Natural Products News and Research

US Pharm. 2006;3:54-62.

Finding accurate, reliable, scientific information about natural products can be a difficult task. For health care providers interested in disease prevention and wellness, however, access to such information is important. For the past six years, the Office of Dietary Supplements (ODS) of the National Institutes of Health has published the Annual Bibliography of Significant Advances in Dietary Supplement Research , a compilation of significant research examining the use of dietary supplements.¹ Each year, an international team of reviewers in the fields of nutrition, botanical sciences, and public health evaluates articles nominated by peer-reviewed journals and ranks them. Last year, 325 papers were nominated, and ODS selected the top 25 articles of 2004 for publication in the bibliography, which was published in October.¹

According to the Dietary Supplements Health and Education Act of 1994, a dietary supplement is defined as a product, other than tobacco, intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (a) a vitamin; (b) a mineral; (c) an herb or other botanical; (d) an amino acid; (e) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (f) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (a), (b), (c), (d), or (e). ¹ This year's bibliography is divided into the following categories: antioxidants, phenolics, and flavonoids; vitamins; minerals; botanicals; fatty acids; and other. The purpose of this article is to provide a summary of these findings.

Research involving antioxidants, phenolics, and flavonoids examined the effect of these supplements on Alzheimer's disease, cancer, and cholesterol levels. Other research of antioxidants looked at the chemoprotective properties of green tea, black tea, and green tea extract in cancer patients; the antiatherogenic properties of oat phenolic compounds; and the inhibition of tumor cell proliferation and angiogenesis by luteolin. Positive results were described in research studying the effect of vitamin E and vitamin C supplementation on the incidence and progression of Alzheimer's disease in elderly subjects in Utah.² While the combined use of vitamin E and vitamin C was associated with a reduced prevalence and incidence of Alzheimer's disease, no benefit was seen with the use of vitamin E or vitamin C alone, with multivitamins alone, or with vitamin B–complex supplements.²

Antioxidant supplementation was also associated with a lowered total cancer incidence and overall mortality in men in a French study.³ A cocktail of antioxidants provided at doses that could be achieved with a healthy diet was associated with a lowered total cancer incidence and overall mortality in men but not women. Researchers concluded that antioxidant supplementation may have protective effects against cancer in men because of their low or marginal baseline intakes of certain antioxidants, especially beta-carotene.³

The effect of antioxidants on other cancers was also studied. A systemic review and meta-analysis of all randomized trials conducted between 1945 and 2003 comparing antioxidant supplements with placebo for the prevention of gastrointestinal (GI) cancers suggested that there might be an overall harmful effect on mortality from supplementation. This suggests that antioxidant supplementation might not be helpful to prevent GI cancers and may actually increase overall mortality.⁴ The effect of antioxidant supplementation on prostate cancer in mice was the subject of a Canadian study.⁵ At the end of the study, prostate cancer had developed in 73.7% of the mice consuming a standard diet and in all of the mice consuming a high-fat diet. Only 10.5% of the mice receiving a standard diet plus antioxidant supplementation and 15.8% of the mice receiving a high-fat diet plus supplementation developed cancer, leading the researchers to suggest that further study in humans was warranted. Antioxidant supplementation in this study was proportional to the equivalent of 800 IU of vitamin E, 200 mcg of selenium, and 50 mg of lycopene in humans.⁵

A study comparing the bioavailability of tea polyphenols in green tea extract versus in green tea and black tea aimed to determine if the extract's antioxidant activity compared favorably to that of tea. Results of the study indicated that polyphenols might have greater bioavailability from green tea extract than from tea.⁶ Extract supplementation may be a method of administering large doses of tea polyphenols to cancer patients without the side effects of caffeine that are associated with green and black tea beverages. Polyphenols in green and black tea leaves have been studied extensively for their antioxidant activity and as cancer chemoprotective agents.⁶

