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Articles from 2002 In December


Risk Assessment Could Be The Basis For Codex

International

A majority of countries now support risk assessment in setting global guidelines for upper safe levels for dietary supplements following a recent meeting of the Codex Committee on Nutrition for Foods for Special Dietary Uses in Berlin. The hard-fought battle in Europe that established risk-assessment as a credible mechanism for establishing USLs looks set to influence the global guidelines which Codex is preparing.

However, Codex Committee chairman Professor Rolf Grossklaus, from the German Institute for Risk Assessment (BfR), said that in view of some opposition from Denmark, France and Norway, there is still not a consensus and therefore no change would be made to the Codex guidelines that remain at Step 3 in an eight-stage process. Those opposing the proposal argued that risk alone was not sufficient and that a nutrition-based approach should also be integrated.

In total, 24 countries including the 15 EU members support the risk-assessment approach to supplements as opposed to seven who favour the RDA-based approach.

IADSA has welcomed the development, calling it the best move toward a scientific approach since discussions began in the mid-1990s. "We welcome the progress that has been made in this meeting toward a scientific risk assessment based approach to food supplements," said IADSA Executive Director Simon Pettman. "It will be many years before a final guideline is adopted, but the discussion at Codex sends a clear positive signal to governments around the world."

Three options exist for establishing maximum levels for nutrients:

  1. 100% of RDA.
  2. Risk assessment based on the text of the EU Directive—supported by Europe, Japan, Australia, New Zealand, Russia and Korea.
  3. Risk assessment based on the text of the EU Directive but without the phrase: "due account shall be taken of the PRI/RDA"—supported by IADSA, US, Canada, Switzerland and Peru.

The FAO/WHO will now proceed to establish the principles underlying risk-assessment and Australia will circulate a document explaining the reasoning behind it. A meeting early this year is expected to address the issues, and Pettman called on the industry to influence the process. "We need to ensure an appropriate model is used, offer help to those managing the process, and encourage the involvement of trusted experts such as the US Food and Nutrition Board who have already undertaken this process."

How Potent Are Patents?

Companies heavily tout their patented ingredients, but just how valuable are patents? And more to the point—can they stand up to scrutiny? Shane Starling investigates.

Are patents worth the paper they are printed on? In two words: it depends. Sometimes the 17-year promise (in most jurisdictions, 20 years for US utility patents) of commercial exclusivity is indeed valuable. Patents can enhance a product's profit-making prospects considerably and thereby ensure it has a chance of recouping monies invested to develop it to its end-point of genuine 'uniqueness.'

In other instances, the funds forked out to gain a patent (which can amount to hundreds of thousands of dollars) may have been better spent on making the label look prettier or the product harder to mimic even without a patent. Coca-Cola, for instance, has never had a patent.

So what determines a good patent from a bad one? First, there are different kinds of patents. Patents awarded to functional foods and nutraceuticals products typically come in two forms: those that recognise the molecular composition of a product and those that recognise the application of a product. In either case, the strength of the patent is generally determined by the strength of the science behind it. No surprises there. Genuine novelty in this business does not often come without copious hours in the lab and extensive research on a potential USP substance.

Threadbare Science
More surprising is the number of patents granted to products or processes for which the science is threadbare at best, or patent application claims simply go unverified by the patent office, whether backed by scientific data or not.

To Anthony Almada, founder and chief scientific officer of California-based industry research consultancy IMAGINutrition, the patenting system is being undervalued by the granting of so many patents with holes in them.

"There are solid patents, but there are too many patents issued in the functional foods and nutraceuticals area that do not have 'proof of concept' evidence," Almada says. "They simply don't have the necessary data, and yet the patent office seems quite willing to issue patents to these kinds of applications. It's abominable. For this reason the idea that 'patent equals potent' is very far from the truth."

Almada highlights one patent granted to a US company for a product containing antioxidant fractions. In the patent application, the company provided no data, not even animal studies. "Patents like this are so weak [that] consumers could challenge their validity in court and render them invalid," he says.

IMAGINutrition: www.imaginutrition.com

Lonza Group: www.lonza.com

NNFA: www.nnfa.org

Kemin Foods: www.kemin.com

DuPont: www.dupont.com

In other cases, competitors may ignore what they consider to be a weak patent by launching similar products of their own. It is then up to the patent holder to enforce the patent by launching a civil action. More often than not, the holder of a weak patent will not go to court because they know the patent will not stand up to legal scrutiny. Their bluff called, the patent holder must then be prepared to battle it out in the free market, patent-free, or come to some arrangement with their new rivals.

"Most companies in this industry do not challenge patents," Almada notes. "Mostly they infringe them, and the patent holder doesn't pursue them in court, or they pay a small licensing fee."

Dan Murray, associate director of marketing and sales and nutrition at Georgia-based Lonza Group, agrees patent holders can come under attack and find themselves in a quandary as to how best to react. "One company will violate a patent because they know it is weak," he observes. "It is then a tough one for the company that owns the patent because if they go to court and lose the patent, the whole market may get flooded and that could be worse for them anyway."

According to Phil Harvey, PhD, the US-based National Nutritional Foods Association's (NNFA) director of science & quality assurance, weak patents reflect an industry that is yet to fully come to terms with the importance of the scientific method in product development. "In the drug, medical devices and biotechnology industries there is more investment in patents," he says. "But in those industries the marketing follows the science, whereas in our industry the science follows the marketing."

Phil Brown, brand manager for Ester-C (now owned by Zila, formerly Inter-Cal) believes much of the problem with weak patents lies in an increase in the number of patents being filed. This has led to the patent office being inundated with more applications than its resources will allow it to thoroughly scrutinise. "The patent office can only do so much. It's a problem with any regulatory authority—they don't have the expertise, and there are so many patents being filed now," he observes, noting that in an ideal world, "patents would be more thoroughly investigated by the people that approve them so that once a patent is approved it is closer to being incontestable."

Vitamin C variant Ester-C has about eight years of patent protection remaining, which is cause for concern at Zila, but hardly a cause for panic. The patent has allowed them time to establish their brand name in a market dominated by large pharmaceutical players. Indeed, it is smaller companies that often have the most to gain from the patenting process—if they can afford the cost involved to get one in the first place.

