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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