Cosmeceuticals :

Practical Applications
Anetta E. Reszko, MD, PhDa,*, Diane Berson, MDa,b,
Mary P. Lupo, MDc

KEYWORDS
 Antioxidants  Cosmeceuticals
 Procedure protocols  Vitamins  Pigment-lightening
 Anti-inflammatory  Peptides

Cosmeceutical is a term coined approximately 2 whereas evening/night protocols should be

decades ago by Albert Kligman to refer to topically centered on tissue repair (retinoid).
applied products that are not merely cosmetics This article highlights several common diag-
that adorn or camouflage, yet are not true drugs noses and discusses how and which cosmeceuti-
that have undergone rigorous placebo-controlled cals should help, or at least compliment,
studies for safety and efficacy.1 This continues to procedures or prescriptions. Furthermore, the use
be an area of new product development, with an of cosmeceuticals in conjunction with commonly
ever-growing marketplace as baby boomers performed office-based procedures, such as
continue to age. There are many review articles chemical peels, microdermabrasion, photorejuve-
that outline the theoretical biologic and clinical nation, and laser resurfacing, is discussed.
actions of these cosmeceuticals and their various
ingredients.2–7 This article reviews how to incorpo-
MELASMA
rate various cosmeceuticals into the treatment
Introduction
regime of patients, depending on the diagnosis
and treatment chosen. The practical application Even skin pigmentation is considered to be
of when, why, and on whom to use different prod- a universal sign of youth and beauty. Pigmentary
ucts will enable dermatologists to improve the alterations seen in melasma are sharply demar-
methodology of product selection and, ultimately, cated, brown patches, typically located on the
improve patient’s clinical results. malar prominences and forehead. Three clinically
Cosmeceuticals can be divided into 7 main apparent patterns are centrofacial, malar, and
product categories (Box 1). mandibular (rare). Melasma is more frequent in
In choosing an effective cosmeceuticals higher skin types (III, IV, and V) and is especially
regimen it is critical to match patients and their prominent among Asian and Hispanic people.
problems with the appropriate products. Most The pigment deposition in melasma is epidermally
patients have multiple needs, and they should be or dermally based, with most cases showing both.
matched with products that offer ingredients with Treatment of melasma is often difficult and
multifactorial benefits. might require multiple treatment modalities.
Certain treatment principles apply to all thera- Sunlight protection with a broad-spectrum
peutic protocols. Morning treatment protocols sunscreen with ultraviolet A (UVA) and ultraviolet
should provide environmental (antioxidant, B (UVB) coverage is the cornerstone of the
sunscreen, sun block) and antimicrobial protection therapy, because UVB, UVA, and visible light are

a
Department of Dermatology, Weill Cornell Medical College of Cornell University, 1305 York Avenue, 9th
Floor, New York, New York 10021, USA
[Link]

b
Private Practice, 211 East 53 Street, New York, New York 10022, USA
c
Department of Dermatology, Tulane Medical School, Private Practice Lupo Center for Aesthetic and General
Dermatology, 145 Robert E Lee Boulevard, Suite 302, New Orleans, LA 70124, USA
* Corresponding author.
E-mail address: [Link]@[Link] (A.E. Reszko).

Dermatol Clin 27 (2009) 401–416

doi:10.1016/[Link].2009.08.005
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402 Reszko et al

Box 1 tyrosine oxidation in active melanocytes. The cyto-

Cosmeceuticals product categories toxic effect of HQ is mediated by reversible inhibi-
tion of DNA and RNA synthesis.
 Sunscreen Clinical improvement with over-the-counter 2%
 Antioxidant HQ as monotherapy is usually seen in 4 to 6 weeks,
 Anti-inflammatory with improvement approaching a plateau at 4
 Pigment lightening
months. Because of its irritant properties and
 Collagen repair
 Exfoliation increased risk of postinflammatory hyperpigmenta-
 Hydration/barrier repair tion (PIH), HQ is often combined with topical medium
potency steroids. Compounded HQ is available in
the United States as Tri-Luma (Galderma, Fort
Worth, Texas; 0.01% fluocinolone, 4% HQ and
all capable of stimulating melanogenesis. 0.05% tretinoin) in a cream formulation.5
Sunscreens and sun blockers containing physical In recent years, the use of HQ has become
blockers, such as titanium dioxide and zinc oxide, a subject of marked controversy, that led to its
are preferable to chemical blockers because of removal from markets in Europe and in parts of
their broader protection. Asia.5 In recent months, the Food and Drug
The mainstay of treatment of melasma is topical Administration (FDA) voiced concerns about the
depigmenting agents (Box 2). safety of HQ for topical application. The basis for
In addition, retinoids, exfoliation with superficial the FDA’s concern was the increasing number of
chemical peels, mechanical dermabrasion, or non- reports of ochronosis, (bluish-black discoloration)
ablative (intense pulsed light [IPL]) or fractional of HQ topically treated sites,8 and reports of
microablative technologies may provide added potential carcinogenicity of systemic HQ. The
benefit. Combination therapy centers on the fact mechanism of HQ-induced ochronosis remains
that if melanogenesis is inhibited (depigmenting unknown. It is usually observed in patients of
agents) and keratinocyte turnover is increased African descent who have been treated with high
(chemical peels, retinoids, lasers/IPL), the time to concentrations of HQ for several years. Histologi-
clinical improvement can be reduced. cally, the initial stages of ochronosis are character-
ized by the degeneration of collagen and elastic
Pigment Modifying Agents fibers. In later stages, ochronotic deposits are
Currently available pigment lightening products seen, consisting of crescent-shaped, ochre-
target individual stages of melanogenesis or block colored fibers in the dermis. It is unclear whether
melanin transfer from melanocytes to keratino- HQ itself, high concentrations of HQ, or other
cytes. The following are commercially available, substances that exist in the topical preparations
highly effective pigment lightening preparations. contribute to the onset of ochronosis.
The carcinogenic properties of HQ were demon-
Hydroquinone strated in rodent models following systemic
Hydroquinone (HQ), benzene-1,4-diol, is an inhib- administration of high quantities of HQ. The human
itor of melanogenesis by (1) inhibiting tyrosinase, potential for carcinogenicity has not been demon-
and (2) a direct melanocyte cytotoxic effect. HQ strated. Nonetheless, because of the rapid uptake
is a poor substrate of tyrosinase, competing for and distribution of HQ applied to the skin, it has
been speculated that the risks of topical applica-
tion are similar to, or greater than, those of pulmo-
Box 2
Pigment modifying agents
nary or gastrointestinal exposure.9 With topical
application, the first-pass liver metabolism of HQ
Hydroquinone is circumvented and HQ, a benzene derivate, can
Kojic acid reach systemic circulation without prior
detoxification.
Vitamins C and E
Azelaic acid Azelaic acid
Ellagic acid (polyphenol) Azelaic acid is a naturally occurring, saturated 9-
Pycnogenol carbon dicarboxylic acid derived from Pityrospo-
rum ovale. It is a weak competitive inhibitor of
Fatty acids (linoloic acid)
tyrosinase. Azelaic acid also exhibits antiprolifera-
Niacinamide (B3) tive and cytotoxic effects on melanocytes via
Soy (STI) inhibition of thioredoxin reductase, an enzyme
involved in mitochondrial oxidoreductase

