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					THERAPEUTICS                                                                         DOI 10.1111/j.1365-2133.2007.07814.x

Evaluation of efficacy and safety of rucinol serum in
patients with melasma: a randomized controlled trial
A. Khemis, A. Kaiafa, C. Queille-Roussel,* L. Duteil* and J.P. Ortonne
                                                                                             ˆ
Dermatology Department and *CPCAD (Centre of Clinical Pharmacology Applied to Dermatology), Hopital de L’Archet 2, 06202 Nice cedex 3, France

                                                    Summary

Correspondence                                      Background Melasma is a hyperpigmentation disorder predominantly affecting sun-
J.P. Ortonne.                                       exposed areas in women, which is often refractory to treatment. Most commer-
E-mail: Jean-Paul.Ortonne@unice.fr                  cially available treatments incorporate inhibitors of tyrosinase, a key enzyme in
                                                    melanin production within the melanocyte. In general, however, the efficacy of
Accepted for publication
13 October 2006
                                                    these therapies is somewhat limited. Recent studies have identified other enzymes
                                                    that play an important role in melanogenesis, including tyrosinase-related pro-
Key words                                           tein-1 (TRP-1), which catalyses the oxidation of the melanogenetic intermediate
melasma, randomized controlled trial, rucinol       5,6-dihydroxyindole-2-carbolylic acid. Rucinol (4-n-butylresorcinol) has been
serum, split-face design, vehicle-controlled        shown to inhibit the activity of both tyrosinase and TRP-1.
comparison
                                                    Objectives To assess the efficacy of rucinol serum 0Æ3% vs. the corresponding vehi-
Conflicts of interest                                cle as a treatment for melasma. Secondary objectives were to evaluate local and
                                             ´
J.P.O. has acted as a paid consultant to l’Oreal,   general tolerability and to assess the skin acceptability of rucinol serum in the
Galderma, Pierre Fabre, Abbott and UCB and          target population.
as a paid speaker for Serono, Wyeth, Biogen,        Methods In this prospective, single-centre, double-blind, randomized, vehicle-
                                       ´
Schering-Plough, 3M, IBSA, Merck Medication
                                                    controlled, bilateral (split-face) comparative trial, 32 women with melasma were
Familial and Roche-Posay.
                                                    provided with two identical tubes containing rucinol serum 0Æ3% or vehicle. The
                                                    products were each applied to one-half of the face, according to the randomiza-
                                                    tion scheme, twice daily for 12 weeks (phase 1). A broad-spectrum sunscreen
                                                    (sun protection factor 60) was also applied daily. Assessments at baseline, 4, 8
                                                    and 12 weeks included clinical evaluations by a dermatologist, chromametry,
                                                    ultraviolet and standard photography, and assessments of skin acceptability and
                                                    tolerability. After 12 weeks, patients were given the option of an additional
                                                    3-month treatment period of open full-face rucinol treatment, with reviews at
                                                    16, 20 and 24 weeks (phase 2).
                                                    Results Twenty-eight patients completed phase 1 and 26 patients completed phase
                                                    2. After 12 weeks, the clinical pigmentation score for rucinol-treated skin was
                                                    significantly lower than for vehicle-treated skin (P ¼ 0Æ027). During phase 2,
                                                    rucinol induced a significant reduction in mean pigmentation score on the half
                                                    of the face previously treated with vehicle. There was also a further, significant
                                                    improvement on the rucinol-treated side of the face. Chromametry measurements
                                                    showed that skin was significantly lighter and less yellow, with a strong trend
                                                    towards reduced redness, following rucinol therapy compared with vehicle. Ruci-
                                                    nol serum showed good tolerability and acceptability and was considered to have
                                                    good or fair efficacy by 78% of the patient population.
                                                    Conclusions Rucinol serum was shown to have significant efficacy compared with
                                                    vehicle alone in improving melasma after 3 months of treatment, according to
                                                    clinical and objective assessments of skin colour.

Melasma is a common skin pigmentary disorder that predom-                    skin1 and can have a major psychological impact.2,3 Import-
inantly affects women of child-bearing age, especially those of              antly, treatment of melasma has been shown to enhance
Asian and Hispanic origin. The condition is characterized by                 patients’ health-related quality of life.3 The pathogenesis
varying degrees of hyperpigmentation on sun-exposed areas of                 of melasma is not fully understood but factors such as sun



Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004                                              997
998 Rucinol serum in melasma, A. Khemis et al.


