Formulated to help support the liver * Scientifically Tested for Safety and Efficacy.

Transcription

1 Detox FORMULA Healthcare Professionals Product Guide Formulated to help support the liver * Scientifically Tested for Safety and Efficacy. This is an educational publication provided to help licensed healthcare professionals understand the science upon which Detox Formula is based and the mechanism of action by which Detox Formula works. This guide should not be used to sell Detox Formula and is intended for healthcare professionals only. The only claims that can be made for Detox Formula are those that have been approved by the Company. A Scientific Product Review COMPREHENSIVE MULTI NUTRIENT SUPPLEMENT FOR LIVER DETOXIFICATION * A Scientific Product Review by Josh Zhu, M.D., Ph.D. and Michael Chang, Ph.D. * These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

2 Detox FORMULA For Liver Detoxification * Summary Pharmanex Detox Formula is a proprietary blend of nutrients to help support the liver the body s detoxifying organ. A proprietary blend of patented D-glucarate, milk thistle extract, N-acetyl-L-cysteine and vitamin C promotes the neutralization and elimination of toxic metabolites and foreign chemicals in the liver. Each of these ingredients has been shown individually to support normal liver health, liver detoxification, bile flow, and glutathione synthesis. Detox Formula provides scientifically supported levels of active ingredients standardized for optimal results. Detox Formula is recommended to be taken on a daily basis and is intended for individuals who desire to provide dietary support for normal liver function. * Liver Detoxification Toxicity is a state of excessive concentration of harmful agents in the body. Your body defends itself from toxicity by detoxifying harmful substances that are made in the body, that invade our environment, or that are found in our diet. The liver performs many important functions including detoxification of blood, carbohydrate and lipid metabolism, protein synthesis, and secretion of bile. The products of digestion that are absorbed into the blood capillaries do not directly enter general circulation. Instead, this blood is first delivered to the liver for metabolism and detoxification. Many of these substances must be detoxified by the liver in order to become inactive and be excreted from the body. These toxic metabolites and foreign chemicals can be produced endogenously as byproducts of normal metabolism, or can be ingested in pharmaceutical drugs, nicotine, industrial and environmental chemicals, food additives or cooking byproducts (nitrates, polycyclic aromatic hydrocarbons), and alcohol. Many of the substances that must be modified by the liver are fat-soluble nonpolar compounds that must be converted into watersoluble compounds to be excreted. Water-soluble derivatives of these toxic metabolites and foreign chemicals are less biologically active and, because of their increased water solubility, are more easily excreted by the kidneys into the urine (Fox SI, 1993). Phase I Detoxification The first phase of detoxification chemically alters the composition of toxic metabolites or foreign chemicals through the cytochrome P450 monooxygenase system. Cytochrome p450 (CYP) enzymes are found in most tissues but are predominantly found in the liver (Guengerich FP, 1988). According to Hardman, humans have 12 genetically determined cytochrome P450 enzyme families, of which three, the CYP1, CYP2, and CYP3 families are involved with most drug transformations (1996). The P450 enzymes are involved in hydroxylation reactions (addition of OH- groups) that result in increased solubility in metabolism and excretion of toxic compounds. In most cases, these compounds are made inactive and are readily excreted, primarily via the kidneys (urine), and also via the gut (bile). However, this process occasionally leads to either formation of the active substance or formation of even more toxic metabolites (Guengerich FP, 1988). Phase II Detoxification Many substances require additional detoxification after phase I to become inactivated and excreted. During phase II