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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 40  |  Issue : 1  |  Page : 45-52

Tranexamic acid versus topical mesolightening mixture using the dermaroller in the treatment of melisma


1 Professor of Dermatology and Venereology, Faculty of Medicine, University of Alexandria, Egypt
2 Assisstant Professor of Dermatology and Venereology, Faculty of Medicine, University of Alexandria, Egypt
3 Master Degree of Dermatology and Venereology, Faculty of Medicine, University of Alexandria, Egypt

Date of Submission13-Jul-2019
Date of Acceptance14-Nov-2019
Date of Web Publication6-Jan-2020

Correspondence Address:
Rania E.A. AbdElMaksoud
Assisstant Professor of Dermatology and Venereology, Faculty of Medicine, University of Alexandria, 10 Mahmoud Sidky street Louran Alexandria, 21613
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejdv.ejdv_36_19

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  Abstract 


Background Use of localized microinjection of tranexamic acid (TA) has been studied for the treatment of melasma and was proved to be effective, but transdermal delivery of this agent has not been well studied. The use of Dermaroller may increase the effective delivery of active ingredients in topical mesolightening mixture and TA.
Aim The aim of this split-face study was to compare the safety and efficacy of transdermal delivery of TA versus topical mesolightening mixture using the Dermaroller in the treatment of melasma.
Patients and methods This split-face study was carried out on 15 patients having melasma. For each patient, the following was done after taking an informed consent: history taking, dermatological examination, Wood’s light examination, Melanin Area and Severity Index (MASI) score calculation, photography, physician’s global assessment by independent investigators, patient’s global evaluation, eight sessions of transdermal delivery of TA and topical mesolightening mixture, with a session every week (mixture of kojic acid 3%, TA 0.01%, azelaic acid 4% (19,20), L-ascorbic acid 1 g, and water for injection), and recording of the adverse effects every session. This was followed by 3 months of follow-up.
Results The initial (pre-4) reduction of MASI (after the first four sessions) on the left side (TA treated) was significantly higher than that on the right side. Similarly, the later (four to eight sessions) (upon comparing the second set with the first set of sessions) and overall reduction was higher on the left side compared with that on the right side; however, these differences were not statistically significant in terms of MASI.
Conclusion TA and topical mesolightening mixture are individually effective in the treatment of melasma. TA is superior to mesolightening, as well as cost-effective in the treatment of melasma.

Keywords: Dermaroller, Melanin Area and Severity Index score, melasma, mesolighten, tranexamic acid


How to cite this article:
Aly AA, AbdElMaksoud RE, Ismail I. Tranexamic acid versus topical mesolightening mixture using the dermaroller in the treatment of melisma. Egypt J Dermatol Venerol 2020;40:45-52

How to cite this URL:
Aly AA, AbdElMaksoud RE, Ismail I. Tranexamic acid versus topical mesolightening mixture using the dermaroller in the treatment of melisma. Egypt J Dermatol Venerol [serial online] 2020 [cited 2020 Jan 19];40:45-52. Available from: http://www.ejdv.eg.net/text.asp?2020/40/1/45/275184




  Introduction Top


Treatment of melasma remains a great challenge as there is no proven treatment modality. The main treatment is based on removal of any possible pathological factors and the use of a sunscreen and hypopigmenting agent, in combination with others such as tretinoin, topical steroids, or superficial peeling agents [1].

Tranexamic acid (TA) is also known as trans-4-(aminomethyl) cyclohexanecarboxylic acid. Nijor in Japan found in 1979 that severity of melasma was significantly reduced after 2–3 weeks [2]. Since then, it has been proven that administration of TA is useful in the treatment of melasma. TA has been used through transdermal delivery using microneedling, oral administration of 250 mg twice daily for 6 months [3], topical 5% TA [4], topical TA in liposome formulation [5], topical 2% TA emulsion [6], and intradermal microinjection [7] or intravenous administration.

