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CES Medicine
ISSN:0120-8705
revistamedica@ces.edu.co
CES University
Colombia

VASQUEZ-YASSER, ISABEL CRISTINA; MANTILLA-CABALLERO, MARÍA STELLA; TORRES DE GALVIS,

YOLANDA; MANRIQUE-HERNADEZ, RUBEN DARIO; MONTOYA-V, LILIANA PATRICIA;
ZULUAGA DE CADENA, ANGELA I.
Efficacy and safety of topical retinaldehyde and retinoic acid in the treatment of
photoaging
CES Medicine, vol. 23, no. 1, 2009, p. s9-s25
CES University
Medellin Colombia

Available at: http://www.redalyc.org/articulo.oa?id=261120999002

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Scientific or technological research articles

Efficacy and safety of topical retinaldehyde

and retinoic acid in the treatment
photoaging
Efficacy and safety of retinaldehyde and topical retinoic acid in the treatment of photoaging

ISABEL CRISTINA VASQUEZ-YASSER1, MARÍA STELLA MANTILLA-CABALLERO1YOLANDA TORRES DE GALVIS2,

RUBEN DARIO MANRIQUE-HERNADEZ3; LILIANA PATRICIA MONTOYA-V4, ANGELA I. ZULUAGA DE CADENA1
Manner of citing: Vásquez-Yasser IC, Mantilla-Caballero MS, Torres de Galvis Y, Manrique-Hernández RD, Montoya-Vélez LP, Zuluaga de Cadena A.
Efficacy and safety of topical retinaldehyde and retinoic acid in the treatment of photoaging.
Rev CES Med 2009;23(1) Suppl. Dermatology: s9-s25

SUMMARY

AND Topical retinoic acid is effective for the treatment of photoaging. However, skin
irritation secondary to its use is a limiting factor in treatment. Retinaldehyde is
an immediate precursor of retinoic acid that has biological activity on the skin, with
fewer side effects.

Aim:to compare the efficacy and tolerance of topical retinaldehyde and retinoic acid in the
treatment of photoaging, through profilometric profile and clinical-photographic analysis
and to determine the side effects of these drugs.

Methods:126 Colombian women (35 to 60 years old) were included, who had not received
previous treatments, were not pregnant or lactating. In total 119 patients completed
24 weeks of follow-up: 61 patients received retinaldehyde and 58 retinoic acid. A clinical follow-up
(which evaluated improvement and tolerance) was carried out at weeks 4, 8, 16 and

1
Dermatologist. Dermatology Research Group. CES University. Master in Public
2
Health. Public Health Observatory Group. CES University.
3
Master in Epidemiology. Research Group in Epidemiology and Biostatistics. CES University.
4
Master in Epidemiology. Research Group Observes Orioyouof Public Health. CES University.

Received August 2009. Revised September 2009. Accepted October 2009.

MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009

s9
20, and in addition, profilometry of the chicken's foot area and
photographic follow-up were performed on admission and at
week 24.
Results:A significant reduction in the presence
of isolated telangiectasias was found in the
retinaldehyde treatment group at weeks 12, 16,
and 24 (p= 0.007; p=0.017 and p=0.034,
respectively), and a statistically significant
decrease at week 12. (p= 0.042) of facial
sagging in the peri-orbital and mandibular area
in the same group. At week 24, a significant
increase was found in the proportion of
patients without telangiectasias in the
treatment group compared to the other group
(p= 0.008). In the photographic evaluation, no
statistically significant difference was found
between the two groups. During follow-up, the
proportions of erythema and scaling showed a
statistically significant difference between the
groups, always being higher in the retinoic acid
group, except at week 24.
Conclusion:The regular use of retinoic acid and
retinaldehyde improved the clinical manifestations of
photoaging, the latter with the lowest proportion of
side effects.
KEYWORDS
photoaging
retinaldehyde
Retinoic acid
profilometry
ABSTRACT
Topical retinoic acid has been effectively used to
treat photoaging; Nevertheless, cutaneous
irritation as a side effect is a limiting factor for
treatment. Retinaldehyde is an immediate precur-
sor of retinoic acid that has biologic activity in
the skin, with few side effects. The goal of this
s10
Research was to compare efficacy and tolerability of
topical retinoic acid and retinaldehyde in the
treatment of photoaging, by means of profilometry
and clinical-photographic analysis and to determine
side effects from both medications.
methods:Were included 160 Colombian women
(aged 35 to 60 years), who hadn't had previous
treatments and weren't pregnant or breast
feeding. A total of 119 patients completed 24
weeks of treatment. Of these, 61 used
retinaldehyde and 58 retinoic acid. Clinical
evaluation was carried out on weeks 4, 8, 16 and
20, and profilometry of the “crow's feet” area was
done at the beginning and at week 24.
Results:A significant reduction of isolated
telangiectasias at weeks 12, 16 and 24 was found
in the retinaldehyde group (p values of 0.007,
0.017 and 0.034, respectively), and on week 12, a
statistically significant reduction of loosening of
the tissue in the periocular and maxillary area (p=
0.042). On week 24 a significant rise of
telangiectasias free patients was found on the
retinaldehyde group as compared to the other
(p=0.0081). On the photographic evaluation no
statistically significant differences were found.
Side effects like erythema and desquamation
were significantly fewer in the retinaldehyde
group, except at week 24. On profilometry, a
global and significant reduction on relief was
found on both groups.
Conclusion: regular use of both retinoic acid
and retinaldehyde are effective on photoaging,
the last one with fewer side effects.
KEY WORDS
Photo aging
Retinaldehyde
Retinoic acid
Profilometry
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
INTRODUCTION
Skin aging occurs simultaneously by two
independent processes: photoaging and
chronological aging (1). Chronological aging
includes those changes that occur due to the
slow and irreversible degeneration of tissues,
affects the skin and internal organs (2) and is
genetically programmed. Photoaging refers
to premature aging of the skin caused by
repeated exposure to ultraviolet (UV)
radiation from the sun over years (3). It is
characterized by the development of wrinkles
and telangiectasias, cracking, atrophy and
yellowish pigmentation of the skin. There are
also pigmentation irregularities and
increased fragility of blood vessels leading to
purpura (4). Its severity depends on the
extent of sun exposure and the patient's skin
phototype; thus, people with fair skin have a
higher risk of severe photoaging (5).
Histologically it is characterized by solar
elastosis, changes in the dermal
microvasculature and chronic inflammation
with an increase in degranulated mast cells,
macrophages and lymphocytes (6,7). Clinical
signs of photoaging can be graded into a
scheme that reflects the progression of
photoaging from minimal to severe (8).
Treatments for photoaging are grouped into
two broad categories: topical treatments and
surgical rejuvenation (9,10). Topical
treatments have the advantage of being non-
invasive; and among its disadvantages are:
prolonged and indefinite use, contact
irritation and allergy. Retinoids have been
one of the most studied and most commonly
used substances for the treatment of
photoaging (11). Effective treatment with
tretinoin depends on the dose and duration.
tion, requiring a minimum of 24 weeks for
the visible signs of
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
improvement. Kligman et al. (2) were the first
to propose that the application of a retinoid,
all-trans-retinoic acid (tretinoin), could be
effective in improving the clinical
consequences of photoaging. Subsequently,
Weiss et al. (12) demonstrated in a controlled
double-blind study that the use of 0.1%
tretinoin cream improved photoaging.
Unfortunately, in clinical practice, some
patients do not benefit from this treatment,
due to the high incidence of adverse effects,
as demonstrated by the Weiss study, in which
92% of patients experienced some degree of
dermatitis, erythema, inflammation, xerosis,
desquamation, burning sensation and
pruritus (12). Although other retinoids
appear to be better tolerated,
Topical retinaldehyde can be used as an
endogenous retinoid precursor, since it is
converted to the storage form (retinyl esters)
and to the biologically active form of vitamin
A; Additionally, previous studies have shown
that retinaldehyde is better tolerated without
