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黄褐斑的治疗(英文综述)

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黄褐斑的治疗(英文综述) tain tyrosinase, a copper-containing enzyme, that catalyzes the conversion of L-tyrosine to L-dopa and L-dopa to L-dopa-quinone in melanin synthesis.1 Melasma is a dysfunction of this pigmentary system, resulting in an irregular brown or grayish-brown facial hyper...
黄褐斑的治疗(英文综述)
tain tyrosinase, a copper-containing enzyme, that catalyzes the conversion of L-tyrosine to L-dopa and L-dopa to L-dopa-quinone in melanin synthesis.1 Melasma is a dysfunction of this pigmentary system, resulting in an irregular brown or grayish-brown facial hypermelanosis. Although it can occur in both sexes and any skin type, it is more commonly seen in women2 and those with darker complexions— Fitzpatrick’s skin types IV to VI—especially those living in areas of intense UV radiation, such as Hispanics/Latinos, Asians, and African Americans.3-6 The condition usually develops slowly and symmet- rically, and can last formany years, withworsening in the summer and improvement during the winter.7 Melasma is sometimes used interchangeably with the term ‘‘chloasma,’’ which is a hyperpigmentation that often results from pregnancy or changes in uterine and ovarian hormones; melasma, however, can have a variety of possible causes. The common HQ: hydroquinone IPC: isopropylcatechol IPL: intense pulsed light MASI: Melasma Area and Severity Index MKF: modified Kligman’s hydroquinone formula PIH: postinflammatory hyperpigmentation RA: retinoic acid RCT: randomized controlled trial SWC: skin-whitening complex TCA: trichloroacetic acid YAG: yttrium-aluminum-garnet From the Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Sciences Center (Sunnybrook site) and the University of Torontoa; Mediprobe Research Inc, London, Ontario, Canadab; Department of Der- matology and Cutaneous Surgery, University of Miami School of Medicinec; Skin of Color Center, New Yorkd and College of Physicians and Surgeons, Columbia University, New York.e Funding sources: None. Disclosure: Dr Taylor has received previous honoraria/grants or acted as a consultant or an investigator for the following companies: Allergan, Astellas, Barrier Therapeutics, Bieresdorf, Connetics, Dermik, Doak (Bradley), Galderma, Intendis, Johnson& Johnson, L’Oreal, Medicis, Palomar, Stiefel. Reprint requests: Aditya K. Gupta, MD, PhD, FRCP (C), 645 Windermere Rd, London, Ontario, Canada N5X 2P1. E-mail: agupta@execulink.com. Published online October 4, 2006. 0190-9622/$32.00 REVI The treatment of m of clinic Aditya K. Gupta, MD, PhD, MBA/HCM, Keyvan Nouri, MD,c an Toronto and London, Ontari and New Yor Melasma is an irregular brown or grayish-brown facia those living in areas of intense UV radiation. The pre there are many possible contributing factors. Because melasma is often difficult to treat. The use of broad-s topical hydroquinone, the most common treatment fo acid (tretinoin) and azelaic acid. Combination therap roids have been used in the treatment of melasma, an monotherapy. Kojic acid, isopropylcatechol, N-acet other compounds that have been investigated for th efficacy, safety, or trial design indicates that the interv be recommended. Chemical peels, laser treatments, a apeutic modalities that have been used to treat melas M elanin is produced in melanocytes and stored in melanosomes within the kerati- nocytes. The number, melanin content, and location of these melanized cells (along with oxygenated and deoxygenated hemoglobin) help determine the color of the skin. Melanosomes con- ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.02.009 1048 EWS elasma: A review al trials FRCP (C),a,b Melissa D. Gover, BSc,b d Susan Taylor, MDd,e o, Canada; Miami, Florida; k, New York l hypermelanosis, often affecting women, especially cise cause of melasma remains unknown; however, of its dermal component and tendency to relapse, pectrum (UVA 1 UVB) sunscreen is important, as is r melasma. Other lightening agents include retinoic ies such as hydroquinone, tretinoin, and corticoste- d are