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How Much Do We Really Know About Our Favorite Cosmeceutical Ingredients?

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To date, we are unaware of a review that has investigated common cosmeceutical ingredients in order to answer the three specific questions proposed by the father of cosmeceuticals, Dr. Albert Kligman. It is the goal of this review to gather all the published scientific data on five common cosmeceutical ingredients, answer the three major questions about the scientific rationale for their use, and ascertain how much we really know about consumers' favorite cosmeceutical ingredients.Most of the research concerning cosmeceutical retinoid ingredients is based upon the effects of retinoic acid on the skin. Clinical trials concerning retinol and retinaldehyde are scant and lacking in statistical evaluation for significance. There is research substantiating the effects of kinetin in plants and also in-vitro antioxidant effects. However, proof of anti-aging activity remains elusive, and the clinical efficacy of kinetin is based on limited data. Niacinamide is the ingredient investigated that most closely upholds the "Kligman standards" of cosmeceutical-ingredient analysis. With the available scientific evidence on topical niacinamide, clinicians are able to adequately answer questions about permeability, mechanism, and clinical effect. Both green tea and soy have been popularized commercially based on their antioxidant effects, yet there is a paucity of clinical studies concerning their efficacy as topical anti-aging agents. It may be that soy and green tea are better at preventing the signs and symptoms of skin aging than actually reversing them. Since cosmeceutical products are claiming to therapeutically affect the structure and function of the skin, it is rational and necessary to hold them to specified scientific standards that substantiate efficacy claims.
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[February 2010 • Volume 3 • Number 2]
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QUESTIONS • CHALLENGES • CONTROVERSIES
Abstract
To date, we are unaware of a review
that has investigated common
cosmeceutical ingredients in order to
answer the three specific questions
proposed by the father of
cosmeceuticals, Dr. Albert Kligman. It
is the goal of this review to gather all
the published scientific data on five
common cosmeceutical ingredients,
answer the three major questions
about the scientific rationale for their
use, and ascertain how much we really
know about consumers’ favorite
cosmeceutical ingredients.
Most of the research concerning
cosmeceutical retinoid ingredients is
based upon the effects of retinoic acid
on the skin. Clinical trials concerning
retinol and retinaldehyde are scant
and lacking in statistical evaluation for
significance. There is research
substantiating the effects of kinetin in
plants and also in-vitro antioxidant
effects. However, proof of anti-aging
activity remains elusive, and the
clinical efficacy of kinetin is based on
limited data. Niacinamide is the
ingredient investigated that most
closely upholds the “Kligman
standards” of cosmeceutical-ingredient
analysis. With the available scientific
evidence on topical niacinamide,
clinicians are able to adequately
answer questions about permeability,
mechanism, and clinical effect. Both
green tea and soy have been
popularized commercially based on
their antioxidant effects, yet there is a
paucity of clinical studies concerning
their efficacy as topical anti-aging
agents. It may be that soy and green
tea are better at preventing the signs
and symptoms of skin aging than
actually reversing them. Since
cosmeceutical products are claiming to
therapeutically affect the structure
and function of the skin, it is rational
and necessary to hold them to
specified scientific standards that
substantiate efficacy claims.
Introduction
Increasingly, patients are looking for
cost-effective noninvasive methods to
improve the appearance of their skin.
Many patients are turning away from
prescription medications and medical
procedures and are instead
considering over-the-counter (OTC)
treatments, such as cosmeceuticals.
Factors that cause patients to switch
to OTC products include lack of
adequate insurance coverage for
prescription products used to treat
photoaging, the need to pay for
physician visits to obtain prescription
products, and failure to discern “fiction
from fact” related to unsubstantiated
claims made by some OTC anti-aging
skin care products. A cosmeceutical
product by definition is a cosmetic
product in which the active ingredient
is meant to have a beneficial
physiological effect due to an
enhanced pharmacological action
when compared with an inert
cosmetic.1
Every day in clinical practice,
dermatologists see patients who ask
them if cosmeceutical products are
beneficial. Accurate advice is a
challenge that requires knowledge of
the structure and function of human
skin and the available scientific data,
which may or may not support the
efficacy of a given cosmeceutical
product. As dermatologists, it is very
hard for us to keep up with the latest
evidence on the popular cosmeceutical
ingredients due to the vastness of
ingredients, the multitude of
commercially available products and
their efficacy claims, and the validity
or accuracy of data gleaned from in-
vitro and clinical studies, if available.
What questions need to be asked
when scientifically evaluating the
potential therapeutic merits of a
cosmeceutical?
According to Dr. Albert Kligman,
when asked to evaluate a new
cosmeceutical product that claims a
beneficial physiological effect, it is
important to ask three questions:
1. Can the active ingredient penetrate
the stratum corneum (SC) and be
delivered in sufficient
concentrations to its intended
target in the skin over a time course
consistent with its mechanism of
action?
2. Does the active ingredient have a
known specific biochemical
mechanism of action in the target
cell or tissue in human skin?
QUESTIONS • CHALLENGES • CONTROVERSIES
Section Editor: James Q. Del Rosso, DO, FAOCD
How Much Do We Really
Know About Our Favorite
Cosmeceutical Ingredients?
Jacquelyn Levin, DO; James Q. Del Rosso, DO, FAOCD;
Saira B. Momin, DO
[February 2010 • Volume 3 • Number 2] 23
2323232323
3. Are there published, peer-reviewed,
double-blind, placebo-controlled,
statistically significant, clinical trials
to substantiate the efficacy claims?1
(Table 1.)
To date, we are unaware of a review
that has investigated common
cosmeceutical ingredients in order to
answer these three specific questions.
It is the goal of this review to gather
the available published scientific data
on five common cosmeceutical
ingredients, to answer the three major
questions described above, and to
ascertain how much we really know
about our consumers’ favorite
cosmeceutical ingredients.
The first question addresses
whether the active ingredient
penetrates the SC. The SC is an
effective barrier to transepidermal
water loss (TEWL) and to the
penetration of exogenous substances.
Typically, the substances that cannot
penetrate the SC easily include:
proteins, sugars, peptides and nucleic
acids with molecular weights greater
than approximately 1000kDa, and
highly charged molecules.1
In addition, it is important to
determine if the ingredient is delivered
in sufficient concentrations to its
intended target in the skin to produce
the desired effect. The minimum
concentration of ingredient required to
produce the desired effect is termed
the threshold concentration and is
important for evaluating cosmetic
formulas.
If the agent meets the first
criterion, that is penetration of the SC
in an amount exceeding the threshold
concentration, the second question
follows intuitively. The second
question asks if there is a known
biochemical or pharmacological
mechanism of action for this active
ingredient to substantiate the
marketing claim. Most
pharmacologically active ingredients
have mechanisms of action on cellular
components that regulate
physiological functions (i.e., inhibition
or activation of enzymes involved in
signal transduction or gene
expression).2Surprisingly, some
popular cosmeceutical ingredients
have mechanisms that are currently
unknown and require further research.
If a viable biochemical or
pharmacological mechanism of action
exists, and the product can reach its
target at sufficient concentrations for a
long enough duration, the product
deserves further clinical
experimentation, preferably a
randomized, double-blind, vehicle-
controlled clinical trial.
Clinical trials should include the use
of noninvasive instrumentation, which
measures characteristics such as
TEWL, corneometry, skin elasticity,
colorimetry, surface replica analysis,
and other techniques that can be used
to assess efficacy claims. Pretreatment
and post-treatment photography alone
are not adequate because there are
major pitfalls in standardized clinical
photography. In addition, it is difficult
to measure appearance clinically
because it is highly subjective and
endpoints are difficult to establish.
The pitfalls of published clinical trials
to date are that many of the reports
are anecdotal, have been performed
on small groups of patients, and
statistical significance has not been
well established.
Another way to demonstrate the
effects of a product is histology. The
histological changes of photoaged skin
are well documented. Demonstration
of reversal of histological features of
photoaging is another approach to
substantiate efficacy claims for the
reversal of photoaging.3
This next section presents a
summary of the published scientific
data of five popular cosmeceutical
ingredients. Specifically, this article
reviews the evidence on penetration of
the SC, the mechanism of action, and
the anti-aging effects on skin based on
clinical studies.
What background information is
available on cosmeceutical
retinoids?
Retinoids consist of natural and
synthetic derivatives of vitamin A that
can be found in both prescription
medications and OTC cosmeceuticals.
Retinoic acid (RA) as well as the
synthetic napthalene derivatives
adapalene, tazarotene, and bexarotene
are registered prescription drugs. The
topical cosmeceutical retinoids include
retinyl esters, retinol, retinaldehyde,
and the group of oxoretinoids.4
RA has been extensively studied
and used as an effective topical
treatment for photoaging, acne, and
numerous other dermatological
disorders. RA can, however, be
irritating to the skin, limiting its use in
some patients. Retinol (ROL) and
retinaldehyde (RAL) are of interest to
the scientific community and cosmetic
industry as gentler yet still effective
alternatives to RA. However, the other
cosmeceutical retinoids, retinyl
palmitate and retinyl-acetate, are
retinoid esters and are not considered
effective against photoaging and
therefore are not discussed in this
review.4,5
In the skin, ROL is oxidized into
RAL, which in turn is oxidized into
RA, the biologically active form of
vitamin A. Topical cosmeceuticals
containing ROL and RAL are
theoreticized to work because once
absorbed they are metabolized to RA,
which induces pharmacological
activity. Given this consideration, not
only is the percutaneous absorption
profile of ROL and RAL important to
its effectiveness, but the metabolism
of ROL and RAL to RA is just as
important.
QUESTIONS • CHALLENGES • CONTROVERSIES
[February 2010 • Volume 3 • Number 2]
24242424242424
What data is available on the
percutaneous absorption and
metabolic activity of retinoids?
In general, retinoids are lipophilic
molecules that can penetrate the
epidermis.6One study demonstrated
the specific penetration characteristics
of ROL and RAL in human skin in
vivo by measuring levels of the skin
enzyme cytochrome P-450-dependent
RA 4-hydroxylase (CP450-RAH)
(Table 2A).7The enzyme CP450-RAH
is induced by presence of RA in the
skin and therefore its induction can be
used as an indicator of ROL and RAL
penetration and metabolism to RA.
