Dietary Supplements Defined Dietary Supplement Research Facts And

Introduction to Dietary Supplements

Since 1994, many non-traditional food components have been launched under the Dietary Supplements Health Education Act (DSHEA). Some of these include fish oil (a source of omega-3 fatty acids), glucosamine and chondroitin for joint health, and s-adenosylmethionine (SAMe) for depression, osteoarthritis and some liver diseases. Dietary Supplements Defined

The DSHEA determined that dietary supplements would be defined by the following criteria:

1. A dietary supplement is "any product (except tobacco) that contains at least one of the following: (1) a vitamin, (2) a mineral, (3) an herb or botanical, (4) an amino acid, (5) a dietary substance for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combinations of these ingredients."

2. A dietary supplement is "intended for ingestion in pill, capsule, tablet or liquid form."

3. A dietary supplement is "not represented for use as a conventional food or as the sole item of a meal or diet."

4. A dietary supplement is "labeled as a 'dietary supplement'."

5. A dietary supplement "includes products such as an approved new drug, certified antibiotic, or licensed biologic that was marketed as a dietary supplement food before approval, certification, or license (unless the Secretary of Health and Human Services waives this provision)."

Dietary Supplement Research

Research on dietary supplements is growing each year, providing healthcare professionals with evidence of both safety and efficacy.

For example, the U.S. Health and Human Services Department reported that SAMe is as effective as standard therapy for depression and osteoarthritis (HHS Hand Report 2002).

In addition, strong evidence exists that omega-3 fatty acids may reduce the risk of cardiovascular disease (JAMA 2002; 287 (14):1815-1821; N Engl J Med. 2002; 346(15):1113-1118). The FDA has approved qualified health claims for fish oil, fiber, and soy protein for heart health.

Because research on dietary supplements is dynamic, it is important to periodically review updates to text and references for guidelines on use and new applications. Facts and Functions

In the Vitamin Herb University website we provide facts and functions of various dietary supplements, their recommended dosages and toxicity levels, possible herb drug supplement interaction, and summarize current dietary supplements research. Dietary Acidophilus Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin Facts Back to sub-topics -Coenzyme Q10 -Conjugated Linoleic Acid • Lactobacillus acidophilus is one of the bacterial species that produce lactic acid in the -Fiber digestive tract. • The human digestive system contains more than 400 different bacterial species. The -Fish Oil number of bacteria has been estimated to be approximately 1014. -Flaxseed Oil • The prevalent bacteria in the human adult digestive tract include bacteroides, -Glucosamine eubacteria, peptostreptococci, bifidobacteria, enterobacteria, streptococci, lactobaccili, -Kelp clostridia and staphylococci. -L-Arginine • Lactobacilli are commercially available in yogurt, fermented milk, capsule and powder forms. -Lecithin -L-Lysine -Lycopene Functions Back to sub-topics -Melatonin -Methylsulfonylmethane L. acidophilus has been suggested to: • Improve intestinal motility and relieve constipation -Pantethine • Enhance immune function -Phytonutrients • Improve digestibility and increase availability of dietary nutrients -Plant Sterols/Stanols • Alleviate lactose intolerance -S-adenosyl-L-methionine • Reduce risk of cancer development -Soy Isoflavones • Decrease allergic response by improving mucosal barrier function • Speed recovery from diarrhea caused by antibiotics or pathogens -Vinpocetine • Block adhesion of pathogens to digestive tract

Dosage Back to sub-topics About 10 9 to 10 10 live bacteria daily are required from various sources (tablet, yogurt, etc.) to promote intestinal health or prevent antibiotic-associated diarrhea.

Toxicity Back to sub-topics Not known.

Dietary Sources Back to sub-topics Lactobacillus acidophilus and other Lactobacilli are available commercially as freeze-dried powders and capsules and in yogurts and fermented milk products.

Drug-Supplement Interaction Back to sub-topics 1 2 3

• Lactobacillus acidophilus and related species are known as "friendly" bacteria that help reduce common side effects (i.e. diarrhea) of antibiotic therapy. Taking acidophilus-containing products may be recommended during and after antibiotic therapy. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship. Research Summary Back to sub-topics

References Back to sub-topics 1 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society of GK: Information. Health-System Pharmacists. 2001; 3 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 4 Effect of bifidobacterium bifidum and Immunopharm Immunotox DeSimone lactobacillus acidophilus on gut mucosa and 14:331-340. C, et al: peripheral blood B lymphocytes. 5 Adherence of probiotic bacteria to human Clin Diag Lab Immun 8:293-296. Juntunen intestinal mucus in healthy infants and M, et al: during rotavirus infection. 6 Michetti Effect of whey-based culture supernatant of Digestion 60:203-209. P, et al: lactobacillus acidophilus (johnsonii) La1 on helicobacter pylori infection in humans. 7 Rao CV, Prevention of colonic preneoplastic lesions Int J Onc 14:939-944. et al: by the probiotic lactobacillus acidophilus NCFMTM in F344 rats. 8 Biomodulation of the toxic and nutritional Mine Electrolyte Metab 22:92-96. Simenhoff effects of small bowl bacterial overgrowth in ML, et al: end-stage kidney disease using freeze-dried lactobacillus acidophilus. 9 Sazawal Efficacy of probiotics in prevention of acute Lancet Infect Dis 2006 6:374-382 S, et al diarrhoea: a masked, randomized, placebo-controlled trials. 10 Ishida Clinical effects of Lactobacillus acidophilus J Dairy Sci 2005 88: 527-533 Y, et al strain L-92 on perennial allergic rhinitis: a double-blind, placebo-controlled study. 11 Gluck U Ingested probiotics reduce nasal Am J Clin Nutr 2003 77: 517-520 and colonization with pathogenic bacteria Gebbers (Staphylococcus aureus, Streptococcus JO pneumoniae, and beta-hemolytic Streptococci) 12 Ishida Effect of milk fermented with Lactobacillus Biosci Biotechnol Biochem 2005 Y, et al acidophilus strain L-92 on symptoms of 69:1652-1660 Japanese cedar pollen allergy: a randomized placebo-controlled trial 13 Chen Nonsurgical management of partial adhesive CMAJ 2005 173:1165-1169 SC, et al small-bowel obstruction with oral therapy: a randomized controlled trial 14 Lieske Use of a probiotic to decrease enteric Kidney Int 2005 68:1244-1249 JC, et al hyperoxaluria. Dietary Alpha Lipoic Acid Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Lipoic acid is a water- and fat-soluble antioxidant. -Fish Oil • Dihyrolipoic acid (DHLA), reduced lipoic acid, has more antioxidant activity than lipoic -Flaxseed Oil acid. -Glucosamine • Lipoic acid is found in mitochondria and plays a role in energy production. • Lipoic acid acts as a cofactor in oxidative decarboxylation. -Kelp • Lipoic acid is bound to proteins and free lipoic acid has not been found in humans. -L-Arginine • -Lecithin -L-Lysine Lipoic acid has been used in Germany for several decades for the treatment of acute -Lycopene painful diabetic neuropathy. -Melatonin -Methylsulfonylmethane -Pantethine -Phytonutrients Functions Back to sub-topics -Plant Sterols/Stanols -S-adenosyl-L-methionine • Alpha-lipoic acid (ALA) is an antioxidant formed in the body. Alpha-lipoic acid and its -Soy Isoflavones reduced form, dihydrolipoic acid, may quench various reactive oxygen species. (i.e. -Vinpocetine hydroxyl radicals, hypochlorous acid, peroxynitrite and singlet oxygen). • As a chelator, lipoic acid can trap metals in the blood circulation, thus preventing cellular damage. • Lipoic acid may enter nerve tissue and prevent glucose-related oxidative damage. •

Reduced glutathione, a major cellular antioxidant, can be regenerated by alpha lipoic acid in concert with other antioxidants. 10

•

Dehydroascorbate, reduced vitamin C, can be recycled into ascorbate, vitamin C, by dihydroxylipoic acid. Alpha-lipoic acid may indirectly participate in the regeneration of vitamin E.

•

Alpha-lipoic acid has a role in enhancing energy production (ATP synthesis).

•

Alpha-lipoic acid is a cofactor of a-keto-dehydrogenase. Dosage Back to sub-topics Six hundred to 1200 mg of ALA has been shown to be well-tolerated in treating patients with diseases such as diabetes and Alzheimers disease.

Toxicity Back to sub-topics Not known.

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

Although it has not been supported by animal studies, ALA increases the antioxidant effects of vitamins C and E, and of glutathione (peptide containing amino acids, functioning as a coenzyme in oxidation-reduction reactions) and supports the detoxifying abilities of the liver.

Research Summary Back to sub-topics Diabetes and Oxidative Stress: In diabetes mellitus, enhanced reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and a decrease in antioxidant capacity occurs and is thought to play a key role in the pathogenesis of late diabetic complications.

• A 2002 review reported that hyperglycemia and elevated free fatty acids (FFA) caused by type 2 diabetes and other states of insulin resistance (obesity), results in the generation of ROS and RNS. Enhanced ROS and RNS production activates stress-signaling pathways leading to cellular damage, insulin resistance, and ultimately long-term complications of diabetes. Alpha lipoic acids antioxidant properties have been shown to reduce oxidative stress-activated signaling pathways in vitro and in patients with type 2 diabetes. The use of ALA and other antioxidants may be important in preventing activation of these stress-signaling pathways. 10

Diabetes: Nephropathy

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In a prospective open and non-randomized study, the effect of ALA on renal endothelial damage and nephropathy was examined in 84 diabetic patients for 18 months. The progression of renal endothelial cell damage and nephropathy were evaluated by thrombomodulation and urinary albumin concentration. Patients received either a placebo or 600 mg of ALA per day. Treatment with ALA decreased thrombomodulation significantly, but did not change urinary albumin concentrations. However, urinary albumin concentration significantly increased in patients without ALA. This result indicates that ALA may inhibit progression of renal endothelial cell damage by oxidative stress in diabetic patients. 5

Diabetes: GlucoseUptake:ALA increases glucose uptake through recruitment of the glucose transporter-4 to plasma membranes, a mechanism that is shared with insulin-stimulated glucose uptake. It has been demonstrated that ALA improves glucose disposal in patients with type 2 diabetes. 15

• The effect of LA supplementation (600 mg, twice a day) on glucose metabolism was studied in lean and obese patients with type 2 diabetes. Four-week treatment increased glucose effectiveness, which is a dominant factor regulating glucose uptake in diabetic patients. Higher insulin sensitivity and lower fasting blood glucose concentrations were observed only in lean subjects. Supplementation with ALA reduced fasting blood pyruvate and lactate and prevented increases in pyruvate and lactate after glucose loading, indicating that ALA may improve glucose utilization. 4

Diabetes: Neuropathy: Past animal data show that ALA corrects energy metabolism in diabetes neural tissue, possibly by improving glucose uptake. This suggests that while ALA may not have a direct antioxidant effect on neural tissue it may be effective by other mechanisms. 11

•

In a randomized, double-blind, placebo-controlled multicenter trial, 800 mg of ALA was administered to patients with type 2 diabetes to assess the effect of ALA on cardiac autonomic neuropathy. After 4 months of treatment, the authors concluded that oral doses of 800 mg daily slightly improved cardiac autonomic neuropathy. 6

•

Another study on 509 patients with type 2 diabetes, treatment with 600 mg of ALA intravenously for 3 weeks, followed by 600 mg 3 times a day orally for 6 months, did not effect neuropathic symptoms. 7

• In a 2002 review, van Dam summarized studies on ALA and neuropathy published in the mid-to-late 1990s. ALADIN, in 1995, reported reductions of neuropathic symptoms (when compared to placebo) following 3 weeks of IV administration with similar effects of oral treatment reported in another study. 11 12 In 1999 a 2-year placebo-controlled study administered ALA orally (1200 or 600 mg/day) to patients with diabetes and polyneuropathy. Results showed significant improvements in sural and tibial nerve conduction velocities. 11 13 Ziegler and colleagues, in 1999, revealed limited beneficial results of ALA on neuropathic signs and symptoms after IV treatment followed by 6 months oral intake (1800 mg/day.) 11 14 Van Dam concludes that the limited number of clinical studies using antioxidants in persons with diabetes and neuropathic symptoms is tempting. He also concludes that substantial evidence for such an approach is lacking, although the current data are promising and results from additional studies will be available soon. 11 •

Haak and colleagues (2000) administered 1200 mg ALA orally to 8 patients with both type I and type II diabetes and peripheral neuropathy for 6 weeks. The second group of 9 patients with diabetes, both types, and peripheral neuropathy received 600 mg ALA or placebo intravenously. In both groups, results demonstrated that for patients with diabetic polyneuropathy, ALA improved microcirculation. The observed effects are apparently acute effects. A randomized, placebo-controlled study with a larger population of patients is currently under way. 16 Alzheimer's Disease:Excessive lipid peroxidation, protein oxidation, DNA oxidation, and glyco-oxidation have all been documented in the brain in Alzheimers disease (AD) 17 . A number of epidemiological studies have found a link between antioxidant intake and a reduced incidence of dementia, AD and cognitive decline in elderly populations 17 .

• In an open study using nine patients with Alzheimer's disease, 600 mg of ALA was given for almost one year and cognitive functions were measured. Treatment with ALA showed a neuroprotective effect as measured by mini-mental state examination and AD assessment scores. 8

Depression: In a review paper, Salazar suggested a possible therapeutic role of ALA for patients with depression. 9 Studies showed that insulin plays a role in serotonergic activity by increasing the flow of tryptophan, a precursor of serotonin, into the brain. Synthesis of serotonin appears to be dependent on the concentration of plasma tryptophan and activity of tryptophan hydroxylase, which converts tryptophan to serotonin. Insulin stimulates uptake of glucose and amino acids by muscle cells and promotes influx of tryptophan into the brain, which in turn facilitates serotonin synthesis. Since a large number of people with depression have insulin resistance and ALA plays a key role in insulin metabolism, well-controlled clinical studies are needed to support this hypothesis.

References Back to sub-topics 1 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society of GK: Information. Health-System Pharmacists. 2001; 3 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 4 Konrad a-lipoic acid treatment decreases serum Diabetes Care 22: 280-287. T, et al: lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. 5 Morcos Effect of a-lipoic acid on the progression of Diabetes Res and Clin Prac 52: M, et al: endothelial cell damage and albuminuria in 175-183. patients with diabetes mellitus: an exploratory study. 6 Ziegler D, Effects of treatment with the antioxidant Diabetes Care 20: 369-373. et al: a-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. 7 Ziegler D, Treatment of symptomatic diabetic Diabetes Care 1999 22:1296-1301 et al polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III). ALADIN III Study Group. Alpha-lipoic acid in diabetic neuropathy. 8 Hager K, Alpha-lipoic acid as a new treatment option Arch Geront Geriat 32: 275-282. et al: for Alzheimer type dementia. 9 Salazar Alpha lipoic acid: a novel treatment for Medical Hypotheses 55;510-512. MR: depression. 10 Joseph Oxidative Stress and Stress-Activated Endocrine Reviews 2002 L. Evans, Signaling Pathways: A Unifying Hypothesis 23:599-622 Ira D. of Type 2 Diabetes Goldfine, et al 11 van Dam Oxidative stess and diabetic neuropathy: Diabetes Metab Res Rev 2002 P. Sytze pathophysiological mechanisms and 18:176-184 treatment perspectives 12 Ziegler Treatment of symptomatic diabetic Diabetologia 1995 38:1425-1433 D, peripheral neuropathy with the antioxidant Hanefeld alpha-lipoic acid - a 3-week multicenter M, Ruhnau randomized controlled trial (ALADIN Study). KJ, et al 13 Treatment of diabetic polyneuropathy with Free Radic Res 1999 31:171-179 Reljanovic the antioxidant thioctic acid (alpha-lipoic M, acid) a two-year multicenter randomized Hanefeld double-blind placebo-controlled trial M, et al (ALADIN II) 14 Ziegler, Treatment of symptomatic diabetic Diabetes Care 1999 22: 1296-1301. D, et al: polyneuropathy with the antioxidant a-lipoic acid. 15 Packer Molecular Aspects of Lipoic Acid in the Nutrition 2001 17:888-895 L, Kraemer Prevention of Diabetes Complications K, Rimbach G 16 Haak E, Effects of alpha-lipoic acid on Exp Clin Endocrinol Diabetes 2000 Usadel KH, microcirculation in patients with peripheral 108:168-174 et al diabetic neuropathy 17 Antioxidant strategies for Alzheimer's Proceeds of the Nutrition Society Grundman disease 2002 61:191-202 M, Delaney P Dietary Chondroitin Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Chondroitin sulfate (CS) is one of the glycosaminoglycans, which is essential in the -Fish Oil extracellular matrix of connective tissues. CS is found in cartilage, bone, the cornea, -Flaxseed Oil skin and the arterial walls. -Glucosamine • CS is made up of D-galactosamine and D-glurcoronic acid. • CS has been used by itself or in combination with glucosamine to treat or prevent -Kelp osteoarthritis. -L-Arginine -Lecithin -L-Lysine Functions Back to sub-topics -Lycopene -Melatonin • CS regulates collagen synthesis in chondrocytes, forming cartilage. -Methylsulfonylmethane • CS inhibits proteolytic and lysomal enzymes which damage joint cartilage. -Pantethine • CS possesses anti-inflammatory actions. -Phytonutrients -Plant Sterols/Stanols -S-adenosyl-L-methionine Dosage Back to sub-topics -Soy Isoflavones Based on efficacy and safety from clinical studies, daily intake of 800 to 1200 mg of CS is -Vinpocetine recommended to ease pain or improve mobility of joints.

Toxicity Back to sub-topics CS is well tolerated. Side effects reported in clinical studies are mostly mild, including nausea, diarrhea and gastrointestinal discomfort. Because of the lack of sufficient safety data, children, pregnant and lactating women should avoid taking CS.

According to a review article on the safety of glucosamine and chondroitin sulfate, glucosamine has not exhibited toxicity when tested in doses that far exceed what has been used in human clinical trials. Glucosamine also fared much better than indomethacin regarding prolonged treatment with a therapeutic margin of 10-30 times more favorable than indomethacin. 10 12

Some individuals are allergic to sulfur-containing (sulfa) drugs, where it is the sulfonamides that cause an allergic reaction, not the sulfur group. Currently there are no reports or references in the literature on cross hypersensitivity between sulfate salts and sulfonamides. However, individuals with a sensitivity to sulfonamides should be prudent and start with a minimal dose of chondroitin and observe any side effects or adverse reaction. 12

Recently there has been a growing concern about the possibility of bovine spongiform encephalopathy (BSE) cases in the U.S. Chondroitin sulfate is derived from tracheal cartilage, which has shown to be free of BSE. With regards to dietary supplements containing chondroitin sulfate, currently there appears to be no risk of BSE, provided that the material for manufacturing chondroitin is handled correctly. Therefore, it is important to choose chondroitin sulfate supplements from a good quality manufacturer. 12 Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

• No health hazards or side effects are known. • Caution with pregnancy or nursing, consult physician before using. • Theoretically, because chondroitin has some structural similarity to heparin, it might have weak anticoagulant activity. At recommended doses of glucosamine, chondroitin, or the combination of the two, it is unlikely that there will be an interaction with warfarin. There have been no reports of interactions with warfarin at recommended dosages of glucosamine or chondroitin. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary Back to sub-topics Mechanism of Action: • In cell culture using bovine chondrocytes, glycosaminoglycan synthesis was measured by incorporation of 35-sulfate. Either glucosamine or chondroitin sulfate alone slightly increased glycosaminoglycan synthesis while the combination of glucosamine and chondroitin dramatically stimulated the incorporation of 35-sulfate. 4 • Mast cells are stimulated by various chemicals, such as IgE, and specific antigens-secreting pro-inflammatory molecules, including cytokines and proteolytic enzymes. Incubation of umbilical cord-derived human mast cells with chondroitin sulfate showed that chondroitin sulfate had an inhibitory effect on histamine release, indicating that chondroitin sulfate may be a potent mast cell inhibitor of allergic stimulation. 5 • Monfort and colleagues analyzed the effect of chondroitin sulfate and hyaluronic acid on stromelysin-1 (metalloprotease-3 [MMP-3]) synthesis induced by interleukin-1 beta in chondrocytes from patients with hip osteoarthritis. MMP-3 is a cartilage enzyme which induces cartilage destruction and acts as a mediator of the inflammatory response. Both chondroitin sulfate and hyaluronic acid inhibited MMP-3 synthesis and reduced MMP-3 expression levels in human osteoarthritis chondrocytes. The authors conclude that this mechanism of action of these substances could help explain their clinical efficacy in osteoarthritis. 13 • Chan and colleagues studied the effects of physiologically relevant concentrations of glucosamine and chondroitin sulfate on gene expression and synthesis of nitric oxide and prostaglandin E-2 (PGE-2) in cytokine stimulated articular cartilage explants. Results show that chondroitin sulfate and the glucosamine/chondroitin combination at concentrations attainable in the blood down-regulated interleukin-1 induced mRNA expression of inducible nitric oxide synthase at 24 and 48 hour post culture. Additionally, synthesis of nitric oxide was reduced with chondroitin sulfate alone and the glucosamine/chondroitin combination. Repression of COX-2 transcripts by glucosamine and chondroitin was accompanied by a simultaneous reduction in PGE-2. The authors conclude that physiologically relevant concentrations of glucosamine and chondroitin sulfate can regulate expression of genese related to inflammation, and the synthesis of nitric oxide and PGE-2 (both having pro-inflammatory roles in diseased joints), providing a plausible explanation for their supposed anti-inflammatory properties. 14

Osteoarthritis:

• A randomized, double-blind placebo-controlled multi-center study on ~80 male and female patients examined the effect of 800 mg/day chondroitin sulfate (CS) supplementation for 6 months on treating osteoarthritis of the knee. Patients with symptomatic knee osteoarthritis for at least 6 months and a Kellgren and Lawrence radiological score I-III upon entry were enrolled in the study. Compared with placebo, the group receiving CS reduced pain and walking time significantly; they also experienced a reduction in Lequesnes Index, which was used to measure the daily functional status of patients. A significantly positive global efficacy judgement for CS was observed and overall tolerability of CS was also excellent. 11 • Michel and colleagues conducted a randomized, double-blind, placebo-controlled trial to determine whether chondroitin sulfate is effective in inhibiting cartilage loss in knee osteoarthritis. 300 patients with knee osteoarthritis were randomly assigned to receive either 800 mg chondroitin sulfate or placebo once daily for 2 years. The 150 patients receiving placebo had progressive joint space narrowing while the 150 patients taking chondroitin had no change in mean joint space. The authors conclude that while there was no significant symptomatic effect (i.e., pain reduction) in this study, long-term treatment with chondroitin sulfate may retard radiographic progression (and presumably cartilage degradation) in those with knee osteoarthritis. 15 • Uebelhart and colleagues investigated the efficacy and tolerability of intermittent treatment with 800 mg chondroitin sulfate for a 3-month duration, twice/year in patients with knee osteoarthritis. 120 patients with symptomatic knee osteoarthritis received either chondroitin sulfate or placebo daily for two periods of 3 months during 1 year. Lequesnes algo-functional index decreased significantly by 36% in the chondroitin group after 1 year verses 23% in placebo group Similar results were found for secondary outcome parameters which included walking time and global clinical judgment. The placebo group experienced significantly decreased joint space width after one year, but no changes in the chondroitin group occurred. The authors conclude that oral chondroitin sulfate treatment in this study decreased pain, improved knee function, and shows evidence that chondroitin sulfate may have structure-modifying properties in knee osteoarthritis. 17 Based on this evidence, it is a reasonable and science-based conclusion that chondroitin sulfate in the range of 800-1200 mg/day is effective for reducing the pain of osteoarthritis. Meta-analyses on Chondroitin:

• More than 15 papers were reviewed. In most studies, glucosamine sulfate and chondroitin sulfate moderately improved symptoms of osteoarthritis. Analysis also suggested that efficacy of glucosamine sulfate or chondroitin sulfate might be recognized in patients consuming these products for longer than a month. 8 • A comprehensive meta-analysis on randomized placebo controlled trials was performed to assess the efficacy of glucosamine and/or chondroitin in knee osteoarthritis (OA). Analyses were based on the outcomes that are required for demonstrating the efficacy of a prescription drugs commonly to be used in the treatment of OA: radiological evolution assessed by JSN (joint space narrowing); evaluation of pain by visual analog scale (VAS pain); joint mobility; Lequesne Index (LI) and Western Ontario MacMaster University Osteoarthritis Index (WOMAC). Results from analyses demonstrated the efficacy of glucosamine on all outcomes, including JSN and WOMAC. Chondroitin was found to be efficacious on the LI, VAS pain and joint mobility. Regarding LI scores, similar results were seen for 2000, 1200, 1000, and 800 mg doses of chondroitin. An outstanding finding was the structural efficacy (disease-modifying property) of glucosamine on JSN. This finding suggests that long-term (at least 3 years) glucosamine supplementation at a dose of 1500mg/day can slow the degenerative process of the joint cartilage. Further studies are warranted to confirm the long-term effects of glucosamine. Further studies are also needed to confirm and evaluate the structural efficacy of chondroitin. Safety for both of these compounds was well-established. 9 • A meta-analysis was conducted to assess the efficacy of chondroitin sulfate (CS) in the treatment of osteoarthritis. Out of 16 publications, 7 controlled clinical trials were included in the meta-analysis, which involved 372 patients taking CS. In some studies, CS was given along with non-steroidal anti-inflammatory drugs (NSAIDS) or analgesics, therefore, dosage of co-medication must be considered. Patients taking CS were followed for at least 120 days, and results of pooled data indicated that the CS was superior to placebo according to the Lequesne Index and Visual Analog Scale (VAS) for pain. It was determined that CS may be useful in treatment of osteoarthritis. Further investigations in larger patient cohorts over longer time periods are warranted to confirm its effectiveness in treating symptoms of osteoarthritis. 10 • In a review of the clinical use of glucosamine and chondroitin sulfate, Brief and colleagues conclude that both agents demonstrate efficacy with regard to reduction of joint pain/tenderness and improved mobility. Additionally, there was no evidence of toxicity. 18 Psoriasis

• Eleven patients with moderate to severe psoriasis, who were resistant to conventional therapy, received 800 mg daily of chondroitin sulfate for 2 months. All but one patient experienced a dramatic improvement in the condition of the skin with a reduction in swelling, redness, flaking, itching, scaling, and an increase in the hydration and softening of the skin. Other effects included a statistically significant decrease in epidermal thickness and a significant improvement of the degree of psoriasis activity. The authors suggest that confirmation of these findings in controlled prospective studies could represent an important advance in the treatment methods used for psoriasis patients. 16

