Facial Plast Surg Clin N Am 12 (2004) 363 372

Anti-aging products and cosmeceuticals

Dee Anna Glaser, MD
Department of Dermatology, Saint Louis University, 1402 South Grand Blvd, St. Louis, MO 63104, USA

When patients seek advice on the treatment of their aging face, it is important that we review the medical therapies as well as the procedural options available to them. Topical therapies can be used as solo treatment or as an adjunct to the various surgical options to improve upon and maintain the desired anti-aging results. These products may be used as a preventative therapy as well, and more often, younger women are seeking out these therapies. Few drugs currently are marketed for the treatment and prevention of skin aging, whereas many cosmeceuticals and herbal remedies are touted in the lay press. In fact, cosmeceuticals now represent the fastest growing segment of the skin-care market [1]. More than ever, patients are looking for a magical elixir that is easy to use, effective, and inexpensive. This article covers the more commonly used products.

Retinoids Topical retinoids have been the sine qua non of topical therapies for the prevention and treatment of photoaging. Numerous formulations and brands currently are on the market. Improvement in global appearance, fine and coarse wrinkling, roughness, pigmentation, and sallowness has been shown in several double-blind placebo-controlled trials [2]. The effects are dose-dependent and increase with the duration of therapy for at least 12 months. The effects are believed to be mediated through binding to retinoic acid receptors (RAR) with subsequent binding of these complexes to specific genes. At the molecular level, retinoids regulate gene transcription

E-mail address: glasermd@slu.edu

and affect activities such as cellular differentiation and proliferation [3]. Tretinoin is capable of reversing histologic changes associated with intrinsic aging both in vivo and in vitro. Structurally, tretinoin can improve epidermal acanthosis, hypergranulosis, and stratum corneum compaction. The reduction and redistribution of epidermal melanin results in an improvement in lentigenes and mottled hyperpigmentation. The improvement in wrinkling is related to increased papillary dermal collagen, although there are many ultrastructural changes that take place. An increased vascularity of the papillary dermis is beneficial but can be problematic in some individuals, especially those with acne rosacea. The greatest obstacle in using topical retinoids is the high incidence of irritation. A retinoid dermatitis can develop, manifesting as redness and flakiness or as an increase in skin sensitivity. This typically occurs between 2 and 4 weeks after the initiation of therapy and usually subsides if the treatment is continued; however, patients often stop the therapy if not prepared for this possible reaction. Rarely, a true allergic reaction can cause erythema and flakiness. A preservative used in tretinoin (Retin A), butylated hydroxy-toluene, is believed to be the cause of the reaction. Another problem commonly attributed to the use of tretinoin is photosensitivity related to the sustained thinning of the stratum corneum. This is different than the degradation of the product by sun exposure, for which nightly application is recommended [4]. Precautions are necessary in individuals with considerable sun exposure or those taking drugs known to be photosensitizers such as tetracycline, phenonthiazines, fluoroquinolones, or sulfonamides because of the enhanced phototoxicity. Tretinoin can aggravate preexisting conditions such as rosacea and atopic dermatitis. Many patients with acne experience

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a flare-up of their disease after beginning therapy with tretinoin. This also improves with continued therapy. Tretinoin (Retin AR) is available in several formulations, including a cream, gel, and solution. The cream is supplied in a hydrophilic cream vehicle with 0.025%, 0.05%, and 0.1% concentrations. The gel is available in both a 0.01% and 0.025% strength, whereas the solution is available only in a 0.05% concentration. In general, the higher concentrations induce greater irritation as do the gel and liquid formulations. RenovaR contains tretinoin 0.05% in a water in oil emulsion formulation with light mineral oil. The hydrophilic cream is more moisturizing and more tolerable for many patients, especially those with fair or dry skin. It may help to reduce the incidence of irritant dermatitis. A lower concentration of Renova, 0.02%, is also available and may induce less irritation than the original formulation at 0.05%. Retin A microgelR contains 0.1% tretinoin in a patented aqueous gel. The Microsponge system is based on cross-linked polymers that form microscopic porous beads without the use of oils or organic solvents such as acetone or ethanol. The latter can contribute to skin drying and irritation. According to the package insert, Retin A microgel was found to be less irritating than tretinoin 0.1% cream in half-face comparison trials. Patients should apply the drug in the evening to a completely dry face (patients are generally instructed to wait 20 minutes after washing) and can begin on a two to three times weekly basis to minimize irritation. Moisturizers should be used if needed. Many other brands of tretinoin are now marketed, as are generic formulations. Adapalene gel, a naphthoic acid derivative, is a third generation retinoid approved for the treatment of acne. It is reported to have a much lower irritation potential, no phototoxicity, and fewer problems with sensitization [5]. At the time of this writing, there are no published data on its use in photoaging, but one can deduce that it should have benefit similar to other retinoids. Tazarotene is a novel acetylenic retinoid with selective binding to RARs, RAR-g, and RAR-b. Approximately 90% of the retinoid receptors in the skin are of the RAR-g subtype. This is different from tretinoin, which is nonselective and activates all RAR pathways (RAR-a, RAR-b, and RAR-g) directly and the retinoid X receptor (RXR) indirectly. It is not clear at the time of this writing if receptor selectivity has any major clinical significance in treating skin disease. Tazarotene is currently available as TazoracR, which is FDA-approved to treat acne vulgaris and psoriasis, and as Avage, which is FDA-approved to

