Antioxidants

Overview

The term “antioxidant” refers to the activity possessed by numerous vitamins, minerals and other phytochemicals to serve as protection against the damaging effects of highly reactive molecules known as free radicals. Free radicals have the ability to chemically react with, and damage, many structures in the body. Particularly susceptible to oxidative damage are the cellular membranes, mitochondrial membranes, and DNA of virtually all cells. Free radical reactions and oxidative damage have been linked to many of the “diseases of aging” such as heart disease and cancer. Antioxidant dietary supplements are routinely marketed with direct and implied claims for cellular protection, anti-aging effects, prevention of cancer and heart disease, reduction of wrinkles, enhancement of immune function, and prmotion of vision and eyesight.

The free radical theory of aging (and disease promotion) holds that through a gradual accumulation of microscopic damage to our cell membranes, DNA, tissue structures and enzyme systems, we begin to lose function and are predisposed to disease. In response to free radical exposure, the body increases its production of endogenous antioxidant enzymes (glutathione peroxidase, catalase, superoxide dismutase), but it has been theorized that supplemental levels of dietary antioxidants may be warranted in some situations to help prevent excessive oxidative damage to muscles, mitochondria and other tissues (such as during/following intense exercise and exposure to pollutants such as second hand smoke and oxidizing radiation such as sunlight).

Comments

The 4 key nutritional antioxidants, vitamins C and E, beta-carotene and selenium, are well studied, relatively inexpensive, and widely available as dietary supplements. There are also a multitude of fruit and vegetable phytonutrient extracts that also possess significant antioxidant activity. In most cases, phytonutrient extracts tend to be quite expensive, although their potent antioxidant activity may allow dosages to be fairly small. Some of the more popular antioxidant nutrients found in commercial dietary supplements also include Zinc, Copper, Ginkgo biloba extract, Grape seed extract , Pine bark extract, Lycopene, Lutein, Quercetin, and Alpha lipoic acid as well as dozens of others.

When it comes to antioxidant supplementation, it is the overall collection of several antioxidants that is important (rather than any single “super” antioxidant). This concept of balancing supplemental antioxidants is referred to as the “Antioxidant Network.” and is generally comprised of 5 major classes of antioxidants: Carotenoids, Tocopherols/Tocotrienols (Vitamin E), Vitamin C, Thiols (e.g. sulfur-containing compounds such as alpha-lipoic acid and cysteine), and Bioflavonoids. In theory, smaller doses of these antioxidant agents, when given in combination, will help to regenerate one another following free radical quenching – thus delivering a more effective and safer antioxidant regimen than with higher doses of isolated antioxidant nutrients. This combined approach to antioxidant supplementation is also logical because certain antioxidants will work primarily against certain free radicals and in specific parts of the body (e.g. vitamin E against hydroxyl radicals and within cell membranes or vitamin C against superoxide and within aqueous spaces).

Scientific Support

Thousands of studies have clearly documented the beneficial effects of dozens of antioxidant nutrients – and there are thousands of nutrients and phytochemicals that possess significant antioxidant activity in the test tube. Increased dietary intake of antioxidant nutrients, such as vitamins C and E, minerals such as selenium and various phytonutrients such as extracts from grape seed, pine bark and green tea have all been linked to reduced rates of oxidative damage and may help reduce the incidence of chronic diseases such as heart disease and cancer. Readers are referred to the specific sections dealing with each antioxidant nutrient for a full discussion of the pros and cons of supplementation with a given nutrient.

Safety / Dosage

At the typically recommended levels, the majority of antioxidants appear to be quite safe. For example, vitamin E, one of the most powerful membrane-bound antioxidants, also has one of the best safety profiles. Doses of 100-400 IU of vitamin E have been linked to significant cardiovascular benefits with no side effects. Vitamin C, another powerful antioxidant, can help to protect and restore the antioxidant activity of vitamin E, and is considered safe up to doses of 500-1,000mg. Higher doses of vitamin C are not recommended because of concerns that such levels may cause an “unbalancing” of the oxidative systems and actually promote oxidative damage instead of preventing it. Another popular antioxidant, beta-carotene, is somewhat controversial as a dietary supplement. Although diets high in fruits and vegetables deliver approximately 5-6 mg of carotenes daily, these would be a mixture of beta-carotene and other naturally occurring carotenoids. Concern was raised several years ago by studies in which high dose beta-carotene supplements appeared to promote lung cancer in heavy smokers. Those studies provided beta-carotene supplements of 20-60mg/day – about 5-10 times the levels that could reasonably be expected in the diet.

