Hyperpigmentation management

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#1

Topical Agents Used in the Management of Hyperpigmentation
Posted 07/19/2004
R. M. Halder, MD; G. M. Richards, MD

Abstract and Introduction

Abstract

Disorders of hyperpigmentation are difficult to treat, particularly in dark-skinned individuals. The goal is to reduce the hyperpigmentation without causing undesirable hypopigmentation or irritation in the surrounding normally pigmented skin. The psychosocial impact caused by these disorders must be considered. Although there are many effective therapeutic modalities available, there are potentially significant side-effects associated with treatment. The most commonly used treatment is topical hydroquinone. There are other phenolic agents, such as N-acetyl-4-cystaminylphenol (NCAP), that are currently being studied and developed. The non-phenolic agents, which include tretinoin, adapalene, topical corticosteroids, azelaic acid, arbutin, kojic acid, and licorice extract, are also used for hyperpigmentation disorders.

Introduction

Hyperpigmentation is a common and distressing problem caused by various inflammatory skin disorders, such as eczema, allergic contact dermatitis, and irritant contact dermatitis Acne is also a frequent cause. Papulosquamous disorders in general commonly predispose a patient to postinflammatory hyperpigmentation. Melasma is a common form of non-inflammatory hyperpigmentation.

Sun exposure often reverses the results of therapy, compromising the lengthy treatment process. Consequently, the first line of therapy for hyperpigmentation is a broad-spectrum sunscreen used in conjunction with a phenolic agent such as a hydroquinone, or with a non-phenolic agent such as tretinoin, azelaic acid, or kojic acid. There are hundreds of sunscreen formulations with different UV absorbing chemicals in various concentrations. [1] The UVB and UVA absorbing chemicals used in the formulation of topical sunscreens include para-aminobenzoic acid-related products, salicylates, cinnamates, benzophenones, zinc oxide, and titanium oxide. Almost all sunscreen products contain a mixture of one or more UVB absorbing chemicals. [1]

Hydroquinone and related compounds reduce the production of melanin by their inhibition of the enzyme tyrosinase. Topical corticosteroids also inhibit tyrosinase activity and affect endoplasmic reticulum secretory function of melanocytes. Agents such as salicylic acid and glycolic acid act to remove melanin in the epidermis by their peeling action. Tretinoin, which has a mild peeling effect, acts in a similar manner. It may also inhibit tyrosinase.

Hydroquinone

Hydroquinone, which is a hydroxyphenolic chemical, has been the gold standard for treatment of hyperpigmentation for over 50 years. It acts by inhibiting the enzyme tyrosinase, thereby reducing the conversion of DOPA to melanin. Some of the other possible mechanisms of action are the destruction of melanocytes, degradation of melanosomes, and the inhibition of the synthesis of DNA and RNA. [2]

Hydroquinone can be compounded into 5%-10% concentrations, but at these strengths, may be irritating and unstable. The 2% concentrations of hydroquinone available over the counter in the US and Canada are not as efficacious as the 3% and 4% prescription formulations, as their onset of action is later than with the higher concentrations. Antioxidants, such as vitamin C and retinoids, as well as alpha-hydroxy acids may be used as additives to increase penetration and enhance efficacy. Exogenous ochronosis with the use of hydroquinone has been reported in dark-skinned patients, in particular South African women who frequently use very high concentrations of hydroquinone over large surface areas. [3] Although hydroquinone is used extensively in North America, there have only been about 30 reported cases of exogenous ochronosis from hydroquinone use in North America.

Adverse reactions from hydroquinone use include irritant and allergic contact dermatitis, and nail discoloration. Postinflammatory hyperpigmentation may occur from the contact dermatitis. Hypopigmentation of the normal skin surrounding the treated areas may also occur. These usually resolve with the discontinuation of the hydroquinone treatment. [2]

Other Phenolic Agents

Monobenzone, the monobenzyl ether of hydroquinone, is a special topical phenolic agent, which is indicated only for the final depigmentation of disfiguring vitiligo. It is applied topically to permanently depigment normal skin surrounding vitiliginous areas in patients with disseminated vitiligo (greater than 50% body surface area). The cream is applied in a thin layer, rubbed into the normally pigmented areas two or three times daily. Depigmentation is usually achieved after 6-12 months with 20% monobenzone treatment. It should then be applied only as often as required to maintain depigmentation. Monobenzone cream can produce satellite depigmentation at sites distant from the site of initial application.

