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Drugs 2011; 71 (18): 2421-2434
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REVIEW ARTICLE
ª 2011 Adis Data Information BV. All rights reserved.
Use of Herbal Medicines and Nutritional
Supplements in Ocular Disorders
An Evidence-Based Review
Justin T. Wilkinson1 and Frederick W. Fraunfelder1,2
1 Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA
2 National Registry of Drug-Induced Ocular Side Effects, Casey Eye Institute, Portland, OR, USA
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1
Methods of Literature Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Age-Related Macular Degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Cataracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Diabetic Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Glaucoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1
b-Carotene and Vitamin A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2
Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3
Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4
Ginkgo biloba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5
Canthaxanthine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.6
Chamomile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.7
Niacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.8
Datura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9
Echinacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.10 Liquorice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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We sought to examine the evidence regarding the use of herbal medicines and
nutritional supplements in age-related macular degeneration (AMD), cataracts,
diabetic retinopathy and glaucoma, and to review the ocular adverse effects of
herbal and nutritional agents of clinical importance to ophthalmologists. We
performed a literature search of Ovid MEDLINE and selected websites including the American Academy of Ophthalmology (AAO), the Centers for
Disease Control and Prevention (CDC), the National Institutes of Health
(NIH) and the World Health Organization (WHO).
There is strong evidence supporting the use of antioxidants and zinc in
patients with certain forms of intermediate and advanced AMD. However,
there has been growing evidence regarding potential significant adverse effects associated with the AREDS (Age-Related Eye Disease Study) formula
Wilkinson & Fraunfelder
2422
vitamins. Current data does not support the use of antioxidants or herbal
medications in the prevention or treatment of cataracts, glaucoma or diabetic
retinopathy.
It is important for providers to be aware of the benefits and the significant
potential adverse effects that have been associated with nutritional supplements and herbal medications, and to properly inform their patients when
making decisions about supplementation. Further rigorous evaluation of
nutritional supplements and herbal medicines in the treatment of eye disease
is needed to determine their safety and efficacy.
1. Introduction
Complementary and alternative medicine (CAM)
is defined as a group of diverse medical and
healthcare systems, practices and products that
presently are not considered to be part of conventional (allopathic) medicine.[1] The use of
CAM is widespread and there appears to be tremendous growth in its use among the US population. From 1990 to 1997, CAM use increased
from 33.8% to 42.1%, with a nearly 4-fold rise in
herbal remedies.[2] A follow-up study showed
that CAM use remained stable through 2002,
with an estimated use in approximately 72 million
adults in the US.[3] In 2007, it is estimated
that adults in the US spent $US33.9 billion out of
pocket on visits to CAM practitioners and purchases of CAM products, classes and materials.
Of this, 44% was spent on non-vitamin, nonmineral, natural products alone.[4] Similarly, the
use of dietary supplements in the US adult
population has grown tremendously. A total of
42% of adults used dietary supplements during
1988–1994, increasing to 53% of adults using
supplements during 2003–6.[5] Dietary supplement sales have increased to an estimated $US27
billion in 2010.[6]
Well designed clinical trials for CAM therapies
are often lacking; therefore, the safety and effectiveness of many CAM therapies are uncertain.
There has been increasing scrutiny on the monitoring of herbal medicines and nutritional supplements. In 2004, the World Health Organization
(WHO) published guidelines on the use of herbal
medicines including recommendations on cultivation, collection, classification, quality control, storage, labelling and distribution.[7]
ª 2011 Adis Data Information BV. All rights reserved.
In the US, prescription drugs and over-thecounter non-prescription drugs are monitored by
the US Food and Drug Administration (FDA)
because they are sold for a specific indication and
are marketed over state lines. By contrast, herbal
medicines and nutritional supplements are not
marketed to treat specific diseases, are exempt
from the interstate commerce law, and fall under
the purview of the Dietary Supplement and Health
Education Act of 1994. No efficacy or safety has to
be proven to sell these agents. In addition, there are
no official standards governing the production of
alternative therapies in the US, and the potency
and purity of these products are subject to substantial variation. For example, ginseng (Panax
ginseng) was evaluated by the American Botanical
Council in 2001. This group found that only 52%
of products marketed as containing ginseng actually contained any of this botanical.[8]
Herbal medicines and nutritional supplements
are of clinical importance to ophthalmologists
because many of these therapies are touted as
beneficial for eye disease (table I) and many are
associated with ocular (table II) or systemic
adverse effects, and can interfere with prescription medications. Many patients do not report
CAM usage to their physicians. In a survey of
1516 glaucoma patients, 13.7% reported current
or past use of CAM therapy specifically for
glaucoma. Of the patients who reported CAM
use, 62.5% had not disclosed the use of CAM to
their ophthalmologist and 40.5% believed that
the treatments were helping their glaucoma.[9]
The purpose of this review was to examine the
evidence regarding the use of herbal medicines and
nutritional supplements in age-related macular degeneration (AMD), cataracts, diabetic retinopathy
Drugs 2011; 71 (18)
Herbs and Nutritional Supplements in Ocular Disorders
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Table I. Herbal medicines commonly used to treat eye diseases
in the English language. Studies providing level I or
II evidence were included in the review.
Selected websites were also searched including
the American Academy of Ophthalmology (AAO),
the Centers for Disease Control and Prevention
(CDC), the National Institutes of Health (NIH)
and the WHO.
Condition
Herb used
Age-related macular
degeneration
Ginkgo (Ginkgo biloba)
Bilberry (Vaccinium myrtillus)
Lutein
Salvia miltiorrhiza
Zeaxanthin
Cataract
Balloon flower (Platycodon grandiflorum)
Bilberry (Vaccinium myrtillus)
Euphrasia officinalis
Ginkgo (Ginkgo biloba)
Marigold (Calendula arvensis)
Diabetic retinopathy
Bilberry (Vaccinium myrtillus)
Ginkgo (Ginkgo biloba)
Guar gum (Cyamopsis tetragonoloba)
Qi Ming granule
Salvia miltiorrhiza
Glaucoma
Bilberry (Vaccinium myrtillus)
Centaurium umbellatum
Coleus forskohlii
Euphrasia officinalis
Ginkgo (Ginkgo biloba)
Jaborandi (Pilocarpus jaborandi)
Lobelia inflate
Marijuana (Cannabis sativa)
Salvia miltiorrhiza
Vinpocetine (Vinca minor)
Witch hazel (Hamamelis virginiana)
and glaucoma, and to review the ocular adverse
effects of herbal and nutritional agents of clinical
importance to ophthalmologists.
