ATC Class:A11HA03

VA Class:VT600

AHFS Class:

• Vitamin E 88:20

Generic Name(s):

• Vitamin E

Vitamin E is a fat-soluble vitamin and an antioxidant.

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.159 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).162 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).159

The NAS has established an EAR and RDA for vitamin E for adults based on induced vitamin E deficiency in humans and the correlation between hydrogen peroxide-induced erythrocyte lysis and plasma α-tocopherol concentrations.159 The EAR and RDA for children and adolescents 1-18 years of age were estimated using metabolic formulas, which were extrapolated from adult values based on lean body mass and growth need, since specific data in children and adolescents currently are unavailable.159 An AI for adults 19-50 years of age currently cannot be determined reliably from available data on intakes.159 An AI has been set for infants through 6 months of age based on the observed mean vitamin E intake of infants fed principally human milk.159 Since the usual intake of vitamin E from solid foods consumed by infants 7-12 months of age has not been determined, an AI for infants in this age group has been set by extrapolating upward from the AI value for infants through 6 months of age, adjusting for metabolic body size and growth, and adding a variability factor.159 (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, see Uses: Dietary Requirements in Folic Acid 88:08.)

The principal goal of maintaining adequate intake of vitamin E in the US and Canada is to prevent deficiency manifestations such as peripheral neuropathy.159 Vitamin E deficiency is very rare; deficiency occurs as a result of genetic abnormalities in α-tocopherol transfer protein (α- TTP), fat malabsorption syndromes, or protein-calorie malnutrition.159 Vitamin E principally is obtained from food that contains fat.159

For specific information on currently recommended AIs and RDAs of vitamin E for various life-stage and gender groups, see Dosage: Dietary Dosage and Replacement Requirements, under Dosage and Administration.

Vitamin E deficiency may occur in patients with abetalipoproteinemia. Patients with abnormal fat absorption or malabsorption syndromes generally have low plasma concentrations of vitamin E and may require supplementation with vitamin E and other fat-soluble vitamins; malabsorption syndromes should be corrected if possible. Increased vitamin E requirements may occur in patients whose diets contain large amounts of polyunsaturated fats (greater than 20 g/day) for long periods or in patients who abruptly discontinue such a diet; vitamin E may be indicated in these patients.

Alzheimer's Disease

Vitamin E has been used for the palliative treatment of moderately severe dementia of the Alzheimer's type† (Alzheimer's disease, presenile or senile dementia).146,147,148,149 In a large, double-blind, controlled study comparing vitamin E (2000 units daily), selegiline (10 mg daily), combined therapy with both drugs, and placebo in patients with moderately severe dementia of the Alzheimer's type,146 vitamin E or selegiline was more effective than combined therapy, and all therapies were more effective than placebo, in decreasing the rate of functional decline (e.g., delaying the onset of poor outcome such as death, need for institutionalization, loss of ability to perform basic living tasks, deterioration in clinical dementia rating) when analysis of the results was adjusted for differences in baseline values for the study groups, but not for unadjusted data.146,147,148,149 However, there was no evidence of improvement in function compared with baseline, and all groups showed similar rates of cognitive decline over 2 years.146,147,148,149 In addition, methodologic concerns about this study and the associated conclusions have been raised.147,148,149 In a double-blind, controlled study comparing vitamin E (2000 units daily), donepezil (10 mg daily), or placebo in patients with amnestic mild cognitive impairment, vitamin E had no clinically important effect on progression from mild cognitive impairment to Alzheimer's disease.167 The effect of vitamin E in patients with severe impairment or when combined with other agents currently is not known.148,149 If vitamin E is used, a dosage of 2000 units daily has been suggested based on limited evidence to date.146,149,163 However, it should be taken into consideration that these recommendations were made before results of a pooled analysis linking use of high dosages of vitamin E (400 units daily or greater) with an increase in all-cause mortality were available.166 (See Cautions.) While vitamin E has been considered an option for the prevention of further decline in Alzheimer's patients,149,163 this recommendation is based on limited evidence and may be premature until larger randomized clinical studies evaluate the safety and efficacy of high-dosage vitamin E therapy in these patients.149,163,166,168

The role, if any, of vitamin E in other dementing illnesses currently is not known.149

Macular Degeneration

Some clinicians have recommended high-dose antioxidant supplements containing ascorbic acid, beta carotene, and vitamin E with zinc in high-risk patients with age-related macular degeneration†.164,165 This recommendation is based on results of a randomized, placebo-controlled study in adults 55-80 years of age with age-related macular degeneration who received a high-dose antioxidant vitamin supplement (ascorbic acid 500 mg, vitamin E 400 units, beta carotene 15 mg) daily, zinc 80 mg (as zinc oxide) daily (with copper 2 mg [as cupric oxide] daily to prevent potential anemia), high-dose antioxidant vitamin supplement plus zinc, or placebo for about 6.3 years.164,165 Although patients in all treatment groups continued to progress toward advanced macular degeneration and lost vision over the study period, results indicated that administration of zinc or high-dose antioxidant vitamin supplement plus zinc lowered the risk of developing advanced age-related macular degeneration in high-risk patients (i.e., those with intermediate stage age-related macular degeneration or advanced stage macular degeneration in only one eye).164,165 In addition, administration of high-dose antioxidant vitamin supplement plus zinc reduced the risk of visual acuity loss caused by advanced age-related macular degeneration in high-risk patients.164 Administration of a high-dose antioxidant vitamin supplement, zinc, or high-dose antioxidant vitamin supplement plus zinc did not delay progression of age-related macular degeneration in adults with early disease.164,165 However, patients in these groups had a lower incidence of developing advanced age-related macular degeneration during the study period, and it is not known whether long-term (e.g., 10-20 years) supplementation with high-dose antioxidant vitamins and zinc would be effective in these patients. 164,165 Based on results of this study, some clinicians suggest that adults with extensive intermediate size drusen, at least one large drusen, noncentral geographic atrophy in one or both eyes, or advanced age-related macular degeneration or vision loss due to macular degeneration in one eye should consider taking a vitamin and zinc supplement similar to the one evaluated in this study.164,165 Because beta carotene has been associated with an increased incidence of lung cancer in smokers, these individuals may choose a vitamin and zinc supplement with only some of the ingredients used in this study.164

Cardiovascular Disease

There is epidemiologic evidence from descriptive, case-control, and prospective cohort studies that vitamin E is associated inversely with the frequency of coronary heart disease (CHD) and with the risk of associated morbidity (e.g., nonfatal myocardial infarction, coronary revascularization)†.119,120,121,122,123,124,125,128,131,145,159 However, despite the epidemiologic evidence showing a decreased risk of CHD from an increased intake of antioxidants such as vitamin E, results from most large, randomized, double-blind clinical intervention studies using vitamin E have failed to show a statistically significant reduction in cardiovascular morbidity and mortality with the vitamin.124,135,159,160,161,169,171 In addition, results from one meta-analysis indicate that use of high dosages of vitamin E (400 units daily or greater) is associated with an increase in all-cause mortality.166 (See Cautions.) Current evidence does not support use of vitamin E to reduce the risk of cardiovascular disease.168,169,172