losing the biological effect of retinoids
(15-27).
The purpose of this study was to compare the
efficacy and tolerance of topical retinaldehyde
and retinoic acid in the treatment of
photoaging by profilometric profile and clinical-
photographic analysis and to determine the
side effects of these medications in
photoaging treatment.
METHODOLOGY
patients
126 Colombian women were chosen, between 35
and 60 years of age, who attended the consultation
at the CES in Sabaneta (Medellín), with
moderate photoaging -type II- or
s11
advanced photoaging -type III-, according to
Glogau's 1994 photoaging classification (8)
and Fitzpatrick skin phototypes I to IV (28,29);
who had not used topical retinoids in the
facial area in the 45 days prior to the start of
the study, nor for more than four weeks
during the prior six months. Those who had
undergone chemical peels, or used exfoliants
or any abrasive substance on their faces in
the last six months were also not included.
The following were excluded: pregnant or
lactating women; patients on current
treatment with PUVA or scheduled to start it;
with suspicion of skin cancer and other
dermatological conditions that could
interfere with the profilometric or clinical
evaluation of photoaging as an alteration in
the texture or color of the skin, such as:
inflammatory, immunological or infectious
dermatoses -which were evaluated by the
investigators -; patients who, due to their
occupational needs or recreational habits,
were exposed to the sun for more than three
hours a day, for at least four days a week,
between 10 am and 2 pm; patients who at
the time of inclusion showed aversion to
treatment, disinterest or inability to comply
with it; Fitzpatrick skin phototypes V and VI
(28,29);
Method
A double-blind controlled clinical trial was carried
out with a total of 126 patients, who were
randomly chosen to make a selection of two
comparative treatment groups: an experimental
group that received retinaldehyde and a control
or comparison group, which received
retinaldehyde. received retinoic acid. In addition,
the beneficial and adverse effects were evaluated,
whose criteria were specified in advance.
in order to make unbiased comparisons. The
study was carried out between November
s12
The two treatments labeled as 1
(retinaldehyde) and 2 (retinoic acid) were
randomly assigned to the randomization
process, whose labeling and packaging was
done from the supplier's office located in a
different city. (Bogotá) to the one where the
study was carried out (Medellín). Both drugs
are authorized for therapeutic use in
Colombia by the National Institute for Food
and Drug Surveillance INVIMA. The project
was submitted to the consideration of the
Research Operative Committee of the Faculty
of Medicine of the CES University, which
found no objections to its implementation. In
addition, the protocol was approved by the
Ethics Committee of the CES University,
according to the international criteria that
apply to this type of study.
Experimental or treatment group: 0.05%
retinaldehyde emulsion (Ystheal ® , Avene
laboratories, Boulogne, France) was applied.
Control or comparison group: 0.05% retinoic
acid cream (Reticrem® Laboratorios Busié)
was applied.
All medication presentation tubes contained
30 grams of cream, in white boxes of the
same size and configuration, marked with
the number corresponding to each patient.
The patients were instructed to apply 0.5
grams of cream to the face at night for 24
weeks and to apply a sunscreen the next
morning (Creme Ecran Extreme®, Avene
Laboratories, SPF 50). The application of any
other topical medication was not allowed,
nor of other therapies that could affect the
follow-up of the effects of the two
interventions, such as collagen injections,
facial filler products, laser treatments, etc.
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To assess compliance with therapy, the
medication tubes given at the previous visit
were returned empty in the box to the
investigator at the next visit.
Considering that each tube contains a total of
30 grams and that 0.5 grams were used per
night, each tube lasted an average of 60
days, so three drug deliveries were made
during the study.
Evaluation of results
The investigators were also unaware of the
treatment group to which the patients
belonged and were equally oblivious to the
profilometric analysis process. Likewise, the
profilometric profile analysts were unaware
of the treatment group to which the patients
were assigned. The evaluation of the results
was carried out through profilometric
analysis, clinical evaluation and photographic
follow-up as follows:
profilometry
Optical profilometry is an objective method
to quantify facial wrinkles, with which
Photo 1. ADHESIVE LOCATOR AND
MEASURING CALIPER
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
Changes in texture pre and post treatment
are documented. This technique, previously
described by Grove in 1991 (30), consists of
making silicone replicas of the skin, taken
from identical sites, in the periorbital area.
Ring-shaped adhesive locators with a central
hole one centimeter in diameter are placed
on the crow's foot. A measuring caliper was
used as an aid to ensure that the distances
from the reference points of the lateral orbit
(outer canthus) and superior auricular
(tragus) were consistent. With this and with
the adhesive rings placed appropriately in
place for each subject, subsequent
placement was facilitated for samples taken
at the end of the study (photo 1).
The replicas were marked with the patient's
identification number and sent to an evaluation
center in France, where they were processed
using the Magiscan® system; the resulting
images were digitally analyzed and numerical
values were assigned to reflect the
characteristics of the surface (photo 3).
Photo 2. APPLICATION OF SILICONE
s13

