Article Type : Research Article
Authors : Khanam R, Sultana N, Siddique MR and Sharmin S
Keywords : Oral tranexamic acid; Oral pycnogenol; Melasma
Background: Melasma is an acquired, chronic recurrent hypermelanosis occuring exclusively in sun exposed area of the body especially in women. Melasma is recalcitrant to treatment and relapses are common. Tranexamic acid, a plasmin inhibitor is effective in the treatment of Melasma. Now-a-days pycnogenol containing monomeric phenolic compounds has been reported to be more effective.
Objective: The aim of the study was to compare the efficacy of oral tranexamic acid and oral pycnogenol in the treatment of Melasma. Methods: A comparative study was conducted on 100 women and men with facial Melasma were randomly selected and divided into the following two groups. Group A (Tranexamic acid 250mg orally twice daily) or group-B (Pycnogenol 50 mg twice daily). Evaluations were performed before and 3 months after treatment by clinical assessment and also MASI and MELASQoL scoring system. All patients were instructed to use sunscreen.
Result: Among 100 patients 89% are female and 46% belong to 30-40 years age. 81% patients had central facial Melasma and epidermal type is 60%, Dermal 10% and mixed 30%. After treatment with oral tranexamic acid MASI score and MELASQoL score improved (P value <0.04 and <0.365), whereas with oral pycnogenol MASI score and MELASQoL score improved significantly (both p value <0.001).
Conclusion: Pycnogenol is well tolerated and more effective orally (50mg 12 hourly for 3 months) than oral tramexamic acid (250mg 12 hourly for 3 months).
Melasma
is the most common pigmentary disorder affecting sun exposed areas such as:
forehead, checks, nose, upper lip and chin and occasionally the neck and
forearms [1]. It is commoner in asian women (90%) but also occurs in male
(10%). It is common in 3rd and 4th decade of life [2]. Melasma causes cosmetic
morbidity and psychological embarrassment affecting quality of life [3,4].
There is a higher incidence of genetic predisposition (70%) in developing
Melasma. Other etiological factors are pregnancy, Oral contraceptives,
endocrine dysfunction, hormone replacement therapy, thyroid disorders, drugs,
cosmetic contact sensitivity, light exposure including both sun and artificial
light and stress [5,6]. Pigmentation is usually confined to the epidermis but
dermis is also affected. Ultra violet ray causes dermal vascular proliferation
and dermal proangiogenic factors such as, vascular endothelial growth factor
(VEGF), basic fibroblast growth factor (eFGF), Interleukin-8 which are implicated
in pathogenesis of Melasma [7,8]. Interaction between VEGF on epidermal
keratinocytes and dermal proangiogenic factors lead to release of mediators
such as arachidonic acid metabolites and plasminogen from proliferated vessels
which enhances melanogenesis in Melasma [9]. Role of mast cells in the
pathogenesis of Melasma is now- a- days highlighted. The mast cell tryptase
degrades type IV collagen that might be the cause of weak basement membrane
observed in Melasma. Solar elastosis is another histological feature of
Melasma. The “Fitzpatrick macule”a confetti like macule of regularly pigmented
skin observed in about 89% chemical photographs of large hyper pigmented patch
of Melasma compared with 1% cases of poikiloderma of civatte and 6% of solar
lentigenosis. Clinically Melasma are Centro facial (55-75%), malar (43-24%) and
mandibular types (15-2%) and histologically epidermal (Melanin increased in the
epidermis), dermal (many melanophages present in the dermis) and mixed type.
Melasma area severity index (MASI) is used to measure severity before and after
treatment. MASI score is calculated by dividing the face into four areas and
each area is weighted such that the forehead (F)30%, right malar area (MR)30%,
left malar area (ML) 30% and the chin (10%). The final formula for MASI score=
0.3 (DF+HF). AF +0.3 (DMR + HMR) AMR + 0.3 (DML+HML) AML + 0.1 (DC+HC) AC.
