`of acne vulgaris
`
`R E V I E W
`
`Suleyman Piskin
`Erol Uzunali
`Trakya University, Faculty of Medicine,
`Department of Dermatology, Edirne,
`Turkey
`
`Correspondence: Suleyman Piskin
`Trakya University, Faculty of Medicine,
`Department of Dermatology, Edirne,
`Turkey
`Tel +90 284 235 7641
`Fax + 90 284 235 7652
`Email spiskin@trakya.edu.tr
`
`Abstract: Acne is a disease of the pilosebaceous unit with involving abnormalities in sebum
`production, microbial fl ora changes, abnormal keratinization, and infl ammation. There are
`several therapeutic options like topical and systemic retinoids, antibiotics, and systemic hor-
`monal drugs. The topical retinoids a play very important role in the treatment of acne vulgaris.
`However, their use is limited due to skin irritation. A new generation product, adapalene is a
`good choice in the treatment of acne vulgaris with less side effects and high effi cacy confi rmed
`by numerous clinical studies.
`Keywords: adapalene, acne vulgaris, treatment
`
`Introduction
`Acne vulgaris is a chronic, infl ammatory disease of the pilosebaceous unit, that affects
`seborrhoeic areas like face, back, and chest and characterized by comedones, papules,
`pustules, nodules, cysts, and scars. Almost every individual has some degree of acne
`during puberty with spontaneous resolution occurring in early adult life. Occasionally,
`the disease persists into the fourth decade or even remains a lifelong problem. Because
`of the involvement of the face with considerable cosmetic problems, acne is a major
`psychosocial problem for many teenagers and young adults (Cunliffe and Simpson
`1998; Strauss and Thiboutot 1999; Braun-Falco et al 2001).
`
`The pathogenesis of acne
`In the pathogenesis of acne, the most important site is pilosebaceous unit which consists
`of a hair follicle and several sebaceous glands. These units are found everywhere on
`the body except the palms and soles. Pilosebaceous density is greatest on the face,
`upper neck, and chest, in roughly nine times the concentration found elsewhere on
`the body (Leyden 1995; Habif and Habie 1996).
`There are four main interacting factors in the pathogenesis of acne vulgaris:
`a) Increased sebum production,
`b) Microbial fl ora changes,
`c) Abnormal keratinization,
`d) Infl ammation (Strasburger 1997; Cunliffe and Simpson 1998; Braun-Falco et al
`2001; Korkut and Piskin 2005).
`To be able to treat acne, these factors should be targeted. The aim is to reduce
`or eliminate the primary clinical lesion, microcomedone, which is the precursor of
`almost all other acne lesions (Cunliffe et al 2003). There are a lot of topical or systemic
`agents for this purpose.
`
`Treatment
`The treatment of acne vulgaris is not curative. The purpose is to reduce discomfort
`due to infl amed lesions, to improve the appearance, and to prevent scars. Acne
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`management is a long-term treatment and requires patience.
`The patient should be informed on the issue (Cunliffe and
`Simpson 1998; Oberomok and Shalita 2002).
`Topical preparations constitute the sole treatment in
`many patients with acne vulgaris and are a part of therapeutic
`regimen in almost all patients. Topical treatment is enough
`for comedonal acne. In case of more severe acne, topical
`treatment can be combined with systemic treatment (Cunliffe
`and Simpson 1998).
`Topical treatment of acne vulgaris has changed over the
`years. Agents containing sulphur or resorcinol were used in
`especially fi rst part of 20th century. Salicylic acid which is a
`keratolytic agent was popular in some time. Nowadays, the
`most popular topical agents were retinoids, benzoyl peroxide,
`azelaic acid, and topical antibiotics (Bergfeld 1998).
`
`Topical retinoids
`Topical retinoids, derivatives of vitamin A have been used
`to treat acne for almost three decades. They are the most
`effective comedolytic agents for the treatment of acne
`vulgaris by normalizing or even increasing the desquamation
`process, thereby decreasing the formation and the number of
`microcomedones. They also promote the clearing of preexist-
`ing comedones (Bergfel 1998) and decrease in papulopustular
`lesions (Ellis et al 1998; Thiboutot et al 2001; Bershad et al
`2002). In addition, they have a marked anti-infl ammatory
`effect by inhibiting the activity of leukocytes, the release
`of pro-infl ammatory cytokines and other mediators, and the
`expression of transcription factors and toll-like receptors
`involved in immunomodulation. They also help penetra-
`tion of other active agents. Thus, they should be utilized in
`nearly every patient with acne and are the preferred agents
`in maintenance therapy (James et al 2000).
