Journal of Dermatological Treatment (2004) 15, 200–207

# 2004 Journal of Dermatological Treatment. All rights reserved. ISSN 0954-6634

DOI: 10.1080/09546630410033006 200

Topical tretinoin or adapalene in acne vulgaris: an

overview
S Jain Retinoids target several patho-
etiologic events of acne vulgaris.
Skin Care Clinic, New Delhi, India The undisputed efficacy of treti-
noin, and yet its underutilization,
due to apprehension of retinoid
dermatitis, triggered a search for
newer, well-tolerated retinoids.
The discovery of nuclear retinoic
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the formulation of a novel reti-
noid with specific pharmacologic
profile and clinical objectives.
Accordingly, numerous clinical
trials have compared adapalene
and tretinoin in the management
of acne vulgaris and concluded
that tretinoin 0.05% gel exhibits

acid receptors has provided clues a greater anti-acne efficacy than

to a rational design of synthetic,
receptor-selective retinoic acid
agonists. Adapalene is an addi-
tion to the arsenal of topical
retinoids. It possesses the biolo-
gical properties of tretinoin, but
has a distinct physiochemical
profile, including high lipophili-
city and increased chemical and
photostability. It exhibits selec-
For personal use only.
adapalene 0.1% gel, but has
higher skin irritation potential.
This article reviews the pharma-
cology of adapalene, including its
retinoid receptor binding profile,
antiproliferative effects, cell dif-
ferentiation modulation, come-
dolytic and anti-inflammatory
activity, and specifically focuses
on the comparison of the efficacy

tive affinity for nuclear retinoic and irritation profile of adapa-

acid receptors and does not lene and tretinoin. (J Dermatol
bind to cytosolic retinoic acid Treat (2004) 15: 200–207)
binding proteins. It exemplifies

Received 2nd September 2003

Keywords: acne vulgaris — adapalene — tretinoin
Accepted 31st March 2004

Introduction Cytosolic retinoic acid binding proteins (CRABP)

The biological effects of retinoids are mediated by nuclear
receptors and cytosolic binding proteins.1–3 Two main types
of nuclear receptors have been characterized: retinoic acid
receptors (RARs) and retinoid X receptors (RXRs). Each
receptor family includes three subtypes: alpha, beta, and
gamma. RARs induce the expression of certain genes in a
ligand-dependent manner by binding to the retinoic acid
receptor element. They also downregulate the expression of
other genes by antagonizing the effect of the transcription
factor AP1. RAR gamma is predominantly expressed in the
epidermis.4–6 It is associated with keratinocyte differentia-
tion and is most significant in the pathogenesis of acne.3
Correspondence:
Sanjiv Jain, MD, MNAMS, FIAMS, FIMSA, Skin Care Clinic, 108 Darya Ganj,
New Delhi – 110002, India. Tel z91 11 23261880 / z91 11 23263668;
Fax z91 11 23261880 / z91 11 23263668; E-mail:
drsanjivjain@yahoo.com
modulate the concentration of intracellular active
retinoic acid and influence retinoid transport to cell
nuclei, but are not relevant to the control exerted by
retinoids on the differentiation of cultured keratino-
cytes.7–10 A few cell lines devoid of CRABP, however,
respond to retinoids,11 and certain synthetic retinoids,
with no affinity for CRABP, may bind retinoic acid
nuclear receptors,12 although it remains unclear how
such retinoids (adapalene) reach their cognate nuclear
receptors.
Pharmacology
Structure and retinoid-receptor binding
profile
Adapalene is a receptor-selective retinoid analog.4 The
relative affinity of adapalene and tretinoin for the
members of the RAR family was determined by
 S Jain Topical tretinoin or adapalene in acne vulgaris 201

kd value (nm)
inflammatory response to Propionibacterium acnes-induced
Retinoid antigens. Adapalene affects a number of inflammatory
RAR RAR RAR processes. In vitro, adapalene produced inhibition of 5- and
alpha beta gamma CRABP
15-lipoxygenase activity.19 However, in animal models of
Adapalene 1100 34 130 w1000 anti-inflammatory activity, adapalene is active, but at
All-trans-retinoic 15 4 5 4 concentrations much higher than those used clinically.20
acid