The study found a significant
induction in this enzyme following
topical application of ROL and RAL to
human skin in vivo. After 48 hours of
occlusion, both ROL and RAL (0.025%
and greater) increased the enzyme
activity significantly while lower
concentrations did not cause
significant induction.7Interestingly, the
increase in enzyme induction was not
linear and higher doses of ROL and
RAL only caused small increases in
enzyme activity. However, it should be
noted that at lower doses (0.01% and
0.025%), RAL was a greater inducer of
CD450-RAH than ROL.7Given the
results of this study, it seems the
threshold concentration for adequate
penetration and metabolism of RAL
and ROL into RA is 0.025%. Hence, it
is important that the concentration of
RAL and ROL in cosmetic formularies
be at least 0.025%. However, it must
also be considered that concentrations
above 0.025% may not induce greater
penetration or metabolism to RA.
In another experiment, metabolism
of ROL, RAL, and RA was studied
utilizing in-vitro human skin and
dermal fibroblasts.8Radiolabeled ROL
and RAL were applied either topically
to the skin biopsies or to the culture
media of the fibroblast suspension and
the metabolites were identified by
high-performance liquid
chromatography (HPLC) after 24
hours of incubation. The skin cultures
demonstrated a gradient distribution
of the retinoids within the skin: 75
percent of absorbed activity was in the
epidermis, 20 percent in the dermis,
and 2 to 6 percent in the culture
medium for the three retinoids tested.
Of the epidermal extracts, 60 percent
of applied ROL remained
unmetabolized. The main ROL
metabolites in the epidermis were
retinyl esters (18.5%), RA (2%), RAL
(1.6%), 13-cis-retinoic acid (1%), and
polar compounds. The dermis yielded
similar metabolites, but a higher
proportion of polar compounds. RAL
was also metabolized in the epidermis,
with 43 percent of the absorbed
radioactivity being RAL, 9 percent
retinyl esters, 14 percent ROL, and 0.8
percent RA.8
Collectively, several studies have
therefore demonstrated an absorption
and metabolic capacity for topical ROL
and RAL.7,8 Retinyl esters appear to be
the major metabolite, while the
formation of RA from these substances
constitutes a small proportion of the
metabolites formed. However, whether
this conversion is sufficient for
pharmacological activity is unknown.
In-vivo studies may better quantify
both metabolism and dose-response
relationships.6
What are the potential mechanisms
of action of retinoids?
ROL and RAL are metabolized to
RA in the skin and therefore, are
assumed to exhibit the same
mechanism and clinical effects as RA
(Table 2B). Of these effects, the
surface roughness, mottled
hyperpigmentation, and fine wrinkles
demonstrate the most significant
improvement with RA therapy.9
Although ROL- and RAL-containing
cosmeceuticals have not been shown
to produce the magnitude of clinical
results obtained with the prescription
products that are approved and used
to treat photoaging (tretinoin,
tazarotene), many consumers appear
to be pleased with their cosmetic
results anecdotally.
Hyperpigmentation. RA is
thought to reduce mottled
hyperpigmentation by enhancing
epidermal cell turnover. Enhancing
epidermal cell turnover decreases the
contact time between keratinocytes
and melanocytes and promotes a rapid
loss of pigment through
epidermopoiesis.10
Fine lines and wrinkles. RA
therapy reduces fine lines and
wrinkles by increasing the capacity of
the epidermis to hold water through
stimulation of glycosaminoglycan
(GAG) synthesis and by stimulating
collagen synthesis through increases in
transforming growth factor (TGF-
beta) and procollagen.9–12 Furthermore,
it is believed that RA may also retard
or prevent further dermal matrix
degradation by inhibiting the enzymes
QUESTIONS • CHALLENGES • CONTROVERSIES
TABLE 1. Three major questions used to evaluate cosmeceutical ingredients1
QUESTION 1 Can the active ingredient penetrate the stratum corneum and be
delivered in sufficient concentrations to its intended target in the skin?
QUESTION 2 Does the active ingredient have a known specific biochemical
mechanism of action in the target cell or tissue in human skin?
QUESTION 3 Are there published, peer-reviewed, double-blind, placebo-controlled,
statistically significant, clinical trials to substantiate the efficacy claims?
[February 2010 • Volume 3 • Number 2] 25
25
that break down collagen and
preventing oxidative stress.11,13–17
Roughness. RA therapy reduces
skin roughness by modulating the
expression of genes involved in cellular
differentiation and proliferation, hence
promoting epidermal cell turnover.9,11
The effects are believed to be
mediated through binding to retinoic
acid receptors (RAR) and subsequent
binding of these complexes to specific
genes affecting gene transcription.18,19
What clinical studies are available
on cosmeceutical retinoids?
There are extensive clinical trials
investigating the anti-aging effects of
topical RA (Table 2C). RA is
considered to be one of most effective
and well-substantiated compounds for
treating the signs and symptoms of
aging and/or photodamaged skin,
including fine lines, hyperpigmented
spots, and wrinkles.10,20,21 However, few
studies have been reported for the
OTC retinoids. Here, the authors
present the results of studies
investigating the anti-aging effects of
RAL and ROL.
Some studies have reported that
RAL can produce significant clinical
improvement in the appearance of fine
and deep wrinkles.10,22 In one study, the
efficacy of RAL 0.05% cream for the
treatment of photoaging was
compared to 0.05% RA and vehicle
creams over an 18-week time period.22
A total of 125 patients (40 in the RA
group, 40 in the RAL group, and 45 in
the vehicle group) were studied. This
study demonstrated that RAL can
produce clinical improvement in fine
and deep wrinkles.22 However,
statistical significance was not
reported and no intra-individual
comparisons were made.
Topical ROL has been shown in
vivo to have only a modest effect
compared with topical RAL and RA
while two randomized controlled trials
showed a significant improvement in
fine wrinkles after 12 and 24 weeks of
treatment with the use of ROL versus
placebo.10,23 One of the randomized,
controlled trials was completed by
Sorg et al10 who evaluated the
effectiveness of topical ROL in
improving the clinical signs of naturally
aged skin in a randomized, double-
blind, vehicle-controlled, left and right
arm comparison study.10 The study
population comprised 36 elderly
subjects (mean age 87 years) residing
in two senior citizen facilities. Topical
0.4% ROL lotion or its vehicle was
applied at each visit by study
personnel to either the right or the left
arm, up to three times a week for 24
weeks. Clinical assessment was made
by using a semiquantitative scale and
TABLE 2A. Summary of penetration data
INGREDIENT DOES IT PENETRATE?*
Retinoids
Retinoids are lipophilic molecules that penetrate the epidermis.6
Penetration of ROL and RAL investigated
in vivo
by measuring
levels of the skin enzyme CP450-RAH with results showing
significant penetration and metabolism of ROL and RA.7
Metabolism of ROL, RAL, and RA was studied using
in-vitro
human skin and dermal fibroblasts. Radiolabeled ROL and RAL
were applied to skin biopsies or to a culture media of the
fibroblasts. Metabolites were identified by HPLC. Analyses
demonstrated a gradient distribution of the retinoids within the
skin and metabolism of ROL and RAL to RA (2% and 0.8%,
respectively).8
Kinetin No published studies found to date on permeation alone.
Niacinamide
Studies demonstrate significant penetration into human skin.48,49
Increased levels of NAD have been used as evidence of
percutaneous penetration.50
Soy isoflavones
Results demonstrate that the ionized form of soy isoflavone
has lower percutaneous absorption compared to non-ionized
form of soy.98,99
Results showed that soy can permeate through the SC and can
reach viable layers of the epidermis and dermis.95,96
Soy protease
inhibitors No published studies found to date on permeation alone.
Green tea
EGCG is inherently hydrophilic, limiting its penetration in
human skin.113
No published studies found to date on permeation alone
*Common abbreviations: AGE (Advanced glycation end products), BBI (Bowman-Birk
Inhibitor), CP450-PAH (cytochrome P-450-dependent RA 4-hydroxylase), DNA
(deoxyribonucleic acid), EGCG (epigallocatechin gallate), GAG (glycosaminoglycans), GSH
(glutathione), GST (glutathione-S-tarnsferase), H2O2(hydrogen peroxide), HPLC (high
performance liquid chromatography), NAD (niacinamide adenosine dinucleotide), RA
(retinoic acid), RAL (retinaldehyde), ROL (retinol), ROS (reactive oxygen species), SC
(stratum corneum), SOD (superoxide dismutase), STI (soybean trypsin inhibitor), TEWL
(transepidermal water loss), TGF-B (transforming growth factor-beta), UV (ultraviolet light)
QUESTIONS • CHALLENGES • CONTROVERSIES
[February 2010 • Volume 3 • Number 2]
26
TABLE 2B. Summary of mechanisms of action and clinical significance
INGREDIENT WHAT IS THE MECHANISM?* DOES IT SHOW CLINICAL SIGNIFICANCE?*
RETINOIDS
1. Decrease fine lines and wrinkles
• By decreasing the activity of enzymes that break down
collagen, increasing GAG synthesis, and increasing collagen
synthesis by increasing TGF-B and procollagen synthesis9–17
2. Decrease hyperpigmentation
• By increasing epidermal cell turnover which decreases the
amount of contact between melanocytes and keratinocytes10
3. Decrease skin roughness
• By promoting epidermal cell turnover. RA binds to retinoic
acid receptors (RAR) which then binds to specific genes. This
affects the transcription of genes which promote epidermal
cell turnover18–19
0.05% RAL vs. 0.05% RA vs. vehicle in 125 patients over 18
weeks in a nondouble-blind and nonrandomized study. This
study reported that RAL can produce significant clinical
improvement in fine and deep wrinkles however specific
significance (the
p
value) was not reported and no
intra-individual comparisons were made.22
0.4% ROL vs. vehicle in a randomized, double-blind, vehicle-
controlled, left and right arm comparison study in 36 elderly
patients three times a week for 24 weeks. Clinically, ROL
improved fine wrinkling with significance (
p
<0.001).
