Escolar Documentos
Profissional Documentos
Cultura Documentos
Mostre mais
https://doi.org/10.1016/j.ijwd.2018.09.004
Obtenha direitos e conteúdo
Abstrato
O melasma é um distúrbio de hiperpigmentação comum, terapeuticamente desafiador e
universalmente recidivante, observado com mais frequência em mulheres e indivíduos com tipos de
pele Fitzpatrick III a VI. A patogênese do melasma é complexa e multifacetada. Os fatores
contribuintes que estão frequentemente implicados na etiopatogenia desta condição incluem uma
predisposição genética , exposição intensa à radiação ultravioleta e influências hormonais. As
intervenções terapêuticas para o melasma incluem uma abordagem multimodal que incorpora
agentes fotoprotetores, clareadores de pele tópicos e orais e procedimentos de recapeamento. Dado o
nosso conhecimento crescente sobre a patogénese do melasma, tratamentos novos e eficazes estão a
expandir o nosso arsenal terapêutico. Este artigo analisa tratamentos orais e tópicos novos e
emergentes para o melasma.
anterior Próximo
Palavras-chave
Melasma; fotoproteção; agentes clareadores; tratamentos orais; tratamentos tópicos; novo e
emergente
Introdução
https://www.sciencedirect.com/science/article/pii/S2352647518300431 1/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Uma miríade de estudos sobre qualidade de vida relatam a turbulência emocional e a devastação
psicológica que são vivenciadas pelos indivíduos afetados ( Balkrishnan et al., 2003 , Ikino et al., 2015 ,
Pawaskar et al., 2007 ). Os pacientes experimentam um impacto emocional significativo e muitas
vezes sentem-se incomodados, frustrados, envergonhados e deprimidos com a aparência da pele (
Ikino et al., 2015 ).
De uma perspectiva histórica, os agentes comumente usados para o tratamento do melasma incluem
hidroquinona , ácido azelaico , ácido kójico , ácido glicólico , ácido salicílico e tretinoína . Destes
https://www.sciencedirect.com/science/article/pii/S2352647518300431 2/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
tratamentos, a hidroquinona continua a ser o padrão ouro. Vários estudos sugerem que as
formulações combinadas oferecem os melhores resultados ( Halder et al., 1983 , Kim et al., 2007 ,
Moin et al., 2006 , Werlinger et al., 2007 ). Essas fórmulas de combinação tripla geralmente contêm
hidroquinona, um retinóide e um corticosteróide em concentrações variadas. As terapias comumente
usadas acima mencionadas são frequentemente associadas a recaídas universais. Os tratamentos de
segunda linha, como peelings químicos e lasers, são eficazes em alguns pacientes, mas estas
abordagens podem estar associadas a complicações agudas e de longo prazo, particularmente em
indivíduos com tipos de pele mais escuros. Dado o impacto negativo global do melasma na qualidade
de vida , está em curso uma busca para encontrar tratamentos mais eficazes que ofereçam remissão
sustentada a longo prazo para pacientes com este distúrbio frustrante e terapeuticamente desafiador.
Intervenções terapêuticas
O tratamento do melasma deve incluir uma abordagem multimodal que incorpore agentes
fotoprotetores, tratamentos antioxidantes, clareadores de pele, esfoliantes e procedimentos de
recapeamento, conforme necessário. Estudos baseados em evidências sugerem que as terapias de
primeira linha para o melasma abrangem fotoproteção intensa e agentes clareadores tópicos ( Jutley et
al., 2014 , Rivas e Pandya, 2013 ; Sarkar et al., 2013 ; Sarma et al., 2017 ). Além disso, muitos estudos
abordaram a segurança e eficácia de peelings químicos e fontes de laser/luz para redução de
pigmentação no melasma. Tais procedimentos são mais frequentemente considerados abordagens
terapêuticas de segunda e terceira linha.
Os lasers devem ser usados com cuidado e cautela, dada a alta taxa de recorrência do melasma. Além
disso, a intervenção a laser é frequentemente complicada pela hiperpigmentação pós-inflamatória em
indivíduos com pele mais escura.
Esta revisão aborda agentes orais e tópicos novos e emergentes para o tratamento do melasma.
Fotoproteção
A fotoproteção diária é fundamental no tratamento deste distúrbio terapeuticamente desafiador e
universalmente recorrente. O uso de protetores solares de amplo espectro é essencial. Cuidadores de
pacientes com melasma relatam frequentemente a ocorrência comum de recaídas rápidas e
frequentes após intensa exposição aos raios UV. Lakhdar et al. (2007) avaliaram o papel de um filtro
solar de amplo espectro na prevenção e tratamento do cloasma em mulheres grávidas durante um
ensaio clínico de 12 meses . Das 185 pacientes que completaram o estudo, foram observados apenas
cinco novos casos de cloasma (melasma), uma taxa de ocorrência de 2,7% e muito inferior aos 53%
observados anteriormente durante a gravidez.
