© Springer India 2017
Evangeline B. Handog and Maria Juliet Enriquez-Macarayo (eds.)Melasma and Vitiligo in Brown Skin10.1007/978-81-322-3664-1_1212. Topical Agents in Melasma
(1)
Department of Dermatology, Jose R. Reyes Memorial Medical Center, Rizal Avenue Extension, Sta. Cruz, Manila, Philippines
Keywords
Topical agentsHydroquinoneTriple combination creamAzelaic acidVitamin CKojic acidRetinoidsTranexamic acidArbutinVitamin ENiacinamide12.1 Introduction
Melasma is often difficult to treat, and the condition may be refractory. Principles of therapy include protection from ultraviolet (UV) light, inhibition of melanocyte activity and melanin synthesis, and the disruption and removal of melanin granules [1]. Due to the multiple treatment modalities available, the choice of treatment must take into account the type of melasma (whether epidermal, dermal, or mixed), the skin complexion of the patient, previous treatments, patient expectations, as well as compliance [2].
Topical therapy remains the standard of melasma treatment. It aims to retard the proliferation of melanocytes, inhibit melanosome formation, and enhance melanosome degradation [3]. The epitome of a depigmenting agent should provide powerful, quick, yet selective lightening on hyperactive melanocytes. Resultant elimination of unwanted pigment must be lasting, with no undesirable side effects. Despite the numerous topical therapeutic options in the market, the ideal depigmenting agent has yet to be found. Depigmenting agents can target melanin production at the level of transcription and tyrosinase glycosylation, during the synthesis of melanin as well as the uptake and distribution of melanosomes into recipient keratinocytes, and during tyrosinase degradation and turnover of pigmented keratinocytes. Simply put, depigmenting agents target melanin synthesis before, during, and after the process [4]. Topical agents are especially efficacious in the epidermal type of melasma [5].
This chapter will cover the different types of topical therapy, administered as monotherapy or in combination with different agents. While monotherapy for melasma has been in use the longest, the current trend is toward combination therapy, which has shown greater efficacy.
12.2 Monotherapy
12.2.1 Hydroquinone (HQ)
Hydroquinone is the most extensively studied medication in the management of melasma, although most recent studies have hydroquinone in combination with other substances. A dihydric phenol, HQ is an aromatic organic compound with a primary function of hindering melanin production by inhibiting the tyrosinase enzyme [6, 7]. As monotherapy, HQ in itself is effective and used at concentrations ranging from 2 to 5 % [8]. After prolonged use, however, it can cause permanent depigmentation. Other adverse effects include irritant dermatitis, ochronosis, and postinflammatory pigmentation [9].
HQ is often the standard therapy to which other treatment regimens are compared. While it is the gold standard in depigmentation, issues of safety have arisen with this product, thus, it has been banned in several countries. With the risk of exogenous ochronosis and permanent depigmentation following long-term use, it has been banned by the European Committee, with formulations withdrawn from cosmetics in these countries [10]. This has spurred research for its use with other agents and for other equally potent, but safer depigmenting agents.
12.2.2 Azelaic Acid
A dicarboxylic acid derived from Pityrosporum mold, azelaic acid is a reversible inhibitor of tyrosinase activity. While it does not affect normal melanocytes, it is antiproliferative and cytotoxic to abnormal melanocytes [3]. This is especially advantageous to patients who only wish to lighten the sites affected with melasma, but not their baseline skin color. In a study by Balina and Graupe, 20 % azelaic acid was found to be comparable with 4 % HQ [11]. In a Thai population comparing 2 % HQ with 20 % azelaic acid, the latter was found to be more efficacious; however this population had a greater incidence of adverse effects which include pruritus, transient erythema, scaling, and, occasionally, sensitization [12].
12.2.3 Kojic Acid
A 7-pyrone compound, produced from fermentation of Aspergillus and Penicillium [10], kojic acid is a fungal metabolic product that inhibits the catecholate activity of tyrosinase. In addition, kojic acid functions as a potent antioxidant. For the management of hyperpigmentation, a concentration of 1–4 % is often used. While it is more chemically stable than HQ, it is less effective than HQ in its lightening property [13]. The Kojyl-APPA 5-[(3-aminopropyl)phosphinooxy]-2-(hydroxymethyl)-4H-pyran-4-one) synthesized by Kim et al. showed increased skin penetration and pigment lightening efficacy in melanoma and normal human melanocytes [14]. Adverse effects include sensitization, contact dermatitis, and erythema [15, 16].
12.2.4 Vitamin C
Vitamin C chelates copper ions necessary in the enzymatic steps for melanin production. In addition, it can convert melanin from its usual jet-black color to light tan. Vitamin C, however, is very easily oxidized in an aqueous solution. In a study by Espinal-Perez and colleagues, 5 % L-ascorbic acid was found to be equal in efficacy to 4 % HQ [17]. More stable derivatives, such as magnesium 5 % L-ascorbyl-2-phosphate in a 10 % cream compound, have also been found effective in the management of melasma [18]. Iontophoresis has also been used to increase cutaneous penetration of vitamin C [19].
