International Journal of Dermatology© 1999 Blackwell Science Ltd. Tretinoin-iontophoresis in atrophic acne scars[Pharmacology and Therapeutics]Schmidt, Jolanta B. MD; Donath, Peter MD; Hannes, Johanna MD; Perl, Sylvia MD; Neumayer, Renate MD;Reiner, Angelika MDFrom the Department of Dermatology, Division of Special and Environmental Dermatology and Institute ofClinical Pathology, University of
Vitamin e in the treatment of alzheimer’s diseaseVITAMIN E & CHRONIC DISEASES: FROM RUGS TO RICHES ?
Ever since its discovery in 1992, vitamin E has been the subject of controversy and indeed,
for several decades many scientists were not even sure as to whether vitamin E was an
essential nutrient for humans. It was not until the 60’s that deficiency states were
documented in humans and it was not until the 80’s and 90’s that scientists finally understood
the crucial role of vitamin E in the prevention of long-term oxidative damage to body cells and
tissues. Today, vitamin E has become one of the hottest topics in the nutrition research and
practice arena. The emerging concepts indicate that vitamin E has an important role to play
not only in the preventive but also the therapeutic aspects of disease. In this regard, the
purpose of this Update is to highlight some recent findings in this area of nutrition.
Vitamin E in the Treatment of Alzheimer’s Disease
One of the newest and most exciting developments in vitamin E research is the discovery that
high doses of this vitamin may help to slow the loss of function that occurs in Alzheimer’s
disease. Researchers from 23 US medical centers recently completed a trial in which 341
patients with moderately severe Alzheimer’s disease were randomly assigned to receive one
of four treatments: vitamin E (2000 IU / day), selegiline which is also being tested as a
possible treatment for Alzheimer’s disease, both vitamin E and selegiline, or an inactive
placebo. 1 The primary outcome of the study was the time to occurrence of any of the
following : death, institutionalisation, loss of the ability to perform basic activities of daily
living, or severe dementia. The investigators specifically chose these outcomes because they
reflect the loss of the ability to function independently - an important practical consideration
for Alzheimer’s patients and their families.
Both selegiline and vitamin E slowed the progression of functional deterioration significantly
(p<0.01, median time for selegiline = 655 days, for vitamin E 670 days or combination therapy
585 days) as compared with the placebo group (440 days). The patients in the three
treatment groups, therefore reached the study endpoints several months later than those in
the placebo group. The results of this study indicate that vitamin E may be of value in the
treatment of Alzheimer’s disease patients – probably as one component of a combined
strategy to slow the course of the disease.2
Further trials are needed to determine whether vitamin E might also be helpful in delaying the
onset of Alzheimer’s disease in people who have not yet developed any of the obvious
symptoms.3 It should be noted that there was no difference in the reported beneficial effects
between the groups receiving the combination or individual therapy. The absence of an
additive effect of treatment may be due to either the two agents exerting their effect through
the same mechanism with each agent providing a maximum benefit or to the two agents
exerting their effect through an independent mechanism, but the disease was too progressed
for an additive effect to be shown. Alternatively, one agent may have interfered with the
absorption of the other, thus resulting in an effect that was not additive.
It is also to note that in this study there was no improvement in cognitive test scores in any of
the treatment groups. Additionally, falls and syncope were significantly more frequent in the
treatment groups, especially the group receiving the combination treatment as compared to
placebo. These events, however, did not lead to the discontinuation of any of the treatment
modalities and the authors concluded that each agent alone was relatively well tolerated by
the patients. Despite these limitations, the reported findings remain of great interest,
because of the important clinical nature of the documented outcomes and also because no
other treatment of such patients has shown similar benefits.
The effect of vitamin E on Alzheimer’s disease is probably attributable to the vitamin’s
antioxidant activity. There is evidence that oxidative mechanisms may play a role in the
pathological changes characteristic of Alzheimer’s disease.3 Several studies have found
evidence of increased oxidative damage, including increased lipid peroxidation and oxidative
damage to DNA in patients with this disease.4-8
Vitamin E and Immune Function in the Elderly
It is well known that the proportion of elderly people in the developed and developing world is
continuously increasing with major and very significant demands on health care costs. In
France for instance, although the elderly population represents about 17 % of the total
population, nearly half of the health care resources are used by the elderly primarily due to
chronic diseases and increased susceptibility to infections. In general, aging is well known to
be associated with a reduction in immune responses such as decreased delayed
hypersensitivity, decreased lymphocyte response to antigens, low levels of sereconversion,
reduced interleukin-2 production and decreased antibody titre after vaccination.
