelmont L, Neyts J. Antiviral therapy for hepatitis C virus: beyond the standard of care. Viruses 2010; 2:826-866. [PMID: 21994657 PMCID: PMC3185663 DOI: 10.3390/v2040826] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Revised: 03/09/2010] [Accepted: 03/17/2010] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed.
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Affiliation(s)
| | | | - Johan Neyts
- Rega Institute for Medical Research, KULeuven, Minderbroedersstraat 10, 3000 Leuven, Belgium; E-Mails: (L.D.); (L.C.)
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Abdel Salam OME, Sleem AA, Shafee N. Hepatoprotective effects of the nitric oxide donor isosorbide-5-mononitrate alone and in combination with the natural hepatoprotectant, silymarin, on carbon tetrachloride-induced hepatic injury in rats. Inflammopharmacology 2010; 18:87-94. [PMID: 20069380 DOI: 10.1007/s10787-009-0027-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2009] [Accepted: 12/10/2009] [Indexed: 12/23/2022]
Abstract
The aim of this study was to investigate the effect of the nitric oxide donor isosorbide-5-mononitrate (5-ISMN) alone or in combination with the natural hepatoprotectant with anti-oxidant activity silymarin on the carbon tetrachloride (CCl(4))-induced hepatic injury in rats. 5-ISMN (1.8, 3.6 or 7.2 mg/kg), silymarin (25 mg/kg) or 5-ISMN (1.8, 3.6 or 7.2 mg/kg) combined with silymarin was given once daily orally simultaneously with CCl(4) and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. 5-ISMN given at the above doses conferred significant protection against the hepatotoxic actions of CCl(4) in rats, reducing serum alanine aminotransferase (ALT) levels by 31.2, 39.3 and 61.6%, respectively, when compared with controls. Serum aspartate aminotransferase (AST) levels decreased by 19.8, 22.7 and 59.4%, respectively, while alkaline phosphatase (ALP) decreased by 26.1 and 32.6% by the drug at 3.6 and 7.2 mg/kg, respectively. When silymarin was added to 5-ISMN (1.8, 3.6 or 7.2 mg/kg), ALT decreased by 32.8, 59.6, 70.2% and AST by 28.7, 50.3, 60%, when compared with CCl(4) control group levels. Silymarin in combination with 3.6 or 7.2 mg/kg 5-ISMN resulted in 37.5 and 39.2% reductions in ALP when compared with CCl(4) control group. Meanwhile, silymarin alone reduced ALT, AST and ALP levels by 65.9, 52 and 62.3%, respectively. Blood levels of reduced glutathione were markedly decreased in CCl(4)-treated rats. Reduced glutathione levels were increased by the administration of 5-ISMN and restored to near normal values by silymarin treatment. Histopathological alterations by CCl(4) were markedly reduced after treatment with 5-ISMN alone or in combination with silymarin. Histopathologic examination of the livers of CCl(4)-treated rats administered 5-ISMN at 7.2 mg/kg showed marked restoration of the normal architecture of the liver tissue and minimal fibrosis. Silymarin co-administered with 5-ISMN resulted in further improvement of the histologic picture. These results indicates that treatment with 5-ISMN protects against hepatocellular necrosis induced by CCl(4). The study suggests a potential therapeutic use for 5-ISMN in combination with silymarin in liver injury.
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Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ, Berman J, Liu QY, Doo E, Fried MW. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol 2009; 50:434-49. [PMID: 19841158 DOI: 10.1177/0091270009347475] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.
