Emerging treatments

Tranexamic acid

The specific mechanism of action of this competitive inhibitor of plasminogen in melasma remains unknown; it is believed to decrease melanogenesis in epidermal melanocytes and produce a downregulation of endothelin 1.[56] In one meta-analysis, tranexamic acid showed positive results as a single agent or in combination therapy for melasma.[57] The results are more notable after 3 months of treatment; shorter treatments are more likely to lead to relapse.[57] The most frequent adverse events observed with oral tranexamic acid are oligomenorrhea and gastrointestinal discomfort; other potential adverse events include thromboembolic events such as deep vein thrombosis, myocardial infarction, and pulmonary embolism, which are more likely to occur with higher doses than those used for melasma.[58][59] Additional data suggest that intradermal tranexamic acid (including microinjection and microneedling) is equally as effective as oral administration and may have fewer side effects.[59] Topical tranexamic acid has been studied at different concentrations. It is usually well tolerated and no severe side effects have been reported.[58] When comparing topical tranexamic acid with hydroquinone, no significant difference in Melasma Area and Severity Index (MASI) score was found; however, those treated with topical tranexamic acid had higher satisfaction with their treatment and fewer skin-related adverse events compared with those receiving hydroquinone.[60] One 2019 systematic review of randomized controlled trials gave a strong recommendation for tranexamic acid as a treatment for melasma.[29] Owing to the lack of controls in some studies, the efficacy and administration route (oral, topical, or transdermal) for melasma needs further study.

Cysteamine

Cysteamine is the decarboxylated derivative of the amino acid cysteine. At high concentrations, it can inhibit melanogenesis. There are two double-blind randomized controlled trials with melasma patients treated with 5% cysteamine or placebo daily for 4 months.[61][62] In both studies, cysteamine significantly reduced MASI scores compared to placebo. Cysteamine was well tolerated and the reported side effects were dryness, burning sensation, itching, redness, and irritation. One 2019 systematic review of randomized controlled trials gave a strong recommendation for cysteamine as a treatment for melasma.[29]

Dioic acid

One small, open-label study comparing dioic acid versus hydroquinone (2%) in the treatment of melasma found both agents to be equally effective. Combination therapy was not found to be better than either treatment alone. However, less irritation was reported with dioic acid than with hydroquinone.[63]

Rucinol (4-n-butylresorcinol)

A resorcinol derivative that inhibits the activity of tyrosinase and tyrosinase-related protein-1 (TRP-1). It inhibits melanin production in a similar degree to hydroquinone and is more effective than arbutin or kojic acid. Efficacy in melasma has been reported to be between 70% and 80%.[64] One study reported that the 0.1% cream has a fast onset of effect compared with other vehicles, decreasing the melanin index significantly after 4 weeks and 8 weeks.[65]

Procyanidin plus vitamins A, C, and E

Procyanidin is a condensed flavonoid and an active component of the bark extract of the French maritime pine (Pinus pinaster ssp. atlantica), which has anti-inflammatory and antioxidant properties. The overall efficacy in improving the MASI score and decreasing the pigment intensity is 80%.[66][67]

Microphthalmia-associated transcription factor (MITF)-siRNA

MITF regulates melanogenesis and is also involved in melanocyte development, function, and survival. MITF-siRNA significantly decreases the levels of tyrosinase, melanocortin-1 receptor (MC1R), and TRP-1, which suppresses melanin levels. In a small sample size, MITF-siRNA cream resulted in a good or excellent response in 90% of patients.[68]

Amino fruit acid (AFA) peels

AFAs are carboxylated amino acids that act as an antioxidant, antiaging agent and have a significant antiphotopigmentation effect. In a small comparative study, AFA peels showed good efficacy. When compared with glycolic acid peels, AFA peels have fewer adverse effects and are better tolerated.[1][69]

Ellagic acid

Ellagic acid is a natural antioxidant that can be found in different fruits and plants. It acts as a substrate for tyrosinase and it may have effects on the melanogenesis pathway. Twice-daily application has shown a decrease in the amount of melanin.[1]

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