Formulation optimization, skin irritation, and efficacy characterization of a novel skin-lightening agent

Background Skin‐lightening preparations are used by people all over the world for a diverse range of dermatologic indications. The gold standard treatment for skin lightening is with hydroquinone but has been controversial because of the presence of several side effects. Therefore, there has been a constant search for developing new treatment alternatives. Furthermore, the new amendments and bans on animal testing by ECVAM have made the three‐dimensional models like EpiDerm^? and MelanoDerm^? increasingly popular. Objective This work aims at the formulation development for a new skin‐lightening agent, SMA‐012, followed by testing for skin irritation and efficacy. Methods Formulation parameters such as concentration of SMA‐012, amount of ethanol, effect of permeation enhancers and pH were first optimized using Franz cell experiments. Tape stripping and underlying skin assays were performed to analyze the amounts of SMA‐012 in different layers of skin. The irritation potential and efficacy of the screened formulation were evaluated using Epiderm^? and Melanoderm^? models. Results Skin permeation experiments suggested that concentrations of 0.1% SMA‐012, 35% ethanol, and pH of 8.5 to be the best formulation characteristics. This particular formulation was found to be nonirritant for short‐term exposure, when tested in Epiderm^? model and also significantly effective in decreasing the amount of melanin in pigmented skin equivalent models. Conclusion SMA‐012 shows a good promise as a skin‐lightening agent for cosmetic and therapeutic applications. Additionally, our study demonstrates the application of skin equivalent models as alternatives to animal testing in studying the regulation of skin pigmentation.     

Skin lightening preparations and the hydroquinone controversy

ABSTRACT:  Skin lightening preparations are widely used in dermatology by persons of all Fitzpatrick skin types. Fitzpatrick skin types I–III require local pigment lightening for the treatment of hormonally induced melasma and postinflammatory hyperpigmentation caused by acne and trauma. Fitzpatrick skin types IV and darker have an even greater need for skin lightening for social reasons, as well as pigmentary changes that occur around the eyes, in the intertriginous areas, following dermatitis, or with acne and trauma. The gold standard dermatologic agent for skin lightening was hydroquinone, until regulatory agencies in Japan, Europe, and most recently in the United States questioned the safety of this substance. This has encouraged research into alternative agents to inhibit skin pigmentation such as retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbic acid, soy proteins, and N-acetyl glucosamine. The efficacy and safety of each of these ingredients is examined as possible topical alternatives to hydroquinone.     

The widespread use of skin lightening creams in Senegal: a persistent public health problem in West Africa

BACKGROUND: The use of skin lightening creams is common in the female population of some African countries. The long-term use of certain products for several months to years may cause cutaneous adverse effects. METHODS: From 1992 to 1993, we conducted an epidemiologic and clinical study in Dakar, Senegal. Women were questioned about the use of skin lightening creams and examined for potential adverse skin reactions. Six hundred and eighty-five Senegalese women participated in the study. RESULTS: Twenty-six per cent of women were using skin lightening creams at the time and 36% had used them at some time. The most common products used were hydroquinone and corticosteroids, but 25% of women had used products of unknown composition. Seventy-five per cent of women using such creams showed cutaneous adverse effects. Facial acne was the most common adverse effect. CONCLUSIONS: A major part of the female adult population of Senegal used skin lightening creams. The long-term use of these creams is responsible for a high rate of cutaneous adverse effects. This practice has also been reported in other countries from sub-Saharan Africa and suggests a widespread use in the African population.     

Clinical efficacy and safety of 4-hexyl-1,3-phenylenediol for improving skin hyperpigmentation

Hyperpigmentation disorders are of social and cosmetic concerns to many individuals due to their prevalent locations on highly visible parts of the body. Topical formulation containing hydroquinone is the most widely used remedy for the treatment of hyperpigmentation disorders. However, reports of side effects in long-term usage have raised concerns for its use in cosmetic products. Thus, it is highly desirable to develop a safe and effective alternative to treat hyperpigmentation disorders. The objective of the current study is to investigate the de-pigmenting efficacy of 4-hexyl-1,3-phenylenediol in various in vitro models and in a randomized controlled clinical study. We showed that 4-hexyl-1,3-phenylenediol significantly reduced melanogenesis in primary human melanocytes, murine melanoma cells, and pigmented human epidermal equivalents. It was determined that the reduction in melanogenesis is mediated through inhibition of tyrosinase enzyme activity and protein expression. Further investigation revealed that the inhibition of melanogenesis is reversible and is not associated with cellular toxicity in melanocytes. In addition, significant improvements in key clinical parameters such as overall skin lightening, appearance of spots on the cheeks, overall contrast between spots and surrounding skin, and overall pigmentation size were detected in a double-blinded, randomized controlled clinical study. In conclusion, our findings clearly demonstrated the potency of 4-hexyl-1,3-phenylenediol in modulating skin pigmentation, and it is safe and well tolerated after 12-week topical application.     

