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Cosmeceuticals: New hope for ageing skin

Recent clinical trials are adding substance to marketing claims, giving muscle to an already vibrant market in skincare products. Mark J Tallon, PhD, examines some of the latest evidence

In 1980, Dr Albert Kligman coined the term 'cosmeceutical' to indicate a topical preparation that is sold as a cosmetic but has performance characteristics that suggest pharmaceutical action.1 Since then, cosmeceuticals have become a multi-billion dollar industry with an increasing focus searching for pain-free, non-invasive rejuvenators of damaged and ageing skin. According to recently released reports, skincare products account for more than half the total cosmeceutical market, with growth destined to increase by 8.5 per cent by 2007, grossing no less than $5.1 billion,2 with a category potential of $16 billion by 2010.3 There can be little doubt a vibrant cosmeceutical revolution is well and truly underway.

Despite a severe lack of solid scientific evidence, many non-invasive topical cosmeceuticals have been applied as treatment modalities for everything from telangiectasias (dilated superficial blood vessels) to dyspigmentation (abnormal change in skin color). However, tighter enforcement of marketing claim substantiation through the Food, Drug and Cosmetic Act (USA) and the European directive (76/768/EEC) has led to a radical upsurge in prospective clinical trials.

In this month's ingredient focus I will review the latest concepts and science surrounding the cosmeceutical sciences, highlighting the dermaceutical science behind quercetin, evodia extract, pomegranate extracts, eicosapentaenoic acid, promoters of hyaluronan, and finally a novel nitric oxide inducer.

Quercetin: testing a radical formulation
UV radiation can result in an imbalance of the body's antioxidant system leading to increased free radical formation and inflammation. The result can be precancerous and cancerous melanomas, and accelerated skin ageing. In this regard, quercetin, a powerful flavonoid with antioxidant activity, may be an effective therapy for UV-induced skin damage.4 Researchers investigated the possible beneficial effects of a topical formulation containing quercetin to inhibit UVB irradiation-induced oxidative skin damage.

Quercetin was applied to the skin of hairless mice using two formulations. Formulation one had a high lipid quercetin content and formulation two a low lipid quercetin content. The UVB irradiation induced a dose-dependent increase in the myeloperoxidase (MPO) activity (inflammatory biomarker) and depletion of the antioxidant glutathione in the skin after 6h.

Following topical administration of formulations one and two, MPO activity increase following UVB exposure was inhibited 62 per cent and 59 per cent; and GSH depletion 119 per cent and 53 per cent, respectively.5

This is the first study to demonstrate the effectiveness of topical formulations containing quercetin to inhibit the UVB irradiation-induced skin damage.5 This data suggests the possible usefulness of topical formulations containing quercetin to ameliorate UVB radiation-associated skin damage. However, further work in humans is needed before any firm conclusions about potential applications in cosmeceuticals can be extrapolated.

Evodia vs inflammation
A whole host of botanicals hailing from China have supposed dermaceutical benefits, of which some are anti-inflammatory-based influences.6 Recent work has attempted to narrow the botanical line when it comes to the actives that bring about these beneficial effects. Dr Yarosh and colleagues recently prepared indole quinazoline alkaloid extracts from Evodia rutaecarpa,7 using a model that brings about microinflammation and erythema (reddening of the skin) within 30 minutes following topical application to the skin. Twice-daily topical application of evodia extract over seven-14 days significantly inhibited chemically induced erythema.7 These results demonstrate that the bioactive compounds present in Evodia rutaecarpa have powerful anti-inflammatory activity when applied topically to human skin. This preliminary data may give further impetus for the use of botanicals as effective nutrients in cosmeceuticals.