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 Cosmeceuticals 403

activation and DNA synthesis. Unlike HQ, azelaic flavenoids, liquirtin and isoliquertin. Licorice
acid seems to target only abnormally hyperactive extract leads to skin lightening primarily by
melanocytes, and thus will not lighten skin with dispersing melanin.16 In cultured B16 melanoma
normally functioning melanocytes. Thus, the bene- cells, glabridin inhibits tyrosinase activity without
fits of azelaic acid might extend beyond the realm affecting DNA synthesis rates.17 Topical applica-
of cosmetic medicine, as it may play a role in pre- tion of glabridin has been shown to reduce UVB-
venting development of, or in therapy for, lentigo induced pigmentation and erythema in the skin
maligna and lentigo maligna melanoma.5,6 of guinea pigs. In vitro anti-inflammatory effects
The clinical efficacy and pigment lightening of glabridin relate to inhibition of superoxide
properties of azelaic acid have been studied in production and activity of cyclooxygenase.17
large groups of diverse skin types, including skin For clinical efficacy, glabridin must be applied at
types III to VI, and its efficacy has been compared a dosage of 1 g/d for at least 4 weeks. Licorice
with that of 4% HQ cream, although with a slightly extract is considered a weak lightening agent
higher rate of local irritation.10,11 Azelaic acid is and must be combined with other agents for
commercially available as a topical 20% cream. optimal clinical results.
The primary adverse effect of topical application
is skin irritation. For added benefit, azelaic acid Arbutin and deoxyarbutin
may be combined with 15–20% glycolic acid (GA). Derived from the leaves of the Vaccinium vitisi-
daea, arbutin is a gluconopyranoside that inhibits
Niacinamide tyrosinase. It also inhibits melanosome maturation
Niacinamide, also known as nicotinamide, is without associated melanocyte toxicity.18 Arbutin
a water-soluble component of the vitamin B at a concentration of 3% is available in Japan in
complex group. In vivo, nicotinamide is incorpo- several over-the-counter preparations. Higher
rated into nicotinamide adenine dinucleotide concentrations may provide additional therapeutic
(NAD) and nicotinamide adenine dinucleotide benefit, but paradoxic darkening may occur. De-
phosphate (NADP), coenzymes essential for enzy- oxyarbutin is a synthetically modified derivative
matic oxidation reduction reactions, including of arbutin with enhanced pigment lightening
tissue mitochondrial respiration and lipid properties.19
metabolism.
Niacinamide inhibits melanine transfer to kerati- Aloesin
nocyte. Bissett and colleagues12–15 showed that Aloesis is a low-molecular-weight glycoprotein
niacinamide reduced the appearance of hyperpig- derived from the aloe vera plant. It functions
mented macules, fine lines and wrinkles, red through the competitive inhibition of tyrosinase at
blotchiness, skin sallowness, and increased skin the dihydroxyphenylalanine (DOPA) oxidation
elasticity. In addition, niacinamide helped alleviate site.20–22 Therapeutic application of aloesin is
some of the symptoms of rosacea by increasing limited by its hydrophilic nature and inability to
hydration, reducing transepidermal water loss, penetrate the skin.
and improving the barrier function of the stratum
corneum. Edelweiss complex
Kojic acid Edelweiss complex is a new approach targeting
Kojic acid, 5-hydroxymethyl-4H-pyrane-4-one, is skin discoloration. It relies on antisense oligonu-
a hydrophilic fungal derivative derived from Asper- cleotides that block targeted gene transcription
gillus and Penicillium species, exerting its biologic and modulate melanogenesis. This technology
activity by inhibiting copper binding to tyrosinase. offers unique specificity, biologic stability, and
It is one of the most commonly used over-the- safety in whitening of all skin types. In a clinical
counter skin lightening agents sold worldwide. study of 30 Asian patients with dyschromia of the
Albeit Kojic acid was recently removed from the hands, the test product applied twice daily for 8
market in Japan due its sensitizing properties. weeks significantly whitened hyperpigmented
and normal skin.23
Licorice extract
Licorice (Glycyrrhiza glabra, Glycyrrhiza inflate) Vitamin C
extract has been used as a natural remedy for Numerous studies have confirmed the beneficial
centuries for its anti-inflammatory and anti-irritant effects of systemic (oral and intravenous [IV]
properties. Licorice extract derived from the root administration24) and topically applied ascorbic
of Glycyrrhiza glabra, glabridin, has dual pigment acid (vitamin C) in the treatment of melasma.5,25,26
modulating and anti-inflammatory properties. In a randomized, split-face clinical trial 16 women
Active ingredients in licorice extract are the were treated with a nightly application of 5%

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404 Reszko et al

ascorbic acid cream on one side of the face and The major adverse effect of retinoids is skin irri-
4% HQ cream on the opposite side, for 16 weeks. tation, especially when the more effective, higher
The HQ and ascorbic acid treated sides had concentrations are used. Temporary photosensi-
good and excellent results in 93% and 62.5% of tivity and paradoxic hyperpigmentation can also
patients, respectively. Colorimetric measures occur.
showed no statistical differences. Topically
applied ascorbic acid was well tolerated with low
Chemical Peels, Microdermabrasion,
rates of side effects reported (6.2% vs 68.7% in
Nonablative and Fractional Ablative Light,
HQ group).26
and Laser Technologies
Vitamin C can also be combined with other
treatment modalities such as trichloroacetic acid Chemical peels (superficial peels, including 20%–
(TCA) peel for synergistic effect.25 One limitation 30% salicylic acid, 30%–40% GA, b-lipohydroxy
of topically applied ascorbic acid is its inherent acid [LHA]), microdermabrasion, and nonablative
instability (for a detailed discussion see section and fractional ablative technologies31,32 have
on Rosacea). been used extensively for the treatment of melasma.
Periprocedural use of appropriate cosmeceuticals
may enhance postprocedural healing and their
continued use may extend the duration of treat-
Retinoids
ment benefits.
Retinoids are synthetic and natural compounds A few general principles apply. First, a thorough
with structure and activity similar to that of vitamin medical history, including any hypertrophic scar-
A. Vitamin A exists as retinol (a vitamin A alcohol), ring, viral (herpetic), bacterial (Staphylococcus),
retinal (a vitamin A aldehyde, and retinoic acid (a and yeast infections, must be obtained. Appro-
vitamin A acid). All these forms are interconvert- priate antiviral, antibacterial, and antiyeast treat-
ible. Biologic activity of retinoids relates to their ments should be initiated immediately before,
ability to activate RAR abg and RXR abg recep- and continued for 7 to 10 days following the treat-
tors, and increases from retinol to retinaldehyde ment to prevent infection, as cutaneous infection
to retinoic acid. in the immediate postsurgical period might lead
A plethora of prescription and over-the-counter to significant PIH and possible scarring. All medi-
retinoids exist. Topical retinoid’s ability to depig- cations should be known and oral contraceptives
ment is based on its ability to disperse melano- and known photosensitizers should be discontin-
somes, interfere with melanocyte-keratinocyte ued if medically possible. Second, medium to
pigment transfer, and accelerate epidermal turn- high potency topical fluorinated steroids adminis-
over and, subsequently, pigment loss.27,28 In addi- tered 2 to 3 days before treatment and continued
tion, retinoids may inhibit melanogenesis by for up to 1 to 2 weeks after the treatment might
inhibiting tyrosinase and DOPAchrome conversion lead to decreased swelling and bleeding. Third,
factor.29 all medications that increase the risk of bleeding
Topical tretinoin (trans-retinoic acid) can be (eg, aspirin, nonsteroidal anti-inflammatories,
effective in the treatment of melasma as mono- vitamin E, ginkgo) should be stopped unless medi-
therapy. In a large-scale, double-blind, placebo- cally necessary. Fourth, to minimize the risk of
controlled study of 50 white women, topical scarring and PIH, retinoids or chemical peels
0.1% tretinoin caused a marked clinical improve- should be stopped 3 days (superficial chemical
ment, 68% and 5% for tretinoin and placebo peels) to 2 weeks (nonablative, fractional ablative
groups, respectively, at 40 weeks. Clinical resurfacing) before the procedure. Systemic iso-
improvement was consistent with calorimetric tretinoin should be stopped within 6 (nonablative)
and histologic assessment.30 Epidermal pigment to 12 (fractional ablative and ablative) months of
was reduced by 36% in the tretinoin-treated the procedure. Fifth, dark-skinned or tanned indi-
group. viduals are at higher risk of postinflammatory dys-
Overall, the response to tretinoin treatment is chromia. The risk of postinflammatory dyschromia
less than with HQ and can be slow, with improve- after fractional resurfacing may be minimized by
ment seen after 6 months or longer. Tretinoin as pretreatment with HQ.31
a monotherapy is not an approved treatment of Postprocedure patients may resume preopera-
melasma. Nonetheless, a forementioned combi- tive treatment regimens including depigmenting
nation regimen of tretinoin, HQ, and a topical agents. Following nonablative procedures and
corticosteroid (fluocinolone acetonide) is FDA fractional ablative procedures, depigmenting
approved and commercially available as Tri- agents may be initiated after 1 to 2 weeks or at
Luma.29 the first sign of hyperpigmentation. Use of