Two other antioxidant studies looked at the effect of antioxidants on atherosclerosis and serum low-density lipoprotein (LDL) cholesterol levels.⁷ The first looked at the role that major components of soluble phenolic fractions in oats have in modulating the inflammatory process associated with atherosclerosis. Oat avenanthramides inhibited adhesion to endothelial cells and proinflammatory cytokines and chemokines, which have important roles in recruiting immune cells and leukocytes to the site of inflammation.⁷ The second study, a meta-analysis of eight randomized clinical trials conducted between 1966 and 2003, examined the effects of soy isoflavones on LDL cholesterol levels.⁸ Reductions in serum LDL cholesterol were observed in individuals with normal and high blood cholesterol levels, which suggests that consumption of 90 mg/day of soy isoflavones, independent of soy protein, can significantly reduce serum LDL cholesterol.⁸

The effects of luteolin, a plant flavonoid, on tumor growth and angiogenesis (i.e., the growth of new blood vessels from preexisting vessels) was evaluated in a series of animal and lab experiments. ⁹ Angiogenesis has a key role in tumor growth. Luteolin reduced tumor volume by 50% compared to control. Luteolin also significantly reduced angiogenesis in tumors that were formed. These results add to the growing body of evidence that luteolin and other flavonoids have chemoprotective effects. ⁹

Vitamin research looked at the link between vitamin C and the risk of cardiovascular disease in women with diabetes, vitamin D and the risk of fracture, vitamin E and respiratory tract infections in the elderly, folate therapy and the risk of cardiovascular disease, folate therapy and coronary stent restenosis, multivitamin supplements and HIV disease, multiple vitamin supplementation in early infancy and the effect on immune response, and plant sterols' effect on the bioavailability of fat-soluble vitamins and cholesterol levels.¹⁰

Data from the Iowa Women's Health Study Cohort were analyzed for the association between vitamin C supplementation and mortality from cardiovascular disease in 1,923 postmenopausal women with diabetes but not coronary artery disease at baseline.¹⁰ The women were monitored over a period of 15 years or until death, whichever occurred first. Participants were categorized by total vitamin C intake from food and supplements, from food alone, or from supplements alone. The data were adjusted for age, total energy and alcohol intake, smoking status, hypertension history, and waist–hip ratio. Vitamin C intake greater than 300 mg/day from supplements was positively associated with increased mortality in diabetic, postmenopausal women, but not in women without diabetes. Intake of vitamin C greater than 300 mg/day from food sources was not associated with increased mortality. The studies suggest high doses of supplemental vitamin C could be harmful to elderly women with diabetes.¹⁰

A meta-analysis of five randomized controlled trials between 2002 and 2004 examined the effect of vitamin D supplementation, with or without calcium, on preventing falls in the elderly (mean age, 60 years and older).¹¹ Vitamin D supplementation reduced the risk of falling by 22%. The combination of vitamin D and calcium resulted in a 9% improvement in body sway (as measured by balance and stability), as compared with calcium alone. The findings suggest that further research is needed to confirm that vitamin D supplementation reduces the risk of falls. ¹¹

The effect of vitamin E supplementation on respiratory tract infections in the elderly was the subject of a study involving 617 people 65 years or older who were given either 200 IU of vitamin E (DL-alpha-tocopherol) or placebo for one year.¹² The study showed no effect of vitamin E on the incidence or duration of all upper or lower respiratory tract infections, or on antibiotic use. However, data analysis showed a protective effect of vitamin E supplementation, regardless of gender or smoking status, in lowering the incidence of the common cold.¹²

The effects of folic acid supplementation on cardiovascular health were the subject of two studies. A randomized double-blind trial compared high-dose folate therapy (25 mg vitamin B₆ , 0.4 mg vitamin B₁₂, 2.5 mg folic acid) and low-dose folate therapy (200 mcg vitamin B₆, 6 mcg vitamin B₁₂, 20 mcg folic acid) with the risk of recurrent stroke.¹³ After a two-year follow-up, no differences in the incidence of recurrent stroke, coronary heart disease events, or death were found; however, the mean reduction in homocysteine levels were greater in the high-dose group. The study was unable to demonstrate a benefit of folate therapy on cardiovascular disease outcomes but did show that high-dose folate therapy lowered homocysteine levels more effectively.¹³

