Natural Products (Professional)

Vitamin E

Scientific Name(s): Alpha-tocopherol

Common Name(s): Vitamin E

Clinical Overview

Uses of Vitamin E

Vitamin E is used as part of a diet rich in antioxidants to reduce the risk of coronary artery disease. Under medical supervision, it is used for the treatment of neuroleptic-induced tardive dyskinesia, rheumatoid arthritis, type 2 diabetes mellitus, treatment of age-related macular degeneration, and mucositis. The role of vitamin E in many other conditions also has been reported in the literature.

Vitamin E Dosing

Supplementation with vitamin E has been widely studied for a variety of conditions, including arterial stiffness, pediatric obesity-related liver disease, alcoholic hepatitis, nonalcoholic steatohepatitis, athletic training, beta-thalassemia, the common cold, IgA nephropathy, tardive dyskinesia and cancer prevention. Doses range from 400 to 1600 IU daily, equivalent to 50 to 400 mg of alpha-tocopherol. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Vitamin E Interactions

Orlistat may decrease vitamin E absorption, reducing the therapeutic effect. This interaction should be considered in patients with vitamin E deficiency who are undergoing orlistat therapy. Vitamin E may increase the anticoagulant effect of warfarin.

Vitamin E Adverse Reactions

Vitamin E (200 to 800 mg daily) does not have any serious side effects in most adults with the possible exception of individuals taking oral anticoagulant therapy and those with vitamin K-related clotting disorders.

Toxicology

The toxicity of vitamin E in adults appears to be low.

History

Vitamin E was first discovered in 1922, when it was found that reproductive abnormalities in rats reared on a basic diet were cured by a substance isolated from vegetable oils. A pure fraction was chemically identified in 1938 and named tocopherol after the Greek words tokos , which means childbirth, and phero , which means to bring forth. 13

Chemistry

Vitamin E is a generic term for a group of tocol and tocotrienol derivatives. It is a fat-soluble vitamin that exists in a variety of forms in many foods (eg, spinach, nuts, sunflower seeds, olives, asparagus, vegetable oils, mangoes, wheat germ, whole-wheat breads). Its most common form in a Western diet is α-tocopherol. 14 The most important chemical characteristic is its antioxidant property.

Vitamin E is fairly stable to heat and acids and unstable to alkalis, ultraviolet light, and oxygen. It is destroyed when in contact with rancid fats, lead, and iron. Esters of tocopherol such as tocopherol acetate, the most naturally occurring form, are more stable. 13

One IU of vitamin E activity is equivalent to 1 mg of tocopheryl acetate.

Vitamin E Uses and Pharmacology

Vitamin E has been extensively studied over a number of decades. A role for its use in atherosclerosis, coronary artery disease, cancer, diabetes, and rheumatoid arthritis as well as a number of neurologic diseases has been reported. Positive outcomes have been suggested for prevention of stretch marks in pregnancy, 15 nitrate tolerance in patients with coronary heart disease, 16 and pre-eclampsia in women at increased risk of the disease. 17 Vitamin E also may be effective in the treatment of chronic hepatitis B, 18 delaying the onset of Parkinson disease, 19 enhancing T-cell function, 20 and improving immune responses. 21

Atherosclerosis

Over the past 2 decades, considerable evidence has been gathered in support of the hypothesis that free-radical-mediated oxidative processes and specific products arising from this play a key role in atherogenesis. Low-density lipoproteins (LDLs) undergo multiple changes upon oxidation that are thought to be pro-atherogenic. 22 Laboratory evidence is available illustrating that vitamin E is carried within LDL particles and prevents LDL oxidation. 22

Animal data

Research reveals no animal data regarding the use of vitamin E for atherosclerosis.

Clinical data

A double-blind study has proposed that doses of vitamin E as low as 500 mg daily can prevent LDL oxidation. This preventative effect has been measured ex vivo 23 and observed in studies in postmenopausal women. 24

Coronary artery disease
Animal data

Research reveals no animal data regarding the use of vitamin E for coronary artery disease.

