Integrity Nutraceuticals International in Florida was founded in 1999 as a raw materials supplier, specializing in novel ingredients from China and India — but it was its launch of Cinnulin PF in 2003 that the company has become best known for.

Cinnulin PF is a water extract of cinnamon that contains insulin-potentiating fractions that may be helpful for type 2 diabetes, obesity, syndrome X and other ailments associated with insulin resistance. It is the only patented and USDA-tested natural cinnamon water extract on the North American market.

Studies conducted at universities worldwide illustrate the benefits of cinnamon, including the prevention of insulin resistance, and improved glucose and lipid profiles. It wasn?t until 2004, however, and a US Department of Agriculture study published in the Journal of Agricultural and Food Chemistry, that the bioactives responsible for these positive effects were isolated. The study found that polyphenolic polymers in cinnamon water extract "may function as antioxidants, potentiate insulin action and be beneficial in the control of diabetes."

What makes Cinnulin PF unique among cinnamon extracts is its high concentration of these polymer compounds.

"We have isolated bioactive compounds, specifically trimers and tetramer, that are classified as Type-A Polymers," explains Tim Romero, INI vice president. "Cinnulin PF is the only extract on the market to be standardized for these compounds."

US sales from 2004 to 2005 increased more than 400 per cent

Cinnulin PF also is unique in that it contains double-linked polymers rather than single-linked. "This is due to the unique raw material source we use," Romero explains. "Even though it is classified as Cinnamomum cassia, not all of the barks included in this botanical class contain the double linkage, which is the active compound in cinnamon."

These distinctions have earned attention in the marketplace. US sales from 2004 to 2005 increased more than 400 per cent. Still, with much of its customer base centered in the US, there is plenty of room to grow."Distribution outside the US is minimal, therefore, we have yet to pursue any special ?certifications? there," Romero says. "The European market is similar to the US, as many sell plain extracts and whole cinnamon, unaware of a superior option."

Safety concerns have been an issue when evaluating cinnamon because some straight cinnamon extracts may contain harmful, fat-soluble compounds, the US Department of Agriculture has said. By contrast, an aqueous extract like Cinnulin PF removes the potentially harmful compounds while leaving the active Type-A polymers intact, the company says.

Integrity Nutraceuticals has formed an exclusive partnership with the USDA to further research this area.

Cinnulin PF can be used in capsules, tablets, powders, drinks, bars as well as other food products. The challenge is that the active components are sensitive to heat, appearing to oxidize, so the key, Romero says, is to minimize the time and temperature area under the curve.

At the November SupplySide West convention, INI unveiled results from its first clinical study on Cinnulin PF.1 Twenty-four prediabetic men and women were matched according to baseline FBG and then randomly assigned to supplement their diet with either Cinnulin PF (250mg twice daily) or placebo for 12 weeks. All subjects were tested for changes in total and regional body fat as well as body fat distribution prior to and after six and 12 weeks of supplementation. Subjects in the Cinnulin PF group noted significant increases in lean mass (+1.1%: from 53.7 ? 11.8 kg [pre] to 54.3 ? 11.8 kg [post], p<0.002), decreases in FBG (-8.4%: from 116.3 ? 12.8 mg/dL [pre] to 106.5 ? 20.1 mg/dL [post], p<0.01), and decreases in systolic blood pressure (-3.8%: from 133 ? 14 mm Hg [pre] to 128 ? 18 mm Hg [post], p<0.001) compared to the placebo group (lean mass: from 43.9 ? 11.1 kg [pre] to 43.1 ? 10.9 kg [post]; FBG: from 112.0 ? 10.0 mg/dL [pre] to 113.1 ? 14.7 g/dL [post]; systolic blood pressure: from 133 ? 22 mm Hg [pre] to 142 ? 20 mm Hg [post]). Additionally, within-group analyses uncovered small, but statistically significant decreases in body fat (-0.7%: from 37.9 ? 9.2 % [pre] to 37.2 ? 8.9 % [post], p<0.02) in the Cinnulin PF group. The team concluded this data supports the efficacy of Cinnulin PF. The extract can also favourably alter body composition when consumed for at least 12 weeks. References 1 Ziegenfuss, TN, Hofheins, JE et al. Effects of a proprietary aqueous cinnamon extract on glucose regulation, lipid profiles, and body composition in prediabetic men and women. Ohio Research Group. Wadsworth, Ohio 44281. [email protected]

The Traditional Herbal Medicinal Products Directive, now law across the European Union, will make life difficult for smaller herb manufacturers and restrict consumer choice, according to a leading industry group.

Ric Hobby, chairman of the UK's Council for Responsible Nutrition (CRN), said the costs of registering herbal medicines, establishing Good Manufacturing Processes and tracing herbs back to the farm will compel some traders to pull products from the market, others to increase prices and others to go out of business completely.

"It is going to make it very tough on small companies, especially those that want to bring new products to market," Hobby told FF&N."If they haven't got a long history of safe use, it is a time-consuming process that could cost companies more than $150,000 per product."

Even the UK's Medicines and Healthcare products Regulatory Agency (MHRA), a strong advocate of the directive, estimates the average cost of a single-herb product registration at about $70,000.

It is expected some products will become exclusively available from licensed herbalists whom it appears the legislation allows to use unregistered herbs. Some see this as a loophole that may allow some herbs to gain free-market status under the directive's history-of-safe-use criteria (because if they are being dispensed by herbalists, it can be argued this is creating a history of safe use).

Others fear the directive's licensing requirements will mean fewer herbs available to practitioners as well.

INDUSTRY SUPPORT
Some support CRN, along with others such as the Herbal Forum, which represents herbal practitioner associations across Europe, that continue to lobby for some herbal products to be regulated under food and food supplements law.

Others are more optimistic, such as Rachel Dale, sales and marketing manager at UK-based Herbal Concepts. "There is a lot of confusion about the issue and many consumers are unaware that many herbal products on the market are not currently tested or regulated," she said."The EU Directive will help manufacturers and retailers communicate to consumers."

June Crisp, sales and marketing director at UK manufacturer Bio-Health, expressed commitment to the directive. "We have always been aware of the frailty of the herbal medicines industry because until now, consumers could not be sure of the quality of the products they were buying," she said."The directive will help raise herbal medicine to a new platform that will allow the use of herbal medicines for the treatment of an array of health conditions to be taken seriously by health professionals."

Organisations such as the European Herbal Practitioners Association and the British Herbal Medicine Association support the directive on similar grounds.

Robin Ward, commercial manager at Swiss-based botanicals supplier Linnea, said his company supported the directive, but held reservations about the difficulty in gaining health claims for herbs that do not meet the history-of-safe-use criteria.

EXPECT HIGH COSTS
The directive applies pharmaceutical-style checks to herbal products that cannot demonstrate a 30-year history of safe use within the EU, or 15 years within the EU and 15 years' use elsewhere. While not as exacting as pharmaceutical registration procedures, meeting these standards will be costly.

For products that combine herbs with other nutrients, fresh registrations will often be required because such offerings have no history of safe use as combinations.

"If a company changes the formulation of a product, they will have to apply afresh," Hobby at CRN noted. "Very few products in the combination area will qualify under this directive. We would like to see an extension of the Food Supplements Directive to cover the majority of these kinds of products."

Similarly, new herbal products that arrive in Europe in the form of Indian or Chinese medicines, or from the relatively liberal US market, will have to go through the registration process, even if they have decades of safe use in their own jurisdictions.

While this aspect of the directive is potentially exclusionary, in European markets that previously prohibited the mixing of herbs with other nutrients, the directive will have a liberalising effect.

The MHRA said the directive sought to ensure quality and boost consumer confidence in herbal products."Until now, unlicensed herbal remedies in the UK have not had to meet set standards for safety, quality and consumer information," it said in a statement. "Responsible companies following high standards have been at a commercial disadvantage."

An adjustment period is built into the directive that permits products legally on the market on April 30, 2004, to retain their status until 2011, at which point registration will be required.

The average American falls short by nearly 20g per day of the recommended dietary fibre intake. L Steven Young, PhD, surveys the plethora of ingredient sources available today, and explains the costs, functionality and nutritional issues to consider when fortifying foods with dietary fibre

The US Food and Drug Administration and the US Department of Agriculture have clearly stated the importance of dietary fibre to the diet, but neither has directly defined the term ?dietary fibre?.

The FDA does mandate its inclusion as part of the nutrition label. To paraphrase The Code of Federal Regulations,¹ ?dietary fibre? for nutrition-labelling purposes is defined by the methods used to measure it. Further, the code makes it voluntary to list either or both ?soluble fibre? and ?insoluble fibre.?

But what exactly is dietary fibre? Since 1987, no fewer than 20 definitions have been proposed. The most recent are by the American Association of Cereal Chemists in 2000² and the Food and Nutrition Board of the Institute of Medicine, National Academy of Sciences in 2001.³ The exacting detail of these definitions and the background science are quite lengthy. However, to date and after much ongoing debate, neither definition has been adopted for nutrition-labelling purposes. It remains that ?dietary fibre? is defined, at least in the US, by officially approved analyses.

From a digestibility perspective, dietary fibre can be defined as the sum total of all carbohydrate polymers greater than degree of polymerization three (ie, three or more monosaccha-rides, or DP 3, in length) that are 1) not digested nor absorbed in the small intestine, 2) partially or totally fermented in the colon, and/or 3) partially or totally excreted in the faeces. This covers a lot of ground and may be too simplistic, but is consistent with most proposed definitions and recognizes the indigestibility of dietary fibre.

Definitions and methods of analysis keep evolving as does ingredient science and technology. Multiple benefits of dietary fibre are assumed. Key functional and nutritional benefits will differ according to the amount and type of dietary fibre to be considered and the specific application. It is the food technologist?s responsibility to understand and manage all key considerations.

