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Depigmenting Agents

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

Abstract

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.

Keywords

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

Introduction

Depigmenting agents are widely used in the treatment of melasma and other disorders of hyperpigmentation. Some agents are used widely in cosmetic skin lightening products. Depigmenting agents are sometimes misused in ethnicities with pigmented skin. Although a large number of products are available as depigmenting agents, most agents have only limited evidence of their efficacy and long-term safety [1]. Most of the agents used as depigmenting agents target melanin found in pigment-producing cells, the melanocytes, which are responsible for skin pigmentation. The depigmenting agents act by inhibiting melanogenesis, interrupting melanosome transfer, accelerating epidermal desquamation and melanin turnover, antioxidant effects and by other methods [2].

Melanogenesis

Production of melanin in melanocytes is a key step which is targeted by several depigmenting agents as increased melanogenesis is responsible for pigmentation in most hyperpigmentory disorders. UV radiation activates tyrosinase, the key enzyme of melanogenesis [2]. Tyrosinase is a glycoprotein located in the membrane of the melanosome, where melanogenesis takes place. Tyrosinase catalyses the first two steps of melanin production (Fig. 18.1), the hydroxylation of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) and, the next step, oxidation of L-DOPA to L-dopaquinone which is subsequently converted to melanin [3, 4]. Oestrogens have shown to stimulate melanogenesis through the synthesis of melanogenic enzymes such as tyrosinase, tyrosinase-related proteins 1 and 2 (TRP-1, TRP-2). As tyrosinase catalyses main steps in melanin production, tyrosinase inhibitors are a main class of depigmenting agents .
Fig. 18.1

Schematic of the melanin biosynthetic pathway. DHI - 5,6-dihydroxyindole, DHICA - 5,6-dihydroxyindole-2-carboxylic acid, TRP - tyrosinase-related protein, DOPA - 3,4-dihydroxyphenylalanine (Reproduced with permission from John Wiley and Sons and Copyright Clearance Center (License number 3982371163774, dated 5th Nov 2016) [146])

Agents That Act by Tyrosinase Inhibition or Inhibiting Melanogenesis

Hydroquinone

Hydroquinone (HQ ) is a hydroxyphenolic compound, and its depigmenting properties were discovered about 50 years ago [5]. HQ has been the gold standard for treating hyperpigmentation ever since. HQ acts by inhibiting tyrosinase, the rate-limiting enzyme in melanogenesis [6]. It inhibits the conversion of l-3,4-dihydroxyphenylalanine to melanin by the competitive inhibition of tyrosinase. HQ also induces degradation of melanosomes and destruction of melanocytes by inhibiting DNA and RNA synthesis. HQ’s oxidative products also cause oxidative damage to membrane lipids and proteins. HQ is a ubiquitous chemical found in many foods such as red wine, coffee, tea, wheat and fruits and herbal medications [5].

When applied to the skin, 45% of total dose of hydroquinone is absorbed quickly, and 30% reach the bloodstream in 1 h [7]. HQ is excreted slowly via urine, 35% getting excreted after 24 h [8]. The major part of HQ is metabolised and detoxified via the glucuronide and sulphate route which is excreted via the kidney. In humans, a small amount of HQ is not metabolised in the liver, and another small amount is converted into p-benzoquinone. The non-metabolised HQ and the p-benzoquinone are further conjugated with glutathione. These glutathione conjugates of HQ, which impair mitochondrial function, are known to be nephrotoxins [7]. With normal use, the cream is applied every 24 h, and as excretion takes approximately every 72 h, it is likely that accumulation of HQ could occur.

HQ concentrations of 2–4% are commonly used to treat hyperpigmentation, but higher concentrations up to 10% can be compounded and used in refractory cases [9, 10]. HQ is widely prescribed by medical practitioners for the treatment of hyperpigmentation, and preparations with lower concentrations can be obtained over the counter in many parts of the world. HQ is also misused as skin whitening agents especially in dark-skinned populations.

Clinical Efficacy

A double-blind comparative placebo-controlled study comparing efficacy and tolerability of 4% HQ versus sunscreens used as placebo in melasma showed 40% of the patients having complete improvement compared to 10% in placebo group after 12 weeks of the treatment [11]. All patients given HQ showed some improvement, while 20% of the patients on placebo did not have any improvement. No serious adverse events were reported. Studies comparing HQ 4% cream versus 3% and 6% formulations did not show a significant difference in efficacy. However higher concentration showed more skin irritation [11]. It usually takes 5–7 weeks before the effect is apparent, and the treatment needs to be continued for 3–12 months [12]. HQ is also effective in the treatment of postinflammatory hyperpigmentation (PIH) [13, 14], which is seen more in darker-skinned patients [15].

HQ can be combined with other depigmenting agents to enhance efficacy. HQ 4% in combination with fluocinolone acetonide 0.01% and tretinoin 0.05% (triple-combination cream, TCC ) is widely used in the treatment of melasma. Exfoliating effects of retinoid enhance penetration of HQ and steroids reduce skin irritation. TCC is approved by the US FDA for the treatment of facial melasma. Complete clearance of melasma was seen in 26% of patients after 8 weeks of TCC in one study [16]. Extended daily use of TCC for 12 months showed clearance of lesions in over 90% of patients. Although over 50% of participants experienced some form of side effects, these were transient and minimal and were confined to the application site. Only 1% withdrew from the study due to side effects [17]. A multicentre, randomised, controlled, blinded, parallel comparison study comparing TCC therapy with 4% hydroquinone in Asian patients for melasma showed TC therapy to be more effective [18]. Current evidence suggests that TCC treatment is an effective and safe treatment in melasma.

HQ 4% is also used in combinations with 10% buffered glycolic acid, vitamin C, vitamin E and sunscreen with good results [19]. Skin irritation was more common compared to control group which used sunscreen alone but could be managed with moisturisers [19]. Sequential treatment with TCC alternating with glycolic acid peels in patients with moderate to severe melasma showed excellent improvement of objectively assessed parameters of efficacy in over 90% of the participants, and treatments were well tolerated [20].

