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1.  Refractory Postinflammatory Hyperpigmentation Treated Fractional CO2 Laser 
Objective: Postinflammatory hyperpigmentation is a reactive hypermelanosis of the skin that occurs as a consequence of an inflammatory process, such as acne, eczema, drug reactions, burns, chemical peelings, and laser applications. Although topical agents remain to be the first-line treatment of postinflammatory hyperpigmentation, treatment of recalcitrant cases is challenging. The Q-switched ruby laser, the low-dose Q-switched neodymium-doped yttrium aluminum garnet laser, and the fractional 1550nm erbium-doped fiber laser have been reported to improve postinflammatory hyperpigmentation. Design/setting/participants: The authors present a case of refractory postinflammatory hyperpigmentation successfully treated with two sessions of fractional CO2 laser in a 24-year-old woman with Fitzpatrick skin type III. Results: After two treatment sessions with a one-month interval, the lesion totally cleared without any complications. Conclusion: Although many laser systems, including fractional CO2 lasers, can cause postinflammatory hyperpigmentation, they also can be very efficacious tools by using conservative laser settings and by providing appropriate post-treatment care in recalcitrant postinflammatory hyperpigmentation treatment.
PMCID: PMC3970832  PMID: 24688626
2.  Kojic Acid vis-a-vis its Combinations with Hydroquinone and Betamethasone Valerate in Melasma: A Randomized, Single Blind, Comparative Study of Efficacy and Safety 
Indian Journal of Dermatology  2013;58(4):281-285.
Melasma is a relatively common, acquired symmetric hypermelanosis characterized by irregular light to gray-brown macules involving sun-exposed areas. Kojic acid, with its depigmenting potential due to tyrosinase inhibition and suppression of melanogenesis, has become a vital component of the dermatologists’ armamentarium against melasma.
To study and compare the efficacy of kojic acid 1% alone, vis-a-vis its separate combinations with 2% hydroquinone or 0.1% betamethasone valerate and a combination of all these three agents with respect to the duration of symptoms and level of pigmentation in the therapy of melasma.
Materials and Methods:
Eighty patients from a single tertiary care center objectively assessed by calculating the melasma area severity index (MASI) and randomized (simple randomization) into four parallel groups (A, B, C, and D) of 20 each were prescribed once daily local application at night, (participants blinded regarding the difference in identity of interventions), as follows:
Group A – kojic acid 1% cream.
Group B – kojic acid 1% and hydroquinone 2% cream.
Group C – kojic acid 1% and betamethasone valerate 0.1% cream.
Group D – kojic acid 1%, hydroquinone 2%, and betamethasone valerate 0.1% cream.
Strict photoprotection and use of a SPF 15 sunscreen was advised during the day. Patients were evaluated every 2 weeks and a fall in MASI score was calculated at the end of the study period of 12 weeks by the same investigator.
The response was compared according to percentage decrease in MASI score. Efficacy was evaluated among the groups at the end of 3 months using bivariate analysis and calculated by using the paired ‘t’ test. The clinical efficacy of group B was the highest followed closely by group D and group A, that of group C being the lowest.
Kojic acid in synergy with hydroquinone is a superior depigmenting agent as compared with other combinations.
PMCID: PMC3726874  PMID: 23918998
Kojic acid; melasma; MASI score
3.  Resveratrol-Enriched Rice Down-Regulates Melanin Synthesis in UVB-Induced Guinea Pigs Epidermal Skin Tissue 
Biomolecules & Therapeutics  2014;22(5):431-437.
Synthetic compounds that are used in the clinic to regulate skin hyperpigmentation, such as arbutin, hydroquinone, and kojic acid, are only moderately effective. But, their use is limited by side effects. As part of an effort to overcome the limitations, we developed resveratrol-enriched rice (RR) using genetic engineering technique. Each of resveratrol and rice has been reported to produce anti-melanogenic effects. Therefore, we hypothesized that RR would show more anti-melanogenic effects than those of resveratrol or rice alone. Anti-melanogenic effect of RR was done by using melan-a mouse melanocytes. The depigmenting efficacy was then observed following topical application of the RR to UVB-stimulated hyperpigmented dorsal skin of guinea pigs. Treatment with RR extract resulted a 21.4 ± 0.7% decrease in tyrosinase expression at melan-a cells. Colorimetric analysis showed a significantly lower depigmenting value by day 9 following treatment with RR in UVB-irradiated guinea pigs the dorsal skin (p<0.01), indicating that RR produced a depigmentation effect. By staining with Fontana-Masson stain, we found that the RR-treated group had more effect histopathologically in epidermal melanin production than resveratrol or rice alone-treated group. RR was associated with reduction in the levels of microphthalmia-associated transcription factor (MITF), and downregulation of tyrosinase and tyrosinase-related protein (TRP-2) expression, leading to inhibit epidermal melanin production by western blot analysis. This study suggests that the resveratrol-enriched rice may be a promising candidate in regulating skin pigmentation with UVB exposure.
