ALLNatural Liver Health

Silymarin, a Powerful Natural Health Supplement

Milk Thistle is one of the most researched and recommended herbs for liver health and more! Almost everyone can benefit from Liver Health, including persons with liver and gallbladder problems such as hepatitis, cirrhosis and jaundice; other long-term health problems; suffering or recovering from alcoholism; exposure to environmental toxins and athletes looking to improve performance.

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The Health Benefits of ALLNatural Milk Thistle Extract

Milk Thistle Extract is prepared from an extract of Silymarin (milk thistle seeds). This extract has been used for over 2,000 years to prevent a range of liver and gallbladder disorders.

The protective benefits of Milk Thistle Extract have been used for many abnormalities and are mainly attributable to its anti-oxidant and free-radical scavenging properties. This includes protection against lipid peroxidation (rancidity of fats) and restoration of essential antioxidant enzymes. Moreover, it also helps maintain levels of vitamins E and C, and β-carotene. Other Benefits include:

Liver Health

Milk Thistle has been shown in clinical studies to protect against the effects of several alcoholic liver diseases, liver cirrhosis (fibrosis), mushroom poisoning, viral hepatitis, and toxic and drug induced diseases.

Digestive Disturbances

Milk Thistle can be used to prevent certain digestive problems and disturbances such as protection against colitis (inflammation) in the large intestine and inflammation of the pancreas.

Cholesterol Lowering

Protects against oxidation of low-density lipoprotein (LDL, bad cholesterol) resulting in the lowering of blood cholesterol. It also increases the amount of high density lipoprotein (HDL, good cholesterol).

Cancer Prevention

Provides protection against bladder, hepatic and liver cancers but mainly those steroid hormone-dependent cancers such as cervical and prostate cancers. The antioxidant properties of Silymarin appears to be mainly responsible for its protective effects.

Aids in the Prevention of Diabetes

Silymarin can help reduce fasting blood levels and glycated hemoglobin in diabetics.

Mitigates Effect of Alcohol Induced Hangover

Studies have shown that Silymarin can help prevent hangover headaches by reducing the oxidative stress resulting from alcohol consumption.

Protects Against Sunburns

Silymarin has been shown to protect skin from sunburn photoaging and carcinogenesis.

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Authorized for Sale by Health Canada

Liver Health is of high quality and strength. All Natural Nutritional Products Inc. has been issued a Natural Product Number (NPN 80015611), a requirement by Health Canada for the sale of nutraceuticals. This number insures you that the product has been reviewed and approved by Health Canada and it is safe, effective and of high quality.

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Frequently Asked Questions

Milk thistle extract, silymarin, from seeds and fruits, is used for the prevention of liver diseases caused by alcohol consumption, chronic hepatitis and gall bladder problems. It is a popular complimentary medicine for cancer, various menstrual problems and by helping to control blood sugar levels, type II diabetes.

The active ingredient of milk thistle is known as silymarin. Silymarin acts upon the liver to increase the concentration of glutathione, up to 35% and to reduce the concentration of reactive oxygen species (free racicals). Glutathione is natural antioxidant involved in liver detoxification. The results of numerous studies suggest that silymarin not only protects liver cells by preventing the actions of toxic substances but that it also stimulates protein synthesis to accelerate the regeneration and production of liver cells.

Almost everyone can benefit from Milk Thistle Extract, including persons with liver and gallbladder problems such as hepatitis, cirrhosis of the liver and jaundice; diabetics; alcoholism related problems; exposure to environmental toxins; athletes looking to improve performance and other long-term health problems;

Milk thistle has been shown to be beneficial for diabetics.  One study suggested that milk thistle can reduce fasting blood sugar levels. Persons in a double-blind, Type 2 Diabetics study had dramatic reductions in fasting blood sugar levels after patients took 200 mg of Silymarin for 4 months. They also had reductions in glycated hemoglobin which is another measure of blood sugar control (Huseini, 2006).

Many diabetes-related complications are linked to oxidative stress (a process that results from overproduction of free radicals). Milk thistle being a powerful antioxidant (natural substance known to knock out free radicals) should aid in the protection from diabetes.

If you’re considering the use of milk thistle (or any other herbal remedy) for diabetes, it’s crucial to consult your physician before starting your supplement regimen.

The quality of similar milk thistle products on the market varies dramatically.  ALLNatural Milk Thistle Extract contains 250 mg per vegetable capsule of a potent and standardized extract of milk thistle (80% silymarin). ALLNatural’s Milk Thistle Extract are licensed with Health Canada and are sold at the recommended dosage and packaged by a GMP manufacturer in Canada.

Remember, if a supplier does not list its concentration, don’t buy it because there’s no way of knowing what you are getting.

Science and Research

Summary of the Literature on Milk Thistle (Silymarin)

Milk thistle seeds have been used for centuries as a herbal medicine to prevent liver disease and has recently been found to be highly beneficial for the prevention of other diseases as well.

Milk thistle extract contains 70 to 80% silymarin. The main component of silymarin is silybin which occurs as two diasteromeric compounds, (silybin A and B). Silymarin offers good protection in various toxic models of experimental liver disease in laboratory animals. It is an anti-oxidative, anti-lipid peroxidative, anti-fibrotic, anti-inflammatory, and membrane immunodulatory and liver stabilizing agent. It protects the liver from oxidative stress and sustained inflammation processes that are mainly driven by reactive oxygen species (ROS) and secondary cytokines.

Silymarin has clinical applications in alcoholic liver diseases, liver cirrhosis, mushroom poisonings, viral hepatitis, toxic and drug induced liver diseases and in diabetic patients. Silymarin helps in regenerating liver tissue, control inflammation, enhances glucuronidation and protects against glutathione deletion. Milk thistle also protects social drinkers against the debilitating effects of hangover.