RAR=retinoic acid receptor; CRABP=cytosolic retinoic acid Clinical evaluation

binding proteins.
Table I
Equilibrium dissociation constants (kd value) for human RAR
subtypes and rats testes (CRABP) (in nmol/I)
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A series of large-scale, multicentre, comparative trials of
adapalene 0.1% gel versus tretinoin have been under-
taken (Table III). The outcome of individual primary
trials were not completely homogeneous and demon-
strated varying results regarding efficacy. European and

comparative binding studies using 3H-labelled CD 367
as the reference compound and high-performance size
exclusion chromatography to separate free ligands.
Table I summarizes the equilibrium dissociation con-
stants (kd values) for tretinoin and adapalene.13 It is
evident that tretinoin binds all three RAR subtypes.
However, it has a higher affinity for gamma-retinoic
acid receptors. Adapalene showed a 10-fold lower
affinity for RAR-alpha, but bound strongly to RAR-
beta and gamma.14 Furthermore, it induces CRABP
II synthesis, resulting in the buffering of excessive free
For personal use only.
US multicentre trials were planned as parallel studies
with similar designs, methodologies, and patient
selection criteria to minimize variables, yet the results
of one study favoured adapalene while another revealed
parity.24 The inconclusive and equivocal outcomes
necessitated a meta-analysis that concluded that
adapalene 0.1% gel was equally as efficacious as
tretinoin 0.025% gel.32 As it is not rational to
extrapolate the conclusions derived from the compar-
ison of adapalene 0.1% gel with tretinoin 0.025% gel to
tretinoin 0.05% gel, it prompted a scrutiny of the

retinoic acid, while its lack of binding to CRABP itself
prevents possible problems of intraepidermal storage.3
Antiproliferative effects and modulation of
cell differentiation
The ability to alter cellular proliferation and diff-
erentiation is a prerequisite for retinoids in the
treatment of acne. The in vitro studies comparing the
antiproliferative and differentiation activity of adapalene
and tretinoin are summarized in Table II.
Anti-inflammatory activity
The use of anti-inflammatory drugs for acne is
supported by recent studies that have inducted a key
role for interleukin-1 (IL-1) in hypercornification of
infundibulum17 and leukotriene B4 (LTB4) in the
development of tissue inflammation.18 The clinical
efficacy of tretinoin reflects its ability to modulate
comparative efficacy of 0.1% adapalene gel and
tretinoin 0.05% gel. A split-face clinical and bio-
instrumental comparison of 0.1% adapalene gel and
0.05% tretinoin gel in facial acne was undertaken. In
contrast to previous studies, the present trial revealed
the greater efficacy of tretinoin 0.05% gel over
adapalene 0.1% gel. This may be ascribed to the
higher concentration of tretinoin,27 and its higher
affinity for gamma receptors.33
The adverse reactions to adapalene are of the same
type, but of significantly lower frequency and lesser
severity than for tretinoin (Table IV). Most studies
concluded that adverse effects such as erythema,
scaling, pruritus, and burning could occur in a
significant percentage of patients. Overall, 45.7% of
the tretinoin-treated patients experienced some form of
irritation, compared with 32.4% of those treated with
adapalene.29 These studies had relied upon visual
examination and/or photography that did not permit
consistent visualization of subtle cutaneous characteristics
such as minimal erythema and scaling. In contrast, in a

Compound Proliferation Differentiation TG-1 expression

Hela IC50 (nM)15 F9 AC50 (nM)16 IC50 (nM)

Tretinoin 6 200 24
Adapalene 16 40 2.5
Ratio 2.7:1 1:5 1:10

F9=F9 embryonic carcinoma cell lines; TG=transglutaminase.

