Re-emergence of topical retinol in dermatology LH Kligman and EH Gans

Journal of Dermatological Treatment (2000) 11, 47±52
2000 Journal of Dermatological Treatment. All rights reserved. ISSN 0954-6634
47
Re-emergence of topical retinol in dermatology
LH Kligman 1 and EH Gans2
All-trans-retinol
was the first vitamin to be
1
synthesized in the laboratory.
University of Pennsylvania, School of
Dermatologic research with this
Medicine, Department of Dermatology,
agent, first begun in the 1960s,
Philadelphia, PA, USA;
2
Medicis Pharmaceuticals, Inc., Phoenix, was discontinued because of its
instability. Investigations since
AZ, USA
then have focused primarily on
a metabolite of vitamin A, alltrans-retinoic acid, for the treatment of various dermatological
disorders.
TREATMENT:
While
topically
applied retinoic acid is effective
in reducing the signs of intrinsic
aging and repairing photodamaged skin, depending on the
concentration it causes a number of irritant effects, including
Received 7th February 1999
Accepted 21st September 1999
BACKGROUND:
erythema, peeling, dryness, and
pruritus in some patients. This
drawback stimulated renewed
efforts to find a less irritating
retinoid.
ADVANCES:
As a result of
advances in the cosmetic industry, retinol is now being produced in a stable formulation,
and is again commanding the
attention of investigators.
CONCLUSION: Clinical trials conducted so far indicate that,
like retinoic acid, retinol can
induce changes that have a
beneficial effect on the epidermis but with decreased irritation. (J Dermatol Treat (2000) 11:
47–52)
Keywords: Retinol Ð Photodamage Ð Tretinoin
Introduction
Vitamin A and its natural metabolites and synthetic
analogues comprise a class of biologically active
compounds known as retinoids.1 These agents play a
vital role in certain biologic functions, such as vision,
embryogenesis, growth, tissue maintenance and
differentiation. In normal epidermis, retinoids
increase cell proliferation, while in hyperproliferative
epithelia they may have a normalizing effect.2
Early investigations described the clinical use of
all-trans-retinol (ROL), the first vitamin to be synthesized in the laboratory, in the treatment of skin
diseases due to abnormal keratinization3; 4 and in
acne.5; 6 These studies used high doses of ROL and
produced multiple disagreeable side effects.7 In the
early 1960s, two researchers, AM Kligman in the
USA and G Stuttgen in Germany, attempted to study
the effect of topical ROL in the treatment of acne.
However, these early unpublished trials were
Correspondence:
Lorraine H Kligman, PhD, University of Pennsylvania, School of Medicine,
Department of Dermatology, Rm. 227 CRB ± 415 Curie Blvd, Philadelphia,
PA 19104, USA. Fax: ‡1 215 573 2116
unsuccessful because of the inherent light sensitivity
and instability of ROL.
Investigators then turned their attention to a more
stable metabolite of vitamin A, all-trans-retinoic acid
(RA).8; 9 Topical RA, also known as tretinoin, was
shown to be effective in the treatment of acne.10
Later, because retinoids had been shown to
enhance wound healing in animal models by
increasing deposition of granulation tissue11 and to
stimulate fibroblast mitogenesis,12 it was thought
that retinoids might induce repair of the dermal
changes characteristic of photoaging. Studies in
humans and hairless mice proved this to be true.13; 14
Characteristics of aged and
photoaged skin
Skin that is chronically overexposed to sunlight
undergoes slow but cumulative damage in the
epidermis and in the connective tissues of the
dermis.15; 16 While the use of sunscreens is strongly
advised, it may not always provide complete protection against photodamage. Approximately 7% of
solar radiation is able to penetrate a sunscreen with
48 LH Kligman and EH Gans
a sun protection factor of 15. Therefore, during longterm chronic sun exposure, photodamage may occur
despite the use of sunscreens. Such damage has been
shown to occur in mice and in humans17; 18 even in
the absence of erythema.
Although it was once thought that only UVB
radiation was harmful to skin, recent research has
shown that UVA also can cause severe damage.18¡20
Both wavebands can produce erythema, inflammation, increased levels of proteoglycans and glycosaminoglycans, collagen damage, elastosis and,
ultimately, an increasing occurrence of skin cancer.