Cancer Risk Reduction

Prostate Cancer

Findings from the selenium and vitamin E cancer prevention trial (SELECT), a primary prevention study in over 30,000 men, indicate that use of vitamin E, selenium, or vitamin E in conjunction with selenium was not associated with a decreased risk of prostate cancer in these men.175 Enrollment in this study began in 2001 and ended in 2004; participants were randomized to receive vitamin E (400 mg daily) and placebo, selenium (200 mcg daily) and placebo, vitamin E (400 mg daily) and selenium (200 mcg) daily, or placebos.174 The intended duration of the study is 12 years.174 The planned duration of therapy was 7-12 years.174 The primary end point was incidence of prostate cancer; secondary end points include prostate cancer-free survival, all-cause mortality, and incidence of and mortality due to other cancers and diseases (e.g., cardiovascular disease).174 In late 2008, the data and monitoring committee reviewed the study data; the review indicated that vitamin E and selenium, taken alone or together for about 5 years, did not prevent prostate cancer.175 Study participants discontinued the study supplements; participants will continue to be monitored.175

Other Cancers

Findings from the Women's Health Study (WHS), a 10-year, primary prevention study in almost 40,000 healthy women, indicated that use of vitamin E (600 units every other day) was not associated with a decreased risk of cancer in these women.169 In a large randomized study in adults 55 years of age or older with vascular disease or diabetes mellitus, long-term use of vitamin E (400 units daily) did not prevent cancer.171 Current evidence does not support use of vitamin E to reduce the risk of cancer.168,169,172

Other Uses

Vitamin E has been used in low-birthweight neonates for the prevention and treatment of hemolytic anemia caused by vitamin E deficiency.

Although some evidence indicates that vitamin E may be useful in preventing the retinopathy of prematurity (retrolental fibroplasia) or bronchopulmonary dysplasia secondary to oxygen therapy in neonates and in preventing intraventricular hemorrhage in premature neonates†, other evidence suggests that vitamin E does not prevent retinopathy of prematurity and may be associated with an increased risk of serious adverse effects in infants weighing less than 1 kg. Therefore, the American Academy of Pediatrics (AAP) currently states that use of pharmacologic doses of vitamin E for prevention or treatment of retinopathy of prematurity, bronchopulmonary dysplasia, or intraventricular hemorrhage are not recommended.108 Use of vitamin E to prevent deficiency (i.e., as a dietary supplement) in premature infants during the first several weeks of life is recommended, however.108

Plasma vitamin E concentrations have been found to be low in patients with β-thalassemia, hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency, and sickle-cell anemia; administration of the vitamin may correct some of the secondary erythrocyte-membrane abnormalities which occur in these diseases.

Current evidence is inadequate to establish the efficacy of vitamin E alone or in combination with quinine sulfate for the treatment and/or prevention of nocturnal recumbency leg muscle cramps† (night cramps).144

Administration

Vitamin E is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be given parenterally as a component of a multivitamin injection. Some clinicians use water-miscible oral vitamin E preparations in patients with malabsorption syndromes.

Dosage

Vitamin E activity is generally expressed in USP or International Units which are equivalent; the International Unit of vitamin E is no longer officially recognized but continues to be used in the labeling of some preparations. It should be noted that vitamin E preparations are historically and incorrectly labeled as d - or dl -α-tocopherol and their respective esters.159 Vitamin E compounds include the all racemic ( all rac )-α-tocopherol ( dl -α-tocopherol [ RRR -, RRS -, RSR -, RSS -, SSS -, SRS -, SSR -, and SRR -] or synthetic) form and its esters and the RRR -α-tocopherol ( d -α-tocopherol or natural) form and its esters, and any of these compounds may be present in fortified foods and vitamin preparations.159

One unit of vitamin E equals the biologic activity of 1 mg of all rac -α-tocopheryl acetate ( dl -α-tocopheryl acetate), 1.12 mg of all rac -α-tocopheryl succinate ( dl -α-tocopheryl acid succinate), 910 mcg of all rac -α-tocopherol ( dl -α-tocopherol), 735 mcg of RRR -α-tocopheryl acetate (d -α-tocopheryl acetate), 830 mcg of RRR -α-tocopheryl succinate ( d -α-tocopheryl acid succinate), and 670 mcg of RRR -α-tocopherol ( d -α-tocopherol). However, because the USP potency unit for vitamin E was defined before studies showed a lack of human activity for the 2 S -stereoisomers, the National Academy of Sciences (NAS) Food and Nutrition Board recommended in 2000 that the current equivalency defined in the USP standard be redefined based on the R -stereoisomeric forms of α-tocopherol, which are the forms that are active in humans.159 According to the NAS definition, each USP unit of vitamin E is equivalent to the biologic activity of 450 mcg of the synthetic all rac -α-forms of tocopherol and its esters or 670 mcg of the RRR -α-forms of tocopherol and its esters.159

Dietary and Replacement Requirements

Reference values for vitamin E recommended by the NAS are based on the 2 R -stereoisomeric forms of α-tocopherol; the 2 S -stereoisomeric forms of α-tocopherol, the other tocopherols (β-, γ-, δ-tocopherol), and the tocotrienols are not used to estimate vitamin E requirements because these forms do not bind to α-tocopherol transfer protein (α- TTP).159 To achieve a Recommended Dietary Allowance (RDA) of 15 mg of α-tocopherol daily, an individual could consume 15 mg of RRR -α-tocopherol, 15 mg of the 2 R -stereoisomeric forms of α-tocopherol (e.g., 30 mg of all rac -α-tocopherol), or a combination of the two.159

The Adequate Intake (AI) (see Uses: Dietary Requirements) of vitamin E currently recommended by the NAS for healthy infants through 6 months of age is 4 mg (about 0.6 mg/kg) of α-tocopherol daily and for those 7-12 months of age is 5 mg (about 0.6 mg/kg) of α-tocopherol daily.159 The RDA of vitamin E currently recommended by the NAS for healthy children (boys and girls) 1-3, 4-8, 9-13, or 14-18 years of age is 6, 7, 11, or 15 mg of α-tocopherol daily, respectively.159 The RDA for healthy men and women 19-50 years of age and 51 years of age and older is 15 mg of α-tocopherol daily.159

