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Abstract

Milk thistle (Silybum marianum) is an herbal supplement used to treat liver and biliary disorders. Silymarin, a mixture of flavanoid complexes, is the active component that protects liver and kidney cells from toxic effects of drugs, including chemotherapy. Although milk thistle has not significantly altered the course of chronic liver disease, it has reduced liver enzyme levels and demonstrated anti-inflammatory and T cell-modulating effects. There is strong preclinical evidence for silymarin's hepatoprotective and anticarcinogenic effects, including inhibition of cancer cell growth in human prostate, skin, breast, and cervical cells. Milk thistle is considered safe and well-tolerated, with gastrointestinal upset, a mild laxative effect, and rare allergic reaction being the only adverse events reported when taken within the recommended dose range. More clinical trials of rigorous methodology, using standardized and well-defined products and dosages, are needed to evaluate the potential of silymarin against liver toxicity, chronic liver disease, and human cancers.
104 INTEGRATIVE CANCER THERAPIES 6(2); 2007 pp. 104-109
Advances in the Use of Milk Thistle
(Silybum marianum)
Janice Post-White, RN, PhD, FAAN, Elena J. Ladas, MS, RD, and Kara M. Kelly, MD
Milk thistle (Silybum marianum) is an herbal supplement used
to treat liver and biliary disorders. Silymarin, a mixture of
flavanoid complexes, is the active component that protects
liver and kidney cells from toxic effects of drugs, including
chemotherapy. Although milk thistle has not significantly
altered the course of chronic liver disease, it has reduced
liver enzyme levels and demonstrated anti-inflammatory and
T cell–modulating effects. There is strong preclinical evi-
dence for silymarin’s hepatoprotective and anticarcinogenic
effects, including inhibition of cancer cell growth in human
prostate, skin, breast, and cervical cells. Milk thistle is con-
sidered safe and well-tolerated, with gastrointestinal upset,
a mild laxative effect, and rare allergic reaction being the
only adverse events reported when taken within the recom-
mended dose range. More clinical trials of rigorous method-
ology, using standardized and well-defined products and
dosages, are needed to evaluate the potential of silymarin
against liver toxicity, chronic liver disease, and human cancers.
Keywords: milk thistle; silymarin; cancer; liver disease; mecha-
nism; safety; efficacy
What Is Milk Thistle?
Milk thistle is available in the United States as a dietary
supplement. The fruit and seeds of the milk thistle
plant have been used for more than 2000 years as a
treatment for liver and biliary disorders. The seeds are
the medicinal part of the plant,1which is indigenous
to Europe but also can be found in the United States
and South America.
The botanical name for milk thistle is Silybum mari-
anum (L.) Gaertn., a member of the plant family
Asteraceae. The active constituent of milk thistle is sily-
marin, a mixture of flavonolignans comprised of 4 iso-
mers: silibinin, isosilibinin, silichristin, and silidianin.
Most supplements are standardized according to their
silibinin (often called silybin) content. In turn, silibinin
and isosilibinin are both mixtures of 2 diastereomers,
silibinin A and B and isosilibinins A and B, respectively.2
Because of milk thistle’s lipophilic nature, it is usually
administered in capsule or tablet form rather than as an
herbal tea. Special formulations of silibinin have been
developed to enhance the bioavailability of the herbal
product; these forms are sold as a dietary supplement
under the names Legalon, Silipide, and Siliphos. As
a supplement, milk thistle is regulated as a food and
has not been approved by the US Food and Drug
Administration as a treatment for cancer or for any
other medical condition.
History of Use of Milk Thistle
The oldest reported use of milk thistle was by
Dioscorides, who recommended the herb as a treat-
ment for serpent bites. Pliny the Elder (AD 23-79)
reported that the juice of the plant mixed with honey
was indicated for “carrying off bile.” Milk thistle was
first revered as an antidote for liver toxins in the
Middle Ages3,4 and was later used by the British herbal-
ist Culpepper to relieve obstructions of the liver.3,4 In
1898, Eclectic physicians Felter and Lloyd recognized
that the herb was good for “congestion” of the liver,
spleen, and kidney.3,4 Native Americans have used
milk thistle to treat boils and other skin diseases.