Based on the available scientific evidence, daily supplementation with Vitamin E (100 to 400 IU), Vitamin C (250 to 1,000mg), Beta-carotene (5 to 6mg), and Selenium (70 to 200mcg) appears to be prudent.

References

1.Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001 Oct;119(10):1439-52.

2.Age-Related Eye Disease Study Research Group. The effect of five-year zinc supplementation on serum zinc, serum cholesterol and hematocrit in persons randomly assigned to treatment group in the age-related eye disease study: AREDS Report No. 7. J Nutr. 2002 Apr;132(4):697-702.

3.Balakrishnan SD, Anuradha CV. Exercise, depletion of antioxidants and antioxidant manipulation. Cell Biochem Funct. 1998 Dec;16(4):269-75.

4.Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials. Ophthalmic Physiol Opt. 2003 Sep;23(5):383-99.

5.Dragan I, Dinu V, Mohora M, Cristea E, Ploesteanu E, Stroescu V. Studies regarding the antioxidant effects of selenium on top swimmers. Rev Roum Physiol. 1990 Jan-Mar;27(1):15-20.

6.Evans JR, Henshaw K. Antioxidant vitamin and mineral supplementation for preventing age-related macular degeneration. Cochrane Database Syst Rev. 2000;(2):CD000253.

7.Gale CR, Ashurst HE, Powers HJ, Martyn CN. Antioxidant vitamin status and carotid atherosclerosis in the elderly. Am J Clin Nutr. 2001 Sep;74(3):402-8.

8.Girodon F, Blache D, Monget AL, Lombart M, Brunet-Lecompte P, Arnaud J, Richard MJ, Galan P. Effect of a two-year supplementation with low doses of antioxidant vitamins and/or minerals in elderly subjects on levels of nutrients and antioxidant defense parameters. J Am Coll Nutr. 1997 Aug;16(4):357-65.

9.Grievink L, Smit HA, Veer P, Brunekreef B, Kromhout D. Plasma concentrations of the antioxidants beta-carotene and alpha-tocopherol in relation to lung function. Eur J Clin Nutr. 1999 Oct;53(10):813-7.

10.Grievink L, Zijlstra AG, Ke X, Brunekreef B. Double-blind intervention trial on modulation of ozone effects on pulmonary function by antioxidant supplements. Am J Epidemiol. 1999 Feb 15;149(4):306-14.

11.Hammond BR Jr, Johnson MA. The age-related eye disease study (AREDS). Nutr Rev. 2002 Sep;60(9):283-8.

12.Jacques PF, Halpner AD, Blumberg JB. Influence of combined antioxidant nutrient intakes on their plasma concentrations in an elderly population. Am J Clin Nutr. 1995 Dec;62(6):1228-33.

13.Ji LL. Oxidative stress during exercise: implication of antioxidant nutrients. Free Radic Biol Med. 1995 Jun;18(6):1079-86.

14.Kaikkonen J, Kosonen L, Nyyssonen K, Porkkala-Sarataho E, Salonen R, Korpela H, Salonen JT. Effect of combined coenzyme Q10 and d-alpha-tocopheryl acetate supplementation on exercise-induced lipid peroxidation and muscular damage: a placebo-controlled double-blind study in marathon runners. Free Radic Res. 1998 Jul;29(1):85-92.

15.Kanter M. Free radicals, exercise and antioxidant supplementation. Proc Nutr Soc. 1998 Feb;57(1):9-13.

16.Marangon K, Herbeth B, Lecomte E, Paul-Dauphin A, Grolier P, Chancerelle Y, Artur Y, Siest G. Diet, antioxidant status, and smoking habits in French men. Am J Clin Nutr. 1998 Feb;67(2):231-9.

17.McBee WL, Lindblad AS, Ferris FL 3rd. Who should receive oral supplement treatment for age-related macular degeneration? Curr Opin Ophthalmol. 2003 Jun;14(3):159-62.

18.McQuillan BM, Hung J, Beilby JP, Nidorf M, Thompson PL. Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS). J Am Coll Cardiol. 2001 Dec;38(7):1788-94.