Além do impacto deletério da luz UV como fator desencadeante e recidivante, estudos recentes
implicaram um papel para a luz visível ( Duteil et al., 2014 , Duteil et al., 2017 , Mahmoud et al., 2010 ).
Foi demonstrado recentemente que a luz azul visível estimula a opsina-3, que ativa o fator de
transcrição associado à melanogênese e outras enzimas melanogênicas, como tirosinase e dopacromo
tautomersae ( Regazzetti et al., 2018 ). A tirosinase e o dopacromo formam um complexo proteico
gerado principalmente nos melanócitos de indivíduos de pele escura. Portanto, acredita-se que os
efeitos sustentados da irradiação de luz azul visível em indivíduos com tipos de pele mais escuros
induzam hiperpigmentação duradoura em indivíduos com tipo de pele III e superior ( Regazzetti et al.,
https://www.sciencedirect.com/science/article/pii/S2352647518300431 3/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
2018 ). Portanto, a fotoproteção que incorpore luz visível, como os filtros solares de óxido de ferro , é
essencial. Existem poucas formulações de óxido de ferro prontamente disponíveis e tais formulações
bloqueiam de forma ideal a luz UV no espectro visível.
Castanedo-Cazares et al. (2014) compararam os efeitos de um protetor solar com luz UV-visível com
um protetor solar apenas com UV, ambos com fator de proteção solar ≥ 50. Sessenta e oito pacientes
foram incluídos neste estudo de 8 semanas ( Castanedo-Cazares et al., 2014 ) . . O protetor solar
somente UV continha mexoryl SX, dióxido de titânio, octocrileno , Tinasorb-S e avobenzona . O
protetor solar com luz UV-visível continha o mesmo regime mais óxido de ferro. Ambos os grupos
receberam hidroquinona 4% diariamente. Uma melhora significativamente maior foi observada no
grupo que foi tratado com o regime de luz UV-visível.
Em um estudo de 6 meses com 40 pacientes, Boukari et al. (2015) avaliaram a eficácia de um protetor
solar com luz UV-visível que continha óxido de ferro. O grupo controle utilizou o mesmo protetor
solar UV que proporcionou a mesma proteção UV-B e UV-A sem o óxido de ferro. Uma redução
significativamente maior na pontuação do Índice de Gravidade da Área do Melasma (MASI) ocorreu
em pacientes tratados com a fórmula combinada de luz UV-visível. Ambos os estudos documentam os
efeitos benéficos da proteção contra luz visível em pacientes com melasma.
Leucotomos polipódios
Tem havido muito interesse recentemente no uso de Polypodium leucotomos (PL) como agente
fotoprotetor adjuvante no melasma. Polypodium é uma samambaia da família Polypodiaceae exclusiva
da América Central e do Sul. Os mecanismos de ação do PL incluem a promoção da expressão do gene
supressor p53 , modulação de citocinas inflamatórias , regulação positiva de sistemas antioxidantes
endógenos e bloqueio da expressão da ciclooxigenase-2 induzida pela radiação UV ( Nestor et al., 2014
, Siscovick et al., 2008 ).
Vários estudos recentes documentaram um efeito benéfico em pacientes com melasma ( Goh et al.,
2018 , Martin et al., 2013 ). Em um estudo randomizado e controlado por placebo com 40 pacientes,
Martin et al. (2013) avaliaram a eficácia de PL 240 mg duas vezes ao dia versus placebo. Os autores
relataram um efeito estatisticamente significativo do PL em comparação com o placebo. Num recente
ensaio duplo-cego controlado por placebo, Goh et al. (2018) relataram a eficácia do PL no melasma. Os
pacientes foram randomizados para receber 240 mg de PL oral duas vezes ao dia ou placebo por 12
semanas. Os grupos ativo e placebo também foram tratados com filtro solar de amplo espectro e
hidroquinona 4% ao dia. O grupo tratado com PL obteve uma redução significativamente maior no
escore MASI aos 56 e 84 dias de tratamento ( Goh et al., 2018 ).
