Milk thistle
Scientific Name(s): Silybum marianum (L.) Gaertn. Family: Compositae; may be referred to in older texts as Carduus marianus .
Common Name(s): Holy thistle , lady's thistle , marian thistle , Mary thistle , milk thistle , St. Mary thistle , silybum
Clinical Overview
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Uses of Milk thistle
Pharmacological studies for milk thistle fruit document antioxidant, anti-inflammatory, antifibrotic, and anticancer properties. Additional pharmacological studies include inhibition of lipid peroxidation and stimulation of protein biosynthesis. However, the majority of the literature concerns the hepatoprotective efficacy of silymarin and silibinin in particular against Amanita phalloides mushroom poisoning.
Milk thistle Dosing
Crude milk thistle seed has been administered at 12 to 15 g/day in clinical trials for hepatitis and other liver conditions. The most effective doses in clinical trials ranged from 420 to 600 mg/day of extracts, tablets, or capsules standardized to 70% silymarin.
Contraindications
There are no known contraindications.
Pregnancy/Lactation
There is no information on appropriate use in pregnancy or lactation.
Milk thistle Interactions
Care should be taken when using milk thistle. Silybin inhibits phase I and phase II enzymes and inactivates cytochromes P-450 3A4 and 2C9. Silybin is a potent selective inhibitor of the enzyme UGT1A1. The clinical relevance of these interactions is not well defined because of the absence of carefully controlled clinical studies. Milk thistle has been reported to reduce indinavir trough plasma concentrations.
Milk thistle Adverse Reactions
The most common reactions after oral ingestion of milk thistle include brief disturbances of GI function (eg, abdominal bloating, abdominal fullness or pain, anorexia, changes in bowel habits, diarrhea, dyspepsia, flatulence, nausea). Other reported adverse reactions include headache, skin reactions (eg, eczema, pruritus, rash, urticaria), neuropsychological events (eg, asthenia, insomnia, malaise), arthralgia, rhinoconjunctivitis, impotence, and anaphylaxis. For most clinical trials reporting adverse reactions, incidence was approximately equal in milk thistle and control groups.
Toxicology
There are no reports of milk thistle toxicities in humans.
Botany
Milk thistle is indigenous to Europe and Asia but has been naturalized in North and South America. It grows 1.5 to 3 m in height and has large, prickly leaves. When broken, the leaves and stems exude a milky sap. The reddish-purple flowers are ridged with sharp spines. The drug includes the shiny, mottled, black or grey-toned fruits that often are referred to as seeds. These make up the thistle portion, along with its silvery pappus, which readily falls away. 1
History
Milk thistle has been used medicinally since the fourth century BCE. Its use in treating hepatobiliary diseases dates back to the 1700s, and its use as a liver protectant can be traced back to Greek references. Pliny the Elder, a first century Roman writer, (AD 23 to 79) noted that the plant's juice was excellent for “carrying off bile.” Nicholas Culpepper, the 17th century English herbalist, noted milk thistle to be useful against jaundice and for removing liver and spleen obstructions. The Eclectic medical system (19th to 20th century) used milk thistle for varicose veins, menstrual difficulty, and congestion in the liver, spleen, and kidneys. In homeopathy, a tincture of the seeds has been used to treat liver disorders, jaundice, gallstones, peritonitis, hemorrhage, bronchitis, and varicose veins. The fruit, stem, and seeds are all considered to have medicinal value. 2 , 3 , 4 , 5
Early colonists introduced milk thistle to North America. The plant was grown in Europe as a vegetable and the de-spined leaves were used in salads and as a green; the stalks and root parts also were consumed. The flower portion was eaten “artichoke-style.” The roasted seeds were used as a coffee substitute. 2 , 5
Chemistry
The ripe fruit or seed contains 4% to 6% silymarin, a mixture of 3 isomeric flavonolignans, first isolated in 1968. Silymarin has a molecular formula of C 25 H 22 O 10 and a molecular weight of 482.45. The isomeric flavonolignans are silybin (silibinin), silychristin (silichristin), and silidianin (silidianin). These 3 stereoisomers differ only by the chemical link between the taxifolin moiety and coniferyl alcohol. A review of the isolation and structure of these components is available. Other flavonolignans include dehydrosilibinin, 3-desoxysilichristin, deoxysilydianin (silymonin), siliandrin, silybinome, silyhermin, and neosilyhermin.