Effect of glucosamine on Insulin/Glucose:There has been concern regarding glucosamine supplementation and its effect on blood glucose levels. Past experimental research has examined the effect of glucosamine on insulin and glucose but many of these studies intravenously infused a large amount of glucosamine in a short period of time, which makes it difficult to extrapolate direct effects of oral consumption of glucosamine. Some animal research has examined the effects of a combination of oral glucosamine hydrochloride and chondroitin sulfate. Results showed that 1 month of oral administration in twice the recommended amount on the label for glucosamine and chondroitin had no effect on blood sugar. 9 12 Now, human studies have been done and 2 are summarized below:

References Back to sub-topics 1 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society GK: Information. of Health-System Pharmacists. 2001; 3 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 4 Lippiello L, In vivo chondroprotection and metabolic Clin Orthopaedics Related Res et al: synergy of glucosamine and chondroitin 2000; 381: 229-240. sulfate. 5 Chondroitin sulphate inhibits connective Brit J Pharm 2000 131: Theoharides tissue mast cells. 1039-1049. TC, et al: 6 Mazieres B, Chondroitin sulfate in osteoarthritis of the J Rheum 2001 28:173-181. et al: knee: a prospective, double blind, placebo controlled multicenter clinical study. 7 Morreale P, Comparison of the antiinflammatory efficacy J Rheumatol 1996 23: 1385-1391. et al: of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. 8 McAlindon Glucosamine and chondroitin for treatment JAMA 2000; 283: 1469-1475. TE, et al: of osteoarthritis: a systematic quality assessment and meta-analysis. 9 Richy F, et Structural and symptomatic efficacy of Arch Intern Med 2003; al. glucosamine and chondroitin in knee 163:1514-1522. osteoarthritis. 10 Leeb BF, A meta-analysis of chondroitin sulfate in the J Rheumatol 2000; 27:205-11. et al. treatment of osteoarthritis. 11 Bucsi L Efficacy and tolerability of oral chondroitin Osteoarthritis and Cartilage 1998; and Poor G. sulfate as a symptomatic slow-acting drug 6 (Supplement A):31-36. for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. 12 Chondroitin and glucosamine: A review of JANA 2001; 3:16-23. AbdelFattah their safety profile. W, et al. 13 Monfort J, Chondroitin sulfate and hyaluronic acid Drugs Exp Clin Res 2005 Nacher M, (500-730 kda) inhibit stromelysin-1 synthesis 31(2):71-6. Montell E, et in human osteoarthritic chondrocytes. al. 14 Chan PS, Glucosamine and chondroitin sulfate Osteoarthritis Cartilage 2005 May Caron JP, et regulate gene expression and synthesis of 13(5):387-94. al. nitric oxide and prostaglandin E(2) in articular cartilage explants. 15 Michel BA, Chondroitins 4 and 6 sulfate in osteoarthritis Arthritis Rheum. 2005 March Stucki G, of the knee: a randomized, controlled trial. 52(3):779-86. Frey D, et al. 16 Verges J, Clinical and histopathological improvement Dermatol Online J 2005 March Montell E, of psoriasis with oral chondroitin sulfate: a 11(1):31 Herrero M, et serendipitous finding. al. 17 Uebelhart Intermittent treatment of knee osteoarthritis Osteoarthritis Cartilage 2004 Apr D, Malaise M, with oral chondroitin sulfate: a one-year, 12(4):269-76. Marcolongo randomized, double-blind, multicenter study R, et al. versus placebo. 18 Brief AA, Use of glucosamine and chondroitin sulfate J Am Acad Orthop Surg. 2001 Maurer SG, in the management of osteoarthritis. 9:71-78 Di Cesare PE. 19 Scroggie The effect of glucosamine-chondroitin Arch Intern Med 2003; DA, et al. supplementation on glycosylated 163:1587-1590. hemoglobin levels in patients with type 2 diabetes mellitus. 20 Tannis AJ, Effect of glucosamine supplementation on Osteoarthritis Cartilage 2004 Barban J, fasting and non-fasting plasma glucose and 12(6):506-11. Conquer JA serum insulin concentrations in healthy individuals. 21 Daniel O Glucosamine, Chondroitin Sulfate, and the New England Journal of Medicine Clegg, Two in Combination for Painful Knee 2006 354:795-808 Domenic J Osteoarthritis Reda, Crystal L Harris, Marguerite A Klein, et al. Dietary Coenzyme Q10 Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Coenzyme Q is a family of ubiquinones. -Fish Oil • The structure of Coenzyme Q contains a benzoquinone with various numbers of -Flaxseed Oil isoprenes as a side chain. CoQ 10 has 10 isoprene units.

-Glucosamine • CoQ 10 is lipophilic, water insoluble chemical. -Kelp • CoQ 10 is a vitamin-like substance and is found in virtually all cells of the human body. -L-Arginine • CoQ 10 is mainly carried by LDL in the blood. -Lecithin • The average daily intake of CoQ 10 is 2 to 5 mg. -L-Lysine • CoQ 10 is synthesized in all body tissues. -Lycopene • Circulating concentrations of CoQ 10 decrease with age. -Melatonin -Methylsulfonylmethane -Pantethine Functions Back to sub-topics -Phytonutrients -Plant Sterols/Stanols -S-adenosyl-L-methionine • CoQ 10 acts as a powerful antioxidant. -Soy Isoflavones • CoQ 10 is an electron carrier in the lipid phase of the -Vinpocetine mitochondrial membrane, producing energy. Therefore, it is essential for ATP production. • CoQ 10 may prevent initiation and/or propagation of lipid peroxidation in plasma lipoprotein biological membranes. • CoQ 10 prevents LDL oxidation, indicating a role in reducing risk of cardiovascular disease. • CoQ 10 may have an antihypertensive function.

Dosage Back to sub-topics

For therapeutic purposes, 100 mg or more of CoQ 10 may be used to increase blood concentrations of this antioxidant.

Toxicity Back to sub-topics None known.

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

• HMG-CoA reductase inhibitors such as lovastatin and pravastatin significantly decrease blood concentrations of CoQ 10 . Approximately 100 mg of CoQ 10 is recommended to prevent a decrease in blood CoQ 10 . • Tricyclic antidepressants inhibit CoQ 10 -dependent enzyme activity. A dose of 30 - 100 mg of CoQ 10 is advised. • Since CoQ 10 is structurally similar to vitamin K, it may interfere with Warfarin, an anticoagulant.

• Proparanolol [Inderalâ], a beta-blocker to treat hypertension, can inhibit CoQ 10 -dependent enzymes.

Research Summary Back to sub-topics Antioxidant Activity: CoQ10 is present in cell membranes in high amounts, acting as a powerful antioxidant scavenger of free radicals and taking part in regeneration of other key antioxidants such as tocopherol (vitamin E) and ascorbate (vitamin C). 10

Coenzyme Q10 (CoQ10) supplementation has shown to decrease oxidative stress/damage in vivo. Supplementing with CoQ10 alone for 13 weeks, resulted in elevated CoQ homologues in tissue and mitochondria, as well as decreased oxidative damage and increased oxidative potential in rodents. Supplementation with CoQ10 as part of a low-dose antioxidant combination (vitamins C and E, beta-carotene, selenium, zinc) was also shown in humans, to reduce oxidative potential. Eleven men and three women received either: 5mg zinc, 48 mcg selenium, 400 mcg vitamin A, 50 mcg beta-carotene, 15 mg vitamin E and 10 mg cysteine (Formula 1); 30 mg citrus bioflavonoids, 30 mg vitamin C, 10 mg coenzyme Q(10) and 1 mg vitamin B-6 (Formula 2); or a combination of Formula 1 and 2 (Formula 3). Each formula was administered for 1 week in a cross-over design. D-Roms test was used to detect oxygen metabolite derivatives as Carratelli units (U.CARR). Formulas 1 and 3 reduced mean U.CARR concentrations, which suggests that an antioxidant combination, including CoQ10, reduces oxidative stress in humans. 11 12

Antioxidant activity of 90 mg/day supplementation in humans was determined before and after induction of an oxidative stress by fish oil supplementation. CoQ 10 decreased TBARS concentrations, an antioxidant marker, and increased a-tocopherol content. This indicated an 4 antioxidant role of CoQ 10 in blood.

Blood Pressure:

CoQ10 supplementation has shown to improve blood pressure and glycemic control in patients with type II diabetes. A randomized double-blind placebo controlled trial on seventy-four patients with type II diabetes and dyslipidemia received either 100mg CoQ10 twice daily, 200 mg fenofibrate, both CoQ10 and fenofibrate, or placebo for 12 weeks. CoQ10 supplementation significantly decreased systolic and diastolic blood pressure and HbA 1 C, whereas fenofibrate did not alter blood pressure, HbA 1 C, or plasma F(2)-isoprostanes (a marker of oxidative stress). Although plasma F(2)-isoprostane concentrations were not decreased, supplementation with CoQ10 can help improve blood pressure and long-term glycemic control in patients with Type II diabetes. 14

Hypertensive subjects with coronary artery disease were given 120 mg/day of CoQ 10 for 8 weeks. Blood pressure, 2-hour plasma insulin, lipids and oxidized lipids concentrations were measured. Researchers found that CoQ 10 decreased blood pressure, which was accompanied with lowered oxidative stress. Insulin response was also significantly improved. 5 Burke et al 6 reported a mean reduction in systolic blood pressure of 17 + 7.3 mmHg (mean + SEM) in subjects treated with CoQ 10 (60 mg oral) for 12 weeks.

Cardiovascular Disease (CVD): Vitamin E has shown to be beneficial for the heart by reducing oxidation of LDL cholesterol, which over time can cause plaque to build up in arteries. One study examined vitamin E and CoQ10 supplementation in combination (0.2% + 0.5% wt/wt, respectively) in apolipotprotein E knockout mice fed a high-fat diet, to determine whether it is more anti-atherogenic than either vitamin E (0.2%) or CoQ10 (0.5%) supplementation alone. CoQ10 + vitamin E supplementation significantly decreased tissue lipid peroxidation after 24 weeks. This supports other data on CoQ10 and vitamin E working together as a powerful antioxidant team. In addition, HPLC determined that CoQ10 significantly inhibited atherosclerosis at the aortic arch and root. Vitamin E and CoQ10 supplementation taken together are more anti-atherogenic in apoE-/- mice than either CoQ10 or vitamin E alone. Further studies need to establish whether the anti-atherogenic activity of vitamin E + CoQ10 reflects the ability of antioxidants to inhibit the oxidation of lipoproteins in the vessel wall. 13

Over 400 patients with various forms of CVD were treated with 75 - 600 mg/day of CoQ 10 . Some patients took CoQ 10 for less than 1 year and a third of the patients took it for more than 3 years. CoQ 10 supplementation significantly improved echocardiographic parameters such as left ventricular wall thickness, mitral valve inflow slope and fractional shortening. Treatment 7 with CoQ 10 also reduced medication requirements.

Congestive Heart Failure:CoQ10 has been studied quite extensively in congestive heart failure (CHF). CoQ10 has been determined to be an important part of myocardium and myocardial energy function, along with L-carnitine, creatine, thiamine, taurine, and antioxidants: vitamins C and E and selenium. A randomized study comparing supplementation with taurine, CoQ10, carnitine, thiamine, creatine, and vitamins C and E and selenium against a placebo diet in hamsters with late-stage cardiomyopathy, found improvement in myocyte sarcomeric structure, developed pressure, and +dp/dt and dp/dt after 3 months. In addition, biopsies have indicated a correlation between CoQ10 and ventricular function in human failing hearts. Supplementation with carnitine, taurine and CoQ10 (via MayoviveÒ) for 30 days resulted in restored myocardial levels and a significant decrease in left ventricular end-diastolic volume. CoQ10 supplementation should be considered as part of a therapeutic strategy to manage patients suffering from CHF. 15

A meta-analysis with 8 studies reported the effect of supplemental CoQ 10 on congestive heart failure. More than 350 patients were included in the meta-analysis. CoQ 10 varied from 60 to 200 mg. Treatment with CoQ 10 improved stroke volume, cardiac output, ejection fraction, cardiac index and end diastolic volume index, which suggested that CoQ 10 may be an adjuvant treatment of congestive heart failure. 8

Exercise: Since CoQ 10 is essential for energy production, researchers have hypothesized that CoQ 10 supplementation can increase exercise tolerance. Fifteen middle-aged men were given 150 mg/day CoQ 10 for 2 months. The forearm-hand grip test and the Lactate Threshold test were evaluated. VO2 max and the Lactate Threshold were not modified by antioxidant treatment. In addition, CoQ 10 did not improve the forearm-handgrip test, suggesting that short-term dosing with CoQ 10 does not enhance aerobic capacity and forearm exercise metabolism. 9

Diabetes - Type II: CoQ10 supplementation has been shown to improve endothelial dysfunction of the brachial artery in patients with type II diabetes and dyslipidemia. Forty patients with type II diabetes and dyslipidemia were randomized to receive either 200 mg supplemental CoQ10 or placebo for 12 weeks. Flow-mediated dilation of the brachial artery increased with CoQ10 supplementation and decreased with placebo. Supplementing with CoQ10 improved endothelial function of the peripheral circulation in dyslipidemic patients with Type II diabetes. This finding may be the result of increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress. 16

The glycerol-3-phosphate shuttle is important for single transduction of plasma glucose and insulin release from pancreatic beta cells. Glycerol-3-phophate dehydrogenase (G3PD), the rate-limiting enzyme in the shuttle, is underexpressed in pancreatic beta cells of humans with type II diabetes, as well as rodents that are models for this disorder. It is thought that sub-optimal tissue concentrations of CoQ10 may further impair GSPD activity. Correcting a deficiency of tissue CoQ10 may improve glucose-stimulated insulin secretion from pancreatic beta cells of patients with diabetes. CoQ10 supplementation may play an important role with glycemic control in patients with diabetes. 17

Neurodegenerative disorders: Oxidative stress is characteristic of neurodegenerative disorders, such as Parkinsons disease. Complex I and complex II/III activity in platelet mitochondria have shown to be reduced in patients with untreated Parkinsons disease in its early stage. CoQ10 is the electron acceptor for Complex I and complex II. Mitochondrial CoQ10 concentrations have been found to be low in patients with Parkinson's disease, which directly correlates with decreases in complex I and complex II/III activity. A pilot study using oral supplementation of 200 mg of CoQ10 either twice, 3 times or 4 times daily for 1 month in Parkinsonian patients, resulted in dose-dependent increases in plasma CoQ10 concentrations as well as an increase in complex I activity. However, there was no change in motor functions in these patients. Although CoQ10 was well-tolerated at these high doses, mild changes in urine were noted for the highest dose (800 mg/day). 18

A randomized controlled multi-center study was conducted in 80 patients with early Parkinsons disease to determine if CoQ10 supplementation could slow the functional decline. Functional decline was assessed in patients undergoing evaluation with the Unified Parkinsons Disease Rating Scale at screening, baseline, and at 1-,4-,8-,12- and 16-month visits. CoQ10 supplementation was suggested to be safe and well-tolerated at dosages up to 1200 mg/day over the 16-month period. Less disability developed in subjects assigned to CoQ10 than placebo, and benefit was greatest in patients receiving the highest dose (1200 mg/day). CoQ10 supplementation at 1200 mg/day appears to slow the progressive deterioration of function in patients with Parkinsons disease. 19

References Back to sub-topics 1 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society GK: Information. of Health-System Pharmacists. 2001; 3 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 4 Weber C, Antioxidative effect of dietary coenzyme Q10 Int J Vit Nutr Res 64: 311-315. et al: in human blood plasma. 5 Singh RB, Effect of hydrosoluble coenzyme Q10 on J Hum Hypertension 13: 203-208. et al: blood pressures and insulin resistance in hypertensive patients with coronary artery disease. 6 Burke BE, Randomized, double-blind, South Med J 94: 1112-1117. et al: placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. 7 Langsjoen Usefulness of coenzyme Q10 in clinical Molec Aspects Med 15: H, et al: cardiology: a long-term study. S165-S175. 8 Soja AM Treatment of congestive hearth failure on Molec Aspects Med 18S: and Coenzyme Q10 illuminated by S159-S168. Mortensen meta-analyses of clinical trials. SA: 9 Porter DA, The effect of coenzyme Q10 on the exercise Int J Sports Med 16: 421-427. et al: tolerance of middle-aged, untrained men. 10 Crane, FL Biochemical functions of coenzyme Q10. J Am Coll Nutr 2002 20: 591-8 11 Kwong Effects of coenzyme Q(10) administration on Free Radic Biol Med 2002 LK, et al. its tissue concentrations, mitochondrial 1:627-38. oxidant generation, and oxidative stress in the rat. 12 Cornelli Bioavailability and antioxidant activity of J Nutr 2001 131:3208-11. U, et al. some food supplements in men and women using the D-Roms test as a marker of oxidative stress. 13 Thomas Dietary cosupplementation with vitamin E Arterioscler Thromb Vasc Biol SR et al. and coenzyme Q(10) inhibits atherosclerosis 2001; 21:585-93. in apolipoprotein E gene knockout mice 14 Hodgson Coenzyme Q (10) improves blood pressure Eur J Clin Nutr 2002; 56:1137-42. JM, et al. and glycemic control: a controlled trial in subjects with type 2 diabetes. 15 Sole MJ Conditioned nutritional requirements: Herz 2002; 27:174-8. and therapeutic relevance to heart failure. Jeejeebhoy KN. 16 Watts GF, Coenzyme Q(10) improves endothelial Diabetologia 2002; 45:420-6 et al. dysfunction of the brachial artery in Type II diabetes mellitus. 17 McCarty, Can correction of sub-optimal co-enzyme Q Med Hypotheses 1999; MF. status improve beta-cell function in type II 52:397-400. diabetics? 18 Shults Coenzyme Q10 levels correlate with the Ann Neurol 1997; 42:261-4 CW, et al. activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. 19 Shults Effects of coenzyme Q10 in early Parkinson Arch Neurol 2002; 59:1541-50 CW, et al. disease: evidence of slowing of the functional decline. Dietary Conjugated Linoleic Acid Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Conjugated linoleic acid, or CLA, is a generic term referring to a mixture of geometrical -Fish Oil and positional isomers of linoleic acid in which up to 16 members have been identified. -Flaxseed Oil • Representative CLAs are cis-9, trans-11-octadecadienoic acid and trans-9, Cis-11 -Glucosamine octadecadienoic acid. The various health benefits are linked predominantly to the c9 t11- (also called rumenic acid) and t10 c12-CLA isomers. -Kelp • CLA is found in foods such beef, lamb, and dairy products. -L-Arginine • CLA concentrations in dairy products range from 2.9 to 8.92 mg/g of fat. More than -Lecithin 70% of CLA, the 9-cis,11-trans isomer, is from dairy products. Vegetable oils contain -L-Lysine little CLA. -Lycopene • A synthetic mixture of CLA may be found in nutritional supplements and is composed primarily of the c9 t11-CLA isomer and the t10 c12-CLA isomer. -Melatonin • Over the past 2 decades, numerous health benefits have been attributed to CLA -Methylsulfonylmethane including actions to reduce carcinogenesis, atherosclerosis, onset of diabetes, and -Pantethine body fat mass. -Phytonutrients • Ruminal bacteria are able to convert linoleic acid to CLA while the intestinal bacteria -Plant Sterols/Stanols from non-ruminants have a limited capacity to produce CLA. -S-adenosyl-L-methionine -Soy Isoflavones -Vinpocetine Functions Back to sub-topics

• CLA has been shown to have antioxidant properties. • In many cancer cell lines, CLA inhibits growth of cancer cells. • CLA may reduce concentrations of blood lipids such as cholesterol and triacylglycerol. • CLA may reduce body fat. Data demonstrate that CLA may modulate body composition by reducing the accumulation of adipose tissue. In both animal and humans, dietary CLA reduces adipose tissue depots. • Molecular mechanisms of action appear to include modulation of eicosanoid formation as well as regulation of the expression of genes coding for enzymes known to modulate macronutrient metabolism.

Dosage Back to sub-topics

• Variable; average range 1- 5 g/day • Because such small amounts of CLA (0.5% diet) have been shown to alter the expression of genes and impact conditions such as carcinogenesis, obesity, diabetes, and atherosclerosis in experimental animals, its possible that small amounts consumed over a pro-longed period of time may exert similar beneficial effects in human beings. 10 Toxicity Back to sub-topics Further research is needed to fully elucidate the safety and efficacy of isomers and doses that are required for CLAs potential health benefits. 10

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

Conjugated linoleic acid interacts with and may be incorporated into the body at the expense of other fatty acids, such as palmitic acid and stearic acid, fundamental constituents of many important lipids.

Research Summary Back to sub-topics Obesity and Body Composition: Animal studies have shown that CLA leads to a reduction in body fat accumulation. 4 Studies continue to demonstrate that supplementation with CLA for short periods (up to 12 weeks) reduces body weight, leptin, and body adiposity in people. 10 How strain/species-, age-, and sex-specific effects of various isomers of CLA affect adipose tissue accumulation, either in obese humans or those seeking to prevent adipose gain, is yet to be determined. 10 • Although several clinical studies were conducted to see if CLA modifies body composition, a conclusive result has not been reached. Sixty overweight or obese people were given a placebo (0.9 g olive oil) or CLA (1.7, 3.4, 5.1, or 6.8 g/day for 12 weeks. Body fat mass was decreased more in the CLA-fed group than in the placebo group. The significant reduction was found in the 3.4 g and 6.8 g CLA supplemented groups. No difference was observed in these two groups. However, CLA did not affect lean body mass, body mass index or blood lipids. 5 • In a double-blind, randomized, controlled trial using 25 abdominally obese men aged 39 to 64, the effect of CLA (4.2 g/day) on abdominal fat and cardiovascular risk factors were measured. As a result, CLA supplementation significantly decreased sagittal abdominal diameter, but did not change measurements of anthropometry or blood lipid profile. 6 • Seventeen healthy women were supplemented with either placebo or CLA (3 g/day) for 64 days. Fat-free mass, fat mass and percentage body fat were not affected by CLA. Body weight was also not changed. In addition, CLA had no significant effect on energy expenditure, fat oxidation and respiratory exchange ratio. 7

Atherosclerosis: • Rabbits were fed CLA (0.5 g/day) in addition to a 0.1% cholesterol diet for 22 weeks. During the study rabbits with or without CLA gained body weight similarly. LDL cholesterol concentrations increased less in CLA-fed rabbits as compared to the control rabbits. No difference in serum HDL cholesterol concentrations were found in either group, resulting in a low ratio of LDL/HDL cholesterol in CLA-treated rabbits. Furthermore, CLA-fed rabbits showed less histological evidence of atherogenesis in lipid deposition and in connective tissue development. 8 • Whigham (2000) reviewed studies using hamster models that suggested certain CLA isomers are capable of lowering total cholesterol, non-HDL cholesterol, and triglycerides. Although the specific effects of CLA differ somewhat from study to study, the t10 c12-CLA isomer appears to be the active isomer for the anti-atherogenic effects. It was suggested that the ability of CLA to reduce aortic plaque formation could be due to changes in LDL oxidative susceptibility. Further studies using models of atherosclerosis are needed to address conflicting reports and to elucidate other mechanisms by which CLA may be having these effects.

Immunity: Immunological studies to date indicate that CLA may have implications for human health in promoting maintenance of lean body mass during immune stimulation, especially in diseases that cause wasting such as cancer and AIDS and during late stages of auto-immune diseases. 11 • Whigham (2000) reviews studies suggesting CLA may down-regulate type I hypersensitivity reactions, leading to less severe immune responses to allergens. CLA may shift the immune response from a TH-2 response (allergic reactions) in favor of a TH-1 type response (cell-mediated functions.) 11 • In humans supplemented with CLA (3.9 grams/day) for 93 days, no apparent alterations in eicosanoids or cytokines were observed. The discrepency of data between different models of immune function and between animal and human models argues that further study of the role of CLA in immunity is needed. 10 12 • Young (4 month-old) and old (22 month-old) mice were fed a diet with or without CLA (1 g/100g diet) for 8 weeks. Proliferation of splenocyte, production of prostaglandin E2 (PGE2) and interleukin-2 (IL-2) were compared. In both young and old mice, CLA significantly increased splenocyte proliferation. In young mice, feeding CLA enhanced IL-2 production. However, CLA did not modify PGE2 production and natural killer cell activity. This indicates that CLA may play a role in immune response. 9

Anticarcinogenesis: • Whigham (2000) suggested that the most direct evidence for a protective effect of CLA in human cancer to date is from a preliminary study using human breast adipose tissue obtained from patients at the time of surgery for carcinomas or benign tumors. Adjusting for age, menopausal status, and BMI, an inverse association was found between the concentration of CLA in breast adipose and the risk of breast cancer. 11 13 • Belury (2002) noted that while some studies showed that CLA-rich dairy products are associated with reduced breast cancer risk, others showed either no effect or even enhanced risk. 10 • Other animal and in vitro data suggest CLAs anti-cancer activities include increasing retinol concentrations, inhibiting tumor growth, suppressing metastasis of cancer cells, and decreasing growth of estrogen-responsive human breast cancer cells. Evidence for the anti-cancer abilities of CLA indicate a need to implement clinical investigations of CLAs effect in human patients. 11

Diabetes:Data presented by Belury (2002) suggested that supplementation with CLA for 8 weeks could be associated with favorable alterations of several metabolic parameters of subjects with type 2 diabetes and may delay the onset of diabetes. 10 • Male ZDF rats were fed semi-purified diets containing no CLA (control), 1.5% CLA, or an anti-diabetic drug for 2 weeks. Rats fed the CLA or anti-diabetic drug diet exhibited significantly reduced fasting glucose, insulinemia, triglyceridemia, free fatty acid concentrations, and leptinemia compared with controls. 10 14 • Another study using similar protocol, but with various sources of CLA, demonstrated that a mixture of CLA isomers induces adipose-lowering effects in ZDF rats and enhances glucose uptake into the muscle. 10 15 • This double-blind study hypothesized that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes. One group received 8.0 grams of CLA-mix and the other a placebo. When concentrations of plasma t10 c12-CLA isomer were correlated with changes in body weight or serum leptin, t10 c12-CLA isomer but not c9 t11-CLA isomer was inversely associated with body weights and serum leptin. The findings strongly suggest that the t10 c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in type 2 diabetes subjects. 16 References Back to sub-topics 1 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society GK: Information. of Health-System Pharmacists. 2001; 3 Bratman S: The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. Interactions Bible. 2001; 4 DeLany JP Changes in body composition with J Am Coll Nutr 19: 487S-493S. and West conjugated linoleic acid. DB: 5 Blackson Conjugated linoleic acid reduces body fat J Nutr 130: 2943-2948. H: mass in overweight and obese humans. 6 Riserus U: Conjugated linoleic acid (CLA) reduced Int J Obesity 25: 1129-1135. abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trial. 7 Zambell, Conjugated linoleic acid supplementation in Lipids 35: 777-782. KL: humans: effects on body composition and energy expenditure. 8 Lee KN, et Conjugated linoleic acid and atherosclerosis Atherosclerosis 108: 19-25. al: in rabbits. 9 Hayek MG, Dietary conjugated linoleic acid influences J Nutr 129: 32-38. et al: the immune response of young and old C57BL/6NCrlBR mice. 10 Martha A. Dietary Conjugated Linoleic Acid in Health: Annu Rev Nutr 2002 22:505-531 Belury Physiological Effects and Mechanisms of Action. 11 Leah D. Conjugated linoleic acid: implications for Pharmacological Research 2000 Whigham, et human health. Vol 42 No 6 al. 12 Kelley DS Dietary supplementation with conjugated Lipids 2001 36:669-74 linoleic acid increased its concentration in human peripheral blood mononuclear cells, but did not alter their function 13 Bougnoux Inverse relation between CLA in adipose Inform 1999 10(5):S43 P, et al. breast tissue and risk of breast cancer: a case-control study in France. 14 Dietary conjugated linoleic acid normalizes Biochem Biophys Res Commun Houseknecht impaired glucose tolerance in the Zucker 1998 244:678-82 KL, et al. diabetic fatty fa/fa rat. 15 Ryder JW, Isomer-specific antidiabetic properties of Diabetes 60:1149-57 et al. conjugated linoleic acid. 16 Martha A. The Conjugated Linoleic Acid (CLA) Isomer, J. Nutr 2003 133:257S-260S. Belury, et al. t10c12-CLA, Is Inversely Associated with Changes in Body Weight and Serum Leptin in Subjects with Type 2 Diabetes Mellitus. Dietary Fiber Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Dietary fiber consists of complex carbohydrates found in plant-based foods that are -Fish Oil indigestible and unabsorbed. -Flaxseed Oil • Fibers are primarily components in the plant cell wall, such as cellulose, hemicellulose -Glucosamine and pectin, and a variety of gums, mucilages and algal polysaccharides. • Fibers contribute negligible calorie value to the diet. -Kelp • There are two types of fibers, soluble and insoluble. Insoluble fibers are cellulose, -L-Arginine hemicellulose, and lignin. Soluble ones are pectins, gums and mucilages. -Lecithin • Fibers have little nutritional value but may have physiological effects in the digestive -L-Lysine system. -Lycopene • The health claim on fiber that is approved by the FDA is that diets low in saturated fat and cholesterol and high in fruits, vegetables, and grain products that contain fiber, -Melatonin particularly soluble fiber, reduce the risk of coronary heart disease. -Methylsulfonylmethane • Daily intakes of fibers in the US have been estimated to be 15 g a day. -Pantethine -Phytonutrients Functions Back to sub-topics -Plant Sterols/Stanols -S-adenosyl-L-methionine • Fibers are not digested in the upper digestive tract, but may be fermented by intestinal -Soy Isoflavones microflora in the lower digestive tract, producing acetic and butyric, propionic acids and -Vinpocetine gases such as methane and hydrogen. • Among short chain fatty acids, butyric acid can be used by enterocytes. Propionic and acetic acids are transported into circulation and utilized by the liver and many tissues. • Insoluble fibers provide bulk to the gastrointestinal contents. Fibers like lignins adsorb cholesterol and some types of toxic compounds, inhibit their absorption into the bloodstream and excrete them to feces. This type of fiber stimulates peristalsis and results in shorter passage time (more frequent defecation). • Soluble fibers slow down gastric emptying due to a gel-forming capacity, delaying the digestion and absorption of sugars, starches and fats. • Fibers alter population of intestinal microflora, probably inducing functional changes in the digestive system, including intestinal immunity. • Based on physiological functions mentioned above, fiber may be used to prevent and treat chronic diseases such as constipation, hypercholesterolemia and diabetes.