The mechanism of TA’s action in the reduction of hyperpigmentation of melasma has not been fully understood. Maeda and Naganuma [8] performed a study showing that TA is a plasmin inhibitor that works by preventing ultraviolet-induced pigmentation in guinea pigs by stopping the binding of plasminogen to the keratinocytes, which results in the decrease of melanocyte tyrosinase activity, leading to reduction of prostaglandins and arachidonic acid, which are inflammatory mediators involved in melanogenesis. Another study by Maeda and Tomitab [9] suggested that TA inhibits melanin synthesis in melanocytes by interfering with the interaction of melanocytes and keratinocytes by inhibition of the plasminogen/plasmin system. The research by Zhang et al. [10] showed that TA can inhibit melanogenesis by interfering with the catalytic reaction of tyrosinase. TA can decrease the activity of mast cells, as mast cell activation after ischemia and reperfusion injury is almost completely abolished by TA treatment [11].

Topical mesolightening mixture is a mixture of kojic acid [12],[13],[14] 3%, TA 0.01%, azelaic acid 4% [15],[16], L-ascorbic acid 1 g [17], and water for injection.

The Dermaroller is a breakthrough device, simple in concept but yielding magnificent results.

Over the past decade, microneedles have been developed to deliver drugs into the skin in a minimally invasive manner [18]. Microneedles work by creation of thousands of microclefts through the epidermis into the papillary dermis to facilitate transdermal drug delivery and stimulate skin’s natural repair without causing permanent epidermal damage. A study by Fabbrocini et al. [1] compared combined skin needling and depigmenting serum (containing two principal topical agents: rucinol and sophora-alpha) with depigmenting serum alone in the treatment of melasma to evaluate the use of skin needling as a means to enhance the transdermal penetration of a serum containing rucinol and sophora-alpha in managing abnormal skin hyperpigmentation. They found that in the areas treated with skin needling in combination with depigmenting serum, hyperpigmentation was significantly reduced compared with areas treated using depigmenting serum alone.


  Aim Top


The aim of this split-face study was to compare the safety and efficacy of transdermal delivery of TA versus topical mesolightening mixture using the Dermaroller in the treatment of melasma.


  Patients and methods Top


Patients

This split-face study was carried on 15 women having melasma. We obtained ethics committee approval, and informed consent was taken from the patients before the beginning of the study. This consent included that the patient will be notified that she is subjected to treatment by two different agents. Then the patient was informed that she will be subjected to further sessions on the side that has improved less using the treatment that has proved to be efficacious until homogeneity is obtained on both sides. The procedures, risks, benefits, potential side effects, and complications were explained to each subject.

The cases were recruited from the Dermatology Outpatient Clinic of The Main University Hospital, Faculty of Medicine, Alexandria University. The study was done from October to end of December.

The sessions were held at the Dermatology Department, The Main University Hospital, Faculty of Medicine, Alexandria University.

Inclusion criteria were patients having almost symmetrical melisma, and the patients stopped any cosmetic depigmenting agent 6 months before inclusion. Exclusion criteria were patients who had a history of keloid scarring, warts, solar keratoses, any skin infection, presence of skin cancers, or any known bleeding disorders, pregnant women or lactating mothers, and women on hormonal contraception.

A detailed history was taken, including medical, surgical, and dermatological histories, emphasizing on history of recurrent herpes simplex infection, nature of wound healing process, and other dermatological diseases.

Procedure

During the first session, each patient underwent a careful dermatologic examination. All the participants were subjected to Wood’s light to determine the type of melasma (epidermal from dermal or mixed). Every patient was photographed by the researcher under natural daylight at the baseline and fourth and eighth week of treatment.

Melanin Area and Severity Index (MASI) scores of the right and left side of the face were calculated for each patient at the baseline and at fourth and eighth week of treatment. The percentage area (A) involved is graded on a scale of 0–6; the darkness of melasma (D) is compared with the normal skin and graded on a scale of 0–4, and the homogeneity of hyperpigmentation (H) was also graded on a scale of 0–4 [5].