外用维A酸治疗皮肤病的进展

维A酸由于具有抗增殖、抗炎、调节免疫、促进胶原生成等作用,目前已广泛治疗皮肤病.近年来临床上对于外用维A酸的研究主要针对不同种类、不同浓度维A酸之间的比较以及与其他药物联用的疗效及不良反应,并在瘢痕疙瘩、寻常痤疮、光老化、色素沉着性疾病以及再生效果等方面取得了一些新进展,但其抗皮肤肿瘤的疗效尚不确切.不同于系统应用,目前尚无证据表明外用维A酸可致胎儿畸形,但仍不推荐用于孕妇.外用维A酸的不良反应主要表现为局部皮肤刺激症状,口唇干燥等系统性不良反应可见,新型给药系统的发展优化了外用维A酸的理化性质,将进一步减少其不良反应并提高疗效.     

Evaluation of cutaneous body image dissatisfaction in the dermatology patient

Cutaneous body image (CBI), defined as the individual's mental representation of his or her skin, hair, and nails, is an important clinical factor in dermatologic disorders and often the primary consideration in deciding whether to proceed with cosmetic procedures or institute treatment in some skin disorders such as acne. CBI is a highly subjective construct that can be significantly confounded by cultural, psychosocial, and psychiatric factors. Assessment of CBI in the dermatology patient is best accomplished using a biopsychosocial model that involves (1) evaluation of concerns about the appearance of the skin, hair, and nails, (2) assessment of comorbid body image pathologies, especially body dysmorphic disorder, and (3) assessment of other psychiatric comorbidities such as major depressive disorder that can confound the presentation of the CBI complaint. Depending on the psychiatric comobidities, an assessment of suicide risk may have to be done, and if necessary, a referral made to a mental health professional. The clinician should consider the patient's developmental stage (eg, body image concerns are likely to be much greater in the adolescent patient independent of his or her dermatologic disorder) and sociocultural background (eg, a desire for lighter skin in some ethnic groups), factors that can also have a major effect on CBI.     

Hydroquinone and its analogues in dermatology - a risk-benefit viewpoint

Hydroquinone (HQ) has been used since the 1950s in commercially available over-the-counter skin lightener products and since the 1960s as a commercially available medical product. It is also used in cosmetic products such as hair dyes and products for coating finger nails. Beginning in 2001, HQ is no longer authorized for use in cosmetic skin lightening formulations in European Union countries, although products containing arbutin, an analogue of HQ, and botanicals, including plants that naturally contain HQ and arbutin, continue to remain available in European countries. The potential toxicity of HQ is dependent on the route of exposure, and toxicity in rodents is highly sex-, species-, and strain-specific. Subchronic and chronic toxicity in experimental animals is primarily limited to nephrotoxicity in male F-344 rats. Dermal toxicity studies, even those conducted in the sensitive male F-344 rat, are essentially devoid of systemic toxicity. Developmental and reproductive toxicity studies with HQ in rats and rabbits have not demonstrated significant effects. Cancer bioassay data for HQ demonstrate limited effects and are not sufficient to classify HQ for human carcinogenicity. Epidemiology and occupational studies of workers with extensive exposure to HQ have not reported any evidence of adverse systemic health effects or carcinogenicity. A risk-benefit approach is recommended for assessing the available data for HQ, arbutin, and other materials in use as, or proposed for use as, skin lighteners to provide optimal therapeutic benefits to patients with pigmentary changes of the skin.     

Natural options for the management of hyperpigmentation

Facial hyperpigmented disorders are a common complaint in the adult population of all races. First‐line topical treatments are usually hydroquinone or topical retinoids, which can cause irritant reactions. The need for better tolerated, yet effective, skin lightening agents that could be utilized by a wider population has led to the investigation of several potential botanical/natural compounds. There are currently many topical cosmetic formulations claiming skin depigmenting effects. A few of the ingredients (e.g. soy) are supported not only by in vitro results but also by a body of controlled clinical efficacy studies; other ingredients, instead, are backed mostly by in vitro data and a few small uncontrolled clinical studies. In this review, we describe the most common natural ingredients used for skin depigmentation and their major published studies: soy, licorice extracts, kojic acid, arbutin, niacinamide, N‐acetylglucosamine, COFFEEBERRY^? and green tea.     