While exposure to cigarette smoke damages antioxidant defenses, it is not known whether any adjustment in vitamin E requirements is needed in individuals who smoke or are routinely exposed to smoke.159 In addition, while high levels of physical activity also might increase oxidative damage and thus increase the need for antioxidants, it currently is not known whether any adjustment in vitamin E intake is needed as a result of regular or strenuous exercise.159

Because there is no evidence that vitamin E requirements in pregnant women differ from women who are not pregnant, the EAR and RDA during pregnancy are the same as the usual requirements.159 The RDA of vitamin E recommended by the NAS for pregnant women 14-50 years of age is 15 mg of α-tocopherol daily.159 The NAS recommends a RDA of 19 mg of α-tocopherol daily for lactating women 14-50 years of age.159

Requirement for vitamin E increases as the intake of polyunsaturated fats increases. In vitamin E-deficient adults, 60-75 units may be given orally. In vitamin E-deficient children with malabsorption syndromes, some clinicians have recommended oral administration of water-miscible vitamin E in a dosage of 1 unit/kg daily to raise plasma tocopherol concentrations to the normal range within 2 months and to maintain normal plasma concentrations. In one study in low-birthweight, premature neonates, oral administration of 25 units of vitamin E daily resulted in normal plasma concentrations of vitamin E within 1 week.

Vitamin E supplements are regularly used by many adults in the US.166,170 Because dosages of 400 units daily or greater may be associated with an increase in all-cause mortality, high dosages of vitamin E (400 units daily or greater) generally should be avoided.166 (See Cautions.)

Alzheimer's Disease

For the palliative treatment of dementia of the Alzheimer's type† (Alzheimer's disease, presenile or senile dementia), a vitamin E dosage of 2000 units daily has been suggested based on limited evidence to date.146,149,163 However, because of an association between high-dosage vitamin E and worsening of coagulation defects in patients with vitamin K deficiency, vitamin E therapy in such patients probably should be limited to conventional dosages (e.g., 200-800 units daily).149 In addition, vitamin E dosages of 400 units daily or greater may be associated with an increase in all-cause mortality.166 (See Cautions.)

Macular Degeneration

To reduce the risk of advanced age-related macular degeneration† in patients at high risk, some clinicians recommend vitamin E dosages of 400 units daily in combination with ascorbic acid 500 mg daily, beta carotene 15 mg daily, and zinc (as zinc oxide) 80 mg daily, with copper (as cupric oxide) 2 mg daily (to prevent anemia).164,165 This recommendation is based on results of a clinical study in adults with age-related macular degeneration which demonstrated beneficial results in high-risk individuals receiving these antioxidant vitamin and zinc dosages.164,165

Cardiovascular Disease

To potentially reduce the risk of coronary artery disease†, some clinicians have suggested that vitamin E dosages of at least 100 units daily be used.120,121,122,124,126,131 Some clinicians recommend vitamin E dosages of 400-800 units daily (the dosage used in the CHAOS study) in patients with coronary heart disease (CHD).159 However, vitamin E dosages of 400 units daily or greater may be associated with an increase in all-cause mortality.166 (See Cautions.) The NAS currently considers the data insufficient to include a specific recommendation for supplemental vitamin E for cardiovascular disease prevention in the general population.159

Other Uses

To prevent vitamin E deficiency in premature, low-birthweight neonates, some clinicians recommend that 6-12 units/kg of oral vitamin E be given daily to preterm infants weighing less than 1000 g at birth.108

Dosages and route of administration of vitamin E used for the prevention of the retinopathy of prematurity or bronchopulmonary dysplasia secondary to oxygen therapy in neonates and for the prevention of intraventricular hemorrhage in neonates have varied, and clinicians should consult published protocols for specific information. In one study, the dosage of oral vitamin E used to prevent the retinopathy of prematurity in infants was 15-30 units/kg daily as needed to maintain plasma tocopherol concentrations between 1.5-2 mcg/mL; in another study, the oral dosage was 100 units/kg daily. To prevent bronchopulmonary dysplasia in infants, 20 units/kg daily have been administered IM, but a parenteral formulation containing vitamin E alone is not currently commercially available. If high-dose vitamin E therapy is used in premature infants, some clinicians recommend that plasma tocopherol or vitamin E concentrations be monitored; however, the relationship between these concentrations and therapeutic and toxic effects currently has not been established.106,107

Patients with β-thalassemia have been given 750 units/day orally, and patients with sickle-cell anemia have been given 450 units/day orally.

Vitamin E is usually nontoxic. However, the vitamin (e.g., at dosages exceeding 300 units daily) has rarely caused nausea, diarrhea, intestinal cramps, fatigue, emotional disturbances, weakness, thrombophlebitis, headache, blurred vision, rash, gonadal dysfunction, breast soreness, creatinuria, increased serum creatine kinase (CK, creatine phosphokinase, CPK), increased serum cholesterol and triglycerides, increased urinary estrogens and androgens, and decreased serum thyroxine and triiodothyronine. These effects generally disappeared after discontinuing the vitamin. Necrotizing enterocolitis has been associated with oral administration of large dosages (e.g., 200 units daily) of a hyperosmolar (measured osmolality of 2025 mOsm/kg for a twofold dilution of the preparation) vitamin E preparation in low-birthweight infants.110,159

Current evidence suggests that the toxic potential of all the stereoisomers of α-tocopherol should be equivalent.159 While current evidence has shown few adverse effects with supplemental vitamin E dosages less than 2100 units daily, most studies on the effects of supplemental vitamin E have been conducted over a few weeks to a few months, and therefore the possible chronic effects of lifetime exposures to such high supplemental dosages of the vitamin remain unclear.159 High dosages of vitamin E (400 units daily or greater) for 1 year or longer in individuals with chronic disease was associated with an increase in all-cause mortality in one pooled analysis that evaluated the dose-dependent effect of vitamin E on all-cause mortality.166 Findings from this pooled analysis of data were unclear regarding risks and benefits of lower dosages of vitamin E.166 However, a dose-response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with an increased risk at dosages exceeding 150 units daily.166

Vitamin E can cause hemorrhage, increase prothrombin time, and cause blood coagulation abnormalities at very high dosages in animals.159 Although evidence from several large clinical intervention studies in which adult humans receiving 300-800 units of vitamin E daily for 1.4-4.5 years showed no increased risk of stroke,159 at least one study (the α-Tocopherol, Beta-carotene [ATBC] Cancer Prevention study) reported an increased mortality from hemorrhagic stroke in male smokers receiving 50 units of vitamin E daily.159 In another study that was designed to evaluate neurologic function in patients with Alzheimer's disease receiving 2100 units of vitamin E daily for 2 years, an increase in hemorrhagic stroke was not detected.150 No increase in hemorrhagic strokes was observed in women receiving vitamin E (600 units every other day) compared with those receiving placebo in the Women's Health Study.169 The unexpected result from the ATBC study requires confirmation or additional refutation from ongoing studies (e.g., Physicians' Health Study II, Women's Antioxidant Cardiovascular Study).159

Although vitamin E appears to inhibit platelet aggregation and adhesion in vitro, it is unclear whether such effects would be deleterious in healthy individuals.159 Oral vitamin E dosages of up to 600 units daily for up to 3 years in healthy individuals did not adversely affect blood coagulation.159 However, the possibility that relatively high dosages of vitamin E could exacerbate coagulation defects in individuals who are deficient in vitamin K or are receiving anticoagulant therapy should be considered.159 (See Drug Interactions.)

