Mini-Reviews in Medicinal Chemistry, 2009, 9, 1-10 1

Acne in the Adult

A. Ascenso* and H. Cabral Marques

iMed, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal

Abstract: This paper is a general overview that contributes for the knowledge systematization concerning the characteris-
tics of the acne in the adult, its prevalence, causes, diagnosis, classification and drugs available for treatment. The refer-
ence therapy is the combination between topical retinoids and oral antibiotics. Oral isotretinoin is still the only available
therapy that may modify the different acne physiopathologic factors and therefore it is the standard treatment for severe
acne. The importance of the acne treatment in the adult should be enhanced as it can also lead to symptoms of serious
depression and anxiety.
Key Words: Acne, adult, hormones, prevalence, physiopathology, retinoids, antibiotics, chemical structures.

INTRODUCTION: ACNE AND THE PATIENTS´ likely the physical scars could be permanent. Furthermore
QUALITY OF LIFE [3], the acne in women who are pregnant or breast-feeding,
is a major challenge to the level of therapy, given the impos-
A sudden interest for acne in the adult has been appear-
sibility of their inclusion in clinical trials.
ing, and consequently each time is more evident that the psy-
chological, social and physical effects of this condition do PREVALENCE
not decrease with the age. Acne and some of its treatments
Most acne cases are said to occur during adolescence and
may lead to depression and other psychiatric problems that,
spontaneously resolved in adulthood; therefore epidemiol-
if not properly diagnosed, could have serious consequences
[1-3]. Previous studies have examined the relationship ogical studies have mainly focused on acne in adolescents.
However, there has been a remarkable increase in the num-
between having acne and various psychological factors [4].
ber of these studies in adults; even if the results are not al-
The measurement focus shifted from psychological corre-
ways consistent. For example, an epidemiological study re-
lates (eg, personality) and emotional triggers (eg, stress) to
ported 4597 cases of acne (16%) among 28714 patients ex-
measuring the effect of acne on patients' quality of life.
amined in five dermatology clinics in France [5]. The aver-
Skindex [4] is a validated 29-item instrument to measure the
effects of skin disease on patients' quality of life. Results are age age of patients corresponded to 24 years old and 66%
were male. A study performed in Boston in 20749 patients
reported as 3 scale scores (functioning, emotions, and symp-
aged from 15 to 44 years old concluded that 27% of women
toms) and a composite score (average scale score). In addi-
and 34% of men had acne. In another study with 200 patients
tion, dermatologists rated the clinical severity of patients'
aged over 25 years old and who had mild to moderate acne,
skin disease, and patients responded to a global question
76% were female and 24% male. According to this study,
about how they are bothered by acne. Higher Skindex scores
indicate greater effects on quality of life. Second, in a multi- acne in the adult is defined as the acne that emerges from 25
years old, occurring in 18.4% of women and 8.3% of men. In
variate analysis, older adults with acne vulgaris reported
another study in 2000 healthy men and women aged 18-70
significantly greater overall effects on their quality of life
years old, it was observed that the first 16 years old, acne is
than did younger patients, even when controlling for the
more prevalent in men and that after 23 years old, becomes
clinical severity of the acne. Finally, this study confirmed
more prevalent in women. In a sample of 300 women, it was
other research suggesting that more severe acne is more
likely to be associated with psychological factors such as determined that 70% had clinically evident acne according to
the results of questionnaires (WHO-5). Another survey es-
anxiety, and with greater effects on patients' lives. However,
tablished a prevalence of 42% of women with acne aged 26-
there are other factors that contribute to the effects of acne
45 years old. A more recent study confirmed that the preva-
on patients' quality of life, including patient age. In fact, in a
lence of acne in adult women is high with more than 41% of
previous study, the psychosocial effects of acne on quality of
acne. However, only about 22% looked for medical treat-
life were found to be influenced more by patients' self-
perception of their acne severity than by the objective ment [5]. It was also observed that the acne in adult occurred
mainly in sensitive and slightly seborrheic skin, which is
severity of the disease [4].
quite important to decide about the type of treatment to use
Acne in the adult becomes a drawn out problem and with [5].
lasting effects. With aging, the skin loses collagen and more
PHYSIOPATHOLOGY
*Address correspondence to this author at the iMed, Faculdade de Farmácia, Acne vulgaris is a pathological dysfunction in the seba-
Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; ceous follicles with multifactorial etiology. The acne etiol-
Tel: ++ 351 217946427; Fax: ++ 351 217946470;
E-mail: andreiaascenso@ff.ul.pt / hcmarques@ff.ul.pt
ogy is not very well clarified, but it has been accepted that its

