Natural Therapies for Ocular Disorders              Part Two: Cataracts and Glaucoma                                      ...
A large percentage of blindness in the      is often a symptom, whereas posterior   world is nutritionally preventable.1 T...
Ocular DisordersFigure 1: Synthesis of Glutathione in the Lens                                                            ...
this phenomenon in an attempt to determine         have found an increase in disulfide bonds in   whether low GSH is due t...
Ocular Disorders  Figure 2: Metabolism of Hydrogen Peroxide by Glutathione                                                ...
oxygen species generated by exposure to             population of healthy volunteers, ages 55-80   ultraviolet light.25   ...
Ocular Disorders   (1) vitamin E decreases oxidative stress in cata-            It is not surprising then that a defi-   r...
Dramatic improvement was reported within            butter, total fat, salt, and oil (except olive oil).8   24-48 hours, a...
Ocular Disorders   with melatonin and half were not. In one study,      Flavonoids as Aldose Reductase Inhibitors   18/18 ...
Table 1: The Aldose Reductase Inhibitor  Activity of Some Flavonoids.60                            comparable (average 380...
Ocular Disorders   potencies were nearly identical (Table 1). The       to halt progression of diabetic cataracts despite ...
Table 2: Nutrients and Botanicals for the Prevention and Treatment of Cataracts                                           ...
Ocular Disorders                 Figure 4: Flow of Fluids in the Eye                            Aqueous humor             ...
chamber. Outflow occurs through the angle          Other researchers, examining human post-   between the cornea and the i...
Ocular Disorders   Table 3: Conventional Glaucoma Medications and Their Potential Side Effects4,83    Drug Category       ...
Potential Nutrient Deficiencies in                Nutrients that Effect GAGs: Vitamin C and   Glaucoma                    ...
Ocular Disorders           Table 4: Decreases in IOP after Oral Ascorbic Acid at 0.5 mg/kg           body weight89        ...
from glaucoma and vasospasm seems war-              melatonin secretion, resulted in a blunting of   ranted.              ...
Ocular Disorders   Botanical Treatment of Glaucoma                       supplementation. Subjects crossed over to the    ...
Table 5: Potential Nutrient and Botanical Approaches to Glaucoma    Supplement           Route of Administration        Me...
Ocular Disorders   needed. Forskolin eye drops are available           already existing cataracts. Maintaining normal   th...
Nutritional therapies for ocular disorders pa rça iki
Nutritional therapies for ocular disorders pa rça iki
Nutritional therapies for ocular disorders pa rça iki
Nutritional therapies for ocular disorders pa rça iki
Nutritional therapies for ocular disorders pa rça iki
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Nutritional therapies for ocular disorders pa rça iki

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Nutritional therapies for ocular disorders pa rça iki

  1. 1. Natural Therapies for Ocular Disorders Part Two: Cataracts and Glaucoma Kathleen Head, ND Abstract Pathophysiological mechanisms of cataract formation include deficient glutathione levels contributing to a faulty antioxidant defense system within the lens of the eye. Nutrients to increase glutathione levels and activity include lipoic acid, vitamins E and C, and selenium. Cataract patients also tend to be deficient in vitamin A and the carotenes, lutein and zeaxanthin. The B vitamin riboflavin appears to play an essential role as a precursor to flavin adenine dinucleotide (FAD), a co-factor for glutathione reductase activity. Other nutrients and botanicals, which may benefit cataract patients or help prevent cataracts, include pantethine, folic acid, melatonin, and bilberry. Diabetic cataracts are caused by an elevation of polyols within the lens of the eye catalyzed by the enzyme aldose reductase. Flavonoids, particularly quercetin and its derivatives, are potent inhibitors of aldose reductase. Glaucoma is characterized by increased intraocular pressure (IOP) in some but not all cases. Some patients with glaucoma have normal IOP but poor circulation, resulting in damage to the optic nerve. Faulty glycosaminoglycan (GAG) synthesis or breakdown in the trabecular meshwork associated with aqueous outflow has also been implicated. Similar to patients with cataracts, those with glaucoma typically have compromised antioxidant defense systems as well. Nutrients that can impact GAGs such as vitamin C and glucosamine sulfate may hold promise for glaucoma treatment. Vitamin C in high doses has been found to lower IOP via its osmotic effect. Other nutrients holding some potential benefit for glaucoma include lipoic acid, vitamin B12, magnesium, and melatonin. Botanicals may offer some therapeutic potential. Ginkgo biloba increases circulation to the optic nerve; forskolin (an extract from Coleus forskohlii) has been used successfully as a topical agent to lower IOP; and intramuscular injections of Salvia miltiorrhiza have shown benefit in improving visual acuity and peripheral vision in people with glaucoma. (Altern Med Rev 2001;6(2):141-166) Introduction Part one of this article was published in the October 1999 issue of Alternative Medicine Review and discussed nutritional and botanical approaches to conditions of the retina. This second part covers alternative treatments for nonretinal disorders: senile cataracts, diabetic cata- racts, and chronic open-angle glaucoma. Kathleen A. Head, ND – Technical Advisor, Thorne Research, Inc.; Senior Editor, Alternative Medicine Review. Correspondence address: PO Box 25, Dover, ID 83825. E-mail: kathi@thorne.comAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 141Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  2. 2. A large percentage of blindness in the is often a symptom, whereas posterior world is nutritionally preventable.1 The author subcapsular cataracts tend to be most of this comment was referring primarily to the noticeable in bright light.4 Ophthalmoscopic use of vitamin A to prevent corneal degenera- examination is best conducted on a dilated tion associated with a vitamin A deficiency; pupil, holding the scope approximately one however, there is considerable evidence that foot away. Small cataracts appear as dark many other eye conditions, which are leading defects against the red reflex, whereas a large causes of vision impairment and blindness, cataract may completely obliterate the red also may be preventable with nutritional reflex. Once a cataract has been established, a supplementation, botanical medicines, diet, referral for slit-lamp examination, which and other lifestyle changes. In addition, a num- provides more detail on location and extent of ber of nutrients hold promise for the treatment opacity, is recommended. of already existing cataracts and glaucoma. Etiological/Risk Factors Senile Cataracts Factors contributing to cataract forma- Senile cataracts are the leading cause tion include aging, smoking,5 exposure to UV- of impaired vision in the United States, with a B and ionizing radiation,6 oxidative stress (sec- large percentage of the geriatric population ondary to other risk factors such as aging or exhibiting some signs of the lesion. Over one smoking),7 dietary factors,8 increased body million cataract surgeries are performed yearly weight (above 22-percent body fat), central in this country alone.2 Cataracts are develop- obesity,9 and family history. Medications and mental or degenerative opacities of the lens of environmental exposures which may contrib- the eye, generally characterized by a gradual ute to cataract formation include steroids, gout painless loss of vision. The extent of the vi- medications, and heavy metal exposure. Cad- sion loss depends on the size and location of mium, copper, lead,10 iron, and nickel11 have the cataract. Cataracts may be located in the all been found in cataractous lenses. A high center of the lens (nuclear), in the superficial level of cadmium in the lens is associated with cortex (cortical), or in the posterior subcapsu- smoking and can contribute to accumulation lar area. Cataracts are also classified accord- of other heavy metals.10 Conditions which pre- ing to their color, which is consistent with lo- dispose to cataracts include diabetes, galac- cation and density of the cataract. Pale yellow tosemia, neurofibromatosis, hypothyroidism, cataracts are typically slight opacities of the hyperparathyroidism, hypervitaminosis D, in- cortex, subcapsular region, or both; yellow or fectious diseases such as toxoplasmosis, and light brown cataracts are consistent with mod- several syndromes caused by chromosomal erate to intense opacities of the cortex, nucleus, disorders.2 or both; and brown cataracts are associated with dense nuclear cataracts.3 Mechanisms Involved in the Diagnosis Pathophysiology of Cataracts Cataracts are characterized by electro- Symptoms include near vision image lyte disturbances resulting in osmotic imbal- blur, abnormal color perception, monocular ances. Derangements in the function of the diplopia, glare, and impaired visual acuity, and membrane resulting in ion imbalance may be may vary depending on location of the cataract. due to increased membrane permeability or to For example, if the opacity is located in the a depression of the Na+/K+ pump because of center of the lens (nuclear cataract), myopia interference with the enzyme Na+/K+ ATPase.12Page 142 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  3. 