Clinical data

Epidemiological studies report strong inverse associations between intake of antioxidant vitamins and coronary artery disease. However, this is probably overly simplistic as the results from these studies may reflect the overall behavioral attitudes of the people regularly taking high doses of antioxidants over many years. 25 A number of large studies have investigated these proposed effects of vitamin E and have provided conflicting results.

The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico) prevention trial examined the use of vitamin E (300 mg daily) in MI survivors. This multicenter open-label trial was performed over a period of 3.5 years and included 11,324 patients. Vitamin E did not affect long-term complications post-MI (eg, death, nonfatal MI, nonfatal stroke) to any clinically important extent. However, subsequent results of a secondary analysis suggested that there was a possible benefit of vitamin E with regard to cardiovascular deaths. A relative risk reduction of 23% (95% CI 3% to 39%) was demonstrated. 25

The HOPE (Heart Outcomes Prevention Evaluation) study investigated vitamin E (400 mg daily) in patients with a high risk for cardiovascular events. This randomized, placebo-controlled, double-blind trial was performed over a period of 4.5 years and included 9541 patients. HOPE demonstrated that vitamin E has no effect on cardiovascular outcomes. 26 SECURE (Study to Evaluate Carotid Ultrasound Changes in patients treated with Ramipril and vitamin E), a substudy of the HOPE trial, showed that vitamin E had a neutral effect on atherosclerosis progression. 27 Another trial of 4495 patients also showed lack of effect. 28

Another randomized, double-blind, placebo-controlled study illustrated that the frequency of coronary events in 1862 men who had a previous MI was not affected by 50 mg of vitamin E per day. 29 The same investigators also found no effect on the recurrence and progression of angina. 30 This is in contrast to a previous case-control study (much smaller number of patients enrolled) demonstrating that some populations with a high incidence of coronary artery disease may benefit. This case study also suggested that plasma concentrations of vitamins C and E and carotene were significantly inversely related to the risk of angina. 31

The SPACE (Secondary Prevention with Antioxidants of Cardiovascular disease in Endstage renal disease) study investigated cardiovascular mortality in hemodialysis patients with pre-existing cardiovascular disease. The trial was randomized, double-blind, and placebo-controlled (n = 196). Patients receiving 800 mg of vitamin E per day had a reduction in the incidence of total MI. It was proposed that antioxidant therapy would be expected to have greater effects in patients with the most oxidative stress, ie, high-risk populations such as hemodialysis patients. 32

In CHAOS (Cambridge Heart Antioxidant Study), 2002 patients were randomized in a double-blind manner to receive vitamin E (800 mg daily) or placebo. A reduction in the risk of nonfatal MI was observed but there was no benefit in terms of cardiovascular death or total mortality. 33

To summarize, these studies emphasize that, to date, neither the dose of vitamin E that is most effective and safe nor the minimum duration of treatment are known. In view of these findings, the American Heart Association considers the most prudent and scientifically supportable recommendation for the general population is to consume a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains. This advice considers the role of the total diet in influencing disease risk. 22

Cancer
Animal data

Research reveals no animal data regarding the use of vitamin E for cancer.

Clinical data

Vitamin E acts as an antioxidant, protecting polyunsaturated fats and other lipids and lipid-soluble substances from oxidation. Dietary intake of antioxidants, particularly vitamins C, E, and β-carotene, has been associated with a diminished risk of various malignancies. It has been suggested that the primary mechanism of chemoprevention by antioxidants is through the reduction of DNA-damaging free radicals. 34

Trials in colorectal cancer patients have provided disparate results. Two small studies showed no positive effect of vitamin E. The first enrolled 12 patients with incurable colorectal cancer. They were treated conventionally with 5-fluorouracil (5-FU) and leucovorin. Vitamin E 3200 IU daily for 14 days was added. The authors concluded that their study appeared to be too small to determine efficacy. 34 In the second study, 77 patients with resected colorectal cancer, Dukes stage B-C, were randomized to receive daily 30,000 IU of vitamin A, 1 g of vitamin C, 70 mg of vitamin E, and 2 g of calcium or placebo for 6 months. The trial did not show any effect on cell kinetics of colon epithelium. 35 The Alpha Tocopherol, Beta Carotene cancer prevention (ATBC) study investigators published their results of the effects of vitamin E and β-carotene on colorectal cancer. This large study of 29,133 male smokers, randomly allocated to receive vitamin E, β-carotene, both, or placebo suggests that vitamin E supplementation may have a modest preventative effect. However, the 22% reduction in incidence was not significant. Additionally, vitamin E did not affect colorectal cancer survival time. 36