thought to increase efficacy as compared with yl-4-cysteaminylphenol, and flavonoid extracts are eir ability to produce hypopigmentation, but their entions would need further study before they could nd intense pulsed light therapy are additional ther- ma. ( J Am Acad Dermatol 2006;55:1048-65.) Abbreviations used: AEs: adverse effects AzA: azelaic acid CO2: carbon dioxide FA: fluocinolone acetonide GA: glycolic acid contributing factors include genetic predisposi- tion,4,8 pregnancy,9 use of oral contraceptives,10 J AM ACAD DERMATOL endocrine dysfunction or hormone treatments,11,12 and exposure to UV light.4,8,13 In addition, cosmetics and drugs containing phototoxic agents (eg, antisei- zure medications) have also been linked to me- lasma.3 Interestingly, Wolf et al14 suggests that some cases of melasma could be stress induced, because the release of melanocyte-stimulating hormone can be influenced by stress. When melasma occurs with pregnancy, also termed ‘‘themaskof pregnancy,’’ it can resolvewithin a few months after delivery and treatment may not be necessary. However, there are many cases in which the disorder persists indefinitely.15 Pregnancy- associated melasma may be caused by an increase in placenta, ovarian, and pituitary hormones.16 Me- lasma has also been attributed to an elevation of melanocyte-stimulating hormone, estrogen, and pro- gesterone leading to increased melanogenesis.10 Vazquez et al8 reports that melasma in men shares the same clinicohistologic characteristics as in women, with the exception that hormonal factors may not play a major role. The main associated fac- tors among men appear to be sun-induced aggrava- tion and a significant family history of the condition.8 A study of melasma in Indian men implicated sun exposure and cosmetic use including topical mus- tard oil.17 It is helpful, before treatment, to perform an examination using Wood’s lamp; this will identify the depth of the melanin pigmentation, thus, helping to delineate the type of melasma.18 Generally, me- lasma is classified into one of 3 histologic types: epi- dermal, dermal, and mixed.13 However, some also include a fourth type known as Wood’s light inap- parent.4 UnderWood’s light the epidermal type often shows a darkening of color when examined, as the light emitted by Wood’s lamp is absorbed by the excess melanin. The dermal type, however, will not show this accentuation.1,4 The mixed type involves a deposition of melanin in both the epidermis and the dermis and color enhancement with Wood’s light is seen is some places of the skin, but not others.4 It is interesting to note that when histologically assessing 56 patients, Kang et al13 did not find any cases of entirely dermal-based melasma. Further- more, Sanchez et al4 describe dermal type me- lasma as having melanin-laden macrophages in the perivascular array, both in the papillary and retic- ular dermis. Epidermal hyperpigmentation in the dermal type was found to be similar to the epider- mal type, but not as prominent.4 It has, thus, been suggested that there may be no truly pure dermal type of melasma.13 There are 3 clinical patterns recognized on the VOLUME 55, NUMBER 6 basis of clinical examination. These include a centrofacial, malar, and mandibular pattern. The centrofacial is the most common pattern of melasma and involves the cheeks, forehead, upper lip, nose, and chin. The malar pattern has lesions limited to the cheeks and nose, and the mandibular pattern has lesions that occur over the ramus of the mandible.4 Other sites (eg, forearm and neck) may also be involved in any of these patterns.7 METHODS MEDLINE (1966-2005) was searched using the key words melasma, chloasma, hyperpigmentation, and hypermelanosis. This article outlines published ran- domized controlled trials (RCTs) of the interventions that have been studied for use in the treatment melasma.When RCTs were not present, nonrandom- ized or open clinical trials were reviewed. General management Because of its refractory and recurrent nature, melasma is often difficult to treat. The goals of treatment often include prevention