Treatment Of Hyperpigmentation Disorders Research Articles

Comparison between the efficacy of cysteamine cream and combined hydroquinone cream in the treatment of melasma using skin analytical systems: An open-label quasi-randomized controlled trial in Asia patients

Abstract Background: The mainstay of treatment for melasma is topical hydroquinone or preparations containing hydroquinone. In recent years, cysteamine cream has gained popularity in the treatment of hyperpigmentation disorders. Objectives: This study aimed to compare the efficacy of combined hydroquinone/betamethasone to cysteamine in the treatment of melasma. Methods: Eighteen patients had completed this open-label controlled trial. Subjects received either 5% cysteamine cream or a combination of 4% hydroquinone cream and 0.06% betamethasone valerate for 12 weeks according to standardized protocols. Patients were assessed at recruitment, 4 weeks, and 12 weeks after treatment for Melasma Area and Severity Index (MASI) scores. Other parameters relating to skin complexions and patient satisfaction were also assessed. Results: Patients treated with hydroquinone (n = 7) and cysteamine (n = 11) both showed significant decreases in MASI score at week 12: 33.1% (P = 0.009) and 37.9% (P = 0.009), respectively. There was no statistically significant difference between the two treatment groups (P = 0.236). Melanin content at week 12 decreased by 8.8% (P = 0.016) in the hydroquinone group and 11.5% (P = 0.046) in the cysteamine group, with no significant difference between the groups (P = 0.253). No significant differences were observed between the groups for other parameters or patient satisfaction. Conclusion: Cysteamine cream may provide an alternative treatment option for individuals with melasma, offering fewer side effects while delivering comparable results.

Oral tranexamic acid in the treatment of hyperpigmentation disorder beyond melasma: A review.

Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic, procoagulant agent approved by the Food and Drug Administration for the treatment of cyclic heavy menstrual bleeding and prevention of bleeding in patients with hemophilia undergoing tooth extraction. Oral tranexamic acid has been used off-label in dermatology in the treatment of melasma and other hyperpigmentation disorders. In a recent study, oral tranexamic acid was reviewed thoroughly in treating melasma, and its effectiveness was demonstrated. Their role in treating other hyperpigmentation disorders has also been tried in several studies. To review the evidence regarding the use of tranexamic acid in treating different types of hyperpigmentation disorders other than melasma. A comprehensive literature review was searched using the electronic online database "PubMed" and "google scholar" using key words "Postinflammatory hyperpigmentation," "lichen planus pigmentosus," "ashy dermatosis," "riehl melanosis". After that, a full-text review of the studies was performed. Oral tranexamic acid has been used in different types of hyperpigmentation disorder, including postinflammatory hyperpigmentation treatment and prevention, lichen planus pigmentosus, ashy dermatosis, and Riehl melanosis in a dose range from 250 mg per day to 1500 mg per day for a period range from 2 weeks to 6 months with variable efficacy and a good safety profile. Oral tranexamic acid is a promising treatment option in a different type of hyperpigmentation disorders refractory to topical treatment. However, more evidence from blinded randomized controlled trials and case-control studies is needed to determine their efficacy in treating various hyperpigmentation disorders.

Review on the Use of Kojic Acid—A Skin-Lightening Ingredient

This article reviews the use of Kojic Acid (KA) as a skin-lightening ingredient in the cosmetics industry. In 1907, Saito discovered KA, a natural product; it has since become one of the most investigated skin-lightening agents. This paper highlights the findings of the research conducted on this agent. It has been found that KA has certain disadvantages, and researchers have attempted to mitigate these disadvantages by designing new equivalents of KA that are more efficient in tyrosinase inhibition. These equivalents are also safe to use and have improved properties and solubility. The Cosmeceutical Ingredient Review (CIR) indicates that this ingredient can be safely used at a concentration not higher than 1% due to its cytotoxicity. Other scientific data also support its safety at a concentration of 2% or less. It was shown to be helpful in the treatment of hyper pigmentary disorders, such as freckles, age spots, post-inflammatory hyperpigmentation, and melasma, which has been proven clinically.

