Efficacy and safety of innovative cosmeceuticals

Clinics in Dermatology (2008) 26, 367–374
Efficacy and safety of innovative cosmeceuticals ☆
Xing-Hua Gao, MD a , Li Zhang, MD a , Huachen Wei, MD b , Hong-Duo Chen, MD a, ⁎
a Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China
b Department of Dermatology, The Mount Sinai Medical Center, New York, USA
Abstract The research and development of cosmeceuticals is booming in recent years. Many substances,
either from botanical, animal, or chemically synthesized sources, are tested or investigated as the active
ingredients in cosmeceuticals. The interactions between cosmeceuticals and skin are complex,
depending on the specific composites in cosmeceutical products, condition of the skin or general health
status of a subject, and the environment where the action occurs. As such, careful preclinical or clinical
evaluation of efficacy and safety is a prerequisite for the development of a specific cosmeceutical
product. This article reviews some of the ingredients that are currently in use or might be potential
candidates in cosmeceuticals of different categories.
© 2008 Elsevier Inc. All rights reserved.
Introduction
The term cosmeceutical was first introduced by Albert
Kligman 1 during a meeting about 20 years ago. It is a
category of cosmetic products claimed to have biologically
active ingredients with medicinal or druglike benefits.
Furthermore, they satisfy the needs of beauty and health.
Many substances, either chemically synthesized or extracted
from plants or animals, can be used as functional ingredients.
Nowadays, many cosmetic products with biologically active
ingredients have been developed and marketed, though there
are discrepancies about their regulations and approvals by
the government. 2
Cosmeceuticals are intended to carry out their functions as
protection, whitening, tanning, antiwrinkling, deodorants,
antiaging, and nail and hair care. Cosmeceuticals may,
however, cause some unwanted problems. The common ones
☆ This article was supported by the Program for New Century Excellent
Talents in University (NCEP-04-0287).
⁎ Corresponding author. Tel.: +86 24 83282642; fax: +86 24 83282633.
E-mail address: chenhd@cae.cn (H.-D. Chen).
are irritability to the skin, contact dermatitis, photosensitivity,
comedogenicity, hair and nail damage, hyper- or
hypopigmentation, infectivity, carcinogenicity, and even
systemic adverse effects. The research and development of
cosmeceuticals, especially the composite active ingredients,
should be based on their clarified sources, structures,
interactive mechanisms with the skin, and, most importantly,
their efficacy and safety on the targeted components of skin.
Here we review some of the cosmeceuticals with different
categories of functions, with special focuses on their
biologically active ingredients.
Skin-whitening and/or depigmenting
cosmeceuticals
The number and amount of melanocytes, as well as the
type and distribution of melanin in the skin, are the main
factors to determine the color of skin. The synthesis of
melanin pigment is completed by a series of oxidative
reactions, along which tyrosinase is the key enzyme.
0738-081X/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2008.01.013

368 X.-H. Gao et al.
Tyrosinase converts tyrosine to dihydroxyphenylalanine
(DOPA) and then to dopaquinone; dopaquinone autooxidates
to dopachrome and, finally, to dihydroxyindole or dihydroxyindole-2-carboxylic
acid to form eumelanin (black-brown
pigment). Dopaquinone can also be converted to cysteinyl
DOPA or glutathione DOPA and subsequently form
pheomelanin (yellow-red pigment). The etiology of hyperpigmentation
includes postinflammatory hyperpigmentation,
pregnancy, drugs, photosensitizing agents, UV light, or
systemic diseases (eg, Addison's disease, liver disease,
pituitary tumors). There are many pigmentary disorders that
pose cosmetic problems in humans. Melasma, freckles, and
aging spots are among the most common ones. 3
Hydroquinone, with a phenol structure, is well known for
its suppressive effect on melanin synthesis. Topical hydroquinone
in 2% to 4% concentrations, alone or in combination
with tretinoin 0.05% to 0.1%, has been successfully used for
years in treating melasma. 4 The problem with hydroquinone
use is that it can be a skin irritant causing contact dermatitis,
particularly in higher concentrations of 4% or greater, or
when combined with tretinoin. Hydroquinone is also an
unstable and easily oxidized ingredient in cosmetic formulations.
