Showing posts with label herb. Show all posts
Showing posts with label herb. Show all posts

Tuesday, June 12, 2018

NIH launches HerbList, app with information about safety and effectiveness of herbal products


NIH launches HerbList, a mobile app on herbal products

To help consumers navigate information about popular herbs and herbal supplements, the National Institutes of Health’s National Center for Complementary and Integrative Health has launched HerbList™ – an app for research-based information about the safety and effectiveness of herbal products. Developed by NCCIH and launched through the National Library of Medicine’s app pages, HerbList is available on the Apple App Store (link is external) and Google Play Store (link is external).

HerbList helps consumers, patients, healthcare providers, and other users to quickly access information about the science of popular herbs and herbal supplements including kava, acai, ginkgo, turmeric, and more than 50 others marketed for health purposes.

Users can access information on potential safety problems, side effects, and herb-drug interactions with additional links to resources for more information. They can also mark favorite herbs for quick recall and offline accessibility.

HerbList provides only scientific, research-driven information to provide consumers and health care practitioners with unbiased information to make informed decisions about supplement use.

"Providing an app for users is part of NCCIH's effort to inform consumers and health care providers within the complementary and integrative health space," said David Shurtleff, Ph.D., acting director of NCCIH. "People are considering herbs and herbal supplements for various reasons, and it is important that they are aware of what the research says about safety and effectiveness."

The app was built using NCCIH's Herbs at a Glance webpage; a series of brief fact sheets that provide basic information about specific herbs or botanicals—common names, what the science says, potential side effects and cautions, and resources for more information.

HerbList is available to download for your iPhone or iPad from the Apple App Store (link is external) or to your Android device via Google Play (link is external).

About the National Center for Complementary and Integrative Health (NCCIH): NCCIH’s mission is to define, through rigorous scientific investigation, the usefulness and safety of complementary and integrative health approaches and their roles in improving health and health care. For additional information, call NCCIH’s Clearinghouse toll free at 1-888-644-6226. Follow us on Twitter (link is external), Facebook (link is external), and YouTube.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

On This Blog
Hepatitis C and Dietary Supplements

Tuesday, April 3, 2018

FDA orders mandatory recall for kratom products - Triangle Pharmanaturals refused to cooperate

FDA News Release
FDA orders mandatory recall for kratom products due to risk of salmonella


Triangle Pharmanaturals refused to cooperate with FDA despite repeated attempts to encourage voluntary recall

The agency took this action after the company failed to cooperate with the FDA’s request to conduct a voluntary recall. This is the first time the agency has issued a mandatory recall order to protect Americans from contaminated food products.

Today, the U.S. Food and Drug Administration announced it has issued a mandatory recall order for all food products containing powdered kratom manufactured, processed, packed, or held by Triangle Pharmanaturals LLC, after several were found to contain salmonella. The agency took this action after the company failed to cooperate with the FDA’s request to conduct a voluntary recall. This is the first time the agency has issued a mandatory recall order to protect Americans from contaminated food products.

The FDA is advising consumers to discard the products that are part of the mandatory recall, which include, but are not limited to: Raw Form Organics Maeng Da Kratom Emerald Green, Raw Form Organics Maeng Da Kratom Ivory White, and Raw Form Organics Maeng Da Kratom Ruby Red. The FDA understands that Triangle Pharmanaturals may manufacture, process, pack and/or hold additional brands of food products containing powdered kratom, including powder and encapsulated powder forms.

“This action is based on the imminent health risk posed by the contamination of this product with salmonella, and the refusal of this company to voluntarily act to protect its customers and issue a recall, despite our repeated requests and actions,” said FDA Commissioner Scott Gottlieb, M.D. “We continue to have serious concerns about the safety of any kratom-containing product and we are pursuing these concerns separately. But the action today is based on the risks posed by the contamination of this particular product with a potentially dangerous pathogen. Our first approach is to encourage voluntary compliance, but when we have a company like this one, which refuses to cooperate, is violating the law and is endangering consumers, we will pursue all avenues of enforcement under our authority.”

Mitragyna speciosa, commonly known as kratom, is a plant that grows naturally in Thailand, Malaysia, Indonesia and Papua New Guinea. Importantly, the FDA advises consumers to avoid kratom or its psychoactive compounds, mitragynine and 7-hydroxymitragynine, in any form and from any manufacturer. The agency also has received concerning reports about the safety of kratom, including deaths associated with its use. There is strong evidence that kratom affects the same opioid brain receptors as morphine and appears to have properties that expose people who consume kratom to the risks of addiction, abuse and dependence. The agency also remains concerned about the use of kratom as an alternative to FDA-approved pain medications or to treat opioid withdrawal symptoms, as neither kratom nor its compounds have been proven safe and effective for any use and should not be used to treat any medical conditions.

In this instance, two samples of kratom products manufactured by Triangle Pharmanaturals of Las Vegas, Nevada, sold through the retail location Torched Illusions in Tigard, Oregon and collected by the Oregon Public Health Division, tested positive for salmonella, as did four additional samples of various types of kratom product associated with the firm collected by the FDA. Adding to the concerns, in the course of investigating a multi-state outbreak of salmonella infections linked to kratom products in conjunction with local officials, FDA investigators were denied access to the company’s records relating to potentially affected products and Triangle employees refused attempts to discuss the agency’s findings.

Under the FDA Food Safety Modernization Act, the FDA has the authority to order the recall of certain food products when the FDA determines that there is a reasonable probability that the article of food is adulterated or in violation of certain allergen labeling requirements and that the use of or exposure to such article will cause serious adverse health consequences or death to humans or animals.

On March 30, the FDA issued Triangle Pharmanaturals a Notification of Opportunity to Initiate a Voluntary Recall, a formal request that advised the company that the agency could order the firm to cease distribution and notify applicable parties within 24 hours if the company did not conduct a voluntary recall. However, Triangle Pharmanaturals did not comply with the request. On March 31, the FDA then ordered the company to cease distribution of the products and the company was provided with an opportunity to request an informal hearing. The company did not respond within the timeframe specified, therefore waiving its opportunity for an informal hearing, and the agency ultimately issued the mandatory recall order in the interest of public safety. This is the third time the FDA has started the process of using its mandatory recall authority, but the first time the agency has gotten to the step of ordering a mandatory recall because a company has opted not to voluntarily recall after the FDA’s notification of an opportunity to initiate a voluntary recall.

Numerous brands of kratom-containing products have been linked to a multi-state outbreak of salmonellosis from multiple strains of salmonella. The FDA continues to advise consumers to avoid kratom and kratom-containing products and discard any in their possession. All salmonella bacteria can cause the foodborne illness salmonellosis, although the strains found in Triangle Pharmanaturals’ products are not currently linked to the outbreak. The FDA is working with the U.S. Centers for Disease Control and Prevention to continue to investigate the ongoing outbreak. Most people infected with salmonella develop diarrhea, fever and abdominal cramps 12 to 72 hours after infection. The illness usually lasts 4 to 7 days, and most people recover without treatment. However, in the current salmonellosis outbreak associated with kratom products, unusually high rates of individuals have been hospitalized for their illness.

