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 glycyrrhizin
11:1077-1083.
[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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