1389-5575/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

2 Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 Ascenso and Marques

Fig. (1). Algorithm of acne etiology (adapted from Krautheim [7]).

pathogenesis is multifactorial, with abnormal follicular dif- ing from the degradation of triglycerides. This change may
ferentiation and increased cornification, abnormal activity of contribute to hyperkeratinization by increasing cell adhesion.
the sebaceous gland and bacterial hyper-colonization, as well The hyperkeratinization, with consequent follicular obstruc-
as inflammation and immunologic reaction (Fig. (1)) [6]. tion results in the formation of non-inflammatory lesions
Probably acne vulgaris is an authentic inflammatory dis- (Fig. (2)): comedones, initially closed – “white spots”, and,
ease, and the androgeneous hormones, PPAR (peroximal months later, opened “black spots” [8].
proliferators activated receptor), neuropeptides and environ- Although the causes of acne are not completely clarified,
ment factors are able to interrupt the natural cycle of the se- it seems that one of the main causes is the hormonal origin,
baceous follicles and form the micro-comedones. Pro-inflam- both in adolescences and adults [9]. The major hormones
matory lipids and cytokines seem to act as mediators for the involved in the etiology of acne are androgens, taking into
beginning of the acne lesions. Propionibacterium acnes (P. account that 5
-reductase type 1, responsible for the conver-
acnes), a Gram positive microaerophile bacteria is responsi- sion of testosterone into dehydrotestosterone (DHT), appears
ble for the local inflammatory response of acne, with the to be most prevalent in the sebaceous glands of isolated acne
activation of monocytes and production of cytokines. The areas and to have greater activity in women with moderate to
inflammatory lesions may include: papules, pustules and severe acne. Concerning to suprarenal androgens, the serum
cystic nodules. It is believed that greater sensitivity to P. androsterone glucuronide is increased in women adult, and
acnes and their metabolites might be related to the severity the testosterone and dehydroepiandrosterone sulphate
of acne [6]. (DHEAS) are within the normal values. Other hormones
There are no changes in the composition of sebum in such as corticotrophin-releasing hormone (CRH) and mela-
hyperseborrheic skin, predominantly free fatty acids, result- nocytes stimulating hormone (MSH) express their receptors

Fig. (2). Internal structure of the skin (normal and with acne inflammation).
1- Hair; 2- Skin Surface; 3- Sebum; 4- Follicle; 5- Sebaceous Gland; 6- Blockage of Follicle opening; 7- Bacteria. (Adapted from
http://www.herbalremedies.com/acne.html)
Acne in the Adult Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 3