Most of the patients who were treated with TCC were able to achieve a good improvement of their melasma after 12 weeks of treatment. About half of treated patients were able to commence twice-weekly maintenance therapy after 12 weeks. However, majority of patients relapse during maintenance therapy [21]. In a multicentre study done in Brazil and Mexico, about 78% of patients were able to commence maintenance therapy after 8 weeks of daily treatment with TCC [22]. Twice-weekly maintenance therapy showed to be more effective in postponing relapses compared to tapering regimen (thrice weekly for 1 month, twice weekly for 1 month, weekly for 1 month). Therefore maintenance treatment is an important aspect in management of melasma [22]. However TCC should not be used beyond 6 months because of the possibility of steroid-induced atrophy and it cannot be used as maintenance therapy for melasma.

Tolerability and Safety

Even though HQ is an effective treatment for hyperpigmentation, controversies exist regarding its safety [23]. The side effects of HQ are dose and duration dependent. Skin irritation, erythema and transient hypopigmentation are common but do not need stopping medication. Small dots of depigmentation within the macules of melasma have been reported in some patients.

Paradoxical postinflammatory hyperpigmentation also can occur. Nail discoloration has been reported in some cases which is self-limiting on discontinuation of treatment [24, 25]. Exogenous ochronosis is an often feared side effect that can occur after prolonged use of high-concentration HQ [26]. It occurs due to accumulation of homogentisic acid causing degeneration of collagen and elastic fibres, leading to deposition of ochre-coloured fibres. This is usually a rare side effect seen mostly in dark-skinned people and clinically manifests as grey-brown hyperpigmentation and pinpoints hyperchromic papules. As exogenous ochronosis is difficult to treat, differentiating it from melasma and stopping of HQ is necessary. Dermoscopy is an important tool in diagnosing exogenous ochronosis [27] which shows densely pigmented structures obliterating some follicular openings. This typical appearance helps in early diagnosis and spares the need for a biopsy. Maintenance therapy with HQ has shown that daily treatment for 8 weeks is safe and able to maintain the effects achieved [28].

Nephrotoxicity, hepatic and renal adenomas and leukaemia have been reported in animal models following systemic absorption of HQ [7]. Because of the concerns of these side effects in humans, US FDA and many other regulatory authorities have banned HQ in over-the-counter skin lightening products. However some dermatologists are not in agreement with the ban as cancers are not reported in humans, and exogenous ochronosis is a very rare side effect with only 22 cases reported in the USA over the last 50 years [29]. The ban on hydroquinone in cosmetic products has led to research on many HQ-free skin lightening products which have shown promising results [30, 31, 32].

Monobenzyl Ether of Hydroquinone

Monobenzyl ether of hydroquinone (MBEH ) destroys melanocytes causing permanent depigmentation [33]. It is approved by the US Food and Drug Administration (USFDA) in treatment of extensive vitiligo to permanently depigment the remaining normal skin. Confetti-like depigmentation occurs in parts other than where it is used when MBEH is wrongly used in melasma. It should never be used in melasma as it almost always causes permanent depigmentation .

Arbutin and Deoxyarbutin

Arbutin (hydroquinone-O-β-d-glucopyranoside) , a derivative of hydroquinone, is a botanically derived compound found in cranberries, blueberries, wheat and pears. Deoxyarbutin is a synthetic form of arbutin. Arbutin acts as a depigmenting agent by inhibiting tyrosinase and thereby production of melanin [34]. Arbutin inhibit tyrosinase activity without affecting its mRNA expression. However arbutin and deoxyarbutin have less cytotoxicity on melanocytes than HQ. Deoxyarbutin is as effective as HQ in treating hyperpigmentation and considered safe and less cytotoxic than HQ [35, 36]. Therefore arbutin and derivatives were considered to have the potential to become an important agent in cosmetic skin lightning creams [37].

The mild effect of arbutin is attributed to the controlled release of hydroquinone as a result of in vivo cleavage of the glycosidic bond. Concentrations up to 3% are used as skin whitening agents [38]. Higher concentrations of arbutin are more efficacious than lower concentrations but may cause paradoxical hyperpigmentation [39]. Arbutin derivatives may release hydroquinone under high temperature due to in vivo cleavage of the glycosidic bond, or they can be hydrolysed to HQ by skin bacteria during use [40].

Tolerability and Safety

The Scientific Committee on Consumer Safety (SCCS) recently reviewed the evidence on safety of deoxyarbutin for use in cosmetic products. As significant amounts of HQ can be formed when using 3% deoxyarbutin in face creams, the committee concluded that cosmetic products containing up to 3% deoxyarbutin are not safe to use [41].

Kojic Acid

Kojic acid (5-hydroxy-2-[hydroxymethyl]-4H-pyran-4-one) is derived from naturally occurring fungi like Acetobacter and Aspergillus . It reduces pigmentation by inhibiting production of free tyrosinase through chelation of copper in tyrosinase and inhibiting NF-κB in keratinocytes [42]. Kojic acid (KA ) is used as a skin lightening agent in several cosmetic products [43]. KA originated in Japan and is also used as a food additive for preventing enzymatic browning of foods. KA is often produced during the fermentation of normal dietary food items . KA is used in concentrations ranging from 1% to 4% in topical preparations , and percutaneous absorption is 17% [44]. It is metabolised probably similar to dietary hexoses. Toxicity resulting from oral administration has not been reported [45].

Clinical Efficacy

KA 2% combined with HQ 2% was shown to be superior to glycolic acid (GA) 10% and HQ 2% in one double-blind study [46]. GA 5% with either 4% HQ or 4% KA for 3 months has shown equal efficacy in another study [47]. Concentrations over 2% have shown similar efficacy with other commonly used depigmenting agents, and adding KA has further improved melasma. One Indian study has shown that combination of KA and HQ has better synergistic effects in treating melasma than HQ and betamethasone valerate [48]. Concentrations lower than 1% are not as effective as 2% [49].

