Depigmenting Agents

  • Priyadarshani GalappatthyEmail author
  • Deepani Rathnayake
Part of the Updates in Clinical Dermatology book series (UCD)


Several depigmenting agents are now available both for topical and systemic use with varying degrees of evidence on their efficacy and safety. These agents act by inhibiting melanogenesis, interrupting melanosome transfer, accelerating epidermal desquamation with melanin turnover, antioxidant effects and by other methods. The topical agents that act mainly by inhibiting melanogenesis through tyrosinase inhibition include hydroquinone and derivatives, arbutin, kojic acid, azelaic acid, methimazole, gentisic acid, flavonoids (aloesin, licorice) and antioxidants (ascorbic acid, alpha tocopherols and grapeseed extracts). Examples of agents that interrupt melanosome transfer are niacinamide, soybeans and lectins. Topical agents that accelerate epidermal desquamation and melanin turnover include retinoids, hydroxy acids, salicylic acids and linoleic acids. Other agents that act by varying mechanisms are tranexamic acid, steroids and other active ingredients found in various plant extracts. Topical therapies in combination are found to be more effective as add-on agents to optimise the effects of the other agents and mitigate the side effects of primary agents. They are often used as first-line therapy. The systemic agents used include tranexamic acid, glutathione, oral vitamin C and vitamin E. Some systemic agents such as glutathione are often misused without adequate evidence of its efficacy and long-term safety.


Depigmenting agents Topical depigmenting therapies Systemic depigmenting agents Inhibiting melanogenesis Tyrosinase inhibitors Hydroquinone Retinoids 


  1. 1.
    Jutley GS, Rajaratnam R, Halpern J, Salim A, Emmett C. Systematic review of randomized controlled trials on interventions for melasma: an abridged Cochrane review. J Am Acad Dermatol. 2014;70(2):369–73.PubMedCrossRefGoogle Scholar
  2. 2.
    Gillbro JM, Olsson MJ. The melanogenesis and mechanisms of skin-lightening agents–existing and new approaches. Int J Cosmet Sci. 2011;33(3):210–21.PubMedCrossRefGoogle Scholar
  3. 3.
    Hearing V. Unraveling the melanocyte. Am J Hum Genet. 1993;52(1):1.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Ito S, Fujita K, Takahashi H, Jimbow K. Characterization of melanogenesis in mouse and guinea pig hair by chemical analysis of melanins and of free and bound dopa and 5-S-cysteinyldopa. J Investig Dermatol. 1984;83(1):12–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Nordlund JJ. Hyperpigmentation: its historical treatment and the development of hydroquinone. J Pigment Disord. 2015;2: 221. doi:10.4172/2376-0427.1000221Google Scholar
  6. 6.
    Palumbo A, d’Ischia M, Misuraca G, Prota G. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta. 1991;1073(1):85–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Westerhof W, Kooyers T. Hydroquinone and its analogues in dermatology–a potential health risk. J Cosmet Dermatol. 2005;4(2):55–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Xiaoying RCWJM, Hongbo HRCSS, Maibach ZDQHI. Human in vivo and in vitro hydroquinone topical bioavailability, metabolism, and disposition. J Toxicol Environ Health A. 1998;54(4):301–17.CrossRefGoogle Scholar
  9. 9.
    Katsambas AD, Stratigos AJ. Depigmenting and bleaching agents: coping with hyperpigmentation. Clin Dermatol. 2001;19(4):483–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Rendon M, Berneburg M, Arellano I, Picardo M. Treatment of melasma. J Am Acad Dermatol. 2006;54(5):S272–S81.PubMedCrossRefGoogle Scholar
  11. 11.
    Ennes SBP, Paschoalick RC, Alchorne MMDA. A double-blind, comparative, placebo-controlled study of the efficacy and tolerability of 4% hydroquinone as a depigmenting agent in melasma. J Dermatol Treat. 2000;11(3):173–9.CrossRefGoogle Scholar
  12. 12.
    Prignano F, Ortonne J-P, Buggiani G, Lotti T. Therapeutical approaches in melasma. Dermatol Clin. 2007;25(3):337–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Grimes PE. A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation. Cutis. 2004;74(6):362–8.PubMedGoogle Scholar
  14. 14.