Photoaged skin, clinically called dermatoheliosis,21
has the following visible expressions: substantial
coarseness, yellowing, laxness, sagging, dyspigmentation and wrinkles. Few of these changes are seen
in skin that is intrinsically aged but has been
protected from chronic solar radiation. Innately aged
but otherwise healthy skin may be thin, dry and
scaly with mild sagging and fine lines. Moreover,
innately aged skin does not exhibit the striking histologic degradation that occurs, particularly in the
dermis, in response to photodamage.16
Treatment of photoaging
Hairless mice
Since hairless mice respond to UV exposure in a
manner that is accelerated but similar to that of
humans,22 this species has been used as a model for
human photoaging and its treatment with RA.23¡25
RA, applied topically to photoaged mice, has ameliorated UV-induced wrinkles25 and has induced the
synthesis of new, normal appearing collagen in the
upper dermis.13; 23; 25 Furthermore, RA reduced the
level of the UV-induced glycosaminoglycans and
encouraged the synthesis of new elastic fibers.24
Clinical
Numerous controlled clinical studies have assessed
the effect of RA on human photoaged skin.14; 26¡28
One of these26 evaluated the efficacy of 0.1% RA
cream applied to photodamaged skin for 16 weeks.
Two studies, one of which was multicentered,27; 28
evaluated 0.05% RA in a more emollient cream in
more than 250 patients for 24 weeks. Features of
substantial photodamage, such as coarse wrinkling
and extensive dyspigmentation, were reduced. There
were also cosmetic improvements, such as production of smoother skin texture, more uniform color
and reduction in fine lines. With even longer treatment (10–22 months) improvements continued.29
The formation of type I collagen, which is significantly decreased in the papillary dermis of
Re-emerge nce of topical retinol in dermatology
photodamaged human skin, was found to become
partly restored by topical treatment with 0.1% RA
cream with long-term use.30
These studies also demonstrated that RA can
produce irritancy and scaling in some patients
depending on concentration, skin type and age.
Therefore, various delivery systems have been developed to improve the acceptability of RA in patients
undergoing treatment of moderate to severe acne
and dermal photodamage.
Attention refocused on ROL
The UV-induced visible epidermal changes result in
an unacceptable feel and appearance of the skin such
as dryness, coarseness, uneven tone, fine lines and
wrinkling. These conditions are treated every day by
many people, but particularly by women, with a
wide range of skin types who desire effective cosmetic
products that will ameliorate these conditions
without irritation. As a result, ROL, long used at
very low concentrations in cosmetic products, is
again of interest. Once abandoned because of its
instability, ROL can now be sequestered in Microsponge polymers (Advanced Polymer Systems, Inc.,
Redwood City, CA, USA) with low irritancy and
cosmetic acceptability for treating the visible signs of
aging and photoaging. Protected from oxidation by
antioxidants such as vitamins C and E, it remains
stable with a shelf life of at least 2 years. By obviating
the rapid degradation that ROL would otherwise
undergo, the new formulation has permitted the
resumption of research with this agent.
Metabolism of ROL
The metabolism and biological activity of ROL have
been investigated in vitro in cultured human
keratinocytes. 31 It was found that ROL was metabolized primarily to retinyl esters and to relatively small
amounts of RA which activated nuclear RA receptors
and RA-receptor-dependent gene transcription.
However, these findings were not supported by a
1995 in vivo study by Kang et al32 in which ROL
was applied in increasing doses to human skin under
occlusion for periods ranging from 6 hours to 4 days.
Some ROL remained as free ROL whereas some was
metabolized to retinyl ester, retro-retinoids and
didehydroretinol. However, RA levels were undetectable or detectable only in trace amounts even though
RA-like effects on the epidermis were noted.
In a later paper from the same laboratory, the
penetration into human skin of occluded and
unoccluded ROL versus occluded and unoccluded RA
was studied.33 RA levels within the skin were not
measured but, instead, activity of the enzyme retinoic
LH Kligman and EH Gans
acid-4 hydroxylase (RA-4-OHase) was assayed.