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Affiliation(s)
- Roy L Hawke
- Clinical Assistant Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, CB #7360, Kerr Hall Rm 3310, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
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Fehér J, Lengyel G. Silymarin in the treatment of chronic liver diseases: Past and future. ACTA ACUST UNITED AC 2009. [DOI: 10.1556/cemed.3.2009.28519] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Salam OMEA, Sleem AA, Omara EA, Hassan NS. Hepatoprotective effects of misoprostol and silymarin on carbon tetrachloride-induced hepatic damage in rats. Fundam Clin Pharmacol 2009; 23:179-188. [PMID: 19298238 DOI: 10.1111/j.1472-8206.2008.00654.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The aim of this study was to investigate the effect of misoprostol, silymarin or the co-administration of misoprostol + silymarin on the carbon tetrachloride (CCl(4))-induced hepatic injury in rats. Misoprostol (10, 100, 1000 microg/kg), silymarin (25 mg/kg) or misoprostol (100 microg/kg) + silymarin (25 mg/kg) was given once daily orally simultaneously with CCl(4) and for 15 days thereafter. The results showed that misoprostol (10, 100 or 1000 microg/kg) conferred significant protection against the hepatotoxic actions of CCl(4) in rats, reducing serum alanine aminotransferase (ALT) levels by 24.7%, 42.6% and 49.4%, respectively compared with controls. Misoprostol, given at 100 or 1000 microg/kg, decreased aspartate aminotransferase (AST) by 28 and 43.6% and alkaline phosphatase (ALP) by 19.3% and 53.4% respectively. Meanwhile, silymarin reduced ALT, AST and ALP levels by 62.7%, 66.1% and 65.1% respectively. The co-administration of misoprostol (100 microg/kg) and silymarin (25 mg/kg) resulted in 61.4%, 66.1% and 57.5% reduction in ALT, AST and ALP levels respectively. Histopathological alterations and depletion of hepatocyte glycogen and DNA content by CCl(4) were markedly reduced after treatment with misoprostol, silymarin or misoprostol + silymarin. Image analysis of liver specimens revealed a marked reduction in liver necrosis; area of damage: 32.4%, 24% and 10.2% after misoprostol (10, 100 or 1000 microg/kg), 7.2% after silymarin and 10.9% after treatment with misoprostol 100 microg/kg + silymarin, compared with CCl(4) control group (46.7%). These results indicate that treatment with misoprostol protects against hepatocellular necrosis induced by CCl(4). This study suggests a potential therapeutic use for misoprostol in liver injury.
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Pár A, Rőth E, Miseta A, Hegedűs G, Pár G, Hunyady B, Vincze Á. Effects of silymarin supplementation in patients with chronic hepatitis C receiving PEG-IFN + ribavirin antiviral therapy. A placebo-controlled double blind study. ACTA ACUST UNITED AC 2009. [DOI: 10.1556/cemed.3.2009.28517] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Gupta NK, Lewis JH. Review article: The use of potentially hepatotoxic drugs in patients with liver disease. Aliment Pharmacol Ther 2008; 28:1021-41. [PMID: 18671777 DOI: 10.1111/j.1365-2036.2008.03822.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Misconceptions surround the use of hepatotoxic drugs in chronic liver disease. While many prescription and over-the-counter (OTC) agents can be used safely, this often runs counter to labelled warnings/contraindications, especially for the statins and other commonly used agents. AIM To evaluate published data on the use of hepatotoxic drugs in chronic liver disease including pharmacokinetic changes in cirrhosis and drug interactions, where available, to formulate recommendations on their use. METHODS Using a combination of PubMed searches, review texts, the Physicians' Desk Reference and expert opinion, drugs considered at higher risk of hepatotoxicity in chronic liver disease were evaluated. RESULTS Most drugs and OTC products including herbals have not been formally studied in chronic liver disease, but available data suggest that several of the most commonly used agents, especially the statins, can be used safely. While there is an increased risk of drug-induced liver injury for drugs used in the treatment of tuberculosis and HIV patients with hepatitis B or C, recommendations for their safe use are emerging. CONCLUSIONS Although many clinicians remain hesitant to use hepatotoxic drugs in chronic liver disease, the database supporting this view is limited to just a few agents. Most medications can be used safely in patients with chronic liver disease with appropriate monitoring.