Histologically, biopsies showed ROL significantly increased
GAG expression (
p
=0.02 [n = 6]) and procollagen I (
p
=0.049
[n=4]).10
KINETIN
1. Delay aging in fibroblasts
• Delays alteration in cell size and shape, growth rates,
cytoskeletal structure, macromolecular synthesis, and
quantity of lipofuscin associated with aging in
in-vitro
human
fibroblasts. However, the exact mechanism remains elusive. 23
2. Antioxidant effects
• By inhibiting the formation of ROS and acting as free radical
scavenger. Specifically, it activates both SOD and catalase
expression and mimics SOD’s antioxidant activity. Also,
prevents the oxidation of unsaturated fatty acids and DNA
and prevents the oxidation and glycation/glycoxidation of
proteins. Therefore inhibiting the formation of AGE
products.28,29,35–38
Kinetin lotion (0.01%–0.1%) used twice daily for 24 weeks
on 96 subjects. Results showed improvement in skin texture,
color, blotchiness, fine wrinkles, and skin barrier function.
Average improvements ranged from 17–63% over baseline.39
Kinetin 0.03% + niacinamide 4% vs. niacinamide 4% on
Asian skin. Both products showed an improvement in
hyperpigmentation, blotchiness, and hydration status, but the
combination product had significantly better results.
Therefore, possibly indicating the role of kinetin in the
formula.26,27
NIACINAMIDE
1. Antioxidant effects
• Niacinamide increases the reduced forms of NAD(P), which
have potent antioxidant properties.53–55
2. Improves epidermal barrier function
• Evidenced by reduced TEWL and an increase in the skin’s
resistance to potential harmful topical agents. Proposed
mechanisms include increased synthesis of ceramides via
upregulation of serine palmitoyltransferase, the rate-limiting
enzyme in sphingolipid synthesis, and stimulating
keratinocyte differentiation via an influence on keratin K1,
which results in an increase in epidermal turnover.56–59
3. Decreases yellowing of skin
• Through its antioxidant capabilities, niacinamide inhibits
oxidative processes, such as protein oxidation, glycation, and
the Maillard reaction, which produces Amadori products.
Amadori products are yellowish-brown in color and
accumulate in skin matrix components, like collagen,
in response to oxidative stress as we age.65–68
4. Decreases erythema and blotchiness
• Increasing barrier function may result in less irritation when
the skin encounters environmental insults and hence less
redness. This theory has not been substantiated.50,60–61
5. Decreases fine lines and wrinkles
• By reducing GAGs and increasing dermal collagen and
protein production (i.e., keratin, fillagrin, and
involucrin).51,58,66,69
6. Hyperpigmentation
• Reduces melanosome transfer from melanocytes to
surrounding keratinocytes. One study showed that 5% niaci-
namide moisturizer provided 35–68 percent inhibition of
melanosome transfer from melanocytes to keratinocytes.71
Analysis by multiple angle reflectance spectrophotometer
demonstrated that 2.5% niacinamide resulted in smoother
skin surface compared to vehicle alone (
p
<0.05).59
3.5% niacinamide cream was compared with placebo for four
weeks and demonstrated a 14.8% reduction in skin
roughness (
p
=0.05).56,74,75
In a randomized, double-blind, split-face, placebo-controlled,
clinical trial, 50 white females applied 5% niacinamide and
vehicle twice daily for 12 weeks. Results showed significant
improvement in fine lines and wrinkles, hyperpigmentation,
redness, yellowing, and skin elasticity (
p
<0.05).51
This study using niacinamide 5% and niacinamide 2% +
UVB/UVA sunscreen moisturizer reported reduced facial
hyperpigmentation in Japanese women.56
In a randomized, split-faced trial, 5% niacinamide was used
on 18 Japanese women vs. vehicle. Pigmentation change was
evaluated qualitatively and quantitatively using high resolution
digital images and subjective judgments. After 8 weeks, there
was significant lightening of hyperpigmentation on the side
treated with niacinamide compared to vehicle (
p
<0.05).56
QUESTIONS • CHALLENGES • CONTROVERSIES
[February 2010 • Volume 3 • Number 2] 27
TABLE 2B (Continued). Summary of mechanisms of action and clinical significance
INGREDIENT WHAT IS THE MECHANISM?* DOES IT SHOW CLINICAL SIGNIFICANCE?*
SOY ISOFLAVONES
1. Antioxidant effects
• By raising cellular GSH content (
p
<0.05) and GST activity (
p
<0.05),
decreasing H2O2formation (
p
<0.05), and preventing DNA degradation
(
p
<0.01).101
2. Phytoestrogen effect
• Couples with estrogen receptors in the cell’s nucleus.104 Therefore may
have a similar potential to retard skin thinning and collagen loss
comparable to topical estrogen formulas.116
3. Increases collagen synthesis
• One study demonstrated
in vitro
that genistein was able to increase
collagen (COL1A2) gene expression in human fibroblasts.112
• One study showed genistein was able to stimulate collagen levels in
human dermal fibroblasts.111
4. Increases glycosaminoglycans (GAG)
• Increases levels of GAG, specifically hyaluronic acid, in aging skin.114,115
No published
in-vivo
human clinical trials
found to date with greater than 50 patients.
SOY PROTEASE
INHIBITORS
1. Decreases hyperpigmentation
• STI and BBI inhibit the keratinocyte protease-activated receptor 2
(PAR-2). Inhibition of PAR-2 decreases
keratinocyte-melanocyte contact hence decreasing the
transfer of melanosomes into the keratinocytes.116–121
STI and BBI was used on 65 women with
moderate facial photodamage in a 12-week
vehicle-controlled study. Efficacy was
measured by clinical evaluation, colorimetry,
digital photography, and self assessment.
Results showed improved mottled
pigmentation, blotchiness, dullness, fine
lines, overall texture, overall skin tone, and
overall appearance. Differences were
significant (
p
<0.05) from Week 2 to Week 12
for all above parameters (except dullness
which started at Week 4).83
GREEN TEA
1. Antioxidant effects
• By quenching the following ROS: singlet oxygen, superoxide radical,
hydroxyl radical, hydrogen peroxide, and peroxyl radical.133–138 In addition,
by limiting UV-induced lipid peroxidation and reducing the oxidation of
proteins
in vitro
.139,140
2. Anti-inflammatory effects
• By down regulating nuclear transcription factor-kappa B (NF-kB).
NF-kB up-regulates transcription of pro-inflammatory mediators, such as
interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha.143
3. Decreases collagen breakdown
• Down-regulates transcription factors activator protein 1 (AP-1).
AP-1 is responsible for production of metalloproteinases, which break
down collagen.132
4. Photoprotectant effect
• Green tea shows dose-dependent inhibition of UV-induced erythema
likely due to its antioxidant and anti-inflammatory effects.150
Randomized, double-blind, 8-week trial on 40
women with moderate photoaging used
300mg green tea supplements and applied
green tea cream twice daily vs. placebo.
Subjects were graded based on wrinkling,
roughness, skin laxity, and pigmentation.
There were no statistically significant clinical
improvements; however, an improvement in
the elastic tissue content of treated
specimens (
p
<0.5) was observed upon
histological examination of skin biopsies.152
*Common Abbreviations: AGE (advanced glycation end products), BBI ( Bowman-Birk Inhibitor), CP450-PAH (cytochrome P-450-dependent
RA 4-hydroxylase ), DNA (deoxyribonucleic acid), EGCG (epigallocatechin gallate), GAG (glycosaminoglycans) , GSH (glutathione), GST
(glutathione-S-tarnsferase) , H2O2(hydrogen peroxide), HPLC (high performance liquid chromatography), NAD (niacinamide adenosine
dinucleotide), RA (retinoic acid), RAL (retinaldehyde), ROL (retinol), ROS (reactive oxygen species), SC (stratum corneum), SOD (superoxide
dismutase), STI (soybean trypsin inhibitor), TEWL (transepidermal water loss), TGF-B (transforming growth factor-beta), UV (ultraviolet light)
QUESTIONS • CHALLENGES • CONTROVERSIES
biochemical measurements from skin
biopsy specimens. After 24 weeks,
there were significant differences
between ROL-treated and vehicle-
treated sides for fine wrinkling scores
(p<0.001). In addition, histology
showed ROL treatment significantly
increased GAG expression (p=.02 [n =
6]) and procollagen I (p=0.049 [n = 4])
compared with vehicle. This data
provided support that topical ROL
improves fine wrinkles via its
metabolism to RA and subsequent
increases in GAGs and collagen
production.
What conclusions can be drawn
from data on cosmeceutical
retinoids?
After sunscreens, many believe
topical retinoids are the most
important drug class to combat and
reverse the signs of aging. With more
than two decades of experimentation,
there is a vast amount of evidence that
regular retinoid use over several
months results in clinical improvement
in skin texture, wrinkles, and
pigmentation.24 However, most of this
knowledge and experience is about
prescription products containing RA
and not about OTC retinoids, ROL and
RAL. Of the limited data available
concerning OTC retinoids, RAL seems
to be the most efficacious.10,22
Therefore, those patients who are
looking to decrease and or prevent the
signs of aging without use of a
prescription product should use RAL
containing cosmeceuticals as they
have the best scientific evidence
supporting their efficacy in reducing
the signs and symptoms of aging.
So what do we tell our patients
concerning retinoid cosmeceuticals?
The authors have presented sufficient
evidence on cutaneous penetration
and concerning mechanism of action
and semi-sufficient evidence on the
clinical anti-aging effects of ROL and
RAL. They believe it is important to
remind the patients that while the
most effective anti-aging treatment is
achieved with prescription retinoids,
there is some evidence to support the
use of RAL and ROL to decrease fine
lines and wrinkles.
What is kinetin (N-furfuryladenine
growth factor)?
Kinetin is an essential plant growth
hormone that regulates aspects of
growth and differentiation, retards leaf
yellowing and senescence, and slows
down fruit ripening and
degeneration.25,26
What data is available on the
percutaneous absorption of kinetin?
The authors were unable to find
any studies investigating the
percutaneous absorption of kinetin.
However, kinetin has been shown to be
nonirritating to the skin, easily
formulated, chemically stable, and
compatible with other formulation
components.27
What are the potential mechanisms
of action of kinetin?