Dosage Back to sub-topics Although there is no RDA for dietary fiber, the American Diabetes Association, the American Dietetic Association, the American Medical Association and other health organizations have recommended dietary intake of fibers, ranging from 20 to 35 g a day. For children 2 years and older, daily intake of an amount of dietary fiber equal to or greater than their age plus 5 g is recommended. 1 2 • To reduce serum total cholesterol, 10 g of soluble fiber should be consumed daily. • For weight loss, 14 g of fiber a day (insoluble or soluble) may be required. Toxicity Back to sub-topics Not known. Excess intake of insoluble fiber, especially from cereal grains, may reduce the absorption of minerals such as calcium, magnesium, zinc and iron. This reduction is attributed to the high phytate content of such foods which binds to minerals and prevents their absorption.

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 5 6 7

• No health hazards or side effects are known. • Caution with pregnancy or nursing, consult physician before using. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary Back to sub-topics Risk for Diabetes: More than 65,000 U.S. women, 40 to 65 years of age, were followed for 6 years to see whether dietary glycemic index, glycemic load and dietary fiber were associated with development of type 2 diabetes. It was found that cereal fiber intake was inversely related to risk of diabetes. The combination of high glycemic load and a low cereal fiber content further increased risk of diabetes. 8 • In a randomized, crossover study, 13 patients with type 2 diabetes were given two fiber diets, each for 6 weeks. One diet contained 24 g of total fiber (8 g soluble and 16 g insoluble fiber), as recommended by the ADA, and the other 50 g of total fiber (25 g of soluble and 25 g of insoluble fiber). As a result, preprandial plasma glucose concentrations were 13 mg lower as compared with the ADA diet. The high fiber diet decreased urinary excretion of glucose significantly. In addition, plasma total cholesterol, VLDL cholesterol and triacylglycerol concentrations were significantly reduced by the 50 g fiber diet. The authors concluded that high fiber intake, especially soluble fiber, improved glycemic control and plasma lipid profile. 9 Coronary Heart Disease: A study on the relation between dietary fiber and risk of coronary heart disease (CHD) among women was conducted in the Nurses' Health Study. During the 10 year follow up, 591 major incidents of CHD were documented. The age-adjusted relative risk for major CHD was 0.53 for women in the highest quintile of the total dietary fiber intake (22.9 g/day), compared with women in the lowest quintile (11.5 g/day). Only cereal fiber was strongly associated with a reduced risk of CHD among different sources of dietary fiber. 10

Colon: Some types of fiber have been shown to bind carcinogens or dilute fecal concentrations of bile acids, which suggests that dietary fiber may reduce risk of cancer, especially colorectal cancer. A study was reported on 88,000 women followed for 16 years in the Nurses' Health Study to identify the association of colorectal cancer, adenoma and dietary fiber. During the 16 year follow up, 787 cases of colorectal cancer and 1012 cases of adenoma were found. After adjustment of confounding factors, no significant association between fiber intake and risk of colorectal adenoma was observed. 11 Furthermore, another paper reported similar results. Diets low in fat and high in fiber, fruits and vegetables did not affect the risk of recurrent of colorectal adenomas in people who had previously confirmed colorectal adenomas. 12

Gastric Cardia Cancer: In a large-scale population-based case-control study, risk factors on adenocarcinoma of the gastric cardia and esophagus and squamous cell carcinoma of the esophagus were determined. A strong inverse relation was found between total dietary intake of fiber, especially from cereal, and gastric cardia adenocarcinoma. Cereal fiber also showed a protective effect against adenocarcinoma of the esophagus. 13

Cholesterol-lowering Action: In a meta-analysis, consumption of 10.2 g/day of soluble fiber, including psyllium, reduced total cholesterol by 4% and LDL cholesterol by 7% as compared to placebo in subjects. No significant effect was observed on serum HDL cholesterol and triacylglycerol concentrations. 3

• A meta-analysis including 67 controlled trials was performed to determine if dietary fibers affected blood lipid. Soluble fiber, 2 - 10 g/day exerted small but significant effects on total cholesterol and LDL cholesterol concentrations. There was no difference on cholesterol-lowering action among major fibers such as oat, psyllium and pectin. However, plasma triacylglycerol and HDL cholesterol concentrations were not influenced by dietary fibers. 3 Stroke: In the Health Professionals Follow-up Study, the association of various nutrient intake and risk of stroke was analyzed. In addition to potassium, intake of dietary fiber, especially from cereal, was inversely correlated to the incidence of stroke. This relation was stronger in hypertensive than normotensive men. 14

Weight Reduction: It has been suggested that dietary fiber may have an affect on weight control. However, definitive conclusions still remain unanswered. In a review, researchers at Tufts University analyzed data on the effect of dietary fiber on hunger, satiety, energy intake and body composition in healthy individuals. The beneficial effects of fiber were found with both soluble and insoluble fibers. Researchers concluded that consumption of an additional 14 g/day of fiber (regardless of solubility) for > 2 days is associated with a 10% decrease in energy intake and body weight loss of 1.9 kg over 3.8 months. The efficacy was greater in obese people than lean people. 4

References Back to sub-topics 1 Nutrition recommendations and principles Diab Care 17: 519-522. for people with diabetes mellitus. 2 Position of the American Diabetic J Am Dietetic Assn 99: 1157 1159. Association: health implications of dietary fiber. 3 Brown L, Cholesterol-lowering effects of dietary fiber: Am J Clin Nutr 69: 30-42. et al: a meta-analysis. 4 Howarth Dietary fiber and weight regulation. Nutr Rev 59: 129-139. NC, et al: 5 Drug Facts and Comparisons. St. Louis, MO: Facts and Burnham Comparisons. 2001; TH: 6 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society of GK: Information. Health-System Pharmacists. 2001; 7 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 8 Dietary fiber, glycemic load, and risk of JAMA 277: 472-477. Salmeron non-insulin-dependent diabetes mellitus in J, et al: women. 9 Beneficial effect of high dietary fiber intake NEJM 342: 1392-1398. Chandalia in patients with type 2 diabetes mellitus. M, et al: 10 Wolk A, Long-term intake of dietary fiber and JAMA 281: 1998-2004. et al: decreased risk of coronary heart disease among women. 11 Fuchs Dietary fiber and the risk of colorectal cancer NEJM 340: 169-176. CS, et al: and adenoma in women. 12 Lack of effect of a low-fat, high-fiber diet on NEJM 342: 1149-1155. Schatzkin the recurrent of colorectal adenomas. A, et al: 13 Terry P, Inverse association between intake of cereal Gastroenterology 120: 387-391. et al: fiber and risk of gastric cardia cancer. 14 Intake of potassium, magnesium, calcium, Circulation 1998; 98:1198 1204. Ascherio and fiber and risk of stroke among US men. A, et al: Dietary Fish Oil Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid Consumption of omega-3 fatty acids may reduce the risk of coronary heart disease. -Fiber FDA evaluated the data and determined that although there is scientific evidence -Fish Oil supporting the claim, the evidence is not conclusive. -Flaxseed Oil -Glucosamine • Omega-6 (©-6) fatty acids in the diet are in the form of, for example, linoleic acid, while omega-3 (©-3) fatty acids in the diet are primarily in the form of alpha-linolenic acid -Kelp (ALA, plant source), eicosapentaenoic acid (EPA, marine source) or docosahexaenoic -L-Arginine acid (DHA, marine source). These fatty acids are dietary essential fatty acids because -Lecithin human cells do not have the capacity to synthesize them de novo, and must be -L-Lysine obtained from our diet. -Lycopene • Fish oil derived from cold-water fish and certain shellfish are naturally enriched in ©-3 fatty acid. These principal ©-3 fatty acids are eicosapentanoic acid (EPA, 20: 5n-3) and -Melatonin docosahexanoic acid (DHA, 22: 6n-3). -Methylsulfonylmethane • DHA is essential for healthy brain and retinal development and function for the fetus -Pantethine and infants. -Phytonutrients • Fish oil decreases serum triacylglycerol concentrations by 25 - 30% in those with 1 -Plant Sterols/Stanols hypertriglyceridemia, although this is a function of the dose. • Fish oil does not really effect plasma cholesterol. It may slightly increase LDL -S-adenosyl-L-methionine cholesterol. 1 -Soy Isoflavones • DHA and EPA can be metabolized to biologically active chemicals called eicosanoids. -Vinpocetine These hormone-like compounds are prostaglandins, prostacyclins, thromboxanes, and leukotrienes. • Eicosanoids derived from fish oil inhibit platelet aggregation, lower blood pressure and reduce plasma fibrinogen. As a result, fish oil reduces risk of developing coronary heart disease. • Because fish oil alters eicosanoid synthesis, immune functions such as inflammation may also be altered. •

Functions Back to sub-topics

• ©-3 fatty acids, EPA and DHA, are incorporated into cell membrane phospholipids. These fatty acids are removed from phospholipids by phospholipase, and enzymatically converted to eicosanoids. Eicosanoids have many biological functions: platelet aggregation, vasodilation, thrombus-forming potential, and inflammation.

• Fish oil decreases production of prostaglandin E 2 metabolites (a potent inflammatory chemical) and thromboxane A 2 (a potent platelet aggregator and vasoconstrictor), possibly reducing the risk of stroke.

• EPA and DHA lead to a decrease in leukotriene B 4 (a potent chemotactic agent and an inducer of inflammation), resulting in less inflammation (especially allergic). • ©-3 fatty acids are incorporated into membrane phospholipids and alter membrane fluidity, signal transduction and gene expression. • Fish oil inhibits hepatic lipogenesis and stimulates fatty acid oxidation in the liver, resulting in decreased triglyceride (triacylglycerol) concentrations. • As long as essential fatty acids (linoleic acid and alpha-linolenic acid) are consumed through the diet, no deficiency exists. In cases where not enough essential fatty acids are consumed, symptoms are flaky and itchy skin. In severe cases diarrhea and frequent infection can be seen. However, about one tablespoon of polyunsaturated plant oil such as soybean and canola oil meet essential fatty acid needs. • Dosage Back to sub-topics

• There is no DRI for fish oil. Certain ©-3 fatty acids such as a-linolenic acid can be obtained from nuts and soybeans. Since a-linolenic acid (18:3 w3) cannot be synthesized in animal cells, dietary sources are very important. Alpha-linolenic acid is converted to EPA and DHA in the body, however this conversion is somewhat inefficient in terms of providing DHA and EPA directly to cells. Premature infants appear to have a limited ability to make EPA and DHA. Since DHA and EPA are precursors to eicosanoids with many biological functions and a component in brain structure lipids, fish oil should be incorporated into daily diets throughout life. • High intake of fatty fish (one serving per day) can result in intakes of EPA and DHA of ~ 900 mg/day, an amount shown to beneficially affect coronary heart disease development. To decrease triacylglycerol concentrations, 3 - 5 g of fish oil (depending on purity) should be taken daily with a physician's consultation. Consumption of at least 2 fish servings per week is now recommended by the American Heart Association because of the cardiovascular benefits of fish. 2 • For total dietary intake of omega-6 and omega-3 fatty acids, a ratio of no more than 5:1 (5g ©6 for every 1 g of ©3) is recommended. • According to the Agency for Healthcare Research and Quality (ARHQ) in 2004, mean intakes of EPA and DHA were only 40 and 70 mg/day, respectively. This suggests a great need for increased intakes of EPA and DHA to meet the recommended levels for promoting heart health. 30 • The American Heart Association (AHA) recommends at least 1 gram/day of EPA + DHA for patients with coronary heart disease. Fish oil supplements can be considered to achieve this daily dose in consultation with a physician. 29 • The American Heart Association (AHA) also recommends 2-4 grams/day of EPA + DHA as capsules (e.g. fish oil supplements) under a physicians care for patients requiring triglyceride-lowering therapy. 29

Toxicity Back to sub-topics 3 15

• In 2000, the FDA final ruling regarding intake of EPA and DHA from diet and supplements (such as fish oil), should not exceed 3 grams/day. 50 • Possible side effects of very high doses of fish oil include diarrhea, upset stomach and other types of gastrointestinal distress. • Manufacturers of fish oil supplements who pass independent testing measures and/or employ high quality-control measures, carry a fish oil product free of detectable total mercury content. Analysis using special cold vapor atomic absorption spectroscopy can detect if as little as 0.1 micrograms of total mercury per gram is present. 11

•

Women of child-bearing age and women who are pregnant or lactating need to be aware of consuming certain fish in their diet, due to the mercury content of some fish that can damage the developing brain of an unborn baby:

-Fish to avoid: women who are pregnant should avoid eating swordfish, shark, king mackerel, tilefish and large tuna steaks. Pregnant women should also not eat raw meat or fish (sushi).

-Fish known to be safe to eat: wild salmon, oysters, shrimp, farm-raised channel catfish, farm-raised rainbow trout, flounder, perch, tialpia, clams, scallops and red swamp crayfish. These fish have the lowest level of mercury and can be eaten more than once a week. Dietary Sources Back to sub-topics

• Rich dietary sources of w-3 fatty acids such as EPA and DHA come from cold-water marine fish including: cod tuna salmon halibut shark mackerel herring bluefish flounder swordfish • Certain types of shellfish, such as shrimp, also contain ©-3 fatty acids. A seven ounce portion herring usually provides 3.2 g salmon or bluefish 2.4 Seven ounces tuna approximately 1 • Supplements generally contain oils from marine fish or seal oil. Concentrations of ©-3 fatty acids, EPA and DHA, are described on the labels. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Drug-Supplement Interaction Back to sub-topics 3

• Although specific studies have not been conducted, the possibility of drug interactions exists. Specifically, ©-3 fatty acids (contained in fish oils) can have an effect on the clotting system, and excessive concentrations could lead to bleeding problems. • Patients on anticoagulant therapy (i.e. warfarin or heparin) need to consult with their physician regarding appropriateness and safety of using fish oils. It is not recommended to consume more than 3 grams of EPA and DHA from the diet and/or supplementation. 50 • Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen [Motrinâ] and aspirin (salicylic acid), may conceivably present an increased risk of bleeding if combined with high amounts of fish oil. • Fish oil may impair blood's ability to coagulate when combined with pentoxifylline [Trentalâ], used for treatment of intermittent claudication. Patients on this medication should consult a physician or pharmacist before concomitant use of fish oil.

Research Summary Back to sub-topics Serum Triacylglycerol Concentrations: More than half of all Americans adults have high serum cholesterol concentrations (hypercholesterolemia). Nearly 20% have serum cholesterol concentrations over 240 mg/day, which is considered very high. Elevated serum cholesterol concentrations increase the risk for heart disease and stroke. 4 5 6 Hypertriacylglycerolemia is also a risk factor of cardiovascular disease. A randomized controlled trial on 31 women who were assigned to receive either 4 g EPA/DHA (4:0 control group), 4g EPA/DHA plus 1g gamma-linolenic acid (GLA) (4:1), 2 g GLA (4:2), or 4g GLA (4:4) daily for 28 days. Measurement of plasma lipids and fatty acids at 0 and 28 days revealed plasma triacylglycerol concentrations were significantly lower on day 28 than on day 0 in the 4:0, 4:1, and 4:2 groups. It was estimated that the 4:2 group provided a 43% reduction in 10 year risk of myocardial infarction. Supplemental fish oil and GLA helped to improve plasma lipids and fatty acid profiles in women. 18 Another study on 59 overweight, non-smoking men with mild hyperlipidemia, who consumed 4 g of EPA, DHA or olive oil for 6 weeks, reported decreased serum triacylglycerol concentrations in those taking EPA or DHA, both found in fish oil. In addition, the DHA-supplemented group also had a significant increase in serum HDL 2 cholesterol concentrations. 19

Immunity:Studies have shown that the ratio of w-3 fatty acids to w-6 fatty acids (common in the typical American diet) may play an important role in immunity and inflammation. Studies involving very high daily intake of (9.4 g EPA plus 5 g DHA per day) have shown improvements in people with inflammatory disorders. A study of low to moderate concentrations of fish oil supplementation, using a daily intake of 0.58 g of EPA and 1.67 g of DHA demonstrated modest improvements in indicators of immunity and possible reductions in inflammation. 7 Perioperative administration of n-3 fatty acids has shown beneficial effects on inflammatory and immune responses in patients undergoing abdominal surgery. A downregulation of inflammatory response prior to surgery, as well as a reduction in post operative immune suppression, occurred in those patients supplemented with n-3 fatty acids. N-3 fatty acids may be beneficial for patients undergoing severe surgical interventions by modulating immune response. 20

Cancer: It has been well established that dietary intake of fat is correlated with the incidence of certain types of cancer. However, researchers have discovered that increasing w-3 fatty acids, found in oils from cold water fish, inhibit growth of many types of cancerous cells. Studies have shown that w-3 fatty acids inhibit growth of human papillomavirus-infected cells, a known type of precancerous cell. Researchers suggest that increasing the amounts of w-3 fatty acids in the diet may help protect against certain types of cancer and that decreased tumor cell growth may be due to an inhibitory effect of w-3 fatty acids on lipid peroxidation. 8 9 n-6 polyunsaturated fatty acids (PUFAs) may be a contributor to the risk of breast cancer in the United States. The American diet contains higher amounts of n-6 PUFA and is low in n-3 PUFAs. One recent case-control study examined breast adipose tissue from breast cancer patients and controls. When adjusted for age, levels of n-6 PUFAs were significantly higher in the breast cancer cases than in controls. N-3 PUFAs derived from fish oils may have a protective effect on breast tissue. 21 Another case-control study confirming the findings of Bagga, et al., measured the fatty acid composition in breast adipose tissue of patients with invasive, nonmetastatic breast carcinoma and benign breast disease. Results from biopsies of breast adipose tissue indicated an inverse relationship between breast cancer risk and n-3 fatty acid levels in breast adipose tissue. These data suggests a protective effect of n-3 fatty acids on breast cancer risk. 21

Atherosclerosis: Atherosclerosis is a disorder characterized by the formation of fatty streaks and eventually hard plaques inside the arteries. These fatty streaks and hard plaques damage the arteries, reducing elasticity and blood flow. Atherosclerosis is a contributing factor to arteriosclerosis (hardening of the arteries) and is the cause of coronary artery disease. A recent meta-analysis was conducted on the effects of dietary and supplemental intake of n-3 polyunsaturated fatty acids (PUFAs) on CHD. Eleven randomized controlled trials including 7,951 patients in the intervention group and 7855 patients in the control group. There was no difference in summary estimates between dietary and non-dietary (supplemental) interventions of n-3 PUFAs. Results from various risk ratios suggested that both dietary and supplemental n-3 PUFAs, such as in fish oil, reduced overall mortality, mortality due to MI, and sudden death in patients with CHD. 15 Two recent reports substantiate the role of omega-3 fatty acid consumption in risk reduction for sudden death. 16

Menstrual Pain:Women who suffer from menstrual pain often have significantly lower daily intake of w-3 fatty acids. It has been suggested that a high ratio of w-6 to w-3 fatty acids could lead to increased pain and other symptoms of dysmenorrhea.Omega-3 fatty acids found in fish oil have been shown to relieve pain from dysmenorrhea over placebo. 22 Dysmenorrhea, or pain and cramping during menstruation, may be common among young women. A randomized controlled trial was conducted to determine if omega-3 fatty acid supplementation relieves symptoms of dysmenorrhea in adolescent girls. One group of girls received either fish oil (1080 mg EPA, 720 mg DHA) for two months and a placebo for an additional two months. The second group of girls received placebo for the first two months, then fish oil for the next two months. After the 2-month period of fish oil supplementation, there was a significant reduction in the Cox Menstrual Symptom Scale from baseline. These results suggested a beneficial effect of omega-3 supplementation on symptoms of dysmenorrhea in adolescents. 23

Depression: Several small studies have recently indicated that fish oil intake may help to alleviate depression. A recent double-blind placebo controlled clinical trial was conducted on patients with persistent depression undergoing standard antidepressant therapy. Patients were randomized to receive various dosages of ethyl-eicosapentaenoate (1, 2, or 4 grams/day) or placebo for 12 weeks in addition to their antidepressant medication. Assessment was conducted by depression rating scales and a depression inventory. Results indicated that treatment with 1 gram/day of ethyl-eicosapentaenoate was effective in treating depressed patients despite adequate antidepressant therapy. 24 A case report on a severely depressed suicidal male patient, resistant to treatment by standard antidepressant therapy, was given the n-3 essential fatty acid, eicosapentaenoic acid (EPA). Supplemental EPA clinically improved all symptoms of depression and improved social phobia within one month. Treatment with EPA also accompanied by a reduction in lateral ventricular volume and reduced neuronal phospholipid turnover. 25 The omega-3 fatty acid, docosahexanoic acid (DHA), may also play a role in depression. Geographic areas with a higher DHA consumption are associated with decreased rates of depression, and conversely, a deficiency of DHA has been linked with depression. Massachusetts General Hospital and Harvard Medical School are currently conducting controlled trials with DHA to help determine the potential role of DHA supplementation in depression in comparison to standard antidepressants. More large-scale, placebo controlled, double-blind trials comparing the efficacy and safety of DHA against standard antidepressants are warranted. 26

Inflammatory Conditions/Diseases:A recent review from the Center for Genetics, Nutrition and Health discusses a number of the placebo-controlled trials on the benefits of fish oil in chronic inflammatory and autoimmune disorders, such as rheumatoid arthritis, Crohns disease, ulcerative colitis, multiple sclerosis, migraines, etc. Many of the trials reveal benefit of fish oil supplementation, including a reduction in disease activity and decreased use of anti-inflammatory drugs. 27 The major therapy for arthritis diseases is nonsteroidal anti-inflammatory drugs, which often cause undesirable side effects. One study showed that combined incubation of cartilage condrocyte membranes and n-3 fatty acids resulted in decreased proteoglycan degrading enzymes (aggrecanases) and expression of inflammation-inducible cytokines (TNF-a) and cyclooxygenase (COX-2). This suggested possible beneficial effects of fish oil on arthritis diseases. 14 It is suggested that a minimum daily intake of 3 g of fish oil is necessary to decrease inflammation in rheumatoid arthritis. 28 One double-blind, randomized controlled clinical trial studied the efficacy of fish oil supplementation in patients with rheumatoid arthritis over 15 weeks. The study examined the effects of fish oil supplementation (3-6 capsules/day) in 50 patients with rheumatoid arthritis, who were consuming a diet low in omega-6 fatty acids. Supplementation with fish oil (40 mg/kg/BW) with a low dietary omega-6 intake ( 28

Note: The Arthritis Foundation now recommends increasing intake of omega-3 fatty acids for joint health, either by diet and/or omega-3 fatty acid supplements, such as fish oil.