https://www.sciencedirect.com/science/article/pii/S2352647518300431 4/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
2018 , Nordlund et al., 2006 , Olejnik et al., 2018 , Paine et al., 2001 , Picardo et al., 2007 , Pires et al.,
2018, Schulte et al., 2018 , Schulte et al. ., 2015 , Tse, 2010 ; Videira et al., 2013 ; Wargniez et al., 2017 ,
Wohlrab e Kreft, 2014 ). Estudos baseados em evidências sugeriram que produtos combinados que
contêm hidroquinona 4%, tretinoína e um esteróide produzem a melhor resposta ( Jutley et al., 2014 ,
Rivas e Pandya, 2013 ; Sarkar, 2013 ; Sarma et al., 2017 ). (Ver Tabela 2. )
Ácido azelaico Inibição da tirosinase Ardor, queimação, coceira, secura Hashim et al., 2018 ,
Schulte et al., 2015
Ácido kójico Inibição da tirosinase Irritação, dermatite de contato Deo et al., 2013 , Lajis
et al., 2012 , Monteiro
et al., 2013
Ácido ascórbico Inibição de espécies reativas de Nenhum evento adverso Al-Niaimi e Chiang,
oxigênio significativo 2017 , Pires et al.,
2018
https://www.sciencedirect.com/science/article/pii/S2352647518300431 5/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Fotoproteção Tópico Protetores Boukari et Bloqueia a luz FPS ≥ 50 O regime de luz Nenhum
solares de al., 2015 , visível azul UV-visível teve
óxido de Castanedo melhora
ferro -Cazares et significativa
al., 2014 ,
Duteil et
al., 2017 ,
Lakhdar et
al., 2007 ,
Mahmoud
et al., 2010
,
Regazzetti
et al., 2018
Promoção da
expressão do
gene supressor
Goh et al., p53/modulação
2018 , de citocinas
Martin et inflamatórias
Efeito benéfico Distúrbios
Leucotomos al., 2013 , ↑ sistemas 240 mg
Oral Maior redução no gastrointestinais
polipódios Nestor et antioxidantes BID
MASI leves
al., 2014 , endógenos
Siscovick bloqueio da
et al., 2008 expressão da
ciclooxigenase-
2 induzida pela
radiação UV
https://www.sciencedirect.com/science/article/pii/S2352647518300431 6/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Agentes Oral e Ácido Banihashe Blocks 2-5% BID Global studies Oral: mild
clareadores tópico tranexâmico mi et al., conversion of 250 mg document gastrointestinal
2015 ; Del plasminogen to BID significant discomfort,
Rosario et plasmin reduction in hypomenorrhea
al., 2018 ; Blocks binding MASI score allergic skin
Ebrahimi e of plasminogen rashes, alopecia,
Naeini, to keratinocytes and mild
2014 , ↓ arachidonic elevations in
George, acid release, alanine
2016 , Kim prostaglandin transaminase
et al., 2016 synthesis and Topical:
, Lee et al., FGF erythema,
2016 , Lee ↓ melanin scaling, dryness
et al., 2017 synthesis Propensity to
, Na et al., ↓ mast cells ↓ induce
2013 , angiogenesis thromboembolic
Perper et phenomena
al., 2017 ,
Taraz et al.,
2017 , Wu
et al., 2012
Potent
antioxidant/free
radical
scavenger
Decreased MASI,
Hamadi et ↑ super oxide
5% BID malondialdehyde
al., 2009, dismutase,
Melatonin 3 mg decreased Not reported
Ryoo et al., glutathione
daily GSH levels
2001 reductase,
increased
glutathione
peroxidase
↓ α-MSH
receptors
Handog et
decreases Intravenous:
al., 2016,
tyrosinase Stevens-Johnson
Sonthalia 2% daily Melanin index
skews Syndrome,
GSH et al., 500 mg significantly
conversion of anaphylaxis
2016, daily reduced
eumelanin to Oral and topical:
Watanabe
pheomelanin none
et al., 2014
https://www.sciencedirect.com/science/article/pii/S2352647518300431 7/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Radio protector
(via direct
scavenging
Besouw et
effects of Reduced MASI
al., 2013,
Cysteamine hydroxy 5% daily compared to None reported
Mansouri
radicals) placebo
et al., 2015
Tyrosinase
peroxidase
inhibition
Melanocyte
activation,
melanosome
development,
Pigment- melanin Comparable
Makino et
correcting synthesis, efficacy to Mild irritation
al., 2016
Serum melanosome hydroquinone
Topical transfer
keratinocyte
differentiation
and desquation
No significant
Potent
Kasraee et changes in serum
peroxidase Minimal
al., 2005, TSH, free
Methimazole inhibitor 5% daily cutaneous side
Kasraee et thyroxine, free
blocks melanin effects
al., 2008 triiodothymine
synthesis
levels
BID, twice daily; FGF, fibroblast growth factor; GSH, glutathione; MASI, Melasma Area Severity Index; MSH,
melanocyte-stimulating hormone; SPF, sun protection factor; TSH, thyroid-stimulating hormone; UV, ultraviolet
Hydroquinone is used globally for melasma (De Caprio, 1999, Grimes, 2009, Nordlund et al., 2006, Tse,
2010), and although used for more than 60 years, it remains our most efficacious topical agent.
Hydroquinone inhibits tyrosinase, which is the rate-limiting enzyme for pigment production, and is
well tolerated in most patients. The most common side effect is irritant contact dermatitis.
https://www.sciencedirect.com/science/article/pii/S2352647518300431 8/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
The majority of clinical trials that have assessed the efficacy and safety of hydroquinone have not
extended beyond 6 months. Nonetheless, physicians have enormous variability in prescribing
practices for hydroquinone, so there is no universal standard of treatment. In the authors’ experience,
hydroquinone can be safely and effectively used beyond 6 months. However, optimal results are often
best achieved using a 6-month rotational algorithm that cycles on and off hydroquinone. Other
lightening agents are often essential to maintain the results achieved with hydroquinone use.