If consumers have one or more of these products in their homes, they should discard them immediately. As a precaution, kratom no longer stored in its original packaging should be discarded and the containers used to store it should be thoroughly washed and sanitized. In order to prevent cross-contamination, consumers should wash their hands, work surfaces and utensils thoroughly after contact with these products, and not prepare any food in the area at the same time.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm603517.htm

Thursday, January 25, 2018

Time - Herbal Supplements May Be Dangerous When You Take Certain Prescription Drugs

Herbal Supplements May Be Dangerous When You Take Certain Prescription Drugs
By Amanda MacMillan
January 24, 2018 
A number of common herbal supplements, including green tea and Ginkgo biloba, can interact with prescription medications, according to a new research review published in the British Journal of Clinical Pharmacology. These interactions can make drugs less effective—and may even be dangerous or deadly. 
The new review analyzed 49 case reports of adverse drug reactions, along with two observational studies. Most people in the analysis were being treated for heart disease, cancer or kidney transplants, and were taking warfarin, statins, chemotherapy drugs or immunosuppressants. Some also had depression, anxiety or neurological disorders, and were being treated with antidepressant, antipsychotic or anticonvulsant medications.

Tuesday, January 9, 2018

Healio - Herbal, dietary supplement-induced liver injury more common in young women


Herbal, dietary supplement-induced liver injury more common in young women
Medina-Cáliz I, et al. Clin Gastroenterol Hepatol. 2017;doi:10.1016/j.cgh.2017.12.051.
January 9, 2018

Analysis of the Spanish Drug-Induced Liver Injury registry showed that cases of herbal and dietary supplement-induced liver injury were more common in young women than older patients or men and correlated with hepatocellular injury and high levels of transaminases.

“Herbal and dietary supplement-induced liver injury is an increasing healthcare problem,” Inmaculada Medina-Cáliz, PhD, from the University of Málaga, Spain, and colleagues wrote. “In contrast to medicinal products including Traditional Herbal Medicinal Products which are regulated in the European Union with regard to efficacy, safety and quality standards, the lack of regulation of ‘natural’ dietary supplemental products, together with the limited awareness of physicians and consumers about possible harmful effects of these supplements, reflect the need for research and reporting in this field.”

Tuesday, November 14, 2017

FDA warns of ‘deadly risks’ of the herb kratom, citing 36 deaths

FDA warns of ‘deadly risks’ of the herb kratom, citing 36 deaths

Friday, October 27, 2017

A new study shows that liver cancer in Asia is linked to herbal remedies

A new study shows that liver cancer in Asia is linked to herbal remedies Researchers have uncovered widespread evidence of a link between traditional Chinese herbal remedies and liver cancer across Asia, a study said Wednesday.

The findings suggest stronger measures are needed to prevent people from consuming chemicals called aristolochic acids (AA), which are derived from the woody vines of the Aristolochia plant family, said the report in the journal Science Translational Medicine.

The acids can be found in some traditional Chinese medicines that are given during childbirth, to prevent parasites and promote healing.
Read the article.....

Full Text Article
Science Translational Medicine

Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia
Alvin W. T. Ng1,2,3,*, Song Ling Poon4,*, Mi Ni Huang1,2, Jing Quan Lim4,5, Arnoud Boot1,2, Willie Yu1,2, Yuka Suzuki1,2, Saranya Thangaraju4, Cedric C. Y. Ng4, Patrick Tan2,6,7,8, See-Tong Pang9, Hao-Yi Huang10, Ming-Chin Yu11, Po-Huang Lee12, Sen-Yung Hsieh10,†, Alex Y. Chang13,†, Bin T. Teh2,4,7,14,† and Steven G. Rozen
Science Translational Medicine  18 Oct 2017:Vol. 9, Issue 412, eaan6446
DOI: 10.1126/scitranslmed.aan6446

The dark side of an herbal medicine
Aristolochic acid, an herbal compound found in many traditional medicines, had been previously linked to kidney failure, as well as cancers of the urinary tract. Because of these known toxicities, herbs containing this compound have been restricted or banned in some countries, but it is still available on the internet and in alternate formulations. By analyzing numerous samples from Taiwan and other countries in Asia and elsewhere, Ng et al. demonstrated the effects of aristolochic acid in hepatocellular carcinoma, a much more common tumor type. The authors showed that the use of this drug remains widespread in Asia and particularly in Taiwan, and that it appears to increase the risk of multiple different cancer types.

Abstract
Many traditional pharmacopeias include Aristolochia and related plants, which contain nephrotoxins and mutagens in the form of aristolochic acids and similar compounds (collectively, AA). AA is implicated in multiple cancer types, sometimes with very high mutational burdens, especially in upper tract urothelial cancers (UTUCs). AA-associated kidney failure and UTUCs are prevalent in Taiwan, but AA’s role in hepatocellular carcinomas (HCCs) there remains unexplored. Therefore, we sequenced the whole exomes of 98 HCCs from two hospitals in Taiwan and found that 78% showed the distinctive mutational signature of AA exposure, accounting for most of the nonsilent mutations in known cancer driver genes. We then searched for the AA signature in 1400 HCCs from diverse geographic regions. Consistent with exposure through known herbal medicines, 47% of Chinese HCCs showed the signature, albeit with lower mutation loads than in Taiwan. In addition, 29% of HCCs from Southeast Asia showed the signature. The AA signature was also detected in 13 and 2.7% of HCCs from Korea and Japan as well as in 4.8 and 1.7% of HCCs from North America and Europe, respectively, excluding one U.S. hospital where 22% of 87 “Asian” HCCs had the signature. Thus, AA exposure is geographically widespread. Asia, especially Taiwan, appears to be much more extensively affected, which is consistent with other evidence of patterns of AA exposure. We propose that additional measures aimed at primary prevention through avoidance of AA exposure and investigation of possible approaches to secondary prevention are warranted.
Full Text Article - http://stm.sciencemag.org/content/9/412/eaan6446.full

Tuesday, May 10, 2016

5 Things You Should Know About Dietary Supplements for Hepatitis C


National Institutes of Health
On This Blog
June 2018
NIH launches HerbList, app with information about safety and effectiveness of herbal products

May 2018
Hepatitis C and Dietary Supplements 

Hepatitis C Is Our Featured Topic
5 Things You Should Know About Dietary Supplements for Hepatitis C
Clinical Digest:
Hepatitis C and Dietary Supplements  
Several dietary and herbal supplements have been studied for hepatitis C, and substantial numbers of people with hepatitis C have tried herbal supplements. For example, a survey of 1,145 participants in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial found that 23 percent of the participants were using herbal products. Although participants reported using many different herbal products, silymarin (milk thistle) was by far the most common. However, no dietary supplement has been shown to be efficacious for hepatitis C.

This issue provides information on the evidence base of several dietary supplements studied for hepatitis C.
Continue reading...

Tuesday, April 7, 2015

States ask U.S. Congress to launch inquiry of herbal supplements

States ask U.S. Congress to launch inquiry of herbal supplements
NEW YORK | By Karen Freifeld

NEW YORK (Reuters) - A group of 14 state attorneys general on Thursday asked the U.S. Congress to investigate the herbal supplements industry after a New York probe of the products turned up ingredients that were not listed on labels and raised safety concerns.

The group, led by New York Attorney General Eric Schneiderman and Indiana Attorney General Greg Zoeller, also asked Congress to consider giving the U.S. Food and Drug Administration more oversight of herbal supplements.

"We believe the safety and efficacy of these supplements is a matter of deep public concern across the country," the attorneys general said in the letter, urging "swift action."