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Affiliation(s)
- N K Gupta
- Division of Gastroenterology, Georgetown University Medical Center, Washington, DC 20007, USA
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Ferenci P, Scherzer TM, Kerschner H, Rutter K, Beinhardt S, Hofer H, Schöniger-Hekele M, Holzmann H, Steindl-Munda P. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008; 135:1561-1567. [PMID: 18771667 DOI: 10.1053/j.gastro.2008.07.072] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2008] [Revised: 07/14/2008] [Accepted: 07/24/2008] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Oral Silibinin (SIL) is widely used for treatment of hepatitis C, but its efficacy is unclear. Substantially higher doses can be administered intravenously (IV). METHODS Pedigreed nonresponders to full-dose pegylated (Peg)-interferon/ribavirin (PegIFN/RBV) were studied. First, 16 patients received 10 mg/kg/day SIL IV (Legalon Sil; Madaus, Köln, Germany) for 7 days. In a subsequent dose-finding study, 20 patients received 5, 10, 15, or 20 mg/kg/day SIL for 14 days. In both protocols, PegIFN alpha-2a/RBV were started on day 8. Viral load was determined daily. RESULTS Unexpectedly, in the first study, HCV-RNA declined on IV SIL by 1.32 +/- 0.55 log (mean +/- SD), P < .001 but increased again in spite of PegIFN/RBV after the infusion period. The viral load decrease was dose dependent (log drop after 7 days SIL: 0.55 +/- 0.5 [5 mg/kg, n = 3], 1.41 +/- 0.59 [10 mg/kg, n = 19], 2.11 +/- 1.34 [15 mg/kg, n = 5], and 3.02 +/- 1.01 [20 mg/kg, n = 9]; P < .001), decreased further after 7 days combined SIL/PegIFN/RBV (1.63 +/- 0.78 [5 mg/kg, n = 3], 4.16 +/- 1.28 [10 mg/kg, n = 3], 3.69 +/- 1.29 [15 mg/kg, n = 5], and 4.85 +/- 0.89 [20 mg/kg, n = 9]; P < .001), and became undetectable in 7 patients on 15 or 20 mg/kg SIL, at week 12. Beside mild gastrointestinal symptoms, IV SIL monotherapy was well tolerated. CONCLUSIONS IV SIL is well tolerated and shows a substantial antiviral effect against HCV in nonresponders.
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Affiliation(s)
- Peter Ferenci
- Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
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Turgut F, Bayrak O, Catal F, Bayrak R, Atmaca AF, Koc A, Akbas A, Akcay A, Unal D. Antioxidant and protective effects of silymarin on ischemia and reperfusion injury in the kidney tissues of rats. Int Urol Nephrol 2008; 40:453-60. [PMID: 18368506 DOI: 10.1007/s11255-008-9365-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2007] [Accepted: 03/04/2008] [Indexed: 11/28/2022]
Abstract
BACKGROUND Renal ischemia/reperfusion (I/R) injury is a major cause of acute renal failure. Silymarin is extracted from Silybum marianum and Cynara cardunculus seeds and fruits. The aim of this study is to investigate whether silymarin administration prevents the damage induced by I/R in rat kidneys. MATERIALS AND METHODS Thirty male Wistar rats were randomly divided into five experimental groups (n = 6, each) as follows; control group, sham-operated group, I/R group, silymarin group, and I/R + silymarin group. In the I/R and I/R + silymarin groups, both renal arteries were occluded using nontraumatic microvascular clamps for 45 min. Then, at the end of 24 h of reperfusion, the animals were killed. Kidney function tests, the serum and tissue antioxidant enzymes and oxidant products were determined. RESULTS Animals that were subjected to I/R exhibited significant increase in serum urea, creatinine, and cystatin C levels compared with the rats treated with silymarin prior to the I/R process (P < 0.001). The serum enzymatic activities of superoxide dismutase and glutathione peroxidase significantly decreased in the I/R group; however, this reduction was significantly improved by the treatment with silymarin (P < 0.001 and P < 0.05, respectively). Renal I/R produced a significant increase in serum and tissue malondialdehyde, nitric oxide, and protein carbonyl as compared with controls. Treatment with silymarin resulted in significant reduction in these markers (P < 0.001). CONCLUSION Based on our findings, silymarin protects the kidneys against I/R injury. This finding may provide a basis for the development of novel therapeutic strategies for protection against the damages caused by I/R.
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Affiliation(s)
- Faruk Turgut
- Department of Nephrology, Fatih University, School of Medicine, Hosdere cad no: 145, Y. Ayranci, 06540 Ankara, Turkey.