PMCID: PMC4201217  PMID: 25414774
Resveratrol; Rice; Melanogenesis; Resveratrol-enriched rice; Ultraviolet B; Guinea pig
4.  Efficacy and Safety of Clindamycin Phosphate 1.2% and Tretinoin 0.025% Gel for the Treatment of Acne and Acne-induced Post-inflammatory Hyperpigmentation in Patients with Skin of Color 
Objective: To assess the efficacy and safety of a topical gel containing clindamycin 1.2% and tretinoin 0.025% for the treatment of acne and acne-induced postinflammatory hyperpigmentation (PIH) in darker skinned patients. Design: Randomized, double-blind, placebo-controlled study. Setting: Two United States clinical sites. Participants: Thirty-three patients 12 years of age or older with skin types IV to VI, mild-to-moderate facial acne, and PIH were enrolled. Measurements: Patients applied clindamycin phosphate/tretinoin gel or a nonmedicated vehicle each evening and a sun protection factor 30 sunscreen daily. Changes in skin erythema and hyperpigmentation were measured using a chromameter and photographic images. Efficacy was assessed using the Evaluators Global Acne Severity Scale, lesion counts, Post-inflammatory Hyperpigmentation Severity Scales and Patient’s Global Assessment Scale. Safety and tolerability were assessed by adverse event reports and a Safety Assessment Scale. Results: The mean (SD) baseline inflammatory lesion count was 11.9 (11.1) in clindamycin/tretinoin-treated patients, decreasing by 5.5 (6.56) after 12 weeks while the mean baseline inflammatory lesion count was 13.6 (11.15) in placebo-treated patients, decreasing by 4.1 (11.36) (p=0.05 for change from baseline, clindamycin/tretinoin vs. placebo). Clindamycin/tretinoin-treated patients generally demonstrated superior efficacy versus placebo treatment. The clindamycin/tretinoin topical gel was well tolerated, causing little or no irritation, although one patient withdrew due to periorbital edema of moderate severity possibly related to clindamycin/tretinoin gel. Conclusion: Although limited by small sample size, the results of this pilot study suggest clindamycin phosphate 1.2% and tretinoin 0.025% topical gel is a safe and effective option for treating mild-to-moderate acne in patients with skin of color.
PMCID: PMC3396458  PMID: 22798973
Indian Journal of Dermatology  2009;54(1):41-45.
Melasma is a symmetric progressive hyperpigmentation of the facial skin that occurs in all races but has a predilection for darker skin phenotypes. Depigmenting agents, laser and chemical peeling as classic Jessner's solution, modified Jessner's solution and trichloroacetic acid have been used alone and in combination in the treatment of melasma.
The aim of the study was to compare the therapeutic effect of combined 15% Trichloroacetic acid (TCA) and modified Jessner's solution with 15% TCA on melasma.
Materials and Methods:
Twenty married females with melasma (epidermal type), with a mean age of 38.25 years, were included in this study. All were of skin type III or IV. Fifteen percent TCA was applied to the whole face, with the exception of the left malar area to which combined TCA 15% and modified Jessner's solution was applied.
Our results revealed statistically highly significant difference between MASI Score (Melasma Area and Severity Index) between the right malar area and the left malar area.
Modified Jessner's solution proved to be useful as an adjuvant treatment with TCA in the treatment of melasma, improving the results and minimizing postinflammatory hyperpigmentation.
PMCID: PMC2800869  PMID: 20049268
Classic Jessner's solution; chemical peeling; melasma; modified Jessner's solution; trichloroacetic acid
6.  Polypodium leucotomos as an Adjunct Treatment of Pigmentary Disorders 
Introduction: Extracts of the tropical fern Polypodium leucotomos appear to possess beneficial properties for the skin attributed to the presence of numerous compounds within the extract that have antioxidant and photoprotective properties. Orally administered Polypodium leucotomos may provide protection against the detrimental photoaging effects of sunlight and can also help reduce the frequency and severity of polymorphous light eruption. Polypodium leucotomos has also been shown to be beneficial for the prevention and potential treatment of several aesthetically relevant conditions. Objective: The purpose of this review is to investigate the beneficial role of Polypodium leucotomos as an adjunct treatment for vitiligo, melasma, and postinflammatory hyperpigmentation. Results: Based on a review of relevant literature including the results of a randomized, placebo-controlled study, the oral administration of Polypodium leucotomos significantly improved the severity of melasma in women after 12 weeks. Three randomized, double-blind, placebo-controlled studies have demonstrated significant improvements in vitiligo when oral Polypodium leucotomos therapy was combined with psoralens plus ultraviolet A and narrowband ultraviolet B. No controlled studies have assessed the efficacy of Polypodium leucotomos for the treatment of postinflammatory hyperpigmentation; however, its known antioxidant and anti-inflammatory properties and demonstrated effectiveness for melasma support its use for treating this condition. No adverse events have been associated with the use of Polypodium leucotomos. Conclusion: In addition to preventing many harmful effects associated with sunlight exposure, orally administered Polypodium leucotomos also appears to provide adjunctive benefits in treating vitiligo, melasma, and may have the potential to help with postinflammatory hyperpigmentation.