Continue reading...
(Reporting By Karen Freifeld; Editing by David Gregorio)

Thursday, June 26, 2014

Linking Herbal Supplements with Liver Injury

Linking Herbal Supplements with Liver Injury

 
Despite the perceived safety of herbal and dietary supplements, they can cause serious liver injury. In the July issue of Clinical Gastroenterology and Hepatology, Simona Rossi and Victor J. Navarro discuss the scope, use, and regulation of herbal and dietary supplements, as well as the diagnosis of herbal and dietary supplement-induced liver injury.

Patients take dietary supplements for many reasons, including anxiety, obesity, diabetes, rheumatoid arthritis, cancer, cardiovascular disease, and pain.

Almost a quarter of patients enrolled in a long-term hepatitis C treatment trial reported using herbal and dietary supplements.

Rossi and Navarro explain that the ease of access to these supplements allows consumers to assume that they are safe and can be used without consequences. Most patients do not divulge use of dietary supplements to health care providers.

However, in the US National Health and Nutrition Examination Survey, 52% of respondents reported using a dietary supplement, and other surveys have reported even higher use. In some Asian and African countries, up to 80% of the population use herbal supplements as their primary means of medical care.

Rossi and Navarro discuss the incidences of injury caused by different supplements in different countries. These range from 1%–2% of cases of liver injury in Spain (with antibiotics being among the most common class implicated) to Singapore, where 71% of cases of drug-related liver injury have been attributed to medicinal herbs—many adulterated with active drugs.

The authors discuss preliminary findings from the US Drug-Induced Liver Injury Network (DILIN) showing that herbal and dietary supplements are responsible for an increasing proportion of hepatotoxicity cases.

Rossi and Navarro discuss the US Dietary Supplement Health and Education Act of 1994, in which manufacturers are required to attest to a product’s safety, but give no authority to the Food and Drug Administration (FDA) to approve the supplements before marketing. Routine analysis of products’ contents by the FDA is performed on only a random basis.

They present strategies for diagnosis of herbal and dietary supplement–induced liver injury, and the process for linking a drug or dietary supplement to liver injury. Products and ingredients associated with hepatotoxicity include weight loss supplements (Hydroxycut, Herbalife/green tea, and usnic acid), joint health supplements (flavocoxid- and glucosamine-based supplements), and bodybuilding supplements.

Attributing liver injury to any specific ingredient in herbal and dietary supplements is the single greatest challenge to clinicians and researchers interested in liver injury. Rossi and Navarro explain that even detailed chemical analyses of products, which are expensive and complex, do not always identify the agents responsible for injury. The authors propose using chemical analyses to identify ingredients common to products implicated in injury; proposed culprits could then be tested in formal toxicologic analyses.

Nonetheless, Rossi and Navarro state that a better understanding of the epidemiology of supplement-induced liver injury is needed, to identify the scope of the problem and the groups most affected, as well as to develop management and prevention strategies. Without more accurate estimates of the overall use of herbal and dietary supplements and more complete reporting of adverse events, it is impossible to determine disease prevalence and incidence.

 Source

Saturday, February 15, 2014

2014 - Complementary and alternative medications in hepatitis C infection

Complementary and alternative medications in hepatitis C infection

Good afternoon folks, welcome to another edition of Weekend Reading.

On this fine Saturday a couple review articles evaluating the safety and efficacy of treating HCV using complementary and alternative medicine is our topic.

Sadly, we know not everyone can tolerate the currently available treatments, nor does everyone respond. Recently, two oral agents simeprevir and sofosbuvir were FDA approved, improving cure rates with shorter treatment duration and for some people even without interferon.

Over the last few years with grave desperation we have witnessed an era where new agents are rapidly being developed to eradicate this serious disease. Possibly Gilead's combination pill - consisting of both agents sovaldi and ledipasvir, may hold great promise. Gilead's clinical trials seem encouraging, for example in one trial deemed ION 2 that included 440 treatment-experience or difficult to treat genotype one patients, (88) with cirrhosis; SVR rates were at 93.6 percent after 12 weeks of therapy - while the cure rate rose to 99.1 percent with 24 weeks of treatment.

Last week Gilead filed for U.S. approval of Ledipasvir/Sofosbuvir Fixed-Dose Combination Tablet for Genotype 1 Hepatitis C

Again, not everyone who needs HCV treatment will be cured, and not everyone who needs treatment will be treated, thus complementary and alternative medications will be part of the equation aimed at trying to control symptoms or in some aspect manage HCV, especially in developing countries.

Complementary Health Approaches
Previously, The National Institutes of Health reported many people living with the virus try complementary approaches to manage HCV, such as massage, deep breathing exercises, meditation, progressive relaxation, and yoga, others use complementary and alternative medications, especially dietary supplements. Although these alternative options may offer therapeutic benefits, no complementary or alternative medications has been shown to be effective against the hepatitis C virus.

Review Articles
The first article provided below; "Complementary and alternative medications in hepatitis C infection," published in World J Hepatol, 2014 January, offers a look at the therapeutic potential of complementary and alternative medications (CAM), and drug interactions between medical and complementary treatments, including drug-CAM interactions which may lead to a reduced therapeutic effect when used with HCV oral drugs simeprevir and sofosbuvir.

A second review article; Management of chronic hepatitis C in patients with contraindications to anti-viral therapy, published this year in Alimentary Pharmacology & Therapeutics, provides information on alternative treatments for people who cannot tolerate or decide against interferon-based treatments. In the article researchers reported on life interventions which were associated with biochemical improvement, and treatments that had anti-inflammatory and/or anti-fibrotic effects. However, they found other alternatives such as (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) did not have any beneficial effect or need to be tested in larger clinical studies, view the full article, here.

Complementary and alternative medications in hepatitis C infection

World J Hepatol 2014 January 27; 6(1): 9-16
Published online 2014 January 27. doi: 10.4254/wjh.v6.i1.9.

Dina L Halegoua-De Marzio and Jonathan M Fenkel. Dina L Halegoua-De Marzio, Jonathan M Fenkel, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States Author contributions: Halegoua-De Marzio DL and Fenkel JM both outlined, researched the topics wrote, and wrote the manuscript.

Abstract
Chronic hepatitis C (CHC) infection affects almost 3% of the global population and can lead to cirrhosis, liver failure, and hepatocellular carcinoma in a significant number of those infected. Until recently, the only treatments available were pegylated interferon and ribavirin, which traditionally were not very effective and have considerable side effects. For this reason, interest in complementary and alternative medications (CAM) in the management of hepatitis C has been investigated. Some CAM has demonstrated therapeutic potential in chronic hepatitis C treatment. Unfortunately, some CAM has been shown to have the potential to cause drug-induced liver injury. This article will review and evaluate many of the natural molecules that interact with the hepatitis C virus (HCV) life cycle and discuss their potential use and safety in HCV therapy, as well as highlight some important interactions between medical and complementary treatments.

Core tip: Over the last 10 years there has been a substantial increase in reports of natural compounds displaying anti-viral activity against hepatitis C. At this time, there is no firm evidence supporting complementary and alternative medications for hepatitis C virus infection. Due to a limited number of trials and small numbers of subjects included in them, it is not possible to fully evaluate the risk of adverse events connected with the use of these products.