3. Ocular DisordersFigure 1: Synthesis of Glutathione in the Lens creating a vicious cycle. The Step 1 Glutamic acid Step 2 γ-Glutamylcysteine researchers + + hypothesized that, cysteine glycine “chelation therapy + + could be beneficial ATP ATP in delaying γ-Glutamylcysteine Glutathione cataractogenesis.”14 synthetase synthetase Other researchers have confirmed the involvement of γ-Glutamylcysteine Glutathione transition metals, + + copper and iron, as ADP ADP instigators of + + ascorbyl and Pi Pi hydroxyl radical formation in cataracts.15 Cataracts are also characterized by aggregates The Role of of insoluble proteins.12 Glutathione in Lens Metabolism Oxidative insult appears to be involved In order to fully understand the mecha- as a precipitating factor in all cataracts. Lens nisms involved in cataract formation and the proteins typically remain in their reduced form. link to nutritional prevention, it is important However, in cataractous lenses, the proteins to understand the role glutathione and its en- are found in an insoluble, oxidized form. Oxi- zyme co-factors play in metabolism within the dation may occur as a result of many factors lens. In vitro studies of incubated lenses from (see Etiological Factors). Higher levels of hy- animals as well as humans have helped eluci- drogen peroxide have been found in catarac- date the mechanisms involved. tous lenses when compared to normal con- The lens of the eye is avascular, de- trols.13 Normally the lens contains significant pending entirely on passive diffusion, active levels of reduced glutathione (GSH), which transport, and intra-lens synthesis for nutrients keeps the proteins in their reduced form. How- and other substances important for metabo- ever, there are significantly lower levels of lism. As a result, the content of the surround- GSH in cataractous lenses. ing intraocular fluids (aqueous humor) is rel- Advanced glycation end products evant. While levels of GSH are high in the lens, (AGE) appear to play a role in cataract they are relatively low in the aqueous humor; formation. Researchers have tested the thus, glutathione appears to be synthesized hypothesis that the major AGE formed in the within the lens. Glutathione is composed of lens has an EDTA-like structure, capable of the amino acids cysteine, glutamic acid, and binding to copper. They found copper binding glycine, and its synthesis within the lens takes was 20-30 percent greater in the older, place in two steps (Figure 1). Cataractous cataractous lens protein fractions than in lenses can demonstrate dramatic decreases in young, non-cataractous fractions. The pro- GSH, as much as 81 percent, when compared oxidant copper precipitates further oxidation, to normal lenses.3 Researchers have examinedAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 143Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  4. 4. this phenomenon in an attempt to determine have found an increase in disulfide bonds in whether low GSH is due to decreased synthe- human cataractous lenses.17 sis or increased degradation. Decreases in the Maintaining normal cell volume and enzymes involved in both synthesis (γ- transport of electrolytes are important factors glutamyl transferase) and recycling (glu- in lens transparency. Glutathione may play a tathione reductase) of GSH from oxidized glu- role in maintaining normal lens permeability tathione (GSSG) lend credence to the theory and active cation transport by protecting sulf- that synthesis is diminished in cataractous hydryl groups in the cell membrane from oxi- lenses.3 These same researchers found a de- dation. Oxidation of SH groups on the surface crease in the activity of enzymes of GSH deg- of the cell membrane results in increased per- radation (glutathione peroxidase and glu- meability, and oxidation of important SH tathione s-transferase) which should result in groups of Na+/K+ ATPase impedes active trans- an increased rather than a decreased accumu- port. Reddy et al examined the effect of GSH lation of GSH. They therefore concluded that depletion on rabbit lenses and found it directly the loss of activity of these enzymes was not led to increased membrane permeability.18 enough to offset the losses associated with While GSH depletion did not directly impair decreased synthesis. They also did not rule out active transport, it resulted in increased sus- the possible loss of GSH from the lens via ceptibility of the Na+/K+ pump to oxidative membrane leakage. damage by H2O2. Oxidation of GSH resulted There are several ways in which glu- in a 70-percent decrease in active transport and tathione or its depletion can affect the opacity a two-fold increase in membrane permeabil- of the lens. A review by primary researchers ity. Other experiments have found that lens- on glutathione metabolism and its relationship epithelial-GSH needs to be depleted by about to cataract formation outlines three possible 60 percent for these changes to occur. The mechanisms of cataract prevention by glu- authors point out that, “the lens has a remark- tathione:16 (1) maintaining sulfhydryl (SH) able ability to regenerate reduced glutathione.” groups on proteins in their reduced form pre- However, they found that, although the change venting disulfide cross-linkage; (2) protecting in membrane permeability was reversible with SH groups on proteins important for active the regeneration of GSH, the decrease in pump transport and membrane permeability; and (3) activity was irreversibly affected.16 preventing oxidative damage from hydrogen H2O2 is found in the aqueous humor in peroxide (H2O2). humans as well as other species. GSH is in- Considering the first mechanism by volved in detoxifying this reactive oxygen spe- which GSH can protect lenses from opacities, cies to water in a coupled reaction involving there is an increase in high molecular weight NADPH (Figure 2). Without detoxification the (HMW) proteins in cataractous lenses. These peroxide radicals would damage the lens mem- protein aggregates contribute to lens opacity branes and susceptible protein groups. The and are found particularly in dense cataracts. researchers found both normal human and rab- Reddy and Giblin examined x-ray-induced bit lenses with high GSH content were rap- cataracts in rabbits and found increased levels idly able to detoxify H2O2 in culture medium.16 of disulfide bonds, confirming their assertion Lenses pretreated with methyl mercury, which that oxidation of SH groups resulted in disul- decreased the concentration of GSH by 75 fide bond formation and HMW proteins. They percent, were less able to detoxify the perox- also found that SH groups on proteins only ide radicals. become oxidized when levels of GSH drop below some critical level.16 Other researchersPage 144 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  5. 