Implications of Oxidative Stress in the Pathogenesis and Treatment of Hyperpigmentation Disorders.

Oxidative stress represents an imbalance between the generation of reactive oxygen and nitrogen species and the ability of antioxidant systems to decompose those products. Oxidative stress is implicated in the pathogenesis of hyperpigmentation, hypopigmentation, melanoma, and other skin diseases. Regulatory networks involving oxidative stress and related pathways are widely represented in hypopigmentation diseases, particularly vitiligo. However, there is no complete review into the role of oxidative stress in the pathogenesis of hyperpigmentation disorders, especially regarding associations involving oxidative stress and cellular signaling pathways. Here, we review oxidative and antioxidant systems, oxidative stress-induced signal transduction mechanisms, and effects of antioxidant drugs used in preclinical and clinical settings in hyperpigmentation disorders.

Various Plants and Bioactive Constituents for Pigmentation Control: A Review

Hyperpigmentation disorders caused by excessive melanin synthesis may significantly affect the psychosocial aspect of an individual. Being the current gold standard used for the treatment of hyperpigmentation disorders, hydroquinone is associated with several adverse effects including skin irritation, contact dermatitis, mutagenic to mammalian cells, cytotoxic to melanocytes as well as exogenous ochronosis in darker-complexioned individuals. Botanically derived agents have received increased attention in treating hyperpigmentation as they are perceived to be milder, safer, healthier and more cost-effective. Several herbs, plant extracts and phytochemicals with multitude mechanisms of action have been reported to be effective depigmenting agents with milder side effects. Some of the agents were studied in combination and their hypopigmentation effects may be resulting from synergistic effects of the various components. Mechanisms involved in depigmentation include tyrosinase inhibition, inhibition of α-melanocyte-stimulating hormone-induced melanogenesis and antioxidant properties. Use of plant-derived agents for the treatment of hyperpigmentation disorders is promising with the need for more rigorous clinical studies to support the use of these agents. This review summarizes the use of various plants and bioactive constituents and their effectiveness in the control of pigmentation.

Di (Isoquinolin-1-Yl) Sulfane (DIQS) Inhibits Melaninogenesis by Modulating PKA/CREB and MAPK Signaling Pathways

The novel synthetic compound Di (isoquinolin-1-yl) sulfane (DIQS) was identified by zebrafish larva screening during the development of an agent to inhibit abnormal hyperpigmentation. In this study, we investigated the inhibitory effect of DIQS on melanogenesis and its underlying mechanism. DIQS inhibited melanin production and tyrosinase activity in B16F10 cells stimulated with α-melanocyte-stimulating hormone (α-MSH), as well as zebrafish embryos and reconstituted human skin tissue containing melanocytes. DIQS decreased the mRNA and protein expression of microphthalmia-associated transcription factor (MITF) and tyrosinase at a concentration of 10 μM. DIQS also inhibited the phosphorylation of cAMP response element-binding protein (CREB) and p-p38 and p-JNK stimulated by α-MSH. These results suggest that DIQS attenuates hyperpigmentation via inhibition of the cAMP/PKA/CREB/MITF/tyrosinase axis and MAPK pathways. Liquid chromatography–tandem mass spectrometry analysis revealed that DIQS blocked the conversion of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) in zebrafish embryos. Finally, we confirmed that DIQS was non-toxic in reconstituted human tissues such as the epidermis, used to test skin sensitization, and the cornea, used to test eye irritation. In summary, the results of this study suggest the potential of DIQS as a small-molecule agent for skin-whitening cosmetics and the treatment of hyperpigmentation disorders without biological toxicity.