The importance of dietary fibre is clearly outlined in Table 1 below, which shows the total number of dietary fibre-related references made on packaged foods in 2005. Such labelling declarations include, but may not be limited to,?high fibre,??low carb,? ?no carb,? ?low sugar,? ?sugar free,? etc. It is interesting to note that although ?low carb? and ?no carb? are purely US marketing terms, worldwide references to dietary fibre on packaged foods outpace US references nearly 12 to one.

The reason dietary fibre is of interest is not only is it a key nutrient for good health, but there is also the apparent ?gap? between need as expressed as daily value and actual consumption. Most nutritionists agree that adults need to consume a minimum of 25g fibre per day.

Actually, recommendations have been made (National Academy of Sciences) that dietary fibre consumption should be 30-35g per day and in some instances up to 50g per day. As we actually consume only 12-13g dietary fibre per day, the gap between consumption and need is increasing, not decreasing. This puts pressure on food technologists to find dietary fibre ingredients that can easily and benignly be added to foods.

A PLETHORA OF CHOICES
Key considerations include the food that is to be formulated, the amount of dietary fibre to add to the food, the composition and function of dietary fibre-containing ingredients available, and what you want to say about the finished food.

There are more than 60 sources of dietary fibre (Table 2) with more being commercialized daily, so selection of the right ingredient for the right purpose can be daunting. Composition (soluble and insoluble dietary fibre) is critical, as are minor constituents such as sugars, fats/oils, proteins, salts, etc., that could limit utility of any given ingredient (Table 3). Functionality is measured in terms of water binding, flavour, colour and texture of not only the ingredient itself but how that ingredient affects the functionality of the finished food.

Labelling becomes important based on what you want (principal display panel) and need (ingredient listing, nutrition facts panel) to declare. Further, nutritional efficacy can influence the amount and type of dietary fibre to be used as several health claims or structure/function claims may or may not be available for consideration. Finally, as always, economics play a role.

The cost of dietary-fibre ingredients, of course, depends on availability. The per-unit raw-material cost is important, but does not tell the whole story. The cost per unit dietary fibre and the cost per unit of functionality (the real reason the ingredient is being used) of dietary fibre need also be considered. Many times, raw-material costs may seem excessive, but the cost per unit of real functionality may, in fact, be the least-cost option. Care is necessary when considering costs, but extremely critical to success.

Key ingredient functionalities necessary to take into account include colour, flavour, particle size, density, solubility, contribution of food structure, dispersability (or lack thereof), water binding (moisture retention), sugar content, fat content, calorie content, and effect on overall shelf life and acceptability.

In applications, dietary fibre can function to allow formulation of fibre-enhanced foods of all types. ?Low/no sugar added? or ?sugar-free? foods,?low/no net? carbohydrate foods, fat-modified foods, caloric-modified foods, medical foods and various dietary supplements are included. These all can take advantage of the nutritional efficacy of dietary fibre that can typically include one or more of the following:

• Effect on regularity and reduction of certain intestinal diseases, including certain types of cancers
• Effect on healthful intestinal function
  ? Effect on maintaining healthful blood sugar (low-glycaemic index, low-glycaemic load)
• Effect on maintaining healthful serum lipids (triglycerides, cholesterol, etc)
• Effect on maintenance of healthful deposition of fat
• Effect on growth of healthful micro flora in the colon. From these effects, implied claims, nutrient content claims, structure/function claims, and a variety of health-related claims may be available to the food technologist. It is important to make sure that scientific evidence is available to support the appropriate claim.

APPLICATION OPTIONS
Applications for dietary fibre can vary from the old to the truly new and novel.

Beverages: Care is necessary when selecting dietary-fibre ingredients for beverages. Dietary fibres for this application most always will be water soluble; however, each must be compatible with the conditions under which the final product is processed, packaged, stored and distributed. If the ingredient is not compatible, expect to see declining dietary-fibre content accompanied by increases in simple sugars; sweetness; and other quality factors such as colour, flavour and viscosity changes. This is true for all applications, not just beverages.

Processed meats: Processed meats are not typical applications for dietary fibre ingredients; however, when control of moisture loss in cooking is necessary, many dietary fibres have great utility. Typically, high water-binding fibres can also add to dry, mealy, grainy texture in the finished meat product so proper selection and use is important.

Cereals: Extruded, flaked or baked cereals are classical application areas for dietary fibre. Colour, texture and water binding make water-insoluble dietary fibres particularly attractive. However, when limits are met that create functional or sensory problems, judicial use of a select water-soluble fibre can help attain total dietary-fibre contents worth promoting.

Snack foods: Fried and baked snacks are also good products to fortify with dietary fibre. As with other applications there are limits to use, typically defined by flavour and colour, and functional limits if the snack item is extruded or not. There are also significant factors to be considered between cold and high-pressure extrusion executions.

Confectionery: Dietary-fibre fortification of hard and soft confections is possible.

Certainly, the cold extrusion of shelf-stable bars or baked confections can limit the amount and type of dietary fibre to consider.

The utility of any given fibre is a function of its flavour, colour, performance and cost; not all fibres are meant for all applications

Miscellaneous applications: The dietary-fibre content of products such as sauces, dressings, soups, etc, can be enhanced simply. Again, use good judgement to select the most effective dietary fibre for the application at hand.

Medical foods, dietary supplements:

The gap between consumption and need makes the delivery of true fibre dietary supplements of great interest. Powders, tablets, capsules, etc, all have utility in offering ways to truly add supplementation to the diet.

MATCHING SCIENCE WITH CLAIMS
Adding dietary fibre to foods is desirable and demand for packaged foods with enhanced dietary-fibre contents is real and sustainable. Claims and opportunities are market and applications dependent.

The utility of any given dietary-fibre ingredient is a function of its flavour, colour, performance and cost. Not all dietary fibres are meant for all applications. Combinations of dietary-fibre ingredients are fine and many times desirable when appropriate to overcome individual limitations of use.

It is critical to match nutrition science to the intended dietary fibre and application of choice. Matching science with the appropriate claim to be made can help a formulator get to the finish line more efficiently and more accurately.

Finally, it is all about flavour and taste. However, matching product features (facts) to consumer benefits (reasons to buy) across the entire intended shelf life of the food is critical to ultimate product development success.

REFERENCES
1 21CFR101.9(c) (6) and 21 CFR 101.9(g) (2)
2 www.aacc.org
3 www.iom.edu

Steven Young, PhD, is principal of Steven Young Worldwide in Houston, Texas, a technical and nontechnical consulting firm specializing in the development and use of novel new food ingredients.
www.stevenyoung.net
Respond: [email protected] All correspondence will be forwarded to the author.

TABLE 1: NEW FOODS AND BEVERAGES 2005* Package claim Total new products Worldwide US High fibre (or similar) 2,078 918 Low carb 1,200 1,200 No carb 173 159 Low sugar 754 754 Sugar-free 1,200 918 *DataMonitor, compliments of David Michael & Co; annualized for 2005

TABLE 2: SELECT DIETARY FIBRE INGREDIENTS Acacia Agar Alginates Amaranth Apple Apricot Arabinogalactan Barley Buckwheat Carrageenans Carrot fibre Cellulosics Citrus fibre Cocoa bran Date Dry plum Fig Flaxseed Ghatti Guar Gum arabic Inulin Karaya Locust bean gum Nutmeat brans Oat bran Oat fibre (hulls) Oligosaccharides Pea bran Pectins Polydextrose Psyllium Resistant maltodextrins Resistant starches Rice bran Sesame hulls Soy bran (hulls)-Cellulose Soy oligosaccharides-CMC, MCC Sugar beet fibre-MC, HPMC Tomato fibre Tragacanth Vegetable fibres Walnut bran Wheat bran White bran Xanthan gum

TABLE 3: DIETARY FIBRE (DF) COMPOSITION OF SELECT INGREDIENTS Basis Total Insoluble DF Soluble DF per cent dry Apple fibre 40 30 10 Alginate 90 0 90 Corn bran 42-88 42-88 0 Rice bran 24 22 2 Oat bran (hulls) 92 87-92 0.5-5 Soy bran(hulls) 80-922 79-92 1-2 Soy oligosaccharide 90 0 90-92 Cellulose 95 95 0 Modified cellulosics 95 0 95 Resistant maltodextrin 90 0 90 Wheat bran (hard) 50 42 8 Wheat bran (soft) 27 21 6 Resistant starches Varies Varies Varies

Prostate support, cardio protection, repair from UV radiation — lycopene can do it all.

Mark J Tallon, PhD, uncovers the growing body of science behind this multi-faceted ingredient

The lovable tomato has caused quite a stir scientifically speaking over the past few years. Recent market projections by the Business Communication Co (BCC)¹ suggest the carotenoid market will breach the $1 billion mark by 2009 and lycopene sales will surpass $26 million, according to Frost & Sullivan.²

Although at present the food colourant market is the leading carotenoid outlet, the fastest-growing segment for carotenoid sales is poised to boom from dietary supplements and fortified foods. These rapid upturns in possible market revenue have not gone unnoticed.

Such is the case for European behemoths DSM (Roche) and BASF, who at present control three-fourths of the global carotenoid market. Word on the street, as reported by BCC, suggests these market statistics are unlikely to change for at least the next five years.

So how have these statistics been impacted by the scientific turnover of lycopene research over the past 10 years? Where is the research heading? And what are the immediate and long-term challenges facing both the carotenoid and lycopene market?

A DECADE OF GROWTH
Over the past 10 years, we have seen some remarkable growth in the academic interest in tomatoes, carotanoids, and, ultimately, lycopene. The yearly lycopene publication number over the past 10 years has increased by more than 400 per cent (tomatoes and carotenoids by 80 and 170 per cent, respectively).

This vast increase in research is reflective of the global growth of carotenoids sales for the enhancement of health. From the early beginnings of Dr Giovannuchi?s epidemiological-based insights, the antioxidant activities of carotenoid intake³ has now been confirmed by clinically validated, double-blinded and randomized interventions.