It is, therefore, essential to package it in a
nontransparent and airtight container to avoid light and air
exposure. An uncommon adverse effect is exogenous
ochronosis, characterized by progressive sooty darkening
of the skin area exposed to hydroquinone. Derivatives of
hydroquinone have also shown some promises for lightening
skin. For example, arbutin contains a form of hydroquinone
(β-D-glucopyranoside) derived from the leaves of bearberry,
cranberry, mulberry, or blueberry shrubs, and in most types
of pears. Pure forms of arbutin derivatives, such as α-arbutin,
β-arbutin, and deoxyarbutin, are considered more potent for
lightening skin. It was reported that deoxyarbutin effectively
inhibits mushroom tyrosinase in vitro with a Ki that is
10-fold lower than hydroquinone and 350-fold lower than
arbutin. In a human clinical trial, topical treatment of
deoxyarbutin for 12 weeks resulted in a significant or slight
reduction in overall skin lightness and improvement of solar
lentigines in a population of light skin or dark skin
individuals, respectively. 5 Arbutin inhibits melanin synthesis
in a dose-dependent manner. 6 So far, most of the
research describing arbutin's effectiveness has been done in
vitro. Clinical studies are needed to test at what concentration
or in what vehicle arbutin is more effective to lighten
the skin, and what possible hazards it may pose to skin. 7
Another study screened several phenolic derivatives using
B16 melanoma cells and found that a biphenyl derivative,
2,2′-dihydroxy-5,5′-dipropyl-biphenyl (DDB), down-regulated
melanin synthesis effectively. DDB down-regulates
melanin synthesis by inhibiting the maturation of tyrosinase,
leading to acceleration of tyrosinase degradation. 8 DDB,
thus, might be a potential depigmenting candidate as a
cosmeceutical, given careful and sufficient testing and trials.
There are many forms and various sources of α hydroxy
acids (AHAs), such as lactic acid, glycolic acid, malic acid,
citric acid, mixed fruit acid, triple fruit acid, sugar cane
extract, and so on. Primarily, lactic acid and glycolic acid are
the most widely studied forms of AHAs because they have a
molecular size that allows effective penetration into the top
layers of skin. α Hydroxy acids have been used for years in
chemical peels. It is generally assumed that AHAs at
concentrations of 4% to 15% are not effective for inhibiting
melanin production. Rather, it is believed that they can
accelerate cell turnover rates and exfoliate the stratum
corneum. Other research, however, has shown that lactic and
glycolic acids can indeed inhibit melanin production in
addition to their actions as an exfoliant on skin. 9 There are
reports that glycolic acid, or glycolic acid with hydroquinone,
is highly effective in reducing the pigment in melasma
patients. 10 There have been, however, accumulating reports
on adverse effects of cosmetics containing AHA. They
include severe redness, swelling, blistering, burning, itching,
discoloration, and increased photosensitivity. The side
effects are related to the pH and concentration of AHA,
vehicles used, and frequency of application.
Kojic acid (5-hydroxy-4-pyran-4-one-2-methyl), a natural
substance produced by fungi or bacteria, such as Aspergillus,
Penicillium, or Acetobacter spp, is present in traditional
Japanese fermented foods. There is convincing evidence, in
vitro and in vivo, showing kojic acid to be effective for
inhibiting melanin production. 11,12 Kojic acid is highly
effective in reducing the pigment in melasma patients. 13 The
problem with kojic acid is that it is an extremely unstable
ingredient in cosmetic formulations. Upon exposure to air or
sunlight, it can turn to a strange shade of brown and lose its
efficacy. Furthermore, some controversial studies have
shown that kojic acid has some mutagenic properties, at
least in some strains of bacteria. 12,13 A stable derivative of
kojic acid, 5-[(3-aminopropyl)phosphinooxy]-2-(hydroxymethyl)-4H-pyran-4-one
(Kojyl-APPA), was synthesized.