detoxification, drugs and toxins are conjugated with (attached to) a polar group via seven different pathways leading to a water-soluble compound that can be excreted. These pathways include conjugation with glutathione, acetate, glucuronic acid, sulfate, or amino acids. Most of these toxins undergo conjugation via glucuronidation (Shils ME, 1999, Hardman JG, 1996). Glucuronidation uses the oxidation of glucuronic acid to generate three metabolites: D-glucaric acid, D-glucaro-6,3-lactone, and D-glucaro-1,4-lactone. These compounds promote the binding and removal of harmful substances during phase II detoxification. As discussed by Walaszek, Detoxification of toxins and foreign substances is not only restricted to the rate of conjugation, but also to the rate of glucuronidation reversal by beta glucuronidase (1990). Beta glucuronidase is an enzyme that has the capacity to prevent or reverse glucuronidation. The role of glucuronidation and beta glucuronidase in the body is very clear in the scientific literature (Walaszek Z, 1990). Once a toxin is conjugated, it can be taken to the kidneys or gut for excretion. Beta glucuronidase is able to reverse the conjugation in the gut, allowing the toxin to be reabsorbed and circulate through the blood stream again. This reversal process can result in re-circulation of toxins and foreign substances in an active form, which must be re-directed through liver detoxification before they can be excreted. 1 * These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

3 Liver Glutathione Glutathione is the liver s most important antioxidant for both phase I and II detoxification pathways. Phase I detoxification enzymes also rely on liver glutathione as a cofactor and can deplete the supply of liver glutathione to the point that there is not enough left for phase II detoxification. It is essential to have enough liver glutathione reserves to enable detoxification of toxic metabolites and foreign chemicals to complete detoxification by phase II enzymes. An adequate supply of glutathione (GSH) is necessary for the formation of glutathione S-transferase (GST), which catalyzes the conjugation of glutathione to water-soluble substances produced from cytochrome p450 activity. These transformed metabolites are rendered less toxic and more soluble for excretion (Casseaud LF, 1979). Common Limiting Factors There are two phases of liver detoxification, as described below. Liver enzyme activity, nutrient availability, and differences in enzyme expression due to genetics, disease, and age can affect liver detoxification. According to Shils (1999), there are large genetic differences in detoxification in individuals, and this is supported by the observed individual differences in metabolism for many drugs. Phase II detoxification may be inhibited by the lack of necessary cofactors or substrates; this lack may often be attributed to the diet. The substrates needed for detoxification include a sufficient energy source, protein, fatty acids, iron, glucose, sulfur-containing amino acids, and glutathione. With aging, decreases in liver blood flow and liver mass contribute to a decline in detoxification capacity with a corresponding increase in circulating active drug levels. The decrease in phase I detoxification is more commonly affected than that in phase II (Shils ME, 1999). Primary Active Constiuents Detox Formula provides a proprietary blend of calcium D-glucarate, milk thistle extract, N-acetyl-L-cysteine and vitamin C. Calcium D-glucarate provides glucaric acid in a salt form chemically bound to calcium. Glucaric acid is a compound produced endogenously in humans and is found in highest concentrations in grapefruit, apples, oranges, and cruciferous vegetables (Walaszek Z, 1997). Calcium D-glucarate has been shown to be converted to and provide a sustained release of D-glucaro-1,4 lactone (Wattenberg LW, 1992, Walaszek Z, 1997). * Milk thistle fruit consists of ripe seed of Silybum marianum (L.) Gaertner [Fam. Asteraceae]. Milk thistle seeds contain a variety of chemical components that contribute to its liver protective activity, including flavonoids, flavonolignans, and others. Milk thistle