19.Mitchell P, Smith W, Cumming RG, Flood V, Rochtchina E, Wang JJ. Nutritional factors in the development of age-related eye disease. Asia Pac J Clin Nutr. 2003;12 Suppl:S5.

20.Rousseau AS, Hininger I, Palazzetti S, Faure H, Roussel AM, Margaritis I. Antioxidant vitamin status in high exposure to oxidative stress in competitive athletes. Br J Nutr. 2004 Sep;92(3):461-8.

21.Sackett CS, Schenning S. The age-related eye disease study: the results of the clinical trial. Insight. 2002 Jan-Mar;27(1):5-7.

22.Sanchez-Quesada JL, Jorba O, Payes A, Otal C, Serra-Grima R, Gonzalez-Sastre F, Ordonez-Llanos J. Ascorbic acid inhibits the increase in low-density lipoprotein (LDL) susceptibility to oxidation and the proportion of electronegative LDL induced by intense aerobic exercise. Coron Artery Dis. 1998;9(5):249-55.

23.Schunemann HJ, Grant BJ, Freudenheim JL, Muti P, Browne RW, Drake JA, Klocke RA, Trevisan M. The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population. Am J Respir Crit Care Med. 2001 Apr;163(5):1246-55.

24.Singh RB, Ghosh S, Niaz MA, Singh R, Beegum R, Chibo H, Shoumin Z, Postiglione A. Dietary intake, plasma levels of antioxidant vitamins, and oxidative stress in relation to coronary artery disease in elderly subjects. Am J Cardiol. 1995 Dec 15;76(17):1233-8.

25.Singh RB, Niaz MA, Bishnoi I, Sharma JP, Gupta S, Rastogi SS, Singh R, Begum R, Chibo H, Shoumin Z. Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: the Peerzada Prospective Study. Acta Cardiol. 1994;49(5):453-67.

26.Ward JA. Should antioxidant vitamins be routinely recommended for older people? Drugs Aging. 1998 Mar;12(3):169-75.

27.Wolters M, Hermann S, Hahn A. Effects of 6-month multivitamin supplementation on serum concentrations of alpha-tocopherol, beta-carotene, and vitamin C in healthy elderly women. Int J Vitam Nutr Res. 2004 Mar;74(2):161-8.

28.Wood LG, Fitzgerald DA, Lee AK, Garg ML. Improved antioxidant and fatty acid status of patients with cystic fibrosis after antioxidant supplementation is linked to improved lung function. Am J Clin Nutr. 2003 Jan;77(1):150-9.

29.Yu BP, Kang CM, Han JS, Kim DS. Can antioxidant supplementation slow the aging process? Biofactors. 1998;7(1-2):93-101.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

Beta-Carotene

Overview

Beta-carotene is part of a large family of compounds known as carotenoids (which includes over 600 members such as lycopene and lutein). Carotenoids are widely distributed in fruits and vegetables and are responsible, along with flavonoids, for contributing the color to many plants (a rule of thumb is the brighter the fruit/vegetable, then the higher the content of flavonoids and carotenoids). In terms of nutrition, beta-carotene’s primary role is as a precursor to vitamin A (the body can convert beta-carotene into vitamin A as it is needed). It is important to note that while beta-carotene and vitamin A are described together in many nutrition texts, they are not the same compound and they have vastly different effects in the body. Although beta-carotene can be converted to vitamin A in the body, there are important differences in terms of action and safety between the two compounds. Beta-carotene, like most carotenoids, is also a powerful antioxidant – so it has been recommended to protect against a variety of diseases such as cancer, cataracts and heart disease. The best food sources are brightly colored fruits and veggies such as cantaloupe, apricots, carrots, red peppers, sweet potatoes and dark leafy greens.

Evidence from population studies suggests that mixed sources of carotenoids from foods (eating lots of fruits and veggies) can help protect against many forms of cancer and heart disease as well as slow the progression of eye diseases such as cataracts and macular degeneration. As an antioxidant, it is logical (perhaps) to assume that beta-carotene (which is the primary carotenoid in the diet), may be responsible for a significant portion of the observed beneficial health effects of carotenoid-rich diets – but it is not logical to then assume that high doses of isolated beta-carotene supplements will deliver the same anti-cancer and cardioprotective effects observed with diets high in fruits and vegetables.