Kojyl-APPA significantly inhibited tyrosinase activity at
24 hours after treatment in normal human melanocytes. In
addition, Kojyl-APPA decreased melanin content to 75% of
control in melanoma cells and decreased the newly
synthesized melanin to 43% of control in normal human
melanocytes. Its permeation through skin increased by about
8 times as compared with kojic acid. 14 Again, there have
been no reports on its clinical usefulness and safety issues.
Azelaic acid is a naturally occurring saturated dicarboxylic
acid originally isolated from Pityrosporum ovale. It
is an effective therapeutic agent in treatment of a number of
skin disorders (eg, acne and rosacea) when applied in a
cream or gel at concentrations of 15% to 20%. It can also
inhibit melanin production. A double-blind study with
329 women showed that 20% azelaic acid cream in
conjunction with a broad-spectrum sunscreen yielded 65%
good or excellent results against melasma. Over the treatment
period of 24 weeks, the azelaic acid cream had comparable
effects to 4% hydroquinone cream with regard to overall
rating, reduction in lesion size, and pigment intensity. Severe
side effects such as allergic sensitization were not observed

Efficacy and safety of innovative cosmeceuticals
with azelaic acid. 15 Additional research, however, suggests
that azelaic acid is more irritating than hydroquinone mixed
with glycolic acid (source, eMedicine Journal, http://www.
emedicine.com/, November 5, 2001). Nevertheless, azelaic
acid is an optional candidate for skin lightening if a patient
has acne and postinflammatory hyperpigmentation or has
allergic reaction with hydroquinone.
Retinoids are compounds that have the basic core structure
of vitamin A and its oxidized metabolites, or synthetic
compounds that share similar mechanisms of action as
naturally occurring retinoids. 16 Topical retinoids such as alltrans-retinoic
acid (RA), 13-cis-retinoic acid (isotretinoin),
retinol, retinaldehyde, tazarotene, and adapalene have been
shown to improve dyspigmentation of photodamaged skin,
including mottling and actinic lentigines. All-trans-retinoic
acid has been demonstrated to improve melasma and
postinflammatory hypermelanosis. Furthermore, RA, in
combination with hydroquinone or 4-hydroxyanisole, or
azelaic acid increases the potency of depigmenting agents for
the treatment of melasma, actinic lentigines, and postinflammatory
hypermelanosis. There are several possible
mechanisms underlying these effects. All-trans-retinoic acid
inhibits melanin synthesis through down-regulation of
tyrosinase and tyrosinase-related protein 1 expression in
melanocytes. All-trans-retinoic acid could also act as a
selective melanocytotoxin in relatively high doses. In
addition, RA increases keratinocyte turnover and augments
melanin loss from the epidermis. The inhibition of glutathione
S-transferase by RA explains its synergistic depigmenting
action with other melanocytotoxins such as hydroquinone. 17
Topical retinoids could irritate the skin causing redness,
dryness, swelling, desquamation, and subjective feelings
such as itching, stinging, and burning sensation. 18
A pomegranate extract (PE) from the rind containing 90%
ellagic acid showed inhibitory activity against mushroom
tyrosinase in vitro, and the inhibition by the extract was
comparable with that of arbutin. Orally taken PE also
inhibited UV-induced skin pigmentation on the back of
brownish guinea pigs. The intensity of the skin-whitening
effect was similar between guinea pigs fed with PE and those
fed with L-ascorbic acid. Pomegranate extract reduced the
number of DOPA-positive melanocytes in the epidermis of
UV-irradiated guinea pigs, but L-ascorbic acid did not. These
results suggest that the skin-whitening effect of PE was
probably due to inhibition of the proliferation of melanocytes
and melanin synthesis by tyrosinase. Further clinical studies
are needed to test its efficacy and safety. 19
Glabridin was extracted from licorice. It could inhibit
tyrosinase activity of melanocytes without cytotoxicity, and
it also inhibited UV-B–induced pigmentation and erythema
by topical application in a 0.5% concentration. 20 There are
also more potent ingredients extracted from licorice that may
become potential depigmenting agents. They include
glabrene, isoliquiritigenin, glycyrrhisoflavone, and glyasperin;
all of them could inhibit tyrosinase activity with
different power. 21,22
Magnesium-L-ascorbyl-2-phosphate (MAP) is a stable
derivative of ascorbic acid. When used as a 10% cream,
MAP showed significant lightening effect in more than half
of patients with melasma and solar lentigines. Furthermore,
MAP has been shown to have a protective effect against skin
damage induced by UV-B irradiation. 23
Alkyl esters of the natural product gentisic acid are also
tyrosinase inhibitors. The smaller esters (eg, methyl and
ethyl) were more effective. 24 Sphingosylphosphorylcholine
is emerging as a potent signaling-lipid mediator. It
significantly inhibits melanin synthesis in a concentrationdependent
manner, and further, that it reduces the activity
of tyrosinase. 25
Some amides obtained from coupling p-hydroxycinnamic
acid derivatives with phenylalkylamines were also very
potent in inhibiting melanin synthesis. The most active
amides were trans-N-caffeoyltyramine, N-dihydrocaffeoyltyramine,
and trans-N-dihydro-p-hydroxycinnamoyltyramine.