    Davis EC, Callender VD. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color. J Clin Aesthet Dermatol. 2010;3(7):20.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Hexsel D, Arellano I, Rendon M. Ethnic considerations in the treatment of Hispanic and Latin-American patients with hyperpigmentation. Br J Dermatol. 2006;156(s1):7–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Taylor SC, Torok H, Jones T, Lowe N, Rich P, Tschen E, et al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis. 2003;72(1):67–72.PubMedGoogle Scholar
  17. 17.
    Torok HM, Jones T, Rich P, Smith S, Tschen E. Hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-month treatment for melasma. Cutis. 2005;75(1):57–62.PubMedGoogle Scholar
  18. 18.
    Chan R, Park KC, Lee MH, Lee ES, Chang SE, Leow YH, et al. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0· 01%, hydroquinone 4%, tretinoin 0· 05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol. 2008;159(3):697–703.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma. Int J Dermatol. 2003;42(12):966–72.PubMedCrossRefGoogle Scholar
  20. 20.
    Rendon M, Cardona LM, Bussear EW, Benitez AL, Colon LE, Johnson LA. Successful treatment of moderate to severe melasma with triple-combination cream and glycolic acid peels: a pilot study. Cutis. 2008;82(5):372–8.PubMedGoogle Scholar
  21. 21.
    Grimes PE, Bhawan J, Guevara IL, Colón LE, Johnson LA, Gottschalk RW, et al. Continuous therapy followed by a maintenance therapy regimen with a triple combination cream for melasma. J Am Acad Dermatol. 2010;62(6):962–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Arellano I, Cestari T, Ocampo-Candiani J, Azulay-Abulafia L, Bezerra Trindade Neto P, Hexsel D, et al. Preventing melasma recurrence: prescribing a maintenance regimen with an effective triple combination cream based on long-standing clinical severity. J Eur Acad Dermatol Venereol. 2012;26(5):611–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Draelos ZD. Skin lightening preparations and the hydroquinone controversy. Dermatol Ther. 2007;20(5):308–13.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Glazer A, Sofen BD, Gallo ES. Nail discoloration after use of hydroquinone. JAAD Case Rep. 2016;2(1):57.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Ozluer SM, Muir J. Nail staining from hydroquinone cream. Australas J Dermatol. 2000;41(4):255–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Charlín R, Barcaui CB, Kac BK, Soares DB, Rabello-Fonseca R, Azulay-Abulafia L. Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy. Int J Dermatol. 2008;47(1):19–23.PubMedCrossRefGoogle Scholar
  27. 27.
    Mishra SN, Dhurat RS, Deshpande DJ, Nayak CS. Diagnostic utility of dermatoscopy in hydroquinone-induced exogenous ochronosis. Int J Dermatol. 2013;52(4):413–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Tse TW. Hydroquinone for skin lightening: safety profile, duration of use and when should we stop? J Dermatol Treat. 2010;21(5):272–5.CrossRefGoogle Scholar
  29. 29.
    Levitt J. The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register. J Am Acad Dermatol. 2007;57(5):854–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Makino ET, Mehta RC, Garruto J, Gotz V, Sigler ML, Herndon JH. Clinical efficacy and safety of a multimodality skin brightener composition compared with 4% hydroquinone. J Drugs Dermatol. 2013;12(3):s21–6.PubMedGoogle Scholar
  31. 31.
    Herndon JH Jr, Makino ET, Stephens TJ, Mehta RC. Hydroquinone-free skin brightener system for the treatment of moderate-to-severe facial hyperpigmentation. J Clin Aesthet Dermatol. 2014;7(5):27.PubMedGoogle Scholar
  32. 32.
    Doris Hexsel MD, Bsca CS. Objective assessment of erythema and pigmentation of melasma lesions and surrounding areas in long-term management regimens with triple combination. J Drugs Dermatol. 2014;13(4):444–8.PubMedGoogle Scholar
  33. 33.
    Oakley AMM. Rapid repigmentation after depigmentation therapy: vitiligo treated with monobenzyl ether of hydroquinone. Australas J Dermatol. 1996;37(2):96–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Maeda K, Fukuda M. Arbutin: mechanism of its depigmenting action in human melanocyte culture. J Pharmacol Exp Ther. 1996;276(2):765–9.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Chawla S, DeLong MA, Visscher MO, Wickett RR, Manga P, Boissy RE. Mechanism of tyrosinase inhibition by deoxyArbutin and its second-generation derivatives. Br J Dermatol. 2008;159(6):1267–74.PubMedCrossRefGoogle Scholar
  36. 36.