More recently promising results have been reported on the protective effect of the silymarin in certain types of cancer and in hyper-cholesterolemic patients. Milk thistle extracts containing silymarin are known to be safe and well tolerated, with toxic or adverse effects being minimal. There have been more than 900 scientific peer reviewed publications on milk thistle (silymarin) since 2000 (Google Scholar) which is an indication of its importance to human health and well being.

Amount and Duration of Milk Thistle Intake

Milk thistle, in order to receive its full benefits, should be taken over long periods of time at the Health Canada recommended rate of 500-750 mg/day (80% silymarin) or 2-3 capsules/day.

ALLNatural Nutritional Products Inc. has been issued a licence from Health Canada to market its milk thistle under the brand names of ALLNatural Liver Health and ALLNatural Clear Head. The Natural Product Number (NPN) for these products, a requirement for their sale, is 80015611.

The following sections provide detailed scientific information on what milk thistle is and it main components (silymarin), and its biological activities, beneficial effects and safety. A link to the abstract of each cited reference and in some cases the full publication can be accessed by clicking on the quoted referred. The list of topics covered is given below in the Table of Contents.

Silymarin: Milk thistle [Silybum marianum (L.) Gaertn., Asteraceae] seeds have been used for centuries as herbal medicine mainly to prevent liver disease but has recently been found to be highly beneficial for the prevention of other diseases as well.

Silymarin Diagrams
The active extract of Milk Thistle is a mixture of the flavonolignans, containing approximately 70 to 80% of silymarin and 20 to 30% of a chemically undefined fraction, comprising polymaric and oxidized polyphenolics. The main component of silymarin is silybin (synonymous with silibinin and sometimes incorrectly referred to as silybinin)

Natural silybin (Gažák et al., 2007) is a nearly equimolar mixture of two diastereomers (Fig. 1) (Křen et al., 1997Lee and Liu, 2003).

Other main compounds in silymain inaddition to silybin A and B, are isosilybin A and B, silychristin and isosilychristin (Gažák et al., 2007Liu et al., 2009Kumar et al., 2011). The importance of milk thistle extracts as a nutraceutical is indicated by the fact that in the past 10 years over 1000 scientific papers on silybin/silymarin have been published (Google Scholar).

Silybin and silymarin are active components in numerous phytopreparations used in the prevention of various liver diseases and as protectants against a number of hepatotoxins and mycotoxins (Morazzoni and Bombardelli, 1995Flora et al., 1998Gallo et al., 2003Kumar et al., 2011).

The cytoprotectivity of silybin consists of several mechanisms operating at various cell levels. Silybin acts mainly as an effective antioxidant (Mira et al., 1994Valenzuela and Garrido, 1994Saller et al., 2001Wellington and Adis, 2001). The radical-scavenging activity of silybin could also be partly involved in cell regulatory pathways based on reactive oxygen species (ROS) (Winterbourn, 2008).

In the past decade, silybin (and/or silymarin) has been in the spotlight owing to its multiple beneficial activities (Gažák et al., 2007Comelli et al., 2007Deep and Agarwal, 2007) that are not directly related to its hepatoprotective and antioxidant (radical scavenging) activities. These include mostly anti-cancer and chemoprotective behavior, as well as hypocholesterolemic (Hertog et al., 1993Škottová et al., 1999), cardioprotective (Ágoston et al., 2003Ágoston et al., 2001), neuroactive, and neuroprotective activities (Wang et al., 2002).

Moreover, the scope of its application has been extended to organ systems other than the liver and gastrointestinal tract, e.g., the prevention of pancreatic problems (Soto et al., 19982003), balancing glycemia (von Schönfeld et al., 1997), and the prevention of skin disorders, including a use in cosmetic preparations. The prevention of prostate hyperplasia involving adenocarcinoma is an up-to-date silymarin application, which is also documented by current successful clinical tests (clinical phase II) (Singh and Agarwal, 2006).

This is linked to the discovery of numerous effects of silybin and its derivatives at the cellular and molecular levels, such as estrogenic activity (Seidlová-Wuttke et al., 2003Plíšková et al., 2005Davis-Searles et al., 2005) and a specific action on DNA expression via the suppression of nuclear factor κB (Manna et al., 1999Yoo et al., 2004). These discoveries are also linked to progress in silybin chemistry and pharmacology, including the separation of both diastereomers (Křen et al., 1997), their absolute structure determination (Lee and Liu, 2003Kim et al., 2003), studies on their molecular mechanisms of action (Gažák et al., 2009), and the synthesis of new derivatives with better and/or modified pharmacokinetic and pharmacodynamic parameters (Gažák et al., 2004).

Approximately 20% to 50% of silymarin is absorbed following oral administration in humans, and roughly 80% of the dose is excreted in bile, while about 10% enters enterohepatic circulation (Lee et al., 2006). Pharmacokinetic stud­ies, however, have been performed primarily using silybin.

The bioavailability of silybin is low and appears to depend on several factors, such as (i) the content of accompanying substances that have solubilizing properties, such as other flavonoids, phenol derivates, amino acids, proteins, tocoph­erol, fat, cholesterol, and other substances that are found in the preparation; and (ii) the concentration of the prepara­tion itself (Voinovich et al., 2009). The systemic bioavailability can be enhanced by adding solubilizers to the extract (Saller, et al., 2001).

