Document 6474423

Pharmacology and therapeutics, clinical trial
Oxford, UK
International
IJD
Blackwell
0011-9059
41
Science,
Journal
Ltdof Dermatology
2002
A clinical, prospective, randomized, double-blind trial
comparing skin whitening complex with hydroquinone vs.
placebo in the treatment of melasma
Skin whitening
Haddad
et al. complex and hydroquinone in melasma treatment
Alessandra Lima Haddad, MD, Luiz Fernando Matos, MD, Flavia Brunstein,
Lydia Masako Ferreira, MD, PhD, Ademir Silva, and Divaldo Costa Jr
From Escola Paulista de Medicina,
Federal University of São Paulo, São Paulo,
Brazil UNIFESP-EPM
Correspondence
Alessandra Haddad, MD
Rua Dr Alceu de Campos Rodrigues
229 cj. 711/ 712
São Paulo SP
Brazil
E-mail: [email protected]
Abstract
Objectives To compare, in a double-blind, randomized, prospective study, the clinical
improvement of hyperpigmentation in 30 patients with melasma using hydroquinone or skin
whitening complex topically on one side of the face vs. a placebo cream on the other. The study
was performed during the period November 2000 to March 2001 at the Federal University of
São Paulo, Escola Paulista de Medicina.
Methods Thirty patients received three tubes of cream and were divided into two groups: group
1, one tube containing hydroquinone 4% cream and one tube containing placebo to be applied
to opposite sides of the face at night, and standardized sunscreen [sun protection factor (SPF)
25] for daily use; group 2, one tube containing skin whitening complex 5% cream and one tube
containing placebo to be applied to opposite sides of the face at night, and standardized
sunscreen (SPF 25). All of the tubes had the same appearance and the creams had the same
characteristics. The only person who knew what was being used by each patient on each side
of the face was the pharmacist. A professional photographer took photographs before and after
treatment, which lasted for 3 months. Clinical evaluation was performed by two independent
observers and by the patients themselves. Statistical evaluation was by the chi-squared and
kappa methods.
Results Twenty-five patients completed the study, with an overall improvement of 72% in
comparison with placebo. Group 1 (hydroquinone and placebo) presented an improvement of
76.9% with 25% side-effects, and group 2 (skin whitening complex and placebo) presented an
improvement of 66.7% with 0% side-effects.
Conclusions Both depigmentation agents were useful in the treatment of melasma. The
hydroquinone group presented more collateral effects than the skin whitening complex group.
Considering that the patients showed Fitzpatrick skin types IV to VI and the study was conducted in
the summer, skin whitening complex seems to be an excellent choice for the treatment of melasma.
Introduction
Melasma is a frequent clinical condition, characterized by a
slowly progressive symmetrical hypermelanosis with an irregular coloration, ranging from light brown to gray and dark
brown, which affects patients of all races and both sexes, with
a greater frequency in females (90%)1 due to pregnancy and
the use of oral contraceptives. Although less frequent, other
factors involved in the pathogenesis deserve to be mentioned,
such as genetic influences, exposure to ultraviolet rays, cosmetics, phototoxic drugs, and anticonvulsants.
Melasma can be classified clinically into: (i) epidermal: light
brown color – melanin in the basal and suprabasal layer of
the epidermis; (ii) dermal: grayish coloration – melanophages
© 2003 The International Society of Dermatology
loaded with melanin in the papillary dermis; (iii) mixed:
dark brown (iv) indeterminate or not apparent; occurs in
black-skinned patients in visible in daylight but is not visible
under wood’s lamp examination. In all subtypes, there is a
moderate increase in the number of melanocytes and also in
the cellular activity.2
The management of melasma is a challenge, as there is no
gold standard treatment and recurrences are common. The
principles which govern therapy are based on the following
strategies: (i) sunscreen use; (ii) inhibition of the exacerbated
activity of melanocytes; (iii) removal of melanin; (iv) dispersion of melanin granules.
Hydroquinone, a hydroxyphenol that blocks the synthesis of melanin by inhibiting the tyrosinase enzyme, is the
International Journal of Dermatology 2003, 42, 153 – 156
153
154
Pharmacology and therapeutics, clinical trial Skin whitening complex and hydroquinone in melasma treatment
depigmentation agent of choice, offering the best response. Its
use is associated with several side-effects, however, such as
irritant or allergic contact dermatitis, telangiectasis, epidermal
atrophy, acneiform lesions,2 ochronosis after prolonged use,
and systemic anaphylactic reactions in extreme cases. Fitzpatrick
skin types V and VI are more susceptible to side-effects, and
focal depigmentation may also occur, known as “confetti
leukoderma,” due to the definitive destruction of melanocytes.