or reduction in the severity of recurrence, reduction of the affected area, improvement in the cosmetic defect, and re- duced time to clearance, all with the fewest possible side effects.19 The principles of therapy include pro- tection from UV light, inhibition of melanocyte activity and melanin synthesis, and the disruption and removal of melanin granules.20 General management recommendations that assist in the clearing of melasma include discontinu- ation of birth control pills, scented cosmetic products, and phototoxic drugs, coupled with UV protection with use of broad-spectrum (UVA 1 UVB) sun- screens.20 Solar exposure exacerbates melasma, and its avoidance is fundamental for the successful man- agement of the disease.21 Most patients using bleach- ing agents can expect a recurrence of the disease on exposure to sunlight and artificial UVA and UVB light.21 This supports the importance of the use of broad-spectrum sunscreens (SPF[ 30) in melasma therapies. Broad-spectrum sunscreens must be ap- plied daily throughout the year and continued indef- initely to minimize the reactivation of melanocytes by incidental exposure to the sun.21 Although sunscreens are a vitally important com- ponent of therapy, other forms of treatment are nonetheless necessary.22 Topical treatments include the application of creams such as hydroquinone (HQ). Although some negative reactions have been described, HQ remains one of the most prescribed agents for melasma and is considered the gold standard of therapy, especially for epidermal me- lasma. The epidermal type generally has a good Gupta et al 1049 response to topical therapy, whereas skin with mainly dermal deposition of melanin responds poorly.4 Alternative therapies such as chemical peel- ing agents or laser therapy are sometimes also used. Table I outlines the various treatments for melasma and their proposed mechanism of action. Table II outlines efficacy studies for the most common forms of topical treatment, whereas Table III focuses on the efficacy studies for chemical peeling agents. Hydroquinone Mechanism of action. HQ (1,4-dihydroxyben- zene) is a hydroxyphenol, which, in the presence of catalytic amounts of dopa, will compete with tyro- sine, the natural substrate of tyrosinase. This process prevents the enzymatic oxidation of tyrosine to dopa, thus, preventing the synthesis of melanin. This is consistent with the selective mode of action toward cells with active tyrosinase activity.23 Efficacy. Amer and Metwalli24 assessed the effi- cacy of HQ 4% cream used in conjunction with broad-spectrum sunscreen in patients with various pigmentary disorders. Of the 70 patients entered into the study, 50 had melasma, 10 freckles, and 10 postinflammatory hyperpigmentation (PIH). The pigment intensity relative to nonaffected areas of skin was determined on a 4-point scale with 1 being no difference, 2 mild pigmentation, 3 moderate pig- mentation, and 4 severe pigmentation. From week 0 to 12 (treatment end) the number of patients with melasma and moderate pigmentation decreased from 28 (56%) to 1 (2.1%), and patients with severe pigmentation decreased from 22 (44%) to 4 (8.4%). In addition, the number of patients with melasma with no difference between affected and nonaffected areas increased from none at week 0 to 41 patients (85.4%) at week 12. The study deemed that there was Table I. The mechanisms by which various treatments for melasma achieve their depigmenting effect Mechanism of action Therapy Tyrosinase inhibitor Hydroquinone Tretinoin* Azelaic acid Kojic acid Nonselective suppression of melanogenesis Corticosteroids Inhibition of ROS Azelaic acid Removal of melanin Chemical peels Thermal damage Laser treatments ROS, Reactive oxygen species. *Tretinoin may also disperse keratinocyte pigment granules and accelerate epidermal turnover.31 1050 Gupta et al a good to excellent response achieved in 89.5% of patients with melasma and that treatment with HQ is beneficial in patients with hyperpigmentary disor- ders.24 However, these results should be considered with caution, as this study is not