The bioavailability of silybin can also be increased by complexation with phosphatidylcholine or ß-cyclodextrin and, possibly, by the choice of the capsule material (Morazzoni and Bombardelli, 1995). Phar­macokinetic studies on the silybin-phosphatidylcholine complex have demonstrated increased oral bioavailability of silybin in healthy human subjects, likely due to facilita­tion of the passage of the drug across the gastrointestinal tract by the drug complex (Barzaghi et al., 1990).

The variations in the content, dissolution, and oral bioavailability of silybin among commercially available silymarin-containing products (de­spite the same declaration of content) are significant (Schulz et al., 1995). Therefore, comparisons between studies should be made with caution, based on analytical methods (TLC vs. HPLC) and whether free, conjugated, or total silybin is being measured. Systemic plasma concentrations are usually mea­sured—although silymarin is active in the liver—because they are an estimate of the quantity of the drug that is absorbed from the gastrointestinal tract. The adequate bioavailability accounts for the dose-related oral activity of silymarin in the liver (Saller, et al., 2001Morazzoni and Bombardelli, 1995Barzaghi et al., 1990Schulz et al., 1995Gatti and Perucca, 1994).

In male volunteers, after a single administration of a standard dose of oral silybin 100 to 360 mg, the Cmax of plasma silybin was reached after approximately 2 hours and ranged between 200 and 1400 μg/L, of which approxi­mately 75% was present in conjugated form (Barzaghi et al., 1990Schulz et al., 1995Fraschini  et al., 2002).

The elimination half-life of total silybin was approximately 6 hours (Yu et al., 2010Saller et al., 2008). Between 3% and 8% of the oral dose was ex­creted in the urine, and 20% to 40% was recovered from the bile as glucuronide and sulfate conjugates. The remainder was excreted in feces. silybin concentrations in the bile were approximately 100-fold higher than in the serum (10-5 to 10-4 µmol/L of silibinin in bile), with concentrations peak­ing within 2 to 9 hours (Yu et al., 2010).

Overview of the anti-oxidant properties of silymarin

Silymarin is an antioxidant and free-radical scavenger. It can also interact directly with the cell membrane components to prevent any abnormalities in the content of lipid fraction responsible for maintaining normal fluidity.

The mechanism of free-radical damage include reactive oxygen species (ROS)- induced peroxidation of polyunsaturated fatty acid in the cell membrane bilayer, which causes a chain reaction of lipid peroxidation, thus damaging the cellular membrane and causing further oxidation of membrane lipids and proteins. Subsequently, cell contents including DNA, RNA, and other cellular components are damaged.

Activity against Lipid Peroxidation

Lipid peroxidation is caused by interaction of free-radicals with unsaturated fatty acids in lipids resulting in broad spectrum of alterations and the consequent degeneration of cell membranes. Silymarin appears to act as an antioxidant not only because it acts as a scavenger of the free radicals that induce lipid peroxidation, but also because it influences enzyme systems associated with glutathione and superoxide dismutase which are involved in the neutralization of free radicals.

Molecular mechanism of Silybin and 2, 3-dehydrosilybin anti-radical activity

Molecular mechanism of silybin and 2, 3-dehydrosilybin anti-radical activity has been reported by Gažák et al. (2009). They demonstrated that the 20-OH group played a vital role in radical – mediated reactions involving silybin and that the 20-OH group was imported in this respect for 2, 3-dehydrosilybin.

NAFLD is common and one of the most serious liver diseases worldwide

Nonalcoholic fatty liver disease (NAFLD) is one the most common causes of chronic liver disorders in the Western world. These patients have many significant comorbidities (e.g., diabetes, hypothyroidism and metabolic syndrome) (Angulo, 2002). Its incidence in adults and children is rising rapidly due to the current obesity and type 2 diabetes epidemics (Vuppalanchi and Chalasani, 2009).

It is a multifaceted metabolic disorder and is encountered in clinical practice by many health care specialists-from primary care physicians and gastroenterologists to cardiologists, radiologists, and gynecologists. The umbrella term “NAFLD” encompasses simple steatosis, nonalcoholic steatohepatitis (NASH), and advanced fibrosis or cirrhosis that is related to this pathological entity.

Obesity, insulin resistance, oxidative stress, and cytokine and adipokines mediate the pathogenesis of NAFLD. These factors can promote and enhance inflammation, cell injury, apoptosis, fibrinogenesis, and carcinogenesis, leading to the accumulation of fat, reflecting the development and progression of the disease.

With regard to therapy, the approach to NAFLD is based on lifestyle intervention, and there is no consensus on the ideal pharmacological therapy (Petta et al., 2009). Accordingly, weight reduction, regular physical activity, and insulin-sensitizing drugs have been used widely and examined in several studies. Other approaches include the consumption of special diets, antioxidants, and cytoprotective therapy.

Hepatoprotective effects of Silymarin

The active extract has antioxidant, anti-inflammatory, and antifibrotic properties; in addition, it stimulates protein biosynthesis and liver regeneration. There are four overarching hepatoprotective activities of silymarin: (i) its effects against lipid peroxidation due to free radical scavenging and the ability to increase the cellular content of glutathione (GSH); (ii) its ability to regulate membrane permeability and increase membrane stability in the presence of xenobiotic damage; (iii) its capacity to regulate nuclear expression through steroid-like effects; and (iv) its inhibition of the transformation of stellate hepatocytes into myofibroblasts, which mediate the deposition of collagen fibers, leading to cirrhosis (Polyak et al., 2010Kiruthiga et al., 2007Post-White et al., 2007Dehmlow et al., 1996).

In addition, milk thistle inhibits the absorption of toxins, such as phalloidin and α-amanitin, preventing them from binding to the cell surface and inhibiting membrane transport systems. Further, by interacting with the lipid component of cell membranes, silymarin and silibinin can modulate their chemical and physical properties.