Photo 3. FOOTPRINT FOR ANALYSIS
PROPHILOMETRIC
Optical profilometric techniques were used to
generate a graphical representation analysis
of the skin surface topography by means of
the silicone replicas. The analysis of these
fields generated parameters proportional to
the degree of wrinkling, roughness and other
surface markers, which were measured from
four different angles, related to the
orientation of the major lines of the skin.
The explanation and mathematical model were
taken verbatim from the statistical report sent by
Laboratorio Percos SA and carried out by
statisticians Christophe Lauze and Alain Taberly.
To ensure consistency of computer
measurements, lighting, and other technical
variables, the same operator performed image
analysis of all replicates until the end of the study.
Analysis was performed without knowledge of
assigned treatment or clinical data.
Silicone skin replicas of the right periorbital
area were made at the beginning of the
study (time 0) and at week 24.
Efficacy assessment according
to clinical follow-up
At weeks 4, 8, 16, and 20, signs of clinical improvement
were assessed based on subjective opinion.
s14
of each patient and the investigator's criteria. The
parameters were evaluated according to the
following severity scale:
Wrinkles:0 = no wrinkles, 1 = wrinkles only
with movement, 2 = wrinkles at rest (hidden
with makeup), 3 = wrinkles at rest (not hidden
with makeup).
Coloration:0 = bright pink skin, 1 = dull pink
skin, 2 = dull patchy yellow skin, 3 =
generalized dull sallow yellow skin.
Telangiectasias:0 = no telangiectasias, 1 =
isolated telangiectasias, 2 = grouped
telangiectasias.
Texture:0 = Smooth, 1 = Patchy roughness, 2 =
Generalized roughness
Firmness:0 = generalized firm skin, 1 = facial
sagging in one of the following areas:
periorbital and mandibular, 2 = facial sagging
in the two aforementioned areas.
Assessment of adverse effects according to
clinical follow-up
At weeks 4, 8, 16, and 20, local signs of
intolerance were assessed according to the
following parameters on a severity scale:
Erythema:0 = No erythema, 1 = Patchy
erythema, 2 = Generalized erythema.
Peeling:0 = No scaling, 1 = Patchy scaling, 2 =
Generalized scaling.
The following parameters were evaluated
according to the subjective opinion of each
patient, according to the parameters of the survey
carried out at each visit:
Pruritus:0 = No pruritus, 1 = Mild pruritus, 2 =
Moderate pruritus, 3 = Severe pruritus
Burning sensation:0 = No burning, 1 = Mild burning, 2 =
Moderate burning, 3 = Severe burning.
Each patient issued a global evaluation of clinical
improvement and tolerance to treatment.
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
using a visual analog scale at the end of each
visit.
In addition to the previously mentioned
parameters, compliance with the treatment
by the patients, the use of concomitant
substances not allowed and the appearance
of undesirable clinical manifestations
different from those expected for the adverse
effects of the drugs used in the study were
also evaluated.
Based on the evaluation of adverse effects, the
application of the topical medication was modified,
according to the criteria of the researchers and with
precise instructions for each patient.
A scale was also created to compare the evolution
of the treatment with respect to the previous visit,
from -1 to 3, where -1 means worsening, 0: no
changes, 1: slight improvement, 2: moderate
improvement, and 3: improvement. significant.
This same scale was used by the experts who
evaluated the photographs.
photographic tracking
At weeks 0 and 24, photographs of the face were
also taken, which were analyzed by five expert
observers different from those who carried out
the work, to determine the overall degree of
improvement from zero to one hundred percent.
The photographs were taken with a Sony Mavica
Digital MPEG movie 2X® camera in the frontal
plane and ¾ previously removing the makeup of
the evaluated patients.
Statistic analysis
For each of the parameters studied, an analysis
was performed using the non-parametric
Mann-Whitney U test to compare the baseline
values (time 0); as well as the possible
differences within the groups (variation
between time 0 and time 1 for each of the
two groups); and the possible differences between
the groups (comparison of times 1 and com-
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
stop of the variation between times 0 and times
1). For the analysis of the response to treatment
of the clinical-photographic evaluation, the non-
parametric test of the Wilcoxon signed ranks was
applied. All the analyzes were made considering
as significant those
the differences that had p values less than
0.05.
RESULTS
Description of the population for clinical and
subjective analysis
Of the 150 potentially eligible patients, 24
met some of the exclusion criteria or did not
meet all the inclusion criteria. Of the
remaining 126 chosen to participate in the
study, 63 were randomly assigned to the
retinaldehyde group and 63 to the retinoic
acid group.
Among the total population of patients recruited,
seven women withdrew from the study, five from
the control group treated with retinoic acid and
two from the experimental group treated with
retinaldehyde. In the experimental group, one
woman was excluded by the investigators due to
the presence of adverse effects (worsening of
previous melasma) and another withdrew due to
lack of time to attend follow-up visits. In the
control group, three people withdrew voluntarily
without clinical evidence of side effects and two
withdrew due to lack of time to attend follow-up
visits. This represents an adherence to treatment
of 94.4%.
Because there was low patient loss and because
the groups were clinically and demographically
comparable, patients who dropped out of the
study were excluded from the statistical analysis.
The total population subject to follow-up and analysis
lysis (clinical-photographic) was 119 patients, of
which when revealing the code, 61 were from the
s15
experimental group and 58 from the control group. The of both groups were similar, as
data demographics and background no
you clinic cyou I will be add in table 1.

