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Herbal products for liver diseases: A therapeutic challenge for the new millennium

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  • University Hospital Erlangen, Erlangen, Germany

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Clinical Challenge
Herbal Products for Liver Diseases: A Therapeutic Challenge for
the New Millennium
DETLEF SCHUPPAN,1JI-DONG JIA,1,2 BENNO BRINKHAUS,1AND ECKHART G. HAHN1
Use of herbal drugs in the treatment of liver diseases has a
long tradition, especially in Eastern medicine. Standardiza-
tion 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. How-
ever, some of these extracts have yielded molecules, often
related to flavonoids, with proven antioxidative, antifibrotic,
antiviral, or anticarcinogenic properties, including glycyrrhi-
zin, 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.1Marketing of herbals
tripled between 1992 and 1996,1and nearly a third of
outpatients attending liver clinics use these products.2This 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. Expan-
sion 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 Aristote-
lian Western world, which preferred the analytical approach
to medicine, even when based on unfounded assumptions,
the Eastern hemisphere always considered disease a manifes-
tation 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, moist-
ness, 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 neces-
sary 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
intoxication).
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 extract-
ing 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.
Abbreviation: HBsAg, hepatitis B surface antigen.
From the 1Department of Medicine I, University of Erlangen-Nuernberg, and the
2Department of Gastroenterology and Hepatology, Klinikum B. Franklin, Free Univer-
sity of Berlin, Berlin, Germany.
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.
Copyright r1999 by the American Association for the Study of Liver Diseases.
0270-9139/99/3004-0037$3.00/0
1099
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 con-
firmed adverse reactions to herbal drugs, among which
hepatotoxicity was the most frequent.3The 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 re-
ported.4There are groups of plant alkaloids with well
established hepatotoxicity (Table 1).4-6 The pyrrolizidine
alkaloids found in herbal teas or enemas containing Crota-
laria, Senecio, Heliotropium, or Symphytum damage the
hepatic central vein endothelia, causing veno-occlusive dis-
ease 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 disorganiza-
tion.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.9Hepatotoxic-
ity 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 individu-
alized 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.
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 usu-
ally 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 ex-
tract 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 hepati-
tis 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 com-
pared 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 polyphe-
noles with antiviral properties. An aqueous extract inhibited
TABLE 1. Selection of Herbal Preparations With Proven Hepatotoxicity
Causative Plants Toxic Agents Symptoms Mechanism/Pathology
Crotalaria
Senecio
Heliotropium
Symphytum officinale (Comfrey)
Pyrrolizidine alkaloids Veno-occlusive disease Endothelial cell glutathione depletion,
central vein necrosis, thrombosis,
and fibrosis
Atractylis gummifera Atractylate, gummiferin Hepatitis Inhibition of oxidative phosphoryla-
tion, hepatic necrosis
Callilepsis laureola Atractylate Hepatitis Hepatocyte necrosis
Chelidonum majus (greater celandine) Chelidonine, sanguinarine, berberine,
coptisine?
Hepatitis (cholestatic) Lymphocyte infiltration
Larrea tridentata (chaparral) Guaiaretic acid derivatives Hepatitis ?
Teucrium chamaedrys (germander) Furano-diterpenoids Hepatitis Hepatocyte glutathione depletion and
apoptosis
Chinese herbal mixtures (artemisia,
hare’s ear, chrysanthemum, plantago
seed, gardinia, red peony root, etc.)
Largely undefined Hepatitis ?
