BACKGROUND
Retinoic Acid (tretinoin)
Topically applied retinoic acid (RA), or tretinoin, has been
formally established as an effective treatment for photodamaged
skin. With over thirty years of research data to
support its clinical and histological effects, tretinoin is also the
most extensively studied therapy for photodamage.1-12 Clinical
signs of photodamage include the presence of fine and coarse
wrinkles, mottled pigmentation, uneven skin tone, and rough
skin texture. These characteristics also manifest in intrinsically
or chronologically-aged skin and have also been shown to respond
to treatment with tretinoin.14-16 Numerous clinical studies
with tretinoin have shown significant improvements in these
parameters, along with supporting histological evidence of increased
epidermal thickness, stratum corneum compaction,
decreased melanin content, as well as an increased deposition
and organization of collagen and elastin fibers.8, 9, 12, 13 Tretinoin
achieves these effects by binding nuclear retinoic acid receptors,
and inducing a variety of molecular changes in the skin including
keratolytic activity, inhibition of matrix metalloproteinase production,
and stimulation of collagen synthesis.17-19 Currently, topical
tretinoin is available in concentrations ranging from 0.02% to
0.1%, with the most frequently recommended products available
in the following concentrations: 0.025%, 0.05%, and 0.1%.20
formally established as an effective treatment for photodamaged
skin. With over thirty years of research data to
support its clinical and histological effects, tretinoin is also the
most extensively studied therapy for photodamage.1-12 Clinical
signs of photodamage include the presence of fine and coarse
wrinkles, mottled pigmentation, uneven skin tone, and rough
skin texture. These characteristics also manifest in intrinsically
or chronologically-aged skin and have also been shown to respond
to treatment with tretinoin.14-16 Numerous clinical studies
with tretinoin have shown significant improvements in these
parameters, along with supporting histological evidence of increased
epidermal thickness, stratum corneum compaction,
decreased melanin content, as well as an increased deposition
and organization of collagen and elastin fibers.8, 9, 12, 13 Tretinoin
achieves these effects by binding nuclear retinoic acid receptors,
and inducing a variety of molecular changes in the skin including
keratolytic activity, inhibition of matrix metalloproteinase production,
and stimulation of collagen synthesis.17-19 Currently, topical
tretinoin is available in concentrations ranging from 0.02% to
0.1%, with the most frequently recommended products available
in the following concentrations: 0.025%, 0.05%, and 0.1%.20
Retinol is a cosmetic ingredient and is one of the most active vitamin
A derivatives, that is a metabolic precursor of RA. Topically
applied retinol has been shown to improve the appearance of
photodamaged skin.21, 22 The bioactivity of retinol in the skin relates
to its conversion to RA, the “active†form, which then exerts
a variety of effects discussed above. A simplified overview of RA’s
metabolic precursors converting to RA is provided in Figure 1.
A derivatives, that is a metabolic precursor of RA. Topically
applied retinol has been shown to improve the appearance of
photodamaged skin.21, 22 The bioactivity of retinol in the skin relates
to its conversion to RA, the “active†form, which then exerts
a variety of effects discussed above. A simplified overview of RA’s
metabolic precursors converting to RA is provided in Figure 1.
Cosmetic products are generally perceived as less effective or
unable to produce the clinical improvements in photodamaged
skin achieved with prescription products such as RA. Taking into
account that retinol is a metabolic precursor to RA, an established
treatment for photodamaged skin, it follows that retinol
may have a greater potential to achieve similar clinical effects.
unable to produce the clinical improvements in photodamaged
skin achieved with prescription products such as RA. Taking into
account that retinol is a metabolic precursor to RA, an established
treatment for photodamaged skin, it follows that retinol
may have a greater potential to achieve similar clinical effects.
Retinol is theoretically considered to be ten times less effective
than tretinoin.23 However, there have been limited or no clinical
studies that compare retinol to tretinoin using this theoretical
conversion as a basis.
than tretinoin.23 However, there have been limited or no clinical
studies that compare retinol to tretinoin using this theoretical
conversion as a basis.