Hydroquinone should not be used in pregnant or breastfeeding women due to its Category C
characterization.
Hydroquinone has been banned in some countries due to concerns of ochronosis and possible cases of
depigmentation. Ochronosis is characterized by hyperpigmented lichenoid, which are cavier-like
papules that appear in cutaneous areas treated with hydroquinone. Ochronosis was first reported in
Africa and is usually caused by the long-term use of high concentrations of hydroquinone with
inadequate sun protection (Bhattar et al., 2015, Grimes, 2009). In contrast to common case reports
from Africa, this condition is uncommon in the United States where most cases are secondary to the
prolonged use of over-the-counter, low-concentration, cosmetic formulations of 2% hydroquinone.
Cases of depigmentation caused by hydroquinone are rare.
Additional concerns with regard to the safety of hydroquinone is based on studies that suggest that
benzene, which is a known leukemogenic agent, is metabolized into hydroquinone as a major by-
product (Norlund et al., 2006). Benzene metabolites, including hydroquinone, phenol, or
benzoquinone, do not exhibit the potency and level of the myelotoxic effect of benzene. In addition,
individuals who are occupationally exposed to long-term hydroquinone have not demonstrated
myelotoxic changes (De Caprio, 1999, Tse, 2010). Hydroquinone has now been used and manufactured
for more than 60 years, and a review of the literature reveals no cases of skin cancer, internal
malignancies, or liver damage related to the topical application of hydroquinone for skin lightening.
Tranexamic acid
Tranexamic acid (TA), a synthetic derivative of lysine, is a fibrinolytic agent that blocks the conversion
of plasminogen to plasmin and thereby impedes the binding of plasminogen to keratinocytes (Fig. 1).
Downstream effects include diminished arachidonic acid release and decreased prostaglandin and
fibroblast growth factor synthesis. Prostaglandins and fibroblast growth factor both stimulate melanin
synthesis. TA also decreases mast cells and angiogenesis (Kim et al., 2015). Nijo Sadako first reported
the efficacy of TA in 1979 in a patient with melasma treated for chronic urticaria (George, 2016).
https://www.sciencedirect.com/science/article/pii/S2352647518300431 9/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Fig. 1. Melasma (A) before treatment and (B) after treatment with topical 3% tranexamic acid and
hydroquinone. Significant improvement in areas of hyperpigmentation of the cheek and upper lip.
TA is currently used via a spectrum of delivery routes including oral, topical, intradermal, and
microneedling (Taraz et al., 2017). The current oral dosing is significantly less than doses used to treat
hemophilia, heavy menstrual bleeding, or other hemorrhagic conditions. Oral dosing for melasma is,
on average, 250 mg twice daily compared with 3900 mg daily for bleeding diatheses (Taraz et al.,
2017). Multiple studies have documented the efficacy of TA in patients with melasma (Banihashemi et
al., 2015, Del Rosario et al., 2018, Ebrahimi and Naeini, 2014; Kim et al., 2017; Lee et al., 2016, Na et al.,
2013, Perper et al., 2017, Wu et al., 2012).
TA has been predominantly used in Asian patients and was recently evaluated in a cohort of patients
in the United States. Del Rosario et al. (2018) assessed the efficacy of TA 250 mg twice daily versus
placebo in a 3-month study, followed by 3 months of sunscreen only. Thirty-nine patients completed
the trial. At 3 months, there was a 49% reduction in MASI score versus 18% for the placebo control
group. No serious adverse events were reported (Del Rosario et al., 2018).
The largest retrospective study of TA treatment was conducted in Singapore. The authors reviewed
data from 561 patients with melasma who were treated with TA, and improvement was noted in 90%
of patients. Adverse events were reported in 40 patients (7.1%), and most side effects were mild.
However, one patient developed deep vein thrombosis and was later discovered to have familial
protein S deficiency. There was a personal history of spontaneous miscarriage and a family history of
thromboembolic issues in two siblings (Lee et al., 2016).
General concerns linger with regard to the safety profile given TA’s propensity to induce
thromboembolic phenomena. Hence, TA is contraindicated in patients with clotting disorders or a
https://www.sciencedirect.com/science/article/pii/S2352647518300431 10/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
history of thromboembolism (Kim et al., 2017). Major side effects in melasma clinical trials are rarely
reported. Other adverse events related to TA use include mild gastrointestinal discomfort,
hypomenorrhea, allergic skin rashes, alopecia, and mild elevations in alanine transaminase levels. Oral
TA should be prescribed with care and caution. A detailed history should be taken for each patient to
exclude individuals at risk for untoward complications.
Several studies have addressed the efficacy and safety of topical TA (Banihashemi et al., 2015,
Ebrahimi and Naeini, 2014, Kim et al., 2016). In a 12-week, split-face, prospective trial, Banihashemi et
al. (2015) compared the efficacy of a liposomal 5% TA formulation to hydroquinone 4%. Both
treatments showed significant clinical improvement without significant differences between the two
groups, which suggests comparable efficacy.