Tolerability and Safety

Allergic contact dermatitis is a concern when using KA concentrations higher than 1% in cosmetic skin lightening products [50, 51]. In vitro and in vivo mammalian studies have not shown mutagenicity or genotoxicity [44]. KA reversibly inhibits iodine uptake by the thyroid gland, leading to decreased thyroid hormone production and increased TSH, promoting thyroid hyperplasia and carcinogenesis (adenomas) in animal studies. However risk of affecting iodine metabolism and inducing thyroid adenomas in humans appears to be extremely low. Evaluation of toxicity of consuming KA at levels normally found in food and in topical applications has concluded that it does not present a concern for safety [44, 45]. Cosmetic Ingredient Review (CIR) expert panel concluded that KA concentrations up to 1% are safe to use in cosmetic products [52].

Azelaic Acid

Azelaic acid (AzA ) is a naturally occurring compound originally derived from Pityrosporum ovale . It was discovered after investigation of hypopigmentation observed in pityriasis versicolor infections. AzA was initially developed as a topical treatment for acne. It is also used as a treatment for hyperpigmentation like melasma and PIH. Mechanisms of action include tyrosinase inhibition, inhibition of DNA synthesis and inhibiting mitochondrial enzymes in abnormal and hyperactive melanocytes inducing direct cytotoxic effects [53, 54]. Topical AzA has no depigmentation effect on normally pigmented skin as AzA has selective effects on abnormal melanocytes [55]. Free radicals are believed to contribute to hyperpigmentation following acne, and AzA also act by reducing free radical production [56]. AzA also has antibacterial properties on several dermal microflora including Staphylococcus aureus, Staphylococcus epidermidis and Propionibacterium acnes making it useful in treatment of acne. Percutaneous absorption is 3% from application of 20% AzA, but increased absorption up to 8% was noted with different vehicles used. Parenterally administered AzA is rapidly distributed and extensively eliminated via urinary excretion [57]. Animal studies have shown that AzA is non-toxic, non-mutagenic and non-teratogenic [54].

Clinical Efficacy

Topical AzA 20% cream is used as an off-label treatment in melasma. However it is available by prescription and should be applied twice daily, and treatment should be given for at least 2–3 months. AzA 20% is available to treat acne as well as for treatment of postinflammatory hyperpigmentation in acne. A 16-week controlled study of 15% AzA in mild to moderate acne in patients with dark skin showed improvement of both acne and the hyperpigmentation [58]. A 24-week multicentre, randomised, double-blind, parallel-group study of assessing the efficacy, safety and tolerability of AzA 20% cream, compared with its vehicle for the treatment of facial hyperpigmentation, showed that the AzA group had significant improvement of the pigmentation [56]. AzA 20% cream has also shown to be as effective as 4% HQ in the treatment of melasma [59]. An open-label study of 20% AzA twice-daily application found that it is more effective than 4% HQ cream daily for melasma [60]. Combination of AzA 20% with glycolic acid 15% showed comparable efficacy when compared to 4% HQ in treating facial pigmentation with more irritation in Aza and GA group. This study did not show any benefit of adding GA to AzA, but patients had more irritant side effects [61]. Combining AzA and retinoic acid is especially helpful in PIH in acne [62].

Tolerability and Safety

Side effects of AzA are mostly mild and transient and do not need stopping the medication. Pruritus, burning, stinging, tingling, erythema and skin peeling had been reported in less than 5% of patients. Skin peeling and dermatitis are rarer side effects. After 4 weeks of use, significantly more burning and stinging were seen in patients compared to vehicle [56].

4-n-Butylresorcinol

Anti-melanogenic compound, 4-n-butylresorcinol , has been shown to inhibit the activities of tyrosinase and tyrosinase-related protein-1 (TRP-1) in vitro [63]. A randomised, double-blind split-face study of liposome-encapsulated 4-n-butylresorcinol showed a significant improvement in the treated side of the face compared with the control side without any adverse events [64].

Antioxidants

Antioxidants are thought to cause skin lightening effects primarily by preventing melanogenesis induced by ultraviolet radiation. Oxidative effects and production of reactive oxygen species (ROS) by UV radiation induce melanogenesis by activating tyrosinase. Antioxidants can also reduce direct photo-oxidation of pre-existing melanin. Ascorbic acid and alpha tocopherol are two main antioxidants used in skin lightening products.

Ascorbic Acid

Ascorbic acid (AsA) or vitamin C is a water-soluble vitamin and is the most abundant antioxidant in the human skin. AsA interferes with melanin synthesis by inhibiting tyrosinase through chelation of copper ions at the active site of tyrosinase. AsA also acts by scavenging ROS by neutralising free radicals [65]. Vitamin C and its several derivatives are available as creams, serum and dermal patches in the market. Magnesium ascorbyl phosphate (MAP) is the most stable derivative. MAP is a lipophilic molecule and theoretically easily absorbed in to the skin. Active form of vitamin C, L-ascorbic acid, is colourless and unstable and on exposure to light is converted to dehydroascorbic acid giving it a yellow colour [66]. The stability of vitamin C is maintained at pH less than 3, at which it is non-ionised and penetrates well through the stratum corneum [67].

Optimum percutaneous absorption is seen at maximum concentration of 20%. Daily application for 3 days saturates dermal concentration and takes 4 days to disappear from the skin. As UV light reduces vitamin C levels, it is better to apply after exposure to UV light. Other derivatives of vitamin C such as MAP , ascorbyl-6-parmitate and dehydroascorbic acid were shown to be poorly absorbed through the skin [67]. Recommended oral dose of ascorbic acid is 60 mg daily. When vitamin C is taken more than 60 mg daily orally, tissue stores get saturated and urinary elimination occurs. However in some healthy volunteers, urinary excretion does not occur until 100 mg is taken and absorption and bioavailability declines after 500 mg [68]. 1000–3000 mg daily dose is recommended for skin lightening effects, and lower than 400 mg daily probably has no clinical value. Even though toxicity of vitamin C is rare, doses over 1000 mg daily can cause gastrointestinal discomfort. Therefore, topical application of vitamin C can achieve higher concentration in the skin than oral vitamin C and more beneficial as a skin whitening agent.