References Back to sub-topics 1 Harris WS: n-3 fatty acids and serum lipoproteins: Am J Clin Nutr 65: 1645S-1654S. human studies. 2 Krauss RA: AHA guideline revision 2000:a statement for Circulation 102: 2284-2299. healthcare professionals from the Nutrition Committee of the American Heart Association. 3 Burnham TH: Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons. 2001; 4 Goodfellow J, et al: Dietary supplementation with marine J Am Coll Cardiol 35: 265-270. omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. 5 Lu G, et al: Omega-3 fatty acids alter lipoprotein J Nutr Biochem 10: 151-158. subfraction distributions and the in vitro conversion of very low density lipoproteins to low density lipoproteins. 6 Fisher WR, et al: Apolipoprotein B metabolism in J Lipid Res 39: 388-401. hypertriglyceridemic diabetic patients administered either a fish oil- or vegetable oil-enriched diet. 7 Healy DA, et al: Effect of low-to-moderate amounts of dietary Lipids 35 : 763-768. fish oil in nuetrophil lipid composition and function. 8 Chen D and Fish oil constituent docosahexa-enoic acid Carcinogenisis 20: 249-254. Auborn K: selectively inhibits growth of human papillomavirus immortalized keratinocytes. 9 Welsch C: The role of lipid peroxidation in growth Ad Exp Med Biol 400B: 849-860. suppression of human breast carcinoma by dietary fish oil. 10 von Schacky C, et The effect of dietary omega-3 fatty acids on Ann Int Med 130: 554-562. al: coronary atherosclerosis-a randomized double-blind placebo-controlled trial. 11 Deutch B, et al: Menstrual discomfort in Danish women Nutr Res 20: 621-631. reduced by dietary supplements of omege-3 PUFA and B12 (fish oil or seal oil capsules). 12 Stoll AL, et al: Omega 3 fatty acids in bipolar disorder-a Arch Gen Psychiat 56: 407-412. preliminary double-blind, placebo controlled trial. 13 Edwards R, et al: Omega-3 polyunsaturated fatty acid levels in J Affective Disorders 48: 149-155. the diet and in red blood cell membranes of depressed patients. 14 Curtis C, et al: n-3 fatty acids specifically modulate J Biol Chem 274: 721-724. catabolic factors involved in articular cartilage degradation. 15 Schaller, JL. Mercury and Fish Oil Supplements. Medscape General Medicine 2001 April 13, 2001 Letter. 16 Bucher HC, et al. N-3 polyunsaturated fatty acids in coronary Am J Med 2002; 112:298-304 heart disease: a meta-analysis of randomized controlled trials. 17 Jones, PJ,and Effect of n-3 polyunsaturated fatty acids on Nutr Rev 2002; 60:407-9. Lau, VW. risk reduction of sudden death. 18 Laidlaw, M and Effects of supplementation with fish oil Am J Clin Nutr 2003; 77:37-42 Holub, BJ. derived n-3 fatty acids and gamma-linolenic acid on circulating plasma lipids and fatty acid profiles in women. 19 Mori, TA, et al. Purified eicosapentaenoic and Am J Clin Nutr 2000; 71:1085-1094. docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hypercholesterolemic men. 20 Weiss, G, et al. Immunomodulation by perioperative Br J Nutr 2002; 87 Suppl 1:S89-94. administration of n-3 fatty acids. 21 Bagga, D, et al. Long-chain n-3-to-n-6 polyunsaturated fatty Nutr Cancer 2002; 42:180-5. acid ratios in breast adipose tissue from women with and without breast cancer. 22 Wilson, ML and Herbal and dietary therapies for primary and Cochrane Database Syst Rev 2001; Murphy, PA. secondary dysmenorrhea. CD002124 23 Harel Z, et al. Supplementation with omega-3 Am J Obstet Gynecol 1996; polyunsaturated fatty acids in the 174:1335-8. management of dysmennorrhea in adolescents. 24 Peet M and A dose-ranging study of the effects of Arch Gen Psychiatry 2002; 59:913-9. Horrobin DF. ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. 25 Puri BK, et al. Eicosapentaenoic acid in treatment-resistant Int J Clin Pract 2001; 55:560-3. depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover. 26 Mischoulon, D Docosahexanoic acid and omega-3 fatty Psychiatr Clin North Am 2000; and Fava, M. acids in depression. 23:785-94. 27 Simopoulos, AP. Omega-3 Fatty acids in inflammation and J Am Coll Nutr 2002; 21:495-505. autoimmune diseases. 28 Volker D, et al. Efficacy of fish oil concentrate in the J Rheumatol 2000; 27:2343-6 treatment of rheumatoid arthritis. 29 Kris-Etherton P, et American Heart Association Scientific Circulation 2002; 106:2747-2757. al. Statement: Fish Consumption, fish oil, omega-3 fatty acids, and cardiovascular disease risk. 30 Agency for Evidence Report Number 94. Effects of March 2004, ARHQ website. Healthcare Research omega-3 fatty acids on cardiovascular Quality (ARHQ). disease. 31 Lewis A, et al. Treatment of hypertriglyceridemia with J Am Acad Nurse Pract 2004; omega-3 fatty acids: a systematic review. 16:384-95 32 Jeyaraj S, et al. Effect of Combined Supplementation of Fish Indian Heart J 2005; 57:327-31. Oil with Garlic Pearls on the Serum Lipid Profile in Hypercholesterolemic Subjects. 33 Kew S, et al. Effects of oils rich in eicosapentaenoic and Am J Clin Nutr 2004; 79:674-81. docosahexaenoic acids on immune cell composition and function in healthy humans. 34 Trebble T, et al. Prostaglandin E2 production and T cell Am J Clin Nutr 2003; 78:376-382. function after fish oil supplementation: response to antioxidant co-supplementation. 35 Lopez-Garcia E, et Consumption of (n-3) fatty acids is related to J Nutr 2004; 134:1806-1811. al. Plasma Biomarkers of Inflammation and Endothelial Activation in Women. 36 Mickleborough Protective effect of Fish Oil Supplementation CHEST 2006; 129:39-49. TD, et al. on Exercise-Induced Bronchoconstriction in Asthma. 37 Low fat dietary intervention with omega-3 Prostaglandins Leukot Essent Fatty Weinstock-Guttman fatty acid supplementation in multiple Acids 2005; 73:397-404. B, et al. sclerosis patients. 38 Berbert AA, et al. Supplementation of fish oil and olive oil in Nutrition 2005; 21:131-6. patients with rheumatoid arthritis. 39 Adam O, et al. Anti-inflammatory effects of a low Rheumatol Int 2003; 23:27-36. arachidonic acid diet and fish oil in patients with rheumatoid arthritis. 40 Duffy EM, et al. The clinical effect of dietary supplementation J Rheumatol 2004; 31:1551-6. with omega-3 fish oils and/or copper in systemic lupus erythematosus. 41 MacLean CH, et Effects of omega-3 fatty acids on cancer JAMA 2006; 295:403-15. al. risk: a systematic review. 42 Saldeen P, and Women and omega-3 fatty acids. Obstet Gynecol Surv 2004; Saldeen T. 59:722-30;quiz 745-6. 43 Fugh-Berman A Complementary and alternative medicine Reprod Toxicol 2003; 17:137-52. and Kronenberg F. (CAM) in reproductive-age women: a review of randomized controlled trials. 44 Silvers K, et al. Randomised double-blind placebo-controlled Prostaglandins, Leukotrienes and trial of fish oil in the treatment of Essential Fatty Acids 2005; 72:211-18. depression. 45 Otto SJ, et al. Increased risk of postpartum depressive Prostaglandins Leukot Essent Fatty symptoms is associated with slower Acids 2003; 69:237-43. normalization after pregnancy of the functional docosahexaenoic acid status. 46 Freeman MP, et Randomized dose-ranging pilot trial of Acta Psychiatr Scand 2006; 113:31-5. al. omega-3 fatty acids for postpartum depression. 47 Lauritzen L, et al. Maternal fish oil supplementation in lactation Pediatr Res 2005; 58:235-42. and growth during the first 2.5 years of life. 48 Lauritzen L, et al. Maternal fish oil supplementation in Reprod Nutr Dev 2005; 45:535-47. lactation: effect on developmental outcome in breast-fed infants. 49 Olsen SF, et al. Randomised clinical trials of fish oil BJOG 2000; 107:382-95. supplementation in high risk pregnancies. Fish Oil Trials in Pregnancy (FOTIP) Team. 50 U.S.FDA Center Letter Regarding Dietary Supplement Health www.cfsan.fda.gov/~dms/ds-ltr11.html for Food Safety and Claim for Omega-3 Fatty Acids and October 31, 2000 Applied Nutrition Coronary Heart Disease. October 31, 2000. 51 Young GS, et al. Effect of randomized supplementation with Reprod Nutr Dev 2005; 45:549-58. high dose olive, flax, or fish oil on serum phospholipid fatty acid levels in adults with attention deficit hyperactivity disorder. 52 Voigt RG, et al. A randomized, double-blind, J Pediatr 2001; 139:173-4. placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. Dietary Flaxseed Oil Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Flaxseed has been used for constipation and dry, itching skin. -Fish Oil • Flaxseed is also called linseed and was used to make fabric, called linen. -Flaxseed Oil • Flaxseed is an oil seed and contains 41% fat, 28% fiber and 21% protein. -Glucosamine • Flaxseeds and ground flaxseed contain three important components: alpha-linolenic acid, soluble fiber, and lignans. -Kelp • Flaxseed oil is rich in polyunsaturated fatty acids, and is the richest known source of -L-Arginine alpha-linolenic acid, one of the omega-3 (n-3) fatty acids. -Lecithin • Flaxseed is the richest known source of the lignan secoisolariciresinol diglucoside -L-Lysine (SDG), the main mammalian lignan precursor. -Lycopene • Alpha-linolenic acid and lignans may have chemopreventive actions. -Melatonin -Methylsulfonylmethane Functions Back to sub-topics -Pantethine -Phytonutrients • Alpha-linolenic acid (ALA) is converted to eicosapentaenoic acid (EPA) and -Plant Sterols/Stanols docosahexaenoic acid (DHA). EPA is a precursor for the series-3 prostaglandins, the series-5 leukotrienes, and the series-3 thromboxanes. -S-adenosyl-L-methionine • EPA and DHA modify cell membrane fluidity and the products of EPA (prostaglandins, -Soy Isoflavones leukotrienes, and thromboxanes) have anti-inflammatory and anti-thrombotic activities. -Vinpocetine • The n-3 fatty acids are important for development of an infants brain and retina, and are thus essential during pregnancy and breastfeeding. • Lignan is metabolized by intestinal microflora to form enterolactone and enterodiol, which have phytoestrogenic activity.

Dosage Back to sub-topics Three to 5 g daily.

Toxicity Back to sub-topics Not known.

Dietary Sources Back to sub-topics Flaxseeds, ground flaxseed, crushed flaxseeds, and flaxseed oil are available. These different forms have slightly different activities, due to differences in bioavailability and content. Ground or crushed seeds have higher bioavailability than whole flaxseeds. Flaxseed oils have higher concentrations of lignans and alpha-linolenic acid, but do not contain fiber.

Drug-Supplement Interaction Back to sub-topics 1 2 3

Patients taking anticoagulant agents, such as warfarin [Coumadinâ], may experience abnormal bleeding. Patients may benefit by starting the medication at a lower dose with concomitant ingestion of flaxseed oil, and those with a bleeding disorder should consult a physician or pharmacist before starting the therapy.

Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship. Research Summary Back to sub-topics Platelet Aggregation: Healthy young subjects were given either flaxseed oil (40 g/day) or sunflower seed oil for 23 days and platelet aggregation was measured. Platelets from the flaxseed oil group were rich in EPA, compared to the control group did not. Aggregation response induced by 0.75 and 2 mcg of collagen was decreased in the flaxseed oil-fed group. The authors suggested that ingesting flaxseed oil may protect against cardiovascular disease through a decreased platelet aggregation. 4

Inflammation: It is known that dietary fat changes fatty acid composition in cell membranes, thus resulting in altered production of inflammatory mediator. 5 In healthy subjects, tumor necrosis factor a (TNFa) and interleukin 1b (IL-1b) were measured. Healthy male subjects were given flaxseed oil (daily average intake 13.7 g) or sunflower oil (daily average intake 1.1 g) for 4 weeks and switched to fish oil (9 g/day) for a further 4 weeks. As a result, flaxseed oil decreased TNFa and IL-1b production in mononuclear cells by ~ 30%. Further intake of fish oil inhibited cytokine production by ~ 80%. Cytokine production was inversely related to the increase of EPA, a n-3 fatty acid derived from flaxseed oil and fish oil. This result may indicate that feeding n-3 fatty acid, e.g. from flaxseed oil, may reduce the risk of inflammatory disorders such as rheumatoid arthritis and atherosclerosis. 6

References Back to sub-topics 1 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society GK: Information. of Health-System Pharmacists. 2001; 3 Bratman S: The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. Interactions Bible. 2001; 4 Allman MA, Supplementation with flaxseed oil versus Eur J Clin Nutr 49: 169-178. et al: sunflower seed oil in healthy young men consuming a low fat diet: effects on platelet composition and function. 5 Caughey GE The effect on human tumor necrosis factor Am J Clin Nutr 1996 63: 116-122 alpha and interleukin 1b production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. 6 Francois Supplementing lactating women with Am J Clin Nutr 2003 77: 226 CA, et al flaxseed oil does not increase 233 docosahexaenoic acid in their milk 7 Brooks JD, Supplementation with flaxseed alters Am J Clin Nutr 2004 79: 318 et al. estrogen metabolism in postmenopausal 325 women to a greater extent than does supplementation with an equal amount of soy. 8 Thompson Dietary flaxseed alters tumor biological Clin Cancer Res 2005 11: 3828 LU, et al markers in postmenopausal breast cancer. 3835 9 Lucas EA, et Flaxseed improves lipid profile without J Clin Endocrinol Metab 2002 87: al. altering biomarkers of bone metabolism in 1527 1532 postmenopausal women. 10 Dodin S, et The effects of flaxseed dietary supplement J Clin Endocrinol Metab 2005 90: al on lipid profile, bone mineral density, and 1390-1397 symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial. 11 Harper CR, Flaxseed oil increases the plasma J Nutr 2006 136: 83-87 et al concentrations of cardioprotective (n-3) fatty acids in humans. 12 Fish consumption, fish oil, omega-3 fatty Circulation 2002 106: 2747-2757 Kris-Etherton acids, and cardiovascular disease. PM, et al Dietary Glucosamine Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Glucosamine (GS) has been used for the treatment and prevention of osteoarthritis, by -Fish Oil itself or in combination with chondroitin sulfate (CS). Osteoarthritis is a major cause of -Flaxseed Oil disability among the elderly. Osteoarthritis is an age-related disease of joint cartilage, -Glucosamine which results from structural change of the joints. • GS is an amino monosaccharide found in most tissues in the body. -Kelp • GS is involved in the biosynthesis of glycosaminoglycans and proteoglycans, essential -L-Arginine for the extracellular matrix of connective tissues. -Lecithin • Glucosamine is synthesized in chondrocytes in the body from glucose and glutamine. -L-Lysine • The sources of glucosamine are natural (marine exoskeletons) and synthetic. -Lycopene -Melatonin -Methylsulfonylmethane Functions Back to sub-topics -Pantethine -Phytonutrients • Glucosamine is found in hyaluronic acid, an essential component of extracellular matrix -Plant Sterols/Stanols of connective tissue and chitin. • Glucosamine enhances proteoglycan synthesis, a fundamental component found in -S-adenosyl-L-methionine articular cartilage. -Soy Isoflavones • Glucosamine inhibits the cartilage-destructive enzyme collagenase. -Vinpocetine • Glucosamine has anti-inflammatory and antioxidant actions. • Glucosamine blocks the generation of superoxide free radicals by macrophages.

Dosage Back to sub-topics Recommended dosage of GS for osteoarthritis is 1500 mg daily to treat osteoarthritis. GS is commercially available in a hydrochloride sulfate and N-acetyl form.

Toxicity Back to sub-topics

• GS is well tolerated. In a 3-year study using 1500 mgs of GS daily, no severe side effects were found. 1 • The most common side effect from GS intake is mild gastrointestinal discomfort. • In animals with or without diabetes, intravenous injection of GS resulted in glucose resistance. However, after 3 years of treatment with 1500 mg GS daily, routine laboratory tests did not show any change in glycemic homeostasis. 1 • According to a review article on the safety of glucosamine and chondroitin sulfate, glucosamine has not exhibited toxicity when tested in doses that far exceed what has been used in human clinical trials. Glucosamine also fared much better than indomethacin regarding prolonged treatment with a therapeutic margin of 10-30 times more favorable than indomethacin. Because of the lack of sufficient safety data, children, pregnant and lactating women should avoid taking GS. 10 11 • Those with shellfish allergies should use glucosamine with caution or choose a vegetarian glucosamine source. Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 2 3 4

• No health hazards or side effects are known. • Caution with pregnancy or nursing; consult physician before using. • From a theoretical standpoint, chondroitin does have some structural similarity to heparin and it might have weak anticoagulant activity. Glucosamine, by itself, most likely has no anticoagulant activity. There have been no reports of interactions with warfarin at recommended dosages of glucosamine or chondroitin. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary Back to sub-topics Mechanism of Action: • In cell culture using bovine chondrocytes, glycosaminoglycan synthesis was measured by incorporation of 35-sulfate. Either glucosamine or chondroitin sulfate alone slightly increased glycosaminoglycan synthesis while the combination of glucosamine and chondroitin dramatically stimulated the incorporation of 35-sulfate. 16 • Chan and colleagues studied the effects of physiologically relevant concentrations of glucosamine and chondroitin sulfate on gene expression and synthesis of nitric oxide and prostaglandin E-2 (PGE-2) in cytokine stimulated articular cartilage explants. Results show that chondroitin sulfate and the glucosamine/chondroitin combination at concentrations attainable in the blood down-regulated interleukin-1 induced mRNA expression of inducible nitric oxide synthase at 24 and 48 hour post culture. Additionally, synthesis of nitric oxide was reduced with chondroitin sulfate alone and the glucosamine/chondroitin combination. Repression of COX-2 transcripts by glucosamine and chondroitin was accompanied by a simultaneous reduction in PGE-2. The authors conclude that physiologically relevant concentrations of glucosamine and chondroitin sulfate can regulate expression of genes related to inflammation, and the synthesis of nitric oxide and PGE-2 (both having pro-inflammatory roles in diseased joints), providing a plausible explanation for their supposed anti-inflammatory properties. 17 • Proteoglycan Synthesis: Proteoglycans synthesized in monkey arterial smooth muscle cells in the presence of glucosamine were less sulfated, smaller and found to have lower affinity to LDL, thus indicating that glucosamine may be favorable to atheroclerosis. 8 In cell culture system, using chondrocytes from human osteoarthritic articular cartilage, GS increased proteoglycan synthesis. 9 Osteoarthritis: Meta-Analyses, Reviews:

• A 2005 systematic review of randomized controlled studies investigated the structural and symptomatic efficacy and safety of glucosamine in knee osteoarthritis (OA). The studies included were double-blind, randomized, controlled trials that evaluated oral glucosamine for long-term treatment in knee OA and lasted at least one year. Reported outcome measures were symptom severity and disease progression as assessed by joint space narrowing. Results show glucosamine was more effective than placebo in delaying joint space narrowing in knee OA and risk of disease progression was reduced by 54%. The pooled effect sizes for pain reduction and improvement in physical function were positive for glucosamine. The evidence suggests that glucosamine may be effective and safe in delaying the progression and improving the symptoms of knee OA. In the studies, glucosamine caused no more adverse effects than placebo. Due to the sparse data on structural efficacy and safety, further studies are needed. 25 • A comprehensive meta-analysis on randomized placebo controlled trials was performed to assess the efficacy of glucosamine and/or chondroitin in knee osteoarthritis (OA). Analyses were based on the outcomes that are required for demonstrating the efficacy of a drug to be used in the treatment of OA: radiological evolution assessed by JSN (joint space narrowing); evaluation of pain by visual analog scale (VAS pain); joint mobility; Lequesne Index (LI) and Western Ontario MacMaster University Osteoarthritis Index (WOMAC). Results from analyses demonstrated the efficacy of glucosamine on all outcomes, including JSN and WOMAC. An outstanding finding was the structural efficacy (disease-modifying property) of glucosamine on JSN. This finding suggests that long-term (at least 3 years) glucosamine supplementation at a dose of 1500mg/day can slow the degenerative process of the joint cartilage. Further studies are warranted to confirm the long-term effects of glucosamine. Chondroitin was found to be efficacious on the LI, VAS pain and mobility. Further studies are also needed to confirm and evaluate the structural efficacy of chondroitin. Safety for both of these compounds was well-established. 12 • Another meta-analysis of GS reviewed more than 15 papers. It was found that in most studies GS and CS moderately improved symptoms of osteoarthritis. Analysis also suggested that efficacy of GS or CS might be recognized in longer than a month. 6 • In a review of the clinical use of glucosamine and chondroitin sulfate, Brief and colleagues conclude that both agents demonstrate efficacy with regard to reduction of joint pain/tenderness and improved mobility. Additionally, there was no evidence of toxicity. 18 Osteoarthritis: Clinical Trials

• The Glucosamin/chondroitin Arthritis Intervention Trial (GAIT) was a multi-center, double-blind, placebo-controlled study designed to evaluate the efficacy of glucosamine, chondroitin, and the two combined in treating knee pain related to osteoarthritis. The researchers randomly assigned 1,538 patients with symptomatic knee osteoarthritis to receive 1500 mg glucosamine hydrochloride, 1200 mg chondroitin sulfate, a combination of the two, 200 mg celecoxib or placebo every day for 24 weeks. Primary outcome measures did not show that either supplement alone or combined was efficacious. However, analysis of a subgroup of patients with moderate-to-severe pain demonstrated that combination therapy (glucosamine + chondroitin) significantly decreased knee pain related to osteoarthritis. This finding, which suggests efficacy for glucosamine and chondroitin in those with moderate-to-severe symptoms, is the first one to demonstrate efficacy of the combination, and adds to the existing body of research which demonstrates efficacy of these components. 26 • A 2004 double-blind, placebo-controlled study compared the efficacy and safety of glucosamine alone, MSM alone, or the combination of the two in knee osteoarthritis. 118 patients were randomized to receive either 500 mg glucosamine, 500 mg MSM, 500 mg glucosamine plus 500 mg MSM, or placebo 3 times daily for 12 weeks. Results revealed glucosamine, MSM, and their combination significantly improved signs and symptoms of osteoarthritis compared to placebo. Additionally, the combination therapy (glucosamine + MSM) showed better efficacy than either agent alone in reducing pain and swelling, improving joint function, and had a more rapid onset of analgesic and anti-inflammatory activitiy. The authors conclude that the combination of MSM with glucosamine provides better and more rapid improvement in patients with osteoarthritis. 19 • Post-menopausal women are the most frequently affected by knee osteoarthritis. A pre-planned combination of two three-year randomized, placebo-controlled, prospective, independent studies was done to evaluate the effects of glucosamine sulfate in 319 post-menopausal women with knee osteoarthritis. After 3 years, post-menopausal participants in the glucosamine group showed no joint space narrowing and WOMAC index scores improved. Those in the placebo group did experience joint space narrowing and WOMAC scores revealed a trend for worsening. This analysis demonstrates that a pharmacological intervention for osteoarthritis has a disease-modifying effect in this particular group. 21 • Cibere and colleagues assessed the efficacy of glucosamine sulfate in knee osteoarthritis in 137 current users who experienced moderate improvement in kee pain after starting glucosamine. The study was a 6 month randomized, double-blind, placebo-controlled glucosamine discontinuation trial. Primary outcome was proportion of disease flares in both glucosamine and placebo groups. Disease flare was seen in 42% (28 of 66) of placebo participants and 45% (32 of 71) of glucosamine participants. The data from this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate. 22 • Christgau and colleagues investigated whether early response in a newly developed biochemical marker of collagen type II degradation (CTX-II) could reflect long term preservation of hyaline cartilage. Researchers collected urine samples from 212 knee osteoarthritis patients participating in a clinical trial. Results revealed those with high cartilage turnover presented a significant decrease in CTX-II after 12 months of glucosamine treatment. The 12 months change in CTX-II in osteoarthritis patients with elevated CTX-II at baseline correlated with the change in average joint space width after 36 months. Increased baseline levels of CTX-II were associated with a worsening WOMAC score. These results indicate the measurement of urinary collagen type II C-telopeptide fragments enables the identification of osteoarthritis patients with high cartilage turnover who at the same time are most responsive to therapy with structure modifying drugs. 23 • A 3-year randomized, double-blind, placebo-controlled trial was conducted on the effects of 1500 mg of glucosamine sulfate versus placebo in delaying the progression of osteoarthritis (OA) of the knee. Two hundred and two patients were included in the study with mild to moderately severe knee OA for 10 years or greater. Amongst the patients who did not complete the 3-year treatment course (either receiving placebo or glucosamine sulfate), there was no significant difference. After each year of treatment, patients receiving glucosamine sulfate did not experience joint space narrowing (loss in joint space width) as compared to the placebo group (p 13 • A randomized, double blind, placebo-controlled study was conducted in 212 patients using 1500 mg glucosamine daily for 3 years. During the study, patients on placebo had a progressive joint-space narrowing, while patients on glucosamine did not have significant joint-space loss. Incidence of side effects such as GI discomfort were similar in both groups. Results of this study indicated that glucosamine may be a choice in the treatment of osteoarthritis. 1 • GS vs. NSAIDs: Glucosamine was compared with ibuprofen to see the effect on symptoms of osteoarthritis of the knee. Almost 200 patients were given either 1500 mg glucosamine sulfate or 1200 mg daily ibuprofen for 4 weeks. Results revealed both treatments improved the symptoms of osteoarthritis. Although ibuprofen showed a slightly faster effect, there was no difference in effectiveness between treatments. Glucosamine sulfate was significantly better tolerated than ibuprofen, with fewer adverse effects (6% in GS vs.35% in ibuprofen group,p 7 Glucosamine Effect on Insulin/Glucose There has been concern regarding glucosamine supplementation and its effect on blood glucose levels. Past experimental research has examined the effect of glucosamine on insulin and glucose but many of these studies intravenously infused a large amount of glucosamine in a short period of time, which makes it difficult to extrapolate direct effects of oral consumption of glucosamine. Some animal research has examined the effects of a combination of oral glucosamine hydrochloride and chondroitin sulfate. Results showed that 1 month of oral administration in twice the recommended amount on the label for glucosamine and chondroitin had no effect on blood sugar. 10 15 Recent clinical studies are summarized below:

• One study was conducted to determine the effect of glucosamine hydrochloride supplementation on hemoglobin A 1 C (HbA 1 C) concentrations in 38 elderly patients with stable, well-controlled type 2 diabetes mellitus over a 90-day period. Patients must have been consistently taking an oral antihyperglycemic agent or under strict diet control; have a stable HbA 1 C level for at least 2 consecutive measurements separated by atleast 90 days. Twenty-six patients were randomized to 1500 mg glucosamine daily and 12 to placebo. At baseline, both groups had similar HbA 1 C levels and the HbA 1 C mean values did not significantly change during the study. There was no significant difference in the glycemic control between the glucosamine and placebo group (p=.20). In the glucosamine group, mean HbA 1 C increased from 6.45% to 6.5%; in the placebo group the mean HbA 1 C decreased from 6.25% to 6.09%. This study suggests that oral glucosamine hydrochloride supplementation at the recommended dose (1500 mg/day) does not adversely effect glycemic control in patients with type II diabetes. 14 • To evaluate glucosamine's effects on glucose tolerance, 1500 mg of glucosamine sulfate was given to healthy adults for 12 weeks. Results reveal supplemention with glucosamine sulfate did not alter serum insulin or plasma glucose during the oral glucose tolerance test. Glycated hemoglobin measurements showed no significant change over time. The authors conclude their data suggests that normal recommended doses of glucosamine supplementation does not cause glucose intolerance in healthy adults. These findings are not conclusive until further studies are done using alternative types of testing. 20 • A recent review was done evaluating glucosamine's safety and effects on glucose metabolism from clinical trial data on 3036 human subjects. Altered glucose metabolism has been associated with parenteral administration of large doses of glucosamine in animals, and with high concentrations in in vitro studies. In some in vitro studies which demonstrated effects of glucosamine on glucose metabolism, concentrations are 100-200 times higher than tissue levels expected if oral glucosamine administration were used. This review noted that in some, fasting plasma glucose values decreased slightly after oral glucosamine was given for approximately 66 weeks. In addition, there were no adverse effects of oral glucosamine administration on blood, urine or fecal parameters. Side effects were significantly less common with glucosamine than placebo or non-steroidal anti-inflammatory drugs (NSAID). In comparison to NSAIDs, no serious or fatal side effects have been reported for glucosamine. The results from the review indicate that glucosamine is safe under current conditions of use and does not affect glucose metabolism. 24