"Gaining patents is not cheap," Brown says. "Plus you have to pay patent fees every year. There is a lot of paperwork involved. But our patents have given us protection, and that has proved invaluable." Ester-C obviously possessed good science as Zila has defended infringements on its patents and come out the other side with its temporary monopoly intact.

Research Is Critical
Harvey believes smaller companies can help themselves to improve patents by leveraging university research. "Companies don't utilise academia enough when they are researching products," he says. "I would like to see more university/private sector relationships, because universities do have resources that some of the companies in our industry don't have. The disadvantage is that university research can be very slow."

Kemin Foods is one company that has made the most of university research. Many of its patents have been licensed from academic institutions. Kemin Marketing Director Steve Hanson is buoyant about the power and potential of patents.

If you can weave your unique product together with solid science, you have a double layer of protection against people using your science and attributing it to their product

"Patents are extremely valuable in terms of having a proprietary position in the marketplace," he says. "If the work is done behind them, and they are written well, they are a great way for companies to develop products that are truly novel. We have patents in the US, Japan, the EU, Australia and New Zealand. They are very important in protecting our position in the marketplace and providing advanced technology to any companies that provide products of value to consumers."

He noted that the Patent Cooperation Treaty, the aim of which is to link patent offices around the world, would reduce the cost and time involved in establishing patented products in global markets.

Business Benefits
A spokesperson for DuPont notes that while the patenting system may not be perfect, its benefits are manifold and far outweigh its flaws and occasional inequities. "Patents exist because at the end of the day they confer value to society," he says. "It's a legal monopoly for a given period of time, but there are societal benefits, and they do much more than just restrict competition for a period of time. The pace of product development, the pace of knowledge creation, the pace of value to consumers would be slower if the investors in that knowledge didn't have some way of ensuring they could recoup that investment over time. If we go to a marketer and a retailer, they are going to want to find ways to differentiate offerings in the marketplace, and patents are a principal means to do that."

Almada agrees. "If you can weave your unique product together with solid science, you have a double layer of protection against people using your science and attributing it to their product."

As a case in point, Lonza is about to do just such a 'weaving.' "We've got a product we are in the process of launching," says Murray. "Because we have a strong patent, we can make significant investments to back it up. This helps the whole chain from manufacturing to promotion to retail. It allows you to establish a price premium as well, without the worry that someone will come along and chop your legs out from under you."

Ingredients for skin care: a new layer in anti-ageing

Just because a supplement works in an oral dose doesn't mean it will necessarily work topically. Dermal remedies applied topically need certain properties, such as the ability to permeate the epidermis, in order to produce benefits in the skin's inner dermis living cells. But because the skin's primary function is to protect the body from external pathogens, it poses a penetration challenge for some ingredients.

On the other hand, a compound that penetrates the skin entirely and reaches the blood stream may be considered a trans-dermal delivery system and could be regulated as a drug.

Optimally, a topical ingredient should penetrate the entire epidermis/dermis if it is to provide benefits. Using oil-based ingredients, or adding an oil or penetration agent to the product, can help the compounds get through the epidermis.

Good-looking ingredients
The primary causes of skin damage and ageing are exposure to sunlight—UVB and UVA—oxidation and inflammation of the skin, decreases in supportive collagen, loss of muscle tone, and dryness. Topical anti-ageing ingredients seek to ameliorate these conditions. Many supplements and herbs are potential skin remedies based on their demonstrated internal antioxidant and anti-inflammatory properties, but few have solid research to date. Popular vitamins, such as C and E, are well-studied for topical benefits. Other compounds, such as DMAE and Co-Q10, are supported by emerging research. The following are some of the popular, scientifically backed inclusions for today's anti-ageing skin care products.

VITAMIN C is a water-soluble antioxidant that traps free radicals and blocks the formation of nitrosamines—molecules suspected to be carcinogens. 1 Vitamin C has been found, in vitro, to be an indispensable player in the formation of the connective tissue collagen. 2 Collagen is the supportive framework of the skin and is crucial to optimal skin tone. The collagen molecule is a rod-like, triple-helix formed by three protein chains. When linked together, multiple collagen molecules form a matrix with the tensile strength of steel. The natural decrease of collagen with age leads to the formation of wrinkles when troughs of skin sag through a weakened support framework.

French researchers determined through human studies that the topical application of vitamin C stimulates collagen biosynthesis.3 At the 2000 World Congress of the International Academy of Cosmetic Surgery, researchers presented a double-blind, placebo-controlled trial of 20 female subjects, aged 55 to 60, who received a 5 per cent vitamin C cream or placebo for six months. At the study's conclusion, researchers discovered that the vitamin C cream had significantly reduced wrinkles and had rearranged wrinkle lines from deeper ruts into shallow, random order, a sign of younger skin and a stronger collagen matrix. The mechanism of action, in part, was C's stimulation of enzyme activity in the skin that created cross-linkages in the helices of collagen molecules.4

The same researchers further tested vitamin C on post-menopausal women—previously thought to have severely limited skin-collagen-production capacity—and found that topical vitamin C significantly increased the production of collagen vs. placebo.5

UV rays deplete vitamin C by as much as 30 per cent under minimal exposure and up to 55 per cent in ozone-depleted environments, dermatologist Karen E Burke, MD, PhD, reported at the 2002 American Academy of Dermatology annual meeting. A recent review from the Department of Dermatology at the University of California, San Francisco, states that topical application of vitamin C prevents UV damage, both UVB-induced erythema formation (skin inflammation and redness from capillary dilation) and UVA-related oxidative damage.6

The photoprotective effects of vitamin C can be enhanced by using combinations of antioxidants. In a randomised, double-blind human study, researchers determined, by applying C, or combinations of C, melatonin and vitamin E, 30 minutes prior to ultraviolet irradiation of the skin, that C in combination with other antioxidants exhibited greater photoprotectivity against UV exposure than vitamin C alone.7

VITAMIN E, probably the reigning antioxidant of our time and used to support everything from cancer therapy to cholesterol reduction and improved cardiac function, is also good for the skin.