Phosphodiesterase inhibitors and prostaglandin analogues in dermatology: A comprehensive review

Due to immune‐mediated nature, medicines with immunomodulatory and anti‐inflammatory effects can used to treat many dermatologic diseases. Phosphodiesterase and prostaglandins are involved in many inflammatory pathways that cause cutaneous disorders. Phosphodiesterase inhibitors (PDEIs) and prostaglandin analogues are currently employed to treat several dermatologic disorders. Given the few comprehensive reviews in this context, focusing on the dermatologic applications and efficacy of these medicines appears valuable. The present comprehensive review was, therefore, performed on the applications of PDEIs and prostaglandin analogues in different cutaneous disorders. All the relevant articles were selected to perform this review by searching databases such as Medline, Google Scholar, Scopus, and Web of Science. Oral PDEIs, especially apremilast, is an effective medicine in psoriasis and a number of other cutaneous disorders such as vitiligo. Topical PDEIs, including crisaborole ointment 2%, is a safe and effective treatment in atopic dermatitis. Prostaglandin analogues, especially their topical forms such as latanoprost and bimatoprost, have different applications in cutaneous disorders, including pigmentary disorders, especially vitiligo and hair repigmentation; for instance, bimatoprost is used for eyelash repigmentation. Prostaglandin analogues are also used in alopecia, including androgenetic alopecia and alopecia areata. Oral (apremilast) and topical (crisaborole) PDEIs and topical prostaglandin analogues, including latanoprost and bimatoprost, were found safe and effective in different skin diseases. In terms of efficiency and safety, these medicines compete with other medications of similar use even with higher efficacy and fewer side effects that necessitate further studies.     

Systemic Glucocorticosteroid Therapy of Skin Disease in Children

The role of systemic glucocorticosteroid therapy in the management of dermatologic disorders in children is limited. Most skin diseases requiring the antiinflammatory or antiproliferative effects of steroids are best managed with topical preparations, because they exert local effects almost exclusively and cause few if any systemic side effects when used properly. There are, however, certain skin diseases, which because of their severity or their intrinsic nature, do not respond adequately to these agents. We propose the indications for pharmacologic doses of systemic glucocorticosteroids in dermatologic disease, the preferred route of administration, the most common as well as the more rare side effects of this therapy. Withdrawal of patients from chronic use of these drugs is also discussed.     

Origin, clinical presentation, and diagnosis of hypomelanotic skin disorders

Hypomelanotic skin disorders are cutaneous pigmentary disorders characterized by a reduced melanin content in the skin that results in a lightening of the skin. Establishing the correct diagnosis for hypomelanotic skin disorders requires a good history, a detailed physical examination, the use of special lighting techniques, such as Wood's light, and sometimes a biopsy of the abnormally pigmented skin and the normally pigmented skin. This article focuses on the origin, clinical presentation, and diagnosis of acquired hypomelanotic skin disorders. An algorithm for the diagnostic approach to these hypomelanoses is given.     

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

Background 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. Method Female customers arriving at selected pharmacy stores were randomly asked to complete a questionnaire. Results 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. Conclusion 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.     

Skin subtype categorization based on a new questionnaire for Korean women

Background: Several terms have been used to characterize skin types. However, these are not based on evident dermatologic definitions, which usually include subjective and psychological properties. Objective: The objective of this study is to establish a new practical questionnaire to classify skin subtypes in Korean women to establish treatment and skin care guidance. Methods: Eight experts developed consensus statements about skin types and created a questionnaire. The content was categorized into four major subtypes: dry or non-dry; oily or nonoily; sensitive or nonsensitive; and pigmented or nonpigmented. A total of 512 patients completed the questionnaire. Correlations with age, skin Fitzpatrick’s phototypes, and dermatologic comorbidities were analyzed. Results: Korean women commonly have oily skin but complain of dryness after cleansing. They are especially sensitive to skin care products and prone to developing pigmentary lesions. There was a trend in the proportion of dry skin subtype that increased as pigmented skin increased and oily skin decreased with advanced age. The proportion of sensitive skin was higher in patients with dermatologic comorbidities. The proportion of the pigmented skin was higher in darker Fitzpatrick skin phototypes. Conclusion: This is the first questionnaire established for Korean women to classify practical skin subtypes and may provide a basis for treating various skin conditions.     

Traditional and ethnobotanical dermatology practices in Africa

More than 80% of the global population depends on traditional medicine for their basic primary health care needs. Africa has a well-established history of botanicals use. These include a vast array of compounds that can be used to treat various skin-related conditions. The rationale for the use of traditional medicine in skincare stems from the physical effects these compounds have on skin, such as the ability to control bleeding and speed up wound healing, as well as the potential to treat burns and other disorders of pigmentation. Most African traditional healers employ decoctions and infusion methods in medicinal plant preparations; the former entails boiling of the whole or parts of the plant in water or other solvents to extract the active ingredients. Infusions involve immersion of the plant in hot or cold water for some time, followed by topically application to the affected skin area.The cosmetic skincare products are formulated to protect, enhance, and preserve the skin in its healthiest state to maintain its barrier function, thus protecting the human body. This review examines a number of botanicals that are used across Africa and the phytochemical actives that are responsible for skincare.     