Three independent dermatologists not involved in the study examined the serial photographs and gave their judgments of overall improvements of melasma using a scoring system. Patient’s global evaluation was done using a questionnaire. These questionnaires were answered by the patients after treatment sessions, whether the lesions had almost cleared or had marked improvement, moderate improvement, or slight improvement.

For every patient, a topical anesthetic cream was applied on both sides of the face for 1 2 h. The area was occluded with plastic wrap. Topical anesthetic was wiped off immediately before the session. Gentle skin cleansing with 70% alcohol was done. Using gentle pressure, the Dermaroller was passed three times over each area in the right side of the face in each direction, vertically, horizontally, and in both diagonals. TA 100 mg/ml solution for injection was diluted in sterile water for injection to obtain a 4 mg/ml solution equivalent to 0.4%. Dermaroller was utilized in this study with a needle length of 1 mm. Mesolighten (0.5 ml) was applied over the treated area, after which the Dermaroller was passed three times again over each area in each direction, vertically, horizontally, and in both diagonals. Then another 0.5 ml of mesolighten is applied to the treated area. For the other side, 0.5 ml of TA was applied to the left side of the face, after which the Dermaroller was passed three times again over each area in each direction, vertically, horizontally, and in both diagonals. Then another 0.5 ml of TA is applied to the treated area. The participants applied soothing antibacterial agent. The patients were advised to avoid excessive sun exposure and to apply a broad-spectrum sunscreen in the morning during and after therapy. The sessions were repeated every week or may be delayed for the following week if the patient had any adverse effects. Sessions were repeated for a maximum of eight sessions. Follow-up was done after 3 months to check for complications and any adverse effects present.

Statistical analysis

Statistical analyses were performed suing SPSS Statistics 21 (SPSS Inc., Chicago, Illinois, USA). Comparison between quantitative data was done using number and percent, whereas comparison between qualitative done was done using median, minimum, maximum, mean, and SD, where P value less than 0.005 was considered to be statistically different.


  Results Top


A total of 15 patients were enrolled in this study, with 14 completing up to 8 weeks of treatment, and one patient dropped out after the fifth session.

Age of the patients ranged between 22 and 50 years, with a mean of 38.27±9.70 years. Skin types I, II, and VI were not represented in this study. A total of 11 (73.3%) patients had centrofacial and four (26.7%) patients had malar distribution of melasma. Using the Wood’s light, seven (46.7%) patients were of the mixed type, four (26.7%) patients were of the dermal type, and four (26.7%) patients were of the epidermal type.

The commonest cause of melasma found among the 15 patients was sun exposure in six (40%) patients, followed by pregnancy in five (33.3%) patients, then genetic cause in two (13.3%) patients, oral contraceptive pills (OCP) in one (6.7%) patient, and stress in one (6.7%) patient.

As shown in [Table 1], the initial reduction of MASI (i.e. before the first session till the fourth session) on the left side (M=3.62, SD=2.21) was significantly higher than that on the right side (M=2.49, SD=1–94). Similarly, the later (i.e. from the fourth till the eighth session) and overall reduction of MASI score was higher on the left side (Mdn=1.92) compared with that on the right side (Mdn=1.25), though these differences were not statistically significant (P>0.005).
Table 1 Comparison of the initial, later, and overall reduction of Melanin Area and Severity Index score on the right side with that of the left side among studied patients with melasma

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In conjunction with the previous results, the investigator’s global evaluation showed that there is significantly more improvement on the left side (TA treated) than that on the right side (Mesolighten treated), and the patient’s global evaluation found that 93.3% of the patients showed marked improvement to clearance of melasma on the left side, whereas only 66.6% of the patients reported that on the right side. However, the difference did not reach significance.

Change over time on the right side

On the right side, when the percent score decrease was compared between the baseline till session 4 and session 4 till session 8, the difference was nonsignificant (Z=−0.567, P=0.59) ([Table 2] and [Table 3).
Table 2 Difference between sessions in both sides (% change)

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Table 3 Difference between sessions in right and letf sides separately (% change)

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When the percent score decrease was compared between the baseline till fourth session and the baseline till session 8, a significant difference was noted (Z=−2.053, P=0.04).

