natural therapies for ocular disorders part two: cataracts ... · use of vitamin a to prevent...

Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

Alternative Medicine Review ◆ Volume 6, Number 2 ◆ 2001 41

IntroductionPart 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. Thissecond part covers alternative treatments for nonretinal disorders: senile cataracts, diabetic cata-racts, and chronic open-angle glaucoma.

Natural Therapies for Ocular DisordersPart Two: Cataracts and Glaucoma

Kathleen Head, ND

AbstractPathophysiological mechanisms of cataract formation include deficient glutathione levelscontributing to a faulty antioxidant defense system within the lens of the eye. Nutrientsto increase glutathione levels and activity include lipoic acid, vitamins E and C, andselenium. 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 aprecursor to flavin adenine dinucleotide (FAD), a co-factor for glutathione reductaseactivity. Other nutrients and botanicals, which may benefit cataract patients or helpprevent cataracts, include pantethine, folic acid, melatonin, and bilberry. Diabeticcataracts are caused by an elevation of polyols within the lens of the eye catalyzed bythe 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 allcases. Some patients with glaucoma have normal IOP but poor circulation, resulting indamage to the optic nerve. Faulty glycosaminoglycan (GAG) synthesis or breakdownin the trabecular meshwork associated with aqueous outflow has also been implicated.Similar to patients with cataracts, those with glaucoma typically have compromisedantioxidant defense systems as well. Nutrients that can impact GAGs such as vitaminC and glucosamine sulfate may hold promise for glaucoma treatment. Vitamin C inhigh doses has been found to lower IOP via its osmotic effect. Other nutrients holdingsome potential benefit for glaucoma include lipoic acid, vitamin B12, magnesium, andmelatonin. Botanicals may offer some therapeutic potential. Ginkgo biloba increasescirculation to the optic nerve; forskolin (an extract from Coleus forskohlii) has beenused successfully as a topical agent to lower IOP; and intramuscular injections of Salviamiltiorrhiza have shown benefit in improving visual acuity and peripheral vision in peoplewith glaucoma.(Altern Med Rev 2001;6(2):141-166)

Kathleen A. Head, ND – Technical Advisor, Thorne Research, Inc.; Senior Editor, Alternative Medicine Review.Correspondence address: PO Box 25, Dover, ID 83825. E-mail: [email protected]


Alternative Medicine Review ◆ Volume 6, Number 2 ◆ 2001


A large percentage of blindness in theworld is nutritionally preventable.1 The authorof this comment was referring primarily to theuse of vitamin A to prevent corneal degenera-tion associated with a vitamin A deficiency;however, there is considerable evidence thatmany other eye conditions, which are leadingcauses of vision impairment and blindness,also may be preventable with nutritionalsupplementation, botanical medicines, diet,and other lifestyle changes. In addition, a num-ber of nutrients hold promise for the treatmentof already existing cataracts and glaucoma.

Senile CataractsSenile cataracts are the leading cause

of impaired vision in the United States, with alarge percentage of the geriatric populationexhibiting some signs of the lesion. Over onemillion cataract surgeries are performed yearlyin this country alone.2 Cataracts are develop-mental or degenerative opacities of the lens ofthe eye, generally characterized by a gradualpainless loss of vision. The extent of the vi-sion loss depends on the size and location ofthe cataract. Cataracts may be located in thecenter of the lens (nuclear), in the superficialcortex (cortical), or in the posterior subcapsu-lar area. Cataracts are also classified accord-ing to their color, which is consistent with lo-cation and density of the cataract. Pale yellowcataracts are typically slight opacities of thecortex, subcapsular region, or both; yellow orlight brown cataracts are consistent with mod-erate to intense opacities of the cortex, nucleus,or both; and brown cataracts are associatedwith dense nuclear cataracts.3

DiagnosisSymptoms include near vision image

blur, abnormal color perception, monoculardiplopia, glare, and impaired visual acuity, andmay vary depending on location of the cataract.For example, if the opacity is located in thecenter of the lens (nuclear cataract), myopia

is often a symptom, whereas posteriorsubcapsular cataracts tend to be mostnoticeable in bright light.4 Ophthalmoscopicexamination is best conducted on a dilatedpupil, holding the scope approximately onefoot away. Small cataracts appear as darkdefects against the red reflex, whereas a largecataract may completely obliterate the redreflex. Once a cataract has been established, areferral for slit-lamp examination, whichprovides more detail on location and extent ofopacity, is recommended.

Etiological/Risk FactorsFactors contributing to cataract forma-

tion include aging, smoking,5 exposure to UV-B and ionizing radiation,6 oxidative stress (sec-ondary to other risk factors such as aging orsmoking),7 dietary factors,8 increased bodyweight (above 22-percent body fat), centralobesity,9 and family history. Medications andenvironmental exposures which may contrib-ute to cataract formation include steroids, goutmedications, and heavy metal exposure. Cad-mium, copper, lead,10 iron, and nickel11 haveall been found in cataractous lenses. A highlevel of cadmium in the lens is associated withsmoking and can contribute to accumulationof other heavy metals.10 Conditions which pre-dispose to cataracts include diabetes, galac-tosemia, neurofibromatosis, hypothyroidism,hyperparathyroidism, hypervitaminosis D, in-fectious diseases such as toxoplasmosis, andseveral syndromes caused by chromosomaldisorders.2

Mechanisms Involved in thePathophysiology of Cataracts

Cataracts are characterized by electro-lyte disturbances resulting in osmotic imbal-ances. Derangements in the function of themembrane resulting in ion imbalance may bedue to increased membrane permeability or toa depression of the Na+/K+ pump because ofinterference with the enzyme Na+/K+ ATPase.12

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Alternative Medicine Review ◆ Volume 6, Number 2 ◆ 2001 Page 143


Cataracts are also characterized by aggregatesof insoluble proteins.12

Oxidative insult appears to be involvedas a precipitating factor in all cataracts. Lensproteins typically remain in their reduced form.However, in cataractous lenses, the proteinsare found in an insoluble, oxidized form. Oxi-dation may occur as a result of many factors(see Etiological Factors). Higher levels of hy-drogen peroxide have been found in catarac-tous lenses when compared to normal con-trols.13 Normally the lens contains significantlevels of reduced glutathione (GSH), whichkeeps the proteins in their reduced form. How-ever, there are significantly lower levels ofGSH in cataractous lenses.

Advanced glycation end products(AGE) appear to play a role in cataractformation. Researchers have tested thehypothesis that the major AGE formed in thelens has an EDTA-like structure, capable ofbinding to copper. They found copper bindingwas 20-30 percent greater in the older,cataractous lens protein fractions than inyoung, non-cataractous fractions. The pro-oxidant copper precipitates further oxidation,

creating a viciouscycle. Ther e s e a r c h e r shypothesized that,“chelation therapycould be beneficialin delayingcataractogenesis.”14

Other researchershave confirmedthe involvement oftransition metals,copper and iron, asinstigators ofascorbyl andhydroxyl radicalformation incataracts.15

The Role ofGlutathione in Lens Metabolism

In order to fully understand the mecha-nisms involved in cataract formation and thelink to nutritional prevention, it is importantto understand the role glutathione and its en-zyme co-factors play in metabolism within thelens. In vitro studies of incubated lenses fromanimals as well as humans have helped eluci-date the mechanisms involved.

