An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology
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34 JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY Feburary 2018 • Volume 11 • Number 2 R E V I E W hyperpigmentation than the vehicle control. 23 In a nine-week, randomized, double-blind, left-right axilla, placebo-controlled trial, the efficacy of niacinamide 4% and desonide 0.05% emulsions were compared to placebo in the treatment of axillary hyperpigmentation. Twenty-four women of Phototypes III to V were included in the study. Niacinamide and desonide both induced significant colorimetric improvement compared to placebo, but desonide showed the best depigmenting effect overall. 24 A derivative of niacinamide has also shown potential as a skin lightener. Through an in-vitro study, Kim et al 25 synthesized a novel derivative niacinamide, N-nicotinoyl dopamine (NND), which was shown to have high antioxidant activity and ability to decrease melanin production and induce skin lightening in a skin model. A recent open-label, single-center study investigated a compound containing 0.5% retinol, 4.4% niacinamide, 1% resveratrol, and 1.1% hexylresorcinol in a moisturizing base on 25 subjects with mild-to-moderate hyperpigmentation. This skin-brightening compound improved hyperpigmentation with statistical significance compared to baseline by Week 4. Further evaluation of niacinamide and NND should be performed in the form of clinical studies. Ellagic acid. Ellagic acid is a polyphenol antioxidant found in trees, nuts, and fruit. 27 In-vitro studies suggest that ellagic acid inhibits melanogenesis through the reduction of tyrosinase activity. 28 Two randomized, controlled trials (RCT) have evaluated its skin lightening effects. The first study compared the efficacy of 1% arbutin, synthetic 1% ellagic acid, and synthetic 1% ellagic acid combined with plant extracts containing natural ellagic acid in treating 30 patients with melasma. 29 All three treatment groups showed significant improvement according to a skin colorimeter (Mexameter) evaluation before and after treatment. The study was limited by the fact that the natural plant extracts were not studied independently. The second RCT compared the effects of a compound containing 0.5% ellagic acid combined with 0.1% salicylic acid to 4% hydroquinone in 54 patients with hyperpigmentation and dark spots. 30 Based on clinical grading, physical measurement of spot size by chromameter, and patient questionnaire analysis, the compound had comparable efficacy to hydroquinone but better aesthetics. However, this study was limited because ellagic acid was studied in combination with salicylic acid. Since ellagic acid has not been independently studied, further studies need to be performed to support its clinical utility. Arbutin. Arbutin is a b-D-glucopyranoside derivative of hydroquinone found in herbs such as bearberry. 31 In-vitro studies have shown it to have reversible tyrosinase activity. The previously mentioned RCT that compared 1% arbutin with 1% ellagic acid in treating melasma demonstrated arbutin to be clinically efficacious as evidenced by the clinical improvement of all 10 patients in the arbutin treatment group. 32 Another prospective study investigating the use of 7% alpha arbutin in conjunction with a frequency- doubled Q-switched Nd:YAG laser (MedLite C6®, Cynosure®, Westford, Massachusetts) also showed favorable results in treating melasma patients. 33 However, this study was limited because arbutin was not studied independent of the laser treatment. Since there has only been a single RCT independently supporting arbutin's clinical efficacy in treating pigmentary disorders, further studies are needed. Green Tea. Green tea has long been studied for its antioxidant and anti-inflammatory properties. 28 Green tea extracts comprise multiple polyphenolic antioxidants, of which epigallo-catechin-3-gallate (ECGC) is the main active ingredient. 34,35 According to the abstract of a single RCT, green tea has shown clinical efficacy in treating melasma. 36 In the study, 60 women with melasma were treated with a 2% analogue of green tea extract (ECGC) in a hydrophilic cream or placebo and were tracked using dermatologic and photographic methods. Lesions cleared in 60 percent of the experimental group versus three percent of the placebo group, a clinically significant difference. However, this study is limited because it has not yet been published in a peer-reviewed journal. Additionally, more studies are required to validate therapeutic effects of green tea extracts on pigmentary disorders. In addition to treating melasma, green tea extracts might have prophylactic properties, including inhibiting UV-induced erythema, reducing the number of sunburn cells, and protecting DNA from UV radiation in human studies. 37 Turmeric. Turmeric (Curcuma longa) is a widely-used Ayurvedic herbal supplement and spice. 38,39 The active ingredient of turmeric is curcumin, a hydrophobic polyphenol characterized by yellow pigment. 39 Studies have shown curcumin to possess anti-inflammatory and anti-carcinogenic properties. 40–42 Recently, an in-vitro study has suggested that curcumin might induce apoptosis of human melanoma cells via mitochondrial pathway and caspases activation. 43 According to the abstract of a dual study RCT, application of topical turmeric extract reduced the appearance of facial hyperpigmentation and fine lines and wrinkles. 38 The first study was a split-face study among Caucasian women that compared turmeric extract combined with niacinamide in cream to niacinamide alone. The combination product was significantly better at improving fine lines and wrinkles according to a group of judges. The second study was a split-face study among Chinese women that compared a turmeric extract cream formulation to an unknown control. The formulation improved areas of hyperpigmentation by 14.16 percent (p<0.0001) at four weeks according to negative cofactor-2 (NC2) image analysis. However, this RCT is limited because the study has not yet been published in a peer-reviewed journal. Further clinical studies need to be performed that evaluate the therapeutic effects of turmeric Soy. Soybean, a legume commonly grown in East Asia, consists of many biologically active substances, including isoflavones and serine protease inhibitors. 44 In-vitro studies have uncovered the anti-aging, antioxidant, pigment-reducing, photoprotective, and melanosome transfer inhibiting properties of soybean extract. 45–50 Several clinical studies support the hypothesized skin-lightening role of soybean. In a controlled trial, Hermanns et al 52 compared the effect of different topical hypopigmenting agents in treating facial hypermelanosis in 44 Celtic-complexioned men. Soybean extract had skin-lightening effects in the study. Another study involving Caucasian and Hispanic women found that application of soy extract to melasma lesions once daily for three months led to an average reduction of hyperpigmentation of 12 percent. 53 Fourteen out of the 16 women showed some degree of improvement. Additionally, a recent double- blind, parallel-group RCT compared the efficacy of a nondenatured novel soy moisturizer to the vehicle alone in treating 65 women with moderate facial photodamage. 45 Evaluation through clinical observation, self-assessment,