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Milk Thistle
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Silybum marianum (L.) Gaertn.
[Fam. Asteraceae]
Overview
Milk thistle preparations have been used in European
medicine for over 2,000 years to treat liver and biliary tract diseases (Der
Marderosian and Liberti, 1997; Flora et
al., 1998; Foster, 1991). In 1998, $180 million was spent on milk thistle
preparations in Germany alone (McCaleb et
al., 2000). In the U.S. in 2000, milk thistle ranked 11th in sales of all herbal products sold in
food, drug, and mass market outlets, reaching about $9 million in retail sales
(Blumenthal, 2001). With an estimated 50 clinical studies involving over 2,400
patients carried out using a proprietary milk thistle preparation from Germany
(Blumenthal et al., 2000), it is
perhaps the best documented therapeutic agent available to treat various types
of liver intoxication (Morazzoni and Bombardelli, 1995).
Description
Milk thistle preparations consist of the dried fruits (also
known as achenes) of Silybum marianum
(L.) Gaertn. [Fam. Asteraceae], freed
from the pappus. The U.S. National
Formulary requires that milk thistle preparations contain no less than 20%
silymarin, calculated as silybin (USP, 2002). Silymarin is the collective name
for the flavonolignans silibinin (silybin), silydianin, and silychristin. The German Pharmacopoeia requires that
preparations made of the crude milk thistle fruits, contain at least 1.5%
silymarin (DAB, 1999). The semi-purified standardized dry extract, which has
been the subject of numerous clinical studies, has a drug-to-extract ratio
range of 40–70:1 (w/w) and contains
no less than 70% silymarin (Blumenthal et
al., 1998).
Primary Uses
Liver Disorders
Liver disease, alcoholic (Bunout et al., 1992; Deák et al., 1990; Müzes et al.,
1990; Fehér et al., 1989; Salmi and
Sarna, 1982; Fintelmann and Albert,
1980)
Liver cirrhosis, alcoholic (Ferenci et al., 1989; DiMario et al., 1981)
Infectious hepatitis (Buzzelli et al., 1993; Magliulo et al., 1978; Hammerl et al., 1971; Poser, 1971; Sarre, 1971)
Drug-induced hepatitis (Palasciano et al, 1994; Kurz-Dimitrowa, 1971)
Other Potential Uses
Liver disease secondary to diabetes mellitus
(Velussi et al., 1997)
To decrease toxicity of narcotics used in
cholecystectomy surgery (gallbladder removal) (Fintelmann, 1973)
Amanita
mushroom poisoning (Hruby et al.,
1984; Serne et al., 1996)
Combinations
The German Commission E has approved a fixed
combination of milk thistle seed (crude), peppermint leaf (Mentha x piperita), and
wormwood (Artemisia absinthium) for
treatment of dyspeptic discomfort, especially functional disorders of the
biliary tract (Blumenthal et al.,
1998)
Dosage
Internal
Crude Preparations
Powdered seed:
12–15 g daily for making infusions and other oral galenical preparations
(Blumenthal et al., 1998).
Decoction: 3–4
times daily, 3 g seed is placed in
150 ml cold water, boiled, simmered
for 20–30 minutes, and strained
(Wichtl and Bisset, 1994).
Infusion: 150
ml boiling water is poured over 3.5 g crushed seed and steeped for 10–15
minutes, 3 to 4 times per day, one-half hour before meals, for mild digestive
disorders (Braun et al., 1996). A
small amount of peppermint leaf may be added to improve efficacy and flavor
(Weiss and Fintelmann, 2000).
Note: The
infusion form is indicated only for mild dyspeptic complaints, whereas high
dosage and/or standardized extract forms are required for serious liver
diseases. Due to the poor water solubility of silymarin, only a small fraction
(<10%) of silymarin is released into an aqueous infusion (Foster and Tyler,
1999; Meyer-Buchtela, 1999; Wichtl, 1989).
Standardized Preparations
Dry extract:
40–70:1 (w/w), 70–80% silymarin,
daily equivalent to 200–400 mg of
silymarin, calculated as silibinin (Blumenthal et al., 1998) in divided
doses. Many clinical trials have used a daily dose equivalent to 420 mg of
silymarin, delivered in three divided
doses. The dose of 140 mg is swallowed with sufficient amounts of fluid
(Blumenthal et al., 2000). Note:
Most clinical studies on milk thistle have employed the extract
concentrated and standardized to 70% silymarin.
Duration of Administration
Crude Preparations
For chronic conditions, milk thistle must be taken over an
extended period for efficacy. For acute conditions that last longer than one
week or recur periodically, consult a healthcare provider (Braun et al, 1996).