treat photoaging. When compared with vehicle, tazarotene 0.1% gel has been shown to reduce skin roughness and fine wrinkling. Epidermal atrophy and atypia were improved, as were skin hydration properties [3]. Tazarotene cream can be used to treat photodamage as well and has been shown to improve mottled hyperpigmentation and fine wrinkles significantly [6]. In a comparison of 0.1%, 0.05%, 0.025%, and 0.01% tazarotene creams with 0.05% tretinoin emollient cream, all induced positive changes in photodamaged facial skin. At 24 weeks, global responses were found to be 67%, 52%, 35%, 41%, and 55%, respectively. In this study, 59% of patients had treatment-related adverse events generally rated as mild to moderate. Typical of topical retinoid use, they were related to local skin irritation, including moderate desquamation, burning sensation, erythema, pruritus, and dry skin. They were found to be more frequent in patients using tazarotene at higher concentrations, but patient compliance was high in all groups. It is pregnancy category X and women of childbearing age should be counseled before use. It can be irritating and thus patient education on proper use is crucial. I have patients apply a small amount of Retin A or Renova to a clean dry face at night. Patients may begin the regimen using the product two or three nights weekly and increasing as tolerated.

Systemic retinoids Isotretinoin, most commonly used to treat acne, psoriasis, and other systemic diseases, has been advocated by some as a therapy for aging skin. In one study, 60 patients were treated with oral isotretinoin, 10 to 20 mg three times a week, following other rejuvenation treatments and compared with 60 patients who had undergone the same procedures but did not receive isotretinoin. After 6 months, all the patients treated with isotretinoin were noted to have an improvement in wrinkles, thickness, and color of skin, size of pores, and general skin improvement. Skin tone and elasticity was noted to be improved, as was the degree of wrinkling. The difference between the treated and control group did reach statistical significance. Side effects were minimal and included dryness of the lips. [7] No comparisons have been made between topical and systemic retinoids in the treatment of photoaging, but clearly there are risks with systemic therapy, especially to women of childbearing age. At low doses as used in the cited study, the risks of hyperlipidemia and other systemic side effects should be quite low, but further studies are needed to assess the real usefulness of this drug in the treatment of aging skin.

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Vitamin A As noted previously, retinoic acid (RA) has been extensively studied and used as an effective topical treatment for photoaging, acne, skin cancer, and numerous other dermatologic disorders. RA can, however, be irritating to the skin, limiting its use in many patients. Vitamin A or retinol (ROL), a RA precursor, is of interest to the scientific community and cosmetic industry as a gentler yet still effective alternative. Other retinoids of interest include retinaldehyde (RAL), an intermediate compound in the conversion of ROL to RA, retinyl propionate (RP), and retinyl palmitate (ROL palm). By studying repeated insult patch testing for 14 days, Fluhr et al [8] have shown RA to be significantly more irritating than ROL and RAL, although both RA and RAL induced more scaling than ROL. When studying tolerance after 44 weeks of use, the incidence of erythema, scaling, and burning/pruritus was significantly less with RAL than with RA. Researchers have reported that ROL, RAL, and ROL palm did not produce the irritant effect (erythema) of RA but did induce cellular and molecular changes observed with application of RA, namely increased epidermal thickness and induction of RA 4hydroxylase activity [9,10]. Skin penetration of ROL was also more effective than RA or ROL palm. They concluded that although ROL is a weaker retinoid than RA, its increased penetration, less irritating side effects, and similar cellular activity may allow it to become clinically useful. In one study, RP was compared with a placebo and produced no significant difference in any of the clinical, histologic, or profilometric parameters of photoaging [11]. In another study, topical RP improved the appearance of skin wrinkles and hyperpigmentation that was comparable to those of ROL, and ROL palm did not produce any observable skin benefit. [12] At this time, I do not recommend these types of vitamin A products to my patients but rather concentrate our efforts on tretinoin or tazarotene. Many patients do seek these out, however, in their moisturizers and other skin care products.

