Download Treatment of melasma with Pycnogenol

PHYTOTHERAPY RESEARCH
Phytother. Res. 16, 567–571 (2002)
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ptr.1085
Treatment of Melasma with Pycnogenol1
Z. Ni,1 Y. Mu1 and O. Gulati2*
1
Beijing PHT Nutriment Science Technology Development Co. Ltd, Xiyuan Hospital of China Academy of Traditional Chinese Medicine,
Institute of Food Safety Control and Inspection, Ministry of Public Health, Beijing, P. R. China
2
Horphag Research Management, Geneva, Switzerland
Melasma (or chloasma) is a common disorder of cutaneous hyperpigmentation predominantly affecting
sun-exposed areas in women. The pathogenesis of melasma is not fully understood and treatments are
frequently disappointing and often associated with side effects.
Pycnogenol1 is a standardized extract of the bark of the French maritime pine (Pinus pinaster), a wellknown, potent antioxidant. Studies in vitro show that Pycnogenol1 is several times more powerful than
vitamin E and vitamin C. In addition, it recycles vitamin C, regenerates vitamin E and increases the
endogenous antioxidant enzyme system. Pycnogenol1 protects against ultraviolet (UV) radiation. Therefore
its efficacy in the treatment of melasma was investigated.
Thirty women with melasma completed a 30-day clinical trial in which they took one 25 mg tablet of
Pycnogenol1 with meals three times daily, i.e. 75 mg Pycnogenol1 per day. These patients were evaluated
clinically by parameters such as the melasma area index, pigmentary intensity index and by routine blood
and urine tests.
After a 30-day treatment, the average melasma area of the patients decreased by 25.86 20.39 mm2
( p < 0.001) and the average pigmentary intensity decreased by 0.47 0.51 unit ( p < 0.001). The general
effective rate was 80%. No side effect was observed. The results of the blood and urine test parameters at
baseline and at day 30 were within the normal range. Moreover, several other associated symptoms such as
fatigue, constipation, pains in the body and anxiety were also improved.
To conclude, Pycnogenol1 was shown to be therapeutically effective and safe in patients suffering from
melasma. Copyright # 2002 John Wiley & Sons, Ltd.
Keywords: Pycnogenol1; melasma; chloasma; hyperpigmentation; dietary supplement; plant extract.
INTRODUCTION
Melasma (or chloasma) is a common disorder of macular
hyperpigmentation, which involves mostly the sunexposed areas of the face and neck (Grimes, 1995; Kauh
and Zachian, 1999). Although melasma is seen in both
sexes and all races, women are most commonly affected
(Muzaffar et al., 1998; Goh and Dlova, 1999). The
pathogenesis of melasma is not fully understood.
Aetiological factors in the pathogenesis of melasma
include genetic factors, exposure to UV radiation,
pregnancy, oral contraceptives, cosmetics, photo-toxic
drugs and anti-seizure medications (Pathak et al., 1986;
Grimes, 1995). Three clinical patterns of hyperpigmentation are recognized in patients with melasma. These
include a centrofacial, a malar and a mandibular pattern.
Histologically, increased pigment may be situated
epidermally, dermally or on both sites (Sanchez et al.,
1981; Pathak et al., 1986).
Ultraviolet radiation is known to generate reactive
oxygen species (Cunningham et al., 1985) and thus lead
to oxidative stress. Oxidative stress plays a major role in
the biological effects produced by UV radiation (Hruza
and Pentland, 1993). Accordingly, UVR exposure of the
skin causes oxidative damage to the skin and its
components (Hattori et al., 1996).
* Correspondence to: Dr. O. Gulati, Horphag Research Management, Geneva,
Switzerland.
Copyright # 2002 John Wiley & Sons, Ltd.
Current treatments can be divided into two categories,
i.e. local treatment (or external therapy) and general
treatment (internal therapy). The former includes external
application (Griffiths et al., 1993) of hypopigmenting
agents (tretnoin/hydroquinones), chemical peels and laser
therapy; the latter includes the oral administration of
vitamin C or/and vitamin E, intravenous injection of
vitamin C or/and glutathione (Grimes, 1995). Although
these treatments are effective, their efficacy is not fully
established and often they are associated with side
effects.