on the sebaceous glands. While MSH is related to the in- tions: lack of palpation; small comedones and inflammatory
flammatory process, CRH may be considered a hormone that lesions are generally not viewed; residual erythema, changes
promotes lipogenesis in sebocytes (testosterone and growth in pigmentation or excoriations are minimized. However, the
hormone induce the negative feed back of CRH). Thus, re- polarized light and fluorescence photography can partly im-
search suggests that CRH is involved in the clinical devel- prove this assessment [14]. A study was designed with the
opment of acne, androgenetic alopecia, skin aging, xerosis objective to achieve a reliable method of lesions counting
and other skin disorders associated with variations in the based on a facial diagram divided into five segments. It was
production of lipid sebum [8, 10]. concluded that the reliability of the method is acceptable if it
To examine the influence of neurogenic factors in the is implemented by the same technician. The variability be-
pathogenesis of acne, were evaluated quantitatively the ef- tween these technical specialists seems to be reduced
fects of neuropeptides in the morphology of the sebaceous through a standardized training. The papules are the easiest
glands in vitro using the electron microscopy. It was found lesions to assess, perhaps because they are more visible, es-
that substance P promoted the proliferation and differentia- pecially in Caucasian patients, besides that the number of
tion of the sebaceous glands [11]. papules is usually lower than the number of comedones [15].
Genetic and environmental factors are other external fac- In 1997, Doshi et al. developed a comprehensive system
tors mentioned, even though empirically, in the pathogenesis of acne graduation [14]. This system divides the face, chest
of acne. Regarding inheritance, there is some evidence based and back in six areas (forehead, cheeks, nose, chin; bust and
on studies of twins that suggests that acne may have a he- back) and assigns a factor 1, 2 or 3 to each area in accor-
reditary component [12]. dance with the extension. To each type of lesion is assigned
a value depending on the severity: absence of lesions = 0;
According to Christos Zouboulis [13] (from the derma-
comedones = 1; papules = 2; pustules = 3; nodules = 4. The
tology department of the Medicine University in Berlin), the
scores for each area results from the scores of lesions more
current research is modifying the classic vision of acne
severe multiplied by the relevant factor. The final sum total
pathogenesis through the identification of the upstream score is classified as: slight (1-18), moderate (19-30), severe
mechanisms. A causal linking between stress and emotional
(31-38); very severe (> 39). A very similar system has been
acne has been claimed during a long time. There are some
proposed by Dreno et al. [16] in 1999. Recently Rizova and
evidences that the underlying molecular mechanism is re-
Kligman [14] used the photography with parallel polarized
lated to the expression of the neuro-endocrine mediators’
light and cross in combination with video microscopy and
receptors by the sebaceous gland. Recent studies have indi-
measurement of the production of the sebum.
cated that the human sebocytes express functional receptors
for hormonal release of corticotrophin, melanocortin, vaso- Concerning differential diagnosis, there are two diseases
active intestinal polypeptide,
-endorphin, neuropeptide Y, that are rather frequently confused with acne: the rosacea
among others. After ligand connection, these receptors (often called acne rosacea in the older literature), the perioral
modulate the production of the cytokines inflammatory me- dermatitis and the malassezia folliculitis. Rosacea may be
tabolism, the proliferation, the differentiation, the lipogenesis distinguished from acne by several features, such as: age
and the androgeneous metabolism in sebocytes, as men- (rosacea patients are generally older than are acne patients,
tioned before. These neuro-endocrin factors seem to mediate except in acne in the adult), type of lesion (acne lesions are
stress systemically and topically, stimulating the sebaceous follicular, while rosacea lesions are not) and distribution
gland, affecting finally the clinical manifestation of acne pattern (rosacea usually affects primarily the central third of
[13]. the face, while acne is generally more widespread on the
face, neck, back, and chest). Table 1 summarizes the referral
This new concept of acne pathogenesis will certainly lead
guidelines for acne and rosacea [17].
to the introduction of new drugs for the acne treatment, espe-
cially those whose action includes the inhibition of the main Perioral dermatitis is a difficult disorder to define be-
inflammatory mechanisms involved. cause of variable clinical presentations. Its distribution pat-
tern is generally perioral, although occasionally it may be
DIAGNOSIS AND ESTABLISHMENT OF GRADING
more widely distributed on the face. This disorder is seen
CRITERIA FOR ACNE SEVERITY
most commonly in young adult women, but may affect both
The basic morphology of acne and the variation in the genders and all ages. Clinically, it is characterized by a com-
number of acne lesions over time does not permit an assess- bination of eczematous and acneiform features. When ec-
ment and a simple diagnosis purpose of this pathology. zematous features are absent, it may be difficult to differen-
There have been developed various measurements based on tiate from acne, with the perioral pattern often the most use-
clinical examinations and photographic documentation. ful clue [17]. Malassezia folliculitis (previously called ‘pity-
rosporum folliculitis’) is due to proliferation of a yeast,
Historically, the measurements of acne are divided into called malassezia, within the hair follicles. It presents as
two groups: the lesions countdown and the graduation. an itchy, acne-like eruption and most often affects the trunk
Graduation is an estimation of the degree of severity which and it can also cause pityriasis versicolor and seborrhoeic
is quite subjective. It is based on observations of dominant dermatitis [18]. Some adolescents with recalcitrant follicular
lesions, evaluating the presence or absence of inflammation. pustules or papules may have acne and malassezia folliculitis
Sometimes it is problematic because many variables are in- simultaneously. According to Zargari [20], the malassezia
volved. Some graduators (technical specialists) use reference folliculitis can be differentiate from acne vulgaris in some
scales based on photographs. This method has several limita- aspects: 1) malassezia folliculitis is pruritic, especially after
4 Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 Ascenso and Marques

Table 1. Referral Guidelines for Acne and Rosacea Generally, the adult acne is characterized by presenting a
more inflammatory component with fewer comedones and
lesions tend to allocate more at the bottom of the face [5].
Acne
TREATMENT
Acne that has not responded to appropriate therapy

