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Skin Lightening Preparations

Skin Lightening Preparations

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Published by: Marina Bessel on Dec 07, 2012
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 Dermatologic Therapy, Vol. 20, 2007, 308–313 Printed in the United States·All rights reserved Copyright © Blackwell Publishing, Inc., 2007 
 ISSN 1396-0296 
 Skin lightening preparations andthe hydroquinone controversy 
 Department of Dermatology, Wake Forest University School of Medicine,Winston-Salem, North Carolina and Dermatology Consulting Services, High Point, North Ccarolina 
 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 aspigmentary 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 thesafety of this substance. This has encouraged research into alternative agents to inhibit skin pigmen-tation such as retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbicacid, soy proteins, and N-acetyl glucosamine. The efficacy and safety of each of these ingredients isexamined as possible topical alternatives to hydroquinone.
 hydroquinone safety, pigment lightening, topical skin-lightening cosmeceuticals
 Even skin color is considered a universal sign of  youth and beauty. Pigmentation problems typically do not arise without injury and/or advancing age, creating a tremendous market for productsdesigned to lighten skin. These products exist inthe prescription, over-the-counter (OTC) drug,cosmeceutical, and cosmetic realm. Yet, the perfectskin-lightening ingredient has yet to be developed.There is a fine line between substances that aretoxic to the melanocyte and agents that interruptone of the key steps in melanogenesis. Many chem-icals induce decreased pigment production in aPetri dish, but few can translate this in vitro obser-vation into clinical efficacy. The stratum corneumand superficial epidermis present formidablebarriers protecting the fragile melanocytes fromtoxic substances. After all, injury to the melanocytesresults in the pigmentary abnormalities requiring dermatologic intervention.Pigmentary abnormalities can take severalforms, depending on skin type. The most commonabnormal pigmentation results from mild tomoderately photodamaged skin characterized by dyspigmentation, in addition to fine wrinkles andtactile roughness (1,2). Individuals with Fitzpatrick skin types I–III demonstrate this photoinducedchange. The irregular pigmentation is labeledfreckling in young persons and lentigenes in moremature individuals. Although this type of clonalproliferation of melanin is seen in fair-complectedindividuals, it may also be seen in Fitzpatrick skintypes IV and darker. In addition to photodamage,there are some types of familial dyspigmentationthat can be observed in all skin types. These conditionsinclude melasma, hormonal effects of estrogen onpigment production, and periorbital darkening, which is particularly common in persons whosegene pool can be traced to India. Acquired forms of pigment darkening are termed postinflammatory hyperpigmentation and may be the result of acne,trauma, thermal burns, etc. This is the most common
  Address correspondence and reprint requests to: Zoe DianaDraelos, MD, 2444 North Main Street, High Point, NorthCarolina 27262, or email: zdraelos@northstate.net.
 Hydroquinone and skin lightening preparations 
 form of abnormal pigmentation in all skin types.This diversity of causes accounts for the tremen-dous popularity of skin-lightening agents.The most effective pigment-lightening agentcurrently known is hydroquinone; however, thisingredient has become somewhat controversial.It has been banned in Europe and the Orient, anda ban is under consideration in the United States.This has encouraged research into alternativeagents to inhibit skin pigmentation such as retin-oids, mequinol, azelaic acid, arbutin, kojic acid,aleosin, licorice extract, ascorbic acid, soy proteins,and N-acetyl glucosamine. This article examinesthe efficacy and safety of each of these ingredientsas possible topical alternatives to hydroquinone
 The gold standard for hyperpigmentation therapy in the United States remains hydroquinone. Thissubstance predated formation of the Food andDrug Administration (FDA), and many formula-tions currently on the market have never beenstudied for safety and efficacy. These formulationsinclude those that contain 2% hydroquinone, themaximum concentration allowed in OTC drugs,and some of the generic 4% hydroquinone formu-lations, only available by prescription. Otherproprietary hydroquinone-containing drugs thathave undergone FDA scrutiny through the investi-gational new drug pathway have well-establishedsafety and efficacy validated through carefully controlled large-scale vehicle-controlled clinicaltrials. Many new hydroquinone formulations haveappeared in the last 2 years in physician-dispensedlines, but these products have not undergoneclinical study. It is this plethora of hydroquinone-containing creams for sale in many differentmarkets that has caused health concerns.There are several important health issuesthat need to be considered before determining the safety of hydroquinone. For many years, it hasbeen known that hydroquinone can cause ochro-nosis (3). Whether this is a result of the effect of hydroquinone alone or other substances presentin the formulation or higher concentrations of hydroquinone is unknown. Additional concernarose when oral hydroquinone was reported tocause cancer in rodents fed with large amounts of the substance, yet human carcinogenicity has notbeen established (4). Although oral consumptionprobably is not related to topical application,hydroquinone remains controversial because it may be toxic to melanocytes.Hydroquinone, a phenolic compound chemically known as 1,4 dihydroxybenzene, functions by inhibiting the enzymatic oxidation of tyrosine andphenol oxidases. It covalently binds to histidine orinteracts with copper at the active site of tyrosi-nase. It also inhibits RNA and DNA synthesis andmay alter melanosome formation, thus selectively damaging melanocytes. These activities suppressthe melanocyte metabolic processes inducing gradual decrease of melanin pigment production(5). Issues regarding the topical toxicity of hydro-quinone arise because it is a strong oxidant rapidly converted to the melanocyte toxic products, p-benzoquinone and hydroxybenzoquinone. Thesebyproducts may cause depigmentation.Hydroquinone is very