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 Cosmeceuticals 405

emollients, gentle skin care with toners, and mild combination with topical HQ plus 10% GA. The
cleansers and sun blocks is crucial for optimal best clinical improvement was noted in women
healing in the immediate postoperative period. treated with the combination therapy, although
Laser treatments with Q-switched lasers results did not reach statistical significance.
(neodymium:yttrium-aluminum-garnet [Nd:YAG],
frequency-doubled [532 nm] and nonfrequency- ROSACEA
doubled [1064 nm]), ruby laser (694 nm), and abla- Introduction
tive carbon dioxide and erbium:YAG (2940 nm),
seem to show limited usefulness in the treatment Rosacea is a common, chronic skin disorder that
of melasma, with high rates of melasma recur- primarily affects the central and convex areas of
rence and a high incidence of PIH.29 the face. The nose, cheeks, chin, forehead, and
Recently, fractional resurfacing with a 1550-nm glabella are the most frequently affected sites.
erbium:glass laser (Fraxel SR 750, Reliant Tech- The disease has a variety of clinical manifestations
nologies, Inc, Mountain View, CA) has proved to ranging from flushing, persistent erythema, telan-
be a promising treatment modality with marked giectasias, papules, pustules, tissue hyperplasia,
postprocedural clinical, histologic, and ultrastruc- and sebaceous gland hyperplasia. Diagnosis of ro-
tural improvement.32–34 sacea is based primarily on clinically recognizable
morphologic characteristics. An expert committee
assembled by the National Rosacea Society on
Microdermabrasion
the Classification and Staging of Rosacea defined
In a large study of 533 patients with melasma, and classified rosacea in April 2002 into 4 clinical
Kunachak and colleagues35 reported a melasma subtypes based primarily on morphologic charac-
clearance rate of 97% after microdermabrasion teristics. The subtypes include erythemato-
at long-term follow-up. PIH and postprocedural telangiectatic rosacea, papulopustular rosacea,
hyperemia were responsive to 3% to 5% topical phymatous rosacea, and ocular rosacea. The
HQ or 0.1% triamcinolone. pathogenesis of rosacea is complex, with genetic
and vascular elements, climatic exposures, matrix
Chemical Peels degeneration, chemicals and ingested agents, pi-
losebaceous unit abnormalities, and microbial
Salicylic acid organisms likely playing a role.39
Grimes36 reported moderate to significant FDA approved rosacea treatment options
improvement of melasma in 4 of 6 patients with include systemic and topical antibiotics with anti-
skin types V and VI, treated with a series of 20% microbial and anti-inflammatory properties, aze-
to 30% salicylic acid (SA) peels (every 2 weeks) laic acid, and topical immunomodulators. These
plus HQ (administered for 2 weeks before initiation medical therapy options are often insufficient,
of SA series). The treatment protocol was well especially for erythematotelangiectatic rosacea
tolerated with no reported postinflammatory dys- motivating patients to search for alternative herbal
chromia. SA peels without pretreatment with HQ anti-inflammatories and botanicals. ‘‘Anti-red’’
were associated with higher risk of hyperpigmen- cosmeceuticals can be combined with prescrip-
tation (Diane Berson, MD, unpublished observa- tion medications and in-office procedures.
tion, personal communication, 2008).
Anti-inflammatory Botanicals
GA
The usefulness of serial GA (an a hydroxyl acid) Licochalcone A (licorice extract)
peels (increasing concentrations 35%, 50%, and Licorice extract has marked anti-inflammatory
70%) with topical therapy with azaleic acid and properties. In in vitro studies, licochalcone A
adapalene was studied in 28 women with recalci- isolated from the roots of Glycyrrhiza inflate
trant melasma.37 The combination therapy (GA suppresses inflammation via indirect inhibition
peels, retinoid, and azaleic acid) group had of the cyclooxygenase (COX) and lipoxygenase
superior clinical improvement compared with the pathways. Licochalcone A in vivo decreases
retinoid plus azaleic acid group. Combined treat- UVB-induced erythema, reduces proinflammatory
ment with serial GA peels, azelaic acid cream, cytokines, and UVB-induced prostaglandin E2
and adapalene gel may be an effective and safe (PGE2) release by keratinocytes.17,40 In an
therapy for recalcitrant melasma. 8-week clinical trial of 32 women with mild to
Lim and Tham38 conducted a 26-week, single- moderate rosacea and 30 women with facial
blind, split-face study of 10 Asian women treated erythema, application of 4 test products contain-
with GA peels ranging in concentration from 20% ing licochalcone A (cleanser, moisturizer with sun
to 70%, administered every 3 weeks alone or in protection factor [SPF] 15, spot concealer, and