The term vitamin E is the common description of one form of the vitamin, d-alpha-tocopherol, which is the natural form and is more active and better absorbed than a synthetic variety (referred to as dl-alpha-tocopherol), which is, however, less costly to produce and thus is more commonly used. Vitamin E in its entirety includes tocopherols and tocotrienols, each with four possible isomers for a total of eight varieties. Both tocopherols and tocotrienols are viable skin product ingredients, though tocopherols are most available and most widely used.

Tocotrienols, extracted from palm fruit, are considered more potent antioxidants.8 Research also suggests that tocotrienols are more biologically acceptable and are preferentially absorbed by the body and skin, based on their chemical structure.9 Studies show that topical tocotrienols prevent oxidation of the skin's collagen matrix.10

Burke reported that supplementing orally with 400mg vitamin E daily can reduce photodamage and wrinkles and can improve skin texture, while topical applications, including blends with vitamin C, can soothe dry skin and protect against sun damage. In an animal study, researchers found the topical application of alpha-tocopherol to be more effective than internal supplementation at preventing UV damage.11 In another animal study, researchers found that a topical solution of alpha-tocopherol inhibited UVR-induced epidermal lipid peroxidation.12

Scientists have produced the best skin-protecting effects using a topical blend of vitamins E and C, especially when combined with a UVA sunscreen ingredient such as oxybenzone.13 According to one trial, topical application of the C-E combination completely protects against UVB-radiation-induced lipid peroxidation.14

But vitamin E's propensity to rapidly oxidise raises concern about potentially harmful effects of topical application. In one study, researchers tested alpha-tocopherol succinate and acetate (synthetic vitamin E) on UV-irradiated mice and found that the topical application enhanced, rather than prevented, photocarcinogenesis. The researchers speculate that instability of vitamin E esters at room temperature may have contributed to the contrary findings. They call for more studies and consideration of the potential danger by manufacturers who include vitamin E esters in creams and lotions.15

DIMETHYLAMINOETHANOL (DMAE) made its debut years ago as a cure-all antioxidant aimed at enhancing cognitive functioning and reducing fatigue and depression. Nicholas Perricone, MD, author of The Perricone Prescription, claims that it is even more potent topically, adding to DMAE's credentials as a membrane stabilizer, anti-inflammatory and penetration enhancer.

A young face is characterized by short, thick muscles that prevent sagging. As we get older, the muscles get thinner and longer, causing a flatter and increasingly saggy face. Cosmetic surgeons cut muscles shorter to pull up the sags and round out the face.

"DMAE stimulates the contraction of muscles so you correct the sagging and get a more rounded look and a physiologically younger face," Perricone says, based on his 15 years of private practice and research. A possible mechanism of action is DMAE's stimulation of acetylcholine, a key component in muscle contraction. Perricone also says DMAE helps stabilize skin-cell membranes. An animal study found that one of DMAE's actions is to limit the tissue-damaging cross-linking of proteins by scavenging hydroxyl radicals.16

In a recent, unpublished, Johnson & Johnson-funded, controlled study presented at the AAD's 2002 annual meeting, researchers reported a 75 to 90 per cent facial improvement in the eye area, as well as improvements in facial lifting and contouring following topical application of DMAE for one week. The test included 33 subjects aged 36 to 59, and improvement ratings were calculated by expert evaluation of before-and-after photographs.17 DMAE's safety and efficacy was confirmed in a follow-up study in which 156 subjects aged 35 to 60 underwent an 18-week, double-blind, placebo-controlled study. At 16 weeks, the DMAE group showed significant improvement in overall skin appearance and the reduction of forehead-frown lines. Subjects continued to use DMAE for 12 months, at which point cumulative assessments confirmed DMAE's safety as a topical ingredient.18 An animal study found DMAE to be non-toxic and non-allergenic to the skin.19

In a recent randomised, double-blind study, researchers found that the application of a gel containing three per cent DMAE on human skin increased the skin's resistance to stretching, citing DMAE as a potential skin-firming agent.20

Though published DMAE research is scant, Johnson & Johnson's interest in its topical benefits supports Perricone's prediction that it could be one of the next big anti-ageing ingredients for skin.

CO-ENZYME Q10 has some research to support topical amelioration of periodontitis. In one study, 10 male patients with a combined total of 30 periodontal pockets received Co-Q10 in all pockets for three weeks, then Co-Q10 in 20 pockets and soybean oil in the remaining 10 for six weeks. Improvement in fluid levels and detachment loss occurred after the first three weeks and continued throughout the study using Co-Q10, but did not continue with soybean oil.21

Products composed of individually validated ingredients, or at least one or more researched ingredients, may have measures of success in the current environment
In an animal study, researchers found that treating rabbit corneas with a topical Co-Q10/vitamin E blend prior to radiation exposure decreased the incidence of corneal cell death. 22 These studies indicate Co-Q10 may be an effective topical agent, though additional research specifically related to skin care is warranted. A German review determined that Co-Q10 is a viable photoprotectant with the ability to penetrate into the skin, protect collagen and reduce wrinkles in human skin. 23

FATTY ACIDS, specifically linoleic acid and gamma linoleic acid, are required for the skin to retain moisture. Science has found that linoleic acid is necessary to the enzymatic activity that develops skin cells into proper water-maintaining barriers.24 A deficiency of linoleic acid is characteristic of dry skin.25 Studies have found that a deficiency of linoleic acid is linked to conditions of poor skin such as acne.26 When applied topically, these two compounds reduce trans-epidermal water loss.27

Linoleic acid is also a major component of dermal ceramides, the binding 'mortars' between cells that provide both skin strength and barrier function.28,29 An animal study found that essential fatty acid-deficient skin has a weakened water-retaining barrier and that linoleic acid applied topically metabolizes into ceramides and unsaturated omega-hydroxy fatty acids, restoring the moisture and barrier-integrity of the skin.30

The skin-inflammation disorder atopic dermatitis is partially caused by deficiency in ceramide production and the subsequent weakened barrier membrane.31 Ceramide balance is also linked to ageing skin. In an in vitro study, researchers took skin samples from the face, hand and leg of different-aged female Caucasians and found an age-related decrease of all lipids and an altered ceramides-to-fatty acids ratio, which they claim causes the loss of skin-barrier function with age.32

Researchers at the University of California, San Francisco, tested a topical, ceramide-dominant, lipid-based emollient on 24 children with atopic dermatitis. After three weeks, 22 children showed a reduction in trans-epidermal water loss with improvements in skin integrity and hydration. Improvements continued through six and 21 weeks.33

Well-known skin care companies such as Borlind of Germany are now including plant-derived ceramides as novel topical ingredients in premium formulas.

