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Hepatology, October 1999, p. 1099-1104, Vol. 30, No. 4
HEPATOLOGY Clinical Challenge
Herbal Products for Liver Diseases:
A Therapeutic Challenge for the New Millennium
Detlef Schuppan1, Ji-Dong
Jia1,2,Benno Brinkhaus1, and
Eckhart G. Hahn1
From the 1Department of Medicine I, University of
Erlangen-Nuernberg, and the 2Department of
Gastroenterology and Hepatology, Klinikum B. Franklin, Free
University of Berlin, Berlin, Germany.
INTRODUCTION
Use of herbal drugs in the treatment of liver diseases has a
long tradition, especially in Eastern medicine. Standardization has
been a problem, and randomized, placebo-controlled clinical trials
to support efficacy are lacking. Some herbal extracts promoted for
gastrointestinal or biliary disorders contain potent hepatotoxic
alkaloids and are harmful. However, some of these extracts have
yielded molecules, often related to flavonoids, with proven
antioxidative, antifibrotic, antiviral, or anticarcinogenic
properties, including glycyrrhizin, phyllanthin, silibinin,
picroside, and baicalein, which derive from licorice root,
Phyllanthus amarus, milk thistle, Picrorhiza kurroa,
and sho-saiko-to, respectively, that can serve as primary compounds
for the development of specific hepatotropic drugs.
BACKGROUND
Natural remedies represent a $1.8 billion market in the United
States, and a single herbal preparation, silymarin, which is used
almost exclusively for liver diseases, amounts to $180 million in
Germany alone.1 Marketing of herbals
tripled between 1992 and 1996,1 and
nearly a third of outpatients attending liver clinics use these
products.2 This is reflected in the
internet home pages of hepatitis foundations. Herbal products have
been classified as food supplements and thus are exempt from
regulations on quality control and proof of efficacy that govern
standard pharmaceuticals. This is contentious in view of the
biological activity of many herbals and, more worrisome, their
occasionally severe toxicity.
Use of herbal medicines can be traced back as far as
2100 B.C. in ancient China (Xia dynasty) and India (Vedic
period). The first written reports date back to 600 B.C. with
the Caraka Samhita of India and the early notes of the Eastern Zhou
dynasty of China that became systematized around 400 B.C. The
recipes, once formulated, were usually expanded rather than
abandoned during subsequent centuries. Expansion was stimulated by
a growing understanding of the natural evolution of frequently
encountered diseases and by emerging hypotheses regarding their
causes. Hepatitis was and continues to be prominent. Biliary stasis
in patients with jaundice, often associated with ascites and
encephalopathy, led to the discovery that the liver is responsible
for bile production and excretion. However, contrary to the
Aristotelian Western world, which preferred the analytical approach
to medicine, even when based on unfounded assumptions, the Eastern
hemisphere always considered disease a manifestation of a more
general imbalance of the dichotomous energies that govern life as a
whole and human life in particular. In China these energies are
represented by the complementary Yin (representing earth and moon,
moistness, darkness and passivity the female aspect) and Yang
(representing sun, dryness, light, and activity the male aspect),
the balance and timely sequence of which is necessary to maintain
health. In the Ayurveda (sanskrit: ayur, life; veda, knowledge) of
India, similar forces are agni (strength, health, and innovation)
and ama (weakness, disease, and ntoxication).
With the revolution of the natural sciences and evidence-based
medicine, the divide between Western and Eastern medicines appeared
to widen. However, given the limitations of conventional treatment
for chronic diseases and tumors, both patients and scientifically
trained physicians are giving increased attention to the more
holistic approach of Eastern medicine. Although this may represent
in part a trend towards mysticism in our modern world, the
effectiveness of Eastern medicine is amenable to Western analysis.
One explanation is the placebo effect, part of which can be
explained by modulation of neurotransmitters or the immune system
in the brain, and another is the fact that some herbal drugs
contain ingredients that specifically treat disease.
EFFICACY AND SAFETY OF HERBAL PRODUCTS
Any evaluation of herbal products faces major problems. The
first is the use of mixed extracts (concoctions) and variations in
methods of harvesting, preparing, and extracting the herb, which
can result in dramatically different levels of certain alkaloids.
The biologically active substances have been structurally defined
and standardized for only a few of the herbs. Even then, it may not
be known if this molecule is the sole active principle or if
efficacy depends on the mixture of compounds.