N-acetyl-4-cysteaminylphenol (NCAP) is another phenolic agent that is currently being developed and is not yet available in North America. NCAP acts to decrease intracellular glutathione by stimulating pheomelanin rather than eumelanin. [4] It also inhibits tyrosinase activity, has been found to be more stable, and causes less irritation than hydroquinone. In a retrospective study of 12 patients with melasma using 4% NCAP, 66% showed marked improvement, and 8% showed complete loss of melasma lesions. Changes of melanoderma were evident after 2-4 weeks of daily topical application of NCAP. [5]

Azelaic Acid

Azelaic acid is a naturally occurring non-phenolic, saturated, nine-carbon dicarboxylic acid. Its use originated from the finding that Pityrosporum species can oxidize unsaturated fatty acids to dicarboxylic acids, which competitively inhibit tyrosinase. Azelaic acid was initially developed as a topical drug with therapeutic effects for the treatment of acne. However, because of its effect on tyrosinase, it has also been used to treat melasma, lentigo maligna and other disorders of hyperpigmention. [2,6] Azelaic acid has been reported to be effective for hypermelanosis caused by physical or photochemical agents, and lentigo maligna melanoma as well as other disorders characterized by abnormal proliferation of melanocytes. Its mechanism of action is to inhibit DNA synthesis and mitochondrial enzymes, thereby inducing direct cytotoxic effects toward the melanocyte. [6] Topical azelaic acid has no depigmentation effect on normally pigmented skin, freckles, senile lentigines, and nevi. This specificity may be attributed to its selective effects on abnormal melanocytes.

Azelaic acid can be used for postinflammatory hyperpigmentation in acne. [7] Free radicals are believed to contribute to hyperpigmentation, and azelaic acid acts by reducing free radical production. [8] Azelaic acid 20% is currently available in the US and is only indicated for the treatment of acne, although it has off-label use for hyperpigmentation. In the treatment of melasma, a 24-week study in South America found that a 20% concentration of azelaic acid was equivalent to 2% hydroquinone. [9] In the Philippines, a study found that 20% azelaic acid was better than 2% hydroquinone. [10]

Kojic Acid

Kojic acid (5-hydroxy-2-(hydroxy methyl)-4-pyrone), a naturally occurring hydrophilic fungal derivative evolved from certain species of Acetobacter ,Aspergillus and Penicillium , is used in the treatment of hyperpigmentation disorders. [11] It acts by inhibiting the production of free tyrosinase with efficacy similar to hydroquinone. In Japan, kojic acid has been increasingly used in skin care products. This is because, until recently, topically applied kojic acid at 1% concentration had not exhibited any sensitizing activity. [12] However, more recent long-term Japanese studies have shown that kojic acid has the potential for causing contact dermatitis and erythema. [12]

Arbutin and Licorice Extract

Arbutin

Arbutin, which is the b-D-glucopyranoside derivative of hydroquinone, is a naturally occurring plant derived compound that has been used for postinflammatory hyperpigmentation. [13] It is effective in the treatment of disorders of hyperpigmentation characterized by hyperactive melanocytes. [13] The action of arbutin is dependent on its concentration. Higher concentrations are more efficacious than lower concentrations, but they may also result in a paradoxical hyperpigmentation. [13] In comparative in vitro studies of various compounds used to improve the appearance of disorders of hyperpigmentation, arbutin was found to be less toxic than hydroquinone. A dose-dependent reduction in tyrosinase activity, as well as melanin content in melanocytes, was also demonstrated. [14]

Licorice Extract

Licorice extract is not yet available in North America, but has been used in other parts of the world, particularly in Egypt. Its mechanism of action is similar to that of kojic acid. The main component of the hydrophobic fraction of licorice extract is glabridin, which has an effect on the skin. Studies investigating the inhibitory effects of glabridin on melanogenesis and inflammation have shown that it inhibits tyrosinase activity of melanocytes. No effect on DNA synthesis was detectable. [15]

Topical Retinoids

The efficacy of topical tretinoin 0.05-0.1% as monotherapy for postinflammatory hyperpigmentation has been reported. [16] Tretinoin was also used as monotherapy in a study on 38 African-American patients with melasma and 68%-73% of patients improved. In 88% of the patients, moderate side-effects of desquamation and erythema were observed. [17,18] Darker skinned patients who develop a dermatitis from tretinoin may develop postinflammatory hyperpigmentation secondary to the dermatitis.

The mechanism of action of tretinoin in the treatment of melasma is poorly understood. Clinical improvement has been found to be associated with a reduction in epidermal melanin, possibly as a result of the inhibition of tyrosinase by the action of tretinoin. [19]

Although tretinoin can be effective as monotherapy for hyperpigmentation and melasma, it requires 20 to 40-week treatment periods. Tretinoin can also be used in conjunction with hydroquinone or other depigmenting agents to improve efficacy. The first published study of combination therapy used tretinoin 0.1%, hydroquinone 5%, and dexamethasone 0.1% for postinflammatory hyperpigmentation. [20] Tretinoin was shown to reduce the atrophy of the corticosteroid and facilitated the epidermal penetration of the hydroquinone. The tretinoin-induced irritation was reduced by the corticosteroid. The first triple combination topical therapy approved by the US FDA for melasma is a modified formulation comprising fluocinolone acetonide, hydroquinone 4% and tretinoin 0.05%. In studies of patients with melasma, 78% had complete or near clearing after 8 weeks of therapy. Similar results and favorable safety profile were seen in a 12-month study. [21]

