SCIENCE, SAFETY AND EFFICACY OF VITAMIN E

Transcription

1 VITAMIN E E SCIENCE, SAFETY AND EFFICACY OF VITAMIN E Like all vitamins that exist within the human body, vitamin E is essential for life. Natural vitamin E has a trusted reputation after decades of extensive scientific research, which shows that vitamin E is a safe and effective antioxidant that provides critical health-protective benefits. However, recent media coverage on high-dose vitamin E has raised a number of important questions: What are the health benefits of vitamin E? Can I get enough through my diet? Does scientific research support high-dose vitamin E supplementation? Is high-dose vitamin E safe? What is meta-analysis? What are the strengths and weaknesses of this type of research? WHAT EXACTLY IS VITAMIN E? Vitamin E is a powerful antioxidant that helps ensure the stability and integrity of cellular tissues and prevents their damage from free radicals. Free radicals are highly reactive and unstable compounds created in the body during normal metabolic functions although they can be introduced into the body from the environment. They react with certain chemicals in the body, and in the process, interfere with the cells ability to function normally. Antioxidants like vitamin E work in several ways: by reducing the energy of the free radical, preventing free radical formation altogether or interrupting an oxidizing chain reaction minimizing the damage. In reality, vitamin E refers to a family of eight different substances called tocopherols and tocotrienols each with their own subfamilies; alpha, beta, delta and gamma. Each unique substance has a powerful but different effect on the body. Alpha-tocopherol (a-tocopherol), is the most active form of vitamin E in humans. 1, 2 Vitamin E is found naturally in foods like nuts, seeds, vegetable oils, leafy greens and whole grains. But, the average North American consumer gets only about 10 international units (IU) daily from their diet. While some studies show 2,000 IUs to be beneficial, the dietary intake of most people is significantly below the recommended daily amounts. This is why it is recommended that people augment their diet with a high quality, natural Vitamin E supplement. HOW SAFE IS HIGH-DOSE VITAMIN E? According to leading researchers, physicians and health experts from America s top medical schools, vitamin E supplements are very safe when taken in accordance with proper dosage guidelines. In fact, the general risk of too much vitamin E to your health is low. 3 One study found that elderly individuals who took vitamin E supplements for up to four months at daily doses of 530 mg or 800 IU (35 times the current recommended daily allowance, had no significant change in general health, body weight, levels of body proteins, lipid levels, liver or kidney function, thyroid hormone levels, amount or kinds of blood cells, and bleeding time. 4 The Institute of Medicine has set an upper tolerable intake level for vitamin E at 1,000 mg (1,500 international units (IU)), for any supplementary form of a-tocopherol (the most active form of vitamin E) per day. Upper tolerable intake levels represent the maximum intake of a nutrient that is likely to pose no risk of adverse health effects in almost all healthy individuals in the general population. 5 The Institute of Medicine is one of four organizations of the National Academy of Sciences. The National Academy of Sciences was created by the U.S. federal government to be an adviser on scientific and technological matters.) The U.S. Dietary Guidelines, which reflect the totality of scientific evidence on a nutrient, also recommends a daily upper limit of 1,500 IU of vitamin E. The use of supplementary vitamin E along with prescription drugs and/or prior to surgery should be done under medical supervision. We have carefully reviewed almost 100 articles about vitamin E, its benefits, activity, etc. There is almost no evidence of toxicity or adverse effects in doses used by the average American. In fact, multitudinous animal and human studies proclaim it has limited toxicity and significant benefits. The huge amounts of data and studies on vitamin E suggest that it should be considered in supplement programs to promote health, especially in seniors. Dr. Ronald Watson, Professor, College of Public Health and School of Medicine, University of Arizona Page 1 Science, Safety & Efficacy of Vitamin E March 2005