Candidates for isotretinoin

Currently, there is a huge variety of topical and systemic
drugs for the acne treatment (Table 3) [24]. The topical
Rarer variants of acne (acne excoriée, chloracne, acne fulminans) treatment is indicated for mild to moderate acne as adjunc-
Suspected Demodex folliculitis, Pityrosporum folliculitis
tive treatment of inflammatory and nodulocystic acne. The
drugs can be absorbed through the transdermal or transfol-
Female patients with suspected endocrine disorder licular route, which will depend on the solubility, polarity
Pregnant patients with acne and the particles size in the formulation. Particles with sizes
between 3-10 >m can penetrate into the follicular ducts,
Patients with acne scarring while larger particles are retained on the skin surface and
Rosacea smaller particles are distributed by the stratum corneum and
hair follicle [8, 25].
Rosacea that has not responded to appropriate therapy
Table 3. Acne Treatments and the Physiopathologic Factors
Candidates for isotretinoin and Acne Type Associated (adapted from Fernandes
Candidates for electrosurgery, laser surgery, or dermabrasion for the
& Rodrigues [8]; Usatine et al. [24] )
treatment of telangiectasia or phymatous changes

Patients with ocular rosacea (dermatologist and ophthalmologist referral) Acne Physiopathologic Treatment
Factors
sweating; 2) trunk involvement and sparing of the face are
among the other features of malassezia; 3) antibiotics have Hyperkeratinization Tazaroten; tretinoin; adapalen; azelaic
no role in treating malassezia [19, 20]. acid; salicilic acid; oral isotretinoin

Hyperseborrhea Anti-androgens (women); topical/

TYPES OF ACNE systemic retinoids
According to age criteria, acne can be classified as neo- Bacterial proliferation Benzoyl peroxide; antibiotics; tazaro-
natal acne, infant acne, puberty acne and acne in the adult ten; tretinoin; adapalen; azelaic acid;
[5]. oral isotretinoin
Different types of acne exist with several severity degrees Inflammation Intralesional corticosteroid; antibiotics;
that could characterize the acne in the adult (Table 2) [5, 21- azelaic acid; benzoyl peroxide
23].
Hormonal disregulation Oral contraceptives; anti-androgens;
Table 2. Types of Acne and its Characterization spironolactone

Acne Type Treatment

Type of Acne Characterization
Comedogenic Tazaroten; tretinoin; adapalen; azelaic
common type of acne with presence of black acid; benzoyl peroxide
Acne vulgaris
spots, white spots, papules and/or pustules
Light Papulopustular Antibiotics and benzoyl peroxide;
Acne conglo- very severe type of acne with presence of some tazaroten; tretinoin; adapalen; azelaic
bata/nodular nodules and cutaneous injuries acid
Acne papulopustu- type of acne characterized by the presence of Moderated Inflammatory Begin with antibiotics and benzoyl
lar pustules and papules
(papulopustular or nodulo- peroxide; Addition of: tazaroten; treti-
type of acne characterized by the presence of cystic) noin or adapalen if the inflammation
scratched or picked pimples. increases
Acne excorie
It is more common in females than males, and can
Severe cystic Isotretinoin
be a sign of stress or depression

type of acne that is originated by the reaction to a

The hydroalcoholic solutions and gels are those that gen-
Acne mechanics constant pressure on the skin, friction, heat or
when the skin is always covered
erally cause a more efficient drug release in topical formula-
tions [3]. The systemic treatment is indicated in cases of
cutaneous rash characterized by many comedones moderate to severe acne, especially when the acne scars start
Chloroacne due to the exposition of chlorinated or chemical to appear. The antibiotics with anti-inflammatory properties,
herbicides agents such as tetracyclines and macrolides are the therapeutic
acne that appears after a long exposition to the choice for papulopustular acne, even if there is some bacte-
Acne steroid
corticosteroids rial resistance. Isotretinoin is the best therapeutic treatment
Acne in the Adult Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 5