Table 1. GENERAL CHARACTERISTICS OF THE

TREATMENT AND CONTROL GROUPS

Retinaldehyde % (n) Retinoic acid % (n)

Age (mean ± SD) 45.74±6.81 47.34±7.52
Clinical features
Telangiectasias 68.9 (43) 77.6 (48)
lentigines 82 (51) 87.9 (55)
Wrinkles with movement 100 (63) 100 (63)
dyschromia 67.2 (42) 70.7 (44)
Wrinkles at rest 100 (63) 100 (63)
Skin phototype
II 19.7 (12) 12.1(8)
II 27.9 (17) 37.9 (23)
IV. 52.5 (33) 50 (31)
smoking habit 14.8 (9) 17.5 (11)
Sun exposure intensity
Mild: 0-2 hours per day 100 (63) 100 (63)

Clinical criteria for improvement
A significant reduction in the presence of
isolated telangiectasias was found in the
retinaldehyde treatment group at weeks 12,
16 and 24 (p= 0.007, 0.017 and 0.034,
respectively) and a statistically significant
decrease at week 12 (p= 0.042 ) of facial
sagging in the peri-orbital and mandibular
area in the same group. No significant
differences (p>0.05) were found in the
behavior of other characteristics related to
wrinkles, coloration and texture. At week 24,
a significant increase in the proportion of
patients without telangiectasias in the
treatment group compared to the control
group was also found (p= 0.008) (graph 1).
treatment and control regarding the behavior
of wrinkles, lightening, telangiectasias, texture
and firmness of the skin (Graph 2).
Subjective criterion of improvement
Regarding the subjective criterion of
improvement in the parameters of wrinkles,
coloration, telangiectasias, texture and firmness
during the 24-week follow-up, it was found at
week 12 that a significantly higher proportion in
the control group of patients considered having a
moderate improvement in the reduction of
telangiectasias (p= 0.003); while there was a
significantly higher proportion of patients in the
treatment group who considered this
improvement to be significant (p=0.015).

At weeks 4, 8 and 20, no statistical differences At week 12, a higher proportion of patients was
(p>0.05) were found between the groups of found in the control group than in the control group.

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s16
considered that they had a slight improvement type of treatment that considered a moderate
in wrinkles (p= 0.026), while at week 24 the improvement in wrinkles with respect to the control
proportion of patients in the group was higher. (p= 0.046).

* p<0.05

Graph 1. REDUCTION OF TELANGIECTASIS

Graph 2. REDUCTION IN THE DEPTH OF WRINKLES ACCORDING TO CLINICAL CRITERIA,

yes
(no statistically significant difference)

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s17
At week 20 and 24 there was a significantly
greater perception by patients in the treatment
group of mild improvement and moderate
improvement of telangiectasias compared to
the control group (p values = 0.0002, 0.002, 0.
0008 and 0.002, respectively).
At weeks 4, 8, and 16, no statistically significant
differences were found in the parameters of
wrinkles, coloration, telangiectasias, texture, and
firmness in the two groups (p>0.05). Regarding
the subjective perception of improvement of each
patient according to a visual analogue scale, no
statistically significant difference in the six
visits made (p>0.05) (Table 2).
photographic evaluation
In the photographic evaluation carried out by
consensus of five experts, no statistically significant
difference was found between the proportions of
improvement, worsening or no change produced by
the treatment in the experimental group and in the
control group. a chi was found2overall score of 1.16
between the groups and a p value of 0.560 (graph 3,
photos 4 and 5).

Table 2. GLOBAL IMPROVEMENT ACCORDING TO SUBJECTIVE CRITERIA BY SCALE

VISUAL ANALOGUE DURING THE 24 WEEKS OF TREATMENT
(no statistically significant difference between groups)

Week
4 8 12 16 twenty 24
retinaldehyde 18 27.43 35.3 44.92 52.1 52.63
Ac. retinoic 16.53 26.47 36.93 44.69 51.53 59.03

Graph 3. GLOBAL IMPROVEMENT DURING THE 24 WEEKS

FOLLOW-UP ACCORDING TO PHOTOGRAPHIC EVALUATION
(no statistically significant difference between groups)

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 Photo 4
Adverse effects according to clinical and
subjective criteria
Regarding the evaluation of adverse effects
by the researchers and the subjective criteria
of the patients, it was found that during all
the weeks of follow-up the proportions of
erythema and desquamation in the control
and treatment groups showed a statistically
significant difference, always being higher.
Graph 4. ERYTHEMA DURING THE 24 WEEKS OF TREATMENT.
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
Photo 5
in the control group with a value of p<0.05, except
at week 24, in which there was no difference.
A statistically significant difference was only
found in the appearance of pruritus at weeks
4, 8 and 16, always being greater in the
control group (p<0.05). No statistically
significant difference was found with respect
to burning during the 24 weeks of treatment
(Graphs 4 and 5).
s19
 Graph 5. SCALING DURING THE 24 WEEKS OF TREATMENT
Taking into account the adverse effects such as
erythema, burning, desquamation and pruritus in the
patients, it was necessary to modify the frequency of
application of the cream in the treatment group to an
"every other day" manner (every other day). to a patient
at weeks 4, 8, 12 and 16.
In the control group, the frequency of application
of the cream was modified "every other day" to
one patient at week 4 and to two patients at
weeks 12, 16 and 20; In addition, in week 16, the
frequency of application of the cream was
changed to three times a week for one patient.
profilometric evaluation
For the profilometric analysis, of the 126
patients initially included in the study,
week 0
Photo 6. PROPHILOMETRIC COMPARISON AT WEEK 0 AND 24 WITH RETINALDEHYDE
s20
seven were excluded for the reasons
previously described and five patients were
excluded because their silicone footprints did
not meet the technical requirements. A total
of 114 patients -59 in the treatment group
and 55 in the control group- were finally
studied with profilometry. 13 parameters
were studied, the five amplitude parameters
were considered as the most relevant for the
study.
An overall and significant decrease in relief
amplitude parameters was observed in both
groups. These evaluations reflected a flattening
of the relief comparable between the 2 groups
(photos 6 to 9).
Retinaldehyde - Week 24
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 Photo 7. PROPHILOMETRIC COMPARISON AT WEEK 0 AND 24 WITH RETINOIC ACID