HYALURONIC ACID (HA) is a disaccharide (alternating sugar-like molecules of glucosamine and glucuronic acid) that is the major water-holding molecule in the dermis and epidermis as well as all connective tissue and synovial fluid and in the vitreous gel that fills the eye. HA was long thought to be an inert filler in body fluids and connective tissues, but recent findings show it also plays an important role as an active anti-inflammatory compound.

Injected forms of HA have been used for arthritis, wrinkle-removal and ophthalmic surgery, and research supports its critical role in scarless wound healing.34Small facial cuts heal without scarring because of high HA levels. HA's multi-faceted role in wound repair—carefully regulating inflammation, formation of granulation tissue, re-epithelisation and remodeling—has prompted its topical use.35

Researchers in one study found that the combination of HA and diclofenac—a pharmaceutical benzeneacetic acid derivative indicated for osteoarthritis and ankylosing spondylitis—was effective at treating actinic keratoses, potential precursors to squamous cell carcinoma. Of the 29 subjects studied for six months, 81 per cent had a complete response and another 15 per cent showed marked clinical improvement.36

Other skin-deep treatments
Beyond the most familiar and most commonly used skin care ingredients, other herbs and ingredients are showing their face on the anti-ageing scene. Sabinsa Corporation has recently entered the skin care market with herbal preparations. One ingredient being used is boswellin from the plant Boswellia serrata. When tested on mice, researchers found it acted as a topical anti-inflammatory.37 Curcumin, which had the same effect,37 is being offered by Sabinsa as a patented, colour-free ingredient under the name tetrahydrocurcuminoids.

Beyond the most familiar skin care ingredients, other herbs and ingredients are showing their face on the anti-ageing scene
The French company Arkopharma offers the topical ingredient Hodeol, a patented fatty acid (9-hydroxy.10.12-octadecadienoic acid) extract from ivy, which it markets as a cellulite reducer. In a company-funded study, 21 women 25 to 49 years old applied Hodeol daily for 24 days. The results included an average 1cm reduction in thigh circumference and a report by participants of increased suppleness, firmness and smooth appearance. 38

Green tea, though a popular topical inclusion based on its health and antioxidant merits, still awaits more scientific research. However, the outcome of an experimental study showed that green tea's polyphenolic compounds, including epigallocatechin-3-gallate, protect against chemical carcinogenesis and photocarcinogenesis in mouse skin.39

Alpha-lipoic acid (ALA) is another compound touted as a potential winner in the future facial market. An animal study confirms the effective penetration of ALA into the skin as well as the immediate conversion of ALA to dihydrolipoic acid (DHLA).40

"The effectiveness of lipoic acid is believed to be from its by-product, DHLA," says Leslie Baumann, MD, director of cosmetic dermatology at the University of Miami. "DHLA has a more powerful anti-oxidative effect in the skin."

An in vitro study conducted at the Univeristy of California, Berkeley, researchers found that ALA selectively activated NF-kappaB, preventing photo-oxidative damage in UVB-exposed human skin.41

Baumann is currently studying the topical use of ALA for repairing photodamaged skin. "Preliminary results of our unpublished trials indicate that the use of topical lipoic acid has comparable results to glycolic-containing products," she says.

In a human study, a 12 per cent glycolic acid cream was found to elicit an SPF of 2.4 and improve photodamaged skin by 16 per cent within seven days.42 In a double-blind, randomised, placebo-controlled human study, 75 volunteers used either a five per cent glycolic acid topical or placebo on the face and neck for three months. The test group reported overall improvement in the reduction of photoageing characteristics including statistically significant improvement in skin texture and discoloration and a trend toward reduction of wrinkles.43

Although supported by smaller or company-funded studies, the inclusion of lesser-known topical ingredients in the anti-ageing skin care arena is a sure sign that the studies are positive enough for companies to risk creating products using them and that this market segment is expanding. Along with the old stand-bys, a host of new cosmeceuticals—some deemed efficacious, some awaiting further research—are now already adding value to creams, lotions and soaps.

Chris O'Brien is a researcher and writer in Rollinsville, Colorado.

References

1. Weber P, et al. Vitamin C and human health—a review of recent data relevant to human requirement. Int J Vit Nutr Res 1996;66:19-30.

2. Pinnel SR, et al. Induction of collagen synthesis by ascorbic acid. A possible mechanism. Arch Dermatol 1987 Dec;123(12):1684-6.

3. Nusgens BV, et al. Stimulation of collagen biosynthesis by topically applied vitamin C. Eur J Dermatol 2002;12(4):32-4.

4. Rougier A, et al. Clinical and biological effects of topical vitamin C in the treatment of skin aging. 2nd World Congress of the IACD. 2000 Nov 9-11, Rio de Janeiro, Brazil (http://www.dermato.med.br/iacd/congress/papers/papers-b.htm).

5. Rougier A, et al. Clinical and biological effects of topical vitamin C in the treatment of skin aging. 2nd World Congress of the IACD. 2000 Nov 9-11, Rio de Janeiro, Brazil (http://www.dermato.med.br/iacd/congress/papers/papers-b.htm).

6. Dreher F, et al. Protective effects of topical antioxidants in humans. Curr Prob Dermatol 2001;29:157-64.

7. Dreher F, et al. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. Br J Dermatol 1998;139(2):332-9.

8. Packer L, et al. Molecular aspects of alpha tocotrienol antioxidant action and cell signaling. J Nutr 2001;131:369S-73S.