Gel absorption and column chromatography methods have been employed to investigate flavones in milk thistle 6 ; constituents from aerial parts and fruits have been analyzed. 7 Betaine hydrochloride was isolated from milk thistle seeds and analyzed by chemical and spectroscopic methods. 8 Spectrophotometric assay to determine flavone lignans from milk thistle and its preparations have been described. 9 A near infrared (NIR) reflectance spectroscopic method was capable of identifying silybum samples from different geographical locations. 10 Silymarin has been analyzed by extraction in small amounts using liquid carbon dioxide (supercritical conditions) in high-performance liquid chromatography (HPLC)-packed columns. The separation by this method may be useful for flavonolignan analysis 11 ; solubility and bioequivalence analyses of silymarin products has been performed. 12
Silybin is the most biologically active component with regard to milk thistle's antioxidant and hepatoprotective properties. A standardized milk thistle extract composed of silymarin and silybin was developed in Europe as Legalon . 13 Silymarin is poorly soluble in water, so aqueous preparations such as teas are ineffective, except for use as supportive treatment in gallbladder disorders because of cholagogic and spasmolytic effects. 14 The drug is best administered parenterally because of poor silymarin absorption from the GI tract (23% to 47%). The drug must be concentrated for oral use. 15
The compound 5,7-dihydroxychromone has been isolated from S. marianum . Other seed components include apigenin; silybonol, a fixed oil (16% to 18%) consisting largely of linoleic and oleic acids, plus myristic, palmitic, and stearic acids; betaine hydrochloride; triamine; histamine and others. 16 , 17 , 18
From the roots of S. marianum Gaertn, 12 polyacetylenes and 1 polyene have been detected. 19
Milk thistle Uses and Pharmacology
Several pharmacological studies of milk thistle fruit document antioxidant, anti-inflammatory, antifibrotic, and anticancer properties. Inhibition of lipid peroxidation and stimulation of protein biosynthesis also have been studied.
The majority of studies document the clinical efficacy of silymarin and silibinin and their hepatoprotective pharmacological effects. 20 , 21 Selected studies are categorically presented below.
Antibacterial activitySilybin inhibited RNA and protein synthesis on gram-positive bacteria.
In vitroSilybin has potent antibacterial activity against gram-positive bacteria without hemolytic activity and no antibacterial activity against gram-negative bacteria or fungi. 22
Antioxidant and cytoprotective actionsThe proposed mechanism of action involves silymarin and silibinin reacting with free radicals, transforming them into more stable and less reactive compounds.
Animal dataTopical treatment with silymarin inhibited skin carcinogenesis induced by 7,12-dimethylbenz [a] anthracene, 12-O-tetradecanoylphorbol-13-acetate, mezerein, benzoyal peroxide, and okadaic acid in mouse models. Silymarin inhibited lipopolysaccharide-induced neurotoxicity in mesencephalic mixed neuron-glia culture by inhibiting microglia activation through inhibition of NF-kappaB activation. Milk thistle extract exhibited neuroprotective effects in cultured rat hippocampal neurons against oxidative stress-induced cell death. 23 , 24 , 25
Lipid and biliary effectsSilymarin inhibits the peroxidation of lipids within the hepatic cell, while silibinin decreases synthesis of cholesterol in the liver.
Animal dataSilybin reduced biliary cholesterol and phospholipid concentrations in rats by decreasing liver cholesterol synthesis. An antiaggregant effect of silymarin in cholesterol atherosclerosis in rabbits also was reported. 26 , 27 Biliary excretion of silybin was evaluated by HPLC. Bioavailability of silybin is higher after silipide (a lipophilic silybin-phosphatidylcholine complex) administration than after silymarin administration; therefore, increased delivery of silipide to the liver results.