Kinetin is shown to exert its anti-
aging effects in different systems
including plants, fruit flies, and
cultured human skin fibroblasts.28–31
Studies on human fibroblasts in vitro
have demonstrated that kinetin may
have the ability to delay the onset of
age-related changes as well as
decrease the severity of these
changes.23 These age-related changes
include the alteration in cell size and
shape, growth rates, cytoskeletal
structure, macromolecular synthesis,
and quantity of lipofuscin. The delay of
age-related cellular characteristics
were most pronounced in cultures
where kinetin was continuously
present. It was noted that some aging
characteristics began to reappear upon
removal of kinetin, and youthful
characteristics in general were better
maintained in younger cells compared
to older cells. This suggests that
continued use of kinetin is necessary
to maintain results and that there may
be additional benefit to starting kinetin
at a younger age.32 However, the
mechanism by which kinetin exerts its
effects on human fibroblasts remains
elusive.
Antioxidant effects. Investigators
have surmised that the mechanism of
action that results in age retardation
may involve the genes that influence
aging and may involve kinetin acting as
both an inhibitor of reactive oxygen
species (ROS) formation and a
[February 2010 • Volume 3 • Number 2]
28
TABLE 2C. Levels of evidence for substantiation of clinical data
INGREDIENT LEVEL OF EVIDENCE*
Retinoids B
Kinetin B
Niacinamide A
Soy isoflavones
Soy protease inhibitors A
Green tea B
*Level A: High-quality randomized, controlled trial (RCT) that considers all important
outcomes. High-quality meta-analysis using comprehensive search strategies. Level B: A
well-designed, nonrandomized, clinical trial. A nonquantitative systemic review with
appropriate search strategies and well-substantiated conclusions. Includes lower quality
RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study
participants and consistent findings. Level C: Consensus viewpoint or expert opinion
QUESTIONS • CHALLENGES • CONTROVERSIES
scavenger of ROS.28,33 Many studies
have shown kinetin to be a powerful
antioxidant. Kinetin has the ability
to mimic superoxide dismutase
(SOD) activity, activate both SOD
and catalase expression, and quench
ROS.28,29,35,36 Also, kinetin has been
shown to prevent the oxidation of
unsaturated fatty acids and inhibit
the in-vitro oxidation of DNA.36,37
Also, Verbeke et al38 demonstrated
that kinetin can inhibit the oxidation
and glycation/glycoxidation of
proteins. By inhibiting the oxidation
and glycation/glycoxidation of
proteins, kinetin inhibits the
formation of advanced
glycation/glycoxidation end
products (AGE). These results
strengthen the view that kinetin is a
powerful antioxidant with significant
biological properties and useful
potential for the prevention of
oxidative damage.38
Other effects. Although clinical
studies of topical kinetin have
suggested improvement in skin
texture, a decrease in
hyperpigmentation, and a decrease in
TEWL, there appears to be no
reported mechanisms for how kinetin
improves skin texture, fine wrinkles,
hyperpigmentation, and/or the SC
permeability barrier.
What clinical studies are available
on kinetin?
One open-label study about the
clinical safety and efficacy of kinetin
0.1% lotion on human skin was
published by McCullough et al.39
Ninety-six subjects with
photodamaged skin showed
improvement in the categories of skin
texture, color, blotchiness, and fine
wrinkles after 24 weeks of twice-daily
application of 0.01%, 0.05%, or 0.10%
kinetin. Average improvements ranged
from 17 to 63 percent over baseline. In
addition, the results of this study
suggest that kinetin improves barrier
function of the SC, as evidenced by a
mean decrease in TEWL after 14
weeks of use. Hence, this
demonstrated that topical kinetin
(0.01%–0.1%) can partially improve
some of the clinical signs of mild-to-
moderately photodamaged skin, such
as skin texture, fine wrinkles, skin
color, and blotchiness, and can help
restore normal skin barrier function
with 12 to 24 weeks of topical
application.39
Another study investigated the anti-
aging effects of topical kinetin 0.03%
in combination with niacinamide 4%
versus niacinamide 4% alone in Asians.
Amasino et al26 found that the
combination of kinetin and
niacinamide and niacinamide alone
effectively improved many of the facial
aging signs in Asians. This combination
of ingredients reduced the number of
hyperpigmented spots and red
blotchiness as well as increased SC
hydration status with more persistence
than the formula containing
niacinamide alone. The authors believe
that this indicates a decisive role for
kinetin in the formulation and that
kinetin plus niacinamide may be used
as an adjunctive therapy for anti-aging
purposes of the skin.27
What conclusions can be drawn
from data on kinetin?
In summary, kinetin is a relatively
new ingredient in the cosmeceutical
world with anti-aging potential given
its anti-aging role in plants and its in-
vitro antioxidant effects. In order to
recommend kinetin, the authors feel
that the scientific evidence supporting
kinetin is still lacking in permeation
studies and mechanistic discoveries as
to how this growth factor reduces
hyperpigmentation, improves skin
barrier function, and improves skin
texture. There is modest support of its
efficacy based on clinical studies.
What background information is
available on niacinamide and
nicotinic acid?
While the nutritional value of
niacin (vitamin B3) may be well
recognized, the skin care benefit of
topically applied niacin is a recent
discovery based on recently published
studies. Niacin (vitamin B3) has two
potential forms that can be used in
cosmeceuticals: niacinamide
[February 2010 • Volume 3 • Number 2] 29
TABLE 3. Summary for ingredient substantiation: Answering the three major questions
INGREDIENT DOES IT
PENETRATE?
DO WE KNOW HOW
IT WORKS?
DOES IT SHOW
CLINICAL
SIGNIFICANCE?
Retinoids Yes Yes Limited data
Kinetin No Partially Partially
Niacinamide Yes Yes Yes
Soy isoflavones Limited Data Yes No
Soy protease inhibitors No Yes Yes
Green tea Limited Data Yes No
QUESTIONS • CHALLENGES • CONTROVERSIES
(nicotinamide) and nicotinic acid. It is
debatable as to whether these two
forms of niacin are interchangeable as
topical cosmeceuticals. Some studies
claim that niacinamide and nicotinic
acid are readily converted into each
other in vivo40 while other studies
speculate that niacinamide and
nicotinic acid may have very different
pharmaceutical activities despite
having identical vitamin activities.41 In
other words, nicotinic acid may have
more benefits than topical
niacinamide on the skin due to the
fact that in addition to having the
vitamin effects on skin (increasing
levels of niacinamide adenosine
dinucleotide [NAD]), it may also have
drug-mediated effects on skin via
interacting with nicotinic acid
receptors present in the skin.41–44 Yet,
the disadvantage of using nicotinic
acid as a topical cosmeceutical is its
unpleasant side effect of vasodilation
that results in skin flushing. This is an
effect that is not harmful but
intensely disliked by most patients.45,46
In contrast to nicotinic acid,
niacinamide does not cause skin
flushing nor does it cause changes in
blood pressure, pulse, or body
temperature.47 Due to the decreased
number of side effects of topical
niacinamide compared to nicotinic
acid, the effects of niacinamide as a
topical cosmeceutical agent have
been studied more to date.
Niacinamide, also known as
nicotinamide, is the precursor of
important cofactors niacinamide
adenosine dinucleotide (NAD) and its
phosphate derivative, niacinamide
adenosine dinucleotide phosphate
(NADP). These cofactors and their
reduced forms (NADH and NADPH)
serve as reduction-oxidation (redox)
coenzymes in more than 40 cellular
biochemical reactions. Thus,
niacinamide has the potential to exert
multiple effects on skin and is a
promising anti-aging cosmeceutical
ingredient.
What data is available on the
percutaneous absorption of
niacinamide?
Feldmann et al48 highlighted the
possibilities for the topical application
of niacinamide because they were able
to prove sufficient percutaneous
penetration into human skin.48,49 In
addition, several other studies have
used increased levels of NAD in skin
cells after the topical application of
niacinamide as evidence of
percutaneous penetration.50
What are the potential mechanisms
of action of niacinamide?
Studies have shown that
niacinamide has the potential to act as
an antioxidant, can improve epidermal
barrier function, decrease skin
hyperpigmentation, reduce fine lines
and wrinkles, decrease
redness/blotchiness, decrease skin
yellowness (sallowness), and improve
skin elasticity.51,52 The mechanisms by
which niacinamide provides this array
of skin benefits is not completely
understood, but the role of
niacinamide as a precursor to the
NADP family of coenzymes may play a
significant role in all of these
improvements.50
Antioxidant capacity.
Niacinamide increases the antioxidant
capacity of skin after topical
application by increasing the reduced
forms (NADPH), which have potent
antioxidant properties.53–55 This is
probably the most well-studied anti-
aging effect of niacinamide.
Epidermal barrier function.
Niacinamide may improve the skin
barrier function in two ways: first, by
its ability to upregulate the synthesis
of ceramides as well as other SC
intercellular lipids, and second, by
stimulating keratinocyte
differentiation.56,57 Ceramides and other
intercellular SC lipids are known to
play a central role in the structural and
functional integrity of the epidermal
barrier function. The responsible
mechanism for the increase of
ceramide synthesis in niacinamide-
treated, cultured keratinocytes was
found to be based on the upregulation
of serine palmitoyltransferase, the
rate-limiting enzyme in sphingolipid
synthesis. The increase in ceramide
synthesis has been confirmed in an in-
vivo trial after topical application of
2% niacinamide emulsion for four
weeks applied twice daily.56 The
elevation of ceramides after treatment
with niacinamide is associated with an
improved barrier function as
evidenced by a reduced TEWL and an
increase in the cutaneous resistance to
potential harmful topical agents.56 The
second mechanism likely responsible
for improved barrier function is a
stimulation of keratinocyte
differentiation seen both in cell
cultures in vitro and in-vivo studies
conducted by Tanno et al.56,57 In cell
cultures, more rapid keratinocyte
differentiation following treatment
with niacinamide was established.56 In
particular, it was possible to determine
an influence on keratin, K1. K1 is a
basic keratin synthesized mainly in the
lowest layers of the stratum spinosum.