References Back to sub-topics 1 Reginster JY, et Long-term effects of glucosamine sulphate Lancet 2001; 357: 251-256. al: on osteoarthritis progression: a randomised, placebo-controlled clinical trial. 2 Burnham TH: Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons. 2001; 3 McEvoy GK: American Hospital Formulary Service Drug Bethesda, MD:American Information. Society of Health-System Pharmacists. 2001; 4 Bratman S: The Natural Pharmacist Drug Herb Roseville, CA:Prima Interactions Bible. Publishing. 2001; 5 Förster KK, et Efficacy of glucosamine sulfate in Arth Rheum 2000; 43 (S): al: osteoarthritis of the lumbar spine: a 1613. placebo-controlled, randomized, double-blind study. 6 McAlindon TE, Glucosamine and chondroitin for treatment JAMA 2000; 283: et al: of osteoarthritis: a systematic quality 1469-1475. assessment and meta-analysis. 7 Glucosamine sulfate compared to ibuprofen Osteo Cartilage 1994; 2: Müller-Fasbender in osteoarthritis. 61-69. H, et al: 8 Tannock L, et Glucosamine supplementation may result in Circulation 2000; 102:39. al: the synthesis of vascular proteoglycans that may be protective against atherosclerosis. 9 Bassleer C, et al: Stimulation of proteoglycan production by Osteoarthritis and Cartilage glucosamine sulfate in chondrocytes 1998; 6: 427-434. isolated from human osteoarthritic articular cartilage in vitro. 10 AbdelFattah W, Chondroitin and glucosamine: A review of JANA 2001; 3:16-23. et al. their safety profile. 11 Setnikar I, et al. Antireactive properties of glucosamine Arzneimittel-forschung 1991; sulfate. 41:157-161. 12 Richy F, et al. Structural and symptomatic efficacy of Arch Intern Med 2003; glucosamine and chondroitin in knee 163:1514-1522. osteoarthritis. 13 Pavelka K, et Glucosamine sulfate use and delay of Arch Intern Med 2002; al. progression of knee osteoarthritis. 162:2113-2123. 14 Scroggie DA, et The effect of glucosamine-chondroitin Arch Intern Med 2003; al. supplementation on glycosylated 163:1587-1590. hemoglobin levels in patients with type 2 diabetes mellitus. 15 McNamara PS, Hematologic, hemostatic, and biochemical Am J Vet Res 1996; et al. effects in dogs receiving an oral 57:1390-1394. chondroprotective agent for thirty days. 16 Lippiello L, et In vivo chondroprotection and metabolic Clin Orthopaedics Related al. synergy of glucosamine and chondroitin Res 2000; 381:229-240 sulfate. 17 Chan PS, Caron Glucosamine and chondroitin sulfate Osteoarthritis Cartilage JP, et al. regulate gene expression and synthesis of 2005; 13:387-94. nitric oxide and prostaglandin E(2) in articular cartilage explants. 18 Brief AA, Use of glucosamine and chondroitin sulfate J Am Acad Orthop Surg. Maurer SG, Di in the management of osteoarthritis. 2001 9:71-78 Cesare PE. 19 P.R. Usha and Randomised, Double-blind, Parallel, Clin Drug Invest 2004 M.U.R. Naidu Placebo-Controlled Study of Oral 24(6):353-363. Glucosamine, Methylsulfonylmethane and their Combination in Osteoarthritis 20 Tannis AJ, Effect of glucosamine supplementation on Osteoarthritis Cartilage 2004 Barban J, fasting and non-fasting plasma glucose and 12(6):506-11. Conquer JA serum insulin concentrations in healthy individuals. 21 Bruyere O, Glucosamine sulfate reduces osteoarthritis Menopause 2004 Pavelka K, Rovati progression in postmenopausal women with 11(2):138-43 LC, et al. knee osteoarthritis: evidence from two 3-year studies. 22 Cibere J, Kopec Randomized, double-blind, Arthritis Rheum. 2004 JA, Thorne A, et placebo-controlled glucosamine 51(5):738-45 al. discontinuation trial in knee osteoarthritis. 23 Christgau S, Osteoarthritic patients with high cartilage Clin Exp Rheumatol 2004 Henrotin Y, Tanko turnover show increased responsiveness to 22(1):36-42 LB, et al. the cartilage protecting effects of glucosamine sulphate. 24 Anderson JW, Glucosamine effects in humans: a review of Food Chem Toxicol 2005; et al. effects on glucose metabolism, side effects, 43:187-201. safety considerations and efficacy. 25 Poolsup N, et Glucosamine long-term treatment and the Ann Pharmacother. 2005; al. progression of knee osteoarthritis: 39:1080-7. Epub 2005 Apr systematic review of randomized controlled 26. trials. 26 Daniel O Clegg, Glucosamine, Chondroitin Sulfate, and the New England Journal of Domenic J Reda, Two in Combination for Painful Knee Medicine 2006 354:795-808 Crystal L Harris, Osteoarthritis Marguerite A Klein, et al. Dietary Kelp Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Kelp is large brown algae from the Pacific Ocean. Any plant growing in the sea is -Fish Oil seaweed. Seaweeds are algae. -Flaxseed Oil • The large brown algae, kelp, is harvested, dried and ground. This material is used for -Glucosamine kelp tablets and seaweed powder. • The composition of seaweed is 5.7% protein 2.6% fat, 7.0% fiber, 58.6% nitrogen free -Kelp extract, 15.4% ash and 10.7% moisture. -L-Arginine • Nutritional value of kelp is dependent on the species, season, temperature of the water -Lecithin and geographic area. -L-Lysine -Lycopene Functions Back to sub-topics -Melatonin -Methylsulfonylmethane • Kelp may provide certain nutrients for humans. -Pantethine • Dried kelp is rich in iodine. Iodine is important in numerous biological functions such as -Phytonutrients thyroid hormones. -Plant Sterols/Stanols • Kelp contains 62,400 mcg of iodine /100g. -S-adenosyl-L-methionine -Soy Isoflavones Dosage Back to sub-topics -Vinpocetine Not known.

Toxicity Back to sub-topics Since kelp is rich in iodine, caution should be taken when one consumes it for a prolonged period (Also see Iodine).

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

• No health hazards or side effects are known. • Caution with pregnancy or nursing, consult physician before using (Also see "Iodine"). Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

-Fish Oil • L-arginine is involved in the urea cycle, which converts ammonia to urea, synthesis of creatine, and production agmatine (which may be a neurotransmitter).

-Flaxseed Oil • Arginine is a basic amino acid which considered semi-essential. Although it can be synthesized from amphibolic intermediates and 7 enzymes, cannot produced at rates sufficient to support growth must therefore ingested in the diet. -Glucosamine -Kelp Functions Back to sub-topics

-L-Arginine • L-arginine is the principal physiologic precursor of nitric oxide (a key signaling molecule) which plays a versatile role in physiology.

-Lecithin • L-arginine is the substrate for enzyme nitric oxide synthase (NOS).

-L-Lysine • L-arginine also plays a role in maintaining the physiology of gastrointestinal tract, and leads to production nitric oxide which affects number regulatory mechanisms including: vasodilatation endothelial function, neurotransmission neuromodulation, modulation leukocyte adhesion, insulin sensitivity, inhibition platelet aggregation, reduction oxidative stress. -Lycopene -Melatonin Dosage Back to sub-topics -Methylsulfonylmethane Arginine is classified as a semi-essential or conditionally essential amino acid. Although it can -Pantethine be made in the body from L-citrulline in an ATP-dependent process, it appears that dietary or supplemental L-arginine is key to adequate production of nitric oxide. Production of nitric oxide -Phytonutrients is mediated by nitric oxide synthase which is inhibited by hypercholesterolemia, oxidative -Plant Sterols/Stanols stress, and asymmetrical dimethyl arginine (ADMA) which a methylated isomer of L-arginine -S-adenosyl-L-methionine derived from protein. Arginine is essential for critically ill patients, young children, certain rare -Soy Isoflavones genetic disorders causing impaired L-arginine synthesis, stress conditions including trauma, -Vinpocetine surgery, sepsis, and burns, vascular disease, and chronic renal failure.

Toxicity Back to sub-topics L-arginine has been generally well tolerated by healthy volunteers as well as patients who have taken oral doses up 30 grams. Although the vasodilator action of L-arginine may lead to hypotension, the effects on blood pressure are usually low. Side effects are rare, mild, and dose dependent. Side effects include a bitter taste, nausea, and vomiting in about 3% of patients taking L-arginine higher doses. A metabolic condition involving elevated arginine levels is known as hyperargininemia results from a defect in urea synthesis. This condition is characterized by increased arginine levels in cerebrospinal fluid, low erythrocyte levels of arginase and a urinary amino acid pattern similar to that seen in patients with lysine-cystinuria. Hyperargininemia is not associated with L-arginine supplements

Dietary Sources Back to sub-topics The typical dietary intake of L-arginine is 3.5 to 5.0 grams daily mainly derived from plant or animal foods. Small amounts of free L-arginine are found in fruits and vegetables and in some fermented foods such as miso and yogurt. Soy protein is particularly high in L-arginine, whereas other protein sources tend to be high in lysine which competes with L-arginine.

Drug-Supplement Interaction Back to sub-topics • L-arginine may enhance the intestinal absorption of low molecular weight heparin. • Ornithine and lysine (amino acids) compete with arginine for absorption from the gut. • L-arginine may counteract the sodium preserving (antinatriuretic) effect of cyclosporine. • Absorption of ibuprofen is enhanced by arginine. • Ascorbic acid is necessary to convert L-arginine nitric oxide • Sidenafil citrate has theoretically been noted to have an increased effect when taken concomitantly with L-arginine. Information on the relationship between substances and disease is provided for general information, in order convey a balanced review of scientific literature. In many cases substance tentative additional research needed confirm such relationship. Research Summary Back to sub-topics

References Back to sub-topics 1 Wolf A, et Dietary L-arginine supplementation J Am Coll Cardiol 1997 al. normalizes platelet aggregation in 29:479-485. hypercholesterolemic humans 2 Lerman A, Long-term L-arginine supplementation Circulation. 1998; 97:2123-2128. et al improves small-vessel coronary endothelial function in humans. 3 Yin WH, et L-arginine improves endothelial function and Clin Nutr 2005; 24:988-997. al. reduces LDL oxidation in patients with stable coronary artery disease. . 4 Hambrecht Correction of endothelial dysfunction in J Am Coll Cardiol 2000 R, et al. chronic heart failure: additional effects of ;35:706-713. exercise training and oral L-arginine supplementation. . 5 Adams Oral L-arginine improves Atherosclerosis 1997 MR, et al endothelium-dependent dilatation and 129:261-269. reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. 6 Chan JR, Asymmetric dimethylarginine increases Arterioscler Thromb Vasc Biol et al mononuclear cell adhesiveness in 2000; 20:1040-1046. hypercholesterolemic humans 7 Adams Oral L-arginine improves Atherosclerosis 1997 MR, et al. endothelium-dependent dilatation and ;129:261-269 reduces monocyte adhesion to endothelial cells in young men with coronary artery disease 8 Oral L-arginine improves endothelial Vasc Med 2003 8:77-81 Bode-Boger function in healthy individuals older than 70 SM, et al. years. 9 Oka RK, et A pilot study of L-arginine supplementation Vasc Med 2005 10:265-274. al. on functional capacity in peripheral arterial disease. 10 Lekakis Oral L-arginine improves endothelial Int J Cardiol 2002; 86:317-323 JP, et al. dysfunction in patients with essential hypertension. 11 Miller AL. The effects of sustained-release-L-arginine Altern Med Rev 2006 11:23-29. formulation on blood pressure and vascular compliance in 29 healthy individuals. 12 Koga Y, et Endothelial dysfunction in MELAS improved Neurology. 2006; 66:1766-1769. al by L-arginine supplementation. 13 Piatti PM, Long-term oral L-arginine administration Diabetes Care 2001 24:875-880. et al. improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. 14 Lucotti P, Beneficial effects of a long-term oral Am J Physiol Endocrinol Metab et al. L-arginine treatment added to a hypocaloric 2006 291:E906-912. diet and exercise training program in obese, insulin-resistant type 2 diabetic patients 15 Lubec B, -Arginine reduces lipid peroxidation in Free Radic Biol Med 1997 et al. patients with diabetes mellitus. 22:355-357. 16 Chen J, et Effect of oral administration of high-dose BJU Int 1999 83:269-273. al. nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study 17 Cartledge A randomized double-blind BJU Int 2000 85:421-426. JJ, et al placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis. 18 Korting randomized double-blind trial of oral J Urol 1999; 161:558-565. GE, et al. L-arginine for treatment of interstitial cystitis. Dietary Lecithin Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Lecithin is a phospholipid, often referred to as phophatidylcholine. -Fish Oil • Lecithin is found in all living organisms. -Flaxseed Oil • Lecithin comes from the diet or is synthesized in the body. Therefore, it is not an -Glucosamine essential nutrient. • Lecithin is one of the major components in cell membranes, along with protein and -Kelp cholesterol. -L-Arginine • Lecithin is synthesized from choline. (See also "Choline.") -Lecithin • Lecithin is used as a stabilizer and emulsifier in foods. -L-Lysine -Lycopene Functions Back to sub-topics -Melatonin -Methylsulfonylmethane • Lecithin (phosphatidylcholine) is a structural element of the membranes of various -Pantethine cells. Phosphatidylcholine is a part of lipoproteins such as chylomicron, LDL and HDL, -Phytonutrients which carry dietary fat and transport them to various tissues. -Plant Sterols/Stanols • Dietary fat incorporated into phospholipids such as lecithin are used for eicosanoid synthesis. -S-adenosyl-L-methionine -Soy Isoflavones -Vinpocetine Dosage Back to sub-topics Not known.

Toxicity Back to sub-topics Not known.

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

Research Summary Back to sub-topics Not available. References Back to sub-topics 1 Drug Facts and Comparisons. St. Louis, MO: Facts and Burnham Comparisons. 2001; TH: 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society of GK: Information. Health-System Pharmacists. 2001; 3 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; Dietary L-Lysine Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Lysine is one of the essential amino acids that cannot be synthesized in the human -Fish Oil body. -Flaxseed Oil • Lysine is the first limiting amino acid in proteins derived from grains. -Glucosamine • Lysine has two amino groups (NH2), unlike other amino acids. • Cereals are often fortified with lysine to improve their nutritional value. High biologic -Kelp value proteins (e.g. meat, fish, poultry, dairy) are rich sources of lysine. -L-Arginine • Due to its extra amino group, lysine forms an amino-sugar complex with glucose or -Lecithin lactose. This process is called the Maillard reaction. This complex cannot be digested -L-Lysine in the digestive tract, resulting in a lowered bioavailability. This reaction occurs during -Lycopene extensive heating or prolonged storage. • Vitamin C aids lysine in formation of collagen. -Melatonin -Methylsulfonylmethane -Pantethine Functions Back to sub-topics -Phytonutrients -Plant Sterols/Stanols • Lysine is used to synthesize muscle and visceral proteins. • Lysine-rich regions in proteins have a high affinity to receptors such as the LDL -S-adenosyl-L-methionine receptor. -Soy Isoflavones • Peptide hormones are initially synthesized as large, inactive prohormones, then are -Vinpocetine cleaved by proteolytic enzymes, forming the active hormone. Enzymes recognize pairs of basic residues such as lysine-arginine as a cleavage point. • Oral supplementation of lysine may prevent recurrence of herpes simplex infections. • Lysine is important in collagen and bone formation.

Dosage Back to sub-topics One to 3 g of lysine per day may be effective in inhibiting herpes simplex infections.

Toxicity Back to sub-topics Intake of lysine of up to 3 g per day appears to be safe for chronic use, even when taken with foods. 1

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 2 3 4

Vitamin C aids lysine in the formation of collagen. Taking vitamin C with L-lysine may be beneficial.

Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship. Research Summary Back to sub-topics Diet: To asses if lysine-deficient rats would alter their diet selection patterns on the basis of small changes in dietary lysine concentration, growing rats were adapted to diets in which the protein fraction was limited in lysine. Then they were given a choice between the adaptation diet containing lysine at the level of 0.25% (approximately 35% of the requirement for maximal growth) and a slightly more deficient diet. The adaptation diet allows for a slow rate of growth. Only rats adapted to the diets containing lysine below the requirement for growth selected the adaptation diet. This result indicates that lysine may act as a dietary stimulus to control diet selection. 5

References Back to sub-topics 1 Flodin The metabolic roles, pharmacology, and J Am Coll Nutr 16:7-21. NW: toxicology of lysine. 2 Drug Facts and Comparisons. St. Louis, MO: Facts and Burnham Comparisons. 2001; TH: 3 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society of GK: Information. Health-System Pharmacists. 2001; 4 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 5 Hrupka Lysine deficiency alters diet selection J Nutr 129:424-430. B, et al: without depressing food intake in rats. Dietary Lycopene Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Lycopene is carotenoid which is present in tomatoes, processed tomato products, and -Fish Oil other fruits. -Flaxseed Oil • Lycopene is one of the most potent antioxidants in the diet. -Glucosamine • Lycopenes antioxidant property is twice as high as that of beta carotene and ten times higher than that of alpha tocopherol. -Kelp • Lycopene is an acrylic isomer of beta carotene and it is synthesized by plants and -L-Arginine microorganisms. -Lecithin • Lycopene is a 40-carbon molecule which is highly unsaturated and it contains 11 -L-Lysine conjugated and 2 unconjugated double bonds. In nature, lycopene is predominantly -Lycopene found in an all-trans configuration. • Lycopene is the most predominant carotenoid in human plasma. In human plasma, e is -Melatonin present in an isomeric mixture, with 50% as cis isomers. Lycopene is also found to -Methylsulfonylmethane concentrate in the adrenal glands, testes, liver, and prostate gland. -Pantethine -Phytonutrients Functions Back to sub-topics -Plant Sterols/Stanols -S-adenosyl-L-methionine • Lycopene increases gap-junctional intercellular communication, and this action is -Soy Isoflavones believed to be responsible for enabling the transfer of growth-regulatory signals. -Vinpocetine • Lycopene has been hypothesized to prevent carcinogenesis and atherogenesis by protecting critical cellular biomolecules, lipids, lipoproteins, proteins, and DNA. Though the exact mechanism of action has not been defined, researchers have found that patients with prostate cancer were found to have low levels of lycopene and high levels of oxidation of serum lipids and proteins. • Strong evidence exists from numerous studies which associate high serum or plasma lycopene with decreased risks of cancer of the lung, stomach, gastrointestinal tract and cancers of the colorectum. • Recent studies have also reported a decrease in the risk of total cardiovascular disease with higher concentrations of plasma lycopene. • Other studies have shown an inverse association between plasma lycopene and mortality in patients with prior cancers particularly in Oral, Pharynx, or Larynx Cancers.

Dosage Back to sub-topics

• Dietary intake of tomatoes and tomato products has been found to be associated with lower risk of a variety of cancers. One study observed a 35% reduction in the risk of developing prostate cancer among men who consumed 10 or more servings of tomato products per week. Other studies have shown that high levels of serum lycopene were inversely associated with the risk of breast cancer and prostate cancer. • Estimating the average daily intake of lycopene has been difficult due to the variability in reported levels in different foods. In the United States it has been estimated that the average daily intake of lycopene is about 3.7 mg to 6.5 per day (Schweitzer and others 1999 and NCC database). • In a recent study (Kucuk and Wood Jr., 2002), patients with diagnosed prostate cancer showed a decrease in plasma prostate specific antigen (PSA) after three weeks of lycopene supplementation in the amount of 15 mg twice/day. Tumor volume was also found to be smaller in the group which took Lycopene, and they also found the surgical stage of the tumors to be delayed. These observations suggest that lycopene may play a role in the treatment of cancers. Toxicity Back to sub-topics None of the studies have shown adverse effects of high tomato intake or high lycopene levels.

Dietary Sources Back to sub-topics Lycopene is naturally present in red fruits and vegetables, including tomatoes, watermelons, pink grapefruits, apricots, and pink guavas. Processed tomato products such as juice, ketchup, paste, sauce, and soup are also good sources of lycopene. In comparing bioavailability values for lycopene, it appears that lycopene is more bioavailable from processed tomato products than from raw tomatoes. Estimating the average daily intake of lycopene has been difficult due to the variability in reported levels in different foods. In the United States it has been estimated that the average daily intake of lycopene is about 3.7 mg to 6.5 per day (Schweitzer and others 1999).

Drug-Supplement Interaction Back to sub-topics It is believed that processing and the presence of dietary lipids enhance lycopene bioavailability. Johnson and associates also found that the bioavailability of lycopene is significantly higher when it is was ingested along with other carotenoids than when ingested alone.

Research Summary Back to sub-topics

• In recent studies serum and tissue levels of lycopene were shown to be inversely associated with the risk of breast cancer and prostate cancer. In a recent interventional study (Kucuk and Wood Jr., 2002) patients diagnosed with prostate cancer were given either 15 mg of lycopene twice/day or placebo capsules without lycopene for three weeks before surgery. The group supplemented with lycopene showed higher levels of plasma lycopene when compared to the control group. The plasma PSA levels in the treated group were also lower after receiving lycopene. In addition, the tumor volume in the treated group was also found to be smaller and the surgical stage of the tumors delayed. These observations led the researchers to conclude that lycopene may play a role in the treatment of cancers. 1 • Lycopene has been hypothesized to prevent carcinogenesis and atherogenesis by protecting critical cellular biomolecules, including lipids, lipoproteins, proteins, and DNA. The most impressive results come from the US Health Professional Follow-up Study, which evaluated intakes of various carotenoids implementing the use of food frequency questionnaires, in relation to risk of prostate cancer. Prostate cancer risk decreased as lycopene intake increased. 2 3 • A study published in the American Journal of Epidemiology in 2002 suggests that low concentrations of serum lycopene may be more strongly associated with aggressive prostate cancer. In their discussion, researchers state that their findings imply that disease progression may be especially susceptible to the protective effects of lycopene. This study was of particular importance because it included large numbers of US African Americans and they concluded that the results apply to this racial group. 4 • In 2002, Kucuk and others discussed the effects on Lycopene supplementation in patients with localized prostate cancer. They once again confirmed what had been stated by Zhang and Bertram in 1991 and in 1992, that lycopene increased gap-junctional intercellular communication by increasing expression of the gap junctional gene, connexin 43. The report went on to state that their results suggest that lycopene may have an anti-tumor effect and perhaps be useful as an adjunct to standard treatments of prostate cancer, such as surgery, radiation therapy, hormones, and chemotherapy. 1 5 6 • According to Erdhardt 2003, strong evidence exists from numerous experimental and epidemiological studies that high intakes of tomatoes and tomato-based products, as well as high serum or plasma lycopene concentrations, are associated with decreased risks of cancer of the lung, stomach, and prostate. Further published evidence suggests that lycopene may also play a role in protecting against cancers of the gastrointestinal tract, including cancers of the colorectum. 7 8 • More recently, in 2004, Sesso and others reported that higher plasma lycopene concentrations are associated with lower risk of CVD in women. This analysis corrected for age, smoking, and adjustment for randomized treatment assignments and plasma cholesterol concentrations. The conclusion was that the risk of total CVD appeared to decrease with higher concentrations of plasma lycopene. Women with concentrations of plasma lycopene greater than 16.5 micrograms/dL had a possible 34% reduction in total CVD compared with those women in the lowest quartile, after multivariate adjustment. 9 10 • In vitro studies indicate that of all major dietary carotenoids, lycopene is the most potent scavenger of reactive oxygen species. Preliminary in vitro evidence indicates that lycopene reduces cellular proliferation induced by insulin-like growth factors, which are potent mitogens, in various cancer cell lines. Lycopene also has been shown to act as a hypocholesterolemic agent by inhibiting HMG-CoA reductase (Fuhram 1997). 11 12 • Giovannucci recently reviewed 72 epidemiological studies including ecological, case control, dietary and blood-specimen-based investigations of tomatoes, tomato products, lycopene and cancer. 57 demonstrated an inverse relationship between circulating lycopene levels and the risk of several types of cancer; in 35 of these cases, the association was statically significant. 13 14 15

References Back to sub-topics 1 Kucuk O, Effects of Lycopene Supplementation in 2002 Exp Biol Med 227:881-885 Sarkar F, Patients with Localized Prostate Cancer. Djuric Z, Sakf Exp Biol Med W, Pollak M, Khachik F, Banerjee M, Betra J, Wood DP Jr. 2 Rao AV, Rao Lycopene and Human Health. Current 2004 pp. 127-136 LG Topics in Nutraceutical Research Vol. 2, No.3 3 Pool-Zobel Consumption of vegetables reduces genetic 1997 18:1847-50. BL, Bub A, damage in humans: first result of a human Muller H, intervention trial with carotenoid-rich foods. Wollowski I, Carcinogenesis Rechkemmer G. 4 Vogt TM, Serum Lycopene, Other Serum Carotenoids, Am J Epidemiol 2002 Mayne ST, and Risk of Prostate Cancer in US Blacks 155:1023-32. Graubard BI, and Whites. Swanson CA, Sowell AL, Schoenberg JB, Swanson GM, Greensberg RS, 5 Zhang L-X, Carotenoids up-regulate connexin 43 gene 1992. 52:5707-5712 Cooney RV, expression independent of their pro-vitamin Bertram JS. A or antioxidant properties. Cancer Res 6 Bertram JS, Diverse Carotenoids protect against 1991. 12:671-678 Pung A, chemically induced neoplastic Churley M, transformation. Carcinogenesis Kappock TJ IV. Wilkins L.R, Cooney RV 7 Erhardt JG, Lycopene, beta carotene, and colorectal 2003 1219-24. Meisner C, adenomas. Am J Clin Nutr Bode JC, Bode C. 8 Franceschi Tomatoes and risk of digestive tract cancers International Journal of Cancer S, Bidoli E, La 1994 59:181-4. Vecchia C, Talamini R, DAvanzo B, Negri E 9 Sesso HD, Plasma Lycopene, other carotenoids, and 2004 79:47-53. Buring JE, retinol and the risk of cardiovascular disease Norkus EP, in women. Am J. Clin Nutr Gaziano JM. 10 Sesso HW, Dietary Lycopene, Tomato-Based Food 2003 133:2336-2341 Liu S, Gaziano Products and Cardiovascular Disease in JM, Buring J. women. J. Nutr. 11 Fhuraman Hypocholesterolemic effect of Lycopene and 1997 233:658-62 B, Elis A, beta carotene is related to suppression of Aviram M cholesterol synthesis and augmentation of LDL receptor activity in macrophage. Biochem Biophys Res Commun 12 Agarwal S, Tomato Lycopene and its role in human 2000 163 (6):739-44. Rao V A. health and chronic diseases. CMAJ 13 Tomatoes, tomato-based products, 1999 91:317-31 Giovannucci Lycopene and cancer: review of the E epidemiologic literature. Journal of the National Cancer Institute 14 . A prospective study of tomato products, 2002 94:391-8. Giovannucci Lycopene, and prostate cancer risk. Journal E, Rimm EB, of the National Cancer Institute Liu Y, Stampfer MJ, Willet WC. 15 Schweitzer Dietary intake of carotenoids, fruits, and 1999 p19 C, Park Y, vegetables in the US: CSFII 1994-1996, a Song W. national survey. In: Abstracts 12th International Carotenoid Symposium Cairns, Australia, July 18-23, 1999 Dietary Melatonin Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Melatonin is a principal hormone of the vertebrate pineal gland. It is synthesized -Fish Oil endogenously by the pinealocytes of the pineal gland. -Flaxseed Oil • In the biosynthesis of melatonin, tryptophan is first converted by tryptophan -Glucosamine hydroxylase to 5-hydroxytryptophan, which is then decarboxylated to serotonin. The synthesis of melatonin from serotonin is catalyzed by two enzymes (arylalkylamine -Kelp N-acetyltransferase and hydroxyindole-O-methyltransferase) both which are largely -L-Arginine confined to the pineal gland. -Lecithin • The synthesis of melatonin displays a circadian rhythm that is reflected in serum -L-Lysine melatonin concentrations. Synthesis and release of melatonin are stimulated by -Lycopene darkness and inhibited by light. • As synthesis of melatonin increases the hormone enters the bloodstream through -Melatonin passive diffusion. Melatonin secretion increases soon after darkness peaks and then -Methylsulfonylmethane gradually falls during the second half of the night. -Pantethine • Melatonin can be found in plants and animals, although concentration in plants is a -Phytonutrients much lower than in animals. -Plant Sterols/Stanols • Infants younger than three months of age secrete very little melatonin. The secretion of melatonin peaks from age one to three (325 pg per milliliter) and then declines -S-adenosyl-L-methionine gradually with age (adult: 10 and 60 pg per milliliter). -Soy Isoflavones • Melatonin is rapidly metabolized, mainly in liver, by hydroxylation and after conjugation -Vinpocetine with sulfuric or glucuronic acid it is secreted into the urine. The bioavailability of oral melatonin varies widely. • Many blind individuals with no pupillary light reflexes and no conscious visual perception have light-induced suppression of melatonin secretion.