Another randomized controlled trial analyzed the effect of folate therapy on coronary stenting.¹⁴ A total of 636 patients who had successful coronary stenting were randomly assigned to receive either an intravenous bolus dose of 1 mg folic acid, 5 mg vitamin B ₆, and 1 mg vitamin B₁₂ followed by daily oral administration of 1.2 mg folic acid, 48 mg vitamin B₆, and 60 mcg vitamin B₁₂ , or placebo for six months. Patients on folate therapy had a greater progression of disease and extent of restenosis than did the placebo group. These data suggest that individuals with coronary artery stents should not routinely use folate therapy to reduce the risk of restenosis.¹⁴

The effect of multivitamin supplements on the progression of HIV disease and mortality was examined in a randomized placebo-controlled study in Tanzania from 1995 to 2003.¹⁵ Over 1,000 HIV-positive pregnant women were randomly assigned to receive either vitamin A alone, multivitamins without vitamin A, multivitamins with vitamin A, or placebo. During the course of the study, 7% of the women receiving multivitamins progressed to stage 4 AIDS, as compared to 12% of women in the placebo group. Of the women receiving multivitamins, 19% died, as compared to 25% of those given placebo. In addition, the women taking multivitamins had fewer symptoms of late-stage HIV disease and significantly lower HIV virus levels than women who did not. Women receiving vitamin A alone did not vary significantly from the placebo group, and adding vitamin A did not increase the benefit of multivitamins. The results suggest multivitamin supplementation delays the need to initiate treatment with anti-AIDS drugs.¹⁵

A complex, observational study tested the hypothesis that multivitamin use in infancy may increase the risk of food allergies and asthma.¹⁶ Data were collected from the 1988 National Maternal and Infant Health Survey and included perinatal, maternal, and child data (from birth to age 3 years) from over 8,000 mothers and were combined with data from the same cohort in the 1991 Longitudinal Follow-up. Early vitamin use (before 6 months of age) was associated with an increased risk of food allergies in both formula-fed and breast-fed children and with an increased risk of asthma in African-Amercian children. These results indicate a need for randomized controlled clinical trials to determine the relationship between early multivitamin use and asthma and food allergies.¹⁶

Sterols from plant foods such as soy reduce the absorption of dietary cholesterol and lower LDL serum levels. However, the effect of plant sterols on the absorption of fat-soluble, health-promoting compounds such as beta-carotene and vitamin E has raised concern. These effects were analyzed in a randomized, placebo-controlled, double-blind, crossover study of young adult men with normal cholesterol levels.¹⁷ Both free and esterified plant sterols from soy reduced the absorption of cholesterol in the gut by 60% and reduced the bioavailability of
beta-carotene by about 50% and of vitamin E by about 20%. While the clinical significance of these reductions is not clear, the authors suggested regular consumption of carotenoid-rich foods to counterbalance these effects when taking plant sterols to reduce cholesterol levels.¹⁷

Zinc supplementation in conjunction with antibiotic therapy was shown to shorten the duration of severe pneumonia and the length of hospitalization in children ages 2 to 23 months in a Bangladesh study.¹⁸ Children were randomized to receive 20 mg of zinc acetate syrup or placebo. The zinc supplement was safe and well-tolerated in children as young as 2 months. Given that pneumonia is a leading cause of morbidity and mortality in children younger than 5 years, these findings may help significantly reduce health care costs for children with marginal zinc status and pneumonia.¹⁸

The absorption of zinc supplements was studied to determine optimal dosages.¹⁹ The proportion of absorbed zinc declined steadily when doses were above 10 mg; absorption was marginal at doses over 20 mg. These results suggest that zinc supplementation should not exceed 20 mg. These findings may be important because zinc is often used to prevent and treat conditions such as diarrhea, common cold, and pneumonia. ¹⁹

The trace element selenium is considered to have preventative cancer properties. Several observational studies have shown an increased risk of cancer in people living in areas with low selenium levels in the soil. A pooled analysis of three large, randomized trials determined there is a decreased risk of colorectal cancer with
optimal selenium status.²⁰