Clinical Efficacy

A double-blind study comparing 5% AsA and 4% HQ in melasma found 62.5% and 93% improvement in the two groups, respectively [69]. Side effects were present in 68.7% with HQ versus 6.2% with AsA. The study concluded that even though HQ showed better efficacy, AsA may play a role in melasma and as a skin whitening product as it is almost devoid of any side effects [69]. In another study, 25% l-ascorbic acid and a chemical penetration enhancer showed significant improvement of pigmentation in melasma patients after 16 weeks [70].

MAP is part of many cosmetic products. Although one in vitro study has shown poor absorption of MAP [67], another clinical study has shown 10% MAP to have significant skin lightening effects in melasma and senile freckles [71]. More patient satisfaction and improvement had been seen in melasma patients treated with Q-switched Nd:YAG combining with ultrasonic application of vitamin C in a split-face study [72].

Human studies of oral vitamin C in melasma have been mostly done in combination with other oral agents. A randomised, double-blind, placebo-controlled trial was done comparing an oral product containing procyanidin with vitamins A, C and E for melasma among 60 Filipino women [73]. This trial which used 60 mg of vitamin C evaluated changes in pigmentation using a mexameter. The study showed significant improvement in the Melasma Area and Severity Index (MASI) and concluded that oral procyanidin given with vitamins A, C and E was safe and effective for epidermal melasma when given orally for a period of 8 weeks.

Tolerability and Safety

Topical vitamin C has high safety profile. It can be used on a daily basis for a long duration. AsA can safely be combined with other depigmenting and anti-ageing products like retinoic acid, glycolic acid and sunscreens. Oxidative changes of topical vitamin C on the skin can cause yellowish discoloration of the skin and can stain cloths. Stinging and erythema are rare side effects [74].

Vitamin E

Vitamin E is a lipophilic antioxidant in the body. Increasing intracellular glutathione, interference with lipid peroxidation of melanocyte membranes and inhibiting tyrosinase bring about its depigmenting effects. Vitamin E consists of eight naturally occurring compounds having vitamin E activity, four tocopherols and four tocotrienols [75]. In humans, alpha tocopherol is the most abundant vitamin E derivative, followed by gamma tocopherol. Alpha tocopherol is the most commonly used compound [76]. There is limited data on the efficacy of vitamin E in treating hyperpigmentation or as a skin lightening agent. It is however commonly used in combination with other products.

Alpha tocopherol is the predominant vitamin E in the human skin, and gamma tocopherol is also found in epidermis, dermis and stratum corneum [77]. After exposure to UV light, the amount of alpha tocopherol decreases by about 50%. Depletion of alpha tocopherol in the skin is an early and sensitive indicator of photo-oxidative damage to the skin. Alpha tocopherol is regenerated from photo-oxidised alpha tocopherol in the presence of other antioxidants such as ascorbate which gets regenerated by glutathione. Vitamin E is shown to be the predominant antioxidant barrier in the human skin [78]. Nonnucleated stratum corneum lacks antioxidants compared to the nucleated epidermal and dermal layers. Therefore application of these antioxidants, vitamin E and vitamin C, prior to UV exposure reduces acute sun damage as well as chronic photoaging and also improves pigmentation [79]. Most vitamin E products are available as esters for stability which act as prodrugs and have to be hydrolysed to active vitamin E after dermal absorption. Bioconversion of vitamin E esters to vitamin E is much less in stratum corneum than in dermal layers [80]. Different skincare products contain variable amounts of vitamin E esters ranging from 2% to 36%, and there is a lack of data on dose-response relationship of effects of different vitamin E preparations.

Clinical Efficacy

A double-blind study showed a significant improvement of melasma and pigmented contact dermatitis lesions using topical vitamins E and C [81]. Combination of vitamins has been more effective than either agent as monotherapy. Another randomised double-blind trial using a facial lotion containing 4% niacinamide, 0.5% panthenol and 0.5% tocopheryl acetate daily in Indian women showed skin lightening effects and improvement of pigmentation [82]. An animal study investigating the effects of oral and topical preparations of vitamin E in mice has shown that supplementation with topical α-tocopherol or topical tocopheryl succinate or oral α-tocopheryl acetate can reduce the incidence of acute and chronic damage to the skin induced by UVR such as sunburn, pigmentation and skin cancer [83]. Another study in mice showed oral vitamin E alone or combined with L-selenomethionine was effective in protection against UV-induced blistering, pigmentation and skin cancer [84]. The study which showed efficacy of an oral product containing procyanidin with vitamins A, C and E for melasma had 15IU of D-alpha-tocopherol acetate [73].

Tolerability and Safety

Topical application of vitamin E is well tolerated except for mild transient burning sensation. However long-term use of oral vitamin E supplements above daily requirement could be harmful and has potential haemorrhagic risks.

Glutathione

Glutathione is a ubiquitous compound found in our body containing SH groups which interact with biological systems. It exists in cells in reduced form (GSH ) and gets oxidised into oxidised glutathione (GSSG ) which gets converted back to GSH catalysed by glutathione reductase [85]. Glutathione has depigmenting effects due to inhibition of tyrosinase by binding to copper containing active site of the enzyme and antioxidant effects due to the presence of SH groups and shifting melanogenesis from eumelanin to pheomelanin synthesis.

Glutathione is available as topical preparations (creams and face washes), oral preparations (capsules and sublingual tablets) and intravenous injections. Oral glutathione is marketed as a dietary supplement or a nutraceutical either alone or in combination with vitamin C and other antioxidants. It is absorbed by upper jejunum and excreted via the kidneys. After absorption, it is broken down to the amino acids and reformed intracellularly [79].