Clinical dataAdministration of silymarin 420 mg/day for 3 months to 14 type 2 hyperlipidemic patients resulted in slightly decreased total cholesterol and high-density lipoprotein (HDL)-cholesterol levels. 31 The pharmacokinetics of silybin have been evaluated in patients with cholestasis. Use of silymarin increases bile, cholate, and bilirubin excretion. 28 , 29 , 30
Blood and immunomodulationIn vitro
In vitro effects of silybin on human polymorphonuclear leukocyte (PMN) have been reported. Inhibition of hydrogen peroxide may be a mechanism by which silybin inhibits luminol-enhanced chemiluminescence generated by stimulated PMNs. Another report on PMN activity showed silybin to be effective in enhancing spontaneous motility of leukocytes. Prolonged application of silymarin preparations improved immunity by increasing T-lymphoctyes and reducing all classes of immunoglobulins. 30 , 31 , 32
In vivoSilymarin's immunomodulatory activity in liver disease may be involved in its hepatoprotective action. Silybin can increase activity of superoxide dismutase and glutathione peroxidase, which may explain its protective effects against free radicals. Silymarin had an anti-inflammatory effect on human blood platelets. Silybin may have antiallergic activity; its effect on histamine release from human basophils was reversed and may be caused by membrane-stabilizing activity. Silybin inhibition of human T-lymphocyte activation also has been reported. 33 , 34 , 35 , 36 , 37
Viral hepatitisSilymarin may inhibit the inflammatory and cytotoxic mediators that activate viral infection. Several small trials have been published; however, some experts suggest the research is methodologically outdated. 21
Clinical dataIn patients with acute viral hepatitis, silymarin shortened treatment time and showed improvement in serum levels of bilirubin, AST, and ALT. Biochemical values returned to normal sooner in silymarin-treated patients. Histological improvement was seen in patients with chronic hepatitis versus placebo in another controlled trial. 38 , 39 , 40 , 41
In a double-blind study of 116 patients comparing silymarin with placebo, giving silymarin 420 mg/day to histologically proven alcoholic hepatitis patients was shown not to be clinically useful in treating this disease. A later report suggests stable remission in a 6- to 12-month study evaluating treatment of chronic persistent hepatitis. In 20 chronic, active hepatitis patients given silybin 240 mg twice daily versus placebo, improved liver function tests related to hepatocellular necrosis were reported. A report evaluated 2 silymarin preparations, Carsil and Legalon , in treatment of various hepatitis types. The preparations did not differ from each other. 30 , 42 , 43 , 44
In a 12-month, double-blind, randomized study, 177 patients were treated for chronic viral hepatitis C with silymarin or multivitamin supplements. Primary outcomes included quality of life assessments, baseline and follow-up clinical blood tests, and ultrasounds. At 12 months, 141 of 177 patients remained in the study. Patients in both treatment groups reported improvement in quality of life; however, silymarin had no effect on hepatitis C virus viremia, serum ALT, or serum and ultrasound markers for hepatic fibrosis. 45
Hypoglycemic activityAnimal data
Silybin inhibited glucose-stimulated insulin resistance in rats receiving cyclosporin and protected the exocrine pancreas from cyclosporin toxicity. Silybin also prevented mono-ADP-ribosylation of proteins, helping to preserve substance P-like proteins usually decreased in diabetic neuropathy. Silymarin prevented alloxan-induced diabetes mellitus in rats and increased pancreatic and blood glutathione. Oral administration of S. marianum aqueous extract (20 mg/kg) for 2 weeks in streptozotocin diabetic rats decreased blood glucose levels ( P < 0.001). The hypoglycemic effect appears to be independent of insulin secretion by pancreatic B cells of Langerhans. 21 , 46
Silybin has a direct inhibitory effect on the activity of IKK- alpha (a common mediator of fat-induced insulin resistance). 47
Clinical dataSilybin and silymarin have been evaluated (including case reports) in patients with diabetes for possible value in prophylaxis of diabetic complications. 48
Hepatoprotective actionsSilymarin's therapeutic efficacy may involve a variety of molecular mechanisms, mainly because of flavonolignans. Medicinal value also may be attributed in part to the presence of trace metals in the plant. 49 , 50