In the choice of therapies for melasma, the treating
physician has to establish a risk–benefit ratio for each
therapeutic modality. There is a need to develop a more
effective product with no or fewer side effects for better
management of melasma.
Pycnogenol1 is a French maritime pine (Pinus
pinaster) bark extract produced by a standardized and
validated extraction process. It contains monomeric
phenolic compounds (catechin, epicatechin and taxifolin)
and condensed flavonoids (procyanidins). In addition, it
contains phenolic acids: p-hydroxy benzoic, protocatechuic, gallic, vanillic, p-coumaric, caffeic and ferulic
acids (Rohdewald, 1998).
There is ample experimental evidence to support the
antioxidant (Noda et al., 1997; Packer et al., 1999) and
antiinflammatory (Blazsó et al., 1994; 1997) activities of
Pycnogenol1. Considering the strong antioxidant and
antiinflammatory profile of Pycnogenol1, this study was
conducted to assess the efficacy of Pycnogenol1 in
Received 12 September 2001
Accepted 4 October 2001
568
Z. NI ET AL.
melasma, at the Xiyuan Hospital of China, Academy of
Traditional Chinese Medicine appointed by the Institute
of Food Safety Control and Inspection, Ministry of Public
Health of China (MPHC), according to the standard
method proposed and approved by the MPHC.
PATIENTS AND METHODS
Patients. Thirty non-pregnant, non-nursing women
suffering from abnormal pigmentation of melasma were
enrolled in this 30-day open design study. They were
aged between 29 and 59 years (mean age, 41 years) and
their mean course of disease was 8 years. None of the
patients took health foods, medication or used cosmetics
that could relieve melasma.
The patients were instructed to take one 25 mg tablet of
Pycnogenol1 with meals three times a day, i.e. a total
daily dose 75 mg.
Clinical evaluation. Clinical evaluation of the therapeutic effects was made at the first visit (before treatment,
day 0) and then at the end of the 30-day treatment (day
30). The evaluation of subjective symptoms (fatigue,
pain, constipation and feelings of impatience) was made
on day 0, day 15 and day 30.
At the first visit, the history of melasma, its duration,
relationship to pregnancy, hormonal therapy, sun exposure and cosmetic use was taken. Patients were asked
about their previous use of hydroquinones and family
history of melasma.
Efficacy. At each visit, the melasma area was determined
planimetrically, and the pigmentary intensity of melasma
was rated colorimetrically. For the melasma area, the
diameter of the melasma area was measured by a ruler at
three different places and the mean values were
determined. The pigmentary intensity was rated using
the national standard colour chart. On day 30, the overall
response was scored with a 3-point semi-quantitative
scale: 2, markedly improved; 1, effective and 0,
ineffective.
The therapeutic effects were assessed at the end of the
treatment. When a patient achieved a reduction of
pigmentary intensity of melasma by two units or a
reduction of the initial melasma area by >1/3 and no new
melasma appeared, the case was considered to be
‘markedly improved’ and the overall response was
scored as 2. When the reduction of the pigmentary
intensity was one unit and the reduction of the initial size
was <1/3, and no new melasma appeared, the treatment
was considered ‘effective’ and the overall response was
scored as 1. When no change occurred in the skin lesions
or the pigmentary intensity, the treatment was considered
ineffective and scored as 0.
Other associated subjective symptoms of the patients
such as fatigue, pains, state of anxiety and constipation
were also observed and recorded. These symptoms were
graded according to their degree of seriousness on a 3point semi-quantitative scale: 3 represents major symptoms; 2 moderate; and 1 minor. These were integrated on
day 0, day 15 and day 30. The improvement of the
symptoms was graded on a scale where 2 represents
markedly improved; 1 represents effective and 0
ineffective for each symptom. The scores of the
improvements were calculated on day 15 and at the end
of the treatment.
Safety. The patients were examined on day 0 and on day
30 for routine blood and urine examinations. These
included red blood cell (RBC) count, haemoglobin (Hb)
and white blood cell (WBC) count. Biochemical parameters included serum albumin (ALB), total protein
(TP), alanine-aminotransferase (ALT), AST, UREA,
creatinine (CRA), plasma glucose (GLU), plasma lipids
(total cholesterol; triglycerides (TG); high-density lipoprotein-cholesterol (HDL) and urinalysis.
