Volume 2, Number 1 (Summer 2008)
Harvard Medical School, Boston, Massachusetts
The 1938 Food, Drug, and Cosmetic Act differentiated clearly between drugs and cosmetics and charged the US Food and Drug Administration with regulating these products. This document allows the use of raw materials and ingredients in cosmetics for “cleansing, beautifying, promoting attractiveness, or altering the appearance” without approval by a government agency; however, no therapeutic claims for these products may be made. The production and marketing of pharmaceuticals are more closely regulated, and claims about health benefits for drugs may be made. The line between cosmetics and drugs has been blurred in recent years as consumers have become increasingly interested in fighting the effects of aging and in rejuvenating their appearance. Of course, industry rose to meet this need, and the concept of the “cosmeceutical” was born. At the 4th Annual Advances in Cosmetic and Medical Dermatology Meeting, dermatologic experts discussed the aging of skin and the “natural” and synthetic compounds currently on the market to combat the effects of passing years.
|Dr. Vleugels is Chief Resident in Dermatology at Harvard Medical School, Boston, Massachusetts.|
In 1984, Albert Kligman, MD, PhD, coined the term “cosmeceutical” to describe products that combine the concepts of a “cosmetic” (a product meant to beautify or improve appearance) and a “drug” (a product designed to mitigate or prevent disease).1 He believed that a “cosmeceutical” would represent a product that “does something more than coloring the skin and something less than a therapeutic drug.” Thus, cosmeceuticals have a unique niche in dermatologyand some 90% of cosmetics now fall into this growing category.
The differences between cosmeceuticals and drugs may involve a simple difference in terminology. For example, although a drug and a cosmeceutical may contain the same active ingredient, the drug may be marketed as an “antiaging” substance, while the cosmeceutical must be marketed as an agent that may “improve the appearance of wrinkles,” given that therapeutic claims may be made only for drugs. Importantly, cosmeceuticals are not a category that is either recognized or regulated by the US Food and Drug Administration (FDA), and cosmeceutical research is, for the most part, performed by the cosmetic industry.
During the 4th annual Advances in Cosmetic and Medical Dermatology meeting, held in Wailea, Maui, Hawaii, from February 25 to March 1, 2008, several experts in cosmeceutical production and use discussed current knowledge about the path to aging skin and products that can slow or correct these effects. Among the subjects covered were active ingredients of topical products, including peptides, herbal active ingredients, and antioxidants. Speakers included Patricia K. Farris, MD, Old Metairie Dermatology, Metairie, Louisiana; Neil Brody, MD, PhD, Psoriasis Care Center, Manhasset, NY; and Carl Thornfeldt, MD, Founder and Chief Executive Officer, Episciences Inc, Boise, Idaho.
Several concepts about aging skin must be considered to understand the mechanism of cosmeceutical peptides. Chronologically aged skin demonstrates lower procollagen type I messenger RNA and protein, resulting in decreased production of new collagen.2,3 In addition, aging skin, and particularly aging skin that is exposed to ultraviolet (UV) light, overexpresses proteolytic activity of matrix metalloproteinase-1, also known as interstitial collagenase.3,4 Finally, aging fibroblasts have a lower rate of proliferation than do fetal fibroblasts.3,5
Research on wound healing produced much of the evidence showing the importance of peptides in improving the signs of aging.6 The design of peptides that either stimulate collagen production or downregulate collagenase activity could cosmetically benefit aging skin. These peptides are small-sequence amino-acid chains that may stimulate angiogenesis, production of granulation tissue, and new collagen synthesis. Three classes of peptides have been designed with these goals in mind (Table 1).
Signal peptides may trigger wound-healing mechanisms that activate fibroblasts and result in increased collagen production. The linking of the lysine-threonine-threonine-lysine-serine chain to palmitic acid (Pal-KTTKS; Matrixyl®; Sederma, SAS, Le Perray en Yvelines, France) results in a product that features enhanced delivery across the epidermis. This procollagen 1 fragment stimulates cultured fibroblasts to synthesize collagen I, II, and fibronectin.6,7 Matrixyl, the most popular signal peptide currently on the market, is an ingredient in such heavily marketed products as Olay Regenerist® and StriVectin-SD® (Klein-Becker, Salt Lake City, Utah).
In a 12-week, double-blind, placebo-controlled, split-face, randomized clinical study of 93 Caucasian women between 35 and 55 years of age, Robinson and others8 found that pal-KTTKS was well tolerated and significantly reduced fine lines by both qualitative technical and expert grader image analysis.