The second problem is a lack of randomized, placebo-controlled
clinical studies. Traditional Eastern medicine relies on empiricism
and a holistic philosophy, and controlled studies are considered
unnecessary. This is a view shared by many Western supporters of
alternative medicine. Also, trials may not use end points, such as
death from liver disease, histological fibrosis or inflammation,
cancer, and transplantation.
Related to these issues is concern about the safety of herbal
remedies. Numerous reports of toxic effects contradict the popular
view that herbals are natural and therefore harmless. A survey of
the National Poison Information Service for the years 1991-1995
documented 785 cases of possible or confirmed adverse
reactions to herbal drugs, among which hepatotoxicity was the most
frequent.3 The real number is probably
much higher because of underreporting. Although abnormal liver
function tests mostly return to normal once the offending drug is
withdrawn, cases of chronic disease and acute liver failure
requiring transplantation have been reported.4 There are groups of plant alkaloids with
well established hepatotoxicity (table 1).4-6 The pyrrolizidine alkaloids found in
herbal teas or enemas containing Crotalaria, Senecio, Heliotropium,
or Symphytum damage the hepatic central vein endothelia, causing
veno-occlusive disease that may be lethal or require
transplantation. Germander (Teucrium chamaedrys L.), broadly
used in France as an antipyretic for treatment of abdominal
discomfort and for weight reduction, contains hepatotoxic alkaloids
identified as furano-diterpenoids that, after activation by the
hepatic cytochrome P450 3A, deplete glutathione and precipitate
hepatocyte necrosis, apoptosis, and cytoskeletal disorganization.7,8 Greater celandine (Chelidonium majus)
has resulted in acute hepatitis; extracts of this herb are broadly
used in Europe to treat gallstone disease and dyspepsia.9 Hepatotoxicity can result also from
misidentification or mislabeling of a plant, contamination by
chemicals such as heavy metals, and incorrect storage that leads to
microbial or fungal growth and toxin production. Safety testing is
needed. Before this can be implemented, however, preparations must
be standardized and must replace in the market the uncontrolled and
individualized concoctions currently being offered. Safety concerns
notwithstanding, sufficient scientifically useful data have
accumulated during the last few years to allow an overview of
herbal compounds, some of which appear to be beneficial and may
serve as a basis for future drug development.
table 1. Selection of Herbal
Preparations With Proven Hepatotoxicity
STUDIES OF DEFINED FORMULATIONS OF HERBAL MEDICINES
Some herbal preparations exist as standardized extracts with
major known ingredients or even pure compounds, for which
pharmacodynamic and pharmacokinetic data are usually available.
These resemble the medications of traditional Western medicine. In
only a few cases, however, have studies documented their efficacy
using accepted parameters of disease progression.
Glycyrrhizin. This group of
related, sulfated saponins and lectins from the licorice root has
been used for over 20 years to treat chronic viral hepatitis
in Japan. It has a well-documented transaminase-lowering effect.
The standardized aqueous extract (Stronger Neo-Minophagen C) has to
be administered parenterally. A daily dose of 80 mg given for
2 weeks can normalize aspartate transaminase and alanine
transaminase in over 60% of patients.10 The preparation has immunosuppressive and
anti-inflammatory effects in cell culture, where glycyrrhizin
inhibits CD4+-T cell- and tumor necrosis factor-mediated
cytotoxicity.11 Furthermore, the
extract modifies glycosylation and blocks sialylation of hepatitis
B surface antigen (HBsAg), which leads to its retention in the
trans-Golgi apparatus.12 In an
uncontrolled trial of 17 hepatitis Be antigen-positive
patients with chronic hepatitis B, a 4-week course of glycyrrhizin
followed by 4 weeks of interferon-alfa produced loss of
hepatitis B e antigen in 10 of 17 patients after
6 months.13 However, only
3 of the 10 patients underwent seroconversion to
antibodies to e antigen, and virus titers were not reported. In a
small randomized study of 28 patients with chronic hepatitis C
who were nonresponders to interferon monotherapy, 13.3% became
hepatitis C virus-RNA negative after interferon alone compared with
33.3% after a glycyrrhizin/interferon combination therapy over
3 months.14 However, this was
not statistically significant. In a retrospective analysis of
84 patients with chronic hepatitis C virus infection who were
treated with intravenous glycyrrhizin 2 to 7 times weekly
for a median of 10.1 years, comparison with a matched group of
109 patients who remained untreated over 9.2
years revealed a 2.5-fold reduction of the relative risk of
hepatocellular carcinoma.15 This
could be due to an anti-inflammatory effect of the preparation
rather than to its weak antiviral effect. Because of its
aldosterone-like activities,16 use of
the drug requires caution and monitoring for hypertension,
hyperkalemia, and worsening ascites.