Formulation and Physicochemical Evaluation of a 3% Cream Using Crude 70% Ethanolic Extract of Morus alba L. Leaves for Skin Hyperpigmentation

Background: Treatment of hyperpigmentation disorders is a challenge because of the side effects of current topical treatments. Thus, research for potent alternatives, especially of herbal origin, with comparable potency and less side effects is ongoing. Morus alba L. is a perennial plant with multiple established pharmacological effects, including antimelanogenesis effect. This effect has been demonstrated from different parts of the plant, including twigs, root barks, and leaves by measuring tyrosinase inhibition, melanin content, and melanin index, and it has been attributed to phenolic compounds such as oxyresveratrol and moracin M, to name a few. However, no study has considered formulating the total phenolic compounds from the leaves of this plant so far. Objectives: The aim of this study was to extract phenolic compounds of leaves with repeated maceration using 70% ethanol, formulate the crude extract, inspect its physicochemical stability under accelerated conditions, and assay for microbial growth and active phenolic compounds. Methods: Total phenolic compounds were extracted using 70% ethanol with repeated maceration, and then they were concentrated. The extract was then assayed for total phenolic content using Folin-Ciocalteu’s reagent. A 3% cream of this extract was manufactured, and its physicochemical parameters, microbial growth, preservative effectiveness, and total phenolic content were examined. Results: The prepared 3% cream was completely stable and homogeneous during the accelerated conditions and passed the physicochemical, total phenolic content, and microbial tests. Conclusions: The manufactured cream is a promising formulation for in vivo use as a skin lightening agent.

Screening of an Epigenetic Drug Library Identifies 4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-Phenyl-Benzeneacetamide that Reduces Melanin Synthesis by Inhibiting Tyrosinase Activity Independently of Epigenetic Mechanisms.

The aim of this study was to identify novel antimelanogenic drugs from an epigenetic screening library containing various modulators targeting DNA methyltransferases, histone deacetylases, and other related enzymes/proteins. Of 141 drugs tested, K8 (4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-phenyl-benzeneacetamide; HPOB) was found to effectively inhibit the α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis in B16-F10 murine melanoma cells without accompanying cytotoxicity. Additional experiments showed that K8 did not significantly reduce the mRNA and protein level of tyrosinase (TYR) or microphthalmia-associated transcription factor (MITF) in cells, but it potently inhibited the catalytic activity TYR in vitro (IC50, 1.1–1.5 µM) as compared to β-arbutin (IC50, 500–700 µM) or kojic acid (IC50, 63 µM). K8 showed copper chelating activity similar to kojic acid. Therefore, these data suggest that K8 inhibits cellular melanin synthesis not by downregulation of TYR protein expression through an epigenetic mechanism, but by direct inhibition of TYR catalytic activity through copper chelation. Metal chelating activity of K8 is not surprising because it is known to inhibit histone deacetylase (HDAC) 6 through zinc chelation. This study identified K8 as a potent inhibitor of cellular melanin synthesis, which may be useful for the treatment of hyperpigmentation disorders

A novel method for evaluating sun visible light protection factor and pigmentation protection factor of sunscreens.

IntroductionThe role of visible light (VL) in the process of skin pigmentation by solar radiation has been demonstrated. Sunscreens with the presence of pigments, particularly iron oxide (IO), have a greater protective effect against VL and are, therefore, highly recommended for prevention and treatment of hyperpigmentation disorders. This study aimed to evaluate 33 sunscreen formulations, and through spectrophotometric measurements, proposes new methods to evaluate the VL protection factor and the pigmentation protection factor.Methods33 sunscreen formulations marketed in Brazil were evaluated, including 17 products containing pigments and 16 products with no pigments. Spectrophotometric measurements were taken to determine solar VL protection factor and the pigmentation protection factor, based on the absorption curve of the product, the pigmentation action spectrum and sun spectrum.ResultsSunscreen with pigments presented a higher solar VL protection factor and pigmentation protection factor compared to products without pigment. The statistical analysis showed a strong correlation between the solar VL protection factor and the integral of the absorption curve in the VL range and the transmittance reduction (%) in the same range. The correlation between the VL protection factor and the pigmentation protection factor was also demonstrated.ConclusionThe VL protection factor and the pigmentation protection factor showed to be adequate metrics to estimate the effectiveness of sunscreens in the prevention of the pigmentary effect of solar VL and the pigmentary effect of the complete spectrum of immediate pigmentation.