In a randomized clinical trial, the efficacy of adapalene 0.1% was found to be comparable to that of tretrinoin 0.05% cream in the treatment of melasma (mainly epidermal type). The results showed fewer side-effects and greater acceptability among patients using adapalene. [19]

Conclusion

The treatment of hyperpigmentation disorders can be a long process. The psychosocial impact of these disorders should be taken into consideration. There are several topical treatment options available, the most common of which is hydroquinone. The use of combination therapy and monotherapy with non-phenolic agents is increasingly common. These treatment options are primarily for epidermal disorders of hyperpigmentation. Dermal disorders of hyperpigmentation are difficult to treat, and have not been effectively managed using currently available therapy.

Topical Agents Used in the Management of Hyperpigmentation

[Skin Therapy Lett 9(6):1-3, 2004. © 2004 SkinCareGuide.com]

  1. Pathak MA, Fitzpatrick TB, Nghiem P, Aghassi DS. Sun-protective agents: formulations, effects, and side effects. In: Fitzpatrick TB, Editor. Dermatology in General Medicine, 4th ed, New York: McGraw-Hill, pp 2742-60 (1993).
  2. Grimes PE. Melasma Etiologic and Therapeutic Considerations. Arch Dermatol 131(12):1453-7 (1995 Dec).
  3. Levin CY, Maibach H. Exogenous ochronosis. An update on clinical features, causative agents and treatment options. Am J Clin Dermatol 2(4):213-7 (2001).
  4. Alena F, Dixon W, Thomas P, Jimbow K. Glutathione plays a key role in the depigmenting and melanocytotoxic action of N-acetyl-4-S-cysteaminylphenol in black and yellow hair follicles. J Invest Dermatol 104(5):792-7 (1995 May).
  5. Jimbow K. N-Acetyl-4-S-Cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma. Arch Dermatol 127(10):1528-34 (1991 Oct).
  6. Nguyen QH, Bui TP. Azelaic acid: pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentary disorders and acne. Int J Dermatol 34(2)75-84 (1995 Feb).
  7. Breathnach AS. Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid, and other therapies. Cutis 57(1 Suppl.):36-45 (1996 Jan).
  8. Lowe NJ, Rizk D, Grimes P, Billips M, Pincus S. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther 20(5):945-59 (1998 Sep-Oct).
  9. Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 30(12):893-5 (1991 Dec).
  10. Verallo-Rowell VM, Verallo V, Graupe K, Lopez-Villafuerte L, Garcia-Lopez M. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol Suppl (Stockh) 143:58-61 (1989).
  11. Serra-Baldrich E, Tribo MJ, Camarasa JG. Allergic contact dermatitis from kojic acid. Contact Dermatitis 39(2):86-7 (1998 Aug).
  12. Nakagawa M, Kawai K, Kawai K. Contact allergy to kojic acid in skin care products. Contact Dermatitis 32(1):9-13 (1995 Jan).
  13. Maeda K, Fukuda M. Arbutin: mechanism of its depigmenting action in human melanocyte culture. J Pharmacol Exp Ther 276(2):765-9 (1996 Feb).
  14. Lei TC, Virador VM, Vieira WD, Hearing VJ. A melanocyte-keratinocyte coculture model to assess regulators of pigmentation in vitro. Anal Biochem 305(2):260-8 (2002 Jun).
  15. Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res 11(6):355-61 (1998 Dec).
  16. Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med 328(20):1438-43 (1993 May).
  17. Kimbrough-Green CK, Griffiths CE, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial. Arch Dermatol 130(6):727-33 (1994 Jun).
  18. Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol 129(4):415-21 (1993 Oct).
  19. Dogra S, Kanwar AJ, Parsad D. Adapalene in the treatment of melasma: a preliminary report. J Dermatol 29(8):539-40 (2002 Aug).
  20. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol 111(1):40-48 (1975 Jan).
  21. Galderma laboratories. Data on file.
#2

This article is from Skin and Allergy News, January 2007:

"Derms React to Possible FDA Ban Of Hydroquinone: Cite poor scientific reasoning, ethnic bias.
BETSY BATES (Los Angeles Bureau)

Article Outline
• Ban May Send Desperate Patients in Search of Dubious Alternative Therapies

• Copyright

LAS VEGAS — The Food and Drug Administration soon could remove from the market hundreds of products containing hydroquinone, and dermatologists across the United States are decrying the anticipated move, which they say would most harm minorities and the poor.

At the annual meeting of the American Society of Cosmetic Dermatology and Aesthetic Surgery, incoming society president Dr. Joel Schlessinger questioned the relevance of evidence used by the FDA to justify withdrawing approval of over-the-counter skin bleaching drug products traditionally classified as generally recognized as safe and effective (GRASE).