Phyllanthus amarus. This
herb and related species are Indian plants that contain
phyllantins, hypophyllantins, and polyphenoles with antiviral
properties. An aqueous extract inhibited woodchuck hepatitis virus
DNA polymerase and surface antigen expression17,18 and several protein kinases such as
cAMP-dependent protein kinase, protein kinase C, and myosin
light-chain kinase in rat liver.19 A
nonrandomized clinical study showed a remarkable 59% (22 of
37 patients) clearance of HBsAg in chronic carriers who were
treated for 30 days compared with only 4% (1 of
23 patients) given placebo.20
However, these results await confirmation. There was no effect of
P. amarus on duck hepatitis B virus.21
Daphnoretin. This
dicoumarin drug extracted from the Chinese herb Wilkstroemia
indica was shown to suppress HBsAg in Hep3B cells, an effect
mediated by activation of protein kinase C.22 The same investigators reported a powerful
suppression of HBsAg by costunlite and dehydrocostus lactone, two
alkaloids from Saussurea lappa Clarks root.23 However, no clinical studies with these
compounds have been reported.
Silymarin. A standardized
extract from the milk thistle Silybum marianum contains as
its main constituents the flavonoids silybinin, silydianin, and
silychristin.24 Milk thistle extracts
were used as early as the 4th century B.C., became a favored
medicine for hepatobiliary diseases in the 16th century, and
experienced a revival in central Europe in the late 1960s (table 2). The flavonoid silibinin, which constitutes 60%
to 70% of silymarin, has been identified as the major active
ingredient.25,26 Its pharmacological profile is well
defined, and studies in cell culture and animal models clearly show
its hepatoprotective action with little or no toxicity.26,27,33-41 Silymarin enhances the activity of
hepatocyte RNA-polymerase I,26
complexes toxic free iron,33 protects
the cell membrane from radical-induced damage,34 and blocks the uptake of toxins such as
Amanita phalloides toxin.32,35 A potent scavenger, it prevents lipid
peroxidation and normalizes the lipid profile of hepatocyte
membranes.36 Silymarin provided liver
protection in rat models of liver damage induced by carbon
tetrachloride and paracetamol.37,38 Four of 12 dogs fed lyophilized
Amanita toxin and given supportive care died from hepatic failure
and coma within 35 to 54 hours, whereas all 11 dogs
receiving high-dose silymarin survived.39 In a retrospective analysis of
205 patients with Amanita intoxication, of whom
30 received treatment, the death rate of those given
intravenous silymarin was reduced significantly (12.8% vs.
22.4%).40
table 2. History of the Milk
Thistle as a Liver Remedy
In recent in vitro studies, silymarin down-regulated the
proinflammatory leukotriene B4 in Kupffer cells.41 In randomized clinical trials for acute
viral hepatitis A or B, oral silymarin either exerted no benefit29 or accelerated clinical recovery,
causing a significantly more rapid normalization of bilirubin and
aspartate transaminase than did the control.30 Similarly, in alcohol-related hepatitis
treated with silymarin, transaminase levels dropped more rapidly
than in the untreated disease.42 A
4-month course of silymarin in patients with moderately active
alcohol-related liver disease led to a 41% reduction of alanine
transaminase, compared with no change in controls.43 In a randomized trial,
170 biopsy-proven cirrhotic patients, 92 with
alcohol-related and 78 with nonalcohol-related liver disease,
were treated with silymarin or placebo for a mean of
41 months.44 Although serum
biochemistry values did not differ between the 2 groups, the
number of surviving cirrhotic patients with alcohol-related liver
disease was significantly higher in the silymarin group, especially
in those with Child-Pugh class A cirrhosis. Most of the latter
patients continued to drink, which may have influenced the results.