Total MASI score is 0-48. The physician’s global assessment (PGA) is the most
commonly used scoring system for outcome of treatment where likert scale is
used [10]. A likert scale is a questionnaire based psychometric ordinal scale
in which patients satisfaction score is measured by the following: Score-1
strongly disagree, score-2 undecided, score-3, Neither agree nor disagree,
Score-4 agree, score-5 strongly agree [11]. Hydroquinone bleaching cream is the
gold standard treatment of Melasma. Current treatment modalities are topical
preparations of phenol derivatives-hydroquinone (HQ) 2-4%, Retinoids: Tretinoin
0.05%-0.1%, Adapalene, lsotretionin 0.05%. Azelaic acid (10-20%) combinations-1)HQ
2%+ Tretinoin 0.05% + Fuocinolone acetonide 0.01%, 2)HQ 2% + Tretinoin 0.05%+
Dexamethasone(0.01%) modified kligman's formula, 3)Modified KF + glycolic acid (30-40%) 4) kojic acid 4% + glycolic
acid 5% 5) HQ 4% + glycolic acid (10%)
6) Azelaic acid (20%) + Retinoic acid (0.05%). Chemical peels with (i) Alpha
hydroxy acid, glycolic acid (30%-70%)
ii) phytic acid, pyruvic acid iii) Trichloroacetic acid, lactic acid, salicylic
acid, Jessner's solution iv) dermabrasion. Laser therapy: i) laser therapy
alone or in combination with chemical peels and or topical therapy ii) pulsed
CO2 laser followed by Q-switched alexandrite laser [12]. Mild
itching, burning sensation, erythema, irritant and allergic contact dermatitis,
transient hypopigmentation, nail discoloration, post inflammatory hyper
pigmentation, risk of possible bone marrow toxicity, development of renal
adenomas or carcinogenic effect may occur with hydro quinine. Non hydroquinone
based therapies are Arbutin (? or ?) e.g; (deoxyarbutin, aleosin, Azelaic acid,
kojic acid,gentisic acid, mequinol, flavonoids) Glabridin. Liqourice extract,
Mulberry extract, N-acetyl glucosamine, These agents causes skin lightening by
tyrosinase inhibition, Others are: i) Melanosome transfer inhibitor (Niacinamide), ii) Melanosome
maturation inhibition (Arbutin, Deoxyarbutin), iii) Antioxidant (Vit E, Vit-C),
iv) Epidermal turnover enhancer (Retinoic acid, ?-Hydroxy acids, salicylic acid, Linoleic acid), v)
Plasma inhibitor (Tranexamic acid), vi)
?-MSH induced melanin reduction (?-Carotene), vii) protease activator
receptor-2 inhibitor, viii) Flavonoids (Pycnogenol) [13]. Tranexamic acid is a
synthetic derivative of amino acid lysine is plasmin inhibitor and
anti-fibrinolytic agent. It also used for herditary angioedema which works by
indirect effect by reducing complement activation. By reducing plasmin
activity, it reduces the consumption of C1 esterase inhibitor and hence
decrease ?- MSH which stimulates melamine synthesis [14]. It is temperature
stable, not UV sensitive and does not get oxidized easily. Oral tranexamic acid
500mg/day for upto 6 months is efficacious for Melasma. Commonly reported
complications are nausea, diarrhoea, abdominal pain, skin rash, orthostatic
hypotension, acute cortical necrosis and disturbance of color vision. It is
contra indicated in acquired color vision abnormalities, active coagulopathies
and known hypersensitivity to tranexamic acid. Pycnogenol, extract of French
pine bark represents a concentrate of phenol compounds consisting of phenolic
acid, catechin, taxifolin and procyanidins. It has antioxidant and
anti-inflammatory properties as it doubles the intracellular synthesis of anti
oxidative enzyme and scavenges free radicals due to the aromatic ring bearing
one or more hydroxyl groups. It also causes regeneration and protection of
vit-C and Vit-E. It has a protective action against ultraviolet radiation. It
has ability to inhibit tyrosine kinase and also regulation of bio synthesis of
melanin and suppressing super oxides, Nitric oxide and radical hydroxyl. Orally
100mg/day pycnogenol is effective in Melasma. No side effects were observed,
more over improvement of several symptoms as fatigue, constipation, body ache
and anxiety [15].
Materials and Methods
This
was a multicentre (Laser Aesthetics, Dhaka Bangladesh, US- Bangla Medical
College & Hospital, Narayangonj, Bangladesh), comparative study performed on
100 patients with Melasma according to inclusion and exclusion criteria.
Inclusion
Criteria
· Men
and women without co-morbidities between 20 and 60 years old showing Melasma.
Exclusion
criteria
· Pregnancy
or intention to get pregnant
· Breast
feeding
· History
of thrombosis, smoking, oral or injectable contraceptive
There
were 2 group of patients which were selected randomly. Group-A patients got cap
tranexamic acid 250mg twice daily and group-B patients got cap pycnogenol 50mg
twice daily. The evaluations were performed before and 3 months after treatment
by following methods:
· MASI
(Melasma area severity index)
·
Patient evaluation with validated
questionnaire for satisfaction before and after the end of treatment (MELASQoL)
[16].
Statistical
evaluation of the results was processed and compelled by window-based computer
software program with SPSS-24(Statistical Packages for social sciences)
Table
1 shows total no of patients were 100. Age distribution were 20-30 years
26(26%), 31-40 years (46%), 41-50 years 20 (20%), 51-60 years 8(8%). According to sex distribution male 20-30
years 4(15%), 31-40 years 5(10%) 41-50 years 2(10%) and Female 20-30 years
22(85%), 31-40 years 41(90%), 41-50 years 18(90%), 51-60 years 8(100%) Location
of Melasma were frontal 10(10%), central facial 81(81%), Chin 8(8%) and type of
Melasma were epidermal 60(60%) dermal 10(10%) and mixed 30(30%) (Figure 1).