After oral vitamin E therapy for a skin disorder, white hair reportedly grew at a site of alopecia. Topical application of vitamin E has caused contact dermatitis.

A complex, potentially fatal syndrome of thrombocytopenia, hepatomegaly, splenomegaly, ascites, and renal, pulmonary, and hepatic (e.g., cholestasis) dysfunction has occurred in several premature infants who received IV therapy with dl -α-tocopheryl acetate solubilized in polysorbates 20 and 80 (E-Ferol^® for IV Infusion).101,102,103,104,105,147 Infants at greatest risk appeared to be those with low birthweights, and development of the syndrome appeared to be related to daily and total vitamin E and polysorbates doses.102,147 A progressive, vasculocentric hepatotoxicity has been described in these infants, characterized initially by degeneration and exfoliation of Kupffer's cells, central lobular accumulation of these cells, and centrally accentuated panlobular congestion; prolonged exposure to the IV vitamin E formulation was associated with progressive intralobular cholestasis, inflammation of hepatic venules, and extensive fibrotic, sinusoidal veno-occlusion.102,147 The exact mechanism of this syndrome in these infants is not known,101,102,103,104,105,106,107,147 but it may result from a cumulative toxic effect of one or more of the ingredients in the injection (e.g., polysorbates).101,102,104,106,107,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147 E-Ferol^® is no longer commercially available for IV use.

Mutagenicity and Carcinogenicity

Vitamin E has not been shown to be mutagenic or carcinogenic.159

Pregnancy

Pregnancy

Vitamin E has not been shown to be teratogenic.159 There is no evidence that vitamin E requirements in pregnant women differ from women who are not pregnant.159 (See Dosage: Dietary and Replacement Requirements, under Dosage and Administration.)

Vitamin E may increase the absorption, utilization, and storage of vitamin A and may protect against hypervitaminosis A; however, these effects are controversial.

Vitamin E in dosages of greater than 10 units/kg daily may delay the response to iron therapy in children with iron-deficiency anemia, and low-birthweight infants treated with iron supplements may develop vitamin E-deficiency hemolytic anemia.

Vitamin E or one of its metabolites reportedly may have anti-vitamin K effects; patients receiving oral anticoagulants may be at risk of hemorrhage after large doses of vitamin E. In normal healthy individuals, vitamin E caused no change in blood clotting.

Excessive use of mineral oil may decrease the absorption of vitamin E.

Orlistat may result in decreased GI absorption of fat-soluble vitamins such as vitamin E.150 At least 2 hours should elapse between (before or after) any orlistat dose and vitamin E administration; administering fat-soluble vitamins at bedtime may be a convenient time.150,152,156,158 Although the manufacturer of orlistat recommends that a vitamin supplement containing fat-soluble vitamins (A, D, E and K) be used during orlistat therapy,150,156 such vitamin concentrations in clinical studies with the drug remained within the normal range for most patients despite decreases, and vitamin supplementation was only occasionally needed.151,152,153,154,155,157

Pharmacology

The exact biologic function of vitamin E in humans is unknown, although the vitamin is believed to act as an antioxidant. Vitamin E functions as a chain-breaking antioxidant that prevents propagation of free-radical reactions (e.g., lipid peroxidation), and one indicator of vitamin E requirements that has been used is the intake of the vitamin that would prevent hydrogen peroxide-induced lysis of erythrocytes.159 Vitamin E is a peroxyl radical scavenger and especially protects polyunsaturated fatty acids (PUFAs, which are components of cellular membranes, phospholipids, and plasma lipoproteins) and other oxygen-sensitive substances such as vitamin A and ascorbic acid (vitamin C) from oxidation. Peroxyl radicals react with vitamin E 1000 times more rapidly than they do with PUFAs.159 The phenolic hydroxyl group of tocopherol reacts with an organic peroxyl radical to form the corresponding hydroperoxide and the tocopheroxyl radical; this latter radical then can be reduced by other antioxidants to tocopherol or can react with another tocopheroxyl radical to form nonreactive products (e.g., tocopherol dimers), undergo further oxidation to tocopheryl quinone, or act as a prooxidant and oxidize other lipids.159

Low plasma tocopherol concentrations are generally associated with increased erythrocyte susceptibility to in vitro hemolysis by oxidizing agents. Most, but not all, studies have found that vitamin E decreases platelet aggregation. Coenzyme Q (ubiquinone), selenium, synthetic antioxidants, and some sulfur-containing amino acids can prevent vitamin E-deficiency syndromes in animals.

Antioxidant Effects

Dietary antioxidants are substances found in foods that decrease the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on normal physiologic function.159 There is considerable biologic evidence that reactive oxygen and nitrogen species can be damaging to cells at high concentrations and this may contribute to cellular dysfunction and disease.159 Because the entire population is exposed to oxidative stresses through oxidative metabolism but only some individuals develop a potentially associated chronic disease, the precise role of oxidative stress on the development of chronic disease currently is unclear.159 Some chronic diseases in which oxidative stresses and damage have been implicated include cancer,159 cardiovascular disease (e.g., coronary atherosclerosis and heart disease [CHD]),119,120,121,122,123,124,125,126,127,145,159 cataracts,159 age-related macular degeneration,159 central neurodegenerative diseases (e.g., Alzheimer's disease, parkinsonian syndrome, amylotrophic lateral sclerosis),118,146,147,149,159 and diabetes mellitus;159 however, there currently is insufficient evidence to clearly establish causal relationships.159

The exact mechanism(s) of action of vitamin E in patients with dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia) currently is not known; however, it has been postulated that the pathology of Alzheimer's disease may involve oxidative stress and the accumulation of free radicals resulting in excessive lipid peroxidation and CNS neuronal generation, and that the antioxidant properties of the vitamin may have beneficial effects in delaying the onset or slowing the progress of these changes.118,146,147,149 Antioxidants may disrupt or prevent the free radical/β-amyloid recirculating cascade and resultant neuronal degeneration.118,146 Vitamin E interacts with cell membranes, traps free radicals, and interrupts the chain reaction that damages cells.146 In animals, the vitamin has reduced degeneration of hippocampal cells associated with cerebral ischemia and enhanced the recovery of motor function after spinal injury.146 In hypoxic cultured neurons, vitamin E inhibited lipid peroxidation and reduced cell death associated with β-amyloid protein.146