Comments

Beta-carotene supplements are relatively inexpensive and widely available. There are synthetic and natural sources of beta-carotene supplements. The natural forms typically come from algae (Dunaliella salina), fungi (Blakeslea trispora) or palm oil. In terms of conversion to vitamin A, the “trans-” form of beta-carotene has the maximum conversion rate. Synthetic beta-carotene is nearly all in the trans form (98%), while natural forms vary in the form of beta-carotene that they provide (the different forms are known as isomers). Among natural forms of beta-carotene, the fungal form provides the highest concentration of trans beta-carotene (94%) followed by algae sources (64%) and palm oil sources (34%) – so from the perspective of vitamin A conversion, either the synthetic form or the fungal form of beta-carotene will provide the highest conversion into active vitamin A. From a “mixed” carotenoid perspective, however, beta-carotene derived from algae also provides the “cis-” isomer of beta-carotene (about 31%) as well as alpha-carotene (3-4%) and other carotenoids (1-2%). Beta-carotene derived from palm oil provides the most “balanced” mixture of carotenoid isomers (34% trans-beta, 27% cis-beta, 30% alpha and 9% other carotenoids) – but it also has the lowest vitamin A conversion (because it only provides 34% as the trans form).

Based on the current scientific evidence, beta-carotene supplements should be utilized/recommended primarily as a way to supply adequate levels of vitamin A for proper nutrition – and not for prevention of cancer, heart disease or eye problems (although a “dietary” level of mixed carotenoids of up to 10mg/day probably poses no significant health risk). There may also be some benefit in consuming beta-carotene supplements for skin protection (reduced risk of sunburn) – but this effect may be more pronounced when taken in conjunction with other antioxidants such as lycopene, lutein, selenium, and vitamins C and E.

Scientific Support

It is important to note that the vast majority of the scientific evidence for the health benefits of beta-carotene comes from studies that looked at food sources of beta-carotene (and other carotenoids, often referred to as “mixed” carotenoids) – not supplements. From population (epidemiological) studies, we know that a high consumption of fruits and vegetables is associated with a significant reduction in many diseases – especially several forms of cancer (lung, stomach, colon, breast, prostate, and bladder). Because the data suggested that the “active” components in a plant-based diet may be carotenoids, and because beta-carotene is the chief carotenoid in our diets, it was widely believed (until about the mid-1990’s) that the majority of the health benefits attributable to fruits and vegetables may be due to beta-carotene.

One of the largest epidemiological studies, the Physicians’ Health Study (PHS - over 22,000 male physicians) found that while high levels of carotenoids obtained from the diet were associated with reduced cancer risk, beta-carotene from supplements (about 25mg/day) had no effect on cancer risk (Comstock et al. 1997). A possible explanation for this finding may be that while purified beta-carotene may contribute some antioxidant benefits, a “blend” of carotenoids (and/or other compounds in fruits and veggies) is probably even more important for preventing cancer. It may even be possible that isolated beta-carotene supplements could interfere with absorption or metabolism of other beneficial carotenoids from the diet.

Unfortunately, intervention studies that have looked at purified beta-carotene supplements (not mixed carotenoids) have not cleared up any of the confusion. In 1994, the results from a large (almost 30,000 subjects) supplementation study (ATBC – the Alpha-Tocopherol and Beta-Carotene study) showed not only that beta-carotene supplements (20mg/day for 5-8 years) did not prevent lung cancer in high risk subjects (long-time male smokers), but actually caused an increase in lung cancer risk by almost 20% (Pietinen et al. 1997). This same study also found a 10% increase in heart disease and a 20% increase in strokes among the beta-carotene users. In 1996, another large study (CARET – the Beta-Carotene and Retinol Efficacy Trial) found virtually the same thing – with subjects receiving beta-carotene showing almost 50% more cases of lung cancer (Goodman et al. 1996). These results were so alarming that the National Cancer Institute decided to halt the $40 million study nearly 2 years early. The ATBC study examined long-time heavy smokers, while the CARET study looked at present and former smokers as well as workers exposed to asbestos – all of which can be considered “high-risk” populations for developing lung cancer (which may or may not have contributed to the surprising study results).