Clinical Studies

Topical GSSG 2% lotion twice-daily application was found to significantly improve melanin index, moisture content of the stratum corneum, skin smoothness, skin elasticity and wrinkle formation over placebo after 10 weeks [86]. GSSG was preferred as GSH is unstable in aqueous solutions. There are only two studies published up to now on efficacy and safety of oral glutathione. One randomised, double-blind, placebo-controlled study conducted among 60 Thai medical students demonstrated skin lightening with oral glutathione 250 mg twice daily taken for 1 month compared to placebo [87]. A second recent open-label study also demonstrated similar skin lightening effects in 30 subjects who received a lozenge formulation containing reduced L-glutathione with selenium, vitamin C, vitamin D3, vitamin E and grapeseed extract [88]. There is one published clinical trial to date evaluating efficacy and safety of parenteral glutathione for skin lightening. Sixteen healthy Pakistani women aged 25–47 years were given iv glutathione with vitamin C twice weekly for 6 weeks compared to placebo group who were given iv normal saline. There was improvement of skin tone in 37%, but the improvement was gradually lost after stopping treatment in all participants but one. There were significant side effects with the treatment [89].

However this route is now increasingly used without much evidence of its efficacy and with serious risks of side effects particularly when used by unqualified practitioners .

Tolerability and Safety

Postulated and observed adverse effects of glutathione include lightening of hair colour, hypopigmented patches and depletion of natural hepatic stores of glutathione with long-term supplementation, which could have potentially dangerous consequences. Systemic glutathione could also increase the susceptibility to melanoma as long-term administration switches eumelanin to pheomelanin [79]. As there is insufficient data on efficacy and safety of glutathione products, no regulatory authority has granted approval for its use as a skin whitening agent. US FDA in 2015 issued a warning to consumers on the dangers associated with the use of injectable skin lightening agents, such as glutathione [90]. Philippine FDA also has issued a similar warning where use of glutathione is common. Other recent publications have also warned about the dangers and unethical use of glutathione for skin whitening [91, 92, 93]. The other adverse effects reported with the use of intravenous glutathione include toxicity to the kidneys, liver and nervous system and serious cutaneous eruptions such as Stevens–Johnson syndrome and toxic epidermal necrolysis .

Methimazole

Methimazole is an oral antithyroid agent which has been used for that purpose over 50 years. It causes depigmentation of the skin when used topically due to inhibition of melanin synthesis [94]. Methimazole causes inhibition of peroxidase both in thyroid cells and melanocytes interfering with different steps in the biosynthesis of eumelanin and pheomelanin pigments. It is also an inhibitor of tyrosinase. Topical methimazole had been tested as a hydroquinone free skin depigmenting agent over the recent years after concerns of cytotoxic and mutagenic side effects of HQ. After a single topical application of 5% methimazole, it was undetectable in the serum from 15 min up to 24 h, but after oral administration, methimazole was detected in serum in 15 min and remained detectable in serum up to 24 h [95]. Long-term topical methimazole applications in melasma patients did not induce any significant changes in thyroid functions.

Clinical Efficacy

Depigmenting effects of topical methimazole in the human skin was first reported in 2005 by Kasraee et al. in a single case report [94]. Topical application of 5% methimazole daily showed improvement of PIH following acid burns in a 27-year-old male after 6 weeks. Two patients with melasma who were resistant to topical HQ reported significant improvement after 8 weeks of topical 5% methimazole [96]. Current data on the efficacy of methimazole as a depigmenting agents are limited to a few case studies. There is a need for randomised controlled trials using a large number of patients to further determine its efficacy.

Tolerability and Safety

Topical methimazole is very well tolerated and not melanocytotoxic. Long-term topical use of 5% methimazole in 20 melasma patients did not show significant changes in serum TSH, free thyroxine and free triiodothyronine levels [95]. There were no reported cutaneous side effects. However topical methimazole is not recommended as a skin bleaching cream on a large skin area in normal individuals.

Agents Interrupting Melanosome Transfer

Niacinamide

Niacinamide is a biologically active form of niacin (vitamin B3) and is an important precursor of cellular coenzymes, NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate). The effect of niacinamide on hyperpigmentation is believed to occur through inhibition of melanosome transfer from melanocytes to keratinocytes. Niacinamide has shown to inhibit 35–68% of melanosome transfer [97].

Topical niacin and niacinamide in concentrations up to 5% are used as hypopigmenting agents [98]. Both are readily absorbed from the skin, blood and the intestines and are widely distributed throughout the body. Excretion is primarily through the urinary tract. Both are relatively non-toxic [99]. They have shown efficacy when used alone or in combination with other agents such as HQ [100], N-acetyl glucosamine [101], vitamin C [102], sunscreens and N-undecyl-10-enoyl-L-phenylalanine [103]. Although oral niacinamide is used as a pharmacological agent for a variety of other conditions [104], there were no studies showing efficacy of oral niacinamide in skin whitening.

Clinical Efficacy

A double-blind, randomised clinical trial of niacinamide 4% versus HQ 4% in a split-face study in 27 patients with melasma showed improvement in MASI score in 44% of patients in nicotinamide group compared to 55% in HQ group [100]. The effects were evident in 4 weeks in HQ group and in 8 weeks in nicotinamide group. Topical nicotinamide had significantly less side effects. The study concluded that nicotinamide is safe and effective for treatment of melasma and safe to use over long term. Daily use of niacinamide and sunscreens showed better skin lightening effects compared to sunscreens alone [90].

Five percent topical niacinamide had shown improvement of pigmentation in another 12-week double-blind placebo-controlled split-face study, compared to the control [105]. The study also showed improvement of features of skin ageing such as fine wrinkles, texture, blotchiness and yellowing.

Topical nicotinamide works well in combination with other depigmenting agents. Topical formulation containing niacinamide and N-acetyl glucosamine was significantly more effective than vehicle control in one study [101]. Combination of topical vitamin C and niacinamide was an effective treatment for pigmentation and addition of ultrasound radiation-enhanced epidermal delivery of the agents [102].

Tolerability and Safety

Side effects of topical niacinamide are rare and minor and improve with continuous use. Mild skin burning, pruritus and erythema had been reported [100]. Both niacin and niacinamide are accepted for use in cosmetics in Japan and the European Union. The cosmetics ingredient review panel considered niacin and niacinamide at its current low concentrations used in cosmetics as safe [99].