Homeopathic practitioners have used preparations
from the seeds to treat a variety of illnesses, including
jaundice, gallstones, peritonitis, hemorrhage, bronchi-
tis, and varicose veins,4and currently use milk thistle to
treat liver dysfunction. The German Commission E rec-
ommends its use primarily for dyspeptic complaints
and liver conditions, including toxin-induced liver
damage and hepatic cirrhosis, and as a supportive ther-
apy for chronic inflammatory liver conditions.5
Reasons for Milk Thistle Use Today
In the United States, milk thistle is 1 of the most fre-
quently sold herbal products. In 2000, retail sales of
Advances in Milk Thistle
DOI: 10.1177/1534735407301632
JPW is at the University of Minnesota, Minneapolis, Minnesota.
EJL is at the Division of Pediatric Oncology, Columbia University
Medical Center, New York, New York. KMK is at the Division of
Pediatric Oncology, Columbia University Medical Center, New York,
New York.
Correspondence: Janice Post-White, RN, PhD, FAAN, University
of Minnesota, 707 Kenwood Parkway, Minneapolis, MN 55403.
E-mail: postw001@umn.edu.
Advances in Milk Thistle
INTEGRATIVE CANCER THERAPIES 6(2); 2007 105
milk thistle were $8.9 million, a 14% increase over
1999. Patients use milk thistle in a variety of clinical
settings, but it is most commonly used in gastroin-
testinal clinics to help treat hepatitis and cirrhosis.
Despite a paucity of clinical trials investigating the
safety of milk thistle in the oncology setting, surveys
have found that milk thistle is one of the most com-
monly prescribed hepatoprotectants among individ-
uals with cancer. Patients and practitioners report
using milk thistle to aid the liver in detoxification,
anticipating that milk thistle may help clear toxins
from the blood and potentially aid them in tolerating
cancer therapy. This concept was initially proposed
in a case study and has subsequently been supported
by 1 clinical trial that was conducted among children
with acute lymphoblastic leukemia.6
Milk thistle also may have cancer cytotoxic effects.
One phase III clinical trial in adult men with prostate
cancer reported delays in rising prostate specific anti-
gen levels compared with placebo.7This series will
present both preclinical and clinical studies demon-
strating the potential role of milk thistle as a hepato-
protectant and an anticancer agent. Although most of
the cancer investigations are in the preclinical stage,
phase I/II studies suggest potential efficacy and few
adverse events. No other medications or supplements
are currently available that preserve liver function
and provide clinical benefits.
In their article in this issue, Greenlee and col-
leagues8provide an overview of current clinical appli-
cations of milk thistle and studies supporting its use in
the oncology setting. They also present rationales and
preliminary studies supporting the use of milk thistle
in cardiovascular, renal, and diabetic conditions.
Mechanisms of Action
Silymarin is most well known for its antioxidant and
chemoprotectant effects on the liver. It is highly
absorbed after oral ingestion and has a strong first-pass
effect through the liver. In laboratory studies, silibinin
has been found to stabilize cell membranes, thus pre-
venting toxic chemicals from entering the cell9-12 and
exporting toxins out of the cell before damage ensues.9-15
Administration of silymarin to rats challenged with a
toxin resulted in higher levels of glutathione in liver
cells, decreased oxidative stress (measured by malondi-
aldehyde concentrations), and fewer elevations in liver
enzyme tests (aspartate aminotransferase [AST]/ala-
nine aminotransferase [ALT]).13 Silibinin also has been
shown to stimulate or inhibit phase I detoxification
pathways,16,17 stimulate phase II detoxification path-
ways,18 and accelerate liver cell regeneration by stimu-
lating DNA synthesis precursors and enhancing
cellular enzyme production.19-22
In their article in this issue, Comelli and colleagues23
propose a unifying mechanism of action for silymarin
that demonstrates how its scavenging and antioxidant
properties reduce free radical generation, inhibit
nuclear factor-κB and tumor necrosis factor induction,
and balance the cascade of transcriptional processes
that affect cell growth and apoptosis, thereby reducing
inflammation and supporting the liver’s tolerance to
oxidative stress. These authors conclude that the use of
silymarin before or early after a toxic insult is more
likely to provide stronger protective effects than in
chronic liver disease.