1.1 Methods of Literature Review
Information on nutritional supplements and
herbal medicines that are used for eye diseases, and
complications from these agents, was reviewed by a
search of Ovid MEDLINE and Ovid OLDMEDLINE from 1947 to 21 April 2011. Search terms
included ‘macular degeneration’, ‘cataract’, ‘glaucoma’, ‘diabetic retinopathy’, ‘herbal medicine’,
‘herbal supplements’, ‘phytotherapy’, ‘medicinal
plants’, ‘plant preparations’, ‘nutrition therapy’,
‘dietary supplements’, ‘micronutrients’, ‘nutritional
supplements’, ‘vitamin’ and ‘mineral’. Additional
associated search terms included ‘adverse effects’,
‘contraindications’, ‘mortality’, ‘poisoning’, ‘toxicity’, ‘injury’, ‘harm’, ‘damage’, ‘drug effects’ and
‘chemically induced eye diseases’. Results were
limited to studies involving humans and published
ª 2011 Adis Data Information BV. All rights reserved.
2. Age-Related Macular Degeneration
AMD is the leading cause of severe vision loss
in developed nations. The NIH estimates that
1.8 million adults in the US aged >40 years have
advanced AMD with associated vision loss. This
number is projected to increase to 2.9 million by
2020.[10] AMD is caused by complex interactions
between aging, genetics,[11] environmental factors
(such as diet and smoking) and co-morbid
diseases (such as hypertension and obesity).[12-14]
Large epidemiological studies have evaluated
the association between diet or nutritional supplements and AMD. The Beaver Dam Eye Study
found an inverse association between vitamin A
and E intake and the incidence of large drusen,
and between zinc intake and the incidence of
macular pigmentary changes in early AMD.[15]
The Rotterdam Eye Study concluded that a high
dietary intake of b-carotene, vitamins C and E,
and zinc was associated with a substantially reduced risk of AMD in elderly individuals.[16]
Several prospective clinical trials have been
conducted to determine the effect of nutritional
supplements on AMD. The AREDS (AgeRelated Eye Disease Study) randomly assigned
patients to daily oral tablets containing (i) antioxidants (vitamin C 500 mg; vitamin E 400 IU
and b-carotene 15 mg); (ii) zinc 80 mg and copper
2 mg; (iii) antioxidants plus zinc; or (iv) placebo.
The study reported a statistically significant
benefit of the combination of high-dose antioxidant vitamins and zinc, providing a moderate reduction (25%) of the risk of developing
advanced AMD over a median of 6.3 years of
follow-up in those at high risk of developing advanced AMD.[17] The AREDS results suggest
that patients with few intermediate-sized drusen
or extensive small drusen have such a low risk
of developing advanced AMD that treatment
Drugs 2011; 71 (18)
Wilkinson & Fraunfelder
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Table II. Ocular adverse effects associated with herbal medicines and nutritional supplements
Ocular adverse effect
Associated herb or supplement
Accommodation, impaired
Henbane (Hyoscyamus niger)
Kava kava (Piper methysticum)
Scopolia (Scopolia carniolica)
Colour perception, disturbed
Lily of the valley (Convallaria majalis)
Strophanthus (Strophanthus kombe)
Conjunctivitis
Chamomile (Matricaria chamomilla)
Cypress spurge (Euphorbia cyparissias)
Goa powder (Andira araroba)
Propolis
Psyllium (Plantago ovata)
Psyllium seed (Plantago afra)
Conjunctivitis, allergic
German chamomile (Matricaria chamomilla)
Corneal defects
Black tea (Camellia sinensis)
Cypress spurge (Euphorbia cyparissias)
Lady of the Night (Cestrum nocturnum)
Crystalline retinopathy
Canthaxanthine
Cystoid macular oedema
Niacin
Diplopia
Yellow jasmine (Gelsemium sempervirens)
Dry eyes
Niacin
Eye movements, abnormal
Yellow jasmine (Gelsemium sempervirens)
Eyelid swelling
Cypress spurge (Euphorbia cyparissias)
Eyelids, heavy
Yellow jasmine (Gelsemium sempervirens)
Eyes, burning of
Dimethyl sulfoxide (DMSO)
Eyes, irritation of
Black mustard (Brassica nigra)
Hyphaema
Ginkgo (Ginkgo biloba)
Intracranial hypertension
Vitamin A
Intraoperative floppy iris syndrome
Saw palmetto (Serenoa repens)
Maculopathy
Arctostaphylos uva-ursi
Miosis
Herb Paris (Paris quadrifolia)
Mydriasis
Atropa belladona
5-Hydroxytryptophan (oxitriptan)
Henbane (Hyoscyamus niger)
Mandrake (Mandragora officinarum)
Valerian (Valeriana officinalis)
Datura (Datura wrightii)
Photosensitivity
Chlorella spp.
Parsnip (Pastinaca sativa)
Pimpinella (Pimpinella major)
Rue (Ruta graveolens)
St. John’s Wort (Hypericum perforatum)
Phototoxicity
Bishop’s weed (Ammi visnaga)
Bitter orange (Citrus aurantium)
Burning bush (Dictamnus albus)
Celery (Apium graveolens)
Contrayerva (Dorstenia contrayerva)
Haronga (Haronga madagascariensis)
Hogweed (Heracleum sphondylium)
Lovage (Levisticum officinale)
Masterwort (Peucedanum ostruthium)
Parsnip (Pastinaca sativa)
Tolu balsam (Myroxylon balsamum)
Wafer ash (Ptelea trifoliate)
Continued next page
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Drugs 2011; 71 (18)
Herbs and Nutritional Supplements in Ocular Disorders
2425
Table II. Contd
Ocular adverse effect
Associated herb or supplement
Retinal haemorrhage
Ginkgo (Ginkgo biloba)
Retinopathy, hypertensive
Hydroxycut (Pro Clinical, Oakville, ON, Canada) [Garcinia
cambogia, Gymnema sylvestre, chromium polynicotinate,
caffeine and green tea]
Retrobulbar haemorrhage
Ginkgo (Ginkgo biloba)
Uveitis
Goreisan
Vision, blurred
5-Hydroxytryptophan (oxitriptan)
Huperzine A
Niacin
Vision, temporary loss of
Mountain laurel (Kalmia latifolia)
Visual disturbances
Chaulmoogra (Hydnocarpus spp.)
Horse chestnut (Aesculus hippocastanum)
Wormseed (Artemisia cina)
Liquorice (Glycyrrhiza glabra)
targeting progression to advanced AMD is not
warranted.[18]
A recent Cochrane systematic review of randomized controlled trials (RCTs) evaluating the
effect of a-tocopherol and b-carotene concluded
that there was no evidence that these substances
prevented or delayed the onset of AMD.[19] The
Vitamin E, Cataract, and Age-Related Maculopathy trial found no beneficial effect in the reduction of incidence or progression of AMD
among patients administered vitamin E supplementation compared with placebo over 4 years.[20]
A recent review of the literature regarding the
efficacy of omega-3 fatty acids in preventing
AMD concluded that, although there is some
clinical evidence for protection of AMD from
omega-3 fatty acids, the results are not consistent.
Thus, the authors concluded that the evidence
neither clearly supports nor refutes the use of
omega-3 fatty acids for AMD.[21] Further research is needed to evaluate this question.