26 There have been no studies on what other effects
these amides have on melanocytes, apart from their strong
tyrosinase inhibition activities.
Melanin content of the cells was significantly decreased
by C(2)-ceramide. The tyrosinase activity of cell extracts was
reduced by C(2)-ceramide treatment. In the cell-free system,
however, C(2)-ceramide could not suppress tyrosinase,
whereas kojic acid directly inhibited tyrosinase. These
results suggest that C(2)-ceramide decreases the pigmentation
of melanocytes indirectly by regulating tyrosinase.
Furthermore, C(2)-ceramide decreased the protein expression
of microphthalmia-associated transcription factor,
which is required for tyrosinase expression. 27
Zinc α-2-glycoprotein inhibits melanin production by
B16 melanoma cells via posttranscriptional effects on
tyrosinase protein. Because zinc α-2-glycoprotein is normally
produced by epidermal keratinocytes, these studies
raise the possibility that epidermal-derived zinc α-2-
glycoprotein may play a part in normal regulation of melanin
production in vivo. 28 It is interesting to note that endogenous
substances might be a potential candidate in a cosmeceutical.
Moisturizing cosmeceuticals
369
The stratum corneum is composed mainly of lipids,
proteins, enzymes, and water. The extracellular lipid
membrane of the stratum corneum is composed mainly of
ceramides and its derivatives (40%), cholesterol (25%), and
free fatty acids (10%-15%), followed by smaller amounts of
triglycerides, stearyl esters, and cholesterol sulfate. These
lipids are synthesized throughout the epidermis where they
are packaged in lamellar granules and subsequently undergo
differentiation and constitute the water barrier. Many factors
could disturb their synthesis pathway, such as essential fatty
acid deficiency, enzyme inhibitors, defective enzymes,
enzyme deficiency, environmental constituents, topically

370 X.-H. Gao et al.
applied agents, or water content of the stratum corneum.
High amounts of cholesteryl sulfate, the intercellular cement,
have been shown to inhibit desquamation. Cornified cell
envelope, a structure synthesized at late stages of keratinocyte
differentiation, is composed of structural proteins,
including involucrin, loricrin, and the small proline-rich
proteins. The stratum corneum possesses approximately 30%
water, which is mainly associated with its elasticity. A
healthy stratum corneum contains about 10% tightly held
water. The tightly bound water is closely dependent on the
presence of natural moisturizing factor. Natural moisturizing
factor is composed of amino acids and their metabolites,
which are byproducts formed from the breakdown of
filaggrin. Natural moisturizing factor is found exclusively
inside the cells. 29 Perturbation of the aforementioned
composites in stratum corneum might cause functional
defect and clinical symptoms. Dry skin is one of the
common problems due to defective stratum corneum. It is a
condition featured by some subjective or objective denominators,
including sensory characteristics with dry, uncomfortable,
itchy, stinging, and tingling sensation; tactile
characteristics with a rough, uneven, and sandlike feeling;
and visible characteristics with redness, lackluster surface,
dry, white patches, flaky appearance, cracks, and even
fissures. 30,31 In addition, several skin diseases are also
featured by dry skin, including atopic dermatitis, ichthyosis,
and the like. Moisturizers are agents designed to repair the
damaged stratum corneum to make the stratum corneum
softer and more pliant by increasing its hydration, resulting
in smooth, more supple, and healthier looking skin. Moreover,
moisturizers are also designed to act as adjuvant
treatment option for some dermatologic diseases with feature
of dry skin. From the view of safety, therapeutic moisturizers
should be noncomedogenic, devoid of irritant ingredients,
and compatible with many other therapeutic regimens.