There is strong preclinical evidence through in
vitro and in vivo models that silymarin (more specifi-
cally, the silibinin flavonoid components) interferes
with promotion and progression of cancer. In preclin-
ical studies, silymarin appeared to have direct anti-
cancer effects against prostate, breast, and ectocervical
tumor cells.24,25 When the silibinin flavonoid compo-
nent was tested in vitro, it enhanced the efficacy of cis-
platin and doxorubicin against ovarian, breast, and
prostate cancer cells26-28 and was synergistic with vin-
cristine, but not L-asparaginase, against CCRF-CEM
T cell, acute lymphoblastic leukemia cell lines.29 When
tested in vitro, silibinin did not stimulate growth in sev-
eral cancer cell lines, including leukemia, colon (Caco-2),
and hepatoma (HepG2).30
In their article in this issue, Deep and Agarwal31
describe their and others’ numerous studies showing
the efficacy of silymarin and its flavonoid components
against skin and prostate cancer and synergistic effects
with chemotherapy and their work to identify the asso-
ciated molecular mechanisms. The potential clinical
efficacy, along with no known negative interactions
with chemotherapy agents, lack of toxicity to normal
cells, and ready absorption after oral administration,
suggests silymarin’s potential as a chemopreventive,
protective, and therapeutic agent.
One of the limitations of silymarin studies is the lack
of standardization of products and components. In this
issue, Kroll and colleagues32 clearly define the need to
use consistent nomenclature and define the actual
components and composition of products tested
because each component may have different biological
effects. Another limitation is the variation in doses used
in clinical trials. Kroll and colleagues32 emphasize the
need to conduct adequate pharmacokinetic analyses to
determine pharmacological concentrations of the
product that correlate with plasma and tissue concen-
trations and desired in vitro and in vivo effects.
Although some preliminary studies of pharmacokinet-
ics and pharmacodynamics of milk thistle extracts have
been conducted, additional studies are needed to
define bioavailability and concentrations required to
Post-White et al
106 INTEGRATIVE CANCER THERAPIES 6(2); 2007
produce biological and clinical effects, with considera-
tion for potential interaction with chemotherapy drugs
metabolized through cytochrome P450 isoenzyme
(CYP) pathways, particularly when higher dosages of
milk thistle extracts are administered.
Evidence for Safety and Efficacy
Efficacy
Most early clinical trials investigated milk thistle’s effec-
tiveness in the treatment of patients with hepatitis, cir-
rhosis, or biliary disorders.33-40 These studies used a
wide range of products and doses (120-560 mg/d) and
yielded conflicting results. In one of the largest obser-
vational studies, involving 2637 patients with chronic
liver disease, 8 weeks of silymarin (560 mg/d) reduced
serum AST, ALT, and gamma-glutamyl-transpeptidase
(a marker of bile duct disease) and decreased the fre-
quency of palpable hepatomegaly.41 Other more recent
studies have shown no effects.42-44 In other reports,
reviewed in this issue by Greenlee and colleagues,8milk
thistle was used to treat hyperlipidemia, diabetes melli-
tus,40 and Amanita phalloides mushroom poisoning.10,45
In their article in this issue, Tamayo and Diamond46
review clinical trials of milk thistle extracts conducted
in the past 5 years. Although milk thistle has not signif-
icantly altered the course of chronic liver disease, it has
reduced liver enzymes in some studies and exhibited
select effects on anti-inflammatory measures in chronic
liver disease and diabetes mellitus.46,47
Milk thistle has only recently begun clinical trial
testing in cancer. Two clinical trials have followed in
the footsteps of 2 well-publicized case studies.48,49 In 50
children with acute lymphoblastic leukemia (ALL)
with grade 2 or greater chemotherapy-related hepato-
toxicity, milk thistle (Siliphos 5.1 mg/kg/d) was asso-
ciated with a significant reduction in AST and a trend
in reduction of ALT levels after 56 days.6In a phase III
trial of men with prostate cancer, silymarin (160 mg/d
for 10 weeks), in conjunction with soy isoflavones and
other antioxidants, delayed prostate specific antigen
level increases, whereas the placebo group had a
2.6-fold increase.50
Safety
Milk thistle has been used safely during pregnancy,51 in
children,6,10 and in adults older than 75 years.52 There
were no reported toxicities at doses of 560 mg/d
for pregnant women with intrahepatic cholestasis,
20 to 50 mg/kg body weight intravenously for children
with mushroom poisoning, and 420 mg/d in older
adults.52
One recent phase I study suggested that 13 g
of Siliphos (30% silibinin) was the recommended
tolerated dose, with hyperbilirubinemia observed in
higher doses (15-20 g/d).53 However, as Dr. Kroll and
colleagues32 address in their article, these large doses
are not recommended for patients receiving cancer
chemotherapy because such doses may interact with
chemotherapy metabolized through CYP pathways.