The main herbal medications recommended
for AMD are Ginkgo biloba, lutein and zeaxanthin. The effects of Ginkgo biloba are related to
its antioxidant activity,[22,23] the inhibition of
platelet-activating factor,[24] and enhanced blood
flow by decreasing blood viscosity and increasing
erythrocyte deformation.[25]
Macular pigment is composed primarily of the
xanthophylls lutein and zeaxanthin, also members of the carotenoid family. They are believed
ª 2011 Adis Data Information BV. All rights reserved.
to have a protective effect on the outer retina and
retinal pigment epithelium by absorbing short
wavelength light and minimizing oxidative damage, thus aiding cell membrane stability.[26,27] A
small study of patients with AMD compared with
age-matched controls revealed increased plasma
lutein and increased macular pigment optical
density in both groups after 18–20 weeks of
treatment with lutein supplementation.[28] The
Eye Disease Case Control study found that the
risk for advanced AMD was reduced by 43% in
participants in the highest quintile of dietary
carotenoid intake, when compared with those in
the lowest quintile.[29]
In 2005, the FDA reviewed the available literature and determined that there were no interventional or observational studies from which
scientific conclusions could be drawn about the
relationship between the intake of lutein or
zeaxanthin and the risk of AMD or cataracts.[30]
However, more recently, there has been increasing evidence that these agents may be beneficial.
In 2006, CAREDS (Carotenoids in Age-Related
Eye Disease Study) concluded that lutein- and
zeaxanthin-rich diets may protect against intermediate AMD in female patients aged <75 years.[31]
The Blue Mountain Eye Study[32] reported that
higher dietary lutein and zeaxanthin intake reduced
the risk of AMD progression and development of
choroidal neovascularization. AREDS reported
that dietary lutein and zeaxanthin intake was
Drugs 2011; 71 (18)
2426
inversely associated with neovascular AMD, geographic atrophy and large or extensive intermediate drusen.[33]
The effect of supplementation with omega-3
fatty acids and macular xanthophylls on AMD is
currently being evaluated prospectively in an
RCT, AREDS2. Of note, the AREDS2 formula
is already being marketed and sold to consumers;
however, the efficacy of the formula is not yet
known as the estimated primary completion date
of the trial is December 2012.
3. Cataracts
Cataracts are the leading cause of low vision
among all Americans, responsible for about 50% of
all cases. Advancements in cataract surgery, along
with an aging population, have contributed to increasing rates of cataract surgery. The NIH estimates that 20.5 million adults in the US aged
>40 years have cataracts. This number is projected
to increase to 30.1 million by 2020.[10] Cataract
surgery has become the most frequently performed
surgical procedure in the Medicare-insured population in the US.[34-36] Interest in preventing or
delaying the development of cataracts has grown in
order to limit healthcare costs, in addition to improving patient visual function.
Numerous observational studies and prospective clinical trials have been performed to evaluate
the effect of nutritional supplements and herbal
medications on the formation and progression of
cataracts. Some large observational studies have
reported benefit from nutritional supplements in
delaying cataract formation or progression.
The Nurses’ Health Study found that high
dietary intake of lutein and zeaxanthin reduced
the risk of cataract surgery by 22%. Vitamin C
supplementation for more than 10 years reduced
the risk of cataract surgery by 45%.[37]
The Australian Blue Mountains Eye Study revealed that participants with the highest total intake
(diet + supplements) of vitamin C had a reduced risk
of nuclear cataract. An above-median intake of combined antioxidants (vitamins C and E, b-carotene
and zinc) was associated with a reduced risk of
nuclear cataract. No effect was observed on cortical or posterior subcapsular cataracts.[38]
ª 2011 Adis Data Information BV. All rights reserved.
Wilkinson & Fraunfelder
The Wisconsin Beaver Dam Eye Study found
that people with the highest levels of lutein intake
in the distant past were half as likely to develop
incident cataract as those with the lowest intake.
Nuclear cataracts were not significantly related
to intake of vitamin C or E unless the patients
had other risk factors for cataracts. Vitamin C
reduced cataract risk in heavy smokers, and vitamin E reduced cataract risk in individuals with
hypertension or aged >65 years.[39]
Several prospective clinical trials have been
completed to evaluate the effectiveness of antioxidants in reducing the risk of cataract development or progression.
The lens opacity component of AREDS tested
antioxidants versus no antioxidant and found no
effect overall or for specific opacity types (nuclear, posterior subcapsular or cortical cataract, or
cataract surgery).[40] The Vitamin E, Cataract,
and Age-Related Maculopathy Trial found vitamin E supplementation for up to 4 years did not
reduce the rate of any type of cataract.[41] The
a-Tocopherol, b-Carotene Study found that neither a-tocopherol nor b-carotene supplementation
affected the incidence of cataract surgery among
Finnish male smokers.[42] The Roche European
American Cataract Trial reported a small reduction
in the rate of cataract formation among patients
in the US taking combination b-carotene, vitamin C and vitamin E supplements. There was no
statistically significant benefit of treatment in the
UK group.[43]
The Linxian Cataract studies reported a 36%
decrease in nuclear cataract in patients taking vitamin and mineral supplements for 5–6 years.[44]
These studies were conducted in the relatively nutritionally deprived area of Linxian, China, which
suggests baseline nutritional status may influence
the effectiveness of nutrient supplementation on
cataract formation.
The Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract
examined the effect of a multivitamin/mineral
formulation (Centrum) on the development of
cataract among participants over an average of
9 years. Multivitamin supplementation decreased
the risk of nuclear opacities, but was found to increase the risk of posterior subcapsular opacities.
Drugs 2011; 71 (18)
Herbs and Nutritional Supplements in Ocular Disorders
There was no difference in the rate of cortical
opacities, vision loss or cataract surgery.[45]
The Women’s Health Study, a large RCT with
9.7 years of treatment and follow-up, revealed no
significant difference in the incidence of cataract
between the vitamin E and placebo groups.[46]
The Physician’s Health Study, a large RCT with
8 years of treatment and follow-up, reported that
long-term supplementation with vitamins C and
E had no notable beneficial or harmful effect on
the risk of cataract.[47]
There are no large observational studies or
clinical trials examining the effectiveness of herbal medications on the development of cataracts.
4. Diabetic Retinopathy
Diabetic retinopathy is the most common microvascular complication of diabetes mellitus and
is one of the leading causes of blindness worldwide. One in every 12 people with diabetes aged
‡40 years has vision-threatening diabetic retinopathy. The NIH estimates that 4.1 million adults
in the US aged >40 years have diabetic retinopathy. This number is projected to increase to
7.2 million by 2020.[10] Standard treatments for
diabetic retinopathy include glycaemic control,
laser photocoagulation, vitrectomy, intravitreal
triamcinolone and intravitreal anti-vascular endothelial growth factor (VEGF) agents.