Functions Back to sub-topics

• Supplemental melatonin may have a hypnotic action. It is a hormone that has biological effects and that activates through a family of G protein-coupled receptors. The putative effect of melatonin as a hypnotic may be accounted for by receptor-mediated action on the limbic system. • At high doses, melatonin may have antioxidant properties. It may inhibit metal ion-catalyzed oxidation processes, specifically in the Fenton reaction. • Melatonin may have anti-apoptotic activity in the thymus, possibly by down-regulating the glucocorticoid receptor. • Melatonin may be used in the treatment of some forms of sleep disturbances or insomnia. • Melatonin may be used to treat some symptoms of jet lag, although research results are mixed. • Melatonin may be used in the treatment of cancer and immune disorders. Some findings are promising, but they are preliminary.

Dosage Back to sub-topics

• For sleep disturbance or jet lag no more than 0.3 to 3 mg of melatonin should be taken at bedtime and it should not be taken for longer than 2 weeks. Higher doses or for prolonged periods should be done under medical supervision. • Information regarding the precise dose of melatonin is insufficient. Reported dose range has been from 0.3 to 80 mg, but the correct timing of the dose is unclear. 1 • Forms available: capsules, liquid, lozenges, sublingual tablets, tea and time released tablets. Toxicity Back to sub-topics

• No apparent overdose consequences have been seen in people taking up to 24 g a day for one month, although high doses are not recommended. • Melatonin begins to accumulate in fatty tissues after 2 weeks of chronic ingestion.

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 2 3 4

• Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen [Motrinâ] and aspirin (ASA), can decrease melatonin secretion in the body. • Beta-blockers, such as propranolol [Inderalâ], inhibit the nocturnal rise in melatonin concentrations. • Tricyclics (amitriptyline [Elavilâ]), monoamine oxidase inhibitors (MAOIs) (isocarboxazid [Marplanâ]), and some other antidepressants increase the concentrations of brain melatonin. • Benzodiazepines, such as diazepam [Valiumâ], interfere with synthesis of melatonin. • Diuretics such as furosemide [Lasixâ] and calcium-channel blockers such as amlodipine [Norvascâ] can interfere with melatonin production. • Vitamin B12 concentrations influence melatonin secretion in the body. Taking melatonin (1.5 mg of methylcobalamin per day) can improve sleeping disorders. • Alcohol and caffeine can decrease melatonin production. Avoid these substances before taking melatonin right before going to sleep. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary Back to sub-topics Sleep or Insomnia: Sleep disturbance is very common among the elderly population. Fifty percent of people over 65 years of age complain of sleep disturbance. Healthy elderly take longer to fall asleep, awake more often and have more difficulty returning to sleep after midnight awakenings. Impaired melatonin secretion is associated with sleep disorders and old age. • In a study done on elderly melatonin-deficient insomniacs, patients were given 1 to 2 mg of melatonin formulations or placebo for 7-day periods. In the preliminary study, 1week treatment of 2 mg of fast-release melatonin was as effective as the two-month treatment of 1 mg of sustained release melatonin. Researchers concluded that melatonin deficiency seemed to be linked to sleep disorders in the elderly. Melatonin replacement may be beneficial in the initiation and maintenance of sleep in the elderly. 5 • Six healthy male volunteers participated in a study that included a total of 9 test sessions with at least 5 days between sessions. Subjects were given oral doses of 0.3 or 1.0 mg of melatonin at 3 time points. Researchers found that sleep onset provoked by a single dose of melatonin, resulted not from its effect on biological timing mechanisms, but from a direct action of elevated circulating melatonin concentrations. 6 Antioxidant: Melatonin may be an effective free radical scavenger. In vivo and in vitro studies have indicated that melatonin directly scavenges highly toxic hydroxyl radical and other oxygen centered radicals. It is speculated that melatonin may provide protection against diseases that involve degenerative or proliferative changes by shielding macromolecules from free radical damage.

• During nighttime, both melatonin and total antioxidant status (TAS) decreased to basal daytime values and with aging, day to night differences in melatonin and TAS change. A study on healthy volunteers from ages 2 to 89 looked at whether physiological concentrations of melatonin contribute to the antioxidant capacity of human serum. Results showed physiological melatonin concentrations in human serum, especially at night, exhibited significant antioxidative properties. 7 • Ethanol-induced, gastro-duodenal damage is thought to be mediated by the generation of free radicals. Melatonin protection against ethanol-induced gastroduodenal injury was investigated in rats given 10 mg/kg of melatonin intraperitoneal in a single dose. Melatonin administration before ethanol treatment greatly reduced macroscopic and histological gastroduodenal damage. Melatonin administration reduced indomethacin-ethanol-induced polymorphonuclear leukocyte infiltration rise by 57% in the stomach and 40% in the duodenum. Results from these experiments show a significant protection by melatonin against ethanol-induced gastroduodenal injury. 8 Bone Formation: Studies have shown that melatonin can increase expression of the response element of rat bone sialoprotein (BSP) as well as several other essential bone marker proteins, including alkaline phosphatase (ALP) and osteocalcin (OC). In addition, it has shown to stimulate both osteoblast differentiation and mineralization.

• A study looked at whether melatonin could modulate expression of BSP in two cell lines. Concentrations of 10 nm of melatonin were able to stimulate transcription of genes when cells were grown in the presence of beta-glycerophosphate and ascorbic acid. Melatonin-induced gene expression of bone marker proteins occurred on the 5th day after seeding the culture dishes. The results demonstrated that melatonin is capable of promoting osteoblast differentiation and mineralization of matrix in culture and it may play an essential role in regulating bone growth. 9 Blindness: A majority of completely sight-impaired individuals have circadian rhythms that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours. This can cause recurrent insomnia and sleepiness during the day.

• A study on 7 sight-impaired subjects with free running circadian rhythms were given 10 mg of melatonin or placebo daily 1 hour prior to bedtime for 3 to 9 weeks. Subjects were found to spend less time awake after the initial onset of sleep and sleep efficiency was higher. Researchers found free-running circadian rhythms in blind people can be entrained to a 24-hour cycle with a daily dose of melatonin and possibly preventing a sleep disorder. 10 Perimenopause and Menopause: Nocturnal administration of melatonin may postpone endocrine aging and maintain or reconstitute more juvenile sexual function in women during perimenopause or menopause. It may also enhance and improve efficiency of hormone replacement therapy and add more years to a woman's fertile life.

• A study done on perimenopausal and menopausal women ages 42 to 62 took 3 mg of melatonin or placebo at bedtime for 3 and 6 months. Melatonin produced a significant diminution of luteotropic hormone in the women aged 43 to 49, but no effect was seen in the 52 to 62 year old women. The women receiving melatonin reported a general improvement in mood, a significant mitigation of depression and a recovery of pituitary and thyroid functions. Overall, researchers concluded that this showed a more juvenile pattern of regulation. 11

References Back to sub-topics 1 Melatonin in humans. NEJM 336:186-195. Brzezinski A, et al: 2 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 3 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society of GK: Information. Health-System Pharmacists. 2001; 4 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 5 Haimov I Potential of melatonin replacement therapy Drugs & Aging 7:75-78. and Lavie in older patients with sleep disorders. P: 6 Sleep-inducing effects of low doses of Clin Pharmacol Ther 57:552-558. Zhdanova melatonin ingested in the evening. IV, et al: 7 Benot S, Physiological levels of melatonin contribute J Pineal Res 27:59-64 et al: to the antioxidant capacity of human serum. 8 Suppressive effect of melatonin Brit J Pharmacology 121:264-270 Melchiorri administration on ethanol-induced D, et al: gastroduodenal injury in rats in vivo. 9 Roth JA, Melatonin promotes osteoblast J Biological Chem 274:22041-22047 et al: differentiation and bone formation. 10 Sack Entrainment of free-running circadian NEJM 343:1070-1077 RL, et al: rhythms by melatonin in blind people. 11 Effects of melatonin in perimenopausal and Exper Gerontology 2000; Bellipanni menopausal women: a randomized placebo 36:297-310 G, et al: controlled study. Dietary Methylsulfonylmethane Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Methylsulfonylmethane, dimethylsulfone (MSM) is an organic sulfur compound found in -Fish Oil minimal quantities in food and human blood. -Flaxseed Oil • MSM is a metabolite of dimethyl sulfoxide (DMSO), a natural organic form of sulfur. -Glucosamine DMSO is easily absorbed through the skin. Some people use DMSO topically as an arthritis remedy or pain reliever for sore muscles. -Kelp • MSM is a source of sulfur and some evidence has shown that it is incorporated into the -L-Arginine sulfur amino acids, cysteine and methionine. However, the biochemical mechanism for -Lecithin the transfer of sulfur from MSM into these amino acids is unknown. -L-Lysine -Lycopene Functions Back to sub-topics -Melatonin Although further clinical studies are needed, the following functions of MSM have been -Methylsulfonylmethane proposed: -Pantethine • MSM may inhibit oxidative stress of stimulated neutrophils. -Phytonutrients • With DMSO, MSM may improve symptoms of interstitial cystitis. -Plant Sterols/Stanols • MSM may have an anti-inflammatory action. • Because sulfur is needed for the formation of connective tissue, MSM has been studied -S-adenosyl-L-methionine for its use in treating arthritis. -Soy Isoflavones -Vinpocetine Dosage Back to sub-topics 1.5 to 6 g per day for osteoarthritis.

Toxicity Back to sub-topics

• There is a body of evidence that supports the safety of MSM. In the papers reviewed on MSM penetrating the blood-brain barrier (see current research section,) no adverse effects were found at a dose of at least 2 grams/day. • In clinical trials using MSM, up to 6 grams resulted in few or minimal side effects.

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

• No health hazards or side effects are known. • Caution with pregnancy or nursing, consult physician before using. Research Summary Back to sub-topics Bioavailability of MSM: The bioavailability of MSM is reasonably supported by three papers which demonstrate that MSM was found in the brains of human children and adults who were taking this supplement from seven days and up to one year. Magnetic resonance spectroscopy was used to determine presence of MSM. Data suggest that MSM is absorbed (possibly intact) from the intestine and crosses the blood-brain-barrier, absorbed into the brain. 4 5 6

Osteoarthritis

• A 2004 double-blind, placebo-controlled study compared the efficacy and safety of glucosamine alone, MSM alone, or the combination of the two in knee osteoarthritis. 118 patients were randomized to receive either 500 mg glucosamine, 500 mg MSM, 500 mg glucosamine plus 500 mg MSM, or placebo 3 times daily for 12 weeks. Results revealed glucosamine, MSM, and their combination significantly improved signs and symptoms of osteoarthritis compared to placebo. Additionally, the combination therapy (glucosamine + MSM) showed better efficacy than either agent alone in reducing pain and swelling, improving joint function, and had a more rapid onset of analgesic and anti-inflammatory activitiy. The authors conclude that the combination of MSM with glucosamine provides better and more rapid improvement in patients with osteoarthritis. 7 • Kim and colleagues tested the efficacy of MSM on fifty men and women with knee osteoarthritis pain in a randomized, double-blind, placebo-controlled trial. Participants were given either 6 grams of MSM or placebo for 12 weeks. Results showed a significant decrease in pain (using WOMAC scale) and produced improvements in performing activities for daily living. MSM at 6 grams/day improved symptoms of pain and physical function in those suffering from osteoarthritis. 8

References Back to sub-topics 1 Drug Facts and Comparisons. St. Louis, MO: Facts and Burnham Comparisons. 2001; TH: 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society of GK: Information. Health-System Pharmacists. 2001; 3 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 4 Rose S, Detection of dimethyl sulfone in the human Magnetic Resonance Imaging 2000 et al. brain by in vivo proton magnetic resonance 18:95-98. spectroscopy. 5 Lin A, et Accumulation of methylsulfonylmethane in Toxocol Letters 2001 123:169-77 al. the human brain: identification by multinuclear magnetic resonance spectroscopy. 6 Cecil K, Methylsulfonylmethane observed by in vivo J. Computer Assisted Tomography et al. proton magnetic resonance spectroscopy in 2002 26:818-820 a 5-year old child with developmental disorder: effects of dietary supplementation. 7 P.R. Randomised, Double-blind, Parallel, Clin Drug Invest 2004 24(6):353-363. Usha and Placebo-Controlled Study of Oral M.U.R. Glucosamine, Methylsulfonylmethane and Naidu their Combination in Osteoarthritis 8 Linda S. A randomized, double-blind, Abstract only Kim ND, placebo-controlled clinical trial of Leslie J. methylsulfonylmethane (MSM) for knee Axelrod osteoarthritis pain. ND, Paul Howard MD. Dietary Pantethine Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Pantethine is a metabolically active form of pantothenic acid (vitamin B5). -Fish Oil • Pantethine is the disulfide dimer of pantetheine. The 4-phosphate derivative of -Flaxseed Oil pantetheine is a step in the formation of coenzyme A from pantothenic acid (vitamin -Glucosamine B5). • Both plant and animal based foods contain small quantities of pantethine. -Kelp • Pantethine is used as a blood lipid-lowering agent in Europe and Japan. -L-Arginine -Lecithin Functions Back to sub-topics -L-Lysine -Lycopene • Coenzyme A (CoA) is involved in more than 70 enzymatic reactions. Pantethine is a -Melatonin precursor of CoA. CoA is a cofactor in fatty acid oxidation, carbohydrate metabolism, -Methylsulfonylmethane pyruvate degradation, amino acid catabolism, heme synthesis, acetylcholine synthesis, -Pantethine and phase II detoxification acetylation. The metabolic activity of pantethine may be due -Phytonutrients to its relationship to CoA. -Plant Sterols/Stanols • Large doses of pantethine (600 to 1200 mg/day) have lipid-lowering activity. • Animal studies have shown that subcutaneous pantethine can inhibit cataract -S-adenosyl-L-methionine formation. However, studies in humans have not demonstrated a protective effect for -Soy Isoflavones oral pantethine. -Vinpocetine

Dosage Back to sub-topics Most of the clinical trial testing has been 600 to 1200 mg/day, divided across the day in 300 mg doses. People with hyperlipidemia or dyslipidemia may benefit from pantethine supplements. Studies have shown benefits for people with and without diabetes.

Toxicity Back to sub-topics • Up to 1200 mg daily have shown very few side effects. Occasional digestive complaints been the only reported adverse • The most commonly studied pantethine supplements were 300 mg three times daily with only occasional digestive disturbances reported.

Dietary Sources Back to sub-topics None. Food contains inconsequential amounts of pantethine.

Drug-Supplement Interaction Back to sub-topics Pantethine has lipid modulatory activities. Thus, if taken with combination with HMG-CoA inhibitors may produce additive lipid-modulating effects.

References Back to sub-topics 1 Osono Y, The effects of pantethine on fatty liver and J Atheroscler Thromb 2000 et al. fat distribution. 7:55-58. 2 Binaghi Evaluation of the cholesterol-lowering Minerva Med 1990 81(6):475-9 P, Cellina effectiveness of pantethine in women in G, Lo perimenopausal age Cicero G, et al. 3 Coronel Treatment of hyperlipemia in diabetic Am J Nephrol 1991 11(1):32-36 F, Tornero patients on dialysis with a physiological F, Torrente substance. J, et al. 4 Prisco D, Effect of oral treatment with pantethine on Angiology 1987 38:241-247. et al. platelet and plasma phospholipids in IIa hyperlipoproteinemia. 5 Eto M, et Lowering effect of pantethine on plasma Artery 1987 15:1-12 al. beta-thromboglobulin and lipids in diabetes mellitus. 6 Bertolini Lipoprotein changes induced by pantethine Int J Clin Pharmacol Ther Toxicol S, et al. in hyperlipoproteinemic patients: adults and 1986 24:630-637. children. 7 Gensini Changes in fatty acid composition of the Int J Clin Pharmacol Res 1985 GF, et al. single platelet phospholipids induced by 5:309-318. pantethine treatment. 8 Arsenio Effectiveness of long-term treatment with Clin Ther 1986 8:537-545 L, et al. pantethine in patients with dyslipidemia. 9 Murai A, The effects of pantethine on lipid and Artery 1985 12:234-243. et al. lipoprotein abnormalities in survivors of cerebral infarction. 10 Gaddi A, Controlled evaluation of pantethine, a Atherosclerosis 1984 50(1):73-83. Descovich natural hypolipidemic compound, in patients GC, with different forms of hyperlipoproteinemia. Noseda G, et al. 11 Donati C, Pantethine, diabetes mellitus and Clin Ter 1989; 128:411-422. et al. atherosclerosis. Clinical study of 1045 patients Dietary Phytonutrients Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • The term phyto originates from a Greek word meaning plant. -Fish Oil • Phytonutrients (or phytochemicals) are organic components found in plants and some -Flaxseed Oil phytonutrients can promote human health. -Glucosamine • Common classes of phytonutrients include: carotenoids, flavonoids (polyphenols) including isoflavones (phytoestrogens), inositol phosphates (phytates), lignans -Kelp (phytoestrogens), isothiocyanates and indoles, phenols and cyclic compounds, -L-Arginine phyto-sterols and stanols, saponins, sulfides, thiols, terpenes, and some vitamins -Lecithin (carotenoids such as lycopene, beta-carotene, etc.). -L-Lysine • Of all the phytonutrients, the carotenoids have been studied extensively. Carotenoids -Lycopene consist of alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene, zeaxanthin, astaxanthin, and many others. Carotenoids are commonly found in red, -Melatonin orange and yellow pigments in fruits and vegetables. -Methylsulfonylmethane • Polyphenols are natural components of a wide variety of plants and can be classified -Pantethine as non-flavonoids (i.e. ellagic acid) and flavonoids (i.e. anthocyanins, catechins, -Phytonutrients flavonones, flavones, flavonols and isoflavones). Dietary sources rich in polyphenols -Plant Sterols/Stanols are onion, apple, tea, red wine, grapes/grape juice, strawberries, blueberries, raspberries, cranberries and certain nuts. -S-adenosyl-L-methionine • Phytonutrients are not essential like traditional nutrients (protein, fat, vitamins, -Soy Isoflavones minerals). -Vinpocetine • Although many phytonutrients have been identified, there are likely thousands more that remain to be discovered. 1 2

Functions Back to sub-topics Phytonutrients can protect humans against certain diseases, such as cancer, heart disease and age-related macular degeneration. There are some proposed mechanisms by which phytonutrients may protect human health. Phytonutrients may: • serve as antioxidants • enhance immune response • alter estrogen metabolism • convert to vitamin A (beta-carotene) • cause cancer cells to die (via apoptosis) • repair DNA damage caused by toxins or pollutants (e.g. smoking). • detoxify carcinogens through activation of the cytochrome P450 and Phase II enzyme systems. 1 2

Dosage Back to sub-topics None established; highly variable

Toxicity Back to sub-topics Not known at this time. Dietary Sources Back to sub-topics Rich sources of phytonutrients are fruits, vegetables, grains, legumes, nuts and teas. Yellow, orange and red pigmented fruits and vegetables contain carotenoids. Dark, leafy green vegetables contain carotenoids as well. Reddish pigments in grape skins and citrus fruits contain flavonoids. Peanuts, lentils, soy and other legumes contain isoflavones. Foods high in phytonutrients include:

• Broccoli • olives • soybeans • Berries • tomatoes • green tea • Soy nuts • lentils • apples • Pears • cantaloupe • cabbage • Turnips • garlic • flaxseeds • Celery • apricots • kale • Carrots • onions • bok choy • Spinach • seeds • red wine

Drug-Supplement Interaction Back to sub-topics Many interactions are possible with phytonutrients and only a few are listed here. Citrus bioflavonoid preparations, such as grapefruit juice, may interact with drugs containing naringin. Naringin increases the oral bioavailability of calcium channel blocker medications such as: nifedipine, verapramil and felodipine. Naringin may enhance the effect of these drugs and result in a serious drop in blood pressure. Naringin also inhibits the breakdown of various drugs such as caffeine, coumarin, and estrogens. 4 Avoid grapefruit juice and flavonoid preparations containing naringin (e.g. citrangedin, grapefruit, kumquat, and pummelo or bioflavonoid supplements containing naringin) when taking any of these drugs.