In a separate split-face study, a TA 3% suspension was applied to one side of the face and a suspension
with hydroquinone 2%, dexamethasone 0.01%, and vitamin C to the opposite side. Both formulations
showed significant improvement, which suggests similar topical efficacy for hydroquinone-based
formulations (Ebrahimi and Naeini, 2014). Topical side effects included erythema, scaling, irritation,
and dryness (Banihashemi et al., 2015, Ebrahimi and Naeini, 2014, Kim et al., 2016).
Melatonin
The hormone melatonin, which is secreted by the pineal gland, is a potent antioxidant and free-radical
scavenger that stimulates several antioxidant enzymes, including superoxide dismutase, glutathione
reductase, and glutathione peroxidase. Melatonin also inhibits α-melanocyte-stimulating hormone
receptors. Oral and topical melatonin were evaluated in a series of 36 patients with melasma and 10
healthy control participants. Patients were randomized to several groups, including topical melatonin
only, topical melatonin plus screen, and a combination of topical and oral melatonin and
hydroquinone 4% for 90 days. At 90 days, all patients with melasma demonstrated a significant
reduction in MASI score. In addition, malondialdehyde, which is a measure of oxidative stress,
decreased and glutathione (GSH) levels increased and suggest significant improvement in oxidative
stress. These seminal observations also suggest that additional studies to assess the efficacy and safety
of melatonin in patients with melasma are warranted (Hamadi et al., 2009l Ryoo et al., 2001).
Glutathione
GSH is one of the most powerful endogenous antioxidants produced by cells in the human body and is
a tripeptide of glutamate, cysteine, and glycine. Mechanisms that induce lightening of the skin include
inhibition of tyrosinase and the ability to skew production of eumelanin to pheomelanin. There has
been enormous recent publicity with regard to the use of intravenous GSH for general skin lightening
(Sonthalia et al., 2016). Multiple articles have been published in the lay press on the use of GSH for a
variety of diseases including melasma. Intravenous use of GSH has been associated with severe life-
threatening reactions including Stevens–Johnson syndrome and anaphylaxis.
Several studies have evaluated oral and topical GSH for general skin lightening. In an 8-week study,
Handog et al. (2016) treated 30 healthy Filipino women with a 500 mg buccal glutathione lozenge.
The melanin index showed a significant reduction, and global assessments reported moderate
lightening in 90% of subjects (Handog et al., 2016). A topical glutathione 2% suspension was assessed
in a randomized, double-blind, split-face, 10-week study, in which GSH was applied to one side and a
placebo to the opposite side. The melanin index was significantly reduced in the GSH-treated side
https://www.sciencedirect.com/science/article/pii/S2352647518300431 11/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
(Watanabe et al., 2014). Oral and topical GSH are well tolerated with no significant adverse events.
The results of these studies suggest the need to test oral and topical GSH for melasma.
Cysteamine
Cysteamine hydrochloride (ß–mercaptoethylanine hydrochloride) is naturally produced in the human
body and is a degradation product of the amino acid L-cysteine. Cysteamine is also a radio protector
that protects cells from the mutagenic and other lethal effects of ionizing radiation via its direct
scavenging effects on hydroxy radicals (Besouw et al., 2013).
Recently, several studies have documented the efficacy of cysteamine in patients with melasma. In a
randomized, double-blind trial of 40 patients, a significant improvement in melasma lesions was
observed compared with patients who were treated with placebo. Mansouri et al. (2015) assessed the
efficacy of 5% cysteamine in 50 patients with melasma. Cysteamine induced significant reductions in
MASI scores at 16 weeks compared with placebo.
Pigment-correcting serum
Pigment-correcting serum was recently reformulated to address the multiple pathways involved in
the induction of hyperpigmentation. These pathways include melanocyte activation, melanosome
development, melanin synthesis, melanosome transfer, and keratinocyte differentiation and
desquamation. Pigment-correcting serum contains TA, tetrapeptides, plankton extracts, niacinamide,
phenylethyl resorcinol, and undecylenol phenylalanine. In a randomized, double-blind comparison
trial of 43 patients, pigment-correcting serum was compared with hydroquinone 4% and showed
overall comparable efficacy to hydroquinone in patients with melasma and postinflammatory
hyperpigmentation (Makino et al., 2016).
Methimazole
Methimazole is an oral anti-thyroid medication used to treat patients with hyperthyroidism and has
been shown to cause depigmentation when applied topically. Methimazole has been used in patients
with melasma and postinflammatory hyperpigmentation and causes significant skin lightening.