PMCID: PMC3970827  PMID: 24688621
Indian Journal of Dermatology  2009;54(4):303-309.
Melasma is a common hypermelanotic disorder affecting the face that is associated with considerable psychological impacts. The management of melasma is challenging and requires a long-term treatment plan. In addition to avoidance of aggravating factors like oral pills and ultraviolet exposure, topical therapy has remained the mainstay of treatment. Multiple options for topical treatment are available, of which hydroquinone (HQ) is the most commonly prescribed agent. Besides HQ, other topical agents for which varying degrees of evidence for clinical efficacy exist include azelaic acid, kojic acid, retinoids, topical steroids, glycolic acid, mequinol, and arbutin. Topical medications modify various stages of melanogenesis, the most common mode of action being inhibition of the enzyme, tyrosinase. Combination therapy is the preferred mode of treatment for the synergism and reduction of untoward effects. The most popular combination consists of HQ, a topical steroid, and retinoic acid. Prolonged HQ usage may lead to untoward effects like depigmentation and exogenous ochronosis. The search for safer alternatives has given rise to the development of many newer agents, several of them from natural sources. Well-designed controlled clinical trials are needed to clarify their role in the routine management of melasma.
PMCID: PMC2807702  PMID: 20101327
Melasma; newer agents; topical treatment
8.  Depigmenting Effect of Kojic Acid Esters in Hyperpigmented B16F1 Melanoma Cells 
The depigmenting effect of kojic acid esters synthesized by the esterification of kojic acid using Rhizomucor miehei immobilized lipase was investigated in B16F1 melanoma cells. The depigmenting effect of kojic acid and kojic acid esters was evaluated by the inhibitory effect of melanin formation and tyrosinase activity on alpha-stimulating hormone- (α-MSH-) induced melanin synthesis in B16F1 melanoma cells. The cellular tyrosinase inhibitory effect of kojic acid monooleate, kojic acid monolaurate, and kojic acid monopalmitate was found similar to kojic acid at nontoxic doses ranging from 1.95 to 62.5 μg/mL. However, kojic acid monopalmitate gave slightly higher inhibition to melanin formation compared to other inhibitors at doses ranging from 15.63 to 62.5 μg/mL. Kojic acid and kojic acid esters also show antioxidant activity that will enhance the depigmenting effect. The cytotoxicity of kojic acid esters in B16F1 melanoma cells was significantly lower than kojic acid at high doses, ranging from 125 and 500 μg/mL. Since kojic acid esters have lower cytotoxic effect than kojic acid, it is suggested that kojic acid esters can be used as alternatives for a safe skin whitening agent and potential depigmenting agents to treat hyperpigmentation.
PMCID: PMC3468271  PMID: 23091364
9.  A Comparative Study of the Efficacy of 4% Hydroquinone vs 0.75% Kojic Acid Cream in the Treatment of Facial Melasma 
Melasma is a common acquired cause of facial hyperpigmentation seen predominantly among females with significant psychological and social impact. It is often recalcitrant to treatment. Several topical hypopigmenting agents have been used to combat melasma. Hydroquinone and Kojic Acid are well established monotherapeutic agents for treating melasma.
This study focuses mainly on the efficacy of once daily application of 4% Hydroquinone and 0.75% Kojic Acid cream (containing 0.75% Kojic acid and 2.5% vitamin C) so as to determine an effective modality of treatment for facial melasma.
Materials and Methods:
A total number of 60 patients with facial melasma attending the Out-patient department of Dermatology, Venerology and Leprosy, Fr. Muller Medical College Hospital, Mangalore from Oct 2008-April 2010 were studied. Patients were allocated alternately to group A and group B. Group A patients received 4% Hydroquinone cream and group B patient received a Kojic Acid cream (which contained 0.75% Kojic acid and 2.5% vitamin C) and were advised to apply topically once daily at night. Patients were followed up on 4th, 8th and 12th week. At each visit side effects were noted and clinical response to treatment was calculated using the MASI score.
Statistical Methods:
Chi square test, student ‘t’ test.
At the 4th week post treatment evaluation, facial hyperpigmentation responded early to 4% Hydroquinone cream than to 0.75% Kojic Acid cream. At the end of 12 week treatment period, 4% Hydroquinone cream had an overall superiority to 0.75% Kojic Acid cream as a topical hypopigmenting agent.
The results of the study show that 4% Hydroquinone cream is a better topical hypopigmenting agent with rapid rate of clinical improvement when compared to 0.75% Kojic Acid cream.