INTRODUCTION
Hepatitis C virus (HCV) infection affects an estimated 180 million people globally and is a leading cause of chronic hepatitis, cirrhosis, and liver cancer[1,2]. To prevent the complications of chronic hepatitis C (CHC), the goal of therapy is complete viral eradication. For the past decade, a combination of pegylated interferon-α (peg-IFN) and ribavirin was used to treat CHC with disappointing viral eradication rates. These rates were particularly suboptimal in patients with genotype 1 HCV, which is responsible for approximately 60% of worldwide infections[3]. Sustained virological response (SVR) rates for genotype 1 HCV are approximately 40% following 48 wk of peg-IFN/ribavirin and are even lower in patients with HIV co-infection, high baseline viral load, advanced fibrosis, or those of African descent[4-7].

The life cycle of HCV can be divided into three major steps: (1) entry of the virus into its target cells by receptor-mediated endocytosis; (2) cytoplasmic and membrane-associated replication of the RNA genome; and (3) assembly and release of the progeny virions[8]. In recent years, there has been improvement in SVR rates with the development and approval of the first HCV-specific direct-acting antiviral agents (DAAs), namely boceprevir and telaprevir[9,10]. In contrast to the non-specific antiviral activity of peg-IFN and ribavirin, DAA are designed to inhibit viral proteins involved in the HCV life cycle. Still, the first DAAs require coadministration with peg-IFN and ribavirin, and many patients remain intolerant to treatment-associated side effects, including fevers, influenza-like symptoms, headache, cytopenias, fatigue, anorexia, rash, and depressive symptoms.

CAM is being used increasingly across the globe for many chronic diseases[11,12]. The Cochrane Library included nearly 50 systematic reviews of complementary medicine interventions as of 2003[13]. Many people turn to CAM when conventional medicine fails, or they believe strongly in its effectiveness. During the last few years, a substantial increase of reports on natural compounds displaying an anti-HCV activity has been published. There is data that some of these medicinal herbs might have therapeutic potential in CHC, or may alleviate side effects of conventional therapy[13]. CAM use is common among people with CHC. A survey of 1145 participants in the National Institutes of Health (NIH)-supported HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial found that 23% of the participants used herbal products[14]. Although sometimes thought by the public to be safer then conventional therapy, there are many reports about liver toxicity and other adverse events from some herbal products[11,15].

The aim of this review is to evaluate the efficacy and safety of treating HCV infection using complementary and alternative medicine.

MEDICINAL HERBAL AND DIETARY SUPPLEMENTS WITH ANTI-HCV ACTIVITY 

Silymarin
An extract of the milk thistle plant, silymarin (Silybum marianum), has been used to treat chronic liver disease since the time of the ancient Greeks[16]. Owing to its purported hepatoprotective properties, it is the most commonly used herbal product by individuals with chronic liver disease in the United States[16,17]. A recent publication from the HALT-C study group indicated that 33% of patients with CHC and cirrhosis reported current or past use of silymarin[14]. A follow-up study found silymarin use among CHC patients was associated with reduced progression from fibrosis to cirrhosis, but had no impact on clinical outcomes[16].

The major active component of silymarin, silibinin (a mixture of the two diastereoisomers silybin A and silybin B), is thought to be responsible for silymarin’s hepatoprotective properties[18]. Silymarin appears to inhibit HCV infection at two or more different levels: (1) it inhibits HCV replication in cell culture; and (2) it displays anti-inflammatory and immunomodulatory actions that may contribute to its hepatoprotective effect[19,20]. The inhibition of HCV replication has been attributed to inhibitory action on the NS5B RNA-dependent RNA polymerase.

Clinical studies that have evaluated milk thistle for a variety of liver diseases have yielded inconsistent results and low bioavailability of oral silymarin components[21]. Studies with IV silibinin have shown substantial antiviral effect against HCV in liver transplant recipients, and even in nonresponders with good safety outcomes[22-24]. Although oral administration of silymarin is not effective for the treatment of HCV, intravenous silibinin formulation may represent a future potential therapeutic option.

Green tea extract
Green tea, made from the unfermented leaves of Camellia sinensis, is comprised of several polyphenolic compounds called catechins, and can be concentrated into a green tea extract (GTE). Epigallocatechin-3-gallate (EGCG) is the most abundant and potent catechin contained within GTE, comprising typically approximately 40% of the total polyphenol content[25]. EGCG is a potent inhibitor of HCV entry in primary human hepatocytes independent of the genotype, by blocking virus attachment. This novel inhibitor may provide a new approach to prevent HCV infection, especially in the setting of liver transplantation of chronically infected HCV patients[26,27]. Beyond its antiviral effect on HCV, EGCG may have potential use as a chemopreventative agent for hepatocellular cancer as EGCG may inhibit cancer cell growth. This mechanism of action is thought to be due to tyrosine kinase inhibition and modulation of target gene expression associated with induction of apoptosis and cell cycle arrest in cancer cells[28-34].

GTE is a common ingredient in several dietary supplements, some of which have been withdrawn from the market due to safety concerns. An example of this is Exolise (Arkopharma, France), a weight loss supplement containing high EGCG levels that was withdrawn from the market in April 2003 due to 13 cases of attributable liver injury[35]. Between 1966 and 2008, 216 case reports of toxicity with green tea extracts were identified by the United States Pharmacopeia, of which 34 were concerning for liver toxicity[36]. Recent animal studies with high doses of GTE and EGCG have described dose-dependent hepatotoxicity resulting in severe morbidity and mortality[37]. However, chronic moderate to high dose daily GTE and EGCG use in healthy human volunteers, and selected patients with cirrhosis, was safe and did not impair liver function[38-40]. Although GTE may be very useful in further treatment of CHC and prevention of HCC, its hepatotoxic potential must be acknowledged and monitored carefully in future studies.

Naringenin

HCV associates with β-lipoproteins [very low density lipoprotein (vLDL) and low-density lipoprotein (LDL)] circulating in blood[41]. In addition, HCV replication can be up-regulated by fatty acids and inhibited by statins; this suggests an interaction between HCV, cholesterol, and lipid metabolism[42]. Recent research has found that of HCV secretion is dependent on both apolipoprotein B (ApoB) expression and vLDL assembly in a chromosomally integrated complementary DNA (cDNA) model of HCV secretion[43].

Naringenin is the predominant flavanone present in the grapefruit and is responsible for its bitter taste. Naringenin has been shown to reduce cholesterol levels both in vitro and in vivo[44,45]. Furthermore, naringenin inhibits ApoB secretion by reducing the activity and the expression of the microsomal triglyceride transfer protein (MTP) and the acyl-coenzyme A cholesterol acyltransferase 2 (ACAT)[44,46]. Due to the close link between HCV assembly/secretion and lipoprotein metabolism, there has been extensive study on the impact of naringenin on the secretion of HCV particles[43]. A dose-dependent decrease of core protein, HCV-positive strand RNA, infectious particles, and ApoB has been observed in the supernatant of infected primary hepatocytes in culture after naringenin treatment[43]. Overall, naringenin blocked the assembly of intracellular infectious viral particles without affecting intracellular levels of the viral RNA or protein. Although still at the cell culture phase, naringenin may offer new insight into a promising and novel HCV therapeutic target.