A formulation of lactic acid 12% neutralized with
ammonium hydroxide and pramoxine hydrochloride 1%
was tested on dry itchy skin for 7 days. Patients had
statistically significant improvement in skin surface hydration
by day 3, with further improvement by day 7, as
compared with control. 32
Pantothenic acid, a component of coenzyme A, serves as a
cofactor for a variety of enzyme-catalyzed reactions that are
important in the metabolism of carbohydrates, fatty acids,
proteins, sterols, steroid hormones, and porphyrins. The
topical use of dexpanthenol, the stable alcoholic analog of
pantothenic acid, improved stratum corneum hydration,
reduced transepidermal water loss, and maintained skin
softness and elasticity. 33
A ceramide-dominant physiologic lipid-based emollient
showed satisfactory results in the treatment of childhood
atopic dermatitis, which is featured by dry skin. 34 A
nicotinamide cream containing 2% nicotinamide was tested
on atopic dry skin over 4 or 8 weeks; white petrolatum was
used as control. The results showed that nicotinamide
significantly decreased transepidermal water loss, but white
petrolatum did not show any significant effect, though
nicotinamide and white petrolatum increased stratum
corneum hydration. 35 Another study showed that a niacinamide-containing
facial moisturizer improved the stratum
corneum barrier and, thus, provided a clinical benefit to
subjects with rosacea. 36
In xerotic skin, the proteolysis of desmosomes is reduced,
leading to the accumulation of corneocytes on the surface of
the skin. Soap-induced xerosis could be ameliorated by the
topical application of exogenous protease, such as bovine
pancreatic chymotrypsin, papain, and a bacterial protease
from Bacillus licheniformis. Alcalase and optimase, both
broad specificity alkaline bacterial proteases, were the most
efficient ones. Morphological and immunologic analysis of
bacterial enzyme-treated skin revealed that topically applied
protease specifically induced the degradation of the desmosomes,
thereby promoting desquamation. 37
Antiwrinkle cosmeceuticals
Wrinkle is one of the key features of aging skin, including
photoaging and chronological aging. 38 The exact pathogenesis
of wrinkle is not fully understood yet. Changes in the
dermis are most prominent in aged skin. Aged dermis has
fragmented elastic fibers, decreased collagen, and disproportionate
types I and III collagens. At the bottom of a wrinkle,
type IV collagen is decreased. Glycosaminoglycans, especially
hyaluronic acid, are decreased. Collagen damage is
attributed to several types of collagen-degrading enzymes
known as matrix metalloproteinases (MMPs). Metalloproteinases
activation can result in production of collagenase,
gelatinase, and stromelysin. The degradation of elastins
might also be caused by MMP-2. 30
Paeoniflorin (PF), partially purified from roots of Paeonia
lactiflora, protected cells from DNA damage induced by
UV-B irradiation in cultured normal human keratinocytes
and hairless mouse keratinocytes. It was also revealed that
0.5% PF-containing formulation reduced facial wrinkles
during an 8-week clinical trial. These results suggest that
the partially purified PF has potent antiaging and antiwrinkle
activities, and should be a useful ingredient for
these purposes. 39
It was found that Morinda citrifolia fruit extract upregulated
biosynthesis of type I collagen and glycosaminoglycans
in primary cultures of normal human fibroblasts. 1,4-
Dihydroxy-2-methoxy-7-methylanthraquinone, an active
ingredient with a type I collagen–stimulating effect, was
isolated and identified from M. citrifolia fruit. It was
revealed that anthraquinone showed significantly increased
elaboration of type I procollagen C-terminal peptide and
glycosaminoglycans, and reduced expression of the collagenase
MMP-1 dose dependently in human dermal fibroblasts.
