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Comparison of the therapeutic efficacy of combined glycolic acid 50% peeling
and topical silymarin cream vs. combined intradermal injection of tranexamic
acid and topical silymarin cream in the treatment of epidermal melasma among
Filipino women: prospective, randomized, single-blind split-face trial
Janelle G. Go, M.D.1
Zharlah Gulmatico-Flores, M.D., F.P.D.S.2
Department of Dermatology
Jose R. Reyes Memorial Medical Center
Manila, Philippines
1
Resident, Department of Dermatology, Jose R. Reyes Memorial Medical Center
2
Consultant, Department of Dermatology, Jose R. Reyes Memorial Medical Center
TABLE OF CONTENTS
Page Number
Introduction ------------------------------------------------------------------------------------- 3
Review of Related Literature --------------------------------------------------------------- 4
Statement of the Problem ------------------------------------------------------------------- 7
Significance of the Study -------------------------------------------------------------------- 8
Objectives of the Study ---------------------------------------------------------------------- 8
Methodology ------------------------------------------------------------------------------------9
Dummy Tables ------------------------------------------------------------------------------- 11
Budget Proposal ----------------------------------------------------------------------------- 12
Gantt Chart ----------------------------------------------------------------------------------- 12
References ----------------------------------------------------------------------------------- 13
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INTRODUCTION
Melasma is a relatively common acquired hyperpigmentation of the
skin usually affecting the sun-exposed areas of the face, mostly around the
cheeks, forehead, upper lip, nose and chin. 1 Pathogenesis lies in the
dysfunction of the pigmentary system resulting to irregularly shaped macules
or patches, with color ranging from light to dark brown or ash/blue. It can occur
in both sexes and any skin type, however, it is more frequently observed in
women and those with Fitzpatrick skin types IV to IV, especially to those
residing in areas with intense ultraviolet (UV) radiation, such as Asians, African
American and Hispanic/Latinos.2
Although a benign condition, it causes significant cosmetic disfigurement
bringing psychosocial burden, and creating a negative impact on the quality of
life, social and emotional well-being.3 Moreover, variable outcomes of the
current therapeutic options along with its refractory and recurrent nature
augment the psychological stress of the patient.
Treatment for melasma includes topical bleaching agents, chemical peels,
oral medications, lasers, lights, intradermal injections and other therapies.
While no single therapy has proven to be of benefit to all patients, combination
of modalities can be used to optimize management in difficult cases. 4 Silymarin,
a natural flavonoid derived from milk thistle plant, offers photoprotective
mechanisms for the skin making it a promising agent for melasma.
The investigator aims to compare the efficacy of topical silymarin cream
with intradermal injection of tranexamic acid versus topical silymarin cream
with glycolic acid 50% peeling in the treatment of melasma.
REVIEW OF RELATED LITERATURE
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Melasma is an acquired disorder of symmetrical hyperpigmentation
appearing as light brown to dark muddy brown macules and patches, affecting
most commonly the sun-exposed areas of the face.1,5 The reported prevalence
of melasma ranges from 8.8% among Latino females in the Southern United
States to as high as 40% in Southeast Asia.5 It predominantly affects female of
reproductive age with Fitzpatrick skin type III-VI, and those living in areas with
intense ultraviolet light exposure.1
The etiopathogenesis of melasma is still poorly understood. Several
well-known risk factors exist, which include UV exposure, hormonal changes
(pregnancy, use of oral contraceptives), genetic predisposition, cosmetic use,
thyroid dysfunction, and phototoxic medications.1, 5 Sun exposure plays a key
role in the development of melasma being supported by the centrofacial
pattern of distribution and UV-induced upregulation of melanocyte-stimulating
cytokines resulting to melanocyte proliferation, migration and melanogenesis. 5
The treatment of melasma can be challenging because of its chronic and
relapsing nature. Combination of modalities is often used, especially in
recalcitrant cases. The goals of treatment include reduction of recurrence,
improvement in the cosmetic defect, and shorter time for clearance, with the
least possible side effects.6 Principle of therapy includes protection from UV
light, inhibition of melanocyte activity, and removal of melanin granules. In an
abridged Cochrane review, a large number of different treatments evaluated
showed that there is no standard therapy for melasma.7 Management includes
utilization of skin-lightening agents, chemical peels, laser and light therapies,
and measures to avoid UV exposure.
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Among the first-line therapies currently employed are phenolic compounds
(hydroquinone, mequinol), azelaic acid, kojic acid, topical retinoid, and
combination formulations (hydroquinone/retinoid/steroid).1,4 Several peeling
agents are also being widely used with glycolic acid being the most popular.