2 FAQs SCIENTIFIC RESEARCH FREQUENTLY ASKED QUESTIONS Q. Can I get all the vitamin E I need through my diet? A. You can get vitamin E into your diet by eating such foods as nuts, green leafy vegetables and fortified cereals. However, according to the U.S. Department of Agriculture s Healthy Eating Index, 90 percent of diets score poor or need improvement when rated for overall quality and nutrient intake. In fact, the recent report from the Dietary Guidelines Advisory Committee concluded that nearly all Americans fall short in their intake of vitamin E. Taking a vitamin E supplement is an effective way to ensure adequate intake of this important nutrient, which helps prevent disease and promote long-term health. Q. Is there any difference between natural and synthetic Vitamin E? A. Yes. Studies have shown that the body utilizes natural source Vitamin E approximately 50 per cent better than synthetic vitamin E. It is important to read the label and make sure it contains the natural form of Vitamin E, called d-alpha tocopherol while the synthetic is dl-alpha tocopherol. Q. What is the common dose of vitamin E? A. The most commonly marketed dose of single-nutrient vitamin E in Canada is 400 IU. Q. Is it safe to take more vitamin E than what I get in a multi-vitamin? A. Yes. Health experts at America s top medical schools have concluded that vitamin E supplements are not only safe for healthy individuals, but may also provide protection against chronic disease. The Institute of Medicine, a scientific advisory body in the United States, has set an upper level (a dose at which there is no known harm) for vitamin E at 1000 mg (1500 IU natural vitamin E). Q. A recent media report indicated that high-dose vitamin E could have serious side effects, or even be fatal. Is this accurate? A. Media reports of a recent metaanalysis took initial findings out of context and drew the conclusion that there may be a very small increase in mortality associated with high-dose vitamin E supplements. It should be noted that meta-analysis is not an exact science, but rather is a method used to statistically analyze pre-existing data. It is well recognized by researchers that there are inherent weaknesses in this type of data analysis. In truth, the benefits of vitamin E supplementation are well documented. Thousands of studies support its role in maintaining good health. (See Meta-Analysis ) SCIENTIFIC RESEARCH SUPPORTS HIGH-DOSE VITAMIN E SUPPLEMENTATION Vitamin E was discovered in 1922 and since then, hundreds of studies have been conducted to determine its health benefits and outline how it works in the body. Many of these studies indicate that vitamin E can help prevent coronary heart disease, decrease the incidence of prostate, breast and colon cancers, boost the immune system, reduce the risk of developing various vision disorders, including cataracts and macular degeneration, improve brain function, and play a role in DNA repair and other metabolic processes. 1, 2 The following is a review of some of the vitamin E research to date. Nearly all of the studies referenced below used high-dose vitamin E; 400 IU or higher per day. VITAMIN E & CARDIOVASCULAR HEALTH 6,7 Supports overall cardiovascular and circulatory health Lessens the severity of many symptoms of atherosclerosis Reduces the risk of a second heart attack A 1993 Harvard study of almost 90,000 nurses found a 41 per cent reduction in the risk of heart disease in the nurses with the highest intake of vitamin E from diet and supplements. Researchers found that the apparent benefit was mainly associated with intake of vitamin E from dietary supplements. 8 A second Harvard study in 1993 of almost 40,000 male health professionals found that men who took vitamin E supplements for more than two years had a 37 per cent reduced risk of heart disease. 9 A 1994 review of 5,133 Finnish men and women aged years suggested that an increased dietary intake of vitamin E was associated with decreased mortality from heart disease. 10 The Cambridge Heart Anti-Oxidant Study (CHAOS) published in 1996, found that vitamin E supplementation was dramatically effective in reducing the risk of heart attacks in patients known to be at high risk. As a result, the primary author of this study said that he would be recommending that patients with angina and those who are at risk of heart disease should be given supplementary vitamin E at a high dose. 11 In a 1996 study of over 2300 men in Quebec, the men who took vitamin supplements had a 70 per cent reduced risk of dying from ischemic heart disease and almost a 50 per cent lower risk of myocardial infarction. The vitamin that appeared to be most protective was vitamin E. 12 There is a great body of evidence documenting the health benefits of vitamin E. To maintain good health, I recommend 100 to 400 IU of vitamin E every day, in addition to maintaining a diet rich in antioxidant nutrients (i.e., vegetables, fruits, nuts, seeds, and legumes) and a strong foundation of nutritional supplementation. Dr. Michael Murray, Board of Trustees, Bastyr University, Washington. Page 2 Science, Safety & Efficacy of Vitamin E March 2005