On Aug. 28, the FDA published a proposed rule that would eliminate GRASE status for most prescription, over-the-counter, and physician-dispensed hydroquinones and allowed interested parties to submit comments on the proposed rule until Dec. 27.

According to Crystal Rice, spokesperson for FDA’s Center for Drug Evaluation and Research, “if the rule is finalized as proposed, [companies manufacturing prescription or physician-dispensed products containing hydroquinone] would need an NDA [new drug application].”

Impact of the potential loss reverberated throughout the dermatology community.

Dr. Eva Hurst of the American Society of Dermatologic Surgery filed a comment to the proposed rule saying that the action would be “in many respects punitive in nature for dyschromia patients and is potentially inequitable for patients of various minority groups.”

In Dr. Hurst’s letter, which is posted on FDA’s Web site, she maintained that the FDA position outlined in an Aug. 28 proposed ruling both underestimates the impact of dyschromia, “an important cutaneous disorder with significant patient morbidity,” and overestimates the “exceedingly low risk … of exogenous ochronosis, “a remarkably uncommon adverse event from the use of hydroquinone containing products.”

Dr. Kathy Fields, a dermatologist in private practice in San Francisco, said the move would certainly harm patients.

“It would be tragic … if we lose this drug. There’s nothing else that does what hydroquinone can do,” she said at the ASCDAS meeting.

Other physicians drew attention to the science FDA used to justify the proposed ban. According to the proposed ruling, studies during the 1980s and 1990s in rats and mice delivered huge concentrations of hydroquinone via lavage, not skin application, to produce “some evidence” of carcinogenicity. Dermal applications produced irritation after 13 weeks.

Scientific evidence more powerful than animal data and anecdotal reports should be required before the FDA can “tar and feather a very useful drug,” said Dr. Schlessinger, who is a dermatologist in private practice in Omaha, Neb.

He noted that absorption of hydroquinone is species specific, with humans metabolizing the drug in the liver, where it is deactivated and detoxified. In rats, the drug is activated upon absorption.

Dr. Valerie Callender, a dermatologist in private practice in Mitchellville, Md., said that it would be “ridiculous” to suggest that this animal data could be used to raise concerns about human carcinogenicity.

“There’s no connection whatsoever. No causal link,” she said in an interview with this newspaper.

The Food and Drug Administration maintains that manufacturers of hydroquinone-containing products “should have known for some time that if additional adequate data were not provided to support safety, a nonmonograph status for these products would occur,” according to the proposed rule.

The Consumer Healthcare Products Association in 1999 proposed that more safety studies be conducted, but no data were ever received, the proposed ruling noted.

Ochronosis was also cited as a concern by the FDA, which detailed 16 cases from the literature of paradoxical darkening of the skin following the use of bleaching creams that contained hydroquinone. The concentrations of those creams were as high as 7.5% hydroquinone, but also as low as 1%.

In Africa, where high concentrations of the drug once were used widely, ochronosis occurrences were not surprising, Dr. Schlessinger explained.

“We all know ochronosis can occur with hydroquinone 4% or greater,” he said.

In the audience of approximately 600 physicians who were attending the ASCDAS meeting, 6 raised their hands to say they had seen ochronosis, mostly in using a greater than 4% concentration.

“It’s incredibly rare, given the fact that this drug is over the counter in the U.S.,” Dr. Schlessinger said.

Dr. Callender agreed that hydroquinone-associated ochronosis is rare, to the point where it would be an “absurd” reason to pull more than 200 products off the market. As a specialist, she has seen four or five cases in 20 years of treating patients with hyperpigmentation with hydroquinone. All of these have been in patients using 2% products for years and years, she said. She is unaware of any case documented after the use of 4% hydroquinone.

“When you do see it, it’s devastating, because there is no treatment available,” she said.

However, what the FDA may not realize is the “devastating psychological impact” that melasma and other hyperpigmentation disorders have on people, many of them ethnic minorities, Dr. Callender noted.

The proposed ruling stated that the risks posed by a drug must be low if it is used by healthy people, while acknowledging that “the actual risk to humans from the use of hydroquinone has yet to be fully determined.”

FDA went on to acknowledge that “this proposed rule would have an impact on consumers who use OTC skin bleaching drug products containing hydroquinone to lighten limited areas of hyperpigmented skin. They will no longer be able to purchase these OTC drug products after current inventories are depleted. The benefit of removing OTC skin bleaching drug products from the market will be a reduction in the number of cases of ochronosis that would otherwise occur each year.”

The agency acknowledged it could not calculate the “monetary value” or reduction of psychological suffering due to the prevention of “disfigurement due to ochronosis.”

Its benefit-to-risk analysis of hydroquinone tentatively concluded that “there is no benefit to physical health that would justify the continued marketing of these products,” and that “the sole intended benefit would be to improve the user’s appearance by bleaching the skin.”

If the proposed rule is enacted, hydroquinone-containing prescription and OTC products could be off the market as early as April and be absent for 2–4 years, until extensive research studies could be undertaken, Dr. Schlessinger said.