    Chawla S, Kvalnes K, de Long MA, Wickett R, Manga P, Boissy RE. DeoxyArbutin and its derivatives inhibit tyrosinase activity and melanin synthesis without inducing reactive oxygen species or apoptosis. J Drugs Dermatol. 2012;11(10):e28–34.PubMedGoogle Scholar
  37. 37.
    Mov REB. Comparative efficacy and safety of deoxyarbutin, a new tyrosinase-inhibiting agent. J Cosmet Sci. 2006;57:291–308.Google Scholar
  38. 38.
    Lim Y-J, Lee EH, Kang TH, Ha SK, MS O, Kim SM, et al. Inhibitory effects of arbutin on melanin biosynthesis of α-melanocyte stimulating hormone-induced hyperpigmentation in cultured brownish guinea pig skin tissues. Arch Pharm Res. 2009;32(3):367–73.PubMedCrossRefGoogle Scholar
  39. 39.
    Parvez S, Kang M, Chung HS, Cho C, Hong MC, Shin MK, et al. Survey and mechanism of skin depigmenting and lightening agents. Phytother Res. 2006;20(11):921–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Bang SH, Han SJ, Kim DH. Hydrolysis of arbutin to hydroquinone by human skin bacteria and its effect on antioxidant activity. J Cosmet Dermatol. 2008;7(3):189–93.PubMedCrossRefGoogle Scholar
  41. 41.
    Degen GH. Opinion of the Scientific Committee on Consumer safety (SCCS)–opinion on the safety of the use of deoxyarbutin in cosmetic products. Regul Toxicol Pharmacol. 2016;74:77–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Kahn V. Effect of kojic acid on the oxidation of DL-DOPA, norepinephrine, and dopamine by mushroom tyrosinase. Pigment Cell Res. 1995;8(5):234–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Cabanes J, Chazarra S, Garcia-Carmona F. Kojic acid, a cosmetic skin whitening agent, is a slow-binding inhibitor of Catecholase activity of tyrosinase. J Pharm Pharmacol. 1994;46(12):982–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Nohynek GJ, Kirkland D, Marzin D, Toutain H, Leclerc-Ribaud C, Jinnai H. An assessment of the genotoxicity and human health risk of topical use of kojic acid [5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one]. Food Chem Toxicol. 2004;42(1):93–105.PubMedCrossRefGoogle Scholar
  45. 45.
    Burdock GA, Soni MG, Carabin IG. Evaluation of health aspects of kojic acid in food. Regul Toxicol Pharmacol. 2001;33(1):80–101.PubMedCrossRefGoogle Scholar
  46. 46.
    Lim JTE. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg. 1999;25(4):282–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Garcia A, Fulton JE. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg. 1996;22(5):443–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Deo KS, Dash KN, Sharma YK, Virmani NC, Oberai C. 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 J Dermatol. 2013;58(4):281.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Monteiro RC, Kishore BN, Bhat RM, Sukumar D, Martis J, Ganesh HK. A comparative study of the efficacy of 4% hydroquinone vs 0.75% kojic acid cream in the treatment of facial melasma. Indian J Dermatol. 2013;58(2):157.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Nakagawa M, Kawai K, Kawai K. Contact allergy to kojic acid in skin care products. Contact Dermatitis. 1995;32(1):9–13.PubMedCrossRefGoogle Scholar
  51. 51.
    García-Gavín J, González-Vilas D, Fernández-Redondo V, Toribio J. Pigmented contact dermatitis due to kojic acid. A paradoxical side effect of a skin lightener. Contact Dermatitis. 2010;62(1):63–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Burnett CL, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, et al. Final report of the safety assessment of kojic acid as used in cosmetics. Int J Toxicol. 2010;29(6 suppl):244S–73S.PubMedCrossRefGoogle Scholar
  53. 53.
    Briganti S, Camera E, Picardo M. Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Res. 2003;16(2):101–10.PubMedCrossRefGoogle Scholar
  54. 54.
    Nguyen QH, Bui TP. Azelaic acid: pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentary disorders and acne. Int J Dermatol. 1995;34(2):75–84.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Halder RM, Richards GM. Topical agents used in the management of hyperpigmentation. Skin Therapy Lett. 2004;9(6):1–3.PubMedGoogle Scholar
  56. 56.