9. Traber MG, et al. Diet-derived and topically applied tocotrienols accumulated in the skin and protected the tissue against UV light-induced oxidative stress. Asia Pacific J Clin Nutr 1997;6(1):63-67.

10. Thiele JJ, et al. In vivo exposure to ozone depletes vitamin C and E and induces lipid peroxidation in epidermal layers of murine skin Free Rad Biol & Med 1997;23:385-9.

11. Record IR, et al. The influence of topical and systemic vitamin E on ultraviolet light-induced skin damage in hairless mice. Nutr Cancer 1991;16(3-4):219-25.

12. Yuen KS, et al. Alpha-tocopherol, an inhibitor of epidermal lipid peroxidation, prevents ultraviolet radiation from suppressing the skin immune system. Photochem Photobiol 1997;65(3):587-92.

13. Darr D, et al Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants. Acta Derm Venereol 1996;76(4):264-8.

14. Moison RM, et al. Topical antioxidant vitamins C and E prevent UVB-radiation-induced peroxidation of eicosapentaenoic acid in pig skin. Radiat Res 2002;157(4):402-9.

15. Gensler HL, et al. Importance of the form of topical vitamin E for prevention of photocarcinogenesis. Nutr Cancer 1996;26(2):183-91.

16. Nagy I, et al. On the role of cross-linking of cellular proteins in aging. Mech Ageing Dev 1980;14(1-2):245-51.

17. Wallo, W, Johnson & Johnson CPWW, et al. Clinical instrumental documentation of the skin firming effects of topical dimethylaminoethanol. Presented at AAD annual meeting 2002 Feb 22-26; New Orleans (LA).

18. Grossman RM, Johnson & Johnson CPWW, et al. Long-term safety and efficacy evaluation of a new skin firming technology: dimethylaminoethanol. Presented at AAD annual meeting 2002 Feb 22-26; New Orleans (LA).

19. Leung HW, et al. The skin sensitization potential of four alkylalkanolamines. Vet Hum Toxicol 1998 Apr;40(2):65-7.

20. Uhoda I, et al. Split face study on the cutaneous tensile effect of 2-dimethylaminoethanol (deanol) gel. Skin Res Technol 2002;8(3):164-7.

21. Hanioka T, et al. Effect of topical application of coenzyme Q10 on adult periodontitis. Mol Aspects Med 1994;15 S:S241-8.

22. Brancato R, et al. Concomitant effect of topical ubiquinone Q10 and vitamin E to prevent keratocyte apoptosis after excimer laser photoablation in rabbits. J Refract Surg 2002;18(2):135-9.

23. Hoppe U, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors 1999;9(2-4):371-8.

24. Nugteren DH, et al. Conversion of linoleic acid and arachidonic acid by skin epidermal lipoxygenases. BiochimBiophys Acta 1987; 921(1):135-41.

25. Wertz PW, et al. Essential fatty acids and epidermal integrity. Arch Dermatol 1987;123(10):1381-4.

26. Wertz PW, et al. The composition of the ceramides from human stratum corneum and from comedones. J Invest Dermatol 1985;84(5):410-2.

27. Hartop PJ. Changes in transepidermal water loss and the composition of epidermal lecithin after applications of pure fatty acid triglycerides to skin of essential fatty acid-deficient rats. Br J Dermatol 1976;95(3):255-64.

28. Bowser PA, et al. Identification, isolation and characterization of epidermal lipids containing linoleic acid. Biochim Biophys Acta 1985;834(3):419-28.

29. Hamanaka S, et al. Human epidermal glucosylceramides are major precursors of stratum corneum ceramides. J Invest Dermatol 2002;119(2):416-23.

30. Nugteren DH, et al. Metabolism of linoleic acid and other essential fatty acids in the epidermis of the rat. Biochim Biophys Acta 1985;834(3):429-36.

31. Macheleidt O, et al. Deficiency of epidermal protein-bound omega-hydroxyceramides in atopic dermatitis. J Invest Dermatol 2002;119(1):166-73.

32. Rogers J, et al. Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res 1996;288(12):765-70.

33. Chamlin SL, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002;47(2):198-208.

34. Anderson I. The properties of hyaluronan and its role in wound healing. Prof Nurse 2001 Dec;17(4):232-5.

35. Chen WY, et al. Functions of hyaluronan in wound repair. Wound Repair Regen 1999 Mar-Apr;7(2):79-89.

36. Rivers JK, et al. An open study to assess the efficacy and safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the treatment of actinic keratoses. Arch Dermatol 1997;133:1239-42.

37. Huang MT, et al. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 1998;48(21):5941-6.

38. Jacquet A. Clinical evaluation of the efficacy and tolerance of a 15% Hodoel solution, applied topically. Arkopharma Laboratories 1996; Bordeaux, France.

39. Katiyar SK, et al. Green tea and skin. Arch Dermatol 2000;136:989-94.

40. Podda M, et al. Kinetic study of cutaneous and subcutaneous distribution following topical application of [7,8-14C]rac-alpha-lipoic acid onto hairless mice. Biochem Pharmacol 1996 Aug 23;52(4):627-33.

41. Saliou C, et al. Antioxidants modulate acute solar ultraviolet radiation-induced NF-kappaB activation in a human keratinocyte cell line. Free Rad Biol Med 1999 Jan;26(1-2):174-83.

42. Perricone NV, et al. Photoprotective and anti-inflammatory effects of topical glycolic acid. Dermatol Surg 1996;22(5):435-7.

43. Thibault PK, et al. A double-blind randomised clinical trial on the effectiveness of a daily glycolic acid 5% formulation in the treatment of photoaging. Dermatol Surg 1998;24(5):573-7.

Marketing applications: Six degrees of success
As with dietary ingredients before it, cosmetic ingredients that are truly naturally occuring molecules or agricultural materials are starting to take a leap forward. Products derived from nature have always lurked in the realm of cosmetics. However, as most cosmetics chemists and cosmetics brand marketers would admit, the use has been trivial and fashion-oriented, not truly functional.