seeds contain flavonoids such as dehydrokaempferol, quercetin, and taxifolin (Hobbs C, 1984, Morazzoni P, 1995); however, the primary active constituents of milk thistle are the flavonolignans, also known as silymarin, which is an entire group of active principles found only in the seeds of milk thistle. Silymarin consists of three isomers, named silybin, silydianin, and silychristin (Wagner H, 1974, Tittel G, 1997). Detox Formula provides a 30:1 milk thistle extract standardized to 80% silymarin. * N-acetyl-L-cysteine (NAC) is a specially modified form of the dietary amino acid cysteine. When taken orally, N- acetyl-l-cysteine is converted into the amino acids L-cysteine and glutathione. Detox Formula also provides vitamin C as calcium ascorbate, a well-tolerated and bioavailable form of buffered vitamin C. Vitamin C has also been shown to promote glutathione levels in the liver * (Nakano H, 1995). Health Benefits Detox Formula is a proprietary blend of nutrients to help support the liver and liver detoxification by supporting both phases of liver detoxification for comprehensive protection from harmful toxins. The ingredients in Detox Formula also protect and maintain healthy liver cells, stimulate the normal growth of healthy liver cells, promote liver glutathione synthesis, and stimulate normal bile flow. These mechanisms of action address various aspects of liver health, and are described below whenever appropriate. * Calcium D-Glucarate Calcium D-glucarate supports the liver s phase II detoxification system by providing a dietary substrate for production of D-glucaro-1,4 lactone. Calcium D-glucarate (as D-glucaro-1,4 lactone) is able to bind to beta glucuronidase, which inhibits the enzyme from binding to the toxins, allowing the conjugated toxin to be excreted from the body (Wattenberg LW, 1992). A review published in the August 2002 issue of Alternative Medicine Review discusses research demonstrating that short and long-term supplementation in animals with calcium D-glucarate can inhibit as much as 70 percent of beta glucuronidase s activity (Altern Med Rev, 2002, Dwivedi C, 1990). D-glucarate metabolites have been identified and shown to inhibit beta glucuronidase s activity in key organs such as the liver, gastrointestinal tract (small & large intestines, microflora), lungs, * These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. 2

4 and the blood (Dwivedi C, 1990). In another study, Walaszek identified that calcium D-glucarate has been shown to be absorbed and utilized by the body and is held in the liver and gastrointestinal tract three to four times higher than the blood (Walaszek Z, 1997). Calcium D-glucarate has been studied for over 30 years and has been used in animal and in-vitro studies to show significant effects against toxic metabolites and foreign chemicals, including polycyclic aromatic hydrocarbons, aromatic and heterocyclic amines, nitrates, steroid hormones, and fungus (Dutton GJ, 1980, Dwivedi C, 1990, Walaszek Z, 1990, Walaszek Z, 1997, Anonymous, 2002, Walaszek Z, 1988, Walaszek Z, 1986, Walaszek Z, 1990). Over 20 animal studies have been performed showing that calcium D-glucarate s powerful action protects normal cell growth and replication in the presence of these toxic metabolites and foreign chemicals (Oredipe OA, 1992, Walaszek Z, 1990, Abou-Issa H, 1998, Walaszek Z, 1986, Walaszek Z, 1988). Milk Thistle Milk thistle naturally contains the antioxidant silymarin, which helps support the liver by helping to counter the effects of pollutants, alcohol, pesticides and other toxins from our environment, diet and lifestyles. The therapeutic activity of milk thistle in liver detoxification can be attributed to multiple mechanisms of action. Key constituents in milk thistle, including silymarin, may enhance the activity of liver enzymes involved in phase I detoxification and boost liver antioxidant glutathione levels (Valenzuela A, 1985). In addition, milk thistle may also promote the stimulation of normal bile flow the liver s second line of defense against toxic chemicals. Bile manufactured by the liver acts as a carrier to effectively eliminate toxins from the body, so