    Lowe NJ, Rizk D, Grimes P, Billips M, Pincus S. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther. 1998;20(5):945–59.PubMedCrossRefGoogle Scholar
  57. 57.
    Bertuzzi A, Gandolfi A, Salinari S, Mingrone G, Arcieri-Mastromattei E, Finotti E, et al. Pharmacokinetic analysis of azelaic acid disodium salt. Clin Pharmacokinet. 1991;20(5):411–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Kircik LH. Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study. J Drugs Dermatol. 2011;10(6):586–90.PubMedGoogle Scholar
  59. 59.
    Baliña LM, Graupe K. The treatment of melasma 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol. 1991;30(12):893–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol. 2011;10(4):282–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Kakita LS, Lowe NJ. Azelaic acid and glycolic acid combination therapy for facial hyperpigmentation in darker-skinned patients: a clinical comparison with hydroquinone. Clin Ther. 1998;20(5):960–70.PubMedCrossRefGoogle Scholar
  62. 62.
    Woolery-Lloyd HC, Keri J, Doig S. Retinoids and azelaic acid to treat acne and hyperpigmentation in skin of color. J Drugs Dermatol. 2013;12(4):434–7.PubMedGoogle Scholar
  63. 63.
    Kim D-S, Kim S-Y, Park S-H, Choi Y-G, Kwon S-B, Kim M-K, et al. Inhibitory effects of 4-n-butylresorcinol on tyrosinase activity and melanin synthesis. Biol Pharm Bull. 2005;28(12):2216–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Huh SY, Shin JW, Na JI, Huh CH, Youn SW, Park KC. Efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream for the treatment of melasma: a randomized controlled split-face trial. J Dermatol. 2010;37(4):311–5.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Farris PK. Topical vitamin C: a useful agent for treating photoaging and other dermatologic conditions. Dermatol Surg. 2005;31(s1):814–8.PubMedGoogle Scholar
  66. 66.
    Telang PS. Vitamin C in dermatology. Indian Dermatol Online J. 2013;4(2):143.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Pinnell SR, Yang H, Omar M, Riviere NM, Debuys HV, Walker LC, et al. Topical L-ascorbic acid: percutaneous absorption studies. Dermatol Surg. 2001;27(2):137–42.PubMedGoogle Scholar
  68. 68.
    Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci. 1996;93(8):3704–9.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double-blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma. Int J Dermatol. 2004;43(8):604–7.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Hwang S-W, Oh D-J, Lee D, Kim J-W, Park S-W. Clinical efficacy of 25% L-ascorbic acid (C’ensil) in the treatment of melasma. J Cutan Med Surg. 2009;13(2):74–81.PubMedCrossRefGoogle Scholar
  71. 71.
    Kameyama K, Sakai C, Kondoh S, Yonemoto K, Nishiyama S, Tagawa M, et al. Inhibitory effect of magnesium L-ascorbyl-2-phosphate (VC-PMG) on melanogenesis in vitro and in vivo. J Am Acad Dermatol. 1996;34(1):29–33.PubMedCrossRefGoogle Scholar
  72. 72.
    Lee M-C, Chang C-S, Huang Y-L, Chang S-L, Chang C-H, Lin Y-F, et al. Treatment of melasma with mixed parameters of 1,064-nm Q-switched Nd: YAG laser toning and an enhanced effect of ultrasonic application of vitamin C: a split-face study. Lasers Med Sci. 2015;30(1):159–63.PubMedCrossRefGoogle Scholar
  73. 73.
    Handog EB, Galang DAVF, Leon-Godinez D, Azirrel M, Chan GP. A randomized, double-blind, placebo-controlled trial of oral procyanidin with vitamins A, C, E for melasma among Filipino women. Int J Dermatol. 2009;48(8):896–901.PubMedCrossRefGoogle Scholar
  74. 74.
    Traikovich SS. Use of topical ascorbic acid and its effects on photodamaged skin topography. Arch Otolaryngol Head Neck Surg. 1999;125(10):1091–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Sarkar R, Arora P, Garg KV. Cosmeceuticals for hyperpigmentation: what is available? J Cutan Aesthet Surg. 2013;6(1):4.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Thiele JJ, Hsieh SN, Ekanayake-Mudiyanselage S. Vitamin E: critical review of its current use in cosmetic and clinical dermatology. Dermatol Surg. 2005;31(s1):805–13.PubMedGoogle Scholar
  77. 77.