Also, the dropout rate was high, although dropouts were counted as
therapy failures. A subsequent randomized, placebo-controlled study
of 200 patients with alcohol-related cirrhosis, 75 of
whom dropped out, could not confirm a survival benefit.45
These data point up the difficulty of studying a heterogeneous
group of patients and of using death as the endpoint for a
condition that progresses over many years. An intermediate endpoint
is progression of fibrosis to cirrhosis, which is the primary
determinant of morbidity and mortality in patients with chronic
liver diseases. In vitro, silymarin blocks proliferation of
hepatic stellate cells, the main source of excess collagen in
fibrosis. This is accompanied by down-regulation of the
profibrogenic transforming growth factor .46 In liver injury induced by complete
occlusion of the biliary system in the rat, oral silymarin reduced
collagen accumulation in a dose-dependent fashion.47 It was similarly antifibrotic when
administered from weeks 4 to 6, i.e., starting at
a time when liver collagen is already increased 4-fold, a situation
encountered in most patients with chronic liver disease. The
antifibrotic effect was accompanied by reduced numbers of activated
stellate cells48 and a greater than
50% reduction of both procollagen I and tissue inhibitor of
metalloproteinase messenger RNA, both being major effectors of
fibrogenesis.49 These data have
spawned randomized, placebo-controlled studies of silymarin in
patients with chronic viral hepatitis that include follow-up
biopsies and a panel of serum markers of liver fibrosis.50
Picroliv. Picroliv is an
alcoholic extract from the root of Picrorhiza kurroa that
contains the iridoid glycosides kutkoside and picroside. In the rat
these glycosides act as antioxidants51 and ameliorate the hepatotoxic effects of
carbon tetrachloride,52
thioacetamide, galactosamine,53 and
paracetamol.54 Despite their wide
oral usage in India, no reliable data for human liver disease
exist.
TJ-9. TJ-9, commonly
prescribed in China as xiao-chai-hu-tang and in Japan as
sho-saiko-to, is an aqueous extract from the roots of scutellaria,
glycyrrhiza, bupleurum, and ginseng; the pinella tuber; the jujube
fruit; and the thew ginger rhizome. Two major alkaloids from
scutellaria, baicalin and baicalein, are strong inhibitors of lipid
peroxidation.55 The extract prevented
hepatocellular membrane damage and restored mitochondrial function
in endotoxin-treated rats, increasing hepatic levels of superoxide
dismutase and glutathione.56,57 Other in vitro effects that are
related to the observed antitumour activity of sho-saiko-to include
up-regulation of the inducible nitric oxide synthase in hepatocytes
cultured in the presence of interferon 58 and inhibition of proliferation and
induction of apoptosis in hepatoma cells.59,60 The extract modulated the in vitro
cytokine production in peripheral blood mononuclear cells,
stimulated release of tumor necrosis factor- and
granulocyte-colony-stimulating factor in patients with
hepatocellular carcinoma and down-regulated synthesis of
interleukin-4 and -5 in favor of interleukin-10 in patients
with chronic hepatitis C.61,62 Other in vitro effects include
stimulation of inducible nitric oxide synthase and down-regulation
of interleukin-4 and -5 in favor of interleukin-10 in patients
with chronic hepatitis C.61,62 In the rat model of
dimethylnitrosamine-induced liver injury, the extract sho-saiko-to
protected liver synthetic function63
and restored hepatic retinoid levels.64 Sho-saiko-to reduced hepatic collagen
content in the rat models of fibrosis due to choline-deficiency,65 dimethylnitrosamine, and pig serum.66 The latter work identified baicalin
and baicalein, which are structurally similar to silibinin,67 as major active compounds, leading to the
hypothesis that these agents may have an antifibrotic activity
separable from their effect as inhibitors of lipid peroxidation.
Whereas information on the antiviral efficacy of sho-saiko-to is at
best rudimentary,68 a prospective
randomized 5-year study of 260 patients with cirrhosis showed
a near-significant (P < .053)
survival benefit for the treated patients; this reached
significance in those patients without HBs-Ag.69
FORMULAS CONTAINING MIXTURES OF HERBS WITH PARTIALLY KNOWN OR
LARGELY UNKNOWN INGREDIENTS
The literature is replete with experimental studies using herbs
of largely unknown composition. The following are those
preparations for which human studies or mechanistic data exist.