Similarly, when the percent score decrease was compared between fourth till eighth session and baseline till eighth session, a significant difference was noted (Z=−2.046, P=0.04).

Change over time on the left side

When the percent score decrease was compared between baseline till session 4 and session 4 till session 8, a significant difference was noted (Z=−2.009, P=0.0045).

Similarly, when the percent score decrease was compared between the baseline till session 4 and baseline till session 8, a significant difference was noted (Z=−1.987, P=0.047).

Moreover, the same was noted when comparing sessions 4–8 on one hand and baseline till the eighth session on the other hand (Z=−3.493, P=0.001).

Patient’s global evaluation, the investigator’s global evaluation, and the overall reduction of MASI on the right and left sides of the patients.

A reliability analysis using the intraclass correlation coefficient (ICC) was performed to determine absolute agreement among investigators. On the right side, the interrater reliability for the average score given by a group of investigators was almost perfect [ICC=0.970 (P<0.001), 95% confidence interval (CI): 0.917–0.989]. The interrater reliability for a score given by one investigator was substantial to almost perfect [ICC=0.914 (P<0.001), 95% CI: 0.786–0.969].

On the left side, the interrater reliability was almost similar. The interrater reliability for the average score given by a group of investigators was substantial to almost perfect [ICC=0.954 (P<0.001), 95% CI: 0.871–0.984]. The interrater reliability for a score given by one investigator was substantial to almost perfect [ICC=0.874 (P<0.001), 95% CI: 0.692–0.984].

Patient global evaluation strongly correlated with the investigator global evaluation on the right and left sides (ρ=0.932, P<0.001 and ρ=0.812, P<0.001, respectively). However, neither the patient’s nor investigators’ global evaluation correlated with the overall reduction of MASI score.

Treatment and patient global evaluation

Although the percentage of patients’ global evaluations ranged from marked improvement to clearance of melasma was 93.3% on the left side, it was considerably lower on the right side (66.6%). Yet, this difference did not reach statistical significance (Z=1.90, P=−0.058).

Adverse effects

There were no differences between treatment-related adverse effects developed on the right side and that developed on the left side ([Table 4]). Pain was the most common adverse effect. Two-thirds of the patients experienced pain on both sides. None developed pain on either side only. Postinflammatory hyperpigmentation, persistent erythema, and allergy to anesthesia were the second most common adverse effects of treatment. Regarding postinflammatory hyperpigmentation, one patient developed it bilaterally, whereas two other patients developed it unilaterally.
Table 4 Adverse effects among the 15 patients with melasma included in the study

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None of the patients developed allergy either to TA or to topical mesolightening mixture. There is no difference between the two sides. Statistical test cannot be performed as the values of the discordant cells were zeros ([Figure 1] and [Figure 2]).
Figure 1 (a) Right side before treatment, MASI score14.7. (b) MASI 1.8 after treatment. (c) Left side before treatment, MASI score 12.45, and (d) MASI 1.8 after treatment. MASI, Melanin Area and Severity Index.

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Figure 2 (a) Right side before treatment, MASI score 15.85. (b) MASI 8.25 after treatment. (c) Left side before treatment, MASI score 15.85, and (d) MASI 7.2 after treatment. MASI, Melanin Area and Severity Index.

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  Discussion Top


In this study, all patients were females for many reasons. First of all, females are more concerned about their appearance and look than males, and also owing to hormonal factors, which is the main factor causing melasma in the present study [13].

Regarding the ages of the patients, the mean age of onset of melasma was 38.27±9.70 years. This is in accordance with Leeyaphan et al. [13], where the mean age of onset of melasma in their patients was almost the same. This is owing to the cumulative effect of sun exposure, and hormonal disturbance over years that lead to melasma by that age.