5. Ocular Disorders Figure 2: Metabolism of Hydrogen Peroxide by Glutathione studies have NADP GSH H2O2 quantified (reduced significant glutathione) levels of lutein, zeaxanthin, Glutathione Glutathione and alpha- and reductase peroxidase g a m m a - tocopherol in the lens.21 A pro- NADPH GSSG 2H2O spective study (oxidized glutathione) of the effect of carotenes and vitamin A on the risk of cata- ract formation Other researchers have postulated a was conducted as part of the Nurses’ Health possible diffusion problem. Normally GSH is Study. A total of 77,466 female nurses, ages synthesized and regenerated in the lens cortex 45-71 years, were included in the study, which and then diffuses to other areas of the lens. involved food-frequency questionnaires over Cataracts of the elderly are primarily in the a 12-year period. After other risk factors were nucleus. Researchers examined normal human controlled for, including smoking and age, lenses in vitro and found the older ones ap- those in the highest quintile for consumption peared to have a barrier to diffusion of GSH of lutein and zeaxanthin had a 22-percent de- 19 from the cortex to the nucleus. creased risk of cataract extraction compared with those in the lowest quintile.22 Specific Nutrients and Prevention of Another cohort of the Nurses’ Health Cataracts Study followed 50,823 women, ages 45-67, for eight years and found women in the high- Oxidation of lens proteins is part of the est quintile of vitamin A consumption had a pathophysiology of cataracts. Therefore, it is 39-percent lower risk of developing cataracts no surprise that antioxidants may help prevent compared to women in the lowest quintile.23 the formation of cataracts. In a similar study of male health professionals in the United States, 36,644 Carotenes and Vitamin A: Epidemiological participants, ages 45-75 years, were followed Evidence for eight years with periodic dietary Levels of nutrients, including questionnaires. Men in the highest quintile for carotenoids, have been examined in human lutein and zeaxanthin intake had a 19-percent cataractous lenses after extraction using high decreased risk of cataract extraction when performance liquid chromatography. Vitamins smoking, age, and other risk factors were A and E and the carotenoids lutein and controlled for.24 Neither the women nor the zeaxanthin were found. The newer, epithelial/ men demonstrated a decreased risk of cataract outer cortex layer had more carotenoids, with intakes of other carotenoids (α-carotene, tocopherol, and retinol (approximately 3-, 1.8- β-carotene, lycopene, or beta-cryptoxanthin). , and 1.3-fold higher, respectively) than the It is hypothesized the protective effect of the older, inner cortex/nuclear portion.20 Other carotenoids may be due to quenching reactiveAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 145Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  6. 6. oxygen species generated by exposure to population of healthy volunteers, ages 55-80 ultraviolet light.25 years.31 Although results are still pending, data The Beaver Dam Eye Study examined was collected on prior use of vitamin E and risk for developing nuclear cataracts in 252 incidence of cataract in 1,111 participants. A subjects who were followed over a five-year statistically significant relationship was found period. Only a trend toward an inverse rela- between past vitamin E supplementation and tionship between serum lutein and cryptoxan- prevention of cortical cataract but not nuclear thin and risk of cataract development was cataract.32 noted.26 The Lens Opacities Case-Control Study was designed to determine risk factors Vitamin E: Animal, Epidemiological, and for cataracts in 1,380 participants, ages 40-79 Clinical Studies years. Blood chemistry and levels of vitamin As a fat-soluble antioxidant, it is rea- E and selenium were performed on all patients. sonable to predict a positive role for vitamin The risk of developing cataracts was reduced E as a cataract preventive in the lens cell mem- to less than one-half (odds ratio 0.44 for brane. Animal, epidemiological, and clinical nuclear cataracts) in subjects with higher lev- studies help confirm this hypothesis. A pla- els of vitamin E.33 Some of these same re- cebo-controlled animal study found 100 IU d- searchers examined the association between alpha-tocopherol injected subcutaneously pre- antioxidants and the risk of cataract in the vented ionizing radiation damage to the lens, Longitudinal Study of Cataract. Dietary intake, which did occur in rats not supplemented with use of supplements, and plasma vitamin E lev- vitamin E.27 Two other animal studies using els were assessed on 764 participants. Lens vitamin E instilled in the eyes as drops con- opacities were examined on a yearly basis and firmed the preventive effect of vitamin E, at the risk of development of cataract was 30- least when used topically.28,29 percent less in regular users of a multiple vi- Several human studies have found low tamin, 57-percent less in regular users of levels of vitamin E intake are associated with supplemental vitamin E, and 42-percent less increased risk for cataract development. An is those with higher plasma levels of vitamin epidemiological investigation examined self- E.34 reported supplementary vitamin consumption In a randomized trial of 50 patients of 175 cataract patients compared to 175 with early cataracts, subjects were assigned to matched individuals without cataracts. The receive either 100 mg vitamin E twice daily cataract-free group used significantly more or placebo for 30 days. There was a signifi- vitamin E (p=0.004) and vitamin C (p=0.01) cantly smaller increase in the size of cortical than the cataract group, resulting in at least a cataracts in the vitamin E group compared to 50-percent reduction in cataract risk in the placebo. While increases of vitamin E were supplemented group.30 An Italian study com- found in both nuclear and cortical lens pared 207 patients with cataracts to 706 con- homogenates after surgical removal, GSH lev- trol subjects in a hospital setting. Vitamin E, els were increased significantly only in those in addition to a number of other nutritional with cortical cataracts receiving vitamin E. In factors, was associated with a decreased risk addition, the malondialdehyde (MDA) — a for cataract.8 measure of oxidative stress — levels and glu- The Vitamin E and Cataract Preven- tathione peroxidase levels were higher in cor- tion Study (VECAT) is a four-year, prospec- tical cataract/vitamin E users than in the tive, randomized, controlled trial of vitamin E nuclear cataract/vitamin E group.35 Some con- versus placebo for cataract prevention in a clusions that can be drawn from this study are:Page 146 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  7. 7. Ocular Disorders (1) vitamin E decreases oxidative stress in cata- It is not surprising then that a defi- ractous lenses; (2) part of vitamin E’s protec- ciency of riboflavin has been implicated as a tive effect is due to enhancement of GSH lev- cause of cataract formation. A study of B vita- els; and (3) vitamin E seems to be more pro- min nutritional status of cataract patients tective for cortical than nuclear cataracts, at (n=37) compared to age-matched controls least in this short-term study. without cataract (n=16) found that 80 percent of those with cataracts and only 12.5 percent Vitamin C and Risk of Cataracts of control subjects had a riboflavin defi- Animal experimentation has shed ciency.41 The same researcher tested for, but some light on ascorbic acid and its role in cata- did not find, a deficiency of thiamin or pyri- ract formation. Cataracts induced in chick doxine in cataract patients. Other researchers embryos by the application of hydrocortisone have found a relationship between riboflavin were prevented by the introduction of vitamin deficiency and later-stage cataracts, but not in C to the developing embryo. In addition, vita- early cataract formation.42 The Lens Opacities min C slowed the decline in GSH levels, which Case-Control Study found that lens opacities occurred with the cortisone treatment.36 were associated with lower levels of ribofla- Ascorbic acid is normally found in vin which were assessed by RBC enzyme as- high concentrations in the aqueous humor and says and dietary intake reports. lens in humans. A group of 44 subjects were Data collected during cancer interven- supplemented with 2 g daily ascorbic acid. tion trials in Linxian, China, were assessed for Significant increases in vitamin C in lens, nutrient effects on other conditions, including aqueous humor, and plasma were noted.37 In cataracts. Two randomized, double-blind, con- another study, lenses were exposed in vitro to trolled studies of cataract risk resulted from light, which caused an increase in superoxide the Linxian study. In the first trial 12,141 par- radicals and subsequent damage to the Na+/ ticipants, ages 45-74, were supplemented for K+ pump. The damage was prevented by ad- five to six years with either a multiple vita- dition of vitamin C in doses comparable to min-mineral or placebo. There was a statisti- what would be found in the aqueous humor.38 cally significant 36-percent reduction in inci- In the Nurses’ Health Study supple- dence of nuclear cataract for subjects ages 65- mental vitamin C for a period of 10 years or 74 years given the multiple vitamin. In the greater was associated with a 77-percent lower second trial 23,249 participants were given one incidence of early lens opacities and an 83- of four different vitamin/mineral combina- percent lower incidence of moderate lens tions: (1) retinol/zinc, (2) riboflavin/niacin, (3) opacities. In this study, no significant protec- ascorbic acid/molybdenum, or (4) selenium/ tion was noted from vitamin C supplementa- alpha-tocopherol/beta carotene. Again, the tion of less than 10 years.39 most significant effect was noted in people age 65-74, with a 44-percent decrease in nuclear Riboflavin cataract risk in the group taking riboflavin/nia- Riboflavin is a precursor to flavin ad- cin (3 mg riboflavin/40 mg niacin). No sig- enine dinucleotide (FAD), which is a coen- nificant protection was noted for the other zyme for glutathione reductase. In vitro evalu- nutrient combinations or for protection from ations of surgically removed cataracts have cortical cataracts.43 confirmed inactivity of glutathione reductase A series of case reports from the Uni- enzyme activity in a significant number of versity of Georgia treated 24 cataract patients cataracts examined. Furthermore, the activity (18 with lens opacities and six with fully-de- was restored by the addition of FAD.40 veloped cataracts) with 15 mg riboflavin daily.Alternative Medicine Review x Volume 6, Number 2 x 2001 Page 147Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  8. 