Lectins

Lectins improve hyperpigmentation by reversibly inhibiting melanosome transfer from melanocytes to keratinocytes. Lectins and niacinamide combination has enhanced depigmenting effects [98]. Lectins have shown 15–44% inhibition of melanosome transfer under experimental conditions [2].

Agents Accelerating Epidermal Desquamation and Melanin Turnover

Retinoids

Depigmenting effects of retinoids are brought about by interfering with pigment transfer, accelerating epidermal desquamation, enhancing cell turnover and, therefore, pigment loss. Tretinoin , or retinoic acid (RA) , also inhibits transcription of the key melanin synthesis enzyme tyrosinase. Retinoids are used in combination with HQ and enhance its penetration and efficacy [53, 106, 107]. Topical retinoids, tretinoin and adapalene are used in gel, cream and liquid forms in concentrations ranging from 0.01% to 0.1%. Adapalene is a synthetic retinoid having greater selectivity than tretinoin for certain retinoic acid receptors. When used in combination with HQ and steroids, retinoids enhance the depigmenting effect of HQ and minimise skin atrophy caused by steroids.

Clinical Efficacy

Topical retinoids are commonly used in treatment of acne and photoaging. It is a useful therapy in PIH following acne. It is not approved as monotherapy in the treatment of melasma. However retinoid, HQ and steroid triple therapy is FDA approved to treat melasma.

Several studies showed improvement of melasma and PIH with topical retinoids given as monotherapy. Griffiths et al. showed 68% clinical improvement of melasma in Caucasian women after treatment with 0.1% tretinoin, while worsening of pigmentation was noted in control group [108]. Another double-blind, randomised controlled study in 30 African-American patients showed improvement of melasma with 0.1% tretinoin compared to vehicle group at 40 weeks [109]. Tretinoin 0.1% cream showed 40% improvement of PIH on the face and arms after 40 weeks of treatment in patients with black skin [110]. Topical tretinoin 0.1% cream showed 90% improvement of pigmentation associated with photoaging, after 40 weeks in Chinese and Japanese patients [111].

Adapalene 0.1% was found to have comparable efficacy to tretinoin 0.05% cream in melasma with fewer side effects [112]. Even though available clinical studies show good clinical efficacy of topical retinoids as monotherapy in treating melasma and PIH, better results are obtained in combination with other depigmenting agents. Moreover retinoids as monotherapy needs to be used for a longer periods to obtain the results. Topical tretinoin 0.1% has been effective in treating PIH in combination with GA peels and hydroquinone in dark-skinned individuals [113].

Tolerability and Safety

Retinoid dermatitis is the most common side effects of topical retinoids and usually seen in the first few weeks of starting treatment. Burning sensation, itching, erythema, scaling and dry skin are commonly seen. These side effects are reversible on discontinuation of therapy. Mild skin irritation settle after a few weeks of usage. PIH or hypopigmentation is more common in dark skin and can persist for few months after discontinuation of treatment. In the study done by Griffith et al., the cutaneous reactions were reported in 88% of patients compared to 29% on vehicle group [108]. Photosensitivity has been reported with topical retinoids. Therefore retinoid creams should be used at night, and sunscreens are needed during daytime. Topical retinoids should not be used in pregnant women due to potential teratogenic effects .

Hydroxy Acids and Other Acids

Hydroxy acids are a group of natural compounds found in sugar cane, citrus fruits and milk. Alpha hydroxy acid has the smallest molecule size of the group and has the advantage of better penetration of the epidermis. Alpha hydroxy acid accelerates the epidermal desquamation and improves skin pigmentation [114]. Concentrations up to 10% are commonly available in skincare products like creams, cleansers and soaps. Alpha hydroxy acids are more commonly used in chemical peels for melasma, acne and in products used for treatment of skin wrinkling. Higher concentrations are used in chemical peels. Skin irritation, erythema and itching are some commonly reported side effects of alpha hydroxy acids, and concomitant use of sunscreens are recommended to minimise skin irritation.

Salicylic acid and linoleic acid improve hyperpigmentation by accelerating turnover of stratum corneum. Salicylic acid is also used as a peeling agent to treat hyperpigmentation.

Other Agents

Tranexamic Acid

Tranexamic acid (TXA) is a synthetic derivative of lysine, indicated in preventing abnormal fibrinolysis to reduce blood loss. It reversibly blocks the lysine-binding sites on plasminogen molecules, inhibiting the plasminogen activator from converting plasminogen to plasmin. Plasminogen also exists in human epidermal keratinocytes. Ultraviolet light induces plasmin activity which can activate precursors of the melanogenesis like membrane phospholipids, arachidonic acid and prostaglandins [115]. TXA inhibits plasminogen activation, binding of plasminogen to the keratinocytes resulting in reduction in formation of prostaglandins and arachidonic acid, which are inflammatory mediators involved in melanogenesis. TXA is probably the only treatment that can prevent the activation of melanocyte by various stimuli such as sunlight, hormones and injured keratinocytes through the inhibition of the plasminogen activation. It can also reduce the likelihood of recurrence of pigmentation after other treatments that damage the melanocytes (peels, lasers), which activate melanogenesis. TXA also inhibits the melanin synthesis via decreasing the α-melanocyte-stimulating hormone (α-MSH). TXA has also been reported to suppress neovascularization induced by basic fibroblast growth factor.

Topical , oral, intradermal, intravenous and other methods of delivery of TXA have been used as hypopigmenting agents with varying results [115]. Topical TXA up to 5% are used as monotherapy or in combination with HQ and steroids for treatment of melasma. A liposomal formulation of topical TXA is available [116]. Iontophoresis of TA using chemical enhancer and constant electric current is also possible [117]. Oral doses of 250 mg twice a day for 6 months [118] and 750 mg three times a day for 2 months have been used in treating melasma [119]. Usual effective dose of TXA for depigmentation is 250 mg 2–3 times daily, much lower than the doses used to reduce excessive bleeding. Clinical response is seen in about 1 month [120]. Intravenous TXA is also used at a dose of 500 mg every 2–4 weeks, as a bolus intravenous injection or as an infusion with normal saline together with ascorbic acid. Absorption of TXA is not affected by food, and peak plasma concentrations are reached within 3 h, and 90% of the drug is eliminated in 1 day. TA can cross the blood–brain barrier and the placenta. TXA seems to have a very safe profile in recent studies involving over 20,000 patients given TXA following trauma, and the theoretical thrombotic risk is shown to be very low [120].