Glycyrrhizin
Glycyrrhizin, a natural compound extracted from the roots of Glycyrrhiza glabra, has been used for more than 20 years as a treatment for chronic hepatitis[47]. It has been used for many centuries in traditional Chinese medicine as an anti-allergic agent. Because of its sweet taste it is also used as a food additive, for example in beverages and licorice[48]. In an attempt to use glycyrrhizin as a treatment for “allergic” hepatitis it was found to lower the transaminases. In a study by Suzuki et al[49] in 1977, plasma transaminases activity improved significantly with glycyrrhizin in patients with chronic liver disease compared to a placebo group.

The mechanism by which glycyrrhizin improves the biochemistry and histology in liver disease is unknown. It is thought to have anti-inflammatory, antioxidant and immunomodulatory activities. Due to this there has been much interest in use of glycyrrhizin in CHC. In the only randomized clinical trial of glycyrrhizin, ALT levels declined modestly during treatment, compared with placebo, but this was not sustained after cessation of treatment and there was no significant effect on HCV RNA levels[50]. In the another trial, statistically significant differences in liver enzyme levels, but not viral loads, between treatment groups were identified during treatment, however, again no sustained response occurred at follow-up[51]. Use of glycyrrhizin is not without side effects. It has been found to cause pseudo-aldosteronism, manifested by sodium retention, hypokalemia and hypertension[52]. Cardiac arrhythmia and acute rhabdomyolysis due to severe hypokalemia caused by excess licorice consumption have also been reported[52-54].

Oxymatrine
Oxymatrine is the major alkaloid extract from the root of sophora flavescens, a deciduous shrub native to China, Japan, South Korea and Russia. It is reported to have antiviral activity against HCV in cell cultures and in animal studies[55-57]. Clinical studies have shown that oxymatrine has some hepatoprotective activity in alcohol toxicity and hepatitis B infection, but not carbon tetrachloride, acetaminophen or cadmium chloride-induced acute hepatitis[58,59].


Oxymatrine is considered to be an antifibrotic, likely through inhibition of lipid peroxidation[60-62]. In a study of HCV-infected subjects randomized subjects to receive either an intramuscular injection of oxymatrine 600 mg/d or other support products such as oral vitamins 47% of the treated cases had complete HCV viral suppression after 3 mo, compared with only 5% in the control group[61]. No serious adverse events were reported. The treated group had significantly more ALT normalizations than the control group in the first 2 mo, but this improvement waned by the end of the third month of treatment. While treatment with oxymatrine holds promise, it is difficult to draw conclusions from the small studies currently available.

Traditional chinese herbal medications
The primary goal of Chinese traditional medicine is to create wholeness and harmony within a person, allowing the mind/body/spirit to heal itself. There have been several randomized clinical trials of traditional Chinese medicine in the treatment of hepatitis C, however, the methodological quality of these studies is generally considered poor[63-70].

In two trials of herbal formulations in combination with interferon-alfa, there was a trend toward greater clearance of HCV RNA and ALT normalization with the combination treatment compared with patients receiving monotherapy[63,64]. In the only placebo-controlled trial of solo therapy with traditional Chinese medicine, a significant reduction in ALT levels during treatment occurred, though no virologic effect was identified[69]. Detailed descriptions of adverse events were not provided for most of these trials. The safety of these medicines is unclear due to the individualized nature of many of the herbal compounds involved, the large number of different herbs in each formulation, and the relatively small number of subjects within each clinical trial.

Vitamin D
The traditional role of Vitamin D (Vit D) was thought to be based upon its interaction in calcium homeostasis, via regulation of intestinal calcium absorption and of bone health. However, over the last several years Vit D has been shown to have a much more complex role in many other host functions, including its interaction with chronic hepatitis C. 25-OH Vit D is made in the liver via cytochrome P450 (CYP27A1) activated hydroxylation of Vit D, brought into the body either by intestinal absorption or endogenous synthesis through sun-exposed skin. It is then converted to 1.25 OH Vit D (calcitriol) in the kidneys, the most active form, where it becomes available to bind to Vit D receptors throughout the body[71,72].

A growing body of clinical evidence has demonstrated an increased prevalence of Vit D deficiency in patients with CHC. As such, Vit D supplementation has been proposed as an adjunct to current standard regimens for treatment of hepatitis C[72]. One study found that mean 25-OH Vit D serum levels were significantly lower in CHC (25 μg/L) than in the controls (43 μg/L)[73]. Importantly, low Vit D has been linked to increased fibrosis and impaired sustained virologic response (SVR) in IFN-based therapy[71].

One clinical trial demonstrated that the addition of Vit D to the standard IFN plus ribavirin treatment significantly increased SVR in patients with genotype 1 CHC[74]. Regarding the underlying molecular mechanisms, an in vitro study showed that Vit D remarkably inhibits HCV production in Huh7.5 hepatoma cells[75]. These cells express Vit D hydroxylases and can eventually generate calcitriol. Notably, treatment with calcitriol resulted in HCV inhibition through induction of IFN-beta. Overall, 25-OH Vit D levels appear to be an important prognostic marker in helping determine the likelihood of SVR. 25-OH Vit D levels should be checked routinely before HCV treatment and supplementation provided to deficient patients, in an effort to enhance treatment response.

Antioxidants
Antioxidants are one of the most common dietary supplements taken by patients with CHC[14]. The use of these supplements is based on the fact that oxidative stress has been attributed to both host inflammatory processes and induction by viral proteins. By increasing antioxidants, one may be able to decrease oxidative stress and therefore decrease liver injury[76]. Existence of oxidative stress in CHC is well documented, as oxidized protein and nucleic acid markers are increased and antioxidant levels are decreased[77-80]. Studies have shown levels of oxidative stress markers to correlate with disease severity, HCV RNA, iron overload, and insulin sensitivity[78,79]. Oxidative stress has also been shown to be an early event in carcinogenesis and is a risk factor for development of HCC in patients with chronic HCV[81].

Multiple trials have shown antioxidants, such as Vitamin E and N-acetyl cysteine, only lead to small reductions in ALT after chronic administration in some instances[82-93]. Further, the decrease in ALT levels in most studies is marginal and is not sustained after stopping the treatment, raising the question of their clinical significance. No study has shown an improvement in outcome. In addition, no study has shown clear benefit of antioxidants as adjuvant to interferon based therapy of HCV. At the doses studied, these antioxidants appear to be well-tolerated, with no specific adverse events reported in any of the trials. However, very large oral doses of N-acetyl cysteine are commonly associated with nausea and vomiting and intravenous administration of N-acetyl cysteine can result in anaphylactoid reactions, which may be more common in patients with chronic liver disease[94]. Therefore, evidence supporting use of antioxidants as useful therapeutic agents in CHC is lacking.

HERBAL SUPPLEMENTS AND DRUG INDUCED LIVER INJURY IN CHRONIC HCV


Drug-related hepatotoxicity is a serious health problem, with broad implications for patients, healthcare providers, the pharmaceutical industry and governmental regulatory agencies. The Drug Induced Liver Injury Network (DILIN), a federally funded consortium of 12 centers in the United States, recently reported the preliminary results of its prospective study[94]. Dietary supplements were implicated in 9% of reported DILI cases. This may be potentially related to increasing use of herbal or dietary supplements in the US population. The importance of these supplements as a cause of DILI is further underscored by a retrospective Japanese study, in which 10% of 879 cases of single agent DILI from 1997 to 2006 were attributed to dietary supplements and 7% to Chinese herbal drugs[95]. 