12.2.5 Retinoids
Retinoids have been found to be moderately effective in the management of melasma. It promotes rapid loss of pigment through its effect in increasing epidermopoiesis, thereby decreasing keratinocyte contact time with melanocytes [20]. They also function by decreasing melanosome transfer and inhibiting tyrosinase transcription [21]. Adverse effects include erythema and peeling on application sites. Postinflammatory hyperpigmentation (PIH) should also be considered as a potential adverse effect.
Tretinoin concentrations used for melasma range from 0.05 to 0.1 %. Studies in a predominantly white population [22] have proven moderate effectivity.
Topical isotretinoin studied among Thai patients showed no statistically significant difference in MASI and colorimetry in the 0.05 % isotretinoin group versus a placebo group [23].
Adapalene is a second-generation retinoid. In an RCT of 30 Indian female patients diagnosed with melasma, efficacy and safety of adapalene 0.1 % was compared to that of tretinoin 0.05 %. Melasma area severity index (MASI) scores were recorded at baseline, 2 weeks, 6 weeks, 10 weeks, and 14 weeks. Results showed equal efficacy between the two agents: 37 % reduction in MASI score in tretinoin compared to 41 % reduction in adapalene group, with no statistical difference. There was a greater incidence of adverse effects in the tretinoin group [24].
12.2.6 Tranexamic Acid (TA)
Tranexamic acid is a trans-4(aminomethyl) cyclohexane carboxylic acid, which has been used in medical practice as a fibrinolytic agent. It has shown promise in the management of melasma through inhibition of melanin production. TA binds to plasmin and plasminogen leading to a decrease in the amount of free arachidonic acid. Prostaglandin production is then decreased and so is the melanocyte tyrosinase activity [6].
The injectable and oral forms have been noted to lighten melasma in patients. However, results have been conflicting. In a split-face trial by Kanechorn et al., there appeared to be no significant difference with topical tranexamic acid versus placebo, with a greater incidence of adverse effects in the tranexamic acid group [25]. Banihashemi et al. studied 5 % tranexamic in a liposomal form, a vehicle which may prolong the action of the substance, as well as improve its moisturizing effect. In this form, TA was comparable to HQ [26]. In another randomized, double-blind split-face trial, Ebrahimi et al. compared a topical solution of 3 % tranexamic acid to 0.01 % dexamethasone-3 % hydroquinone combination. Effects were comparable [27]. Velasquez et al. discussed the use of TA intradermally, with favorable results [28]. Due to the paucity of literature, more studies are needed to evaluate this substance for use in melasma.
12.2.7 Arbutin
Arbutin is a β-glycosylated form of HQ present in bearberry extracts [10]. It exists in two forms, α-arbutin and deoxyarbutin, both of which are inhibitors of tyrosinase and melanosome maturation. The synthetic deoxyarbutin, however, is more potent. Arbutin functions through reversible inhibition of melanosomal tyrosinase activity rather than suppression of expression and synthesis of tyrosinase. It shows less melanocyte cytotoxicity than HQ. While higher concentrations appear more efficacious, they may also cause paradoxical hyperpigmentation. In comparison to HQ, where the skin lightening effect is very difficult to sustain, deoxyarbutin-induced skin lightening was maintained without the use of maintenance therapy [29].
12.2.8 Vitamin E
In an in vitro study by Funasaka et al., alpha-tocopheryl ferulate dissolved in lecithin inhibited melanization without significantly inhibiting cell growth, via inhibition of tyrosinase. Added to this is the antioxidant effect of both α-tocopherol and α-tocopheryl through the inhibition of biological reactions induced by reactive oxygen species [30]. Topical vitamin E has been shown to be effective for wrinkles and other signs of photoaging. In porcine skin, vitamin E combination with ascorbic acid works synergistically, providing fourfold protection against UV-induced erythema [31, 32].
12.2.9 Niacinamide
12.2.10 Novel Therapeutic Agents
Rucinol serum, a derivative of resorcinol, functions via tyrosinase inhibition [6, 34]. A split-face trial comparing 4-n-butylresorcinol 0.1 % cream to placebo showed the former to be more effective [35].
Related posts:
Pathogenesis of Vitiligo
Camouflage for Brown Skin with Melasma or Vitiligo
Vitiligo: Definition, Incidence, Etiology
Classification and Clinical Presentations of Melasma in Brown Skin
Iontophoresis and Mesotherapy in Melasma
Diagnosis of Melasma in Brown Skin: Wood’s Lamp, Dermoscopy, and Confocal Microscopy
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