Although toxicities were not observed in doses up to
1200 mg/d,44 most clinical studies continued to test
smaller dose ranges of 160 to 600 mg/d, divided into
3 daily doses.46 Absorption is rapid, with peak plasma
levels occurring within a few hours and an elimina-
tion half-life of 6 hours.54 Because of the short half-
life, it is recommended that milk thistle be taken in 3
divided doses throughout the day. Silibinin is pre-
dominantly excreted in bile (80%), with the remain-
der secreted in the urine.
Silymarin has been shown to decrease cytochrome
P450 enzyme activity, potentially affecting clearance of
some chemotherapy drugs.17 However, this inhibition
was not observed with oral intake of milk thistle,16 and
no interference with several chemotherapy agents (cis-
platin, doxorubicin, vincristine, L-asparaginase) has
been shown in preclinical studies at the concentra-
tions used.26-29 Several recent studies report no interac-
tion with chemotherapy agents or interference with
enzymes involved in metabolism of drugs (CYP3A,
CYP1A2, CYP2D6, CYP2Ea, UGT1A1, P-glycoprotein)
(reviewed in this issue by Tamayo and Diamond46).
These effects may be dose responsive, however, and
require further study at higher dosages.32
Adverse Events
Milk thistle is considered safe and well-tolerated, with
reported adverse events similar to placebo.47,55,56
Although infrequent, the most commonly reported
adverse events are a mild laxative effect and gastroin-
testinal upset.57 Mild allergic reactions were reported
at doses greater than 1500 mg/d.1According to the
German Commission E, there are no reported side
effects of milk thistle within the recommended dose
range.5Milk thistle appears to be safe for up to 41
months of use.55
In a systematic review of 13 clinical trials involving
915 subjects, there were no effects on mortality or
complications of alcohol-induced or virally induced
chronic liver disease. Milk thistle was not associated
with an increased risk of adverse events compared
with placebo (3.5% vs 4.4% in placebo). The symp-
toms reported in both groups were pruritus, nausea
and epigastric distress, and headache.47
Research Strengths and Weaknesses
There is strong preclinical evidence through in vitro
and in vivo models that silymarin protects and regener-
ates liver and kidney cells and interferes with promo-
tion and progression of cancer. Some of these effects
Advances in Milk Thistle
INTEGRATIVE CANCER THERAPIES 6(2); 2007 107
may be dose related. Milk thistle’s effect on clinical out-
comes is not well established, and reported effects on
liver enzyme levels are inconsistent and inconclusive.
The methodological quality of the majority of the
clinical trials conducted in patients with chronic liver
disease is low, with most of the studies including het-
erogenous populations, lacking in standardized prepa-
rations, and having poorly defined nonobjective
endpoints.58 When high-quality trials were analyzed
apart from low-quality trials, the beneficial effect of
milk thistle on liver enzymes was lessened,47 suggesting
either a lack of effect, sample bias, or type I error in
lower quality studies. This review excluded acute liver
disease, including studies of drug or mushroom toxi-
city. Considering that most of the reported clinical tri-
als tested milk thistle in chronic liver disease and that
the biological effects may be more active in an acute
model,23,31 additional clinical trials are needed to test
efficacy of milk thistle as a hepatoprotectant and treat-
ment for acute liver-related disorders. Such efficacy tri-
als should ensure sample sizes sufficient for power,
randomization and inclusion of a placebo/reference
group, blinding of assessors and subjects, standardized
dose and product, and intention-to-treat analyses.
Oftentimes, randomized controlled trials are done
under controlled and ideal conditions and may fail to
account for real-life practices in which supplements
are taken with many other over-the-counter and pre-
scription medications.59 Individual subject character-
istics and practices, such as use of other herbs and
supplements, should be controlled for or assessed
and considered as potential covariates in the clinical
efficacy trials.60 Although systematic reviews and ran-
domized controlled trials are considered the best evi-
dence for practice, making clinical decisions to add
milk thistle requires consideration of the quality of
the studies and clinical judgment.