After 3 Months treatment with oral tranexamic acid (Group-A) and oral
pycnogenol (Group-B) we evaluated the patients. In group-A MASI score were
before treatment 20.9 (±9.1) and after treatment 10.8 (±4.6) (P value <0.04)
and MELASQoL score were 55.4 (±9.8) before treatment and 38.2(±11.1) after
treatment (P value <0.365) In group-B MASI score were 19.2 (±7.1) before
treatment and 7.2 (±4.1) after treatment (P value <0.001). MELASQoL score
were 43.9(±8.2) before treatment and 25.5(±9.1) after treatment (P value
<0.001).
Discussion
Melasma is a chronic skin disease that results in facial pigmentaton characterized by brownish spot. It is more common in female which causes embarrassment and distress to patient. But no treatment guarantees satisfactory result as because pathogenesis of Melasma is not still well defined. Use of hydroquinone topical cream is this gold standard but it is associated with some adverse effects. Now- a- days oral tranexanic acid are used widely. It has better outcome than traditional hydroquinone cream. But oral tranexamic acid has some drawbacks. In our study, treatment with oral tranexamic acid MASI score and MELASQoL score were significantly improved (P value <0.04 and <0.36 respectively). But tranexanic acid is not free of adverse effects such as erythema (14%), desquamation (22%) and burning sensation (12%).
Figure 1: Types of Melasma (Histological).
Table1: Demographic distribution of Patients (n=100).
Age distribution |
Total |
Male |
Female |
20-30 |
26 |
4(15%) |
22(85%) |
31-40 |
46 |
5(10%) |
41(90%) |
41-50 |
20 |
2(10%) |
18(90%) |
51-60 |
8 |
0 |
8(100%) |
Table 2: Types of Melasma.
location of Melasma |
|
Frontal |
10 (10%) |
Central facial |
81(81%) |
Chin |
8(8%) |
Table 3: Evaluation after treatment.
|
Group-A |
Group-B |
||||
Before treatment |
After 3 Months treatment |
P value |
Before treatment |
After 3 Months treatment |
P value |
|
MASI Score |
20.9
(±9.1) |
10.8(±4.6) |
<0.04 |
19.2
(±7.1) |
7.2
(±4.1) |
<
0.001 |
MELASQoL Score |
55.4
(±9.8) |
38.2
(±11.1) |
<0.365 |
43.9
(±8.2) |
25.5
(±9.1) |
<0.001 |
In
our study use of oral pycnogenol had better outcome. Pycnogenol a standardized
plant extract, obtained from the bark of the French maritime pine pinus
pinaster has evoked great interest in the management of Melasma. About 70%
pycnogenol are procyanidins, comprising catechin and epicatechin. Its main
advantage is high bioavailability, synergistic action of its ingredients and
nearly zero side effects. Pycnogenol is potent antioxidant with
anti-inflammatory properties may be also effective in venous ulcers,
climacteric syndrome, arterial hypertension and rheumatological diseases [17].
For instance, a sample of 30 Chinese women with facial Melasma were followed
for a month using 25mg pycnogenol orally 3 times daily had improvement in 80%
participants with a reduction of 22% in the mean colour intensity and 38% in
the affected facial area. A case series performed in venezuela evaluated 48
women and 2 men with high Melasma who took 50mg pycnogenol orally 3 times daily
for 12 weeks. After 12 weeks of follow up the mean reductions in mMASI and
MELASQoL scores were 31% and 47% respectively. Most participants had pigmented
skin (phototype IV) and the author perceived that fairer skin had a greater
improvement in Melasma [18]. In our study group B patients receiving oral
pycnogenol 50mg 12 hourly we got better outcome than oral tranexamic acid. MASI
score were 19.2(±7.1) before treatment and 7.2 (±4.1) after treatment and
MELASQoL score were 43.9(±8.2) and 25.5(±9.1) respectively before and after
treatment. Both p-value were significant. More over pycnogenol have no side
effects but also had some beneficiary effects.
Limitations of the Study
This
study had potential limitations due to its short follow up. Specific design for
long term efficacy of pycnogenol, as well as its use as maintenance treatment
to reduce the risk of relapses after treatment discontinuation are needed to
evaluate the best option among these existing strategies for the management of
Melasma.
Conclusion
Pycnogenol
is well tolerated and more effective orally (50mg 12 hourly for 3 months) than
oral tramexamic acid (250mg 12 hourly for 3 months). It can be also used as
triple combination cream with tinted sun screen in Melasma.
3.
Picardo R,
Vallejos Q, Feldman SR, et al. The prevalence of Melasma and its association
with quality of life among male migrant Latino workers. Int J Dermatol. 2009;
48: 22-26.
15.
Ni Z, Mu Y,
Gulati O. Treatment of Melasma with Pycnogenol. Phytother Res. 2002; 16:
567-571.