Although several retinoids induce the enzyme, its
only substrate is all-trans-RA, which it metabolizes to
4-hydroxyretinoic acid.34 Occluded ROL induced
similar amounts of RA-4-OHase as did occluded RA,
whereas in unoccluded tests ROL was a more effective inducer than was RA. These authors suggest
that the inability to find, even at the detection level
of one nanogram of RA, measurable amounts of RA
when ROL is applied to human skin may be due to
the induction of RA-4-OHase, which prevents the
accumulation of RA.35
Safety
Because orally administered high doses of retinoids
have caused congenital deformities in both animals
and humans, studies have been conducted to investigate their safety when administered topically. In
studies with RA, using amounts that are usually
applied to normal skin once or repeatedly36 or to
inflamed skin with a damaged barrier,37 the
systemic absorption was either non-existent or nonsignificant. In another study, subtotal body inunction with 0.025% RA twice daily or total inunction
with 1% RA resulted in undetectable levels of RA in
the blood using a sensitive gas chromatographicmass spectrometric assay.38 Thus, teratogenesis as a
result of topical application of RA to skin is highly
unlikely.
Finally, using standardized risk assessment
methods for developmental toxicity,39 Johnson
analyzed topical RA compared with known toxic
agents such as oral 13-cis-RA and methotrexate.40 A
safety margin of more than 100 for RA contrasted
sharply with values close to 1 for the other drugs
examined, thus supporting the epidemiologic and
animal data that topical RA is not a human
developmental toxicant.
With regard to retinol, the results of the Ames test,
both with and without metabolic activation, showed
that vitamin A, like RA is non-mutagenic.41 It also
appears to be non-carcinogenic, inhibiting the development of malignant phenotypes in vitro and carcinogenesis in laboratory animals.42 Furthermore,
studies have demonstrated that ROL, whether under
occlusion or not, does not produce the irritation
caused by RA under occlusion.32; 33
Ef®cacy of ROL
Recent basic scientific studies have demonstrated
that ROL can be effective in inducing beneficial
epidermal changes with less irritation than RA.32; 33
On buttock skin occluded for 4 days and compared
with the vehicle, 1.6% ROL induced significant
epidermal thickening similar to that of 0.025% RA.32
Re-emergence of topical retinol in dermatology
49
Trace erythema, not significantly different from
vehicle, occurred with ROL whereas RA induced
measurable erythema.
A second study tested skin penetration of ROL and
RA with 4-day occlusion versus once-daily application for 4 days on unoccluded sites.33 Under occlusion both retinoids penetrated the skin similarly as
judged by the induction of RA-4-OHase. In the
unoccluded mode, which corresponds with actual
usage conditions, ROL penetration was more effective
than that of RA, but required a 10-fold higher
concentration than RA. As in the first study,32 ROL
increased epidermal thickness without the erythema
induced by RA.
These studies demonstrated that ROL has lower
potency than RA, requiring higher concentrations
than RA to produce similar epidermal effects. Despite
this, ROL is more effectively delivered into skin,
inducing retinoid changes in the epidermis without
irritation.
A number of clinical trials of ROL have been
completed and others are in progress. In one coded
but uncontrolled study two topical preparations
containing either ROL or vitamin E were applied on
opposite forearms of 14 women between 33 and 47
years old who described their skin as sensitive.43
Application was for 3 months, but in the final month
the sites were exposed twice a week to UV radiation
equal to 1.5 times each subject’s minimal erythemal
dose as previously determined. A measurement of
the looseness/adhesiveness of the stratum corneum
showed a significant decrease in the ratio indicating
a reduction in scaliness with ROL compared with the
vitamin E-treated arm. Additionally, there was a
reduction in the UV-induced shallow wrinkling with
the ROL cream.
An open, uncontrolled pilot study was conducted
in which 0.15% ROL was sequestered in Microsponges (Kligman AM, Kligman D. A pilot clinical
assessment study of an 0.15% Retinol delivery
system. Clinical Research Dept., Advanced Polymer
System, Inc., Redwood City, CA). Ten caucasian
women, aged 37–53 years were treated on the face
once daily for 3 months. At the beginning of the
study, all subjects displayed mottling, fine wrinkling,
skin laxity and dry, rough skin texture. These
features were clinically evaluated using a 0–9 ordinal
scale. In addition, a desquamation index was determined with a D’Squames test kit (Cuderm, Inc.,
Dallas, TX, USA). Evaluations were made at baseline
and after 3 months of treatment. The results were
expressed as percentage improvement over baseline
(Figure 1). All parameters evaluated exhibited significant improvement with the retinol treatment. Before
and after photographs from one of the subjects are
shown in Figure 2. Improvement in skin texture and
in the fine lines around the eye is seen.