Furthermore, a nanoemulsion containing anthraquinone
predominantly increased the dermal type I procollagen in

Efficacy and safety of innovative cosmeceuticals
nude mouse skin. These results suggest that anthraquinone
derived from M. citrifolia fruit extract is a good candidate for
a novel antiwrinkle agent. 40
The inner shell of the chestnut has been used as an
antiwrinkle or skin-firming agent in East Asia. A 70%
ethanol extract from this plant can prevent cell detachment of
skin fibroblasts from culture plates, possibly through
enhancing the expression of the cell-associated fibronectin
and vitronectin. Scoparone (6,7-dimethoxycoumarin), isolated
from the extract of inner shell of the chestnut, possessed
similar properties. These findings underline the usefulness of
these substances as antiwrinkle/skin-firming agents. 41
Dimethylaminoethanol (DMAE) is an analog of the B
vitamin choline and is a precursor of acetylcholine. In a
randomized clinical study, 3% DMAE facial gel applied
daily for 16 weeks has been shown to be safe and efficacious
in the mitigation of forehead lines and periorbital fine
wrinkles, and in improving lip shape and fullness and the
overall appearance of aging skin. Application was well
tolerated; an open-label extension of the trial showed that the
long-term application of DMAE gel for up to 1 year was
associated with a good safety profile. The benefits of DMAE
may include a potential anti-inflammatory effect and an
increase in skin firmness with possible improvement in
underlying facial muscle tone. 42
Ubiquinone (coenzyme 10) is present in almost all
living cells, excluding some bacteria and fungi. It is a
strong antioxidant in cells. Ubiquinone can suppress UV-
A–induced production of collagenase in fibroblasts and,
thus, protect from the UV-A–induced degradation of
collagen. It can also retard loss of hyaluronic acid, increase
levels of glycosaminoglycan, and slowdown cell division. 16
Ubiquinone can penetrate into the viable layers of the
epidermis. Topical use of ubiquinone could reduce the
depth of wrinkle. 43
Sunscreens and antiphotoaging cosmeceuticals
Exposure of skin to UV irradiation can cause acute
inflammatory changes, such as erythema, edema, and subsequently
pigmentation or tanning, and chronic changes, such as
photoaging, immunosuppression, or photocarcinogenesis.
Sunscreens are intended to counteract these detrimental effects
of UV through direct blocking of light or by absorbing UV
radiation. Many substances are commonly used in cosmetics,
such as para-aminobenzoic acid derivatives, cinnamates,
salicylates, octocrylene, and ensulizole as UV-B filter, and
benzophenones, butyl methoxydibenzoyl, and meradimate as
UV-A filter. Still, many other ingredients from different
sources are tested as candidates in a cosmeceutical, including
calcitriol, caffeic acid, polyphenols compound, isoflavones,
and so on, as excellently reviewed by Kullavanijaya and
Lim. 44 The common adverse effects of sunscreens are irritant
or allergic dermatitis and comedogenicity.
371
There are 2 distinct types of aging. One is intrinsic aging,
which is the natural aging process. The other is extrinsic
aging, which is caused by environmental factors such as
repetitive facial expressions, gravity, sleeping positions,
smoking, and, above all, exposure to the sunlight. The
commonly seen features of intrinsic aging are fine wrinkles,
thin and transparent skin, hollowed cheeks and eye sockets,
loss of firmness on the hands and neck, sagging, dry skin that
may itch, inability to sweat sufficiently, graying hair that
eventually turns white, and hair loss. Extrinsic factors,
especially sun exposure, often act together with the normal
aging process to cause skin aging prematurely. Photoaging is
the term especially reserved to describe extrinsic aging
caused by sun exposure. Photoaging is often featured by age
spots, spider veins on the face, rough and leathery skin, fine
wrinkles that disappear when stretched, loose skin, a blotchy
complexion, solar elastosis, actinic keratoses, and skin
cancer. In photoaged skin, the epidermis has thinning of
stratum spinosum and flattening of the dermoepidermal
junction. Decrease in the numbers of melanocytes and
dysregulation of melanocyte density result in guttate hypoor
hypermelanosis and a blotchy complexion. The number of
Langerhans cells also decreases, and the cells have less
dendrites. There are thickened, tangled, and degraded
nonfunctional fibers in the dermis. 45 The interaction between
collagen fibers and fibroblast is also decreased. 46 In an
experimental study, chronic UV-A irradiation of normal
human fibroblasts induced shortening of the cellular life span
and an increase of cellular diameter; MMP-1 was overexpressed
after repeated UV-A irradiation. 47
Photoaged skin has variable manifestations produced by
changes of different cellular or noncellular components of
the skin and caused by different mechanisms. It is difficult to
invent a cosmeceutical with multifunctions to meet all the
needs. Some of the aforementioned cosmeceuticals, such as
depigmenting, moisturizing, and antiwrinkle cosmeceuticals,
have the potency to relieve part of photoaging signs. The
following describes some agents that might be of potential
antiphotoaging properties.