Dermabrasion, intense pulse light therapy and laser treatments are useful
adjunct in the treatment of melasma minimizing the risk of more serious side
effects of prolong application of topical medications.6
Silymarin Cream
Silymarin is a natural polyphenolic flavonoid derived from the milk thistle
plant. It has potent antioxidant properties reducing the harmful effects of solar
UV radiation, which involves UV-induced oxidative stress, inflammation,
immunosuppression, and DNA damage leading to apoptosis.8 Moreover, it
prevents melanin production in a dose-dependent manner with no significant
toxic or harmful effects.9 In a study made by Tagreed Altaei, twice daily
application of silymarin cream over the course of 4 weeks among patients with
melasma showed significant excellent pigment improvement and lesion size
reduction. All patients were fully satisfied with no reported side effects.10 The
main mechanism of action in the treatments of melasma lies on its ability to
inhibit L-DOPA oxidation activity of tyrosinase, which is the rate-limiting
enzyme in melanin production. Western blot assay also showed its ability to
decrease expression of tyrosinase protein.11 Because of its radical-scavenging
activity and inhibition of melanin production; it has gained much interest in the
treatment of melasma. In a comparative study made by Efar NN and
El-Maghraby GM, there was no statistically significant difference among topical
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silymarin, and glycolic acid 50% peeling, and has shown better outcome
compared with intradermal tranexamic acid injection.12
Intradermal Tranexamic Acid Injection
Tranexamic acid, also known as trans–4-aminomethylcyclohexanecarboxylic acid, is a plasmin inhibitor and lysine analog, which prevents the
binding of plasminogen to keratinocytes, leading to less free arachidonic acid
and subsequent prostaglandin production. This ultimately leads to a decrease
in tyrosinase activity of melanocytes.4 Due to irritating and allergic side effects
brought about by topical tranexamic acid in the treatment of melasma, newer
liposomal delivery systems have been created to improve tolerability. Lee et al
have investigated intradermal tranexamic acid injection among 85 patients with
melasma showing significant decrease in the MASI scores from baseline to 8
and 12 weeks.13 Furthermore, only minimal burning and mild wheal at the
injection site were reported. No other significant side effects were noted.
Glycolic Acid Peel
Glycolic acid, an alpha hydroxyl acids, is often used as an ingredient of
skin-lightening agent for the treatment of pigment disorders.4 It has shown
modest benefits in clinical studies of melasma. A doe-response trial showed
that 52.5% glycolic acid applied for 3 minutes led to clinical improvement. 14
Another study made among Indian females revealed a decrease in the MASI
scores after nightly application of glycolic acid 10% lotion for 2 weeks followed
by monthly facial peels with 50% glycolic acid for 3 months.15 Among the
reported side effects include erythema, superficial desquamation and post
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inflammatory hyperpigmentation. Based on the current evidence, glycolic acid
peel is a useful adjunct treatment for melasma especially in refractory cases.
Melasma Area and Severity Index (MASI)
Kimbrough-Green et al created The Melasma Area and Severity Index
(MASI) to standardize the subjective evaluation of melasma. It is calculated by
dividing the face into four areas: the forehead, right malar area, left malar area,
and the chin. Each area is weighted such that forehead, right malar and left
malar area accounts for 30% each, and the chin is 10%. . The area (A) of
melasma involvement is graded from 0 to 6: 0 = no involvement, 1 = less than
10% involvement, 2 = 10% to 29% involvement, 3 = 30% to 49% involvement,
4 = 50% to 69% involvement, 5 = 70% to 89% involvement and 6 = 90% to 100%
involvement. The degree of pigmentation (P) and homogeneity (H) graded
from 0 to 4: 0 = absent, 1 = slight, 2 = mild, 3= marked, 4 = maximum The total
score is calculated as follows: MASI = 0.3A (P+H) [forehead] + 0.3A (P+H) [R
malar] + 0.3A (P+H) [L malar] + 0.1A (P+H) [chin]. The range of score is 0 to 48.
It is the most commonly used measurement technique for the study of
melasma.5
STATEMENT OF THE PROBLEM
1. Is silymarin cream combined with glycolic acid peel effective in the
treatment of melasma?
2. Is silymarin cream combined with intradermal tranexamic acid injection
effective in the treatment of melasma?
3. Is silymarin cream combined with glycolic acid peel more effective than
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silymarin cream combined with intradermal tranexamic acid injection?