8. Dramatic improvement was reported within butter, total fat, salt, and oil (except olive oil).8 24-48 hours, and after nine months all lens The Nurses’ Health Study found regular con- opacities disappeared.44 Larger, double-blind, sumption of spinach and kale was moderately placebo-controlled trials are needed to confirm protective for cataracts in women.22 The Health these seemingly dramatic improvements. Professionals Follow-up Study found spinach and broccoli decreased risk of cataract in Other B Vitamins men.24 Pantethine is the active coenzyme form of pantothenic acid (vitamin B5). Several ani- Bilberry and Cataracts mal studies have found pantethine can prevent Vaccinium myrtillus or bilberry has a chemically-induced cataracts if given within long history of use for various eye conditions. eight hours of exposure to lens insult.45-47 The The active components, flavonoid proposed mechanism of action was the pre- anthocyanosides, are potent antioxidants with vention of the formation of insoluble proteins a particular affinity for the eye and vascular in the lens.45 tissues. The anthocyanosides are typically con- Folic acid has been found to be low in centrated in a 25-percent standardized extract. those prone to cataracts. An Italian epidemio- In a report of 50 patients with senile cataracts, logical survey found those in the highest a combination of bilberry, standardized to con- quintile for folic acid consumption were only tain 25-percent anthocyanosides, (180 mg 40 percent as likely to develop cataracts than twice daily) and vitamin E, in the form of dl- those in the lowest quintile.8 tocopheryl acetate, (100 mg twice daily) for four months stopped the progression of cata- Selenium and Cataracts racts in 96 percent of the subjects treated A decrease in glutathione peroxidase (n=25) compared to 76-percent in the control activity has been found in the lenses of sele- group (n=25).50 nium-deficient rats. Concomitantly, an in- crease in MDA and free radicals was also noted Melatonin in both the selenium-deficient and vitamin-E The pineal hormone, melatonin, is a deficient groups.48 Evaluation of selenium lev- potent antioxidant and because of its known els in humans has found lower than normal antioxidant effects, several animal studies have levels of selenium in sera and aqueous humor been conducted to determine its effect on pre- in cataract patients.49 The significance of low vention of cataracts. Injections of melatonin serum levels is unclear and the relationship have been found to inhibit both chemical- and between selenium and cataract risk demands UVB-induced cataracts.51-53 In the UV-B and further evaluation. melatonin study cataract formation and MDA levels were significantly lower than the UV-B Dietary Factors in Cataract Risk only group, leading the researchers to con- Several epidemiological studies have clude, “These results suggest that melatonin found dietary links to increased or decreased may protect against the UVB-induced cataract risk of cataract. An Italian in-hospital study development by directly quenching lipid per- examined dietary patterns and incidence of oxides and indirectly by enhancing the pro- cataract extraction. Significant inverse rela- duction of the endogenous antioxidant GSH.”51 tionships were seen between meat, spinach, In studies examining chemically-in- cheese, cruciferous vegetables, tomatoes, pep- duced cataracts, the animals were administered pers, citrus fruits, and melon. An increased risk buthionine sulfoxamine (BSO), a known in- was found in those with the highest intakes of hibitor of GSH synthesis. Half were treatedPage 148 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  9. 9. Ocular Disorders with melatonin and half were not. In one study, Flavonoids as Aldose Reductase Inhibitors 18/18 rats given BSO alone developed cata- A number of compounds, both natural racts compared to only 1/15 in the group and synthetic, have been found to inhibit al- treated with melatonin.52 In the other study, dose reductase. These so-called aldose reduc- 16/18 in the BSO-only group developed cata- tase inhibitors (ARIs) bind to aldose reduc- racts, whereas only 3/18 treated with melato- tase, inhibiting polyol production.54 As a group, nin developed cataracts.53 The researchers flavonoids are among the most potent natu- were unsure whether the protection was due rally occurring ARIs. Several evaluations of to a direct free-radical scavenging effect or to in vitro animal lenses incubated in high sugar a stimulation of GSH production by melato- mediums have found flavonoids to inhibit al- nin. dose reductase.55,56 A group of researchers examined the Diabetic (Sugar) Cataracts effect of an orally administered ARI in inhib- Polyol Accumulation iting polyol accumulation. They reported the Some of the mechanisms involved in arrest of cataracts in galactosemic rats by oral the formation of diabetic cataracts are some- feeding of a synthetic ARI.57 Building on this what different from senile research, another group studied the effect of a cataracts. The accumula- tion of polyols within the lens is a primary contrib- uting factor. Certain tis- Figure 3: The Polyol Pathway sues of the body, including the lens of the eye, do not require insulin for glucose Aldose or other simple sugars Reductase such as galactose to enter. D-Glucose D-Sorbitol In diabetes sugar is in high concentrations in the aque- ous humor and can diffuse NADPH NADP+ NAD+ passively into the lens. The + H+ enzyme aldose reductase within the lens converts Sorbitol glucose to sorbitol or ga- Dehydrogenase NADPH lactose to galactitol (Fig- + H+ ure 3). These polyols can- not diffuse passively out of the lens and accumulate or D-Fructose are converted to fructose. The accumulation of polyols results in an os- motic gradient, which encourages diffusion of fluids from the aqueous humor. The water flavonoid ARI, quercetrin (a glycoside of quer- drags sodium with it and the swelling and elec- cetin). Rats were divided into two groups, one trolyte imbalances result in cataract formation. receiving lab chow only, while the experimen- tal group was fed quercetrin in rat chow plusAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 149Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  10. 10. Table 1: The Aldose Reductase Inhibitor Activity of Some Flavonoids.60 comparable (average 380 mg/100 mL), had not developed cataracts by the 25th day.58 A French study examining the ef- Molar Percent fect of oral doses of quercetin did not find Flavonoid Concentration Inhibition an inhibition of cataract formation in dia- -4 Quercetrin-2-acetate 10 100 betic animals.59 In the positive study -5 10 100 -6 100 quercetrin rather than quercetin was used, 10 10 -7 87 the former administered in a water sus- pension which was undoubtedly more ab- -4 Quercetrin 10 100 sorbable. The latter study was in French -5 10 95 -6 88 with only the abstract available so a dos- 10 10 -7 55 age comparison was not possible. Varma and associates performed -4 Quercetin 10 100 an in vitro experiment to determine which -5 10 83 -6 60 aspects of flavonoids conferred the most 10 10 -7 15 ARI activity, and ultimately which fla- vonoids were the most potent in that re- -4 Rutin 10 95 spect.60 Their earlier more limited research -5 10 95 -6 20 had found quercetin, quercetrin, and 10 10 -7 10 myricitrin to possess the most potent ARI activity.56 -4 Hesperidin 10 88 In the more recent experiment 44 -5 10 10 -6 0 flavonoids and their derivatives were ex- 10 10 -7 0 amined for the ability to inhibit aldose reductase and polyol accumulation in rat -4 Hesperidin chalcone 10 82 lenses incubated in the sugar xylose. All -5 10 10 -6 0 flavonoids tested exhibited some inhibi- 10 10 -7 0 tory activity. The two most potent inhibi- tors were derivatives of quercetin, -4 Naringin 10 80 quercetrin and quercetrin-2-acetate, the -5 10 59 -6 0 latter the most potent ARI inhibitor 10 10 -7 0 known. Table 1 demonstrates some of the most common commercially available fla- vonoids and their comparative inhibitions. In decreasing order of potency they in- clude quercetin, rutin, hesperidin and hes- an additional 70 mg oral quercetrin daily in peridin chalcone, and naringin. Although in- aqueous suspension. Three days after begin- hibition was also noted by isoflavones, cat- ning flavonoid supplementation diabetes was echins, coumarins, and anthocyanins, they chemically induced and three days later lenses were found to be much less potent than fla- were assessed for sorbitol and fructose. The vones. When dissolved, flavones easily con- flavonoid group demonstrated a 50-percent vert to their corresponding chalcone by the inhibition of sorbitol and fructose accumula- opening of the center or B-ring of the flavone tion. The control group developed cataracts by structure. Because this may occur in vivo as the tenth day, whereas the group receiving well, the researchers tested hesperidin and quercetrin, although their blood sugar was hesperidin chalcone and found their inhibitoryPage 150 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  11. 