The ATBC study investigators also showed that supplementation with vitamin E and β-carotene does not have a statistically significant effect on the rate of incidence of pancreatic carcinoma or the rate of mortality caused by this disease. 37 The SELECT (Selenium and vitamin E Cancer prevention Trial) study investigating this patient population is currently underway with results anticipated in 2013. 38

Other cancers studied in the literature are those of the urinary tract and lung. 39 , 40 The incidence is not influenced by vitamin E supplementation.

Mucositis

Mucositis is a common complication of chemotherapy, usually presenting as erythematous areas that undergo desquamation, leaving ulcers behind that are covered by exudate. The pain of mucositis may be sufficient to interfere with normal dietary intake. Vitamin E prevents the peroxidation of membrane polyunsaturated fatty acids and has a stabilizing function on many membranes.

Animal data

Research reveals no animal data regarding the use of vitamin E for mucositis.

Clinical data

The Cochrane Collaboration identified 15 trials involving 876 patients that investigated agents with the ability to improve or eradicate mucositis. They located 1 trial that demonstrated that vitamin E was an effective eradication agent. 41 , 42 However, they do emphasize that their conclusions are based on weak and unreliable evidence as the study only evaluated 24 patients.

Age-related macular degeneration and visual loss

Age-related macular degeneration is a disease affecting the central area of the retina. Lipid material accumulates in deposits underneath the retinal pigment epithelium. These deposits, known as drusen, can be seen as pale yellow spots on the retina. It is the most common cause of blindness and visual impairment in industrialized countries.

Photoreceptors in the retina are subject to oxidative stress caused by exposure to light and oxygen. It has been proposed that antioxidants may prevent cellular damage in the retina by reacting with free radicals produced in the process of light absorption.

Animal data

Research reveals no animal data regarding the use of vitamin E for age-related macular degeneration and visual loss.

Clinical data

A systematic review reports the effects of vitamin E in the primary prevention and progression of age-related macular degeneration. To assess prevention, 3 large, high-quality trials that randomized a total of 4879 participants were identified. There was no evidence that people without age-related macular degeneration should take antioxidant vitamin and mineral supplements to prevent or delay the onset of the disease. 43 It should be noted that because there were only a very few cases of late-stage, age-related macular degeneration, these studies may have limited power to detect efficacy.

To assess progression of age-related macular degeneration, 7 trials were located. In total, these trials randomized 4119 people with signs of disease. Most of the patients were from trials conducted by the Age-Related Eye Disease Study Research Group. 44 , 45 Antioxidant vitamin (including vitamin E) and mineral supplementation was addressed. The authors concluded that people with moderate to severe age-related macular degeneration may experience a modest delay in progression of their disease with antioxidant supplementation. Given that there are few other interventions that offer much in the way of disease prevention or cure, this is an important consideration. There is no evidence that people with early signs of the disease would benefit. 46

Diabetes mellitus

Elevated levels of urinary albumin predict high risk for progression to end-stage renal disease in type 2 diabetes mellitus.

Animal data

Research reveals no animal data regarding the use of vitamin E for diabetes mellitus.

Clinical data

Several studies support the concept that reduction in albumin excretion rate is a valid renoprotective treatment goal. 47 Short-term treatment with vitamin C and E in pharmacological doses was shown to lower urinary albumin excretion rate in type 2 diabetic patients with micro/macroalbuminuria. The study was small (n = 29), but a statistically significant reduction of 19% was noted. 47 Additionally, chronic vitamin E administration has been proposed to improve the ratio of cardiac sympathetic-to-parasympathetic tone in patients with type 2 diabetes, possibly by a decline in oxidative stress. 48

Rheumatoid arthritis
Animal data

Research reveals no animal data regarding the use of vitamin E for rheumatoid arthritis.