exposure, pregnancy, oral contraceptives, cosmetics and ethni-        ticular relevance for cosmetic applications, was that rucinol
city have all been implicated in its development or progres-          was effective in reducing melanin production in B16 mouse
sion.1 Exposure to ultraviolet (UV) radiation is widely thought       melanoma cells without inducing cytotoxicity, instead show-
to be the most important environmental factor in the develop-         ing a tendency to promote cell growth. In contrast, hydroqui-
ment of melasma.                                                      none caused a significant suppression of cell growth when
   It is well established that tyrosinase is a key enzyme in the      tested at the same concentrations. In terms of inhibition of
synthesis of melanin within the melanocyte by virtue of its           melanin production, rucinol showed a potency similar to that
activity in the melanin synthetic pathway, catalysing the             of hydroquinone, but much greater than that of either arbutin
hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine               or kojic acid.
(DOPA) and the oxidation of DOPA to dopaquinone. Tyrosin-                The depigmenting efficacy of rucinol in human subjects has
ase inhibitors are thus the active ingredients in most commer-        been demonstrated in a number of studies. In a placebo-
cially available skin-lightening cosmetics. Historically, the         controlled study, UVB-induced hyperpigmentation in healthy
mainstays of melasma therapy have been hydroquinone, reti-            male volunteers was reduced by the application of 0Æ3%
noic acid, topical corticosteroids and kojic acid. However,           rucinol serum, the difference in pigmentation becoming signi-
clinical results with these agents have been varied and, in           ficant after 6 weeks compared with placebo.7 Another pla-
some cases, the benefits of treatment have been limited by the         cebo-controlled study evaluated the efficacy of rucinol 0Æ3%
potential side-effects. Hydroquinone, a tyrosinase inhibitor          on postlaser pigmented lesions. The rucinol group showed an
and the most commonly used topical agent for hyperpigmen-             improvement of the lightness (progressive decrease in delta L)
tation disorders, is effective in reducing skin colour when           with a significant difference compared with the placebo group
used in a 3–5% formulation. However, this concentration is            (P < 0Æ05).8 When rucinol was tested in 14 women with
associated with a high frequency of irritant reactions on pro-        hyperpigmentation including liver spots, age spots and
longed use, which may result in postinflammatory hyper-                freckles, the extent of the pigmented area was reduced and
pigmentation. Furthermore, excessive use carries the risk of          the skin colour lightened after 3 months.7 In a further,
exogenous ochronosis and increased pigmentation, particularly         24-week, open-treatment study, rucinol was evaluated in 62
in dark-skinned patients.1,4,5 Hydroquinone 2% formulations,          women with melasma (referred to as chloasma) and was
which until recently were available without prescription, lack        found to be efficacious in 84% of patients.9 Rucinol treatment
the efficacy of higher-concentration formulations as they have         has also been assessed in an open study involving 30 patients
a later onset of action. Topical tretinoin creams have also           with melasma or senescence spots on the face. After 2 months
shown some efficacy as monotherapy for melasma but require             of treatment a reduction in pigmentation was noted in 70% of
a long treatment time of 20–40 weeks to produce a thera-              the patients, with a 40% decrease in pigmented spots, accord-
peutic effect.4 Furthermore, contact dermatitis, erythema and         ing to objective colorimetric measurements.10
desquamation are common side-effects of tretinoin therapy.1,6            The primary objective of this study was to assess the effi-
Kojic acid, a tyrosinase inhibitor with similar depigmenting          cacy of rucinol serum 0Æ3% as a treatment for melasma com-
efficacy to hydroquinone, has recently been shown to have a            pared with a vehicle control. Secondary objectives were to
high sensitizing potential and has been associated with a high        assess both local and general safety and tolerability and to
frequency of contact dermatitis in Japanese studies.4 Cortico-        evaluate the skin acceptability of rucinol serum in patients
steroids are frequently used in conjunction with the other            with melasma.
topical depigmenting agents to reduce irritation and pre-
vent postinflammatory hyperpigmentation. The potential side-
                                                                      Patients and methods
effects of corticosteroids include skin atrophy, telangiectasia
and acneiform reactions.
                                                                      Study design
   Recent investigations have highlighted the role of other
enzymes in melanogenesis, including tyrosinase-related pro-           This prospective, single-centre, double-blind, randomized,
tein-1 (TRP-1), which catalyses the oxidation of the melano-          vehicle-controlled study was undertaken in two 12-week
genetic intermediate 5,6-dihydroxyindole-2-carbolylic acid.7          phases, in the outpatient dermatology department of the Uni-
This has led to the development of rucinol (IklenÒ; Merck             versity Hospital of Nice from January to October 2004. The
   ´
Medication Familiale, Lyon, France), a resorcinol derivative          study protocol was reviewed and approved on 12 September
and the first substance to have been shown to inhibit the              2003 by the CCPPRB (IEC/IRB) of Marseille 2. In phase 1 a
activity of both tyrosinase and TRP-1. In vitro data show that        bilateral (split-face) design was used: rucinol (4-n-butylresorci-
rucinol has a strong and dose-dependent inhibitory effect on          nol) and vehicle were applied to opposite sides of the face
B16 mouse melanoma TRP-1, with a 50% inhibitory concen-               in a double-blinded fashion, enabling intraindividual paired
tration (IC50) of 9Æ3 · 10)7mol L)1.7 Furthermore, the inhibi-        comparisons to be made. In the second, optional stage of the
tory potency of rucinol against B16 mouse melanoma                    study (phase 2), open treatment of the whole face was carried
tyrosinase (IC50 ¼ 44 lmol L)1) was found to be 5Æ6, 100              out using the active product. The vehicle formulation con-
and 380 times greater than that of kojic acid, hydroquinone           tained (International Nomenclature Cosmetic Ingredient list):
and arbutin, respectively. Another important finding, of par-          aqua (water), alcohol, butylene glycol, polyethylene glycol