The functional limitations of aging skin
include reduced “turnover of the
epidermis” (i.e., a slower epidermal
cell cycle) due to a deficiency of
NADP in aging cells.58,59 Tanno et al
also demonstrated an in-vivo
improvement in epidermal barrier
function with improved keratinocyte
differentiation after the application of
topical niacinamide. Once again, the
improved barrier function was evident
by a decrease in TEWL and increase in
SC moisture content. Similar results
were also obtained by Ertel et al.57 In
conclusion, it seems that topical
[February 2010 • Volume 3 • Number 2]
30
QUESTIONS • CHALLENGES • CONTROVERSIES
application of niacinamide increases
NADP levels, which in turn stimulates
keratinocyte differentiation. This
results in a thicker SC, which is not
only associated with an improved
barrier, but is also associated with
greater hydration retention capacity in
the SC.59
Erythema and blotchiness. The
mechanism by which
redness/blotchiness is improved may
be related to the improved skin barrier
function for reasons discussed
above.50,60,61 Increased barrier function
may mean less irritation and redness
when the skin encounters
environmental insults, such as
detergents and soaps, and hence less
reddening of the skin. However, this
theory has not been substantiated.
Yellowing of skin. The yellowing
of skin that comes with aging may be a
result of glycation of proteins in the
skin called the Maillard reaction. The
Maillard reaction is a spontaneous
oxidative reaction between protein
and sugar that results in cross-linked
proteins (Amadori products) that are
yellowish-brown in color and are
fluorescent.62–64 These proteins can
accumulate in the skin matrix
components, similar to collagen, in
response to oxidative stress as we age.
Published data show a fivefold
increase in collagen oxidation products
in human skin from age 20 to 80.65
Since NADH and NADPH are
antioxidants and their levels can be
increased with niacinamide, a possible
effect of topical niacinamide is
inhibition of oxidative processes, such
as protein oxidation, glycation, and the
Maillard reaction, and hence the
inhibition of skin yellowing.66–68
Fine lines and wrinkles. Multiple
mechanisms may be involved in the
ability of niacinamide to reduce the
appearance of fine lines and wrinkles.
The first to consider is that
niacinamide may have the ability to
increase dermal collagen and protein
production. The development of
wrinkles is a result of the decrease in
epidermal cell layers and dermal
components from a reduction in
protein and collagen synthesis.
Reduced protein synthesis is reflected
in the levels of keratin, fillagrin, and
involucrin in the skin. Keratin
deficiency has an effect on the
epidermal cell structure and its water-
binding capacity. Fillagrin is an
antecedent of natural moisturizing
factor (NMF) and hence affects skin
hydration. Involucrin is seen as
significant for the cell envelope and
structure of the SC. In summary, the
effects of reduced collagen and protein
synthesis are poor skin structure and
reduced skin elasticity as well as a
decrease in epidermal barrier function
with a reduction in SC hydration. In
studies on cell cultures, Oblong et al58
found that in aging cells it was possible
to prove that niacinamide, as a
precursor of NAD/NADP, stimulated
collagen synthesis and the epidermal
proteins keratin, fillagrin, and
involucrin.51,58 In addition, another
study was able to show niacinamide’s
ability to increase dermal matrix
collagen production.66
The second mechanism that may be
relevant to decreasing the appearance
of wrinkles is the ability of niacinamide
to reduce excess dermal
glycosaminoglycans (GAGs). This is a
controversial theory because both the
elevation and depletion of dermal
GAGs are associated with
photodamaged or wrinkled skin.52,69
What is known is that the presence of
GAGs is required for normal structure
and function of the dermal matrix and
increasing the levels of GAGs can
increase the moisture content of skin.
Testing has indicated that niacinamide
reduces excess production of GAGs in
old human dermal fibroblasts, thus
supporting the potential involvement
of this mechanism in reducing the
appearance of fine lines and
wrinkles.51,70 Given the above analysis
and scientific data, it seems more
likely that an increase in dermal
proteins (including collagen) may play
a bigger role in reducing fine lines and
wrinkles than decreasing the level of
GAGs.
Hyperpigmentation. Topical
niacinamide may be effective in
decreasing epidermal
hyperpigmentation and reducing
pigmented spots as we age.71
Hakozaki et al71 showed that the
reduction of cutaneous pigmentation,
surprisingly, was not due to the direct
influence of niacinamide on melanin
synthesis by melanocytes. Instead,
they showed that niacinamide
reduced melanosome transfer from
melanocytes to surrounding
keratinocytes in a co-culture system,
although the specific mechanism
remains unknown.71 This was
supported by a study using 5%
niacinamide moisturizer, which
provided 35 to 68 percent inhibition
of melanosome transfer from
melanocytes to keratinocytes.71
What clinical studies are available
on niacinamide?
Tanno et al56 showed a reduction in
pigmentation as a result of
niacinamide. Eighteen Japanese
women with hyperpigmentation were
treated on one side of the face with
5% niacinamide and on the other side
with vehicle only. The pigmentation
change was evaluated qualitatively
and quantitatively using high-
resolution digital images and
subjective judgments. In both forms
of evaluation, it was found that after
eight weeks of treatment there was
significant lightening of
hyperpigmentation on the side
treated with niacinamide when
compared with the effect of the
[February 2010 • Volume 3 • Number 2] 31
QUESTIONS • CHALLENGES • CONTROVERSIES
vehicle (p<0.05).56
In a separate study also reported by
Tanno et al performed with 120
Japanese women, comparisons were
made among a sun protection factor
(SPF) 15 cream with and without 2%
niacinamide and the relevant vehicle.
As a result of niacinamide treatment,
there was a lightening of the skin after
four and six weeks, which was noted
to be markedly better than the formula
without niacinamide.56
It is theoreticized that niacinamide
may improve the texture of skin by
speeding up epidermal turnover hence
functioning as a mild exfoliant.72 Using
a multiple angle reflectance
spectrophotometer in an in-vivo test
of the back of the hand, Matts and
Solenick73 established a beneficial
effect for the topical application of
niacinamide in smoothing the skin
surface structure. This study
demonstrates that the long-term
application of 2.5% niacinamide can
correct the skin surface damage that
results from aging. These results were
statistically significant compared with
the influence of the vehicle alone
(p<0.05).59 In agreement with the
above, another clinical trial using 3.5%
niacinamide cream was compared with
placebo for four weeks and
demonstrated a 14.8-percent
reduction in skin roughness
(p=0.05).56,74,75
One of the best randomized, double-
blind, split-face, placebo-controlled,
clinical trials published on the anti-
aging effects of topical niacinamide was
done by Bissett et al.51 In this study, 50
white females with clinical signs of
photodamage applied 5% niacinamide
to half of the face and its vehicle
control to the other half twice daily for
12 weeks. Analyses of the data
revealed a variety of effects related to
improvements in skin appearance for
topical niacinamide including
reductions in fine lines and wrinkles,
hyperpigmented spots, red blotchiness,
skin sallowness, and improvement in
skin elasticity.51 Matts and Solenick
later confirmed the results of Bissett et
al with 5% and 2% niacinamide.59 The
results also demonstrated that the anti-
aging effects of niacinamide were dose
dependent.
What conclusions can be drawn
from data on niacinamide?
The topical use of niacinamide for
anti-aging has proven to be effective
not only when there are signs of a
niacin deficiency. Despite the recent
discovery of the cosmetic benefit of
niacin for the skin, there have been
sufficient studies completed to answer
all three “Kligman questions.” It is the
opinion of the authors that
niacinamide is one of the best studied
cosmeceutical ingredients for anti-
aging. However, further research is
required to uncover the specific
mechanisms of niacinamide in the skin
and to optimize the concentration of
niacinamide in cosmeceutical
formulations.
Is there additional information on
nicotinic acid?
As mentioned earlier, a major
obstacle in the topical delivery of
therapeutic amounts of nicotinic acid
to any tissue is its ability to cause a
peripheral vasodilation that leads to a
skin flushing response. While this
effect is not harmful, it is intensely
disliked by most patients.45,46 This issue
may be avoided by using the long
chain ester derivative of nicotinic acid,
myristyl nicotinate (MN), which is able
to deliver large amounts (in
concentrations near 5%) of nicotinic
acid without flushing.76,77
The advantage of using nicotinic
acid over niacinamide is its drug-
mediated effect on skin as a result of
its ability to interact with nicotinic acid
receptors present in the skin.42–44
Nicotinic acid receptors are G protein
coupled receptors that when
stimulated lead to an increase in skin
leptin, which in turn activates several
signaling pathways to enhance
epidermal differentiation and stimulate
wound healing.78,82
In a clinical study by Jacobson et
al,76 MN increased skin cell NAD by 25
percent (p=0.0001) demonstrating
effective delivery. Relative to placebo,
MN treatment of photodamaged facial
skin increased SC thickness by
approximately 70 percent (p=0.0001)
and increased epidermal thickness by
approximately 20 percent (p=0.001).
In two separate studies, MN treatment
increased rates of epidermal renewal
by six (p=0.003) to 11 percent
(p=0.001) and increased the minimal
erythemal dose by 8.9 (p=0.07) and
10 percent (p=0.05) relative to
placebo. MN treatment also resulted
in reductions in the rates of TEWL of
approximately 20 percent relative to
placebo on cheeks and arms of study
subjects.
The above data demonstrates that
topical nicotinic acid preparations
can enhance epidermal
differentiation and barrier function,
suggesting that it may be effective in
the treatment of photodamaged skin
and other conditions (such as atopic
dermatitis) with skin barrier
impairments. However, it is hard to
compare these results with the
results presented above on
niacinamide since not all of the same
attributes were monitored (such as
redness, yellowing, wrinkling, etc).
Further investigation is needed to
compare the efficacy of MN to
niacinamide. Both niacinamide and
nicotinic acid have significant
numbers of published studies to
answer all three major questions to
date. However, there is more data
available on the anti-aging effects and
mechanisms of topical niacinamide.
[February 2010 • Volume 3 • Number 2]
32
QUESTIONS • CHALLENGES • CONTROVERSIES
What background information is
available on soy?
Soybeans are known to contain
many components with biological
activity in the skin.83 The major
components of soy are phospholipids
(45–60%) and essential fatty oils
(30–35%) while the minor
components include the most active
compounds, such as isoflavones and
the proteases soybean trypsin inhibitor
(STI) and Bowman-Birk inhibitor
(BBI).84–86 In this review, the authors
will focus on the effects of topical
isoflavones and their ability to reduce
ROS, stimulate collagen synthesis,
increase moisture in the skin and also
the proteases STI and BBI,83,87–94 and
reduce skin hyperpigmentation.
What data is available on the
percutaneous absorption of soy?