On the positive side, beta-carotene has been successfully used for nearly 20 years to treat photosensitivity diseases, such as erythropoietic protoporphyria (EPP) and other skin conditions (Malvy et al. 2001). As such, beta-carotene has found its way into a variety of topical and internally consumed products meant for skin protection. In Europe, one of the most popular uses for carotenoid supplements (primarily beta-carotene and lycopene) is for skin protection during the summer sunbathing months (for “inside-out” sun protection).

Overall, it is interesting to note that of the 3 large-scale clinical trials on beta-carotene supplementation and cancer risk (ATBC, CARET and PHS), all 3 concluded that beta-carotene provided no protection against lung cancer – while 2 of them found a higher risk for lung cancer. However, the association between eating a diet high in fruits and vegetables and a reduced risk for cancer and heart disease remains strong – and there is no current evidence that small amounts of supplemental beta-carotene (such as a multivitamin) is unsafe. A prudent approach to carotenoid supplementation for disease prevention may be to strive to obtain a balanced blend of mixed carotenoids from foods – while reserving purified beta-carotene supplements for skin protection and as a source of vitamin A (see dosage suggestions below).

Safety / Dosage

At recommended dosages, beta-carotene is thought to be quite safe – although at least two large studies have shown that high-dose beta-carotene (20-50mg/day) can increase the risk of heart disease and cancer in smokers. Other reported side effects from high dose beta-carotene supplements (100,000IU or 60mg per day) include nausea, diarrhea and a yellow/orange tinge to the skin (especially hands and feet), which fades at lower doses of beta-carotene. The safest way to get your beta-carotene and other carotenoids is from eating a wide variety of fruits and vegetables.

Beta-carotene (the “trans-“ form) can be converted to vitamin A (3mg of beta-carotene supplies 5,000IU of vitamin A). Although beta-carotene supplements are commonly available in doses of 25,000IU (15mg) per day, and many people consume as much as 100,000IU (60mg) per day, the current state of the scientific literature does not support doses of beta-carotene much higher than those levels recommended for supplying vitamin A precursors (about 5,000-10,000IU per day of beta-carotene = 3-6mg).

References

1.Collins AR, Olmedilla B, Southon S, Granado F, Duthie SJ. Serum carotenoids and oxidative DNA damage in human lymphocytes. Carcinogenesis. 1998 Dec;19(12):2159-62.

2.Comstock GW, Alberg AJ, Huang HY, Wu K, Burke AE, Hoffman SC, Norkus EP, Gross M, Cutler RG, Morris JS, Spate VL, Helzlsouer KJ. The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity. Cancer Epidemiol Biomarkers Prev. 1997 Nov;6(11):907-16.

3.Daviglus ML, Dyer AR, Persky V, Chavez N, Drum M, Goldberg J, Liu K, Morris DK, Shekelle RB, Stamler J. Dietary beta-carotene, vitamin C, and risk of prostate cancer: results from the Western Electric Study. Epidemiology. 1996 Sep;7(5):472-7.

4.Goodman GE, Thornquist M, Kestin M, Metch B, Anderson G, Omenn GS. The association between participant characteristics and serum concentrations of beta-carotene, retinol, retinyl palmitate, and alpha-tocopherol among participants in the Carotene and Retinol Efficacy Trial (CARET) for prevention of lung cancer. Cancer Epidemiol Biomarkers Prev. 1996 Oct;5(10):815-21.

5.Hininger IA, Meyer-Wenger A, Moser U, Wright A, Southon S, Thurnham D, Chopra M, Van Den Berg H, Olmedilla B, Favier AE, Roussel AM. No significant effects of lutein, lycopene or beta-carotene supplementation on biological markers of oxidative stress and LDL oxidizability in healthy adult subjects. J Am Coll Nutr. 2001 Jun;20(3):232-8.

6.Kiokias S, Gordon MH. Dietary supplementation with a natural carotenoid mixture decreases oxidative stress. Eur J Clin Nutr. 2003 Sep;57(9):1135-40.

7.Malila N, Virtamo J, Virtanen M, Pietinen P, Albanes D, Teppo L. Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers. Eur J Clin Nutr. 2002 Jul;56(7):615-21.

8.Malvy DJ, Favier A, Faure H, Preziosi P, Galan P, Arnaud J, Roussel AM, Briancon S, Hercberg S. Effect of two years' supplementation with natural antioxidants on vitamin and trace element status biomarkers: preliminary data of the SU.VI.MAX study. Cancer Detect Prev. 2001;25(5):479-85.