The lens of the eye is avascular, de-pending entirely on passive diffusion, activetransport, and intra-lens synthesis for nutrientsand other substances important for metabo-lism. As a result, the content of the surround-ing intraocular fluids (aqueous humor) is rel-evant. While levels of GSH are high in the lens,they are relatively low in the aqueous humor;thus, glutathione appears to be synthesizedwithin the lens. Glutathione is composed ofthe amino acids cysteine, glutamic acid, andglycine, and its synthesis within the lens takesplace in two steps (Figure 1). Cataractouslenses can demonstrate dramatic decreases inGSH, as much as 81 percent, when comparedto normal lenses.3 Researchers have examined

Figure 1: Synthesis of Glutathione in the Lens

γ-Glutamylcysteinesynthetase

Glutathionesynthetase

Glutamic acid+

cysteine+

ATP

γ-Glutamylcysteine+

ADP+P

γ-Glutamylcysteine+

glycine+

ATP

Glutathione+

ADP+P

Step 1 Step 2

i i



this phenomenon in an attempt to determinewhether low GSH is due to decreased synthe-sis or increased degradation. Decreases in theenzymes involved in both synthesis (γ-glutamyl transferase) and recycling (glu-tathione reductase) of GSH from oxidized glu-tathione (GSSG) lend credence to the theorythat synthesis is diminished in cataractouslenses.3 These same researchers found a de-crease in the activity of enzymes of GSH deg-radation (glutathione peroxidase and glu-tathione s-transferase) which should result inan increased rather than a decreased accumu-lation of GSH. They therefore concluded thatthe loss of activity of these enzymes was notenough to offset the losses associated withdecreased synthesis. They also did not rule outthe possible loss of GSH from the lens viamembrane leakage.

There are several ways in which glu-tathione or its depletion can affect the opacityof the lens. A review by primary researcherson glutathione metabolism and its relationshipto cataract formation outlines three possiblemechanisms of cataract prevention by glu-tathione:16 (1) maintaining sulfhydryl (SH)groups on proteins in their reduced form pre-venting disulfide cross-linkage; (2) protectingSH groups on proteins important for activetransport and membrane permeability; and (3)preventing oxidative damage from hydrogenperoxide (H

2O

2).

Considering the first mechanism bywhich GSH can protect lenses from opacities,there is an increase in high molecular weight(HMW) proteins in cataractous lenses. Theseprotein aggregates contribute to lens opacityand are found particularly in dense cataracts.Reddy and Giblin examined x-ray-inducedcataracts in rabbits and found increased levelsof disulfide bonds, confirming their assertionthat oxidation of SH groups resulted in disul-fide bond formation and HMW proteins. Theyalso found that SH groups on proteins onlybecome oxidized when levels of GSH dropbelow some critical level.16 Other researchers

have found an increase in disulfide bonds inhuman cataractous lenses.17

Maintaining normal cell volume andtransport of electrolytes are important factorsin lens transparency. Glutathione may play arole in maintaining normal lens permeabilityand active cation transport by protecting sulf-hydryl groups in the cell membrane from oxi-dation. Oxidation of SH groups on the surfaceof the cell membrane results in increased per-meability, and oxidation of important SHgroups of Na+/K+ ATPase impedes active trans-port. Reddy et al examined the effect of GSHdepletion on rabbit lenses and found it directlyled to increased membrane permeability.18

While GSH depletion did not directly impairactive transport, it resulted in increased sus-ceptibility of the Na+/K+ pump to oxidativedamage by H

2O

2. Oxidation of GSH resulted

in a 70-percent decrease in active transport anda two-fold increase in membrane permeabil-ity. Other experiments have found that lens-epithelial-GSH needs to be depleted by about60 percent for these changes to occur. Theauthors point out that, “the lens has a remark-able ability to regenerate reduced glutathione.”However, they found that, although the changein membrane permeability was reversible withthe regeneration of GSH, the decrease in pumpactivity was irreversibly affected.16

H2O

2 is found in the aqueous humor in

humans as well as other species. GSH is in-volved in detoxifying this reactive oxygen spe-cies to water in a coupled reaction involvingNADPH (Figure 2). Without detoxification theperoxide radicals would damage the lens mem-branes and susceptible protein groups. Theresearchers found both normal human and rab-bit lenses with high GSH content were rap-idly able to detoxify H

2O

2 in culture medium.16

Lenses pretreated with methyl mercury, whichdecreased the concentration of GSH by 75percent, were less able to detoxify the perox-ide radicals.

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Other researchers have postulated apossible diffusion problem. Normally GSH issynthesized and regenerated in the lens cortexand then diffuses to other areas of the lens.Cataracts of the elderly are primarily in thenucleus. Researchers examined normal humanlenses in vitro and found the older ones ap-peared to have a barrier to diffusion of GSHfrom the cortex to the nucleus.19

Specific Nutrients and Prevention ofCataracts

Oxidation of lens proteins is part of thepathophysiology of cataracts. Therefore, it isno surprise that antioxidants may help preventthe formation of cataracts.

Carotenes and Vitamin A: EpidemiologicalEvidence

Levels of nutrients, includingcarotenoids, have been examined in humancataractous lenses after extraction using highperformance liquid chromatography. VitaminsA and E and the carotenoids lutein andzeaxanthin were found. The newer, epithelial/outer cortex layer had more carotenoids,tocopherol, and retinol (approximately 3-, 1.8-, and 1.3-fold higher, respectively) than theolder, inner cortex/nuclear portion.20 Other

studies haveq u a n t i f i e ds i g n i f i c a n tlevels of lutein,zeaxan th i n ,and alpha- andg a m m a -tocopherol inthe lens.21

A pro-spective studyof the effect ofcarotenes andvitamin A onthe risk of cata-ract formation

was conducted as part of the Nurses’ HealthStudy. A total of 77,466 female nurses, ages45-71 years, were included in the study, whichinvolved food-frequency questionnaires overa 12-year period. After other risk factors werecontrolled for, including smoking and age,those in the highest quintile for consumptionof lutein and zeaxanthin had a 22-percent de-creased risk of cataract extraction comparedwith those in the lowest quintile.22

Another cohort of the Nurses’ HealthStudy followed 50,823 women, ages 45-67,for eight years and found women in the high-est quintile of vitamin A consumption had a39-percent lower risk of developing cataractscompared to women in the lowest quintile.23

In a similar study of male healthprofessionals in the United States, 36,644participants, ages 45-75 years, were followedfor eight years with periodic dietaryquestionnaires. Men in the highest quintile forlutein and zeaxanthin intake had a 19-percentdecreased risk of cataract extraction whensmoking, age, and other risk factors werecontrolled for.24 Neither the women nor themen demonstrated a decreased risk of cataractwith intakes of other carotenoids (α-carotene,β-carotene, lycopene, or beta-cryptoxanthin).It is hypothesized the protective effect of thecarotenoids may be due to quenching reactive

Figure 2: Metabolism of Hydrogen Peroxide by Glutathione

NADP

NADPH

GSH(reduced

glutathione)

Glutathionereductase

GSSG(oxidized glutathione)

H2O2

Glutathioneperoxidase

2H2O



oxygen species generated by exposure toultraviolet light.25

The Beaver Dam Eye Study examinedrisk for developing nuclear cataracts in 252subjects who were followed over a five-yearperiod. Only a trend toward an inverse rela-tionship between serum lutein and cryptoxan-thin and risk of cataract development wasnoted.26