There is a chance that the FDA, inundated by protests from the American Academy of Dermatology, National Medical Association, American Society of Dermatologic Surgery, and ASCDAS, among other groups, might stop short of a ban in favor of a boxed warning, said Dr. Callender.

Dr. Schlessinger, however, was not so optimistic.

Still stinging from recent FDA decisions imposing warnings and restrictions on topical immunomodulators and isotretinoin, he held out little hope that dermatologists could convince the agency to hold off unless there was proof of harm to humans.

“Nobody is able to fight the FDA. The FDA is the 2-ton gorilla,” Dr. Schlessinger said after urging colleagues at the meeting to flood the FDA with comments.

Should hydroquinones be reclassified and need approved new drug applications, the extensive approval process “will cost millions and millions of dollars and many of these products won’t shake out,” he predicted.

ELSEVIER GLOBAL MEDICAL NEWS

Ban May Send Desperate Patients in Search of Dubious Alternative Therapies
Should the FDA withdraw GRASE status for hydroquinone creams, dermatologists and their patients will have options, but many are less than ideal, according to experts who spoke with SKIN & ALLERGY NEWS.

The recently approved combination product Tri-Luma (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) would remain on the market since it was approved by the FDA in spring 2002, and its manufacturer, Galderma, filed an new drug application and conducted all other FDA-required tests.

Tri-Luma is “a great drug but … not a reasonable choice for every patient given the fact that it has retinoic acid and a steroid in it,” said Dr. Schlessinger, who disclosed that he has conducted research for Galderma. “For the great majority of patients who are using straight hydroquinones, this would be overkill.”

Further, Tri-Luma is fairly expensive—about $100 for a 30 g tube—compared with OTC products.

Some patients will undoubtedly decide to obtain prescriptions for Tri-Luma, and they may realize that the prescription product is better than what they had been purchasing over the counter, predicted Dr. Jeffrey Dover, a dermatologist in private practice in Chestnut Hill, Mass., in an interview.

But he expressed concerned that a “significant minority will look for alternatives, some of which may be not only ineffective but potentially dangerous.”

Dr. Callendar said patients already use products that are inappropriate for skin lightening. “A month doesn’t goes by that I don’t see patients using high-potency corticosteroids to lighten their skin. They have striae, atrophy, and their skin feels like cigarette paper,” she said in an interview.

If a ban is implemented, some patients are likely to turn to soy, licorice extract, kojic acid, and other alternatives, she predicted, which will drive the incidence of adverse events up, not down.

Certain retinoids, acid-based peels, and Solagé, an FDA-approved product containing hydroxyanisole (mequinol) and 0.01% tretinoin would remain as treatment options along with Tri-Luma, she noted.

Ironically, the proposed FDA ban would mean the only OTC hydroquinone product left on the market would contain 4% of the active ingredient, a far higher concentration than many of the products that would disappear."

PII: S0037-6337(06)71781-8

doi:10.1016/S0037-6337(06)71781-8

© 2007 Elsevier Inc. All rights reserved.

#3

Update on hydroquinone from “Skin and Allergy News” February 2007

Hydroquinone
LESLIE S. BAUMANN, M.D.

Article Outline
• The Search for Mutagenic Effects

• Adverse Clinical Effects

• Safety of Combination Agents

• Possible Alternatives

• Decision Time at the FDA

• Copyright

DR. BAUMANN is director of cosmetic dermatology at the University of Miami. To respond to this column, or to suggest topics for future columns, write to Dr. Baumann at our editorial offices via e-mail atsknews@elsevier.com.

With a track record of safety and efficacy spanning more than 40 years, hydroquinone, a hydroxyphenolic derivative of benzene, is considered the most effective skin-lightening product for treatment of hyperpigmentary disorders (J. Eur. Acad. Dermatol. Venereol. 2006;20:781–7; Skin Therapy Lett. 2004;9:1–3). Globally, the most widely prescribed skin-lightening and depigmenting agents include magnesium l-ascorbyl-2-phosphate, hydroxyanisole, N-acetyl-4-S-cysteaminylphenol, arbutin (hydroquinone-b-d-glucopyranoside), and hydroquinone (Phytother. Res. 2006;20:921–34).

Used in over-the-counter products as well as prescription drugs, hydroquinone (HQ) is found in vegetables, fruits, and grains, as well as in plant-derived products such as coffee, tea, beer, and wine. It is known to reversibly inhibit cellular metabolism by affecting DNA and RNA synthesis.

For many years, HQ has been the first-line therapy for postinflammatory hyperpigmentation and melasma.

HQ exerts its depigmenting effect by efficiently inhibiting tyrosinase, decreasing its activity by 90%. It also is cytotoxic to melanocytes (Dermatol. Clin. 1988;6:185–92; J. Invest. Dermatol. 1984;82:308–10).