                                            Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004
                                                                                                Rucinol serum in melasma, A. Khemis et al. 999


(PEG)-32, PEG-6, Pyrus cydonia (seed) extract, 2-amino-                     and the other to the right side of the face, as indicated by the
2-methyl-1,3-propanediol–isostearoyl hydrolysed collagen,                   dispenser labelling, in the morning and evening after washing
sucrose cocoate, disodium ethylenediamine tetraacetic acid,                 the face, for a period of 12 weeks. All patients were provided
methylparaben and tocopherol.                                               with a broad-spectrum sunscreen [sun protection factor (SPF)
                                                                            60+, UVA immediate pigment darkening 80/persistent pig-
                                                                            ment darkening 28] to use for the duration of the study and
Inclusion and exclusion criteria
                                                                            were instructed to avoid sun exposure.
Patients from the clinic database were eligible for inclusion if
they were aged 18–50 years, had skin type III, IV or V and
                                                                            Clinical evaluation
showed moderate-to-severe melasma. Patients were excluded
from the study if they were pregnant or breastfeeding, if they              Clinical evaluations by a dermatologist, chromametry measure-
were receiving hormone or corticosteroid therapy or if they                 ments, photographs and assessments of skin acceptability of
had a history of endocrine disorders or allergies. The use of               the products were undertaken at baseline, 4, 8 and 12 weeks.
depigmenting cream in the previous 2 weeks, a topical prod-                 Further reviews were conducted at 16, 20 and 24 weeks in
uct containing tretinoin within the previous 3 months, or a                 patients who elected to join the optional second phase of the
topical product containing hydroquinone within the previous                 study.
6 months were also grounds for exclusion. Patients were
enrolled by the Clinical Trial Unit physicians under the super-
                                                                            Clinical assessments of efficacy
vision of J.P.O.
                                                                            At baseline and each review, a clinical pigmentation score was
                                                                            allocated for the different regions of the face (forehead, malar
Initial assessment
                                                                            region and chin on left and right sides) using a 0–10 scoring
Women with melasma were invited to attend a baseline                        system, as follows: scores of 0 and 1 indicate no pigmentation
assessment, during which a medical history was taken and a                  and equivocal pigmentation, respectively; scores of 2, 3 and 4
physical examination was carried out by a dermatologist. Mel-               denote very pale brown pigmentation of low ()), medium
asma was characterized according to pattern (centrofacial,                  and high (+) intensity, respectively; scores of 5, 6 and 7 rep-
mandibular or malar), type (epidermal, dermal or mixed)                     resent pale brown pigmentation of low ()), medium and
determined using Wood’s light, and overall severity, assessed               high (+) intensity, respectively; and scores of 8, 9 and 10
via the Melasma Area and Severity Index.6                                   indicate brown pigmentation of low ()), medium and high
                                                                            (+) intensity, respectively. The scoring was based on visual
                                                                            inspection by a dermatologist. The degree of improvement in
Randomization and blinding procedures
                                                                            colour of melasma following treatment was also graded by a
Upon enrolment each subject was assigned a unique number                    dermatologist at each review appointment according to the
corresponding to the chronological order of first application                following scoring system: )1, worsened; 0, unchanged; 1,
of the investigational product. Randomization was achieved                  slightly improved; 2, moderately improved; 3, markedly
using a computer-generated list accessed only by the biostatis-             improved; 4, totally disappeared.
tician and designated personnel directly responsible for pack-                 At the last visit of each phase of the study (weeks 12 and
aging and labelling of study materials. Both study substance                24), the overall response to treatment was rated on a five-
and vehicle were determined to be identical in appearance, so               point scale (0, no response; 1, poor; 2, fair; 3, good; 4,
in phase 1 each subject was supplied with two identical pump                excellent) by both the dermatologist and the patient.
dispensers, one containing vehicle plus rucinol 0Æ3% and the                   Colorimetric measurements were performed with a chrom-
other containing vehicle alone, labelled with their unique                  ameter (CR 200; Minolta, Osaka, Japan) operating in the
                                           ´
identifier number and either left side (‘cote gauche’) or right              L*a*b* system. Two successive measurements were made on
          ´
side (‘cote droit’) according to the randomization scheme.                  each target area: right forehead, left forehead, right malar
Using this method both patient and investigator were blinded                area, left malar area, left chin and right chin. In addition, two
to the contents of the pump dispensers. Unblinding of the                   areas of uninvolved skin (one per side and symmetrically
study occurred only once the database had been formally                     located relative to each other) served as normal skin controls.
locked. In phase 2 the commercially available product was                   The mean value of the data obtained from sites on each side
supplied. All study materials were dispensed by the investi-                of the face was calculated and compared both with the base-
gator or designer.                                                          line value and that of the opposite side of the face.
                                                                               Both standard and UV photographs were taken at baseline
                                                                            and weeks 4, 8, 12, 16 and 24, using a standardized position
Treatment regimen
                                                                            technique. The equipment used comprised a digital UV kit
Patients accepted for inclusion were provided with two identi-              and UV Twin Flash (Canfield Clinical Systems, Fairfield, NJ,
cal product dispensers labelled with their unique identifier                 U.S.A.) and a digital camera (FinePix S1 ProÒ; Fuji, Tokyo,
number. They were instructed to apply one product to the left               Japan) connected to a computer with Mirror DPSÒ (Canfield



Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004
1000 Rucinol serum in melasma, A. Khemis et al.


Clinical Systems) software. Three angles were standardized for        Table 1 Baseline melasma characteristics of study participants
photographing the face of each patient before and after treat-
ment: front, 45° left and 45° right.                                                                                           Overall severity:
   After 12 weeks and, if applicable, 24 weeks, patients com-                                                                  mean MASI
pleted a questionnaire concerning the effectiveness of the               Melasma pattern             Melasma type              score (range)
study products, their skin acceptability and effects on quality          Centrofacial (n ¼ 2)        Epidermal (n ¼ 2)          5Æ6 (5Æ6–5Æ6)
of life.                                                                 Centrofacial malar          Epidermal (n ¼ 6)         10Æ8 (2Æ7–27Æ5)
                                                                          (n ¼ 11)                   Mixed (n ¼ 5)
                                                                         Centrofacial mandibular     Epidermal (n ¼ 1)           2Æ5
Clinical assessments of safety and tolerability                           (n ¼ 1)
                                                                         Centrofacial mandibular-    Epidermal (n ¼ 7) 10Æ9 (4Æ7–17Æ6)
Patients graded the degree of stinging, burning and pruritus at           malar (n ¼ 11)             Mixed (n ¼ 4)
each review, using a 0–4 scale in which 0 represents the                 Malar (n ¼ 1)               Mixed (n ¼ 1)      7Æ5
absence of symptoms and 4 denotes severe symptoms. The                   Mandibular-malar            Epidermal (n ¼ 1)  8Æ1 (1Æ7–27Æ5)
same scale was used by the investigator to score the intensity            (n ¼ 4)                    Mixed (n ¼ 3)
of erythema, dryness, peeling and desquamation. Any adverse              Total (n ¼ 30)              Epidermal (n ¼ 17) 9Æ6 (1Æ7–27Æ5)
                                                                                                     Mixed (n ¼ 13)
events were recorded.
                                                                         MASI, Melasma Area and Severity Index.
Statistical analyses
A sample size of 30 was selected based on consideration of            Table 2 Mean ± SD clinical pigmentation scores for rucinol-treated
relevant literature data.11 The statistical analyses were per-        and vehicle-treated skin during phase 1 of the study (baseline to
formed using SYSTAT 11.0 software (Richmond, CA, U.S.A.).             12 weeks)
   All participants who received at least one application of the
study products were included in the intention-to-treat analysis                                     Rucinol
group used in the safety evaluation analysis. All variables were                                    serum            Vehicle            P-value
analysed descriptively using the mean ± SD or the percentage             Baseline visit             7Æ5   ±   1Æ9    7Æ5   ±   1Æ9      1Æ0
and frequency of distribution. Analysis of variables with a              Visit 2 (4 weeks)          7Æ1   ±   1Æ9    7Æ3   ±   2Æ0      0Æ157
non-normal distribution, such as clinical scores of pigmenta-            Visit 3 (8 weeks)          6Æ8   ±   2Æ1    6Æ9   ±   2Æ0      0Æ314
tion and degree of improvement of melasma, was carried out               Visit 4 (12 weeks)         6Æ2   ±   2Æ3    6Æ7   ±   2Æ1      0Æ027*
using the Wilcoxon signed-rank test for paired data. Variables           *P < 0Æ05, significant product difference.
with a normal distribution, such as colorimetric data, were
analysed by means of Student’s t-test for paired data.
                                                                      (Wilcoxon test). A decrease in the mean pigmentation score
                                                                      over time was observed for both rucinol and vehicle. How-
Results
                                                                      ever, at visit 4 (12 weeks) the mean pigmentation score was
                                                                      found to be significantly lower with rucinol than with vehicle
Study population
                                                                      (P ¼ 0Æ027). Figure 1(a–c) displays the decrease of skin
Thirty-two women aged 30–51 years (mean ± SD 40 ± 6)                  pigmentation compared with baseline (Fig. 1a), first on the
with skin type III (n ¼ 11), IV (n ¼ 10) and V (n ¼ 11) were          right side of the face (Fig. 1b) and then on both sides of the
enrolled into the study. Their ethnic groups were Europeans           face (Fig. 1c).
(n ¼ 18), Arabians (n ¼ 13) and Indians (n ¼ 1). Two indi-               At visit 5 (16 weeks), after 4 weeks of rucinol therapy, a
viduals left the study shortly after visit 1 (baseline) and thus      decrease in pigmentation score was observed on the side trea-
30 patients attended at least one efficacy assessment and were         ted with vehicle during phase 1, such that there was no lon-
included in the analysis. A total of 28 patients completed            ger a significant difference in pigmentation score between the
phase 1 of the study and 26 completed the whole study                 two sides of the face. On the side treated with rucinol from
period.                                                               the start of the study, there was a further significant reduction
   The baseline melasma characteristics of the study partici-         in pigmentation score at visit 5 compared with visit 4, but no
pants are described in Table 1. The most common patterns of           additional reductions thereafter.
melasma observed were centrofacial malar (n ¼ 11) and cen-               When pigmentation scores at visits 5, 6 and 7 were com-
trofacial mandibular-malar (n ¼ 11).                                  pared with those recorded at visit 4 (at the end of phase 1),
                                                                      the differences were found to be highly statistically significant
                                                                      at each visit for the side previously treated with vehicle
Efficacy analysis
                                                                      (Table 3). For the side treated with rucinol throughout the
Table 2 shows the mean clinical pigmentation scores for ruci-         study, there was also a statistically significant improvement at
nol- and vehicle-treated skin during phase 1 of the study and         visit 5 compared with visit 4 (P ¼ 0Æ039). Despite a slight
the results of the statistical comparison of the two products         increase in mean pigmentation scores during the summer