NOTE. Data are selected from Larrey and Pageaux,5Kaplowitz,6Benninger et al.,9and Yoshida et al.4
1100 SCHUPPAN ET AL. HEPATOLOGY October 1999
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 power-
ful 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 consti-
tutes 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 normal-
izes 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
In recent in vitro studies, silymarin down-regulated the
proinflammatory leukotriene B4 in Kupffer cells.41 In random-
ized 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 un-
treated 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 heteroge-
neous 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 prolifera-
tion 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 encoun-
tered in most patients with chronic liver disease. The
antifibrotic effect was accompanied by reduced numbers
TABLE 2. History of the Milk Thistle as a Liver Remedy
Century/Year Use/Indication Source
4th Century B.C. General medicinal herb Theophrastus
1st Century A.D. Emetic, general
medicinal herb
Dioskurides
11th Century A.D. Ulcers, shingles Hildegard von Bingen,
Causae et curae
1564 Stitch in the side,
astringent
A. Lonicerus, Kreuter-
buch, Frankfurt
1626 Stitch in the side, pesti-
lence, renal calculi
P.A. Matthiolus, Neues
Kreuterbuch, Prague
1755 Liver disease, liver pain A. von Haller, Medici-
nisches Lexikon,
Frankfurt
1846/1951 Liver disease, icterus,
biliary colic
J.G. Rademacher,
Erfahrungsheillehre,
Berlin
1938 Hepato-cholangiopa-
thies, chronic leg
ulcers
G. Madaus, Lehrbuch
der biologischen
Heilmittel, Leipzig
Year
Characterization/First
Clinical Studies Source (reference)
1968-1974 Characterization of
active compounds
Wagner et al.25 and
Sonnenbichler et
al.26
1971 First animal experi-
mental studies on
liver protection
Platt et al.27
Antidote for Amanita
phalloides intoxica-
tion in the rat
Schriewer et al.28
1976-1988 Elucidation of
molecular actions of
silibinin
Sonnenbichler et al.26
1977/1978 First controlled clinical
studies in acute viral
hepatitis
Bode et al.29 and
Magliulo et al.30
1980 First controlled study
in alcoholic cirrhosis
Benda et al.31
1980-1981 Amanita phalloides
antidote in clinical
studies
Hruby et al.32
HEPATOLOGY Vol. 30, No. 4, 1999 SCHUPPAN ET AL. 1101
of activated stellate cells48 and a greater than 50% reduction
of both procollagen I and tissue inhibitor of metalloprotein-
ase messenger RNA, both being major effectors of fibrogen-
esis.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 kutko-
side and picroside. In the rat these glycosides act as antioxi-
dants51 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 gluta-
thione.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 hepato-
cytes 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 produc-
tion in peripheral blood mononuclear cells, stimulated re-
lease 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 resolu-
tion 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 signifi-
cant 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. Standard-
ization, chemical characterization, functional, and pharmaco-
logical 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 pa-
tients 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.
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1104 SCHUPPAN ET AL. HEPATOLOGY October 1999
... The taking of medicinal plants can be done in different types. These can be capsules, tablets, infusions, tinctures, extracts, raw herbs or in different forms including enemas or poultice applications 4,5 . Herbal medicines can be toxic if misused and cause damage to organs such as the liver and kidneys. ...
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In Benin as in the African sub-region, the burden of Non-Communicable Diseases (NCDs) and the threats they represent constitute a major public health problem which hinders their economic and social development. NCDs kill 36 million people each year and 80% of deaths occur in developing countries, including Benin. The objective of our work is to evaluate the acute, subacute toxicity and the anti-hyperglycemic activity of five plants listed through an ethno pharmacological survey which is used for the treatment of type 2 diabetes in Benin. The acute toxicity test was conducted on male and female wistar rats at a single dose of 2000 mg/kg. The subacute toxicity test was carried out over a period of 28 days, with 6 batches of 3 rats. Batch 1 received daily 1 ml/100 g of distilled water and batches 2, 3, 4 and 5 respectively the leaf extracts of Bambusa vulgaris Schrad. Ex-Wendel; Parkia biglobosa (Jacq.) R. Br. Ex G. Don; Mangifera indica L.; Saccharum officinarum L.; And Annona muricata L. at a daily dose of 200mg/kg per day for 28 days. Administration of the single dose of the extract did not cause any deaths. In rats treated with repeated doses of 200mg/kg for 28 days the variation in weight depends on the extracts. The level of transaminases (AST and ALT) did not vary. Plant extracts did not induce any significant change in creatinine level. All five extracts have anti-hyperglycemic activity. Our results allow us to deduce that these plants can be used to prevent and treat diabetes without the risk of hepatic and renal toxicity. Keywords: Medicinal plants; Type 2 diabetes; Toxicity; efficacy
... Due to these important issues, it is necessary to search for alternative drugs for treatment of liver diseases [8]. Number of different medicinal plants and herbal formulations are being used for liver disorders in ethno-medical practices and in traditional medicine system [9][10][11][12][13][14]. Herbs play a major role in the management of various liver disorders as evidenced by several research articles based on experimental and clinical studies [4,[15][16][17]. ...