Methimazole is a potent peroxidase inhibitor that blocks melanin synthesis. Absorption studies of
topically applied methimazole 5% revealed minimal detectable serum levels and no abnormalities in
thyroid function tests (Kasraee et al., 2005, Kasraee et al., 2008). Methimazole 5% was applied daily in
20 patients with epidermal melasma and did not induce any significant changes in serum thyroid-
stimulating hormone, free thyroxine, and free triiodothyronine levels. Methimazole was well tolerated
with minimal cutaneous side effects. However, Kasraee et al. (2008) recommend that methimazole
only be applied to areas affected by melasma and should not be used as a general cosmetic lightening
agent.
Flutamide
A recent paper evaluated the efficacy of topical flutamide in patients with melasma. Flutamide is a
nonsteroidal antiandrogen that blocks the action of endogenous and exogenous testosterone by
binding to the androgen receptor. Seventy-four women were enrolled in a parallel, randomized, 16-
https://www.sciencedirect.com/science/article/pii/S2352647518300431 12/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
week trial that compared once daily flutamide 1% with hydroquinone 4%. Skin hyperpigmentation
improved, and the results of MASI and colorimetry scores revealed similar efficacy for flutamide and
hydroquinone 4%. However, patient satisfaction scores were significantly higher in the flutamide
group (Adalatkhah and Sadeghi-Bazargani, 2015).
Conclusions
Melasma remains a chronic, therapeutically challenging, and universally relapsing condition. This
psychologically devastating disorder should be treated with a multimodality approach that
incorporates photoprotective agents, antioxidant treatments, skin lighteners, exfoliants, and
resurfacing procedures in severe cases. A myriad of new oral, topical, and combination therapies for
melasma have been introduced to expand our repertoire of therapies, and warrant additional trials to
substantiate their efficacy and safety.
Conflicts of interest
None.
Funding
None.
Study Approval
The authors confirm that any aspect of the work covered in this manuscript that has involved human
patients has been conducted with the ethical approval of all relevant bodies.
References
Adalatkhah et al., 2011 H. Adalatkhah, F. Pourfarzi, H. Sadeghi-Bazargani
Flutamide versus a cyproterone acetate-ethinyl estradiol combination in moderate
acne: a pilot randomized clinical trial
Clin Cosmet Investig Dermatol, 4 (2011), p. 117
CrossRef View in Scopus Google Scholar
https://www.sciencedirect.com/science/article/pii/S2352647518300431 13/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Bhattar et al., 2015 P.A. Bhattar, V.P. Zawar, K.V. Godse, S.P. Patil, N.J. Nadkarni, M.M. Gautam
Exogenous ochronosis
Indian J Dermatol, 60 (6) (2015), pp. 537-543
CrossRef View in Scopus Google Scholar
Boukari et al., 2015 F. Boukari, E. Jourdan, E. Fontas, H. Montaudié, E. Castela, J.P. Lacour, et al.
Prevention of melasma relapses with sunscreen combining protection against UV
and short wavelengths of visible light: A prospective randomized comparative trial
J Am Acad Dermatol, 72 (1) (2015), pp. 189-190
e1
View in Scopus Google Scholar
https://www.sciencedirect.com/science/article/pii/S2352647518300431 14/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Del Rosario et al., 2018 E. Del Rosario, S. Florez-Pollack, L. Zapata Jr., K. Hernandez, A. Tovar-Garza, M.
Rodrigues, et al.
Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the
treatment of moderate to severe melasma
J Am Acad Dermatol, 78 (2) (2018), pp. 363-369
View PDF View article View in Scopus Google Scholar
Deo et al., 2013 K.S. Deo, K.N. Dash, Y.K. Sharma, N.C. Virmani, C. Oberai
Kojic acid vis-a-vis its combinations with hydroquinone and betamethasone valerate
in melasma: A randomized, single blind, comparative study of efficacy and safety
Indian J Dermatol, 58 (4) (2013), pp. 281-285
CrossRef View in Scopus Google Scholar
Duteil et al., 2014 L. Duteil, N. Cardot-Leccia, C. Queille-Roussel, Y. Maubert, Y. Harmelin, F. Boukari, et al.
Differences in visible light-induced pigmentation according to wavelengths: A
clinical and histological study in comparison with UVB exposure
Pigment Cell Melanoma Res, 27 (5) (2014), pp. 822-826
CrossRef View in Scopus Google Scholar
Duteil et al., 2017 L. Duteil, J. Esdaile, Y. Maubert, A.C. Cathelineau, A. Bouloc, C. Queille-Roussel, et al.
A method to assess the protective efficacy of sunscreens against visible light-induced
pigmentation
Photodermatol Photoimmunol Photomed, 33 (5) (2017), pp. 260-266
CrossRef View in Scopus Google Scholar
https://www.sciencedirect.com/science/article/pii/S2352647518300431 15/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Google Scholar
Goh et al., 2018 C.L. Goh, S.Y. Chuah, S. Tien, G. Thng, M.A. Vitale, A. Delgado-Rubin
Double-blind, placebo-controlled trial to evaluate the effectiveness of Polypodium
leucotomos extract in the treatment of melasma in Asian skin: A pilot study
J Clin Aesthet Dermatol, 11 (3) (2018), pp. 14-19
View in Scopus Google Scholar
Halder et al., 1983 R.M. Halder, P.E. Grimes, C.I. McLaurin, M.A. Kress, J.A. Kenney Jr.