3 SCIENTIFIC RESEARCH VITAMIN E & CANCER Protects against the effects of carcinogens, suppresses tumor growth and reduces the toxicity of several anti-cancer therapies Reduces the risk of prostate cancer A retrospective, case-control study in Washington State involving almost 450 colon cancer patients showed that the use of multivitamins, including vitamin E supplements was associated with a reduced risk of colon cancer. Men and women who averaged 200 IU or more of vitamin E per day over the 10 years had a 57 per cent reduction in risk compared with non-users of vitamin E. 13 In a Finnish study of vitamin E and betacarotene, there was a 32 per cent reduction in prostate cancer incidence and a 41 per cent reduction in prostate cancer mortality among the men who received supplementary vitamin E. 14 A study of women in Iowa provides evidence that an increased dietary intake of vitamin E may decrease the risk of colon cancer, especially in women under 65 years of age. 15 In 2002 the American Cancer society released the results of a long-term study that evaluated the effects of regular use of vitamin C and vitamin E supplements on bladder cancer mortality in almost 1,000,000 adults in the U.S. The study found that subjects who regularly consumed a vitamin E supplement for longer than 10 years had a reduced risk of death from bladder cancer. 16 VITAMIN E & DIABETES Enhances insulin therapy for diabetics Reduces the risk of medical complications in individuals with Type II diabetes Lowers the risk of cardiovascular disease in diabetics A group of researchers examined the effects of 750 IU of vitamin E supplementation for a period of one year, given as 250 IU three times a day. During vitamin E treatment, there was a decrease in lipoprotein peroxidizability. Within three months after stopping supplementation, serum vitamin E levels returned to baseline. Since the benefits of the supplement are conferred only while supplementation is continuing, researchers suggest life-long supplementation with vitamin E should be considered in patients with Type 1 diabetes. 17 In the SPACE study (Secondary Prevention with Antioxidants of Cardiovascular Disease in End stage Renal Disease.), researchers tested the effect of 800 IU per day of vitamin E supplementation on cardiovascular disease in diabetic patients. In the study, almost 200 patients received the vitamin E supplement or a placebo for a period of about two years. The vitamin E treatment was associated with a significant protective effect against cardiovascular death and non-fatal myocardial infarction (heart attack). 18 A study published in the November 2004 issue of Diabetes Care, outlines that diabetics with a particular form of a blood protein called haptoglobin had as much as a 500 per cent increased risk of developing heart disease. This study showed that when these at-risk patients took 400 IU of vitamin E daily, they reduced their risk of heart attack by 43 per cent, and their risk of dying of heart disease by 55 per cent. 19 VITAMIN E & EYE HEALTH Reduces the risk of developing various vision disorders including cataracts and age-related maclar degeneration The National Eye Institute supported a Longitudinal Study of Cataract involving 764 participants whose eyes were examined yearly over a period of about five years. The average age of the subjects was 65. Participants who were regular users of multivitamin supplements or vitamin E supplements were less likely to have an increase in lens opacity during the study period. 20 The Age-Related Eye Disease Study (AREDS) is an 11-year multi-center trial involving more than 3600 people who had evidence of Age-Related Macular Degeneration (AMD), when they entered the trial. The antioxidant supplement given to participants included 500 mg vitamin C, 400 IU vitamin E and 15 mg beta-carotene. The zinc supplement included 80 mg zinc and 2 mg copper. The participants that received both the antioxidant and the zinc supplements were significantly protected from developing advanced AMD. The authors concluded that people at risk of AMD should consider taking a supplement of antioxidants plus zinc such as that used in this study. 21 VITAMIN E & THE IMMUNE SYSTEM & LUNG FUNCTION Protects against upper respiratory tract infections Improves lung function and protects against oxidative damage in the lungs A study published in the August 18, 2004 issue of JAMA (included 617 elderly, long-term care facility patients), concluded that fewer people in the vitamin E group suffered one or more upper respiratory tract infections. The researchers also observed that those given a vitamin E supplement had a 20 per cent lower risk of catching a cold than the participants given the placebo. 