Previously, a randomized, double-blind clinical study compared
the efficacy and tolerability of a cosmetic tri-retinol 1.1%
product vs. tretinoin 0.025%.24 Results from this study demonstrated
comparable efficacy between the two products in
reducing the appearance of photodamage when applied topically
for 12 weeks. Although the study was novel in comparing
the clinical effects of topically applied retinol vs. tretinoin, and
furthered our understanding that retinol could indeed produce
similar effects to the appearance of photodamaged skin, it did
not support the conversion theory that retinol is approximately
ten times less potent than tretinoin; in the study, retinol was
used at a much higher concentration in comparison to tretinoin
(approximately forty-four to one).
the efficacy and tolerability of a cosmetic tri-retinol 1.1%
product vs. tretinoin 0.025%.24 Results from this study demonstrated
comparable efficacy between the two products in
reducing the appearance of photodamage when applied topically
for 12 weeks. Although the study was novel in comparing
the clinical effects of topically applied retinol vs. tretinoin, and
furthered our understanding that retinol could indeed produce
similar effects to the appearance of photodamaged skin, it did
not support the conversion theory that retinol is approximately
ten times less potent than tretinoin; in the study, retinol was
used at a much higher concentration in comparison to tretinoin
(approximately forty-four to one).
However, this ten to one ratio comparison between retinol and
tretinoin was studied in EpidermFT (EFT-400) tissues and showed
comparable effects of retinol 0.5% vs. tretinoin 0.05% in UV damaged
tissues. Total mRNA isolation and RT-PCR of the treated
tissues resulted in similar induction of efficacy markers (COL1A1,
ELN, LOXL1, and MFAP2) for both retinol and tretinoin.25
tretinoin was studied in EpidermFT (EFT-400) tissues and showed
comparable effects of retinol 0.5% vs. tretinoin 0.05% in UV damaged
tissues. Total mRNA isolation and RT-PCR of the treated
tissues resulted in similar induction of efficacy markers (COL1A1,
ELN, LOXL1, and MFAP2) for both retinol and tretinoin.25
To assess if a lower (ten to one) ratio of retinol compared to
tretinoin could provide similar clinical effects in photodamage
when topically applied, three formulations containing
0.25%, 0.5%, and 1.0% retinol were developed to correspond
to the three commonly prescribed concentrations of tretinoin
(0.025%, 0.05%, and 0.1%).
tretinoin could provide similar clinical effects in photodamage
when topically applied, three formulations containing
0.25%, 0.5%, and 1.0% retinol were developed to correspond
to the three commonly prescribed concentrations of tretinoin
(0.025%, 0.05%, and 0.1%).
CLINICAL STUDY
Study Objectives
A randomized, double-blind, split-face comparison study was
conducted to compare the efficacy and tolerability of three concentrations
of a retinol formulation (Ret) including 0.25%, 0.5%,
and 1.0%, against three corresponding strengths of tretinoin
(0.025%, 0.05%, and 0.1%) in subjects with moderate to severe
facial photodamage.
conducted to compare the efficacy and tolerability of three concentrations
of a retinol formulation (Ret) including 0.25%, 0.5%,
and 1.0%, against three corresponding strengths of tretinoin
(0.025%, 0.05%, and 0.1%) in subjects with moderate to severe
facial photodamage.
MATERIALS AND METHODS
Institutional Review Board approval was obtained prior to
the initiation of the study. The study was conducted according
to ethical and regulatory principles from the International
Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use. All subjects
signed an informed consent form prior to study entry. The study
was conducted from March 2013 to July 2013.
the initiation of the study. The study was conducted according
to ethical and regulatory principles from the International
Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use. All subjects
signed an informed consent form prior to study entry. The study
was conducted from March 2013 to July 2013.
