Advances in the Use of Milk Thistle (Silybum marianum)

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.

Full text

http://ict.sagepub.com
Integrative Cancer Therapies
DOI: 10.1177/1534735407301632
2007; 6; 104 Integr Cancer Ther
Janice Post-White, Elena J. Ladas and Kara M. Kelly
)Silybum marianumAdvances in the Use of Milk Thistle (
http://ict.sagepub.com/cgi/content/abstract/6/2/104
The online version of this article can be found at:
Published by:
http://www.sagepublications.com
can be found at:Integrative Cancer Therapies Additional services and information for
http://ict.sagepub.com/cgi/alerts Email Alerts:
http://ict.sagepub.com/subscriptions Subscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
http://ict.sagepub.com/cgi/content/abstract/6/2/104#BIBL
SAGE Journals Online and HighWire Press platforms):
(this article cites 51 articles hosted on the Citations
© 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
by guest on June 14, 2007 http://ict.sagepub.comDownloaded from

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,
1
which 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 Ages
3,4
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,
4
and 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.
© 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
by guest on June 14, 2007 http://ict.sagepub.comDownloaded from

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.
7
This 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-
leagues
8
provide 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 cell
9-12
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 colleagues
23
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 cells
26-28
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 Agarwal
31
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 colleagues
32
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 colleagues
32
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
© 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
by guest on June 14, 2007 http://ict.sagepub.comDownloaded from

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,
8
milk
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 Diamond
46
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.
6
In 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
colleagues
32
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 Diamond
46
).
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.
1
According to the
German Commission E, there are no reported side
effects of milk thistle within the recommended dose
range.
5
Milk 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
© 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
by guest on June 14, 2007 http://ict.sagepub.comDownloaded from

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.
References
1. PDR® for Herbal Medicines. 3rd ed. Montvale, NJ: Medical
Economics; 2004.
2. Lee DY, Liu Y. Molecular structure and stereochemistry of sily-
bin A, silybin B, isosilybin A, and isosilybin B, isolated from
Silybum marianum (milk thistle). J Nat Prod. 2003;66:1171-1174.
3. Flora K, Hahn M, Rosen H, et al. Milk thistle (Silybum mari-