Sesamol is a highly acclaimed antioxidant. An experiment
on mouse skin showed that it has a good effect on prevention
of photodamage, observed on biochemical and histopathologic
changes. 48
Several topically applied retinoids, such as tretinoin,
isotretinoin, retinaldehyde, and tazarotene, have been proven
clinically and histologically effective for treating the
appearance of photoaging. Adverse effects are also documented
as irritant reaction of variable intensity presenting
with dryness, scaling, and erythema. 49 Alitretinoin (9-cisretinoic
acid) is a naturally occurring endogenous retinoid. It
has the ability to bind and activate all known intracellular
retinoic acid receptors, which might promote the repair
mechanisms in damaged skin. A small-scale clinical trial
showed that topical alitretinoin gel 0.1% was well tolerated
by participants and showed improvement of benign skin
lesions (eg, seborrheic keratoses) and precancerous lesions

372 X.-H. Gao et al.
(eg, actinic keratoses). 50 Large, blinded, controlled trials are
needed to investigate the role of this novel retinoid in the
treatment of photoaging.
Genistein is a soybean isoflavone with diverse biologic
activities. It substantially inhibits skin carcinogenesis and
cutaneous aging induced by UV light in mice and photodamage
in humans. The mechanisms of action involve
protection of oxidatively and photodynamically damaged
DNA, down-regulation of UV-B–activated signal transduction
cascades, and antioxidant activities. 51 Clinical trials are
required to further substantiate its clinical applications.
A newly formulated vitamin C complex having 10%
ascorbic acid (water soluble) and 7% tetrahexyldecyl
ascorbate (lipid soluble) in an anhydrous polysilicone gel
base was tested to one half of the face and the inactive
polysilicone gel base to the opposite side. The effects were
evaluated clinically and histologically. A statistically
significant improvement of the vitamin C–treated side
was seen in the decreased photoaging scores of the cheeks
and the perioral area. Biopsies showed increased Grenz
zone collagen, as well as increased staining for messenger
RNA for type I collagen. No patients were found to have
any evidence of irritation and inflammation during the
12-week trial. 52
Green tea polyphenol inhibits the activity of collagenase
and increases collagen biosynthesis rate of human fibroblasts.