Photo 8. PROPHILOMETRIC COMPARISON AT WEEK 0 AND 24 WITH RETINALDEHYDE

Photo 9. PROPHILOMETRIC COMPARISON AT WEEK 0 AND 24 WITH RETINOIC ACID

DISCUSSION subjective with respect to reliability and poor

Numerous clinical studies have been carried
out to evaluate the subjective response to
topical therapy in photoaging, which have
demonstrated the efficacy of retinoic acid.
2
(2,11-14,22,26,30) and retinaldehyde (21-7);
however limitations in these studies
reproducibility to assess beneficial and adverse
effects (12,14), have led to the development of
objective measurement techniques such as
computerized image analysis, with a very good
correlation between clinical results
and profilometrics, in addition to the overall
decrease in bias (22, 30).

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s21
The veracity and reproducibility of computerized
image analysis of silicone skin replicas has been
previously established (22,30). We chose this
method to objectively determine changes in the
skin profile after treatment with retinaldehyde or
retinoic acid, complementing it with clinical and
photographic follow-up to further document
clinical changes in texture, color, and adverse
effects that cannot be measured through
profilometric analysis.
Retinoic acid has been the most researched
retinoid in the treatment of photoaging. Only
from the 80's was it used in dermatology for
this purpose. The efficacy of retinoic acid in
this disease was first demonstrated by
Kligman et al. (1984), using an animal model
of photoaging, found that treatment lasted
for 10 weeks with retinoic acid in mice
aged, better raba significantly you the ceither-
either
lagen in the papillary dermis, correlated with
the reduction of wrinkles. This observation
led to investigation of the potential of
retinoic acid in the treatment of photoaging.
Later ex-vivo investigations by Fisher et al.
(1996) helped to understand the molecular
basis of this finding. These authors found
that treatment of photodamaged skin with
0.1% tretinoin cream produced a complete
blockade of the synthesis of interstitial
collagenases and gelatinases, preventing
collagen degradation. It was also found that
retinoic acid blocks activation. of the nuclear
transcription factors AP-1 and NF-B, induced
by ultraviolet radiation.
Multiple studies have been conducted to
evaluate the role of retinoic acid in photoaging;
Of these, the most relevant are those that
use the molecule for a period of 6 months, the
which ones can nosummarize in table 3:

Table 3. CLINICAL TRIALS WITH RETINOIC ACID IN PHOTOAGING

Reference Type of study Duration No. of patients Observations

Leiden et al (1989) Randomized, double 6 months 30 Improvement of fine and thick
blind, tretinoin 0.05% wrinkles, discoloration and
cream vs vehicle hyperpigmentation

Caputo et al (1990) Tretinoin cream 6 months 89 Improvement of fine and

in ascending doses thick wrinkles, mottled
hyperpigmentation, texture
and laxity
Weinstein et al (1990) Double blind, tretin- 6 months 251 Dose dependent response,
0.05% and 0.01% best with 0.05%.
oin cream vs
vehicle Improvement in all
photoaging parameters

Bhawan et al (1991) Randomized, double 6 months 533 Dose dependent response,

blind, tretinoin in best with 0.05%.
0.001% cream,
0.01% and 0.05% vs Improvement in all
vehicle photoaging parameters