anum) for the therapy of liver disease. Am J Gastroenterol. 1998;
93:139-143.
4. Foster S. Milk Thistle: Silybum marianum. Rev ed. Austin, Tex:
American Botanical Council; 1999.
5. Blumenthal M, Busse WR, eds. The Complete German Commission
E Monographs: Therapeutic Guide to Herbal Medicines. Austin, Tex:
American Botanical Council; 1998.
6. Ladas EJ, Cheng B, Hughes D, et al. Milk thistle (Silybum mari-
anum) is associated with reductions in liver function tests
(LFTs) in children undergoing therapy for acute lymphoblastic
leukemia (ALL). Abstract presented at: Society of Integrative
Oncology; November 11, 2006; Boston, Mass.
7. Schroder FH, Roobol MJ, Boeve ER, et al. A randomized,
double-blind, placebo-controlled crossover study in men with
prostate cancer and rising PSA: effectiveness of a dietary sup-
plement. Eur Urol. 2005;48:922-930.
8. Greenlee H, Abascal K, Yarnell E, Ladas E. Clinical applica-
tion of Silybum marianum in oncology. Integr Cancer Ther. 2007;
6:158-165.
9. Campos R, Garrido A, Guerra R, et al. Silybin dihemisuccinate
protects against glutathione depletion and lipid peroxidation
induced by acetaminophen on rat liver. Planta Med. 1989;55:
417-419.
10. Hruby K, Csomos G, Fuhrmann M, et al. Chemotherapy of
Amanita phalloides poisoning with intravenous silibinin. Hum
Toxicol. 1983;2:183-195.
11. Farghali H, Kameniková L, Hynie S, et al. Silymarin effects on
intracellular calcium and cytotoxicity: a study in perfused rat
hepatocytes after oxidative stress injury. Pharmacol Res. 2000;
41:231-237.
12. Lettéron P, Labbe G, Degott C, et al. Mechanism for the protec-
tive effects of silymarin against carbon tetrachloride-induced
lipid peroxidation and hepatotoxicity in mice: evidence that
silymarin acts both as an inhibitor of metabolic activation and
as a chain-breaking antioxidant. Biochem Pharmacol. 1990;39:
2027-2034.
13. Campos R, Garrido A, Guerra R, et al. Acetaminophen hepa-
totoxicity in rats is attenuated by silybin dihemisuccinate. Prog
Clin Biol Res. 1988;280:375-378.
14. Shear NH, Malkiewicz IM, Klein D, et al. Acetaminophen-
induced toxicity to human epidermoid cell line A431 and
hepatoblastoma cell line Hep G2, in vitro, is diminished by sily-
marin. Skin Pharmacol. 1995;8:279-291.
15. Valenzuela A, Guerra R, Garrido A. Silybin dihemisuccinate
protects rat erythrocytes against phenylhydrazine-induced
lipid peroxidation and hemolysis. Planta Med. 1987;53:402-405.
16. Zuber R, Modrianský M, Dvorák Z, et al. Effect of silybin and
its congeners on human liver microsomal cytochrome P450
activities. Phytother Res. 2002;16:632-638.
17. Venkataramanan R, Ramachandran V, Komoroski BJ, et al. Milk
thistle, a herbal supplement, decreases the activity of CYP3A4
and uridine diphosphoglucuronosyl transferase in human
hepatocyte cultures. Drug Metab Dispos. 2000;28:1270-1273.
18. Zhao J, Agarwal R. Tissue distribution of silibinin, the major
active constituent of silymarin, in mice and its association
with enhancement of phase II enzymes: implications in can-
cer chemoprevention. Carcinogenesis. 1999;20:2101-2108.
© 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
by guest on June 14, 2007 http://ict.sagepub.comDownloaded from