Research Summary Back to sub-topics Evidence from epidemiological studies has demonstrated that fruit and vegetable consumption is protective of human health and is linked to a lower risk for chronic diseases, including certain cancers and heart disease. General Health: It has been notes that Americans are not consuming the recommended amount of fruits and vegetables daily. Research suggests consuming an array of colorful fruits and vegetables, rich in phytonutrients on a daily basis. Among some of the phytonutrient-rich fruits and vegetables are: red foods (tomatoes, strawberries, apples, cranberries, red grapes), green foods or cruciferous vegetables (broccoli, brussel sprouts, kale), white-green foods (garlic, onions), and other food/substances such as soybeans and green tea. 5 6 7 8 A key consideration is whether a purified phytonutrient has the same health benefit as the whole food or mixture of foods where the phytonutrient is present. One study found that the vitamin C in apples with skin accounted for only 0.4% of the total antioxidant activity of the fruit. This suggests that most of the antioxidant activity of fruits and vegetables may come from phenolics and flavonoids. It is possible that an additive or synergistic effect from whole fruits and vegetables is the best way to provide potent antioxidant activity. 9 Cancer: There is an abundance of epidemiological evidence linking a diet high in certain phytochemicals and a reduced risk for developing cancer. Phytopolyphenols such as apigenin, curcumin, genistein, catechins and theaflavins have shown to be effective with inhibiting carcinogenesis in animals. 10 Phytochemicals in foods may affect production and early growth of tumors in humans by altering how cells respond to genetic damage or a carcinogenic agent. 11 Cruciferous vegetables have shown to blunt tumor growth in animal models; phytoestrogens from soybeans may help reduce risk for breast cancer; and plant anthocyanins can reduce the rate of oxidative damage within the human body. 12 13 Epidemiological data suggests that consumption of cruciferous vegetables may reduce cancer risk. Cruciferous plants are rich in glucosinolates and converted to isothiocyanates by plant enzymes and gastrointestinal microflora. Certain isothiocyanates and glucosinolates have shown to effectively block chemical carcinogenesis in animal models. A number of isothiocyanates are also potent inducers of phase 2 proteins. A significant amount of experimental evidence supports the view that phase 2 enzyme induction is a highly effective strategy for reducing susceptibility to carcinogens. 14 The anti-cancer properties in berry extracts have been documented. One paper describes the protective effect of strawberries, blueberries and raspberries against cervical and breast cancer. Freeze-dried fruits of blueberry and strawberry cultivars were extracted with solvents and tested against cultures of two aggressive cancer lines: 9MCF-7 and T47-D with different requirements for estrogen. Researchers found extracts from blueberry and strawberry significantly decreased the growth of cervical and breast cancer cells. One strawberry extract decreased the growth of breast cancer cells by 77%; a blueberry extract decreased growth of cervical cancer cells by 81%. 11 In another study, the Ames assay was used to determine that ethanol extracts from raspberry extract strongly inhibited two aggressive cervical and breast cancer cell lines. 15 Cranberries contain flavonol glycosides, anthocyanins, proanthocyanins (condensed tannins), and organic and phenolic acids. The antiproliferative effects of total cranberry extract (TCE) (200 microg/mL) versus all fractions were evaluated against human oral (KB, CAL27), colon (HT-29, HCT116, SW480, SW620), and prostate (RWPE-1, RWPE-2, 22Rv1) cancer cell lines. Antiproliferative activity of total polyphenols in TCE suggests synergistic or additive antiproliferative interactions of the anthocyanins, proanthocyanidins, and flavonol glycosides within the cranberry extract as compared to the individual phytochemicals in TCE. 16 One study examined the combined effects of dietary soy phytochemicals and tea components on breast tumor progression in a clinically relevant in vivo model of MCF-7 androgen-dependent human breast tumor in female SCID mice. Mice were treated with genistein-rich soy isoflavones (GSI), soy phytochemical concentrate (SPC), black tea (BT), green tea (GT), SPC/BT combination and SPC/GT combination. Analysis of serum and tumor biomarkers showed that the combined effects of SPC and GT inhibited tumor angiogenesis, and reduced estrogen receptor (ER)-alpha and serum levels of insulin-like growth factor (IGF)-I. Results of this study suggest that dietary SPC plus GT may be used as part of a dietary regimen to effectively inhibit progression of estrogen-dependent breast cancer. 17 Epigallocatechin gallate (EGCG), a powerful antioxidant derived from green tea extract, and genistein, a pharmacologically active isoflavone present in soy, are referred to as chemoprotective agents, due to their antioxidative and anti-inflammatory properties. 18 Anthocyanins in tart cherries have been examined for their potential to inhibit intestinal tumor development in Apc(Min) mice and growth of human colon cancer cell lines. Results from mice consuming the cherry diet, anthocyanins or cyanidins show smaller and fewer cecal adenomas and reduce cell growth of cancer lines, as compared to the mice consuming the control diet. These results suggest that anthocyanins and cyanidins from tart cherry may reduce the risk of colon cancer. 19 Cardiovascular disease: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the U.S. One hundred forty-seven original investigations and reviews of metabolic and epidemiologic studies, as well as dietary intervention trials regarding diet and coronary heart disease (CHD) prevention were reviewed. It was determined that consuming a diet high in fruits and vegetables, nuts, and whole grains, and low in refined grain products, is one of the successful dietary strategies to prevent CHD. It is well known that consuming a diet high in fruits and vegetables can help reduce risk for CHD, and phytonutrient content of fruits and vegetables are thought to play a role in this process. 20 A high flavonoid intake may be beneficial for lowering risk for heart disease women. A cross sectional analysis of the SU.VI.MAX Study (an 8-year trial evaluating the effect of antioxidant supplementation on the incidence of major chronic diseases), involving 1286 women and 1005 men was performed. The relationship between flavonoid intake and cardiovascular risk factors was evaluated with covariance analyses with logistic regression analyses. Results showed flavonoid-rich food consumption was inversely related to systolic blood pressure in women (p= 0.005), but not in men. Women in the highest tertile of flavonoid-rich food consumption were at lower risk for cardiovascular disease [odds ratio (OR): 0.31; 95%CI: 0.14, 0.68]. These results suggest that a high consumption of flavonoids may help prevent cardiovascular disease in women. 21 Aging/Cognitive Effects: Some research suggests that antioxidant-rich foods may be beneficial in delaying or reversing neuronal and behavioral aging. 22 One study determined that a blueberry-supplemented diet may retard aging of the brain, and prevent elevated levels of the oxidative stress-responsive protein, nuclear factor-kappa B (NF-kappaB), in aged Fischer-344 rats. A blueberry-supplemented diet was given to 12 aged rats 4 months prior to testing, while 11 aged and 12 young rats were fed a control diet. The rats were tested for object recognition memory on the visual paired comparison task. Young rats and aged rats fed the blueberry diet, performed similarly and significantly better than the aged control diet group. In four brain regions, aged control diet rats had significantly higher average NF-kappaB levels than young animals on the control diet. Conversely, in four regions, aged blueberry diet rats had significantly lower levels of NF-kappaB than aged control diet rats. [ Note: Higher NF-kappa B levels are associated with poorer memory scores.] Results suggest that a blueberry-enriched antioxidant diet can prevent an age-related increase in NF-kappaB, a protein that responds to oxidative stress and is related to aging of the brain. 23 A few studies examined whether long-term feeding of fruit and vegetable extracts (blueberry, strawberry or spinach extracts) could retard neuronal and cognitive function in Fischer 344 rats. One study found that antioxidant-rich supplements of fruit and vegetable extracts given to rats for 8 months beginning at 6 months of age decreased age-related declines in neuronal and cognitive function. 24 Another follow-up study using strawberry, spinach or blueberry supplements reversed age-related deficits in 19-month old Fischer 344 rats fed for 8 weeks. These findings suggest that phytonutrients in antioxidant rich foods may be beneficial in slowing and/or reversing some neuronal and behavioral effects of aging. 22 24 Much is known about a high fruit and vegetable intake and a reduced risk of chronic diseases. One aspect of future research should focus on specific biomarkers or early predictors of these diseases to test the ability of foods and their components to prevent them. 12

References Back to sub-topics 1 USDA Frequently Asked Questions About Beltsville Phytonutrients. http://www.barc.usda.gov/bhnrc/pl/pl_faq.html Agricultural Research Center (BARC). Phytonutrients Laboratory. 2 Meskin, Phytochemicals Mechanisms of Action. Boca Raton, FL CRC Press LLC. 2004 MS et al. 3 The Continuing Survey of Food Intakes by Individuals (CSFII) and the Diet and http://www.barc.usda.gov/bhnrc/foodsurvey/Csfii94.html Health Knowledge Survey (DHKS), 1994-96. http://www.barc.usda.gov/bhnrc/foodsurvey/Csfii94.html 4 Fuhr U The fate of naringin in humans: A key Clin Pharmocol Ther 1995; 58:365-373. and to grapefruit-juice drug interactions? Kummert AL. 5 Heber Vegetables, fruits and phytoestrogens J Postgrad Med 2004; 50:145-9. D. in the prevention of diseases. 6 Boyer J Apple phytochemicals and their health Nutr J 2004; 3:5. and Lui benefits. RH. 7 Potential impact of strawberries on Crit Rev Food Sci Nutr 2004; 44:1-17. Hannum human health: a review of the science. SM. 8 Sun J, Antioxidant and antiproliferative J Agric Food Chem 2002; 50:7449-54. et al. activities of common fruits. 9 Lui RH. Health benefits of fruits and vegetables Am J Clin Nutr 2003; 78:517S-520S. are from additive and synergistic combinations of phytochemicals. 10 Lin, Mechanisms of cancer Food Sci Agricul Chem 2000; 2:189-201. Jen-Kun. chemoprevention by phytochemicals and phytopolyphenols. 11 Agricultural Research 2001: 22 http://www.ars.usda.gov/is/AR/archive/may01/berry0501.htm. 12 Fjeld, Foods, phytonutrients and health. CJ. USDA Agricultural Research Service, http://www.ars.usda.gov/is/AR/archive/mar98/food0398.htm?pf=1 National Program Leader for Human Nutrition. 13 Gill CI, The effect of cruciferous and Cancer Epidemiol Biomarkers Prev 2004; et al. leguminous sprouts on genotoxicity, in 13:1199-205. vitro and in vivo. 14 Talalay Phytochemicals from cruciferous plants J Nutr 2001; 131:3027S-33S. P and protect against cancer by modulating Fahey carcinogen metabolism. JW. 15 Wedge Anticarcinogenic activity of strawberry, J Medicinal Food 2001; 4:49-51. DE, et al. blueberry, and raspberry extracts to breast and cervical cancer cells. 16 Total cranberry extract versus its J Agric Food Chem 2004; 52:2512-7. Seeram phytochemical constituents: NP, et al. antiproliferative and synergistic effects against human tumor cell lines. 17 Zhou Combined inhibition of Int J Cancer 2004; 108:8-14. JR, et al. estrogen-dependent human breast carcinoma by soy and tea bioactive compounds in mice. 18 Park Chemopreventive potential of Toxicol Lett 2004; 150:43-56. OJ and epigallocatechin gallate and genistein: Surh YJ. evidence from epidemiological and laboratory studies. 19 Kang Tart cherry anthocyanins inhibit tumor Cancer Lett 2003; 194:13-9. SY, et al. development in Apc(Min) mice and reduce proliferation of human colon cancer cells. 20 Hu FB Optimal diets for prevention of coronary JAMA 2002; 288:2569-78. and heart disease. Willett WC. 21 Consumption of foods rich in flavonoids J Nutr 2004; 134:923-6. Mennen is related to decreased cardiovascular LI, et al. risk in apparently healthy French women. 22 Joseph Reversals of age-related declines in J Neurosci 1999; 19:114-21. JA, et al. neuronal signal transduction, cognitive, motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. 23 Blueberry supplemented diet: effects on Nutr Neurosci 2004; 7:75-83. Goyarzu object recognition memory and nuclear P, et al. factor kappa B levels in aged rats. 24 Joseph Long-term dietary strawberry, spinach J Neurosci 1998; 18:8047-8055. JA, et al. or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. Dietary Plant Sterols/Stanols Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Plant sterols are structurally similar to cholesterol and are often called phytosterols. -Fish Oil • More than 40 sterols have been identified from plants, of which beta-sitosterol, -Flaxseed Oil campesterol and stigmasterol are the most abundant. Beta-sitosterol comprises 50% of -Glucosamine dietary plant sterols. • Stanols are saturated sterols and have no double bond in the ring structure. -Kelp • The average daily intake of phytosterol from the diet is ~250 mg/day, while that of -L-Arginine stanol is ~25 mg/day. -Lecithin • Plant sterols and stanols may be esterified to increase solubility in water and oil. -L-Lysine • More than 30 clinical studies have shown that plant sterols and stanols may lower total -Lycopene plasma cholesterol concentrations. • The FDA has approved 'health claims' on plant sterol and stanol products. The possible -Melatonin claim is that phytosterols may maintain healthy cholesterol with a low fat diet. -Methylsulfonylmethane • b-sitosterol is the most abundant phytosterol, comprising 50% of dietary phytosterols. -Pantethine • Sterols and stanols are equally effective in lowering total plasma cholesterol -Phytonutrients concentrations. -Plant Sterols/Stanols -S-adenosyl-L-methionine -Soy Isoflavones Functions Back to sub-topics -Vinpocetine • Plant sterols are poorly absorbed. In the case of sitosterol, only 5% is absorbed. • Plant sterols decrease total serum cholesterol and LDL cholesterol concentrations in a dose dependent manner, but not serum HDL cholesterol. • The mechanism by which plant sterols lower cholesterol has not been fully determined. The following theories have been proposed. • Compete efficiently with dietary cholesterol for micelle incorporation • Displace cholesterol from bile, decreasing reabsorption. • Decrease hydrolysis of cholesterol esters in the small intestine. • Since plant sterols and stanols may alter micelle formation, it is possible that absorption of fat-soluble nutrients (such as vitamin E and carotenoids) is diminished. • b-sitosterol may suppress tumor cell growth.

Dosage Back to sub-topics

• To reduce serum cholesterol, 1.5-3.0 grams of plant sterols or stanols as supplements or supplemented foods should be taken daily. 1 2 • Regardless of the origin of sterols, saturation of sterols (phytosterol or phytostanol), or the esterification of sterols and stanols, hypocholesterolemic action has been found. 3

Toxicity Back to sub-topics More than 30 studies have been conducted with plant sterols and stanols and found no adverse effects. Minor side effects are mild gastrointestinal discomfort including gas, diarrhea and constipation. In general, phytosterols and phytostanols are well tolerated. 4 Dietary Sources Back to sub-topics Phytosterols and stanols are found in fruits and vegetables. Plant sterols, stanols, esterified sterols or stanols, and mixtures are available both as supplemented foods (such as margarines or yogurts) and as dietary supplements (such as softgels or tablets).

Drug-Supplement Interaction Back to sub-topics 5 6 7 • No health hazards or side effects are known. • Caution with pregnancy or nursing, consult physician before using.

Research Summary Back to sub-topics Cholesterol lowering action: Numerous studies have shown the antihypercholesterolemic action of plant sterols and stanols in normo- and hypercholesterolemic subjects.

One study on 15 hypercholesterolemic men and women received a total dosage of 1.8 grams/day of either unesterified plant sterols (NS), plant stanols (SS), 50:50 mixture of sterols and stanols (NSS), or cornstarch (placebo). Each dietary treatment phase was a 21-day feeding period, followed by a 4-week washout period in which subjects consumed their habitual diets. Although the NS and SS group lowered plasma total cholesterol (p 15

A study was done on subjects with normal blood cholesterol concentrations to examine the effect of plant stanol esters on fasting concentrations of plasma lipids and lipid-soluble antioxidants. Sixty subjects consumed 3 cups yoghurt/day emulsified with 3 grams of plant stanol esters or placebo yoghurt for 4 weeks. A 13.7% reduction in LDL cholesterol concentration (p 16

According to a recent review, little difference has been observed between Delta(5)-sterols and 5-alpha reduced stanols. It was suggested that 2 grams/day of plant sterol or stanol esters lower LDL cholesterol concentrations by 10%. Current research on plant sterols and stanols also suggest that phytosterols are safe when added to a varied diet. 17

Preliminary data suggest that there is a greater risk reduction in coronary artery disease in patients achieving lower blood LDL cholesterol concentrations. Although plant stanols/sterols cannot replace statin medications for the aggressive treatment to lower LDL cholesterol (especially in the high-risk patient), plant sterol/stanols are considered an effective and well-tolerated lipid-lowering therapy. Moreover, combination therapy with statin medication plus plant stanols/sterols can be useful to achieve aggressive blood lipid concentration goals in high-risk patients with dyslipidemia. 18

American Dietetic Association (ADA) Statement on Plant Stanol/Sterol esters ADAs new evidence-based guidelines for Hyperlipidemia state: 'stanol/sterol esters are effective in lowering serum total cholesterol and LDL cholesterol by approximately 10-15%. Consider using plant stanol/sterol products incorporating 2-3 grams of plant stanol/sterol esters per day& 19

FDA Statement on Plant Sterols/Stanols: On February 14, 2003, the FDA published the interim final rule (IFR) authorizing the use of a health claim for plant sterol/stanol esters and reduced risk for coronary heart disease (CHD) on food labels. The IFR authorizes the use of a health claim relating between plant sterol/stanol esters and reduced risk of CHD on labeling of:

1. spreads and dressings for salad containing at least 0.65 grams of plant sterol esters per serving,

2. spreads, dressings for salad, snack bars, and dietary supplements in softgel form containing at least 1.7 grams plant stanol esters per serving. 20

Effect on plasma fat-soluble vitamin/carotenoid concentrations:

There has been conflicting evidence on the consumption of plant sterols/stanols and their effect on plasma fat-soluble vitamin and carotenoid concentrations:

One study compared the consumption of plant sterol/stanol esters on serum fat-soluble vitamin and carotenoid concentrations. Fifteen subjects were randomly fed a diet containing either margarine (control), margarine with sterol esters (1.92 grams/day), or margarine with stanol esters (1.76 grams/day) over 21 days. No significant differences were found in initial or final serum concentrations of fat-soluble vitamins or carotenoids among the 3 phases. These results suggest that consumption of esterified plant sterols or stanols does not effect fat-soluble vitamin or carotenoid concentrations when compared to a control diet. 21

Forty-six subjects with hypercholesterolemia consumed a sterol-free spread (control), a sterol ester spread (2.3 grams) and a stanol ester spread (2.5 grams). With each treatment, subjects were advised to eat 5 or more servings of fruits and vegetables, and one or more the servings was to be carrots, sweet potatoes, pumpkin, tomatoes, apricots, spinach or broccoli. Adding 1 daily serving of vitamin A-rich fruit or vegetable while consuming plant sterol or stanols esters, allowed subjects to maintain normal plasma carotenoid concentrations. Thus, it is recommended for individuals to consume an additional serving of a carotenoid-containing fruit or vegetable when consuming plant sterol or stanol products. 22

A recent mini-review discusses how regular consumption of plant sterols/stanols may result in a 10-20% decrease in plasma carotenoid concentrations. Although it is believed that there is no health risk associated with slight decrease in blood concentrations of carotenoids due to intake of plant sterol/stanols, the mechanism of how plant sterols/stanols affect plasma carotenoid concentrations is unclear. Data on carotenoids was pooled from 2 studies on plant sterols. Plasma carotenoid concentrations were presented as tertile values, showing that subjects with the lowest plasma carotenoid concentrations had the least decrease in their plasma alpha-, beta-carotene and lycopene levels. The mid and high-tertile subjects demonstrated a higher decrease in alpha and beta-carotene concentrations, more so than the lowest tertile group. However, the plasma levels of carotenoids in the mid and high tertile groups did not reach the level found in the low tertile group. The same was found for lycopene. From this, the importance of variability in baseline carotenoid levels among subjects was highlighted. Numerous factors affect plasma carotenoid levels (dietary habits, vegetable/fruit intake, seasonal variation (10-40%), bioavailability of carotenoids, etc.) 23

A one-year, randomized, double-blind study was conducted using placebo and either 1.8 or 2.6 g of sitostanol per day as margarine. The result showed that margarine containing stanols significantly lowered serum total and LDL cholesterol concentrations compared to placebo. Although no difference was found for the first 6 months between the 1.8 g and 2.6 g sitostanol groups, higher amounts of sitostanol in margarine (2.6 g) showed slightly but significantly greater decrease between 6 and 12 months of study. 8

A double-blind study with 55 hypercholesterolemic subjects for 8 weeks was conducted to see if plant stanols decrease serum cholesterol concentrations using two different sources of stanols. Plant stanols were derived from soy oil or wood. The stanol composition in wood and vegetable oil was 2.15 g and 0.19 or 1.50 g and .07 g of sitostanol and campestanol, respectively. The basic diet was low fat (25 26% of energy) during the experiment. The reduction in serum total cholesterol concentrations was 10.6% and 8.1% greater than in the control group. The same trend was observed on serum LDL cholesterol concentrations. Results suggested that plant stanol esters with a low fat diet can diminish serum cholesterol concentrations. 9

In one study with healthy or mildly hypercholesterolemic subjects, three different levels of plant sterol margarine spreads were given to see the effect on blood lipid and fat-soluble nutrients. Plant sterols at the level of 0.83, 1.61 and 3.24 g/day or placebo were fed for 3.5 weeks. Compared to the control spreads, total serum cholesterol concentration significantly decreased by 0.26 0.35 mmol/L for the 3 plant sterol groups. However, there was no difference of cholsterol-lowering action among sterol groups. Lipid standardized carotene concentrations were decreased by 0.83 and 3.24 g plant sterols. The author concluded that daily ingestion of 1.6 g plant sterols may favorably influence serum cholesterol concentrations. 10

In a review paper, Law found the reduction of serum LDL cholesterol concentration was significantly greater in old people than in young people. Plant sterols or stanols decreased serum LDL cholesterol concentrations in a dose-dependent manner up to 2 g/day. 11

Prostate Cancer: An animal study was done to examine the effect of phytosterols (PS) versus cholesterol on the growth and metastasis of the PC-3 human prostate cancer cells in SCID mice. The SCID mice were fed a diet containing 2% of either a PS mixture or cholesterol plus 0.2% cholic acid, and implanted with 2x10(6) tumour cells per mouse. The experimental diet consisted of 39.7% cornstarch, 20% casein, 13.2% maltodextrin, 10% sucrose, 7% soybean oil, 5% cellulose, 3.5% mineral mix, 1% vitamin mix, 0.3% L-cystine, 0.25% choline bitartrate and 0.0014% t-butylhydroquinone. Diets were supplemented with 0.2% cholic acid plus 2% of either cholesterol (control diet) or PS mixture. Tumour growth was monitored for 8 weeks post inoculation, and animals fed the PS diet had tumours 40-43% smaller than those fed the cholesterol diet. The number of mice with lymph node and lung metastasis was almost one-half that of cholesterol-fed group. In addition, an analysis of the growth and migration of these cancer cells in vitro was conducted. Results found that both beta-sitosterol and campesterol inhibited the growth of PC-3 cells by 70 % and 14%, respectively, while cholesterol supplementation increased growth by 18% when compared with controls. PS taken as a dietary supplement can indirectly inhibit the growth and metastasis of PC-3 cells, and PS directly (in tissue culture media) inhibited the growth and metastasis of PC-3 cells. 24

In a randomized, double-blind, placebo-controlled multicenter study, 200 subjects with symptomatic benign prostatic hyperplasia were given 20 mg b-sitosterol three times a day for 6 months. Treatment with plant sterol significantly lowered modified Boyarsky scores as compared to the placebo group. The peak of urine flow was improved while mean residual urinary volume decreased. Prostatic volume was not influenced in either group. 12

Stomach Cancer: An epidemiological study in Uruguay showed there was a strong inverse relationship between total phytosterol intake and stomach cancer in a dose response effect. This risk of association remained similar after adjustment for vegetables, fruits and other nutrients. Furthermore, when combined, b-sitosterol and a-carotene showed stronger inverse association with risk of stomach cancer. A similar inverse relationship was epidemiologically observed in lung cancer. 13 14

References Back to sub-topics 1 Normen L, et Soy sterol esters and b-sitostanol ester as Am J Clin Nutr 71:908-913. al: inhibitors of cholesterol absorption in human small bowel. 2 Hallikainen Plant stanol esters affect serum cholesterol J Nutr 130:767-776. MA, et al: concentrations of hypercholesterolemic men and women in a dose-dependent manner. 3 Jones PJH Comparable efficacy of hydrogenated Nutr Rev 56:245-252. and Ntanios F: versus nonhydrogenated plant sterol esters on circulating cholesterol concentrations in humans. 4 Hick KB and Phytosterols and phytostanols: functional Food Tech 55:63-67. Moreau RA: food cholesterol busters. 5 Burnham TH: Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons. 2001; 6 McEvoy GK: American Hospital Formulary Service Drug Bethesda, MD:American Society of Information. Health-System Pharmacists. 2001; 7 Bratman S: The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. 2001; Interactions Bible. 8 Miettinen TA, Reduction of serum cholesterol with NEJM 333:1308-1312. et al: sitostanol-ester margarine in a mildly hypercholesterolemic population. 9 Hallikainen Effects of 2 low-fat stanol ester-containing Am J Clin Nutr 69:403-410. MA and margarines on serum cholesterol Uusitupa MIJ: concentrations as part of a low-fat diet in hypercholesterolemic subjects. 10 Hendriks HJ, Spreads enriched with three different Eur J Clin Nutr 53:319-327. et al: concentrations of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. 11 Law M: Plant sterol and stanol margarines and BMJ 320:861-864. health. 12 Berges RR, et Randomised, placebo-controlled, Lancet 345:1529-1532. al: double-blind clinical trial of b-sitosterol in patients with benign prostatic hyperplasia. 13 DiStafani E, Plant sterols and risk of stomach cancer: a Nutr and Cancer 37:140141. et al: case-control study in Uruguay. 14 Mendilaharsu Phytosterols and risk of lung cancer: a Lung Cancer 21:37-45. M: case-control study in Uruguay. 15 Vanstone CA, Unesterified plant sterols and stanols lower Am J Clin Nutr 2002; 76:1272-8 et al. LDL-cholesterol concnetrations equivalently in hypercholesterolemic persons. 16 Mensink R, et Effects of plant stanol esters supplied in Atherosclerosis 2002; 160:205-13 al. low-fat yoghurt on serum lipids and lipoproteins, non-cholesterol sterols and fat soluble antioxidant concentrations. 17 Ostlund RE, Phytosterols in human nutrition. Annu Rev Nutr 2002; 22:533-49. Jr. 18 Stein, EA. Managing dyslipidemia in the high-risk Am J Cardiol 2002; 89:50C-57C. patient. 19 American American Dietetic Association (ADA) JADA 2002; 102:81. Dietetic Statement on Plant Stanol/Sterol esters Association 20 Food and FDA Statement on Plant Sterols/Stanols http://vm.cfscan.fda.gov/~dms/ds-ltr30.html Drug Administration (FDA) 21 Raeini S, et No changes in serum fat-soluble vitamin and Metabolism 2002; 51:652-6. al. carotenoid concentrations with the intake of plant sterol/stanol esters in the context of a controlled diet. 22 Noakes MC, An increase in dietary carotenoids when Am J Clin Nutr 2002; 75:79-86. et al. consuming plant sterols or stanols is effective in maintaining plasma carotenoid concentrations. 23 Ntanios FY, A healthy diet rich in carotenoids is effective Int J Vitam Nutr Res 2002; 72:32-9. and Duchateau in maintaining normal blood carotenoid GS. levels during the daily use of plant sterol-enriched spreads. 24 Awad AB, et In vitro and in vivo (SCID mice) effects of Eur J Cancer Prev 2001; 10:507-13. al. phytosterols on the growth and dissemination of human prostate cancer PC-3 cells. 25 Richelle M, et Both free and esterified plant sterols reduce Am J Clin Nutr 2004 80:171-7. al. cholesterol absorption and the bioavailability of beta-carotene and alpha-tocopherol in normocholesterolemic humans. 26 Berges RR, et Treatment of symptomatic benign prostatic BJU Intl 2000 85:842-6. al. hyperplasia with beta-sitosterol: an 18-month follow-up. 27 Goldberg AC, Effect of plant stanol tablets on low-density Am J Cardiol 2006 97:376-9. et al. lipoprotein cholesterol lowering in patients on statin drugs. 28 McPherson Phytostanol tablets reduce human J Pharm Pharmacol 2005 57:889-96. TB, et al. LDL-cholesterol. 29 Lau VW, et al Plant sterols are efficacious in lowering Am J Clin Nutr 2005 81:1351-8. plasma LDL and non-HDL cholesterol in hypercholesterolemic type 2 diabetic and nondiabetic persons. 30 ONeill FH, et Comparison of efficacy of plant stanol ester Am J Cardiol 2005 96:29D-36D. al. and sterol ester: short-term and longer-term studies. 31 Third report of the National Cholesterol Circulation 2002 106:3143-3421. Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) Final Report. Dietary S-adenosyl-L-methionine Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • S-adenosyl-L-methionine (SAMe) is synthesized from methionine, an essential amino -Fish Oil acid. -Flaxseed Oil • SAMe is a naturally occurring molecule that is found in all living cells and, in humans. -Glucosamine • Up to half of the daily intake of methionine is metabolized into SAMe in the liver. • SAMe is present only in minute amounts in the diet, and its principle source in the body -Kelp is through methionine metabolism. -L-Arginine • SAMe plays an important role as a one-carbon methyl donor in transmethylation -Lecithin processes. Methylation is a key step in the biosynthesis of DNA, RNA, phospholipid, -L-Lysine proteins, epinephrine, melatonin and neurotransmitter.

-Lycopene • Metabolism of SAMe requires cofactors such as vitamin B 6 , B 12 , folic acid or -Melatonin betaine. -Methylsulfonylmethane • An average adult produces 7-8 g of SAMe each day. • SAMe was first marketed as a prescription drug in 1976 in Italy and became available -Pantethine as a dietary supplement in the U.S. in 1999. -Phytonutrients • SAMe has been used in treating depression, joint pain and liver conditions such as -Plant Sterols/Stanols cholestatis and cirrhosis. -S-adenosyl-L-methionine -Soy Isoflavones • SAMe is available in some countries outside the U.S. as a prescription drug therapy for -Vinpocetine depression, osteoarthritis, and liver disease.