The most plentiful isoflavones in
soy are genistein and daidzein. The
permeation of isoflavonoids through
the skin barrier is poorly investigated.
However, the data that is available
indicates that the compounds of this
group can permeate through the SC
and can reach viable layers of the
epidermis and dermis.95,96 The
permeation rate of soy through the SC
is dependent upon the isoflavonoid’s
structure and vehicle composition.97 In
general, the ionized form of a
compound has lower percutaneous
absorption compared to non-ionized
form. This is due to the lipophilic
nature of the SC.98,99 This theory
explains why genistein in a completely
neutral condition (pH 6) shows higher
skin accumulation compared to the
ionized form (pH 10.8). The same
result was observed for permeation
profiles of daidzein.
What are the potential mechanisms
of action of soy?
Soy has been purported to exhibit a
few potential modes of action, which
may correlate with topical treatment
of photoaging.
Antioxidant effects. Free radical
formation plays a crucial role in aging
skin.100 A clinical study by Sharma et
al101 found that soy isoflavones
(genistein and daidzein) have a
fourfold mechanism of action to fight
oxidative process in the skin.101 In this
study, soy isoflavones were shown to
raise cellular glutathione (GSH)
content and glutathione S-transferase
(GST) activity (p<0.05), prevent
antioxidant enzyme depletion,
decrease H2O2formation (p<0.05),
and prevent ornithine decarboxylase
(ODC) induction and DNA
degradation (p<0.01). Given the wide
array of antioxidant effects, the
authors speculate that soy isoflavones
may not act as antioxidants
themselves but instead affect cell
signaling processes that increase the
skin’s own antioxidant capabilities.
However, there is a lack of evidence
supporting soy isoflavones as a cell-
signaling molecule, and the antioxidant
nature of soy isoflavones cannot be
sidelined completely because of the
polyphenolic structure. Given its
structure, genistein can donate
hydrogen atoms to deleterious oxygen
free radicals and form less reactive
phenoxy radicals in the process.
Further research is required to
determine soy’s true antioxidant
mechanism in skin. However, the
topical application of soy isoflavones
has been shown to increase the
antioxidant capability of skin
compared to control via increases in
the four mechanisms mentioned
above. In one study, genistein was able
to decrease the H2O2increment in
human keratinocytes caused by
ultraviolet B rays by 71 percent and
daidzein almost completely inhibited
H2O2production by UVB. Daidzein was
expected to be a less effective
antioxidant due to its chemical
structure; however, this was not the
case in this present study.102 Thus, the
authors conclude that soy isoflavones
may have inhibitory activity against
oxidative damage and may be capable
of preventing the biochemical
alteration associated with aging.101
Phytoestrogen effects. The
primary metabolites of soy isoflavones,
genistein and daidzein, have been
identified in various studies in animal
and human cell cultures as
phytoestrogens. Phytoestrogens are
plant compounds with a weak
estrogenic effect. In soy, genistein and
daidzein are present as glycosides,
which do not have estrogenic activity,
and only upon conversion to their free
isoflavone form do they demonstrate
phytoestrogen activity.103
Phytoestrogens, just like estrogen,
work by coupling with estrogen
receptors (ERs) in the cell’s nucleus.
Two types of receptors, alpha and
beta, have been identified and both are
present in the skin.104 One study
demonstrated a higher affinity of
genistein for ER-beta;105 however,
another study reported a higher
affinity of genistein for ER-alpha
agonist activity.106 In comparison with
genistein, estradiol has 700-fold more
ER-alpha and 45-fold more ER-beta
activity.107 Even though phytoestrogens
are weak estrogens, soy may contain
as much as 1/1000 of its content as
phytoestrogens. Therefore, circulating
levels of phytoestrogens may be high
and the subsequent biological effect
may be great.
Several studies have shown that
postmenopausal women have a
measurably thinner dermis and less
collagen compared to premenopausal
women.108,109 Topical estrogen is able to
retard skin thinning and collagen loss
in postmenopausal women because
estrogen receptor levels are highest in
the granular layer of skin. Therefore,
the phytoestrogens, genistein and
[February 2010 • Volume 3 • Number 2] 33
QUESTIONS • CHALLENGES • CONTROVERSIES
daidzein, have a similar potential to
retard skin thinning and collagen loss
due to estrogenic stimulation.116
Further research is needed to compare
the estrogenic activity of whole soy
versus genistein and daidzein in their
free isoflavone form.
Collagen synthesis effects. In
other studies, soy isoflavones were
investigated for their potential to
stimulate collagen synthesis.111,112 One
study demonstrated in vitro that
genistein was able to increase collagen
(COL1A2) gene expression in in-vitro
human fibroblasts.112 Another study
tested four different formulas in terms
of their capacity to stimulate de novo
collagen synthesis.111 Depending on the
respective method of extraction, the
four formulas contained different
amounts of isoflavones. The isoflavone
daidzein did not elicit any effect, but
genistein was able to stimulate
collagen levels in human dermal
fibroblasts (HDF). Interestingly, the
effect on collagen status did not
correlate with the isoflavone content
of the respective formulas. In other
words, the formula with the highest
amount of isoflavones did not display
the highest efficacy in terms of
collagen stimulation. In this study, the
specific soy extract that was the most
effective contained 10 to 12 percent
genistein. The authors speculate that
compounds other than isoflavones may
play an important role for the collagen
stimulatory effect. This fits well with
their observation that purified
isoflavones stimulated collagen
synthesis to a lesser extent than whole
topical soy. Therefore, it appears that
the pronounced collagen stimulation of
soy is only in part because of the
isoflavones genistein and daidzein and
other ingredients in soy, such as
saponins, may play a larger role.111
Potential effects on breast
cancer. Due to soy’s potential as a
phytoestrogen, there is some concern
regarding an increased risk of breast
cancer and uterine cancer with the use
of soy products. However, data
concerning this risk is contradictory.
On one hand, the majority of breast
cancers are estrogen dependent and
the use of phytoestrogens could
potentiate cancer cell growth, while on
the other hand, epidemiological data
suggest a protective effect of soy
against the development of cancer
(including breast cancer).113 The
authors of this review speculate that
soy’s protective effect may be due to
its antioxidant abilities while potential
carcinogenic ability may be related to
binding to estrogen receptors.
Although the amount of
phytoestrogens that are systemically
absorbed from a topical preparation is
likely very low, it would be prudent to
avoid these products in a person with
active breast cancer.116
Glucosaminoglycan effects.
Finally, it has been shown that soy
isoflavones can increase levels of GAG
and specifically hyaluronic acid (HA)
in aging skin although the exact
mechanism of action, as far as we are
aware, has not been discovered. HA is
an anionic, nonsulfated GAG
distributed widely throughout the skin.
Hyaluronic acid is important for tissue
repair and maintaining skin
hydration.111 It is widely accepted that
the HA content in skin, as well as all
the GAG content, declines with
age.114,115 Given the importance of HA
for connective tissue overall, and the
proven decline of HA in aged skin,
there appears to be a necessity for
compounds that stimulate HA
production in aging skin. More
research needs to be completed to
demonstrate the efficacy of soy in
stimulating HA synthesis and how
clinically this increase in HA affects
the appearance of skin.
Hyperpigmentation. Soybean
trypsin inhibitor (STI) and Bowman-
Birk protease inhibitors (BBI) in soy
milk exhibit depigmenting activity and
prevent UV-induced pigmentation in
vitro and in vivo. It has been shown
that STI and BBI inhibit the
keratinocyte protease-activated
receptor 2 (PAR-2), which is involved
in the regulation of pigmentation.116–121
PAR-2 is expressed on keratinocytes
and has been shown to increase
keratinocyte phagocytosis.117,118 Several
in-vitro and preclinical investigations
have demonstrated that the
modulation of PAR-2 activation
facilitates keratinocyte-melanocyte
contact and therefore enhances the
transfer of melanosomes into the
keratinocytes and produces reversible
depigmentation.116,119
What clinical studies are available
on soy?
Recently, a topical soy formulation
was developed containing
nondenatured STI and BBI.122 This is
important because STI in particular is
inactivated by heat and the processing
of soybeans and soy milk can destroy
their therapeutic effects, including
depigmenting activity.123 Preliminary
in-vivo human studies support the
skin-lightening effect of nondenatured
soy extracts.122,124–126 A study by Wallo et
al83 investigated the efficacy of a novel
soy moisturizer containing
nondenatured STI and BBI for the
improvement of skin tone,
pigmentation, and other photoaging
attributes.83 Sixty-five women, with
moderate facial photodamage, were
enrolled in the 12-week, parallel,
vehicle-controlled study. Efficacy was
measured by clinical evaluation,
colorimetry, digital photography, and
self assessment. Improvement of skin
tone was clinically defined as a
reduction in mottled
hyperpigmentation, lentigines, and
blotchiness, with an increase in skin
brightness (i.e., reflection of light from
skin’s surface). Improvement of skin
texture was defined as a reduction in
the surface roughness and/or an
[February 2010 • Volume 3 • Number 2]
34
QUESTIONS • CHALLENGES • CONTROVERSIES
improvement in fine lines and
wrinkling. The results showed that the
novel soy moisturizer was significantly
more efficacious than the vehicle in
improving mottled pigmentation,
blotchiness, dullness, fine lines, overall
texture, overall skin tone, and overall
appearance. Differences were marked
from Week 2 to Week 12 for all above
parameters (except dullness, which
started at Week 4).83
Given STI and BBI’s efficacy for
treating hyperpigmentation, one might
consider using whole soy for the
treatment of melasma. Currently, there
are conflicting views as to whether soy
should be used to treat patients with
melasma. On the one hand, one study
found that treatment with topical soy
twice daily for 12 weeks was shown to
be effective for the treatment of
melasma.127 On the other hand, high
levels of estrogen have been shown to
cause melasma and since soy has
estrogen receptor bind capacity, it may
be advisable to avoid soy in patients
with melasma. Obviously further
research is required; however, it
should be noted that the isolated
constituents of soy STI and BBI do not
contain phytoestrogenic abilities and
may be a good option for the
treatment of melasma.
What conclusions can be drawn
from data on soy?
All three of the “Kligman questions”
are adequately answered for soy’s
protease inhibitor depigmentation
effects. However, soy isoflavones,
despite all the research into its
antioxidant effects is lacking in-vivo,
human, clinical trials with greater than
50 patients to prove the efficacy of soy
isoflavones efficacy as an anti-aging
topical cosmeceutical.