PMCID: PMC3657227  PMID: 23716817
Melasma; 4% Hydroquinone cream; 0.75% Kojic Acid cream
10.  Glycolic acid peel therapy – a current review 
Chemical peels have been time-tested and are here to stay. Alpha-hydroxy peels are highly popular in the dermatologist’s arsenal of procedures. Glycolic acid peel is the most common alpha-hydroxy acid peel, also known as fruit peel. It is simple, inexpensive, and has no downtime. This review talks about various studies of glycolic acid peels for various indications, such as acne, acne scars, melasma, postinflammatory hyperpigmentation, photoaging, and seborrhea. Combination therapies and treatment procedure are also discussed. Careful review of medical history, examination of the skin, and pre-peel priming of skin are important before every peel. Proper patient selection, peel timing, and neutralization on-time will ensure good results, with no side effects. Depth of the glycolic acid peel depends on the concentration of the acid used, the number of coats applied, and the time for which it is applied. Hence, it can be used as a very superficial peel, or even a medium depth peel. It has been found to be very safe with Fitzpatrick skin types I–IV. All in all, it is a peel that is here to stay.
PMCID: PMC3875240  PMID: 24399880
acne scar; melasma; photoaging; chemical peel; alpha-hydroxy peel
11.  Cosmeceuticals for Hyperpigmentation: What is Available? 
Cosmeceuticals are topical cosmetic-pharmaceutical hybrids that enhance the beauty through constituents that provide additional health-related benefit. Cosmeceuticals are commonly used for hyperpigmentation. These disorders are generally difficult to treat, hence the need for skin lightening agents including, cosmeceuticals. These agents selectively target hyperplastic melanocytes and inhibit key regulatory steps in melanin synthesis. With the recent safety concern regarding use of hydroquinone, the need for alternative natural, safe and efficacious skin lightening agents is becoming all the more necessary and the article attempts to look at other alternative cosmeceuticals available or maybe upcoming in the future. We carried out a PUBMED search using the following terms “cosmeceuticals, hyperpigmentation, skin lightening agents.” We cited the use of various agents used for the treatment of hyperpigmentation, mainly melasma and post-inflammatory hyperpigmentation. We describe the safety and efficacy of these agents and their advantage over the conventional therapy.
PMCID: PMC3663177  PMID: 23723597
Cosmeceuticals; hyperpigmentation; melasma
12.  Synergistic Combination of an In-office Procedure and Home Regimen for the Treatment of Facial Hyperpigmentation 
Hyperpigmentation disorders, such as melasma and solar lentigines, pose a significant treatment challenge for most patients. Combining a series of in-office procedures, such as chemical peels and light- and laser-based treatments, with maintenance therapies have been shown to provide greater efficacy than one treatment alone. However, receiving multiple in-office procedures may be cost prohibitive for patients. A series of eight case studies were conducted to evaluate the efficacy and tolerability of a novel treatment regimen combining one in-office superficial chemical peel procedure followed by a 12-week topical maintenance program consisting of micro-entrapped 4% hydroquinone, tri-retinol, and sunscreen with sun protection factor (SPF) 30+. Patients presented with Fitzpatrick skin types II and III and mild-to-moderate solar lentigines and/or melasma on their facial skin. Physician-graded overall improvement in hyperpigmentation, standardized photography, and patient satisfaction were evaluated at Weeks 4, 8, and 12. At Week 12, all eight patients demonstrated improvements of at least 25 percent in overall facial hyperpigmentation, with six of the patients demonstrating a 50- or 75-percent overall improvement. One hundred percent of the patients rated their experience with the novel treatment regimen as “excellent” or “good” reflecting high patient satisfaction. Standardized photographs also support the physician and patient findings. Results from these case studies demonstrate that this unique treatment regimen combining one in-office procedure followed by 12 weeks of topical maintenance therapy, may provide an effective, simple, and cost-effective option for patients with facial hyperpigmentation.
PMCID: PMC3366447  PMID: 22708006
13.  A Meta-analysis to Investigate the Relation Between Fitzpatrick Skin Types and Tolerability of Adapalene-Benzoyl Peroxide Topical Gel in Subjects with Mild or Moderate Acne 
The overall goal of acne management for all patients is to select treatments that effectively address as many pathogenic factors as possible while minimizing side effects. Acne therapy in darker skin patients presents unique challenges due to differences in the risk of postinflammatory hyperpigmentation, which may develop in response to acne itself or to irritation secondary to treatment. One combination treatment currently available is a gel formulation containing a retinoid (adapalene 0.1%) in fixed combination with an antimicrobial (benzoyl peroxide 2.5%). Results from three randomized, double-blind, vehicle-controlled, clinical trials of adapalene-benzoyl peroxide were combined in a retrospective meta-analysis that included 909 patients treated for 12 weeks and assessed at each visit for erythema, scaling, dryness, and stinging/burning. Only Week 1 results were included in the meta-analysis because the worst severity of cutaneous irritation was found to occur at this timepoint in all three trials. For each study, and for the meta-analysis, comparisons were made using the Cochran-Mantel-Haenszel test. There were no statistically significant differences in dryness, scaling, and stinging/burning with adapalene-benzoyl peroxide treatment when subjects with Fitzpatrick skin types I to III were compared to subjects with Fitzpatrick skin types IV to VI (P=NS). Erythema assessments were statistically different based on skin types, as subjects with Fitzpatrick skin types IV to VI were rated as having “none” more often than those with Fitzpatrick skin types I to III (P<0.001). This could be due to the difficulty in visualizing erythema in patients with darker skin types, mainly Fitzpatrick skin types VI. Acne patients with Fitzpatrick skin types IV to VI were not found to be more susceptible to cutaneous irritation from treatment with the adapalene-benzoyl peroxide gel than patients with Fitzpatrick skin types I to III.