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Schrieber SJ, Wen Z, Vourvahis M, Smith PC, Fried MW, Kashuba ADM, Hawke RL. The pharmacokinetics of silymarin is altered in patients with hepatitis C virus and nonalcoholic Fatty liver disease and correlates with plasma caspase-3/7 activity. Drug Metab Dispos 2008; 36:1909-16. [PMID: 18566043 DOI: 10.1124/dmd.107.019604] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Silymarin, used by 30 to 40% of liver disease patients, is composed of six major flavonolignans, each of which may contribute to silymarin's hepatoprotective properties. Previous studies have only described the pharmacokinetics for two flavonolignans, silybin A and silybin B, in healthy volunteers. The aim of this study was to determine the pharmacokinetics of the major silymarin flavonolignans in liver disease patients. Healthy volunteers and three patient cohorts were administered a single, 600-mg p.o. dose of milk thistle extract, and 14 blood samples were obtained over 24 h. Silybin A and B accounted for 43% of the exposure to the sum of total silymarin flavonolignans in healthy volunteers and only 31 to 38% in liver disease cohorts as a result of accumulation of silychristin (20-36%). Area under the curve (AUC(0-24h)) for the sum of total silymarin flavonolignans was 2.4-, 3.3-, and 4.7-fold higher for hepatitis C virus (HCV) noncirrhosis, nonalcoholic fatty liver disease (p
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Affiliation(s)
- Sarah J Schrieber
- Division of Pharmacotherapy and Experimental Therapeutics,School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7360, USA
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Bares JM, Berger J, Nelson JE, Messner DJ, Schildt S, Standish LJ, Kowdley KV. Silybin treatment is associated with reduction in serum ferritin in patients with chronic hepatitis C. J Clin Gastroenterol 2008; 42:937-44. [PMID: 18458640 DOI: 10.1097/mcg.0b013e31815cff36] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
GOALS The goal of this study was to examine the effect of a standardized silybin and soy phosphatidylcholine complex (IdB 1016) on serum markers of iron status. BACKGROUND Milk thistle and its components are widely used as an alternative therapy for liver disease because of purported antioxidant, anti-inflammatory, and iron chelating properties. STUDY Thirty-seven patients with chronic hepatitis C and Batts-Ludwig fibrosis stage II, III, or IV were randomized to 1 of 3 doses of IdB 1016 for 12 weeks. Serum ferritin, serum iron, total iron binding capacity, and transferrin-iron saturation were measured at baseline, during treatment, and 4 weeks thereafter. Wilcoxon signed rank tests were used to compare baseline and posttreatment values. RESULTS There was a significant decrease in serum ferritin from baseline to end of treatment (mean, 244 vs. 215 mug/L; median, 178 vs. 148 mug/L; P=0.0005); 78% of subjects had a decrease in serum ferritin level. There was no significant change in serum iron or transferrin-iron saturation. Multivariate logistic regression analysis in a model that included dose, age, sex, HFE genotype, history of alcohol use, and elevated baseline ferritin levels demonstrated that stage III or IV fibrosis was independently associated with decreased posttreatment serum ferritin level. CONCLUSIONS Treatment with IdB 1016 is associated with reduced body iron stores, especially among patients with advanced fibrosis stage.
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Affiliation(s)
- Julie M Bares
- Department of Medicine, University of Washington Medical Center, Seattle, WA, USA
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Saller R, Brignoli R, Melzer J, Meier R. An updated systematic review with meta-analysis for the clinical evidence of silymarin. ACTA ACUST UNITED AC 2008; 15:9-20. [PMID: 18334810 DOI: 10.1159/000113648] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The potential benefit of silymarin (special extract from the fruits of Silybum marianum) in the treatment of liver diseases remains a controversial issue. METHODS For this systematic review electronic databases identified 65 papers for the search terms silymarin, silibinin, silicristin or milk thistle and clinical trial. Only 19 complied with the criteria'double-' or 'single-blind'. These publications were analysed from a clinical point of view and meta-analytic calculations were performed. RESULTS The clinical evidence ofa therapeutic effect of silymarin in toxic liver diseases is scarce. There is no evidence of a favourable influence on the evolution of viral hepatitis, particularly hepatitis C. In alcoholic liver disease, comparing with placebo, aspartate aminotransferase was reduced in the silymarin-treated groups (p = 0.01) while alkaline phosphatase was not. In liver cirrhosis, mostly alcoholic, total mortality was 16.1% with silymarin vs. 20.5% with placebo (n.s.); liver-related mortality was 10.0% with silymarin vs. 17.3% with placebo(p = 0.01). CONCLUSIONS Based on the available clinical evidence it can be concluded - concerning possible risks /probable benefits - that it is reasonable to employ silymarin as a supportive element in the therapy of Amanita phalloides poisoning but also (alcoholic and grade Child 'A') liver cirrhosis. A consistent research programme, consolidating existing evidence and exploring new potential uses,would be very welcome.