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In today's world, liver diseases are serious health problem. Liver plays key role in regulating the nutritional state and the energy balance in the body. Nutritional supplements and traditional medicinal plants can provide many invaluable drugs to the modern drug industry. Hepatoprotective agents, nutritional supplements and herbal formulations with scientifically documented hepatocellular proliferation activities can be included in treatment for liver diseases. Due to their efficacy and safety, these therapies are in great demand in the developed world for primary health care. With the availability of modern techniques, it is now possible to standardize, optimize, and test these herbal plants and nutritional supplements clinically, for their effective use. Many medicinal plants and nutritional supplements are being used since ancient time owing to their spectrum of activities like antimicrobial, cytotoxic, anti-diabetic, anti-inflammatory etc. Treatment of liver disorders can be revitalised by developing standardized and clinically tested alternative medicines with high safety and efficacy profile. This review provides up-to-date information about drug-induced hepatotoxicity and hepatoprotective effects of different interventions (Nutritional supplements, Medicinal plants and Herbal formulations) for liver disease or hepatotoxicity.
... In India, this plant is commonly found in Jammu and Kashmir at 1800-2400 m [4]. Silymarin, the standardized seed extract of milk thistle, has been extensively utilized as a broad-spectrum medicinal herb for a very long time [5,6]. From an ethnopharmacological point of view, silymarin has been employed for more than two centuries as a herbal therapy for protecting the liver from varied toxic matters, treating hepatic damage and for treatment of hepatitis as well cirrhosis [7,8]. ...
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Medicinal plants are considered the reservoir of diverse therapeutic agents and have been traditionally employed worldwide to heal various ailments for several decades. Silymarin is a plant-derived mixture of polyphenolic flavonoids originating from the fruits and akenes of Silybum mari-anum and contains three flavonolignans, silibinins (silybins), silychristin and silydianin, along with taxifolin. Silybins are the major constituents in silymarin with almost 70-80% abundance and are accountable for most of the observed therapeutic activity. Silymarin has also been acknowledged from the ancient period and is utilized in European and Asian systems of traditional medicine for treating various liver disorders. The contemporary literature reveals that silymarin is employed significantly as a neuroprotective, hepatoprotective, cardioprotective, antioxidant, anti-cancer, anti-diabetic, anti-viral, anti-hypertensive, immunomodulator, anti-inflammatory, photoprotective and detoxification agent by targeting various cellular and molecular pathways, including MAPK, mTOR, β-catenin and Akt, different receptors and growth factors, as well as inhibiting numerous enzymes and the gene expression of several apoptotic proteins and inflammatory cytokines. Therefore , the current review aims to recapitulate and update the existing knowledge regarding the pharmacological potential of silymarin as evidenced by vast cellular, animal, and clinical studies, with a particular emphasis on its mechanisms of action.
... However, since centrilobular hepatic necrosis commonly occurs during intoxication, a differential diagnosis with several poisonous plants is essential. Plants of the genera Senecio, Crotalaria, and Heliotropium, are known to cause centrilobular hepatic necrosis, similar to cocklebur (Benninger et al. 1999;Schuppan et al. 1999;Botha et al. 2014). However, Cestrum and Heliotropium were ruled out in this case because they cannot survive the winter in South Korea. ...