Carrier peptides deliver trace elements, particularly copper, that are necessary for enzymatic activation and wound healing of the skin. Multiple enzymes (eg, lysyl oxidase, superoxide dismutase, tyrosinase, cytochrome-c oxidase) require copper for proper functioning.
One carrier peptide, glycyl-l-histidyl- l-lysine (GHK), spontaneously complexes with copper and, therefore, facilitates cellular copper uptake. Given its multiple actions at the cellular level, GHK is believed to improve fine lines, skin texture, and hyperpigmentation and to influence wound healing.6
Topical formulations of neurotransmitter-inhibiting peptides produce a botulinum-neurotoxin-like effect. These products have been effective in vitro; however, whether they can penetrate to the level of the neuromuscular junction (NMJ), where they could affect neurotransmission, is unclear.3
The most popular cosmeceutical peptide in this category is acetyl hexapeptide-3, marketed as Argireline® (McEit International Trade Co, Ltd; Tianjin, China). Argireline also is found in such products such as Avotone® (Avotox®), No-Tox®, and DDF Wrinkle Relax™. By inhibiting syntaxin, synaptobrevin, and soluble N-ethylmaleimide sensitive fusion attachment proteins-25 complex proteins that mediate exocytosis in vitro, Argireline inhibits acetylcholine release at the NMJ.6 In essence, patients using this product should find an end result that mimics the actions of injected botulinum toxin (BTX), even though the intracellular target is different, as long as the topical application is able to reach the NMJ.
In 2006, a randomized, investigator-blinded, parallel study of 77 female subjects compared four products that purported to improve wrinklesBTX type A (BTX-A), StriVectin-SD, DDF Wrinkle Relax, and Hydroderm™with a placebo injection.9 This study, supported by Allergan, Inc, evaluated the products based on the safety and efficacy of treating moderate-to-severe glabellar rhytides. The products were assessed according to blinded investigators’ assessments of glabellar line severity on the Facial Wrinkle Scale (FWS) and subjects’ global assessments of overall change in appearance, ratings of glabellar-related self-perception before and after treatment, and satisfaction with the results. Figure 1 illustrates results based upon the FWS.9 Statistically significant reductions in wrinkle severity on the FWS were found with the use of BTX-A but not with the application of the other agents. Further, only injection of BTX-A resulted in statistically significant improvements in subject-reported outcomes and satisfaction.
Overall, many peptides clearly play various roles in the aging of skin. The potential for new treatment options, as represented by cosmeceutical peptides, is a developing field, with most ongoing research occurring within the industry. It is important that the final marketed product is stable in formula, deliverable to its target dermal site, and biologically active at this target site.3 Consumer demand for products that improve appearance and counteract the signs of aging likely will lead to more research and development into cosmeceutical peptides for primary and adjunctive treatment of the signs of aging.
Another evolving technology in cosmeceuticals is topical preparations that incorporate herbal active ingredients. Phytomedicine actives use herbs, defined as botanicals with medicinal properties, and their secondary metabolites. Although more than 14,000 known secondary metabolites, most with multiple cellular targets, have been recognized, only 170 have undergone rigorous testing. Currently, over 60 botanicals are marketed in cosmeceuticals; thus, knowledge of these herbal actives is necessary for dermatologists.10
In achieving quality control with phytomedicine actives, clinical researchers must take several precautionary steps. The herb and active ingredient must be correctly identified, and the therapeutic concentration of the secondary metabolites must be accurately determined. In addition, purity is officially defined as the concentration of foreign organic matter that does not exceed 2% by weight, a percentage that still may impact the efficacy and safety of a product.
Over the past 1015 years, complementary and alternative medicine, including herbal therapies, has become increasingly popular in the United States.11 Some of the countless indications for herbals appear in Table 2.10 Further, many botanical treatments for cutaneous diseases are commonly prescribed or purchased on an over-the-counter basis. For example, capsaicin, a substance extracted from cayenne peppers, is a nonprescription topical therapy for pruritus and pain. Podophyllotoxin, an extract of mayapple, is a prescribed purified podophyllin resin.10 The dozens of botanical actives identified demonstrate the nearly endless possibilities for developing additional botanical therapiesbut these possibilities also underscore the need for human clinical studies to prove the effectiveness and safety of these substances.
