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Drugs 2011; 71 (18): 2421-2434 0012-6667/11/0018-2421/$55.55/0 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 2421 2422 2423 2423 2426 2427 2427 2428 2428 2428 2428 2429 2429 2429 2429 2429 2429 2429 2430 2430 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 2423 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 2424 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 ª 2011 Adis Data Information BV. All rights reserved. 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)