Clinical Studies

Topical TXA 2% showed improvement in the pigmentation in 80% of subjects when given for 5–18 weeks with no significant side effects [121]. A study using 5% TXA in Asian patients in a split-face study showed no effect after 3 months of application compared to the vehicle, with more skin irritation seen with TXA [122]. In another study comparing the safety and efficacy of 3% topical TXA with 3% hydroquinone and 0.01% dexamethasone showed that the TXA is as effective as the cumulative effect of hydroquinone and dexamethasone, with lesser side effects [123]. Another split-face study comparing 5% liposomal TXA with 4% HQ showed equal results after 12 weeks [121, 122]. Skin irritation was noticed in HQ group without any irritation noted with TXA. In 100 women with melasma, intradermal microinjection of TXA for 12 weeks resulted in 76.5% improvement of MASI score with no significant side effects [124].

A number of studies reported in literature have evaluated varying doses of oral TXA either alone or in combination with other agents for treatment of melasma. In one of the first studies, Hajime et al. in 1985 showed reduction of melasma severity in 33 out of 40 patients following 10 weeks of oral TA 1–1.5 g daily [115]. Over 90% of 74 patients showed improvement of melasma with oral TA 250 mg twice daily taken for 6 months in another study [125]. A prospective, randomised controlled trial with TA at a dose of 250 mg twice a day for 3 months compared to usual topical therapy in 260 patients with melasma showed significant decrease in the mean MASI score at 8 and 12 weeks [126]. Addition of oral tranexamic acid to fluocinolone-based TCC was shown to produce faster and sustained improvement of melasma. Oral TXA has also shown efficacy when given in combination with light or laser therapy in patients with melasma without serious adverse effects [127, 128]. Oral TXA 250 mg twice daily in 25 patients with refractory melasma showed 70% improvement of MASI score after 3–4 months of use in another study [129]. A recent retrospective study done by Lee HC et al. in 561 Asian patients with melasma showed 89% of patients showing improvement in pigmentation with oral TXA [1]. There was one case of DVT reported who was later found to have familial protein S deficiency. The authors suggested screening for coagulation disorders before commencing oral TXA for melasma. According to available clinical studies, the usual effective dose of TXA in treating pigmentary disorders is 250–500 mg daily, much lower than the doses used to treat bleeding. The duration of treatment and repeated courses of treatments appear to be more effective than increasing dose.

Tolerability and Safety

The commonly reported side effects of TXA are nausea, diarrhoea and orthostatic hypotension. No mutagenic activity or harmful foetal effects have been reported. Adverse events that have been reported include anaphylactic shock, skin reaction and acute renal cortical necrosis. TXA has no effect on coagulation parameters. TXA seems to have a very safe profile, and the theoretical thrombotic risk is very low. However proper history should be taken, and a clinical examination should be done to exclude any potential risk of thromboembolism. Coagulation screening needs to be done when relevant. Skin irritation could occur with topical TXA.

Steroids

The exact mechanisms of skin lightening effects of topical steroids are not completely known, but possible mechanisms include vasoconstriction, reduction of activity and number of melanocytes and reducing MSH activity. Steroids might also alter melanocyte function by inhibition of prostaglandin or production of melanogenic cytokines such as endothelin-1 and granulocyte macrophage colony-stimulating factor [131]. Steroids can inhibit these cytokine mediated UV-induced melanogenesis by various cells of the epidermis.

It is used in treatment of hyperpigmentation as part of triple-combination treatment under regular medical supervision [18, 21, 22, 32]. When used in TCC, steroids reduce skin irritation caused by retinoids. Topical hydrocortisone, mometasone, and fluocinolone acetonide are used in combination with other depigmenting agents to treat melasma [132]. The use of stronger topical steroids in skin lightening creams in large body areas had been reported in some African countries. The misuse of potent topical steroids for long term causes significant side effects such as steroid-induced acne, skin infections, striae, telangiectasia and even systemic effects such as diabetes mellitus and Cushing’s disease [132]. Therefore steroid-containing preparations should not be used for more than 6 months for maintenance therapy in hyperpigmented conditions.

Natural and Other Agents

Many natural plant extracts have been identified to have potentially active compounds which inhibit melanin synthesis and having skin lightening properties [133, 134]. Most of these agents which act by different methods have been tested in combination with other agents for their hypopigmenting effects . N-acetylglucosamine , tested alone or with niacinamide, inhibits enzymatic glycosylation in converting inactive pro-tyrosinase to active tyrosinase, inhibiting melanin production [101]. Anti-inflammatory and antioxidant properties are also proposed for glucosamine compounds. N-undecyl-10-enoyl-L-phenylalanine acts by antagonising alpha melanocyte-stimulating hormone (MSH) receptor, reducing melanin production [101]. Resveratrol, a natural extract derived from the roots of the Japanese Knotweed, is shown to be effective in the treatment of melasma. It has proven antioxidant activity by a 14-fold increase in the action of superoxide dismutase 2 in cells treated with resveratrol 0.05% [135].

Other topical applications that have resulted in hypopigmentation of the skin in animal studies after UV irradiation include linolenic acid , linoleic acid , oleic acid and phospholipase D2 [136]. The effect is via the stimulation of tyrosinase ubiquitination and proteasomal degradation . Other compounds that modify tyrosinase structures at glycosylation sites to induce hypopigmentation in vitro include glucosamine and tunicamycin [137]. Calcium D-pantetheine-S-sulfonate also has shown hypopigmenting effects by modifying glycosylation of tyrosinase and TRP1, which are key enzymes for melanogenesis [138].