They stabilize the membranes of hepatocytes and thus prevent toxins from entering them from enterohepatic circulation. They promote liver regeneration by stimulating nucleolar polymerase A and increasing ribosomal protein synthesis (Basiglio et al., 2009). Silymarin inhibits the expression of adhesion molecules, such as E-selectin, another family of transmembrane molecules, which are expressed preferentially on the surface of leukocytes (Kang et al., 2003). Its hepatoprotective properties against a wide range of liver damage-inducing agents render MT a unique drug.

Pathological mechanisms in the development of NAFLD

Several well-designed experimental studies have suggested that silymarin can help prevent chronic liver diseases, particularly in non-alcoholic fatty liver disease (NAFLD) (Figure 2). For example, silymarin interferes with leukotriene formation in Kupffer cell (KC) cultures, thus inhibiting hepatic stellate cell (HSC) activation, a crucial event in fibrogenesis (Dehmlow et al., 1996). In addition, 10-4 mol/l silymarin blocks the proliferation of HSC cultures and their transformation into myofibroblasts (Fuchs et al., 1997).

Pathogenic mechanisms in the histological progression of NAFLD and the site of action of sylimarin

Figure 2. Pathogenic mechanisms in the histological progression of NAFLD and the site of action of sylimarin (crossed circle) (CYP2E1: cytochrome P450 2E1, ROS: reactive oxygen species, HSCs: hepatic stellate cells, KC: Kupffer cells) (Abenavoli et al., 2011)

Clinical and model animal studies on the beneficial effects of Silymarin in the prevention of NAFLD

Velussi et al. (Velussi et al., 1997) studied the efficacy of Silymarin in reducing lipid peroxidation and insulin resistance in diabetic patients with alcoholic cirrhosis. The study was performed in alcoholic cirrhosis patients, who have similar natural histories and pathological features as alcoholic liver disease and NASH patients.

In this randomized, controlled, unblinded, 12-month study, one group (n = 30) received 600 mg Silymarin per day plus standard therapy, and the control group (n = 30) received standard therapy alone. The efficacy parameters, measured regularly throughout the study, included fasting blood glucose levels; mean daily blood glucose levels, daily glycosuria levels, glycosylated hemoglobin (HbA1c), and malondialdehyde (MDA) levels, a marker of lipid peroxidation.

There was a significant decrease (p < 0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glycosuria, and HbA1c levels after 4 months of receiving silymarin. Moreover, fasting insulin levels and mean exogenous insulin requirements declined in this group (p < 0.01), and the control group experienced an increase (p < 0.05) in fasting insulin levels and stabilized their need for insulin.

These findings were consistent with the significant decrease (p < 0.01) in basal and glucagon-stimulated C-peptide levels in the silymarin group and the rise in both parameters in the control group. Notably, MDA levels fell in the group that received silymarin (p < 0.01). These studies demonstrate that silymarin reduces lipoperoxidation of cell membranes and insulin resistance, decreasing the overproduction of endogenous insulin and the need for exogenous insulin significantly.

Subsequently, Loguercio et al. (2007) evaluated the antioxidant and antifibrotic activity of a complex that comprised silybin, vitamin E, and phospholipids (Realsil ® IBI-Lorenzini Pharmaceutical, Italy) against insulin resistance and liver damage in patients with NAFLD and chronic HCV infection. This study enrolled 85 patients; 59 were affected by primitive NAFLD (group A), and 26 had HCV-related chronic hepatitis C with NAFLD, all HCV genotype-1b, and non-responders to the previous antiviral (group B).

All patients with a diagnosed liver disease in the 2 years prior to the study, based on histological criteria, were enrolled over 6 consecutive months and subdivided using a systematic random sampling procedure: 53 patients (39 NAFLD and 14 HCV) received 4 tablets/day of Realsil ® (one tablet contained 94 mg of silybin, 194 mg of phosphatidylcholine, and 90 mg of vitamin E) for 6 months, followed by another 6 months of follow-up, and 32 patients (20 NAFLD and 12 HCV) constituted the control group (no supplementation). At 0, 6, and 12 months, the following outcomes were measured: body mass index (BMI), bright liver by ultrasonography (US), transaminase and GGT levels, blood glucose and insulin plasma levels with simultaneous measurement of insulin resistance by Homeostasis Model Assessment (HOMA) test, and plasma levels of transforming growth factor ß, hyaluronic acid and metalloproteinase as indices of liver fibrosis.

Group A showed a significant and persistent reduction in US score for liver steatosis that ranged p < 0.01. Plasma levels of liver enzymes fell in patients who received silymarin but not in the control group, but this effect lasted only in NAFLD patients. Hyperinsulinemia, present in both groups, declined only in patients who received Realsil (p < 0.005). Realsil ® significantly reduced all indices of liver fibrosis in both supplemented groups, persisting only in group B.

In a randomized clinical trial, Hajaghamohammadi et al. (2008) examined the efficacy of silymarin in 50 NAFLD patients. The study population, comprising 32 men (64%) and 18 women (36%), was divided into case and control groups. All patients had elevated liver enzymes and increased liver echogenicity by US. The case group was given one tablet that contained 140 mg silymarin per day for 2 months; the control group received a placebo.

Before and after the study, weight, BMI, and liver transaminase levels were measured for each patient. The authors did not observe any significant differences in mean weight or BMI before or after the study in either group. In the case group, mean alkaline transaminase (ALT) and aspartate transaminase (AST) levels deceased from 103.1 to 41.4 U/L and 53.7 to 29.1 IU/ml, respectively (p < 0.001 and p < 0.001, respectively). In the control group, the decreases in mean ALT and AST (7.8 and 2.2 IU/ml respectively) were not significant.