Besides HQ, other known inhibitors of tyrosinase include vitamin C, kojic acid, arbutin, mulberry extract, and licorice extract. Although HQ is useful as a sole therapeutic agent, it is often combined with other compounds such as tretinoin, glycolic acid, kojic acid, and azelaic acid.

The Search for Mutagenic Effects
Despite its long record of medical use, HQ raises concerns because it is derived from benzene and therefore has putative mutagenic properties. In addition, side effects have been associated with the long-term use of cosmetic products containing high HQ concentrations (J. Eur. Acad. Dermatol. Venereol. 2006;20:781–7). Indeed, HQ has been banned as a cosmetic skin-bleaching agent in Europe since January 2001 (Ned. Tijdschr. Geneeskd. 2004;148:768–71), and it is available there only in prescription form. The compound also is highly regulated in Asia.

Recently, investigators conducted a literature search focusing on the biochemistry and toxicology of HQ, benzene, and related molecules, with an eye toward the potential long-term side effects of HQ use in cosmetics. After surveying the large body of literature on the carcinogenicity of these compounds, particularly studies published since 1996, the investigators concluded that the long-term use of topical HQ does pose an increased risk of cancer, and they recommended that this benzene derivative no longer be used as a skin-lightening agent (J. Eur. Acad. Dermatol. Venereol. 2006;20:777–80).

Nevertheless, there are no reports in the medical literature of any human cutaneous or internal malignancies linked to HQ (J. Eur. Acad. Dermatol. Venereol. 2006;20:781–7). Animal experiments have linked HQ use to the induction of leukemia and renal adenomas.

In workers exposed to HQ, the most serious health effects have been pigmentation of the eye and, in a small number of cases, permanent corneal damage (Crit. Rev. Toxicol. 1999;29:283–330).

Because absorption of HQ is more rapid than its elimination through urine, daily use is now known to cause the agent to accumulate in the body (Ned. Tijdschr. Geneeskd. 2004;148:768–71).

Concerns about the effects of intermediate use of HQ, such as exogenous ochronosis and leukomelanoderma en confetti, contributed to the European ban on HQ in cosmetic products that was instituted in 2001 (J. Eur. Acad. Dermatol. Venereol. 2006;20:777–80; Ned. Tijdschr. Geneeskd. 2004;148:768–71).

Adverse Clinical Effects
Ironically, exogenous ochronosis presents as yellow-brown or blue-black hyperpigmentary macules that can result from the treatment of other hyperpigmentary conditions with skin-bleaching formulations containing HQ (Int. J. Dermatol. 2005;44:112–5). Exogenous ochronosis occurs in the area of HQ application, usually after prolonged use of even low concentrations (2%) of HQ, and more often in patients with darker skin types.

This adverse response is thought to be caused by the inhibition of the enzyme homogentisic acid oxidase in the skin, resulting in the local accumulation of homogentisic acid that then polymerizes to form ochronotic pigment (J. Am. Acad. Dermatol. 2000;42:869–71).

Despite the widespread use of HQ in North America, the number of reported cases of exogenous ochronosis due to HQ use has been only 30 on this continent (Skin Therapy Lett. 2004;9:1–3). To limit the adverse effects seen with HQ, it is best to use it in 4-month cycles, alternating it with kojic acid, azelaic acid, and other bleaching agents.

Irritant and allergic contact dermatitis and nail discoloration have been associated with HQ use, with postinflammatory hyperpigmentation also resulting from contact dermatitis. Hypopigmentation also has been seen around sites treated with HQ. Discontinuing HQ therapy resolves these side effects (Skin Therapy Lett. 2004;9:1–3; Arch. Dermatol. 1995;131:1453–7).

In a study of 16 women with idiopathic melasma, patients nightly applied 5% ascorbic acid cream on one side of the face and 4% HQ cream on the other side for 16 weeks, and applied sunscreen daily. The best subjective results were seen on the HQ side (93% vs. 62.5%), although no statistical differences were identified through colorimetric analysis. The side effect profile strongly favored the ascorbic acid side, with adverse reactions seen in 11 of 16 HQ sides as opposed to only 1 of 16 ascorbic acid sides (Int. J. Dermatol. 2004;43:604–7).

Recently, the Pigmentary Disorders Academy came to a consensus that the ideal first-line approach to melasma consists of topical therapies, primarily those with triple combinations of effective agents. The recommended alternatives included single agents (4% HQ, 0.1% retinoic acid, or 20% azelaic acid) or agents with dual ingredients (HQ plus glycolic acid) (J. Am. Acad. Dermatol. 2006;54:S272–81).

Safety of Combination Agents
Because of escalating concerns about HQ monotherapy, numerous studies have included HQ in combination topical therapy. Although HQ, tretinoin, and topical corticosteroids are well established as effective single agents for treating melasma and hyperpigmentation, the once-daily triple combination cream containing 0.05% tretinoin, 4% HQ, and 0.01% fluocinolone acetonide (Tri-Luma) is the only commercially available combination of all three agents. In fact, it is the only HQ-containing product that has been approved by the Food and Drug Administration for treatment of facial melasma (Am. J. Clin. Dermatol. 2006;7:223–30).