difficult to formulate in astable preparation. It is a highly reactive oxidantthat rapidly combines with oxygen. Typically,hydroquinone skin-lightening creams are a creamy color that changes to a darker yellow or brown asoxidation occurs. As the discoloration progresses,the activity of the hydroquinone decreases. Products with any off-color change should be immediately discarded.Prescription hydroquinone formulations havetried to increase the skin-lightening potency of formulations by adding penetration enhancerssuch as glycolic acid or tretinoin as a supplementalpigment-lightening agent. Other prescriptionformulations have added microsponges to createtime delivery of hydroquinone to the skin, whereasothers have placed the hydroquinone in a specialone-way airtight dispenser. Some formulationshave added sunscreen ingredients to the hydro-quinone to prevent UV-induced pigment darkening.The future of hydroquinone in the United Statesis still uncertain as of this writing. Apparently,some of the controversy arose when the FDA askedthe industry to perform some collaborative self-funded studies on the safety of hydroquinone andsubmit a written report detailing the findings.The report was not submitted as requested, andthe FDA acted by stating that it would withdraw all OTC 2% hydroquinone preparations and pre-scription formulations that were not studied asinvestigational new drugs once currently manu-factured supplies are depleted. Whether thisruling will be enforced and how it will be enforcedis unknown. More details regarding the future of hydroquinone in the United States should beforthcoming shortly.The potential withdrawal of hydroquinonefrom some of the US markets and its removalfrom European and Japanese markets hasspurred interest in developing pigment-lightening 
 alternatives. The remainder of this discussion willfocus on other pigment-lightening ingredientsand their relative efficacy and safety as comparedto hydroquinone.
 The primary prescription lightening alternative tohydroquinone is mequinol, approved for use in theUnited States and Europe. Mequinol is chemically known as 4-hydroxyanisole. Other names includemethoxyphenol, hydroquinone monomethyl ether,and p-hydroxyanisole. Mequinol is available in theUnited States in 2% concentration and is com-mercially marketed as a prescription skin lightenerin combination with 0.01% tretinoin, functioning as a penetration enhancer, and vitamin C, in theform of ascorbic acid and ascorbyl palmitate, toenhance skin lightening. These active agents aredissolved in an ethyl alcohol vehicle.The exact mechanism of action accounting for the skin-lightening properties of mequinol isunknown; however, it is a substrate for tyrosinasethereby acting as a competitive inhibitor in theformation of melanin precursors. It does not dam-age the melanocyte like hydroquinone, but is notgenerally felt to be as effective. Mequinol has beenobserved to cause long-standing depigmentationin some Caucasian patients, but repigmentationgenerally occurs with time. Tretinoin in combina-tion with mequinol may cause postinflammatory hyperpigmentation in some African Americanpatients; but again the skin darkening lightens with time when the product is discontinued.
 Retinoids have been used both directly and indi-rectly as pigment-lightening agents. The prescrip-tion retinoids used for direct improvement in skinpigmentation are tretinoin and tazarotene (6,7).These retinoids have an effect on skin pigmenta-tion as demonstrated by a decrease in cutaneousfreckling and lentigenes (8). It is the irregulargrouping and activation of melanocytes thataccounts for the dyspigmentation associated withphotoaging (9), which is normalized by retinoids(10). Although this effect is more dramatic withprescription topical tretinoin and tazarotene,topical OTC retinol has been thought to providesimilar effects as a cosmeceutical.Retinol, the dietary form of vitamin A, induceschanges in the skin similar to those produced by tretinoin, but without the irritation of retinoicacid (11). Retinol has been shown to convert toretinoic acid in a two-step oxidation process inthe skin. Although retinol has a lower potency than retinoic acid and requires 10-fold higherconcentrations to produce similar epidermal effects,it can be effective in improving the appearance of photodamage (12). The main challenge to retinolformulations has been the successful develop-ment of high concentration stabilized formulas.Retinol is not nearly as effective as tretinoin ortazarotene in pigment lightening.Retinoids are sometimes used to indirectly lighten dyspigmentation. In this case, the retinoidsare used as penetration enhancers. A side effect of retinoids is an irritant dermatitis characterizedby erythema, dryness, and scaling (8,13). Thesecutaneous changes damage the skin barrier, allow-ing increased access of other pigment-lightening agents, such as hydroquinone and mequinol, tothe melanocytes. Some preparations that combinetretinoin and hydroquinone must also incorporate apotent topical corticosteroid to prevent excessirritation resulting in decrease patient complianceand/or postinflammatory hyperpigmentation.
  Azelaic acid
 The irritation profiles of hydroquinone and retin-oids have led to the search for other pigment-lightening ingredients in the prescription realm.One such ingredient is azelaic acid. Azelaic acid isavailable currently as a 15% gel approved in theUnited States for the treatment of rosacea. It is a9-carbon dicarboxylic acid obtained from culturesof 
Pityrosporum ovale 
 . Although its lightening effects are mild, several large studies carried out with a diverse ethnic background population havecompared its efficacy to that of hydroquinone(14,15). It too interferes with tyrosinase activity, butmay also interfere with DNA synthesis. It appearsto have a specificity for abnormal melanocytes,and for this reason has been used to suppress theprogression of lentigo maligna to lentigo malignamelanoma. Azelaic acid has an excellent safety profile, butmay cause short-lived stinging when topically applied in some individuals. It can be safely com-bined with retinoids to yield an additive benefit,but it is not as effective as hydroquinone in treating dyschromias. Thus, hydroquinone, mequinol, andazelaic acid are the only three prescription activeingredients used for pigment lightening, which isremarkable, given the size of the dyschromia

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