22 In a study of over 1600 adults in western New York state, researchers examined the association between serum levels of vitamins A, C, E and lung function. Lung function was found to improve as blood levels of the antioxidant vitamins increased, with the strongest impact being associated with vitamin E and beta-cryptoxanthin. As a result, these compounds have been thought to protect against the development of lung cancer and other respiratory illnesses. 23 In a 1995 British study of lung function in more than 2600 people, it was found that higher dietary intakes of vitamin C and vitamin E were associated with improved lung function. 24 VITAMIN E & THE AGING PROCESS Slows the development of Alzheimer s and dementia Decreases oxidative stress and blood pressure in older individuals In a long-term study of more than 3000 Japanese-American men over 70 years of age in Hawaii, researchers found that the use of vitamin C and vitamin E supplements significantly reduced the risk of dementia. In those without dementia, use of vitamin C or vitamin E supplements was associated with improved cognitive function. 25 A study by Johns Hopkins researchers published in the Annals of Neurology showed that 400 IUs of vitamin E, taken in concert with 500 mg of vitamin C, reduced the risk of Alzheimer s by 60 percent. 26 A study involving 341 patients revealed that treatment with vitamin E or with selegiline delayed progression of the Alzheimer s, including delays in the deterioration of the performance of activities of daily living and the need for care. During the two-year study, patients received a monoamine oxidase inhibitor called selegiline, or 2000 IU per day of vitamin E, or both treatments, or a placebo. According to the authors of this study, there is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer s disease. 27 A second clinical trial of vitamin E and selegiline in patients with moderate Alzheimer s disease showed that these treatments slowed the rate of functional decline to a significant degree. 28 The July 1, 2004 issue of The New England Journal of Medicine included antioxidant supplements in a review of therapies for the treatment of Alzheimer s disease. The review noted that studies have shown the most widely administered antioxidant therapy, which uses vitamin E with the drug selegiline, can help delay placement in a nursing home, the development of severe dementia and death better than a placebo. The review states that many doctors have added daily supplementation of 2000 IU of vitamin E to their standard Alzheimer s treatment because of the study results. 29 Clearly, there is overwhelming scientific evidence that vitamin E is essential for overall good health. In addition, scientific evidence shows that high doses of vitamin E is a safe and effective antioxidant that provides health-protective benefits. In this regard, nearly all of the studies used 400 IU of vitamin E per day. Page 3 Science, Safety & Efficacy of Vitamin E March 2005

4 UNDERSTANDING META-ANALYSIS META-ANALYSES READING BETWEEN THE LINES WHAT IS A META-ANALYSIS? First, a meta-analysis is not a clinical trial. Nor does it represent new research. Rather, it is a statistical technique that combines the results of a number of scientific studies that have already been conducted in an effort to help clarify the benefits, or the lack of benefits, of a given healthcare treatment. Another widely quoted definition of meta-analysis is: a statistical analysis which combines or integrates the results of several independent clinical trials considered by the analyst to be combinable. 30 WHAT ARE SOME OF THE LIMITATIONS OF A META-ANALYSIS? A meta-analysis is subject to many potential biases in both the manner in which it is conducted and in the interpretation of the data. 31 However competent the meta-analysis, if one or a number of the original studies were partial, flawed or otherwise unsystematic, then the meta-analysis may provide a precise quantitative estimate that is simply wrong. Therefore, the main requirements of a quality metaanalysis are: a complete, unbiased collection of original, high-quality studies that examine the same therapeutic question. Defining a high quality meta-analysis is easier to state than to execute, however. The key difficulty lies in deciding which sets of studies are combinable. A meta-analysis is only as good as the set of studies on which it is based. The studies included may be incomplete or biased in many ways. Even failure to find all relevant studies may produce misleading meta-analyses. Another major concern is the extent to which researchers mix different kinds of studies (heterogeneity). Clearly, to get a precise answer to a specific question it makes sense to only select studies exactly matching that question. Unfortunately, all studies differ in a number of different dimensions, such as: patient groups may differ, severity of disease varies, treatments may differ from a single treatment to multiple treatments, purpose of the