when bile production is inhibited, this can lead to increased retention of toxic substances (Lawrence Review, 1998). A number of studies suggest that it is the antioxidant characteristics of the silymarin-flavonolignan complex that are primarily responsible for liver-protecting activity (Lawrence Review, 1985, Valenzuela A, 1989, Werback M, 1994, Bindoli A, 1977, Carallini L, 1978, Valenzuela A, 1986, Muzes G, 1991, Locher R, 1998). Milk thistle can alter and stabilize the structure of the outer cell membrane of the hepatocytes in such a way as to prevent penetration of a toxin, and can stimulate the regenerative ability of the liver and the formation of new hepatocytes (Blumenthal M, 2000, McPartland, 1996). Several reviews of double-blind studies discuss results showing the therapeutic benefits of milk thistle silymarin in protecting the liver from toxic agents (Carallini L, 1978, Feher J, 1989, Feher J, 1990, Ferenci P, 1989, Hikino H, 1988, Bone K, 1996, Morazzoni P, 1995). Liver toxicity induced by toxic agents produce free radicals and lipid peroxidation and silymarin has been shown to fight against lipid peroxidation in liver microsomes (Bosiso E, 1992). Several studies suggest that milk thistle provides liver protective effects against hepatotoxic agents, including pharmaceutical drugs and alcohol (Hahn G, 1968, Bone K, 1996, Davila J, 1989, Fintelmann V, 1980, Grungreiff K, 1995, Kurz-Dimitrova D, 1971, Szilard S, 1988). It was shown that milk thistle could also counter metabolic changes in cases of altered hepatic functions affecting the bioavailability of aspirin (Mourelle M, 1988). An in vitro study also suggested that milk thistle has cytoprotective activity against toxicity induced by acetaminophen (Shear N, 1995). In a double-blind, placebo controlled trial, biochemical parameters for hepatic function returned to normal much sooner in the milk thistle control group compared to those given a placebo (Fintelmann V, 1980). Results of a number of investigations have shown that milk thistle may improve liver function in alcoholic patients without adverse side effects and counter alcohol-induced liver damage when administered prior to alcohol consumption (Der Marderosian A, 1988, Desplaces A, 1975, DiMario ER, 1981, Fantozzi R, 1986). Lastly, research over the past four decades in Europe has confirmed repeatedly the effectiveness of milk thistle in treating a wide array of liver conditions, with extracts of the seed being shown to protect liver cells from damage stemming from chronic and acute hepatitis (Lawrence Review, 1985, Bode JC, 1977, Foster S, 1996). N-Acetyl-L-Cysteine N-acetyl-L-cysteine boosts liver glutathione levels for both phase I enzyme activity and phase II glutathione conjugations. N-acetyl-L-cysteine is an excellent source of sulfhydryl groups and is converted in the body into metabolites capable of stimulating glutathione synthesis, promoting detoxification and acting directly as a free radical scavenger. Studies have provided evidence that multiple mechanisms contribute to N-acetyl-L-cysteine s role in liver detoxification and liver protection. These include detoxification of reactive compounds due to the antioxidant and nucleophilic properties and replenishment of liver glutathione stores (De Flora S, 1995). N-acetyl-L-cysteine and vitamin C administration have been shown to improve levels of phase I detoxification enzymes, including total CYP content (+35%) and 3 * These statements have not been evaluated by the Food and Drug Administration. This product is is not intended to to diagnose, treat, cure or or prevent any disease.