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A 19-month-old Korean native cow died the following day after consuming new silage. Grossly, the liver showed enlargement, redness, and haemorrhages in all the lobes. Additionally, many of the bur-shaped fruits of the cocklebur (Xanthium strumarium) were found in the gastric contents. The histological evaluation confirmed centrilobular hepatic necrosis. Additionally, carboxyatractyloside (CATR), a material fatal to animals found in the cocklebur, was detected in the gastric contents using high-performance liquid chromatography-quadrupole-time of flight mass spectrometry (HPLC-Q-TOF-MS). Based on the pathological findings and analytical confirmation, CATR intoxication was diagnosed. Therefore, careful feeding and elimination of the cocklebur is essential for minimising economic loss.
... Even scientifically proven hepatoprotective plant was found to contain hepatotoxins as well (Mac Gregor et al., 1989;Oshima et al., 1995). Thus, work on hepatoprotective herbal remedies remain a challenge (Schuppan et al., 1999). ...
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Beta vulgaris root is claimed by traditional medicine to treat a wide variety of ailments such as fevers and constipation, liver diseases, amongst other ailments. The objectives of this study were to assess the possible hepatoprotective effect of the extract on carbon tetrachloride (CCl 4)-induced hepatotoxicity and to assess the possible general toxicity of the root, in albino rat. The hepatoprotective assessment was determined biochemically (using Liver Function Test, LFTs), morphologically (histopathological) in albino rat. In general toxicological assessment, the effects of the extract on haematological, biochemical, morphological and in organo-body ratio assessment were performed. The extract was found to possess profound therapeutic ability as it decreased bilirubin levels from 5.2±0.1 μmol/L in the group treated with CCl 4 only to 4.2±0.5 μmol/L in the group that received CCl4 and 1000 mg/kg of extract. Additionally, alanine aminotransferase (ALT) levels decreased from 219.7±30.02 U/L in CCl 4 only treated group to 40.25 ± 2.39 U/L in groups treated with CCl 4 and 1000 mg/kg respectively. This effect was clearly evident in histopathological studies of livers of rats. The therapeutic ability of the aqueous extract was comparable to Silymarin, a standard hepatoprotective agent. The extract was also found to be effective in both prophylactic and concomitant administrations. This reduction was comparable to the control (316.6 ± 28.2 minutes), and more significant than in the group that received CCl 4 and Silymarin (432.6±42.0 minutes). Acute toxicity studies preliminarily carried out on the aqueous extract revealed no lethality. With the exception of food intake (that dose-dependently increased), no physical, physiological and behavioural effects on mice were observed in the study. The LD 50 of the aqueous extract was found to exceed 5000 mg/kg body weight. Sub-acute toxicity studies on the extract also showed no significant physical, physiological and behavioural effects. Haematological and biochemical studies also revealed no effect on rats administered with doses from 300 mg/kg to 1500 mg/kg body weight of extract. This effect was clearly confirmed by histopathological studies, as they showed no pathological difference in the target organs, livers and kidneys of treated rats when compared to those of the control rat group. It is concluded that the aqueous leaf extract of Beta vulgaris root is safe at doses of 50-1500mg/kg in albino rats. It is also hepatoprotective against CCl 4 induced liver damage. This hepatoprotective ability should have a role in the traditional use of the extract in the management of hepatitis related jaundice.
... During last four decades, more than 200 plant species have been screened for hepatoprotective activity and most of them belong to Asteraceae and Fabaceae family (Schuppan et al., 1999) (Table 2). According to World Health Organization (WHO) approximately 80% population from developing countries are still rely on traditional medicine for their primary health care (Ekor, 2014). ...