Natural Tyrosinase Inhibitors: Role of Herbals in the Treatment of Hyperpigmentary Disorders.

Cutaneous pigmentation plays critical role in determining the color of skin along with photo protection of skin from dreadful effects of ultraviolet radiations. Conversely, abnormal accumulation of melanin is responsible for hyper pigmentary disorders such as melasma, senile lentigines and freckles. Because of the visible nature of dermatologic diseases, they have a considerable psychosomatic effect on affected patients. Tyrosinase inhibitors are molecules that interrelate in some way with the enzyme to prevent it from working in the normal manner. Past many decades witnessed the quest for the development of natural tyrosinase inhibitors due to imperative role played by tyrosinase in the process of melanogenesis and fungi or fruit enzymatic browning. Mechanism of pigmentation is characterized by the intact process of the synthesis of specialized black pigment within melanosomes. Melanin is synthesized by a cascade of enzymatic and chemical reactions. For this reason, melanin production is mainly controlled by the expression and activation of tyrosinase. In the current article, we discussed tyrosinase inhibitors from the natural sources, which can be an essential constituent of cosmetics products and depigmenting agents for the treatment of hyperpigmentory disorders.

Potential benefits of phytochemicals for treatment of hyperpigmentation

UV radiation (UV) is considered as a complete carcinogen as it is both a mutagen and a non-specific damaging agent. It is the most important risk factor for skin cancer and many other skin disorders like Hyperpigmentation. There is a need of long-term topical skin care treatments (both cosmetic and cosmeceutical) to address problems associated with hyperpigmentation. Synthetic depigmenting agents, such as hydroquinone, mequinol, although highly effective, can raise several safety concerns (for example, ochronosis, cataract, impaired wound healing, desquamation, and other local or systemic side effects) with long-term exposure. The benefits of phytochemicals and natural extracts offer opportunities to develop new formulations to treat pigmentation problems. Cosmeceuticals are topical cosmetic-pharmaceutical preparations containing active ingredients which improve the appearance of skin. Among cosmeceuticals, the phytochemicals have been known to have a multitude of cellular actions for various dermatological diseases. Plant-derived compounds and their effectiveness in the treatment of hyperpigmentation disorders (Melasma) are discussed.
 Keywords: UV radiation, Hyperpigmentation, Phytochemicals, Cosmeceuticals

Light-emitting diode 585 nm photomodulation inhibiting melanin synthesis and inducing autophagy in human melanocytes

BackgroundMelasma is a common hyperpigmentation skin disease on face. Light-emitting diode (LED) photomodulation (585nm) is reported to be effective for the treatment of melasma. However, whether and how LED photomodulation would influence melanogenesis of human epidermal melanocytes (HEMs) is unknown. ObjectiveTo evaluate the effects of LED photomodulation (585nm) on melanogenesis in HEMs. MethodsHEMs were irradiated with fluences of 0, 5, 10 and 20J/cm2 585nm LED light. After 5-day treatment, cell viability was analyzed by CCK-8 assay, and apoptosis was assessed by Annexin V APC assay. Melanin content and tyrosinase activity were measured by spectrophotometer. Melanosome stage and autophagosomes were determined under transmission electron microscope (TEM). The formation of autophagic punctate structures was observed under confocal microscope. RT-PCR and western blotting were used to assess the expression of relative mRNA and protein levels. ResultsYellow light LED 585nm had no effects on HEMs cell viability and apoptosis. Treatment with LED 585nm from 5J/cm2 to 20J/cm2 inhibited melanosome maturation, decreased melanin content and tyrosinase activity. Inhibition was accompanied by the decreased expression of tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1) and microphthalmia-associated transcription factor (MITF) on both mRNA and protein levels. Autophagosomes were observed under TEM. Autophagic punctate structures of microtubule-associated protein light chain 3 (LC3) proteins were induced by LED 585nm light. The configuration change of LC3 from LC3-I to LC3-II, and the degradation of p62 protein were observed after LED 585nm. Furthermore, we also revealed that the anti-melanogenic effect of LED 585nm photomodulation was reversed by 3-Methyladenine (3-MA), which inhibits autophagy by blocking autophagosome formation via the inhibition of type III Phosphatidylinositol 3-kinases (PI-3K). ConclusionsOur finding demonstrated that LED photomodulation with 585nm wavelength suppressed melanin content in HEMs, and the effect was caused by its dose-dependent inhibition on melanogenesis and the induction of HEMs autophagy. This may provide new insights into the efficacy of LED photomodulation in the treatment of hyperpigmentation disorders.