Given that there are two active
ingredients in soy, isoflavones and
protease inhibitors, there appears to
be a need for specific labeling of
topical soy products. As a physician
evaluating a product, it is important to
know whether the product contains
whole soy, the isoflavones genistein
and daidzein, or soy protease
inhibitors STI and BBI in the
nondenatured form.
What background information is
available on green tea?
White, green, and black teas are
derived from the leaves and buds of
the tea plant (camellia senensis), with
different varieties dependent on the
type of processing and antioxidation or
fermentation.128,129 Black tea is the most
processed (fermented), while white tea
recently replaced green tea as the least
processed. The main active ingredients
in green tea are polyphenols, also
known as catechins, which include
epicatechin, epicatechin-3-gallate
(ECG), and epigallocatechin-3-gallate
(EGCG).128,129 The largest catechin and
most active antioxidant in any tea is
EGCG. Green tea has the highest
concentration of EGCG.130
Polyphenols comprise 30 to 35
percent of the dry weight of the green
tea leaf.107 These polyphenols are
believed to have anti-aging effects
through decreasing inflammation and
acting as a scavenger of free radicals.
In addition, compounds found in green
tea have been shown to influence
biochemical pathways important in cell
synthesis and responses of tumor
promoters.131 In this review, the
authors focus on the antioxidant and
anti-inflammatory attributes of green
tea, as these are the factors that most
contribute to green tea’s potential as
an anti-aging cosmeceutical.
What data is available on the
percutaneous absorption of
green tea?
The formulary of green tea
polyphenols as active ingredients in
topical products remains a challenge in
the cosmeceutical industry. Green tea
polyphenols, as with most
antioxidants, are highly unstable and
easily oxidized in an ambient
environment. Equally difficult is
ensuring that the active ingredient
penetrates the epidermis and that it
stays in the skin long enough to exert
its desired effect. EGCG is inherently
hydrophilic, limiting its penetration in
human skin. Thus, green tea extract is
among the more difficult botanicals to
formulate.132 Only when these
formulation challenges are met can
this topical antioxidant be effective.
After reviewing available product
information, it appears that there is
little standardization regarding the
minimal concentration of green teas in
cosmeceuticals, and many products
lack active ingredient characterization.
Some authors feel that 5% green tea
extract is an effective concentration.132
However, the flaw in this logic is that it
is the amount of green tea polyphenols
and not the amount of green tea in a
product that should be considered
when evaluating a product. Many
authors recommend products that
contain polyphenols in the 90-percent
range, which turns the product brown.
This brown color does not indicate
that the product has oxidized, as is the
case when vitamin C products
darken.53,116
What are the potential mechanisms
of action of green tea?
Tea polyphenols have been shown
to exhibit antioxidant and anti-
inflammatory activities, which may
potentially exert clinical benefits.
Antioxidant activity. Tea
polyphenols are strong antioxidants.133
The polyphenols in tea have
demonstrated the ability to quench the
following ROS: singlet oxygen,
superoxide radical, hydroxyl radical,
hydrogen peroxide, and peroxyl
radical.133–138 In addition, tea
polyphenols have been shown to limit
UV-induced lipid peroxidation in skin
and reduce the oxidation of proteins in
[February 2010 • Volume 3 • Number 2] 35
QUESTIONS • CHALLENGES • CONTROVERSIES
a free radical-generating system in
vitro.139,140
Anti-inflammatory and collagen
synthesis effects. Free radicals are
known to promote oxidation of nucleic
acids, proteins, and lipids and can
damage intracellular structures
including DNA.141,142 Free radicals also
up-regulate transcription factors, such
as activator protein 1 (AP-1) and
nuclear transcription factor-kappa B
(NF-kB).132 AP-1 is responsible for
production of metalloproteinases that
breakdown existing collagen,
contributing to skin wrinkling.132 NF-kB
up-regulates transcription of pro-
inflammatory mediators, such as
interleukin (IL)-1, IL-6, IL-8, and
tumor necrosis factor-alpha.143 Acting
through the cell surface, these pro-
inflammatory mediators further
activate AP-1 and NF-kB, resulting in
more damage. It is the sum of these
events that are responsible for skin
aging.144
We now know that green tea and
EGCG in addition to being effective
free-radical scavengers, down-regulate
UV-induced expression of AP-1 and
NF-kB and suppress metalloproteinase
and age-related collagen cross-linking
in mice.139,145–149 In addition, it has been
shown in vitro that green tea
polyphenols inhibit the activity of
collagenase and increases collagen
biosynthesis rate of human
fibroblasts.91
Photoprotectant effects. Thus
taken together, a multitude of
scientific evidence exists supporting
the notion that green tea extract may
improve aging skin through its
antioxidant and anti-inflammatory
capabilities. These scientific theories
were put to the test in studies
published by Elmets et al.150 In their
study, human skin was pretreated with
either green tea extract or one of its
constituents and then exposed to two
minimal erythema doses of solar
stimulated light. Application of green
tea extract and/or one of its
constituents resulted in dose-
dependent inhibition of UV-induced
erythema. EGCG and ECG were the
most efficient components in
suppressing UV-induced erythema
when tested individually. It was also
shown that green tea extract can
reduce the DNA damage that occurs
after UV radiation through
mechanisms discussed above.107,132
Thus, it appears that topical
application of green tea extract and
some of its components may be useful
for mitigating the adverse effects of
sunlight on human skin, such as
photoaging.
In another study, topical green tea
was shown to provide photoprotection
anywhere from 24 hours up to 72
hours. It reduced the number of
sunburned cells by 66 percent when
applied 30 minutes prior to UVB
exposure and when applied at 1- to 10-
percent concentrations. A dose-
dependent inhibition of ultra-violet-
induced erythema was evident.150
Green tea extract also prevented
psoralen-UVA photodamage with pre-
and post-treatment by reducing
erythema, hyperplasia, and
hyperkeratosis.151
What clinical studies are available
on green tea?
To date, we are only aware of one
randomized, double-blind, controlled,
clinical trial involving topical green tea
extract. This study was completed by
Chiu et al152 and consisted of 40
women with moderate photoaging.
Eighteen subjects took 300mg green
tea supplements twice a day and
applied green tea cream twice daily;
whereas, the other 18 subjects used a
placebo cream and a placebo
supplement twice daily. All subjects
used the same sunscreen and cleanser.
Experts were blinded and subjects
were graded based on wrinkling,
roughness, course rhytids, skin laxity,
pigmentation, and other stigmata
associated with photoaging at baseline
and at eight weeks. At the end of eight
weeks, investigators found no
statistically significant clinical
improvements in women using the
green tea products. Because trends
toward improvement were seen in the
green tea group, investigators
postulate that a longer study might be
necessary to demonstrate efficacy.
However, an improvement in the
elastic tissue content of treated
specimens (p<0.5) was observed upon
histological examination of skin
biopsies.152
What conclusions can be drawn
from data on green tea?
Although it has been shown that
green tea is able to influence
mechanisms on skin that are beneficial
for anti-aging, via its antioxidant and
anti-inflammatory properties, there
has yet to be a clinical trial to show a
significant clinical improvement in the
signs of aging with the topical
application of green tea. Even so,
green tea products are widely used by
consumers despite the lack of
evidence. For this reason, a healthy
dose of skepticism is appropriate for
dermatologists regarding the
usefulness of many cosmeceuticals
touting green tea until a split-face,
double blind, randomized trial
involving several concentrations of
green tea extract or EGCG is
conducted.
Conclusion
The term cosmeceutical was
created to define a subgroup of topical
products with “drug-like” effects on
skin and to differentiate this subgroup
from purely cosmetic products and
topical prescription drugs. Since
cosmeceutical products are claiming to
affect the structure and function of
skin it makes sense then to hold
cosmeceutical products to higher
[February 2010 • Volume 3 • Number 2]
36
QUESTIONS • CHALLENGES • CONTROVERSIES
standards of scientific substantiation
than cosmetic products. In our
opinion, these higher standards should
include at minimum being able to
substantiate the three major questions
proposed by Dr. Albert Kligman, as
discussed earlier. Thus, there needs to
be a clear understanding that the
ingredient penetrates into skin, that it
has a defined mechanism of action,
and that it has specific clinical effects
with continued topical use.
As discussed here in this review,
even these five very popular
cosmeceutical ingredients fall short of
the “Kligman standards” for
cosmeceutical ingredients. Most of the
research concerning cosmeceutical
retinoid ingredients is based upon data
related to RAs effect on the skin, and
clinical trials concerning ROL and RAL
are scant and lacking in statistical
confirmation. Kinetin is supported by
research substantiating its effects in
plants and antioxidant effects in vitro,
yet its anti-aging mechanism of action
remains elusive. In addition, the
clinical efficacy of kinetin has only
been demonstrated with one study.
Niacinamide is probably the closest
ingredient investigated in this review
to satisfy the three major questions in
cosmeceutical ingredient analysis.
With the available scientific evidence
concerning the topical application of
niacinamide on skin, we are able to
adequately answer questions about
permeability, mechanism, and clinical
effect. Both green tea and soy are well
known for their antioxidant effects, yet
there is a conspicuous absence of
clinical studies concerning the efficacy
of soy and green tea as topical anti-
aging cosmeceutical ingredients. It
may be that antioxidants, such as soy
and green tea, are better at preventing
the signs and symptoms of aging than
actually reversing the signs of aging.
Perhaps clinical trials investigating the
prevention of aging would show better
efficacy for these two ingredients.
When evaluating a cosmeceutical
ingredient, it is important for
physicians to access the scientific
literature, not only in medicine, but
also in basic pharmacology and
biochemistry, to verify that the claims
made for active cosmeceutical
ingredients are backed by a well-
defined body of evidence. It was the
goal of this review to present and
analyze the research available on five
popular cosmeceutical ingredients as
to their ability to permeate the skin,
their mechanisms, and their clinical
effects. It is the authors’ hope that
physicians will be able to use the
information to answer patients’
questions concerning cosmeceutical
products with a clearer understanding
of what we really know about these
ingredients.