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Liver plays a major role in transforming and clearing the chemicals form the body, but same time it is susceptible to the toxicity of these chemicals. Liver diseases are now become major public health problem worldwide, beside viral infection, autoimmune diseases, infectious agents, toxic chemicals and many drugs at higher doses can cause hepatic injury. The drugs used for the treatment of hepatic disorders have many side effects since all drugs detoxified in the liver with the help of cytochrome p-450 system. Several plants are being used for treatment of liver diseases among people in different areas of the world since ancient time. In the current review we have summarized the information regarding the causes of liver diseases and plants used for the treatment of liver diseases.
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Background: Liver diseases remain the most important medical and biological problem. Works devoted to the study of the vitamin A role have shown conflicting results of its effect on the fibrosis development. We tested the hypothesis that an increase of the copper content in the liver, an example of which is Wilson's disease, shifts the balance in the redox system towards pro-oxidants, which leads to the antioxidant systems inhibition, including a decrease in the vitamin A content; this affects the levels of liver function regulation and the development of fibrosis. Methods: In animals with Cu-induced liver fibrosis, neutrophil activity, the immunocompetent cells content, the activity of alanine aminotransferase and γ-glutamylaminotransferase, the content of urea and creatinine in blood serum, as well as the vitamin A content in the liver, copper ions and its regenerative potential were determined. Results: It was found that three consecutive injections of copper sulfate to animals with an interval of 48 h between injections led to the death of 40% of the animals, and 60% showed resistance. The content of vitamin A in "resistant" animals at the beginning of the development of the fibrosis was reduced by 4 times compared to the control, the functional activity of the liver was somewhat reduced, and a connective tissue capsule was formed around the liver lobes in 75% of the animals. If animals with the initial stage of liver fibrosis received daily vitamin A at a dose of 300 IU/100 g of body weight, which was accompanied by its multiple increase in the liver (15 times on day 14), the mortality of animals decreased by almost 7 times, the functional activity of the liver did not differ from control. In the blood of these animals, the number of leukocytes, granulocytes, and monocytes was increased and phagocytic activity was increased. At the same time, the connective tissue capsule was developed more intensively than in animals receiving only copper sulfate, and was detected in 91% of the animals. Fragments of the liver, even more than in the case of fibrosis, lost the ability to regenerate in culture. Conclusion: We came to the conclusion that vitamin A leads to the connective tissue "specialization" formation of the liver and triggers vicious circles of metabolism and includes several levels of regulation systems. Further studies of the vitamin A effect mechanisms on the liver with fibrosis will allow the use of this antioxidant in the treatment.
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5‐Fluorouracil (5‐FU)‐associated cardiotoxicity has been ranked as the second most common cause of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. In the present study, we investigated the protective impacts of silymarin (SIL) and silymarin nanoemulsion (SLN) against cardiotoxicity caused by 5‐FU in rats. Thirty male Wistar rats were divided into six groups as follows: control, SLN (5 mg/kg), SIL (5 mg/kg), 5‐FU + SLN, 5‐FU + SIL, and 5‐FU. Cardiotoxicity was induced by a single intraperitoneal injection of 5‐FU (100 mg/kg). The control group received an intraperitoneal injection (ip) of normal saline and the treatment groups received ips of SIL and SLN for 14 days. 5‐FU resulted in significant cardiotoxicity, represented by an increase in the serum levels of cardiac enzymes and malondialdehyde, as well as cyclooxygenase‐2 (COX‐2) and tumor necrosis factor‐α (TNF‐α) expression, and histopathological degeneration. 5‐FU treatment also induced a decrease in body weight, total antioxidant capacity (TAC), and catalase values. Evaluation of electrocardiographic parameters in 5‐FU‐treated rats showed increases in the ST segment, QRS duration, and RR interval. Treatment with SIL and SLN reduced oxidative stress, cardiac enzymes, histopathological degeneration, and the expression of TNF‐α and COX‐2 in cardiac tissue. Our results demonstrated that treatment with SIL and SLN significantly improved cardiotoxicity induced by 5‐FU in rats. The protective effects of silymarin (SIL) and silymarin nanoemulsion (SLN) against cardiotoxicity caused by 5‐fluorouracil (5‐FU) were investigated in rats. Treatment with SIL and SLN reduced oxidative stress, cardiac enzymes, histopathological degeneration, and the expression of tumor necrosis factor‐α and cyclooxygenase‐2 in cardiac tissue, thus significantly ameliorating the cardiotoxicity induced by 5‐FU in rats.