PMCID: PMC2945860  PMID: 20877537
14.  Identification of Quinolines that Inhibit Melanogenesis by Altering Tyrosinase Family Trafficking 
Molecular pharmacology  2008;74(6):1576-1586.
A series of quinolines, including chloroquine and quinine, were identified as potent pigmentation inhibitors through screening a compound library in murine melanocytes. Structure-activity relationship analysis indicated that 4-substituted amino groups with a tertiary amine side chain, such as chloroquine, were associated with robust inhibitory activity. In contrast to many previously identified pigmentation inhibitors, these newly identified inhibitors had no effect on either the level or the enzymatic activity of tyrosinase, the rate-limiting enzyme in melanin production. Rather, our results showed that these quinolines inhibited melanogenesis by disrupting the intracellular trafficking of tyrosinase-related proteins and lysosome-associated membrane protein 1 (Lamp-1). In treated melanocytes, tyrosinase and tyrosinase-related protein 1 accumulated in Lamp-1-positive perinuclear organelles instead of melanosomes, thus preventing melanogenesis. The depigmenting abilities of chloroquine and quinine salicylate were assessed in a human skin equivalent model (MelanoDerm). Both compounds were considerably more effective than arbutin, a widely used lightening agent. Our results indicate that quinolines may be useful agents for “cosmeceutical” skin lightening and treatment of hyperpigmentation disorders.
PMCID: PMC2747315  PMID: 18801917
15.  Topical niacinamide 4% and desonide 0.05% for treatment of axillary hyperpigmentation: a randomized, double-blind, placebo-controlled study 
Axillary hyperpigmentation is a frequent cause of cosmetic consultations in dark-skinned women from tropical areas, including Latin America. Currently, there is no widely accepted treatment for the disorder, but it is usually treated with bleaching agents because it is considered a variant of inflammatory hyperpigmentation. The purpose of this study was to assess the efficacy of niacinamide 4% and desonide 0.05% emulsions compared with placebo in the treatment of axillary hyperpigmentation.
Twenty-four women aged 19–27 years with hyperpigmented axillae (phototype III–V) were randomly assigned to receive the study treatments in the axillary region. Improvement was assessed at baseline, then clinically and by colorimetry 9 weeks later. Quantitative evaluation including melanin, inflammatory infiltrates, NKI/Beteb, CD1a, CD68, and collagen type IV content was performed by histochemistry and immunohistochemistry, assisted by computerized morphometric analysis.
Both niacinamide and desonide induced significant colorimetric improvement compared with placebo; however, desonide showed a better depigmenting effect than niacinamide. A good to excellent response was achieved in 24% of cases for niacinamide, 30% for desonide, and 6% for placebo. We observed a marked disruption of the basal membrane in axillary hyperpigmentation and an inflammatory infiltrate that improved after treatment. Decreased pigmentation in the desonide-treated axillae was associated with recovery of disruption at the basal membrane.
Niacinamide and desonide showed depigmenting properties in women with axillary hyperpigmentation. These findings may be explained by their antimelanogenic and anti-inflammatory properties, respectively.
PMCID: PMC3552481  PMID: 23355788
post-inflammatory hyperpigmentation; niacinamide; desonide
16.  Discovery of Highly Potent Tyrosinase Inhibitor, T1, with Significant Anti-Melanogenesis Ability by zebrafish in vivo Assay and Computational Molecular Modeling 
Scientific Reports  2015;5:7995.
Tyrosinase is involved in melanin biosynthesis and the abnormal accumulation of melanin pigments leading to hyperpigmentation disorders that can be treated with depigmenting agents. A natural product T1, bis(4-hydroxybenzyl)sulfide, isolated from the Chinese herbal plant, Gastrodia elata, is a strong competitive inhibitor against mushroom tyrosinase (IC50 = 0.53 μM, Ki = 58 ± 6 nM), outperforms than kojic acid. The cell viability and melanin quantification assay demonstrate that 50 μM of T1 apparently attenuates 20% melanin content of human normal melanocytes without significant cell toxicity. Moreover, the zebrafish in vivo assay reveals that T1 effectively reduces melanogenesis with no adverse side effects. The acute oral toxicity study evidently confirms that T1 molecule is free of discernable cytotoxicity in mice. Furthermore, the molecular modeling demonstrates that the sulfur atom of T1 coordinating with the copper ions in the active site of tyrosinase is essential for mushroom tyrosinase inhibition and the ability of diminishing the human melanin synthesis. These results evident that T1 isolated from Gastrodia elata is a promising candidate in developing pharmacological and cosmetic agents of great potency in skin-whitening.