Subject Demographics
The criteria for the study included females aged 35 to 65 years
of age with Fitzpatrick Skin Types II-IV and moderate to se-
of age with Fitzpatrick Skin Types II-IV and moderate to se-
vere facial photodamage as assessed by clinical examination.
Subjects must have discontinued use of topical prescription
drugs similar to tretinoin at least three months of study start
and could not have received facial resurfacing procedures
(chemical peels, laser, dermabrasion, injectables) within the
six months of study start.
Subjects must have discontinued use of topical prescription
drugs similar to tretinoin at least three months of study start
and could not have received facial resurfacing procedures
(chemical peels, laser, dermabrasion, injectables) within the
six months of study start.
Treatment
Eligible subjects were randomly assigned to one of three treatment
cells (Cell 1, Cell 2, and Cell 3). Approximately twenty
subjects were recruited for each treatment cell. Two paired
test products were assigned for each treatment cell and are
presented in Table 1. The three tretinoin products used in the
study were generic cream formulations (manufactured by Ortho
Pharmaceutical a division of Janssen Ortho LLC) and the
three retinol products were lotion formulations (manufactured
by SkinMedica Inc., an Allergan Company).
cells (Cell 1, Cell 2, and Cell 3). Approximately twenty
subjects were recruited for each treatment cell. Two paired
test products were assigned for each treatment cell and are
presented in Table 1. The three tretinoin products used in the
study were generic cream formulations (manufactured by Ortho
Pharmaceutical a division of Janssen Ortho LLC) and the
three retinol products were lotion formulations (manufactured
by SkinMedica Inc., an Allergan Company).
Subjects were instructed to apply the assigned test product to
their left or right facial side based on a predetermined randomization.
During the first week, subjects were instructed to apply
a thin layer of the test products onto their facial skin every
other evening after cleansing. Afterwards, subjects increased
the application frequency to every evening. The test products
were used in conjunction with a basic skincare regimen, which
included a cleanser (SkinMedica Facial Cleanser), moisturizer
(SkinMedica Ultra Sheer Moisturizer), and sunscreen (Daily
Physical Defense SPF30+ Sunscreen).
their left or right facial side based on a predetermined randomization.
During the first week, subjects were instructed to apply
a thin layer of the test products onto their facial skin every
other evening after cleansing. Afterwards, subjects increased
the application frequency to every evening. The test products
were used in conjunction with a basic skincare regimen, which
included a cleanser (SkinMedica Facial Cleanser), moisturizer
(SkinMedica Ultra Sheer Moisturizer), and sunscreen (Daily
Physical Defense SPF30+ Sunscreen).
CLINICAL ASSESSMENTS
Efficacy
Clinical grading of the left and right facials sides were performed
by the investigator at all visits (baseline and weeks 4,
8, and 12) using a modified Griffiths ten point scale according to the following numerical definitions (half-point scores
were allowed as necessary to more accurately describe the
skin condition). To help ensure consistency and reliability in
the visual grading, each subject was graded by the same investigator
throughout the study.
by the investigator at all visits (baseline and weeks 4,
8, and 12) using a modified Griffiths ten point scale according to the following numerical definitions (half-point scores
were allowed as necessary to more accurately describe the
skin condition). To help ensure consistency and reliability in
the visual grading, each subject was graded by the same investigator
throughout the study.
The following photodamage parameters were assessed by the
investigator for the left and right facial sides at all visits:
investigator for the left and right facial sides at all visits:
At all follow-up visits, global improvement in overall photodamage
for each facial side was assessed by the investigator
using the following five point scale: 0=no change, 1=minimal
improvement, 2=mild improvement, 3=moderate improvement,
4=marked or significant improvement.
for each facial side was assessed by the investigator
using the following five point scale: 0=no change, 1=minimal
improvement, 2=mild improvement, 3=moderate improvement,
4=marked or significant improvement.
Subject Questionnaire
Subjects completed a self-assessment questionnaire based on
their experience with the test products at week 12.
their experience with the test products at week 12.