Table II
In vitro studies: antiproliferative and differentiation activity (tretinoin versus adapalene)
 202
S Jain
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Infiammatory acne Non-infianmatory acne

Study Design No. of patients Formulation
week 2 week 4 week 6 week 8 week 10 week 12 week 2 week 4

Verschoore et al21 AwT 48% 38%

Shalita et al22 Investigator-masked, randomized, No. of patients Adapalene 0.1% gel AwT AwT A,T AwT 48% 38%
parallel group, multicentre study enrolled=323 vs tretinoin 0.025% gel (p=0.6)
Alirezai et al23 Clinical study comparing Adapalene 0.1% gel A,T 65% 71%
adapalene and tretinoin gel vs tretinoin 0.02% gel
Cunliffe et al24 US multicentre, randomized, Enrolled=323 Adapalene 0.1% gel AwT 48% 38%
investigator masked trial Evaluated=288 vs tretinoin 0.025% gel (p=0.06)
European multicentred Enrolled=268 Adapalene 0.1% gel A=T A=T A=T A=T A=T A=T
controlled study Evaluated=259 vs tretinoin 0.025% gel
For personal use only.

Ellis et al25 Investigator-masked, randomized, Enrolled=297 Adapalene 0.1% gel A=T 47% 50%
multicentre, parallel group study Evaluated=237 vs tretinoin 0.025 gel
Grosshans et al26 Randomized, multicentre, No. of patients=150 Adapalene 0.1% gel AwT 33% 16% A=T A=T A=T A=T
investigator-masked study vs tretinoin 0.025% gel (pw0.001)
Pierard-Franchimont Split-face clinical and bio-instrumental Adapalene 0.1% gel TwA (p,0.05) TwA (p,0.05) Bio-Instrumental Clinical TwA
et al27 comparison 0.05% vs tretinoin 0.05% gel CFB TwA
(p,0.01)

Zhu et al28 8-week, multicentre, randomized, No. of patients=150 Adapalene 0.1% A=T
controlled, investigator-masked, vs tretinoin 0.025% gel
paralle group study
Tu et al29 Enrolled=150 A,T 29.8% 33% A=T A,T
Evaluated=139

Topical tretinoin or adapalene in acne vulgaris

Thiboutot30 Multicentre, randomized, Enrolled=169 Adapalene 0.1% vs tretinoin A=T
controlled trial microsphere 0.1%
Cunliffe31 Multicentre, randomized, Enrolled=409 Adapalene 0.1% gel A=T
controlled trial vs tretinoin 0.05%

A=adapalene; T=tretinoin; CFB=cyanoacrylate follicular biopsy.

Table III
Comparative efficacy of tretinoin and adapalene in acne vulgaris (result – % decrease – compared with baseline)
 S Jain
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Non-infianmatory acne Total Global

k 10 week 12 week 2 week 4 week 6 week 8 week 10 week 12 week 2 week 4 week 6 week 8 week 10 week 12

AwT 48% 38% A=T 83% 83% AwT 79% 73% A=T 70% 56%

AwT 48% 38% AwT 46% 33% (p=0.02) AwT AwT AwT AwT 49% 37% (p,0.01)
(p=0.6)
A,T 65% 71% A,T 73% 81% A,T 75% 80% AwT 77% 74%

AwT 48% 38% AwT 46% 33% (p=0.02) AwT 49% 37% p,0.01%
(p=0.06)
A=T A=T A=T A=T A=T A=T A=T A=T A=T
For personal use only.

A=T 47% 50% A=T 57% 54% A=T 54% 52%

A=T A=T A=T A=T A=T A=T A=T

Bio-Instrumental Clinical TwA TwA TwA (p,0.001) A=T TwA TwA w50% reduction at end
CFB TwA point TwA 56% 36%
(p,0.01) w50% comedones
TwA

A=T A=T

Topical tretinoin or adapalene in acne vulgaris

A,T A=T A,T A=T

A=T A=T A=T

T A=T A=T A=T

Table III
(continued)

203
 204
Clinical Subjective

S Jain
Vesicles Overall
Study Erythema Desquamation Dry skin Papules dermatitis Edema Tighlness Pruritus Burning tolerability