Standardized Preparations
The duration of use depends on the severity and chronic
nature of the condition. Research has suggested that standardized extracts may be used continuously for
as long as 24 months (Ferenci et al., 1989; Parés, 1998), although longer periods are possible.
Chemistry
Milk thistle seed contains 1.5–3.0% flavonolignans including silybin, silydianin, and silychristin
collectively referred to as silymarin; 20–30% fixed oil, of which approximately 50–60% is linoleic acid, approximately 30% is oleic acid, and approximately 9% is palmitic acid; 25–30% protein; 0.038% tocopherol; 0.63% sterols,
including cholesterol, campesterol, stigmasterol, and sitosterol; and some
mucilage (Morazzoni and Bombardelli, 1995;
Wichtl and Bissett, 1994).
Pharmacological Actions
Internal
Human
Standardized Preparations
Hepatoprotective (BHP, 1996). Reduces serum gamma glutamyl
transpeptidase (GGT), alanine transaminase (ALT), and aspartate transaminase
(AST), reduces triglyceride in serum, normalizes serum-bilirubin and BSP
retention, reduces malondialdehyde concentration in serum, increases superoxide
dismutase (SOD) activity in erythrocytes and lymphocytes, reduces cytotoxic
lymphocytes in blood, and reduces procollagen-III peptide in serum
(Leng-Peschlow 1996a, 1996b).
Animal
Isolated silymarin has anti-inflammatory and anti-arthritic
actions (Gupta et al., 1999);
increases bile flow and bile salt secretion (Crocenzi et al., 2000); increases secretion of bile into duodenum and exerts
gastroprotective effect to prevent ischemic mucosal injury (Alarcon de la
Lastra et al., 1995); is prophylactic
and antidotal for Amanita/deathcap
mushroom poisoning (Desplaces et al.,
1975; Schriewer et al., 1975; Vogel et al., 1984); protects against sawfly (Arge pullata) larvae-induced ruminant
hepatotoxicosis (Thamsborg et al.,
1996); reduces activity level of GGT, ALT, and AST (Wang et al., 1996); increases glutathione level (Vatenzuela et al., 1989); inhibits synthesis of
liver lecithin (Montanini et al., 1977);
and protects against thioacetamide damage (Schriewer et al., 1973).
In vitro
Isolated silymarin is hepatoprotective (Farghali et al., 2000; Mereish and Solow, 1990);
antioxidant (Müzes et al., 1991);
inhibits alpha-amanitin uptake in hepatocyte membrane (Tongiani et al., 1977); stimulates RNA-polymerase
I (Morazzoni and Bombardelli, 1995); enhances human polymorphonuclear leukocyte
(PMN) motility (Kalmar et al., 1990);
and has anticarcinogenic effects in human prostate carcinoma DU145 cells (Zi et al., 1998).
External
Animal
Isolated silymarin inhibits benzoyl peroxide-induced tumor promotion,
oxidative stress and inflammatory responses in skin (Zhao et al., 2000); reduces skin tumor (Katiyar et al., 1997).
Mechanism of Action
Milk thistle’s hepatoprotective mechanism of action is not
clearly understood, though it can be attributed mainly to its flavono-lignan
content (Der Manderosian and Liberti, 1997). Isolated silymarin acts as an
antagonist in preventing liver-damage: phalloidin and amanitin (death-cap
toxins), lanthanides, carbon tetrachloride, galactosantine, thioacetamide, and
the hepatotoxic virus FV3 of cold-blooded vertebrates (Blumenthal et al., 1998).
Anti-inflammatory: Anti-inflammatory and
anti-arthritic actions may be due to silymarin’s inhibition of 5-lipoxygenase
(Gupta et al., 1999).
Antioxidant: Silymarin scavenges
pro-oxidant free radicals, increases glutathione production by the liver,
intestines and stomach; increases intracellular concentration of glutathione in
rats (Valenzuela et al., 1989;
Valenzuela and Garrido, 1994). Semi-purified extract of milk thistle increases activity
of SOD and glutathione peroxidase in human erythrocytes in vitro, which may explain its protective effect against free
radicals and its stabilizing effect on red blood cell membrane (Altorjay et al., 1992).
Cholagogic and choleretic: Silymarin may
increase biliary excretion and endogenous pool of bile salts by stimulating
synthesis of hepatoprotective bile salts such as beta-muricholate and ursodeoxycholate
(Crocenzi et al., 2000).
Regenerative: Silymarin stimulates the
action of nucleolar polymerase A, resulting in an increase in ribosomal protein
synthesis, thereby stimulating regenerative ability of the liver and formation
of new hepatocytes (Blumenthal et al.,
1998). Based on molecular modeling, silibinin appears to initiate a steroid
hormone by binding competitively to RNA-polymerase I, resulting in enzyme
activity stimulation (Sonnenbichler et al.,
1998).