Tolerability
Evaluations of tolerability were assessed at all study visits using
a four-point scale (where 0=none, 1=mild, 2=moderate, and
3=severe). The investigator evaluated local cutaneous tolerability
including erythema, dryness/scaling, and edema and the
subjects reported on the degree of burning/stinging and itching
experienced on the left and right facial sides.
a four-point scale (where 0=none, 1=mild, 2=moderate, and
3=severe). The investigator evaluated local cutaneous tolerability
including erythema, dryness/scaling, and edema and the
subjects reported on the degree of burning/stinging and itching
experienced on the left and right facial sides.
Imaging
Standardized digital photographs were taken of the front, left,
and right facial sides at all visits using the VISIA-CR camera system
(Canfield Scientific, Inc., Fairfield, New Jersey). Subjects
removed all makeup and jewelry prior to imaging procedures
and were instructed to adopt a neutral, non-smiling expression
with eyes gently closed. Subjects were provided with a black
matte headband to prevent hair from covering the face and a
black matte cloth was draped over the subject’s clothing.
and right facial sides at all visits using the VISIA-CR camera system
(Canfield Scientific, Inc., Fairfield, New Jersey). Subjects
removed all makeup and jewelry prior to imaging procedures
and were instructed to adopt a neutral, non-smiling expression
with eyes gently closed. Subjects were provided with a black
matte headband to prevent hair from covering the face and a
black matte cloth was draped over the subject’s clothing.
Biostatistiscs and Data Management
The primary subject population for efficacy and tolerability
analysis included the intent-to-treat (ITT) population. The ITT
population comprises all subjects that completed the baseline
visit evaluations and at least one post-baseline visit. All
statistical tests were performed using SAS software version
analysis included the intent-to-treat (ITT) population. The ITT
population comprises all subjects that completed the baseline
visit evaluations and at least one post-baseline visit. All
statistical tests were performed using SAS software version
9.30 series (SAS Statistical Institute) and were 2-sided at significance
level alpha=0.05. P-values were reported to three
decimal places (0.000).
level alpha=0.05. P-values were reported to three
decimal places (0.000).
A descriptive statistical summary of efficacy and tolerability
parameters was conducted including the mean, median, standard
deviation, minimum and maximum grades at all visits. The
calculation of mean change from baseline, defined as the postbaseline
grade for a parameter minus the baseline grade for
that same parameter was also calculated for each parameter.
The Wilcoxon signed-rank test was used to test the null hypothesis
that the mean change at the post-baseline visit was zero.
In addition the mean percent change from baseline for each parameter
was also calculated using the following formula:
parameters was conducted including the mean, median, standard
deviation, minimum and maximum grades at all visits. The
calculation of mean change from baseline, defined as the postbaseline
grade for a parameter minus the baseline grade for
that same parameter was also calculated for each parameter.
The Wilcoxon signed-rank test was used to test the null hypothesis
that the mean change at the post-baseline visit was zero.
In addition the mean percent change from baseline for each parameter
was also calculated using the following formula:
Comparisons of the change from baseline between the paired
test products within each treatment cell (Test Product A vs. Test
Product B; Test Product C vs. Test Product D; and Test Product
E vs. Test Product F) were conducted using a Wilcoxon signedrank
test for all efficacy and tolerability parameters at all
follow-up visits. For the subject questionnaire, the frequency
and percentage of all responses (strongly agree, agree, disagree,
and strongly disagree) were reported.
test products within each treatment cell (Test Product A vs. Test
Product B; Test Product C vs. Test Product D; and Test Product
E vs. Test Product F) were conducted using a Wilcoxon signedrank
test for all efficacy and tolerability parameters at all
follow-up visits. For the subject questionnaire, the frequency
and percentage of all responses (strongly agree, agree, disagree,
and strongly disagree) were reported.