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406 Reszko et al

night moisturizing cream) resulted in a significant neutrophil chemotaxis, and inhibition of adhesion
reduction of erythema at 4 and 8 weeks after initi- molecule expression.47 One drawback of topical
ation of treatment (7% vs 23%, respectively). Lico- application of feverfew is a high potential for
chalcone A-containing cosmeceuticals were well topical sensitization and irritation. Newly devel-
tolerated for everyday use.40 In another study, oped purified feverfew extract (Feverfew, PFE)
topical application of a licochalcone A-containing retains the anti-inflammatory properties of
extract twice daily for 3 days resulted in a signifi- feverfew with minimal skin sensitization.
cant reduction in UV-induced and shaving- The anti-inflammatory properties of feverfew, as
induced erythema.41 assessed by inhibition of TNFa release, seem to be
far superior to other botanicals including teas
Azelaic acid (green, black, white), echinacea, licorice extract,
Topical azelaic acid is an FDA approved treatment chamomile, and aloe vera.47 In a 4-week,
of rosacea and acne vulgaris and is useful for controlled, full-face clinical trial, 35 women with
acne-induced PIH.42 mild to moderate facial rosacea were treated
with a moisturizing agent containing PFE with an
Aloe vera
SPF of 15, and a nightly moisturizing cream with
Aloe vera has been widely used in traditional medi-
PFE, once daily. At 4 weeks, marked improvement
cine to accelerate healing of wounds and burns.
in erythema, tactile surface roughness, visual
The active ingredients of aloe vera include SA
dryness, and overall facial irritation was noted.
(antimicrobial and anti-inflammatory properties
Application of the feverfew was well tolerated.4,47
via inhibition of thromboxane and prostaglandin
PFE was also shown to reduce UVB-induced
synthesis), magnesium lactate (antipruritic proper-
erythema in a normal skin. Skin treated for 2
ties via inhibition of histidine decarboxylase), and
days with 1% PFE and exposed to increasing
gel polysaccharides (anti-inflammatory activity by
minimal erythema doses (MEDs; 0.5, 1, 1.5 MED)
immunomodulation).43
of UVB showed a marked reduction of erythema
The anti-inflammatory properties and clinical
at 24 and 48 hours compared with untreated
efficacy of aloe vera were tested in a double-blind,
control at all MEDs tested.48
placebo-controlled trial of 60 patients with mild to
moderate psoriasis.44 Treatment 3 times daily for
Oatmeal
5 consecutive days per week for a maximum of
Oatmeal is one of a limited number of natural
4 weeks with 0.5% aloe vera cream resulted in
compounds recognized and regulated by the
clearing of psoriatic plaques in 83% of patients
FDA. Colloidal oatmeal, dehulled oats ground to
compared with only 8% of the placebo group.
a fine powder, is recognized by the FDA as
Chamomile a skin protectant that, in addition to providing
Chamomile (Matricaria recutita) has long been temporary skin protection, relieves minor pruritus
used in traditional folk medicine for the treatment and irritation caused by eczema, rashes, poison
of skin irritation and atopic dermatitis. The active ivy, and other contact allergens and insect bites.49
components of chamomile include a-bis-abolol, Colloidal oatmeal has a combination of compo-
a-bis-abolol oxide A and B, and matricin,45 all of nents and properties well suited for the treatment
which are potent inhibitors of COX and lipoxyge- of inflammatory skin conditions. It cleanses, mois-
nase pathways. Chamomile also contains the turizes, provides barrier protection, and exhibits
flavonoids apigenin, luteolin, and quercetin, all anti-inflammatory activity.
potent inhibitors of histamine release.45 In the The antioxidant constituents of oats are avenan-
skin of healthy volunteers, the anti-inflammatory thramides, which are polyphenolic compounds.
properties of topical chamomile were comparable Isolated avenanthramides reduce proinflammatory
with approximately 60% of that produced by cytokines (IL-8) and transcription factors (NF-kB)
hydrocortisone 0.025% cream application.46 in cultured human keratinocytes,50 reduce hista-
mine-induced pruritus in humans, and decrease
Feverfew UVB-induced erythema. In recent months,
Feverfew (Tanacetum parthenium) is a nonsteroidal a topical formulation of proprietary standardized
anti-inflammatory agent with marked anti-irritant avenanthramide became commercially available
and antioxidant properties. Anti-inflammatory as Avena sativa kernel.
properties of feverfew include inhibition of pro-
inflammatory cytokine (tumor necrosis factor Pycnogenol
a [TNFa], interferon-g [INF-g], interleukin-2 [IL-2], Pycnogenol is a standardized extract from French
IL-4) release, decrease in nuclear factor kB (NF- maritime pine bark (Pinus pinaster). The extract’s
kB) mediated gene transcription, inhibition of active ingredients include proanthocyanidins,

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 Cosmeceuticals 407

shown to have photoprotective, antimicrobial, release. Quercetin also enhances tumor cell
antioxidant, anti-inflammatory, and anticarcino- apoptosis.3 In a mouse model, quercetin reduced
genic effects.51,52 Its anti-inflammatory properties UVA-induced oxidative stress.62 In vitro quercetin
may include the inhibition of INF-g and down- inhibited growth of melanoma cells.63
regulation of expression of interstitial cell adhesion
molecule 1 (ICAM-1) on the surface of keratino- Allantoin
cytes. Pycnogenol also converts the vitamin C Allantoin derived from the comfrey root has anti-
radical to its active form and raises levels of gluta- inflammatory and antioxidant effects. It has been
thione and other free-radical scavengers.3,53 In an shown to repair cutaneous photodamage and
animal model, topical application of 0.05% to reduce inflammation following UVR exposure.64
0.2% Pycnogenol reduced ultraviolet radiation
(UVR)-induced erythema, inflammation, and tumor Chemical Peels
carcinogenesis in a dose-dependent manner.52 In Chemical peels, b-hydroxy acids and a-hydroxy
a clinical trial of healthy volunteers, 8-week-long acids (GA) are widely used for the treatment of
oral Pycnogenol supplementation reduced acne rosacea. Clinical experience has long shown
UV-induced erythema.54 effectiveness of SA in the treatment of acne rosa-
Lycopene cea. SA targets comedonal and inflammatory
Lycopene, a carotinoid, exhibits considerable lesions and has better sustained efficacy and
reductive potential and antioxidant activity.55 fewer side effects than GA peels.65,66
When applied topically before UVA exposure, it Lee and colleagues67 reported improvement in
prevents apoptosis, reduces inflammation, and acne in 35 Korean patients treated with 30% SA
diminishes expression of enzymes implicated in peels. Grimes36 reported moderate clearing of
carcinogenesis.56 In addition, lycopene has the inflammatory acne lesions in 8 of 9 dark-skinned
ability to regenerate vitamin E (a-tocopherol).55 patients (diverse ethnicity including subjects of
The clinical usefulness of lycopene still remains Asian, African, and Hispanic descent) treated
to be proved. In a clinical trial of 10 volunteers, with a series of 20% to 30% SA peels with 4%
6% topical lycopene cream reduced UV-induced HQ pretreatment. This treatment regimen facili-
erythema to a greater extent than a topical mixture tated resolution of PIH, and a decrease in overall
of vitamin C and vitamin E.55 In an in vitro study on pigmentation of the face.
human fibroblasts exposed to UVA radiation, lyco- An SA derivative, lipohydroxyacid (LHA)
pene offered photoprotection and reduced UVA- (commercially available in concentrations up to
induced levels of matrix metalloprotease 1 10%) has recently been introduced in the United
(MMP-1) only when combined with vitamin E.56 States. With an additional fatty chain, LHA has
increased lipophilicity that allows for efficient exfo-
Silymarin liation, and increased antibacterial, anti-inflamma-
Silymarin, a polyphenolic flavonoid from the milk tory, antifungal, and anticomedogenic properties
thistle plant, Silybum marianum, inhibits lipopro- even at low concentrations.68 Studies have shown
tein oxidation and acts as a free-radical scav- strong keratinolytic properties with good penetra-
enger.57 In animal models, silymarin showed tion through the epidermis and into the piloseba-
chemoprotective and anticarcinogenic acitiv- ceous unit.
ity.57,58 It reduced UVB radiation-induced In a randomized, controlled clinical trial, Uhoda
erythema, edema, and keratinocyte apoptosis and colleagues69 studied LHA peels in acne-prone
through the inhibition of inflammatory cytokines women and women with comedonal acne. UV light
and pyrimidine dimers.59,60 Clinically, silymarin video recordings and computerized image anal-
alleviates the symptoms of rosacea. In a double- ysis showed significantly decreased numbers
blinded, placebo-controlled study of 46 patients and sizes of microcomedones and a reduction in
with rosacea, topical application of silymarin and the density of follicular keratotic plugs in the LHA
methylsulfonilmethane for 1 month resulted in treated group.
statistically significant improvements in erythema,
papules, pruritus, and skin hydration.61 Laser Therapy and IPL
Quercetin Laser therapy with pulsed dye lasers (PDL 585-
Found in many fruits and vegetables, the flavonoid 595 nm), potassium-titanyl-phosphate (KTP), and
quercetin has antioxidant and anti-inflammatory IPL for acne rosacea has been used extensively
properties. Its anti-inflammatory activity results for the reduction of telangiectasias, erythema,
from inhibition of the enzymatic actions of lipooxy- flushing, and improving skin texture.70,71 The
genase and COX-2, and from blocking histamine primary mode of action of laser/ILP therapy is