11. Ocular Disorders potencies were nearly identical (Table 1). The to halt progression of diabetic cataracts despite chalcones, being more water-soluble and thus sorbitol, glucose, and fructose accumulation.64 more absorbable, may represent a more logi- cal means of oral administration. In their re- Lipoic Acid view Varma and associates outline a number In both in vitro lenses incubated in a of structural factors contributing to ARI activ- glucose medium and in diabetic animal mod- ity. In the final analysis, the pentahydroxy (five els, lipoic acid (LA) has been found to pre- OH groups) flavones conferred the most po- vent cataract formation.65 Lipoic acid has po- tent effect. tent antioxidant effects in both its oxidized form (LA) and reduced form, dihydrolipoic Vitamin C acid (DHLA). It is this property which un- Ascorbic acid also has potential as an doubtedly is responsible for much of its pro- aldose reductase inhibitor. An experiment was tective effect in diabetic cataracts. Packer, one conducted in which guinea pigs were fed a of the foremost researchers on lipoic acid, hy- normal, high vitamin C diet with 10-percent pothesizes that LA enters the lens (via a fatty galactose or a scorbutic diet (devoid of vita- acid carrier) and is converted to DHLA. DHLA min C) plus 10-percent galactose. The lens has the potential to regenerate ascorbic acid epithelium of scorbutic animals had 2.5 times from ascorbyl radicals; the ascorbic acid can as much galactitol (the polyol of galactose) on then regenerate vitamin E from tocopheryl day 4 than those animals fed vitamin C in their radicals. Alternately, he hypothesized LA diets.61 could directly spare vitamins C and E. The A human study, although not on cells increases in vitamins C and E would result in of the lens, found oral vitamin C at low doses decreased utilization of GSH and a relative of 100-600 mg daily was able to normalize increase in its levels in the lens.63 Due to its sorbitol levels in red blood cells within 30 days antioxidant effects and sparing of GSH and in individuals with type 1 diabetes.62 vitamins E and C, lipoic acid has been found to prevent chemically-induced, non-diabetic Oxidative Stress and Diabetic cataracts in animal models as well.65 Cataracts Another mechanism by which lipoic acid may prevent cataracts in diabetes is via As with senile cataracts, oxidative inhibition of aldose reductase, which was de- stress plays an important role in the pathogen- termined in an in vitro experiment.66 The re- esis of diabetic cataracts. Levels of glutathione searchers also noted the ability of aldose re- peroxidase and vitamin C have been found to ductase inhibitors, including lipoic acid, to be deficient in the lenses of diabetics. Lenses chelate transition metals such as copper. This of humans with diabetes were found to be more may be another way by which ARIs prevent susceptible to oxidation of proteins, a condi- cataracts and other complications of diabetes. tion exacerbated by concurrent retinal dis- ease.63 Protein Glycosylation/AGE Glutathione in Diabetic Cataracts Generation in Diabetic Cataracts Evidence of other mechanisms at work While glycosylated proteins (proteins besides sorbitol accumulation is offered by the with glucose attached) and subsequent forma- work of Ross et al. They found that GSH, ei- tion of AGE have been implicated in many ther in vitro in lens incubation medium or in diabetic complications, there is disagreement vivo when injected into diabetic rats, was able as to how much they contribute to diabetic orAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 151Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  12. 12. Table 2: Nutrients and Botanicals for the Prevention and Treatment of Cataracts and ultimately prevented cataract Supplement Mechanism of Action formation. 67 In vitro studies have Glutathione Deficiency noted in cataractous lenses; important component also found lipoic of the innate antioxidant system in the lens acid prevents Vitamin A Higher levels associated with a decreased risk for cataract p r o t e i n glycosylation, Carotenes Antioxidant; higher levels associated with decreased risk for providing yet (Lutein and cataract Zeaxanthin) a n o t h e r mechanism Vitamin E Antioxidant; increases glutathione; supplementation whereby LA may associated with prevention p r e v e n t Vitamin C Preserves glutathione levels; protects the Na+/K+ pump; cataracts.72 long-term supplementation (>10 years) protective Table 2 Riboflavin Precursor to FAD, a coenzyme for glutathione reductase summarizes po- which recycles GSH tential nutritional Bilberry Anthocyanoside antioxidants; study with vitamin E halted and botanical cataract progression treatments for cataracts. Quercetin Aldose reductase inhibitor – diabetic cataracts Lipoic Acid Spares vitamins C and E, increasing GSH levels; inhibits Chronic aldose reductase and prevents protein glycosylation – diabetic cataracts Open-Angle Glaucoma Currently, there are approxi- galactosemic cataracts. Some researchers have mately two mil- found increased levels of glycosylated proteins lion cases of glaucoma in the United States, and AGE associated with diabetic cataracts,67,68 but due to its insidious nature, only half may while others have not found a strong correla- be diagnosed.4 Chronic open-angle glaucoma tion.69,70 is the most common type, accounting for 60- Despite the controversy, several natural 70 percent of cases. It is the leading cause of substances that inhibit protein glycosylation blindness among African Americans2 and the have been found to attenuate cataract second leading cause of blindness in the U.S. formation in vitro and in animal models. population as a whole.4 Another type, acute Acetyl-L-carnitine, which has been found to angle-closure glaucoma, is a medical emer- be lower than normal in the lens of diabetic gency and will not be addressed here. Glau- animals, was found in calf lenses in vitro to coma is characterized by a neuropathy of the inhibit formation of glycosylated proteins by optic nerve, usually due to increased intraocu- 42 percent and AGE formation by 70 percent.71 lar pressure (IOP). The increased pressure is The proteins became acetylated instead, due to an obstruction in the normal outflow of preventing glucose from attaching. Pyruvate, fluids from the aqueous humor, with most of a normal tissue metabolite, given orally to the outflow normally occurring in the anterior diabetic rats decreased protein glycosylation chamber angle (Figure 4).Page 152 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  13. 13. Ocular Disorders Figure 4: Flow of Fluids in the Eye Aqueous humor Iris Trabecular Canal of Schlemm meshwork Flow of fluid Lens Ciliary body Vitreous Diffusion of fluid humor and other constituents Optic nerve Patients may complain of missing words on Diagnosis and Risk Factors reading or having trouble driving due to poor Although IOP screening is one factor peripheral vision. in diagnosing glaucoma, it is a fairly insensi- Risk factors for the development of tive test. Normal IOP ranges from 7-22 mm/ glaucoma include increased intraocular pres- Hg; however, approximately 90 percent of sure, older age, family history, being of Afri- people with IOPs greater than 22 mm/Hg never can American descent, diabetes, hypertension, develop glaucoma. On the other hand, some and myopia.4 Drugs associated with an in- people with normal IOPs do develop optic creased incidence of glaucoma include corti- nerve injury and glaucoma.4 Ophthalmoscopic costeroids and cholesterol-lowering drugs. As examination may reveal an enlarged cup within an aside, the use of scopolamine (often used the optic disc. If glaucoma is suspected or if by those going on a cruise to prevent seasick- the patient is at high risk for developing glau- ness) can result in acute, angle-closure glau- coma, referral to an optometrist or an ophthal- coma. mologist for further evaluation is essential. Physical symptoms are usually absent in early stages. Once atrophy of the optic nerve Pathophysiology has progressed, loss of peripheral vision oc- Normally aqueous humor is produced curs first; central vision is the last to be lost. in the ciliary processes and flows past the lens, through the pupil, and into the anteriorAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 153Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  14. 