The patients were also examined by abdominal Bultrasonography, electrocardiography (ECG) and thoracic fluoroscopy.
Statistics. A descriptive analysis of data was performed
using SDAS software on an IBM personal computer.
The statistical analysis included analysis of variance
(ANOVA) and Students’s t-test for for parametric data.
Non-parametric data were analysed by means of MannWhitney and Wilcoxon tests. The values in the text and
tables are expressed as mean SEM.
RESULTS
All 30 patients completed the 30 day treatment period.
The results are shown in Table 1. The overall efficacy rate
was 80%. These are further depicted in Fig. 1.
The average pigmentary intensity of the 30 women
decreased significantly ( p < 0.001, Table 2) on day 30,
representing an improvement of 0.47 unit. The average
melasma area was also significantly decreased
( p < 0.001, Table 2), showing a reduction of 25.8 mm2.
The results of the improvement of other associated
symptoms in individual cases are shown in Table 3. It is
interesting to note that Pycnogenol1 produced relief
from fatigue, pain, constipation and feelings of impatience in those patients showing these symptoms. The
overall symptom-index was reduced from 3.93 3.11 to
2.73 2.42 ( p < 0.001) after 15 days and to 2.00 1.95
( p < 0.001) after 30 days of treatment with Pycnogenol1. The efficacy rate varied between 57% and 70%
(Table 3).
The tolerability of Pycnogenol1 was considered very
good and no side effects relating to Pycnogenol1were
reported during the study. Pycnogenol1 was considered
systemically safe based on the evaluation of biochemical
Table 1. Incidence of effectiveness and overall efficacy rate in 30 evaluated patients after 30 days treatment with Pycnogenol1
Markedly improved
Effective
Ineffective
Total effective
7
23.33
17
56.67
6
20.00
24
80.00
Incidence of effectiveness
Ef®cacy rate (%)
Copyright # 2002 John Wiley & Sons, Ltd.
Phytother. Res. 16, 567–571 (2002)
MELASMA AND PYCNOGENOL1
569
Table 4. Results of the haematology and blood chemistry in
30 evaluated cases
Figure 1. Overall rating of therapeutic index achieved after 30
day treatment period
and haemotological parameters as shown in Table 4. All
these values were in the normal biological range. The
results of abdominal B-ultrasonography, electrocardiography and thoracic fluoroscopy determined before and at
the end of the treatment were normal.
Parameter (units)
Day 0
Day 30
TP (g/L)
Alb (g/L)
ALT (u/L)
AST (u/L)
GLU (mmol/L)
TC (mmol/L)
TG (mmol/L)
HDL-C (mmol/L)
UREA (mmol/L)
CRE (mmol/L)
HGB (g/L)
RBC (x 1012)
WBC (x 109)
Urinalysis
75.75 5.19
51.93 7.23
32.57 10.48
35.97 5.19
3.80 0.88
4.73 0.86
1.26 1.04
1.59 0.30
5.70 1.33
78.77 11.65
133.77 8.88
4.41 0.34
5.98 1.83
Normal
77.21 5.42
48.96 3.19
36.30 7.27
42.27 9.09
4.60 0.64
4.38 0.79
1.44 1.06
1.43 0.28
5.59 1.78
73.07 7.45
133.00 9.94
4.71 0.38
5.91 1.53
Normal
Current treatments of melasma can be divided into two
categories, i.e. local treatment (or external therapy) and
general treatment (or internal therapy), the former
includes external application of hypopigmenting agents,
chemical peels and laser therapy; the latter includes the
oral administration of antioxidants such as vitamin C or/
and vitamin E, intravenous injection of vitamin C or/and
glutathione. Local treatment often brings side effects
such as irritant and allergic dermatitis, ochronosis and
atrophy.
Topical treatment with treinoin (retinoic acid 0.1%)
showed significant effectiveness using objective measures (colorimetric and histological), however, moderate
cutaneous side effects of erythema and desquamation
occurred in 88% of tretinoin -treated patients compared
with 29% of vehicle-treated patients (Griffiths et al.,
1993).
The use of hydroquinones is not advised, because of
the risk of depigmentation, allergic contact dermatitis,
nail discoloration and ochronosis (a chronic disfiguring
condition). Use of topical corticosteroids may produce
side effects such as skin atrophy and telangiectasia.