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408 Reszko et al

selective photothermolysis of telangiectatic super- thickening of the skin, elastosis, and a variety of
ficial blood vessels. benign, premalignant, and malignant neoplasms.76
In a recent small pilot study of 10 rosacea Histologically, photodamaged skin shows a 20%
patients treated with either IPL or PDL, 5 patients decrease in total collagen and decreased cellular
(3 after IPL and 2 after PDL) had lower levels of content compared with sun-protected skin.77
cathelicidin, an antimicrobial peptide. Cathelici- Moreover, pigmentary alterations and telangiecta-
dins were recently shown to play a central role in sias contribute to an aged appearance by creating
the pathogenesis of rosecea.72 In addition to shadows and areas of contrast on the face.
directly mediating antimicrobial activity, cathelici-
dins have the potential to trigger the immune Antioxidants
host tissue response by promoting leukocyte Antioxidants have long been used in the cosmetic
chemotaxis, angiogenesis, and the expression of industry for their multifaceted benefits, offering
components of the extracellular matrix.73 Patients antiaging and anti-inflammatory properties. In
with rosacea express higher levels of cathelicidins addition, antioxidants confer a degree of photo-
peptides in affected facial areas compared with protection and anticarcinogenesis by quenching
similar anatomic regions of unaffected controls. free-radical species generated by cellular metabo-
Although the results of the aforementioned trial lism and direct exposure to UV radiation. They also
did not reach statistical significance, the study block UV-induced inflammatory pathways.
raised an interesting mechanism for clinical
improvement of rosacea symptoms after IPL or Tea
laser treatment.74 Natural anti-inflammatory Tea (black, green, white, oolong) is derived from
agents could potentially limit the cathelicidin- the leaves and buds of the tea plant (Camellia si-
medicated inflammatory cascade. nensis). Different varieties of tea result from differ-
ential processing, oxidation, and fermentation of
the tea leaves and buds.78 Active ingredients in
PHOTOAGING (RHYTIDS AND DYSCHROMIA)
tea include polyphenolic catechins such as epica-
Introduction
techin, epicatechin-3-gallate (ECG), epigallocate-
In the treatment of aging skin, a new generation of chin (EGC), and epigallocatechin-3-gallate
cosmeceuticals offers clinical benefits. Ultrapotent (EGCG).4
antioxidants, stem cell modulators, and antisense Green tea offers antioxidant, anti-inflammatory,
DNA technologies are advancing our clinical and anticarcinogenic properties with systemic
understanding of the intrinsic and extrinsic aging and topical administration.79 Early studies on hair-
processes, offering targeted strategies for slowing less mice fed green tea showed a dose-dependent
down or reversing the signs of aging. The aging reduction of UV-induced carcinogenesis.80,81
process has intrinsic and extrinsic bases. These Similar anticarcinogenic and chemoprotective
2 clinically and biologically independent and effects were shown after topical application of
distinct processes affect skin structure and green tea polyphenolic catechins (GTP) in mice.
function. GTP is the active ingredient in green tea and limits
Intrinsic or innate aging is a naturally occurring UV-induced redness, the number of sunburn cells,
process that occurs from slow, but progressive collagen, and cellular DNA damage.81
and irreversible, tissue degeneration. Telomere In healthy volunteers, topical GTP (EGCG and
shortening and metabolic oxidative damage with ECG) inhibited UV-induced erythema and reduced
free reactive oxygen species (ROS) generation all formation of cyclobutane pyrimidine dimers,
play a role in the innate aging process.75 Based a marker of DNA damage.82,83 Green tea has
on a unique genetic imprint, intrinsic aging affects also has been studied for use in cosmetic applica-
everyone at different rates. On a histologic level, tions. In a clinical study of 40 women with
intrinsic aging is characterized by decreased moderate photoaging, Chin and colleagues found
collagen synthesis, degeneration of elastic fiber increased elastic tissue content in the skin of
networks, and loss of hydration. Clinically, fine women treated with 300 mg of green tea supple-
wrinkling of the skin, loss of skin tone, skin laxity, ments twice daily and topical 10% green tea
and loss of subcutaneous fat occur. cream daily. Histologic improvement nonetheless
Of the extrinsic factors, UV and infrared (IR) radi- did not correlate with clinical improvement after 8
ation, environmental pollutants, and physical weeks of treatment, suggesting that (1) histologic
factors (cold, wind) play a crucial role. UVA radia- improvement (especially mild to moderate) may
tion is the prime driver of premature aging. Clini- not translate into short-term clinical improvement,
cally, extrinsic photoaging is characterized by and (2) clinical correlation of all histologic findings
coarse wrinkling and furrowing with an apparent is essential.84