The power of pomegranate
Pomegranate (Punica granatum) is an ancient fruit with a long history of medicinal use. The peel (pericarp) is well regarded for its astringent properties. In a study carried out at the University of Michigan Medical School, aqueous fractions prepared from pomegranate peel, fermented juice and lipophilic fractions of the pomegranate were examined for effects on human epidermal keratinocyte and dermal fibroblast function.8

Results indicate pomegranate's potential to facilitate skin repair by promoting regeneration of the dermis and epidermis
Pomegranate seed oil, but not aqueous extracts of fermented juice, peel or seed cake, was shown to stimulate keratinocyte proliferation in monolayer culture. In parallel, a mild thickening of the epidermis was observed but without effect on fibroblast function. 8 In contrast, pomegranate peel extract stimulated type I procollagen synthesis and inhibited matrix metalloproteinase (MMPs can break down skin proteins) production by dermal fibroblasts, but had no growth-supporting effect on keratinocytes. 8 These results indicate the potential of pomegranate fractions for facilitating skin repair by promoting regeneration of the dermis and epidermis.

Eicosapentaenoic acid and UV damage
Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with years of research regarding inflammatory and immunomodulating activity in the human body.9 In a previous study EPA was found to inhibit UV-induced Matrix metalloproteinase expression in human dermal fibroblasts.10 Therefore, the authors of the current study investigated the effects of EPA on UV-induced skin damage and intrinsic ageing by applying EPA topically to young and aged human skin.10

The topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease
The authors found that the topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease. EPA also inhibited UV-induced cyclooxygenase (COX)-2 without altering COX-1 expression suggestive of an anti-inflammatory effect. Moreover, it was found that EPA increased collagen and elastic fibre expression in aged human skin. Taken together, the results of these studies demonstrate that topical EPA has potential as an anti-skin ageing agent.

Targeting hyaluronan
In another study from the American Academy of Dermatology, a topical combination of N-acetyl glucosamine and niacinamide on fine lines and wrinkle formation was assessed by a team from Procter & Gamble (Cincinnati, Ohio).11 Hyaluronan is a mucopolysaccharide in the epidermis, responsible in part for maintaining overall hydration of the skin. N-acetyl-glucosamine is a precursor of hyaluronan, and niacinamide is an essential co-factor of hyaluronan synthesis.

Real beneficial effects of cosmeceuticals were suggested by the results of combining N-acetyl-glucosamine and niacinimide
In previous in vitro studies, N-acetyl-glucosamine and niacinamide applied separately have been shown to stimulate hyaluronan synthesis. 12,13 In this study, the combination applied topically was assessed. 11 The two actives, in a facial moisturizer, were applied twice daily for four-eight weeks by women with moderate-to-severe fine lines and wrinkles. 11 Following treatment, a reduction in the appearance of facial fine lines and wrinkles was observed, particularly in the eye area. This exciting data suggests real beneficial effects of cosmeceuticals in human subjects by manipulating hyaluronan synthesis.

Activating nitric oxide
Nitric oxide (NO) is a unique, gaseous free radical that is an important physiologic mediator for autonomic functions such as vasodilation, neurotransmission and intestinal peristalsis. Recent wound-healing studies indicate NO-mediated tissue repair may play an important role in epidermal health.14,16 Previous studies have shown that bi-cyclic monoterpene diols (BMTd) stimulate nitric oxide synthesis in melanoma and neuronal cells.17

In a study published this year, authors hypothesized that increasing nitric oxide in the skin would lead to beneficial enhancements in microcirculation as measured by skin temperature.18 Following the application of a 1-mM BMTd lotion, arm temperature increased by 0.8?F in 14 days compared to placebo lotion. A single application of a 2-mM BMTd lotion applied 30 minutes before a 30-minute cold challenge (43?F) maintained facial temperature 2.5?F above that of untreated controls.

In a final experiment, the researchers assessed the impact of a 2-mM BMTd lotion on people with dark circles under their eyes. Following twice-daily application, a visual evaluation scoring system assessed a significant reduction — 13 per cent — of under-eye dark circles.18 The take-home of these studies is that a mixture of BMTd (2,3-cis/exo-pinanediol and 2,3-cis-camphanediol) in a 1,3-butylene glycol suspension (as in this study) when applied to skin increases nitric oxide and microcirculation, resulting in measurable changes in appearance.