The effect of silymarin on transaminase levels was confirmed by another Iranian study (Hashemi et al., 2009). One hundred subjects with NASH were randomized into two groups: group A, comprising 29 males and 21 females, received placebo, and group B, with 28 males and 22 females, received 280 mg silymarin for 6 months.

The mean serum ALT level in the silymarin group was 113.03 and 73.14 IU/ml before and after the experiment, respectively (p = 0.001). ALT normalization (ALT < 40) was observed in 18% and 52% of patients in groups A and B, respectively (p = 0.001). AST normalization (AST < 40) was observed in 20% of cases in the placebo group and in 62% of cases in the group that was given silymarin (p = 0.0001). Mitochondria regulate hepatocyte metabolism, constituting the site of ß-oxidation and oxidative phosphorylation.

Oxidative stress in NASH is closely related to mitochondrial dysfunction (Caldwell and Crespo, 2004). During the progression of NASH, the excess of free fatty acids increases mitochondrial H²O² production, which in turn oxidizes mitochondrial membranes and regulates the activity of uncoupling protein 2 (UCP2) and carnitine palmitoyl transferase-1 (CPT-1) (Serviddio et al., 2008).

Serviddio et al. (2010) examined the effects of the silybin-phospholipid complex on liver redox balance and mitochondrial function in a dietary model of NASH, measuring glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H2O2 production rate in liver mitochondria from rats that were fed a methionine/choline-deficient diet (MCD) and MCD plus SILIPHOS for 7 and 14 weeks.

Oxidative proteins, hydroxynonenal (HNE) – and MDA-protein adducts, and mitochondrial membrane lipid composition were also assessed. SILIPHOS limited glutathione depletion and mitochondrial H2O2 production. Moreover, this complex preserved mitochondrial bioenergetics and prevented mitochondrial proton leakage and ATP reduction.

The silybin-phospholipid complex limited the formation of HNE- and MDA-protein adducts. In conclusion, this complex prevents severe oxidative stress and preserves hepatic mitochondrial bioenergetics in MCD-induced NASH. The alterations in mitochondrial membrane fatty acid composition that were induced by the MCD diet were prevented in part by silybin and phospholipids, which conferred anti-inflammatory and antifibrotic effects.

Recently Haddad et al. (2011) examined the therapeutic effect of silibinin in an experimental rat model of NASH. The control group was fed a standard liquid diet for 12 weeks, and the test animals were fed a high-fat liquid diet for 12 weeks with or without (NASH) a daily supplement of silibinin-phosphatidylcholine complex (silibinin 200 mg/kg) for the last 5 weeks. The NASH rats developed all hallmarks of the pathology. Silibin improved liver steatosis and inflammation and decreased lipid peroxidation, plasma insulin, and TNF-alpha (p<0.05). In addition, silibinin decreased the release of free radicals and restored relative liver weights and GSH levels (p<0.05). The authors concluded that a complex with phosphatidyl-choline is effective in reversing steatosis, inflammation, oxidative stress, and insulin resistance in an in vivo rat model of diet- induced NASH.

Conclusions; NAFLD and a Role for Silymarin

NAFLD and its various stages affect much of the world’s population. The pathogenic mechanisms of liver damage that are involved in NAFLD are complicated and comprise a series of sequential steps. With regard to therapy, the approach to NAFLD is currently based on lifestyle intervention, but there is no consensus on the ideal pharmacological therapy (Vuppalanchi and Chalasani, 2009).

The drugs that are used in NAFLD therapy should reduce body weight, improve insulin resistance and other metabolic alterations, reduce the link between adipose tissue and liver function by acting as anti-inflammatory and immunomodulatory agents, and modulate the progression of liver steatosis to inflammation and fibrosis by blocking oxidative stress.

A multifaceted approach to NAFLD, entailing several options, is likely to be developed soon. Among these strategies, the use of complementary and alternative medicines, such as natural antioxidants and hepatoprotective plant products, has been widely accepted in the past decade. Silymarin is one of the most successful examples of a modern drug that arose from traditional healing practices. It is favored in preventing various liver diseases due to its oral efficacy, good safety profile, and, most importantly, affordability.

Several pharmacological studies have been performed on the active components of MT, silymarin, and silibinin. These substances have hepatoprotective, antioxidant, anti-inflammatory, and antifibrotic properties; in addition, they stimulate protein biosynthesis and liver regeneration and have immunomodulatory activity (Abenavoli et al., 2010). Particularly with regard to NAFLD patients, the ameliorative effects of silybin in diabetic patients, due to improved insulin activity, reductions in lipid peroxidation, and restoration of GSH levels, might explain its efficacy against liver steatosis (Loguercio et al., 2007Lirussi et al., 2002). Based on the literature, they concluded that milk thistle is a useful medicinal herb that is a viable preventative option for NAFLD.

This article is a comprehensive review of the multiple benefits of silymarin by Gažák et al. (2007). It can be obtained from the following link at (http://www.ncbi.nlm.nih.gov/pubmed/17305535). A summary of the topics covered are given below:

Introduction

This section provides a general overview of benefits of silymarin, tradition usage and the structure of the active components of silymarin.

Molecular mechanisms of the mode of action of Silymarin

This section deals with the molecular mechanisms of silybin activity at the cellular level but not its anti-radical and anti-oxidative mechanisms which are described in Section 4 (Gažák et al., 2009).