There is epidemiologic evidence of an association between increased intake of antioxidants such as vitamin E and a reduction in cardiovascular morbidity and mortality.119,120,121,122,123,124,125,126,127,145,159 In fact, of all the chronic diseases for which excess oxidative stress has been implicated, cardiovascular disease has the strongest supporting evidence.150 Despite the epidemiologic evidence showing a decreased risk of coronary heart disease (CHD) from an increased intake of antioxidants, results from 4 of 5 large, randomized, double-blind clinical intervention studies using vitamin E failed to show a statistically significant reduction in cardiovascular morbidity and mortality with the vitamin.124,135,159,160,161,169 In the one large placebo-controlled study showing some benefit (the Cambridge Heart Antioxidant Study, CHAOS), administration of 400-800 units of vitamin E daily in patients with coronary atherosclerosis was associated with a reduction in the primary end point of a combined reduction in nonfatal myocardial infarction and cardiovascular death; however, this risk reduction was due to a decrease in nonfatal myocardial infarction (which was evident after about 200 days) and not in cardiovascular death.124 In fact, a nonsignificant slight increase in cardiovascular death was observed in patients receiving vitamin E in the CHAOS study.124 In the Heart Outcomes Prevention Evaluation (HOPE) study in over 9000 adults at high risk for cardiovascular events, treatment with 400 units of vitamin E daily for a mean of 4.5 years had no apparent effect on cardiovascular outcomes (e.g., combined effect on myocardial infarction, stroke, and cardiovascular death).159,160 These results were similar to those reported from another study in over 11,000 high-risk individuals conducted by the GISSI-Prevenzione investigators.159,161 In the Women's Health Study (WHS) in almost 40,000 healthy women, treatment with 600 units of vitamin E every other day for 10 years had no effect on cardiovascular events (i.e., combined effect on first major cardiovascular event [nonfatal myocardial infarction, nonfatal stroke, cardiovascular death]); use of vitamin E was associated with decreased cardiovascular mortality.169 No beneficial effect of vitamin E on myocardial infarction rates was reported in a study that had lung cancer as its primary outcome.135

It has been postulated (the oxidative-modification hypothesis of atherosclerosis) that atherogenesis is initiated by oxidation of lipids in low-density lipoproteins (i.e., by lipid peroxidation),119,120,125,126,127,159 and that antioxidants that inhibit lipid peroxidation in LDL should limit atherosclerosis and its clinical manifestations.119,120,125,126,127 It currently is not known whether oxidation of LDL is important in both the initiation and progression of plaque formation or increases the risk of plaque rupture.120 Vitamin E can be incorporated into LDL, resulting in an increased resistance to oxidation.119,120,125 The association between oxidation of LDL and atherosclerosis provides a plausible, simple rationale for the beneficial effect of antioxidants on coronary artery disease;119 however, other mechanisms may be involved,119,125,126,127 and some evidence indicates that simply increasing the resistance of LDL to oxidation does not necessarily result in reduced atherosclerosis.119 In addition, the dynamic nature of coronary artery disease, involving not only atherosclerotic plaque development but also plaque rupture, vasoconstriction, and local thrombosis, complicates interpretation of data.119

Besides increasing the resistance of LDL to oxidation, vitamin E also lowers the cytotoxicity of oxidized LDL toward endothelial cells and thus may increase the stability of lesions and limit plaque rupture and thrombosis.119,126 Vitamin E also may inhibit monocyte adhesion to vascular endothelium119 and may inhibit platelet aggregation and adhesion.119,127 In vitro studies and studies of platelets obtained from healthy individuals receiving vitamin E supplementation with 400-1200 units daily indicate that platelet incorporation of vitamin E at concentrations attained with supplementation inhibits protein kinase C-dependent platelet aggregation.127 Vitamin E also exhibits direct tissue effects (e.g., prevention of oxidized LDL-induced inhibition of nitric oxide release from endothelial cells) that benefit vascular function.119 There is angiographic evidence of an association between vitamin E supplementation and a reduction in coronary lesion progression in men who had undergone coronary artery bypass grafting,128 although the vitamin (700 units daily) combined with other antioxidants (beta carotene 30,000 units daily and ascorbic acid 500 mg daily) was not effective in preventing restenosis following coronary angioplasty in one study.129,130

Although there is epidemiologic evidence that dietary intake (i.e., relatively high fruit and vegetable intake) may positively influence the risk of certain cancers (e.g., of the lung, oral cavity, pharynx, larynx, cervix),133,134,135,159 several placebo-controlled clinical studies assessing the effect of supplementation rather than diet failed to demonstrate a beneficial effect of antioxidants (e.g., vitamin E, beta carotene) in reducing the risk of cancers (total cancer, cancer deaths, lung cancer, colorectal cancer)133,135,136,171 and a prospective cohort study evaluating the effect of antioxidant intake (combined dietary and supplement intake) failed to demonstrate a beneficial effect on the risk of breast cancer.137 In the WHS in almost 40,000 healthy women, treatment with 600 units of vitamin E every other day for 10 years had no effect on the incidence of total cancer or breast, lung, or colon cancers.169 In the selenium and vitamin E cancer prevention trial (SELECT) in over 30,000 men, treatment with 400 units of vitamin E daily for several years was not associated with a decreased risk of prostate cancer.175

Immunologic Effects

Vitamin E has been shown to inhibit prostaglandin E₂ production and enhance immune response in aged mice.141,142 In addition, several aspects of immune function have been shown to decline with increasing age,142,143,159 and vitamin E supplementation can reverse these immune deficits in some individuals.142,143,159 Vitamin E supplementation has enhanced immune response in healthy geriatric humans.142,143,159 In one study in healthy adults 65 years of age and older, long-term (235 days) vitamin E supplementation, particularly at a dosage of 200 units daily (60, 200, and 800 units daily were studied), enhanced certain indices of T-cell-mediated function (e.g., cutaneous delayed-type hypersensitivity [DTH] response, antibody response to certain vaccines and toxoids [e.g., hepatitis B, tetanus]).142,159 Whether increased vitamin E intake affects immune function in younger individuals remains to be established.159