PMCID: PMC4303873  PMID: 25613357
17.  Chemical Peels for Melasma in Dark-Skinned Patients 
Melasma is a common disorder of hyperpigmentation, which has a severe impact on the quality of life. Inspite of tremendous research, the treatment remains frustrating both to the patient and the treating physician. Dark skin types (Fitzpatrick types IV to VI) are especially difficult to treat owing to the increased risk of post-inflammatory hyperpigmentation (PIH). The treatment ranges from a variety of easily applied topical therapies to agents like lasers and chemical peels. Peels are a well-known modality of treatment for melasma, having shown promising results in many clinical trials. However, in darker races, the choice of the peeling agent becomes relatively limited; so, there is the need for priming agents and additional maintenance peels. Although a number of new agents have come up, there is little published evidence supporting their use in day-to -day practice. The traditional glycolic peels prove to be the best both in terms of safety as well as efficacy. Lactic acid peels being relatively inexpensive and having shown equally good results in a few studies, definitely need further experimentation. We also recommend the use of a new peeling agent, the easy phytic solution, which does not require neutralisation unlike the traditional alpha-hydroxy peels. The choice of peeling agent, the peel concentration as well as the frequency and duration of peels are all important to achieve optimum results.
PMCID: PMC3560164  PMID: 23378706
Chemical peels; dark skin; melasma
18.  Inhibitory Effects of Resveratrol on Melanin Synthesis in Ultraviolet B-Induced Pigmentation in Guinea Pig Skin 
Biomolecules & Therapeutics  2014;22(1):35-40.
Resveratrol is a polyphenolic compound found in various natural products such as grapes and berries and possesses anti-cancer, anti-hyperlipidemia, and anti-aging properties. Recently, it has been reported that resveratrol inhibits α-melanocyte-stimulating hormone signaling, viability, and migration in melanoma cells. However, these effects have not been confirmed in vivo, specifically brownish guinea pigs. To evaluate the potential of resveratrol as a regulator of melanin for hyperpigmentation therapy, the influence of resveratrol on pigmentation was investigated by ultraviolet B-induced hyperpigmentation in brownish guinea pig skin. We found that resveratrol reduced the expression of melanogenesis-related proteins tyrosinase, tyrosinase-related proteins 1 and 2, and microphthalmia-associated transcription factor in melanoma cells. Furthermore, topical application of resveratrol was demonstrated to significantly decrease hyperpigmentation on ultraviolet B-stimulated guinea pig skin in vivo. Based on our histological data, resveratrol inhibits melanin synthesis via a reduction in tyrosinase-related protein 2 among the melanogenic enzymes. This study is the first to provide evidence supporting resveratrol as a depigmentation agent, along with further clinical investigation of resveratrol in ultraviolet B-induced skin disorders such as hyperpigmentation and skin photoaging.
PMCID: PMC3936427  PMID: 24596619
Resveratrol; Depigmentation; Hyperpigmentation; Melanogenesis; Guinea pig; Ultraviolet B
19.  Cutaneous Pigmentation Following Photosensitivity Induced by Vandetanib (ZD6474) 
Archives of dermatology  2009;145(8):923-925.
Photosensitivity has been reported in patients treated with vandetanib (ZD6474), an inhibitor of epidermal growth factor receptor, vascular endothelial growth factor receptor, and the RET (rearranged during transfection) kinases.
We describe cutaneous hyperpigmentation following photosensitivity in two patients treated with vandetanib. The pigmentation patterns were variable within and between patients. Biopsies from different sites revealed variability in staining patterns with Perls’ and Fontana stains.
These patients highlight the unusual occurrence of cutaneous hyperpigmentation following vandetanib-associated photosensitivity, emphasizing that medications are important causes of acquired photosensitivity and hyperpigmentation. Aggressive photoprotection may facilitate resolution of diffuse hyperpigmentation. Dermatologists should endeavor to identify and report novel cutaneous side effects as new targeted therapies are developed.
PMCID: PMC3521518  PMID: 19687425
20.  Recipient site preparation for epidermal graft in stable vitiligo by a special fraise* 
The only approach used in the refractory lesions of stable vitiligo is the surgical supply of melanocytes. Suction Blistering Epidermal Graft is one of the most common and effective techniques. There are multiple modalities, including the motor-driven diamond fraise, for the preparation of recipient sites in suction blistering epidermal graft with different repigmentation rates and complications.
To evaluate preparation of recipient site by a motor-driven dental lab finishing carbide bur.