  • Anti-angiogenic activity (inhibits blood vessel growth) of silybin/silymarin: This is associated with up-regulation of vascular endothelium growth factor-1 (VEGFR-1) gene expression.
  • Anti-angiogenic effects of silymarin for prostate cancer prevention
  • Silybin in the regulation of inflammation and apoptosis (programmed cell death): The anti-carcinogenesis and anti-inflammatory effects of silymarin are also related to inhibition of the transcription factor NF-kB, which regulates and coordinates the expression of various genes involved in the inflammatory process, in cytoprotection and carcinogenesis. Silybin appears to expert its anti-cancer effect by inhibiting angiogenesis (growth of new blood vessels, and by modulation of a family of protein and caspases (digestive enzymes). Silymarin also has anti-atheroscerotic activity.
  • Silybin modulates steroid human receptors: Both silymarin and silybin elicit anti-androgenic (hormone) activity in prostate cancer cell lines.

Silybin modulates drug transporters

Silybin can modify the transport of several drugs across the cell membrane.

Silybin as a chemoprotective and anti-carcinogenic agent

  • Silybin acts at the receptor level by affecting various processes involved in either carcinogenesis in cancer proliferation. Modification of various mitogenic, signalling and cell cycle regulators by silybin have been observed.
  • The cancer preventative activity of silymarin and/or silybin has been described in various cancer types, such as bladder, hepatic and lung cancer but mainly in steroid hormone – dependent malignancies such as cervical and prostate cancers.

Silybin in skin protection

Current experimental observation indicates that silymarin/silybin may be beneficial in skin photoprotection against sunburn response, photoaging and carcinogenesis.

Neuroprotective and neurotropic activities of Silybin

Silybin/Silymarin may be useful in the prevention of some neurodegenerative and neurotoxic processes, partly due to their antioxidative activity, but also other, so far unknown, mechanisms. Silymarin may inhibit the activation of microglia that represents resident macrophaye-like population of brain cells acting in host defence and tissue repair of the CNS (central nervous system).

There is growing evidence that activated microglia contribute to neuropathological changes in several CNS diseases (multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, AIDs dementia). Silymarin also inhibits the production of inflammatory mediators, such as TNF-alpha and nitric oxide, and thus reduces damage to dopaminergic neurons. It has been suggested that the inhibiting effect of silymarin on microglia is mediated through the inhibition of nuclear factor kappa beta activation (Gažák et al., 2009).

Silymarin in the prevention of Nephropathy

Diabetic and especially hemodialysis patients are a rich source of oxidative cell damage. Under these conditions the body levels of radical scavenge – free thiol (GSH) are reduced. Use of silybin or silymarin led to restoration of thiol status within 72 h (Gažák et al., 2009).

General benefits of Silymarin

Silymarin which is often used to boost liver health and support detoxification efforts is a powerful antioxidants (natural substance known to knock out free radicals). In turn, many diabetes-related complications are linked to oxidative stress (a process that results from overproduction of free radicals). Therefore, milk thistle will aid in the prevention of diabetes since many diabetes related complications are linked to oxidative stress. Please see other sections for the many other benefits of silymarin for diabetes.

Silymarin, a novel antioxidant with anti-glycation and anti-inflammatory properties

In the previous section the ability of silymarin to reduce the effects of non-alcoholic fatty liver disease and subsequient development of diabetes was reviewed. This section reviews the ability of silymarin to reduce the production of advanced glycation end products in diabetes (Wu et al., 2011).

A significant factor associated with hyperglycemia in diabetics is the resultant nonenzymatic glycation of biological proteins (Cohen, 2003Day et al., 1979), with the irreversible formation of advanced glycation end products (AGEs) (Negre-Salvayre, 2009Schiekofer et al., 2003).

This process occurs in vivo through the covalent binding of aldehyde or ketone groups of reducing sugars to free amino groups of proteins. The AGEs have a propensity to generate reactive oxygen species (ROS) (Bonnefont-Rousselot, 2002). In addition, glucose and other aldehydes, whether free or bound to protein, undergo auto-oxidation reactions to yield radicals and other reactive intermediates (e.g., H2O2 and other peroxides), which can also contribute to the formation of AGEs. These latter processes are often termed glycoxidation (Wolff and Dean, 1987).

Acute exposure to hyperglycemia induces reversible oxidative stress and circulating monocyte activation. Guha et al. (2000) and Shanmugam et al. (2003 ab) have suggested that high glucose levels and AGEs can generate large amounts of proinflammatory cytokines, such as tumor necrosis factor-a (TNFa), interleukin-1b (IL-1b), and chemokines, including MCP-1 and IP-10.

These inflammatory responses were found to be related to the modulation of signaling molecules, such as protein kinase C, p47phox, and/or mitogen-activated protein kinases, through oxidant stress-dependent or independent pathways. These pathways, in turn, control the activation of the nuclear factor-kappaB (NF-kB) transcription factor, thereby influencing the synthesis and expression of downstream inflammatory mediators.

Wu et al. (2011), in a study with diabetic rats, reported that silymarin decreased monocytic interleukin-1b and COX-2 levels and prevented oxidant formation caused by S100b, which appeared to be mediated by inhibition of p47phox membrane translocation. S100b is a specific ligand receptor for AGE.

Chromatin immunoprecipitation demonstrated that S100b increased the recruitment of nuclear factor-kappaB transcription factor as well as cAMP response element-binding–binding protein and coactivator-associated arginine methyltransferase-1 cofactors to the interleukin-1b promoter, whereas these changes were inhibited with silymarin.

In vivo, SM reduced tissue AGE accumulation, tail collagen cross linking, and concentrations of plasma glycated albumin. Levels of oxidative and inflammatory biomarkers were also significantly decreased in silymarin treated groups compared with the diabetic group. These data suggest that silymarin supplementation may reduce the burden of AGEs in diabetics and may prevent resulting complications.