This is beginning to change. The fastest way to profitable change is highlighted in a model used by a television retail marketer. The Proactive Solution product franchise is an excellent example of a performance-based treatment product, without complex technology, communicated in a way that demonstrates excellent command of the marketing value chain. Proactive is an acne treatment system using benzoyl peroxide and other natural ingredients. Its marketing slogan is 'Made by nature, not a chemist.'

Six elements make up this successful model, which is enhanced by the selected media communicating the product's benefits:


  1. Evidence package carefully built and translated for the target consumer.
  2. Emotional selling components and power of testimonial clearly communicated.
  3. Consumer promise backed by credible authorities—in this case, female MDs who match the primary audience
  4. The select incorporation into the final consumer product packaging of validating controlled trials.
  5. A mixture of compelling messages woven into the broadcast programme with appropriate sensibilities.
  6. A product that is perceived as safe and effective while being convenient and affordable.

This community-creating product franchise may allow its marketer to build other successful product launches in the skin-care arena. Products composed of individually validated ingredients, or at least one or more researched ingredients, may have measures of success in the current environment. This is because consumers are becoming increasingly exposed to 'truly functional' product evidence packaging, and the quality of validation needs to increase to break through the clutter. The scientific validation need not become the focus of the promise, as with pharmaceuticals, but a solid base of clinical trial evidence on the actual product needs to clearly support the message mix.

At this stage of cosmeceutical market development, a strong cupboard of new ingredients combined with the pitch of a credible or charismatic health professional will create significant demand. It is reasonable to project that this will not always be the case; how long that will take is also hard to determine at this point.

Yet, for those marketers aspiring to new levels of product launch and sell-through success, the model described above may be the template of the future. Consumers increasingly expect to be able to thwart ageing and will buy from marketers who present a strong likelihood for success or positive product experience in a comprehensive and compelling way. This should result in more successes like Proactive.

Tim Avila


Intellectual property: patents support anti-ageing surge
Most developed countries are experiencing an increase in life expectancy. The rapidly increasing ageing population is driving a lucrative market for products promising anti-ageing benefits. Judy Davis looks at patents for products aimed at satisfying the desire for a long and healthy life

Anti-aging supplements
US company Reliv International has recently been granted a patent for a dietary supplement designed to reduce the effects of ageing by replenishing or stimulating production and release of hormones that improve longevity and health and reduce the effects of cellular ageing. The supplement includes two main components. The first is a so-called 'secretagogue,' aimed at stimulating human growth hormone secretion. Production of this hormone peaks during adolescence, declining significantly as we age. Increased levels of human growth hormone are associated with higher energy levels, improved skin texture, reduced body fat and increased muscle tone.

The other main component is 7-keto-dehydroepiandrosterone (7-keto-DHEA), a natural metabolite of DHEA, another hormone linked with healthy ageing. According to the inventors, 7-keto DHEA is used in preference to DHEA itself because it cannot be converted to active androgens and oestrogens—apparently a problem with DHEA. Scientific studies suggest that 7-keto DHEA can improve immune function and memory. Various antioxidant ingredients and natural herbs for promoting physiological health are also included in the formulation, which is provided as a liquid or powder suitable for making drinks. (US Patent 6,368,617)

Calorie restrictions
Early findings that calorie restriction could help extend the lifespan of mammals came from research in 1935, when it was found that rats fed a diet containing between 30 and 50 per cent fewer calories than controls lived for an average of 33 per cent longer. However, even with these proven benefits, calorie restriction is unlikely to catch on as a lifestyle—some 40 per cent of the population is unable to maintain a healthy body weight as it is. Now, a US inventor may have come up with the answer. His patent describes methods for "promoting longevity and decreasing the incidence of ageing-associated pathologies" by provision of a dietary supplement containing the long-chain free fatty acids (LFFAs) linoleic, oleic and palmitic acids and their co-enzyme A derivatives. This food supplement is said to mimic the physiological effects of calorie restriction.

According to the patent, calorie restriction causes the body to initiate lipolysis in the body's fat stores, resulting in a sudden increase in the levels of circulating LFFAs. The inventor believes that it is these LFFAs that function as stress signals to trigger the same series of protective mechanisms seen in mammals fed calorie-restricted diets, such as reduction in oxidative damage, induction of protective genes and longer life expectancy. (European Patent Application EP 1 220 669)

Green tea powder
Active oxygen is considered to be one of the factors that adversely affects human health and hastens ageing. Green tea contains high levels of superoxide dismutase, an enzyme that plays a key role in elimination of active oxygen. In addition, green tea is rich in other natural antioxidants, such as vitamins E and C, as well as catechins and theanine. Conventional methods of green tea preparation can result in loss of a significant proportion of these beneficial nutrients.

Japanese company Kabushiki KK has now come up with a way to overcome the problem by producing the tea in a microfine powder form. Crude green tea is pulverised to obtain a powder with a particle size of one micron or less. The microfine powder is moistened with distilled water and heated in an infrared irradiation chamber to yield a final product with greatly increased superoxide dismutase activity. (US Patent 6,416,803)

Curcuma extracts
Extracts of plants of the Curcuma genus, and particularly turmeric Curcuma longa, have traditionally been used since ancient times for flavouring foods and for medicinal purposes. Curcuma extracts are yellow pigments known as curcuminoids, and include curcumin, demethoxycurcumin and bis-demethoxycurcumin.

A patent from ASAC Pharmaceutical International describes methods for producing curcuma extracts that can be used in water- or fat-based products. According to the patent, the resulting extracts have high superoxide and free radical-scavenging activities and are particularly suitable for inclusion in dietary supplements or functional foods designed with anti-ageing in mind. The extracts are also claimed to reduce plasma lipid peroxide levels and could therefore be beneficial in conditions related to cell oxidation, such as arteriosclerosis and rheumatoid arthritis. (US Patent 6,440,468)

This information has been compiled by UK-based Leatherhead Food International. For further information, contact Judy Davis, Tel: +44 1372 822241. E-mail: [email protected]


Delicious Living

January 1, 2003

Herb Ban Feared As 'Sensible' Amendments Get Nixed

Europe

Although six amendments to the European Union's proposed Traditional Herbal Medicinal Products Directive were recently passed by the European Parliament and are supported by the industry, the European Commission gave the thumbs-up to only half. The Commission's recommendations have increased concern that the proposed registration scheme for herbal products and ingredients would ban many that are currently available.