studies may be different. Thus, the mixing of diverse studies can make for a strange fruit salad: mixing apples and oranges may seem reasonable enough, but when sprouts, turnips or even an old sock are added, it can cast doubt on the meaning of any combined data from various studies. Yet, this combining data from very different kinds of studies is an unavoidable fact of meta-analysis. The question is not whether it happens, but whether its extent seriously undermines the conclusions being drawn by the researchers. DOES THE RECENT META-ANALYSIS CONDUCTED BY JOHNS HOPKINS UNIVERSITY ON VITAMIN E MEASURE-UP? This meta-analysis did not include new or original research. Rather, their statistical analysis was based on manipulations of existing data. DEFICIENCIES OF THE JOHNS HOPKINS META-ANALYSIS 1. Out of the hundreds of clinical studies on vitamin E, the researchers chose to include 19 older studies that only examined elderly patients who were taking multiple prescription medications due to their chronic illnesses, (Alzheimer s disease, Parkinson s disease, kidney failure or heart disease), making the conclusions impossible to apply to healthy individuals. This limitation is acknowledged in the Johns Hopkins study, where the authors indicated, we could not evaluate the generalizability of our findings to healthy, adult populations. 2. The analysts also chose to to eliminate from the analysis any studies where there were fewer than 10 deaths. This selection criteria introduced a notable bias in the conclusions reached by the authors. 3. The researchers chose not to review long-term studies of the general population that demonstrate vitamin E s positive health benefits, including the Nurses Study, the Finnish Study and the Iowa Women s Study. 4. Most of the studies selected by the authors were conducted using synthetic vitamin E, rather than natural vitamin E. However, the differences in the effects of varying types of vitamin E were not addressed in this metaanalysis. Further, most nutritionally-oriented doctors are now prescribing vitamin E not as an isolaed nutrient, as was the case in most of the studies cited in the meta-analysis, but as component of a balanced program of antioxidan supplementation. As a statistician, I find this paper unpersuasive. Dr. David Freedman, Statistician, University of California, Berkeley Vitamin E is an important antioxidant. If consumers base their lifestyles on this inconclusive meta-analysis, we could see an increased risk of cardiovascular disease, cancers and age-related macular degeneration in an otherwise healthy population. Dr. Barbara Levine, Associate Professor of Nutrition in Medicine, Weill Medical College, Cornell University Page 4 Science, Safety & Efficacy of Vitamin E March 2005

5 VITAMIN E SELECTING A QUALITY VITAMIN E SUPPLEMENT Recent studies have shown that natural E (its molecular structure is the same as that found in food), is not only better absorbed, but also better retained in the body than the synthetic form. In effect, about twice as much of the vitamin ends up in the blood of people taking natural E as in those taking the same amount of synthetic E. The synthetic form of vitamin E sold in some supplements is called alpha-tocopheryl acetate, and the abbreviation DL appears on the label. The natural form is labeled D. In practice, most nutritionally-oriented doctors are now prescribing vitamin E, not as an isolated nutrient, but as a component of a balanced program of antioxidant supplementation, which includes: vitamin C, selenium, mixed carotenoids, beta carotene, alpha lipoic acid and coenzyme Q10. Natural Factors has been manufacturing and distributing premium quality, natural vitamin E for fifty years. NATURAL FACTORS VITAMIN E Vitamin E Complete Tocopherols (d-alpha, beta-, delta-, gamma- tocopheals) 400 IU Contains D-alpha tocopherol 400 IU along with boosted levels of gamma tocopherol 200 mg; delta tocopherol 6 mg; beta tocopherol 4.6 mg. Recent research indicates that gamma tocopherol is important to human health in ways that distinguish it from the alpha-, beta- and delta tocopherols. Vitamin E D Alpha Tocopheryl Acetate Derived and isolated from 100% natural sources, d alpha tocopheryl acetate is vitamin E combined with acetic acid, commonly found in vinegar. This combination provides superior stability and bioavailability, making it particularly beneficial for the cardiovascular system. Clear Base Vitamin E 400 IU Purest and most potent form of D-alpha tocopheryl acetate available on the market; no oils, diluents or other tocopheryls are added. It is 1.8 times more bioavailable than synthetic vitamin E, making it ideal for those with allergies and for therapeutic use. Vitamin E 400 IU, D-alpha Tocopherol Succinate with Selenium Vitamin E works synergistically when combined with a high selenium yeast. This form of selenium is more readily absorbed and utilised than other forms of selenium. No live yeast spores are present and it will not cause candida or other yeast infections or yeast overgrowth. ClearQ Clear Base E with CoQ10 An innovative combination of a new, very absorbable form of Coenzyme Q10 and Clear Base vitamin E that increases CoQ10 absorption by 3 to 5 times and provides superior benefits to the cardiovascular system. Page 5 Science, Safety & Efficacy of Vitamin E March 2005