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This study conducted to evaluate the effect of additional dried moringa leaves on bread and their effects on the chemical and biological of rats fed it. Wheat flour with dried moringa leaves powder (DMLB) is used at different levels (6 and 9%) to produce moringa bread. We performed a sensory evaluation of wheat bread substituted with dried moringa leaves, chemical properties (approximate composition and antioxidants), microbiology (total bacteria, spore-forming bacteria, fungi, and yeast) and biological analysis (Triglycerides, total cholesterol, HDL and LDL, ALT, AST, urea, creatinine). Therefore, histopathology examination for kidney and livers of male albino rats fed fortified bread with dried moringa leaves compared with the control sample. The results of the approximate analysis showed significant differences by adding moringa leaves and the percentage of ash, protein, fat, and fiber increased with the moisture content. Moreover, carbohydrates decreased from fortified bread with dried moringa leaves compared to the control sample. The best treatment was fortified bread with 6% dried moringa leaves for all sensory evaluations compared to the other samples and moringa bread (DMLB 9%) helped reduce the microbial load during storage. The effect of moringa bread on liver cirrhosis was evaluated in rats induced by carbon tetrachloride CCl4. We found out that the effect of moringa leaves on liver and kidney functions in a state of improvement, as for high-density lipoprotein (HDL) and low-density lipoprotein (LDL), the proportion of LDL was less than HDL compared to the control sample. At the same time, moringa leaves have a significant effect on reducing cholesterol, triglycerides, urea, and creatinine in the serum of rats, which may be attributed to the presence of biologically active plant components. It can be concluded that moringa leaves can improve biological and histological of rats feed it.
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COVID-19 is an infectious disease, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) that is rapidly spreading all over the world and responsible for the international health crisis. In an earlier period, various synthetic antiviral drugs and clinical therapies have been used to control the viral infection but at present, there is no specific treatment available for COVID-19 infection. Several approaches like ritonavir, lopinavir, hydroxychloroquine, and chloroquine have been proposed. India is a hub of medicinal plants, so there is a chance to find out the way to combat the COVID-19 pandemic. The medicinal herbal formulations may enhance the immunity and come up with a powerful antiviral drug, which is an urgent need to control the outbreak of coronavirus. In this review article, we have discussed epidemiology, clinical outcomes, treatment, and prevention of this novel epidemic coronavirus from medicinal herbal formulations perspective. We have also emphasized the reported antiviral activity and immunity-boosting property of the Indian medicinal plants. This article also suggests that the drug or formulation obtained from medicinal plant sources may have low fatal outcomes, quick response, and safe in the management and prevention of this pandemic outbreak.