properties in plants, although the mechanism of action has yet to be fully understood [13,14]. Studies on human fibroblasts in vitro have demonstrated that the addition of kinetin delayed the onset of age-related changes as well as decreased the severity of these changes [14]. These include alteration in cell size and shape, growth rates, cytoskeletal structure, macromolecular synthesis, and quantity of lipofuscin. All changes occur without any potential harmful effects, such as altering normal cell lifespan, increasing cell proliferation, or promoting carcinogenesis. The delay of age-related cellular characteristics are most pronounced in cultures in which kinetin was continuously present, and some began to reappear upon removal of kinetin. In addition, youthful characteristics of younger cells were better maintained than was the reversal of older cells age-related characteristics. This suggests that continued use of this new mode of therapy is necessary to maintain results. The current literature does not demonstrate in vivo efficacy of furfuryladenine, but as yet unpublished work by McCullough and Weinstein (ICN Pharmaceuticals, unpublished data) revealed that virtually all of 96 subjects with photodamaged skin showed improvement in the categories of skin texture, color, blotchiness, and fine wrinkles after 24 weeks of twice daily application of 0.01%, 0.05%, or 0.10% furfuryladenine. Average improvements ranged from 17% to 63% over baseline. Results also suggest that furfuryladenine improves the barrier function of the stratum corneum, as evidenced by a mean decrease of 26% in transepidermal water loss after 24 weeks of use. Notably, less than 1% of patients reported erythema, edema, dryness, peeling, burning/stinging, or pruritus. In my practice this product is reserved for patients that have not been able to tolerate one of the retinoids previously discussed. To date, only a rare patient has not been able to tolerate this product due to side effects related to irritation.

Antioxidants Photoaging is known to be caused by ultraviolet (UV) radiation, which penetrates the skin causing free radical production and ultimately damages cell membranes, enzymes, and extracellular matrix proteins. Ideally, any free radicals are removed from the cell via enzymatic and nonenzymatic mechanisms. These antioxidants scavenge free radicals and protect cells from damage. Naturally occurring antioxidants are in short supply in aging skin, and thus the theory for adding such compounds to skin care products. Some

Furfuryladenine Furfuryladenine or kinetin, a cosmeceutical, further expands the physicians and patients age-fighting options. It is a synthetic cytokinin plant growth hormone that has been shown to have age-retarding

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of the more well-known and popular antioxidants include vitamin C, vitamin E, coenzyme Q10, and a-lipoic acid (ALA). Vitamin C The active form of vitamin C is L-ascorbic acid, which acts as an antioxidant by neutralizing reactive oxygen molecules created by UV radiation. It is a necessary co-factor for several enzymes involved in collagen synthesis and cross linking. It also regenerates vitamin E, which inhibits lipid peroxidation [15]. Vitamin C is not naturally synthesized by the human body. Stores from exogenous sources last only a few weeks, as the half-life of vitamin C is about 20 days. Vitamin C is depleted in cells after UV exposure, with one study reporting up to a two-thirds loss [16]. Because the cutaneous tissues receive approximately 8% of systemically absorbed vitamin C, the use of a topical preparation may be able to take advantage of its antioxidant and collagen stimulating properties for the prevention and treatment of photoaging. The photoprotective qualities of vitamin C have been demonstrated by animal models and normal human volunteers. Topical vitamin C or E was shown to minimize low level, chronic UV-B damage to murine skin [17]. Multiple applications of 10% L-ascorbic acid to porcine skin increase vitamin C levels in the skin by 4 to 40 fold. [18] Sites pretreated with vitamin C had significantly fewer sunburned cells after UV exposure. Murray et al [19] compared 10% L-ascorbic acid to vehicle and demonstrated that UV-B radiation to human skin pretreated with vitamin C showed reduced erythema and had a significant increase in the minimal erythema dose. A combination of vitamins C and E taken orally for 8 days caused a significant increase in the minimal erythema dose when compared with placebo [20]. Traikovich [21] investigated the use of topical ascorbic acid versus vehicle for treatment of photodamaged skin. A unique formulation was used, which included L-ascorbic acid, zinc, and tyrosine (CellexC high-potency serum). These additives help stabilize ascorbic acid and allow for greater skin penetration with topical application. Zinc is involved in collagen remodeling, whereas tyrosine functions in cell turnover and may aid in transport of ascorbic acid into the skin. After 3 months of daily application, significant improvement of wrinkles/rhytids, roughness, color, and overall features as determined by subjective and objective measures were achieved. Comparison by Moy et al [22] of ROL palm in combination with glycolic acid versus ascorbic acid demonstrated that the former was more effective in the treatment of