Protective and regulatory: Silymarin alters
the structure of the outer cell membrane of the hepatocytes in such a way as to
prevent penetration of the liver toxin into the interior of the cell
(Blumenthal et al., 1998; Leng-Peschlow, 1996b).
Stabilizes cell membranes by decreasing phospholipid turnover rate and blocking
penetration of liver toxins (such as phalloidin, alpha-amanitin) into the cell
(Montanini et al., 1977). Isolated
silibinin selectively inhibits leukotriene formation by Kupffer cells of the
liver (Dehmlow et al., 1996). Isolated silychristin (silymarin II) inhibits
peroxidase and lipoxygenase (Fugmarm et al., 1997).
Hepatoprotective effect may be due to silymarin’s inhibition of lipid
peroxidation and modulation of hepatocyte Ca(2+)(i) (Farghali et al., 2000).
Anti-fibrotic actions: Animal research (Boigk
et al., 1997) and a human clinical
trial (Shuppan et al., 1999) have
suggested that the hepatoprotective properties of silymarin may include
anti-fibrotic activity, thereby interfering with the process that occurs in the
hepatocytes secondary to inflammation when collagen invades the normal
structure of the hepatocyte, which frequently is a result of alcohol abuse or
chronic active viral hepatitis. The ability of silymarin to block fibrosis in
the liver was first shown in studies with rats subjected to complete bile duct
occlusion (Boigk et al., 1997). This
action was later demonstrated in an open-label, uncontrolled study with 998
patients with liver disease resulting from a variety of factors including
alcohol abuse, chronic active hepatitis B or C, drugs, and chemical exposure in
the workplace (Schuppan et al.,
1998). Treatment with 140 mg of silymarin (equivalent to approximately 60 mg of
silibinin) three times daily for three months led to a significant reduction in
amino terminal procollagen III peptide (PIIINP), a marker of fibrosis, in 19%
of the patients. This measure had dropped to the normal range expected for a
healthy person at three months.
Contraindications
None known (Blumenthal et al., 1998;
Braun et al., 1996; Brinker, 2001).
Pregnancy and Lactation: No known restrictions (Blumenthal et
al., 1998).
Adverse Effects
Crude Preparations
None known (Blumenthal et al., 1998;
Braun et al., 1996).
Standardized Preparations
A mild laxative effect has been observed occasionally
(Blumenthal et al., 1998).
There is one case report of a more severe gastro-intestinal reaction to a milk
thistle product (Adverse Drug Reactions Advisory Committee, 1999); the link to
the standardized extract is unclear.
Drug Interactions
None known, according to the Commission E (Blumenthal et
al., 1998) and other authoritative German pharmaceutical
literature (Braun et al., 1996).
Concomitant use of purified silymarin and butyrophenones or phenothiazines has resulted in the reduction of lipid peroxidation
damage of the liver. In one clinical study, milk thistle was tested for its
potential benefit in reducing the hepatotoxicity of these psychopharmaceutical
agents (Palasciano et al., 1994).
One case report suggests possible protection from dilantin-induced
hepatotoxicity (Brinker, 2001).
American Herbal Products Association (AHPA) Safety Rating
Class 1: Can
be safely consumed when used appropriately (McGuffin et
al., 1997).
Regulatory Status
Australia: Approved as a
Therapeutic Good (Medicine) by the Therapeutic Goods Administration (TGA).
Canada:
Permitted as a component of OTC Traditional Herbal Medicine (THM) products and
as an OTC 1X homeopathic drug, in both cases requiring pre-marketing
authorization and application for a Drug Identification Number (DIN) (Health
Canada, 2000).
France:
Approved as a nonprescription drug.
Germany: Crude
and standardized milk thistle preparations are approved nonprescription drugs
of the Commission E monographs (Blumenthal et
al., 1998) and the tea infusion form is a non-prescription drug of the German Standard License monographs, with
sales limited to pharmacies and drugstores (Braun et al., 1996). The ripe fruit, freed from pappus, containing not
less than 1.5% silymarin is official in the German
Pharmacopoeia (DAB, 1999). The mother tincture and the ethanolic decoction
of the ripe dried fruit are official preparations of the German Homeopathic Pharmacopoeia (GHP, 1993).
Italy:
Approved as a prescription drug.
Sweden: No
milk thistle-containing products are presently registered in the Medical
Products Agency’s (MPA) “Authorized Natural Remedies,” “Homeopathic Remedies”
or “Drugs” listings (MPA, 2001).