Physiologic Effects of Vitamin E Deficiency

Overt vitamin E deficiency is very rare, occurring only in individuals unable to absorb the vitamin or with inherited abnormalities that prevent the maintenance of normal blood concentrations, such as a result of genetic abnormalities in hepatic α-tocopherol transfer protein (α-TTP), various malabsorption syndromes, and protein-energy malnutrition.159 Data on human experimental vitamin E deficiency are very limited, and the recommended dietary allowances (RDAs) for the vitamin currently are based mainly on induced vitamin E deficiency in humans and the correlation between hydrogen peroxide-induced erythrocyte lysis and plasma α-tocopherol concentrations.159 Vitamin E deficiency does not cause specific disease in adults, although a large and growing body of evidence suggests that high intakes of the vitamin may lower the risk of certain chronic diseases, especially heart disease. The principal manifestation of vitamin E deficiency is peripheral neuropathy characterized by degeneration of large-caliber axons in sensory neurons.159 Spinocerebellar ataxia, skeletal myopathy, and pigmented retinopathy also have been reported.159 In premature neonates, irritability, edema, thrombosis, and hemolytic anemia may be caused by vitamin E deficiency. Creatinuria, ceroid deposition, muscle weakness, decreased erythrocyte survival, or increased in vitro hemolysis by oxidizing agents has been identified in adults and children with low serum tocopherol concentrations. Administration of vitamin E completely reverses the signs of vitamin E deficiency, provided that vitamin supplementation is initiated before irreversible neurologic injury ensues.159

A distinct pattern in the progression of neurologic manifestations of vitamin E deficiency has been described.159 Untreated children with chronic cholestatic hepatobiliary disease exhibit spinocerebellar ataxia, neuropathy, and ophthalmoplegia by the end of the first decade of life; in children with cystic fibrosis and abetalipoproteinemia, neurologic progression is slower.159

Pharmacokinetics

Absorption

Absorption of vitamin E from the GI tract depends on the presence of biliary and pancreatic secretions, micelle formation, uptake into erythrocytes, and chylomicron secretion, and only 20-60% of the vitamin obtained from dietary sources is absorbed. As dosage increases, the fraction of vitamin E absorbed decreases. In patients with malabsorption syndromes and in low-birthweight, premature neonates, vitamin E absorption may be further reduced. Water-miscible preparations of the vitamin may be better absorbed from the GI tract than are oil solutions in these patients. Pancreatic enzymes probably split tocopherol esters before absorption.

After absorption, vitamin E reaches the circulation via chylomicrons of lymph and then is transported to the liver. The vitamin is secreted from the liver in very-low-density lipoproteins (VLDLs), and plasma vitamin E concentrations depend on hepatic secretion.159 Only one form of vitamin E, the R -stereoisomers of α-tocopherol, is preferentially resecreted by the liver.159 Thus, the liver, not the GI tract, discriminates between tocopherols; affinity of α-tocopherol for hepatic α-tocopherol transfer protein (α-TTP) is believed to be involved in this discriminatory activity.159

Plasma concentrations of tocopherols vary widely among normal individuals but are highly correlated with plasma lipoprotein and total lipid concentrations. The normal range for plasma tocopherol concentrations is 6-14 mcg/mL. Plasma concentrations of vitamin E may not correlate well with vitamin E nutritional status or total body stores, but levels below 5 mcg/mL of plasma or 800 mcg/g of plasma lipids for several months are considered to reflect vitamin E deficiency. After large doses of vitamin E, plasma tocopherol concentrations may be elevated for 1-2 days.

Distribution

α-Tocopherol is distributed to all tissues and is stored in adipose tissue. Hepatic α-TTP transfers α-tocopherol between liposomes and microsomes.159 Although tissues depend on uptake of vitamin E from plasma, no specific plasma transport proteins have been identified; therefore, it is likely that mechanisms of lipoprotein metabolism determine the delivery of vitamin E to tissues.159 Tissues probably acquire vitamin E principally during lipoprotein lipase-mediated triglyceride-rich lipoprotein catabolism, during low-density lipoprotein (LDL) uptake via the LDL receptor, via high-density lipoprotein (HDL)-mediated delivery systems, and via nonspecific transfers between lipoproteins and tissues.159 Vitamin E transfers rapidly between various lipoproteins and between lipoproteins and membranes, which may enrich membranes with the vitamin; plasma phospholipid transfer protein accelerates this process.159 Tissue α-tocopherol concentrations appear to correspond principally with changes in plasma α-tocopherol concentrations.159 Total body stores have been estimated to be 3-8 g and may be adequate to meet the body's requirements for 4 or more years of a deficient diet. α-Tocopherol distributes into the eye, achieving higher concentrations in the retina than in choroid or vitreous, and concentrations achieved can be increased by vitamin E supplementation.111

Placental transfer of α-tocopherol is incomplete. Neonates are born with plasma tocopherol concentrations 20-30% those of the mother; low-birthweight neonates have even lower plasma concentrations of the vitamin. Milk of nursing mothers on a normal diet contains 2-5 units of vitamin E per liter.

Elimination

Vitamin E is metabolized in the liver to glucuronides of tocopheronic acid and its γ-lactone and is excreted principally in the bile. However, increasing intake of vitamin E results in increasing urinary excretion of carboxyethyl hydroxychroman metabolites (CEHC), and urinary excretion of these metabolites may indicate excessive vitamin E intake; the site of their formation currently is not known.159 Quinone structure metabolites also have been identified. Some enterohepatic circulation may occur, and small amounts of the metabolites are excreted in the urine.

α-Tocopherol can be oxidized to the tocopheroxyl radical, which can be reduced back to the unoxidized form by reducing agents such as vitamin C.159 Further oxidation of the tocopheroxyl radical results in tocopheryl quinone, which is not converted in any physiologically important amounts back to tocopherol.159 Other oxidation products such as dimers, trimers, and adducts can be formed via in vitro oxidation, but the relevance in vivo currently is not known.159

Chemistry and Stability

Chemistry

Vitamin E is a fat-soluble vitamin which is present in many foods including vegetable oils, cereal grains, animal fats, meat, poultry, eggs, fruits, and vegetables. Wheat germ oil is a particularly rich source of vitamin E.

Although naturally occurring vitamin E exists in 8 forms (4 tocopherols and 4 tocotrienols), current information suggests that only the α-tocopherol form, specifically RRR -α-tocopherol (historically and incorrectly labeled as d -α-tocopherol), is maintained in human plasma and has antioxidant activity.159 Other naturally occurring forms described in the past as exhibiting vitamin E antioxidant activity include β-, γ-, and δ-tocopherols and α-, β-, γ-, and δ-tocotrienols.159 While these other forms of natural vitamin E are absorbed and delivered to the liver following oral ingestion, they are not converted to α-tocopherol and are not resecreted by the liver presumably because of their low affinity for hepatic α-tocopherol transfer protein (α-TTP).159 As a result, these other forms do not behave the same metabolically as α-tocopherol in the body.159 Because α-tocopherol contains 3 asymmetric carbons, it can occur as 8 possible stereoisomers.159