Alirezai et al23 A,T A,T A,T A,T A,T A,T AwT

22
Shalita et al week 2 week 12 A,T A,T (p,0.05) week 4 A,T week 12 A,T week 4 A,T week 8 A,T AwT mild
A,T (p,0.05) (p,0.05) (p,0.05) (p,0.05) (p,0.05) retinoid
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(p,0.05) dermatitis
in both
groups
Caron et al34 A=T A,T (p=0.04) A=T A=T A=T A,T A,T A,T AwT
(p=0.016) (p=0.013) (p=0.010)
Clucas et al35 A,T A,T A,T A,T A,T A,T AwT
Cunliffe et al24 A,T A,T (p,0.05) A,T (p,0.05) A,T AwT
US study (p,0.05)

European study A=T A,T (p,0.05) A,T (p,0.05) A,T A,T

(p,0.05) (p,0.05)
Dunlap et al36 week 1 week 1 A=T week 1 A=T week 1 A,T
A=T
For personal use only.

week 2 A,T week 2 A,T (NS) week 2 A,T week 2 A,T

(p,0.05) (p,0.05) (p,0.01)
week 3 A,T week 3 A,T week 3 A,T week 3 A,T (NS)
(p,0.05) (p,0.01) (p,0.01)
week 4 A,T week 4 A,T week 4 A,T week 4 A,T (NS)
(p,0.05) (p,0.05) (p,0.05)
Ellis et al25 A=T A=T A=T A=T A=T A=T
Grosshans et al26 A,T A,T (p,0.07) A,T (p,0.05) A=T (p,0.01) A=T
(p,0.05) (p,0.001)
Pierard-Franchimont week 2 A,T A=T
et al27 week 4 A,T
week 6 A=T

Topical tretinoin or adapalene in acne vulgaris

Egen et al37 A,T AwT
(p,0.05)
Leyden et al38 A=T A=T Comparable
erythema and
dryness amongst
all retinoids
Cunliffe31 A,T (p,0.05) A,T (p,0.05) A,T (p,0.05) A=T AwT

A=adapalene; T=tretinoin.