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Affiliation(s)
- Reinhard Saller
- Institute of Complementary Medicine, Department of Internal Medicine, University Hospital Zurich, Switzerland.
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Polyak SJ, Morishima C, Hawke R. Antiviral effects of silymarin against hepatitis C: the jury is still out. Hepatology 2008; 48:345-6. [PMID: 18509876 DOI: 10.1002/hep.22235] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
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49
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Seeff LB, Curto TM, Szabo G, Everson GT, Bonkovsky HL, Dienstag JL, Shiffman ML, Lindsay KL, Lok ASF, Di Bisceglie AM, Lee WM, Ghany MG. Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology 2008; 47:605-12. [PMID: 18157835 DOI: 10.1002/hep.22044] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Herbal products, used for centuries in Far Eastern countries, are gaining popularity in western countries. Surveys indicate that persons with chronic hepatitis C (CHC) often use herbals, especially silymarin (milk thistle extract), hoping to improve the modest response to antiviral therapy and reduce side effects. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial, involving persons with advanced CHC, nonresponders to prior antiviral therapy but still willing to participate in long-term pegylated interferon treatment, offered the opportunity to examine the use and potential effects of silymarin. Among 1145 study participants, 56% had never taken herbals, 21% admitted past use, and 23% were using them at enrollment. Silymarin constituted 72% of 60 herbals used at enrollment. Among all participants, 67% had never used silymarin, 16% used it in the past, and 17% used it at baseline. Silymarin use varied widely among the 10 participating study centers; men were more frequent users than women, as were non-Hispanic whites than African Americans and Hispanics. Silymarin use correlated strongly with higher education. No beneficial effect of silymarin was found on serum alanine aminotransferase or hepatitis C virus (HCV) RNA levels. Univariate analysis showed significantly fewer liver-related symptoms and better quality-of-life parameters in users than nonusers, but after reanalysis adjusted for covariates of age, race, education, alcohol consumption, exercise, body mass index, and smoking, only fatigue, nausea, liver pain, anorexia, muscle and joint pain, and general health remained significantly better in silymarin users. In conclusion, silymarin users had similar alanine aminotransferase and HCV levels to those of nonusers but fewer symptoms and somewhat better quality-of-life indices. Because its use among these HALT-C participants was self-motivated and uncontrolled, however, only a well-designed prospective study can determine whether silymarin provides benefit to persons with chronic hepatitis C.
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Affiliation(s)
- Leonard B Seeff
- Division of Digestive Diseases and Nutrition, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
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Kaur M, Agarwal R. Silymarin and epithelial cancer chemoprevention: how close we are to bedside? Toxicol Appl Pharmacol 2007; 224:350-9. [PMID: 17184801 PMCID: PMC2692696 DOI: 10.1016/j.taap.2006.11.011] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Revised: 11/08/2006] [Accepted: 11/09/2006] [Indexed: 02/07/2023]
Abstract
Failure and high systemic toxicity of conventional cancer therapies have accelerated the focus on the search for newer agents, which could prevent and/or slow-down cancer growth and have more human acceptability by being less or non-toxic. Silymarin is one such agent, which has been extensively used since ages for the treatment of liver conditions, and thus has possibly the greatest patient acceptability. In recent years, increasing body of evidence has underscored the cancer preventive efficacy of silymarin in both in vitro and in vivo animal models of various epithelial cancers. Apart from chemopreventive effects, other noteworthy aspects of silymarin and its active constituent silibinin in cancer treatment include their capability to potentiate the efficacy of known chemotherapeutic drugs, as an inhibitor of multidrug resistance-associated proteins and as an adjunct to the cancer therapeutic drugs due to their organ-protective efficacy specifically liver, and immunostimulatory effects. Widespread use of silymarin for liver health in humans and commercial availability of its formulations with increased bioavailability, further underscore the necessity of carrying out controlled clinical trials with these agents in cancer patients. In this review, we will briefly discuss the outcomes of clinical trials being conducted by us and others in cancer patients to provide insight into the clinical relevance of the observed chemopreventive effects of these agents in various epithelial cancer models.
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Affiliation(s)
- Manjinder Kaur
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA
- University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA
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