Compound 861. Known as cpd
861, this is an aqueous extract of 10 defined herbs based
on traditional Chinese medicine. The aim of traditional Chinese
medicine is resolution of blood stasis and liver stagnation, two
conditions that form the basis of liver pathology and patient
discomfort.70 The chief herbs used in
cpd 861 are Salvia miltiorrhiza, Astragalus
membranaceous, and Spatholobus suberectus.71 Rats with experimental liver fibrosis
showed a 50% reduction of the 5-fold increased hepatic collagen
level when cpd 861 was administered daily by gavage.72 This was accompanied by a comparable
down-regulation of hepatic messenger RNA for transforming growth
factor 1 and for procollagens I, III, and IV, as well as by
increased hepatic collagenase activity. Because procollagen
messenger RNAs, major effectors of liver fibrogenesis, were also
down-regulated in cultures of hepatic stellate cells, a direct
antifibrotic effect was proposed.73 From 1993 to 1995, 60 patients with chronic
hepatitis B were treated in an open trial with cpd 861.71 After 2 years, subjective improvement
was reported by 50 patients (83%), and this was accompanied by
a reduction in spleen size in 41% and a decrease in liver enzyme
levels and serum fibrosis markers such as PIIINP and laminin. In a
nonrandomized controlled trial, 22 patients with chronic
hepatitis B were treated with cpd 861 for 6 months and
compared with 12 matched patients receiving a control herbal
medicine.74 Follow-up liver biopsy
results showed a statistically significant improvement in both
histological inflammation and fibrosis in the cpd 861 group
but no change in the control subjects.
LIV.52. An extract of
several plants prepared for ayurvedic medicine has been marketed in
the West as LIV.52. Standardization, chemical characterization,
functional, and pharmacological studies are not well documented.
The extract was reported to improve serum biochemistry values in
rats with toxic liver damage,75 and
uncontrolled observations in patients with liver disease seemingly
gave similar results.76 Furthermore,
it lowered circulating levels of acetaldehyde in healthy adults
consuming alcohol.77 Therefore, Fleig
et al.78 performed a randomized,
placebo-controlled, 2-year clinical trial in 188 patients with
alcohol-related cirrhosis. LIV.52 did not affect the survival rate
of Child class A and B patients but increased mortality among the
59 Child class C patients (81% in the treated group, compared
with 40% in the placebo group). Twenty-two of 23 deaths in the
LIV.52 group were related to bleeding or liver disease compared
with only 3 of 11 deaths in the placebo group. This
result led to immediate withdrawal of the drug. It highlights the
danger of ill-defined herbal preparations and the necessity for
in-depth preclinical testing.
FUTURE DIRECTIONS
There is no doubt that certain herbal products contain
chemically defined components that can protect the liver from
oxidative injury, promote virus elimination, block fibrogenesis, or
inhibit tumor growth. Although additive effects may be lost, the
active molecules must be isolated and tested in suitable culture
and animal experiments and finally in randomized,
placebo-controlled studies to enable rational clinical use of the
agents. Biologically active molecules derived from herbal extracts
can serve as suitable primary compounds for effective and targeted
hepatotropic drugs.
Abbreviation
Abbreviation: HBsAg, hepatitis B surface antigen.
FOOTNOTES
Received February 25, 1999; accepted August
4, 1999.
Supported in part by grant IZKF B18 from the Federal Ministry of
Research and by the Balsen and Schoeller Foundations for Research
into Natural Medicine.
Address reprint requests to: Detlef Schuppan, M.D., Ph.D.,
Department of Medicine I, Division of Gastroenterology, Hepatology
and Infectiology, University of Erlangen-Nuernberg, Krankenhausstr.
12, 91054 Erlangen, Germany. E-mail: detlef.schuppan@med1.med.uni-erlangen.de;
fax: (49) 9131.85.36003.
Yoshida EM, McLean CA, Chen ES, Blanc PD, Somberg
KA, Ferrell LD, Lake JR. Chinese herbal medicine, fulminant
hepatitis, and liver transplantation. Am J Gastroenterol
1996;91:1436-1438.
Kaplowitz N. Hepatotoxicity of herbal remedies:
insight into the intricacies of plant-animal warfare and cell
death. Gastroenterology 1997;113:1408-1412.
Lekhehal M, Pessayre D, Lereau JM, Moulis C,
Fouraste F, Fau D. Hepatotoxicity of the herbal medicine germander.
Metabolic activation of its furano diterpenoids by cytochrome P450
3A depletes cytoskeleton-associated protein thiols and forms plasma
membrane blebs in hepatocytes. HEPATOLOGY
1996;24:212-21.