for papulopustular acne, severe acne and nodulocystic / con- dolytic action. Retinoids are considered the first line treat-
globata acne. The hormonal treatment with anti-andro- ment for acne, being also a maintenance therapy. These
geneous properties represents an alternative regimen for drugs cause the desobstruction of the pores, preventing the
women. Corticosteroids in reduced dose (prednisone, predni- formation of white spots and still present the benefit of de-
solone or dexametasone) are indicated in patients with acne creasing the first signals of cutaneous aging, being therefore
or adrenal hyper-androgenism. The future trends of long an essential treatment for acne in the adult. However, it can
term treatment represent regimens of low dose isotretinoin, irritate the skin and provoke sensitization to the solar exposi-
new formulations of isotretinoin (micronised isotretinoin as tion. Therefore it is important to use daily solar protection.
solid lipid nanoparticles (SLN), complexed with cyclodex- According to a recent study, the retinoic acid/
-CD complex
trins (CDs), isotretinoin metabolites, combined treatments to shows a significant increase of the effectiveness and toler-
reduce toxicity and act on more pathological factors, sensibi- ance to the acne vulgaris treatment, which will also increase
lising-insulin agents, type 1 inhibitors of the 5
-reductase, the patients’ compliance to this treatment [28].
new molecules of antisense oligonucleotides, and anti-inflam-
On the other hand, it is usual the topical antibiotic com-
matory agents, such as lipoxigenase inhibitors [26, 27].
bination with retinoids to treat comedogenesis, bacterial
TOPICAL THERAPY growth and inflammation. This combination also increases
the effectiveness and tolerance to the treatment. On the other
Topical retinoids are derived from vitamin A and are
way, benzoyl peroxide can be used in combination with topi-
classified in three groups: non aromatics - tretinoin and isot- cal retinoids to reduce the dose of antibiotic.
retinoin; monoaromatics and polyaromatics - adapalen and
tazaroten. Other classification is the first, second and third The transdermal penetration and systemic bioavailability
generation retinoids (Table 4). of topical retinoids are not yet completely clarified. Thus,
there is not a consensual opinion about the use of topical
Table 4. Retinoids Molecular Structure
retinoids during the pregnancy [29].
FIRST GENERATION The main topical retinoids are:
H3C CH3 CH3 CH3 • Adapalen: one of the most topical retinoids used (Fig.
RETINOL
OH (3)) that is commercially available as 0.1% gel, cream or
solution form. In a randomized study with 268 patients
CH3 with facial acne vulgaris, it was found that the 0.1% gel
H3C CH3 CH3 CH3 was as effective as the 0.025% tretinoin gel. Another
COOH study in the USA showed that the group of patients
TRETINOIN
treated with adapalen showed a greater reduction in in-
CH3 flammatory and non-inflammatory lesions of acne, as
well as the side effects compared with the group treated
H3C CH3 CH3 CH3 with tretinoin [3, 30]. However, a comparison study be-
ISOTRETINOIN tween 0.1% tretinoin microspheres gel, 0.05% tretinoin
COOH gel and 0.1% adapalen gel, has shown that tretinoin was
CH3 more effective [31, 32]. Thus, it appears important to
consider the drug dosage form and the type of formula-
SECOND GENERATION tion in comparative studies between different drugs.
CH3 CH3 CH3
HO O
ETRETINATE H3C COOC2H5

H3OC CH3

CH3 CH3 CH3

ACITRETIN H3C COOH

H3OC CH3

THIRD GENERATION

H3C CH3 CH3 Side chain

AROTINOL
O
H3C

H3C CH3 Fig. (3). Adapalene molecular structure: IUPAC NAME: 6-[3-(1-
adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic acid).

The retinoic acid receptors are
,  and  -RAR and RXR • Tazaroten: introduced in 1997, tazaroten is one of the
receptors and the citosolic skin binding proteins are the most recent topical retinoids for the treatment of acne. It
CRABP, which lead to an anti inflammatory and come- is a synthetic acetilenic molecule which is rapidly con-
6 Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 Ascenso and Marques