Extensive studies have indicated an efficacious and safe profile for this triple combination cream in treating melasma (Am. J. Clin. Dermatol. 2006;7:223–30).

In a multicenter, open-label, 12-month study of once-daily application of Tri-Luma cream for facial melasma, which 173 out of 228 patients completed, the formulation was deemed safe and effective. Patient and physician assessment revealed complete or nearly complete clearing in more than 90% of cases. A total of 129 patients experienced at least one adverse event related to treatment, with most events categorized as mild and transient.

More evidence for the triple combination approach comes from an 8-week, multicenter, open-label, community-based study evaluating Tri-Luma cream in 1,290 patients of diverse races and ethnicities. Global evaluations at the end of the study period revealed that 75% of patients exhibited “moderate or marked improvement” or were deemed to be “almost clear” or “clear.”

A 12-month extension of a randomized, investigator-blinded, multicenter, 8-week trial evaluating the triple combination cream for facial melasma netted 389 patients completing 6 months of treatment and 327 patients completing 12 months. In all, 80% of patients exhibited complete or nearly complete clearance of lesions. This study reinforced a previous smaller study indicating that once-daily application of a triple combination cream containing HQ is effective, safe, and tolerable over a lengthy period for the treatment of moderate to severe melasma (J. Drugs Dermatol. 2005;4:592–7).

In 2004, a 12-week open-label study with 28 patients (25 of whom completed the study) evaluated the safety and efficacy of a then-novel formulation of 4% HQ with 0.15% retinol entrapped in microsponge reservoirs, which were used for the gradual release of HQ to extend treatment exposure and limit skin irritation. Patients applied the study cream to the full face in the morning and evening, and applied a broad-spectrum sunscreen 15 minutes after the morning application. Assessment at 4, 8, and 12 weeks showed improvement in all study end points, including melasma or postinflammatory hyperpigmentation disease severity and intensity, as well as lesion area. The HQ-retinol combination was deemed safe and effective, with only one patient dropping out because of an adverse reaction not judged to be serious.

Other studies of dual combination formulations have yielded encouraging results. A 16-week comparison study revealed that an emollient cream containing 4% HQ and 0.3% retinol more effectively eliminated signs of photodamage (dyspigmentation, fine wrinkles, and tactile roughness) than a 0.05% tretinoin emollient cream. According to the researchers, the cream may represent a viable therapy for hyperpigmentation associated with photoaging (Dermatol. Surg. 2005;31:799–804). Further, in a recent comparison study lasting 24 weeks, topical application of tazarotene plus HQ was found to be more effective in ameliorating the dyspigmentation associated with photodamage than tazarotene alone (J. Cosmet. Laser Ther. 2006;8:121–7).

Possible Alternatives
Several compounds have been proposed as safer alternatives to topical HQ, including azelaic, kojic, glycolic, and thioctic (α-lipoic) acids, as well as deoxyarbutin (Phytother. Res. 2006;20:921–34; J. Cosmet. Sci. 2006;57:291–308; Ned. Tijdschr. Geneeskd. 2004;148:768–71).

Small proteins found in soy, as well as niacinamide, a vitamin B3 derivative, also appear to have potential as alternatives. The soy proteins, such as soybean trypsin inhibitor and Bowman-Birk inhibitor, may inhibit skin pigmentation. These proteins have been found not only to exhibit depigmenting activity but also to prevent UV-induced pigmentation, both in vitro and in vivo (J. Invest. Dermatol. 2001;116:587–95). Niacinamide has also been demonstrated to inhibit melanosome movement from melanocytes to keratinocytes (Br. J. Dermatol. 2002;147:20–31).

Decision Time at the FDA
Hydroquinone has a long record of successful and safe use as a skin-lightening agent for dermatologic use. It is available over the counter in 2% concentrations and by prescription in 4% concentrations. Recently, this agent has come under greater scrutiny because of its putative potential for inducing adverse effects.

At press time, it was not known whether the FDA would finalize a rule it proposed last year to take over-the-counter HQ preparations off the market, a decision that would affect consumers who use skin-bleaching formulations (SKIN & ALLERGY NEWS, January 2007, p. 1). Neither is it known whether the FDA will ban the prescription-strength HQs that have not received FDA approval. In other words, Tri-Luma may soon be the only HQ product available on the market.

Several years ago, the FDA asked companies that sell HQ products to provide data that these products were safe. The only safety data that I know of that were turned in to the FDA were the Tri-Luma data that resulted in FDA approval of its use in melasma. Because of this lack, we are facing a ban on a terrific cosmetic ingredient.

If you treat patients with melasma or postinflammatory hyperpigmentation, you know how important HQ is as a therapy. If HQ is banned, many dermatologists might choose to have these products formulated for them in a pharmacy. (That’s what they do in the United Kingdom.) The bad news is that it is difficult to stabilize a steroid, HQ, and tretinoin in a formulation, so this option may not be the best for your patients.