SIGNIFICANCE OF THE STUDY
Melasma is a chronic relapsing pigmentary disorder, which brings about
psychosocial stress to most patients. Multiple clinical trials have been
conducted to determine the optimum treatment for melasma, however
evidence supporting any intervention is weak. Currently, there has been no
standard therapy for melasma. Monotherapy and combination formulations
have shown variable outcomes; nevertheless a systematic review of clinical
trial supports the efficacy of multiple interventions. Randomized controlled trial
on well-defined participants with long-term follow-up is advised.
In this light, the investigator aims to compare the efficacy of topical
silymarin cream in combination with glycolic acid 50% peel versus topical
silymarin cream with intradermal tranexamic acid injection in the treatment of
melasma. Silymarin, with its anti-melanogenic, anti-oxidant properties and
good safety profile, offers a promising outcome in the treatment of melasma
much more if combined with other treatment modalities.
OBJECTIVES OF THE STUDY
The general objective is to compare the efficacy of topical silymarin cream
in combination with glycolic acid 50% peel versus topical silymarin cream with
intradermal tranexamic acid injection in the treatment of melasma among
Filipino women.
The specific objectives are: 1) to determine the efficacy of topical silymarin
cream in combination with glycolic acid 50% peel in the treatment of melasma
using MASI score within a period of 12 weeks; 2) to determine the efficacy of
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topical silymarin cream with intradermal tranexamic acid injection in the
treatment of melasma using MASI score within a period of 12 weeks; 3) to
compare the efficacy of topical silymarin cream in combination with glycolic
acid 50% peel versus topical silymarin cream with intradermal tranexamic acid
injection in the treatment of melasma among Filipino women using MASI
scores during a period of 12 weeks.
METHODOLOGY
Study Design and Study Population
This is a
prospective, randomize, single blind, split-face trial study to
compare the efficacy of combined glycolic acid 50% peeling and topical
silymarin cream vs. combined intradermal injection of tranexamic acid and
topical silymarin cream in the treatment of Melasma among Filipino women.
The target study population are Filipino women aged 18 and above with
bilateral epidermal melasma, Fitzpatrick skin types III-IV who will consult at
Jose R Reyes Memorial Medical Center, Manila, Philippines starting January
2017 to May 2017. Exclusion criteria include pregnant or nursing women,
those on contraceptive pills at the time of the study or during the past 12
months,
those
anti-inflammatory
taking
drug,
any
photosensitizing
tetracycline,
drugs
spiranolactone,
like
non-steroidal
phenytoin,
and
carbamazepine at the time of the study, those with bleeding disorders or taking
any kind of anticoagulants, active herpes simplex, facial warts, active
dermatoses, hypersensitivity reaction, and administration of any concurrent
therapy for melasma. Moreover, a washout period of 1 month is necessary for
subjects with previously applied topical hypopigmenting agents.
Sample Size Determination
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The researcher set the maximum permissible error at 5%, α at 5% and
confidence level at 5%. Open Epi results indicated that a minimum of 31
patients in each group will be needed to achieve a 95% level of confidence.
An adjusted minimum of 62 patients, 31 in each arm, are needed to
achieve a 95% level of confidence, precision of 5% to accommodate the
expected 20% drop outs.
Data Collection
Approval from the Institutional Review Board and the Chair of the
Department of Dermatology will be obtained before conducting the study.
Wood's lamp examination will be performed at the study entry to determine
the type of melasma (epidermal, mixed or dermal). Patients with bilateral
epidermal facial melasma will be chosen. After screening of eligible
participants, the study will be explained to the participants and informed
consent will be obtained. The researchers will interview and do a physical
examination on the participants who will voluntarily sign the Informed Consent
Form.
Topical silymarin cream (14mg/mL) will be applied on both side of the face
with the amont of about one finger tip of cream, twice daily for 12 weeks.
The left side of the face (side A) will undergo intradermal injection of 0.05
mL of tranexamic acid solution in normal saline (4mg/mL) at 1 cm interval by
using sterile insulin syringe, weekly for 12 weeks.
The right side of the face (side B) will be treated with glycolic acid 50%
peeling within a period of 20-30 seconds, every 2 weeks for 12 weeks.
Participants will be advised to avoid excessive sun exposure and will be
instructed to apply a broad spectrum sunscreen with a sun protection factor of
30 in the morning and every 2 hours .Clinical evaluation of melasma severity
using MASI score will be performed at baseline and at weeks 4, 8 and12 by
two dermatologists.