Post-White et al
108 INTEGRATIVE CANCER THERAPIES 6(2); 2007
19. Sonnenbichler J, Mattersberger J, Rosen H. Stimulation of
RNA synthesis in rat liver and isolated hepatocytes by silybin,
an antihepatotoxic agent from Silybum marianum L. Gaertn.
Hoppe Seylers Z Physiol Chem. 1976;357:1171-1180.
20. Sonnenbichler J, Zetl I. Mechanism of action of silibinin, V:
effect of silibinin on the synthesis of ribosomal RNA, mRNA
and tRNA in rat liver in vivo. Hoppe Seylers Z Physiol Chem. 1984;
365:555-566.
21. Sonnenbichler J, Zetl I. Biochemical effects of the flavonolig-
nane silibinin on RNA, protein and DNA synthesis in rat liv-
ers. Prog Clin Biol Res.1986;213:319-331.
22. Sonnenbichler J, Goldberg M, Hane L, et al. Stimulatory
effect of Silibinin on the DNA synthesis in partially hepatec-
tomized rat livers: non-response in hepatoma and other malig-
nant cell lines. Biochem Pharmacol. 1986;35:538-541.
23. Comelli MC, Mengs U, Prosdocimi M, Schneider C. Toward
the definition of the mechanism of action of silymarin: activi-
ties related to cellular protection from toxic damage induced
by chemotherapy. Integr Cancer Ther. 2007;6:120-129.
24. Bhatia N, Zhao J, Wolf DM, et al. Inhibition of human carci-
noma cell growth and DNA synthesis by silibinin, an active
constituent of milk thistle: comparison with silymarin. Cancer
Lett. 1999;147:77-84.
25. Zi X, Agarwal R. Silibinin decreases prostate-specific anti-
gen with cell growth inhibition via G1 arrest, leading to
differentiation of prostate carcinoma cells: implications for
prostate cancer intervention. Proc Natl Acad Sci U S A. 1999;
96:7490-7495.
26. Scambia G, De Vincenzo R, Ranelletti FO, et al. Anti-
proliferative effect of silybin on gynaecological malignancies:
synergism with cisplatin and doxorubicin. Eur J Cancer. 1996;
32A:877-882.
27. Tyagi AK, Singh RP, Agarwal C, et al. Silibinin strongly syner-
gizes human prostate carcinoma DU145 cells to doxorubicin-
induced growth inhibition, G2-M arrest, and apoptosis. Clin
Cancer Res. 2002;8:3512-3519.
28. Dhanalakshmi S, Agarwal P, Glode LM, Agarwal R. Silibinin
sensitizes human prostate carcinoma DU145 cells to cisplatin-
and carboplatin-induced growth inhibition and apoptotic
death. Int J Cancer. 2003;106:699-705.
29. Ladas EJ, Cheng B, Hughes D, et al. Milk thistle is associated
with reductions in liver function tests in children undergoing
therapy for acute lymphoblastic leukemia. Abstract presented
at: American Society of Hematology; December 10, 2006;
Orlando, Fla.
30. Duthie SJ, Johnson W, Dobson VL. The effect of dietary
flavonoids on DNA damage (strand breaks and oxidised
pyrimdines) and growth in human cells. Mutat Res. 1997;390:
141-151.
31. Deep G, Agarwal R. Chemopreventive efficacy of silymarin in
skin and prostate cancer. Integr Cancer Ther. 2007; \ADD
ISSUE AND PAGE NUMBERS\
32. Kroll DJ, Shaw HS, Oberlies NH. Milk thistle nomenclature:
Why it matters in cancer research and pharmacokinetic studies.
Integr Cancer Ther. 2007; \ADD ISSUE AND PAGE NUMBERS\
33. Vailati A, Aristia L, Sozzé E, et al. Randomized open study of
the dose-effect relationship of a short course of IdB 1016 in
patients with viral or alcoholic hepatitis. Fitoterapia. 1993;64:
219-228.
34. Salmi HA, Sarna S. Effect of silymarin on chemical, func-
tional, and morphological alterations of the liver: a double-
blind controlled study. Scand J Gastroenterol. 1982;17:517-521.
35. Parés A, Planas R, Torres M, et al. Effects of silymarin in alco-
holic patients with cirrhosis of the liver: results of a controlled,
double-blind, randomized and multicenter trial. J Hepatol.
1998;28:615-621.
36. Flisiak R, Prokopowicz D. Effect of misoprostol on the course
of viral hepatitis B. Hepatogastroenterology. 1997;44:1419-1425.
37. Angulo P, Patel T, Jorgensen RA, et al. Silymarin in the treat-
ment of patients with primary biliary cirrhosis with a subopti-
mal response to ursodeoxycholic acid. Hepatology. 2000;32:
897-900.
38. Ferenci P, Dragosics B, Dittrich H, et al. Randomized con-
trolled trial of silymarin treatment in patients with cirrhosis of
the liver. J Hepatol. 1989;9:105-113.