Incidence of common dermatoes in a predominantly black dermatologic practice
Cutis, 32 (4) (1983), pp. 388-390
View in Scopus Google Scholar
Hamadi et al., 2009 S.A. Hamadi, M.M. Mohammed, A.N. Aljaf, A. Abdulrazak
The role of topical and oral melatonin in management of melasma patients
J Arab Univ Basic Appl Sci, 8 (2009), pp. 30-42
Google Scholar
Hashim et al., 2018 P.W. Hashim, T. Chen, J.C. Harper, L.H. Kircik
The efficacy and safety of azelaic acid 15% foam in the treatment of facial acne
vulgaris
J Drugs Dermatol, 17 (6) (2018), pp. 641-645
View in Scopus Google Scholar
Huh et al., 2010 S.Y. Huh, J.W. Shin, J.I. Na, C.H. Huh, S.W. Youn, K.C. Park
https://www.sciencedirect.com/science/article/pii/S2352647518300431 16/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Kang et al., 2006 H.Y. Kang, J.S. Hwang, J.Y. Lee, J.H. Ahn, J.Y. Kim, E.S. Lee, et al.
The dermal stem and c-Kit are overexpressed in melasma
Br J Dermatol, 154 (6) (2006), pp. 1094-1099
CrossRef View in Scopus Google Scholar
Kang et al., 2002 W.H. Kang, K.H. Yoon, E.S. Lee, J. Kim, K.B. Lee, H. Yim, et al.
Melasma: Histopathological characteristics in 56 Korean patients
Br J Dermatol, 146 (2) (2002), pp. 228-237
View in Scopus Google Scholar
Kasraee et al., 2005 B. Kasraee, F. Handjani, A. Parhizgar, G.R. Omrani, M.R. Fallahi, M. Amini, et al.
Topical methimazole as a new treatment for postinflammatory hyperpigmentation:
Report of the first case
Dermatology, 211 (4) (2005), pp. 360-362
CrossRef View in Scopus Google Scholar
Kasraee et al., 2008 B. Kasraee, G.H. Safaee Ardekani, A. Parhizgar, F. Handjani, G.R. Omrani, M. Samani, et al.
Safety of topical methimazole for the treatment of melasma: Transdermal
absorption, the effect on thyroid function and cutaneous adverse effects
Skin Pharmacol Physiol, 21 (6) (2008), pp. 300-305
CrossRef View in Scopus Google Scholar
https://www.sciencedirect.com/science/article/pii/S2352647518300431 17/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Kim et al., 2007 E.H. Kim, Y.C. Kim, E.S. Lee, H.Y. Kang
The vascular characteristics of melasma
J Dermatol Sci, 46 (2) (2007), pp. 111-116
View PDF View article CrossRef View in Scopus Google Scholar
Kim et al., 2015 M.S. Kim, S.H. Bang, J.H. Kim, H.J. Shin, J.H. Choi, S.E. Chang
Tranexamic acid diminishes laser-induced melanogenesis
Ann Dermatol, 27 (3) (2015), pp. 250-256
CrossRef View in Scopus Google Scholar
Kim et al., 2017 H.J. Kim, S.H. Moon, S.H. Cho, J.D. Lee, H. Sung Kim
Efficacy and safety of tranexamic acid in melasma: a meta-analysis and systematic
review
Acta Derm Venereol, 97 (6-7) (2017), pp. 776-781
CrossRef View in Scopus Google Scholar
Kim et al., 2016 S.J. Kim, J.Y. Park, T. Shibata, R. Fujiwara, H.Y. Kang
Efficacy and possible mechanisms of topical tranexamic acid in melasma
Clin Exp Dermatol, 41 (5) (2016), pp. 480-485
View in Scopus Google Scholar
Lakhdar et al., 2007 H. Lakhdar, K. Zouhair, K. Khadir, A. Essari, A. Richard, S. Seite, et al.
Evaluation of the effectiveness of a broad-spectrum sunscreen in the prevention of
chloasma in pregnant women
J Eur Acad Dermatol Venereol, 21 (6) (2007), pp. 738-742
CrossRef View in Scopus Google Scholar
https://www.sciencedirect.com/science/article/pii/S2352647518300431 18/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Mahmoud et al., 2010 B.H. Mahmoud, E. Ruvolo, C.L. Hexsel, Y. Liu, M.R. Owen, N. Kollias, et al.