9.Nelson JL, Bernstein PS, Schmidt MC, Von Tress MS, Askew EW. Dietary modification and moderate antioxidant supplementation differentially affect serum carotenoids, antioxidant levels and markers of oxidative stress in older humans. J Nutr. 2003 Oct;133(10):3117-23.

10.Paolini M, Abdel-Rahman SZ, Sapone A, Pedulli GF, Perocco P, Cantelli-Forti G, Legator MS. Beta-carotene: a cancer chemopreventive agent or a co-carcinogen? Mutat Res. 2003 Jun;543(3):195-200.

11.Pietinen P, Ascherio A, Korhonen P, Hartman AM, Willett WC, Albanes D, Virtamo J. Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Epidemiol. 1997 May 15;145(10):876-87.

12.Pryor WA, Stahl W, Rock CL. Beta carotene: from biochemistry to clinical trials. Nutr Rev. 2000 Feb;58(2 Pt 1):39-53.

13.Vainio H. Chemoprevention of cancer: lessons to be learned from beta-carotene trials. Toxicol Lett. 2000 Mar 15;112-113:513-7.

14.van Poppel G. Epidemiological evidence for beta-carotene in prevention of cancer and cardiovascular disease. Eur J Clin Nutr. 1996 Jul;50 Suppl 3:S57-61.

15.Woodall AA, Britton G, Jackson MJ. Dietary supplementation with carotenoids: effects on alpha-tocopherol levels and susceptibility of tissues to oxidative stress. Br J Nutr. 1996 Aug;76(2):307-17.

16.Woutersen RA, Wolterbeek AP, Appel MJ, van den Berg H, Goldbohm RA, Feron VJ. Safety evaluation of synthetic beta-carotene. Crit Rev Toxicol. 1999 Nov;29(6):515-42.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

Bilberry

Overview

Bilberry is a good example of an herbal medicine that is representative of a current trend in the interest in fruits with high anthocyanin content. Not only are these supplements and foods safe, but they are potent antioxidants, of a class that are just beginning to be understood and appreciated. The anthocyanin antioxidant compounds are also often helpful for maintaining vascular, cardiovascular and eye health. Bilberry’s main active components are the flavonoids called anthocyanidins, of which there are many in bilberry, and the carotenoids (zeaxanthin and lutein) (McKenna et al, 2001).

Bilberry has been used in several therapeutic applications due to its wide range of activities. Bilberry has been reported to be vasoprotective, antiedemic, antioxidant, anti-inflammatory, anti-ulcer, and astringent. The anthocyanosides in bilberry are known to exhibit many functions, including collagen-stabilizing and reinforcing activity, decreasing capillary permeability, relaxing smooth musculature, increasing urinary output, and increasing the contractile strength of the myocardium, a few of the key preclinical studies are listed below (McKenna et al., 2001):

•An extract of bilberry was tested for its effects on microvascular permeability in a hamster cheek pouch model of ischemia reperfusion injury. Bilberry caused a significant reduction in microvascular impairment, preservation of arteriolar tone, reduced number of leukocytes adhering to venular walls, preservation of capillary perfusion, and an increase in microvascular permeability (Bertuglia et al., 1995).

•Detre et al. (1986) tested the effect of bilberry on vascular permeability in rats with induced hypertension. Bilberry was found to bring the vascular permeability, which is increased in hypertensive states, back to normal levels in the hypertensive rat model.

•Bilberry has been shown to have an anti-aggregatory activity similar to acetylsalicylic acid, and in a study with 30 volunteers, it was shown to inhibit aggregation at the first 30 and 60 days, but return to normal after 120 days. This study was able to support the theory that bilberry’s action depends on an increase in cyclic AMP and/or platelet thromboxane A2 (Pulliero et al., 1989).

•Bilberry has been found to exhibit a protective effect on the capillary walls by stabilizing membrane phospholipids and by increasing connective tissue biosynthesis (Mian et al., 1977).

•Bilberry has exhibited antioxidant activity in a number of antioxidant models. An extract in mice with induced liver peroxidation showed significant antioxidant activity at doses of 250 and 500 mg/kg p.o (Martín-Aragón et al., 1999).