Table IV
 S Jain
split-face clinical and bio-instrumental comparison of
0.1% adapalene and 0.05% tretinoin gel in facial acne,
the erythema index39 and squamometry values were
used to quantitate skin irritation.27 The evaluation of
skin colour outside the acne lesion using narrowband
refractive sphectrophotometry showed the development
of minimal erythema on both the treated sides. The
between-product comparison indicated that erythema
was transiently more pronounced on the tretinoin
0.05% gel treated side at weeks 2 and 4, with no
further difference at week 6. Scaliness was explored
using the squamometry method and no significant
difference was yielded between the two test sides.27
Several explanations have been proposed for the greater
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tolerability of adapalene. These too, as will be evident
in the following paragraphs, are debatable.
It is hypothesized that due to its selective affinity
profile for the nuclear RARs, adapalene affects the
keratinocyte differentiation program, rather than pro-
liferation, and its potential for adverse effects arising
from activation of retinoid pathways unrelated to the
pathogenesis of acne is limited. However, these explana-
tions seem an over-simplification, not easily acceptable,
and open new lines of inquiry. First, the predominant
retinoic acid receptor in the skin and probably the most
For personal use only.
important for acne is the gamma subtype. RAR alpha
is minimally expressed in the skin.33,40 The tretinoin-
induced retinoid dermatitis is a non-specific irritant
activity of all-trans-retinoic acid rather than resultant of
binding to the minimally expressed alpha receptors.33
This is further borne out by the fact that tazarotene, the
most recent topical retinoid, has receptor selectivity
similar to that of adapalene. Once-daily tazarotene 0.1%
gel offers superior efficacy to once-daily tretinoin
0.025% gel, and every-other-day tazarotene 0.1% gel
appears to offer comparable efficacy to once-daily
adapalene 0.1% gel. Yet the tazarotene gel irritancy
potential is similar to if not greater than topical
tretinoin.
Adapalene does not break down in the presence of
light.41 While some dermatologists believe that tretinoin is
a photosensitizer, studies have consistently demonstrated
neither phototoxic nor photoallergic reactions.42–44 An
enhanced susceptibility to ultraviolet radiation is most
likely secondary to the desirable thinning of stratum
corneum, that in fact enhances the penetration of topical
antimicrobials. Moreover, if adapalene is so photostable,
why is it recommended that exposure to sunlight and
sunlamps be minimized during the use of adapalene and
that patients use sunscreens?
Alternatively, the explanation of a lower irritation
potential of adapalene may be its intrinsic anti-
inflammatory activity, possibly mediated by inhibition
of the lipoxygenase pathway. This may lead to less early
inflammatory ‘flares’, which are known to occur with
tretinoin therapy26. However, these early inflammatory
pustular flares, which have been reported with all
Topical tretinoin or adapalene in acne vulgaris 205
topical retinoids, are not only transient but also an
indication of the effectiveness of therapy. They are
produced by the breakdown of the follicular epithelium
of microcomedone, extrusion, and subsequent inflam-
mation of subsurface lesions,33 and should not be
unwisely mistaken as adverse events. Although it has
been documented that, in vitro, adapalene was more
active than indomethacin, betamethasone valerate,
tretinoin, and isotretinoin in inhibiting the lipoxygenase
pathway, in animal models of anti-inflammatory
activity, adapalene was only active at concentrations
much higher than those used therapeutically.20
The formulation of adapalene may be contributory to
its better tolerance. The results of the comparative
tolerance of adapalene 0.1% gel and six formulations of
tretinoin showed that adapalene gel was better tolerated
than any of six tretinoin formulations, including two
gels, two creams, and a microsphere formulation,
ranging in potency from 0.01% to 0.1%. It was
presumed that adapalene gel was better tolerated
because it was an aqueous formulation whereas treti-
noin gel contained alcohol.45 Furthermore, although