A recent review of the RCTs regarding the
evidence of nutritional supplementation in type 2
diabetes was conducted. Chromium was the most
studied supplement, accounting for 16 of the
50 trials reviewed. A majority of the trials found a
positive effect of chromium on fasting plasma
glucose. Isoflavones were found to have a positive
effect on insulin resistance and cardiovascular
outcome measures when combined with soy proteins. Furthermore, vitamin E was reported to reduce oxidative stress at levels of ‡200 mg/day.[48]
This evidence supports positive effects on systemic disease markers; however, evidence showing
effects of nutritional supplements on diabetic retinopathy is lacking. A recent Cochrane systematic review found no RCTs that have adequately
examined the treatment of diabetic retinopathy
with vitamin C or superoxide dismutase in such a
ª 2011 Adis Data Information BV. All rights reserved.
2427
way as to indicate whether this form of intervention has a significant impact on the progress of this
clinical condition.[49] The San Luis Valley Diabetes Study found no protective effect between the
antioxidant nutrients b-carotene and vitamin C or
E and diabetic retinopathy.[50] The Third National
Health and Nutrition Examination reported that
serum levels of a-tocopherol and vitamin C were
not associated with diabetic retinopathy.[51] The
Atherosclerosis Risk in Communities Study reported no significant association between diabetic
retinopathy and vitamins C and E intake from
food alone, or combined with supplements.[52]
Certain herbal medications, such as Ginkgo
biloba and Qi Ming granule, have been purported
to improve retinal health by increasing retinal
capillary blood flow in patients with diabetic
retinopathy.[53,54] However, there are no major
observational or prospective clinical studies to
support the use of herbal medications for diabetic
retinopathy.
5. Glaucoma
The NIH estimates that 2.2 million adults in the
US aged >40 years have glaucoma. This number is
projected to increase to 3.3 million by 2020.[10]
Standard therapy of glaucoma includes a combination of topical medications, laser and surgery to
reach a target intraocular pressure. There has been
increasing evidence in the role of oxidative damage
as an important step in the pathogenesis of glaucoma.[55,56] Some patients use alternative therapies
in the management of their glaucoma, especially if
they experience disease progression despite consistent maintenance below their target pressure.
Because of its high concentration in aqueous
humour, vitamin C has been implicated in many
aspects of glaucoma. Therefore, vitamin C supplementation is a commonly suggested CAM therapy
for glaucoma.[57] Intravenous administration of
vitamin C has been shown to transiently reduce
intraocular pressure (IOP) in patients with acute
angle-closure glaucoma. However, the lack of a consistent IOP effect even at large oral doses suggests
that its possible therapeutic role may be similar
to that of intravenous mannitol, i.e. as a hyperosmotic.[58] B vitamins are also often recommended
Drugs 2011; 71 (18)
Wilkinson & Fraunfelder
2428
as alternative therapies for glaucoma.[56] However, epidemiological studies correlating vitamin B1 (thiamine) deficiency and glaucoma have
been inconclusive and contradictory.[57] A nonrandomized, non-placebo-controlled trial of oral
vitamin B12 (cyanocobalamin) 1500 mg/day over
5 years reported a decreased rate of visual field
decline; however, an important confounding variable of the study was that the control group that
received no supplements had a statistically higher
mean IOP at entry (average IOP: 16.6 mmHg
for the treated group and 18.1 mmHg for the
control group), which persisted throughout the
study.
Vitamin A and E supplementation have also
been recommended as alternative therapies for
glaucoma, but the evidence regarding their use has
been inconclusive and circumstantial.[58] The only
large epidemiological study evaluating nutritional
supplements and glaucoma reported no strong association between the risk of primary open-angle
glaucoma and antioxidant consumption.[59]
A variety of herbal medications are commonly
used for glaucoma. Marijuana (Cannabis sativa)
has been shown to decrease IOP in some individuals. The National Eye Institute-sponsored
studies demonstrated that some derivatives of
marijuana did result in lowering of IOP when
administered orally, intravenously or by smoking, but not when topically applied to the eye.
The duration of the pressure-lowering effect is
reported to be in the range of 3–4 hours.[60] Given
the short duration of action, marijuana would
have to be smoked approximately 8 times per day
to control IOP for 24 hours. Considerable systemic toxicity and a short half-life make it a poor
treatment option. Additionally, marijuana may
lower systemic blood pressure and could potentially decrease ocular perfusion.[61]
Bilberry (Vaccinium myrtillus) is commonly
reported to have beneficial effects on glaucoma
and improve eyesight.[58] This probably stems
from two separate uncontrolled case series that
reported a modest improvement in night vision
measured by the Jayle-Blet adapto-perimeter[62]
and the Hartinger’s adaptometer.[63] Ginkgo
biloba has been used in the treatment of glaucoma
in part because of a reported increase in ocular
ª 2011 Adis Data Information BV. All rights reserved.
blood flow.[53,64] The same study demonstrated
no effect on IOP.[64] Ginkgo biloba has also been
reported to improve pre-existing visual field
damage in some patients with normal tension
glaucoma.[65] These reports did not describe any
effect on IOP. Chinese herbal products are often
recommended for glaucoma. Many of these compounds have been shown to increase retinal and
choroidal circulation and facilitate retinal recovery
after ischemic insult in animals. However, their
effect on glaucoma in humans is not known.[58]
6. Adverse Effects
6.1 b-Carotene and Vitamin A
There have been two RCTs involving b-carotene
supplementation among groups of people at high
risk of cancer (smokers and workers exposed to
asbestos) that have shown a significantly increased
incidence of cancer and mortality rate.[66,67] Vitamin A has also been associated with intracranial
hypertension when taken in large doses.[68,69]
6.2 Vitamin E
Vitamin E supplementation has been associated with increased risk of heart failure. The
Heart Outcomes Prevention Evaluation – The
Ongoing Outcomes study reported a 13% increase in heart failure and more than a 21%
increase in hospitalization for heart failure in
those taking vitamin E 400 IU daily and with a
history of diabetes or vascular disease. This difference was most notable after 7 years.[70] In
addition, a recent meta-analysis of 68 RCTs involving antioxidant supplementation concluded
that b-carotene, vitamin A and vitamin E may
increase mortality.[71]
6.3 Zinc
Zinc sulfate supplementation was associated
with an increased risk of hospitalizations for
genitourinary disorders during AREDS.[17] Zinc
has also been associated with gastrointestinal
distress, decreased copper levels and copper deficiency anaemia. For this reason, copper should
be taken with high-dose zinc.[72,73]
Drugs 2011; 71 (18)
Herbs and Nutritional Supplements in Ocular Disorders
6.4 Ginkgo biloba
Ginkgo biloba is one of the best selling and
most popular herbal medicines in the US and
worldwide. The predominant medicinal effect is