verted by esterases in its active metabolite, tazarotenic

acid in keratinocytes (Fig. (4)). The tazarotenic acid has
the ability to bind and activate the nuclear retinoic acid
receptors. The 0.05% and 0.1% concentrations are avail-
able in cream and gel formulations. Tazaroten is also in-
dicated for the treatment of plaque psoriasis and pho-
toaging. Tazaroten is the most irritant topical retinoid. It
can not be used during pregnancy because it caused birth
anomalies in animals’ studies. In a study in which a 0.1
% tazaroten gel was compared to 0.025% tretinoin gel,
the first one has shown to be more effective in reducing
non inflammatory lesions and equally effective in reduc-
ing inflammatory lesions [3,33]. In another study com- Fig. (5). Tretinoin/ DM-
-CD complex: stable form and the instable
paring the 0.1% tazaroten gel and 0.1% tretinoin mi- form The most stable complex has -5723.4322023 Hartrees (Har-
crosponge gel, the tazaroten again showed greater effi- tree  2625.5 kJ/mol) (Molecular Modelling Software: Gaussian 03
cacy. Regarding the comparison between a 0.1% tazaro- Program).
ten cream and a 0.1% adapalen cream, a randomized
double-blind trial showed that the tazaroten cream had • Isotretinoin: exists in 0.05-0.1% cream and 0.05% gel
greater efficacy and tolerability. Tazaroten is currently form. In a double-blind trial with 268 patients, to whom
used as an alternative treatment to tretinoin and adapalen was applied 0.05% isotretinoin gel twice daily for 14
in refractory cases [34, 35]. weeks. It was observed the effectiveness of this drug for
the treatment of mild to moderate acne, reducing both in-
S flammatory and non-inflammatory lesions. The drug was
well tolerated; with withdraw of only two patients be-
cause of skin irritation. Side effects are similar to those of
tretinoin [3, 37].
H3C CH3
There are other topical retinoids used in the treatment of
N O CH3
acne, such as the retinaldehyds and
-glucuronide retinol.
O Topical antibiotics have demonstrated they have not only
bactericidal action, but they also have an anti-inflammatory
Fig. (4). Tazarotene molecular structure: IUPAC NAME: ethyl 6- action through the inhibition of leucocitary chimiotaxy and
[2-(4,4-dimethylthiochroman-6-yl)ethynyl]pyridine-3-carboxylate. lipase production by P. acnes [38].
• Tretinoin: Corresponds to the trans-retinoic acid form. • Sodium Sulfacetamide: a topical antibiotic that inhibits P.
The formulations include 0.025- 0.1% topical creams and acnes and opens the obstructed pores, being efficient for
0.01-0.025% gels. However, there has been emerging the treatment of the inflammatory acne. There is in 10%
new sustaining release systems in which the active sub- topical formulations combined with 5% sulphur.
stance is vehiculated in microsponges or polymers in or-
• Clindamicine: topical gel, lotion or 1% solution proved to
der to remain at the stratum corneum and thus promote
comedolisis and modulation of the keratinocytes prolif- be safe and well tolerated. The possible collateral effects
are dryness and skin irritation. The possible occurrence
eration. The collateral effects include redness, descama-
of pseudomembranous colitis is not clinically relevant
tion, dryness, and burning tingle [3].
[7].
The tretinoin complexation with 2,6-dimethyl-beta- • Eritromicine: available in 1-4% solution, lotion and gel
cyclodextrin (DM-
-CD) will enhance the drug release by form reduces significantly the P.acnes and Micrococ-
promoting skin permeation and alleviation of drug induced caceae in the sebaceous glands ducts.
local irritation. It will also overcome its low solubility in
water and low stability. According to Ascenso & Cabral Several combinations of drugs with therapeutic benefits
Marques (poster presented at the Congresso Nacional de have been already demonstrated: 3% erythromycin and 5%
Ciências Dermatocosméticas, 2007): the obtained complex is benzoyl peroxide gel; 4% erythromycin and 0.025% tretinoin
soluble (AL phase solubility diagram corresponding to 1:1 gel; 2% erythromycin and 0.5% isotretinoin gel; 1.2% eryth-
stoichiometry), the time for maxim complexation goes on for romycin and 0.377% zinc acetate solution; 1% clindamycin
8 days and the complexation constant is quite high, which and 5% peroxide benzoyl gel; 1% clindamycin phosphate
suggests that the complex formed is stable. This study based and 0.025% tretinoin gel [3, 7, 39, 40].
on various analytical techniques including differential scan-
A comparison study between the combination of clin-
ning calorimetry (DSC), nuclear magnetic resonance (NMR),
damycin / benzoyl peroxide and clindamycin / tretinoin
X-ray diffraction and molecular modelling demonstrated that
demonstrated that the first combination is more effective in
it is possible to complex tretinoin with DM-
-CD, leading to
the treatment of acne vulgaris. A similar result was observed
new perspectives in anti-acne formulations for topical appli-
in another comparative study between the combination of
cation (Fig. (5)) [36]. erythromycin / benzoyl peroxide, and erythromycin / treti-
Acne in the Adult Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 7