    Thiele JJ, Ekanayake-Mudiyanselage S. Vitamin E in human skin: organ-specific physiology and considerations for its use in dermatology. Mol Asp Med. 2007;28(5):646–67.CrossRefGoogle Scholar
  78. 78.
    Thiele J, Schroeter C, Hsieh S, Podda M, Packer L. The antioxidant network of the stratum corneum. In: Oxidants and antioxidants in cutaneous biology, vol. 29. New York: Karger Publishers; 2001. p. 26–42.CrossRefGoogle Scholar
  79. 79.
    Ritter EF, Axelrod M, Minn KW, Eades E, Rudner AM, Serafin D, et al. Modulation of ultraviolet light-induced epidermal damage: beneficial effects of tocopherol. Plast Reconstr Surg. 1997;100(4):973–80.PubMedCrossRefGoogle Scholar
  80. 80.
    Baschong W, Artmann C, Hueglin D, Roeding J. Direct evidence for bioconversion of vitamin E acetate into vitamin E: an ex vivo study in viable human skin. J Cosmet Sci. 2000;52(3):155–61.Google Scholar
  81. 81.
    Hayakawa R, Ueda H, Nozaki T, Izawa Y, Yokotake J, Yazaki K, et al. Effects of combination treatment with vitamins E and C on chloasma and pigmented contact dermatitis. A double blind controlled clinical trial. Acta Vitaminol Enzymol. 1980;3(1):31–8.Google Scholar
  82. 82.
    Jerajani HR, Mizoguchi H, Li J, Whittenbarger DJ, Marmor MJ. The effects of a daily facial lotion containing vitamins B3 and E and provitamin B5 on the facial skin of Indian women: a randomized, double-blind trial. Indian J Dermatol Venereol Leprol. 2010;76(1):20.PubMedCrossRefGoogle Scholar
  83. 83.
    Burke KE, Clive J, Combs GF, Commisso J, Keen CL, Nakamura RM. Effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh: 2 hairless mice. Nutr Cancer. 2000;38(1):87–97.PubMedCrossRefGoogle Scholar
  84. 84.
    Burke KE, Clive J, Combs GF, Nakamura RM. Effects of topical L-selenomethionine with topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh: 2 hairless mice. J Am Acad Dermatol. 2003;49(3):458–72.PubMedCrossRefGoogle Scholar
  85. 85.
    Sonthalia S, Daulatabad D, Sarkar R. Glutathione as a skin whitening agent: facts, myths, evidence and controversies. Indian J Dermatol Venereol Leprol. 2016;82(3):262.PubMedCrossRefGoogle Scholar
  86. 86.
    Watanabe F, Hashizume E, Chan GP, Kamimura A. Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women. Clin Cosmet Investig Dermatol. 2014;7:267.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Arjinpathana N, Asawanonda P. Glutathione as an oral whitening agent: a randomized, double-blind, placebo-controlled study. J Dermatol Treat. 2012;23(2):97–102.CrossRefGoogle Scholar
  88. 88.
    Handog EB, Datuin MSL, Singzon IA. An open-label, single-arm trial of the safety and efficacy of a novel preparation of glutathione as a skin-lightening agent in Filipino women. Int J Dermatol. 2016;55(2):153–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Zubair S, Hafeez S, Mujtaba G. Efficacy of intravenous glutathione vs. placebo for skin tone lightening. J Pakistan Assoc Dermatol. 2017;26(3):177–81.Google Scholar
  90. 90.
    FDA Consumer Health Information. Injectable skin lightening products: what you should know. Epub 2015.Google Scholar
  91. 91.
    Dadzie OE. Unethical skin bleaching with glutathione. BMJ. 2016;354:i4386.PubMedCrossRefGoogle Scholar
  92. 92.
    Tate SA. Nadinola and glutathione: refining and advancing a dangerous practice. In: Skin bleaching in black atlantic zones: shade shifters: Springer; Palgrave Pivot, Macmillan UK. 2016. p. 87–114.CrossRefGoogle Scholar
  93. 93.