Comparisons of the change from baseline between the paired
test products within each treatment cell (Test Product A vs. Test
Product B; Test Product C vs. Test Product D; and Test Product
E vs. Test Product F) were conducted using a Wilcoxon signedrank
test for all efficacy and tolerability parameters at all
follow-up visits. For the subject questionnaire, the frequency
and percentage of all responses (strongly agree, agree, disagree,
and strongly disagree) were reported.
test products within each treatment cell (Test Product A vs. Test
Product B; Test Product C vs. Test Product D; and Test Product
E vs. Test Product F) were conducted using a Wilcoxon signedrank
test for all efficacy and tolerability parameters at all
follow-up visits. For the subject questionnaire, the frequency
and percentage of all responses (strongly agree, agree, disagree,
and strongly disagree) were reported.
RESULTS
Seventy-two subjects aged 41-65 years with Fitzpatrick Skin
Types II-IV and moderate to severe facial photodamage were
enrolled into the study. Of these subjects, sixty-nine were
included in the intent-to-treat (ITT) population for statistical
analysis (2 subjects discontinued prior to their week 4 visit
due to an adverse event and were excluded from the intent-totreat
(ITT) population analysis). Three subjects discontinued
after their week 4 visit due to an adverse event and 1 voluntarily
discontinued, unrelated to study product. Sixty-five
subjects completed the twelve- week study. In Treatment Cell
1, a total of 24 subjects completed the study and were included
in the ITT population. In Treatment Cell 2, a total of 20
subjects completed the study and 23 subjects were included
in the ITT population. Lastly, in Treatment Cell 3, 21 subjects
completed the study and 22 subjects were included in the ITT
population. The demographics of the ITT population for each
treatment cell are presented in Table 2.
Efficacy
The test products in all three treatment cells produced statistically
significant decreases (improvements) in mean scores for
fine lines/wrinkles (periocular and cheek areas), coarse lines/
wrinkles (periocular and cheek areas), skin tone brightness,
mottled pigmentation, tactile roughness, and overall photodamage at weeks 8 and 12 when compared to baseline (all
P?0.002). In addition earlier significant decreases were observed
at week 4 compared to baseline for fine lines/wrinkles
(periocular and cheek areas), coarse lines/wrinkles (periocular
and cheek areas) and overall photodamage (all P?0.02).
When comparing the change from baseline for all photodamage
parameters between the paired test products (Test Product
A vs. Test Product B; Test Product C vs. Test Product D; Test Product
E vs. Test Product F), there were no statistically significant
differences at weeks 4, 8, and 12 (all P?0.281). The mean percent
changes in all photodamage parameters at week 12 and
for the Overall Photodamage assessment over time (weeks 4,
8, and 12) are presented for Treatment Cell 1 in Figures 2 and
3, Treatment Cell 2 in Figures 4 and 5, and Treatment Cell 3 in
Figures 6 and 7. Standardized digital photographs of treated
subjects representative of the improvements observed by the
investigator, are shown in Figures 8-10.
parameters between the paired test products (Test Product
A vs. Test Product B; Test Product C vs. Test Product D; Test Product
E vs. Test Product F), there were no statistically significant
differences at weeks 4, 8, and 12 (all P?0.281). The mean percent
changes in all photodamage parameters at week 12 and
for the Overall Photodamage assessment over time (weeks 4,
8, and 12) are presented for Treatment Cell 1 in Figures 2 and
3, Treatment Cell 2 in Figures 4 and 5, and Treatment Cell 3 in
Figures 6 and 7. Standardized digital photographs of treated
subjects representative of the improvements observed by the
investigator, are shown in Figures 8-10.
Tolerability
Mean scores for erythema, dryness/scaling, and burning/stinging
remained mild or below at weeks 4, 8, and 12. At week 4,
mean tolerability scores significantly increased for all treatment
group test products compared to baseline (all P?0.04).
At week 8, there was a significant increase in mean erythema
scores for burning/stinging (Treatment Cell 1 only). By week
12, there were no significant increases in any of the tolerability
parameters for all test products.