noin. The benzoyl peroxide contributes to decrease the resis- granulation tissue, cheilitis, epistaxis, dry skin, ocular and
tance [40, 41]. vaginal dryness, arthralgia, secondary skin infection with S.
aureus, depression, and, rarely, pseudotumor cerebri and
Benzoyl peroxide in systemic and topical dosage forms
skeletal hyperostoses. Occasionally, patients may have
reduces the propagation of P. acnes and removes the dead
mildly to moderately raised liver function test results. Some
cells of the skin, preventing comedones. It is believed that of the adverse effects are treatable: dryness and irritation are
the action mechanism corresponds to the degradation of bac-
treatable with emollients, while pain or stiffness of the bones
terial proteins by the release of free radicals of oxygen. Ben-
and joints can be controlled with aspirin or nonsteriodal anti-
zoyl peroxide exists in 2.5-10% lotions, creams, gels and
inflammatory drugs. Hypertriglyceridemia is usually mild
cleaning products. The main collateral effect is the extreme
and can be controlled by dietary management and weight
dryness of the skin. When compared with antibiotics, it is
control. Elevations of serum triglycerides or liver enzymes
observed that 5% benzoyl peroxide is at least as effective as may occur, but are not usually clinically significant. Baseline
formulations of clindamycin and erythromycin. Then this is a
liver function tests and fasting lipid profile are suggested,
useful adjuvant therapy [3].
with recommendations for follow-up monitoring ranging
Azelaic acid is a saturated dicarboxylic acid found natu- from every 4 to 8 weeks to less frequently if baseline values
rally in wheat, rye, and barley (Fig. (6)). It is a natural sub- are normal [2].
stance that is produced by Malassezia furfur, a yeast that
Oral antibiotics are generally prescribed for six months or
lives on normal skin. It is effective against a number of skin less. However, the P. acnes can become resistant to antibiot-
conditions, such as mild to moderate acne, when applied
ics. It is quite important to take into account the recommen-
topically in a cream formulation of 20%. The drug target is
dations about antibiotics: the choice of the antibiotic type,
3-oxo-5-alpha-steroid 4-dehydrogenase 2 which converts
therapeutic dosage; combination of drugs, duration of treat-
testosterone (T) into 5-alpha-dihydrotestosterone (DHT) and
ment and therapy for maintenance [43].
progesterone or corticosterone into their corresponding 5-
alpha-3-oxosteroids. It plays a central role in sexual differen- • Erythromycin: is effective against a broad spectrum of
tiation and androgen physiology. It works in part by stopping bacteria, including P. acnes. The most common side ef-
the growth of skin bacteria that cause acne, and by keeping fect is gastrointestinal irritation.
skin pores clear. Azelaic acid's antimicrobial action may be • Tetracycline and derivatives: reduce the papules and pus-
attributable to inhibition of microbial cellular protein synthe- tules (inflammatory lesions) of acne. It should not be
sis. It also proved to be efficient for the treatment of the dark taken by women who are pregnant or breast-feeding be-
spots that can appear in black patients with acne. Azelaic cause it may affect the development of children bones
acid is well tolerated by almost everybody and can be safely and teeth. The most common synthetic derivatives are
used during years. minocycline and doxycycline. Minocycline presents
fewer cases of bacterial resistance and doxycycline is ef-
HO OH
fective in inflammatory acne.
O O • Limociclin: in 300-600 mg dosages. A comparative study
between limociclin and minoclin for the treatment of in-
Fig. (6). Azelaic Acid: nonanedioic acid. flammatory acne concluded that limociclin showed
greater efficacy [44, 45].
The collateral effect may include skin dryness and a cer-
tain lack of pigmentation. A comparison study between the • Oral contraceptives can be used as a good treatment for
combination of azelaic acid cream / oral minocycline and many teenage and adult women. The therapy consists on
oral isotretinoin in the treatment of severe acne allowed to blocking the production of ovaric and adrenal androge-
conclude that the combination, although not as effective, it is neous hormones that control the sebum production in the
better tolerated by patients [42]. skin. The hormonal therapy is an option of treatment for
women with acne when the conventional treatment fails.
SYSTEMIC THERAPY Comparative studies of contraceptive therapy indicated
Isotretinoin is a potent oral retinoid that is reserved for that the most effective treatment is still the combination
the treatment of cystic and severe acne. It is still the only of ethinylestradiol 0.035 mg with 2 mg cyproterone ace-
available treatment that acts in four acne physiopathologic tate [46].
factors and therefore the oral isotretinoin is the standard Spironolactone, an androgen receptor blocker, is used in
treatment for severe acne. Isotretinoin has produced an 80% the treatment of hirsutism and acne in women (Fig. (7)). In
reduction in sebum excretion, comedogenesis, and ductal and published studies, it was determined that the range of effec-
surface P. acnes within 4 to 8 weeks of use and demon- tive dose was 100-200 mg / day. However, at this range the
strated anti-inflammatory activity [2]. Therapy should be majority of patients (91%) had side effects dependent on the
started on day 2 or 3 of the menstrual cycle. Therapeutic dose: menstrual irregularities; central nervous system symp-
dose is 0.5-1.0 mg/kg per day and treatment duration is usu- toms; hyperkalemia; slight reduction in blood pressure. A
ally 20 weeks. Improvement may continue for up to 5 retrospective study was performed on 85 women who took
months after ending therapy. Relapse can occur in 15% of 50-100 mg of spironolactone therapy with and without refer-
patients, particularly in younger ones. However, isotretinoin ence treatment for acne. Despite some limitations of this
is a theratogenic drug. Other adverse effects of isotretinoin study, spironolactone was effective and well tolerated in low
include anemia and/or thrombocytopenia, pruritis, exuberant doses [47].
8 Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 Ascenso and Marques