50 LH Kligman and EH Gans
Re-emerge nce of topical retinol in dermatology
80
70
Figure 1
Clinical improvement (§SD)
after 3 months of application
of a 0.15% retinol cream. The
percentage improvement over
baseline for five parameters is
shown. Improvement in all
clinical features examined was
highly significant (P < 1%) as
determined by non-parametric
statistics (Wilcoxon’s signed
rank test).
% improvement
60
Figure 2
Improvement in fine lines in the eye area
as a result of treatment. (A) Before
treatment; (B) after 3 months of 0.15%
retinol cream treatment.
50
40
30
20
10
0
Desquamation
(dryness)
Smoothness
Dyspigmentation
(mottling/age spots)
Fine lines
Texture & laxity
LH Kligman and EH Gans
Treatment
Re-emergence of topical retinol in dermatology
Increase in
epidermal
thickness
Increase in Decrease in
keratinocyte
melanin
orderliness
Epidermal biopsies showing a change
Retinola
0.15%
‡
–
0.15%
‡‡
‡‡
0.30%
‡‡
‡‡
0.30%
‡‡
–
0.30%
–
‡‡
0.60%
‡
–
0.60%
‡‡
–
0.60%
‡‡
‡‡
No treatment
No treatment
No treatment
‡‡
‡‡
‡
–
‡
–
‡‡
‡‡
‡‡
‡
‡‡
‡
‡‡
–
–
–
–
Epidermal biopsies with essentially no change
0.15% ROL
3 specimens
Vitamin C
3 specimens
No treatment
9 specimens
– ˆ No change; ‡ ˆ small to moderate change; ‡‡ ˆ moderate
to substantial change.
a
Retinol – AFIRM.
Table I
Effect of retinol, vitamin C cream and no treatment on forearm
epidermis
In a third study, ROL was evaluated over a longer
period. Female subjects, aged 35–55 years, with
clinical signs of photodamage, applied one of the test
creams to one dorsal forearm twice daily for 9
months (Leyden JJ et al. Clinical safety and efficacy
assessment of 0.15%, 0.30% and 0.60% Retinol
Delivery Systems (AFIRM). Clinical Research Dept.,
Medicis Pharmaceutical Corp., Phoenix, AZ).
The contralateral forearm served as an untreated
control. The creams tested were as follows: ROL
cream at 0.15%, 0.30% and 0.60% (AFIRM 1X,
2X and 3X, respectively: Medicis Pharmaceutical,
Corp., Phoenix, AZ) and 10% vitamin C serum (Cellex
C). Epidermal shave biopsies were taken from both
arms after 9 months and compared with baseline
biopsies. These were assessed for changes in epidermal
thickness, orderliness of keratinocytes, decrease in
melanin and the presence of inflammation.
After 9 months, 15 subjects yielded five biopsies
from 0.15% ROL treatment, three from 0.30% ROL,
three from 0.60% ROL, three from Cellex C and 12
from untreated arms. One biopsy was lost in processing and three were inadequate for study. The results
are shown in Table I. With the exception of three
biopsies from 0.15% ROL-treated skin, all ROL-treated
biopsies showed significant epidermal improvement
without signs of inflammation. This is compared with
no improvement seen in nine of the untreated and in
all Cellex C biopsies.
Conclusions
Taken together, findings from basic scientific and
clinical studies indicate that ROL, like RA, can
reverse some of the changes that occur in the epidermis as a result of photoaging and chronologic aging.
These changes produce an improved visible or
cosmetic appearance of the skin. ROL, although
requiring higher doses than RA, is delivered into the
skin more effectively and with significantly less irritation. The stabilization of ROL in a new vehicle system
permits topical application in a range of useful
concentrations.
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