Olsen et al (1992) Similar to Bhawan's 6 months 296 Similar to above

et al

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Longer-term studies (>12 months) have been
performed. In the study carried out by Ellis et
al., in 1990, 16 patients were observed in 22
months of treatment, continuous improvement
was found until the tenth month and then
maintenance of this until the end of the study.
In 1993 Green et al. studied the effect of 0.05%
tretinoin cream, daily, within a period of 12
months, achieving a greater improvement after
six months of treatment. A study conducted by
Bhawan et al. in 1995 found that changes in
dermal collagen were only seen after six
months of continuous treatment with tretinoin.
Different concentrations of retinoic acid and its
side effects have been evaluated, and it has
been found that the higher the concentration,
the greater the potential for irritation.
erythema and desquamation. In conclusion,
topical retinoic acid is effective for the
treatment of photoaging; however, skin
irritation secondary to its use is a limiting factor
in treatment.
Retinaldehyde, an immediate precursor of
retinoic acid, has shown biological activity on
the skin with fewer side effects than the
former (22,23,25). Saurat et al. were the first
to evaluate the biological activity and
tolerability of retinaldehyde in human skin,
finding that retinaldehyde was well tolerated
and produced an increase in epidermal
thickness, increased keratin 14 expression,
and keratinocyte proliferation.
Retinaldehyde exerts these biological
activities only when it is transformed into
retinoic acid. In an open study, Ochando et
al. in 1994, studied the effect of 0.05%
retinaldehyde cream in 32 women, for four
months, finding a considerable reduction in
wrinkles, with very few adverse effects.
In 1998, 1999 Creidi et al., compa-
confirmed the efficacy of 0.05% retinoic acid
and 0.05% retinaldehyde, using profilome-
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
tria, found that both drugs are equally
effective in reducing photoaging; however,
patients who received treatment with retinoic
acid had a higher percentage of side effects
such as erythema, scaling, and burning,
compared to retinaldehyde. The findings in
our study were similar and comparable with
this one. In another study, Diridollou et al.
(1999), evaluated the effects of 0.05%
retinaldehyde, comparing it with vehicle in 40
patients, found that retinaldehyde increased
epidermal thickness and skin elasticity and
was very well tolerated by patients (34).
This controlled clinical study demonstrated that
the regular use of retinaldehyde and retinoic acid
improved the clinical manifestations of
photoaging, as evidenced by the skin replicas
analyzed by profilometry and the clinical analysis
carried out by the investigators and by the
patients, as well as the photographic study. . It is
important to highlight that the clinical-
photographic (qualitative) and profilometric
(quantitative) follow-up yielded similar results.
It was also evidenced that the patients treated
with retinoic acid presented a higher frequency
of side effects, such as erythema and
desquamation that decreased with continued
therapy over time or with a decrease in the
frequency of application, which is evidenced at
week 24 in which the adverse effects are equal
in frequency in the two groups.
Retinaldehyde is a well-tolerated drug, and
irritative dermatitis is rare, unlike retinoic
acid. Therefore, it can be used in the
treatment of photoaging with very good
clinical results and greater safety.
Because it is a controlled clinical trial in which
there was a high level of adherence (94.4%), very
few side effects (worsening of pre-existing
melasma in a single patient),
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With a representative sample size and a high
concordance between the evaluation of aging
carried out by the researchers, the subjective
criteria of the patients and the profilometric
study, this work allows us to conclude that women
between 35 and 60 years of age, with skin
phototypes II, III and IV and degrees of aging II
and III, benefit from treatment with retinaldehyde
and retinoic acid after six months of
continuous treatment.
REFERENCES
1. Gilchrest BA. Age-associated changes in the
skin. J Am Geriatric Soc 1982; 30:139-43
2. Sewon K. Photoaging and topical tretinoin:
Therapy, Pathogenesis, and Prevention.
Arch Dermatol. 1997; 133:1280–84
3. Kligman AM. Early destructive effects of
sunlight on human skin. NEVER. 1969; 210:
2377–80
4. Drake LA. Guidelines of care for photoaging /
photodamage. J Am Acad Dermatol 1996;
35:462–6.
5. Gilchrest BA: Skin aging and photoaging: an