`Until recently, tretinoin, which is the active form of
`a metabolic product of vitamin A, was the only available
`topical retinoid (Leyden 1998). However, its use has been
`limited by local irritation after initiation of therapy. This side
`effect is a minimal problem with the third generation topical
`retinoids, such as adapalane. Tretinoin is available in a new
`delivery system (Retin-A Micro) to decrease the irritative
`effects. The purpose in this delivery system is to provide the
`drug directly to the follicle by entrapping it in microspheres
`(Skov et al 1997).
`
`Adapalene
`Adapalene is a synthetic naphthoic acid derivative with
`retinoid activity. The chemical name of adapalene is
`6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid.
`
`Adapalene is a white to off-white powder which is soluble in
`tetrahydrofuran, sparingly soluble in ethanol, and practically
`insoluble in water. The molecular formula is C28H28O3 and
`molecular weight is 412.52. Adapalene is represented by the
`structural formula represented on Figure 1.
`Some of its biologic activities are the same with tretinoin,
`however it is chemically more stable and lipophilic. By this
`way, it can reach higher concentrations in pilosebaceous unit.
`In addition, it has higher affi nity towards retinoic acid recep-
`tor (RAR) β and γ unlike tretinoin. It is important because
`epithelial cells have mainly RAR γ. Then, RAR-adapalene
`complex binds retinoid X receptor (RXR) and this regulates
`gene transcription by binding specifi c DNA sites (Leyden
`1998; Czernielewski et al 2001). Adapalene modulates
`cellular keratinization and infl ammatory process. This anti-
`infl ammatory effect is due to inhibition of the lipooxygenase
`activity and also to oxidative metabolism of arachidonic acid.
`These mechanisms may be the reason for decreased risk of
`irritation with adapalene. Adapalene has a very low percu-
`taneous absorption once the drug has penetrated the stratum
`corneum, so that it becomes entrapped in the epidermis and
`hair follicle, which are targeted areas (Millikan 2000).
`Absorption of adapalene through human skin is low.
`Only trace amounts (0.25 ng/ml) of parent substance have
`been found in the plasma of acne patients following chronic
`topical application of adapalene in controlled trials. Excretion
`appears to be primarily by the biliary route. Erythema, peel-
`ing, dryness and burning are the most frequent encountered
`side effects.
`
`Clinical studies
`Over the past five years, numerous clinical trials have
`been conducted on comparing the efficacy and tolerability
`of adapalene and tretinoin in the treatment of acne vul-
`garis. A meta-analysis of five large studies with more than
`900 patients over 12 weeks demonstrated that adapalene
`0.1% gel is as effective as tretinoin 0.025% gel (Cunliffe
`
`Figure 1 Structural formula of adapalene.
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`et al 1998). After 12 weeks, both agents were equally ef-
`fective but adapalene had a faster onset of action and less
`irritation. However, the comparison of adapalene 0.1%
`gel and tretinoin 0.1% microsphere gel in a double-blind
`study demonstrated more rapid comedone reduction with
`the tretinoin gel than with adapalene, but again, there was
`less irritation in patients using adapalene (Nyirady et al
`2001). Grosshans et al (1998) compared 0.1% adapalene
`and 0.025% tretinoin on 105 patients for 3 months and
`Ellis et al (1998) compared 0.1% adapalene and 0.025%
`tretinoin on 297 patients for 3 months. In both of these
`studies, there was no difference between these drugs in
`terms of efficacy. In another study, Cunliffe et al (1997)
`compared 0.1% adapalene and 0.025% tretinoin on 323
`patients for 3 months. They found that adapalene caused
`more decrease in total and noninflammatory lesions than
`tretinoin. However, there was no significant difference in
`terms of inflammatory lesions. Korkut and Piskin (2005)
`demonstrated that adapalane is more effective in nonin-
`flammatory lesions than inflammatory lesions.
`Adapalene 0.1% gel has been studied in 80 patients
`against isotretinoin 0.05% gel, which is the cis-isomer of
`retinoic acid, to compare their effectiveness and tolerance
`by Ioannides et al (2002). Both lesion counts and global
`assessment showed a better degree of effi cacy with adapalene
`than isotretinoin, although the difference between two drugs
`was not signifi cant. Although isotretinoin is less irritating
`than tretinoin, adapalene is signifi cantly less irritating than
`isotretinoin.