    Davids LM, van Wyk JC, Khumalo NP. Intravenous glutathione for skin lightening: inadequate safety data. SAMJ S Afr Med J. 2016;106(8):782–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Kasraee B, Handjani F, Parhizgar A, Omrani GR, Fallahi MR, Amini M, et al. Topical methimazole as a new treatment for postinflammatory hyperpigmentation: report of the first case. Dermatology. 2005;211(4):360–2.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kasraee B, Safaee Ardekani G, Parhizgar A, Handjani F, Omrani G, Samani M, et al. Safety of topical methimazole for the treatment of melasma. Skin Pharmacol Physiol. 2008;21(6):300–5.PubMedCrossRefGoogle Scholar
  96. 96.
    Malek J, Chedraoui A, Nikolic D, Barouti N, Ghosn S, Abbas O. Successful treatment of hydroquinone-resistant melasma using topical methimazole. Dermatol Ther. 2013;26(1):69–72.PubMedCrossRefGoogle Scholar
  97. 97.
    Hakozaki T, Minwalla L, Zhuang J, Chhoa M, Matsubara A, Miyamoto K, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002;147(1):20–31.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Greatens A, Hakozaki T, Koshoffer A, Epstein H, Schwemberger S, Babcock G, et al. Effective inhibition of melanosome transfer to keratinocytes by lectins and niacinamide is reversible. Exp Dermatol. 2005;14(7):498–508.PubMedCrossRefGoogle Scholar
  99. 99.
    Panel CIRE. Final report of the safety assessment of niacinamide and niacin. Int J Toxicol. 2005;24:1.Google Scholar
  100. 100.
    Navarrete-Solís J, Castanedo-Cázares JP, Torres-μlvarez B, Oros-Ovalle C, Fuentes-Ahumada C, González FJ, et al. A double-blind, randomized clinical trial of niacinamide 4% versus hydroquinone 4% in the treatment of melasma. Dermatol Res Pract. 2011;2011:379173.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Kimball AB, Kaczvinsky JR, Li J, Robinson LR, Matts PJ, Berge CA, et al. Reduction in the appearance of facial hyperpigmentation after use of moisturizers with a combination of topical niacinamide and N-acetyl glucosamine: results of a randomized, double-blind, vehicle-controlled trial. Br J Dermatol. 2010;162(2):435–41.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Hakozaki T, Takiwaki H, Miyamoto K, Sato Y, Arase S. Ultrasound enhanced skin-lightening effect of vitamin C and niacinamide. Skin Res Technol. 2006;12(2):105–13.PubMedCrossRefGoogle Scholar
  103. 103.
    Bissett DL, Robinson LR, Raleigh PS, Miyamoto K, Hakozaki T, Li J, et al. Reduction in the appearance of facial hyperpigmentation by topical N-undecyl-10-enoyl-l-phenylalanine and its combination with niacinamide. J Cosmet Dermatol. 2009;8(4):260–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Prousky J, Millman CG, Kirkland JB. Pharmacologic use of niacin. J Evid Based Complementary Altern Med. 2011;16(2):91–101.CrossRefGoogle Scholar
  105. 105.
    Bissett DL, Miyamoto K, Sun P, Li J, Berge CA. Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin1. Int J Cosmet Sci. 2004;26(5):231–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Lee J, Jung E, Huh S, Boo YC, Hyun CG, Kim YS, et al. Mechanisms of melanogenesis inhibition by 2, 5-dimethyl-4-hydroxy-3 (2H)-furanone. Br J Dermatol. 2007;157(2):242–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Solano F, Briganti S, Picardo M, Ghanem G. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res. 2006;19(6):550–71.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Griffiths CEM, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol. 1993;129(4):415–21.PubMedCrossRefGoogle Scholar
  109. 109.
    Kimbrough-Green CK, Griffiths CEM, Finkel LJ, Hamilton TA, Bulengo-Ransby SM, Ellis CN, et al. Topical retinoic acid (tretinoin) for melasma in black patients: a vehicle-controlled clinical trial. Arch Dermatol. 1994;130(6):727–33.PubMedCrossRefGoogle Scholar
  110. 110.
    Bulengo-Ransby SM, Griffiths C, Kimbrough-Green CK, Finkel LJ, Hamilton TA, Ellis CN, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med. 1993;328(20):1438–43.PubMedCrossRefGoogle Scholar
  111. 111.
    Griffiths CEM, Goldfarb MT, Finkel LJ, Roulia V, Bonawitz M, Hamilton TA, et al. Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: a vehicle-controlled trial. J Am Acad Dermatol. 1994;30(1):76–84.PubMedCrossRefGoogle Scholar
  112. 112.