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Photographs will be taken with a standard camera, in a well-lit room, in a
standardized position at baseline and week 12. Melasma improvement will be
graded by the patient and 2 independent investigator along four scales: 1 =
>75% lightening (excellent), 2 = 51-75% (good), 3 = 26-50% (fair), and 4 =
0-25% (poor).
Safety parameter will be evaluated using a 4-point grading system
(0=none; not noticed by the physician or patient; 1=mild; noticed by the
physician and/or patient but not disturbing to the patient; 2=moderate; definitely
present and disturbing to the patient and interferes with some activity or sleep;
3=severe; very marked, very disturbing, interfering with most activities and
sleep). The scores of each parameter will be added. A clinical scoring of mild
(total score of 1-6), moderate (total score of 7-12) and severe (total score of
13-18) will be used.
Stopping Guidelines
The trial will be stopped on a patient who will experience moderate or
severe reaction on 2 consecutive visits as determined by the safety parameter
of the study. Any patient who fails to comply with the treatment, and those who
use other topical medications other than the one provided will be withdrawn.
DUMMY TABLES
Time
Tranexamic Acid
Hydroquinone group
P- value
MASI score
MASI score
group
MASI score
Baseline
Week 4
Week 8
Week 12
BUDGET PROPOSAL
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Price (Php)
Intradermal tranexamic acid PHP 19,200
injection
Silymarin cream
PHP 33,600
Glycolic acid 50% peel
PHP 2000
Printing materials
PHP 500
Tuberculin syringes
PHP 500
Statistician
PHP 5000
TOTAL
PHP 60,8000
GANTT CHART
November
December
January to May
June-August 2017
September 2017
2017
2016
IRB application
Preparation of
materials,
compound
medications
Recruitment of
patients
Completion of treatment
of all enrolled subjects
Data analysis,
Drafting and
finalizing of paper
Page 12 of 15
REFERENCES
1Goldstein
BG, Goldstein AO, Callender VD, et.al Melasma.UpToDate Website.
http://www.uptodate.com/contents/melasma.
Updated
Mar
01,
2016
Accessed November 25, 2016
2
Balkrishnan R, McMichael AJ, Camacho FT, et al. Development and
validation of a health-related quality of life instrument for women with melasma.
Br J Dermarol 2003; 149:572
3
Dominguez AR, Balkrishnan R, Ellzey AR, Pandya AG. Melasma in Latina
patients:cross-cultural
adaptation
and
validation
of
a
quality-of-life
questionnaire in Spanish language. J Am Acad Dermatol Treat 2007; 18:5
4
Sheth VM, Pandya A. Melasma: a comprehensive update part II. J Am Acad
Dermatol 2011; 65:700-714
5Sheth
VM, Pandya A. Melasma: a comprehensive update part II. J Am Acad
Dermatol 2011; 65:689-697
6Gupta
AK, Gover MD, Nouri K, Taylor S. The treatment of melasma: a review
of clinical trials. 2006; 55:1049-1065
7Jutley
GS, Rajaratnam R, Halpern J et al. Systematic review if randomized
controlled trials on interventions for melasma: An abridged Cochrane review.
2014; 70:370-373
8
Vladimir K, Daniela W. Silybin and silymarin-new effects and applications.
Biomed papers 2005; 149: 29-41
9Mereish
KA, Brunner DL, et al. Protection against microcystin-LR-induced
hepatoxicity by Silymarin: biochemistry, histopathology, and lethality. Pharm
Res 1991; 8:273-277
10Altaei
Tagreed. The treatment of melasma by silymarin cream. BMC
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Dermatology 2012; 12:2-6
11Choo
SJ, Ryoo et al. Silymarin inhibits melanin synthesis in melanocyte cells.
J Pharm Pharmacol 2009; 61: 663-667
12
Elfar NN, El-Maghraby GM. Efficacy of intradermal injection of tranexamic
acid, topical silymarin, and glycolic acid peelingin the treatment of melasma: a
comparative studt. J Clin Exp Dermatol Res. 2015; 6: 2-7
13
Lee JH, Park JG, Lim SH et al. Localized intradermal microinjection of
tranexamic acid for treatment of melasma in Asian patients: a preliminary
clinical trial. Dermatol Surg 2006; 32-626-631
14Gupta
RR, Mahajan BB, Garg G. Chemical peeling-evaluation of glycolic
acid in varying concentrations and time intervals. Cosmetology 2001; 67:28-29
15Javaheri
SM, Handa S, Kaur I, Kumar B. Safety and efficacy of glycolic acid
facial peel in Indian women with melasma. Int J Dermatol 2001; 40:354-357
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