Melanin reduction by peroxidase activity in lysosome-related organelle extracts from hen egg whites, HeLa cells, and Saccharomyces cerevisiae

Although melanin plays a biological role in the protection of underlying tissues from harmful ultraviolet radiations, yet large amounts of melanin in light-skinned individuals can make them susceptible to skin cancer. In this study, lysosome-related organelles extracts (LOE) from hen egg whites, HeLa cells, and Saccharomyces cerevisiae have been used to lower melanin color intensity. The results show 80% reduction in melanin upon daily treatment with 100 μg LOE for a period of 19 days. Additionally, the treatment with S. cerevisiae LOE showed the best melanin color reduction, which is consistent with the level of peroxidase activity. The treatment of LOE from S. cerevisiae with NH4Cl decreases melanin reduction activity and peroxidase activity compare to LOE from normal S. cerevisiae. Meanwhile, in contrast, the treatment with H2O2 showed a completely contrary pattern. The above results thus indicate that LOEs can be promising agents for use in cosmeceutical skin lightening as well as for the treatment of hyper pigmentation disorders.

Topical Agents for Melasma: A Perspective on Therapeutic Approaches and their Molecular Bases

Melasma is a common skin disease involving changes in normal skin pigmentation. It results from epidermal melanocyte hyperactivity that causes increased production and accumulation of melanin. The onset of the disease has been associated with sun exposure, drugs, genetic and hormonal factors. The primary focus of this review was to provide an updated overview of the main biological aspects behind skin pigmentation and melasma development. As a second aim of this review, the main mechanisms by which different compounds could reduce melanogenesis were also discussed. Common hypo-pigmenting agents act by reducing the melanogenesis through several mechanisms; they can affect melanin transcription and glycosylation, inhibit tyrosinase (a pivotal enzyme in melanin synthesis), slow the melanosome transfer or increase the skin turnover. Although a number of skin-lightening agents were proposed for treatment of hyperpigmentary disorders, none of these has achieved satisfactory effects. In this light, the most recent therapeutic strategies for melasma, and emerging molecular targets to control skin pigmentation, such as MITF, Wnt and mTOR, were herein described.

Topical treatment of hyperpigmentation disorders

Hyperpigmentation has traditionally been a relatively difficult condition to treat, especially in darker racial ethnic groups. Multiple topical agents available act upon different steps of the pigmentation pathway. We review these topical agents, their mechanisms of action, and their effectiveness as monotherapy and in combination with other compounds. Ultimately, combination therapy is the most efficacious when considering overall depigmentation as well as treatment time required to achieve clinical improvement.

Addendum: Quasi-Drugs Developed in Japan for the Prevention or Treatment of Hyperpigmentary Disorders. Int. J. Mol. Sci. 2010, 11, 2566–2575

One additional skin lightening or whitening quasi-drug (QD) has been developed and officially approved by the Ministry of Health, Labor and Welfare of Japan.

Quasi-Drugs Developed in Japan for the Prevention or Treatment of Hyperpigmentary Disorders

Excess production of melanin or its abnormal distribution, or both, can cause irregular hyperpigmentation of the skin, leading to melasma and age spots. To date, various quasi-drugs that prevent or improve hyperpigmentary disorders have been developed and officially approved by the Ministry of Health, Labor and Welfare of Japan. Many of these inhibit the activity of tyrosinase, an enzyme required for melanin synthesis, for example, by competitive or non-competitive inhibition of its catalytic activity, by inhibiting its maturation, or by accelerating its degradation. In this review, we categorize the quasi-drugs developed in Japan to prevent or treat hyperpigmentary disorders, or both, and discuss perspectives for future development.