Clinical data

Studies suggest that vitamin E could have a positive effect on autoimmune disease by decreasing pro-inflammatory cytokines and lipid mediators. Additionally, it appears that vitamin E might have clinical benefits and has been shown to significantly reduce pain. A trend toward a reduction in the duration of morning stiffness also has been noted. However, this latter effect is controversial. 49

Alzheimer disease

Free radical damage may be one of the mechanisms causing neuronal degeneration in Alzheimer disease.

Animal data

Research reveals no animal data regarding the use of vitamin E for Alzheimer disease.

Clinical data

Many studies have found evidence of increased level of oxidative damage to neurons in Alzheimer disease. There have been reports of an association between low blood levels of vitamin E and impaired cognitive function. Average levels of vitamin E in the blood and cerebrospinal fluid of patients with Alzheimer disease have been found to be lower than normal in several reports, although not in all. For their systematic review, the Cochrane Collaboration searched for all double-blind, randomized trials that examined the effects of vitamin E treatment versus placebo in patients with Alzheimer disease. The 1 study of acceptable methodology was restricted to patients with moderate disease and the results are difficult to interpret. There was an excess of falls in the vitamin E group compared with placebo, which required further evaluation. It was concluded that there was insufficient evidence of possible benefit to justify other studies. 50

Neuroleptic-induced tardive dyskinesia
Animal data

Research reveals no animal data regarding the use of vitamin E for neuroleptic-induced tardive dyskinesia.

Clinical data

There are numerous reports on the positive effects of vitamin E on tardive dyskinesia. A review of 10 controlled trials assessed the clinical effects of vitamin E in people with schizophrenia or other mental illnesses who developed neuroleptic-induced tardive dyskinesia. The reviewers concluded that small trials with uncertain quality of randomization indicate that vitamin E protects against deterioration of tardive dyskinesia but there is no evidence that vitamin E improves symptoms. 51

Dosage

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Orlistat

Orlistat administration may reduce the biologic and therapeutic effect of vitamin E by decreasing gastrointestinal absorption of the vitamin. In 12 healthy subjects receiving orlistat (120 mg 3 times daily for 4 days) administration of vitamin E (400 IU a-tocopheryl acetate), on the fourth day of orlistat treatment, decreased the area under the curve and peak plasma level of vitamin E 60% and 43%, respectively, compared with placebo. 52 , 53

Warfarin

Vitamin E may interfere with vitamin K-dependent clotting factors, adding to the anticoagulant effects of warfarin. A markedly prolonged prothrombin time and bleeding occurred in a 55-year-old man stabilized on warfarin 2 months after he started taking vitamin E supplementation (1200 IU/day or less). It may be necessary to give more than 400 IU/day of vitamin E for the additive hypoprothrombinemic effect to occur. 54 , 55

Adverse Reactions

High levels of vitamin E can adversely affect the absorption of vitamins A and K, and long-term use of high doses may cause nausea, diarrhea, and blurred vision. High-dose therapy in infants may be associated with more serious side effects. 14

Toxicology

The toxicity of vitamin E in adults appears to be low. Clinical trials have shown that large doses (200 to 800 mg daily) do not result in serious side effects, with the possible exception of individuals taking oral anticoagulant therapy and those with vitamin K-related clotting disorders.