photodamaged skin. Although no statistical analysis was reported, vitamin C improved measured parameters by 12% to 56%, and the vitamin A/glycolic acid preparation resulted in improvements ranging from 56% to 89%. A double-blind half-face study looking at a vitamin C complex containing 10% water-soluble ascorbic acid and 7% lipid-soluble tetrahexyldecyl ascorbate in an anhydrous polysilicone gel base did show decreased photoaging scores of the cheeks and perioral areas, but in the periorbital area improvement was no different from the vehicle alone [23]. There are many available preparations of vitamin C-based products. Due to the instability of L-ascorbic acid, formulations commonly include derivatives and esters, which do not penetrate the skin as readily as L-ascorbic acid nor are they efficiently converted to the only active form of vitamin C, L-ascorbic acid. At this time, the clinical role that the vitamin C preparations play is unclear. The therapeutic effects that the currently available vitamin C products can provide our patients is not well established. Vitamin E Vitamin E is the main lipid-soluble antioxidant that protects cell membranes from peroxidation, thereby decreasing free radical production [11]. Protein kinase C (PKC) activity in fibroblasts increases with age, as does collagenase formation. Overexpression of both enzymes leads to increased collagen degradation. Alpha-tocopherol, the biologically active form of vitamin E, inhibits PKC activity and collagenase production, thus protecting against aging [24]. Few clinically relevant studies are available and do not consistently demonstrate benefit in photoaging. Murine skin pretreated with tocopherol was shown to have a 75% reduction in skin wrinkling after UV-B exposure [17]. After UV-A exposure with the same pretreatment, no significant reduction in skin sagging was achieved. In another study, significant reduction in UV-B-induced erythema and edema was noted in mice treated with topical vitamin E after exposure [25]. The oral administration of vitamin E has not been shown to be effective in the prevention of UV-induced skin damage in humans [26]; however, alpha-tocopherol did have a photoprotective effect in human tissue cultures [27]. a-Lipoic acid ALA is a unique antioxidant as it is both lipid- and water-soluble. It penetrates the lipid-containing cell membrane easily and scavenges free radicals from

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within the aqueous intracellular matrix. In addition, ALA protects vitamins C and E. ALA is generally found in 1% to 5% concentrations in cosmeceutical products [1]. Reports from one open-label clinical study involving 15 patients look promising. They were treated with 5% ALA in a lecithin-based cream and after 12 weeks there were significant reductions in the depth of medium vertical lines on the upper lip.