The Brazilian population presents a high incidence of Fitzpatrick skin phototypes IV, V, and VI. Alternative therapies
for the management of melasma are required in these groups,
especially in cases with proven intolerance to topical hydroquinone. In addition, the treatment of melasma in pregnant
women, where the use of hydroquinone is counterindicated,
must be considered, as must the spring and summer seasons
in a tropical country, which limit the use of more aggressive
treatments.
Skin whitening complex (SWC), a depigmenting complex
developed in France, contains the following components:
(i) extract of uva-ursi, which provokes chemical decoloration of
melanin and competes with the tyrosinase enzyme; (ii) biofermented Aspergillus that chelates copper ion, which is essential
for tyrosinase enzyme activity, reducing its activity in the
formation of new melanin; (iii) grapefruit extract, rich in citric
and malic acids, with an exfoliative action and consequent
removal of pigmented cells in the epidermis; (iv) rice extract,
rich in oligosaccharides, with a hydrating function.
As a result of these components, the clarifying action
extends to various levels in the melanin-forming chain. SWC
has been proven to be efficacious in in vitro studies,2 and its
use has been approved at concentrations between 2 and 5%.
Objective
This double-blind, randomized, prospective, clinical study
aimed to evaluate the efficacy of SWC in the treatment of
facial melasma compared with hydroquinone and placebo.
Patients and methods
Inclusion criteria
Thirty patients were selected, aged between 38 and 56 years, with
clinical complaints of melasma, presenting Fitzpatrick skin types
III, IV and V, and with no previous treatment over a period of at least
6 months. All patients gave signed and informed consent prior to
participation in the study.
Exclusion criteria
Exclusion criteria included active dermatologic diseases,
known skin sensitivity to clarifying agents or sunscreens,
recent treatment, pregnant or breast-feeding women, a history
of endocrinopathies, or treatment with oral retinoids in the
last year.
International Journal of Dermatology 2003, 42, 153 – 156
Haddad et al.
Ethical considerations
The project was evaluated and approved by the Committee of
Ethics and Medical Research of the Hospital São Paulo, Federal
University of São Paulo, Escola Paulista de Medicina.
Photographic documentation
This was carried out painstakingly by a professional
photographer in studio conditions with controlled luminosity.
Three angles were standardized for photographing the face
(front, left, and right profiles) for each patient, before and after
treatment.
Methodology
The patients were divided at random into two groups by the
pharmaceutical team responsible for preparing the formulas:
group 1, patients receiving hydroquinone 4% (HQ) in a cream
vehicle for the treatment of one side of the face and placebo for
the other; group 2, patients receiving SWC 5% in a cream
vehicle for the treatment of one side of the face and placebo for
the other.
Only the pharmacist knew the contents of the creams
used to treat the face of each patient after randomization. After
manipulation, according to the technical norms necessary for each
active product, the patients received a set of three personalized
30-g tubes containing the manipulated creams, and identified as
“right side of face,” “left side of face,” and “sunscreen.”
The sets of creams were delivered to the medical team who
undertook the monthly distribution to the patients throughout the
3-month study period.
Guidance was provided regarding the application of the creams
to specific sides of the face at night and of the standardized
sunscreen [sun protection factor (SPF) 25] for use during the day,
without association with any other topically used products. In the
presence of any side-effects, the medical team was consulted to
re-evaluate the treatment.
After three consecutive months of treatment, the patients
completed a questionnaire and were also evaluated by two
independent observers regarding the improvement of melasma,
comparing the treated side of the face with the side that had
received placebo.
Statistical evaluation
Statistical analysis was performed using the chi-squared and
kappa methods.
Results
Of the 30 enrolled patients, 25 completed the study, 12 from
group 1 (HQ) and 13 from group 2 (SWC). The percentage
of patients reporting clinical improvement (72%) agreed with
the findings of the observers (Table 1). The opinions of
observers 1 and 2 using the kappa test (κ > 0.40) were also
considered to be concordant.
© 2003 The International Society of Dermatology
Haddad et al.
Skin whitening complex and hydroquinone in melasma treatment Pharmacology and therapeutics, clinical trial
Table 1 (a) Evaluation of correlation
level between the observers’ opinions;
(a) Observer 1 vs. observer 2
Observer 2
(b) Concordance level between the 2
observers by kappea method
Observer 1
Both
Right
Left
Ind
Respectively
Count
% of total
Count
% of total
Count
% of total
Count
% of total
Count
% of total
Both
Right
1
4.0%
4.0%
10
40.0%
Left
Ind
Total
4
16.0%
1
4.0%
2
8.0%
7
28.0%
1
4.0%
15
60.0%
7
28.0%
2
8.0%
25
100.0%
1
6
24.0%
1
4.0%
11
44.0%
6
24.0%
(b) Symmetric measures
Measure of agreement kappa
N of valid cases
Value
Asymp. std. error*
Approx. T†
Approx. significance
0.566
25
0.126
4.509
0.000
*Not assuming the null hypothesis.