Summary
Silymarin functions as a potent antioxidant that stabi-
lizes cell membranes, stimulates detoxification path-
ways, regenerates liver tissue, inhibits the growth of
some cancer cell lines, exerts direct cytotoxic activity
toward select cancer cell lines, and increases the effi-
cacy of some chemotherapy agents. The action of sily-
marin involves multiple mechanisms affecting the liver
and other digestive organs. Unlike other herbs, milk
thistle has strong preclinical evidence for hepatopro-
tective and anticarcinogenic effects. It has yet to be
determined, however, whether milk thistle yields
better clinical outcomes. The potential of milk thistle
as a hepatoprotectant and adjuvant to chemotherapy
requires further clinical trial testing with standardized
products and quality controls.
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... The plant's medicinal part is its seeds, and silymarin, a mixture of flavonolignans, is its active component (26). Depending on the stage of floral development, flavonolignan accumulation in seeds is greatest during late blooming (25). ...
... People with a history of gastrointestinal disorders should use this herbal medicine cautiously. While the plant is generally well tolerated, some people may experience gastrointestinal discomfort like nausea or vomiting [143,144]. Thus, despite its undeniable therapeutic benefits, its use might be contraindicated in some situations. ...
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Silybum marianum (L.) Gaertn, commonly known as milk thistle, is an herbal medicine rich in silymarin, a bioflavonoid complex. Historically, silymarin was used for treating liver diseases, but recent studies highlight silymarin’s potential for obesity management. This narrative review aims to provide an in-depth examination of the existing knowledge of Silybum marianum (L.) and its secondary compounds concerning obesity and associated comorbidities, summarizing data from in vitro, preclinical, and clinical studies. Obesity is a significant public health issue, exacerbated during the COVID-19 pandemic, as a major risk factor for mortality. It contributes to metabolic dysfunction, including oxidative stress, metainflammation, cardiovascular diseases, and type 2 diabetes development. Silymarin has demonstrated benefits on insulin signaling and lipid metabolism, as well as antioxidant and anti-inflammatory properties at the molecular level. Innovative studies also suggest silymarin’s potential as a prebiotic, positively influencing gut microbiota composition, a key factor affected by obesity. These promising findings support the potential anti-obesity action of silymarin in clinical practice. Looking forward, using silymarin as an innovative complementary therapy could offer substantial benefits for natural health promotion and obesity management. Nevertheless, further research into optimal doses and cellular mechanisms is still needed.
... Pliny the Elder reported that the juice of the plant mixed with honey was indicated to "train bile". Milk thistle was first revered as an antidote for liver toxins in the Middle Ages and was later used by British herbalist Culpeper to relieve liver obstructions [4]. Thus, the fruit of the milk thistle plant has been a remedy for 2000 years. ...
... Silybin, the first member of a new family of natural compounds referred to as flavonolignans, was isolated as a secondary metabolite from the seeds of the blessed milk thistle (Silybum marianum) in 1960. 1) Natural silybin, a roughly 1 : 1 mixture of silybins A (1) and B (2), [2][3][4][5][6][7][8][9][10][11][12] exhibits diverse bioactivities, including anti-viral (against hepatitis C virus (HCV) and human immunodeficiency virus-type 1 (HIV-1)), hepatoprotective, antifibrotic, antioxidant, membrane-stabilizing, anti-cholestatic, anti-atherogenic, anti-inflammatory and anticarcinogenic activities. [13][14][15][16][17][18][19] Structurally, silybins 1 and 2 belong to a class of hybrid natural polyphenols consisting of a flavanonol skeleton and a 7′,8′-trans-configured 1,4-benzodioxane neolignan skeleton. Each fragment features two contiguous stereogenic centers and highly electron-rich aromatic rings. ...