Vitamin E: Animal, Epidemiological, andClinical Studies

As a fat-soluble antioxidant, it is rea-sonable to predict a positive role for vitaminE as a cataract preventive in the lens cell mem-brane. Animal, epidemiological, and clinicalstudies help confirm this hypothesis. A pla-cebo-controlled animal study found 100 IU d-alpha-tocopherol injected subcutaneously pre-vented ionizing radiation damage to the lens,which did occur in rats not supplemented withvitamin E.27 Two other animal studies usingvitamin E instilled in the eyes as drops con-firmed the preventive effect of vitamin E, atleast when used topically.28,29

Several human studies have found lowlevels of vitamin E intake are associated withincreased risk for cataract development. Anepidemiological investigation examined self-reported supplementary vitamin consumptionof 175 cataract patients compared to 175matched individuals without cataracts. Thecataract-free group used significantly morevitamin E (p=0.004) and vitamin C (p=0.01)than the cataract group, resulting in at least a50-percent reduction in cataract risk in thesupplemented group.30 An Italian study com-pared 207 patients with cataracts to 706 con-trol subjects in a hospital setting. Vitamin E,in addition to a number of other nutritionalfactors, was associated with a decreased riskfor cataract.8

The Vitamin E and Cataract Preven-tion Study (VECAT) is a four-year, prospec-tive, randomized, controlled trial of vitamin Eversus placebo for cataract prevention in a

population of healthy volunteers, ages 55-80years.31 Although results are still pending, datawas collected on prior use of vitamin E andincidence of cataract in 1,111 participants. Astatistically significant relationship was foundbetween past vitamin E supplementation andprevention of cortical cataract but not nuclearcataract.32

The Lens Opacities Case-ControlStudy was designed to determine risk factorsfor cataracts in 1,380 participants, ages 40-79years. Blood chemistry and levels of vitaminE and selenium were performed on all patients.The risk of developing cataracts was reducedto less than one-half (odds ratio 0.44 fornuclear cataracts) in subjects with higher lev-els of vitamin E.33 Some of these same re-searchers examined the association betweenantioxidants and the risk of cataract in theLongitudinal Study of Cataract. Dietary intake,use of supplements, and plasma vitamin E lev-els were assessed on 764 participants. Lensopacities were examined on a yearly basis andthe risk of development of cataract was 30-percent less in regular users of a multiple vi-tamin, 57-percent less in regular users ofsupplemental vitamin E, and 42-percent lessis those with higher plasma levels of vitaminE.34

In a randomized trial of 50 patientswith early cataracts, subjects were assigned toreceive either 100 mg vitamin E twice dailyor placebo for 30 days. There was a signifi-cantly smaller increase in the size of corticalcataracts in the vitamin E group compared toplacebo. While increases of vitamin E werefound in both nuclear and cortical lenshomogenates after surgical removal, GSH lev-els were increased significantly only in thosewith cortical cataracts receiving vitamin E. Inaddition, the malondialdehyde (MDA) — ameasure of oxidative stress — levels and glu-tathione peroxidase levels were higher in cor-tical cataract/vitamin E users than in thenuclear cataract/vitamin E group.35 Some con-clusions that can be drawn from this study are:

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(1) vitamin E decreases oxidative stress in cata-ractous lenses; (2) part of vitamin E’s protec-tive effect is due to enhancement of GSH lev-els; and (3) vitamin E seems to be more pro-tective for cortical than nuclear cataracts, atleast in this short-term study.

Vitamin C and Risk of CataractsAnimal experimentation has shed

some light on ascorbic acid and its role in cata-ract formation. Cataracts induced in chickembryos by the application of hydrocortisonewere prevented by the introduction of vitaminC to the developing embryo. In addition, vita-min C slowed the decline in GSH levels, whichoccurred with the cortisone treatment.36

Ascorbic acid is normally found inhigh concentrations in the aqueous humor andlens in humans. A group of 44 subjects weresupplemented with 2 g daily ascorbic acid.Significant increases in vitamin C in lens,aqueous humor, and plasma were noted.37 Inanother study, lenses were exposed in vitro tolight, which caused an increase in superoxideradicals and subsequent damage to the Na+/K+ pump. The damage was prevented by ad-dition of vitamin C in doses comparable towhat would be found in the aqueous humor.38

In the Nurses’ Health Study supple-mental vitamin C for a period of 10 years orgreater was associated with a 77-percent lowerincidence of early lens opacities and an 83-percent lower incidence of moderate lensopacities. In this study, no significant protec-tion was noted from vitamin C supplementa-tion of less than 10 years.39

RiboflavinRiboflavin is a precursor to flavin ad-

enine dinucleotide (FAD), which is a coen-zyme for glutathione reductase. In vitro evalu-ations of surgically removed cataracts haveconfirmed inactivity of glutathione reductaseenzyme activity in a significant number ofcataracts examined. Furthermore, the activitywas restored by the addition of FAD.40

It is not surprising then that a defi-ciency of riboflavin has been implicated as acause of cataract formation. A study of B vita-min nutritional status of cataract patients(n=37) compared to age-matched controlswithout cataract (n=16) found that 80 percentof those with cataracts and only 12.5 percentof control subjects had a riboflavin defi-ciency.41 The same researcher tested for, butdid not find, a deficiency of thiamin or pyri-doxine in cataract patients. Other researchershave found a relationship between riboflavindeficiency and later-stage cataracts, but not inearly cataract formation.42 The Lens OpacitiesCase-Control Study found that lens opacitieswere associated with lower levels of ribofla-vin which were assessed by RBC enzyme as-says and dietary intake reports.

Data collected during cancer interven-tion trials in Linxian, China, were assessed fornutrient effects on other conditions, includingcataracts. Two randomized, double-blind, con-trolled studies of cataract risk resulted fromthe Linxian study. In the first trial 12,141 par-ticipants, ages 45-74, were supplemented forfive to six years with either a multiple vita-min-mineral or placebo. There was a statisti-cally significant 36-percent reduction in inci-dence of nuclear cataract for subjects ages 65-74 years given the multiple vitamin. In thesecond trial 23,249 participants were given oneof four different vitamin/mineral combina-tions: (1) retinol/zinc, (2) riboflavin/niacin, (3)ascorbic acid/molybdenum, or (4) selenium/alpha-tocopherol/beta carotene. Again, themost significant effect was noted in people age65-74, with a 44-percent decrease in nuclearcataract risk in the group taking riboflavin/nia-cin (3 mg riboflavin/40 mg niacin). No sig-nificant protection was noted for the othernutrient combinations or for protection fromcortical cataracts.43

A series of case reports from the Uni-versity of Georgia treated 24 cataract patients(18 with lens opacities and six with fully-de-veloped cataracts) with 15 mg riboflavin daily.



Dramatic improvement was reported within24-48 hours, and after nine months all lensopacities disappeared.44 Larger, double-blind,placebo-controlled trials are needed to confirmthese seemingly dramatic improvements.