Table 1 Examples of some cosmeceutical ingredients (in alphabetical order)
Ingredients Purported action Source
AHAs Exfoliation and improving circulation Fruit acids (glycolic acid, lactic acid,
citric acid, titanic acid, pyruvic acid,
maleic acid, etc)
Allantoin Soothing the skin Comfrey root
Aloe vera power Softening the skin Aloe vera
α-Lipoic acid Free radical scavengers and antioxidant Plants and animals
Arjunolic extract Antioxidant and anti-inflammation Terminalia arjuna
β-Bisabolol Anti-inflammation, antibacteria Chamomile flower
β-Hydroxy acids Antibacteria Plants
Boswellic acids Anti-inflammation and antiaging Boswellia serrata
Calendula oil Soothing, softening, and cell renewal Calendula officinalis
Centella extracts
Skin conditioning, increasing collagen production, Centella asiatica
improving texture and integrity of skin
Coenzyme Q10 (ubiquinone) Cellular antioxidants Naturally occurring in skin
Coleus forskohlii oil Antimicrobial, aromatherapy/perfume C. forskohlii
Coriander seed oil Anti-inflammation, skin lightening Coriandrum sativa
Dry extract from yarrow Treatment of oily hair Achillea millefolium
Essential fatty acids Smoothening, moisturizing, and protection Linoleic, linolenic, and arachidonic acids
Furfuryladenine Improve hydration and texture of skin Plant growth hormone
Ginkgo extracts Antioxidants, smoothing, rejuvenation of skin Ginkgo biloba
Green tea extract Antiaging and antioxidants Green tea
Horse chestnut extract
Supporting blood circulation, wound healing,
Aesculus hippocastanum
and anti-inflammation
Kinetin Free radical scavenger and antioxidant Plants and yeast
Licorice extract
Skin whitening, antioxidant, antimicrobial,
Glycyrrhiza glabra
and anti-inflammation
Lupeol Antioxidant and skin conditioning Cratacva nurvula
Neem oil limonoids Antimicrobial Azadirachta indica
Oleanolic extract Antioxidant, improving texture and integrity of skin Olive leaf
Panthenol Moisturizing and soothing skin Provitamin B 5
Pycnogenol Antiaging Grape seed
Retinoids
Smoothing, promoting cell renewal, and improving
circulation of skin
β-Carotene derivatives or synthetic
compounds with similar mechanisms
of action
Rosemary extract Antioxidants, anti-inflammation Rosemarinus officinalis
Sodium hyaluronate Lubricant, natural moisturizer Natural protein
Tetrahydrocurcuminoides Antioxidant and antiaging Curcuma longa
Turmeric oil Antibacterial and inflammation C. longa
Ursolic acid Anti-inflammatory, collagen building up R. officinalis
Vitamins A, E, and C
Antioxidants
Witch hazel Tones Hamamelis virginiana

Efficacy and safety of innovative cosmeceuticals
It can also inhibit tyrosinase activity. It was interesting to note
that after irradiation at 40 kGy by γ-ray, the abovementioned
effects were all unregulated. 53 Green tea polyphenol or green
tea could protect UV-induced DNA damage in a variety of
cell types, including skin fibroblasts and keratinocytes. When
green tea was taken orally, it also showed photoprotective
effects manifested as low DNA damage of peripheral blood
cells. 54,55 Orally taken green tea or green tea polyphenols
have mild adverse effects, such as excess gas, upset stomach,
nausea, heartburn, abdominal pain, dizziness, headache, and
muscle pain. 56 Though it looks likely that green tea might be a
suitable candidate for antiaging, so far, there have been no
convincing reports on the evaluation of topical use of green
tea or its derivatives on skin. It should be kept in mind that
green tea polyphenols are highly unstable and easily oxidized
in ambient environment. Formulary of green tea polyphenols
as active ingredients in topicals, therefore, remains a
challenge in the cosmeceutical industries.
N-Furfuryladenine is a cytokinin growth factor that can
be obtained from a variety of sources, such as plants, parts
of animals, and even human urine. 57 In the presence of
calcium, it could promote differentiation of human
keratinocytes. 58 It could also inhibit oxidative and glycoxidative
protein damage in vitro, and Fenton reaction–
mediated oxidative damage to DNA. 59,60 Cosmetic products
containing N(6)-F-furfuryladenine have been developed
and marketed for a couple of years. A randomized,
blinded, and controlled clinical trial is needed to evaluate its
efficacy and safety.
Conclusions
The essence of innovative cosmeceuticals is their
functional active ingredients. Hundreds of substances have
been screened, synthesized, and tested (as exampled in
Table 1), 2,16 and many have been included in commercially
available products, for example, chamomile and soy. Prudent
measures should be taken on clinical trials of cosmeceuticals
because the interaction between skin and cosmeceuticals
could be influenced by environmental factors as temperature,
humidity, pollution, microbial, light, and so on. In addition,
the desired functions of a cosmeceutical might require a
coordinating action of multiple ingredients. Moreover, there
are problematic skin conditions that might change the
interactive pattern and outcome between cosmeceuticals
and skin. Scientific clinical evaluation is a must for research,
development, and application of cosmeceuticals.
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