Laser therapy represents a novel approach. Although
studies have demonstrated some success with laser
therapy in the treatment of diseases of hyperpigmenta-
DISCUSSION
The pathogenesis of melasma is not fully understood. A
etiological factors in the pathogenesis of melasma
include genetic influences, exposure to UV radiation,
pregnancy, oral contraceptives, cosmetics, phototoxic
drugs and anti-seizure medications (Pathak et al., 1986;
Grimes, 1995). Familial history, pregnancy, hormonal
therapies, use of cosmetics and other medications were
among the exclusion criteria.
As the outermost organ of the body, the human skin is
frequently and directly exposed to sun and thus to UV
radiation. UV radiation is known to generate reactive
oxygen species (Cunningham et al., 1985) and thus lead
to oxidative stress. Environmental factors such as
exposure to the sun and oxidative stress causing erythema
and inflammatory actions may be considered the main
factors affecting the pathogenesis of melasma in patients
selected in the present study.
Table 2. The reduction of pigmentary intensity and melasma area, after 30 days of treatment with Pycnogenol1
Item
Cases
Day 0
Day 30
Reduction
30
30
2.10 0.71
68.65 44.06
1.63 0.61
42.79 35.59
0.47 0.51
25.8 20.39a
Pigmentary intensity (unit)
Melasma area (mm2)
a
p < 0.001.
Table 3. Improvement of other symptoms after 30 days of treatment with Pycnogenol1
Symptom
Fatigue
Thoracic/costalis pain
Constipation
Impatience
Number of
cases
Markedly
improved
Effective
Ineffective
Ef®cacy
rate (%)
13
10
13
16
3
2
3
2
6
5
5
7
4
3
5
7
69.23
70.00
61.54
56.52
Copyright # 2002 John Wiley & Sons, Ltd.
Phytother. Res. 16, 567–571 (2002)
570
Z. NI ET AL.
tion, such as solar lentigines and cafe-au-lait macules, its
efficacy and place in the treatment of melasma have yet to
be established (Grekin et al., 1993; Fitzpatrick et al.,
1993). The side effects of laser therapy include atrophy,
hypertrophic scarring, hypopigmentation and hyperpigmentation.
Chemical peels have become an established technique
for improving or erasing wrinkles, reducing superficial
acne scarring, removing keratoses and treating pigment
imperfections. Superficial, medium and deep chemical
peels are more often used in lighter-complexioned
whites. Buffered and unbuffered phenol peels, trichloroacetic acid peels, resorcinol paste and b-hydroxy acids
have been used, with mixed results. Glycolic acid peels
(50%–70%) are becoming increasingly popular in the
treatment of melasma (Cotellessa et al., 1999). Chemical
peels tend to induce depigmentation and hypopigmentation. Other side effects of peels include atrophy, bacterial
and viral infections, milia, telangiectasia and pore
enlargement (Moy et al., 1993).
General treatment, however, has no major side effects
and still demonstrates significant efficacy. The activity of
vitamin C is considered to reduce deep, oxidized
pigments to light, reduced pigments, prevent the oxidation of melanin catabolism and inhibit the formation of
melanin. A multiple centre double blind clinical study on
the therapeutic effects of a combination preparation of
vitamins E and C compared with single preparations of
vitamin C in melasma patients, showed that combination
treatments resulted in a significantly better clinical
improvement than vitamin C alone (Hayakawa et al.,
1981) However, abdominal pain, diarrhoea or even
calculus may develop after prolonged use of vitamin C
at a high dosage. such as 2.5 g/d (Teijun et al., 1996).
Considering the strong antioxidant and antiinflammatory profile of Pycnogenol1, this study was conducted to
assess the efficacy of Pycnogenol1 in melasma. As
expected, this study demonstrated that oral administration of Pycnogenol1 at a daily dosage of 75 mg was
therapeutically effective against melasma. No sideeffects or untoward reactions were observed during the
treatment; on the contrary, some associated symptoms of
the patients such as fatigue and constipation were
improved. The patients generally felt that their facial
skin had become finer, smoother and more elastic after
the treatment.