But where is this latter research taking the supply and manufacturing chain? And what opportunities are emerging for hooking new public interest in tomato-based extracts for enhancing health and slowing deleterious disease states?

PROSTATE HEALTH
I would be remiss without giving an overview of a defining disease state regarding lycopene?s action: prostate health. Prostate cancer is a worldwide health problem, with an estimated 230,000 new cases occurring in the US in 2004 and 30,000 deaths.⁴ This places prostate cancer as the second-leading cause of cancer death in US men.⁴

The prostate health crisis led to a search for a prevention strategy that was effective from a clinical and fiscal basis. Soon, epidemiological evidence of the protective role of tomatoes in the US diet provided a possible answer ^3,5 as men who consumed the most tomato products had significantly lower risk of developing prostate cancer. Following these initial observations, many studies have investigated the effects of tomato product extracts, including lycopene, on diseases of the prostate.^6,7

One of the most interesting studies over the last year is that by Ulrich Siler?s group at Charité University Hospital, Humboldt-University Berlin.8 Although lycopene research has been primarily epidemiological and/or looking into disease states, this current study answers the fundamentals about disease prevention as well as its actions on health issues.

Copenhagen male rats were supplemented with 200ug lycopene/g diet and every two weeks starting at day 0 until week 8, groups of 6-8 rats were killed and their prostates analysed for lycopene accumulation and distribution, changes in gene expression, and prostate lobe weight.

In comparison to placebo following the same dietary intake, less lycopene showed increased lycopene in primarily the alltrans isoform with the highest distribution/uptake observed in the lateral lobe of the prostate. Further analysis went on to show that factors involved in prostate cancer prevention were significantly affected including a reduction in androgenic enzymes, IGF-1, and a selection of inflammatory cytokines. These very insightful results suggest lycopene may offer a long-term strategy in reducing the risk of prostate cancers.

Of greater interest is the effectiveness of lycopene as a treatment strategy, which may depend on where prostate cancers occur (ie, which lobe) due to the localized accumulation of lycopene in the prostate. Re-analysis of epidemiological studies should be able to shed light on this and may be an interesting factor in treatment outcomes.

CARDIO PROTECTION
Antioxidants have been shown time and again to slow the progression of atherosclerosis because of their ability to neutralize damaging oxidative processes.^9,10 The oxidation of low-density lipoproteins, which transport cholesterol into the blood stream, is thought to play an integral role in the etiology of cardiovascular diseases including heart attack and ischemic strokes.^11,12

The logical therapeutic step was to look for antioxidants, which were powerful oxidant quenchers. One of the answers came in the form of the most potent singlet oxygen quencher among carotenoids: lycopene.¹³

Following on from studies suggesting lycopene may affect risk factors of coronary heart disease, new research sought to systematically examine the effects of lycopene in the prevention of platelet aggregation and thrombus formation.¹⁴

Lycopene is known to inhibit sunburn and delay light-induced skin ageing

Researchers found a dose-dependency relationship between lycopene and inhibited platelet aggregation (a risk factor in blood-clot formation and stroke). The biochemical pathways suggested to bring about this effect were inhibition of intra-cellular Ca+2 mobilization and activation of cyclic GMP/nitrate in human platelets, resulting in the inhibition of platelet aggregation.

The results may imply that tomato-based foods such as lycopene are especially beneficial in the prevention of platelet aggregation and thrombosis.¹⁴ Extensive human trials are still required to confirm these results.

SKIN: UV RADIATION
The US cosmeceuticals industry is projected to grow to $4.7 billion by 2020¹⁵ and as such, functional foods competitors have been scrambling to carve out their share of the personal health industry over the past decade. One of the most lucrative and under-exploited niches in this category is dermal health.

Dr Karin Wertz, laboratory head at DSM Nutritionals, also believes this is a very important growth area. "In addition to prostate cancer prevention, lycopene has interesting benefits for skin health, such as inhibition of sunburn and delay of light-induced skin ageing," he says.

Exposure to UV light brings about a series of photo-oxidative reactions that can negatively impact dermal health.¹⁶ The biochemical reactions brought about via photo-oxidation damage the integrity of skin cells leading to premature ageing and in some cases melanomas. One initial skin damage sign visible upon excessive exposure to UV light is erythema (redness or inflammation of the skin or mucous membranes) of which the impact of carotenoids and lycopene have been assessed as a method of decreasing photo-damage.^17,18

Investigators assessed the photoprotective properties of synthetic lycopene in comparison with a tomato extract (Lyc-o-Mato) and a drink containing solubilized tomato extracts (Lyc-o-Guard-Drink).¹⁸ These three different sources amounted to about 10mg/day of lycopene. Following 12 weeks of supplementation, significant increases in serum lycopene levels and total skin carotenoids were observed in all groups.

At weeks 0, 4 and 12, erythema was induced with a solar light simulator. A decrease in erythema formation was observed in all groups from weeks 0-12. Compared to week 0, the reduction in erythema was significantly lower (25 per cent) in the synthetic lycopene group. However, the protective effect was more pronounced in the Lyc-o-Mato (38 per cent) and Lyc-o-Guard-Drink (48 per cent) groups.

In the two latter groups, phytofluene and phytoene may have contributed to protection.¹⁸ Both phytofluene and phytoene exhibit absorption maxima at wavelengths of UV light giving additional protection. Absorption of UV light protects skin from photo-damage and might explain the differences observed between groups.¹⁸

Based on these results, a combination of tomato extracts including lycopene may be the most effective way to protect the skin from UV damage. However, topical applications may give different results and are worth further investigation.

EU PAVES THE WAY
Frost & Sullivan forecasts the European carotenoid market will rise to $419.6 million in 2010² driven by health and ageing issues. But with all the science available on carotenoids and lycopene, public awareness seems to be lagging.

In fact, health claims might even confuse consumers and actively turn them away from purchases, according to the UK?s Food Standards Agency (FSA), which last year conducted extensive research into how consumers understand claims.¹⁹ The agency concluded that consumers respond to them in a nonscientific way.

An example of claims typically misinterpreted are those that refer to cholesterol-lowering effects. These claims were viewed as being for sick people and not the average consumer — and in the worst cases, many consumers didn?t even notice them on the packaging. The FSA concluded that issues of brand familiarity, taste, overall product appeal and ?naturalness? of ingredients were much more important to decision-making.

One point to consider in the future exploitation of the growing carotenoid market is to take a lesson from functional foods brands that are highly successful, yet carry no health claims at all. Yakult, for example, a $2.3 billion brand, talks only about ?wellness from the inside.? We already have some focus of noningredient health claims in lycopene marketing such as Redivivo by DSM.

"Imagine a beverage with a red tomato color and providing a health benefit (a healthy red)," explains Dr Wiltrud Baier, global marketing manager at DSM Nutritional Products. "Redivivo, DSM?s lycopene-based products, is optimal for these applications, as it has excellent stability and performance, as well as the highest quality standards."

DSM may try to use the image and color of the healthy tomato as an integral branding tool rather than relying only on science-based claims.

WHAT?S AHEAD
The science behind lycopene has grown radically over the past decade with no immediate slowdown in academic interest. The fields of research have far surpassed its prostate-based roots, leading to new marketing for a host of health and disease conditions including macular degeneration, infertility, high blood pressure (preeclampsia), asthma, drug-induced carotenoid depletion and ameliorating the decline in oxidative stress during intense fatiguing exercise.

Some of the most relevant issues to food technologists and research scientists are primarily issues of bioavailability and of which cis isomers of lycopene are the most effective in providing a positive impact in specific disease cases.

Following the establishment of lycopene as a positive nutrient in food, scientists are now assessing and searching for new sources of lycopene (ie, red carrots, passionflower fruit, red palm oil) and their influence on human health.

Together, peer-reviewed research and increasing public education of tomato-based extracts will surely provide a sustainable and lucrative niche in the carotenoid industry to 2010 and well beyond.

Mark J Tallon, PhD, is chief science officer of OxygeniX, a London-based consultancy firm specialising in claims substantiation, product development and technical writing.www.oxygenix.com Dr Tallon is also co-founder of Cr-Technologies, a raw-ingredients supplier. www.cr-technologies.net

REFERENCES
1. The Global Market for Carotenoids. Connecticut: Business Communications Co Inc, 2001, p117.
2. Frost & Sullivan. European Carotenoids Market (B260). New York, 2003.
3. Giovannucci E, Ascherio A, et al. Intake of carotenoids and retinol in relation to risk of prostate cancer. J. Natl Cancer Inst 1995; 87; 23:1767-76.
4. American Cancer Society, Cancer Facts and Figures 2004, National Home Office. Atlanta, p1-56.
5. Mills PK, Beeson WL, et al. Cohort study of diet, lifestyle and prostate cancer in Adventist men. Cancer; 1989; 64:598-604.
6. Agarwal S, Rao AV. Tomato lycopene and low-density lipoprotein oxidation: A human dietary intervention study. Lipids 1998; 33:981-4.
7. Kucuk O, Sakr, FH, et al. Lycopene supplementation in men with prostate cancer (PCa) reduces grade and of preneoplasia (PIN) and tumor, decreases serum prostate specific antigen and modulates biomarkers of growth and differentiation [Abstract P1.13]. International Conference on Diet and Prevention of Cancer; 1999 Tampere, Finland.
8. Siler U, Herzog A, et al. Lycopene effects on rat normal prostate and prostate tumor tissue. J.Nutr. 2005; 135(8):2050S-2S.
9. Parthasarathy S. Mechanisms by which dietary antioxidants may prevent cardiovascular diseases. J Med Food 1998; 1:45-51.
10. Morris DL, Kritchevsky SB, et al. Serum carotenoids and coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study. JAMA 1994; 272(18):1439-41.
11. Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet. 1994; 344: 793-795.
12. Parthasarathy S, Steinberg D, et al. The role of oxidized low-density lipoproteins in the pathogenesis of atherosclerosis. Annu Rev Med 1992; 43:219-25.
13. Di Mascio P, Kaiser S, et al. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1998; 274(2):532-8.
14. Hsiao G, Wang, Y, et al. Inhibitory effects of lycopene on in vitro platelet activation and in vivo prevention of thrombus formation. J.Lab.Clin.Med. 2005; 146(4):216-26.
15. Freedonia Group. World Nutraceuticals Report. 2001, Cleveland, Ohio
16. Ribaya-Mercado JD, Garmyn M, et al. Skin lycopene is destroyed preferentially over beta-carotene during ultraviolet irradiation in humans. J.Nutr. 1995; 125(7):1854-9.
17. Fazekas Z., Gao D., et al. Protective effects of lycopene against ultraviolet B-induced photodamage. Nutr Cancer 2003; 47(2):181-7.
18. Aust O, Stahl W, et al. Supplementation with tomato-based products increases lycopene, phytofluene, and phytoene levels in human serum and protects against UV-light-induced erythema. Int J Vitam Nutr Res 2005; 75(1):54-60.
19. Food Standard Agency. Consumer attitudes to food standards: UK report. 2004, London, UK p1-130.

