Milk Thistle: Critical of its Application on Human Diseases - Literature review Example

?Milk Thistle: Critical Review of its Application on Human Diseases Introduction From time immemorial, several herbs have been used for the treatmentof various ailments of human body. Though most of these treatments have no scientific basis, expert opinions and traditions have dominated the justification of their use. One such medicinal plant is Milk thistle. Milk thistle is a medicinal herb that has been in use for its medicinal benefits for more than 2,000 years. It is mainly used for various gallbladder and liver disorders. Products of the herb are popular in many countries of the world including United States and Europe. They are mainly used for the treatment of various liver diseases (Mayoclinic, 2011). Milk thistle is known to protect the liver from the effects of several toxins like alcohol, acetaminophen and certain types of mushroom poisoning. It is also being used to protect against nephrotoxicity (Murphy and Kemper, 2000). This literature review evaluates and critically analyzes the uses of the herb, the constituents of the herb, various pharmacological actions of the active component, dosage recommendations, appropriate applications, prognosis and expected response to treatment with the herb. Summary of information about the herb’s use with critical analysis History pertaining to medicinal application Milk thistle is used widely for the treatment of several disorders. In Europe, the herb has been in use for medicinal purposes from the first century. Pliny the Elder has mentioned that the herb is useful in improving the flow of the bile. Milk thistle has been mentioned in Culpepper, Dioscorides and Jacobus wiritings (Murphy and Kemper, 2000). Various parts of the herb, like the flowers, leaves and roots have been part of European diets historically and the fruits were roasted and used for coffee substitution. In some parts of Europe, the leaves are a part of fresh salads and are substituted frequently for spinach (Murphy and Kemper, 2000). In China, milk thistle is a part of Chinese traditional medicine. The seeds of the herb are known popularly as Shui Fei Ji and even in that country, the herb is used for protection of the liver, antioxidant effects and increased biliary secretion (Murphy and Kemper, 2000). However, there is not much literature pertaining to the scientific evidence of its medicinal properties. The component that is active biologically is silymarin. Other ingredients of the seeds are silychristin, silybin and silidianin (Murphy and Kemper, 2000). Silymarin is present in all portions of the plant. However, it is more concentrated in the seeds and hence it is extracted from the seeds of the herb. The biological name for milk thistle is Silybum marianum and milk thistle is used interchangeably frequently with silymarin. Other common names of milk thistle are marian thistle, holy thistle, Our Lady's thistle, wild antichoke, etc. The herb belongs to the botanical family Compositae, also known as Asteraceae (Murphy and Kemper, 2000). The plant is a herb. It is tall and biennial. It is about 5-10 feet in height. It is hard and green and has some shiny leaves. The leaves have spiny edges with longitudinal veins that are white. The flower heads are solitary, reddish-purple with bracts that end in sharp spines. The fruits are small and hard. The herb is mainly grown in North America, Western Europe and South America (Murphy and Kemper, 2000). Uses Silymarin is mainly used for the treatment of chronic liver disease, including gall bladder diseases. Other than liver diseases, milk thistle has also been used on several other conditions. Traditionally, milk thistle has been used to treat a type of mushroom poisoning, the Amanita phalloides poisoning. But there is no evidence to support this aspect (Mayoclinic, 2011). Silymarin causes inhibition of the binding of the dangerous toxins from the mushroom to the hepatocytes, thus causing interruption in the enterohepatic circulation of the fatal toxins. But, it is not useful as the first line management of the poisoning. Hence, treatment with silymarin is often done within other drugs. Other han hepatic conditions and mushroom poisoning, milk thistle has also been used in other medical conditions like dyspepsia, diabetes, hypercholesterolemia and damage to the liver due to toxins. The evidence is however, but not from standard trials (Mayoclinic, 2011). Evaluation of the pharmacology and methods of preparation and therapeutic application Bioavailability Silymarin, the active ingredient