Nutrition plays an important role in the normal functioning of the immune system, and vitamin
E may be particularly crucial. Several years ago, researches from Tufts University
demonstrated that short-term (one month) supplementation with high doses of vitamin E could
improve several measures of immune function in healthy elderly subjects.9 More recently, a
longer term study confirmed and extended these findings and showed that beneficial effects
could occur with more moderate levels of vitamin E supplementation.10 In this study, 88
healthy elderly people were randomly assigned to a placebo group or to groups consuming
60, 200 or 800 mg /day of vitamin E. After four months, supplementation with vitamin E
improved several clinically relevant measures of cell-mediated immunity, such as the
response to immunisation against hepatitis B and tetanus. The best results were obtained at
a vitamin E dose of 200 mg / day. During the study, the incidence of infections in subjects
taking vitamin E was 50 % lower than that in the placebo group. On this basis the authors
recommended increasing the intake of vitamin E for elderly people.
In agreement with these findings, this year a large (n = 755; 2 x 2 factorial design),
randomised, double blind placebo controlled trial of two years duration in institutionalised
elderly (>65 years), has shown that the administration of a micronutrient formulation
containing trace elements (zinc and selenium) as well as vitamins (beta-carotene, vitamin C
and vitamin E) had a beneficial overall effect on defined immunological parameters.
Although the nature of the supplement precludes the definition of the effect of the individual
nutrients in it, the trial nevertheless underscores the importance of micronutrients in optimal
immune function. The trial specifically showed that antibody titres after influenza vaccine
were higher in the groups that received trace element supplements alone or in combination
with vitamins, whereas the vitamin supplemented group had significantly lower antibody titres
(p<0.05). Furthermore, the number of patients without respiratory tract infections was higher
in the group that received trace element supplements (p<0.06). However, the micronutrient
supplements administered had no effect on the incidence of urogenital infections. These
findings are not only of potential public health importance, as the authors conclude, but also
emphasise the care that needs to be exercised in terms of recommendations for the
supplemental use of micronutrients in relation to immune function11.
Coronary Heart Disease
Studies have shown that vitamin E may also help to reduce the risk or slow the progression of
coronary heart disease. The vitamin appears to be of value both in healthy people and in
those who already have established heart disease. In most instances, scientific studies have
shown protective effects primarily for high doses of the vitamin greater than those that can be
obtained from the diet.
The first major studies that provided compelling evidence for a protective effect of vitamin E
on coronary heart disease were two very large studies of middle-aged U.S. health
professionals published in 1993 by researchers from the Harvard School of Public Health. 12,
13 In these studies, which involved more than 80 000 women and more than 40 000 men,
those who had used single-entity vitamin E supplements (generally containing at least 100 IU
of vitamin E) for two or more years had a lower risk of myocardial infarction than those who
did not use supplements. Among men, vitamin E supplementation was associated with a 37
% reduction in heart disease risk; among women 41 %. In both studies, vitamin E intake
from dietary sources or from multivitamins was not associated with any protection against
heart disease, presumably because the amount obtained from these sources is far lower
than that provided by single-entity supplements. Dietary vitamin E intakes are generally less
than 15 IU / day; multivitamins provide 30 IU / day; single entity supplements usually provide
more than 100 IU / day.
The association between vitamin supplementation and a reduced risk of heart disease is not
limited to middle aged people. A 1996 U.S. study has shown a similar relationship in the
elderly – the age group at highest risk of coronary heart disease.14 In this study, which
involved more than 11 000 people aged 67 and older who were followed for up to eight years,
those who took vitamin E supplements had a lower rate of death from coronary heart disease
and a lower rate of death from all causes than those who did not take supplements.
More specifically, vitamin E supplement users had a 47 % reduction in the risk of death from
coronary heart disease when compared with non-users of supplements. Long-term users of
vitamin E supplements (those who reported supplement use at two different interviews,
conducted two years apart) had an even lower risk of dying from heart disease. So did
people who took both vitamin E and vitamin C – a finding that makes good biological sense,
since vitamin C has been shown to reinforce the antioxidant effect of vitamin E.
Vitamin E may be of value in both the primary and secondary prevention of coronary heart
disease. The term primary prevention refers to prevention of the onset of disease in healthy
people; secondary prevention refers to prevention of further damage in people who have
already shown signs or symptoms of the disease.