5 CYP3A content (+100%), in animal studies (Clarke J, 1996, Berg-Candolfi M, 1996). Results from animal studies suggest that N-acetyl-L-cysteine enhances concentrations of L-cysteine within hepatocytes providing a substrate for gone synthesis (Nakano H, 1995, Sener G, 2003). In an eight-week double blind, placebo-controlled trial, blood glutathione levels significantly increased after N-acetyl-L-cysteine administration in HIV patients. These findings suggests that N-acetyl-L-cysteine therapy could be valuable for other clinical situations in which glutathione deficiency or oxidative stress play a role in disease pathology including hepatitis, rheumatoid arthritis, liver cirrhosis, diabetes, Parkinson s disease and septic shock (De Rosa SC, 2000). Interestingly, acetaminophen poisoning causes liver damage by depleting liver glutathione; a high dose treatment course (i.e. 20 grams) of N-acetyl-L-cysteine is currently the mainstay as an acetaminophen antidote (Kelly GS, 1998). Vitamin C Vitamin C is also involved in glutathione synthesis and has also been shown to boost liver glutathione levels for phase I enzyme activity and phase II glutathione conjugations. A study by Das et al, found that administration of vitamin C in animals resulted in a remarkable improvement of glutathione, lipid peroxide, superoxide dismutase, glutathione peroxidase, and catalase (Das KK, 2001). The total liver content of P-450 enzymes has been shown to correlate with the excretion of D-glucaric acid in the urine, and is a method for evaluation of the liver s functional reserve (Hanaue H, 1993). A clinical trial found that after vitamin C administration (1 g), the excretion of urinary D-glucaric acid was significantly lower, suggesting vitamin C-induced activation by P-450 enzymes. Proprietary Processing Manufacturing standards are strictly followed to ensure the creation of natural supplements with pharmaceutical-like quality. Detox Formula provides standardized ingredients with known content and uniform consistency. All ingredients are tested for purity, and where applicable, ingredients are certified pure by microbial testing, such as tests for Salmonella, E. coli, other coliforms, Staphylococcus aureus, total plate counts, yeasts, molds and pesticide residues. Our manufacturers go through a detailed selection and certification process to assure their compliance with Good Manufacturing Practice (GMP) standards set by the Food and Drug Administration (FDA). Side Effects Detox Formula has no side effects when used as recommended. However, a mild laxative effect has been observed in occasional instances with milk thistle administration (Blumenthal M, 1998). Safety and Toxicity Detox Formula is safe when used as recommended. Calcium D-glucarate has been shown to be safe for human consumption (Walazsek Z, 1990, Heerdt AS, 1995). Studies have shown that there is no toxicity with levels of calcium D-glucarate at doses up to 10 grams per day (Slaga T, 1999). Milk thistle has been used as a food for centuries (Foster S, 1996), and in both human and animal studies, seed extracts have been shown to be devoid of significant adverse side effects (Lawrence Review, 1985, Der Marderosian A, 1988, Foster S, 1996). Long-term clinical trials on humans have not generated any evidence of toxicity or teratogenic effects (Bone K, 1996, Foster S, 1996). Administration of N-acetyl-L-cysteine at 1600 mg/day has been shown to be safe and nontoxic. The major toxicities reported were bad taste and gastrointestinal disturbances (Pendyala L, 1995). The Tolerable Upper Intake Level (UL) for adults with vitamin C is set at 2g/day; the adverse effects upon which the UL is based are osmotic diarrhea and gastrointestinal disturbances (NAS, 2000). Considerable evidence from clinical trials has revealed no pattern of adverse effects with intakes up to 10 grams/day over several months. The evidence of adverse effects of vitamin C is so nebulous that no Lower Observed Adverse Effects Level (LOAEL) can be established. The No Observed Adverse Effects Level (NOAEL) has been set at more than 1000 mg (Hathcock, 1997). Contraindications and Drug Interactions If you are allergic to any component of this product, pregnant or nursing, have a medical condition, or are taking a prescription medication, please consult a physician. The ingredients in Detox Formula have been shown to promote liver detoxification, which may affect the metabolism of prescription medicines in some people. Individuals with active liver disease should consult with their physician before taking Detox Formula. * These statements have not been evaluated by the Food and Drug Administration. This product is is not intended to to diagnose, treat, cure or or prevent any disease. 4