This study by Wu et al. (2011) is the first to report silymarin as a promising inhibitor of protein glycation for the prevention of oxidative and inflammatory injury against AGEs in vitro and in vivo, providing evidence to support the health benefits of milk thistle for diabetes prevention. Considering that silymarin behaves similarly to aminoguanide, which was the first inhibitor of AGEs investigated in clinical trials, it has great potential for diabetes prevention.

Hyperlipidaemia, is considered to happen when serum cholesterol and or triglycerides reach levels linked with an increased risk of ischemic heart disease (IHD). For every 1% increase in blood cholesterol levels, there is a 2% increase in the frequency of coronary heart disease, also, for every 1% decrease in high density lipoprotein cholesterol level (HDL–C), there is a 3% increase in coronary heart disease.

Population studies have revealed that total serum cholesterol level increases with age in males and females over the age of 20 year (Hullery et al., 1998). Cholesterol, triglycerides, and other lipids are transported in the body all the way through the blood stream in a spherical particles called lipoproteins which can be divided into (LDL) which accounts for 60 – 70% of total serum cholesterol, and (HDL) constitute 20–30% of total serum cholesterol, and (VLDL) comprising about 10–15% (Schaefer and Levy, 2003). The main two major clinical lipid disorders are acute pancreatitis and atherosclerosis (Ginsberg, 1994).

The hyperlipidaemia description for 60% primary, 40% secondary (Farmes and Gotto, 2005). The most commonly adopted non-pharmacological therapy involves diet and exercise, also omega fatty acid, found in fish oil can induce profound lowering of triglyceride level (Farmes and Gotto, 2005).

A recent clinical study with human was designed to evaluate the effect of 600 mg of Silymarin once per day on the lipid profile of hyperlipidemic patients (Alkuraishy and Alwindy, 2012). The results demonstrated that the sylimarin compared to the placebo considerably reduced the concentration of triglycerides, cholesterol, the low density lipoproteins (LDL) and the very low density of lipoproteins (VLDL) and elevated the concentration of the HDL proteins. The data further suggest that silymarin can beneficially alter the blood lipid levels in human.

Silymarin undergoes excessive enterohepatic circulation, which allows a continuous loop between intestine and liver. It prevents the disturbance of bile secretion, thereby increasing bile secretion, cholate and bilirubin excretion (DerMarderosian, 2001).

Although silymarin does not affect viral replication it has a beneficial role in viral hepatitis by its inhibitory action on inflammatory and cytotoxic processes induced by viral infection. Silibin strongly inhibits growth of both HepG2 (hepatitis B virus negative; p53 intact) and Hep3B (hepatitis B virus positive; p53 matured) cells with relatively more cytotoxicity in Hep3B cells which is associated with apoptosis induction. Silymarin also showed inhibitory activity against other viruses in different cell lines (Das et al., 2008).

El-Shitany et al. (2010) reported the silymarin helped to prevent bone loss in ovariectomized rats by including calcium, phosphorus, osteocalcin and parathyroid hormone. These data suggested that silymarin may be beneficial to women suffering from osteoporosis (bone loss) and that silymarin plus isoflavones may have additional effects.

Beneficial effects of silymarin compared to N-acetyl cysteine for prevention of acetaminophen induced acute liver toxicity: N-acetyl cysteine (commonly used in clinical practice) and silymarin both are known to increase liver glutathione levels. Hau et al. (2010) reported that silymarin greatly reduced morality rates in a model animal, mice, compared to N-acetyl cysteine. They suggested that silymain should be considered as an antidote for patients with acetaminophen acute hepatic injury. The results also suggest that silymarin may be more effective than N-acetyl-cysteine.

Beneficial interaction of silymarin with other s-adenosylmethinone (SAMe): Au et al. (2012) demonstrated for the first time that a combination of SAMe and silybine (SB) inhibited both inflammation and oxidative stress in liver cells through two different mechanisms.

Beneficial effects of silymarin and vitamin E supplementation on oxidative stress in patients on hemodialysis: Hemodialysis results in accelerated atheroscerosis caused by oxidative stress as measured by malondialdehyde (MDA) and altered red blood cell glutathione peroxidase (GPx) activity. Roozbeh et al. (2011) reported that Silymarin (140 mg 3 times/day) alone in combination with vitamin E (100 IU/day) lead to a decrease in plasma MDA levels and an increase in RBC GPx in patients with renal disease. The effect was most pronounced where the two supplements were used in combination. These data suggest that a combination of silymarin and vitamin E therapy may be more effective than vitamin E alone.

What is a hangover

Alcohol hangover comprises the feeling of general misery experienced the day after an evening of excessive alcohol consumption. In humans, a delayed alcohol induced headache (DAIH) is characterized by pain occurring from 4 to 24 hours following ingestion and is not correlated with blood ethanol levels since it returns to zero prior to experiencing a hangover.

In addition migraineurs can experience DAIH with a modest intake of alcohol, whereas, non-migraineurs require larger amounts to produce the effect. The most common characterization of hangover include headache, nausea, sensitivity to light and noise, lethargy, dysphoria, diarrhea and thirst. In addition to the physical symptoms, a hangover may also induce psychological symptoms including a heightened feeling of depression and anxiety.

Prevalence of hangover

Generally, the greater the amount and duration of alcohol consumption, the more prevalent is the hangover, although some people report experiencing a hangover after drinking low levels of alcohol (i.e., one to three alcoholic drinks), and some heavy drinkers do not report experiencing hangovers at all.