    Dogra S, Kanwar AJ, Parsad D. Adapalene in the treatment of melasma: a preliminary report. J Dermatol. 2002;29(8):539–40.PubMedCrossRefGoogle Scholar
  113. 113.
    Burns RL, Prevost-Blank PL, Lawry MA, Lawry TB, Faria DT, Ftvenson DP. Glycolic acid peels for postinflammatory hyperpigmentation in black patients. Dermatol Surg. 1997;23(3):171–5.PubMedCrossRefGoogle Scholar
  114. 114.
    Yamamoto Y, Uede K, Yonei N, Kishioka A, Ohtani T, Furukawa F. Effects of alpha-hydroxy acids on the human skin of Japanese subjects: the rationale for chemical peeling. J Dermatol. 2006;33(1):16–22.PubMedCrossRefGoogle Scholar
  115. 115.
    Tse TW, Hui E. Tranexamic acid: an important adjuvant in the treatment of melasma. J Cosmet Dermatol. 2013;12(1):57–66.PubMedCrossRefGoogle Scholar
  116. 116.
    Manosroi A, Podjanasoonthon K, Manosroi J. Development of novel topical tranexamic acid liposome formulations. Int J Pharm. 2002;235(1):61–70.PubMedCrossRefGoogle Scholar
  117. 117.
    Todo H, Sugibayashi K. Usefulness of transdermal delivery of tranexamic acid with a constant-voltage iontophoresis patch containing chemical enhancer. Arch Pharm Pract. 2012;3(1):2.Google Scholar
  118. 118.
    Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y, et al. Treatment of melasma with oral administration of tranexamic acid. Aesthet Plast Surg. 2012;36(4):964–70.CrossRefGoogle Scholar
  119. 119.
    Mafune E, Morimoto Y, Iizuka Y. Tranexamic acid and melasma. Farumashia. 2008;44:437–42.Google Scholar
  120. 120.
    Cap AP, Baer DG, Orman JA, Aden J, Ryan K, Blackbourne LH. Tranexamic acid for trauma patients: a critical review of the literature. J Trauma Acute Care Surg. 2011;71(1):S9–S14.CrossRefGoogle Scholar
  121. 121.
    Banihashemi M, Zabolinejad N, Jaafari MR, Salehi M, Jabari A. Comparison of therapeutic effects of liposomal tranexamic acid and conventional hydroquinone on melasma. J Cosmet Dermatol. 2015;14(3):174–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, Nakakes A. Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind randomized controlled clinical trial. J Cosmet Laser Ther. 2012;14(3):150–4.PubMedCrossRefGoogle Scholar
  123. 123.
    Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci Off J Isfahan Univ Med Sci. 2014;19(8):753.Google Scholar
  124. 124.
    Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, MY KIM, et al. Localized intradermal microinjection of tranexamic acid for treatment of melasma in Asian patients: a preliminary clinical trial. Dermatol Surg. 2006;32(5):626–31.PubMedGoogle Scholar
  125. 125.
    Higashi N. Treatment of melasma with oral tranexamic acid. Skin Res. 1988;30:676–80.Google Scholar
  126. 126.
    Karn D, Kc S, Amatya A, Razouria E, Timalsina M. Oral tranexamic acid for the treatment of melasma. Kathmandu Univ Med J. 2014;10(4):40–3.CrossRefGoogle Scholar
  127. 127.
    Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in melasma patients treated with IPL and low fluence QS Nd: YAG laser. J Dermatol Treat. 2013;24(4):292–6.CrossRefGoogle Scholar
  128. 128.
    Shin JU, Park J, Oh SH, Lee JH. Oral tranexamic acid enhances the efficacy of low-fluence 1064-nm quality-switched neodymium-doped yttrium aluminum garnet laser treatment for melasma in Koreans: a randomized, prospective trial. Dermatol Surg. 2013;39(3pt1):435–42.PubMedCrossRefGoogle Scholar
  129. 129.
    Tan AW, Sen P, Chua SH, Goh BK. Oral tranexamic acid lightens refractory melasma. Australas J Dermatol. 2016;58(3).PubMedCrossRefGoogle Scholar
  130. 130.