Fau D, Lekehal M, Farrell G, Moreau A, Moulis C,
Feldmann G, Haouzi D, et al. Diterpenoids from germander, a herbal
medicine, induce apoptosis in isolated rat hepatocytes.
Gastroenterology 1997;113:1408-1412.
Yamamura Y, Kotaki H, Tanaka N, Aikawa T, Sawada
Y, Iga T. The pharmacokinetics of glycyrrhizin and its restorative
effect on hepatic function in patients with chronic hepatitis and
in chronically carbon-tetrachloride-intoxicated rats. Biopharm Drug
Dispos 1997;18:717-72.
Yoshikawa M, Matsui Y, Kawamoto H, Umemoto N, Oku
K, Koizumi M, Yamao J, et al. Effects of glycyrrhizin on
immune-mediated cytotoxicity. J Gastroenterol Hepatol
1997;12:243-247.
Takahara T, Watanabe A, Shiraki K. Effects of
glycyrhizin on hepatitis B surface antigen: a biochemical and
morphological study. J Hepatol 1994;21:601-609.
Hayashi J, Kajiyama W, Noguchi A, Nahashima K,
Hirata M, Hayashi S, Kashiwagi S. Glycyrrhizin withdrawal followed
by human lymphoblastoid interferon in the treatment of chronic
hepatitis B. Gastroenterol Jpn 1991;26:742-7.
Abe Y, Ueda T, Kato T, Kohli Y. Effectiveness of
interferon, glycyrrhizin combination therapy in patients with
chronic hepatitis C. Nippon Rinsho 1994;52:1817-18.
Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota
A, Koida I, Suzuki Y, et al. The long-term efficacy of glycyrrhizin
in chronic hepatitis C patients. Cancer 1997;79:1494-150.
Venkateswaran PS, Millman I, Blumberg BS. Effects
of an extract of Phyllanthus niuri on hepatitis B and woodchuck
hepatitis viruses: in vitro and in vivo studies. Proc Natl Acad Sci
U S A 1987;84:274-278
Ott M, Thyagarajan SP, Gupta S. Phyllanthus amarus
suppresses hepatitis B virus by interrupting interactions between
HBV enhancer I and cellular transcription factors. Eur J Clin
Invest 1997;27:908-915
Munshi A, Mehrota R, Panda SK. Evaluation of
Phyllanthus amarus and phyllanthus mederaspatensis as agents for
postexposure prophylaxis in neonatal duck hepatitis B virus
infection. J Med Virol 1993;40:53-58.
Chen HC, Chou CK, Kuo YH, Yeh SF. Identification
of a protein kinase C (PKC) activator, daphnoretin, that suppresses
hepatitis B virus gene expression in human hepatoma cells. Biochem
Pharmacol 1996;52:1025-1032
Chen HC, Chou CK, Lee SD, Wang JC, Yeh SF. Active
compounds from Saussurea lappa Clarks that suppress hepatitis B
surface antigen gene expression in human hepatoma cells. Antiviral
Res 1995;27:99-109
Sonnenbichler J, Zetl I. Biochemical effects of
the flavolignane silibinin on RNA, protein and DNA synthesis in rat
liver. Progr Clin Biol Res 1986;213:319-33
Platt D, Schnorr B. Biochemical and electronoptic
study on the possible effect of silymarin on ethanol-induced liver
damage in rats. Arzneimittelforsch 1971;21:1206-1208
Schriewer D, Kastrup W, Wiemann W, Rauen HM. The
antihepatotoxic effect of silymarin on lipid metabolism in the rat
disturbed by phalloidine intoxication. Arzneimittelforsch
1975;25:188-194
Benda L, Dittrich H, Ferenci P, Frank H, Wewalka
F. The influence of therapy with silymarin on the survival rate of
patients with liver cirrhosis. Wie Klin Wochenschr
1980;92:678-683
Pietrangelo A, Borella F, Casalgrandi G, Montosi
G, Cecarelli D, Gallesi D, Giovanni F, et al. Antioxidant activity
of silybin in vivo during long-term iron overload in rats.
Gastroenterology 1995;109:1941-194
Floersheim GL, Weber O, Tschumi P, Ulbrich M.