14. chamber. Outflow occurs through the angle Other researchers, examining human post- between the cornea and the iris, through a trabeculectomy specimens (surgical procedure meshwork of trabeculae, to the canal of for relieving increased IOP), have found evi- Schlemm (Figure 4). The canal of Schlemm dence of a possible increase in collagen break- is actually a very thin-walled vein that down in glaucoma.79 surrounds the entire eye. Because of its porous Reduced antioxidant defense systems nature, large molecules are able to diffuse into are also evident in early stage glaucoma. Much the canal and, although it is a vein, it carries of the research on the connection between an- aqueous humor, not blood. Aqueous humor is tioxidants and glaucoma has been conducted continually being formed and reabsorbed, and in Russia and published in Russian language it is this balance between formation and journals, requiring dependence on abstracts. reabsorption that regulates IOP.73 Levels of sulfhydryl groups, a reflection of The pathological processes involved in glutathione levels, were found to be signifi- chronic glaucoma are not completely under- cantly lower in the aqueous humor of patients stood. It appears that morphological changes with glaucoma, particularly advanced stages in collagen structure may precede increased of the disease, when compared to normal con- IOP. Glycosaminoglycans (GAGs) contribute trol subjects. Red blood cell GSH levels were to the filtration barrier. Within the trabecular also found to be lower in later stage glaucoma meshwork is an area called the juxtacanalicular patients.80 Deficiencies of sulfhydryl groups tissue (JCT), which is the probable site of im- have also been found in the lacrimal fluid of pedance to aqueous outflow in glaucoma. Re- later stage glaucoma patients.81 In line with the searchers have compared the GAG content of evidence of decreased antioxidant defense sys- the JCT in normal and glaucomatous eyes and tems in glaucomatous eyes is the finding of have found some significant differences. In one an increase in the lipid peroxidation product study GAG content of five eyes from normal MDA – more than twice the normal level – in donors was compared to five with glaucoma. the anterior chamber of patients with glau- A significant decrease in hyaluronic acid and coma.82 increase in chondroitin sulfate was found in In some patients, particularly those the eyes of patients with glaucoma.74 A simi- with normal IOP, an inadequate blood supply lar study found trabecular meshwork of glau- to the optic nerve may be contributing to dam- comatous eyes had a 77-percent lower level age and vision loss. These patients have a of hyaluronic acid with higher levels of chon- higher than normal incidence of migraines, droitin sulfates in trabecular meshwork, iris, suggesting vasospasm as an etiology.4 ciliary body, and sclera of eyes with glaucoma compared to normal donors.75 The research- Conventional Treatment ers postulated that the ability of normal aque- The goal of conventional treatment is ous outflow is regulated by the content of to decrease intraocular pressure to avoid GAGs and their ability to form a highly vis- damage to the optic nerve. There are a number cous, elastic gel-like substance which acts as of topical medications used, including a filtration system.76 Maintaining a critical cholinergic agonists, cholinesterase inhibitors, level of hyaluronic acid appears to be essen- carbonic anhydrase inhibitors, adrenergic tial for maintaining a well hydrated, semi-per- agonists (the newer ones are α2-selective), β- meable meshwork.77 In vitro research on hu- blockers, and prostaglandin analogs. Osmotic man eyes has found a decrease in GAG syn- diuretics are also used orally or IV.4 Laser thesis, particularly hyaluronic acid, in glau- treatment may be tried instead of medications; comatous eyes compared to normal eyes.78 and surgical intervention is usually a last resortPage 154 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  15. 15. Ocular Disorders Table 3: Conventional Glaucoma Medications and Their Potential Side Effects4,83 Drug Category Drug Side Effect Beta-blockers timolol, levobunolol, bronchospasm, shortness of breath carteolol, metipranolol, fatigue, confusion, depression, betaxolol impotence, hair loss, heart failure, bradycardia. Timolol has also been found to decrease HDL levels and adversely effect the total cholesterol:HDL ratio in women 60 years and older84 Non-selective Adrenergic epinephrine, dipivefrin high incidence of allergic or toxic Agonists reactions α2-Selective Adrenergic apraclonidide high rate of allergic reactions, Agonists tachyphylaxis brimonidine dry mouth but less likely to cause allergic reactions Cholinergic Agonists carbachol detached retina, GI disturbances, headache, frequent urination pilocarpine hypertension, tachycardia, bronchial spasm Cholinesterase Inhibitors physostigmine, The latter three in the list cause neostigmine, irreversible rather than reversible demecarium, miosis; they may be cataractogenic; echothiophate iodide, increase risk of retinal detachment. isoflurophate Carbonic Anhydrase acetazolamide, fatigue, anorexia, depression, Inhibitors methazolamide, paresthesias, electrolyte abnormalities, (oral, IV, topical) dichlorphenamide, kidney stones, blood dyscrasias ethoxzolamine dorzolamide topical so does not have the side effects of the others Prostaglandin Analog latanoprost increased pigmentation of the iris; worsening of uveitis strategy but may be used initially in patients common side effects of glaucoma medications who do not tolerate medications. Some are listed in Table 3.4,83Alternative Medicine Review x Volume 6, Number 2 x 2001 Page 155Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  16. 16. Potential Nutrient Deficiencies in Nutrients that Effect GAGs: Vitamin C and Glaucoma Glucosamine Sulfate Deficiencies of specific nutrients have Due to the morphological changes seen been found in patients with glaucoma, and in collagen structures associated with glau- supplementation may play a role in treatment. coma it seems logical to explore the effect of nutrients known to exert specific influences Thiamin on GAGs. Vitamin C has probably been re- Thiamin (vitamin B1) has been found searched more than any one single nutrient in to be deficient in some patients with glaucoma. the treatment of glaucoma. Researchers seem Blood levels and dietary intakes of both vita- to be in disagreement as to whether people with mins C and B1 were examined in 38 patients glaucoma tend to have an ascorbate defi- with glaucoma and compared to 12 controls. ciency.85,88 However, there is convincing re- The glaucoma patients demonstrated a signifi- search on its effectiveness in treating glau- cantly lower level of thiamin (but not vitamin coma. C), which was not a reflection of decreased Researchers first examined the effect intake causing the researchers to postulate an of high dose IV vitamin C on animals and then impaired absorption of thiamin in these pa- humans, and found it successfully decreased tients.85 As thiamin deficiency has been asso- IOP. IV doses used were in the range of 1 g/kg ciated with degeneration of ganglionic cells body weight; oral doses used were half that of the brain and spinal cord, the researchers (500 mg/kg body weight).89 A total of 49 eyes postulated a possible degeneration of the op- were treated, 25 with chronic open-angle glau- tic nerve as well. coma. The others included acute glaucoma, hemorrhagic glaucoma, and glaucoma second- ary to another disease process. Those with Chromium chronic open-angle glaucoma responded the A deficiency of chromium has been most dramatically. Table 4 shows the average implicated in increased IOP in humans and drops in IOP two hours and 4-5 hours after a those afflicted with primary open-angle glau- single dose of ascorbate. The higher the ini- coma have demonstrated decreased erythro- tial IOP, the greater the drop after ascorbate. cyte chromium levels.86 In eyes with normal IOP, the average drop in pressure was 3.5 mmHg. Decreases in pres- Intervention Trials of Specific sure were maintained for as much as eight Nutrients in Glaucoma hours. Due to the almost universal side effect Vitamin B12 of gastric upset and diarrhea from such high While a deficiency of vitamin B12 has doses of vitamin C, the researchers studied the not been implicated in glaucoma, such a defi- effect of divided daily doses (0.1-0.15 g/kg 3- ciency may cause optic atrophy and visual field 5 times daily). All but one patient experienced defects which mimic glaucoma. An open trial decreased IOP during a two-week trial of di- of 5 mg B12 daily in glaucoma patients found vided doses and most experienced mild gas- no change in IOP with supplementation. How- tric upset and diarrhea that disappeared after ever, there was no progression of visual field 3-4 days. Use of IV vitamin C would have al- loss during five years of follow-up.87 leviated the gastric upset and diarrhea. Some patients who had previously been resistant to conventional drug therapy were able to main- tain normal IOPs with the vitamin C regimen.Page 156 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  17. 