inhibition of platelet aggregation. Ginkgo biloba
has been studied for a wide range of disorders,
including dementia, peripheral vascular disease,
equilibrium disorders, tinnitus, asthma, hypertonia, angina pectoris and tonsillitis.[74-76] Significant
adverse effects related to this herb’s anticoagulation properties have been reported, including
subarachnoid haemorrhage and subdural haematoma.[77-80] Ocular complications have also
been reported, such as hyphaema and retinal
haemorrhages.[81-83]
6.5 Canthaxanthine
This carotenoid is used in cosmetics, as a food
colouring and to produce an artificial suntan when
taken orally. Ingestion of large amounts of canthaxanthine can lead to deposition of the drug in all
layers of the retina, especially the superficial layers
of the macula. While most individuals are asymptomatic, there have been reports of decreased visual
acuity, impaired dark adaptation and abnormalities in static threshold perimetry, and electroretinography.[83-85] These adverse effects appear to
be reversible upon cessation of the drug.[83]
2429
cardiovascular and cerebrovascular disease.[89,90]
It has unproven uses, including treatment for
schizophrenia, diabetes, arthritis, hypertension,
sexual dysfunction and migraine headaches.[83]
Niacin has been associated with several significant ocular adverse effects, including decreased
vision, cystoid macular oedema, dry eyes, discoloration of the eyelids, eyelid oedema, proptosis,
loss of eyebrows and eyelashes, and superficial
punctate keratitis.[83,91] Cystoid macular oedema
is a significant adverse effect that has been reported numerous times and can lead to significant vision loss.[83] Optical coherence tomography
(OCT) reveals cystic spaces in the outer plexiform
and inner nuclear layers. OCT findings and visual
acuity usually improve after cessation of the
drug.[92,93]
6.8 Datura
Jimson weed (Datura stramonium) is the main
member of this genus and is used to treat eye inflammation as well as asthma, bronchitis, influenza and coughs. It is also commonly ingested
for its hallucinogenic properties. The leaves have
been shown to contain diverse alkaloids, including scopolamine, hyoscyamine and atropine, in
extremely varying concentrations, which are
anticholinergic and parasympatholytic. Ocular
effects include mydriasis and cycloplegia.[83]
6.6 Chamomile
6.9 Echinacea
Chamomile (Matricaria chamomilla) is commonly used worldwide for the treatment of ocular
and systemic diseases. Ocular indications include
eye irritation, styes, epiphora and inflammation.[86] Systemic indications include insomnia,
indigestion, migraine headaches, bronchitis, fevers, colds, inflammation and burns.[87] There is
strong evidence to suggest that chamomile, when
applied topically in or around the eye, can cause
severe conjunctivitis.[88] This has been hypothesized to be due to a hypersensitivity reaction to
allergens present in Matricaria chamomilla.[83]
6.7 Niacin
Niacin has been shown to lower cholesterol
and triglycerides, and is used in the treatment of
ª 2011 Adis Data Information BV. All rights reserved.
Echinacea (Echinacea purpurea) is used frequently to treat the common cold, cough, fevers,
urinary tract infections, burns and influenza. The
efficacy of echinacea has been studied through
randomized placebo-controlled, double-blind
studies and the results are mixed, especially for
upper respiratory infections.[94,95] Echinacea has
been associated with eye irritation and conjunctivitis that may be due to an anaphylactic
reaction.[83,94] The conjunctivitis resolves upon
cessation of the drug.[83]
6.10 Liquorice
Liquorice (licorice, Glycyrrhiza glabra) inhibits cyclo-oxygenase activity and has both antiDrugs 2011; 71 (18)
Wilkinson & Fraunfelder
2430
inflammatory and anti-platelet effects. It has
been used to treat peptic ulcers, hepatitis C, appendicitis, constipation and upper respiratory
tract infections.[83,96-98] Transient vision loss has
been reported after liquorice ingestion and has
been postulated to be due to vasospasm of the
brain, retinal and/or optic nerve blood supply.
This is thought to be due to its glucocorticoid and
noradrenaline effects.[83,99-101]
7. Discussion
Information touting the beneficial effects of
nutritional supplements and herbal medicines is
widespread in popular culture. These agents are
being used by a large segment of the population,
many times without strong evidence on efficacy
or safety. Ophthalmologists should be aware of
the evidence supporting the use of these agents
to treat ocular diseases as well as their potential
adverse effects. It is especially important for providers to understand the potential risks and benefits of agents they personally prescribe for ocular
conditions.
At the present time, there is insufficient evidence
in the literature to recommend routine nutritional
supplementation in healthy adults for primary
prevention of AMD. There is strong evidence
supporting the use of antioxidants and zinc in
patients with certain forms of intermediate and
advanced AMD. However, there has been growing
evidence regarding potential significant adverse
effects associated with the AREDS formula vitamins. It is important for providers to consider these
risks and properly inform their patients when they
are making decisions about supplementation. Observational studies have also suggested benefit
from increased dietary intake of macular xanthophylls (lutein and zeaxanthin) and omega-3 fatty
acids. These are currently being evaluated prospectively in an RCT, the AREDS2.
Data from observational studies have generally supported the use of antioxidants to prevent or slow cataract progression. However, the
results of completed RCTs have been disappointing. Results of these clinical trials indicate
that supplementation with vitamin E, either
alone or in combination with other antioxidants,
ª 2011 Adis Data Information BV. All rights reserved.
with treatment durations up to 8 years in men and
10 years in women, has little benefit.
At this time, there is no conclusive evidence
that nutritional supplements are beneficial in the
treatment of glaucoma. With the exception of
intravenous vitamin C in acute angle-closure
glaucoma, there is also no evidence that megadoses of vitamins are beneficial for patients with
glaucoma. It is known that certain vitamins can
cause toxicity when ingested in large doses, used
in certain diseases, or used concurrently with
other medications. The current literature does
not support the use of herbal medications in the
treatment or prevention of cataracts, diabetic retinopathy or glaucoma.
CAM is increasingly recognized as an important topic among healthcare providers, and
most US medical schools now include CAM as
part of their formal curriculum. Patients will
continue to turn to alternative therapies in an
effort to prevent or delay the progression of disease. It is important for clinicians to be aware of
the significant potential adverse effects that have
been associated with nutritional supplements and
herbal medications and to query patients regarding their use, as patients frequently do not
disclose this information to their physicians. The
current literature does provide some guidance in
the appropriate use of nutritional supplements
and herbal medicines and it is important that
these agents continue to be rigorously evaluated
to determine their safety and efficacy.