Botanical topical anti-inflammatory agents As already reviewed, many botanicals are added to various skin care products. Some of these possess antiinflammatory agents. They help to block the inflammatory changes that may result in cutaneous aging and thus are purported to reverse the signs of aging. Allantoin is a popular botanical anti-inflammatory additive, although most allantoin used in skin care products today is manufactured by the alkaline oxidation of uric acid. It is believed to promote photodamage repair, induce cell proliferation, and reduce the amount of inflammation induced by UV radiation [29]. Aloe vera is perhaps the best known botanical anti-inflammatory agent. The colorless gel released from plant leaves contains 99.5% water and a complex mixture of mucopolysaccharides, amino acids, and minerals. Several distinct compounds have been isolated from aloe vera juice, including aletinic acid, aloe-emodin, aloin, and choline salicylate. Several different theories exist about the mechanism of action, but in part, the anti-inflammatory effects may result from aloe veras ability to inhibit cyclooxygenase within the arachidonic acid pathway. It is estimated that a 10% concentration of aloe vera must be present to afford the anti-inflammatory effect. Most skin care products use the powdered form of aloe vera, which may not be the same as the juice that is extracted from a broken leaf [29]. Ginkgo biloba leaves contain unique polyphenols, flavonoids, and flavonol glycosides. In vitro an effect on human skin fibroblast proliferation has been demonstrated with increased collagen and extracellular fibronectin. Products promoting the addition of ginkgo biloba usually claim antioxidant properties along with promoters of collagen synthesis [29]. Green tea extract is another popular botanical. It is manufactured from the plant by steaming and drying. If it is to be used as an additive to a topical preparation it must be stabilized with an antioxidant such as butylated hydroxytoluene. The extract has been shown to protect against UV-induced edema and erythema. Green tea polyphenols have been shown to decrease the formation of cyclobutane pyrimidine dimers if applied to the skin before UV exposure. These dimers are believed to play an important role in initiating UV-induced mutagenesis and carcinogenesis [29].

Botanical antioxidants Botanical antioxidants, like other antioxidants, can quench reactive oxygen species. Many botanical antioxidants are available and they are generally classified into one of three categories: carotenoids, flavonoids, and polyphenols [28]. The carotenoids are related to vitamin A and encompass the naturally occurring retinols. The flavonoids have a polyphenolic structure and are reported to provide UV protection and metal chelation in addition to antioxidant properties. The polyphenols are a large class and contain botanicals such as rosmarinic acid (rosemary), hypericin (Saint Johns wort) and oleuropein (olive leaf ). Curcurmin is a polyphenol found in the turmeric root, the latter being used as a yellow coloring for natural foods and skin care products. Because yellow coloring in cosmetics is generally not desirable, tetrahydrocurcumin, which has an off-white color, is added. The latter is a hydrogenated form of curcurmin and it adds antioxidant properties as well as helps to prevent lipids in moisturizers from becoming rancid [28]. Pycnogenol is an extract of French marine pine bark. It is a water-soluble liquid that has demonstrated no allergenicity or chronic toxicity. It can reduce the vitamin C radical to the active form of vitamin C. This in turn helps to regenerate vitamin E to its active form. Pycnogenol is sold as an oral supplement said to improve the appearance of photoaged skin from the inside. The topical application of the product is touted to augment this effect [28]. Silymarin is an extract of the milk thistle plant, which belongs to the aster family. There are three separate flavonoids in silymarin: silybin, silydianin, and silychristine. Together they are strong antioxidants and topical application studies in hairless mice have demonstrated 92% reduction of skin tumors after UV-B exposure [28]. Soybeans are rich in flavonoids called isoflavones. Some of the cutaneous affects may be linked to its estrogenic effect, especially for postmenopausal women. Genistein, one specific isoflavone, was found to increase collagen gene expression in cell culture [28].

Vitamin B Vitamin B is a group of water-soluble vitamins found in many vegetables and whole grains. Niacinamide (nicotinamide) has been formulated into some

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cosmetics and skin-care products [30]. Its stability and compatibility have made it a popular additive to moisturizers. It may have an exfoliative effect along with prevention of photocarcinogenesis [31]. When incubated with human keratinocytes, it increases ceramide synthesis, which naturally decreases with aging. The result is improved barrier function and decreased transepidermal water loss. [32]

Box 1. Common alpha-hydroxy acids Glycolic acid Lactic acid Mandelic acid Malic acid Tartaric acid Citric acid Pyruvic acid Benzylic acid Tropic acid

Coenzyme Q10 Coenzyme Q10 (CoQ10), also known as ubiquinone, is a fat-soluble, vitamin-like substance present in every cell. It serves as a coenzyme for several steps in the production of energy within the cell. It is naturally present in small quantities in a variety of foods, and it is synthesized in human tissues, although CoQ10 levels decrease with age. In addition to the antioxidant properties of CoQ10, it may work synergistically with vitamin E. In vitro studies have shown that pretreatment with CoQ10 protects cultured keratinocytes from UV-A induced oxidative stress and DNA damage. It may be helpful in protecting the dermal matrix from UV radiation as well, based on its ability to significantly reduce fibroblast expression of UV-A induced mRNA collagenase [33]. Clinical studies have demonstrated subjective improvement in skin texture: smoothness, softness, feeling moisturized, and feeling or looking firmer [34].