Poisoning by the deathcup fungus (Amanita phalloides):
prognostic factors and therapeutic measures. Schweiz Med Wochenschr
1982;112:1164-1177
Dehmlow C, Erhard J, de Groot H. Inhibition of
Kupffer cell functions as an explanation for the hepatoprotective
properties of silibinin. HEPATOLOGY
1996;23:749-754
Fintelmann V, Albert A. Nachweis der
therapeutischen Wirsamkeit von Legalon bei toxischen
Leberkrankheiten im Doppelblindversuch. Therapiewoche
1980;30:5589-5594
Salmi HA, Sarna S. Effect of silymarin on
chemical, functional and morphological alterations of the liver: a
double blind study. Scand J Gastroenterol 1982;17:517-522
Ferenci P, Dragosics B, Dittrich H, Frank H, Benda
L, Lochs H, Meryn S, et al. Randomized controlled trial of
silymarin treatment in patients with cirrhosis of the liver. J
Hepatol 1989;9:105-113
Pares A, Planes R, Torres M, Caballeria J, Viver
JM, Acero D, Panes J, et al. Effects of silymarin in alcoholic
patients with cirrhosis of the liver. Results of a controlled,
double-blind, randomized and multicenter trial. J Hepatol
1998;28:615-621
Fuchs EC, Weyhenmeyer R, Meiner OH. Effects of
silybinin and a synthetic analogue on isolated rat hepatic stellate
cells and myofibroblasts. Arzneimittelforschung
1997;47:1383-1387
Boigk G, Stroedter L, Herbst H, Waldschmidt J,
Riecken EO, Schuppan D. Silymarin retards collagen accumulation in
early and advanced biliary fibrosis secondary to complete bile duct
obliteration in rats. HEPATOLOGY
1987;26:643-64
Boigk G, Herbst H, Jia JD, Riecken EO, Schuppan D.
Effect of antifibrotic agent silymarin on liver cell regeneration
in a rat model of secondary biliary fibrosis: a morphometric
analysis. J Phytother Res 1998;12(Suppl):S42-S44
Jia JD, Boigk G, Bauer M, Ruehl M, Strefeld T,
Riecken EO, Schuppan D. Silymarin downregulates TIMP-1 and collagen
I mRNA in rats with secondary biliary cirrhosis [Abstr]. HEPATOLOGY 1998;28(Suppl):546
Chander R, Kapoor NK, Dhawan BN. Picroliv,
picroside I and kutkoside from Picrorhiza kurroa are scavengers of
superoxide anions. Biochem Phamacol 1992;44:180-18
Dwivedi Y, Rastogi R, Chander R, Sharma SK, Kapoor
NK, Garg NK, Dhawan BN. Hepatoprotective activity of picroliv
against carbon tetrachloride-induced liver damage in rats. Indian J
Med Res 1990;92:195-200
Dwivedi Y, Rastogi R, Garg NK, Dhawan BN.
Perfusion with picroliv reverses biochemical changes induced in
livers of rats intoxicated with galactosamine or thioacetamide.
Planta Med 1993;59:418-420
Ansari RA, Tripathi SC, Patnaik GK, Dhawan BN.
Antihepatotoxic effects of picroliv, an active traction from
rhizomes of Picrorhiza kurroa. J Ethnopharmacol 1991;34:61-6
Miyahara M, Tatsumi Y. Suppression of lipid
peroxidation by sho-saiko-to and its components in rat liver
subcellular membranes. Yakugaku Zasshi 1990;110:407-413
Sakaguchi S, Tsutsumi E, Yokota K. Preventive
effects of a traditional Chinese medicine (sho-saiko-to) against
oxygen toxicity and membrane damage during endotoxemia. Biol Pharm
Bull 1993;16:782-786
Sakaguchi S, Tsutsumi E, Yokota K. Defensive
effects of a traditional Chinese medicine (sho-saiko-to) against
metabolic disorders during endotoxemia. Biol Pharm Bull
1994;17:232-23
Hattori Y, Kasai K, Sekiguchi Y, Hattori S, Banba
N, Shimoda S. The herbal medicine sho-saiko-to induces nitric oxide
synthase in rat hepatocytes. Life Sci 1995;56:143-148
Yano H, Mizoguchi A, Fukuda K, Haramaki M,
Ogasawara S, Momosaki S, Kojira M. The herbal medicine sho-saiko-to
inhibits proliferation of cancer cells by inducing apoptosis and
arrest at the G0/G1 phase. Cancer Res 1994;54:448-454
Matsuzaki Y, Kurokawa N, Terai S, Matsumara Y,
Kobayashi N, Okita K. Cell death induced by baicalein in human
hepatocellular carcinoma cells. Jpn J Cancer Res
1996;87:170-177
Yamashiki M, Nishimura A, Nomoto M, Suzuki H,
Kosaka Y. Herbal medicine sho-saiko-to induces tumour necrosis
factor-alpha and granulocyte colony-stimulating factor in vitro in
peripheral blood mononuclear cells of patients with hepatocellular
carcinoma. J Gastroenterol Hepatol 1996;11:137-14
Yamashiki M, Nishimura A, Sakaguchi S, Kosaka Y.