Impact of long-wavelength UVA and visible light on melanocompetent skin
J Invest Dermatol, 130 (8) (2010), pp. 2092-2097
View PDF View article CrossRef View in Scopus Google Scholar
Makino et al., 2016 E.T. Makino, K. Kadoya, M.L. Sigler, P.D. Hino, R.C. Mehta
Development and clinical assessment of a comprehensive product for pigmentation
control in multiple ethnic populations
J Drugs Dermatol, 15 (12) (2016), pp. 1562-1570
View in Scopus Google Scholar
Monteiro et al., 2013 R.C. Monteiro, B.N. Kishore, R.M. Bhat, D. Sukumar, J. Martis, H.K. Ganesh
A comparative study of the efficacy of 4% hydroquinone vs 0.75% Kojic acid cream in
the treatment of facial melasma
Indian J Dermatol, 58 (2) (2013), p. 157
CrossRef View in Scopus Google Scholar
Na et al., 2013 J.I. Na, S.Y. Choi, S.H. Yang, H.R. Choi, H.Y. Kang, K.C. Park
https://www.sciencedirect.com/science/article/pii/S2352647518300431 19/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Nestor et al., 2014 M.S. Nestor, V.W. Bucay, V.D. Callender, J.L. Cohen, N. Sadick, H. Waldorf
Polypodium leucotomos as an adjunct treatment of pigmentary disorders
J Clin Aesthet Dermatol, 7 (3) (2014), pp. 13-17
View in Scopus Google Scholar
Pawaskar et al., 2007 M.D. Pawaskar, P. Parikh, T. Markowski, A.J. McMichael, S.R. Feldman, R. Balkrishnan
Melasma and its impact on health-related quality of life in Hispanic women
J Dermatolog Treat, 18 (1) (2007), pp. 5-9
https://www.sciencedirect.com/science/article/pii/S2352647518300431 20/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Pires et al., 2018 A. Pires, R. Marques, J. Encarnação, A. Abrantes, I.A. Marques, Laranjo, et al.
Ascorbic acid chemosensitizes colorectal cancer cells and synergistically inhibits
tumor growth
Front Physiol, 9 (2018), p. 911
View in Scopus Google Scholar
Regazzetti et al., 2018 C. Regazzetti, L. Sormani, D. Debayle, F. Bernerd, M.K. Tulic, G.M. De Donatis, et al.
Melanocytes sense blue light and regulate pigmentation through the Opsin3
J Invest Dermatol, 138 (1) (2018), pp. 171-178
View PDF View article View in Scopus Google Scholar
Ryoo et al., 2001 Y.W. Ryoo, S.I. Suh, K.C. Mun, B.C. Kim, K.S. Lee
The effects of the melatonin on ultraviolet-B irradiation cultured dermal fibroblasts
J Dermatol Sci, 27 (3) (2001), pp. 162-169
View PDF View article View in Scopus Google Scholar
https://www.sciencedirect.com/science/article/pii/S2352647518300431 21/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Seçkin et al., 2014 H.Y. Seçkin, G. Kalkan, Y. Baş, A. Akbaş, Y. Önder, H. Özyurt, et al.
Oxidative stress status in patients with melasma
Cutan Ocul Toxicol, 33 (3) (2014), pp. 212-217
CrossRef View in Scopus Google Scholar
Siscovick et al., 2008 J.R. Siscovick, T. Zapolanski, C. Magro, K. Carrington, S. Prograis, M. Nussbaum, et al.
Polypodium leucotomos inhibits ultraviolet B radiation-induced immunosuppression
Photodermatol Photoimmunol Photomed, 24 (3) (2008), pp. 134-141
CrossRef View in Scopus Google Scholar
https://www.sciencedirect.com/science/article/pii/S2352647518300431 22/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Werlinger et al., 2007 K.D. Werlinger, I.L. Guevara, C.M. González, E.T. Rincón, R. Caetano, R.W. Haley, et al.
Prevalence of self-diagnosed melasma among premenopausal Latino women in
Dallas and Fort Worth
Tex Arch Dermatol, 143 (3) (2007), pp. 424-425
View in Scopus Google Scholar
Cited by (64)
Best practices in the treatment of melasma with a focus on patients with skin of color
2024, Journal of the American Academy of Dermatology
Show abstract
https://www.sciencedirect.com/science/article/pii/S2352647518300431 23/24
10/03/24, 15:37 Novas abordagens orais e tópicas para o tratamento do melasma - ScienceDirect
Trecho da citação:
…Dermatose é um termo para doenças que acometem a pele e órgãos acessórios da pele, possuindo vários tipos.
Muitos fatores estão associados à ocorrência de doenças de pele, como fatores genéticos, fatores ambientais,
fatores biológicos, fatores alimentares e assim por diante [3.112]. Diferentes tipos de doenças de pele têm
diferentes métodos de tratamento.…
Mostrar resumo
Todo o conteúdo deste site: Copyright © 2024 Elsevier BV, seus licenciadores e colaboradores. Todos os direitos são reservados, incluindo aqueles para mineração de texto e
dados, treinamento em IA e tecnologias similares. Para todo o conteúdo de acesso aberto, aplicam-se os termos de licenciamento Creative Commons.
https://www.sciencedirect.com/science/article/pii/S2352647518300431 24/24