overview. J Am Acad Dermatol 1989;
21:610–3
6. Kelly R.I. The effects of aging on the
cutaneous microvasculature. J Am Acad
Dermatol 1995; 33:749–56.
7. Montagna W, Kirchner S, Carlisle K: Histology
of sun damage human skin. J Am Acad
Dermatol 1989; 21:907–18.
8. Glogau RG. Physiologic and structural changes
associated with aging skin. Dermatol Clin
1997; 15(4):555–9.
9. Laurence N. Understanding premature skin
aging. N Engl J Med 1997; 337(20)
s24
10. Matarasso S, Hanke W. Cutaneus resurfacing.
Dermatol Clin 1997;15(4):569-82
11. Gendler EC. Topical treatment of the aging
face. Dermatol clin 1997; 15(4):561–7.
12. Weiss JS, Ellis CN, Headington JT, Tincoff
T, Hamilton TA, Voorhees JJ. Topical
tretinoin improves photodamaged skin: a
double-blind vehicle-controlled study.
JAMA 1988;259:527-532.
13. Verschoore M, Bouclier M, Czernielewski J, et
al: Topical retinoids: their uses in
dermatology. Dermatol clin 11: 107-115, 193
14. Weintein TP, Nigra PE, Pochi RC, et al: Topical
tretinoin for the treatment of photodamaged
skin. Arch Dermatol 1991; 127:659–65,
15. Sorg O, Didierjean L, Saurat JH. Metabolism
of topical retinaldehyde. Dermatology
1999; 199(suppl 1):13-17
16. Didierjean L, Sorg O. Biological activities of
topical retinaldehyde. Dermatology 1999;
199(suppl 1):19-24
17. Lachgar S, Charveron M, Gall Y, Bonafe JL.
Inhibitory effects of retinoids on vascular
endothelial growth factor production by
cultured human skin keratinocytes.
Dermatology. 1999; 199 (Suppl 1):25-7
18. Vienne MP, Ochando N, Borrel MT, Gall Y,
Lauze C, Dupuy P. Retinaldehyde alleviates
rosacea. Dermatology. 1999; 199(Suppl
1):53-6
19. Pechere M, Pechere JC, Siegenthaler G,
Germanier L, Saurat JH Antibacterial activity of
retinaldehyde against Propionibacterium acnes.
Dermatology. 1999; 199(Suppl 1):29-31.
20. Fort-Lacoste L, Verscheure Y, Tisne-Versailles J,
Navarro R. Comedolytic effect of to-
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
 Pical retinaldehyde in the rhino mouse model.
Dermatology. 1999; 199(Suppl 1):33-5.
21. Diridollou S, Vienne MP, Alibert M, Aquilina C,
Briant A, Dahan S, Denis P, Launais B, Turlier
V, Dupuy P. Efficacy of topical 0.05%
retinaldehyde in skin aging by ultrasound
and rheological techniques. Dermatology.
1999; 199(Suppl 1):37-41.
22. Creidi P, Vienne MP, Ochonisky S, Lauze C,
Turlier V, Lagarde JM, Dupuy P. Profilometric
evaluation of photodamage after topical
retinaldehyde and retinoic acid treatment. J
Am Acad Dermatol. 1998 Dec; 39(6):960-5
23. Creidi P, Humbert P. Clinical use of topical
retinaldehyde on photoaged skin.
Dermatology. 1999; 199(Suppl 1):49-52.
24. Boisnic S, Branchet-Gumila MC, Le Charpentier Y,
Segard C. Repair of UVA-induced elastic fiber
and collagen damage by 0.05% retinaldehyde
cream in an ex vivo human skin model.
Dermatology. 1999; (Suppl 1):43-8.
25. Sachsenberg-Studer EM. Tolerance of topical
retinaldehyde in humans. Dermatology.
1999; (Suppl 1):61-3.
26. Fluhr JW, Vienne MP, Lauze C, Dupuy P,
Gehring W, Gloor M. Tolerance profile of
retinol, retinaldehyde and retinoic acid under
maximized and long-term clinical conditions.
Dermatology. 1999; 199(Suppl 1):57-60.
27. Saurat JH, Didierjean L, Masgrau E, Piletta PA,
Jaconi S, Chatellard-Gruaz D, Gumowski D,
Masouye I, Salomon D, Siegenthaler G.
Topical retinaldehyde on human skin:
MagazineCESMEDICINEVolume 23 No.1(Dermatology Supplement) 2009
biological effects and tolerance. J Invest
Dermatol. 1994 Dec; 103(6):770-4.
28. Rampen FHJ, Fleuren BAM, de Boo TM,
Lemmens WAJG. Unreliability of self-reported
burning tendency and tanning ability. Arch
Dermatol. 1988; 124:885-888
29. McGregor JM. Acute effects of ultraviolet
radiation on the skin. Chapter 134. In:
Fitzpatric et al, eds, 8, pp 1555 – 1561
30. Grove GL, Grove MJ, Leyden JJ, Lufrano
L, Schwab B, Perry BH, et al. Skin replica
analysis of photodamaged skin after
therapy with tretinoin emollient cream. J
Am Acad Dermatol 1991;25:231-237
31. Kafi R, Kwak HS, Schumacher WE, Cho S, Hanft
VN, Hamilton TA, et al. Improvement of
naturally aged skin with vitamin A (retinol).
Arch Dermatol 2007; 143(5): 606-612
32. Sorg O, Antille C, Kaya G, Saurat JH.
Retinoids in cosmeceuticals. Dermatol Ther
2006; 19(5): 289-296
33. Lee MS, Lee KH, Sin HS, Um SJ, Kim JW, Koh BK.
A newly synthesized photostable retinol
derivative (retinyl N-formyl aspartamate) for
photodamaged skin: profilometric evaluation
of 24-week study. J Am Acad Dermatol 2006;
55(2):220-224
34. Mukherjee S, Date A, Patravale V, Korting HC,
Roeder A, Weindl G. Retrinoids in the
treatment of skin aging: an overview of
clinical efficacy and safety. Clinical
interventions in Aging 2006: 1(4) 327-348 .
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