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205 cases of clinical poisoning with the mushroom Amanita phalloides (death cap) in the period 1971 to 1980 have been studied retrospectively. The lethality was 22.4%. Age and latency between the ingestion of the mushrooms and the first clinical symptoms were of prognostic significance. The death rate was 51.3% in children below 10 years of age but only 16.5% in patients older than 10 years. The average latency period was 10.3 hours for the fatal cases and 12.6 hours for the surviving patients. Country, year, sex and time of hospitalization did not influence lethality. Prognostic relevance could also be attributed to the thromboplastin time (Quick). 84% of the patients with values below 10% died, while all patients with minimal values of more than 40% survived. The correlation with the outcome was weaker for the serum transaminases and nil for creatinine. The patients underwent on the average 8 therapeutic measures, but up to 20 therapies could be administered to the same patient. Eight of the 30 recorded treatments involved general support, 7 toxin elimination and the remaining 14 could be classified as pharmacotherapy. With the aid of multiple regression analysis taking into account age, latency period and the effects of all the other measures, penicillin and hyperbaric oxygenation were found to contribute independently to a higher survival rate. As compared to penicillin, the combination of penicillin with silybin was associated with still further increased survival. On the other hand, several measures, including exchange transfusion, thioctic acid, sulfamethoxazole, plasma expanders, haemodialysis, treatment of the hemorrhagic diathesis and THAM/sodium bicarbonate were administered more often to patients who did not survive. For the remaining 20 therapeutic measures our analysis revealed neither a positive nor a negative correlation with the clinical outcome.
Article
Since 1991, the Medical Toxicology Unit (MTU) at Guys’ Hospital, London, has been assessing the toxicological problems associated with the use of traditional and herbal remedies and dietary supplements. This assessment was carried out by evaluating reports to the National Poisons Information Service (London) [NPIS(L)] which provides emergency information to medical professionals. Relevant telephone enquiries to NPIS(L) were identified. Further case details were obtained by follow-up questionnaire, clinical consultation, toxicological analysis of samples from patients and/or products and botanical identification of plant material. Of 1297 symptomatic enquiries evaluated there was a possible/confirmed association in 785 cases. Case series have been identified which substantiate previous reports, including liver problems following the use of Chinese herbal medicine for skin disorders, allergic reactions to royal jelly and propolis and heavy metal poisoning caused by remedies from the Indian subcontinent. Although the overall risk to public health appears to be low, certain groups of traditional remedies have been associated with a number of potentially serious adverse effects. Considering the extent of use of herbal remedies and food supplements a comprehensive surveillance system for monitoring the adverse health effects of these products is essential. Surveillance of a large population is needed for the complex task of identifying the uncommon and unpredictable adverse effects which are potentially serious. In the UK, the Medicines Control Agency responded to the MTU report by recognising the need for vigilance and by incorporating adverse reactions reporting on unlicensed herbal remedies into their drug reaction monitoring function. As a further step to safeguard the patients/consumers an effective single regulatory system is required which would ensure the safety and quality of all herbal remedies and food supplements available in the UK.
Article
Silymarin (SIL), a standardized plant extract containing about 60% polyphenole silibinin, is used as a hepatoprotective agent. Its antifibrotic potential in chronic liver diseases has not been explored. Therefore, we applied SIL to adult Wistar rats that were subjected to complete bile duct occlusion (BDO) by injection of sodium amidotrizoate (Ethibloc). This treatment induces progressive portal fibrosis without significant inflammation. Rats with sham-operation that received SIL at 50 mg/kg/d (n = 10) and rats with BDO alone (n = 20) served as controls, whereas groups of 20 animals were fed SIL at a dose of 25 and 50 mg/kg/d during weeks 1 through 6 or doses of 50 mg/kg/d during weeks 4 through 6 of