Sixty-one stable, depigmented lesions were selected in 14 patients (9 women and 5men), aged 16-29 years, of which 9, 3 and 2 had localized, generalized and segmental vitiligo, respectively. Recipient site was prepared by a motor-driven dental lab finishing carbide bur.
Excellent repigmentation at the recipient site was observed in 53 out of 61 (86.9%) grafted lesions. Postinflammatory hyperpigmentation and perigraft halo were seen in 11 (18%) and 17 (27.9%) patients at the recipient site, respectively.
Using a motor-driven dental lab finishing carbide bur to prepare the recipient site of suction blistering epidermal graft technique is reliable and effective, removing only the depigmented epidermis in a simple and safe manner, even on complex-shaped lesions and scar-prone sites.
PMCID: PMC4323699  PMID: 25672300
Dermabrasion; Graft survival; Vitiligo
21.  Comparison between the efficacy of 10% zinc sulfate solution with 4% hydroquinone cream on improvement of melasma 
Melasma, a common disorder of hyperpigmentation, is often difficult to treat. Although 10% zinc sulfate solution has been reported to be useful for patients with melasma, controlled trials are lacking.
Materials and Methods:
72 women with moderate to severe melasma were divided randomly into 2 groups. Group A were treated with 10% zinc sulfate solution and group B with 4% hydroquinone cream twice-daily. The results were evaluated by photoevaluation by patients based on subjective satisfaction and a blinded dermatologist using MASI score. Assessments were obtained at baseline and at 2 and 6 months after starting treatment.
According to MASI score changes during treatment, there was a reduction in both groups at 2 months, however, the reduction in group B was more significant (the reduction in mean ± SD MASI was 0.7 ± 0.7 in group A vs. 2.7 ± 1.6 in group B). In addition, the patients in group B continued to decrease MASI score for the remainder of the study period at 6 months follow-up (0.3 ± 0.5) in comparison with patients in group A who did not show more reduction in MASI score.
The study indicates that topical zinc sulfate is not as effective in treating disease as was observed in the previous open study. A comparative study with sunscreen and placebo is necessary to determine if topical zinc sulfate is truly superior to sunscreen and placebo in this respect.
PMCID: PMC3544106  PMID: 23326770
Hydroquinone; melasma; zinc sulfate
22.  Hyperpigmentation following Treatment of Frontal Fibrosing Alopecia 
Case Reports in Dermatology  2013;5(3):357-362.
Frontal fibrosing alopecia (FFA) is a scarring alopecia characterized by progressive recession of the frontotemporal hairline. Current treatment is aimed at stopping progression, and the combination of dutasteride and pimecrolimus is the most effective therapy. Side effects associated with dutasteride are erectile dysfunction as well as breast tenderness and enlargement, while pimecrolimus produces a burning sensation.
Case Report
We present a 57-year-old postmenopausal female with a 3-year history of a scarring alopecic plaque in her frontotemporal region. Biopsy confirmed the diagnosis of FFA, and she was started on dutasteride 0.5 mg p.o. q.d., and later, topical pimecrolimus 1% b.i.d. was added. Eight months after initiating treatment, she showed hyperpigmentation on her metacarpophalangeal and interphalangeal joints, as well as on the cheeks and on the chin; dutasteride and pimecrolimus were discontinued. After 5 months of follow-up, her hyperpigmentation improved by 80% only by using photoprotection.
Because of the variable clinical course of FFA, treatment is focused on halting its progression. Several therapeutic agents have been evaluated and the combination of dutasteride and pimecrolimus has shown a high response rate. There is no reported evidence of hyperpigmentation associated with this combination.
PMCID: PMC3861864  PMID: 24348386
Hyperpigmentation; Frontal fibrosing alopecia; Scarring alopecia
23.  Topical tranexamic acid as a promising treatment for melasma 
In recent times, tranexamic acid (TA) is claimed to have whitening effects especially for ultraviolet-induced hyperpigmentation including melasma. The aim of our study was to evaluate the efficacy and safety of topical solution of TA and compare it with combined solution of hydroquinone and dexamethasone as the gold standard treatment of melasma in Iranian women.
Materials and Methods:
This was a double-blind split-face trial of 12 weeks which was conducted in Isfahan, Iran. Fifty Iranian melasma patients applied topical solution of 3% TA on one side of the face, and topical solution of 3% hydroquinone + 0.01% dexamethasone on the other side two times a day. The Melasma Area and Severity Index (MASI) and the side effects were evaluated at baseline and every 4 weeks before and after photographs to be compared by a dermatologist were taken. The patient satisfaction was documented at week 12.
A repeated measurement analysis was used to evaluate the changes in the MASI score before and after treatments. A significant decreasing trend was observed in the MASI score of both groups with no significant difference between them during the study (P < 0.05). No differences were seen in patients’ and investigator's satisfaction of melasma improvement between two groups (P < 0.05). However, the side effects of hydroquinone + dexamethasone were significantly prominent compared with TA (P = 0.01).