Hydroxy acids Alpha hydroxy acids (AHAs) are a group of organic carboxylic acids that have a hydroxy group in the alpha position. These compounds are popular skin rejuvenators and are found in many moisturizers, cleansers, and cosmetic products. They are featured in lay magazines regularly, and patients are familiar with them. This allows for easy incorporation of home maintenance therapy with AHAs. The AHAs are hydrophilic due to their linear aliphatic structure and are water soluable. Box 1 lists the common AHAs, which are found naturally in many foods. Salicylic acid is the only beta hydroxy acid (BHA); it is an organic carboxylic acid with a hydroxy group in the beta position. This phenolic compound is hydrophobic and lipophilic. It can enter the sebaceous unit and has been used for decades by dermatologists as a comedolytic. Unlike the AHA compounds, it works well in the oily areas of the face such as the central forehead, nose, and chin.

The combination hydroxy acids (CHA) combine an AHA and salicylic acid. Optimal formulation is difficult due to the different pKa values of the AHA and BHA compounds. The free acid component is biologically active and products must exist with a pH close to the pKa for optimal free acid concentration and efficacy. The polyhydroxy acids (PHA) are similar to the AHAs but are larger molecules, limiting dermal penetration. This can lead to less stinging, burning, and irritation [35]. Of the hydroxy acids, the AHAs are the most frequently used; glycolic acid is widely used alone or in combination with other agents. The other hydroxy acids are receiving press in consumer magazines and patients may inquire about one of these other classes. Although some physicians report their unique qualities, the exact mechanism of action of the AHA is unknown. At low concentrations the AHAs diminish corneocyte cohesion. Studies with lactic acid have demonstrated an increase in the thickness of the epidermis and a decrease in the thickness of the stratum corneum while increasing the deposition of glycoaminoglycans; however, specific effects in specific situations cannot necessarily be extrapolated, especially in terms of peels. The acidity of a compound can be described in terms of its pH or pKa. The pKa relates the relative strength of the acid to base measured by its proton dissociation. The potency of the biologic action is not directly associated with the pKa and has little relevance for chemical peeling. Still unknown is the ideal concentration, pH, and pKa of the various AHAs to optimize therapeutic outcomes. Hydroxy acids can perform better at a low pH but the optimal pH (which is defined by the pKa) for biologic effects has not been established. Methods used to alter the hydroxy compounds include changing the concentration of the acid, buffering, and neutralizing the formulation.

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Partial neutralization is achieved by adding a base such as sodium bicarbonate or sodium hydroxide, resulting in a weaker acid and higher pH. Buffered solutions are partially neutralized but resist pH changes. Conceptually this would be beneficial as the pH of different intercellular compartments, eccrine, and sebaceous units may vary. It must be remembered though that it is the free acid that has cutaneous effects; the salt form is biologically inactive [36]. In general, there is greater dermal penetration when unbuffered formulations of an acid with a lower pH (especially less than 0.1) are used. The irritancy of a product is often related to the pH, but it is important to remember that the pH is also a function of the vehicle used. As with many of the treatments discussed, the clinician and patient are left to sort out the subtle differences between the brands offered. Once selected, the hydroxy acid should be applied once or twice daily. To maximize compliance, I suggest that patients apply the AHA in the morning followed by moisturizer (if necessary), sunscreen, and make-up. The retinoid is applied in the evening.

Bleaching agents Melasma, lentigos, and other dyschromias make the skin appear older and weathered. Patients frequently request a bleaching agent to improve irregular pigmentation. These agents do not bleach the skin but basically inhibit the synthesis of melanin. They are classified as phenolic or nonphenolic compounds. The phenolic compounds include hydroquinone, isopropylcatechol, and N-acetyl-4-S-cysteaminylphenol. The nonphenolic compounds are kojic acid, azelaic acid, tretinoin, arbutin, licorice, and L-Ascorbyl-2Phosphate [37]. Hydroquinone (HQ) is the most frequently used bleaching agent in the United States. It produces a reversible depigmentation of the skin by inhibition of the enzyme tyrosinase, which catalyzes the oxidation of tyrosine to 3, 4-dihydroxyphenylalanine (dopa). In addition, it inhibits the formation of melanosomes or increases the degradation of melanosomes and can inhibit the DNA and RNA synthesis of melanocytes [37]. Higher concentrations correlate with effectiveness and side effects. HQ 3% to 5% is generally needed to see clinical affect. A concentration of 4% is readily available and should be applied twice daily. Sunscreen use is essential to obtain the full benefit. In addition, the use of an exfoliant and a retinoid such as tretinoin may improve the results. Glyquin XM contains 4% hydroquinone with 2% glycolic