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We report the first total synthesis of silybin A (1). Key synthetic steps include the construction of the 1,4-benzodioxane neolignan skeleton, a modified Julia–Kocienski olefination reaction between m-nitrophenyltetrazole sulfone (m-NPT sulfone) 10 and aldehyde 21, the formation of the flavanol lignan skeleton 28 via a quinomethide intermediate under acidic conditions, and stepwise oxidation of the benzylic position of flavanol 29. Fullsize Image
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ALP ALT FCR Milk thistle Laying hen Introduction: Milk thistle is a useful medicinal plant with antioxidant properties that are good for the body. The purpose of this research was to investigate the effect of different levels of milk thistle meal on the performance and blood metabolites of laying hens of the White Leghorn breed and Highline W-36 strain. Materials & Methods: This study was conducted in the form of a completely randomized design with 4 treatments, 5 repetitions, and 5 observations in each repetition. The length of the research period was 70 days. 10 days were considered as the habituation period. During the research period, the examined traits were measured and recorded. Recorded data were analyzed by LSmeans procedure in SAS statistical software. Results: By examining the results, it was observed that the effect of different levels of milk thistle meal was not significant on the traits under study (P>0.05). But obvious and tangible changes were observed in the traits. In general, the best performance was observed at the level of 3% milk thistle meal. Conclusion: Therefore, the level of 3% milk thistle meal is suggested for the ration of laying hens.
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Endophytic fungi have been shown to synthesize bioactive secondary metabolites, some of which promote plant growth through various mechanisms. In our previous study, endophytic fungi were isolated from mango trees (Mangifera indica L.). The present study examined fifty endophytic fungal isolates for mineral solubilization activity, ammonia production, and siderophore production. It was shown that these isolates could produce phytohormones indole-3-acetic acid and gibberellic acid, as well as inhibit plant pathogens, specifically Colletotrichum gloeosporioides and Lasiodiplodia theobromae. The results showed that all the isolated fungal endophytes exhibited various activities. Based on the findings, two fungal endophytes—Aureobasidium pullulans CY.OS 13 and Aspergillus tamarii CY.OS 144—were selected for dual inoculation in chili plants under pot-scale conditions to investigate their potential to improve growth-related traits such as seed germination, shoot and root length, biomass, and chlorophyll content. Seed treated with A. pullulans CY.OS 13 and/or A. tamarii CY.OS 144 showed a significant (p < 0.05) increase in seed germination and growth parameters of chili plants grown under pot-scale conditions. Particularly, chili plants whose seeds were injected with a combination of the two selected endophytic fungi showed the highest plant development traits. Therefore, the selected endophytic fungi have the potential to be used as biofertilizers, especially when combined. They could eventually replace chemical fertilizers because they are environmentally friendly, beneficial to humans, and can even promote sustainable agriculture.
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Background: Milk Thistle (MT), an herbal plant widely used in Europe for treating liver and biliary disorders, is commonly self prescribed for its hepatoprotectant effects. Chemotherapy associated hepatotoxicity is a primary reason for dose reductions or withdrawal of chemotherapy in children with ALL. Purpose: To investigate the toxicity and efficacy of MT supplementation for treatment of hepatotoxicity in children with ALL during 1 maintenance chemotherapy phase. Methods: Children ages 1–21 yrs with ALL and grade 2 or greater hepatic toxicity (defined by elevations in AST, ALT, or total bilirubin (TB), by NCI CTC v2 criteria) were eligible for participation during a maintenance phase of chemotherapy by Childrens Oncology Group or Dana Farber Cancer Institute ALL protocols. Participants were randomized to MT (Siliphos®, Thorne Research, Dover, ID, 5.1mg/kg/day) or placebo orally for 28 days while receiving the prescribed chemotherapy. LFTs were evaluated at baseline, day 28 (end of supplementation) and day 56 (28 days after MT discontinuation). MT stability was assessed at onset and at 21 mos by HPLC with UV detection relative to standard curves and known retention times of authentic silybin A and B reference standards. CCRF-CEM T-cell ALL cell culture studies were conducted with MT and vincristine (V) or L-asparaginase (A). Results: 50 children, ages 1–19 yrs (median = 7) were enrolled. 1 child withdrew consent before treatment was initiated; 2 had insufficient data. No significant differences in age, gender, ethnicity, or treatment protocols were observed between the 2 groups. Adverse effects from MT/placebo were mild: diarrhea (2/3), anorexia (0/1), flatulence (1/0), abdominal pain (2/2), irritability (2/0). No differences between MT/placebo in grade 3/4 toxicities from chemotherapy were seen: heme-infectious (6/17), non-heme (10/6). Mean AST and ALT declined greater from baseline to day 28 with MT but the differences were not significant. A greater decrease in mean AST from baseline to Day 56 was observed with MT (78 to 47) compared to placebo (71 to 67) (p= 0.05). A trend towards a greater reduction in mean ALT from baseline to Day 56 with MT (187 to 122 vs placebo 140 to 139) was also seen (p=.07). More children in the MT group developed greater than a 50% reduction in TB at day 28 as compared to placebo (p = 0.0069). The decline in day 56 TB was greater with MT but the difference was not significant. MT was composed of 49.6% silybin A and 50.4% silybin B, with no change in total content and ratios at 21 mos. In T-cell ALL cell culture studies, no effect was observed on cytotoxicity with A, but MT enhanced V-mediated CEM cell kill. Conclusions: In children with ALL with established liver toxicity, MT supplementation for 28 days in conjunction with hepatotoxic chemotherapy is associated with significant reductions in LFTs compared with placebo. Future study will evaluate the effect of MT in allowing delivery of full doses of chemotherapy and its subsequent impact on leukemia-free survival, along with xenograft studies to determine whether the beneficial antileukemic potentiation of vincristine persists in vivo.