DRUG-CAM INTERACTIONS
Telaprevir, Boceprevir, Simeprevir and Sofosbuvir
Another major area of awareness when patients are considering using CAM is whether or not drug-CAM interactions may exist that could impact the medical therapy. This issue is becoming even more complicated with the addition of new medications for the treatment of CHC infection such as simeprevir and sofosbuvir approved for use in the U.S. in December 2013. St. John’s wort (Hypericum perforatum), a common CAM used for the treatment of depression, is an inducer of cytochrome P450 3A4[99].

This cytochrome is also the primary metabolizer of many medications, including the HCV protease inhibitors: telaprevir, boceprevir, and simeprevir. Additionally, St. John’s wort is a potent intestinal P-gp inducer and may lead to a reduced therapeutic effect of the HCV nucleotide polymerase inhibitor sofosbuvir[100]. Concomitant use of St. John’s wort and these HCV treatments is contraindicated and can lead to treatment failure by reducing blood concentrations. Additionally, concomitant use of milk thistle use is contraindicated with simeprevir. This combination may increase levels of simeprevir by milk thistle CYP3A inhibition leading to possible toxicity[101] (Table 1). Garlic extracts, grapefruit juice, and germander also have cytochrome P450 3A4 interactions[102].


CONCLUSION
Many human studies have shown improvements in subjective symptoms and liver biochemistries in HCV patients with CAM, but there is no convincing data to suggest a definite histological and/or virologic improvement with any of the herbal agents currently available. Vit D seems to have the best available data as adjunctive therapy to antiviral medications in patients with Vit D deficiency. Poorly designed studies, heterogeneous patient populations, lack of standardized preparations, and poorly defined nonobjective end points may partly explain the conflicting reports in the literature.

The safety profiles of the interventions discussed within this review are encouraging at the doses studied. However, the long-term safety for use in the treatment of hepatitis C, either alone or in combination with conventional medicines, has not been established. Comparative and placebo-controlled trials suggest that patients experience no more adverse events with these interventions than with placebo or comparative medications, although short-term clinical trials are not designed to detect rare or delayed adverse events. Physicians need to be cognizant of known or occult use of CAM by their patients because hepatotoxicity and drug interactions may occur with many herbal medications, and may occur more frequently in patients with chronic liver disease.

There is an undoubted need for further research into the treatment of hepatitis C, and this review has identified several promising compounds, including Vit D, silymarin, oxymatrine, naringenin, and GTE. Some or all of these may be integral components of future HCV management.

References
1.
Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9:331-338. [PubMed] [DOI]
2.
Rosen HR. Clinical practice. Chronic hepatitis C infection. N Engl J Med. 2011;364:2429-2438. [PubMed] [DOI]
3.
Welsch C, Jesudian A, Zeuzem S, Jacobson I. New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives. Gut. 2012;61 Suppl 1:i36-i46. [PubMed] 
4.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-1492. [PubMed] [DOI]
5.
Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. [PubMed] [DOI]
6.
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. [PubMed] [DOI]
7.
McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. [PubMed] 
8.
Belouzard S, Cocquerel L, Dubuisson J. Hepatitis C virus entry into the hepatocyte. Cent Eur J Biol. 2011;6:1-13.
9.
Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416. [PubMed] [DOI]
10.
Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206. [PubMed] [DOI]
11.
Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-1575. [PubMed] [DOI]
12.
Vickers A. Recent advances: complementary medicine. BMJ. 2000;321:683-686. [PubMed] 
13.
Liu J, Manheimer E, Tsutani K, Gluud C. Tomlinson B, Chan TY, Chan JC. Medicinal herbs for hepatitis C virus infection: a Cochrane hepatobiliary systematic review of randomized trials.Toxicity of complementary therapies: An eastern perspective. J Clin Pharmacol. 2000;40:451-456. [PubMed] [DOI]
14.
Seeff LB, Curto TM, Szabo G, Everson GT, Bonkovsky HL, Dienstag JL, Shiffman ML, Lindsay KL, Lok AS, Di Bisceglie AM. Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology. 2008;47:605-612. [PubMed] [DOI]
15.
Gupta NK, Lewis JH. Review article: The use of potentially hepatotoxic drugs in patients with liver disease. Aliment Pharmacol Ther. 2008;28:1021-1041. [PubMed] [DOI]
16.
Freedman ND, Curto TM, Morishima C, Seeff LB, Goodman ZD, Wright EC, Sinha R, Everhart JE. Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther. 2011;33:127-137. [PubMed] [DOI]
17.
Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24:1423-1432. [PubMed] [DOI]
18.
Calland N, Dubuisson J, Rouillé Y, Séron K. Hepatitis C virus and natural compounds: a new antiviral approach?. Viruses. 2012;4:2197-2217. [PubMed] [DOI]
19.
Polyak SJ, Morishima C, Shuhart MC, Wang CC, Liu Y, Lee DY. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology. 2007;132:1925-1936. [PubMed] [DOI]
20.
Morishima C, Shuhart MC, Wang CC, Paschal DM, Apodaca MC, Liu Y, Sloan DD, Graf TN, Oberlies NH, Lee DY. Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. Gastroenterology. 2010;138:671-681, 681.e1-2. [PubMed] [DOI]
21.
Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol. 2010;50:434-449. [PubMed] 
22.
Neumann UP, Biermer M, Eurich D, Neuhaus P, Berg T. Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy. J Hepatol. 2010;52:951-952. [PubMed] [DOI]
23.
Beinhardt S, Rasoul-Rockenschaub S, Scherzer TM, Ferenci P. Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. J Hepatol. 2011;54:591-592; author reply 592-593. [PubMed] [DOI]
24.
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. [PubMed] [DOI]
25.
Yang CS, Landau JM. Effects of tea consumption on nutrition and health. J Nutr. 2000;130:2409-2412. [PubMed] 
26.
Calland N, Albecka A, Belouzard S, Wychowski C, Duverlie G, Descamps V, Hober D, Dubuisson J, Rouillé Y, Séron K. (-)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry. Hepatology. 2012;55:720-729. [PubMed] [DOI]
27.
Ciesek S, von Hahn T, Colpitts CC, Schang LM, Friesland M, Steinmann J, Manns MP, Ott M, Wedemeyer H, Meuleman P. The green tea polyphenol, epigallocatechin-3-gallate, inhibits hepatitis C virus entry. Hepatology. 2011;54:1947-1955. [PubMed] 
28.
Shimizu M, Shirakami Y, Moriwaki H. Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG. Int J Mol Sci. 2008;9:1034-1049. [PubMed] 
29.
Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst. 1997;89:1881-1886. [PubMed] [DOI]
30.
Bushman JL. Green tea and cancer in humans: a review of the literature. Nutr Cancer. 1998;31:151-159. [PubMed] [DOI]
31.
Sun CL, Yuan JM, Koh WP, Yu MC. Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies. Carcinogenesis. 2006;27:1310-1315. [PubMed] 
32.
Mann CD, Neal CP, Garcea G, Manson MM, Dennison AR, Berry DP. Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis. Eur J Cancer Prev. 2009;18:13-25. [PubMed] [DOI]
33.
Lamy S, Gingras D, Béliveau R. Green tea catechins inhibit vascular endothelial growth factor receptor phosphorylation. Cancer Res. 2002;62:381-385. [PubMed] 
34.
Luo H, Tang L, Tang M, Billam M, Huang T, Yu J, Wei Z, Liang Y, Wang K, Zhang ZQ. Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine. Carcinogenesis. 2006;27:262-268. [PubMed] [DOI]
35.
Seddik M, Lucidarme D, Creusy C, Filoche B. [Is Exolise hepatotoxic?]. Gastroenterol Clin Biol. 2001;25:834-835. [PubMed] 
36.
Sarma DN, Barrett ML, Chavez ML, Gardiner P, Ko R, Mahady GB, Marles RJ, Pellicore LS, Giancaspro GI, Low Dog T. Safety of green tea extracts : a systematic review by the US Pharmacopeia. Drug Saf. 2008;31:469-484. [PubMed] [DOI]
37.
Lambert JD, Kennett MJ, Sang S, Reuhl KR, Ju J, Yang CS. Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice. Food Chem Toxicol. 2010;48:409-416. [PubMed] [DOI]
38.
Frank J, George TW, Lodge JK, Rodriguez-Mateos AM, Spencer JP, Minihane AM, Rimbach G. Daily consumption of an aqueous green tea extract supplement does not impair liver function or alter cardiovascular disease risk biomarkers in healthy men. J Nutr. 2009;139:58-62. [PubMed] [DOI]
39.
Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003;9:3312-3319. [PubMed] 
40.
Halegoua-De Marzio D, Kraft WK, Daskalakis C, Ying X, Hawke RL, Navarro VJ. Limited sampling estimates of epigallocatechin gallate exposures in cirrhotic and noncirrhotic patients with hepatitis C after single oral doses of green tea extract. Clin Ther. 2012;34:2279-2285.e1. [PubMed] [DOI]
41.
Thomssen R, Bonk S, Propfe C, Heermann KH, Köchel HG, Uy A. Association of hepatitis C virus in human sera with beta-lipoprotein. Med Microbiol Immunol. 1992;181:293-300. [PubMed] [DOI]
42.
Kapadia SB, Chisari FV. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA. 2005;102:2561-2566. [PubMed] [DOI]
43.
Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung RT, Yarmush ML. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008;47:1437-1445. [PubMed] [DOI]
44.
Allister EM. Borradaile NM, Edwards JY, Huff MW. Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes. 2005;54:1676-1683. [PubMed] [DOI]
45.
Kurowska EM, Borradaile NM, Spence JD, Carroll KK. Hypocholesterolemic effects of dietary citrus juices in rabbits. Nutr Res. 2000;20:121-129. [DOI]
 