17. Ocular Disorders Table 4: Decreases in IOP after Oral Ascorbic Acid at 0.5 mg/kg body weight89 Average Pressure Average Pressure Initial IOP Decrease at 2 Hours Decrease at 4-5 Hours 50-69 mmHg 16 mmHg 25 mmHg 32-49 mmHg 14 mmHg 19 mmHg 20-31 mmHg 6.5 mmHg 6.5 mmHg A previous study of oral ascorbate did seems warranted, not only to prevent poten- not find it effective at lowering IOP in glau- tial harm but to monitor potential benefits of coma. The researchers, however, used only 500 this supplement. Double-blind studies to con- mg twice daily. These same researchers suc- firm the potential benefit of GS in glaucoma cessfully lowered IOP with topical use of a are needed. 10-percent aqueous solution of vitamin C.90,91 There are several postulated mecha- Magnesium in the Treatment of Glaucoma nisms for ascorbate’s ability to lower IOP. In Caused by Vasospasm high doses it acts as a potent osmotic agent.88 A subcategory of glaucoma patients Vitamin C’s ability to halt lipid peroxidation with normal IOP – those for which optic nerve has also been hypothesized to play a role.88 damage is caused by vasospasm leading to Vitamin C has also been found, in vitro, to decreased blood supply to the optic nerve – stimulate synthesis of hyaluronic acid in tra- may benefit from supplemental magnesium. becular meshwork from glaucomatous eyes.78 This patient group is often treated with cal- Ascorbate has also been found to reduce the cium channel blocker drugs. These drugs, viscosity of hyaluronic acid and increase out- however, are not without side effects, includ- flow through the trabeculum.92 ing leg and periorbital edema. Ten patients, Based on the observation that open- six with open-angle glaucoma and four with angle glaucoma may be due in part to a hyalu- normal-tension glaucoma, were supplemented ronic acid deficiency, a researcher has postu- with magnesium, a natural calcium channel lated a beneficial effect of glucosamine sul- blocker.94 All patients in this preliminary open fate (GS) for the treatment of glaucoma.93 He trial suffered from cold-induced vasospasms cites two case reports in which glaucoma pa- of the extremities and all had marked visual tients given 3 g/day GS for osteoarthritis re- field deficits, despite normal or drug-normal- ported substantial drops in IOP. Because glu- ized IOP. Each subject received 121.5 mg cosamine sulfate is also a substrate for chon- magnesium twice daily for one month. At the droitin sulfate, which has been found to be el- end of four weeks there was a non-statistically evated above normal in the trabecular mesh- significant trend toward improvement in vi- work in glaucoma patients, it would seem to sual field tests (eight improved and two dete- have the possible potential of further aggra- riorated, one because of a cataract). While it vation of the condition. While this author has is tempting to assume magnesium can improve not heard reports of exacerbation with glu- blood supply to the optic nerve by dilating the cosamine sulfate, close monitoring of IOP in optic blood vessels, a larger, placebo-con- patients with glaucoma supplemented with GS trolled trial of this subpopulation sufferingAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 157Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  18. 18. from glaucoma and vasospasm seems war- melatonin secretion, resulted in a blunting of ranted. the usual early-morning fall in IOP. Administration of 200 mcg melatonin to half Antioxidants in Glaucoma of the bright-light group resulted in a Low glutathione levels may contrib- significant drop in IOP within an hour; the ute to some of the pathological processes seen effect lasted up to four hours. This experiment in glaucoma. Supplementation of lipoic acid may have important implications, not only for can increase glutathione in red blood cells80 possible treatment of glaucoma with and lacrimal fluid81 of patients with glaucoma. melatonin, but also in regard to timing of In a Russian controlled trial of lipoic acid, 45 medications. It should also be noted that beta- patients with stage I and II glaucoma were blockers, sometimes used for treatment of supplemented with either 75 mg (n=26) or 150 glaucoma, decrease melatonin levels. One mg (n=19) for two months. A control group of researcher found topical use of the beta- glaucoma patients (n=31) were given only lo- blocker, timolol, did not work as well in the cal hypotensive medication. Improvement in evening.100 visual function was seen in approximately 45 percent of subjects supplemented with lipoic Coenzyme Q10 May Prevent acid.95 As mentioned previously, vitamins C Cardiac Side Effects of Timolol and E are also glutathione sparing. The issue The beta-blocker medication timolol of oral supplementation of glutathione is a may have significant cardiac side effects, in- controversial one with some researchers con- cluding bradycardia and heart failure.4 Sixteen tending oral doses of GSH are not effective at glaucoma patients on topical timolol were raising plasma and tissue levels of GSH. How- given 90 mg CoQ10 for six weeks. CoQ10 ever, both animal96,97 and human98 studies have delayed the appearance of negative inotropic found oral doses of glutathione lead to in- effects, including bradycardia, associated with creased plasma and tissue levels. timolol, preventing the negative cardiac effects of the drug without interfering with its effect Melatonin and Diurnal Rhythms in on IOP.101 Intraocular Pressure Intraocular pressure normally varies Omega-3 Fatty Acids throughout the day, with the lowest pressure Epidemiological and animal studies occurring in the very early morning hours. IOP point to a possible protective effect of omega- also parallels fluctuations in cortisol levels, 3 fatty acids in glaucoma. Both topical admin- high cortisol conferring higher IOPs. Diurnal istration of prostaglandin E3 and D3 – end variations in IOP are more pronounced in products of omega-3 fatty acid metabolism – people with glaucoma (>10 mmHg) compared and IM injections of cod liver oil – high in to 3-7 mmHg variations in non-glaucomatous omega-3 fatty acids – led to decreased IOP in eyes. Because melatonin levels peak around 2 rabbits.102,103 Epidemiological evidence has a.m., a time when IOP is on a downward trend, found a low prevalence of chronic open-angle researchers studied its effect on IOP.99 A series glaucoma among Eskimos on a native diet high of experiments on subjects with normal IOPs in omega-3 fatty acids.104 These studies have and no diagnosis of glaucoma were conducted. led researchers to consider the potential for Baseline IOPs showed maximum pressures omega-3 fatty acids in the prevention and treat- from 4-6 p.m. and minimum pressures from ment of glaucoma. Further investigation is 2-5 a.m. In the first experiment, exposure to warranted. bright light, which suppressed normalPage 158 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  19. 