Mark J Tallon, PhD, is chief science officer of OxygeniX, a London-based consultancy firm specialising in claims substantiation, product development and technical writing. www.oxygenix.com. Dr. Tallon is also co-founder of Cr-Technologies, a raw-ingredients supplier. www.cr-technologies.net.

After waiting nearly 18 months for a decision on whether tomatoes and lycopene can have a qualified health claim about prostate cancer reduction, the industry has a qualified answer: yes, sort of.

The Food and Drug Administration responded in November to the petition that American Longevity Inc and H J Heinz Co submitted in May 2004. The FDA stated that there was sufficient scientific evidence to award a qualified health claim for consumption of tomatoes and/or tomato sauce, but not of products containing lycopene.

The claim states: "Very limited and preliminary scientific research suggests that eating one-half to one cup of tomatoes and/or tomato sauce a week may reduce the risk of prostate cancer. FDA concludes that there is little scientific evidence supporting this claim."

To explain why lycopene-containing products were excluded, the FDA stated that lycopene in isolation from other nutritional factors was limited and the research inadequate.

Lycopene supplements manufacturer LycoRed viewed the news positively. "It's a step," said Lizz Stendera with Israel-based LycoRed, maker of Lyc-OMato. "They're all stepping stones to get to the point where we can say, with the FDA backing us … that (lycopene) can shrink tumour size."

San Diego supplements maker American Longevity was less bullish. On its website, the company said it intends to sue the FDA for misleading the public and keeping scientific information out of view.

The vitamin D industry has been boosted by a rush of press highlighting the dangers of deficiency in the nutrient sometimes called the ?sunshine vitamin'. A spate of research has shown how damaging a vitamin D deficiency can be — from bone thinning to oral disease, diabetes, mood disorders and rickets.

While the most readily touted solutions are greater exposure to sunlight or increased consumption of oily fish and dairy products, other solutions are gaining attention. The mandatory fortification of milk and breakfast cereals is a route many countries have embraced.

Supplementation is another obvious alternative, especially in northern hemisphere climates where direct sunlight is sporadic. Along with stand-alone vitamin D supplements, there are many multivitamin options, as well as combo products.

"Vitamin D deficiency is a recognised problem in certain populations," said Ric Hobby, managing director of supplements maker Herbalife Europe. "This kind of research is beneficial to the industry, although we haven't used it in our marketing as yet, mainly because it is our policy not to use scientific evidence as marketing tools."

While the elderly and dark-skinned populations are two groups with higher-than-average rates of deficiency, post-menopausal women are the most at risk; more than half are vitamin D deficient regardless of age, latitude or season.

Another study of nearly 3,000 women in 18 countries found vitamin D deficiency levels of 64 per cent (69 per cent for winter recruits), despite 37 per cent of subjects taking 400IU vitamin D supplements. A US study found more than 90 per cent of women over 70 don't get enough vitamin D.

In Europe, Danish and UK governments have launched campaigns to encourage women to take more vitamin D supplements, while in the US, the American Academy of Dermatology Association has stated it is healthier to gain vitamin D from a supplement than by spending more time in the sun or in tanning salons, because of the associated skin cancer risks, especially in the elderly whose bodies manufacture vitamin D less efficiently.

STUDY CLAIM: L-carnitine supplementation in pregnancy in sufficient doses avoids a striking increase of plasma-free fatty acids, which are thought to be the main cause of insulin resistance and consequently gestational diabetes mellitus.

PUBLISHED: Lohninger A, et al. Carnitine in pregnancy. Chemical Monthly 2005;136:1523-33.

ABSTRACT: Gestational diabetes affects 5-10 per cent of pregnancies. By the 12th week of gestation, mean whole blood and plasma carnitine levels are already significantly lower than those of controls, with a further significant decrease up to parturition. On delivery, maternal plasma carnitine levels are decreased to about half of the concentrations seen in nonpregnant women.

Diminished carnitine levels may cause a downregulation of carnitine palmitoyltransferase1 (CPT1), both the liver isoform (CPT1A) and muscle isoform (CPT1B), carnitine palmitoyltransferase2 (CPT2), and carnitine acetyltransferase (CRAT) in white blood cells of pregnant women, as determined by real time PCR using the LightCyclerSYBR Green technology.

L-carnitine-L-tartrate supplementation of 2g/day resulted in an up to 10-fold increase of the relative mRNA abundances of CPT1B, CPT2 and OCTN2 and a five-fold increase of CPT1A and CRAT.

There is a relationship between the relative mRNA levels of CPT1A and CPT1B and the free fatty acid plasma levels. The substitution of 2g L-carnitine-L-tartrate=d resulted in significantly lower free fatty acid levels compared to untreated controls and the groups substituted with 0.5g/day and 1g/day Lcarnitine, although plasma carnitine levels were not significantly increased.

The most substantial effect was the reduced portion of acylcarnitines on total carnitine in those women receiving 2g/day L-carnitine-L-tartrate. Carnitine substitution resulted in an enhanced excretion of both free carnitine and acylcarnitines, whereas acetylcarnitine accounts for 50-65 per cent of total acylcarnitines.

Due to its excellent safety profile, LCarnipure supplementation may be appropriate for pregnant women to restore their L-carnitine plasma levels and decrease plasma free fatty acids.

POTENTIAL APPLICATIONS: L-Carnipure tartrate consists of 68 per cent L-carnitine and 32 per cent L-tartaric acid. GRAS and kosher-certified, it is ideal for use in food and drink applications.

MORE INFO: +1 678 445 3535
www.lonza.com

STUDY CLAIM: A natural metabolite of dehydropeiandrosterone (DHEA), 3-acetyl-7-oxodehydroepiandrosterone (7-oxo DHEA), when combined with a reduced-calorie diet and an exercise program, resulted in a significant weight loss compared with diet and exercise alone.

PUBLISHED:Zenk JL, et al. Effect of lean system 7 on metabolic rate and body composition. Nutrition 2005 Feb; 21(2):179-85.

ABSTRACT: This randomised, double-blind, placebo-controlled clinical trial evaluated whether a commercial weight-loss product (Lean System 7) would result in less reduction in resting metabolic rate (RMR) in overweight subjects on a calorie-restricted diet and exercise regimen than in subjects using diet and exercise alone.

Forty-seven healthy overweight adults were given three capsules of a commercial weight-loss product twice daily or an identical placebo and followed a calorie-restricted diet and an exercise program for eight weeks. At baseline and week eight, researchers measured RMR, body weight, body mass index, waist and hip circumferences, and body composition by dual-energy X-ray absorptiometry.

Of 47 adults enrolled, 35 completed the study. Subjects taking the weight-loss product had a significant increase in RMR, 7.2 per cent increase vs 0.7 per cent decrease in the placebo group. The treatment group also had a significant decrease in hip circumference, 3.78cm vs 2.07cm in placebo. There were no other statistically significant differences in any other outcome variable, diet composition, exercise compliance or adverse events. The product was well tolerated.

In sum, the supplement produced greater weight loss than exercise alone, mostly from fat. It increased metabolism and weight loss without stimulants.

POTENTIAL APPLICATIONS: 7-Keto, an active ingredient in the Lean System 7 formulation, is sold as a dietary supplement under a wide range of labels.

MORE INFO: +1 952 937 7660
www.humaneticscorp.com

STUDY CLAIM: Sabinsa?s patented Coleus forskohlii extract promotes favourable changes in body composition by significantly increasing lean body mass and decreasing body fat percentages.

PUBLISHED: Godard MP, et al. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res 2005 Aug; 13(8):1335-43.

ABSTRACT: This study examined the effect of forskolin on body composition, testosterone, metabolic rate and blood pressure in overweight and obese (BMI 26kg/m2) men. Thirty subjects were studied in a randomised, double-blind, placebo-controlled study for 12 weeks.

Forskolin was shown to elicit favourable changes in body composition by significantly decreasing body fat percentage (BF%) and fat mass (FM) as determined by DXA compared with the placebo group. Additionally, forskolin administration resulted in a change in bone mass for the 12-week trial compared with the placebo group.

There was a trend toward a significant increase for lean body mass in the forskolin group compared with the placebo group. Serum-free testosterone levels were significantly increased in the forskolin group compared with the placebo group. The actual change in serum total testosterone concentration was not significantly different among groups, but it increased 16.77 +- 33.77% in the forskolin group compared with a decrease of 1.08 +- 18.35% in the placebo group.

Oral ingestion of forskolin (250mg of 10% forskolin extract twice a day) for a 12-week period was shown to favourably alter body composition while concurrently increasing bone mass and serum-free testosterone levels in overweight and obese men.

POTENTIAL APPLICATIONS: Forskolin is a possible supplemental therapeutic agent, available in dietary capsules, for the management of obesity.

MORE INFO: +1 732 777 1111
www.forslean.com

STUDY CLAIM: Patients with osteoarthritis receive fast and effective treatment with SierraSil, a patented mineral complex.