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 Cosmeceuticals 409

Vitamin C, vitamin E, and ferulic acid (combined vitamins C and E) to eightfold (vitamin
Cosmeceutical preparations of vitamins C (L- C, vitamin E, ferulic acid; C E ferulic).80 Clinical
ascorbic acid) and E (D-alpha-tocopherol) play studies show that topical C E ferulic acid provides
a major role in the treatment of photoaged skin. substantial protection for human skin against solar
In vivo, vitamin C blocks UVR-induced erythema. simulator-induced oxidative skin damage,
In vitro, vitamin C stimulates fibroblasts, increases including erythema, sunburn cell formation, and
rates of neocollagenesis, decreases melanin cancer related DNA mutations.86
formation, and exhibits anti-inflammatory activity.
The effects of cutaneous vitamin C application Yquem
were evaluated in a double-blind, half-face trial. Yquem extract is a novel, highly potent antioxi-
A 12-week treatment with vitamin C complex con- dant. In in vitro studies it has been shown to cause
sisting of 10% ascorbic acid (water soluble) and highly significant reduction of oxidative stress. The
7% tetrahexyldecyl ascorbate (lipid soluble provi- antioxidant power of yquem extract at low
tamin C) resulted in significant improvement in concentrations (1.5 mg/mL) is highly superior to
photoaging scores and skin wrinkling. Histologic that of vitamin C (at 50 mM) and that of vitamin E
analysis revealed increased collagen content in (at 25mM). In a clinical study of 10 subjects, the
sites treated with vitamin C complex.85 extract was applied for 1 day to facial skin, and
Diet is the sole source of vitamin C in humans. the rates of free-radical production were
Gastrointestinal absorption is the rate-limiting measured 18 hours after the last application and
factor in cutaneous delivery of vitamin C. There- compared with an untreated zone. Treatment
fore, even supraphysiologic doses of vitamin C with yquem extract decreased the rate of free-
through oral administration do not increase the radical production by 22% compared with
cutaneous concentration to optimal levels. Expo- untreated control. By comparison, grape polyphe-
sure to sunlight and environmental pollutants nols and idebendone formulations decreased free-
deplete cutaneous vitamin C. Even minimal UV radical production by only 2.3% and 4.1%,
exposure of 1.6 times the MED decreases the level respectively.9
of vitamin C to 70% of the normal level. Exposure Coffeeberry
to 10 ppm of ozone in city pollution decreases the Polyphenols including chlorogenic acid, quinic
level of epidermal vitamin C by 55%.79 acid, ferulic acid, and condensed proanthocyani-
Vitamin E is the most important lipid soluble, dins are the active ingredients in coffeeberry, the
membrane-bound antioxidant in plasma, cellular fruit of the coffee plant Coffea arabica.87 The anti-
membranes, and tissues. Similar to vitamin C, oxidant properties of polyphenols are related to
vitamin E is supplied solely through diet. In animal their ability to quench free radicals. In in vitro
studies, vitamin E, decreases the rate of UVR- testing with the oxygen radical absorbance
induced tumor formation. In clinical studies, topi- capacity (ORAC) assay, coffeeberry was superior
cally applied vitamin E decreased the appearance to other commonly used antioxidants, such as
of wrinkles, solar lentigines, and overall green tea extract, pomegranate extract, vitamin
photoaging. C, and vitamin E.81,88 The clinical relevance of in
In tissues, vitamins C and E act synergistically to vitro ORAC testing is controversial, especially
provide antioxidant protection. When used in because the ORAC scale was originally developed
combination, topical L-ascorbic acid (15%) and to determine the antioxidant potential of ingested,
D-a-tocopherol (1%) resulted in a fourfold greater
rather than topically applied, antioxidants.89
protection against UV-induced erythema, In a 6-week double-blind clinical trial, 30
compared with a twofold increase with either patients with significant actinic damage used
agent alone. a skin regimen of 0.1% to 1% coffeeberry in skin
The inherent instability of active vitamin C (L-as- cleansers and facial creams (commercially avail-
corbic acid), however, remains the major thera- able as the RevaléSkin line, Stiefel). Compared
peutic challenge. When exposed to air, L-ascorbic with pretreatment, all patients saw statistically
acid converts to inactive brown dihydroascorbic significant improvements in fine lines, wrinkles,
acid. To overcome the problem of instability, pigmentation, and overall skin appearance88
vitamin C and vitamin E preparations have been
stabilized with ferulic acid. Ferulic acid is a potent Idebenone
antioxidant present in the cell walls of grains, fruits, This is a low-molecular-weight synthetic analog of
and vegetables. The acid itself absorbs UV radia- coenzyme Q10. Because of its lower molecular
tion, acting as a sunscreen. When mixed with vita- weight, idebenone can penetrate the skin more
mins E and C, it stabilizes the formulation and efficiently than coenzyme Q10. In a clinical study
doubles synergistic photoprotection from fourfold of 50 subjects with moderate photoaging, an

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410 Reszko et al

application of 0.5% to 1% idebenone lotion twice UVA radiation plays a key role, because only
daily for 6 weeks reduced fine lines and wrinkles a small percentage of UVB penetrates into the
by 26% and 27%, respectively. Both groups saw superficial papillary dermis.94,95 The mechanism
a 37% improvement in skin hydration and a 30% of UVR mediated dermal damage includes:
to 33% improvement in global photoaging.90
1. Decreased collagen I and III synthesis
Vine shoot 2. Increased collagen degradation by transform-
A new generation of ultrapotent antioxidants ing growth factor-b (TGF-b) and activator
include Vitis vinifera shoot, a polyphenol-rich anti- protein A
oxidant and ectoine/hydroine, a natural blend of 3. Infiltration of inflammatory cells, predominately
compounds found in halophilic microorganisms neutrophils, into the dermis
growing in extreme temperature and salinity. In 4. Release of ROS from neutrophils
a clinical study, 56 subjects were treated with
a combination of Vitis vinifera shoot extract Benzophenones (dioxybenzone, oxybenzone,
(0.045%) and ectoine/hydroine (1%). The combi- sulisobenzone) provide protection in the UVB
nation was applied for a 4-week period twice daily; and UVA II range (320–340 nm). Currently, only
90% of patients experienced a 25% overall oxybenzone is approved for use in the United
improvement (firmness, radiant glow, evenness, States.
smoothness, hydration, texture, softness) as as- Avobenzone (Parson 1789), a dibenzoylmethane,
sessed by an independent investigator. In in vitro absorbs in the UVA I (340–400 nm) range. However,
assays, the antioxidant capacity of Vitis vinifera its use is limited by its relative instability. Estimates
shoot appeared to be significantly more powerful suggest that all avobenzone is inactivated after 5
than that of vitamin C or E.91 hours of sun exposure, equivalent to 50 J of solar
energy. Stability of the avobenzone is markedly
Soy increased by combining with oxybenzone and
Isoflavones, including genistein and diadzein, are 2,6-diethylhexylnaphthalate in commercially avail-
the main active ingredients and chemoprotective able Helioplex (Neutrogena). Another agent
agents derived from soy. Other biologically active offering long-lasting short-wave UVA protection
ingredients include essential fatty acids and amino and photostabilization of avobenzone is ecamsule,
acids, phytosterols, and small protein serine commercially available as Mexoryl (L’Oreal,
protease inhibitors such as Bowman-Birk inhibitor France).
(BBI) and soy trypsin inhibitor (STI). By inhibiting
protease-activated receptor 2 (PAR-2), STI inhibits Retinoids
melanosome transfer to keratinocytes.92 Clinically, The biologic properties of retinoids include free-
soy provides gentle anti-inflammatory, photopro- radical scavenging and antioxidant activity,
tective, and skin lightening properties. Daily, or increasing fibroblast proliferation, modulation of
twice daily, application of a topical soy formulation cellular proliferation and differentiation, increased
over a 12-week period resulted in improved overall collagen and hyaluronate synthesis, and
skin tone and texture, hyperpigmentation, skin decreased matrix metalloproteinase mediated
blotchiness, and dullness (Diane Berson, MD, extracellular matrix degradation. Retinoids are
personal communication, 2009). In a clinical study therefore ideal for the treatment of photoaging.96
of 6 adult patients, genistein showed a dose- Numerous studies have confirmed the clinical
dependent inhibition of UBV-induced erythema.93 efficacy of various retinoids.27,96–101 Histologic
responses to chronic topical retinoid application
Sunscreens include hyperproliferation, leading to a dose-
Broad-spectrum UVA and UVB sunscreens are the dependent expansion of the numbers of cell layers
cornerstone of photoaging therapy. UVR causes of stratum spinosum and stratum granulosum, and
several acute effects in the skin, including photo- elongation of the basal layer keratinocytes.
synthesis of vitamin D, immediate pigment dark-
Chemical Peels
ening, delayed tanning, sunburn, epidermal
thickening, and numerous immunologic effects, The efficacy of chemical peels for the treatment of
from altered antigen presentation to release of photodamage has been widely reported.102,103
immunosuppressive factors. Histologically, different chemical peels, GA, SA
UVA and UVB radiation contribute to the disrup- and LHA, alter the epidermis toward a non–sun-
tion of the extracellular matrix, a hallmark of photo- damaged pattern with keratinocytes showing a re-
aging. The presence of dermal changes in the turn of polarity, and more regular distribution of
deep reticular dermis, however, suggests that melanocytes and melanin granules.