What are we going to do? I am going to cross my fingers that the FDA leaves HQ on the market.

The lesson learned here? The next time the FDA asks for safety data, we need to work together with the companies to ensure that it gets the data it needs, to avoid problems like this in the future.

#4

Volume 38, Issue 4, Page 1,34 (April 2007)

From Skin and Allergy News:

[color:#FF6666]Combo Therapy May Be Hydroquinone Alternative[/color]
GREG MUIRHEAD (Contributing Writer)

Article Outline
• Copyright

MAUI, HAWAII — Combination therapy with mequinol 2% and tretinoin 0.01% solution was slightly more effective than hydroquinone 4% cream in reducing hyperpigmentation in African American patients with postinflammatory hyperpigmentation after 12 weeks, Dr. Susan Taylor said at the annual Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation.

The results suggest that this off-label use of mequinol 2% and tretinoin 0.01% solution (Solagé) may be a viable alternative to hydroquinone, the skin-lightening ingredient that the Food and Drug Administration has proposed banning from over-the-counter cosmetic products, said Dr. Taylor of Columbia University, New York.

The study was an open-label, phase IV trial of treatment with Solagé versus hydroquinone 4% cream in the reduction of facial postinflammatory hyperpigmentation, said Dr. Taylor, an investigator for Barrier Therapeutics (which markets Solagé) who also is affiliated with many other companies.

Each treatment was assigned to one side of the face and applied consistently twice daily, at intervals greater than 8 hours, for 12 weeks. Results were assessed at weeks 4, 8, and 12 using a 7-point investigator and patient global assessment of improvement, with 0 indicating “completely clear” with no hyperpigmentation and 6 indicating hyperpigmentation that was worse than at baseline.

A total of 61 African American patients were enrolled, with 47 completing the 12-week study. Patients’ average age was 33.5 years. At the time of enrollment, facial pigmentation was mild in 31% of patients and moderate in 69%.

“A combination of mequinol 2% and tretinoin 0.01% showed an improvement more gradually than 4% generic hydroquinone,” Dr. Taylor pointed out, but “by 12 weeks the mequinol and tretinoin, in combination, in this particular study, performed very well—and at the very end of the trial outperformed hydroquinone.” (See box.)

The treatments were well tolerated. Eighteen patients were adversely affected by treatment, but no one discontinued the study because of an adverse effect (AE). Most skin-related AEs were mild or moderate, with severe AEs occurring in four patients (22%). Most AEs developed early in the trial, and all were resolved with appropriate treatment. Of the patients who were adversely affected by treatment, nine had multiple AEs: Three needed dosage adjustments; and two temporarily discontinued the study medication. The most frequent AEs were burning (14 Solagé patients vs. 2 hydroquinone patients), scabbing/peeling (7 Solagé patients vs. 0 hydroquinone patients), and dryness (4 Solagé patients vs. 1 hydroquinone patient).

Given these findings, Dr. Taylor said, “we have another safe and effective treatment for the treatment of facial postinflammatory hyperpigmentation secondary to acne.”

To put the study’s results in context, Dr. Taylor explained that postinflammatory hyperpigmentation (PIH) is typically a result of increased melanin production and presents as discrete, hyperpigmented macules that have hazy, feathered margins. It occurs primarily in women of color, including African Americans, Asians, and Hispanics. It occurs on sun-exposed areas of the skin, especially around the center of the face, she said.

Exacerbating factors may include pregnancy, estrogens, and oral contraceptives. PIH forms in an area that has previously experienced inflammation, cutaneous injury, a cosmetic or surgical procedure, or any of a variety of inflammatory dermatoses. “In my practice, I see it most often as a result of acne vulgaris,” Dr. Taylor noted.

She observed that patients with skin of color who have acne often “don’t present with acne. Their chief complaint is the hyperpigmentation.”

Given the association of acne and PIH, “it behooves us to spend some time to explain to our patients that we must treat the acne, as well as the postinflammatory hyperpigmentation,” she said, adding that “patients will take their prescriptions, but they won’t use the acne medicines.”

As preventive measures, patients need to use sunscreens and otherwise protect themselves from ultraviolet radiation, Dr. Taylor explained. Treatment is needed when the first signs of skin irritation/inflammation appear.

Current topical treatments for PIH include phenols, including hydroquinone and mequinol; the retinoids, including tretinoin; corticosteroids that can be used in combination with other treatments; azelaic acid; kojic acid; alpha-hydroxy acids; and combinations of these treatments.

Available procedures include salicylic acid and trichloracetic acid peels. Cryosurgery also can be helpful, as can dermabrasion and microdermabrasion. Lasers, especially fractional lasers, can help with dermal pigmentation. Even with all these therapeutic options, though, “dyschromias remain a therapeutic challenge,” Dr. Taylor said.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.