8. Conclusions
Herbal medicines and nutritional supplements
are of clinical importance to ophthalmologists as
their use is widespread and many of these therapies can cause unwanted adverse effects. A variety of these agents are touted as beneficial for
eye disease and many are associated with ocular
adverse effects. The current medical literature
provides some guidance in the use of nutritional
supplements in the treatment of common eye
diseases. There is strong evidence supporting
the use of antioxidants and zinc in patients with
certain forms of intermediate and advanced
AMD. However, there is growing evidence of
Drugs 2011; 71 (18)
Herbs and Nutritional Supplements in Ocular Disorders
potential significant adverse effects associated
with the AREDS formula vitamins. Current data
do not support the use of antioxidants or herbal
medications in the prevention or treatment of
cataracts, glaucoma or diabetic retinopathy. It is
important for providers to be aware of the benefits and the significant potential adverse effects
that have been associated with nutritional supplements and herbal medications, and to properly
inform their patients when making decisions
about supplementation. Further rigorous evaluation of nutritional supplements and herbal
medicines in the treatment of eye disease is needed
to determine their safety and efficacy.
Acknowledgements
The author is indebted to the national centres mentioned
in this study that contributed data. The opinions and conclusions expressed are not necessarily those of the various centres
or of the WHO.
This study was supported in part by an unrestricted grant
from Research to Prevent Blindness, New York, NY, USA.
The authors have no proprietary interest in these materials, or
other conflicts of interest that are directly relevant to the
content of this review.
References
1. National Center for Complementary and Alternative
Medicine. What is complementary and alternative medicine (CAM)? National Institutes of Health [online].
Available from URL: http://nccam.nih.gov/health/wha
tiscam/ [Accessed 2011 Apr 27]
2. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997:
results of a follow-up national survey. JAMA 1998; 289:
1569-75
3. Tindle HA, Davis RB, Phillips RS, et al. Trends in use of
complementary and alternative medicine by US adults:
1997-2002. Altern Ther Health Med 2005; 11: 42-9
4. Nahin RL, Barnes PM, Stussman BJ, et al. Costs of complementary and alternative medicine (CAM) and frequency
of visits to CAM practitioners: United States, 2007. National Health Statistics Reports, No. 18. Hyattsville (MD):
National Center for Health Statistics, 2009
5. Gahche J, Bailey R, Burt V, et al. Dietary supplement use
among U.S. adults has increased since NHANES III
(1988–1994). NCHS data brief, no 61. Hyattsville (MD):
National Center for Health Statistics, 2011
6. Supplement business report 2010. Nutrition Business
Journal. Penton Media, Inc., 2010
7. WHO guidelines on good agricultural and collection practices for medicinal plants. Geneva: WHO, 2004
8. Dharmananda S. The nature of ginseng: traditional use,
modern research, and the question of dosage. Herbal
Gram 2002; 54: 34-51
ª 2011 Adis Data Information BV. All rights reserved.
2431
9. Wan MJ, Daniel S, Kassam F, et al. Survey of complementary and alternative medicine use in glaucoma
patients. J Glaucoma. Epub 2010 Dec 16
10. National Eye Institute. Prevalence of blindness data: summary of eye disease prevalence data [online]. Available
from URL: http://www.nei.nih.gov/eyedata/pbd_tables.
asp [Accessed 2011 Apr 27]
11. Ting AY, Lee TK, MacDonald IM. Genetics of age-related
macular degeneration. Curr Opin Ophthalmol 2009; 20
(5): 369-76
12. Klein R, Peto T, Bird A, et al. The epidemiology of agerelated macular degeneration. Am J Ophthalmol 2004;
137: 486-95
13. Evans JR. Risk factors for age-related macular degeneration. Prog Retin Eye Res 2001; 20: 227-53
14. Clemons TE, Milton RC, Klein R, et al., Age-Related Eye
Disease Study Research Group. Risk factors for the incidence of Advanced Age-Related Macular Degeneration
in the Age-Related Eye Disease Study (AREDS). AREDS
report no. 19. Ophthalmology 2005; 112 (4): 533-9
15. Van den Langenberg GM, Mares-Perlman JA, Klein R,
et al. Associations between antioxidant and zinc intake
and the 5-year incidence of early age-related maculopathy
in the Beaver Dam Eye Study. Am J Epidemiol 1998; 148:
204-14
16. van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary
intake of antioxidants and risk of age-related macular
degeneration. JAMA 2005; 294: 3101-7
17. 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: AREDS report no. 8. Arch Ophthalmol 2001; 119:
1417-36
18. Chew EY, Lindblad AS, Clemons T. Age-Related Eye
Disease Study Research Group. Summary results and
recommendations from the age-related eye disease study.
Arch Ophthalmol 2009; 127 (12): 1678-9
19. Evans JR, Henshaw K. Antioxidant vitamin and mineral
supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev 2008; (1): CD000253
20. Taylor HR, Tikellis G, Robman LD, et al. Vitamin E
supplementation and macular degeneration: randomised
controlled trial. BMJ 2002; 325: 11
21. Hodge WG, Schachter HM, Barnes D, et al. Efficacy of
omega-3 fatty acids in preventing age-related macular
degeneration: a systematic review. Ophthalmology 2006;
113 (7): 1165-72
22. Seif-El-Nasr M, El-Fattah AA. Lipid peroxide, phospholipids, glutathione levels and superoxide dismutase activity in rat brain after ischaemia: effect of Ginkgo biloba
extract. Pharmacol Res 1995; 32: 273-8
23. Barth SA, Inselmann G, Engemann R, et al. Influences of
Ginkgo biloba on cyclosporin A induced lipid peroxidation in human liver microsomes in comparison to vitamin
E, glutathione and N-acetylcysteine. Biochem Pharmacol
1991; 41: 1521-6
24. Lamant V, Mauco G, Braquet P, et al. Inhibition of the
metabolism of platelet activating factor (PAF-acether) by
Drugs 2011; 71 (18)
Wilkinson & Fraunfelder
2432
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
three specific antagonists from Ginkgo biloba. Biochem
Pharmacol 1987; 36: 2749-52
Zhang J, Fu S, Liu S, et al. The therapeutic effect of Ginkgo
biloba extract in SHR rats and its possible mechanisms
based on cerebral microvascular flow and vasomotion.
Clin Hemorheol Microcirc 2000; 23: 133-8
Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms
of the protective role of lutein and zeaxanthin in the eye.