adapalene 0.1% gel is an oil-free gel, in reality it has a
creamy texture on skin. This is because microcrystals of
lipophilic adapalene are evenly dispersed in the aqueous
medium. However, another study of the irritant effect of
adapalene in an alcoholic vehicle similar to tretinoin,
showed that even alcoholic adapalene gel had less irritation
potential, casting a doubt that formulation alone was a
complete explanation for the decreased irritation noted
with adapalene.46
It can be presumed that retinoids may be cytotoxic
for keratinocytes to a degree that may not correlate
with receptor binding activity. The more neutral
adapalene molecule is probably less cytotoxic to
keratinocytes than the long chain organic acid,
tretinoin.47
Summary
Follicular hyperkeratinization is a critical element in the
pathogenesis of acne vulgaris. Topical retinoids are
potent modulators of cell differentiation. They normalize
follicular keratinization and down-regulate proinflam-
matory signals in the pilosebaceous unit. They exert
their biological effect through multiple gene regulatory
nuclear receptors. They are the logical choice for the
management of acne. The value of tretinoin is, however,
limited by its propensity to induce irritant dermatitis. It is
presumed that indiscriminate activation of all receptors by
pharmacological doses of non-receptor-selective retinoid
ligands invariably results in an unacceptable range of
toxic side effects that accompany the therapeutic effect.
The goal in trying to achieve receptor and function
selectivity of retinoid ligands is to activate only those
 206 S Jain
pathways required for efficacy in a specific disease
application. Optimally, a therapeutic effect can be achieved
with a receptor-selective retinoid while limiting the range
and severity of undesirable side effects. Adapalene is a
topical receptor-selective retinoid that improves both non-
inflammatory and inflammatory acne.
As comparative studies with tretinoin are necessary in
order to provide the database for definitive comparison,
adapalene has been investigated in many well-controlled
international clinical trials that have testified the clinical
benefits of adapalene and concluded that it was at least as
effective as tretinoin 0.025% gel / 0.05% cream in reducing
inflammatory, non-inflammatory, and total lesion counts.
Yet the most recent comparative trial between 0.1%
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adapalene gel and 0.05% tretinoin gel (in contrast to
previously studied supoptimal formulations) concluded a
greater anti-acne efficacy of tretinoin. Unlike previous
studies that had relied on clinical evaluations based on
direct visual examination and ordinary flash photography,
both of which may be compromised by viewers’ sub-
jectivity, the conclusions of this study were derived using a
combined clinical and objective bio-instrument assessment
that markedly improved the possibility of detecting the
subtle differences between the efficacy and tolerability of
two retinoids. These observations seem rational, as the
For personal use only.
predominant retinoic acid receptor expressed in the skin
and probably the most important for acne is the gamma-
subtype and tretinoin has higher affinity for the gamma
receptor than adapalene.
References
1. Shroot B, Michel S, Pharmacology and chemistry of
adapalene. J Am Acad Dermatol (1997) 36: S96–S103.
2. Pfahl M, Signal transduction by retinoid receptors. Skin
Pharmacol (1993) 6(suppl 1): 8–16.
3. Bernard BA, Adapalene, a new chemical entity with a
retinoid activity. Skin Pharmacol (1993) 6(suppl 1): 61–9.
4. Petkovich M, Regulation of gene expression by vitamin
A: the role of nuclear retinoic acid receptors. Annu Rev
Nutr (1992) 12: 443–7.
5. Elder JT, Astrom A, Pettersson U et al, Differential
regulation of retinoic acid receptors and binding proteins
in human skin. J Invest Dermatol (1992) 98: 673–9.
6. Masouye I, Gaub MP, Rochette-Egly C et al, Distribution
of retinoic acid receptors alpha I and gamma I in human
normal epidermis, oral mucosa, and psoriasis. J Invest
Dermatol (1992) 98: 534.
7. Darmom M, Rocher M, Cavey MT et al, Biological
activity of retinoids correlates with affinity for nuclear
receptors, but not for cytosolic binding proteins. Skin