Safety
Twenty-two adverse events (AEs) of moderate skin reactions
commonly associated with retinoid use, such as erythema,
peeling, stinging/burning and dryness, were reported during
the study. The incidence of AEs were evenly distributed among
the three treatment cells and test products (Treatment Cell 1: 7
AEs, Treatment Cell 2: 7 AEs, Treatment Cell 3: 8 AEs). All AEs
resolved without sequelae.
AEs, Treatment Cell 2: 7 AEs, Treatment Cell 3: 8 AEs). All AEs
resolved without sequelae.
CONCLUSION
Results from this comparison study support the theory that
a ten to one ratio of retinol to tretinoin may provide comparable
clinical effects in subjects with moderate to severe
photodamaged facial skin, without relying upon a high ratio
of retinol to tretinoin (approximately forty-four times, as
shown in a previous study). The three retinol formulations
(0.25%, 0.5%, and 1.0%) provided similar significant reductions
in all photodamage parameters when compared to
baseline and when compared to the corresponding three
tretinoin creams (0.025%, 0.05%, and 0.1%). These study results
build upon the comparable induction of key collagen
and elastin markers observed in a previous study with EFT-
400 tissues after treatment with a ten to one ratio of retinol
and tretinoin. However additional studies are needed to further
explore this theory.
a ten to one ratio of retinol to tretinoin may provide comparable
clinical effects in subjects with moderate to severe
photodamaged facial skin, without relying upon a high ratio
of retinol to tretinoin (approximately forty-four times, as
shown in a previous study). The three retinol formulations
(0.25%, 0.5%, and 1.0%) provided similar significant reductions
in all photodamage parameters when compared to
baseline and when compared to the corresponding three
tretinoin creams (0.025%, 0.05%, and 0.1%). These study results
build upon the comparable induction of key collagen
and elastin markers observed in a previous study with EFT-
400 tissues after treatment with a ten to one ratio of retinol
and tretinoin. However additional studies are needed to further
explore this theory.
A limitation of this study design is the lack of histological
endpoints, which could further support the clinical changes
observed by the investigator and the self-perceived changes
observed by the subjects. The histological effects of retinoic
acid on the forearm skin has been compared to salicylic acid
endpoints, which could further support the clinical changes
observed by the investigator and the self-perceived changes
observed by the subjects. The histological effects of retinoic
acid on the forearm skin has been compared to salicylic acid
and 2-hydroxy-5-octanoyl benzoic acid.26 This type of study
design could provide further characterization of the changes
when comparing topically-applied retinol and tretinoin.
design could provide further characterization of the changes
when comparing topically-applied retinol and tretinoin.
Overall, the results from this comparative study suggest potentially
broader topical options with retinol for patients and
physicians seeking improvements in the appearance of photodamaged
skin.
broader topical options with retinol for patients and
physicians seeking improvements in the appearance of photodamaged
skin.
DISCLOSURES
Financial support of this study was provided by SkinMedica,
Inc, an Allergan Company.
Inc, an Allergan Company.
Dr. Babcock performed the clinical study. Dr. Mehta and Ms.
Makino are employees of SkinMedica Inc., an Allergan Company.
Makino are employees of SkinMedica Inc., an Allergan Company.
REFERENCES
- Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol. 15:836-859;1986.
- Dalenski R, Surber C, Fluhr JW. Topical retinoids in the management of photodamaged skin:from theory to evidence-based practical approach. Br J Dermatol. 2010 Dec;163(6):1157-65.
- Baldwin HE, Nighland M, Kendall C, et. al. 40 years of topical tretinoin use in review. J Drugs Dermatol. 2013 Jun;12(6):638-42.
- Kang S, Bergfeld W, Gottlieb AB, et. al. Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial. Am J Clin Dermatol. 2005;6(4):245-53.
- Leyden JJ. Treatment of photodamaged skin with topical tretinoin: an update. Plast Reconstr Surg. 1998 Oct;102(5):1667-71.
- Kang S, Fisher GJ, Voorhees JJ. Photoaging and topical tretinoin: therapy, pathogenesis, and prevention. Arch Dermatol. 1997 Oct;133(10):1280-4.