acid, water- and lipid-soluble vitamin C, and lipid soluble vitamin E. Hydroquinone is frequently combined with other agents to improve efficacy and diminish side effects. Perhaps the most well known is the Kligman formulation, which uses hydroquinone, tretinoin, and dexamethasone. Many different formulas can be prepared using different concentrations or substituting a weaker steroid for the dexamethasone. The chemical stability of HQ formulations is important to consider, because HQ is easily oxidized and loses potency. A commercially prepared product, TRI-LUMAR Cream is now available and indicated for the short-term treatment of moderate to severe melasma. It contains fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05% in a hydrophilic cream. Significant side effects of hydroquinone are rare, but it can cause redness, irritation, and dryness. The use of hydrocortisone 1% to 2.5% is sometimes necessary to control any irritation and inflammation resulting from the use of the drug. In addition, many of the commercially available products contain sodium metabisulfite, which can cause allergic reactions such as hives, wheezing, and anaphylaxis in susceptible persons. Finally, the use of topical hydroquinone can rarely induce exogenous ochranosis. This results in dark blue-black pigmentation in the treated areas and is irreversible [38]. Kojic acid is extracted from a Japanese mushroom and is another tyrosinase inhibitor. It can be used alone or in combination with hydroquinone or alpha-hydroxy acids. Twice daily application is recommended and can also induce irritation and hypersensitivity reactions. It is not as widely available as hydroquinone and can be more irritating in my experience. In the treatment of melasma, kojic acid and hydroquinone have been found to be equally effective [39]. Azalaic acid is a naturally occurring straight chain dicarboxylic acid. It inhibits tyrosinase and acts on hyperactive melanocytes but has little effect on normal melanocytes. Arbutin, an extract of the bearberry plant, and licorice oil-soluble extract can both inhibit tyrosinase activity. They are generally used in combination with HQ. L-ascorbic-2-phosphate is a vitamin C derivative. It suppresses melanin production and reportedly alters melanin from jet black to light tan [37].

Copper Copper is a trace mineral found in meats, grains, and drinking water. It performs several vital roles

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in the human body by serving as a cofactor for enzymes involved with antioxidant function and in the production of collagen. Copper peptide containing formulations are a subset of topical agents, which theoretically can retard the skin changes associated with aging but are lacking supportive clinical data. These products are available for wound, skin, and hair care. A short peptide, which varies with each formulation, surrounds the copper atom for stabilization and aids in delivery of copper to skin cells. Unlike copper salts, copper peptide containing complexes have been shown to facilitate angiogenesis and formation of glycosaminoglycans, collagen, and elastin in animal models and human cell cultures [40 42]. Abdulghani et al [43] compared biopsies of normal skin from 20 patients using copper peptide containing creams to those using creams containing vitamin C, tretinoin, or melatonin. Collagen accumulation was the outcome measured, which was done by detecting procollagen with monoclonal antibodies. Greater than 40% of patients using non copper-containing creams demonstrated significant increase, whereas greater than 70% of the copper-containing group achieved a significant increase in procollagen formation.

Noncomedogenic formulations are best for acneprone individuals.