Other B VitaminsPantethine is the active coenzyme form

of pantothenic acid (vitamin B5). Several ani-mal studies have found pantethine can preventchemically-induced cataracts if given withineight hours of exposure to lens insult.45-47 Theproposed mechanism of action was the pre-vention of the formation of insoluble proteinsin the lens.45

Folic acid has been found to be low inthose prone to cataracts. An Italian epidemio-logical survey found those in the highestquintile for folic acid consumption were only40 percent as likely to develop cataracts thanthose in the lowest quintile.8

Selenium and CataractsA decrease in glutathione peroxidase

activity has been found in the lenses of sele-nium-deficient rats. Concomitantly, an in-crease in MDA and free radicals was also notedin both the selenium-deficient and vitamin-Edeficient groups.48 Evaluation of selenium lev-els in humans has found lower than normallevels of selenium in sera and aqueous humorin cataract patients.49 The significance of lowserum levels is unclear and the relationshipbetween selenium and cataract risk demandsfurther evaluation.

Dietary Factors in Cataract RiskSeveral epidemiological studies have

found dietary links to increased or decreasedrisk of cataract. An Italian in-hospital studyexamined dietary patterns and incidence ofcataract extraction. Significant inverse rela-tionships were seen between meat, spinach,cheese, cruciferous vegetables, tomatoes, pep-pers, citrus fruits, and melon. An increased riskwas found in those with the highest intakes of

butter, total fat, salt, and oil (except olive oil).8

The Nurses’ Health Study found regular con-sumption of spinach and kale was moderatelyprotective for cataracts in women.22 The HealthProfessionals Follow-up Study found spinachand broccoli decreased risk of cataract inmen.24

Bilberry and CataractsVaccinium myrtillus or bilberry has a

long history of use for various eye conditions.The active components, flavonoidanthocyanosides, are potent antioxidants witha particular affinity for the eye and vasculartissues. The anthocyanosides are typically con-centrated in a 25-percent standardized extract.In a report of 50 patients with senile cataracts,a combination of bilberry, standardized to con-tain 25-percent anthocyanosides, (180 mgtwice daily) and vitamin E, in the form of dl-tocopheryl acetate, (100 mg twice daily) forfour months stopped the progression of cata-racts in 96 percent of the subjects treated(n=25) compared to 76-percent in the controlgroup (n=25).50

MelatoninThe pineal hormone, melatonin, is a

potent antioxidant and because of its knownantioxidant effects, several animal studies havebeen conducted to determine its effect on pre-vention of cataracts. Injections of melatoninhave been found to inhibit both chemical- andUVB-induced cataracts.51-53 In the UV-B andmelatonin study cataract formation and MDAlevels were significantly lower than the UV-Bonly group, leading the researchers to con-clude, “These results suggest that melatoninmay protect against the UVB-induced cataractdevelopment by directly quenching lipid per-oxides and indirectly by enhancing the pro-duction of the endogenous antioxidant GSH.”51

In studies examining chemically-in-duced cataracts, the animals were administeredbuthionine sulfoxamine (BSO), a known in-hibitor of GSH synthesis. Half were treated

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with melatonin and half were not. In one study,18/18 rats given BSO alone developed cata-racts compared to only 1/15 in the grouptreated with melatonin.52 In the other study,16/18 in the BSO-only group developed cata-racts, whereas only 3/18 treated with melato-nin developed cataracts.53 The researcherswere unsure whether the protection was dueto a direct free-radical scavenging effect or toa stimulation of GSH production by melato-nin.

Diabetic (Sugar) CataractsPolyol Accumulation

Some of the mechanisms involved inthe formation of diabetic cataracts are some-what different from senilecataracts. The accumula-tion of polyols within thelens is a primary contrib-uting factor. Certain tis-sues of the body, includingthe lens of the eye, do notrequire insulin for glucoseor other simple sugarssuch as galactose to enter.In diabetes sugar is in highconcentrations in the aque-ous humor and can diffusepassively into the lens. Theenzyme aldose reductasewithin the lens convertsglucose to sorbitol or ga-lactose to galactitol (Fig-ure 3). These polyols can-not diffuse passively out ofthe lens and accumulate orare converted to fructose.The accumulation ofpolyols results in an os-motic gradient, which encourages diffusion offluids from the aqueous humor. The waterdrags sodium with it and the swelling and elec-trolyte imbalances result in cataract formation.

Flavonoids as Aldose Reductase InhibitorsA number of compounds, both natural

and synthetic, have been found to inhibit al-dose reductase. These so-called aldose reduc-tase inhibitors (ARIs) bind to aldose reduc-tase, inhibiting polyol production.54 As a group,flavonoids are among the most potent natu-rally occurring ARIs. Several evaluations ofin vitro animal lenses incubated in high sugarmediums have found flavonoids to inhibit al-dose reductase.55,56

A group of researchers examined theeffect of an orally administered ARI in inhib-iting polyol accumulation. They reported thearrest of cataracts in galactosemic rats by oralfeeding of a synthetic ARI.57 Building on thisresearch, another group studied the effect of a

flavonoid ARI, quercetrin (a glycoside of quer-cetin). Rats were divided into two groups, onereceiving lab chow only, while the experimen-tal group was fed quercetrin in rat chow plus

Figure 3: The Polyol Pathway

AldoseReductase

D-Glucose

NADPH+H+

NADP+

D-Sorbitol

SorbitolDehydrogenase

D-Fructose

NAD+

NADPH+H+



an additional 70 mg oral quercetrin daily inaqueous suspension. Three days after begin-ning flavonoid supplementation diabetes waschemically induced and three days later lenseswere assessed for sorbitol and fructose. Theflavonoid group demonstrated a 50-percentinhibition of sorbitol and fructose accumula-tion. The control group developed cataracts bythe tenth day, whereas the group receivingquercetrin, although their blood sugar was

comparable (average 380 mg/100 mL),had not developed cataracts by the 25th

day.58 A French study examining the ef-fect of oral doses of quercetin did not findan inhibition of cataract formation in dia-betic animals.59 In the positive studyquercetrin rather than quercetin was used,the former administered in a water sus-pension which was undoubtedly more ab-sorbable. The latter study was in Frenchwith only the abstract available so a dos-age comparison was not possible.

Varma and associates performedan in vitro experiment to determine whichaspects of flavonoids conferred the mostARI activity, and ultimately which fla-vonoids were the most potent in that re-spect.60 Their earlier more limited researchhad found quercetin, quercetrin, andmyricitrin to possess the most potent ARIactivity.56

In the more recent experiment 44flavonoids and their derivatives were ex-amined for the ability to inhibit aldosereductase and polyol accumulation in ratlenses incubated in the sugar xylose. Allflavonoids tested exhibited some inhibi-tory activity. The two most potent inhibi-tors were derivatives of quercetin,quercetrin and quercetrin-2-acetate, thelatter the most potent ARI inhibitorknown. Table 1 demonstrates some of themost common commercially available fla-vonoids and their comparative inhibitions.In decreasing order of potency they in-clude quercetin, rutin, hesperidin and hes-

peridin chalcone, and naringin. Although in-hibition was also noted by isoflavones, cat-echins, coumarins, and anthocyanins, theywere found to be much less potent than fla-vones. When dissolved, flavones easily con-vert to their corresponding chalcone by theopening of the center or B-ring of the flavonestructure. Because this may occur in vivo aswell, the researchers tested hesperidin andhesperidin chalcone and found their inhibitory

Table 1: The Aldose Reductase InhibitorActivity of Some Flavonoids.60

Quercetrin-2-acetate

Quercetrin

Quercetin

Rutin

Hesperidin

Hesperidin chalcone

Naringin

10-4

10-5

10-6

10-7

10-4

10-5

10-6

10-7

10-4

10-5

10-6

10-7

10-4

10-5

10-6

10-7

10-4

10-5

10-6

10-7

10-4

10-5

10-6

10-7

10-4

10-5

10-6

10-7

10010010087

100958855

100836015

95952010

881000

821000

805900

FlavonoidMolar Concentration

PercentInhibition

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potencies were nearly identical (Table 1). Thechalcones, being more water-soluble and thusmore absorbable, may represent a more logi-cal means of oral administration. In their re-view Varma and associates outline a numberof structural factors contributing to ARI activ-ity. In the final analysis, the pentahydroxy (fiveOH groups) flavones conferred the most po-tent effect.