Comments

Bilberry seems to be a safe and efficacious preventative to degenerating vascular illnesses, and an excellent dietetic aid for diabetics for the prevention of macular degeneration. As the population in the U.S. ages, it is sure to need good, safe, preventatives of age-related degeneration such as bilberry.

Scientific Support

Bilberry extract (Tegens® at 160 mg, 240 mg, or 340 mg daily) administered to pregnant patients exhibiting venous insufficiency of the lower limbs or acute hemorrhoids caused a progressive amelioration of symptoms during the 3 month of treatment. The symptoms were reduced by: 94.6% for pruritus; 87.5% for paresthesias; 80.1% for cramps; 78.5% for pain; 60% exhaustion and the sensation of heaviness; and 75-83% for hemorrhoids. No side effects or adverse reactions were found for either mothers or the babies included in the study (Teglio et al., 1987).

Boniface et al. (1985) confirmed pharmacological evidence in experimental studies that bilberry’s anthocyanosides reduce the biosynthesis of polymeric collagen and glycoproteins (that are responsible for the vascular complications in diabetics), and compared this to a couple of clinical studies involving diabetics. The clinical studies administered bilberry anthocyanosides to diabetics, and found increases in vascular health; thus, confirming the pharmacological findings.

Bilberry anthocyanosides (Tegens® at 480 mg daily for 30 days) administered to patients with venous diseases characterized by phlebopathic stasis significantly improved measures of venous health compared to conventional treatments. Symptoms monitored were limb heaviness, pain levels, dyschromic and dystrophic skin phenomena, and limb edema (Ghiringhelli et al., 1978).

Patients with retinopathies were administered bilberry anthocyanosides (Tegens® at 160 mg daily) in a preliminary study. In the treatment phase of the study, 50% showed improvements vs. only 20% in the control group. In those patients with hard exudates in the back pole, 35% in the control phase worsened over the course of the study vs. 20% of the treatment group. In those with circinate disposition of the hard exudates, 15% worsened in the control group vs. 10% in the treatment group (Repossi et al., 1987).

Bravetti et al. (1987) examined the effects of anthocyanosides from bilberry extract administered with vitamin E (180 mg of a 25% standardized extract and 100 mg vitamin E) in patients with mild senile cortical cataracts. The treatment was found to reduce lens opacity in 97% of the cases examined.

A double-blind, placebo-controlled crossover study examined the effect of bilberry extract (Tegens® at 160 mg, twice daily) in 14 patients with diabetes or hypertension. An improvement of 77-90% in clinical symptomology was found for the patients after one month, and bilberry was concluded to be a safe and effective therapy (Perossini et al., 1987).

Anthocyanosides from bilberry (Tegens® at 480 mg three times daily) were administered to 10 patients with diabetic retinopathy in a pilot study. In the course of the study (6 months) improvements were seen in the retinal picture of all patients. The authors concluded bilberry to be of strong promise in the therapy of diabetic retinopathy (Orsucci et al., 1983).

Patients with various retinopathies were administered bilberry (Difarel 100® at 200 mg, three times daily) and were found to have improvements in their conditions. The authors noted that improvements in the hemorrhagic tendency and vascular permeability, while being improved in all participants, were most evident in those with diabetic retinopathy (Scharrer and Ober, 1981).

Bilberry extract was administered to normal subjects at 300 mg daily in a placebo-controlled study. Significant improvements were found in measures of visual health: adaptive ability to light and dark, macular recuperation time, and chromatic discrimination (Sala et al., 1979).

An anthocyanoside rich extract of bilberry was administered to 40 normal subjects in a placebo-controlled trial to test its effect on various aspects of visual health. In the treatment group, improvements were found in all tested visual functions, including darkness adaptation, macular sensitivity, and adapto-cinematographic thresholds compared to placebo (Jayle and Aubert, 1964).

Under conditions of food rationing and little or no fruits, during WWII, the British Royal Air Force pilots were reported to use bilberry to improve their night vision. Subsequently, numerous clinical studies were performed to try to confirm this effect (McKenna et al., 2001). In one of these studies, the long-term administration of a bilberry extract (Difrarel 100®- 100 mg of anthocyanosides and 0.005 b-carotene; 4 tablets daily for 8 days) showed improvements in visual functions of 14 air traffic controllers. The results found decreased dazzling effect; decreased visual fatigue, and a quicker adaptation of scotopic vision (Belleoud et al., 1966).