Sunscreens Perhaps the single most cost effective therapy we can offer patients is sun protection. It will not only protect our patients from possible hyperpigmentation after treatments but will help to arrest further photodamage. Most patients are aware of the sun protection factor (SPF) afforded by sunscreens and most are comfortable with their use when going outdoors for a prolonged period of time. Many women have even incorporated them into their daily routine when using make-up and moisturizers, but many patients are unaware of the significance that the sun plays in aging their skin and the impact of chronic UV-A and UV-B exposure. Patients must understand the differences between UV-A and UV-B and the ubiquitous nature of UV radiation. The physician should review the cumulative nature of UV-A and the impact of chronic exposure on the skins appearance and then help the patient plan a strategy to minimize further damage. Minimizing sun exposure is impractical for many, but protective clothing such as hats and sunglasses is tolerated by most. The use of the proper sunblock is the most crucial step for most active individuals. Sunscreens have traditionally been divided into chemical agents that absorb specific photons of UV light and physical agents (sunblocks) that serve as a barrier that reflects or scatters the radiation. The UV-B sunscreens are effective in absorbing the entire UV-B spectrum but UV-A sunscreens primarily absorb the shorter wavelengths (320 360 nm) [45] Most UV-B sunscreens are based on p-aminobenzoic acid (PABA) and its esters (padimate A and O) as well as the cinnamates and salicylates. UV-A sunscreens may contain benzophenones, dibenzoylmethanes, and anthralinates but have limited absorption spectrums. Of the currently available UV-A blockers, titanium dioxide, micronized zinc oxide, and avobenzone (Parsol 1789) provide the most complete coverage. Parsol 1789 is better tolerated cosmetically compared with the more opaque zinc oxide and titanium dioxide but can cause allergic reactions. In vitro studies have shown that it can degrade and lose its ability to block UV-A within 1 hour of sun exposure. In addition, Parsol 1789 seems to accelerate the degradation of methoxycinnamate, which is present in most high SPF preparations [46]. Micronized zinc oxide and titanium dioxde have a reputation for being thick and opaque, casting a whitish sheen to the skin. A recent

Moisturizers and emollients Although some form of a moisturizer is used daily by most women, it is important not to underestimate the role they can play in treating aging skin. Technically, emollients are substances that are able to smooth the skin surface and may or may not have moisturizing properties. They intercalate between desquamating corneocytes much like a filler. This differs from moisturizers that come in two basic forms: an occlusive moisturizer that prevents transepidermal water loss and a humectant that absorbs moisture into the stratum corneum. The former generally incorporate petrolatum, silicone, mineral oil, and vegetable oil [44]. Typical humectants contain glycerin, propylene glycol, or sorbitol. Silicone is unique in that is considered to be an astrigent emollient because it cuts down the greasiness from other substances and does not leave any stickiness. These products can be used alone or combined with antioxidants, sunscreens, and other active ingredients. They can help to reduce the affects of irritating products such as RA and help to make the skin feel smooth and less taught. Most women are comfortable shopping for their own moisturizer, but those with sensitive skin or prone to allergic reactions may seek advice. Bland products should be recommended that are fragrance-free, and preservative-free if possible.

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comparison found 2% and 6% microfine zinc oxide to transmit less UV-A radiation than 2% and 6% microfine titanium dioxide, respectively. In addition, the micronized zinc oxide was less white than the titanium dioxide at all concentrations [47]. It is my sunscreen of choice. Neither of these agents are antigenic and they do not produce contact sensitization, phototoxicity, or photoallergy. Adverse reactions to chemical sunscreens include allergic contact dermatitis, irritant contact dermatitis, and phototoxic and photoallergic reactions. The active ingredient, fragrances, and preservatives are the most common causes of contact dermatitis. In general, patients who suffer from any of these symptoms should be switched to a physical blocker such as micronized titanium dioxide or zinc oxide. Other complaints may stem from products that are not noncomedogenic and contribute to an acne flare and cosmetically undesirable formulations that do not go under make-up well or that induce ocular stinging with sweating. In addition to counseling on the daily use and proper selection of sunscreens, patients must be informed that there is no such thing as a safe tan. UV radiation whether obtained naturally or from the use of suntan lamps and beds will promote further photoaging of the skin. Patients are lured into the misconception that tanning beds provide the safest tan and will use their sunscreens but frequent their local tanning parlor. I review with my patients the role of concrete, snow, water, and sand on the reflectance of sunlight and how glass and clouds do not fully block out UV-A.

[4] [5]

[6]

[7]

[8]

[9]

[10] [11]

[12]

Summary Topical agents can be an important treatment and preventative step in the photoaging process. Although they can be used alone, combining them with many of the procedures outlined throughout the rest of this book, will help to maximize results and maintain the desired benefits.

[13]

[14]

[15]

[16]

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[20]

[34]

[21]

[35] [36] [37] [38]

[22]

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[39]

[24]

[40]

[25]

[41]

[26]

[27]

[42]

[43]

[28] [29] [30] [31]

[44] [45]

[46]

[32]

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[33]