                                            Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004
                                                                                                 Rucinol serum in melasma, A. Khemis et al. 1001

                                                                            Table 3 Statistical comparisons of pigmentation scores at visits 5, 6
          (a)
                                                                            and 7 vs. visit 4, with respect to the treatment products used during
                                                                            phase 1


                                                                                                                 Side treated with     Side treated
                                                                                                                 rucinol serum         with vehicle
                                                                                                                 during phase 1        during phase 1
                                                                                                                 (P-value)             (P-value)
                                                                               Visit 5 (16 weeks) vs. visit 4 0Æ039                    0Æ004
                                                                               Visit 6 (20 weeks) vs. visit 4 0Æ020                    0Æ001
                                                                               Visit 7 (24 weeks) vs. visit 4 0Æ012                    0Æ001




                                                                              7·5                                                      Rucinol serum
                                                                                                                                       Vehicle
                                                                                                                                       Rucinol serum
                                                                                                                                       Rucinol serum
                                                                              7·0
          (b)


                                                                              6·5

                                                                                                                     ∗
                                                                              6·0

                                                                                                 Phase 1                       Phase 2
                                                                              5·5
                                                                                    Baseline Visit 2   Visit 3   Visit 4   Visit 5   Visit 6   Visit 7


                                                                            Fig 2. Evolution of the clinical pigmentation score over time as a
                                                                            function of treatment. *P < 0Æ05.


                                                                            months (5Æ8–6Æ0), the level of significance of the improve-
                                                                            ment in pigmentation relative to visit 4 increased progressively
                                                                            at visits 6 and 7 as a result of a decrease in the SD of the
                                                                            pigmentation score over time.
          (c)                                                                  The evolution of the clinical pigmentation score over time
                                                                            as a function of treatment is illustrated in Figure 2. The figure
                                                                            shows that the pigment-reducing effect of rucinol serum
                                                                            reached a plateau after visit 5 at 16 weeks, which coincided
                                                                            with the summer period.
                                                                               When the degree of improvement of hyperpigmentation on
                                                                            the different zones of the face was analysed, a significant dif-
                                                                            ference between the test products was found at visits 3 and 4
                                                                            (P ¼ 0Æ038 and 0Æ031 at 8 and 12 weeks, respectively) for
                                                                            the malar region. There was a trend towards greater improve-
                                                                            ment on the forehead with rucinol compared with vehicle at
                                                                            visits 3 and 4, but this fell slightly short of statistical signifi-
                                                                            cance in each case (P ¼ 0Æ058 and 0Æ057 at 8 and 12 weeks,
                                                                            respectively). The degree of improvement of pigmentation on
                                                                            the chin did not differ significantly between the products.
                                                                               During phase 2 of the study, the degree of improvement
                                                                            achieved at visit 4 was maintained on the rucinol-treated side,
                                                                            with further improvement observed on the forehead. On the
Fig 1. Decrease of skin pigmentation compared with baseline (a), after      previously vehicle-treated side of the face, the degree of
3 months of active treatment only on the right side of the face (b) and     improvement increased in all zones throughout phase 2,
after 6 months of active treatment on both sides of the face (c).           reaching a level similar to that of the comparator side by



Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004
1002 Rucinol serum in melasma, A. Khemis et al.