The potential benefit of vitamin E supplementation in secondary prevention of coronary heart
disease was demonstrated by a recent study from the United Kingdom.15 In this study, which
is known as CHAOS (for Cambridge Heart Antioxidant Study), 2 002 patients with known
coronary disease were randomly assigned to received vitamin E supplements (either 400 or
800 IU / day) or an inactive placebo, and they were observed for about a year and a half.
Vitamin E supplementation led to a statistically significant reduction in the risk of
cardiovascular death and non-fatal heart attacks combined. (41 vs 64 events : Relative Risk
(0.53 (95 % confidence interval (CI) 0.34 – 0.83; P = 0.005) This was due to a large drop in
the risk of non-fatal heart attacks. (14 vs 41; RR 0.23; CI 0.11 – 0.47; P = 0.005) The effect
of vitamin E on the risk of non –fatal heart attacks was detectable after only 200 days of
However, there was a non-significant excess of cardiovascular deaths in the vitamin E
supplemented group (27 vs 23 deaths; RR 1.18; CI 0.67 – 2.27; P <0.61). All cause
mortality was 36 of 1035 vitamin E treated patients and 27 of 967 patients treated with
placebo. Most of the cardiovascular deaths occurred early (before 200 days) in the follow-up
period before any beneficial effect of vitamin E on atheromatous plaques could have
occurred. Whether, therefore, there was a true adverse effect on early mortality must await
the confirmation of these findings as well as the findings of longer-term trials which have
mortality as their primary end point. The authors conclude that in patients with
angiographically proven symptomatic coronary atherosclerosis, vitamin E treatment reduces
the rate of non-fatal heart attacks. They also urge further studies for the better definition of
the effects of vitamin E supplements on early cardiovascular deaths.
Another study that indicates that vitamin E supplementation may be beneficial for patients
with coronary heart disease was conducted at the University of Southern California.16 In this
study 156 patients with previous coronary bypass surgery who were participating in a
controlled trial of a cholesterol lowering drug combination were asked about their self-chosen
use of dietary supplements. Those who consumed more than 100 IU / day of vitamin E in
addition to the cholesterol-lowering drugs showed less progression of the narrowing in their
coronary arteries than those with lower vitamin E intakes. Thus, vitamin E may be of value
as adjunctive therapy in patients who are receiving drug therapy for existing coronary
In a very similar vein, the results of a long-term (4 years duration), large
(n = 3 657), currently on-going, randomised, two-by-two factorial design, placebo controlled
clinical trial (the MICRO-HOPE trial) are being awaited with interest and should become
available within the next three years. The trial compares the effects of an ACE inhibitor and
vitamin E on clinical outcomes in patients with diabetes [prevention of diabetic nephropathy,
cardiovascular disease and microalbuminuria, and the development of microalbuminuria in
normoalbuminuric subjects as well as cardiovascular death, myocardial infarction, and stroke
(MICRO)]. The diabetic subjects are a subset of the 9451 high-risk subjects enrolled in the
Heart Outcomes Prevention Evaluation study (HOPE) which evaluates the effects of an ACE
inhibitor and vitamin E on major cardiovascular events (cardiovascular death, myocardial
infarction, and stroke).
Can Vitamin E Help to Prevent Cancer ?
Most of the scientific evidence about vitamin E concerns heart disease rather than cancer.
Scientific studies on the role of antioxidant nutrients in cancer have focused primarily on
beta-carotene rather than vitamin E. However, vitamin E may also have an important role to
play in cancer prevention. In fact, the results of two large epidemiological studies suggest
that the use of relatively high doses of vitamin E may be associated with a reduced risk of at
least two common types of cancer.
In one of these studies17 , researchers compared the vitamin E intakes of more than a
thousand oral cancer patients with those of healthy people. They found that people who had
ever regularly used single-entity vitamin E supplements for a period of six months or more
had half the risk of oral cancer seen in non-users of supplements. In the other study, which
focused on lung cancer in non smokers, the use of vitamin E supplements was associated
with a 45 % decrease in lung cancer risk. 18
The findings of these two studies should be interpreted with caution, because the studies
were observational rather than experimental. The study participants made their own
decisions about whether to use supplements – they were not assigned randomly to the use or
non-use of vitamin E. In fact, the one large-scale controlled trial of vitamin E
supplementation and lung cancer did not show a beneficial effect of supplementation.19 It is
uncertain, however, whether this finding reflects a true lack of benefit of vitamin E or whether
the dose used in this trial (50 mg / day) was inadequate.