†Using the asymptotic standard error assuming the null hypothesis.
Table 2 Evaluation of improvement
obtained with each active agent (no
significant statistical differences)
Group 1
Hydroquinone
Group 2
Skin whitening complex
Total
No improvement
Improvement
Total
Count
% within group
3
23.1%
10
76.9%
13
100.0%
Count
% within group
4
33.3%
8
66.7%
12
100.0%
Count
% within group
7
28.0%
18
72.0%
25
100.0%
P = 0.673 (Fisher’s exact test).
LR = 1.154 (0.701–1.900), not significant.
The two groups were evaluated separately. Group 1 (HQ
vs. placebo) presented an improvement of 76.9% and group
2 (SWC vs. placebo) showed an improvement of 66.7%;
however, according to Fisher’s test, this difference was not
statistically significant (P = 0.673) (Table 2).
The incidence of side-effects was greater among the patients
in group 1, with 25% of patients reporting an itchy eruption,
although this finding was not statistically significant in relation
to group 2, in which there were no complaints of side-effects.
There was a similarity between the two groups in terms
of compliance to treatment (88% of the patients followed
the treatment correctly) and satisfaction with treatment (84%
classified the treatment as excellent or good and 16% as
poor).
© 2003 The International Society of Dermatology
The patients’ satisfaction levels with treatment were 66.7%
and 69.2%, respectively, in groups 1 and 2.
When questioned about intolerance to the sunscreen, none
of the patients (0%) complained.
Discussion
Due to its refractory and recurrent nature, melasma is difficult
to treat. This is confirmed by the enormous variety of options
for treatment, which range from the isolated use of retinoic acid,
with a 68% improvement within 24 weeks,3 through combinations of the Kligman triad with 75% improvement,4
and including unsuccessful attempts with lasers, such as the
Q-switched ruby equipment.5 In this context, the improvement
International Journal of Dermatology 2003, 42, 153 – 156
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156
Pharmacology and therapeutics, clinical trial Skin whitening complex and hydroquinone in melasma treatment
of 66.7% obtained in this study using SWC 5% over such a short
period (12 weeks) demonstrates that SWC is worth including
in the therapeutic arsenal for the treatment of facial hyperchromia. This percentage is comparable to the 68% improvement obtained with the isolated use of topical retinoic acid, but
without the 88% of moderate to mild side-effects reported.3
The results from group 1 (HQ vs. placebo) demonstrated
an improvement of 76.9%, compatible with the findings
of other authors,6,7 who described rates of improvement
between 64 and 88% with other treatments. In the present
study, there was no statistically significant difference between
the improvement obtained in groups 1 and 2, indicating
that the depigmenting action of SWC was similar to that of
HQ, but without the 25% of side-effects that occurred amongst
HQ users; this percentage of side-effects has been reported
previously by other authors.1
Although HQ has been recognized as the most effective
depigmenting agent8 in skin of phototypes IV and VI, it is
rarely used as, in addition to irritant effects, it can trigger
“confetti leukoderma” (a focal depigmentation of the skin) due
to the definitive destruction of melanocytes.2 This occurs
especially after prolonged use, making SWC an alternative
for initial prescription in these patients, or for long-term
maintenance of the results obtained initially by other
methods.
The study was painstaking in its standardization of the use
of the principal active ingredients and vehicles, which were
prepared by the same team of pharmacists and given by the
doctors to the patients on a monthly basis; this guaranteed
control over the use of the medication and over the ideal validity date of the products, in order not to adversely affect the
final results.
The results obtained in this study should encourage future
investigations of: (i) the long-term use of SWC, including in
the summer in tropical countries; (ii) the advantages arising
from its association with exfoliants, such as retinoids and
International Journal of Dermatology 2003, 42, 153 – 156
Haddad et al.
alpha-hydroxy acids, with a potentially higher efficacy; (iii) its
use during pregnancy.
Conclusions
Both methods used were equally effective in the treatment of
facial melasma. The results obtained mean that a greater
therapeutic arsenal is available for the treatment of melasma in
patients with melanodermic skin phototypes, i.e. the majority
of the Brazilian population.
References
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4 Phiamphongsant T. Treatment of melasma: a review with
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© 2003 The International Society of Dermatology