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Background: The role of silymarin in the treatment of liver cirrhosis is controversial. Aim: Clinical outcome, biochemical profile and the antiperoxidative effects of silymarin MZ-80 during 6 months treatment were investigated in patients with alcoholic liver cirrhosis. Methods: Sixty consecutive patients with alcoholic liver cirrhosis were randomized to receive either silymarin MZ-80 (S) (150 mg t.i.d. per day) or placebo (P) for periods of 6 months. Erythrocyte total glutathione (GSH) content, platelet malondialdehyde (MDA) and serum amino-terminal propeptide of procollagen Type III (PIIINP) were determined at baseline and at the end of treatment. Results: Forty-nine patients completed the study (24 S and 25 P). The 2 groups were well-matched for demographic as well as baseline clinical and laboratory parameters. Silymarin increased total GSH at 6 months (4.5 ± 3.4 to 5.8 ± 4.0 μmol/g Hb) whereas, in the placebo group, GSH remained unchanged (4.1 ± 3.9 to 4.4 ± 4.1 μmol/gHb) (p < 0.001), and platelet-derived non-induced MDA decreased by 33% (p <0.015). A parallel decrease in PIIINP values was seen with silymarin (1.82 ± 1.03 to 1.36 ± 0.5 U/ml, p < 0.033) but not with placebo (1.31 ± 0.4 to 1.27 ± 0.6 U/ml). There were no concurrent changes on laboratory indices of the pathology. Conclusions: Silymarin is well-tolerated and produces a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells in patients with alcoholic liver cirrhosis. Despite these effects no changes in routine liver tests were observed during the course of therapy.
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PurposeMilk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease.
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Administration of silymarin (800 mg/kg i.p.) 30 min before carbon tetrachloride (18 μL/kg i.p.) did not modify total hepatic levels of CCl4 and metabolites in mice, but decreased by 40% the in vivo covalent binding of CCl4 metabolites to hepatic lipids at 2 hr. This pretreatment decreased by 60% the exhalation of ethane during the first hour after CCl4, and decreased by 50% the incidence of liver cell necrosis. In vitro, silymarin (800 μg/mL) decreased by 50 to 70% various monooxygenase activities, and decreased by 20% the covalent binding of CCl4 metabolites to microsomal proteins. Silymarin (800 μg/mL) decreased by 70% in vitro lipid peroxidation mediated by CCl4 metabolites, and decreased by 90% peroxidation mediated by NADPH alone. Silibinin, one of the three isomers composing silymarin, also decreased carbon tetrachloride-induced lipid peroxidation; this effect, however, was less than that of silymarin in vitro, and was more transient in vivo. Pretreatment with silibinin (800 mg/kg i.p.) 30min before CCl4 (18μL/kg i.p.) did not improve SGPT activity or liver histology at 24 hr. We conclude that silymarin prevents carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice, firstly, by decreasing the metabolic activation of CCl4, and, secondly, by acting as a chain-breaking antioxidant.
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The incorporation of [3H] orotic acid into RNA from rat livers is stimulated by the flavonolignane derivative Silybin. The time course of the RNA synthesis and its dose dependence were demonstrated with isolated hepatocytes and [3H]uridine. The specific radioactivity of the newly synthesized RNA in rats treated with silybin is markedly higher than that of the controls. From preliminary experiments there is no indication that the synthesis of a distinct species of RNA is stimulated preferentially.