46.
Wilcox LJ, Borradaile NM, de Dreu LE, Huff MW. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. J Lipid Res. 2001;42:725-734. [PubMed] 
47.
Fujisawa K, Tandon BN. Therapeutic approach to the chronic active liver disease: Summary of a satellite symposium. In: Nishioka K, Suzuki H, Mishiro S, Oda T, editors.Viral Hepatitis and Liver Disease. Tokyo: Springer; 1994.pp.662-665.
48.
Spinks EA, Fenwick GR. The determination of glycyrrhizin in selected UK liquorice products. Food Addit Contam. 1990;7:769-778. [PubMed] [DOI]
49.
Suzuki H, Ohta Y, Takino T, Fujisawa K, Hirayama C. The therapeutic effects of Stronger Neo Minophagen C for chronic hepatitis. Igaku n Ayumi. 1977;102:562.
50.
van Rossum TG, Vulto AG, Hop WC, Brouwer JT, Niesters HG, Schalm SW. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial. J Gastroenterol Hepatol. 1999;14:1093-1099. [PubMed] [DOI]
51.
Tsubota A, Kumada H, Arase Y, Chayama K, Saitoh S, Ikeda K, Kobayashi M, Suzuki Y, Murashima N. Combined ursodeoxycholic acid and glycyrrhizin11:1077-1083. [PubMed] [DOI]
52.
Conn JW, Rovner DR, Cohen EL. Licorice-induced pseudoaldosteronism. Hypertension, hypokalemia, aldosteronopenia, and suppressed plasma renin activity. JAMA. 1968;205:492-496. [PubMed] 
53.
Bannister B, Ginsburg R, Shneerson J. Cardiac arrest due to liquorice induced hypokalaemia. Br Med J. 1977;2:738-739. [PubMed] 
54.
Gross EG, Dexter JD, Roth RG. Hypokalemic myopathy with myoglobinuria associated with licorice ingestion. N Engl J Med. 1966;274:602-606. [PubMed] [DOI]
55.
Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection: a Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol. 2003;98:538-544. [PubMed] [DOI]
56.
Chen XS, Wang GJ, Cai X, Yu HY, Hu YP. Inhibition of hepatitis B virus by oxymatrine in vivo. World J Gastroenterol. 2001;7:49-52. [PubMed] 
57.
Chen Y, Li J, Zeng M, Lu L, Qu D, Mao Y, Fan Z, Hua J. [The inhibitory effect of oxymatrine on hepatitis C virus in vitro]. Zhonghua Ganzangbing Zazhi. 2001;9 Suppl:12-14. [PubMed] 
58.
Lu LG, Zeng MD, Mao YM, Li JQ, Wan MB, Li CZ, Chen CW, Fu QC, Wang JY, She WM. Oxymatrine therapy for chronic hepatitis B: a randomized double-blind and placebo-controlled multi-center trial. World J Gastroenterol. 2003;9:2480-2483. [PubMed] 
59.
Liu J, Liu Y, Klaassen CD. The effect of Chinese hepatoprotective medicines on experimental liver injury in mice. J Ethnopharmacol. 1994;42:183-191. [PubMed] [DOI]
60.
Yang W, Zeng M, Fan Z, Mao Y, Song Y, Jia Y, Lu L, Chen CW, Peng YS, Zhu HY. [Prophylactic and therapeutic effect of oxymatrine on D-galactosamine-induced rat liver fibrosis]. Zhonghua Ganzangbing Zazhi. 2002;10:193-196. [PubMed] 
61.
Li J, Li C, Zeng M. [Preliminary study on therapeutic effect of oxymatrine in treating patients with chronic hepatitis C]. Zhongguo Zhongxiyi Jiehe Zazhi. 1998;18:227-229. [PubMed] 
62.
Azzam HS, Goertz C, Fritts M, Jonas WB. Natural products and chronic hepatitis C virus. Liver Int. 2007;27:17-25. [PubMed] 
63.
Han GP, Wang ZY, Peng SL. Binggan capsule combined with interferon for treatment of 30 cases of hepatitis C. Henan Zhongyi Zazhi. 1997;12:43-44.
64.
Pei ZG, Liu YL, Zhao SM. Therapeutic observation of Binggan decoction combined with interferon in 46 cases of hepatitis C. Pract J Integrating Chin Mod Med. 1996;9:444.
65.
Batey RG, Bensoussan A, Fan YY, Bollipo S, Hossain MA. Preliminary report of a randomized, double-blind placebo-controlled trial of a Chinese herbal medicine preparation CH-100 in the treatment of chronic hepatitis C. J Gastroenterol Hepatol. 1998;13:244-247. [PubMed] [DOI]
66.
You S, Zhou M, Xue B, Fang T, Jiang W, Li C, Xu H, Jiang J, Wang Y, Xu S. A clinical study on bing gan ling oral liquid for treatment of hepatitis C. J Tradit Chin Med. 1998;18:209-214. [PubMed] 
67.
Jiang YH. Treatment of 20 cases of hepatitis C using a self-prescribed Yizhu oral liquid. Nanjing Zhongyiyao Daxue Xuebao. 1999;15:256.
68.
Qin XK, Han M, Liu JP. Compound Chinese herbal medicines, Chinese herbal drugs and their active extracts for treatment of chronic hepatitis C: a systematic review and meta-analysis of randomized clinical trials. Zhongxiyi Jiehe Xuebao. 2009;7:913-928. [PubMed] [DOI]
69.
Yu WJ. Yi Er Gan decoction for treatment of 40 cases of hepatitis C. New J Tradit Chin Med. 1995;27:47.
70.
Coon JT, Ernst E. Complementary and alternative therapies in the treatment of chronic hepatitis C: a systematic review. J Hepatol. 2004;40:491-500. [PubMed] [DOI]
71.
Rahman AH, Branch AD. Vitamin D for your patients with chronic hepatitis C?. J Hepatol. 2013;58:184-189. [PubMed] [DOI]
72.
Han YP, Kong M, Zheng S, Ren Y, Zhu L, Shi H, Duan Z. Vitamin D in liver diseases: from mechanisms to clinical trials. J Gastroenterol Hepatol. 2013;28 Suppl 1:49-55. [PubMed] 
73.
Petta S, Cammà C, Scazzone C, Tripodo C, Di Marco V, Bono A, Cabibi D, Licata G, Porcasi R, Marchesini G. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51:1158-1167. [PubMed] [DOI]
74.
Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011;17:5184-5190. [PubMed] [DOI]
75.
