An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology
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33 JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY February 2018 • Volume 11 • Number 2 R E V I E W controlled trial (RCT) investigating mulberry use in pigmentary disorders. Alvin et al 11 conducted a randomized, single-blind, placebo-controlled trial investigating the safety and efficacy of 75% mulberry extract oil versus placebo in treating melasma. There was significant improvement in the MASI score, average skin colorimeter measurements, and The Melasma Quality of Life Scale (MelasQOL) scores in the treatment group. 10,11 Licorice Extracts. Glabridin, extracted from the root of perennial herb Glycyrrhiza glabra linneva, is the main licorice compound. 12 This ingredient has been shown to scavenge ROS, inhibit UVB-induced pigmentation and tyrosinase without affecting DNA synthesis, and possess anti-inflammatory properties. Glabridin has been shown in vitro to have a skin lightening effect 16 times greater than that of hydroquinone and might reduce UVB pigmentation. 13,14 A single-center, double-blind comparison clinical study with 18 patients compared the efficacy of a hydroquinone- free skin brightener, comprising several ingredients, including glabridin, that target different pathways in melanogenesis, to 4% hydroquinone (HQ) cream in reducing ultraviolet-induced hyperpigmentation. 15 The skin brightener demonstrated significant reductions in pigmentation compared to baseline and produced greater increases in L* brightness compared to HQ. In addition to assessing in-vivo data, this study used an in-vitro model called MelanoDerm™ Skin Model (MatTek Corp., to assess the ability of this product to reduce melanin production and distribution compared to controls. In the MelanoDerm Skin Model in-vitro portion, the test product resulted in greater reduction in melanin as measured by melanin content and histological staining compared to the control. 15 Another single- blinded study compared a cream containing belides, emblica, and licorice applied twice daily to HQ 2% applied nightly in melasma patients of Fitzpatrick Skin Types I to IV after the patients had 60 days of exclusive use of an sun protection factor (SPF) 35 sunscreen. Although depigmentation was noted in both groups, there was no statistical difference between them in the improvement of melasma. 16 Liquiritin, a flavonoid component of licorice, has multiple depigmenting properties, including dispersing melanin, reducing inflammation, and reducing UVB erythema. 10 Amer et al 17 conducted a double-blind, controlled, split-face study of 20 women with epidermal melasma. Subjects applied 20% liquiritin cream on one side of the face and a vehicle cream on the other side twice daily for four weeks. The majority treated with liquiritin showed an "excellent response" compared to the control group, which exhibited no response. In a RCT conducted by Zubair et al 10 in epidermal melasma patients, 4% liquiritin was shown to be significantly more effective than 2% liquiritin and HQ. Lignin peroxidase. The enzyme lignin peroxidase is derived from the tree fungus Phanerochaete chrysosporium and acts by oxidizing and breaking down melanin. In decaying trees, lignin, which is structurally similar to melanin, is broken down by lignin peroxidase, resulting in decolorization. 18 Mauricio et al 18 conducted a randomized, double-blind, controlled, paired, split-face, single-center study of 51 Asian female patients. Lignin peroxidase cream was applied on one side of the face and either 2% HQ or placebo was applied on the other. The primary outcome variable was reduction in the melanin index with a sin colorimeter (Mexameter). Lignin peroxidase cream had a significantly more rapid and observable skin-lightening effect than placebo and 2% HQ. A more recent randomized paired, controlled, split-face study by Draelos et al 19 investigated the pigment lightening efficacy of lignin peroxidase in a cohort of women with mild-to-moderate facial dyspigmentation. In this 12 week study, Cohort 1 applied lignin peroxidase to one side of the face twice daily and nothing to the other side. Cohort 2 applied twice-daily lignin peroxidase to one half of the face and 4% HQ to the other half twice daily. Subjects were assessed at baseline and at Weeks 2, 8, and 12. Subject, investigator, and dermospectrophotometer measurements were obtained. In Cohort 1, lignin peroxidase produced skin lightening superior to the control group. In Cohort 2, lignin peroxidase produced superior results in aesthetics when compared to HQ including skin texture, lack of clarity and radiance, roughness, and overall appearance. However, parity was demonstrated between both agents when evaluating skin lightening efficacy. Lignin peroxidase does show promise as a skin lightener based on the studies available, but more studies are warranted. Kojic Acid. Kojic acid (KA) is a metabolic product of the fungal species Acetobacter, Aspergillus, and Penicillium. It acts as a ROS scavenger, exhibits antioxidant properties, and inhibits tyrosinase. 20 KA is used in several cosmetic skin brighteners and is also used as a food additive to prevent browning. 1,12 Over the years, there have been mixed reports on the efficacy of KA. Based on earlier work, KA as a monotherapy has shown modest effectiveness, but it has been shown to be more beneficial in combination with other ingredients. KA stable derivatives increase skin penetration, which offers better skin lightening. A recent comparative study by Monteiro et al 21 evaluated the efficacy of once-daily application of 4% HQ and 0.75% KA cream, which contained 0.75% KA and 2.5% vitamin C, in the treatment of melasma. Sixty patients were enrolled in this 12-week study. The authors found that at Week 4, patients responded earlier to the HQ than to the KA cream. However, at Week 12, HQ had overall superiority in lightening compared to the KA cream. Draelos et al 63 performed 12- week, paired, double-blind study comparing a preparation containing KA, emblica extract, and glycolic acid to 4% HQ in 80 multiethnic patients with facial dyschromia. Interestingly, the results showed equivalent efficacy in skin lightening capabilities between the two agents. Another 12-week simple, randomized, single-center, single-blinded, parallel-group comparative study comprising 80 subjects with melasma compared the efficacy of KA 1% alone with either 2% HQ or 0.1% betamethasone valerate, and a combination of all these three agents. Patients were assessed using the MASI score. The study found that KA plus HQ was superior in depigmenting when compared with the other three groups. 22 With the conflicting studies and lack of investigation exploring KA's role as monotherapy, more clinical trials are warranted Niacinamide. Niacinamide, an active form of vitamin B3 (niacin) found in yeast and root vegetables, is well known for its role in enzymatic reaction. 12 It combats hyperpigmentation by reversibly inhibiting the transfer of melanosomes to epidermal keratinocytes. A recent eight-week, prospective, randomized, double-blind, vehicle-controlled clinical study evaluated a combination of niacinamide and tranexamic acid (TXA) as a topical moisturizer in the treatment of 42 Korean women with irregular facial hyperpigmentation. This formulation was significantly more effective in reducing the