Pharmacol (1988) 1: 161–75.
8. Asselineau D, Cavey MT, Shroot B, Darmon M, Control
of epidermal differentiation by a retinoid analogue
unable to bind to cytosolic retinoic acid binding protiens
(CRABP). J Invest Dermatol (1992) 98: 128–34.
9. Budhu A, Gillilan R, Noy N, Localization of the RAR
interaction domain of cellular retinoic acid binding
proteins II. J Mol Biol (2001) 305: 939–49.
Topical tretinoin or adapalene in acne vulgaris
Efficacy
non-inflammatory acne TwA
inflammatory acne T¢A
suitability for first-line therapy T¢A
treatment option in severe \ refractory acne TwA
Tolerability T¡A
A=adapalene; T=tretinoin.
Table V
Comparative evaluation of clinically relevant characteristics of
adapalene and tretinoin
Adapalene has been examined for tolerability and all
available data indicate that although both topical retinoids
may induce dryness, pruritus, and erythema, these
untoward effects were more common and severe with
tretinoin. The greater skin irritability induced by tretinoin
appears to be the result of non-specific irritant activity of
the long chain organic acid tretinoin, while the more
neutral adapalene is less cytotoxic to keratinocytes. The
other serial explanations offered for the better tolerability of
newer retinoid are debatable hypothesis.
The conclusions derived from a comparison of the
existing data on the efficacy and tolerability profile of
tretinoin and adapalene in the treatment of acne are
summarized in Table V.
10. Barkai U, Sherman MI, Analysis of the interaction
between retinoid binding proteins and embryonal
carcinoma cell. J Cell Biol (1987) 104: 671–8.
11. Douer D, Koeffler HP, Retinoic acid: inhibition of
the clonal growth of human myeloid leukemia cells.
J Clin Invest (1987) 69: 277–83.
12. Chytil F, Retinoic acid: biochemistry, pharmacology,
toxicology, and therapeutic use. Pharmacol Rev (1984)
36: 93S–100S.
13. Bernard BA, Bernardon JM, Delescluse C et al,
Identification of synthetic retinoids with selectivity for
human nuclear retinoic acid receptors. Biochem
Biophy Res Commun (1992) 186: 977–83.
14. Czernielewski J, Michel S, Bouclier M et al, Adapalene:
biochemistry and the evolution of new topical retinoids
for treatment of acne. J Eur Acad Dermatol Venereol
(2001) 15: 5–12.
15. Lotan R, Kramer RH, Neumann G et al, Retinoic
acid induced modification in the growth and cell surface
components of a human carcinoma (HeLa) cell line.
Exp Cell Res (1980) 130: 401–14.
16. Bailly J, Delescluse C, Bernardon JM et al, Differentiation
of F9 embryonal carcinoma cells by synthetic retinoids:
amplitude of plasminogen activator production does
not depend on retinoid potency or affinity for
F9 nuclear retinoids acid receptor. Skin Pharmacol
(1990) 3: 256–67.
 S Jain
17. Antilla HS, Reitam S, Saurat JH, Interleukin 1
immunoreactivity in sebaceous glands. Br J Dermatol
(1992) 127: 585–8.
18. Crook SW, Stockley RA, Leukotriene B4. Int J Biochem
Cell Biol (1998) 30: 173–8.
19. Hensby C, Cavey D, Bouclier M et al, The in vivo
and in vitro anti-inflammatory activity of CD 271,
a new retinoid like modulator of cell differentiation.
Pharmacol Skin (1989) 3: 160–2.
20. Brodgen RN, Goa KL, Adapalene. A review of
its pharmacological properties and clinical potential in
the management of mild to moderate acne. Drugs
(1997) 53: 1–11.
21. Verschoore M, Langner A, Wolska H et al, Efficacy
and safety of CD 271 alcoholic gels in the topical
treatment of acne vulgaris. Br J Dermatol (1991) 124:
368–71.
J Dermatolog Treat Downloaded from informahealthcare.com by Freie Universitaet Berlin on 06/25/15
22. Shalita A, Weiss JS, Chalker DK et al, comparison of the
efficacy and safety of adapalene gel 0.1% and tretinoin
gel 0.025% in the treatment of acne vulgaris. J Am Acad
Dermatol (1996) 34: 482–5.
23. Alirezai M, Meynadier J, Jablonska et al, [Comparative
study of the efficacy and tolerability of 0.1 and
0.03 p.100 adapalene gel and 0.025 p.100 tretinoin
gel in the treatment of acne.] Ann Dermatol Venereol
(1996) 123: 165–7.
24. Cunliffe WJ, Caputo R, Dreno B et al, Clinical efficacy
and safety comparison of adapalene gel and tretinoin gel
in the treatment of acne vulgaris. Europe and US
multi centre trials. J Am Acad Dermatol (1997) 36:
For personal use only.
S126–S34.