Vitamin CAscorbic acid also has potential as an

aldose reductase inhibitor. An experiment wasconducted in which guinea pigs were fed anormal, high vitamin C diet with 10-percentgalactose or a scorbutic diet (devoid of vita-min C) plus 10-percent galactose. The lensepithelium of scorbutic animals had 2.5 timesas much galactitol (the polyol of galactose) onday 4 than those animals fed vitamin C in theirdiets.61

A human study, although not on cellsof the lens, found oral vitamin C at low dosesof 100-600 mg daily was able to normalizesorbitol levels in red blood cells within 30 daysin individuals with type 1 diabetes.62

Oxidative Stress and DiabeticCataracts

As with senile cataracts, oxidativestress plays an important role in the pathogen-esis of diabetic cataracts. Levels of glutathioneperoxidase and vitamin C have been found tobe deficient in the lenses of diabetics. Lensesof humans with diabetes were found to be moresusceptible to oxidation of proteins, a condi-tion exacerbated by concurrent retinal dis-ease.63

Glutathione in Diabetic CataractsEvidence of other mechanisms at work

besides sorbitol accumulation is offered by thework of Ross et al. They found that GSH, ei-ther in vitro in lens incubation medium or invivo when injected into diabetic rats, was able

to halt progression of diabetic cataracts despitesorbitol, glucose, and fructose accumulation.64

Lipoic AcidIn both in vitro lenses incubated in a

glucose medium and in diabetic animal mod-els, lipoic acid (LA) has been found to pre-vent cataract formation.65 Lipoic acid has po-tent antioxidant effects in both its oxidizedform (LA) and reduced form, dihydrolipoicacid (DHLA). It is this property which un-doubtedly is responsible for much of its pro-tective effect in diabetic cataracts. Packer, oneof the foremost researchers on lipoic acid, hy-pothesizes that LA enters the lens (via a fattyacid carrier) and is converted to DHLA. DHLAhas the potential to regenerate ascorbic acidfrom ascorbyl radicals; the ascorbic acid canthen regenerate vitamin E from tocopherylradicals. Alternately, he hypothesized LAcould directly spare vitamins C and E. Theincreases in vitamins C and E would result indecreased utilization of GSH and a relativeincrease in its levels in the lens.63 Due to itsantioxidant effects and sparing of GSH andvitamins E and C, lipoic acid has been foundto prevent chemically-induced, non-diabeticcataracts in animal models as well.65

Another mechanism by which lipoicacid may prevent cataracts in diabetes is viainhibition of aldose reductase, which was de-termined in an in vitro experiment.66 The re-searchers also noted the ability of aldose re-ductase inhibitors, including lipoic acid, tochelate transition metals such as copper. Thismay be another way by which ARIs preventcataracts and other complications of diabetes.

Protein Glycosylation/AGEGeneration in Diabetic Cataracts

While glycosylated proteins (proteinswith glucose attached) and subsequent forma-tion of AGE have been implicated in manydiabetic complications, there is disagreementas to how much they contribute to diabetic or



galactosemic cataracts. Some researchers havefound increased levels of glycosylated proteinsand AGE associated with diabetic cataracts,67,68

while others have not found a strong correla-tion.69,70

Despite the controversy, several naturalsubstances that inhibit protein glycosylationhave been found to attenuate cataractformation in vitro and in animal models.Acetyl-L-carnitine, which has been found tobe lower than normal in the lens of diabeticanimals, was found in calf lenses in vitro toinhibit formation of glycosylated proteins by42 percent and AGE formation by 70 percent.71

The proteins became acetylated instead,preventing glucose from attaching. Pyruvate,a normal tissue metabolite, given orally todiabetic rats decreased protein glycosylation

and ultimatelyprevented cataractformation.67 Invitro studies havealso found lipoicacid preventsp r o t e i nglycosylat ion,providing yeta n o t h e rm e c h a n i s mwhereby LA mayp r e v e n tcataracts.72

Table 2summarizes po-tential nutritionaland botanicaltreatments forcataracts.

ChronicOpen-AngleGlaucoma

Currently,there are approxi-mately two mil-

lion cases of glaucoma in the United States,but due to its insidious nature, only half maybe diagnosed.4 Chronic open-angle glaucomais the most common type, accounting for 60-70 percent of cases. It is the leading cause ofblindness among African Americans2 and thesecond leading cause of blindness in the U.S.population as a whole.4 Another type, acuteangle-closure glaucoma, is a medical emer-gency and will not be addressed here. Glau-coma is characterized by a neuropathy of theoptic nerve, usually due to increased intraocu-lar pressure (IOP). The increased pressure isdue to an obstruction in the normal outflow offluids from the aqueous humor, with most ofthe outflow normally occurring in the anteriorchamber angle (Figure 4).

Table 2: Nutrients and Botanicals for the Prevention andTreatment of Cataracts

Supplement Mechanism of Action

Glutathione Deficiency noted in cataractous lenses; important component of the innate antioxidant system in the lens

Vitamin A Higher levels associated with a decreased risk for cataract

Carotenes Antioxidant; higher levels associated with decreased risk for(Lutein and cataractZeaxanthin)

Vitamin E Antioxidant; increases glutathione; supplementation associated with prevention

Vitamin C Preserves glutathione levels; protects the Na+/K+ pump; long-term supplementation (>10 years) protective

Riboflavin Precursor to FAD, a coenzyme for glutathione reductase which recycles GSH

Bilberry Anthocyanoside antioxidants; study with vitamin E halted cataract progression

Quercetin Aldose reductase inhibitor – diabetic cataracts

Lipoic Acid Spares vitamins C and E, increasing GSH levels; inhibits aldose reductase and prevents protein glycosylation – diabetic cataracts

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Diagnosis and Risk FactorsAlthough IOP screening is one factor

in diagnosing glaucoma, it is a fairly insensi-tive test. Normal IOP ranges from 7-22 mm/Hg; however, approximately 90 percent ofpeople with IOPs greater than 22 mm/Hg neverdevelop glaucoma. On the other hand, somepeople with normal IOPs do develop opticnerve injury and glaucoma.4 Ophthalmoscopicexamination may reveal an enlarged cup withinthe optic disc. If glaucoma is suspected or ifthe patient is at high risk for developing glau-coma, referral to an optometrist or an ophthal-mologist for further evaluation is essential.

Physical symptoms are usually absentin early stages. Once atrophy of the optic nervehas progressed, loss of peripheral vision oc-curs first; central vision is the last to be lost.

Patients may complain of missing words onreading or having trouble driving due to poorperipheral vision.

Risk factors for the development ofglaucoma include increased intraocular pres-sure, older age, family history, being of Afri-can American descent, diabetes, hypertension,and myopia.4 Drugs associated with an in-creased incidence of glaucoma include corti-costeroids and cholesterol-lowering drugs. Asan aside, the use of scopolamine (often usedby those going on a cruise to prevent seasick-ness) can result in acute, angle-closure glau-coma.