Aspects of the proposed mechanisms include the following: Actions of silymarin are almost entirely on liver and kidneys. It undergoes pronounced enterohepatic circulation between intestine and liver. Silymarin moves from plasma to bile and concentrates in liver cells. 4 In vivo tests proving increased protein synthesis in liver cells because of increased activity of ribosomal RNA were reported. Silybin stimulates DNA and RNA synthesis, resulting in activation of the regenerative capacity of the liver through cell development. 51 Silymarin's hepatoprotective effects have been postulated to involve blockade of toxin uptake mechanisms into the cell. Poisonous mushroom studies, which are discussed later, are examples of this mechanism of action. 3 , 4 , 52 Hepatoprotection by silymarin has been attributed to its antioxidant properties by scavenging prooxidant free radicals and increasing intracellular concentration of glutathione, a substance required for detoxicating reactions in liver cells. Silybin inhibits peroxidizing enzymes like lipoxygenase, thus blocking peroxidation of fatty acids and damage to membrane lipids. 53 , 54 , 55
Animal and in vitro dataIn addition to mushroom toxin protection, silymarin offers liver protection against tetracycline-induced lesions in rats, D-galactosamine-induced toxicity, thallium-induced liver damage, and erythromycin estolate, amitriptyline, nortriptyline, and tert-butylhydroperoxide hepatotoxin exposure of neonatal hepatocyte cell cultures. 56 , 57 , 58 , 59
Silymarin protected against carbon tetrachloride-induced liver cirrhosis in animals and prevented increases in lipid peroxidation by this toxin, among other effects. When injected intravenously in rats and dogs, silymarin blocked liver damage by frog virus-3, a lethal hepatotoxic virus. Although Kupffer cells were injured, the compound protected endothelial cells from destruction, primarily by inhibiting the release or synthesis of hepatotoxic enzymes. Biologically equivalent activities of silybinin at doses of 30 mg/kg are discussed in another report. Cisplatin nephrotoxicity was inhibited by silybin as judged by inhibition of tubular morphology changes and decreased proteinurea. Specific evaluations of silymarin's mechanism of plasma membrane stability have been reported. It is not clear if liver enzyme P-450 2E1 is involved in the hepatoprotective mechanism of silymarin. 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68
Clinical dataSilymarin protects liver cells against many hepatotoxins in humans and animals. Amanita phalloides , the death cup fungus, and its relatives contain 2 classes of toxins: phalloidins, which affect the hepatocyte cell membrane; and amanitins, which enter the cell nucleus and inhibit RNA polymerase B activity, thereby blocking protein synthesis. Silymarin is capable of negating both of these effects by blocking phalloidin and amanitin-transporters, increasing the regenerative capacity of liver cells, and blocking enterohepatic circulation of the toxin. Data from recent reviews involving 452 patients suggest that silybin 50 mg/kg/day is preferred to silymarin for treatment of A. phalloides poisoning. 4 , 21
In one study, 60 patients with severe mushroom poisoning were treated with infusions of silybin 20 mg/kg with good results. Although the death rate following this type of mushroom poisoning can exceed 50%, none of the patients treated in this series died. In a clinical trial of 205 patients with Amanita toxicity, 46 patients died; however, all 16 patients who received silybin survived. Administration of silybin 20 to 50 mg/kg/day within 48 hours of Amanita ingestion was an effective prophylactic measure against severe liver damage. A multicenter trial in European hospitals between 1979 and 1982 was conducted using silybin in supportive treatment of 220 Amanita poisoning cases. A 12.8% mortality rate was reported. The death rate using other modern supportive measures, such as activated charcoal, can be 40%. Silymarin alone or in combination with penicillin reduced death rates from ingestion of death cup fungus to 10%. 4 , 69 , 70 , 71 , 72 , 73
In a double-blind, placebo-controlled report, silymarin was elevated in 60 women on long-term phenothiazine or butyrophenone therapy. Results suggested that silymarin treatment may reduce lipoperoxidative hepatic damage caused by chronic use of these psychotropic drugs. 60
Liver cirrhosisSilymarin's mechanisms offer many types of therapeutic benefit in cirrhosis, with the main benefit being hepatoprotection. Use of milk thistle, however, is inadvisable in decompensated cirrhosis. 30