25. Ellis CN, Millikan LE, Smith EB et al, Comparison of
adapalene 0.01% solution and tretinoin 0.025% gel in
the topical treatment of acne vulgaris. Br J Dermatol
(1998) 139(52S): 41–7.
26. Grosshans E, Mark R, Mascaro JM et al, Evaluation of
clinical efficacy and safety of adapalene 0.1% gel versus
tretinoin 0.025% gel in the treatment of acne vulgaris
with particular reference to the onset of action and
impact on quality of life. Br J Dermatol (1998) 139(52S):
26–33.
27. Pierard-Franchimont C, Henry F, Fraiture AL et al,
Split-face clinical and bioinstrumental comparison of
0.1% adapalene and 0.05% tretinoin in facial acne.
Dermatology (1999) 98: 218–22.
28. Zhu XJ, Tu P, Zhen J, Duan YQ, Adapalene gel 0.1%:
effective and well tolerated in the topical treatment of
acne vulgaris in Chinese patients. Cutis (2001) 68(4S):
55–9.
29. Tu P, Li GQ, Zhu XJ et al, A comparison of adapalene gel
0.1% vs tretinoin gel 0.025% in the treatment of acne
vulgaris in China. J Eur Acad Dermatol Venereol (2001)
15: 31–6.
30. Thiboutot D, Gold MH, Jarratt MT et al,
Randomized controlled trial of the tolerability.
safety and efficacy of adapalene gel 0.1% and tretinoin
microsphere gel 0.1% for the treatment of acne vulgaris.
Cutis (2001) 68(4S): 10–19.
Topical tretinoin or adapalene in acne vulgaris 207
31. Cunliffe WJ, Danby FW, Dunlap F et al, Randomized,
controlled trial of the efficacy and safety of adapalene gel
0.1% and tretinoin cream 0.05% in patients with acne
vulgaris. Eur J Dermatol (2002) 12: 350–4.
32. Cunliffe WJ, Poncet M, Loesche C et al, A comparison of
the efficacy and tolerability of adapalene 0.1% gel versus
tretinoin 0.025% gel in patients with acne vulgaris:
a metaanalysis of five randomized trials. Br J Dermatol
(1998) 139(52S): 48–56.
33. Bershad S, Berson DS, Brodell RT et al, Topical retinoids
in the treatment of acne vulgaris. Proceedings of the Round-
table Meeting, Chicago, Illinois. Cutis (1999) 64(2S): 1–18.
34. Caron D, Sorba V, Kerrouche W, Clucas A, Split-face com-
parison of adapalene 0.1% gel and tretinoin 0.025% gel
in acne patients. J Am Acad Dermatol (1997) 36: S110–S12.
35. Clucas A, Verschoore M, Sorab V et al, Adapalene 0.1%
gel is better tolerated than tretinoin 0.025% gel in acne
patients. J Am Acad Dermatol (1997) 36: S116–S18.
36. Dunlap FE, Mills OH, Tuley MR et al, Adapalene 0.1%
gel for the treatment of acne vulgaris: its superiority
compared to tretinoin 0.025% cream in skin tolerance
and patient preference. Br J Dermatol (1998) 139(52S):
17–22.
37. Egan N, Loesche MC, Baker MM, Randomized, con-
trolled, bilateral (split-face) comparison trial of toler-
ability and patients preference of adapalene gel 0.1%
and tretinoin microsphere gel 0.1% for the treatment of
acne vulgaris. Cutis (2001) 68(4S): 20–4.
38. Leyden J, Grove GL, Randomized facial tolerability
studies comparing gel formulations of retinoids used
to treat acne vulgaris. Cutis (2001) 67(6S): 17–27.
39. Pierard GE, EMCO guidance for the assessment of skin
colour. J Eur Acad Dermatol Venereol (1998) 10: 1–11.
40. Elder JT, Astrom A, Petterson U et al, Retinoic acid
receptors and binding proteins in human skin. J Invest
Dermatol (1992) 98: 36S–41S.
41. Millikan LE, Adapalene: an update on newer com-
parative studies between the various retinoids. Int
J Dermatol (2000) 39: 784–8.
42. Pedace FJ, Stoughton R, Topical retinoic acid in acne
vulgaris. Br J Dermatol (1971) 84: 465–9.
43. Papa CM, The cutaneous safety of topical tretinoin. Acta
Derm Venereol (Stockh) (1975) 74: 128–32.
44. Stoudemayer T, Kligman AM, Effect of ultraviolet
light on tretinoin treated skin. 18th World Congress of
Dermatology Abstracts. In: Shalita AR, Fritsch PO, eds.
Retinoids Present and Future. Proceedings of Sympo-
sium, 18th World Congress of Dermatology, New York,
June 16, 1992. Mosby Year Book INC, ST Louis,
Missouri, 1992: P223A.
45. Galvin SA, Gilbert R, Baker M et al, Comparative toler-
ance of adapalene 0.1% gel and six different tretinoin
formulations. Br J Dermatol (1998) 139(52S): 34–40.
46. Allec J, Chatelus A, Wagner N, Skin distribution and
pharmaceutical aspects of adapalene gel. J Am Acad
Dermatol (1997) 36: S119–25.
47. Verschoore M, Poncet M, Czenielewski J et al, Adapalene
0.1% gel has low skin-irritation potential. J Am Acad
Dermatol (1997) 36: S104–S9.