Many common myths surround the use of herbal medicines. A substantial number of people believe that these products cause no side effects because they are naturally derived. However, Chinese herbalists know that oral herbal medicines may cause hepatotoxicity and that topical herbals have been linked to contact dermatitis.12 For example, photoexposed tea tree oil is a strong sensitizer that causes contact allergy in 10%20% of users. In fact, in 2003, tea tree oil became the most common contact allergen. In addition, 14 herbs, including arnica and comfrey, have induced fatal reactions when applied topically.
Several botanicals have undergone clinical trials for either skin disease or extrinsic aging (Table 3).13 The most significant human cosmeceutical data have been generated from products containing green and black tea, soy, pomegranate, date, and a grapeseed-based mixture.10 Despite these data, there clearly is a paucity of double-blind, prospective, controlled, human clinical trials in this area.
Unfortunately, even though the preparation of botanical-based cosmeceuticals is extremely complex, it is not regulated by the FDA. Most patients still, however, consider these products to be natural and, therefore, safe. And although many herbs and their secondary metabolites may exhibit effects at the cellular level and may contribute broadly to the field of cosmeceuticals, very few have been shown to be effective by existing evidence-based science.
Identification of numerous plant antioxidants demonstrates the significant degree of overlap between botanicals and yet another category of cosmeceuticals, the topical antioxidants.
Oxidative stress leads to inflammation and the formation of free radicals. Further, UV light is a potent inducer of free radicals. An excess of free radicals may lead to inflammation, photodamage, carcinogenesis, and the breakdown of collagen.14 Free radicals cause damage in several ways, including by inducing cellular damage at the level of lipids, proteins, and DNA.
In addition, free radicals upregulate the transcription factors activator protein 1 (AP-1) and nuclear transcription factor-kappaB (NF-kB). AP-1 is involved in the production of metalloproteinases that degrade collagen, and NF-kB upregulates the production of interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-a, all proinflammatory cytokines that further activate AP-1 and NF-kB and cause cumulative damage.15 Because antioxidants neutralize free radicals, they may play a role in reducing these deleterious processes.
In most categorization systems, topical antioxidants are divided into three subsets: vitamins, enzymatic antioxidants, and botanical antioxidants. Vitamins A, B, C, and E all have antioxidant properties, as do a-lipoic acid, Coenzyme Q-10, glutathione, idebenone, polyphenols, carotenoids, flavones, and kinetin. In addition, green tea polyphenols (GTPs) and their beneficial effects have been a subject of great interest for many years.
Tea, the most consumed beverage in the world, boasts an untarnished safety record; thus, GTPs, which are derived from the tea plant Cammelia sinesis, have been studied extensively. Most research in this area has been conducted in mouse models, yet some good human data have been published.
GTPs include extracts such as epicatechin, epigallocatechin, epicatechin-3-gallate, and epigallocatechin 3-gallate (EGCG); the anticarcinogenic effects of green tea are attributed to these extracts and particularly to EGCG.16 Studies in mice showed that GTPs exert chemopreventative effects both after oral consumption and topical application.
Elmets et al17 showed that GTPs may protect against acute UV injury. In this study, human skin was treated with green tea extract or one of its constituents. Thirty minutes later, the skin was exposed to 2 minimal erythema dose (MED), solar-simulated radiation. Green tea extracts diminished the DNA damage resulting from UV radiation, reduced the number of sunburn cells, and protected Langerhans cells from UV damage. In essence, GTPs protected against acute solar radiation and carcinogenesis.
Is the ability of GTPs to limit acute solar injury secondary to a simple sunscreen-like effect? GTPs have almost no absorption of monochromatic 308-nm light (Figure 2).18 Thus, another mechanism or multiple mechanisms must be involved. In fact, GTPs may decrease available free radicals and MAP kinases and influence other signaling pathways as they reduce cell turnover, decrease angiogenesis, and exert many other effects.
We continue to learn more about the many beneficial effects of GTPs and the numerous pathways involved in their antioxidant properties. GTPs are used by millions of consumers in hundreds of formulations and are the forerunners of topical oxidants being tested in formal studies.
Significant controversy about where cosmeceuticals fall in the spectrum of dermatologic therapeutics and how much regulation should be mandated for these products by federal bodies has emerged since Dr. Kligman first described their possible utility. Further, the marketplace for these products is expanding in the midst of a burgeoning industry for anti-aging skin care products.
Most importantly, dermatologists must become comfortable with these products and the evolving field of cosmeceuticals to best care for our patients and understand how these entities interact with regimens that we prescribe. Finally, these products must be tested rigorously to ensure their safety and efficacy when used by our patients.
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