is a very potent antioxidant (Murphy and Kemper, 2000). The bioavailability of silymarin that is administered enterically is actually limited. The active compound is not well soluble in water and it is absorbed only 20- 50 percent after ingestion. When complexed with phosphaidyl choline, the absorption in enhanced significantly. The absorption is rapid and peak plasma levels are achieved within 2- 4 hours after ingestion. The half life is six hours. The active compound follows the enterohepatic circulation. Only 3-8 percent of the ingested medication is excreted through urine. More than 80 percent is excreted as bile sulfate conjugates and glucuronides. The bioavailability of the active compound is actually variable and is dependent on the formulation. The biavailability of legalon is twice as that for other other compounds (Murphy and Kemper, 2000). Silymarin concentrates in urine and the concentration is 60 times higher in bile than in serum (Murphy and Kemper, 2000). Yan-yu conducted to study to evaluate a method by which the oral availability of silymarin could be increased. The product prepared was silymarin proliposome. The study found that bioavailability increased dramatically with silymarin proliposome. and that the product remained stable in the gastrointestinal tract. This study was conducted on beagle dogs and a software program was used to evaluate the pharmacokinetic parameters. Dosing The dosing of milk thistle is based on publications, scientific research, expert opinion and traditional use. But there is no good documented evidence of the efficacy and safety of the herb. There are different brands available in the market and the dosing is different for different drugs. Two popular brands are Legalon and Silipide. The dose of Silimarin is 230- 600 mg every day in 2-3 divided doses, that of Silipide is 160- 480 mg each day in 3 divided doses. This dosing is for adults. There is not much information about dosing of milk thistle among children (Mayoclinic, 2011). Safety perspective and adverse reactions There is no strict regulation of supplements and herbs by many countries in the world including U.S. Food and Drug Administration. Hence, there is no guarantee for safety, strength and purity of the products related to herbs. One of the possible side effect of milk thistle is allergy. Infact, anaphylactic reactions to oral intake of milk thistle in the form of tablets or tea have been reported in a few patients. However, in general the over all safety record of milk thistle is good and milk thistle is considered to be a safe medication. When consumed in recommended doses, the medicine is well tolerated for upto 6 years (Loguercio and Festi, 2011). Other than allergy, other common side effects include itching, frequent head aches and stomach upsets manifesting as nausea and vomiting. Other uncommon side effects include joint pains, gas, loss of appetite, heart burn, diarrhea, nausea and vomiting, collapse and weakness. In one case, the patient demonstrated elevated liver enzymes after initiated of the treatment which subsided after stopping the drug (Rainone, 2005). Theoretically, milk thistle has blood sugar decreasing capacity and can cause hypoglycemia. Hence, it is recommended that serum blood sugar levels be monitored when the patient is on this drug. There is some evidence that the plant extract has estrogenic properties and hence women with hormonal imbalance problems must avoid taking the herb. There is also some evidence that milk thistle can exacerbate hemochromatosis (Mayoclinic, 2011). Traditionally, milk thistle is used to increase breast milk and a few studies which have been done have reported no side effects in pregnant women. There is not much evidence to support the use of milk thistle safely during pregnancy and lactation (Mayoclinic, 2011). The safety of the drug in pediatric age groups, lactation and pregnancy are unknown (Murphy and Kemper, 2000). Critical review of the medical uses of milk thistle Gall bladder and liver diseases Though several studies have been conducted to ascertain the role of this herb in the treatment of gall bladder and liver diseases, as of now, there has been no proper randomized controlled trial to establish the role of the herb in medicinal application. Several studies from European countries have suggested the benefits of oral intake of milk thistle for liver cirrhosis (Abenavoli, 2010). In some studies, it has been demonstrated that persistent oral intake of this herb for about 5 years causes improvement in liver function and decreases mortality related to cirrhosis