Annu Rev Nutr 2003; 23: 171-201
Semba RD, Dagnelie G. Are lutein and zeaxanthin conditionally essential nutrients for eye health? Med Hypotheses 2003; 61: 465-72
Koh HH, Murrah IJ, Nolan D, et al. Plasma and macular
responses to lutein supplement in subjects with and without age-related maculopathy: a pilot study. Exp Eye Res
2004; 79: 21-7
Seddom JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related
macular degeneration. Eye Disease Case-Control Study
Group. JAMA 1994; 272: 1413-20
US Food and Drug Administration. Qualified health
claim: letter of denial – Xangold lutein esters, lutein, or
zeaxanthin and reduced risk of age-related macular degeneration or cataract formation (docket no. 2004Q-0180)
[online]. Available from URL: http://www.fda.gov/Food/
LabelingNutrition/LabelClaims/QualifiedHealthClaims/
ucm073291.htm [Accessed 2011 May 7]
Moeller SM, Parekh N, Tinker L, et al., CAREDS Research Study Group. Associations between intermediate
age-related macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-related Eye Disease
study (CAREDS): ancillary study of the Women’s Health
Initiative. Arch Ophthalmol 2006; 124: 1151-62
Tan JSL, Wang JJ, Flood V, et al. Dietary antioxidants and
the long term incidence of age-related macular degeneration: the Blue Mountain Eye study. Ophthalmology 2008;
115: 334-41
San Giovanni JP, Chew EY, Clemons TE, et al., AgeRelated Eye Disease Study Research Group. The relationship of dietary carotenoid and vitamin A, E, and C
intake with age-related macular degeneration in a casecontrol study: AREDS Report No. 22. Arch Ophthal
2007; 125 (9): 1225-32
Javitt JC, Kendix M, Tielsch JM, et al. Geographic variation in utilization of cataract surgery. Med Care 1995; 33:
90-105
Escarce JJ. Would eliminating differences in physician
practice style reduce geographic variations in cataract
surgery rates? Med Care 1993; 31 (12): 1106-18
Goldzweig CL, Mittman BS, Carter GM, et al. Variations
in cataract extraction rates in Medicare prepaid and feefor-service settings. JAMA 1997; 277: 1765-8
Hankinson SE, Stampfer MJ, Seddon JM. Nutrient intake
and cataract extraction in women: a prospective study.
BMJ 1992; 305 (6849): 335-9
Tan AG, Mitchell P, Flood VM, et al. Antioxidant nutrient
intake and the long-term incidence of age-related cataract:
the Blue Mountains Eye Study. Am J Clin Nutr 2008; 87
(6): 1899-905
ª 2011 Adis Data Information BV. All rights reserved.
39. Lyle BJ, Mares-Perlman JA, Klein BE, et al. Antioxidant
intake and risk of incident age-related nuclear cataracts in
the Beaver Dam Eye Study. Am J Epidemiol 1999; 149:
801-9
40. Age-Related Eye Disease Study Research Group. 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 (10): 1439-52
41. McNeil JJ, Robman L, Tikellis G, et al. Vitamin E supplementation and cataract: randomized controlled trial.
Ophthalmology 2004; 111 (1): 75-84
42. Teikari JM, Rautalahti M, Haukka J, et al. Incidence of
cataract operations in Finnish male smokers unaffected
by alpha tocopherol or beta carotene supplements.
J Epidemiol Community Health 1998; 52: 468-72
43. Chylack Jr LT, Brown NP, Bron A, et al. The Roche
European American Cataract Trial (REACT): a randomized
clinical trial to investigate the efficacy of and oral antioxidant micronutrient mixture to slow progression of agerelated cataract. Ophthalmic Epidemiol 2002; 9: 49-80
44. Sperduto RD, Hu TS, Milton RC, et al. The Linxian cataract studies: two nutrition intervention trials. Arch
Ophthalmol 1993; 111: 1246-53
45. Clinical Trial of Nutritional Supplements and Age-Related
Cataract Study Group, Maraini G, Sperduto RD, et al.
A randomized, double-masked, placebo-controlled clinical
trial of multivitamin supplementation for age-related lens
opacities: clinical trial of nutritional supplements and agerelated cataract no. 3. Ophthalmology 2008; 115: 599-607
46. Christen WG, Glynn RJ, Chew EY, et al. Vitamin E and
age-related cataract in a randomized trial of women.
Ophthalmology 2008; 115: 822-9
47. Christen WG, Glynn RJ, Sesso HD, et al. Age-related
cataract in a randomized trial of vitamins E and C in men.
Arch Ophthalmol 2010; 128: 1397-405
48. Bartlett HE, Eperjesi F. Nutritional supplementation for
type 2 diabetes: a systematic review. Ophthal Physiol Opt
2008; 28: 503-23
49. Lopes de Jesus CC, Atallah AN, Valente O, et al. Vitamin
C and superoxide dismutase (SOD) for diabetic retinopathy. Cochrane Database Syst Rev 2008; (1): CD006695
50. Mayer-Davis EJ, Bell RA, Reboussin BA, et al. Antioxidant nutrient intake and diabetic retinopathy: the San
Luis Valley Diabetes Study. Ophthalmology 1998; 105:
2264-70
51. Millen AE, Gruber M, Klein R, et al. Relations of serum
ascorbic acid and alpha-tocopherol to diabetic retinopathy in the Third National Health and Nutrition
Examination Survey. Am J Epidemiol 2003; 158: 225-33
52. Millen AE, Klein R, Folsom AR, et al. Relation between
intake of vitamins C and E and risk of diabetic retinopathy in the Atherosclerosis Risk in Communities Study.
Am J Clin Nutr 2004; 79: 865-73
53. Huang SY, Jeng C, Kao SC, et al. Improved haemorrheological properties by Ginkgo biloba extract (Egb 761)
in type 2 diabetes mellitus complicated with retinopathy.
Clin Nutr 2004; 23 (4): 615-21
54. Luo XX, Duan J, Liao P, et al. Effect of qiming granule on
retinal blood circulation of diabetic retinopathy: a multi-
Drugs 2011; 71 (18)
Herbs and Nutritional Supplements in Ocular Disorders
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
center clinical trial. Chinese J Integrative Med 2009; 15
(5): 384-8
Sacca SC, Izzotti A. Oxidative stress and glaucoma: injury
in the anterior segment of the eye. Prog Brain Research
2008; 173: 385-407
He Y, Leung KW, Zhang YH, et al. Mitochondrial
complex I defect induces ROS release and degeneration
in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophth Vis Sci 2008; 49 (4):
1447-58
Gunasekera V, Ernst E, Ezra DG. Systematic internetbased review of complementary and alternative medicine
for glaucoma. Ophthalmology 2008; 115 (3): 435-9
Rhee DJ, Katz LJ, Spaeth GL, et al. Complementary and
alternative medicine for glaucoma. Surv Ophthalmology
2001; 46 (1): 43-55
Kang JH, Pasquale LR, Willett W, et al. Antioxidant intake and primary open-angle glaucoma: a prospective
study. Am J Epidemiol 2003; 158: 337-46
National Eye Institute, National Institutes of Health. NEI
statement: the use of marijuana for glaucoma. Bethesda
(MD): NEI/NIH, 1997 Feb 18
Merritt JC, Crawford WJ, Alexander PC, et al. Effect of
marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 1980; 787: 222-8
Jayle GE, Aubry M, Gavini H. Study concerning the action
of anthocyanoside extracts of vaccinium myrtillus on
night vision. Ann Ocul 1965; 198: 556-62
Urso G. Effect of Vaccinium myrtillus anthocyanosides
associated with beta carotenes on light sensitivity. Ann
Ottalmol Clin Ocul 1967; 93: 930-8
Chung HS, Harris A, Kristinsson JK, et al. Ginkgo biloba
extract increases ocular blood flow velocity. J Ocul Pharmacol Ther 1999; 15: 233-40
Quaranta L, Bettelli S, Uva MG, et al. Effect of Ginkgo
biloba extract on preexisting visual field damage in normal tension glaucoma. Ophthalmology 2003; 110: 359-62;
discussion 362-4
The Alpha Tocopherol, Beta Carotene Cancer Prevention
Study Group (ATBC). 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
Omenn GS, Goodman GE, Thornquist MD, et al. Effects
of a combination of beta carotene and vitamin A on lung
cancer and cardiovascular disease. N Engl J Med 1996;
334: 1150-5
Morrice Jr G, Havener WH, Kapetansky F. Vitamin A
intoxication as a cause of pseudotumor cerebri. JAMA
1960; 173: 1802-5
Pasquariello Jr PS, Schut L, Borns P. Benign increased
intracranial hypertension due to chronic vitamin A overdosage in a 26-month old child. Clin Pediatr 1977; 16: 379-82
Lonn E, Bosch J, Yusuf S, et al., HOPE and HOPE-TOO
Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a
randomized controlled trial. JAMA 2005; 293: 1338-47
Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in
randomized trials of antioxidant supplements for primary
and secondary prevention: systematic review and metaanalysis. JAMA 2007; 297: 842-57
ª 2011 Adis Data Information BV. All rights reserved.