Gal-Tanamy M, Bachmetov L, Ravid A, Koren R, Erman A, Tur-Kaspa R, Zemel R. Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology. 2011;54:1570-1579. [PubMed] [DOI]
76.
Moreno-Otero R, Trapero-Marugán M. Hepatoprotective effects of antioxidants in chronic hepatitis C. World J Gastroenterol. 2010;16:1937-1938. [PubMed] [DOI]
77.
Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs. 2005;65:2445-2461. [PubMed] [DOI]
78.
Yadav D, Hertan HI, Schweitzer P, Norkus EP, Pitchumoni CS. Serum and liver micronutrient antioxidants and serum oxidative stress in patients with chronic hepatitis C. Am J Gastroenterol. 2002;97:2634-2639. [PubMed] [DOI]
79.
Ko WS, Guo CH, Yeh MS, Lin LY, Hsu GS, Chen PC, Luo MC, Lin CY. Blood micronutrient, oxidative stress, and viral load in patients with chronic hepatitis C. World J Gastroenterol. 2005;11:4697-4702. [PubMed] 
80.
Singal AK, Jampana SC, Weinman SA. Antioxidants as therapeutic agents for liver disease. Liver Int. 2011;31:1432-1448. [PubMed] [DOI]
81.
Chuma M, Hige S, Nakanishi M, Ogawa K, Natsuizaka M, Yamamoto Y, Asaka M. 8-Hydroxy-2’-deoxy-guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol. 2008;23:1431-1436. [PubMed] [DOI]
82.
Mahmood S, Yamada G, Niiyama G, Kawanaka M, Togawa K, Sho M, Ito T, Sasagawa T, Okita M, Nakamura H. Effect of vitamin E on serum aminotransferase and thioredoxin levels in patients with viral hepatitis C. Free Radic Res. 2003;37:781-785. [PubMed] 
83.
von Herbay A, Stahl W, Niederau C, Sies H. Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C: a randomized, double-blind, placebo-controlled study. Free Radic Res. 1997;27:599-605. [PubMed] [DOI]
84.
Takagi H, Kakizaki S, Sohara N, Sato K, Tsukioka G, Tago Y, Konaka K, Kabeya K, Kaneko M, Takayama H. Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis. Int J Vitam Nutr Res. 2003;73:411-415. [PubMed] [DOI]
85.
Melhem A, Stern M, Shibolet O, Israeli E, Ackerman Z, Pappo O, Hemed N, Rowe M, Ohana H, Zabrecky G. Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial. J Clin Gastroenterol. 2005;39:737-742. [PubMed] [DOI]
86.
Gabbay E, Zigmond E, Pappo O, Hemed N, Rowe M, Zabrecky G, Cohen R, Ilan Y. Antioxidant therapy for chronic hepatitis C after failure of interferon: results of phase II randomized, double-blind placebo controlled clinical trial. World J Gastroenterol. 2007;13:5317-5323. [PubMed] 
87.
Groenbaek K, Friis H, Hansen M, Ring-Larsen H, Krarup HB. The effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status: a randomized trial among chronic hepatitis C virus-infected patients. Eur J Gastroenterol Hepatol. 2006;18:985-989. [PubMed] [DOI]
88.
Gane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM, Frampton CM, Taylor KM, Smith RA, Murphy MP. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int. 2010;30:1019-1026. [PubMed] [DOI]
89.
Look MP, Gerard A, Rao GS, Sudhop T, Fischer HP, Sauerbruch T, Spengler U. Interferon/antioxidant combination therapy for chronic hepatitis C--a controlled pilot trial. Antiviral Res. 1999;43:113-122. [PubMed] [DOI]
90.
Idéo G, Bellobuono A, Tempini S, Mondazzi L, Airoldi A, Benetti G, Bissoli F, Cestari C, Colombo E, Del Poggio P. Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study. Eur J Gastroenterol Hepatol. 1999;11:1203-1207. [PubMed] [DOI]
91.
Beloqui O, Prieto J, Suárez M, Gil B, Qian CH, García N, Civeira MP. N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis C: a pilot study. J Interferon Res. 1993;13:279-282. [PubMed] [DOI]
92.
Grant PR, Black A, Garcia N, Prieto J, Garson JA. Combination therapy with interferon-alpha plus N-acetyl cysteine for chronic hepatitis C: a placebo controlled double-blind multicentre study. J Med Virol. 2000;61:439-442. [PubMed] 
93.
Jones AL, Jarvie DR, Simpson D, Hayes PC, Prescott LF. Pharmacokinetics of N-acetylcysteine are altered in patients with chronic liver disease. Aliment Pharmacol Ther. 1997;11:787-791. [PubMed] [DOI]
94.
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924-1934, 1934.e1-4. [PubMed] [DOI]
95.
Takikawa H, Murata Y, Horiike N, Fukui H, Onji M. Drug-induced liver injury in Japan: An analysis of 1676 cases between 1997 and 2006. Hepatol Res. 2009;39:427-431. [PubMed] [DOI]
96.
Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 2009;29:337-347. [PubMed] 
97.
Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, Tam CM, Leung CC, Lai CL. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology. 2000;31:201-206. [PubMed] [DOI]
98.
Wu JC, Lee SD, Yeh PF, Chan CY, Wang YJ, Huang YS, Tsai YT, Lee PY, Ting LP, Lo KJ. Isoniazid-rifampin-induced hepatitis in hepatitis B carriers. Gastroenterology. 1990;98:502-504. [PubMed] 
99.
Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther. 2001;70:317-326. [PubMed] [DOI]
100.
tablets for the treatment of chronic hepatitis C.. Available from: http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm377920.htm
101.
hepatitis C in combination antiviral treatment.. Available from: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm377234.htm
102.
Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther. 2013;37:3-17. [PubMed] [DOI]

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