PUBLISHED: Miller MJ, et al. Early relief of osteoarthritis symptoms with a natural mineral supplement and a herbomineral combination: a randomized controlled trial. J Inflamm (Lond) 2005 Oct 21; 2:11.

ABSTRACT: This double-blind, placebo-controlled study was designed to determine if a natural mineral supplement, SierraSil, alone and in combination with a cat?s claw extract (Uncaria guianensis), vincaria, has therapeutic potential in mild to moderate osteoarthritis of the knee. A total of 107 patients with mild to moderate osteoarthritis of the knee were randomly assigned to one of four groups: high-dose SierraSil (3g/day), low-dose SierraSil (2g/day), low-dose SierraSil (2g/day) plus cat?s claw extract (100mg/day), or placebo. The trial was for eight weeks. Primary efficacy variables were WOMAC scores (A, B, C and total). Visual analog score (VAS) for pain, consumption of rescue medication (paracetamol), and tolerability were secondary variables. Safety measures included vital signs and laboratory-based assays.

Ninety-one of the 107 patients successfully completed the protocol. All four groups showed improvement in WOMAC and VAS scores after eight weeks. In all three groups receiving SierraSil, the magnitude of benefits were greater vs placebo (WOMAC total 38-43% vs 27%) but this was not statistically significant. In reference to baseline values, the SierraSil-treated groups had a considerably faster onset of benefits. Placebo-treated individuals failed to show significant benefits at four weeks (11% reduction in total WOMAC).

In contrast, after one or two weeks of therapy, all the SierraSil groups displayed significant reductions in WOMAC scores (p < 0.05) and at week four displayed a 38-43% improvement. VAS was significantly improved at four weeks in all groups, but was significantly greater in all SierraSil groups compared to placebo. Rescue medication use was 28-23% lower in the herbomineral combination and high-dose SierraSil groups, although not statistically different from placebo. Tolerability was good for all groups, no serious adverse events were noted and safety parameters remained unchanged.

The natural mineral supplement, aloneand in combination with a cat?s claw extract, improved joint health and function within one to two weeks of treatment, but significant benefits over placebo were not sustained, possibly due to rescue medication masking.

POTENTIAL APPLICATIONS: SierraSil maybe taken as a dietary supplement.

MORE INFO: +1 888 888 1464
www.sierrasil.com

A worldwide research team assesses the evidence for nutrition-based solutions to the world?s number one killer

Active prevention of coronary heart disease (CHD) is usually started immediately after its first clinical manifestation. Secondary prevention focuses on risk reduction in people with established CHD who are at high risk of recurrent cardiac events and death. It is important to remember that the two main causes of death in these patients are sudden cardiac death (SCD) and heart failure, often resulting from myocardial ischemia and subsequent necrosis.

Most investigators agree that atherosclerosis is a chronic low-grade inflammation disease.¹ Proinflammatory factors (free radicals produced by cigarette smoking, hyperhomocysteinaemia, diabetes, per oxidised lipids, hypertension, elevated and modified blood lipids) contribute to injure the vascular endothelium, which results in alterations of its anti-atherosclerotic and antithrombotic properties. This is thought to be a major step in the initiation and formation of arterial fibrostenotic lesions.¹

Whatever the specific clinical aims of the programme, nutritional evaluation and counselling of each individual with CHD must be a key point of the preventive intervention. Nutrition is, however, only one component of such a programme.

Exercise training, behavioural interventions (particularly to help the patient abstain from smoking) and drug therapy have equally important roles.

We now examine whether diet (and more precisely, certain dietary factors) may prevent (or help prevent) SCD in patients with established CHD. We focus our analyses on the effects of the different families of fatty acids, antioxidants and alcohol.²

N-3 FATTY ACIDS AND SCD
The hypothesis that eating fish may protect against SCD is derived from the results of a secondary prevention trial, the Diet and Reinfarction Trial, which showed a significant reduction in total and cardiovascular mortality in patients who had at least two servings of fatty fish per week.³ The authors suggested that the protective effect of fish might be explained by a preventive action on ventricular fibrillation, since no benefit was observed on the incidence of nonfatal acute myocardial infarction.

Nair and colleagues have also shown that an important pool of free (non-esterified) fatty acids exists in the normal myocardium and that the amount of n-3 PUFA in this pool is increased by supplementing the diet in n-3 PUFA.⁴ This illustrates the potential of diet to modify the structure and biochemical composition of cardiac cells. In the case of ischemia, phospholipases and lipases quickly release new fatty acids from phospholipids, including n-3 fatty acids in higher amounts than the other fatty acids,⁴ thus further increasing the pool of free n-3 fatty acids that can exert an anti-arrhythmic effect.

A large prospective study (more than 20,000 participants with a follow-up of 11 years) examined the specific point that fish has anti-arrhythmic properties and may prevent SCD.⁵ Researchers found that the risk of SCD was 50 per cent lower for men who consumed fish at least once a week than for those who had fish less than once a month. Interestingly, the consumption of fish was not related to nonsudden cardiac death, suggesting that the main protective effect of fish (or n-3 PUFA) is related to an effect on arrhythmia.

An important point is that the protective effect of n-3 PUFA on SCD was greater in groups of patients who complied more strictly with the Mediterranean diet. This suggests a positive interaction between n-3 PUFA and some components of the Mediterranean diet, which is, by definition, not high in n-6 PUFA and low in saturated fats, but rich in oleic acid, various antioxidants and fibre, and associated with a moderate consumption of alcohol.

ANTIOXIDANTS AND SCD
Vitamin E: The issue about the effect of dietary antioxidants on the risk of CHD in general and on SCD in particular is more controversial. Regarding vitamin E, for instance, the most widely studied dietary antioxidant, there are discrepant findings between the expected benefits based on epidemiological observations and the results of clinical trials.^6,7

In a recent controlled trial, a significant decrease in nonfatal acute myocardial infarction and a nonsignificant increase in cardiovascular mortality (in particular in the rate of SCD) were reported with a daily regimen of 400-800mg vitamin E in patients with established CHD.⁸

Because of certain methodological shortcomings, this trial was said to confuse rather than clarify the question of the usefulness of vitamin E supplementation in CHD, and provided no indication about possible links between vitamin E and SCD prevention.

The GISSI-Prevenzione trial brings new information in this regard. Unlike those of n-3 PUFA, the results of vitamin E supplementation do not support a significant effect on the primary endpoint, namely a combination of death and nonfatal AMI and stroke.⁹

However, the secondary analysis provides a clearer view of the clinical effect of vitamin E in CHD patients, which cannot be easily dismissed. In fact, among the 193 and 155 cardiac deaths that occurred in the control and vitamin E group, respectively, there were 99 and 65 SCDs, which indicated that the significant decrease in cardiovascular mortality (by 20 per cent) in the vitamin E group was almost entirely due to a decrease in the incidence of SCD (by 35 per cent). In contrast, nonfatal cardiac events and non-sudden cardiac deaths were not influenced.⁹ These data suggest that vitamin E may be useful for the primary prevention of SCD in patients with established CHD.

Despite the mixed results when the outcome measures are myocardial infarction or stroke, there is considerable evidence that vitamin E has a positive effect on other measures of cardiovascular function. For example, a double-blind, placebo-controlled, randomised study found that 1000IU vitamin E (all-racemic alpha-tocopherol) for three months improved endothelial function and blood flow in patients with type I diabetes and reduced the oxidative susceptibility of LDL.¹⁰

Vitamin E therapy (eight weeks, chemical form not identified) was effective in improving brachial artery reactivity.¹¹

Brachial artery reactivity measures the change in brachial artery diameter after release of an occluding cuff and is a measure of endothelial function. It is thought to be a useful marker for atherosclerosis and coronary artery disease.

Vitamin D: In addition to playing a potential role in atherosclerosis, vitamin D nutriture may also be an important factor in the pathogenesis of congestive heart failure.^12,13 Congestive heart failure (CHF) can have multiple aetiologies but is characterised by a reduced amount of blood being pumped from the left ventricle of the heart and, therefore, a reduced amount of blood reaching other organ systems.

This disease is often the end stage of cardiac disease and, as more cardiac patients survive their initial problems, the opportunity for developing CHF increases. Observational studies have demonstrated an association of vitamin D deficiency in patients with severe CHF.¹⁴ These authors speculate that low circulating levels of vitamin D metabolites could contribute to the aetiology of CHF.

Co-Q10: Compared with vitamin E, there has been only very limited research on the potential cardiovascular benefits of co-Q10. Co-Q10 deficiency has been observed in a wide variety of cardiovascular disorders — congestive heart failure, angina pectoris, coronary artery disease, cardiomyopathy, hypertension, mitral value prolapse.¹⁵

In the apoE gene knockout mice (an excellent model of human atherosclerosis) supplementation with both vitamin E and co-Q10 was found to inhibit atherosclerosis better than with vitamin E or co-Q10 alone.¹⁶ It is not known, however, if co-Q10 supplementation in humans can decrease atherosclerosis.

Although co-Q10 may inhibit the formation of oxidised and atherogenic forms of LDL, it is likely that the primary mechanism whereby co-Q10 could prevent heart disease is through its ability to improve ATP synthesis in cells with a high ATP demand such as cardiac myocytes. As an antioxidant, it could also inhibit the free radical damage to the myocardium that arises during ischemia-reperfusion injury. It is logical to suggest that dietary co-Q10 supplementation could increase ATP production and thereby improve myocardial contractility.

A meta-analysis of eight randomised controlled studies looking at the effect of dietary co-Q10 supplementation on congestive heart failure indicates an improvement in stoke volume, ejection fraction, cardiac output, cardiac index, and end diastolic volume index.¹⁷ These results certainly support a role for dietary co-Q10 supplementation as an adjunctive treatment for congestive heart failure.