of liver. The results of these studies appear promising but cannot be applied for evidence based practice because of poor design of the studies. Recently, there has been a surge in the research pertaining to milk thistle. In a recent study by Feher and Lengyel (2011), the researchers studied the implications of administration of silymarin over long duration of time in patients suffering from alcoholic liver cirrhosis. The results of the study have shown that long term administration of silymarin improved survival time of those suffering from alcohol related liver cirrhosis. However, this is a prospective study with no proper design and its implications for evidence based practice are limited. In yet another study by Feher et al (cited in Rainone, 2005), in which the researchers evaluated 36 patients with established diagnosis of chronic alcoholic liver disease, the researchers demonstrated that the group treated with Legalon, a brand of silymain, showed improvement in bilirubin levels, and other liver enzymes along with improvement in histology. These beneficial changes were not noted in the placebo treated group. Thus, there is some evidence to show that silymarin is useful in alcohol liver diseases, but more research with appropriate study design is warranted. Serviddio et al (2010) conducted a study to ascertain the effects of siybin on the redox balance of the liver and also on the function of the mitochondria in animal model of nonalcoholic steatohepatitis. In order to accomplish this, mitochondrial uptake of oxygen, glutathione oxidation, proton leak, H2O production rate and ATP homeostasis were evaluated. From the results of the study, it was evident that silymarin has some effects on chronic nonalcoholic steatohepatitis, but implications of this study on human liver cannot be ascertained. Freedman et al (2011) conducted a study to assess the effects of treatment with silymarin on the progression of liver disease in those with chronic hepatitis C. This study was conducted as a part of Long-term Treatment against Cirrhosis trial. Trial with silymarin was given to those who failed to respond to ribavarin and interferon treatment. The patients were followed up for more than 8 years and Ishak fibrosis scoring method was used for evaluation. From the reports of the study, it was evident that silymarin use decreased the histologic progression of liver disease significantly. However, when compared to standard medical antiviral therapy, the clinical outcomes were not different. The study was a prospective study with no proper designing and case control. Also, there were several confounding factors like male gender, higher liver enzymes, low albumin levels, oesophageal varices, etc. From the results of the study, it was evident that silybin partially alters fatty acid compositon of the mitochondrial membrane and provides antifibrotic and anti-inflammtory effects. The results of the study are on animal models with induced steatohepatitis. Implications on human liver are yet be evaluated and are difficult. As far as the role of silymarin in subacute liver diseases, there is very little research. In a study by Salmi et al (cited in Rainone, 2005), the researchers demonstrated decrease in transamylase levels in those with subacute liver disease after four weeks therapy with milk thistle. There is however, no evidence for the role of milk thistle in the treatment of acute hepatitis. Cancer therapy Milk thistle is also known to prevent toxicity related to cisplatin, a chemotoxic agent (Murphy and Kemper, 2000). Ninsotia et al (2011) conducted a study to ascertain the role of silymarin in the protection of renal cells in patients taking cisplatin. Cisplatin is known for inducing nephrotoxicity and is one of the obstacles for cisplatin treatment for cancer. Cell death due to cisplatin was evaluated in melanoma cells, lung carcinoma and human proximal tubular cells using suitable bioassays. From the results of the study it was evident that "pretreatment with 25-200 µM of silymarin significantly protected against cisplatin-induced cell death in a dose-dependent manner. In contrast, pretreatment of silymarin (25-100 µM) caused no significant change on cisplatin-induced cell death in H460 cells but significantly potentiated cisplatin-induced apoptosis in G361 cells." Based on the results of the study, the authors concluded that silymarin is useful in protecting renal cells from damage induced by cisplatin during cancer treatment. Currently, one interesting application of milk thistle is that it reduces the growth of cancer cells related