6 Directions for Use Detox Formula is intended for individuals who desire to provide dietary support for normal liver function. * Take one (1) capsule with liquids with your morning and evening meals. Take consistently for best results. How Supplied Pharmanex Detox Formula contains a one-month supply of 60 capsules. Each capsule provides 125 mg D-glucarate, 70 mg silymarin (from milk thistle extract), 125 mg N-acetyl-L-cysteine, and 150 mg vitamin C. Storage Store in a cool, dry place. Avoid excessive heat. Protect from light. Shelf Life Expiration date and lot code numbers are stamped on the side of the bottle. Warnings Keep out of reach of children. If you are pregnant or nursing, or taking a prescription medication, consult a physician before using this product. References 1. Anonymous. Artichoke extract: Improves digestion, liver function, and cholesterol levels. Natural Medicine Journal 1998;1: Anonymous. The milk thistles. Lawrence Review of Natural Products 1985;6(January): Berg-Candolfi M, Candolfi E, Benet LZ. Suppression of intestinal and hepatic cytochrome P4503A in murine Toxoplasma infection. Effects of N-acetylcysteine and N(G)-monomethyl-L-arginine on the hepatic suppression. Xenobiotica 1996;26: Bindoli A, Cavallini L, Siliprandi N. Inhibitory action of silymarin of lipid peroxide formation in rat liver mitochondria and microsomes. Biochemical Pharmacology 1977;26: Blumenthal M, Busse WR, Goldberg A, et al (eds). The Complete German Commission E Monographs. Austin, TX:American Botanical Council 1998, pp , Blumenthal M, Golberg A, Brinckmann. Herbal Medicine: Expanded Commission E Monographs. Integrative Medicine Communications, Boston Bode JC, Schmidt V, Durr HK. Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial. Medizinische Klinik 1977;72: Bone K. Silybum marianum. MediHerb 1996;2: Bosisio E, Benelli C, Pirola O. Effect of the flavanolignans of Silybum marianum L on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes Pharmacological Research 1992;25: Cavallini L, Bindoli A, Siliprandi N. Comparative evaluation of antiperoxidative action of silymarin and other flavonoids. Pharmacological Research Communications 1978;10: Chasseaud LF. Adv Cancer Res 1979;29: Clarke J, Snelling J, Ioannides C, Flatt PR, Barnett CR. Effect of vitamin C supplementation on hepatic cytochrome P450 mixed-function oxidase activity in streptozotocin-diabetic rats. Toxicol Lett. 1996;89: Das KK, Das SN, DasGupta S. The influence of ascorbic acid on nickel-induced hepatic lipid peroxidation in rats. J Basic Clin Physiol Pharmacol 2001;12: Davila J, Leuhern A, Acosta D. Protective effect of flavonoids on drug-induced hepatotoxicity in vitro. Toxicology 1989;57: De Flora S, Cesarone CF, Balansky RM et al. Chemopreventive properties and mechanisms of N-acetylcysteine. The experimental background. J Cell Biochem 1995;58 Suppl. 22: De Rosa SC, Zaretsky MD, Dubs JG et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest 2000;30: Der Marderosian A, Liberti L. Natural Product Medicine: A scientific guide to foods, drugs, cosmetics. Philadelphia, PA:George F Stickley Co., Desplaces A, Choppin J, Vogel G, et al. The effects of silymarin on experimental phaloidine poisoning. Arzneimittelforshung/Drug Research 1975;25: DiMario ER, Farni L, Okolicsanyi L, et al. The effects of silymarin on the liver function parameters of patients with alcohol-induced liver diseases:a double-blind study, in: de Ritis E, Csomos G, Braatz R, eds. Der Toxisch-Metabolisliche Leberschaden Hans. Lubeck:Verl-Kontor, Dutton GJ. Glucuronidation of drugs and other compounds. Boca Raton, FL: CRC Press, Dwivedi C, Heck WJ, Downie AA, et al. Effect of calcium glucarate on beta-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metab Biol 1990;43(2): Fantozzi R, Brunelleschi S, Rubino A, et al. FLMP-activated neutrophils evoke histamine release from mast cells. Agents and Actions 1986;18: * These * These statements have not not been evaluated by the Food and Drug Administration.This product product is not is intended not intended to diagnose, to diagnose, treat, cure treat, or cure prevent or prevent any disease. any disease.