    Lee HC, Thng TG, Goh CL. Oral tranexamic acid (TA) in the treatment of melasma: a retrospective analysis. J Am Acad Dermatol. 2016;75(2):385–92.Google Scholar
  131. 131.
    Gupta AK, Gover MD, Nouri K, Taylor S. The treatment of melasma: a review of clinical trials. J Am Acad Dermatol. 2006;55(6):1048–65.PubMedCrossRefGoogle Scholar
  132. 132.
    Nnoruka E, Okoye O. Topical steroid abuse: its use as a depigmenting agent. J Natl Med Assoc. 2006;98(6):934.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Fisk WA, Agbai O, Lev-Tov HA, Sivamani RK. The use of botanically derived agents for hyperpigmentation: a systematic review. J Am Acad Dermatol. 2014;70(2):352–65.PubMedCrossRefGoogle Scholar
  134. 134.
    Zhu W, Gao J, editors. The use of botanical extracts as topical skin-lightening agents for the improvement of skin pigmentation disorders. J Invest Dermatol Symp Proc. 2008;13(1):20–4. Nature Publishing Group.Google Scholar
  135. 135.
    Robb EL, Page MM, Wiens BE, Stuart JA. Molecular mechanisms of oxidative stress resistance induced by resveratrol: specific and progressive induction of MnSOD. Biochem Biophys Res Commun. 2008;367(2):406–12.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Ando H, Ryu A, Hashimoto A, Oka M, Ichihashi M. Linoleic acid and α-linolenic acid lightens ultraviolet-induced hyperpigmentation of the skin. Arch Dermatol Res. 1998;290(7):375–81.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Mishima Y, Imokawa G. Selective aberration and pigment loss in melanosomes of malignant melanoma cells in vitro by glycosylation inhibitors: premelanosomes as glycoprotein. J Investig Dermatol. 1983;81(2):106–14.PubMedCrossRefGoogle Scholar
  138. 138.
    Franchi J, Coutadeur MC, Marteau C, Mersel M, Kupferberg A. Depigmenting effects of calcium d-pantetheine-s-sulfonate on human melanocytes. Pigment Cell Res. 2000;13(3):165–71.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Yamakoshi J, Otsuka F, Sano A, Tokutake S, Saito M, Kikuchi M, et al. Lightening effect on ultraviolet-induced pigmentation of Guinea pig skin by oral administration of a proanthocyanidin-rich extract from grape seeds. Pigment Cell Res. 2003;16(6):629–38.PubMedCrossRefGoogle Scholar
  140. 140.
    Yamakoshi J, Sano A, Tokutake S, Saito M, Kikuchi M, Kubota Y, et al. Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma. Phytother Res. 2004;18(11):895–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T. Inhibitory effect of an ellagic acid-rich pomegranate extract on tyrosinase activity and ultraviolet-induced pigmentation. Biosci Biotechnol Biochem. 2005;69(12):2368–73.PubMedCrossRefGoogle Scholar
  142. 142.
    Ismail T, Sestili P, Akhtar S. Pomegranate peel and fruit extracts: a review of potential anti-inflammatory and anti-infective effects. J Ethnopharmacol. 2012;143(2):397–405.PubMedCrossRefGoogle Scholar
  143. 143.
    Kasai K, Yoshimura M, Koga T, Arii M, Kawasaki S. Effects of oral administration of ellagic acid-rich pomegranate extract on ultraviolet-induced pigmentation in the human skin. J Nutr Sci Vitaminol. 2006;52(5):383–8.PubMedCrossRefGoogle Scholar
  144. 144.
    Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res. 1998;11(6):355–61.PubMedCrossRefGoogle Scholar
  145. 145.
    Wang X, Li ZX, Zhang D, Li L, Sophie S. A double-blind, placebo controlled clinical trial evaluating the efficacy and safety of a new skin whitening combination in patients with chloasma. J Cosmet Dermatol Sci. 2014;4:92–98.
  146. 146.
    Hearing VJ. The regulation of melanin formation. In: Nordlund JJ, Boissy RE, Hearing VJ, King RA, Oetting WS, Ortonne J-P, editors. The pigmentary system: physiology and pathophysiology, vol. 10. 2nd ed. Blackwell Publishing Ltd; 2006. p. 193.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Faculty of MedicineUniversity of ColomboColomboSri Lanka
  2. 2.Sinclair DermatologyEast MelbourneAustralia

Personalised recommendations