Synthetic vitamin E ( all rac -α-tocopherol; historically and incorrectly labeled as dl -αtocopherol) is produced by coupling trimethylhydroquinone with isophytol and contains all 8 stereoisomers in equal amounts.159 Four of the stereoisomers are in the 2 R -stereoisomeric form ( RRR -, RSR -, RRS -, and RSS -α-tocopherol) and 4 are in the 2 S -stereoisomeric form ( SRR -, SSR -, SRS -, and SSS -α-tocopherol).159 Although RRR -α-tocopherol is the most biologically active form in rats, the other 2 R -stereoisomers generally exhibit greater activity than the 2 S -stereoisomers.159 However, since the S -stereoisomers of α-tocopherol (from synthetic all rac -α-tocopherol) are not maintained in human plasma or tissues, they are not considered active components of vitamin E in humans.159

Since 1980, USP has defined one unit of vitamin E as having the activity of 1 mg of all rac -α-tocopheryl acetate, 0.67 mg of RRR -α-tocopherol, or 0.74 mg of RRR -α-tocopheryl acetate.159 However, because the USP potency unit for vitamin E was defined before studies showed a lack of human activity for the 2 S -stereoisomers, the National Academy of Sciences (NAS) Food and Nutrition Board recommended in 2000 that the current equivalency defined in the USP standard be redefined based on the 2 R -stereoisomeric forms of α-tocopherol, which are the forms that are active in humans.159 According to the NAS definition, all rac -α-tocopherol has 50% of the vitamin E activity of RRR -α-tocopherol found in foods or present with the other 2 R -stereoisomeric forms RSR -, RRS -, and RSS -) of α-tocopherol in fortified foods and supplements.159

For drug use, vitamin E is available as RRR - ( d -) or all rac - ( dl -)α-tocopherol, RRR- ( d -) or all rac - ( dl -)α-tocopheryl acid succinate, and RRR- ( d- ) or all rac - ( dl -)α-tocopheryl acetate. The α-tocopherols and their acetates occur as clear, yellow, viscous oils and are insoluble in water, soluble in alcohol, and miscible with vegetable oils. The acid succinate derivative occurs as a white powder and is insoluble in water and soluble in alcohol and in vegetable oils. Water-miscible preparations of vitamin E (prepared with suitable solubilizing agents) are also commercially available.

Stability

The α-tocopheryl esters are stable in air and light; α-tocopherols are unstable in and, therefore, should be protected from air and light. When cold, d -α-tocopheryl acetate may solidify. All α-tocopheryl esters are unstable in the presence of alkalis.

Only references cited for selected revisions after 1984 are available electronically.

100. American Academy of Pediatrics Committee on Fetus and Newborn. Vitamin E and the prevention of retinopathy of prematurity. Pediatrics . 1985; 76:315-6. [PubMed 3895151]

101. Lorch V, Murphy MD, Hoersten LR et al. Unusual syndrome among premature infants: association with a new intravenous vitamin E product. Pediatrics . 1985; 75:598-602. [PubMed 3975131]

102. Bove KE, Kosmetatos N, Wedig KE et al. Vasculopathic hepatotoxicity associated with E-Ferol syndrome in low-birth-weight infants. JAMA . 1985; 254:2422-30. [PubMed 3930760]

103. Centers for Disease Control. Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep . 1984; 33:198-9. [PubMed 6423951]

104. Butler J, Hutchison M, Sandlin M. Deaths in preterm infants associated with intravenous vitamin E supplement. Am J Hosp Pharm . 1984; 41:1514-6. [PubMed 6475969]

105. Bodenstein CJ. Intravenous vitamin E and deaths in the intensive care unit. Pediatrics . 1984; 73:733. [PubMed 6718133]

106. Phelps DL. E-Ferol: what happened and what now? Pediatrics . 1984; 74:1114-6. Editorial.

107. Lemons JA, Maisels MJ. Vitamin E—how much is too much? Pediatrics . 1985; 76:625-7. Editorial.

108. American Academy of Pediatrics Committee on Nutrition. Pediatric nutrition handbook. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2004:35.

109. Committee on Dietary Allowances, Food and Nutrition Board, National Research Council. Recommended dietary allowances. 9th rev ed. Washington, DC: National Academy of Sciences; 1980:63-9.

110. Finer NN, Peters KL, Hayek Z et al. Vitamin E and necrotizing enterocolitis. Pediatrics . 1984; 73:387-93. [PubMed 6546616]

111. Bhat R. Serum, retinal, choroidal vitreal vitamin E concentrations in human infants. Pediatrics . 1986; 78:866-70. [PubMed 3763301]

112. Conyers RAJ, Bais R, Rofe AM. Oxalosis and the E-Ferol toxicity syndrome. JAMA . 1986; 256:2677-8. [PubMed 3773173]

113. Brown RE, Alade SL, Krouse MA. Polysorbates and renal oxalate crystals in the E-Ferol syndrome. JAMA . 1986; 255:2445. [PubMed 3701955]

114. Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics . 1986; 77:593-7. [PubMed 3960626]

115. Balistreri WF, Farrel MK, Bove KE. Lessons from the E-Ferol tragedy. Pediatrics . 1986; 78:503-6. [PubMed 3748688]

116. Phelps DL, Rosenbaum AL, Isenberg SJ et al. Tocopherol efficacy and safety for preventing retinopathy of prematurity: a randomized, controlled, double-masked trial. Pediatrics . 1987; 79:489-500. [PubMed 3547300]

117. National Research Council Food and Nutrition Board Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press; 1989:99-107.

118. Parnetti L, Senin U, Mecocci P. Cognitive enhancement therapy for Alzheimer's disease: the way forward. Drugs . 1997; 53:752-68. [PubMed 9129864]

119. Diaz MN, Frei B, Vita JA et al. Antioxidants and atherosclerotic heart disease. N Engl J Med . 1997; 337:408-16. [PubMed 9241131]

120. Jha P, Flather M, Lonn E et al. The antioxidant vitamins and cardiovascular disease. Ann Intern Med . 1995; 123:860-72. [PubMed 7486470]

121. Stampfer MJ, Hennekens CH, Manson JE et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med . 1993; 328:1444-9. [PubMed 8479463]

122. Rimm EB, Stampfer MJ, Ascherio A et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med . 1993; 328:1450-6. [PubMed 8479464]

123. Kushi LH, Folsom AR, Prineas RJ et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med . 1996; 334:1156-62. [PubMed 8602181]

124. 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; 347:781-6. [PubMed 8622332]

125. Hennekens CH. Platelet inhibitors and antioxidant vitamins in cardiovascular disease. Am Heart J . 1994; 128:1333-6. [PubMed 7977015]

126. Mosca L, Rubenfire M, Mandel C et al. Antioxidant nutrient supplementation reduces the susceptibility of low density lipoprotein to oxidation in patients with coronary artery disease. J Am Coll Cardiol . 1997; 30:392-9. [PubMed 9247510]

127. Freedman JE, Farhat JH, Loscalzo J et al. α-Tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism. Circulation . 1996; 94:2434-40. [PubMed 8921785]

128. Hodis HN, Mack WJ, LaBree L et al. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA . 1995; 273:1849-54. [PubMed 7776501]

129. Tardif JC, Cote G, Lesperance J et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med . 1997; 337:365-72. [PubMed 9241125]

130. Libby P, Ganz P. Restenosis revisited—new targets, new therapies. N Engl J Med . 1997; 337:418-9. [PubMed 9241132]

131. Stephens N. Anti-oxidant therapy for ischaemic heart disease: where do we stand? Lancet . 1997; 349:1710-1. Editorial.