Switzerland:
Positive classification (List D) by Interkantonale
Konstrollstelle für Heilmittel (IKS) and corresponding sales category D
with sale limited to pharmacies and drugstores, without prescription (Morant
and Ruppanner, 2001; WHO, 1998). 11 milk thistle-containing phytomedicines and
21 homeopathic preparations are listed in the Swiss Codex 2000/01 (Ruppanner and Schaefer, 2001).
U.K.: Not
entered in the General Sale List
(GSL).
U.S.: Dietary
supplement (USC, 1994). Milk thistle seed and milk thistle seed powder have
official monographs in the U.S. National
Formulary, 20th edition (USP, 2002). The mother tincture 1:10 (w/v), 65% ethanol (v/v), of the fresh or dried seeds, is an OTC Class C drug official
in the Homoeopathic Pharmacopoeia of the
United States (HPUS, 1990).
Clinical Review
Twenty-one studies are outlined in the following table,
“Clinical Studies on Milk Thistle,” including a total of 2,370 participants.
All but two of these studies (Parés et al.,
1998; Bunout et al., 1992)
demonstrate positive effects for indications including cirrhosis and alcoholic
liver disease, hepatitis, and psychotropic drug-induced liver damage. Eight
double-blind, placebo-controlled (DB, PC) studies investigated cirrhosis and
alcoholic liver disease, involving over 600 patients (Deák et al., 1990; DiMario et al.,
1981; Fehér et al., 1989; Ferenci et al., 1989; Fintelmann and Albert,
1980; Müzes et al., 1990; Parés et al., 1998; Salmi and Sarna, 1982).
The most recent DB, PC study did not result in statistically significant
findings on liver cirrhosis (Parés et al.,
1998). Two randomized (R), DB, PC trials investigated milk thistle extract as a
treatment for acute viral hepatitis A and B (HBV) (Magliulo et al., 1978) and chronic active
hepatitis due to HBV and/or hepatitis C (HCV) (Buzzelli et al., 1993). One observational study on 998 patients showed that
milk thistle extract reduces collagen fibrogenesis in patients with toxic
livers (Schuppan et al., 1998).
Treatment of psychotropic drug-induced hepatic damage with purified silymarin
was the subject of another R, DB, PC study (Palasciano et al., 1994), and one multi-center study involving 220 patients
over four years found intravenous purified silibin complemented standard
treatment, lowering mortality rates in cases of acute Amanita mushroom poisoning (Hruby et al., 1984). A recent systematic review and meta-analysis (Mulrow
et al., 2000) funded by the National
Institutes of Health’s Agency for Healthcare Research and Quality concluded
that (1) the available evidence suggests that milk thistle extract is
relatively safe, associated with few, generally minor, adverse events; (2)
despite substantial in vitro and
animal research, the mechanism of action is not fully defined and may be
mulitfactorial; and (3) clinical efficacy is not clearly established because
interpretation of the evidence is hampered by poor study methods and/or poor
quality of reporting in publications; other problems include heterogeneity in
etiology and extent of liver disease, small sample sizes, variation in
formulation (for products other than Legalon®, the leading
standardized preparation), dosing, and duration of therapy. Possible benefits
have been shown most frequently for improvement in aminotransferases and liver function
tests.
Branded Products
IdB 1016 Silipide: Indena S.p.A. / Viale Ortles 12 / 20139
Milano, Italy / Tel: +39-02-57-4961 / Fax: +39-02-57-4046-20 / Email: indenami@tin.it.
One capsule contains 150 mg purified dry extract of milk thistle seed
standardized to 80% silymarin (120 mg).
Legalon® 35 Dragées: Madaus AG / Ostermerheimer
Strasse 198 / Köln / Germany / Tel: +49-22-18-9984-76 / Fax: +49-22-18-9987-21
/ Email: b.lindener@madaus.de. One tablet contains 43.25 mg–46.6 dry extract
from milk thistle fruits standardized to 35 mg silymarin, calculated as
silibinin. (Introduced in 1966.)
Legalon® 70: Madaus AG. One capsule contains 86.5–93.3
mg dry extract from milk thistle fruits (36–44:1) standardized to 70 mg
silymarin, calculated as silibinin (extractant: ethyl acetate > 96.7%).
(Introduced in 1974.)
Legalon® 140: Madaus AG. One capsule contains
173.0–186.7 mg dry extract from milk thistle fruits (36–44:1) standardized to
140 mg silymarin, calculated as silibinin (extractant: ethyl acetate >
96.7%). (Introduced in 1990.)
American equivalents, if any, are found in the Product Table
beginning on page 398.
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