Regarding the type of melasma according to Wood’s light, mixed type was the predominant type (seven patients; 46.7%) in the current study followed by dermal (four patients; 26.7%) and epidermal (four patients; 26.7%) types. This distribution helped us to validate the results of the present study with the results of Lee et al. [11], who found that 4 mg/ml TA to be useful in dermal and mixed melasma where topical bleaching agent protocols do not give satisfactory results, and Kang and Ortonne [15], who stated that dermal and mixed-type melasma are more difficult to treat than epidermal type. However, epidermal pattern is the commonest type of melasma as reported by Grimes et al. [16], and Farshi [17].

In the current study, we used the Dermaroller as a method to enhance the transdermal drug delivery. This is supported by Fabbrocini et al. [1], who suggested that the use of skin needling improves the absorption of depigmenting agents and offers an important contribution in the treatment of melasma.

In this study, the gradual reduction of the average MASI score over time on the right side (mesolighten treated) was significant, indicating mesolighten efficacy in the treatment of melasma. This result came in accordance with a previous study by Embaby [18].

The efficacy of TA in this study was proved by the gradual reduction of MASI score of the left side (TA treated). This reduction was statistically significant, indicating its efficacy in the treatment of melasma. This result came in agreement with Lee et al. [14].

So both drugs are effective in treatment of melasma with significant reduction in MASI score for each one.When comparing the percent decrease overtime, it was noted on the right side that significant decrease was noted cumulatively when eight sessions were accomplished, when compared with the first sessions versus the second set of sessions (0–4) and (4–8).

On the left side, comparison of both the first and second set of sessions was significantly different where the percent decrease was more in the first set versus the second set of sessions. Moreover, when either the first or the second set was compared alone with the overall percent decrease after the eighth session, significant decrease was noted, which highlights the fact of cumulative effect of the eight sessions.

On the contrary, Lee et al. [14] declared that after localized microinjection of TA 4 mg/ml, the reduction in the mean MASI score was not statistically significant until week 8. This controversy can be simply explained by the probable important contributing role of Dermaroller in the treatment of melasma. In the current study, it appeared that Dermaroller might hasten the effect of the hypopigmenting agents, indicating its main role in the treatment of melasma.

Regarding the relation between the type of melasma determined by Wood’s light and the reduction of MASI score, Lawrence et al. [19] reported that Wood’s light did not help in assessing the response to treatment. Regarding the type of melasma according to Wood’s light and the response to treatment, Kang and Ortonne [15] stated that dermal and mixed types of melasma are more difficult to treat than epidermal type.

When comparing pain, allergy to anesthetic, post inflammatory hyperpigmentation (PIH), and persistent erythema on both topical mesolightening mixture- and TA-treated sides, there were minimal adverse effects related to Dermaroller usage and the type of anesthetic, which can be avoided by using shorter needle and changing the type of anesthetic. Regarding PIH, it can be managed by topical hypopigmenting agent. There were no differences between treatment-related adverse effects developed on the right side and that developed on the left side indicating the safety profile of both agents.

Other important observation we noticed in the present study was that there was significant improvement in the texture and glow of skin appreciated by all of patients owing to collagen remodeling and the rejuvenating effect of Dermaroller. However, this observation was not validated by objective scoring.


  Conclusion Top


TA and topical mesolightening mixture are individually effective in the treatment of melasma.

TA is superior to topical mesolightening mixture, as well as cost-effective in the treatment of melasma regardless of the skin type and age of the patient.

Despite that topical mesolightening mixture cocktail contained four acids (including TA 0.01%) that were expected to give synergistic effect, the final results showed that TA alone in a concentration equivalent to 0.4% appears to be a potentially promising therapeutic tool and better than the cocktail in treating patients with melasma. For this reason, it may be used as a part of melasma treatments.

Regarding skin types of the cases, types III, IV, and V all have good response to the treatment.

Both TA and topical mesolightening mixture are equally effective in epidermal, dermal, and mixed type of melasma.