Safety / Dosage

Bilberry dosages are usually recommended in the range of 240-640 mg daily for most uses (usually 500 mg), and less than 300 mg/daily for eye health. Bilberry extracts are usually based on anthocyanoside content, and a 25% standardized extract is the standard preparation (McKenna et al., 2001):

Bilberry is quite safe, as it is also a traditional food, and the only reported side effects of bilberry have been digestive disturbances. This has not yet been clearly investigated and it is possible that most of these reports were idiosyncratic. Furthermore, bilberry is often formulated with minerals, and these are well-known to cause some digestive disturbance when taken without food (McKenna et al., 2001).

Very high doses of bilberry have a blood thinning action, and should be avoided with use of warfarin or antiplatelet drugs (McKenna et al., 2001).

References

1.Belleoud L, Leluan D, Boyer Y. [Study on the effects of anthocyanin glucosides on the nocturnal vision of air traffic controllers]. Revue de Medecine Aeronautique et Spatiale 1966; 3:45.

2.Bertuglia S, Malandrino S, Colantuoni A Effect of Vaccinium myrtillus anthocyanosides on ischaemia reperfusion injury in hamster cheek pouch microcirculation. Pharmacol Res. 1995 Mar-Apr;31(3-4):183-7.

3.Boniface R, Miskulin M, Robert L et al. Pharmacological properties of myrtillus anthocyanosides: correlation with results of treatment of diabetic microangiopathy, in: Farkas, L.; M. Gabor; and F. Kallay (eds.), Flavonoids and Bioflavonoids: Proceedings of the 7th Hungarian Bioflavonoid Symposium. 1985; Budapest, Hungary: Akademiai Kiado.

4.Bravetti GO, Fraboni E, Maccolini E. Preventive medical treatment of senile cataract with vitamin E and Vaccinium myrtillus anthocyanosides: clinical evaluation. Annali di Ottalmologia e Clinica Oculistica 1987; 115:109-116.

5.Detre Z, Jellinek H, Miskulin M, Robert AM. Studies on vascular permeability in hypertension: action of anthocyanosides. Clin Physiol Biochem. 1986;4(2):143-9.

6.Ghiringhelli C, Gregoratti L, Marastoni F. Capillarotropic action of anthocyanosides in high dosage in phlebopathic statis. Minerva Cardioangiol. 1978 Apr;26(4):255-76.

7.McKenna DJ, Jones K, Hughes K (eds). Botanical Medicines: A Desktop Reference for the Major Herbal Supplements. 2001 Haworth Press: New York

8.Martín-Aragón S, Basabe B, Benedi JM et al. In vitro and in vivo antioxidant properties of Vaccinium myrtillus. Pharmaceutical Biology1999; 37:109-113.

9.Mian E, Curri SB, Lietti A. et al. Anthocyanosides and microvessels wall:new findings on the mechanism of action of their protective effect in syndromes due to abnormal capillary fragility. Minerva Medica 1977; 68:3565-3581.

10.Perossini M, Guidi G, Chiellini S. et al. [Diabetic and hypertensive retinopathy therapy with Vaccinium myrtillus anthocyanosides (Tegens): double-blind, placebo-controlled clinical trial. Annali di Ottalmologia e Clinica Oculistica 1987; 113:1173-1190.

11.Pulliero G, Montin S, Bettini V. et al. Ex vivo study of the inhibitory effects of Vaccinium myrtillus anthocyanosides on human platelet aggregation. Fitoterapia 1989; 55:69-74.

12.Repossi P, Malagola R, De Cadilhac C. The role of anthocyanosides on vascular permeability in diabetic retinopathy. Annali di Ottalmologia e Clinica Oculistica 1987; 113:357.

13.Scharrer A, Ober M. Anthocyanosides in the treatment of retinopathies. Klinische Monatsblatter für Augenheilkunde1981; 178:386-389.

14.Teglio L, Mazzanti C, Tronconi T et al. Vaccinium myrtillus anthocyanosides (Tegens) in the treatment of venous insufficiency of the lower limbs and acute hemorrhoids in pregnancy. Quaderni di Clinica Ostertrica e Ginecologica 1987; 42:221-231.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.