to human breast, liver cervix and prostate. As of now, there have been no high quality trials to ascertain this fact and there is ongoing research in this regard. Wellington and Jarvis (2001) reported in their study that silymarin has no beneficial effects in terms of patient mortality. Mechanism of action Silymarin is mainly a membrane stabilizing agent and because of this property and also antioxidant activity, it causes promotion of the regeneration of liver cells, decreases the inflammatory reaction in the liver tissue and causes inhibition of fibrogenesis in the organ. Several clinical trials and experiments have demonstrated these findings (Feher and Lengyel, 2011). Molecular biology studies have indicated reduction in proliferation of tumor and reduction in angiogenesis and improvement in insulin resistance. Silymarin is also known to exert antiatherosclerotic effect and suppress protein production related tumor necrosis factor (Feher and Lengyel, 2011). According to Wellington and Jarvis (2001), "the mechanisms of action of silymarin involve different biochemical events, such as the stimulation of the synthetic rate of ribosomal RNA (rRNA) species through stimulation of polymerase I and rRNA transcription, protecting the cell membrane from radical-induced damage and blockage of the uptake of toxins such as alpha-amanitin." There is some evidence that silymarin causes an increase in the activity of superoxide dismutase in erythrocytes and lymhocytes. It also increases the serum levels of glutathione peroxidase and also glutathione (Rainone, 2005). Drug interactions with silymarin are common, but are not problemtic. The compound inhibits the activities of CYP2E1, CYP2D6 and CYP3A4 (Rainone, 2005). Contraindications and precautions The main contraindications for silymarin are pregnancy and lactation and history of hypersensitivity (MIMS, 2011). The herb has not been studied in pregnancy and laction. There are not many safety trials with regards to its application in children and hence it is not used frequently in children too. It must be taken with food. Conclusion Milk thistle is an important herb used in various parts of the world including European and American countries and is claimed to be useful in the treatment of various ailments, mainly chronic liver diseases. Currently, its use is studied in the prevention of cisplatin-induced nephrotoxicity. The main active ingredient in the herb is silymarin and the compound has many antineoplastic, anti-fibrogenesis, antiinflammatory and antioxidant properties, because of which its application in medical field has been possible. However, as of now, there is no proper trial to justify its cinical application in evidence based practice. References Abenavoli, L., Capasso, R., Milic, N., Capasso, F. (2010). Milk thistle in liver diseases: past, present, future. Phytother Res., 24(10), 1423-32. Feher, J., Lengyel, G. (2011). Silymarin in the Prevention and Treatment of Liver Diseases and Primary Liver Cancer. Curr Pharm Biotechnol. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21466434. Freedman, N.D., Curtom T.M., ,C., et al. (2011). Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther., 33(1), 127-37. Loguercio C, Festi D. (2011). Silybin and the liver: From basic research to clinical practice. World J Gastroenterol., 17(18), 2288-301. Mayoclinic. (2011). Milk thistle (Silybum marianum). Retrieved from http://www.mayoclinic.com/health/silymarin/NS_patient-milkthistle MIMS.USA. (2011). Silymarin. Retrieved from http://www.mims.com/USA/drug/info/silymarin/ Murphy, J.M., and Kemper, K.J. (2000). Milk Thistle. The Longwood Herbal Task Force. Retrieved from www.longwoodherbal.org/milkthistle/milkthistle.pdf Ninsontia C, Pongjit K, Chaotham C, Chanvorachote P. (2011). Silymarin selectively protects human renal cells from cisplatin-induced cell death. Pharm Biol. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21591838 Rainone, F. (2005). Milk Thistle. American Family Physician. Retrieved from http://www.aafp.org/afp/2005/1001/p1285.html. Serviddio, G., Bellanti, F., Giudetti, A.M., et al. (2010). A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis. J Pharmacol Exp Ther., 332(3), 922-32 Wellington, K., Jarvis, B. (2001). Silymarin: a review of its clinical properties in the management of hepatic disorders. BioDrugs, 15(7), 465-89. Yan-yu, X., Yun-Mei, S., Zhi-peng, C., and Qi-neng, P. (2006). Preparation of silymarin proliposome: A new way to increase oral bioavailability of silymarin in beagle dogs. International Journal of Pharmaceutics, 319 (1-2), 162- 168. Read More