Functions Back to sub-topics 1 2 • SAMe is important to three key metabolic pathways related to transmethylation, transsulfuration, and polyamine synthesis. • In transmethylation reactions, SAMe donates a methyl group to a large variety of acceptor substrates including DNA, proteins, neurotransmitters and phospholipids. • In transsulfuration reactions, SAMe is converted, in a series of enzymatic steps, to cysteine, a precursor of glutathione, a major cellular antioxidant. SAMe also stimulates the synthesis of the proteoglycans used for cartilage regeneration. • Polyamine synthesis is required for normal cell growth, and two polyamines, spermidine and spermine, have anti-inflammatory and analgesic effects. • SAMe may have anti-inflammatory and analgesic activities.

Dosage Back to sub-topics Four hundred to 1600 mg of SAMe has been used in treating depression and osteoarthritis and has been well-tolerated without severe side effects. Stomach ache may occur in some persons. Toxicity Back to sub-topics 3 • SAMe has been administered as a prescription drug in Italy since 1976. During that time, about 17 million people have been exposed to SAMe without any reports of serious adverse events. So far there are no reported adverse interactions with SAMe and other drugs, dietary supplements, or foods. Doses of 3.2 g/day were administered intravenously to pregnant women in clinical trials without any harm to mother or offspring. Because there is little clinical data on doses greater than 1.6 g/day, this should be considered the upper limit. • Patients with bipolar (manic) depression should not take SAMe without physician supervision. SAMe may accentuate the manic phase in these patients. • SAMe is not recommended for use by children. • Lactating and pregnant women should consult their medical supervisors.

Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 4 5 9

• Combining SAMe with monoamine oxidase inhibitors (MAOIs), such as isocarboxazid [Marplanâ], or selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine [Prozacâ], or tricyclic antidepressants (TCAs), such as amitriptyline [Elavilâ], may increase a risk of serotonin syndrome. This syndrome takes place when there are high concentrations of serotonin in the body. This causes anxiety, restlessness, muscle twitching, and tremor. Consulting with a physician or pharmacist before taking these medication with concomitant use of SAMe is required. • Tramadol [Ultramâ] is an analgesic used for the treatment of moderate pain. This medication can increase a risk of serotonin syndrome. It is advisable for people taking tramadol to avoid SAMe supplements.

Research Summary Back to sub-topics

The U.S. Department of Health and Human Services (HHS) Agency for Healthcare Research and Quality (AHRQ) conducted an extensive literature review to determine SAMes efficacy for treatment of depression, osteoarthritis, and cholestasis of pregnancy and intrahepatic cholestasis associated with liver disease. The results were released in late 2002 and summarized below, along with other data.

Depression: Depression will affect 10 to 25 percent of women and 5 to 12 percent of men in the United States . Approximately 10 to 15 million people experience clinical depression in any given year. 10 The antidepressant effects of SAMe administration were first documented in 1974. Further research in depressive disorders was reviewed in 1988, 1989, 1994, 2000, and 2002.

The AHRQ included 28 studies in a meta-analysis of the efficacy of SAMe to decrease symptoms of depression. Compared to placebo, SAMe was associated both statistically and clinically with significant improvements in the score of the Hamilton Rating Scale for Depression. When compared to conventional antidepressants, treatment with SAMe was not associated with a statistically significant difference in outcomes suggesting SAMe is as effective as some antidepressant prescription drugs. 10 A 2002 review concluded that treatment with parenteral or oral SAMe at doses of 200-1600 mg/day was superior to placebo and as effective as tricyclic antidepressants with a faster onset of action. 11

Two multi-center studies were conducted in patients to confirm the efficacy and safety of SAMe in the treatment of major depression. The first study group received 1600 mg/day of SAMe orally, while the second study group received 400 mg/day SAMe intramuscularly. Both studies compared SAMe to 150 mg imipramine/day in a double-blind design. The study concluded the anti-depressive effectiveness of both oral and intramuscular SAMe was comparable to 150 mg imipramine/day. In addition, SAMe had fewer adverse events and was significantly better tolerated. 12

SAMe has been studied in 16 open uncontrolled trials with a total of 660 patients; 13 randomized, double-blind, placebo-controlled trials with 537 patients; 19 controlled trials of SAMe verses other antidepressants involving 1134 patients. SAMe consistently showed significant anti-depressive effects in all 16 open trials and outperformed placebo in all controlled trials with exception of one.

In 18 controlled trials, SAMe was as effective as imipramine, chlorimipramine, amytriptyline, nomifensine and minaprine and caused fewer side effects. The rapid onset of action (5-10 days) was noted in 7 of the depressionstudies. 7

Arthritis: There are more than 100 different types of arthritis, ranging from mild tendinitis to to severe forms such as osteoarthritis (OA), the most common form of arthritis. Arthritis is often categorized by symptoms such as inflammation, redness, heat and pain. An estimated 15 percent of Americans suffer from arthritis, and the annual cost to society is estimated at 95 billion. 10 Standard treatment therapies for osteoarthritis include non-steroidal anti-inflammatory medication, non-pharmacologics (e.g. exercise, heat treatment) and surgery. Because of side-effects from pharmacologic agents, SAM-e was studied for its effects on reducing the pain associated with OA. Out of 13 unique studies considered in the ARHQ study, 10 studies were included in a meta-analysis of the efficacy of SAMe to decrease pain of osteoarthritis.

One large randomized clinical trial showed an effect size in favor of SAMe of 0.20 (95 percent CI [-0.39, - 0.02]) compared to placebo, thus demonstrating a decrease in the pain of osteoarthritis. 10

Compared to treatment with non-steroidal anti-inflammatory medication, treatment with SAMe was not associated with a statistically significant difference in outcomes (effect size 0.11; 95 percent CI [0.56, 0.35]). 10

In November 1987, the American Journal of Medicine published 20 papers from a symposium on SAMe and arthritis including 9 clinical trials with more than 22,000 participants. These studies, as well as others, indicate that SAMe exerts anti-inflammatory and analgesic effects equivalent to those of several prescription, nonsteroidal, anti-inflammatory drugs, but that it does not cause gastrointestinal bleeding. Anti-inflammatory effects require 3 to 4 weeks of treatment (400-600 mg orally every day) in mild to moderate cases. 8

Liver Disease: Abnormal SAMe synthesis is associated with liver disease, regardless of the etiology. Loss of activity in the enzyme methionine adenosyltransferase (MAT) results in decreased concentrations of SAMe and depletion of glutathione. The loss of glutathione further impairs SAMe production because glutathione is needed to stabilize MAT and to protect the enzyme from free radical damage.

The AHRQ included 6 studies in a meta-analysis of the efficacy of SAMe to relieve pruritus and decrease elevated bilirubin levels associated with intrahepatic cholestasis caused by a variety of liver diseases. Patients treated with SAMe were twice as likely as placebo-treated patients to have a reduction in pruritus. 10

The AHRQ included 8 studies in a meta-analysis of the efficacy of SAMe to relieve pruritus and decrease elevated serum bilirubin levels associated with cholestasis of pregnancy. Compared to placebo, treatment with SAMe for cholestasis of pregnancy was associated with a decrease in pruritus and bilirubin levels. 10

A review of 17 clinical trials shows that SAMe improved symptoms and biochemical markers (serum bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, transaminases, cysteine, taurine, and hepatic glutathione) of liver diseases, including alcoholic and nonalcoholic hepatitis and cirrhosis, oral-contraceptive-induced cholestasis, other forms of cholestasis, and metabolic disorders of porphyrin and bilirubin. 9

References Back to sub-topics 1 Brown RP, Adenosylmethionine in the clinical practice Clin Prac Alt Med 1:230-241. et al: of psychiatry, neurology, and internal medicine. 2 McEvoy American Hospital Formulary Service Drug Bethesda, MD:American Society GK: Information. of Health-System Pharmacists. 2001; 3 Burnham Drug Facts and Comparisons. St. Louis, MO: Facts and TH: Comparisons. 2001; 4 Finkelstein Methionine metabolism in mammals. J Nutr Biochem 1:228-237. JD: 5 Cantoni Methylation of nicotinamide with a soluble J Biol Chem 189:203-216. GL: enzyme system from rat liver. 6 Lieber CS: Role of S-adenosylmethionine in the J Hep 30:1155-1159. treatment of liver diseases. 7 Matro JM S-adenosylmethionine synthesis: molecular Pharmacol Ther 73:265-280. et al: mechanisms and clinical implications. 8 Lu SC: S-adenosylmethionine. Int J Biochem Cell Biol; 32:391-395. 9 Bratman The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. S: Interactions Bible. 2001; 10 Agency S-Adenosyl-L-Methionine for Treatment of Evidence Report/Technology for Depression, Osteoarthritis, and Liver Assessment: Number 64, AHRQ Healthcare Disease. Publication no. 02-E033 2002 Research August and Quality 11 Role of S-adenosyl-L-methionine in the Am J Clin Nutr 2002 1158S-61S Mischoulon treatment of depression: a review of the D, Fava M evidence. 12 Delle Efficacy and tolerability of oral and Am J Clin Nutr 2002 Nov Chiaie R, et intramuscular S-adenosyl-L-methionine 76(5):1172S-6S al. 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. 13 Alpert JE, S-adenosyl-L-methionine (SAMe) as an J Clin Psychopharmacol 2004 Dec Papakostas adjunct for resistant major depressive 24(6):661-4. G, disorder: an open trial following partial or Mischoulon nonresponse to selective serotonin reuptake D, et al. inhibitors or venlafaxine. Dietary Soy Isoflavones Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Soy isoflavones are phytoestrogens found in soybeans. Phytoestrogens are -Fish Oil plant-derived nonsteroidal compounds that possess both weak estrogenic and -Flaxseed Oil anti-estrogenic effects. -Glucosamine • The three main isoflavones soy contains are genistein, daidzein and glycitein. The glycosylated forms of these isoflavones are the most abundant forms in soybeans: -Kelp genistin (approximately 50%), daidzin (approximately 40%), and glycitin (approximately -L-Arginine 5-10%). -Lecithin • The malonyl glycosides (genistin, 6-O-malonylgenistin, and 6-O-acetylgenistin)are the -L-Lysine major forms of the genistein glycosides found in soybeans. -Lycopene • Soy isoflavones can bind to both alpha- and beta-estrogen receptors, however, binding affinity to the beta-receptor is higher. -Melatonin • The FDA has approved a cardiovascular health claim for foods that contain at least -Methylsulfonylmethane 6.25 grams of soy protein per serving. Isoflavone concentrations are generally 0.5 to -Pantethine 3.0 mg/g of soy flours and concentrates. -Phytonutrients -Plant Sterols/Stanols Functions Back to sub-topics -S-adenosyl-L-methionine -Soy Isoflavones • Soy isoflavones have estrogenic activity and may have antioxidant, anticarcinogenic, -Vinpocetine anti-atherogenic, hypolipidemic, and anti-osteoporotic activities. • Genistein, the most studied of the soy isoflavones, has been found to have antioxidant activities. It is a scavenger of reactive oxygen species, inhibiting lipid peroxidation and superoxide generation. • In animal experiments genistein has been found to increase the activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase. • Possible anticarcinogenic activities of genistein include upregulation of apoptosis, inhibition of angiogenesis, and inhibition of DNA topoisomerase II and protein tyrosine kinases. • Possible activity against prostate cancer includes inhibition of nuclear factor (NF)-kappa B in prostate cancer cells, downregulation of transferring growth factor (TGF)-beta, and inhibition of epidermal growth factor (EGF)-stimulated growth. • Anti-atherogenic activity of soy isoflavones includes antioxidant abilities, which may inhibit lipid peroxidation and LDL oxidation. Isoflavones may also lower serum cholesterol concentrations. Soy protein also contains other cholesterol-lowering components including trypsin inhibitors, phytic acid, saponins and fiber.

Dosage Back to sub-topics

• In October 1999, the FDA approved a labeling claim for products containing at least 6.25 g of soy protein/serving and is also low in fat, cholesterol, and sodium. • Various observational and epidemiological studies suggest that more than 30 mg daily of soy isoflavones (aglycon, not bound form of sugar) approximates the dose that may have health benefits. Toxicity Back to sub-topics

• Women with estrogen receptor-positive tumors should use caution when taking soy isoflavones and only use when recommended and monitored by your healthcare professional. • According to a recent in-depth review, the available scientific evidence to date supports the safety of isoflavones as typically consumed in diets based on soy, or soy-containing products. 10 • Twenty-four healthy postmenopausal women ingested a single dose of purified isoflavone preparations (from soybeans), delivering a genistein dose of 2, 4, 8, or 16 mg/kg body weight. A single dose administration of purified isoflavones at amounts exceeding normal dietary intakes had minimal clinical toxicity in healthy postmenopausal women. 11

Dietary Sources Back to sub-topics Soy isoflavones are found in soybeans, some soy protein powders, soy-based products, and as purified isoflavone supplements.

Drug-Supplement Interaction Back to sub-topics 1 2 3 • Some phytoestrogens do have significant activities at estrogen receptors. When phytoestrogens are used in combination with estrogen-containing products, the risk of estrogen-related side effects (nausea, bloating, breast fullness, or tenderness) may be increased. Patients should consult a physician or pharmacist before taking estrogen and phytoestrogens. • It is not known if phytoestrogens decrease effectiveness of tamoxifen [Nolvadex], used for breast cancer treatment, or raloxifene [Evista], used for the prevention of postmenopausal osteoporosis. • Trandolapril [Mavik] or verapamil [Isoptin], antihypertensive drugs, when taken concurrently with a bioflavonoid preparation containing naringin (a flavonoid present in grapefruit and soy) may cause serious adverse reactions. Consult with a physician or pharmacist before taking this combination. • Soy products containing tyramine can cause a hypertensive reaction in patients currently taking monoamine oxidase inhibitors (MAOIs), such as phenelzine [Nardil]. Soy foods to avoid during MAOI therapy are fermented soybean and soybean pastes that contain a significant amount of tyramine. Soy products that should be used with caution include soy sauces. • Soy products decrease absorption of L-thyroxine in infants with congenital hypothyroidism. This becomes a problem if the infant is receiving soy-based formula. The L-thyroxine dose should be increased if an infant with congenital hypothyroidism is fed soy-formula. After soy-formula is discontinued, the L-thyroxine dose should be decreased. For adults, staggering doses at least 2 hours apart is recommended. Soy may inhibit thyroid hormone synthesis but research is lacking in this area. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary Back to sub-topics References Back to sub-topics 2 Burnham TH: Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons. 2001; 3 McEvoy GK: American Hospital Formulary Service Drug Bethesda, MD:American Information. Society of Health-System Pharmacists. 2001; 4 Bratman S: The Natural Pharmacist Drug Herb Roseville, CA:Prima Publishing. Interactions Bible. 2001; 5 Erdman JW, Jr: Soy Protein and Cardiovascular Disease, A Circ 102:2555-2559. Statement for the Healthcare Professionals From the Nutrition Committee of the AHA: 6 Crouse JR, III, A randomized trial comparing the effect of Arch Intern Med et al: casein with that of soy protein containing 159:2070-2076. varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins: 7 Wangen KE, et Soy isoflavones improve plasma lipids in Am J Clin Nutr 73:225-31. al: normocholesterolemic and mildly hypercholesterolemic postmenopausal women: 8 Usual dietary isoflavone intake is associated J Nutr 131:1202-1206. Goodman-Gruen with cardiovascular disease risk factors in D, postmenopausal women. Kritz-Silverstein D: 9 Nagata C: Ecological study of the association between Int J Epidem 29:832-836. soy product intake and mortality from cancer and heart disease in Japan: 10 Alekel DL, et Isoflavone-rich soy protein isolate Am J Clin Nutr 72:844-52. al: attenuated bone loss in the lumbar spine of perimenopausal women: 11 Munro IC, et al. Soy Isoflavones: A Safety Review. Nutrition Nutrition Reviews 2003; Reviews 2003 61:1-33. 61:1-33. 12 Bloedon LT, et Safety and pharmacokinetics of purified soy Am J Clin Nutr 2002; al. isoflavones: single-dose administration to 76:1126-37 postmenopausal women. 13 Adams MR, et The atheroprotective effect of dietary soy Arterioscler-Thromb-Vasc-Biol al. isoflavones in apolipoprotein E-/- mice 2002; 22:1859-64 requires the presence of estrogen receptor-alpha. 14 Bhathena SJ Beneficial role of dietary phytoestrogens in Am J Clin Nutr 2002; and Velasquez, obesity and diabetes. 76:1191-201 MT. 15 Jenkins DJA, Effects of high- and low-isoflavone soyfoods Am J Clin Nutr 2002; 365-72 et al. on blood lipids, oxidized LDL, homocysteine, and blood pressure in hyperlipidemic men and women. 16 Sanders TAB, Moderate intakes of intact soy protein rich in Am J Clin Nutr 2002; 76:373-7 et al. isoflavones compared with ethanol-extracted soy protein increase HDL but do not influence transforming growth factor-ß(1) concentrations and hemostatic risk factors for CHD in healthy subjects. 17 Chiechi LM, et The effects of a soy rich diet on serum lipids: Maturitas 2002; 97-104. al. the Menfis randomized trial. 18 Puska P, et al. Soy in hypercholesterolaemia: a Eur J Clin Nutr 2002 56:352-7. double-blind, placebo-controlled trial. 2002; 56:352-7. 19 Dewell A, et al. The effects of soy-derived phytoestrogens J Clin Endocrinol Metab 2002; on serum lipids and lipoproteins in 87:118-121. moderately hypercholesterolemic postmenopausal women. 20 Adlercreutz, H. Phytoestrogens and breast cancer. J Steroid Biochem Mol Biol 2002; 83:113-8. 21 Peeters PH, et Phytoestrogens and breast cancer risk. Breast Cancer Res Treat 2003; al. Review of the epidemiological evidence. 77:171-83 22 Kurzer, MS. Hormonal effects of soy in premenopausal J Nutr 2002; 132:570S-573S. women and men. 23 Kumar NB, et The specific role of isoflavones on estrogen Cancer 2002; 94:1166-74. al. metabolism in premenopausal women. 24 Greendale GA, Dietary Soy Isoflavones and Bone Mineral Am J Epidemiology 2002; et al. Density: Results from the Study of Womens 155:746-54. Health Across the Nation. 25 Kyung K, et al. Benefits of Soy Isoflavone Therapeutic Obstet Gynecol 2002; Regimen on Menopausal Symptoms. 99:389-94. 26 VanPattern CL, Effect of Soy Phytoestrogens on Hot flashes J Clin Oncology 2002; et al. in Postmenopausal Women with Breast 20:1449-1455. Cancer: A Randomized, Controlled Clinical Trial. 27 Persky VW, et Effect of soy protein on endogenous Am J Clin Nutr 2002; al. hormones in postmenopausal women. 75:145-53. 28 Mitchell JH, et Effect of a phytoestrogen food supplement Clin Sci (Lond) 2002; al. on reproductive health in normal males. 100:613-8. 29 Strom BL, et Exposure to soy-based formula in infancy JAMA 2002; 15:807-14. al. and endocrinological and reproductive outcomes in young adulthood. 30 Bryant M, et al. Effect of consumption of soy isoflavones on Br J Nutr 2005 93:731-739 behavioural, somatic and affective symptoms in women with premenstrual syndrome. 31 Messina MJ Emerging evidence on the role of soy in Nutr Rev 2003 61:117-131 reducing prostate cancer risk. 32 Goldin BR, et Hormonal response to diets high in soy or Nutr Cancer 2005 51:1-6 al animal protein without and with isoflavones in moderately hypercholesterolemic subjects. 33 Sagara M, et al Effects of dietary intake of soy protein and J Am Coll Nutr 2004 23:85-91 isoflavones on cardiovascular disease risk factors in high risk, middle-aged men in Scotland. 34 Desroches S, Soy protein favorably affects LDL size J Nutr 2004 134:574-579 et al independently of isoflavones in hypercholesterolemic men and women. Dietary Vinpocetine Supplements Information -Facts -Functions -Toxicity -Dietary Sources Click on any link -Drug-Supplement Interaction -Research Summary -Acidophilus -Dosage -Alpha Lipoic Acid -Chondroitin -Coenzyme Q10 Facts Back to sub-topics -Conjugated Linoleic Acid -Fiber • Vinpocetine and vincamine are both used in Europe, Mexico and Japan for treatment of -Fish Oil cognitive and cerebrovascular disorders. -Flaxseed Oil • Vinpocetine is marketed in the U.S. as a nooptropic or a cognition enhancer. -Glucosamine • Vinpocetine is also known as ethyl apovincaminate. The chemical name is 3a, 16a ebumamenine-14-carboxylic acid ethyl ester. -Kelp -L-Arginine -Lecithin Functions Back to sub-topics -L-Lysine The following have been shown to be functions of vinpocetine in animal and clinical studies: -Lycopene • Regulates calcium-channel blocking activity and voltage-gated sodium channel blocking activity. -Melatonin • Inhibits the acetylcholine release evoked by excitatory amino acids and protects -Methylsulfonylmethane neurons against excitotoxicity. -Pantethine • Inhibits a cyclic GMP phosphodiesterase and this may enhance cyclic GMP -Phytonutrients concentrations in the vascular smooth muscle, which may lead to reduced resistance of -Plant Sterols/Stanols cerebral vessels, therefore enhancing cerebral flow. • May have possible antioxidant activity equivalent to vitamin E, reducing neural -S-adenosyl-L-methionine damages in pathological situations. -Soy Isoflavones • Increases brain glucose concentrations. -Vinpocetine • Provides oxygen for neurons in cases of hypoxia.

Dosage Back to sub-topics

• Vinpocetine is available as an individual supplement and in combination with other therapies. • Typical doses are from 5 mg to 10 mg/day taken with food. Some doses are up to 20 mg/day. • Higher doses are not advised.

Toxicity Back to sub-topics

• Toxicity of vinpocetine has not been detected in either animals or humans. • Adverse reactions include nausea, dizziness, insomnia, drowsiness, dry mouth, transient hypotension, transient tachycardia, pressure-type headache and facial flushing. Slight reductions in systolic, diastolic blood pressure and blood glucose concentrations have been reported. • Pregnant and lactating women should avoid vinpocetine supplements. • Those with a history of allergic reactions or hypersensitivity reactions with other vinca alkaloids, such as vinblastine and vincristine, should avoid vinpocetine. • Individuals with hypotension or orthostatic hypotension may have slight reductions in systolic and diastolic blood pressure and should be monitored by a physician when using vinpocetine. Dietary Sources Back to sub-topics

Drug-Supplement Interaction Back to sub-topics 1 2 3

Vinpocetine may decrease effectiveness of warfarin [Coumadinâ], an anticoagulant agent. Avoiding this combination unless supervised by a physician or pharmacist is advised.

Research Summary Back to sub-topics Ischaemic Stroke: Stroke is the third leading cause of death and one of the most important causes of long-term disability in most Western nations. Currently, recommendations for stroke are antiplatelet therapy and aspirin, otherwise there is no medical or surgical therapy that can be uniformly recommended for patients with acute ischaemic stroke. The synthetic derivative of apovincamine or vinpocetine may help with cerebral ischaemia. • In a study on 12 chronic stroke patients between the ages of 55 and 70 who were hospitalized for 3 days, patients received a MRI the first day, an intravenous infusion of 500 ml physiological solution [Salsolâ], followed by anatomic scanning tests the second day and finally 20 mg of vinpocetine dissolved in 500 ml Salsolâ intravenously the third day. The authors found that single-dose vinpocetine does not affect significantly regional or global metabolic rates of glucose. However, the treatment improved significantly the transport of glucose through the blood-brain barrier in the whole brain. Vinpocetine increases the peripheral vascular resistance in the symptomatic hemisphere, with special regard to the affected region (MCA territory). This results in blood redistribution at the advantage of the less affected brain tissue, thus supplying more blood to brain tissue with higher glucose uptake. 4 • In a pilot, single-blind study, 30 patients with verified diagnosis of acute ishaemic stroke were given 3 g of low-molecular weight dextran in 250 ml of isotonic saline alone or in combination of 10 mg o.d. of vinpocetine for 5 to 7 days followed by oral vinpocetine for 30 days. A relative risk reduction of poor outcome at 3 months follow-up was 30%, as defined by the modified Barthel Index, and 60% as defined by the modified Rankin score. There were no significant adverse effects seen, and a full-scale randomized placebo-controlled double blind trial is warranted to address the issue of effectiveness of vinpocetine treatment in acute ischaemic stroke. 5 • A review was written on all published and unpublished trials comparing vinpocetine to either placebo or another reference treatment for acute stroke. The treatment started no later than 14 days after stroke onset. Researchers found that only one trial fulfilled selection criteria for inclusion in the review and concluded that there is not enough evidence to determine whether vinpocetine does or does not decrease case fatality and dependency in acute stroke. 6 Nootropic Effect: Vinpocetine is known to have significant antiamnesic activity. The beneficial effect of vinpocetine is often attributed to cerebral vasodilation and an increase in the concentration of cyclic nucleotides in blood vessel myoctes. There is evidence that indicates the mechanisms of vinpocetine action may also include its direct interaction with nervous cells. Vinpocetine may be able to protect neurons against Ca2+ induced death.

• A study on isolated neurons of the left and right parietal ganglions of the land snail treated with vinpocetine showed its effects on different types of K+ currents. The data from the research suggested that modulation of different types of K+ currents in neuronal membranes may contribute partially to the nootropic effect of vinpocentine through the regulation of intracellular Ca2+ concentrations. 7 Incontinence: Therapy for the most common types of urinary incontinence is mostly surgical or the use of muscarinergic receptor blockers. These drugs do not exert adequate tissue selectivity and there are side effects that lead to discontinuation of the therapy. By inhibiting phosphodiesterase (PDE)-1 isoenzyme, vinpocetine may assist in the regulation of porcine and human detrusor smooth muscle contractility. • Nineteen patients with urgency urge incontinence, detrusor instablities or low compliance bladder were given 5 mg of vinpocetine for 2 weeks and then 10 mg for another 2 weeks. In 11 out of 19 patients or 57.9%, clinical symptoms and or urodynamic parameters were improved. Overall, data indicated that there might be a role for the PDE-1 inhibitor vinpocetine in the treatment of detrusor instabilities, urge incontinence, and low compliance bladder for patients not responding to anticholinergic pharmacological intervention. 8 Oxidative Stress: Oxidative stress refers to the cytotoxic effects of reactive oxygen species such as hydroxyl radical, superoxide anion and hydrogen peroxide, which may attack cellular components, promoting neuronal degeneration. Antioxidant drugs, such as vinpocetine, may delay or minimize neurodegeneration.

• A study evaluated whether vinpocetine can act as an antioxidant and prevent formation of reactive oxygen species and lipid peroxidation in rat brain synaptosomes. Vinpocetine was found to inhibit ascorbate/Fe2+-stimulated consumption of oxygen and thiobarbituric acid reactive substances accumulation, an indicator of lipid peroxidation, in a concentration-dependent manner. Authors concluded that the antioxidant effect of vinpocetine might enhance the protective role exerted by the drug in reducing neuronal damage in pathological situations. 9