Nebenwirkungen in der Therapie mit hochenergetischen Blitzlampen und Lasern

Dermatologic flashlamp and laser therapy involves photochemical, thermal, photoablative, photoacoustic and phtoodisruptive effects, depending on the wave length, energy density and pulse duration. All of these effects when properly employed can lead to optimal dermatologic and cosmetic results. They also carry a high risk for side effects and damage when not properly used. The risk of side effects depends greatly on the training and experience of the treating physician. Both a solid dermatologic training in order to correctly diagnosis skin changes and knowledge of laser principles are required.     

Body-focused repetitive behaviors and the dermatology patient

Body-focused repetitive behaviors (BFRBs) are psychiatric disorders that involve recurrent pulling and picking one’s own body resulting in skin lesions with varying degrees of severity. For that reason, the interface with dermatology is important. Currently, the classified BFRBs are trichotillomania and excoriation disorder. Both trichotillomania and excoriation disorder appear to be more common than previously thought. Besides that, most patients are unlikely to seek mental health treatment for their condition. Thus, many patients will instead seek dermatologic help due to the cosmetic damage incurred.In trichotillomania, the main characteristic is the pulling out of one’s hair, most commonly from the scalp. It is associated with many negative consequences. Patients may present with different patterns of alopecia. Often, more than one body part will be affected.In excoriation disorder, the pathologic behavior frequently starts with picking at an underlying dermatologic condition such as acne but can continue after dermatologic treatment. The body area most frequently picked is the face, but other sites may also be involved. The dermatologic findings and distribution are atypical and will help the clinician differentiate from other dermatologic conditions.A complete therapeutic plan for BFRBs should include a dermatologic assessment of the affected areas, psychotherapy, and possibly pharmacotherapy.     

Hydroquinone and its analogues in dermatology - a potential health risk

Hydroquinone has been used for decades as a skin lightening agent. Since January 1, 2001, its use in cosmetics has been banned. This ban is as a result of mid-term effects such as leukoderma-en-confetti/occupational vitiligo and exogenous ochronosis. However, a recent literature search on hydroquinone as a skin lightening agent suggests that possible long-term effects such as carcinogenesis may be expected as well. Metabolites of hydroquinone formed in the liver, e.g., p-benzoquinone and glutathione conjugates of hydroquinone, are mainly responsible for this. In the bone marrow, hydroquinone is oxidized into p-benzoquinone because of the high myeloperoxidase activity. Topically applied hydroquinone-containing creams may give rise to accumulation of these compounds, which can cause DNA damage and mutations. They also have the capability to disrupt protective mechanisms, whereby they facilitate further development of cancer. In the bone marrow, long-term effects such as aplastic anemia and acute myeloid leukemias may occur. Most of the evidence stems from research on benzene toxicity, which appears to arise via its metabolite hydroquinone. There is no report yet demonstrating carcinogenesis resulting from the application of hydroquinone-containing creams. However doctors should be aware of these potential health risks which were up until now disregarded.     

Psychiatric and Psychological Co-Morbidity in Patients with Dermatologic Disorders

Psychiatric and psychological factors play an important role in at least 30% of dermatologic disorders. In many cases the impact of the skin disorder upon the quality of life is a stronger predictor of psychiatric morbidity than the clinical severity of the disorder as per physician ratings. Furthermore, in certain disorders such as acne and psoriasis, the psychiatric co-morbidity, which can be associated with psychiatric emergencies such as suicide, is an important measure of the overall disability experienced by the patient. The severity of depression and increased suicide risk are not always directly correlated with the clinical severity of the dermatologic disorder. Consideration of psychiatric and psychosocial factors is important both for the management, and for some aspects of secondary and tertiary prevention of a wide range of dermatologic disorders. It is useful to use a biopsychosocial model which takes into account the psychological (e.g. psychiatric comorbidity such as major depression and the impact of the skin disorder on the psychological aspects of quality of life) and social (e.g. impact upon social and occupational functioning) factors, in addition to the primary dermatologic factors, in the management of the patient. Some dermatology patients are likely to benefit from psychotherapeutic interventions and psychotropic agents for the management of the psychosocial comorbidity, in addition to the standard dermatologic therapies for their skin disorder.