FUTURE TRENDS
The three lipid-soluble nutrients reviewed above all have antioxidant properties and antioxidants are, in general, anti-inflammatory. Dietary supplementation with vitamin E or vitamin D is associated with decreased levels of CRP, which is a marker for inflammation and increased risk of cardiovascular disease as well as in type 2 diabetes.^18,19

Surprisingly, there are no published studies on the potential role of co-Q10 in reducing plasma CRP levels. In the case of vitamin E, there should be increased consideration for the non-alpha-tocopherol forms, particularly the potential anti-inflammatory properties of gamma-tocopherol.

For co-Q10, the available data strongly supports a role for supplementation for the treatment of congestive heart failure

For co-Q10, the available data strongly supports a role for supplementation (along with conventional therapy) for the treatment of congestive heart failure. Vitamin D is remarkably under-researched considering its very promising role as an anti-atherogenic factor. Lifestyle modifications, ie, reasonable exposure to sunlight, may be more important than nutritional considerations in the case of vitamin D.

Moreover, as Steinberg and Witzum suggested,²⁰ the antioxidants might be effective in inhibiting the initial stages of human atherosclerosis and yet ineffective or much less effective in reducing plaque instability and rupture.

If this were the case, it might be necessary to find some way to assess early stages of lesion development (eg, high-resolution ultrasound or magnetic resonance imaging) rather than relying on the usual late clinical endpoints. Of course, if the development of early lesions were successfully inhibited, there should eventually be a decrease in the frequency of clinical events, but in that case, the trials might need to extend beyond the conventional five years.

FLAVONOIDS AND CARDIO HEALTH
Clinical observations, basic science and several epidemiological studies have contributed to an emerging body of evidence for a potential role of flavonoids in the prevention of cardiovascular disease (CVD).²¹ Flavonoids have been shown to inhibit the oxidation of plasma LDL, decrease platelet function and modulate cytokines and eicosanoids involved in inflammatory responses.^22,23 Several epidemiological studies suggest a protection of a high flavonoid intake on the mortality of CHD.^24,25,26,27

Some prospective studies on major flavonoid sources, such as tea, have, however, shown large discrepancies in the relative risk of death from CHD with relative risks ranging from 0.42,²⁸ 0.62,²⁷ 1.0825 to 1.6.²⁹

Also, a recent study on the risk of CVD in women failed to show a protective effect of flavonoid intake on the risk of CVD.³⁰

Although the picture from epidemiological studies on the relationship between risk of CVD and intake of flavonoids is inconsistent, the majority of the studies suggest an inverse association between intake of flavonoids and the risk of CVD, which is supported by basic and clinical studies on flavonoids. These indicate that flavonoids may have a protective action that deserves further investigation before final conclusions can be drawn.

The flavonoids constitute a large class of polyphenols that are found ubiquitously in the plant kingdom and are thus present in fruits and vegetables regularly consumed by humans. They account for a variety of colours in flowers, berries and fruits, from yellow to red and dark purple.

INHIBITING INFLAMMATION
Several studies have investigated the effect of flavonoids on platelet activation and aggregation.^31,32 Recent studies on the flavonoids in cocoa have shown that epicatechin and its related oligomers, the procyanidins, also have potent anti-inflammatory properties.³³

The low-molecular-weight procyanidins and epicatechin itself were shown to be a potent inhibitor of human 5-lipoxygenase,³⁴ and procyanidins from cocoa were demonstrated to decrease platelet function significantly in vivo in humans.²³

Furthermore, another study showed that the combination of quercetin and catechin synergistically inhibited platelet function in collagen-induced platelet aggregation by antagonising the intracellular production of hydrogen peroxide.³⁵

A recent study on flavonoids and the platelet-activating factor and related phospholipids in endothelial cells during oxidative stress showed that the flavonoids hesperedin, naringenin and quercetin were able to mediate these enzy-mes, and thereby limit the inflammatory response.³⁶

Studies on anthocyanins have also demonstrated that they are able to inhibit platelet aggregation. Treatment of humans with blueberry anthocyanins for 60 days was found to reduce the ex vivo platelet aggregation.³⁷

This observation was supported in a study finding after one week of treatment a reduced platelet aggregation by red grape juice, but not by orange or grapefruit juice.³⁸ Further indications of a beneficial effect were observed by researchers who found inhibitory effects on platelet aggregation in dogs and humans by red wine and red grape juice, but not by white wine, which could point to an anti-atherosclerotic effect of the anthocyanins.^39,40

The flavonoids may furthermore mediate other anti-inflammatory mechanisms involved in the development of cardiovascular disease. Studies indicate that they are implicated in the modulation of the monocyte adhesion in the inflammatory process of atherosclerosis.

The expression of intercellular adhesion molecule-1, playing a pivotal role in the inflammatory response, was, for example, shown to be mediated by quercetin in human endothelial cells.⁴¹

Plasma metabolites of (+)-catechin and quercetin modulated monocyte adhesion to human aortic endothelial cells; these researchers also found that the plasma metabolites of catechin, but not of quercetin, were potent inhibitors.⁴²

This underlines the importance of investigating the biological effects of the metabolites present in vivo, eg the flavonoid glucuronic and sulphate conjugates instead of the parent compounds.

The endothelial function plays an important role in regulating the vascular function, and endothelial dysfunction is associated with increased CVD risk. Several animal and human studies have shown that flavonoids also may have favourable effects on the vascular endothelial function.⁴³

EPIDEMIOLOGICAL EVIDENCE
Since the Zutphen Study in 1993,²⁸ a number of epidemiological studies have been undertaken on the association between dietary flavonoid intake and the risk of CVD. The majority of studies revealed an inverse association with the risk of CVD, although the outcomes of some of the studies are conflicting.

Overall, the protective effect of flavonoids was strongest against the mortality of CHD, whereas the effect on risk of nonfatal incidences of CVD was weaker or nonexisting.

The average daily flavonoid intake in studies ranges from 2.6mg/day to 28.6mg/day, with quercetin as the dominating flavonoid in most of the studies. However, the flavonoid intake in these epidemiological studies was based mainly on the food composition tables generated by Hertog et al, covering only the content of selected flavonols and flavones in the food.^44,45

TEA AND WINE TIME
If intake data on additional flavonoids had been included in these studies (eg the citrus flavonoids, the catechins, the anthocyanins and the isoflavonoids), the flavonol quercetin would probably not have been the major dietary flavonoid in the cohorts. Further, tea would perhaps be a less important flavonoid source, and the outcome of studies would then possibly have been different. The quercetin intake originated mainly from tea intake, but apples and onions were also important sources of quercetin in some studies^25,28

Early studies showed a highly protective effect of both quercetin and tea against CVD.^28,46 However, some of the later and larger cohort studies, trying to confirm these early studies, found no association or even aggravating effects of flavonoids and especially of tea consumption.^25,29,30,47

The association of tea and incidences of CVD were later further investigated in several cohort studies. These studies have all been reviewed in a recent meta-analysis on the relationship between tea consumption and stroke, myocardial infarction and all CHD in 10 cohort studies and seven case-control studies.⁴⁸

Anthocyanins are present in red wine, and studies suggest that wine drinkers have a lower mortality from CVD than others

The incidence rate of myocardial infarction was concluded to be weakly inversely associated (11 per cent) with an increase in tea consumption of three cups per day. However, the authors, stressing that the heterogeneity of the studies and the risk of bias due to the larger number of smaller studies show a protective effect, urge caution in interpreting this result.

The mechanism of the protective effect of tea has recently been investigated and does, however, support a beneficial effect of tea intake. For example, consumption of 900 ml black tea for four weeks reversed the endothelial vasomotor dysfunction in patients with proven coronary artery disease.⁴⁹

It has been suggested that the catechin content in tea could be the protective factor, and researchers in 2001 thus estimated the catechin intake to 72 +/-47.8mg/day in the Zutphen Elderly Study and found a significant negative association between ischemic heart disease and intake of tea catechins.⁵⁰

However, in another study on catechin intake by the same authors, in post-menopausal women from Iowa, a protective effect of catechins was seen from only dietary sources other than tea.⁵¹

The intake of red wine has been postulated to explain the French paradox — the low incidence of CHD in France despite the main risk factors for this disease being similar to those in northern European countries.⁵²

Anthocyanins are present in red wine, and several cohort studies have in fact suggested that wine drinkers have a lower mortality from CVD than others.^53,54,55

Other cohort studies have, however, found equally beneficial effects of all alcoholic beverages, and there is no general agreement on this matter.⁵⁶

It has been proposed that the possible lower mortality by CVD in wine drinkers could be due in part to differences in lifestyle ? that is, in dietary habits and exercise, since factors such as dietary fat composition, little exercise and hypertension are major risk factors on the development of atherosclerosis.⁵⁷

FLAVONOID MECHANISMS
The overall picture of the flavonoids as a protective agent against cardiovascular disease has been consolidated during the past decade. The mechanism of action of the flavonoids is, however, still unknown, but recent studies have moved the focus away from the antioxidant properties of the compounds toward a broader view on the potential mechanisms of action including especially the anti-inflammatory effects of flavonoids.

The early research on the dietary protective action of flavonoids has mainly focused on the flavonols, especially on quercetin, in part because of limitations in the available analytical methods at that time, which merely restricted the investigations to this class of compounds.

However, within the past few years, flavonoid research has produced evidence for the importance of other dietary flavonoid classes and subgroups with potential health protective properties and with a similar or even greater impact on our total daily flavonoid intake. Examples are the citrus flavonoids, the red-coloured anthocyanins, the tea catechins, and the procyanidins present in cocoa and wine.

Furthermore, there are indications of the importance of a diet rich in a range of different flavonoids, rather than containing a high concentration of an individual compound, since some studies have shown additive or even synergistically effects of flavonoids.⁵⁸

Authors: N-3 fatty acids: M de Lorgeril and P Salen, Universite Joseph Fourier de Grenoble, France. Fat-soluble antioxidants: W L Stone and G Krishnaswamy, East Tennessee State University, US, and H Yang, Yunnan College of Traditional Chinese Medicine, China. Flavonoids: S E Rasmussen, Danish Institute for Food and Veterinary Research, Denmark.