19. Ocular Disorders Botanical Treatment of Glaucoma supplementation. Subjects crossed over to the There are several botanicals that may other treatment after a two-week washout pe- hold promise for the treatment of glaucoma. riod. Ginkgo significantly increased blood Most studies are merely preliminary, and flow to the ophthalmic artery with no change larger, controlled studies are needed. seen in the placebo group.107 Although Ginkgo did not alter IOP, it may provide potential ben- Vaccinium Myrtillus (bilberry) efit in glaucoma patients who suffer from de- Vaccinium myrtillus holds promise in creased ocular blood flow. the treatment of glaucoma, although there has been just one very limited study. Eight patients Coleus Forskohlii with glaucoma were given a single dose of 200 The triterpene forskolin from the plant mg anthocyanosides from bilberry (most ex- Coleus forskohlii stimulates the enzyme ade- tracts are 25-percent anthocyanosides so as- nylate cyclase.108 Adenylate cyclase then suming this standardization was used, the pa- stimulates the ciliary epithelium to produce tients were given 800 mg bilberry standard- cyclic adenosine monophosphate (cAMP), ized extract). Electroretinography improve- which in turn decreases IOP by decreasing ments were noted.105 Due to the fact that the aqueous humor inflow.109 article is in Italian, further details are unavail- Results of studies using topical able. While this evidence is very preliminary, forskolin applications to decrease IOP have it is not unreasonable to imagine the been mixed. A study of 2-, 1-, and 0.5-percent anthocyanosides’ collagen-stabilizing effect forskolin solutions applied to the eyes of nor- exerting a positive effect on the trabecular mal rabbits found significant, dose-dependent meshwork, facilitating aqueous outflow. decreases in IOP within a half hour, peaking Anthocyanosides also exert potent antioxidant in 2-3 hours, and lasting up to 10 hours.110 On effects. the other hand, a 1-percent forskolin solution failed to significantly decrease IOP in glauco- Ginkgo Biloba matous monkeys after two days of treatment.111 Forty-six patients, some with severe To date, human studies on forskolin’s visual field disturbances, and some with seri- effect on IOP have been limited to healthy ous retinal vascular degeneration, were given volunteers. Several studies have found it ef- 160 mg/day Ginkgo extract for four weeks, fective at lowering IOP and decreasing aque- then 120 mg/day. Progress was assessed ous outflow in this population. Meyer et al monthly by measuring visual acuity, visual compared the effect of 1-percent forskolin fields, fundoscopic exam, IOP, blood pressure, versus placebo in 10 healthy volunteers in a and pulse rate. Although only mild improve- randomized, crossover trial. In the first study, ments were noted, these were deemed relevant both the placebo group and the forskolin group due to the severity of the ocular damage at the experienced a decrease in IOP, which was at- beginning of the study.106 tributed to the local anesthetic oxybuprocaine. A potential therapeutic effect of a In the second trial, proxymetacaine was used Ginkgo extract for the treatment of glaucoma as the topical anesthetic and forskolin was was evaluated in a phase I, placebo-controlled, found to significantly decrease IOP compared crossover trial in 11 healthy volunteers. Sub- to placebo.112 jects were treated with either 40 mg Ginkgo In 20 healthy volunteers one dose of a extract three times daily or placebo for two 1-percent forskolin solution had no effect, days. Ocular blood flow via Color Doppler whereas two instillations five minutes apart led Imaging was measured before and after to significant decreases in IOP and aqueousAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 159Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  20. 20. Table 5: Potential Nutrient and Botanical Approaches to Glaucoma Supplement Route of Administration Mechanism Vitamin C IV or oral Osmotic agent; enhance hyaluronic acid synthesis and reduce its viscosity Vitamin B12 Oral or IM Correct a deficiency which may cause optic nerve atrophy Lipoic acid Oral Antioxidant; increase glutathione levels Magnesium Oral May decrease vasospasm and increase blood supply to the optic nerve Melatonin Oral Normal diurnal rhythms of IOP fluctuation reflect melatonin rhythms; antioxidant CoQ10 Oral Prevent cardiac side effects of timolol Bilberry Oral Anthocyanosides exert antioxidant and collagen stabilizing effect Ginkgo Oral Increase blood flow to the ophthalmic artery and ultimately to the optic nerve forskolin Topical eye drops Decrease IOP by stimulation of cAMP Salvia IM or IV Increase microcirculation to the retinal miltiorrhiza ganglions, improving visual acuity and visual fields flow rate.113 In eight healthy subjects one drop While topical use of forskolin in of forskolin significantly decreased IOP and animals and healthy humans appears flow rate was diminished an average of 34 promising, clinical studies on its use in percent.114 Another study, however, did not find glaucoma patients are lacking. Furthermore, forskolin to have a significant effect at decreas- while oral standardized extracts of Coleus ing flow rate in a group of 15 healthy volun- forskohlii are known to raise cAMP as its teers given one dose of 1-percent forskolin in mechanism of action in various disease each of three situations: during the day, at night conditions, it is not clear whether oral dosages while sleeping, and following pretreatment have any effect on cAMP levels in the eye. with timolol.115 More research on this important topic isPage 160 Alternative Medicine Review x Volume 6, Number 2 x 2001Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
  21. 21. Ocular Disorders needed. Forskolin eye drops are available already existing cataracts. Maintaining normal through compounding pharmacies. glutathione levels seems of utmost importance in prevention of cataracts. Nutrients such as Salvia Miltiorrhiza lipoic acid, vitamins C and E, and selenium Salvia miltiorrhiza is a commonly used increase glutathione levels or act as co-factors botanical in Chinese medicine. Injected IV this for glutathione-dependent enzymes. Since botanical appears to improve microcirculation prevention of lens opacities is easier than of the retinal ganglion cells. Two experiments treating already existing cataracts, use of these on rabbits found it protected the optic nerve and other antioxidants to prevent cataracts from the damaging effects of increased IOP, should be researched more thoroughly, with better results when used in conjunction particularly in view of the high number of with a medication to lower IOP.116,117 cataract surgeries performed each year and the In a human study, 121 patients with fact that cataracts are the leading cause of mid- or late-stage glaucoma with medication- visual impairment in the United States. controlled IOP received daily IM injections of Even with the use of conventional a 2 g/mL solution of Salvia miltiorrhiza alone medications, maintaining normal IOP and pre- or in combination with other Chinese herbs venting damage to the optic nerve in glaucoma (four different groups). After 30 days visual patients can be challenging. There are several acuity had improved in 43.8 percent of the eyes nutrients and botanicals that hold promise in and visual field improvement was noted in improving circulation to the optic nerve and 49.7 percent of eyes. There were no signifi- even lowering IOP including vitamins B12 and cant differences among the four herbal prepa- C, melatonin, lipoic acid, Ginkgo biloba, rations; but the effect was a statistically sig- Vaccinium myrtillus, topical forskolin, and IM nificant (p<0.01) improvement compared to Salvia miltiorrhiza. Many of these studies have 23 untreated eyes. Follow-up on 19 eyes oc- been performed on normal, healthy eyes. Pro- curred 7-30 months after the 30-day treatment spective trials on patients with glaucoma are and 14/19 eyes maintained or demonstrated needed. improvement in visual fields, suggesting a pos- sible long-term benefit from this herbal treat- References ment. Double-blind evaluations of oral admin- 1. Somers A. Avoidable blindness. Aust N Z J istration of Salvia seem warranted.118 Ophthalmol 1988;16:31-35. 2. Horton J. Disorders of the Eye. In: Fauci AS, Table 5 summarizes potential nutri- Braunwald, E, Isselbacher KJ, et al, eds. tional and botanical treatments for glaucoma. Harrison’s Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998:168. Conclusions 3. Rao GN, Sadasivudu B, Cotlier E. Studies of Considerable epidemiological, in vitro, glutathione s-transferase, glutathione peroxi- and animal data point to the benefit of the dase and glutathione reductase in human normal and cataractous lenses. Ophthalmic Res possible prevention and treatment of cataracts 1983;15:173-179. with herbal and particularly nutritional 4. Beers MH, Berkow R, eds. Merck Manual, supplementation. Much of the research has Centennial Edition. Whitehouse Station, NJ: been in vitro due to the ease of cataractous lens Merck Research Laboratories; 1999. evaluation in this experimental model. 5. Christen WG, Manson JE, Seddon JM, et al. A However, there is a definite paucity of good, prospective study of cigarette smoking and risk prospective clinical studies on the use of of cataract in men. JAMA 1992;268:989-993. nutrients and botanicals for the treatment ofAlternative Medicine Review x Volume 6, Number 2 x 2001 Page 161Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

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