6 VITAMIN E REFERENCES 1. Traber, MG., et al., Modern Nutrition in Health and Disease, 10th ed. Baltimore: Williams & Wilkins, 1999: Farrell, P., et al., Modern Nutrition in Health and Disease, 8th ed. Philadelphia, PA: Lea and Febiger, 1994: Kappus, H., et al., Tolerance and safety of vitamin E: A toxicological position report, Free Radic Biol Med 1992;13: Meydani, SN., et al., Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults, Am J Clin Nutr, 1998;68: U.S. Department of Agriculture, Agricultural Research Service USDA National Nutrient Database for Standard Reference, Release Nutrient Data Laboratory Home Page, 6. Lonn, EM., et al., Is there a role for antioxidant vitamins in the prevention of cardiovascular diseases? An update on epidemiological and clinical trials data. Can J Cardiol, 1997;13: Jialal, I., et al., Effect of vitamin E, vitamin C and beta-carotene on LDL oxidation and atherosclerosis. Can J Cardiol, 1995;11 Suppl G:97G-103G. 8. Stampfer, MJ., et al., Vitamin E consumption and the risk of coronary disease in women. N Engl J Med, 1993;328: Rimm, EB., et al., Vitamin E consumption and the risk of coronary heart disease in men. New Engl J Med, 1993;328: Knekt, P., et al., Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol, 1994;139: Stephens, NG., et al., Randomised Controlled Trial of Vitamin E in Patients with Coronary Disease: Cambridge Heart Antioxidant Study (CHAOS), Lancet, 1996 Mar 23, 347(9004): Meyer, F., et al., Lower ischemic heart disease incidence and mortality among vitamin supplement users, Clinical Cardiology, October 1996, vol. 12, No. 10: White, E., et al., Relationship between vitamin and calcium supplement use and colon cancer, Cancer Epidemiology Biomarkers & Prevention, Vol 6, Issue Heinonen, OP, et al., Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial, Journal Of The National Cancer Institute, Vol 90, Bostick, RM., et al., Reduced risk of colon cancer with high intakes of vitamin E: The Iowa Women's Health Study. Cancer Res, 1993;15: Jacobs, EJ., et al., Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. American Journal of Epidemiology, 2002;156: Engelen, W., et al., Effects of long-term supplementation with moderate pharmacologic doses of vitamin E are saturable and reversible in patients with type 1 diabetes, American Journal of Clinical Nutrition, Vol. 72, No. 5, , November Boaz, M, et al., Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial, Lancet, 2000 Oct 7;356(9237): Levy, A., et al., The Effect of Vitamin E Supplementation on Cardiovascular Risk in Diabetic Individuals With Different Haptoglobin Phenotypes, Diabetes Care, 27:2767, Leske, MC., et al., Antioxidant vitamins and nuclear opacities: the longitudinal study of cataract. Ophthalmology, 1998 May;105(5): Age-Related Eye Disease Study Research Group (AREDS), A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E and Beta Carotene for Age-Related Cataract and Vision Loss, Arch Ophthalmol, 2001;119: Meydani, SN., et al., Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial, JAMA, 2004 Aug 18;292(7): Schunemann, HJ., et al., The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population, Am J Respir Crit Care Med, 2001 Apr;163(5): Britton, JR., et al., Dietary antioxidant vitamin intake and lung function in the general population, Am J Respir Crit Care Med, 1995 May;151(5): Masaki, KH., et al., Association of vitamin E and C supplement use with cognitive function and dementia in elderly men, Neurology, 2000;54: Zandi, P., et al., Reduced Risk of Alzheimer Disease in Users of Antioxidant Vitamin Supplements, Archives of Neurology, January 2004, vol. 61, pp Sano, M., et al., A Controlled Trial of Selegiline, Alpha- Tocopherol, or Both as Treatment for Alzheimer's Disease, N Engl J Med, 336: , April 24, 1997, No Grundman, M., Vitamin E and Alzheimer disease: the basis for additional clinical trials, American Journal of Clinical Nutrition, Vol. 71, No. 2, 630S-636s, February Cummings, JL., Alzheimer's Disease, N Engl J Med, 351:56-67, July 1, 2004, No Huque, MF., Experiences with meta-analysis in NDA submissions, Proceedings of the Biopharmaceutical Section of the American Statistical Association, 1988,; 2: Egger, M., et al., Meta-analysis: Principles and procedures, BMJ, 1997, 315: Page 6 Science, Safety & Efficacy of Vitamin E March