This study's results introduce the topical TA as an effective and safe medication for the treatment of melasma.
PMCID: PMC4235096  PMID: 25422661
hydroquinone; dexamethasone; Melanosis; therapy tranexamic acid
24.  Effects of trans-4-(aminomethyl) cyclohexanecarboxylic acid/potassium azeloyl diglycinate/niacinamide topical emulsion in Thai adults with melasma: a single-center, randomized, double-blind, controlled study 
Background: Melasma is an acquired hyperpigmentary disorder characterized by dark patches or macules located on the cheeks, forehead, upper lip, chin, and neck. Treatment of melasma involves the use of topical hypopigmenting agents such as hydroquinone, tretinoin, and azelaic acid and its derivatives.
Objective: The purpose of this study was to assess the efficacy of a formulation containing a combination of trans-4-(aminomethyl) cyclohexanecarboxylic acid/potassium azeloyl diglycinate/niacinamide compared with an emulsion-based control in the treatment of melasma in Thai adults.
Methods: In this single-center, randomized, double-blind, controlled study, Thai patients with mild to moderate facial melasma (relative melanin value [RMV] in range of 20–120) were randomized for the application of either the test or the emulsion-based (control) product in the morning and before bedtime for 8 weeks. The supplemental sunscreen product with sun protection factor 30 was distributed to all patients. Subjects were assessed for the intensity of their hyperpigmented skin area by measuring the difference in the absolute melanin value between hyperpigmented skin and normal skin (RMV). This parameter was used as a primary outcome of this study. Additionally, the severity of melasma was determined visually using the Melasma Area and Severity Index (MASI) scored independently by 3 investigators. The assessments of melasma intensity and other skin properties were performed before administration (week 0) and every 2 weeks thereafter for up to 8 weeks. Other skin properties, including moisture content, pH, and redness (erythema value), were measured. Adverse events (AEs), including erythema, scaling, and edema, were also assessed by a dermatologist using the visual grading scale of Frosch and Kligman and COLIPA.
Results: The resulting primary intent-to-treat (ITT) population included 33 patients in the test group and 34 patients in the control group. Sixty patients completed all 8 weeks of the study (on-treatment [OT] population): 91% (30) of the 33 patients in the test group, and 88% (30) of the 34 patients in the control group. Between-group differences in mean RMV were statistically significant at week 6 in both the primary ITT (P = 0.005) and OT (P = 0.006) populations. The significant differences in mean MASI scores between the test and the control groups were initially observed at weeks 4 (P = 0.005) and 8 (P = 0.027) in the OT and primary ITT populations, respectively. Other parameters, including skin pH, erythema, and moisture content did not significantly change from baseline at any time point of study. The incidence of AEs was not different between the test (4/33 [12%]) and control (5/34 [15%]) groups.
Conclusions: The significant differences in RMVs between the test and control groups were observed after 6 weeks of treatment, both in the primary ITT and OT populations. The incidence of patients with AEs was not significantly different between the test and control groups.
PMCID: PMC3969619  PMID: 24688154
trans-4-(aminomethyl) cyclohexanecarboxylic acid/potassium azeloyl diglycinate/niacinamide; melasma; Thai adults
25.  Mir-434-5p mediates skin whitening and lightening 
Utilization of gene silencing effectors, such as microRNA (miRNA) and small hairpin RNA (shRNA), provides a powerful new strategy for human skin care in vivo, particularly for hyperpigmentation treatment and aging prevention. In this study, tyrosinase (Tyr), the rate-limiting enzyme of melanin (black pigment) biosynthesis, was served as a target for treatment of hyperpigmentation in mouse and human skins. There are over 54 native microRNA capable of silencing human tyrosinase for skin whitening and lightening. To this, we have designed a mir-434-5p homologue and used it to successfully demonstrate the feasibility of miRNA-mediated skin whitening and lightening in vitro and in vivo. Under the same experimental condition in the trials, Pol-II-directed intronic mir-434-5p expression did not cause any detectable sign of cytotoxicity, whereas siRNAs targeting the same sequence often induced certain nonspecific mRNA degradation as previously reported. Because the intronic miRNA-mediated gene silencing pathway is tightly regulated by multiple intracellular surveillance systems, including Pol-II transcription, RNA splicing, exosomal digestion and nonsense-mediated RNA decay (NMD), the current findings underscore the fact that intronic miRNA agents, such as manually re-designed mir-434-5p homologues, are effective, target-specific and safe to be used for skin whitening without any detectable cytotoxic effect. Given that the human skins also express a variety of other native miRNAs, we may re-design these miRNAs based on their individual functions for skin care, which may provide significant insights into areas of opportunity for new cosmetic and/or therapeutical applications.
PMCID: PMC3048595  PMID: 21437136
microRNA; miRNA; mir-434; intron; gene silencing; RNAi; tyrosinase; melanin; cosmetics; pigmentation; skin whitening

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