The hyperforin content of St. John's wort preparations has been found to be responsible for affecting the metabolism of cyclosporine in patients receiving kidney transplants. St. John's wort formulations with a high hyperforin content (42 mg) had a 52% reduction in cyclosporine blood levels and required increased doses of cyclosporine to maintain immunosuppression. Formulations with a low hyperforin content (0.6 mg) did not affect blood concentrations or alter cyclosporine-dosing requirements. It is hypothesized that hyperforin content is responsible for the numerous drug interactions of St. John's wort and that formulations with a low hyperforin content may be safer to use when taking other medications. ²¹

Grape seed extract supplementation was studied in rats to determine if changes in brain proteins might protect against pathologic events. Novel proteins were identified in the brains of rats that were fed grape seed extract as compared to the nontreated group. These proteins may mediate the neuroprotective actions of grape seed extract. The study was the first to identify and quantify specific proteins in animal tissues altered by grape seed extract and indicate a link between these proteins and diseases of the central nervous system. The promise of these findings warrants further animal studies.²²

Conjugated linoleic acid (CLA), a naturally occurring free fatty acid found mainly in meat and dairy products, is sold as a dietary supplement to reduce body fat and increase lean body mass. Short-term studies in humans have produced mixed results. A new study was conducted to determine the long-term efficacy and safety of both free and conjugated CLA on total body fat and lean body mass in overweight adults. Body fat mass was lower in both groups supplemented with CLA at six and 12 months, compared to placebo. Weight and body mass index were lower in the conjugated CLA group but not in the free CLA group at 12 months when compared with placebo. The free CLA group experienced significant increases in lean body mass that were not seen in the conjugated CLA group. The study provides promising evidence for the use CLA supplements in altering body fat in healthy, overweight adults.²³

The role of fish oil supplements in improving cognitive perfor­ mance was the subject of an observational study of individuals born in Scotland in 1936. Cognitive function was tested in 1947 at age 11 and in 2000–2001 at age 64. Self-reported information on supplement use and risk factors for vascular disease were assessed in 2000–2001. Although the study offered little support for fish oil supplementation at a young age, supplement use was associated
with improved cognitive function later in life.²⁴

Dehydroepiandrosterone (DHEA) is a naturally occurring steroid hormone that declines with age in both men and women. Results from animal studies have shown that administration of DHEA reduces abdominal fat and improves insulin resistance, which are both associated with metabolic syndrome and increase a person's risk of heart disease. Confirmation of these findings in human trials was the subject of a study involving 56 men and women ages 65 to 78 years who were randomly assigned to receive either 50 mg/day of DHEA or placebo for six months. After six months, visceral and subcutaneous fat were lower in the DHEA group compared with the placebo group. The insulin area under the curve during the glucose tolerance test was lower in the DHEA versus the placebo group. However, DHEA increased estradiol levels in men and women and increased testosterone levels in women, which warrants concern about the safety of long-term use. Additional long-term studies are needed to assess the safety of DHEA to help manage metabolic syndrome.²⁵

Supplementation with glucosamine sulfate was shown to be helpful in the management of osteoarthritis in postmenopausal women in two three-year studies. Postmenopausal women older than 45 years with primary osteoarthritis received crystallized glucosamine sulfate or placebo for three years. After three years, there was no narrowing of joint space in the glucosamine treated group, but there was narrowing
of joint space (-0.33 mm) in the placebo group. The glucosamine-treated group also showed improvement in the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, a battery of 24 questions that assess pain, disability, and joint stiffness. The women in
the placebo group demonstrated a worsening trend of the WOMAC index.²⁶

Summary
The Annual Bibliography of Significant Advances in Dietary Supplement Research published by the ODS of the National Institutes of Health is an excellent resource for recent dietary supplement research information. Such reliable, scientific information allows pharmacists to intelligently discuss nutritional and dietary supplement issues with their patients. This year's bibliography provided both positive and negative results of dietary supplement research.

Antioxidant supplements appeared to negatively impact the mortality rates from GI cancers. High-dose vitamin C supplementation increased the rate of mortality from cardiovascular diseases in women with diabetes. Folate therapy increased the progression of cardiovascular disease after stenosis and the need for restenosis. Multivitamin supplement use by infants younger than 6 months seemed to increase the risk of asthma and food allergies. Soy plant sterols decreased the bioavailability of beta-carotene and alpha-tocopherol.