Grapeseed Extracts

Grapeseed extracts (GSE) containing proanthocyanidin have shown strong antioxidant properties and reduce melanin biosynthesis as well as UV-induced hyperpigmentation [139]. Oral intake of GSE for 6 months was shown to improve melasma in 10 out of 12 women studied [140].

Pomegranate Extract

A pomegranate extract (PE) containing 90% ellagic acid has skin whitening effects due to inhibition of the tyrosinase in melanocytes and also by inhibiting proliferation of melanocytes [141]. The magnitude of inhibition is comparable to arbutin [142]. In a clinical study involving 13 young women, oral intake of 100 and 200 mg of ellagic acid containing PE was shown to be effective in reducing UVR-induced skin pigmentation [143].

Licorice

Licorice extracts are derived from licorice root. There are number of active ingredients. Glabridin, the main ingredient in hydrophobic fraction of licorice extracts, improves hyperpigmentation mainly by inhibiting tyrosinase [144]. The other main ingredient of licorice extracts, liquiritin, acts by dispersing melanin.

Other Natural Agents

Several other agents such as mequinol, gentisic acid, flavonoids, aloesin and soybeans and a variety of other plant extracts such as mulberry, orchid and green tea are used as depigmenting agents [133, 134]. A skin whitening formula containing ferulic acid, Ginkgo biloba , lipohydroxy acid, niacinamide and thermal spring water was safe and improved melasma compared to placebo after administration for 3 months [145]. Topical plant extracts are increasingly used in skin lightening cosmeceuticals as they have probably less side effects. These products could be considered for combined use with standard depigmenting agents. Further properly conducted clinical trials are needed to assess their efficacy and safety.

A large number of studies had been done in search of newer effective depigmenting agents having a better safety profile. Most of these studies have been done for short periods and have involved a small number of subjects. There is a need for properly designed large-scale studies to evaluate the efficacy and safety of these newer agents (Table 18.1).
Table 18.1

Depigmenting agents

Depigmenting agents classified according to mode of action

Topical agents

Oral agents

Others (intradermal, mesotherapy, intravenous use)

1. Inhibitors of melanogenesis (tyrosinase inhibitors)

Hydroquinone [5, 6, 7, 8, 11, 16, 17, 28, 29, 30] and monobenzyl ether of hydroquinone [33], arbutin [34, 38, 40], deoxyarbutin [35, 36, 37, 41], kojic acid [42, 43, 44, 45, 46, 48, 49, 50, 52], azelaic acid [53, 54, 55, 56, 57, 58, 59, 60, 61, 62], ascorbic acid [65, 66, 67, 68, 69, 70, 71], magnesium ascorbyl phosphate [67, 71], 4-n-butylresorcinol [63], alpha tocopherol [75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85], glutathione [79, 85, 86, 87, 88, 89, 90, 91, 92, 93], methimazole [94, 95, 96], mequinol, gentisic acid, flavonoids, aloesin [133, 134], licorice extracts containing glabridin [144], pomegranate extracts containing ellagic acid [141, 142, 143], resveratrol [135]

Ascorbic acid [73], vitamin E [73], procyanidin [73], glutathione [87, 88, 89], grapeseed extracts

Q-switched Nd:YAG with ultrasonic application of vitamin C [72], ultrasonic application of vitamin C and niacinamide, intravenous glutathione [79, 90, 91, 92]

2. Interrupting melanosome transfer

Niacinamide [89, 97, 98, 99, 100, 101, 102, 103, 104, 105], soybeans [133, 134], lectins and neoglycoproteins [2, 97]

  

3. Accelerating epidermal desquamation and melanin turnover

Retinoids [53, 106, 107, 108, 109, 110, 111], adapalene [112], hydroxy acids [114], glycolic acids [114], salicylic acids, linoleic acids

  

4. Agents acting by other methods and other natural agents

Tranexamic acid [115, 116, 117, 118, 119, 120, 121, 122, 123, 124], steroids (18, 21, 22, 32) [131, 132], other plant extracts [133, 134], grapeseed extracts containing proanthocyanidin [139, 140], gentisic acid, flavonoids, soybeans, lectins, ferulic acid, Ginkgo biloba, lipohydroxy acid [145], thermal spring water [145], N-undecyl-10-enoyl-L-phenylalanine, N-acetyl glucosamine [101], linolenic acid, linoleic acid, oleic acid, and phospholipase D2 [136], glucosamine, tunicamycin [137] and calcium D-pantetheine-S-sulfonate [138]

Tranexamic acid [115, 125, 126, 127, 128, 129, 130]

Intradermal [124], intravenous [121] and iontophoresis of tranexamic acid [119]

Conclusion

Disorders of hyperpigmentation are a common encounter in dermatology practice and often challenging to treat. There is no universal effective treatment. Hyperpigmentation especially in melasma tends to recur. Most of the currently used depigmenting agents act by inhibiting tyrosinase, the rate limiting enzyme in melanin synthesis. Topical modalities still remain the first choice. Hydroquinone is the gold standard for therapy though there are concerns of its safety, especially for long-term use. Combinations of topical therapies are preferred as the agents with different mechanisms of action have synergistic effects, and some agents reduce side effects and skin irritation induced by the other. Triple-combination cream containing hydroquinone, retinoic acid and a topical steroid is the most widely used treatment. Topical tranexamic acid, niacinamide, kojic acid and azelaic acid are the other important topical agents used. Oral tranexamic acid has gained popularity as a safe and effective adjuvant treatment in treating refractory melasma, and it has the benefit of inhibiting pigmentation induced by UV light and postinflammatory pigmentation induced by treatments themselves. Maintenance treatment is an important aspect of managing hyperpigmentation in sustaining clinical improvement. Concomitant use of broad spectrum sunscreens needs to be encouraged to achieve an effective depigmenting effect with any form of treatment. Multiple natural agents like grapeseed extracts, licorice, flavonoids, mequinol and mulberry extracts have been evaluated for their skin lightening properties. Most natural agents are not as effective as hydroquinone and other commonly used depigmenting agents.

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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

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