132. 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; 349:1715-20. [PubMed 9193380]

133. Greenberg ER. Antioxidant vitamins, cancer, and cardiovascular disease. N Engl J Med . 1996; 334:1189-90. [PubMed 8602188]

134. National Research Council, Committee on Diet and Health, Food and Nutrition Board, Commission on Life Sciences. Diet and health: implications for reducing chronic disease risk. Washington, D.C.: National Academy Press, 1989.

135. The 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. N Engl J Med . 1994; 330:1029-35. [PubMed 8127329]

136. Greenberg ER, Baron JA, Tosteson TD et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med . 1994; 331:141-7. [PubMed 8008027]

137. Hunter DJ, Manson JE, Colditz GA et al. A prospective study of the intake of vitamins C, E, and A and the risk of breast cancer. N Engl J Med . 1993; 329:234-40. [PubMed 8292129]

138. Blot WJ, Li JY, Taylor PR et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst . 1993; 85:1483-92. [PubMed 8360931]

139. Blot WJ, Li JY, Taylor PR et al. Lung cancer and vitamin supplementation. N Engl J Med . 1994; 331:614. [PubMed 8047094]

140. Hennekens CH, Buring JE, Peto R. Beta carotene, vitamin E, and lung cancer. N Engl J Med . 1994; 331:613-4.

141. Meydani SN, Meydani M, Verdon CP et al. Vitamin E supplementation suppresses prostaglandin E₂ synthesis and enhances the immune response of aged mice. Mech Ageing Dev . 1986; 34:191-201. [PubMed 3487685]

142. Meydani SN, Meydani M, Blumberg J et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAMA . 1997; 277:1380-6. [PubMed 9134944]

143. Meydani SN, Barklund PM, Liu S et al. Effect of vitamin E supplementation on immune responsiveness of healthy elderly subjects. Am J Clin Nutr . 1990; 52:557-63. [PubMed 2203257]

144. Food and Drug Administration. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use. 21 CFR Part 310. [Docket No. 77N-0094]. Fed Regist . 1994; 59:43234-52.

145. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation . 1999 Aug 31; 100(9):1016-30.

146. Sano M, Ernesto C, Thomas RG et al. A controlled trial of selegiline, alpha- tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med . 1997; 336:1216-22. [PubMed 9110909]

147. Drachman DA, Leber P. Treatment of Alzheimer's disease—searching or a breakthrough, settling for less. N Engl J Med . 1997; 336:1245-7. [PubMed 9110915]

148. Small GW, Rabins PV, Barry PP et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatric Society. JAMA . 1997; 278:1363-71. [PubMed 9343469]

149. American Psychiatric Association. Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life. Am J Psychiatry . 1997; 154(Suppl):1-39.

150. Roche Laboratories Inc. Xenical^® (orlistat) capsules prescribing information. Nutley, NJ; 1999 April.

151. Sjöström L, Rissanen A, Andersen T et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet . 1998; 352:167-72. [PubMed 9683204]

152. Davidson MH, Hauptman J, DiGirolamo M et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. JAMA . 1999; 281:235-42. [PubMed 9918478]

153. Hollander PA, Elbein SC, Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care . 1998; 21:1288-94. [PubMed 9702435]

154. Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol . 1996; 36:647-53. [PubMed 8844448]

155. Zhi J, Melia AT, Koss-Twardy SG et al. The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of β-carotene in healthy volunteers. J Clin Pharmacol . 1996; 36:152-9. [PubMed 8852391]

156. Roche Laboratories Inc. Xenical^® (orlistat) capsules patient information. Nutley, NJ; 1999 April.

157. James WP, Avenell A, Broom J et al. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord . 1997; 21(Suppl 3):S24-30. [PubMedCentral][PubMed 9225173]

158. Roche Laboratories Inc, Nutley, NJ: Personal communication on Orlistat 56:40.

159. Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for Vitamin C, Vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press; 2000.

160. The Heart Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med . 2000; 342:154-60. [PubMed 10639540]

161. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet . 1999; 354:447-55. [PubMed 10465168]

162. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press; 1997. (Uncorrected proofs.)

163. Doody RS, Stevens JC, Beck C et al. Practice parameter: management of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology . 2001; 56:1154-66. [PubMed 11342679]

164. Age-Related Eye Disease Study Research Group. 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. Arch Ophthalmol . 2001; 119:1417-36. [PubMed 11594942]

165. Jampol LM. Antioxidants, zinc, and age-related macular degeneration. Arch Ophthalmol . 2001; 119:1533-4. [PubMed 11594957]

166. Miller ER, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med . 2005:142. From Annals of Internal Medicine website. Accessed 11 Nov 2004. [Web]

167. Peterson RC, Thomas RG, Grundman M et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med . 2005; 352:2379-88. [PubMed 15829527]

168. Gualler E, Hanley DF, Miller ER. An editorial update: Annus horribilis for vitamin E. Ann Intern Med . 2005; 143:143-5. [PubMed 16027457]

169. Lee IM, Cook NR, Gaziano JM et al. Vitamin E in the primary prevention of cardiovascular disease and cancer- The Women's Health Study: a randomized controlled trial. JAMA . 2005; 294:56-65. [PubMed 15998891]

170. Ford ES, Ajani UA, Mokdad AH. Brief communication: The prevalence of high intake of vitamin E from the use of supplements among U.S. adults. Ann Intern Med . 2005: 143:116-20.

171. The HOPE and HOPE-TOO trial investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized trial. JAMA . 2005; 293:1338-47. [PubMed 15769967]

172. Brown BG, Crowley J. Is there any hope for vitamin E? JAMA . 2005; 293:1387-90. Editorial.

174. Klein EA, Thompson IM, Lippman SM et al. SELECT: the selenium and vitamin E cancer prevention trial: rationale and design. Prostate Cancer Prostatic Dis . 2000: 3:145-51

175. National Cancer Institute. Selenium and vitamin E cancer prevention trial (SELECT). 2008 Oct 31. From website. Accessed 2008 Nov 21. [Web]