PathophysiologyNormally aqueous humor is produced

in the ciliary processes and flows past the lens,through the pupil, and into the anterior

Figure 4: Flow of Fluids in the Eye

Aqueous humor Iris

Flow of fluid

Lens

Canal of Schlemm

Ciliary body

Diffusion of fluidand other constituents

Optic nerve

Trabecularmeshwork

Vitreoushumor



chamber. Outflow occurs through the anglebetween the cornea and the iris, through ameshwork of trabeculae, to the canal ofSchlemm (Figure 4). The canal of Schlemmis actually a very thin-walled vein thatsurrounds the entire eye. Because of its porousnature, large molecules are able to diffuse intothe canal and, although it is a vein, it carriesaqueous humor, not blood. Aqueous humor iscontinually being formed and reabsorbed, andit is this balance between formation andreabsorption that regulates IOP.73

The pathological processes involved inchronic glaucoma are not completely under-stood. It appears that morphological changesin collagen structure may precede increasedIOP. Glycosaminoglycans (GAGs) contributeto the filtration barrier. Within the trabecularmeshwork is an area called the juxtacanaliculartissue (JCT), which is the probable site of im-pedance to aqueous outflow in glaucoma. Re-searchers have compared the GAG content ofthe JCT in normal and glaucomatous eyes andhave found some significant differences. In onestudy GAG content of five eyes from normaldonors was compared to five with glaucoma.A significant decrease in hyaluronic acid andincrease in chondroitin sulfate was found inthe eyes of patients with glaucoma.74 A simi-lar study found trabecular meshwork of glau-comatous eyes had a 77-percent lower levelof hyaluronic acid with higher levels of chon-droitin sulfates in trabecular meshwork, iris,ciliary body, and sclera of eyes with glaucomacompared to normal donors.75 The research-ers postulated that the ability of normal aque-ous outflow is regulated by the content ofGAGs and their ability to form a highly vis-cous, elastic gel-like substance which acts asa filtration system.76 Maintaining a criticallevel of hyaluronic acid appears to be essen-tial for maintaining a well hydrated, semi-per-meable meshwork.77 In vitro research on hu-man eyes has found a decrease in GAG syn-thesis, particularly hyaluronic acid, in glau-comatous eyes compared to normal eyes.78

Other researchers, examining human post-trabeculectomy specimens (surgical procedurefor relieving increased IOP), have found evi-dence of a possible increase in collagen break-down in glaucoma.79

Reduced antioxidant defense systemsare also evident in early stage glaucoma. Muchof the research on the connection between an-tioxidants and glaucoma has been conductedin Russia and published in Russian languagejournals, requiring dependence on abstracts.Levels of sulfhydryl groups, a reflection ofglutathione levels, were found to be signifi-cantly lower in the aqueous humor of patientswith glaucoma, particularly advanced stagesof the disease, when compared to normal con-trol subjects. Red blood cell GSH levels werealso found to be lower in later stage glaucomapatients.80 Deficiencies of sulfhydryl groupshave also been found in the lacrimal fluid oflater stage glaucoma patients.81 In line with theevidence of decreased antioxidant defense sys-tems in glaucomatous eyes is the finding ofan increase in the lipid peroxidation productMDA – more than twice the normal level – inthe anterior chamber of patients with glau-coma.82

In some patients, particularly thosewith normal IOP, an inadequate blood supplyto the optic nerve may be contributing to dam-age and vision loss. These patients have ahigher than normal incidence of migraines,suggesting vasospasm as an etiology.4

Conventional TreatmentThe goal of conventional treatment is

to decrease intraocular pressure to avoiddamage to the optic nerve. There are a numberof topical medications used, includingcholinergic agonists, cholinesterase inhibitors,carbonic anhydrase inhibitors, adrenergicagonists (the newer ones are α

2-selective), β-

blockers, and prostaglandin analogs. Osmoticdiuretics are also used orally or IV.4 Lasertreatment may be tried instead of medications;and surgical intervention is usually a last resort

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Alternative Medicine Review ◆ Volume 6, Number 2 ◆ 2001 5


strategy but may be used initially in patientswho do not tolerate medications. Some

common side effects of glaucoma medicationsare listed in Table 3.4,83

Table 3: Conventional Glaucoma Medications and Their Potential Side Effects4,83

Beta-blockers

Non-selective Adrenergic Agonists

α2-Selective Adrenergic Agonists

Cholinergic Agonists

Cholinesterase Inhibitors

Carbonic Anhydrase Inhibitors (oral, IV, topical)

Prostaglandin Analog

timolol, levobunolol, carteolol, metipranolol, betaxolol

epinephrine, dipivefrin

apraclonidide

brimonidine

carbachol

pilocarpine

physostigmine, neostigmine, demecarium, echothiophate iodide, isoflurophate

acetazolamide, methazolamide, dichlorphenamide, ethoxzolamine

dorzolamide

latanoprost

bronchospasm, shortness of breath fatigue, confusion, depression, 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

high incidence of allergic or toxic reactions

high rate of allergic reactions, tachyphylaxis

dry mouth but less likely to cause allergic reactions

detached retina, GI disturbances, headache, frequent urination

hypertension, tachycardia, bronchial spasm

The latter three in the list cause irreversible rather than reversible miosis; they may be cataractogenic; increase risk of retinal detachment.

fatigue, anorexia, depression, paresthesias, electrolyte abnormalities, kidney stones, blood dyscrasias

topical so does not have the side effects of the others

increased pigmentation of the iris; worsening of uveitis

Drug Category Drug Side Effect



Potential Nutrient Deficiencies inGlaucoma

Deficiencies of specific nutrients havebeen found in patients with glaucoma, andsupplementation may play a role in treatment.

ThiaminThiamin (vitamin B1) has been found

to be deficient in some patients with glaucoma.Blood levels and dietary intakes of both vita-mins C and B

1 were examined in 38 patients

with glaucoma and compared to 12 controls.The glaucoma patients demonstrated a signifi-cantly lower level of thiamin (but not vitaminC), which was not a reflection of decreasedintake causing the researchers to postulate animpaired absorption of thiamin in these pa-tients.85 As thiamin deficiency has been asso-ciated with degeneration of ganglionic cellsof the brain and spinal cord, the researcherspostulated a possible degeneration of the op-tic nerve as well.

ChromiumA deficiency of chromium has been

implicated in increased IOP in humans andthose afflicted with primary open-angle glau-coma have demonstrated decreased erythro-cyte chromium levels.86

Intervention Trials of SpecificNutrients in GlaucomaVitamin B12

While a deficiency of vitamin B12

hasnot been implicated in glaucoma, such a defi-ciency may cause optic atrophy and visual fielddefects which mimic glaucoma. An open trialof 5 mg B

12 daily in glaucoma patients found

no change in IOP with supplementation. How-ever, there was no progression of visual fieldloss during five years of follow-up.87

Nutrients that Effect GAGs: Vitamin C andGlucosamine Sulfate

Due to the morphological changes seenin collagen structures associated with glau-coma it seems logical to explore the effect ofnutrients known to exert specific influenceson GAGs. Vitamin C has probably been re-searched more than any one single nutrient inthe treatment of glaucoma. Researchers seemto be in disagreement as to whether people withglaucoma tend to have an ascorbate defi-ciency.85,88 However, there is convincing re-search on its effectiveness in treating glau-coma.

Researchers first examined the effectof high dose IV vitamin C on animals and thenhumans, and found it successfully decreasedIOP. IV doses used were in the range of 1 g/kgbody weight; oral doses used were half that(500 mg/kg body weight).89 A total of 49 eyeswere treated, 25 with chronic open-angle glau-coma. The others included acute glaucoma,hemorrhagic glaucoma, and glaucoma second-ary to another disease process. Those withchronic open-angle glaucoma responded themost dramatically. Table 4 shows the averagedrops in IOP two hours and 4-5 hours after asingle dose of ascorbate. The higher the ini-tial IOP, the greater the drop after ascorbate.In eyes with normal IOP, the average drop inpressure was 3.5 mmHg. Decreases in pres-sure were maintained for as much as eighthours. Due to the almost universal side effectof gastric upset and diarrhea from such highdoses of vitamin C, the researchers studied theeffect of divided daily doses (0.1-0.15 g/kg 3-5 times daily). All but one patient experienceddecreased IOP during a two-week trial of di-vided doses and most experienced mild gas-tric upset and diarrhea that disappeared after3-4 days. Use of IV vitamin C would have al-leviated the gastric upset and diarrhea. Somepatients who had previously been resistant toconventional drug therapy were able to main-tain normal IOPs with the vitamin C regimen.

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A previous study of oral ascorbate didnot find it effective at lowering IOP in glau-coma. The researchers, however, used only 500mg twice daily. These same researchers suc-cessfully lowered IOP with topical use of a10-percent aqueous solution of vitamin C.90,91

There are several postulated mecha-nisms for ascorbate’s ability to lower IOP. Inhigh doses it acts as a potent osmotic agent.88

Vitamin C’s ability to halt lipid peroxidationhas also been hypothesized to play a role.88

Vitamin C has also been found, in vitro, tostimulate synthesis of hyaluronic acid in tra-becular meshwork from glaucomatous eyes.78

Ascorbate has also been found to reduce theviscosity of hyaluronic acid and increase out-flow through the trabeculum.92

Based on the observation that open-angle glaucoma may be due in part to a hyalu-ronic acid deficiency, a researcher has postu-lated a beneficial effect of glucosamine sul-fate (GS) for the treatment of glaucoma.93 Hecites two case reports in which glaucoma pa-tients given 3 g/day GS for osteoarthritis re-ported substantial drops in IOP. Because glu-cosamine sulfate is also a substrate for chon-droitin sulfate, which has been found to be el-evated above normal in the trabecular mesh-work in glaucoma patients, it would seem tohave the possible potential of further aggra-vation of the condition. While this author hasnot heard reports of exacerbation with glu-cosamine sulfate, close monitoring of IOP inpatients with glaucoma supplemented with GS

seems warranted, not only to prevent poten-tial harm but to monitor potential benefits ofthis supplement. Double-blind studies to con-firm the potential benefit of GS in glaucomaare needed.

Magnesium in the Treatment of GlaucomaCaused by Vasospasm

A subcategory of glaucoma patientswith normal IOP – those for which optic nervedamage is caused by vasospasm leading todecreased blood supply to the optic nerve –may benefit from supplemental magnesium.This patient group is often treated with cal-cium channel blocker drugs. These drugs,however, are not without side effects, includ-ing leg and periorbital edema. Ten patients,six with open-angle glaucoma and four withnormal-tension glaucoma, were supplementedwith magnesium, a natural calcium channelblocker.94 All patients in this preliminary opentrial suffered from cold-induced vasospasmsof the extremities and all had marked visualfield deficits, despite normal or drug-normal-ized IOP. Each subject received 121.5 mgmagnesium twice daily for one month. At theend of four weeks there was a non-statisticallysignificant trend toward improvement in vi-sual field tests (eight improved and two dete-riorated, one because of a cataract). While itis tempting to assume magnesium can improveblood supply to the optic nerve by dilating theoptic blood vessels, a larger, placebo-con-trolled trial of this subpopulation suffering

Table 4: Decreases in IOP after Oral Ascorbic Acid at 0.5 mg/kgbody weight89

Average Pressure Average PressureInitial IOP Decrease at 2 Hours Decrease at 4-5 Hours

50-69 mmHg 16 mmHg 25 mmHg32-49 mmHg 14 mmHg 19 mmHg20-31 mmHg 6.5 mmHg 6.5 mmHg



from glaucoma and vasospasm seems war-ranted.

Antioxidants in GlaucomaLow glutathione levels may contrib-

ute to some of the pathological processes seenin glaucoma. Supplementation of lipoic acidcan increase glutathione in red blood cells80

and lacrimal fluid81 of patients with glaucoma.In a Russian controlled trial of lipoic acid, 45patients with stage I and II glaucoma weresupplemented with either 75 mg (n=26) or 150mg (n=19) for two months. A control group ofglaucoma patients (n=31) were given only lo-cal hypotensive medication. Improvement invisual function was seen in approximately 45percent of subjects supplemented with lipoicacid.95 As mentioned previously, vitamins Cand E are also glutathione sparing. The issueof oral supplementation of glutathione is acontroversial one with some researchers con-tending oral doses of GSH are not effective atraising plasma and tissue levels of GSH. How-ever, both animal96,97 and human98 studies havefound oral doses of glutathione lead to in-creased plasma and tissue levels.

Melatonin and Diurnal Rhythms inIntraocular Pressure

Intraocular pressure normally variesthroughout the day, with the lowest pressureoccurring in the very early morning hours. IOPalso parallels fluctuations in cortisol levels,high cortisol conferring higher IOPs. Diurnalvariations in IOP are more pronounced inpeople with glaucoma (>10 mmHg) comparedto 3-7 mmHg variations in non-glaucomatouseyes. Because melatonin levels peak around 2a.m., a time when IOP is on a downward trend,researchers studied its effect on IOP.99 A seriesof experiments on subjects with normal IOPsand no diagnosis of glaucoma were conducted.Baseline IOPs showed maximum pressuresfrom 4-6 p.m. and minimum pressures from2-5 a.m. In the first experiment, exposure tobright light, which suppressed normal

melatonin secretion, resulted in a blunting ofthe usual early-morning fall in IOP.Administration of 200 mcg melatonin to halfof the bright-light group resulted in asignificant drop in IOP within an hour; theeffect lasted up to four hours. This experimentmay have important implications, not only forpossible treatment of glaucoma withmelatonin, but also in regard to timing ofmedications. It should also be noted that beta-blockers, sometimes used for treatment ofglaucoma, decrease melatonin levels. Oneresearcher found topical use of the beta-blocker, timolol, did not work as well in theevening.100

Coenzyme Q10 May PreventCardiac Side Effects of Timolol

The beta-blocker medication timololmay have significant cardiac side effects, in-cluding bradycardia and heart failure.4 Sixteenglaucoma patients on topical timolol weregiven 90 mg CoQ10 for six weeks. CoQ10delayed the appearance of negative inotropiceffects, including bradycardia, associated withtimolol, preventing the negative cardiac effectsof the drug without interfering with its effecton IOP.101

Omega-3 Fatty AcidsEpidemiological and animal studies

point to a possible protective effect of omega-3 fatty acids in glaucoma. Both topical admin-istration of prostaglandin E3 and D3 – endproducts of omega-3 fatty acid metabolism –and IM injections of cod liver oil – high inomega-3 fatty acids – led to decreased IOP inrabbits.102,103 Epidemiological evidence hasfound a low prevalence of chronic open-angleglaucoma among Eskimos on a native diet highin omega-3 fatty acids.104 These studies haveled researchers to consider the potential foromega-3 fatty acids in the prevention and treat-ment of glaucoma. Further investigation iswarranted.