Pycnogenol1 by virtue of its collagen stabilizing
action produces a sealing effect on pathophysiologically
fragile capillaries in oedema- inflammatory conditions
contributing to its antiinflammatory action (Gabor et al.,
1993), smoother and elastic feeling of the skin. It showed
remarkable free radical scavenging activity in vitro and
anti-oedema effects in vivo. It was interesting to note that
these effects were closely correlated (Blazso et al., 1994).
These observations demonstrate the role of oxidative
stress in the inflammatory reaction, and further provide
evidence that the antiinflammatory effect of Pycnogenol1 is related to its free radical scavenging activity.
Pycnogenol1 administered by oral route or applied
topically inhibited the UV radiation induced erythema
response or increased vascular permeability in rats
(Blazsó et al., 1997).
Ultraviolet radiation exposure of the skin causes
inflammation and is linked to photo-aging and photocarcinogenesis. The activation of proinflammatory and
Copyright # 2002 John Wiley & Sons, Ltd.
redox-regulated transcription factor NF-kB is involved in
the UVR-induced erythema. Pycnogenol1 added to a
human skin cell culture medium, inhibited UVR- induced
pro-inflammatory and redox regulated transcription
factor NF-kB, dependent gene expression in a concentration dependent manner. This was further confirmed by
showing that Pycnogenol1 administered in a dose of
1.10 mg/kg for 4 to 8 weeks significantly prevented UVR
induced erythema response in humans (Saliou et al.,
2001). The biological activities and mechanisms described in the literature as discussed above explain the
therapeutic effects Pycnogenol1 in melasma.
Pycnogenol1 is many times more powerful than
vitamins C and E (Chida et al., 1999). In addition, it
recycles vitamin C, regenerates vitamin E (Cossins et al.,
1998) and increases the endogenous antioxidant enzyme
system (Packer et al., 1999). Pycnogenol1 protects
against ultraviolet (UV) radiation in vitro (Guochang,
1993). Pycnogenol1 added to a human skin cell culture
medium, inhibited UVR- induced pro-inflammatory and
redox regulated transcription factor NF-kB, dependent
gene expression in a concentration dependent manner.
This effect was further confirmed in vivo by showing that
Pycnogenol1 administered in a dose of 1.10 mg/kg
significantly protected against UVR induced erythema in
human (Saliou et al., 2001).
Pycnogenol1 modulates gene expression controlled by
NF-kB, a key transcription factor in chronic inflammation. It down-regulates dermal inflammatory markerproteins, calgranulin A and B (Rihn et al., 2001) and
down regulates inducible intracellular adhesion molecule- (ICAM-I), which is generally up-regulated in
inflammatory conditions (Bito et al., 2000). In addition,
Pycnogenol1 produced a dose dependent decrease in the
production of pro-inflammatory mediator, interleukin-1b
(IL-1b) and blocked the activation of two major
transcription factors involved in its production (Cho et
al., 2000). These observations add to Pycnogenol1s
antiinflammatory action.
Considering the interesting antioxidant and antiinflammatory profile of Pycnogenol1 (Packer et al., 1999),
it is not surprising to observe the therapeutic effects of
Pycnogenol1 in melasma in the present study.
According to traditional Chinese medicine, melasma
may be due to a functional imbalance of the internal
organs leading to a derangement of vital energy, and
stagnancy of the blood circulation, which may cause the
formation of patches. Pycnogenol by virtue of its
vasodilator property (Fitzpatrick and Bing, 1998) and
anti-platelet aggregation effect (Pütter et al, 1999) may
enhance blood circulation (Wang et al., 1999).
The results of the routine blood examination and
urinalysis observed in the present study confirm the
results observed in earlier clinical studies (Arcangeli,
2000; Petrassi et al., 2000; Spadea and Balestrazzi, 2001)
and demonstrate that Pycnogenol1 is safe as a food
supplement.
To conclude, treatment with Pycnogenol1 seems to be
an ideal treatment for melasma among the local
treatments as well as the other general treatments with
vitamin C and E, because of its simplicity, efficacy, and
freedom from side effects. It is reasonable that patients
with melasma will achieve better results with daily oral
administration of Pycnogenol1 at a high dosage after a
longer course.
Phytother. Res. 16, 567–571 (2002)
MELASMA AND PYCNOGENOL1
571
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