7 23. Feher J, Deak G, Muzes G, et al. Hepatoprotective activity of silymarin (Legalon ) therapy in patients with chronic alcoholic liver disease. Orvosi Hetilap 1989;130: Feher J, Lang I, Nekam K, et al. In vivo effect of free radical scavenger hepatoprotective agents on superoxide dismutase (SOD) activity in patients. Tokai Journal of Experimental and Clinical Medicine 1990;15: Ferenci P, Dragosics B, Dittroch H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. Journal of Hepatology 1989;9: Fintelmann V and Albert A. The therapeutic activity of Legalon in toxic hepatic disorders demonstrated in a double-blind trial. Therapiewoche 1980;30: Fox SI. Human Physiology. 4th ed. Dubuque, IA: Wm. C. Brown Publishers, Grungreiff K, Albrecht M, Strenge-Hesse A. The value of drug therapy for liver disease in general practice. Medizinische Welt 1995;46: Guengerich FP. Cancer Res 1988;48: Hahn G, Lehmann H, Kurten M, et al. On the pharmacology and toxicology of silymarin, an antihepatotoxic active principle from Silybum marianum (L.) Gaerti. Arzneimittelforschung/Drug Research 1968;18: Hanaue H, Kanno K, Mukai M et al. Estimation of the functional reserve of the human liver by urinary D-glucaric acid excretion after vitamin C administration. Tokai J Exp Clin Med 1993;18: Hardman JG, Limbird LE, eds. Goodman and Gilman s The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw Hill, Hathcock JN. Vitamin and Mineral Safety. Vitamin C. Council for Responsible Nutrition: Washington, DC, 1997, pp Heerdt AS, et al. Calcium D-glucarate as a chemopreventive agent in breast cancer. Isr J Med Sci 1995;31: Hikino H, Kiso Y. Natural products for liver disease. In:Wagner H, Hikino H, Fansworth NR (eds). Economic and Medicinal Plant Research, 2. London, England:Academic Press, Hobbs C. Milk Thistle: The Liver Herb. 2nd edition. Capitola, CA:Botanica Press, Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev 1998;3: Kurz-Dimitrova D. Hepatoprotective treatment for neuropsychiatric patients receiving long-term therapy with psychotropic drugs. Zeitschrift fur Praklinische Geriatri 1971;9: Locher R, Suter PM, Weyhenmeyer R, Vetter W. Inhibitory action of silibinin on low density lipoprotein oxidation. Arzneimittelforschung/Drug Research 1998;48(3): McPartland, J.M Viral hepatitis treated with Phyllanthus amarus and milk thistle (Silybum marianum): a case report. Complementary Medicine International 1996;3(2): Milk Thistle Silybum marianum. In: Foster S, ed. Herbs for Your Health. Loveland, CO: Interweave Press 1996: Morazzoni P and Bombardelli E. Silybum marianum (Carduus marianus). Fitoterapia 1995;66: Mourelle M, Favari L. Silymarin improves metabolism and disposition of aspirin in cirrhotic rats. Life Sciences 1988;43: Muzes G, Deak G, Lang I, et al. Effect of the bioflavonoid silymarin on the in vitro activity and expression of superoxide dismutase (SOD) enzyme. Acta Physiologica Hungarica 1991;78: Nakano H, Boudjema K, Alexandre E et al. Protective effects of N-acetylcysteine on hypothermic ischemia-reperfusion injury of rat liver. Hepatology 1995;22: National Academy of Sciences. Chapter 5 Vitamin C. In: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. A Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Food and Nutrition Board, Institute of Medicine. National Academy Press:Washington, DC, 2000, pp No Authors Listed. Calcium-D-glucarate. Altern Med Rev 2002;7(4): Oredipe OA, et al. Dietary D-glucarate mediated inhibition of initiation of diethylnitrosamine-induced hepatocarcinogenesis. Toxicity 1992;74(2-3): Pendyala L, Creaven PJ. Pharmacokinetic and pharmacodynamic studies of N-acetylcysteine, a potential chemopreventive agent during a phase I trial. Cancer Epidemiol Biomarkers Prev 1995;4: Salmi, H.A. and S. Sarna Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17(4): Sener G, et a,. Melatonin and N-acetyl aysteine have beneficial effects during hepatic ishemia and reperfusion. Life Sci 2003;72: * These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