Some supplements showed mixed positive and negative results. Soy plant sterols not only reduced the bioavailability of fat-soluble nutrients but also greatly reduced the absorption of dietary cholesterol. High-dose folate therapy could not demonstrate a benefit on cardiovascular disease outcomes but did exhibit an increased reduction in homocysteine serum levels compared to low-dose folate therapy. DHEA supplementation reduced both abdominal fat and insulin resis­ tance but also increased estradiol levels in men and women and testosterone levels in women, leaving the safety of its long-term use in doubt. In addition, fish oil supplements did not improve childhood intelligence but did improve cognitive function in later life.

Many studies did demonstrate positive results from dietary supplement use. Combined use of vitamin C and E appears to protect against the progression of Alzheimer's disease. Antioxidant levels achievable with a healthy diet had protective effects against cancer in men with previously low or marginal antioxidant levels. Antioxidants were also very effective in blocking prostate cancer in mice. Oat phenolic compounds had a pronounced effect in modulating inflammatory processes involved in atherosclerosis plaque formation. Luteolin, a plant-food flavonoid, inhibited tumor cell proliferation and angiogenesis.

In addition, soy isoflavones significantly reduced serum LDL levels. Vitamin D supplementation reduced falls in the elderly, while vitamin E supplements reduced the incidence of colds in this population. Multivitamins helped slow the progression of HIV-related disease in pregnant women, and zinc reduced the severity of pneumonia in children. An inverse relationship was demonstrated between blood selenium levels and colorectal cancer incidence. The consumption of grape seed extract in rats demonstrated the development of brain proteins believed to protect against neurological diseases. CLA reduced body fat mass in healthy adults. Finally, glucosamine sulfate reduced the progression of osteoarthritis in postmenopausal women.

REFERENCES
1. Office of Dietary Supplements, National Institutes of Health. Annual Bibliography of Significant Advances in Dietary Supplement Research. October 2005. NIH Publication No. 05-5312.
2. Zandi PP, Anthony JC, et al. Reduced risk of Alzheimer's disease in users of antioxidant supplements: the Cache County Study. Arch Neurol. 2004;61:82-88.
3. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004;164:2335-2342.
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5. Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH. Antioxidants block prostate cancer in lady transgenic mice. Cancer Res. 2004;64:5891-5896.
6. Henning SM, Niu Y, Lee NH, et al. Bioavailability and antioxidant activity of tea flavanols after consumption of green tea, black tea, or a green tea extract supplement. Am J Clin Nutr . 2004;80:1558-1564.
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18. Brooks WA, Yunus M, Santosham M, et al. Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial. Lancet. 2004;363:1683-1688.
19. Tran CD, Miller LV, Krebs NF, et al. Zinc absorption as a function of the dose of zinc sulfate in aqueous solution. Am J Clin Nutr. 2004;80:1570-1573.
20. Jacobs ET, Jiang R, Alberts DS, et al. Selenium and colorectal adenoma: results of a pooled analysis. J Natl Cancer Inst. 2004;96:1669-1675.
21. Mai I, Bauer S, Perloff ES, et al. Hyperforin content determines the magnitude of the St. John's wort–cyclosporine drug interaction. Clin Pharmacol Ther. 2004;76:330-340.
22. Deshane J, Chaves L, Sarikonda KV, et al. Proteomics analysis of rat brain protein modulations by grape seed extract. J Agric Food Chem. 2004;52:7872 -7883.
23. Gaullier JM, Halse J, Hoye K, et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr. 2004;79:1118-1125.
24. Whalley LJ, Fox HC, Wahle KW, et al. Cognitive aging, childhood intelligence, and the use of food supplements: possible involvement of n-3 fatty acids. Am J Clin Nutr. 2004;80:1650-1657.
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26. Bruyere O, Pavelka K, Rovati LC, et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from 3-year studies. Menopause. 2004;11:138-143.

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