Effects of the Japanese herbal medicine sho-saiko-to (TJ-9) on
in vitro interleukin-10 production by peripheral blood
mononuclear cells of patients with chronic hepatitis C. HEPATOLOGY 1997;25:1390-1397
Ohta Y, Nishida K, Sasaki E, Kongo M, Hayashi T,
Nagata M, Ishiguro I. Comparative study of oral and parenteral
administration of sho-saiko-to (xiao-chaihu-tang) extract on
D-galactosamine-induced liver injury in rats. Am J Chinese Med
1997;25:333-342
Miyamura M, Ono M, Kyotani S, Nishioka Y. Effects
of sho-saiko-to extract on fibrosis and regeneration of the liver
in rats. J Pharm Pharmacol 1998;50:97-105
Sakaida I, Matsumura Y, Akiyama S, Hayashi K,
Ishige A, Okita K. Herbal medicine sho-saiko-to (TJ-9) prevents
liver fibrosis and enzyme-altered lesions in rat liver cirrhosis
induced by a choline-deficient L-amino acid-defined diet. J Hepatol
1998;28:298-306
Shimizu I, Ma YR, Mizobuchi Y, Liu F, Nakai Y,
Yasuda M, Shiba M, et al. Effects of sho-saiko-to, a Japanese
herbal medicine, on hepatic fibrosis in rats. HEPATOLOGY 1999;29:149-160
Tajiri H, Kozaiwa K, Ozaki Y, Miki K, Shimizu K,
Okada S. Effect of sho-saiko-to (xiao-chai-hu-tang) on HBeAg
clearance in fourteen children with chronic hepatitis B virus
infection and with sustained liver disease. Am J Chinese Med
1991;19:121-129
Oka H, Yamamoto S, Kuroki T, Harihara S, Marumo T,
Kim SR, Monna T, et al. Prospective study of chemoprevention of
hepatocellular carcinoma with sho-saiko-to (TJ-9). Cancer
1995;76:743-749
Wang HJ, Wang BE. Long-term follow-up result of
compound Dan Shen granule (861 Chong Fu Ji) in treating
hepatofibrosis. Chin J Integr Trad West Med 1995;5:4-5
Jia JD, Wang BE, Dong Z, Cui L, Zhu JX, Che JT.
The effect of herbal compound 861 on mRNA levels for type I,
III and IV collagens and TGF in immune complex rat liver fibrosis.
Chin J Hepatol 1996;4:214-216
Wang TL, Wang BE, Zhang HH, Liu X, Duan ZP, Zhang
J, Ma H, Li XM, Li NZ. Pathological study of the therapeutic effect
on HBV-related liver fibrosis with herbal compound 861. Chin J
Gastroenterol Hepatol 1998;7:148-15
Pandey S, Gujrati VR, Shanker K, Singh N, Dhawan
KN. Hepato- protective effect of LIV.52 against CCl4-induced lipid
peroxidation in liver of rats. In J Exp Biol 1994;32:694-697.
Sama SK, Krishnamurthy L, Ramachandran K, Lal K.
Efficacy of an indigenous compound preparation (LIV.52) in acute
viral hepatitis--a double blind study. Indian J Med Res
1976;64:738-742
Chauhan BL, Kulkarni RD. Effect of LIV.52, a
herbal preparation, on absorption and metabolism of ethanol in
humans. Eur J Clin Pharmacol 1991;40:189-19
Fleig WW, Morgan MY, Hölzer MA, a European
multicenter study group. The ayurvedic drug LIV.52 in patients with
alcoholic cirrhosis. Results of a prospective, randomized,
double-blind, placebo-controlled clinical trial [Abstr]. J Hepatol
1997;26 (Suppl 1):127
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and
granulocyte-colony-stimulating factor in patients with
hepatocellular carcinoma and down-regulated synthesis of
interleukin-4 and -5 in favor of interleukin-10 in patients
with chronic hepatitis C.