8 52. Shear N, Malkiewica I, Klein D, et al. Acetominopheninduced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacology 1995;8: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Lippincott Williams & Wilkins, Slaga T, Quilici-Timmcke J. Calcium D-Glucarate, A Nutrient Against Cancer. Keats Publishing, Los Angeles, CA Szilard S, Szentgyorgi D, Demeter D. Protective effect of Legalon in workers exposed to organic solvents. Acta Medica Hungarica 1988;45: Tittel G and Wagner H. High performance liquid chromatographic seperation of silymarins and their determination in a raw extract of Silybum marianum. Gaertn Journal of Chromatography 1977;135: Valenzuela A and Guerra R. Differential effect of silybin on the Fe2+-ADP and t-butyl hydroperoxide-induced microsomal lipid peroxidation. Experientia 1986;42: Valenzuela A, Aspillaga M, Vial S, et al. Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Medica 1989;55: Valenzuela A, Guerra R, Videla I. Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3:comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Medica 1986;49: Valenzuela A, Lagos C, Schmidt K, et al. Silymarin protection against hepatic lipid peroxidation induced by acute ethanol intoxication in the rat. Biochemical Pharmacology 1985;34: Wagner H, Diesel P, Seitz M. The chemistry and analysis of silymarin from Silybum marianum Gaeertn. Arzneimittelforschung/Drug Research 1974;24: Walaszek Z, Flores E, Adams AK. Effect of dietary glucarate on estrogen receptors and growth of 7-12-dimethylbenz[a]anthracene-induced rat mammary carcinomas. Breast Cancer Res 1988;12: Walaszek Z, Hanausek-Walaszek M, Minton JP, Webb TE. Dietary glucarate as anti-promoter of 7,12- dimethylbenz[a]anthracene-induced mammary tumorigenesis. Carcinogenesis 1986;7: Walaszek Z, Hanausek-Walaszek M, Webb TE. Repression by sustained-release beta-glucuronidase inhibitors of chemical carcinogen-mediated induction of a marker oncofetal protein in rodents. J Toxicol Environ Health 1988;23: Walaszek Z, Szemraj J, Narog M, et al. Metabolism, uptake, and excretion of D-glucaric acid salt and its potential use in cancer prevention. Canc Detect Prevent 1997;21(2): Walaszek Z. Antiproliferative effect of dietary glucarate on the Sprague-Dawley rat mammary gland. Cancer Lett 1990;49: Walaszek Z. Potential use of D-glucaric acid derivatives in cancer prevention. Canc Let 1990;54: Wattenberg LW. Inhibition of carcinogenesis by minor dietary constituents. Cancer Research 1992;52: Werback M and Murray M. Botanical Influences on Illness: A Sourcebook of Clinical Research. Tarzana, CA:Third Line Press, * These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

9 The Pharmanex 6S Quality Process Central to the Pharmanex mission of transforming time-honored, traditional preparations into health promoting botanical products with known content and consistent activity is the Pharmanex 6S Quality Process. Selection Sourcing Structure Standardization Safety Substantiation Exhaustive scientific review of research and databases is conducted. Authenticity, usefulness, and safety standards are determined. Teams of experts investigate potential sources and evaluate quality. Comprehensive botanical and chemical evaluations are completed. Structural analyses of natural compounds are determined. Active ingredients are isolated and studied. Strict standardization to at least one relevant marker molecule is required. Proprietary processing methods to increase consistency and ensure measured dose effectiveness are developed. Safety is assessed from available research. Microbial test, chemical, toxin, and heavy metal analyses are conducted. Documented pre-clinical and clinical studies are reviewed. Pharmanex sponsored studies are initiated when appropriate. For More Information: To learn more about the Pharmanex line of natural healthcare products, please call Product Support Visit our website and access information directly at Pharmanex. All Rights Reserved. 75 West Center Provo, Utah Tel: Fax: