Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

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294 CHAPTER 16 Dyes

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Dietary supplements (vitamins and inorganic essentials) fall under Title 21 of the Federal Register and must comply with regulations for labeling and health claims. The U.S. Food and Drug Administration (FDA) does not require supplement (or drug) companies to submit documentation that each batch of product contains the labeled ingredients. Rather, manufacturers are responsible for following Good Manufacturing Practices, including product validation. Furthermore, dietary supplement manufacturers may be subject to product liability claims if impurities are found, they cause harm, or they are improperly labeled. Advertising for dietary supplements is regulated by the Federal Trade Commission and also falls under The 1994 Dietary Supplement Health and Education Act. Only “StructureFunction” claims are allowed; that is, manufacturers are prohibited from making claims that products prevent or treat diseases.

Vitamins are organic compounds necessary for growth and health and cannot be synthesized in sufficient quantities for physiologic health by the body. Therefore they must be obtained from food sources or supplementation. Inorganic essentials (minerals are trace elements) are required in much smaller quantities than vitamins. In general, minerals and trace elements aid and support physiologic functions and, like vitamins, must be obtained from dietary sources.

The quantity of vitamins and minerals necessary for normal physiologic functioning is the dietary reference intake (DRI), which replaces the recommended dietary allowance. The DRI is a set of dietary recommendations and appears as “DV” (daily values). FDA regulations went into effect in March 1999 that requires such labeling.The DRI designation was formerly the FDA’s reference daily intake. DRIs are reviewed by the Dietary Allowances Committee of the Food and Nutrition Board of the Institute of Medicine of the National Academy of Sciences. Based on age and sex, these amounts are estimated to provide for the physiologic needs of healthy individuals. Vitamins are generally divided into two main categories, fat soluble and water soluble.

A primer of the physiologic effects of the vitamins and inorganic essentials can be found in Tables 17-1 and 17-2.

Vitamins are named alphabetically in the order in which they were discovered or first reported.Therefore the listing intersperses fatand water-soluble members. Food sources and deficiency states of vitamins are listed in Tables 17-3 and 17-4.

It is important to remember that healthy individuals can obtain sufficient vitamins and inorganic essentials from food sources in the normal diet. Unfortunately, many individuals fail to observe healthy eating patterns.A food pyramid has been suggested recently by the U.S. Department of Agriculture (http://www.mypyramid.gov/) as a template. Other factors, such as lack of exercise, may result in nutritional deficiencies as well as diseases such as obesity, diabetes, and other chronic disorders.

Although absolute vitamin deficiency (e.g.,beriberi,pellagra, scurvy) may be relatively rare in developed countries, malabsorption, poor nutritional habits, or other factors may lead to such situations. In fact, many Americans may be vitamin deficient based on recommended daily allowance or recommended daily intake.The interested reader is referred to the U.S. Department of Agriculture food and nutrition information center for recommended daily allowance and recommended daily intake (http://fnic.nal.usda.gov/).These are also summarized in Table 17-1 as DRI values.

Supplementation intervention, therefore, must be considered in specific deficiencies or recommended for clinically proven efficacy. Vitamin A deficiency can be treated readily, for example. The latter becomes difficult to define in the face of studies that offer inconsistent, incomplete, or even conflicting results.

Inorganic essentials and trace elements serve as cofactors in a variety of physiologic functions. These are summarized in Table 17-2.

The most significant vitamins from an ophthalmic standpoint include the antioxidant vitamins (A, C, and E) and are discussed with respect to function and deficiency as well as potential clinical benefits. The B vitamin group has been added because of their widespread representation in foods and supplements.

Zinc is present in a variety of dietary sources, including seafood, liver, and eggs, and is an integral part of superoxide dismutase and catalase, two antioxidant enzymes. In populations at risk for developing age-related macular degeneration (AMD), dietary zinc levels have been shown to be decreased, and other researchers have shown that those with zinc intake from dietary sources had a lower risk for some types of AMD. An early uncontrolled pilot study of zinc supplementation demonstrated reduced visual deterioration in AMD.This probably represented the beginning of the era of clinical trials on the effects of nutrition on visual function and ocular health status. Zinc deficiency leads to a syndrome similar to vitamin A deficiency because the conversion of retinol to retinal requires zinc. Deficiency may result in night blindness, decreased color perception, hyperkeratinization of lid margins with lacrimal punctal stenosis, blepharitis,

Table 17-2

Selected Inorganic Essentials and Their Physiologic

Function

DRI = dietary reference intake.

conjunctivitis, and photophobia. Therefore zinc is thought to be protective of vitamin A in the retina.

Copper stores are decreased by excessive zinc ingestion, so copper supplementation is essential with concomitant zinc administration. Wilson’s disease is a genetic abnormality that leads to progressive accumulation of copper that may manifest in the cornea (KayserFleischer ring). In addition, sunflower cataracts and renal dysfunction may accompany the corneal sign. Copper toxicity results when greater than 15 mg is administered. It is characterized by abdominal pain, nausea, vomiting, diarrhea, myalgia, metabolic acidosis, coma, and death.

Contemporary scientific evidence lacks sufficient consistency to suggest that any single or multiple vitamin and mineral supplementation has specific beneficial effect on ocular diseases such as AMD, cataract development, or glaucoma. For example, lowering the intraocular pressure in patients with ocular hypertension or glaucoma has been demonstrated to slow progression. Multivitamin and mineral supplementation has been shown to be of value in some cases of advanced stages of AMD. No clear evidence exists to suggest that cataract or glaucoma treatment may benefit from supplementation at this time. Vitamin and mineral supplementation, therefore, may benefit selected at-risk patients. Current clinical data on the benefit of nutritional supplements are unclear and, in some cases, contradictory. When confounders of patient age, sample size, supplement use versus intake from foods, supplementation with a single or multivitamin, presence of undisclosed or undiscovered underlying disease processes, gauging disease progression, inconsistent outcomes measures, genetic and ethnic influences, environmental factors such as smoking, and the unavoidable imprecision of data collection from retrospective

analysis are considered, interpretation of even the most promising results may be clouded. Interpretation of any single, large, well-designed and conducted clinical trial is complex and has limitations. Caution is therefore warranted when making generalized recommendations for supplement use. The prudent clinician should recognize that potential benefits are limited but that multivitamin administration is comparatively safe versus certain prescription and over-the-counter preparations.

The following discussion is intended as a guide for those recommendations based on contemporary knowledge of risks and benefits of vitamin and mineral supplementation and considers the potential impact on three ophthalmic disease states: glaucoma, cataract, and AMD. These were selected for reasons of significance as well as the body of literature available. In addition, specific treatment recommendations for disorders resulting from nutritional deficits are discussed. Finally, the role of

complementary and alternative medicine in ophthalmic disorders is outlined.

CLINICAL USES OF VITAMIN AND MINERAL SUPPLEMENTATION

Primary Open-Angle Glaucoma

Antioxidant intake for primary open-angle glaucoma was reported in a prospective study. As part of the Health Professionals Follow-up Study and Nurses’ Health Study, a selected group of patients was evaluated using a food frequency questionnaire to assess antioxidant intake from foods and supplements. The glaucoma diagnosis was confirmed by record review, and the authors found no protective associations with antioxidant intake and reduced risk of primary angle glaucoma progression. The theory of antioxidant protection arises from

Vitamin A (retinyl palmitate) Vitamin C (calcium ascorbate) Vitamin B6 (pyridoxal 5-phosphate) Magnesium (magnesium sulfate) Gamma linolenic acid (GLA) Mucin

Cod liver oil

OR Vitamin E

Mixed tocopherol concentrate Marine lipid oil

EPA

DHA Flaxseed oil

1,040 IU (range: 200–5,000 IU)

90 mg (at least 50 mg)

6.3 mg (range: 2.0–20 mg)

20 mg (range: 10–50 mg)

750 mg (at least 300 mg)

150 mg (range: 100–300 mg)

1.6 mg (range: 0.5–3.0 mg)

187 IU

20 mg

1,541 mg

450 mg

300 mg

1,000 mg

oxidation-reduction agents being protective against glutamate-induced toxicity.

Several characteristics of complementary and alternative medicine have been suggested to be favorable to glaucoma treatment. Neuroprotective agents may offer

such properties as oxidative alterations of low-density lipoproteins, scavenging of oxygen free radicals, and inhibition of glutamate toxicity. The lack of persuasive evidence from placebo-controlled clinical trials limits recommendation of such potentially promising agents as

Ginkgo biloba, which improves cerebral blood flow. Anecdotal reports of ginkgo and other potentially neuroprotective agents may be of value in the future for adjunctive glaucoma treatment. Lowering intraocular pressure in patients with glaucoma continues to be the primary modifiable risk factor worthy of intervention.

Cataract

Because the lens is avascular it might be expected that vitamin or mineral augmentation would not protect against cataract formation. The exception is vitamin C, which is actively transported from the circulation to ocular tissues and the aqueous and therefore is present in greater concentrations than in blood. Selected epidemiologic studies regarding antioxidants and cataract have suggested that single vitamins (vitamin C and E) may have salutary effects on specific types of cataract formation

(nuclear, cortical, or posterior subcapsular) or their progression.A more beneficial strategy may include multivitamin and mineral supplementation begun early in life and taken over long periods.

Although some individual trials present persuasive evidence supporting efficacy or benefit from single or multinutrient supplementation, universal guidance remains obscure. The confounding factors associated with clinical or epidemiologic studies are myriad. Not every study investigates the same population. In some studies benefit was associated with elderly populations whose nutritional habits may be lacking. In other studies efficacy was demonstrated among selected cases such as among cancer patients. Some study populations are assayed by“snapshot”serum samples. Other studies assess single nutrients, whereas some include supplement classes such as antioxidants or carotenoids. Many researchers measure dietary intake using validated food frequency questionnaires that harbor the limitation of depending on patient recall. Studies are inconsistent in whether any lens opacity, specific (nuclear, cortical, or posterior subcapsular) cataract type, or cataract extraction is the endpoint. Finally, some studies use observational approaches, whereas others are prospective and interventional.

Currently, retrospective analysis of auxiliary multivitamin and mineral supplementation in the Age-Related Eye Disease Study (AREDS) is under way. This will assess whether concomitant Centrum© (Wyeth Consumer Healthcare) use will delay the progression of lens opacities, as has been suggested by a statistical appraisal of AREDS data. In fact, AREDS Report No. 9 did not find any protective effect from the AREDS formulations against cataract formation. Risk factors other than nutritional status/intake or in combination with supplement use may influence development, progression, or visual impairment from cataract. Current evidence offers only weak support at best for a recommendation of multivitamin or other nutritional interventions as protective against cataract formation or progression.

Age-Related Macular Degeneration

Necessarily, this term encompasses a variety of clinical presentations. Drusen and pigment changes are recognized as clinically observable risk factors for macular degeneration, but indices in clinical studies include stages of outer retinal changes (examiner specification) as well as visual acuity (patient performance). For these and other reasons mentioned above, making sense of even carefully conducted studies makes deriving consistent clinical recommendations a conundrum.

Fewer than 20 years ago high-dose zinc supplementation was reported to reduce significantly the risk of vision loss in a short-term study that lacked a control arm. Since then, nutritional interventions have become popular with researchers as well as the general public. Unfortunately, subsequent trials have failed to substantiate this initial result.

Nevertheless, at least six randomized, double-blind, placebo-controlled, intervention trials have assessed the effect of vitamin or micronutrient supplements on AMD risk. The consensus from these and other trials seems to suggest a positive response of the retina as well as improved visual performance from vitamin and mineral supplementation such as the AREDS formulation (see above). Specifically, the AREDS results should be interpreted as understanding that the formulation was effective in slowing the risk of progression of AMD in persons 55 years of age and older who had some macular changes consistent with early age-related maculopathy. More recently, substantiation of these results was reported on a primarily white population as part of the Rotterdam Study. An above-median intake of beta-carotene, vitamin C, vitamin E, and zinc was associated with a 35% reduced risk of AMD. Still other clinical research has demonstrated shortterm beneficial effects in small populations for lutein and a combination of lutein and antioxidants in AMD.

Although these studies are promising as a basis for specific clinical guidance, the application to general populations is limited. The interaction of specific nutrients, for example, remains unknown. In AREDS, only patients in intermediate AMD, categories 3 and 4, showed a treatment benefit. And, high-dose beta-carotene supplementation may have adverse effects among smokers.

Because the treatment options are limited for patients suffering from AMD and vision loss is rarely recovered, this information should be portrayed to patients with cautious optimism. Generally, well-nourished patients with AMD may experience some reduced progression

The specific daily amounts of antioxidants and zinc used by the AREDS researchers were 500 mg vitamin C, 400 IU vitamin E, 15 mg betacarotene (often labeled as equivalent to 25,000 IU vitamin A), 80 mg zinc as zinc oxide, and 2 mg copper as cupric oxide. Copper was added to the AREDS formulations containing zinc to prevent copper deficiency anemia, a condition associated with high levels of zinc intake. (Retrieved March 28, 2007, from http://www.nei.nih.gov/amd/summary.asp#2)

300 CHAPTER 17 Nutritional Agents

with antioxidant and mineral supplementation. Recommendations should be based on evidence that many Americans may not, in fact, enjoy optimal nutrition. Because supplements are available without prescription (nor FDA scrutiny) in the United States, a balance needs to be struck between probable benefits and potential risks.

Using the example of AMD, it appears that many patients may benefit from the AREDS formulation as well as a diet high in green leafy vegetables.The potential for adverse effects (increased incidence of lung cancer) among smokers, in particular, from ingestion of high doses of beta-carotene has been suggested. Long-term effects in healthy populations have not been reported. Further characterization of an ideal formulation awaits future research. One such study is currently under way. AREDS II is evaluating the potential benefits of the antioxidants lutein/zeaxanthin as well as omega-3 long-chain polyunsaturated fatty acids in delaying progression of vision loss in AMD.

SPECIFIC VITAMIN AND MINERAL SUPPLEMENTATION FOR NUTRITIONAL DEFICIENCIES

Vitamin A Deficiency

Although rarely encountered in developed countries, vitamin A deficiency remains a global public health problem. The current World Health Organization recommendation for vitamin A treatment in children 1 year of age and older who are at risk (see Table 17-3) is one 200,000 IU oral dose every 3 to 6 months for prophylaxis, and three such doses for treatment and prevention of xerophthalmia. Animal studies (rat model) have shown some improvement in corneal epithelial function with topical vitamin A supplementation. In human trials, evidence is contradictory regarding the beneficial role of topical vitamin A application. The apparent mechanism is reduction of inflammatory components.

Folic Acid Deficiency

Folic acid deficiency may result in neural tube defects in newborns. Folic acid is one of the few nutritional supplements shown in clinical trials to be effective in preventing disease. Maternal prenatal supplementation with 400 mg/day folic acid reduced significantly the incidence of neural tube defects in newborns, which indicates that low maternal folate concentrations were associated with these defects.

Toxic Optic Neuropathy (Cyanocobalamin)

Deficiency of cyanocobalamin, or vitamin B12, can result in reduced visual acuity secondary to optic nerve dysfunction. Causes range from malabsorption to alcohol abuse. Treatment is with oral (1,000 to 2,000 mcg daily)

or intramuscular injections (1,000 mcg daily for 2 weeks or 1,000 mcg twice weekly for 2 weeks followed by weekly injections of 1,000 mcg for 2 months) of cyanocobalamin. In chronic deficiency, lifelong treatment is required.

Vitamin A in Retinitis Pigmentosa

The initial clinical trial examining the effects of vitamins A and E on retinitis pigmentosa showed a modest decline in progression of the disease based on electrophysiologic findings. Recommendations from this and subsequent trials have given rise to a treatment algorithm for retinitis pigmentosa patients.Adults with early or middle stages of retinitis pigmentosa should take 15,000 IU of oral vitamin A palmitate every day and avoid high-dose vitamin E supplements. Beta-carotene is not a suitable substitute for vitamin A because it is not reliably converted to vitamin A. People on this regimen should have annual measurements of fasting vitamin A concentrations in serum and liver function tests, although no cases of toxic effects have been reported.

Omega-3 Fatty Acids in Dry Eye

Oral supplementation with omega-3 fatty acids may play a role in relief of dry eye. Postmenopausal women are most susceptible to the signs and suffer the symptoms to a greater extent than other segments of the population. Intervention may have a positive effect. Recent studies also have demonstrated potential benefits on AMD, as well.

SIDE EFFECTS AND

CONTRAINDICATIONS

Contraindications and adverse reactions associated with the use of nutritional supplements, although rare, should be considered. The risk of side effects from nutrients is reduced compared with that from over-the-counter or prescription drugs. On the other hand, interactions with over-the-counter or prescription drugs may potentiate these reactions. Perhaps the best known interactions are those that interfere with clotting mechanisms. Because nonsteroidal anti-inflammatory drugs and warfarin have the therapeutic effect of blood thinning, caution is advised in recommending vitamin C (doses > 1 g/day), vitamin E, or Ginkgo biloba in these cases.Vitamin C may interfere with normal metabolism of acetaminophen, resulting in liver-damaging accumulation.

Clinicians should be aware that specific recommendations, such as the AREDS formulation, may not be recognized as compounding doses of other over-the-counter supplements.An example would be accumulating a toxic dose of beta-carotene from using the AREDS formulation along with additional sources of beta-carotene. Other examples exist, and a complete enumeration of

supplements that the patient may be taking should be evaluated to ensure that dosing remains within published guidelines.

Other associations have been reported anecdotally. These include competitive absorption among antioxidants such as vitamin A and lutein/zeaxanthin. In general, adhering to the DRI recommendations is safe for patients. The DRIs as well as side effects of overdose of vitamins are listed in Table 17-3.

The ocular side effects from herbal medications and nutritional supplements have been reviewed recently.The Dietary Supplement and Health Education Act of 1994 govern their manufacture and distribution. No efficacy or safety standards are required to be met for marketing some 700 available botanicals and 1,000 nutritional products.There may be significant variation in purity, potency, and even content. Ocular side effects may range from accommodative impairment, secondary to anticholinergic effects (kava kava), to visual disturbances (licorice). The World Health Organization has developed a classification scheme to categorize such side effects. In the United States a registry is available at www.eyedrugregistry.com.

One danger is that because herbal medications are not regulated, few if any clinical trials are performed even for safety or efficacy. One example is bilberry. Bilberry fruit is used to treat diabetes and diabetic retinopathy. Although animal models support the antioxidant role in vasoprotection, no well-designed and conducted clinical trials exist.The antioxidant effect may have benefit in AMD, as well.The antioxidant efficacy in bilberry is likely due to the tannin content, which is also found in grapes.

Another danger of herbal medication supplementation is that anecdotal information rises to a level of truth or even dogma. Various estimates suggest that not only are large sums of money ($60 billion worldwide) spent on complementary and alternative medicine strategies, but a large portion of the population (42% by some estimates) uses them without proof and in many cases without sanction or knowledge of the attending and treating physician.

In summary, nutrients play a vital role in physiologic functioning.The eye is no exception. Consequently, there are potentially useful as well as harmful effects of supplementing vitamins and inorganic essentials.The least studied category, herbal medications, may hold great promise for application in ophthalmic disorders but currently pose too great a risk for wholesale recommendation. Even though many of these compounds were discovered centuries ago, current research has neglected an opportunity to investigate their potential systematically. What does appear to emerge is some benefit from antioxidant supplementation against progression of AMD in selected older individuals. The influence against cataract progression seems to be limited to vitamin C. Primary open-angle glaucoma patients should be offered traditional intraocular pressure–lowering medications at the present time.

SELECTED BIBLIOGRAPHY

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Age-Related Eye Disease Study Research Group. Risk factors associated with age-related nuclear and cortical cataract: a case-control study in the Age-Related Eye Disease Study, AREDS Report No. 5. Ophthalmology 2001;108:1400–1408.

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Evans JR.Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev 2006 Apr 19;(2):CD000254.

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Kang JH, Pasquale LR, Willett W, et al. Antioxidant intake and primary open-angle glaucoma: a prospective study. Am J Epidemiol 2003;158:337–346.

Katz J, West KP Jr, Khatry SK, et al. Impact of vitamin A supplementation on prevalence and incidence of xerophthalmia in Nepal. Invest Ophthalmol Vis Sci 1995;36:2577–2583.

Kaushansky K, Kipps TJ. Hematopoietic agents: growth factors, minerals, and vitamins. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s the pharmacological basis of therapeutics, ed. 11. New York: McGraw-Hill, 2006.

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The rapid development of an ever-increasing variety of drugs for retinal disease has been a boon to individuals living with the vision loss associated with retinal disease, including two conditions for which few treatment options existed: recalcitrant macular edema and agerelated macular degeneration (AMD). Just 10 years ago the only treatment modality for patients with these retinal diseases was laser photocoagulation. Although none of these new medications is perfect, none provides a definitive resolution for conditions that wax and wane, and all require repeated use to maintain the gains in visual acuity and improved retinal status, their appearance in patient care is most welcome.

PHOTODYNAMIC THERAPY

Hematoporphyrin, with its ability to fluoresce red-orange upon exposure to near-ultraviolet light, was the first photosensitizing substance used in clinical care. It was initially used for localizing tumors, but a hematoporphyrin derivative was subsequently used in detection and management of cancer beginning in the 1960s. Because photosensitizing drugs accumulate preferentially in rapidly dividing cells, particularly in the proliferating neovascular tissue of cancers, they offered a potentially more focused and less destructive treatment modality. That principle of focused destruction of neovascularization was borrowed for management of choroidal neovascularization.

Photodynamic therapy (PDT) requires the combination of photosensitizer with both specially selected light and oxygen. A photosensitizer absorbs specifically selected light energy, after which its electrons are increased from the ground state to the excited state. Most sensitizers in the ground state are in the electron singlet state, in which all electron spins in the atom are paired (numbers of electrons spinning to the right equal numbers of electrons spinning to the left). When the photosensitizer absorbs the light energy, that absorbed energy may cause the spin of one electron to reverse direction.When the electron reverses direction, it moves out of the singlet state into the triplet state (in which two

electrons spin in the same direction without the counterbalancing effect of two electrons spinning oppositely).

Oxygen molecules play an essential part in PDT, because oxygen is already in the triplet state (3O2) when in its normal ground state. When ground state oxygen plus the newly excited photosensitizer in its triplet state join, the unstable photosensitizer transfers its energy to the stable triplet oxygen. Oxygen now has one of its unpaired electrons reverse its spin, so there are now no unpaired electron spins and oxygen is now in its atypical singlet excited state. Singlet oxygen must transfer its energy to regain stability, and it does so in the form of peroxides and free radicals, which are presumed to promote most of the desired cascade of destructive tissue changes. After the photosensitizer has released its excess energy, it returns to its ground (singlet) state and can then absorb more light.

Verteporfin (Visudyne)

Verteporfin (Visudyne, Novartis Pharmaceuticals USA and Novartis Ophthalmics International) is a second-generation photosensitizer, synthesized from protoporphyrin. Verteporfin is described as a “benzoporphyrin derivative monoacid ring A,” where ring A refers to the conjugation position of the chlorine structure. Most PDT agents are of the porphyrin class, with four pyrrole rings. If one of the rings is reduced and yields a chlorine molecule, this alters the absorption properties into the far-red end (between 630 and 690 nm). When molecular oxygen is present, verteporfin, upon activation by low-intensity nonthermal laser light at 689 nm, becomes an efficient generator of singlet oxygen (1O2). The light selected is in the far-red spectrum, corresponding to the chemical’s absorbance profile, with greater transmission through both blood and tissue compared with lower wavelengths. As with other photosensitizing substances, verteporfin accumulates preferentially in target tissue after intravenous administration.The drug has a mean serum half-life of 5 hours. There is little metabolism by the liver, and most of the drug is excreted unchanged in the feces.