Pedro Vicente Azua, regulatory affairs director of the European Federation of Health Product Manufacturers, said it was unfortunate the Commission had taken a more conservative position on many of these points and had not supported some of the amendments that had significantly liberalised the original proposal.

Director of lobby group Consumers for Health Choice, Sue Croft, said, "We are very disappointed with the Commission's stance on this, especially after the Parliament had backed what we consider to be a range of very sensible amendments."

Although the legislation covers only a restricted sector of traditional herbal medicines and not other herbal products, many Members of the European Parliament, particularly from Ireland and the UK, remain concerned about the indirect effect of the Directive on products currently on the market.

The Irish Health Trade Association is concerned with the Commission's denial of the amendment that applies to traditional products as opposed to ingredients.

"The emphasis on products presents a further problem in relation to the availability of support data," IHTA stated. "Indeed, while there is likely to be a considerable amount of data available to support a long history of continuous medicinal use of many herbal ingredients, it is much less likely to be available for products."

One industry source played down the concerns, saying the Council of Ministers were just as likely to support the original amendments as they were the Commission's position.

The British Herbal Medicines Association (BHMA), which supports registration of any herbs sold as medicines, welcomed the amendments. "Most of the amendments make the Directive more flexible. We are encouraged by that," BHMA Chairman Simon Mills said. "There are a lot of inadequate herbal medicines on the market because there has been so little control. This Directive will ensure the public get access to reliable herbs.

"At the moment in the UK, you can put any herb in a bag and call it a medicine and sell it without a licence. This new Directive should take over from that unclear area, making the borderline between foods and medicines less broad."

The BHMA is working with the UK-based Medicines Control Agency to assist companies in preparing for the new legislative climate. "We are helping smaller firms to get tooled up so they can produce herbs to the required standard with the requisite science," Mills stated.

The Directive will soon go before the European Council of Ministers before passing back to the Parliament for a second reading and vote. The Directive is expected to become law by early 2004.

Major Amendments: 3 Voted Up, 3 Down

Allows for the inclusion of combination products—products containing herbals and other non-herbal ingredients. This amendment recognises the many herbal medicines prepared with vitamins, minerals or other constituents. (Supported by the Commission)

Reduces the amount of time a product or ingredient must have been used within the EU from 15 to 10 years (plus at least 20 years outside the EU). Recognises the existence of many herbals with a history of safe use in other parts of the world that may only recently have been introduced to the EU. (Supported)

Defines herbal medicinal products as containing ingredients at a pharmacologically active level. Herbals with lower activity will continue to be defined as foods, food supplements or cosmeceuticals. (Not supported by the Commission)

Makes the Directive ingredients-based rather than product-based. Newer medicines containing permitted ingredients may not meet EU history-of-safe-use criteria if only end products are taken into account. (Not supported by the Commission)

Establishes a new Com-mittee on Herbal Medicinal Products to take over from the Committee for Human Medicinal Products. This is a more specialised and efficient body to deal with herbal evaluations. (Sup-ported by the Commission)

Would allow Member States to introduce their own legislations in certain cases. This acknowledges regional differences and herbal practices. (Not supported by the Commission)


Devolution and diversity keys to Directive success

Flexibility is the key to the successful working of the European Union's draft proposal for Nutritional, Functional and Health Claims Made on Foods, according to the UK-based Joint Health Claims Initiative (JHCI).

The proposed legislation aims to establish a governing code for health claims on food labelling throughout Europe. It identifies four different levels of claim: 'functional', 'enhanced function', 'reduction of disease risk factor' and 'reduction of disease risk'.

The proposal is seen as necessary to increase consumer confidence in functional foods by supporting new products with valid health claims.

While welcoming the initiative, Melanie Ruffell, executive secretary of the JHCI, an independent claims assessment agency made up of consumer organisations, enforcement authorities and industry trade associations, highlighted some of the complexities the proposal must negotiate before it becomes law, by 2005 at the earliest.

She pointed out the difficulty of institutionalising pan-European claims in a multicultural, multi-lingual, nutritionally diverse market.

"What is proposed is one central body that does all of the assessments, both from the scientific angle and the application of that science. But there are so many local variations, not only in language and interpretation and translation but also dietary differences and cultural differences," she said. "That's why we would like to see some kind of devolved system where member states retain a certain degree of authority. The scientific link for health claims could be established at the Commission level but then each of the member states could decide how that science is applied within each language and in relation to their particular health issues.

"They have proposed a centralised system but the majority of the feedback the European Commission has received is that it is not terribly realistic to expect health claims to be effective in 22 countries when you may only want to market your products in one country."

Beate Gminder, spokesperson for health and consumer protection for the European Commission, said that a fully harmonised system would have to work centrally but that the EC respected each country's national laws.

"It would be up to the new European Food Safety Authority (EFSA) to establish the science," said Gminder. "And then it will be up to the member states to interpret this and ensure claims are not misleading and that consumers are protected. We couldn't establish claims for each product."

Consumer pressure grows in London

Consumers for Health Choice (CHC) presented a million-strong petition to the British Parliament in November protesting both the European Traditional Herbal Medicinal Products Directive and the Food Supplements Directive. The petition claims the Directives restrict freedom of choice and will see hundreds of products and ingredients removed from the market, sending many manufacturers out of business in the process.

Although the Food Supplements Directive became law in June 2002, the detail of the legislation has yet to be finalised. This includes upper safe levels for nutrients and a positive list of ingredients that will be permitted for use in food supplements.

Scientific dossiers supporting non-listed nutrients and USLs can be submitted to the EU's newly established food safety evaluation body until 2005.

ARCHIVE - Warming Winter Tonic Soup

Warming Winter Tonic Soup
January, 2003

Serves 4 / This hearty and delicious cold-weather soup is full of liver-friendly ingredients to help detoxify your system.