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Botanical Treatment of GlaucomaThere are several botanicals that may

hold promise for the treatment of glaucoma.Most studies are merely preliminary, andlarger, controlled studies are needed.

Vaccinium Myrtillus (bilberry)Vaccinium myrtillus holds promise in

the treatment of glaucoma, although there hasbeen just one very limited study. Eight patientswith glaucoma were given a single dose of 200mg anthocyanosides from bilberry (most ex-tracts are 25-percent anthocyanosides so as-suming this standardization was used, the pa-tients were given 800 mg bilberry standard-ized extract). Electroretinography improve-ments were noted.105 Due to the fact that thearticle is in Italian, further details are unavail-able. While this evidence is very preliminary,it is not unreasonable to imagine theanthocyanosides’ collagen-stabilizing effectexerting a positive effect on the trabecularmeshwork, facilitating aqueous outflow.Anthocyanosides also exert potent antioxidanteffects.

Ginkgo BilobaForty-six patients, some with severe

visual field disturbances, and some with seri-ous retinal vascular degeneration, were given160 mg/day Ginkgo extract for four weeks,then 120 mg/day. Progress was assessedmonthly by measuring visual acuity, visualfields, fundoscopic exam, IOP, blood pressure,and pulse rate. Although only mild improve-ments were noted, these were deemed relevantdue to the severity of the ocular damage at thebeginning of the study.106

A potential therapeutic effect of aGinkgo extract for the treatment of glaucomawas evaluated in a phase I, placebo-controlled,crossover trial in 11 healthy volunteers. Sub-jects were treated with either 40 mg Ginkgoextract three times daily or placebo for twodays. Ocular blood flow via Color DopplerImaging was measured before and after

supplementation. Subjects crossed over to theother treatment after a two-week washout pe-riod. Ginkgo significantly increased bloodflow to the ophthalmic artery with no changeseen in the placebo group.107 Although Ginkgodid not alter IOP, it may provide potential ben-efit in glaucoma patients who suffer from de-creased ocular blood flow.

Coleus ForskohliiThe triterpene forskolin from the plant

Coleus forskohlii stimulates the enzyme ade-nylate cyclase.108 Adenylate cyclase thenstimulates the ciliary epithelium to producecyclic adenosine monophosphate (cAMP),which in turn decreases IOP by decreasingaqueous humor inflow.109

Results of studies using topicalforskolin applications to decrease IOP havebeen mixed. A study of 2-, 1-, and 0.5-percentforskolin solutions applied to the eyes of nor-mal rabbits found significant, dose-dependentdecreases in IOP within a half hour, peakingin 2-3 hours, and lasting up to 10 hours.110 Onthe other hand, a 1-percent forskolin solutionfailed to significantly decrease IOP in glauco-matous monkeys after two days of treatment.111

To date, human studies on forskolin’seffect on IOP have been limited to healthyvolunteers. Several studies have found it ef-fective at lowering IOP and decreasing aque-ous outflow in this population. Meyer et alcompared the effect of 1-percent forskolinversus placebo in 10 healthy volunteers in arandomized, crossover trial. In the first study,both the placebo group and the forskolin groupexperienced a decrease in IOP, which was at-tributed to the local anesthetic oxybuprocaine.In the second trial, proxymetacaine was usedas the topical anesthetic and forskolin wasfound to significantly decrease IOP comparedto placebo.112

In 20 healthy volunteers one dose of a1-percent forskolin solution had no effect,whereas two instillations five minutes apart ledto significant decreases in IOP and aqueous



flow rate.113 In eight healthy subjects one dropof forskolin significantly decreased IOP andflow rate was diminished an average of 34percent.114 Another study, however, did not findforskolin to have a significant effect at decreas-ing flow rate in a group of 15 healthy volun-teers given one dose of 1-percent forskolin ineach of three situations: during the day, at nightwhile sleeping, and following pretreatmentwith timolol.115

While topical use of forskolin inanimals and healthy humans appearspromising, clinical studies on its use inglaucoma patients are lacking. Furthermore,while oral standardized extracts of Coleusforskohlii are known to raise cAMP as itsmechanism of action in various diseaseconditions, it is not clear whether oral dosageshave any effect on cAMP levels in the eye.More research on this important topic is

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

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needed. Forskolin eye drops are availablethrough compounding pharmacies.

Salvia MiltiorrhizaSalvia miltiorrhiza is a commonly used

botanical in Chinese medicine. Injected IV thisbotanical appears to improve microcirculationof the retinal ganglion cells. Two experimentson rabbits found it protected the optic nervefrom the damaging effects of increased IOP,with better results when used in conjunctionwith a medication to lower IOP.116,117

In a human study, 121 patients withmid- or late-stage glaucoma with medication-controlled IOP received daily IM injections ofa 2 g/mL solution of Salvia miltiorrhiza aloneor in combination with other Chinese herbs(four different groups). After 30 days visualacuity had improved in 43.8 percent of the eyesand visual field improvement was noted in49.7 percent of eyes. There were no signifi-cant differences among the four herbal prepa-rations; but the effect was a statistically sig-nificant (p<0.01) improvement compared to23 untreated eyes. Follow-up on 19 eyes oc-curred 7-30 months after the 30-day treatmentand 14/19 eyes maintained or demonstratedimprovement in visual fields, suggesting a pos-sible long-term benefit from this herbal treat-ment. Double-blind evaluations of oral admin-istration of Salvia seem warranted.118

Table 5 summarizes potential nutri-tional and botanical treatments for glaucoma.

ConclusionsConsiderable epidemiological, in vitro,

and animal data point to the benefit of thepossible prevention and treatment of cataractswith herbal and particularly nutritionalsupplementation. Much of the research hasbeen in vitro due to the ease of cataractous lensevaluation in this experimental model.However, there is a definite paucity of good,prospective clinical studies on the use ofnutrients and botanicals for the treatment of

already existing cataracts. Maintaining normalglutathione levels seems of utmost importancein prevention of cataracts. Nutrients such aslipoic acid, vitamins C and E, and seleniumincrease glutathione levels or act as co-factorsfor glutathione-dependent enzymes. Sinceprevention of lens opacities is easier thantreating already existing cataracts, use of theseand other antioxidants to prevent cataractsshould be researched more thoroughly,particularly in view of the high number ofcataract surgeries performed each year and thefact that cataracts are the leading cause ofvisual impairment in the United States.

Even with the use of conventionalmedications, maintaining normal IOP and pre-venting damage to the optic nerve in glaucomapatients can be challenging. There are severalnutrients and botanicals that hold promise inimproving circulation to the optic nerve andeven lowering IOP including vitamins B

12 and

C, melatonin, lipoic acid, Ginkgo biloba,Vaccinium myrtillus, topical forskolin, and IMSalvia miltiorrhiza. Many of these studies havebeen performed on normal, healthy eyes. Pro-spective trials on patients with glaucoma areneeded.

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