Excerpted from Functional Foods, Cardiovascular Disease and Diabetes, A Arnoldi, editor. ISBN 1 85573 735 3. Published by Woodhead Publishing Ltd, England. www.woodheadpublishing.com Respond: [email protected]

VITAMIN E AND C-REACTIVE PROTEIN C-reactive protein (CRP) is emerging as a major risk factor for atherosclerosis and cardiovascular disease.1 The association between atherosclerosis and CRP is strong even in the absence of classical risk factors such as high cholesterol, triglycerides and blood pressure.2 A number of studies have now shown that vitamin E supplementation reduces levels of CRP. In a double-blind, placebo-controlled, randomised study of 57 people with type 2 diabetes, subjects received placebo for four weeks and were then randomised to receive tomato juice (500ml/day), vitamin E (800IU/day, chemical form not specified), vitamin C (500mg/day), or continued placebo treatment for four weeks. Vitamin E supplementation was found to decrease CRP levels.3 Since vitamin E has been shown to reduce levels of CRP, it is reasonable to suggest that vitamin E supplementation could, thereby, reduce the risk of future CVD. This suggestion rests on the assumption that CRP is a causative factor and not just a marker for CVD. The evidence supporting this assumption is not yet conclusive but is certainly intriguing. New research has shown that CRP directly causes the induction of adhesion molecules on the endothelial cells of both human veins and arteries.4 The expression of these adhesion molecules is known to be essential for the development of CVD. —WS, GK, HY References 1. Folsom AR. Exp Gerontol 1999; 34:483-90. 2. Ridker PM, et al. New Engl J Med 2001; 344:1959-65. 3. Upritchard JE, et al. Diabetes Care 2000; 23:733-8. 4. Pasceri V, et al. Circulation 2000; 102:2165-8.

DEFICIENCY IN SPECIFIC MICRONUTRIENTS The human data offers the following conclusions of note to formulators: Calcium: Cases of hypocalcaemia-induced cardiomyopathy (usually in children with a congenital cause for hypocalcaemia) that can respond dramatically to calcium supplementation have been reported.1 Magnesium: Hypomagnesaemia is often associated with a poor prognosis in congestive heart failure (CHF), and correction of the magnesium levels (in anorexia nervosa, for instance) leads to an improvement in cardiac function.2 Zinc: Low serum and high urinary zinc levels are found in CHF,3 possibly as a result of diuretic use, but there is no data regarding the clinical effect of zinc supplementation in that context. In a recent study, plasma copper was slightly higher and zinc slightly lower in CHF subjects than in healthy controls.4 It is not possible to say whether these copper and zinc abnormalities may contribute to the development of CHF or are simply markers for the chronic inflammation known to be associated with CHF.5,6 Further studies are needed to address the point, since the implications for prevention are substantial. Selenium: Selenium deficiency has been identified as a major factor in the aetiology of certain nonischaemic CHF syndromes, especially in low-selenium soil areas such as eastern China and Western Africa.7 Selenium deficiency is also a risk factor for peripartum cardiomyopathy. Vitamin B1: Low whole blood thiamine (vitamin B1) levels have been documented in patients with CHF on loop diuretics and hospitalised elderly patients, and thiamine supplementation induced a significant improvement in cardiac function and symptoms.8 —ML, PS References 1. Rimailho A, et al. Improvement of hypocalcemic cardiomyopathy by correction of serum calcium level. Am Heart J 1985; 109:611-3. 2. Gottlieb SS, et al. Prognostic importance of the serum magnesium concentration in patients with congestive heart failure. J Am Coll Cardiol 1990; 16:827-31. 3. Golik A, et al. Type II diabetes mellitus, congestive cardiac failure and zinc metabolism. Biol Trace Elem Res 1993; 39:171-5. 4. de Lorgeril M, et al. Dietary blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure. Eur J Heart Failure 2001; 3:661-9. 5. Levine B, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323:236-41. 6. Anker SD, et al. Tumor necrosis factor and steroid metabolism in chronic heart failure: possible relation to muscle wasting. J Am Coll Cardiol 1997; 30:997-1001. 7. Ge K, Yang G.The epidemiology of selenium deficiency in the etiological study of endemic diseases in China.Am J Clin Nutr (Suppl) 1993; 57:259S-263S. 8. Shimon I, et al. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med 1995; 98:485-90.

CAN DIET DO IT? The vital importance of micronutrients for health and the fact that several micronutrients have antioxidant properties are now fully recognised. These may be as direct antioxidants, such as vitamins C and E, or as components of antioxidant enzymes: super oxide dismutase or glutathione peroxidase.1 It is now widely believed (but still not causally demonstrated) that diet-derived antioxidants may play a role in the development (and thus in the prevention) of CHF. For instance, clinical and experimental studies have suggested that CHF may be associated with increased free radical formation2 and reduced antioxidant defences5,8 and that vitamin C may improve endothelial function in patients with CHF.3 In the secondary prevention of CHD, in dietary trials in which the tested diet included high intakes of natural antioxidants, the incidence of new episodes of CHF was reduced in the experimental groups.4,5 Taken altogether, these data suggest (but do not demonstrate) that antioxidant nutrients may help prevent CHF in post-infarction patients. Thus, any dietary pattern combining a high intake of natural antioxidants, a low intake of saturated fatty acids, a high intake of oleic acid, a low intake of omega-6 fatty acids and a high intake of omega-3 fatty acids would logically produce a highly cardio protective effect. This is consistent with what we know about the Mediterranean diet pattern,6,7 and with the results of the Lyon Diet Heart Study,5,8,9 and what was recently confirmed by epidemiological studies.10,11 —ML, PS References 1. Evans P, Halliwell B. Micronutrients: oxidant/antioxidant status. Br J Nutr 2001; 85:S67-S74. 2. Dhalla AK, et al. Role of oxidative stress in transition of hypertrophyto heart failure. J Am Coll Cardiol 1996; 28:506-14. 3. Hornig B, et al. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998; 97:363-8. 4. Singh RB, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction : results of one year follow-up. BMJ 1992; 304:1015-9. 5. de Lorgeril M, et al. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation 1999; 99:779-85. 6. de Lorgeril M, Salen P. Modified Mediterranean diet in the prevention of coronary heart disease and cancer.World Rev Nutr Diet 2000; 87:1-23. 7. Simopoulos AP, Sidossis LS. What is so special about the traditional diet of Greece. The scientific evidence.World Rev Nutr Diet 2000; 87:24-42. 8. de Lorgeril M, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343:1454-9. 9. Kris-Etherton P, et al. Lyon Diet Heart Study. Benefits of a Mediterranean-style, National Cholesterol Education Program American Heart Association Step I Dietary pattern on cardiovascular disease. Circulation 2001; 103:1823-5. 10. Marchioli R, et al. Mediterranean dietary habits and risk of death after myocardial infarction. Circulation 2000; 102(Suppl II):379. 11. Trichopoulou A, et al. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003; 348:2599-608.

COMBINATIONS SPUR ON HEART-HEALTH MARKET The meeting of science-backed proprietary ingredients and the condition-specific market is driving innovation today. With a suite of heart-health ingredients that includes vitamin E, coenzyme Q10, sterols and its proprietary Sytrinol, it naturally was not long before SourceOne Global Partners came upon the idea to start offering combinations to manufacturers. The first manifestation will be evidenced in the first quarter of 2006 when the Chicago-based company rolls out Cholesstrinol — a combination of Sytrinol and plant sterols that go at cholesterol reduction from different yet complementary means. "Certainly Sytrinol is our key product," says Jim Roza, vice president of business development, technology and science at SourceOne. "We work with companies to put together Sytrinol with policosanol or Sytrinol with co-Q10." Nordic Naturals is also on the bandwagon, manufacturing Heart Synergy, which includes fish oils EPA and DHA with co-Q10, L-carnitine, magnesium, vitamin E, selenium and folic acid. "Co-Q10 and L-carnitine work better together for heart support," says Gretchrn Vannice, research coordinator for the company. "This formula offers a complete nutritional solution." Sigma-tau HealthScience took its carnitine know-how and partnered with Valen Labs for their D-ribose, and Tishcon for their liposomal LiQsorb co-Q10. Mixing them together, they added a dash of resveratrol, and is now marketing ResveraCarn, a ready-to-drink nutraceutical beverage in its LivingTonics line. Partnering with other branded ingredients has its advantages. "In order to be vertically integrated from a GMP standpoint, you have to understand the pedigree of your raw materials," says Ken Hassen, PhD, Sigma-tau?s chief operating officer. "We?re showing the customer that you get the trademark and identity of our products, but also you can see further back to see you?re getting marks from other trusted suppliers." —Todd Runestad

SELECT INGREDIENTS SUPPLIERS Activin www.activin.com +1 599 458 2500 Amax Nutrasource Inc www.amaxnutrasource.com +1 541 688 4944 BASF Corp www.basf.com +1 800 527 9881 BI Nutraceuticals www.botanicals.com +1 310 669 2100 Cargill Health & Food Technologies www.corowise.com www.cargillhft.com +1 866 456 8872 Charles Bowman & Co www.charlesbowman.com +1 616 786 4000 Cognis www.cognis.com +1 708 579 6150 Croda Health Care www.croda.com/europe/hc +44 1405 860551 DNP Intl www.dnpint.com +1 562 692 8945 Draco Natural Products www.dracoherbs.com +1 408 287 7871 DSM Nutritional Products www.nutraaccess.com +1 973 257 8574 Garuda Intl www.garudaint.com +1 559 594 4380 Geni Herbs www.ggeniherbs.com +1 317 776 3600 Indena www.indena.com +1 206 340 6140 +39 02 574951 InterHealth Nutraceuticals www.interhealthusa.com +1 707 751 2861 Lonza Inc www.carnitine.com +1 201 794 2640 +41 61 316 81 11 Next Pharmaceuticals www.nextpharmaceuticals.com +1 949 450 0203 Nurture www.nurture-inc.com +1 888 395 3300 Ocean Nutrition Canada www.ocean-nutrition.com +1 902 457 2399 Pacific Rainbow Intl Inc www.prinutrition.com +1 909 468 4618 Proliant www.proliantinc.com +1 515 289 5100 +34 93 861 52 87 Pronova Biocare www.epax.biz +47 22 53 4850 Sabinsa Corp www.sabinsa.com +1 732 777 1111 +1 801 465 8400 Sigma-tau HealthScience www.sigmatau.com +1 212 645 5202 +39 0691619712 Soft Gel Technologies www.soft-gel.com +1 323 726 0700 SourceOne Global Partners www.source-1-global.com +1 312 321 8222 Stauber Performance Ingredients www.stauberusa.com +1 714 441 3900 Tishcon Corp www.tishcon.com +1 516 333 3050