39. Lucena MI, Andrade RJ, de la Cruz JP, et al. Effects of silymarin
MZ-80 on oxidative stress in patients with alcoholic cirrhosis:
results of a randomized, double-blind, placebo-controlled clin-
ical study. Int J Clin Pharmacol Ther. 2002;40:2-8.
40. Velussi M, Cernigoi AM, De Monte A, et al. Long-term
(12 months) treatment with an anti-oxidant drug (silymarin) is
effective on hyperinsulinemia, exogenous insulin need and
malondialdehyde levels in cirrhotic diabetic patients. J Hepatol.
1997;26:871-879.
41. Albrecht M, Frerick H, Kuhn U, et al. Therapy of toxic liver
pathologies with Legalon®. Z Klin Med. 1992;47:87-92.
42. Tanamly MD, Tadros F, Labeeb S, et al. Randomised double-
blinded trial evaluating silymarin for chronic hepatitis C in
an Egyptian village: study description and 12-month results.
Dig Liver Dis. 2004;36:752.
43. Strickland GT, Tanamly MD, Tadros F, et al. Two-year results
of a randomised double-blinded trial evaluating silymarin for
chronic hepatitis C. Dig Liver Dis. 2005;37:542-543.
44. Gordon A, Hobbs DA, Bowden DS, et al. Effects of Silybum
marianum on serum hepatitis C virus RNA, alanine amino-
transferase levels and well-being in patients with chronic
hepatitis C. J Gastroenterol Hepatol. 2006;21:275-280.
45. Enjalbert F, Rapior S, Nouguier-Soulé J, et al. Treatment of
amatoxin poisoning: 20-year retrospective analysis. J Toxicol
Clin Toxicol. 2002;40:715-757.
46. Tamayo C, Diamond S. Review of clinical trials evaluating
safety and efficacy of milk thistle (Silybum marianum). Integr
Cancer Ther. 2007;6:146-157
47. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle for
alcoholic and/or hepatitis B or C virus liver diseases. Cochrane
Database Syst Rev. 2005;(2):CD003620.
48. Invernizzi R, Bernuzzi S, Ciani D, et al. Silymarine during
maintenance therapy of acute promyelocytic leukemia. Haema-
tologica. 1993;78:340-341.
49. Grossmann M, Hoermann R, Weiss M, et al. Spontaneous
regression of hepatocellular carcinoma. Am J Gastroenterol. 1995;
90:1500-1503.
50. Schroder FH, Roobol MJ, Boeve ER, et al. A randomized,
double-blind, placebo-controlled crossover study in men with
prostate cancer and rising PSA: effectiveness of a dietary sup-
plement. Eur Urol. 2005;48:922-930.
51. Hernandez R, Nazar E. Effect of silymarin in intrahepatic
cholestasis of pregnancy. Revista chilena de Obstetricia y Ginecologia.
1982;47:22-29.
52. Allain H, Schück S, Lebreton S, et al. Aminotransferase levels and
silymarin in de novo tacrine-treated patients with Alzheimer’s dis-
ease. Dementia Geriatr Cogn Disord. 1999;10:181-185.
53. Flaig T, Gustafson DL, Su LJ, et al. A phase I and pharmaco-
kinetic study of silybin-phytosome in prostate cancer patients.
Invest New Drugs. 2007;25:139-146.
54. Ladas EJ, Kelly KM. Milk thistle: is there a role for its use as an
adjunct therapy in patients with cancer? J Altern Complement
Med. 2003;9:411-416.
© 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
by guest on June 14, 2007 http://ict.sagepub.comDownloaded from

Advances in Milk Thistle
INTEGRATIVE CANCER THERAPIES 6(2); 2007 109
55. Rainone F. Milk thistle. Am Fam Physician. 2005;72:1285-1288.
56. Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk
thistle for the treatment of liver disease: a systematic review
and meta-analysis. Am J Med. 2002;113:506-515.
57. Saller R, Meier R, Brignoli R. The use of silymarin in the
treatment of liver diseases. Drugs. 2001;61:2035-2063.
58. Verma S, Thuluvath PJ. Complementary and alternative med-
icine in hepatology: review of the evidence of efficacy. Clin
Gastroenterol Hepatol. 2007 Jan 10; [Epub ahead of print].
59. Coulter ID. Evidence summaries and synthesis: necessary but
insufficient approach for determining clinical practice of
integrated medicine? Integr Cancer Ther. 2006;5;282-286.
60. Glasgow RE, Lichtenstein E, Marcus AC. Why don’t we see
more translation of health promotion research to practice?
Rethinking the efficacy-to-effectiveness transition. Public Health
Matters. 2003;93:1261-1267.
© 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution.
by guest on June 14, 2007 http://ict.sagepub.comDownloaded from