Skin‐lightening practice among women living in Jordan: prevalence, determinants, and user’s awareness

The use and misuse of skin-lightening products among women living in Arab communities have not been documented previously. This study investigates the determinants, the prevalence and users awareness associated with the use and misuse of skin-lightening products among women living in Jordan. Female customers arriving at selected pharmacy stores were randomly asked to complete a questionnaire. A total of 318 women completed the questionnaire, of which 60.7% reported the use of skin-lightening products. Users included women from different age and economic groups. Main reasons for use were preference of lighter skin tone, the treatment of hyperpigmentary disorders or both. More than a third of the users were not aware of the potential side effects of these products. A significantly larger proportion of skin-lightening product users believed that lighter skin tone plays a role in self-esteem, perception of beauty and youth, marriage and employment opportunities when compared with nonusers. Skin lightening is a common practice among women living in Jordan. It is reinforced by the association of lighter skin tone with a number of perceived benefits including perception of beauty, job and marriage opportunity. User's awareness regarding the safety of skin-lightening products and instructions for proper use are important considerations when developing interventions to control the misuse of these products.

Identification of Quinolines that Inhibit Melanogenesis by Altering Tyrosinase Family Trafficking

A series of quinolines, including chloroquine and quinine, were identified as potent pigmentation inhibitors through screening a compound library in murine melanocytes. Structure-activity relationship analysis indicated that 4-substituted amino groups with a tertiary amine side chain, such as chloroquine, were associated with robust inhibitory activity. In contrast to many previously identified pigmentation inhibitors, these newly identified inhibitors had no effect on either the level or the enzymatic activity of tyrosinase, the rate-limiting enzyme in melanin production. Rather, our results showed that these quinolines inhibited melanogenesis by disrupting the intracellular trafficking of tyrosinase-related proteins and lysosome-associated membrane protein 1 (Lamp-1). In treated melanocytes, tyrosinase and tyrosinase-related protein 1 accumulated in Lamp-1-positive perinuclear organelles instead of melanosomes, thus preventing melanogenesis. The depigmenting abilities of chloroquine and quinine salicylate were assessed in a human skin equivalent model (MelanoDerm). Both compounds were considerably more effective than arbutin, a widely used lightening agent. Our results indicate that quinolines may be useful agents for "cosmeceutical" skin lightening and treatment of hyperpigmentation disorders.

Mechanisms for the Transport of α,ω-Dicarboxylates through the Mitochondrial Inner Membrane

alpha,omega-Dicarboxylates have antibacterial properties, have been used in the treatment of hyperpigmentary disorders, are active against various melanoma cell lines, and can also undergo beta-oxidation. Little, however, is known about their transport. In this paper, we examine the mitochondrial transport of alpha, omega-dicarboxylates ranging from oxalate (DC2) to sebacate (DC10). DC2-DC10 are transported by the inner membrane anion channel (IMAC). DC6-DC10 are also transported by an electroneutral mechanism that appears to reflect transport of the acid through the lipid bilayer. At 37 degrees C and pH 7.0, DC10 is transported very rapidly at 3 micromol/min.mg, and respiring mitochondria swell in the K+ salts of these acids. This transport mechanism is probably the major pathway by which the longer dicarboxylates enter cells, bacteria, and mitochondria. We also demonstrate that DC5-DC10 can also be transported by an electroneutral mechanism mediated by tributyltin, a potent inhibitor of IMAC. The mechanism appears to involve electroneutral exchange of a TBT-dicarboxylate-H complex for TBT-OH. Finally, we present evidence that of all the dicarboxylates tested only DC2-DC4 can be transported by the classical dicarboxylate carrier.