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QUESTIONS • CHALLENGES • CONTROVERSIES
Dr. Levin is from the Mohave Skin & Cancer Clinics, Dermatology Research Center, Las Vegas, Nevada; Dr. Del Rosso is
Dermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada; Dr. Momin is Chief Dermatology
Resident (PGY-4), Valley Hospital Medical Center, Las Vegas, Nevada.
Disclosure: Dr. Levin was a previous employee of and is a consultant to Guthy-Renker Corporation.
Drs. Del Rosso and Momin report no relevant conflicts of interest.
... 33 Soybean extract possess antioxidant properties and can suppress melanosome metastasis. 34 Extracts of Aloe (aloin et al) are known to exhibit moisturizing, anti-inflammatory, and antioxidant properties. They can also promote wound healing and inhibit tyrosine convert into DOPA. ...
... Titanium dioxide Sunscreening properties [20] Niacinamide Inhibiting melanogenesis through interfering with the interaction between keratinocytes and melanocytes, inhibiting melanin transfering by modulating the protease-activated receptor (PAR-2), antioxidant by increasing NADPH, improving the skin barrier function by upregulating the synthesis of ceramides and stimulating keratinocyte differentiation [23,34] Vitamin C Antioxidant, inhibiting tyrosinase through interaction with copper ions at tyrosinase active sites, dcreasing melanogenesis, UV-protective by neutralizing free radicals [24] Vaseline Moisturizing and recovering the skin barrier through AHR pathway [28,40] Tranexamic acid Anti-inflammatory and anti-angiogenic by suppressing of ET-1 [30] Resveratrol Direct and indirect tyrosinase inhibitor by decreasing transcription and post-transcriptional regulation, anti-inflammatory by activating PTEN/PI3K/AKT pathways, regulating inflammatory mediators and affecting arachidonic acid metabolism, UV Protectant through direct antioxidant effects and activation of the nuclear factor erythroid 2-related factor (Nrf2) pathway [31] Orchid extracts Phenolic compounds have antioxidant activities [32] Arbutin Reduces tyrosinase activity [33] Soybean extract Antioxidant through raising cellular glutathione content and glutathione S-transferase activity, preventing antioxidant enzyme depletion, decreasing H 2 O 2 formation, and preventing ornithine decarboxylase induction and DNA degradation, suppressing melanosome metastasis by inhibiting the protease-activated receptor (PAR-2) [34] Aloe extracts Moisturizing, anti-inflammatory by inhibiting cytokines, ROS production, and JAK1-STAT1/3 signaling pathway, antioxidant through free radical scavenging, metal chelation, and enzyme regulation, reducing the production of melanin by inhibiting the hydroxylation of tyrosine to DOPA and oxidation of DOPA, promoting wound healing by increasing cell migration via phosphorylation of Cdc42 and Rak1, cytokines, and growth factors [35,36] Extract of Camellia sinensis Moisturizing by reducing TEWL value, anti-inflammation by inhibiting the production of NO, PGE (2) and ...
... Titanium dioxide Sunscreening properties [20] Niacinamide Inhibiting melanogenesis through interfering with the interaction between keratinocytes and melanocytes, inhibiting melanin transfering by modulating the protease-activated receptor (PAR-2), antioxidant by increasing NADPH, improving the skin barrier function by upregulating the synthesis of ceramides and stimulating keratinocyte differentiation [23,34] Vitamin C Antioxidant, inhibiting tyrosinase through interaction with copper ions at tyrosinase active sites, dcreasing melanogenesis, UV-protective by neutralizing free radicals [24] Vaseline Moisturizing and recovering the skin barrier through AHR pathway [28,40] Tranexamic acid Anti-inflammatory and anti-angiogenic by suppressing of ET-1 [30] Resveratrol Direct and indirect tyrosinase inhibitor by decreasing transcription and post-transcriptional regulation, anti-inflammatory by activating PTEN/PI3K/AKT pathways, regulating inflammatory mediators and affecting arachidonic acid metabolism, UV Protectant through direct antioxidant effects and activation of the nuclear factor erythroid 2-related factor (Nrf2) pathway [31] Orchid extracts Phenolic compounds have antioxidant activities [32] Arbutin Reduces tyrosinase activity [33] Soybean extract Antioxidant through raising cellular glutathione content and glutathione S-transferase activity, preventing antioxidant enzyme depletion, decreasing H 2 O 2 formation, and preventing ornithine decarboxylase induction and DNA degradation, suppressing melanosome metastasis by inhibiting the protease-activated receptor (PAR-2) [34] Aloe extracts Moisturizing, anti-inflammatory by inhibiting cytokines, ROS production, and JAK1-STAT1/3 signaling pathway, antioxidant through free radical scavenging, metal chelation, and enzyme regulation, reducing the production of melanin by inhibiting the hydroxylation of tyrosine to DOPA and oxidation of DOPA, promoting wound healing by increasing cell migration via phosphorylation of Cdc42 and Rak1, cytokines, and growth factors [35,36] Extract of Camellia sinensis Moisturizing by reducing TEWL value, anti-inflammation by inhibiting the production of NO, PGE (2) and ...
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Yu Wang, Jianmei Zhao, Lu Jiang, Yunzhu Mu Department of Dermatology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, 637000, People’s Republic of ChinaCorrespondence: Yunzhu Mu Email hymyz@126.comAbstract: Melasma is an acquired and chronic hyperpigmentation disorder which is recognized as one of the most psychologically distressing and difficult to cure forms of skin hyperpigmentation. It is associated with substantial quality of life impairments. Treatments of melasma include local application, oral medication, physical laser therapy and program combination therapy. However, routine treatment usually leads to the damage of skin barrier function, resulting in adverse reactions such as erythema, pruritus, post-inflammatory pigmentation and even scar. Skin care products contain a variety of active ingredients, which are widely concerned by cosmetic dermatologists because of high safety, good tolerance and the effect of improving the damaged skin barrier. Using skin care products alone or in combination with routine treatment not only can improve the curative effect for melasma, reduce side effects and recurrence rate, but also improve patient satisfaction. This article mainly describes the application of skin care products in the treatment of melasma.Keywords: skin care product, melasma, treatment
... Previous studies indicated that the cause of the significant use of OTC cosmeceuticals was most likely because of a lack of insurance coverage for prescription products used as cosmeceuticals, the inconvenience of having to go to a physician to obtain prescription medications, and the amazing unrealistic claims advertised by some OTC skin and hair care products. 17 The percentage of regular daily users of OTC products for cosmeceutical reasons in this study, however, was less than anticipated (91; 17.7%). This is probably because the current study limited the age groups to those of university students, with most participants being from the same ethnic background, and did not include more diverse groups and older age groups who would need to apply OTC cosmeceuticals more frequently. ...
... A study previously reported that the users of OTC cosmeceuticals might have different potentially false perceptions of the use of such medications and that they would possibly think that, since they are applied topically, such compounds do not have any systemic side effects. 17 The current study focused only on pharmacy-sold OTC cosmeceuticals and did not address homemade chemical or herbal remedies, although these ethnomedicines were long widely used by rural inhabitants, herbalists, traditional healers and even beauty salon hairdressers. 19 It is publicly accepted that phytocompounds of natural plant origins might be safer than synthetic compounds, which was also the case in the current study, in which the majority of participants believed that natural sources were safer than synthetic sources, a belief that was corrected after attending the awareness program. ...
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Background‎: The reckless use of over-‎the-‎counter (OTC) cosmeceuticals among females is alarming due to possible health hazards, ranging from allergy to fatal anaphylaxis and toxicity. Methods‎: In the current study, we investigated the prevalence of cosmeceutical use among female students at Princess Nourah bint Abdulrahman University (PNU) and tested the effect of a pilot health education program in improving their knowledge. A cross-sectional questionnaire-based study was performed with 515 participants. Results‎: A significantly higher percent (81%) of participants used OTC cosmeceuticals than did not use them. The selection of OTC ‎‎cosmeceuticals was not affected by socioeconomic ‎status, chronic illness, cosmeceutical cost, or possible cosmeceutical side effects. Students from non-health colleges demonstrated poorer knowledge scores for the hazards of cosmeceuticals, which directed our attention to the importance of health education in this field. Therefore, a pilot interventional health education program was conducted with 54 participants to compare their ‎‎knowledge before and after the‎ intervention. At the end of the program, a higher‎ percentage of participants had improved their knowledge and realized the need to ‎consult a physician before using ‎OTC ‎‎cosmeceuticals. Conclusion: The health education program had a significant impact on knowledge ‎concerning the use of cosmeceuticals, and it is recommended that such programs be included in ‎undergraduate extracurricular activity, especially for female students.‎.
... Any less as in common cosmeceuticals is ineffective. [28,29] However, they are most widely used because of their fewer irritating effects on the skin and in lower concentrations, they are non-prescription drugs. ey are also dispensed in moisturizers and hair care cosmeceuticals. ...
... Active ingredients in cosmeceuticals are not just bland or inert and may exhibit side effects associated with them, which come under the realm of a topical applicant. [29] Phototoxic and photoallergic reactions, contact dermatitis, skin irritation, and cosmetic intolerance syndrome [63] are all seen with cosmeceuticals. Even though many of the ingredients are botanicals, yet they can cause severe reactions. ...
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A cosmetic is “intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance” while a drug is “intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease, i.e. it affects the structure and function of the body.” Cosmeceuticals attempt to interface between a pure cosmetic and a drug. ey are those which lie between a prescription and a non-prescription over-the-counter product. ey are medical products, which are cosmetics, with functional benefits for the skin, hair, and nails. Cosmeceuticals are disease-treating and disease-modifying. Dermatologists form a unique interface between products with perceived advantages and those with proven efficacy. In an attempt to hard-sell products with minimal side effects, certain compounds may contain sub-therapeutic doses of topical agents hence rendering them ineffective. On the other hand, certain products may form a useful bridge with a safety profile better than cosmetics in their class. is article reviews commonly available and evolving cosmeceuticals, their rationale, side effects, and use in dermatology practice with the aim to sensitize dermatologists about their perceived usefulness.
... Some of these have been used in topical drugs or cosmetic formulations for the treatment of melasma. These botanical products are increasingly popular as they are presumed safe, mild, and available over the counter (18). Only recently, though, the efficacy of some botanical products has been substantiated through clinical trials (3). ...
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