  2·5                                                                        63·3

                                                                             62·8
  2·0                                                                        62·3

                                                                             61·8                                   ∗
  1·5
                                                                             61·3
                                                    Rucinol serum
                                                    Vehicle                  60·8                                                    Rucinol serum
  1·0                         ∗                     Rucinol serum                                                                    Vehicle
                     ∗                                                       60·3                        ∗
                                                    Rucinol serum                                                                    Rucinol serum
                                                                             59·8                                                    Rucinol serum
  0·5
                  Phase 1                 Phase 2                            59·3                Phase 1                       Phase 2
  0·0                                                                        58·8
        Visit 2   Visit 3   Visit 4   Visit 5   Visit 6   Visit 7                   Baseline Visit 2   Visit 3   Visit 4   Visit 5   Visit 6   Visit 7


Fig 3. Changes in the degree of improvement of melasma on the              Fig 5. Changes in the colorimetric component L* (skin brightness)
malar zone over time for the two sides of the face. *P < 0Æ05.             over time for the two sides of the face. *P < 0Æ05.


                                                                           serum was significantly lighter by visit 3 (P ¼ 0Æ002), signi-
                                                                           ficantly less yellow by visit 2 (P ¼ 0Æ016) and showed a
  1·8                                                                      tendency towards reduced redness by visit 4 (P ¼ 0Æ051).
                                                                           After 12 weeks of treatment, L* component measurements
                                                                           (mean ± SD) were 61Æ6 ± 3Æ3 vs. 61Æ1 ± 3Æ4 (P ¼ 0Æ013), b*
  1·4                          ∗                                           component measurements were 14Æ6 ± 2Æ7 vs. 14Æ8 ± 2Æ7
                    ∗∗                                                     (P ¼ 0Æ008) and a* component values were 11Æ6 ± 2Æ6 vs.
  1·0                                                                      11Æ9 ± 2Æ8 (P ¼ 0Æ051) for rucinol- and vehicle-treated skin,
                                                      Rucinol serum        respectively. In the open-treatment phase of the study, the
                                                      Vehicle              colorimetric measurements on the side previously treated
                                                      Rucinol serum
  0·6                                                                      with vehicle reached similar values to those observed on
                                                      Rucinol serum
                                                                           the rucinol-treated skin by visit 5 and there were no signifi-
                  Phase 1                 Phase 2
                                                                           cant differences between the sides at any subsequent visit.
  0·2                                                                      For both sides, however, there were significant differences in
        Visit 2   Visit 3   Visit 4   Visit 5   Visit 6   Visit 7
                                                                           colorimetric values obtained at visits 5, 6 and 7, compared
Fig 4. Changes in the degree of improvement of melasma on                  with visit 4 (P < 0Æ05), with the exception of visit 6, when
the forehead over time for the two sides of the face. *P ¼ 0Æ057,          the difference in the a* component for previously rucinol-
**P ¼ 0Æ058.                                                               treated skin failed to reach significance (P ¼ 0Æ068). The
                                                                           plateau effect observed with the clinical pigmentation
                                                                           scores in the last 8 weeks of the study was not observed
24 weeks. However, there were no significant differences in                 with the colorimetric parameters. Changes over time of the
degree of improvement between the two sides for any facial                 colorimetric component L* (skin brightness) are shown in
zone at any time point.                                                    Figure 5.
   Comparison of the degree of improvement at visits 5, 6                     A total of 17 patients graded their overall response to ruci-
and 7 with that at visit 4 revealed that, on the side previously           nol therapy at visit 7 as excellent (4), good (3), fair (2), poor
treated with rucinol, there were further significant improve-               (1) or no response (0). In addition, a questionnaire concern-
ments in forehead melasma at visits 6 and 7 (P ¼ 0Æ02 and                  ing the product’s effects, skin acceptability and impact on
0Æ008, respectively), while the degree of improvement in                   quality of life was completed by 18 patients. At the end of
other zones was maintained over time. For the side previously              phase 2, the majority (14 of 18, 78%) of the patients found
treated with vehicle, there were significant differences in the             the efficacy of rucinol good or fair on both treated sides,
degree of improvement at all visits in phase 2, compared with              while the same proportion rated the overall tolerance as good
visit 4, for both malar and forehead zones. On the chin, the               or excellent.
difference in degree of improvement vs. visit 4 reached statis-               A poststudy investigation was undertaken 20 months after
tical significance at visit 7 (P ¼ 0Æ034). The evolution of the             the end of the study in order to assess the possible phenom-
degree of improvement of melasma on the malar and forehead                 enon of rebound hyperpigmentation which is a problem
zones is illustrated in Figures 3 and 4.                                   observed with most of the depigmenting therapies. Results of
   The results of the colorimetric analysis showed that, com-              this investigation performed on 26 patients are detailed in
pared with the vehicle-treated side, skin treated with rucinol             Table 4.