1/2 cup minced red onion
1/2 cup sliced shiitake mushrooms
2 cloves garlic, minced
1 tablespoon minced fresh ginger
1/2 cup peeled and thinly sliced burdock root
1/2 cup sliced carrots
1/2 cup thinly sliced cabbage
1/2 cup beets, well-scrubbed and sliced into 1/2-inch quarters
2 leeks, well-rinsed and sliced into 1/4-inch slivers
2 tablespoons olive oil
5 cups vegetable or chicken stock, or water
2 tablespoons light miso
2 tablespoons chopped fresh cilantro
2 scallions, minced

1. In a large pot, sauté first nine ingredients in olive oil for 10 minutes. Add stock or water and bring to a boil. Lower heat, cover, and simmer for 20-25 minutes or until vegetables are tender.
2. Dissolve miso in small amount of hot broth and add to soup. Turn off heat and add cilantro and scallions. Cover and let stand for 5 minutes. Serve hot.

Calories 195,Fat 8,Perfat 36,Cholesterol 0,Carbo 28,Protein 4,Fiber 4,Sodium 430

 

NCCAM Will Establish New CAM Research Centers

The National Center for Complementary and Alternative Medicine (NCCAM) announced it will establish new centers for research on complementary and alternative medicine (CAM). The new initiative will include three companion programs: Centers of Excellence for Research on CAM, Developmental Centers for Research on CAM, and Planning Grants for International Centers for Research on CAM. "These programs are designed to enlist researchers from multiple disciplines--in both conventional medicine and complementary and alternative medicine--to apply their expertise to advance complementary and alternative medicine research," said Stephen E. Straus, MD, NCCAM Director.

Centers of Excellence for Research on CAM will support projects designed to elucidate the action mechanisms of CAM modalities and will provide opportunities for molecular or cellular biologists, imaging scientists, immunologists, neurobiologists, pharmacologists, physiologists, and other scientists. Letters of intent are due March 29, 2003; receipt date is April 29, 2003.

Developmental Centers for Research on CAM will support cooperative agreements in which CAM and conventional institutions and investigators will partner to conduct exploratory and developmental research projects. According to NCCAM, "These awards will provide opportunities for CAM institutions and investigators to strengthen their research expertise and infrastructure while enabling conventional researchers to gain clinical and cultural perspectives critical to the conduct of CAM research." Letters of intent are due March 14, 2003; receipt date is April 15, 2003.

Planning Grants for International Centers for Research on CAM will enable U.S. and international institutions to jointly plan exploratory and developmental studies of traditional/alternative healing approaches. These grants will lay the groundwork for developing applications for an International Center for Research on CAM that will be called for in 2004. Letters of intent are due February 28, 2003; receipt date is March 28, 2003.

Requests for applications for these opportunities are now available at nccam.nih.gov. For further information: 888-644-6226 or [email protected]v

Mannatech Launches GlycoLEAN(R) Body System in Canada

COPPELL, Texas, Dec. 30 /PRNewswire-FirstCall/ -- Canadians hoping to shed unwanted fat and get fit in 2003 will have plenty of help. Mannatech, Inc. (NASDAQ: MTEX) , a leader in the dietary supplement industry, today announced its GlycoLEAN(R) Body System has been made available throughout Canada.

When combined with a healthy low-glycemic diet and exercise, GlycoLEAN(R) Body System is a fat-loss/weight management system designed to contribute significantly to the maintenance of good health. GlycoLEAN(R) Body System consists of four products: GlycoLEAN(R) Catalyst with Ambroglycin(TM), GlycoLEAN Accelerator 2(TM), GlycoLEAN(R) Fiber Full and GlycoLEAN GlycoSlim(R) Meal Replacement Drinks.

"We are very excited to bring this product to Canada," said Dr. Stephen Boyd, Mannatech's Medical Director, Health Sciences. "We strongly believe the basis of any diet should be low-glycemic fruits and vegetables. That philosophy is at the heart of the GlycoLEAN(R) plan. We don't view this plan as a fad diet, but as a common sense approach backed by science. These principles combined with a commitment to live a healthier lifestyle should yield excellent results."

Dr. Boyd, a 1974 graduate with an MD degree from the University of Toronto, will tour Canada throughout January, speaking on the benefits of low-glycemic eating. Boyd, who also boasts a BA and PhD in Chemistry from the University of Glasgow and is a member of the Royal College of Medicine, will speak Jan. 6 @ Moncton, New Brunswick; Jan. 7 @ Mississauga, Ontario; Jan. 8 @ London, Ontario; and Jan. 13 @ Ottawa, Ontario.

At the heart of the GlycoLEAN(R) Body System is a concept known as Glycemic Indexing. That allows for the measurement of how a given food raises blood sugar and insulin response. This GI number is significant because the rate at which blood sugar rises after eating is extremely important in the total equation of weight management. When a high-glycemic load is consumed blood sugars rise. As a result, insulin rises. The increase of blood sugar causes many negative effects, including weight gain. Foods that have a high-glycemic load increase appetite. They may also cause an increase in both stored and circulating fat by increasing triglycerides.

Since only carbohydrates are rated for their glycemic index, most people incorrectly believe that low-glycemic and low-carbohydrate are the same thing. This is definitely not the case. There are a number of significant differences between low-carbohydrate diets and glycemic indexing. Another popular misconception is that GI is based on sugars alone because of the name "glycemic."

Carbohydrates are a factor and will raise sugar levels. Low-carbohydrate dieting alone, without regard to the glycemic index, may result in storage as fat of any amount of sugar that cannot be converted to energy. And, just as there are "good" (essential) fats and "bad" (non-essential) fats, there are also good and bad carbohydrates.

"These concepts are new to most, but are at the heart of what Mannatech has been saying since 1999," said Boyd, who spoke at the sixth annual Jenner Symposium - Glycobiology & Medicine, held in September in Seillac, France. "We are proud that the world is finally learning the proven benefits of Glycemic Indexing and the GlycoLEAN(R) Body System."

Mannatech, Inc. is a wellness solution provider that develops innovative, high-quality, proprietary nutritional supplements, topical products and weight management products, which are sold through a global network-marketing system throughout the United States and the international markets of Canada, Australia, the United Kingdom, Japan and New Zealand.

For more information about Mannatech visit www.mannatech.com.