- Kang S, Voorhees JJ. Photoaging therapy with topical tretinoin: an evidence-based analysis. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S55-61.
- Olsen EA, Katz HI, Levine N, et. al. Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol. 1992 Feb;26(2 Pt 1):215-24.
- Weinstein GD, NIgra TP, Pochi PE, et. al. Topical tretinoin for treatment of photodamaged skin. A multicenter study. Arch Dermatol. 1991 May;127(5):659-65.
- Ting W. Tretinoin for the treatment of photodamaged skin. Cutis 2010 Jul;86(1):47-52.
- Bhawan J. Short and long-term histologic effects of topical tretinoin on photodamaged skin. Int J Dermatol. 1998 Apr;37(4):286-92.
- Kircik LH. Histologic improvement in photodamage after 12 months of treatment with tretinoin emollient cream (0.02%). J Drugs Dermatol. 2012 Sep;11(9):1036-40.
- Kligman AM, Dogadkina D, Lavker RM. Effects of topical tretinoin on nonsun-exposed protected skin of the elderly. J Am Acad Dermatol. 1993 Jul;29(1):25-33.
- Varani J, Fisher GJ, Kang S, Voorhees JJ. Molecular mechanisms of intrinsic skin aging and retinoid-induced repair and reversal. J Invest Dermatol Symp Proc. 1998;3:57-60.
- Varani J, Perone P, Griffiths CEM, et al. All trans retinoic acid (RA) stimulates events in organ cultured human skin that underlie repair: adult skin from sun protected and sun exposed sites responds in identical manner to RA while neonatal foreskin responds differently. J Clin Invest. 1994;94:1747-1756.
- Varani J, Warner RL, Gharaee-Kermani M, et al. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol. 2000;114:480-486.
- Griffiths CEM, Russman AN, Majmudar G, et al. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med. 1993;329:530-535.
- Watson REB, Craven NM, Kang S, et al. A short-term screening protocol, using fibrillin-1 as a reporter molecule, for photoaging repair agents. J Invest Dermatol. 2001;116:672-678.
- U.S. Department of Health & Human Services. (October 30, 2013). Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. FDA U.S. Food and Drug Administration. Retrieved October 30, 2013 from http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm.
- Tucker-Samaras S, Zedayko T, Cole C, et. al. A stabilized 0.1% retinol facial moisturizer improves the appearance of photodamaged skin in an eight-week, double-blind, vehicle-controlled study. J Drugs Dermatol. 2009 Oct;8(10):932-6.
- Kikuchi K, Suetake T, Kumasaka N, et. al. Improvement of photoaged facial skin in middle-aged Japanese females by topical retinol (vitamin A alcohol): a vehicle-controlled, double-blind study. J Dermatolog Treat. 2009;20(5):276-81.
- Duell EA, Kang S, Voorhees JJ. Unoccluded retinol penetrates human skin in vivo more effectively than unoccluded retinyl palmitate or retinoic acid. J Inv Derm. 1997 Sep;109(3):301-305.
- Ho ET, Trookman NS, Sperber BR, et. al. A randomized, double-blind, controlled comparative trial of the anti-aging properties of non-prescription tri-retinol 1.1% vs. prescription tretinoin 0.025%. J Drugs Dermatol. 2012 Jan;11(1):64-9.
- Mehta RC, Vega VL, Bachelor MA, Oldach J, Armento A. Encapsulated retinol (0.5%) and retinoic acid (0.05%) are equally effective at protecting against UV-induced damage in Epiderm FT tissues. J Inv Derm. 2013; 133:s220
- Pierard GE and Kligman AM. Comparative effects of retinoic acid, glycolic acid and a lipophilic derivative of salicylic acid on photodamaged epidermis. Dermatology. 1999;199:50-53.
AUTHOR CORRESPONDENCE
Elizabeth Makino………………….makino_elizabeth@allergan.com