Better science, better skin
Since Kligman's early coining of the term cosmeceuticals, a much more complex understanding of skin damage can now be characterized by investigating the molecular and biochemical impact of internal and external processes of epidermal damage and ageing.

Because of these advances in our scientific understanding of skin damage, new areas of treatment and prevention are now being investigated. The most novel include such areas as nitric oxide manipulation and its positive effects on the dermal matrix via enhanced type I collagen formation. Estrogen receptors are also a target to look out for regarding selective receptor topical applications, which may bring about increased collagen content, skin thickness and improved skin moisture without the systemic effects of hormonal drug therapies.19

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

1. Elsner P, Mailbach H, editors. Cosmeceuticals and active cosmetics. Boca Raton (FL): Taylor & Francis. 2005.
2. No Author. Mark research report: cosmeceuticals to 2008. Freedonia Group, Inc 2004 Cleveland (OH), USA.
3. No Author. Market trends: The US cosmeceuticals and anti-aging products market. Market 2005.
4. Steerenberg PA, Garssen J, et al. The effect of oral quercetin on UVB-induced tumor growth and local immunosuppression in SKH-1. Cancer Lett 1997; 114 (1-2):187-189.
5. Casagrande R, Georgetti SR, et al. Protective effect of topical formulations containing quercetin against UVB-induced oxidative stress in hairless mice. J Photochem Photobiol B 2006 (Ahead of publication).
6. Koo J, Arain S. Traditional Chinese medicine for the treatment of dermatologic disorders. Arch Dermatol 1998;134 (11):1388-1393.
7. Yarosh D, Brown D, et al. Anti-inflammatory activity in skin by indole quinazoline alkaloids from traditional Chinese medicine. J Am Acad Dermatol 2006; 54 (3): 1131.
8. Aslam MN, Lansky EP, et al. Pomegranate as a cosmeceutical source: pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells. J Ethnopharmacol 2006; 20; 103(3): 311-318.
9. Babcock T, Helton WS, et al. Eicosapentaenoic acid (EPA): an anti-inflammatory omega-3 fat with potential clinical applications. Nutrition 2000; 16 (11-12): 1116-1118.
10. Kim HH, Cho S, et al. Photoprotective and anti-skin aging effects of eicosapentaenoic acid in human skin in vivo. J Lipid Res 2006; (Ahead of publication).
11. Osborne R, Mullins L, et al. Topical N-acetyl glucosamine and niacinamide increase hyaluronan in vitro. J Am Acad Dermatol 2006; 54 (3): 1124.
12. Breborowicz A, Kuzlan-Pawlaczyk M, et al. The effect of N-acetylglucosamine as a substrate for in vitro synthesis of glycosaminoglycans by human peritoneal mesothelial cells and fibroblasts. Adv Perit Dial 1998; 14: 31-35.
13. Jonas WB, Rapoza CP, et al. The effect of niacinamide on osteoarthritis: A pilot study. Inflamm Res 1996; 45(7): 330-334.
14. Schaffer MR, Tantry U, et al. Nitric oxide regulates wound healing. J Surg Res 1996; 63(1): 237-240.
15. Schaffer MR, Tantry U, et al. Nitric oxide metabolism in wounds. J Surg Res 1997;71: 25-31.
16. Bruch-Gerharz D, Ruzicka T, et al. Nitric oxide in human skin: current status and future prospects. Invest Dermatol 1998; 110: 1-7.
17. Brown DA, Lesiak K, et al. Bicyclic monoterpene diols induce differentiation of S91 melanoma and PC12 pheochromocytoma cells by a cyclic guanosine-monophosphate-dependent pathway. Pigment Cell Res 1999; 12 (1): 36-47.
18. Yarosh D, Brown D, et al. A bi-cyclic monoterpene diol mixture release of nitric oxide from skin cells increases microcirculation and elevates skin temperature. Am Acad Dermatol 2006; 54(3): 1147.
19. Verdier-Sevrain S, Bonte F, et al. Biology of estrogens in skin: implications for skin aging. Exp Dermatol 2006; 15(2): 83-94.

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