A survey in 1993 on the prevalence of hangovers found that approximately 75% of the subjects who drink to intoxication reported experiencing a hangover at least some of the time. In a study of 2,160 Finnish men, researchers found an association between increased weekly alcohol consumption and the frequency of hangover: 43.8% of the group of heaviest drinkers (i.e., study subjects who drank more than 106 g of alcohol per week or approximately 9 drinks) reported experiencing a hangover monthly or more often, compared with 6.6% of the remaining study subjects (cited by Swift and Davidson, 1998).

Similarly, in a study of 1,041 drinkers in New York State, 50% of the subjects who drank two or more drinks per day reported experiencing hangovers previously, whereas subjects who consumed lower levels of alcohol reported fewer hangovers (Smith and Barnes 1983).

Perhaps the most alarming feature of veisalgia (alcohol hangover) is its high prevalence. In a study involving college students, 25% of the students reported experiencing a hangover in the previous week and 29% reported losing school time for hangover recovery. More than 75% of men and women who have consumed alcohol report that they have experienced hangover at least once, and 15% experienced hangover at least monthly (Crofton, 1987).

Ten percent of British men reported hangover-related problems at work at least monthly. Paradoxically, hangover is much more common in light-to-moderate drinkers (70%) (Crofton, 1987) than in heavier drinkers (Single et al., 1998Gunn 1973Pristach et al., 1983). Clearly there is a need to prevent or treat hangover.

Effect of Silymarin (milk thistle) on alcohol metabolism

The ability of silymarin (milk thistle extract) to reduce the severity of alcohol induced diseases has been recently reviewed by several experts (Saller et al., 2001Ball and Kowdley et al., 2005Pradhan and Girish, 2006Saller et al., 2007). These authors draw several conclusions from the existing research. They show that alcohol induces the production of reactive oxygen species (free‐radicals) which cause damage to cellular constituents including lipids, DNA, protein, carbohydrates and biological membranes.

This results in the formation of lipid peroxides; conjugates of DNA, proteins and carbohydrates; depletion of the anti‐oxidants such as vitamin A and C; a decrease in the level of reduced glutathione and an enhanced level of peroxidation products such as malondialdehyde, conjugated diene and ethane.

Silymarin in the numerous studies reviewed by the above scientists has been shown to prevent these effects. Asghar and Masogo (2008) in a landmark paper clearly demonstrated that silymarin was a powerful agent that protected biological systems against oxidative stress such as that induced by alcohol consumption.

A recent publication by Gažák et al. (2009) have demonstrated the mechanism by which silybin, a major component of silymarin, exerts its anti‐radical role. They demonstrated that the 20‐OH of silybin and a synthetic derivative of silybin (2, 3‐dehydrosilybin) were responsible for its interaction with different free‐radicals. They concluded that their findings not only demonstrated the means by which silybin scavenged radicals but that it has improved our understanding on the means by which silybin is able to induce its beneficial effect.

Collectively these studies demonstrate that ethanol consumption induces oxidative stress and that this effect is counteracted by silymarin.

Tamayo and Diamond (2007) reviewed clinical trials conduct from 2002 to 2007 including those involved in pharmacokinetics analysis (7 trials), cancer (4 trials) and liver disease (8 trials). They reported that promising results were obtained in the protective effect of milk thistle in certain types of cancer and livers diseases

It reduced fasting glucose, serum and glycosylated hemoglobin – dependent diabetes. Milk thistle extracts were shown to be safe and well tolerated and toxic effect or adverse effects were minimal. Oral ingestion of milk thistle resulted in some gastrointestinal problems but these were rare. The many overall benefits of milk thistle have been discussed in detailed in the previous sections.

Human studies demonstrate that milk thistle seed extract (silymarin) is safe and well tolerated (Some of the results were discussed in Section 14). It is generally nontoxic and causes no side effects when administered to adults in a dose range of 200-900 mg/day in two or three divided doses.

Higher dose (> 1500 mg/day) could produce minor gastrointestinal disturbances involving a mild laxative effect which may be due to increased bile secretion and flow. Mild allergic reactions (pruritus, urticaria, arthralgia) may be observed, but rarely enough to discontinue. Commonly noted adverse effects such as bloating, dyspepsia, and epigastria pain, flatulence, nausea, irregular stool and laxation are observed in 2-10 % of patients in clinical trial. Headaches and dermatological symptoms are sometimes noted (Bhattacharya, 2011Barceloux, 2008Kumar, 2011).

Silymarin has low toxicity and no mortality or adverse effects at oral doses of 20 g/kg in mice and 1 g/kg in dogs. These intakes would be equivalent to an oral intake by a 70 kg person of 1400 g and 70 g, respectively. This is much higher (2800 to 140-fold) than the Health Canada recommended dose of 0.5 g (500 mg) of 80% silymarin per person per day.

The Safety of Milk Thistle Seed in Pregnancy and Lactation has not been studied in Humans. Traditionally it has been considered safe during lactation, however, no clinical studies have been performed. Safety in children also has not been reported. No other known contraindications have been reported (Barceloux, 2008Bhattacharya, 2011).

No evidence of ante- or postnatal toxicity in animals has been reported. Silymarin at high concentrations has an inhibitory effect on both phase I and phase II hepatic drug metabolizing (biotransformation) cytochrome enzyme systems. However, the plasma concentrations at therapeutic doses are low compared to that needed for the inhibition. It, therefore, essentially exhibits no beneficial or harmful drug interactions at normal doses. (Barceloux, 2008).

Silymarin shows great promise to be a herbal drug. Its good safety profile, quality standardization and control, easy availability and low cost are added advantages. The Health Canada recommended daily intake of milk thistle (80% silymarin) is 2 × 250 mg capsule.

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