BDO. Animals were sacrificed after 6 weeks for determination of blood chemistries, total and relative liver collagen (as hydroxyproline [HYP]), and the serum aminoterminal propeptide of procollagen type III (PIIINP). BDO in untreated rats caused an almost ninefold increase in total liver collagen (16.1 +/- 3.1 vs. 1.8 +/- 0.4 mg HYP, P < .001). SIL at 50 mg/kg/d reduced total HYP by 30% to 35%, either when given from week 1 through 6 or from week 4 through 6 after BDO (10.6 +/- 2.7 and 10.2 +/- 3.9 mg HYP, both P < .01 vs. BDO alone), whereas 25 mg/kg/d were ineffective. Because SIL at 50 mg/kg/d also reduced the collagen content per gram of liver tissue, it acted as a true antifibrotic agent. The single value of PIIINP at killing paralleled the antifibrotic activity of SIL with 11.6 +/- 3.8 and 9.9 +/- 3.7 vs. 15.3 +/- 5.2 microg/L in both high-dose groups (P < .05 and P < .01, respectively, vs. rats with BDO alone). Except for a decreased alkaline phosphatase and a lower histological fibrosis score in the groups that received SIL, clinical-chemical parameters were not different among all groups with BDO. We therefore conclude that 1) BDO with Ethibloc is a suitable model to test for pure antifibrotic drugs because it induces progressive rat secondary biliary fibrosis without major inflammation; 2) oral SIL can ameliorate hepatic collagen accumulation even in advanced (biliary) fibrosis; and 3) PIIINP appears to be a suitable serum marker to monitor the inhibition of hepatic fibrogenesis in this model of biliary fibrosis. (Hepatology 1997 Sep;26(3):643-9)
Article
BACKGROUND Hepatocellular carcinoma (HCC) occurs in patients with hepatitis C virus-RNA positive chronic liver disease. It is important to prevent HCC with drug administration.METHODSA retrospective study was undertaken to evaluate the long term preventive effect of Stronger Neo-Minophagen C (SNMC) on HCC development. SNMC is a Japanese medicine that is commonly administered to patients with chronic hepatitis C to improve the serum alanine aminotransferase (ALT) level. Of 453 patients diagnosed with chronic hepatitis C retrospectively in the study hospital between January 1979 and April 1984, 84 patients (Group A) had been treated with SNMC; SNMC was given at a dose of 100 mL daily for 8 weeks, then 2-7 times a week for 2-16 years (median, 10.1 years). Another group of 109 patients (Group B) could not be treated with SNMC or interferon for a long period of time (median, 9.2 years) and were given other herbal medicine (such as vitamin K). The patients were retrospectively monitored, and the cumulative incidence of HCC and risk factors for HCC were examined.RESULTSThe 10th-year rates of cumulative HCC incidence for Groups A and B were 7% and 12%, respectively, and the 15th-year rates were 12% and 25%. By Cox regression analysis, the relative risk of HCC incidence in patients not treated with SNMC (Group B) was 2.49 compared with that of patients treated with SNMC (Group A).CONCLUSIONS In this study, long term administration of SNMC in the treatment of chronic hepatitis C was effective in preventing liver carcinogenesis. Cancer 1997; 79:1494-500. © 1997 American Cancer Society.
Article
The therapeutic potential of plant extracts of Phyllanthus amarus and Phyllanthus maderaspatensis for postexposure prophylaxis against infection by Hepadnaviruses was studied in ducklings infected by the duck hepatitis B virus (DHBV). Forty-four Pekin ducklings were inoculated intraperitoneally with DHBV at 24 hr posthatch. They were treated by intraperitoneal injection of Phyllanthus amarus (aqueous extract) (100 mg/kg body weight) or Phyllanthus mad eraspatensis (alcoholic extract) (100 mg/kg body weight) for a period of 4 weeks. Infected ducklings treated with saline served as controls. Weekly serum samples obtained before, during, and after treatment were analysed for the presence of DHBV DNA in serum by dot blot hybridisation using α 32P-labelled probes. Liver tissue was collected after killing the ducks at various time intervals and was studied for replicative status of the viral DNA and liver histopathology; 17 of 21 ducks were viraemic on completion of treatment with Phyllanthus amarus. At 16 week posttreatment follow-up four of seven animals remained viraemic. Similar results were obtained with Phyllanthus maderaspatensis. There was no alteration in DHBV replication in the liver. No toxicity was observed with this treatment. These observations suggest that Phyllanthus amarus and Phyllanthus maderaspatensis are not useful as therapeutic agents for postexposure prophylaxis against DHBV infection. © 1993 Wiley-Liss, Inc.