Regarding safety, both agents are almost equally safe in the treatment of melasma.

The use of Dermaroller was found to hasten the therapeutic response to hypopigmenting agents in our group of patients.

The rejuvenation effect of Dermaroller added a pleasant outcome appreciated by the patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Fabbrocini G, de Vita V, Fardella N, Pastore F, Annunziata MC, Mauriello MC et al. Skin needling to enhance depigmenting serum penetration in the treatment of melasma. Plast Surg Int 2011; 2011:158241.  Back to cited text no. 1
    
2.
Sadako N. Treatment of melasma with tranexamic acid. Clin Rep 1979; 13:3129–3131.  Back to cited text no. 2
    
3.
Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y et al. Treatment of melasma with oral administration of tranexamic acid. Aesth Plast Surg 2012; 36:964–970.  Back to cited text no. 3
    
4.
Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, Nakakes A. Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind randomized controlled clinical trial. J Cosmet Laser Ther 2012; 14:150–154.  Back to cited text no. 4
    
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Manosroi A, Podjanasoonthon K, Manosroi J. Development of novel topical tranexamic acid liposome formulations. Int J Pharma 2002; 235:61–70.  Back to cited text no. 5
    
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Konda S, Okada Y, Tomita Y. Clinical study of effect of tranexamic acid emulsion on melasma and freckles (in Japanese). Skin Res 2007; 6:309–315.  Back to cited text no. 6
    
7.
Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation-induced pigmentation. Photochem Photobiol 1998; 47:130–141.  Back to cited text no. 7
    
8.
Maeda K, Tomitab Y. Mechanism of the inhibitory effect of tranexamic acid on melanogenesis in cultured human melanocytes in the presence of keratinocyte-conditioned medium. J Health Sci 2007; 53:389–396.  Back to cited text no. 8
    
9.
Zhang X, Yang X, Yang H, Yang Y. Study of inhibitory effect of acidum tranexamicum on melanin synthesis. Chin J Dermatovenerol Integr Tradit West Med 2003; 2:227–229.  Back to cited text no. 9
    
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Reichel CA, Lerchenberger M, Uhl B. Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature. PLoS One 2011; 6:e17229.  Back to cited text no. 10
    
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Prausnitz MR, Gill HS, Park JH. Microneedles for drug delivery. In: Rathbone MJ, Hadgraft J, Roberts MS, Lane ME, (eds). Modified release drug delivery. New York: Informa Healthcare; 2008. 2:1295–1309.  Back to cited text no. 11
    
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Sarkar R, Puri P, Jain RK, Singh A, Desai A. Melasma in men: a clinical, aetiological and histological study. JEADV 2010; 24:768–772.  Back to cited text no. 12
    
13.
Leeyaphan C, Wanitphakdeedecha R, Manuskiatti W, Kulthana K. Measuring melasma patients’ quality of life using willingness to pay and time trade-off methods in Thai population. BMC Dermatol 2011; 11:16.  Back to cited text no. 13
    
14.
Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY 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.  Back to cited text no. 14
    
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Kang HY, Ortonne JP. What should be considered in treatment of melasma. Ann Dermatol 2010; 22:373–378.  Back to cited text no. 15
    
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Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alteration in patients with melasma. Am J Dermatopathol 2005; 27:96–101.  Back to cited text no. 16
    
17.
Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol 2011; 10:28–7.  Back to cited text no. 17
    
18.
Embaby AM. Trichloroacetic acid chemical peel versus meolighten for treatment of melasma [MSc thesis]. Alexandria: Dermatology, Venereology and Andrology Department, Faculty of Medicine, Alexandria University; 2012 86–92.  Back to cited text no. 18
    
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Lawrence N, Cox SE, Brody HJ. Treatment of melasma with Jessner’s solution versus glycolic acid: a comparison of clinical efficacy and evaluation of the predictive ability of Wood’s light examination. J Am Acad Dermatol 1997; 36:589–593.  Back to cited text no. 19
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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