Clinical dataIn 1-month, double-blind studies of 50 patients with alcoholic cirrhosis treated with silymarin, elevated liver enzyme levels (AST, ALT), and serum bilirubin levels were normalized. Silymarin also reduced high levels of gamma-glutamyl transferase, increased lectin-induced lymphoblast transformation, and produced other changes not seen in the placebo group. A report on free-radical scavenger activity of silymarin suggested that hepatoprotection could be caused by antioxidant activity. 74 , 75 , 76 , 77
Similar results were obtained in another double-blind study evaluating a 6-month treatment of silymarin ( Legalon ) 420 mg/day. A 41-month, double-blind study performed in 170 patients with alcoholic cirrhosis indicated silymarin to be effective in treatment as well. Silymarin ameliorated indices of cytolysis in a study using ursodeoxycholic acid in active cirrhosis patients. One study, providing contrasting evidence, suggested no change in evolution or mortality of alcoholic liver disease as compared with placebo in a controlled trial of 72 patients using silymarin 280 mg/day. 78 , 79 , 80 , 81
AnticancerSilybin and silymarin therapeutic efficacy involves a variety of molecular mechanisms, including the following:
Alteration of cell-cycle progression. Inhibition of mitogenic and cell survival signaling (including epidermal growth factor receptor, insulin-like growth factor receptor type Ι, and nuclear factor kappa B signaling). Inhibition of secretion of proangiogenic factors from tumor cells. Growth inhibition and apoptotic death of endothelial cells accompanied by disruption of capillary tube formation. 82
In vitroBoth silybin and silymarin, at 100 mcM concentration, demonstrated cell growth inhibition in human, breast, and cervical carcinoma cells. 83 Silybin caused strong down regulation of survivin protein; mRNA expression; activation of caspases-9, capases-3, and poly(ADP-ribose)polymerase (PARP) cleavages; and apoptotic death and growth inhibition in human bladder transitional-cell papilloma RT4 cells. These actions are important because survivin overexpression appears to be a cytologic diagnostic adjunct for progression of superficial bladder cancer; and activation of capases and PARP cleavages are hallmark indicators of apoptosis. 84 Silymarin 500 mcM for 12 hours strongly reduced or inhibited ultra violet-induced apoptosis in human melanoma cells. The mechanism of action may be associated with inhibition of capases and BCL-2 family members and extracellular, signal-regulated, protein kinase. 85
Silymarin and its constituents silibinin, dehydrosilibinin, and silychristin protected rat cardiomyocytes against doxorubicin-induced oxidative stress. The mechanism of action is associated with cell membrane stabilization, radical scavenging, and iron chelating potency. The effects were compared with that of the cardioprotectant dexrasoxane. 86
The anticancer effect of silybin was studied alone and in combination with doxorubicin, cisplatin, and carboplatin in estrogen-dependent and independent human breast carcinoma cells. A synergistic effect for cell growth inhibition in both cell lines was strongly demonstrated with silybin 100 mcM plus doxorubicin 25 nM. 87
Other pharmacological effectsSilybin and silymarin in combination therapy have been effective in treating aging skin. Combination therapy has also been used in oral prevention treatment of ulceration in rats, both by reduction of neutrophils in gastric mucosa and inhibition of mechanisms of enzymatic peroxidation, thus, avoiding leukotriene synthesis. Traditional uses of milk thistle include stimulation of milk production in breast-feeding mothers and antidepressant therapy. Other uses include steroid secretory modulation and as therapy for acute promyelocytic leukemia. 49 , 88 , 89 , 90 , 91 , 92
Indications for milk thistle are for any liver-based problems such as cirrhosis, jaundice, or alcohol abuse. People exposed to hepatotoxic pesticides or heavy metals, such as painters, farmers, chemical workers, and those living in polluted urban environments, may benefit. 4 , 93
Dosage
Crude milk thistle seed has been administered at 12 to 15 g/day in clinical trials for hepatitis and other liver conditions. Extracts, tablets, or capsules (35 to 70 mg) standardized to 70% silymarin are available as commercial preparations in average daily doses of 200 to 400 mg. The most effective dose in clinical trials ranged from 420 to 600 mg/day. 6 , 21 , 60 , 94 , 95
Pregnancy/Lactation
There is no data addressing risk of milk thistle in pregnancy and lactation.