2433
72. Fosmire GJ. Zinc toxicity. Am J Clin Nutr 1990; 51 (2):
225-7
73. Saper RB, Rash R. Zinc: an essential micronutrient. Am
Fam Physician 2009; 79 (9): 768-72
74. Cesarani A, Meloni F, Alpini D. Ginkgo biloba in the
treatment of equilibrium disorders. Adv Ther 1998; 15:
291-304
75. Le Bars PL, Katz MM, Berman N, et al. A placebocontrolled, double-blind, randomized trial of an extract of
Ginkgo biloba for dementia. North American EGb Study
Group. JAMA 1997; 16: 1327-32
76. Peters H, Kieser M, Holscher U. Demonstration of the
efficacy of Ginkgo biloba special extract EGb 761 on intermittent claudication: a placebo-controlled, doubleblind multicenter trial. VASA 1998; 27: 106-10
77. Vale S. Subarachnoid haemorrhage associated with Ginkgo
biloba. Lancet 1998; 352: 36
78. Rowin J, Lewis SL. Spontaneous bilateral subdural haematomas associated with chronic Ginkgo biloba ingestion. Neurology 1996; 46: 1775-6
79. Benjamin J, Muir T, Briggs K, et al. A case of cerebral
haemorrhage: can Ginkgo biloba be implicated? Postgrad
Med J 2001; 77: 112-3
80. Fessenden JM, Wittenborn W, Clarke L. Ginkgo biloba: a
case report of herbal medicine and bleeding postoperatively from a laparoscopic cholecystectomy. Am
Surg 2001; 67: 33-5
81. Fong KCS, Kinnear PE. Retrobulbar haemorrhage associated with chronic Ginkgo biloba ingestion. Postgrad
Med J 2003; 79: 532-3
82. Schneider C, Bord C, Misse P, et al. Spontaneous hyphema
caused by Ginkgo biloba extract. J Fr Ophthalmol 2002;
25: 731-2
83. Fraunfelder FW. Ocular side effects from herbal medicines and
nutritional supplements. Am J Ophthalmol 2004; 138: 639-48
84. Fraunfelder FT, Fraunfelder FW. In: Fraunfelder FT,
Fraunfelder FW, editors. Drug-induced ocular side effects.
5th ed. Woburn (MA): Butterworth-Heinemann, 2001: 824
85. Phillip W. Carotenoid deposits in the retina. Klin Monatsbl
Augenheilkd 1985; 187 (5): 439-40
86. Knefeli U. The 247 most beneficial plants [in Spanish]. In:
War T, editor. Guia practica ilustrade de las plantas
medicinales. Vol. 26. Barcelona: Blume, 1981
87. Physician’s desk reference for herbal medicines. 2nd ed.
Montvale (NJ): Medical Economics, 2000: 858
88. Subiza J, Subiza JL. Allergic conjunctivitis to chamomile
tea. Ann Allergy 1990; 65: 127-32
89. Chazin BJ. Effect of nicotinic acid on blood cholesterol.
Geriatrics 1960; 15: 423-9
90. Parsons WB. Reduction in elevated blood cholesterol levels
by large doses of nicotinic acid. JAMA 1957; 165: 234-8
91. Fraunfelder FW, Fraunfelder FT, Illingworth DR. Adverse ocular effects associated with niacin therapy. Br J
Ophthalmol 1995; 79: 54-6
92. Spirn MJ, Warren FA, Guyer DR, et al. Optical coherence
tomography findings in nicotinic acid maculopathy. Am
J Ophthalmol 2003; 135: 913-4
Drugs 2011; 71 (18)
2434
93. Dajani HM, Lauer AK. Optical coherence tomography
findings in niacin maculopathy. Can J Ophthalmol 2006;
41: 197-200
94. Brinkeborn R, Shah D, Degenring F. Echinaforce and
other Echinacea fresh plant preparations in the treatment of the common cold: a randomized, placebo controlled, double-blind clinical trial. Phytomedicine 1999; 6:
1-6
95. Grimm W, Muller H. A randomized controlled trial of the
effect of fluid extract of Echinacea purpurea on the incidence and severity of colds and respiratory infections.
Am J Med 1999; 106: 138-43
96. Morgan AG, McAdam WAF, Pacsoo C, et al. Comparison
between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut
1982; 23: 545-51
97. Arase Y, Ikeda K, Murashima N, et al. The long term
efficacy of glycyrrhizin in chronic hepatitis C patients.
Cancer 1997; 79: 1494-500
ª 2011 Adis Data Information BV. All rights reserved.
Wilkinson & Fraunfelder
98. Barbara L, Belsasso E, Blasi A, et al. Pirenzepine and carbenozolong in gastric ulcer: preliminary results of a multicentre double-blind controlled clinical trial. Scand J
Gastroenterol Suppl 1979; 57: 21-4
99. Jun R, Zhengang W. Pharmacological research on the effect of licorice. J Tradit Chin Med 1988; 8: 307-9
100. Walker BR, Connacher AA, Webb DJ, et al. Glucocorticoids and blood pressure: a role for the cortisol/cortisone
shuttle in the control of vascular tone in man. Clin Sci
1992; 83: 171-8
101. Walker BR, Sang KS, Williams BC, et al. Direct and indirect
effects of carbenoxolone on responses to glucocorticoids and
noradrenaline in rat aorta. J Hypertens 1994; 12: 33-9
Correspondence: Dr Frederick W. Fraunfelder, MD, Casey
Eye Institute, 3375 SW Terwilliger Blvd., Portland, OR
97239-4197, USA.
E-mail [email protected]
Drugs 2011; 71 (18)