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 Cosmeceuticals 411

In a randomized, right/left split-face controlled technology for dermal delivery of TGF-b1, L-as-
clinical trial of 43 women aged 35 to 60 years corbic acid, and black cohosh (Cimicifuga race-
with fine lines, wrinkles, and dyschromia, applica- mosa). In a split-face clinical study of 12
tion of 4 LHA (5%–10%) treatments was equiva- patients with moderate facial photoaging,
lent to 6 treatment sessions with GA (20%–50%). patients applied CRS cream with TGF-b1 to
Both chemical peels were well tolerated and one side of the face and CRS cream without
showed a significant reduction of all study param- TGF-b1 to the opposite side. The results
eters (fine lines, wrinkles, and hyperpigmentation) showed a statistically significant improvement
(LaRoche Posay, 2008, clinical data on file). of facial rhytids with the CRS cream containing
TGF-b1 compared with the L-ascorbic acid and
Laser Skin Resurfacing black cohosh only CRS preparation.105
NouriCel-MD, a proprietary mix of GFs, cyto-
The carbon dioxide and Er:YAG lasers remain gold
kines, and soluble proteins secreted by cultured
standard for rejuvenation of photoaged skin.
neonatal human dermal fibroblasts during produc-
However, their use is associated with a risk of
tion of extracellular matrix in an oil-free gel, is
side effects and a prolonged postoperative
currently available as TNS Recovery Complex
recovery period. Newer rejuvenating laser systems
(SkinMedica Inc., Carlsbad, California). In a clinical
offer the benefit of stimulation of collagen produc-
study, 14 patients with marked photodamage
tion and remodeling with little or no healing time
applied TNS Recovery Complex twice daily to
and decreased patient discomfort.
facial skin for 60 days. The results showed
Nonablative laser systems currently available
a 15% to 35% decrease in fine lines and wrinkles
include:
as assessed by optical profilometry assay. In addi-
1. Mid-IR lasers targeting the dermis (Nd:YAG tion, thickening of the Grenz zone, new collagen
[1320 nm], diode [1450 mm]) formation (average 36%) and epidermal thickening
2. Visible lasers, such as the PDL (585-595 nm) the (average 30%) were noted.106
pulsed KTP (532 nm) and Nd:YAG (1064 nm) The main ingredients in Bio-Restorative Skin
3. IPL Cream (Neocutis, Inc., San Francisco, CA) are pro-
4. A combination of electrical (radiofrequency) cessed skin-cell proteins, a proprietary blend of
and optical devices GFs, and cytokines extracted from cultured first
trimester fetal human dermal fibroblasts.
Fractional resurfacing offers partial benefits of Compared with adult fibroblasts, fetal fibroblasts
the ablative laser with faster recovery and fewer express only transient and low amounts of TGF-
side effects. In addition to the original Fraxel SR b1, which may contribute to virtually scarless heal-
(1550 nm erbium, Reliant Technologies), the Fraxel ing in the first trimester of pregnancy.107 Clinical
SR1500, Fraxel AFR (both Reliant Technologies), benefits of Bio-Restorative Skin Cream were
Lux 1540 Fractional (1540 nm, Palomar Medical studied in 18 patients with moderate to severe
Technologies, Burlington, Massachusetts), and photodamage. Twice daily application of Bio-
Affirm (1320 nm plus 1440 nm, Cynosure Inc., Restorative Skin Cream for 60 days resulted in
Westford, Massachusetts) have been a 17% and 13% decrease in periorbital and perio-
developed.104 ral rhytids. Improvements in skin texture were also
noted.108
COLLAGEN REPAIR
Introduction Peptides

The use of signaling peptides, growth factors (GF) Cosmeceutical peptides, short-chain sequences
and cytokines in collagen repair and clinical of amino acids, are a rapidly expanding category
rejuvenation has emerged as an exciting new of cosmeceuticals. Biologic effects of peptides
antiaging treatment option. Advances in basic may relate to their ability to enhance collagen
research into wound healing, with the identification production, relax dynamic skin wrinkling, and
of key wound healing mediators, prompted trans- improve skin hydration and barrier function. The
lational clinical research on repair and remodeling three main classes of peptides are signal peptides,
of dermal infrastructure. The GFs implicated in neuropeptides, and carrier peptides.
wound healing are listed in Table 1.
Signal peptides
Signal peptides increase fibroblast production of
GFs
collagen or decrease collagenase breakdown
Cell rejuvenation serum (CRS, Topix Pharma- of existing collagen. Examples of signal peptides
ceuticals, New York) relies on liposomal include valine-glycine-alanine-proline-glycine

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412 Reszko et al

Table 1
GF and cytokine signals involved in wound healing

GF CellTarget and Effect

Heparin-binding epidermal growth factor- Keratinocyte and fibroblast mitogen
like growth factor (HB-EGF)
Fibroblastic growth factor (FGF) 1, 2, 4 Angiogenic, fibroblast mitogen
Platelet-derived growth factor (PDGF) Chemotaxis of macrophages and fibroblasts;
macrophage activation; fibroblasts
mitogen, matrix production
Insulin-like growth factor 1 (IGF-1) Endothelial cells and fibroblast mitogen
TGF-b1 and b2 Keratinocyte migration; chemotaxis for
macrophages and fibroblast
TGF-b3 Antiscarring
IL-1a and -b Early activators of GF expression in
macrophages, keratinocytes and fibroblasts
TNF a Mechanism of action similar to IL-1a and -b

Data from Mehta RC, Fitzpatrick RE. Endogenous growth factors as cosmeceuticals. Dermatol Ther 2007;20(5):350–9.