REFERENCES
1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115-26.
2. de Lorgeril M, et al. Dietary prevention of sudden cardiac death. Eur Heart J 2002; 23:277-85.
3 Burr ML, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet And Reinfarction Trial (DART). Lancet 1989; 2:757-61.
4. Nair SD, et al. Cardiac (n-3) non-esterified fatty acids are selectively increased in fish oil-fed pigs following myocardial ischemia. J Nutr 1999; 129:1518-23.
5. Albert CM, et al. Fish consumption and the risk of sudden cardiac death. JAMA 1998; 279:23-8.
6. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994; 330:1029-35.
7. Rapola JM, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocar-dial infarction. Lancet 1997; 349:1715-20.
8. Stephens NG, et al. Randomised controlled trial of vitamin E in patients with coronary heart disease. The Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347:781-86.
9. GISSI-Prevenzione investigators. Dietary supplementation with n-3 polyunsatu-rated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Lancet 1999; 354:447-55.
10. Skyrme-Jones RA, et al. J Am Coll Cardiol 2000; 36:94-102.
11. Paolisso G, et al. J Clin Endocrinol Metab 2000; 85:109-15.
12. Zittermann A. Fortschr Med 2003; 145:18.
13. Zittermann A, et al. J Am Coll Cardiol 2003; 41:105-12.
14. Shane E, et al.Am J Med 1997; 103:197-207.
15. Singh RB, et al. J Assoc Physicians India 1998; 46:299-306.
16.Thomas SR, et al. Arterioscler Thromb Vasc Biol (Online) 2001; 21:585-93.
17. Soja AM, Mortensen SA. Mol Aspects Med 1997; 18 Suppl:S159-S168.
18. Rodriguez-Moran M, Guerrero-Romero F. J Diabetes Complic 1999;13:211-15.
19. Arnalich F, et al. Hormone Metab Res 2000; 32:407-12.
20. Steinberg D, Witztum JL. Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation 2002; 105:2107-11.
21. Hollman PC, Katan MB. Dietary flavonoids: intake, health effects and bioavail-ability. Food Chem Toxicol 1999; 37:937-42.
22. De Whalley CV, et al. Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages. Biochem Pharmacol 1990; 39:1743-50.
23. Murphy KJ, et al. Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function, Am J Clin Nutr 2003; 77:1466-73.
24. Hollman PC, et al. Role of dietary flavonoids in protection against cancer and coronary heart disease. Biochem Soc Trans 1996; 24:785-9.
25. Rimm EB, et al. Relation between intake of flavonoids and risk for coronary heart disease in male health professionals?,Ann Intern Med 1996; 125:384-9.
26. Knekt P, et al. Flavonoid intake and coronary mortality in Finland: a cohort study?, BMJ 1996; 312:478-81.
27. Yochum L, et al. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women?,Am J Epidemiol 1999; 149:943-9.
28. Hertog MG, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993; 342,1007-11.
29. Hertog MG, et al. Antioxidant flavonols and ischemic heart disease in a Welsh population of men: the Caerphilly Study.Am J Clin Nutr 1997:65; 1489-94.
30. Sesso HD, et al. Flavonoid intake and the risk of cardiovascular disease inwomen. Am J Clin Nutr 2003; 77:1400-08.
31. Middleton E, Kandaswami The impact of flavonoids on mammalian biology: implications for immunity, inflammation and cancer. In Harborne, J. B. (ed.), The Flavonoids: advances in research since 1986. Chapman and Hall 1994, London, pp. 619?652.
32. Harborne JB, Williams CA. Advances in flavonoid research since 1992. Phytochemistry 2000; 55:481-504.
33. Steinberg FM, et al. Cocoa and chocolate flavonoids: implications for cardiovascular health?, J Am Diet Assoc 2003; 103:215-23.
34. Schewe T, et al. Flavonoids of cocoa inhibit recombinant human 5-lipoxygenase?, J Nutr 2002; 132:1825-9.
35. Pignatelli P, et al. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide.Am J Clin Nutr 2000; 72:1150-5.
36. Balestrieri ML, et al. Modulation by flavonoids of PAF and related phospholipids in endothelial cells during oxidative stress. J Lipid Res 2003; 44:380-7.
37. Pulliero G, et al. Ex vivo study of the inhibitory effects of Vaccinium myrtillus anthocyanosides on human platelet aggregation. Fitoterapia 1989; 60:69-75.
38. Keevil JG, et al. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation?, J Nutr 2000; 130:53-6.
39. Demrow HS, et al. Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation 1995; 91:1182-8.
40. Folts JD. Antithrombotic potential of grape juice and red wine for preventing 180 Functional foods, cardiovascular disease and diabetes heart attacks. Pharmaceut Biol 1998; 36:21-7.
41. Kobuchi H, et al. Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol 1999; 277 C403-C411.
42. Koga T, Meydani M. Effect of plasma metabolites of (+)-catechin and quercetin on monocyte adhesion to human aortic endothelial cells?, Am J Clin Nutr 2001; 73:941-8.
43. Duffy SJ, Vita JA. Effects of phenolics on vascular endothelial function. Curr Opin Lipidol 2003; 14:21-7.
44. Hertog MGL, et al. Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the netherlands?, J Agric Chem 1992; 40:2379-83.
45. Hertog MGL, et al. Content of potentially anticarcinogenic flavonoids of tea infusions, wines, and fruit juices?, J Agric Chem 1993; 41:1242-46.
46. Keli SO, et al. Dietary flavonoids, antioxidants vitamins, and incidence of stroke:the Zutphen study.Arch Intern Med 1996; 156:637-42.
47. Hirvonen T, et al. Intake of flavonoids, carotenoids, vitamins C and E, and risk of stroke in male smokers. Stroke 2000; 31:2301-6.
48. Peters U, et al. Does tea affect cardiovascular disease? A meta-analysis. Am J Epidemiol 2001; 154:495-503.
49. Duffy SJ, et al. Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation 2001; 104:151-6.
50. Arts IC, et al. Catechin intake might explain the inverse relation between tea consumption and ischemic heart disease: the Zutphen Elderly Study. Am J Clin Nutr 2001; 74:227-32.
51. Arts IC, et al. Dietary catechins in relation to coronary heart disease death among postmenopausal women. Epidemiology 2001; 12:668-75.
52. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992; 339:1523-6.
53. Nanji AA. Alcohol and ischemic heart disease: wine, beer or both? Int J Cardiol 1985; 8:487-9.
54. Gronbaek M, et al. Mortality associated with moderate intakes of wine, beer, or spirits. BMJ 1995; 310:1165-9.
55. Theobald H, et al. A moderate intake of wine is associated with reduced total mortality and reduced mortality from cardiovascular disease. J Stud Alcohol 2000; 61:652-6.
56. Rimm EB, et al. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits? BMJ 1996; 312:731-6.
57. Tjonneland A, et al. Wine intake and diet in a random sample of 48763 Danish men and women?,Am J Clin Nutr 1999; 69:49-54.

>> Alpha-lipoic acid. Antioxidant properties protect the liver. Dose> 50–100 mg, twice daily. >> Dandelion tea. Contains liver-supportive nutrients that assist with detox. Dose> 1 cup daily. >> Milk thistle (active ingredient: silymarin). Liver-protective; also helps the liver recover from toxic effects. Dose> 60–100 mg, twice daily. >> Vitamin C. Helps protect the liver from viral infections, such as hepatitis B and C. Dose> 500 mg daily. Source: Elson Haas, MD. Note: Always consult your health care provider before taking any supplements.

Q. Besides meat, what are the best blood-building foods, herbs, and supplements?

A. Blood, the liquid essence of life, requires an arsenal of nutrients to supply the body with oxygen, to rid it of waste, and to maintain general health. At certain times in life, blood requires special nutritional fortification. Adolescence, pregnancy, the postpartum period, and old age are times of "weak blood," according to Traditional Chinese Medicine (TCM). Therefore, blood-building is more important for women than men, because women are subject to more life events during which it is necessary.

Particularly during times of blood loss, such as menstruation or blood volume expansion during pregnancy, the blood needs plenty of iron, calcium, potassium, and antioxidants such as selenium and vitamins A, C, and E. Some of the best blood-building foods according to TCM are beets, blackstrap molasses, salmon, cherries, red chard, kale, and sea vegetables (such as nori).

One of the first things you may try for building blood is upping your iron intake. Iron supplements, especially liquid iron, are most effective when taken along with B12 and folic acid. Iron-enhancing herbs include nettles (Urtica dioica) and alfalfa (Medicago sativa). Other iron-boosting foods include brewer's yeast, apricots, greens, soyfoods, oysters, raisins, spinach, and mushrooms. To keep blood flowing smoothly, compounds like fiery capsaicin from red chili peppers, distinctly scented allicin in garlic, and beneficial omega-3 fats in flaxseeds contain anticoagulant, blood-enhancing properties.

This Q&A was written by Victoria Shanta Retelny, RD, LD, owner of LivingWell Communications, a nutrition communications company in Chicago.