`In the study comparing tazarotene applied every other day
`and adapalene applied daily by Guenther (2003), both drugs
`had comparable effi cacy and tolerability. Dosik et al (2005)
`performed a study to compare the ability of epidermis to
`tolerate adapalene 0.1% cream and gel and tazarotene 0.05%
`and 0.1% creams on 26 subjects for a period of three weeks.
`The mean 21-day cumulative irritancy indices for adapalene
`0.1% cream and gel were signifi cantly lower than those for
`tazarotene 0.05% and 0.1% creams and not notably higher
`than that of negative control.
`A multicenter, randomized, double-blind study by
`Thiboutot et al (2006a) on 653 patients demonstrated that
`adapalene 0.3% gel was signifi cantly superior to adapalene
`0.1% gel and well-tolerated. In another study, the effi cacy
`and safety of adapalene 0.3% gel were compared with ada-
`palene 0.1% gel and vehicle on 214 subjects for 12 weeks.
`The results of this study demonstrated that adapalene gel
`0.3% was superior to adapalene 0.1% gel and vehicle in
`moderate to moderately severe acne while retaining a similar
`
`Adapalene in acne vulgaris
`
`study and tolerability profi le to adapalene 0.1% gel (Pariser
`et al 2005).
`Benzoyl peroxide and adapalene are among the most
`effective topical agents used in the treatment of acne vulgaris.
`Despite the fact that there are a lot of studies with benzoyl
`peroxide and adapalene alone, there are only a few studies
`comparing these two drugs. do Nascimento et al (2003)
`compared the effi cacy and safety of benzoyl peroxide 4% gel
`used twice daily with adapalene 0.1% gel used once daily on
`178 patients for 11 weeks. They found benzoyl peroxide more
`effective than adapalane on noninfl ammatory and infl amma-
`tory lesions at weeks 2 and 5, and they found both drugs safe.
`Korkut and Piskin (2005) have compared the effi cacy and
`safety of 5% benzoyl peroxide, 0.1% adapalene, and their
`combination. The study revealed that all three therapeutic
`protocols were effective in treating noninfl ammatory and
`infl ammatory lesions and that there were no signifi cant differ-
`ence between the groups in terms of effi cacy or side effects.
`Adapalene and benzoyl peroxide are effective and well tol-
`erated agents for acne vulgaris; combination therapy has no
`superiority over adapalene or benzoyl peroxide alone. There
`are a few studies that compare the side effects of benzoyl
`peroxide and adapalene. Brand et al (2003) demonstrated
`that 0.1% adapalene and 5% benzoyl peroxide combination
`was safe and well-tolerated.
`Thiboutot et al (2005) compared the effi cacy and safety
`of the combination of adapalene 0.1% gel and doxycycline
`with doxycycline alone for severe acne vulgaris. This study
`demonstrated that the combination of adapalene and an oral
`antibiotic provide a superior and faster benefi t than antibiotic
`alone and should be considered in the initiation treatment.
`Adapalene is also useful in maintenance therapy.
`Thiboutot et al (2006b) performed a study on 253 subjects
`to assess the maintenance effect of adapalene 0.1% gel and
`gel vehicle in subjects successfully treated in a previous
`12 week study of adapalene-doxycycline combination. The
`study demonstrated a clinical benefi t of continued treatment
`with adapalene 0.1% gel as a maintenance therapy. In another
`study by Zhang et al (2004), a total of 300 acne subjects
`entered the multicentre, randomized, investigator-blinded
`study comparing the effi cacy and safety of adapalene 0.1%
`gel plus clindamycin 1% solution versus clindamycin
`1% solution alone. In the second part of the study (weeks
`12–24) completed by 241 subjects, the effi cacy and safety
`of adapalene 0.1% gel alone as a maintenance therapy
`were investigated. This study confi rmed the importance of
`a maintenance therapy after a successful initial treatment
`and underlined the benefi t of a combination therapy with a
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`topical retinoid such as adapalane and a topical antibiotic in
`the treatment of infl ammatory acne.
`Adapalene treatment has a theoretical risk for retinoid
`embryopathy. However, manufacturer reports that only
`trace amounts of adapalene are absorbed into the skin. In
`the manufacturer’s studies on pregnant animals using doses
`120–150 times the human topical dose did not show an
`increased risk of adverse outcome or malformations. There
`have not been performed human studies to date, so the risk
`is undetermined for adapalene usage in pregnancy. However,
`because only trace amounts of the drug absorb into skin, it
`seems unlikely the drug induces malformations.
`In summary, numerous clinical studies demonstrating that
`adapalene treatment is a good choice for topical treatment of
`acne vulgaris with less side effects and high effi cacy.
`
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