Table 2.

New oral and Topical Treatments.

	Agent		Reference	Mechanism of action	Dosing	Study outcomes	Adverse events
Photoprotection	Topical	Iron oxide sunscreens	Boukari et al., 2015, Castanedo-Cazares et al., 2014, Duteil et al., 2017, Lakhdar et al., 2007, Mahmoud et al., 2010, Regazzetti et al., 2018	Blocks blue visible light	SPF ≥ 50	UV-visible light regimen had significant improvement	None
	Oral	Polypodium leucotomos	Goh et al., 2018, Martin et al., 2013, Nestor et al., 2014, Siscovick et al., 2008	Promotion of p53 suppressor gene expression/modulation of inflammatory cytokines  ↑ endogenous antioxidant systems blockade of UV radiation induced cyclooxygenase-2 expression	240 mg BID	Beneficial effect Greater reduction in MASI	Mild gastrointestinal upsets
Lightening agents	Oral and topical	Tranexamic acid	Banihashemi et al., 2015; Del Rosario et al., 2018; Ebrahimi and Naeini, 2014, George, 2016, Kim et al., 2016, Lee et al., 2016, Lee et al., 2017, Na et al., 2013, Perper et al., 2017, Taraz et al., 2017, Wu et al., 2012	Blocks conversion of plasminogen to plasmin Blocks binding of plasminogen to keratinocytes  ↓ arachidonic acid release, prostaglandin synthesis and FGF  ↓ melanin synthesis  ↓ mast cells ↓ angiogenesis	2-5% BID 250 mg BID	Global studies document significant reduction in MASI score	Oral: mild gastrointestinal discomfort, hypomenorrhea, allergic skin rashes, alopecia, and mild elevations in alanine transaminase Topical: erythema, scaling, dryness Propensity to induce thromboembolic phenomena
		Melatonin	Hamadi et al., 2009, Ryoo et al., 2001	Potent antioxidant/free radical scavenger  ↑ super oxide dismutase, glutathione reductase, glutathione peroxidase  ↓ α-MSH receptors	5% BID 3 mg daily	Decreased MASI, malondialdehyde decreased GSH levels increased	Not reported
		GSH	Handog et al., 2016, Sonthalia et al., 2016, Watanabe et al., 2014	decreases tyrosinase skews conversion of eumelanin to pheomelanin	2% daily 500 mg daily	Melanin index significantly reduced	Intravenous: Stevens-Johnson Syndrome, anaphylaxis Oral and topical: none
	Topical	Cysteamine	Besouw et al., 2013, Mansouri et al., 2015	Radio protector (via direct scavenging effects of hydroxy radicals) Tyrosinase peroxidase inhibition	5% daily	Reduced MASI compared to placebo	None reported
		Pigment-correcting Serum	Makino et al., 2016	Melanocyte activation, melanosome development, melanin synthesis, melanosome transfer keratinocyte differentiation and desquation		Comparable efficacy to hydroquinone	Mild irritation
		Methimazole	Kasraee et al., 2005, Kasraee et al., 2008	Potent peroxidase inhibitor blocks melanin synthesis	5% daily	No significant changes in serum TSH, free thyroxine, free triiodothymine levels	Minimal cutaneous side effects
		Flutamide	Adalatkhah et al., 2011	Blocks action of endogenous/ exogenous testosterone by binding to androgen receptor	1% daily	MASI/colorimetry effects similar to hydroquinone 4% Patient satisfaction scores significantly high	None

BID, twice daily; FGF, fibroblast growth factor; GSH, glutathione; MASI, Melasma Area Severity Index; MSH, melanocyte-stimulating hormone; SPF, sun protection factor; TSH, thyroid-stimulating hormone; UV, ultraviolet