Why is Vitamin E Important ?
The ability of vitamin E to inhibit a variety of seemingly unrelated disease processes can
probably be attributed to its antioxidant activity. As an antioxidant nutrient, vitamin E plays a
crucial role in the complex system of defenses by which the body protects itself against free
radicals and other oxidant substances.
In the case of atherosclerosis, vitamin E probably acts at least in part by inhibiting the
oxidation of low-density lipoproteins (LDL) in damaged arteries. LDL is one of the lipoproteins
that carry cholesterol and other fatty substances through the bloodstream. High levels of LDL
are associated with an increased risk of coronary heart disease, but the chemical condition of
LDL may be as important as the amount . Recent studies suggest that LDL must be
converted into its oxidised form in order to exert adverse effects. Vitamin E taken in large
doses has been shown to inhibit the oxidation of LDL in human volunteers.20, 21
Vitamin E may also protect against coronary heart disease by other mechanisms. For example, vitamin E may have beneficial effects on platelets that complement those of aspirin, helping to prevent the blood clots that trigger heart attacks and the most common type of stroke. 22, 23
Vitamin E is also of interest because of its newly emerging role in various phases of the
immune response. Immune and inflammatory responses are now recognised as having a
major role in the atherogenic process. The vitamin E modulation of these responses
suggests a possible link for the beneficial effect of vitamin E on atherosclerosis.
The Safety of Vitamin E
The potential uses of vitamin E in disease prevention may require doses considerably higher
than the amounts usually present in the diet. The safety of these relatively large doses is
therefore an important consideration.
In general, vitamin E has a remarkably good safety record. Extensive reviews of the medical
literature have concluded that doses of more than 50 times the recommended allowance are
safe for long periods of time. 24-27 In clinical trials in older people with Alzheimer’s disease or
Parkinson’s disease, the very high dose of 2000 IU / day was well tolerated by most subjects
for as long as two years. 1, 7
Formal safety evaluations have confirmed the safety of doses of 800 IU / day in elderly
subjects28 and 900 IU / day in young adults.29
Certain individuals, however, may not be able to take high-dose vitamin E supplements safely because of the presence of chronic medical problems or the use of medications that are incompatible with vitamin E. Specifically, patients who expect to have surgery within the next two weeks or who are recovering from surgery, those who are taking anticoagulant medications, those with vitamin K deficiency and those with the hereditary eye disease retinitis pigmentosa should not take vitamin E supplements except on the advice of a physician. 25,,30, 31
How Much Vitamin E Do People Need ?
The question of how much vitamin E people need for optimal health is a very difficult one to
answer. In fact, there may never be a single answer to this question because different
amounts of vitamin E may be needed for different purposes.
In general, however, it appears that doses greater than 100 mg per day may be needed to
produce significant protective effects against cardiovascular disease and other degenerative
diseases of aging and to optimise immune function in older adults. This is far more vitamin E
than can be obtained from even an excellent diet. It has been calculated that a diet meeting
all the current guidelines for the prevention of chronic diseases would provide about 18 mg /
day of vitamin E.32 According to one recent U.S. survey, 33 mean vitamin E intakes in
various age groups of men range from 9-12 mg / day; among women, typical intakes are about 6-8 mg / day. If the potential benefits of vitamin E in disease prevention are to be realised, supplementation – or perhaps food fortification will be needed. Research is also needed to assess the potential benefits of more moderate dosages of Vitamin E , or food fortification, over much longer periods and from a younger age. Most studies have only tested the benefits of vitamin E supplements in high-risk age groups for the emergence of coronary heart disease, or in subjects with established coronary artery lesions. CONCLUSION In conclusion, the accumulating evidence is largely confirmatory of a potentially beneficial role for vitamin E both in the prevention and treatment of disease. It would, however, be rather simplistic and irresponsible to impart the impression that vitamin E can exert its beneficial effect in the absence of overall sound and correct nutrition. At present and for certain defined conditions vitamin E supplements may be seen as an adjuvant to, rather than a replacement for, sound and correct nutrition. Future studies will no doubt close the gaps in our current knowledge and put greater perspective on the role of this vitamin in the prevention of chronic disease and the dose(s) needed to derive such benefits.
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