                                                 Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004
                                                                                               Rucinol serum in melasma, A. Khemis et al. 1003

Table 4 Long-term outcome of treatment effect according to patient opinion, 20 months after the end of treatment (n ¼ 26)


                                        Rebound hyperpigmentation                Rebound hyperpigmentation
  Treatment judged as                   observed 3–5 months after                observed at least 6 months            No rebound observed
  inefficient at EOS, n (%)              EOS, n (%)                               after EOS, n (%)                      since EOS, n (%)
  8 (31)                                5 (19)                                   6 (23)                                7 (27)

  EOS, end of study treatment.




                                                                               In addition to reducing pigmentation scores, rucinol ther-
Safety assessments
                                                                            apy resulted in significant improvements to the colour of the
Very few instances of stinging, burning or pruritus were                    pigmented skin, showing significant superiority over vehicle
reported by patients for either study product and all were                  in terms of its effects on skin lightness and yellowness and a
mild in intensity. Similarly, the investigators observed a very             trend towards reduced redness. Colorimetric measurements
low frequency of erythema, dryness, peeling and desquama-                   continued to improve significantly when rucinol therapy was
tion, and no effects with a greater than mild intensity. During             prolonged for a further 12 weeks, while commencement of
the study, 12 adverse events were experienced by eight                      rucinol treatment on previously vehicle-treated skin produced
patients. Of these 12 events, nine were mild, two were mod-                 highly significant improvements at 20 and 24 weeks, com-
erate and one was severe in intensity (blepharoplasty). How-                pared with 12-week results.
ever, only one of these adverse events, a depigmented spot on                  The apparent efficacy of the vehicle product in reducing
the left malar zone acquired during vehicle treatment, was                  pigmentation scores in phase 1 of this study is probably
judged to be probably related to the study products.                        attributable to the mandatory use of broad-spectrum SPF 60
                                                                            sunscreen by all patients in this study. This level of UV protec-
                                                                            tion is somewhat higher than has been used in other stud-
Discussion
                                                                            ies.6,11,12 In addition, patients were instructed at baseline to
In this prospective, double-blind, split-face study, rucinol serum          avoid sun exposure during the course of the study and it is
was shown by both clinical and objective assessments to pro-                possible that some consequent behavioural change may have
duce significant improvements in melasma pigmentation and                    contributed to the improvement in melasma on the vehicle-
skin colour characteristics after 12 weeks of treatment compared            treated skin. Exposure to UV radiation is known to be an im-
with vehicle alone. In the optional, 12-week, open-treatment                portant factor in the development of melasma and thus solar
phase of the study, there was a further improvement in the level            protection is a key element in its management. Ennes et al.12
of pigmentation on the rucinol-treated side of the face and this            have reported a similar beneficial effect of sunscreen use in
effect was maintained until the end of the study at 24 weeks. In            patients with melasma. In a comparative study of hydro-
addition, initiation of rucinol therapy on the vehicle-treated side         quinone 4% cream vs. placebo, with concomitant use of
induced a highly significant reduction in pigmentation (P ¼                  sunscreen SPF 30, 8Æ3% of patients in the control arm experi-
0Æ004, at 16 weeks) and the two sides showed an equivalent                  enced total improvement, while 58Æ3% achieved partial
degree of improvement at all time points thereafter.                        improvement of their melasma. The authors concluded that
   In phase 1 rucinol was particularly effective in improving               sunscreens induce partial lightening of melasma spots and that
hyperpigmentation in the malar region, with significant differ-              their use is essential in preventing the condition.
ences in the degree of improvement compared with the vehi-                     A further noteworthy observation in this study was that the
cle observed at 8 and 12 weeks. There was also a strong                     depigmenting effects of rucinol appeared to plateau during the
tendency toward greater efficacy on the forehead with rucinol.               last 8 weeks of the study. This phenomenon coincided with
However, on continuation of rucinol treatment in phase 2 of                 the summer months and may have been due to increased
the study, the degree of improvement was significantly                       environmental UV exposure at this time, despite the use of
increased on the forehead at 20 and 24 weeks compared with                  sunscreen. Interestingly, however, a plateau effect was not
at 12 weeks. Regarding the chin zone, although no statistically             observed for any of the colorimetric parameters. The discrep-
significant differences were observed between the two test                   ancy between visually observed and colorimetrically measured
products in phase 1 or between the two sides of the face in                 changes in pigmentation over time may be due in part to the
phase 2, the degree of improvement at the end of the study                  fact that visual assessment involves the comparison of pigmen-
(24 weeks) was significantly greater than at 12 weeks on the                 ted skin with nonpigmented skin surrounding the lesion. A
side of the face previously treated with vehicle. Overall, these            further confounding factor that may contribute to this satura-
findings indicate that all the facial zones examined benefited                tion phenomenon is that during the summer months the level
from rucinol therapy to some degree; this benefit was main-                  of pigmentation is usually increased in ‘normal’ nonpigment-
tained beyond 3 months and, in the case of the forehead, was                ed areas of skin, despite the use of protective sunscreen,
further enhanced with continued treatment.                                  resulting in an overall darkening of the face. With colorimetric



Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004
1004 Rucinol serum in melasma, A. Khemis et al.


evaluation, on the other hand, measurements are made on the              2 Balkrishnan R, McMichael AJ, Hu JY et al. Correlates of health-
pigmented lesions only. In the present study, colorimetry                  related quality of life in women with severe facial blemishes. Int J
measurements suggest that rucinol serum, used in combin-                   Dermatol 2006; 45:111–15.
                                                                         3 Balkrishnan R, Kelly AP, Torok H. Improved quality of life with
ation with sunscreen, is effective in improving pigmentation
                                                                           effective treatment of facial melasma: the pigment trial. J Drugs
even in summer time, particularly in terms of reducing the                 Dermatol 2004; 3:377–1.
yellow component of the pigmented lesion.                                4 Halder RM, Richards GM. Management of dyschromias in ethnic
   Rucinol serum was generally extremely well tolerated by                 skin. Dermatol Ther 2004; 17:151–7.
this patient population. Only a small number of adverse skin             5 Levin CY, Maibach H. Exogenous ochronosis. An update on clinical
reactions were reported by the patients or investigator, all of            features, causative agents and treatment options. Am J Clin Dermatol
which were categorized as mild. Furthermore, only one of 12                2001; 2:213–17.
                                                                         6 Kimbrough-Green CK, Griffiths CE, Finkel LJ et al. Topical retinoic
adverse events – a depigmented spot – was considered likely
                                                                           acid (tretinoin) for melasma in black patients. A vehicle-controlled
to be associated with a study product and this was observed                clinical trial. Arch Dermatol 1994; 130:727–33.
during treatment with vehicle. The majority of patients regar-           7 Katagiri T, Okubo M, Oyobikawa K et al. Novel melanogenic
ded rucinol serum as an effective treatment for melasma and                enzymes for controlling hyperpigmentation. 20th IFSCC International
found it very acceptable in terms of overall tolerance,                    Congress 1998; 39:1–11.
hydration effects and odour.                                             8 Akasaka T, Ohurazaka H, Nishioheda G et al. Topically applied 0.3%
   In conclusion, according to both clinical and objective                 4-n-butylresorcinol decreases pigmentation after laser therapy. Envi-
                                                                           ron Derm 2002; 9:11–15.
assessments, rucinol serum showed significant efficacy com-
                                                                         9 Researching Committee of RucinolÒ. The study on the efficacy of
pared with a vehicle control in improving facial hyperpigmen-              RucinolÒ (4-n-butylresorcinol) in chloasma. Nishinihon J Dermatol
tation in women with melasma after 12 weeks of treatment.                  1999; 61:813–19.
These benefits were maintained during a further 12 weeks of                            ´
                                                                        10 Merck Medication Familiale. Data on file: Evic France, January 2002.
open treatment.                                                         11 Haddad AL, Matos LF, Brunstein F et al. A clinical, prospective, ran-
                                                                           domized, double-blind trial comparing skin whitening complex
                                                                           with hydroquinone vs. placebo in the treatment of melasma. Int J
Acknowledgments                                                            Dermatol 2003; 42:153–6.
                                                                        12 Ennes SBP, Paschoalick RC, Mota de Avelar Alchorne M. A double-
                                   ´
This study was supported by Merck Medication Familiale,                    blind, comparative, placebo-controlled study of the efficacy and tol-
Lyon, France.                                                              erability of 4% hydroquinone as a depigmenting agent in melasma.
                                                                           J Dermatol Treat 2000; 11:173–9.

References
 1 Jimbow K, Minamitsuji Y. Topical therapies for melasma and dis-
   orders of hyperpigmentation. Dermatol Ther 2001; 14:35–45.




                                              Ó 2007 British Association of Dermatologists • British Journal of Dermatology 2007 156, pp997–1004

				
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