Interactions
Care should be taken when using milk thistle. Silybin inhibits phase I and phase II enzymes and inactivates cytochromes P-450 3A4 and 2C9. The clinical relevance of these interactions is not well defined because of the absence of carefully controlled clinical studies. For example, milk thistle may reduce indinavir trough plasma concentrations. Ten healthy subjects received indinavir 800 mg every 8 hours for 4 doses alone and after taking milk thistle 175 mg (containing 153 mg of the active ingredient silymarin) 3 times/day for 3 weeks. Ingestion of milk thistle decreased the area under the curve 9% and reduced trough levels of indinavir 25%. One patient experienced a 60% decrease in the trough level of indinavir, which could be clinically important. Comparable results occurred in a similar study. However, reviewers of both studies argue that no clinically important changes in the pharmacokinetics of indinavir were noted in humans. 96 , 97 , 98 , 99
Silybin is a potent selective inhibitor of the enzyme UGT1A1. The clinical importance of this interaction is unknown. This enzyme is responsible for the glucuronidation of bilirubin and partly responsible for glucuronidation of several drugs, including naltrexone, buprenorphine, estradiol, and irinotecan. 99
Adverse Reactions
Tolerability of silymarin is good; the most common effects after oral ingestion of milk thistle include brief disturbances of GI function (eg, abdominal bloating, abdominal fullness or pain, anorexia, changes in bowel habits, diarrhea, dyspepsia, flatulence, nausea). Other reported adverse reactions include headache, skin reactions (eg, eczema, pruritus, rash, urticaria), neuropsychological events (eg, asthenia, insomnia, malaise), arthralgia, rhinoconjunctivitis, impotence, and anaphylaxis. For most clinical trials reporting adverse reactions, incidence was approximately equal in milk thistle and control groups. Mild laxative effects in isolated cases have been reported. A case of urticaria with a foreign commercial milk thistle preparation was noted in a Russian report. 13 , 30 , 49 , 95 , 100
The Adverse Drug Reactions Advisory Committee of Australia (ADRAC) published a report of a 57-year-old woman suffering from intermittent episodes of sweating, nausea, colicky abdominal pain, fluid diarrhea, vomiting, weakness, and collapse over a 2-month period. The signs and symptoms of these reactions typically lasted up to 24 hours, but she felt well between the attacks. Upon interviewing the patient, the reactions were associated with her administration times after taking a commercial milk thistle product. She stopped taking the product and had no further symptoms. Upon rechallenge with the milk thistle product, the patient experienced a similar reaction. The ADRAC received similar reports of these adverse reactions, with one involving an 83-year-old man suffering from thrombocytopenia; however, no details were provided about the product. 101
Toxicology
Silymarin has proved nontoxic in rats and mice after oral doses of 2,500 or 5,000 mg/kg. In a 12-month study, rats received silymarin 50, 500, and 2,500 mg/kg. Investigations, including urine analysis and postmortem studies, showed no evidence of toxicity. A similar report in dogs was performed; no evidence of ante- or postnatal toxicity in animals was reported, nor did silymarin affect fertility in rats. 55
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