peptide,109,110 lysine-threonine-threonine-lysine- Neuropeptides

serine peptide (KTTKS),111 tyrosine-tyrosine-argi- Also known as neurotransmitter-affecting
nine-alanine-aspartame-aspartame-alanine peptide, peptides, neuropeptides mimic the effects of
and glycyl-L-histadyl-L-lysine (GHK) peptide. botulinum neurotoxin. Clinically, neuropeptides
Application of elastin-derived valine-glycine- decrease facial muscle contraction, reducing lines
alanine-proline-glycine peptide has been shown and wrinkles by raising the threshold for minimal
to significantly stimulate human dermal skin fibro- muscle activity. Over time, they are postulated to
blast production and down-regulate elastin also reduce subconscious muscle movement.
expression. Palmitate-bound valine-glycine- The properties of several neuropeptides are dis-
alanine-proline-glycine peptide is commercially cussed below. For a comprehensive review see
available in a number of cosmetic preparations Lupo and colleagues.2
under the trade name of palmitoyl oligopeptide.2 Neuropeptides are designed to block individual
Palmitate-bound KTTKS peptide (pal-KTTKS, components of the neuromuscular junction
palmitoyl pentapeptide-3, trade name Matrixyl, (NMJ). Most neuropeptides act on the soluble
Sederma, France) is a fragment of type I procolla- N-ethylmaleimide-sensitive factor attachment
gen. Of the many collagen breakdown products, protein receptors (SNARE) complex, a component
pentapeptide KTTKS was shown to have the of the NMJ. Whether topically applied neuropep-
highest fibroblast stimulation properties in in vitro tides can truly penetrate to the level of the NMJ
subconfluent monolayer cultures. Exposure of remains to be tested.
fibroblasts to collagen degradation products is Acetyl-hexapeptide-3 (AC-gly glu-met-gln-arg-
hypothesized to induce cellular collagen repair arg-NH2) is a synthetic peptide patterned after
with enhanced collagen synthesis and down-regu- the N-terminus of SNAP-25, an inhibitor of SNARE
lation of matrix collagenases. Pentapeptide was complex formation and catecholamine release.
shown to stimulate new collagen synthesis and This peptide is currently marketed as Argireline
increase production of extracellular matrix (McEit International Trade Co., Ltd.).114 In one
proteins such as type I and II collagen and fibro- open-label trial, 10 female patients applied a 5%
nectin.112 Matrixyl contains 800 parts per million acetyl-hexapeptide-3 cream twice daily. Subjects
of pal-KTTKS, and currently available cosmetic experienced a 27% improvement in periorbital
preparations contain 1 to 4 parts per million of rhytids after 30 days as measured by silica replica
pal-KTTKS.6 In a 12-week double-blind, placebo- analysis.114
controlled, split-face study of 93 Caucasian Pentapetide-3 (amino acid sequence not pub-
women, pal-KTTKS provided significant improve- lished), currently marketed as Vialox (Cellular
ment of wrinkles and fine lines compared with Skin, Rx) has a mechanism of action similar to
the placebo group by qualitative technical and that of tubocurarine, the main ingredient of curare.
expert grader image analysis.113 Its mechanism of action is competitive inhibition of

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 Cosmeceuticals 413

acetylcholine postsynaptic membrane receptor. 2. Lupo MP, Cole AL. Cosmeceutical peptides.
Acetylcholine receptor blockage in turn prevents Dermatol Ther 2007;20(5):343–9.
muscle contraction.2 3. Choi CM, Berson DS. Cosmeceuticals. Semin
Cutan Med Surg 2006;25(3):163–8.
Carrier peptides 4. Berson DS. Natural antioxidants. J Drugs Dermatol
Carrier peptides stabilize and deliver trace elements 2008;7(7 Suppl):s7–12.
necessary for wound healing, enzymatic processes, 5. Draelos ZD. Skin lightening preparations and the
and collagen regeneration into the skin. The most hydroquinone controversy. Dermatol Ther 2007;
commonly encountered carrier peptides stabilize 20(5):308–13.
and deliver copper, an elemental metal for proper 6. Draelos ZD. The cosmeceutical realm. Clin
wound healing, enzymatic processes (collagen Dermatol 2008;26(6):627–32.
and elastin synthesis, cytochrome c oxidase, 7. Draelos ZD. Topical agents used in association with
down-regulation of MMPs and inhibition of collage- cosmetic surgery. Semin Cutan Med Surg 1999;
nase), and cutaneous aniogenesis.2 The copper 18(2):112–8.
peptide technology is currently adapted for anti- 8. Lawrence N, Bligard CA, Reed R, et al. Exogenous
aging and general skin care in several skin care ochronosis in the United States. J Am Acad Derma-
preparations. The tripeptide complex, GHK sponta- tol 1988;18(5 Pt 2):1207–11.
neously complexes with copper and facilities its 9. Westerhof W, Kooyers TJ. Hydroquinone and its
cellular uptake.115 In vitro GHK-copper complex analogues in dermatology – a potential health
increases levels of tissue inhibitors of MMPs, risk. J Cosmet Dermatol 2005;4(2):55–9.
stimulates collagen I and glycosoaminoglycans 10. Fitton A, Goa KL. Azelaic acid. A review of its phar-
synthesis, and enzymatic actions of cytochrome c macological properties and therapeutic efficacy in
oxidase and tyrosinase.116 Clinically, GHK-copper acne and hyperpigmentary skin disorders. Drugs
application led to an improvement in the appear- 1991;41(5):780–98.
ance of fine lines/wrinkles and an increase in skin 11. Balina LM, Graupe K. The treatment of melasma.
density and skin thickeness.2 20% azelaic acid versus 4% hydroquinone cream.
Int J Dermatol 1991;30(12):893–5.
Nonablative, Fractional and Ablative 12. Bissett D. Topical niacinamide and barrier
Laser Resurfacing enhancement. Cutis 2002;70(6 Suppl):8–12.
13. Bissett DL, Oblong JE, Berge CA. Niacinamide:
Cosmeceuticals directed at collagen repair may A B vitamin that improves aging facial skin
prove to be of pivotal importance when combined appearance. Dermatol Surg 2005;31(7 Pt 2):
with nonablative, fractional, and ablative laser re- 860–5.
surfacing. Laser resurfacing rejuvenates skin by 14. Greatens A, Hakozaki T, Koshoffer A, et al. Effective
producing controlled zones of dermal or epidermal inhibition of melanosome transfer to keratinocytes
wounding (epidermal damage is not seen with by lectins and niacinamide is reversible. Exp
nonablative technologies). Subsequent inflamma- Dermatol 2005;14(7):498–508.
tion and cytokine mediated superficial dermal 15. Bissett DL, Robinson LR, Raleigh PS, et al. Reduc-
healing and remodeling leads to clinical improve- tion in the appearance of facial hyperpigmentation
ment. Application of GFs and collagen repair by topical N-acetyl glucosamine. J Cosmet
peptides might further accelerate or improve the Dermatol 2007;6(1):20–6.
wound healing process. Fractional and ablative, 16. Amer M, Metwalli M. Topical liquiritin improves
compared with nonablative, resurfacing provides melasma. Int J Dermatol 2000;39(4):299–301.
an additional benefit of altering the barrier proper- 17. Yokota T, Nishio H, Kubota Y, et al. The inhibitory
ties of the epidermis and may allow for enhanced effect of glabridin from licorice extracts on melano-
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