O should be considered are the acne recurrence after treatment

and whether there is any risk of developing bacterial resis-
tance to antibiotics.
Finally, there are other procedures for the acne treatment,
O
CH3 such as: chemical peelings, dermabrasion, skin cleaning,
H3C
draining and surgical extraction (of comedones, cysts, etc.),
collagen injection (shallow scars are elevated by collagen
injections), intralesional injection with corticoids (injected
CH3 directly into inflamed cysts) and phototherapy (laser rays at
O
1450 nm) [51].
O
A study has shown that the salicylic acid peelings are
Fig. (7). Spirinolactone IUPAC NAME: S-[(7R,8R,9S,10R,13S, effective and safe for the therapy of acne vulgaris in Asian
14S,17R)-10,13-dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16- patients. Both inflammatory and noninflammatory acne le-
decahydro-1H cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethan- sion counts were decreased in proportion to the duration of
ethioate. treatment. Dr. Cunliffe's acne grade was statistically signifi-
cantly decreased after treatment. The side effects were toler-
Flutamide and other similar compounds, nilutamide and able in most cases, and all patients were pleased with their
bicalutamide are non steroidal anti-androgens (Fig. (8)). peel results. Stratum corneum hydration, skin surface lipid,
Buserelin and similar compounds, goserelin, nafarelin, go- skin pH, and transepidermal water loss were unchanged from
nadorelin and leuprolide are analogues of luteinizing hor- baseline levels [52]. Glycolic acid is also used in chemical
mone-releasing hormone (LH-RH) and have proven its effec- peelings and is applied to peel off the top layer of skin to
tiveness in the treatment for acne [48]. The flutamide's main reduce scarring.
indication is the treatment of hirsutism, as 250 mg the thera- To evaluate the efficacy and tolerability of methyl amino-
peutic dose is. It must be administered concurrently a contra- levulinate with photodynamic therapy (MAL-PDT), a ran-
ceptive device due to its theratogenic effect. After oral ad- domized study was performed in patients with facial moder-
ministration, flutamide is converted into a potent metabolite, ate to severe acne vulgaris. Efficacy evaluation included
a 2-hydroxy-flutamide. A study was performed to compare changes from baseline in numbers of noninflammatory and
the relative effectiveness of two new anti-androgens (flu- inflammatory lesions, changes from baseline in global acne
tamide and finasteride) with ciproterone acetate (CPA) in severity grade and clinical assessments of clinical improve-
low and high doses in the treatment for moderate to severe ment by patient and evaluating dermatologist. Pain scores
acne in hyperandrogenic women. The low and high doses of during treatment and local adverse effects were also evalu-
CPA with ethinylestradiol were equally effective and compa- ated. Twelve weeks after treatment the treatment group
rable to the effects of a reduced dose of flutamide. Finas- showed 68% reduction from baseline in inflammatory le-
teride was less beneficial [49]. However, there are still few sions but no reduction in number of noninflammatory lesions
studies that prove the effectiveness of spironolactone and after treatment. All patients experienced moderate to severe
flutamide as therapeutic agents for acne. pain during treatment and developed severe erythema, pustu-
In relation to various drug interactions, Akhavan & Ber- lar eruptions and epithelial exfoliation. It was concluded that
shad [3] refer the main interactions with the drugs used in the MAL-PDT is an effective treatment, but very painful and it
treatment for acne. should still be made efforts to optimize this therapy [53].
According to recommendations of the International Con- Recently radiation with variable wavelength (peaks 415
sensus on Acne, the reference therapy is the combination of and 660 nm) has been used. These radiations cause the pho-
retinoids and antibiotics [50]. toexcitation of porphyrins produced by P. acnes, production
of oxygen and subsequent bacterial destruction.
According to Galderma investigators, the most adopted
evaluation method in the previous major clinical studies of These techniques are sufficiently useful in the case of
various anti-acne agents is based on the level of effectiveness acne in the adult, mainly because help to eliminate also the
and tolerability of such agents. Two other parameters that lesions of the skin [2, 24].

F F
F
O F F F F
O F F N
N
N O
O O
F
NH N NH
CH3 NH CH3 O
O O O S
CH3 H3C CH3
HO O

Fig. (8). Non steroidal anti-androgens: Flutamide, nilutamide, bicalutamide.

Acne in the Adult Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1 9

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Received: 04 March, 2008 Revised: 30 September, 2008 Accepted: 02 October, 2008