Bibliography

1. Rasool, AH, Rehman A, Wan Yusuf WN, Rahman AR. Vitamin E and its effect on arterial stiffness in postmenopausal women—a randomized controlled trial. Int J Clin Pharmacol Ther . 2003;41:587-592.
2. Mezey E, Potter JJ, Rennie-Tankersley L, Caballeria J, Pares A. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. J Hepatol . 2004;40:40-46.
3. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol . 2003;98:2485-2490.
4. Avery NG, Kaiser JL, Sharman MJ, Scheett TP, Barnes DM, Gomez AL, et al. Effects of vitamin E supplementation on recovery from repeated bouts of resistance exercise. J Strength Cond Res . 2003;17:801-809.
5. Unchern S, Laoharuangpanya N, Phumala N, Sipankapracha P, Pootrakul P, Fucharoen S, et al. The effects of vitamin E on platelet activity in beta-thalassaemia patients. Br J Haematol . 2003;123:738-744.
6. Schneider M, Niess AM, Rozario F, Angres C, Tschositsch K, Battenfeld N, et al. Vitamin E supplementation does not increase the vitamin C radical concentration at rest and after exhaustive exercise in healthy male subjects. Eur J Nutr . 2003;42:195-200.
7. Chan JC, Mahan JD, Trachtman H, Scheinman J, Flynn JT, Alon US, et al. Vitamin E therapy in IgA nephropathy: a double-blind, placebo-controlled study. Pediatr Nephrol . 2003;18:1015-1019.
8. Adler LA, Rotrosen J, Edson R, Lavori P, Lohr J, Hitzemann R, et al. Vitamin E treatment for tardive dyskinesia. Veterans Affairs Cooperative Study #394 Study Group. Arch Gen Psychiatry . 1999;56:836-841.
9. Bryant RJ, Ryder J, Martino P, Kim J, Craig BW. Effects of vitamin E and C supplementation either alone or in combination on exercise-induced lipid peroxidation in trained cyclists. J Strength Cond Res . 2003;17:792-800.
10. Vajro P, Mandato C, Franzese A, Ciccimarra E, Lucariello S, Savoia M, et al. Vitamin E treatment in pediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr . 2004;38:48-55.
11. Hemila H, Virtamo J, Albanes D, Kaprio J. Physical activity and the common cold in men administered vitamin E and beta-carotene. Med Sci Sports Exerc . 2003;35:1815-1820.
12. Virtamo J, Pietinen P, Huttunen JK, Kohonen P, Malila N, Virtanen MJ, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA . 2003;290:476-485.
13. Mahan LK, Arlin MT. Krause's Food, Nutrition and Diet Therapy , 8th ed. Philadelphia, PA: WB Saunders Co; 1992.
14. Kaegi E. Unconventional therapies for cancer: 5. vitamins A, C and E. CMAJ. . 1998;158:1483-1488.
15. Young GL, Jewell D. Creams for preventing stretch marks in pregnancy (Cochrane Review). In: The Cochrane Library , Issue 1, 2002. Oxford: Update Software.
16. Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. Randomized, double-blind, placebo-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance. Circulation . 1997;96:2545-2550.
17. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet . 1999;354:810-816.
18. Andreone P, Fiorino S, Cursaro C, et al. Vitamin E as treatment for chronic hepatitis B: results of a randomized controlled pilot trial. Antiviral Res . 2001;49:75-81.
19. Parkinson Study Group. Effects of tocopherol and diprenyl on the progression of disability in early Parkinson's disease. New Engl J Med . 1993;328:176-183.
20. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAMA . 1997;277:1380-1386.
21. De la Fuente M, Ferrández MD, Burgos MS, Soler A, Prieto A, Miquel J. Immune function in aged women is improved by ingestion of vitamins C and E. Can J Physiol Pharmacol . 1998;76:373-380.
22. Tribble DL. Antioxidant consumption and risk of coronary heart disease: emphasis on vitamin C, vitamin E and β-carotene. A statement for healthcare professionals from the American Heart Association. Circulation . 1999;99:591-595.
23. Simons LA, Von Konigsmark M, Balasubramaniam S. What dose of vitamin E is required to reduce susceptibility of LDL to oxidation? Aust NZ J Med . 1996;26:496-503.
24. Guetta V, Panza JA, Waclawiw MA, Cannon RO ΙΙΙ. Effect of combined 17β-estradiol and vitamin E on low-density lipoprotein oxidation in postmenopausal women. Am J Cardiol . 1995;75:1274-1276.
25. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Preventione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet . 1999;354:447-455.
26. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med . 2000;342:154-160.
27. Lonn EM, Yusef S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation . 2001;103:919-925.
28. Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet . 2001;357:89-95.
29. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of α-tocopherol and β-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet . 1997;349:1715-1720.
30. Rapola JM, Virtamo J, Ripatti S, et al. Effects of α-tocopherol and β-carotene supplements on symptoms, progression and prognosis of angina pectoris. Heart . 1998;79:454-458.
31. Riemersma RA, Wood DA, Macintyre CC, Elton RA, Gey KF, Oliver MF. Risk of angina pectoris and plasma concentrations of vitamins A, C and E and carotene. Lancet . 1991;337:1-5.
32. Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet . 2000;356:1213-1218.
33. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet . 1996;347:781-786.
34. Blanke CD, Stipanov M, Morrow J, et al. A phase I study of vitamin E, 5-fluorouracil and leucovorin for advanced malignancies. Invest New Drugs . 2001;19:21-27.
35. Cascinu S, Ligi M, Del Ferro E, et al. Effects of calcium and vitamin supplementation on colon cell proliferation in colorectal cancer. Cancer Invest . 2000;18:411-416.
36. Albanes D, Malila N, Taylor PR, et al. Effects of supplemental α-tocopherol and β-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes Control . 2000;11:197-205.
37. Rautalahti MT, Virtamo JR, Taylor PR, et al. The effects of supplementation with α-tocopherol and β-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer . 1999;86:37-42.
38. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. J Urol . 2001;166:1311-1315.
39. Virtamo J, Edwards BK, Virtanen M, et al. Effects of supplemental alpha-tocopherol and beta-carotene on urinary tract cancer: incidence and mortality in a controlled trial (Finland). Cancer Causes Control . 2000;11:933-939.
40. Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New Engl J Med . 1994;330:1029-1035.
41. Wadleigh RG, Redman RS, Graham ML, Krasnow SH, Anderson A, Cohen MH. Vitamin E in the treatment of chemotherapy-induced mucositis. Am J Med . 1992;92:481-484.
42. Worthington HV, Clarkson JE, Eden OB. Interventions for treating oral mucositis for patients with cancer receiving treatment (Cochrane Review). Cochrane Database Syst Rev . 2002;CD001973.
43. Evans JR, Henshaw K. Antioxidant vitamin and mineral supplementation for preventing age-related macular degeneration (Cochrane Review). In: The Cochrane Library , Issue 1, 2002. Oxford: Update Software.
44. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Opthalmol . 2001;119:1417-1436.
45. 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: AREDS report no. 9. Arch Ophthalmol . 2001;119:1439-1452.
46. Evans JR. Antioxidant vitamin and mineral supplements for age-related macular degeneration (Cochrane Review). Cochrane Database Syst Rev . 2002;CD000254.
47. Gaede P, Poulsent HE, Parving HH, Pedersen O. Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients. Diabetic Medicine . 2001;18:756-760.
48. Manzella D, Barbieri M, Ragno E, Paolisso G. Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr . 2001;73:1052-1057.
49. Tidow-Kebritchi S, Mobarhan S. Effects of diets containing fish oil and vitamin E on rheumatoid arthritis. Nutr Rev . 2001;59:335-341.
50. Tabet N, Birks J, Grimley Evans J, Orrel M, Spector A. Vitamin E for Alzheimer's disease (Cochrane Review). In: The Cochrane Library , Issue 1, 2002. Oxford: Update Software.
51. Soares KVS, McGrath JJ. Vitamin E for neuroleptic-induced tardive dyskinesia (Cochrane Review). In: The Cochrane Library , Issue 1, 2002. Oxford: Update Software.
52. Melia AT, et al. The effect or orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamin A and E in healthy volunteers. J Clin Pharmacol . 1996;36:647.
53. Corrigan JJ, et al. Caogulopathy associated with vitamin E ingestion. JAMA . 1974;230:1300-1301.
54. Schrogie JJ. Coagulopathy and fat-soluble vitamins. JAMA . 1975;232:19.
55. Corregan JJ, et al. Effect of vitamin E on prothrombin levels in warfarin-induced vitamin K deficiency. Am J Clin Nutr . 1981;34:1701-1705.