randomized or placebo controlled. Furthermore, the study seems to lack a detailed description of the methods under- taken and there appears to have been no statistical analysis of the results. Haddad et al25 in a double-blind, randomized, placebo-controlled study of 30 patients with me- lasma, assessed the efficacy of a skin-whitening complex (SWC) 5% cream versus HQ 4% cream. Patients were randomized into two groups; group 1 received HQ 4% and placebo, and group 2 received SWC and placebo, each to be applied to opposite sides of the face. Efficacy was measured based on two independent investigator evaluations and a patient questionnaire. Of the 30 patients enrolled, 25 completed the study. Group 1 (HQ vs placebo) showed an improvement of 76.9% and group 2 (SWC vs placebo) showed an improvement of 66.7%. This difference was not statistically significant (Fisher’s test, P = .673). Patient satisfaction levels were 66.7% for group 1 and 69.2% for group 2. Despite being a RCT, this study opts to evaluate the compounds involved through amore qualitative approach, rather than using measures of pigment intensity or Melasma Area and Severity Index (MASI) scores. Furthermore, the study fails to provide a description of what comprises SWC. Nonetheless, with a 76.9% improve- ment rate in those treated with HQ, this study does support earlier evidence that HQ is effective in treating hyperpigmentation. Interestingly, while testing glycolic acid (GA) peels for melasma, Hurley et al26 discovered that 4% HQ monotherapy with daily application of sun- screen not only improves melasma, but is as effective as their proposed peeling regimen plus HQ. In this randomized, investigator-blind, split-face prospec- tive trial, 21 Hispanic women (18 of whom com- pleted the study) were treated with 4% HQ and 4 GA peels (20% concentration on first two visits then 30% at next two) on one side and 4% HQ only on the other. Both sides had a statistically significant treat- ment effect (P\ .001). However, between the two groups, there was no significant difference in either the degree of pigmentation lightening or in the MASI scores from baseline to treatment end. HQ 4% cream as a monotherapy was concluded to be an adequate agent for treating melasma.26 The available concentrations of HQ vary from 1.5% to 4% (Table IV). Concentrations of 2% or less are available in the United States in over-the-counter preparations and those with concentrations greater J AM ACAD DERMATOL DECEMBER 2006 that 2% are available only by prescription. In the J AM ACAD DERMATOL Gupta et al 1051 Table II. Studies involving commonly used topical agents for the management of melasma No. of patients Treatment Study Design E C R1 R2 Duration Results Sunscreen Vazquez et al (1983)22 R, DB 59 53 Sunscreen 1 Placebo 1 3 mo R1: 96.3% showed improvement.HQ HQ R2: 80.8% showed improvement. No significant difference between R1 and R2. HQ Amer et al (1998)24 O 50* 48* HQ 4% 12 wk Good to excellent response in 89.5% of those with melasma. Haddad et al (2003)25 R, DB, SF 30 25 HQ 4% vs placebo SWC 5% vs placebo 3 mo R1: improvement of 76.9% on HQ side.R1 = 15 R1 = 12 R2: improvement of 66.7% on SWC side. R2 = 15 R2 = 13 Tretinoin Griffiths et al (1993)32 R, DB 50 38 Tretinoin 0.1% Vehicle 40 wk R1: 68% improved; significant over baseline (P = .0003). R1 = 26 R1 = 19 R2: 5% improved. R2 = 24 R2 = 19 Epidermal pigment reduced by 36% in R1, but increased by 50% in R2 (P = .002). Kimbrough- Green et al (1994)33 R, DB 30 28 Tretinoin 0.1% Vehicle 40 wk R1: 73% improved. R1 = 15 R1 = 15 R2: 46% improved; 15% worsened.R2 = 15 R2 = 13 R1 marginally significant better than R2 (P = .07). Steroid Neering (1975)38 R, O 17 16 Betameth- asone 17-valerate 0.2% 3 mo Depigmentation in 12 patients, attributed to betamethasone (P\ .05). 25% Showed no depigmentation. Combination Gano et al (1979)15 O 20 Tretinoin 0.05% 1 betamethasone valerate 0.1% 1 10 wk 65% Showed improvement. 35% Showed no improvement.HQ 2% Taylor et al (2003)40 R, SB 641 HQ 4% Tretinoin 0.05% 1 FA 0.01% HQ 4% 1 tretinoin 0.05% or tretinoin 0.05% 1 FA 0.01% or HQ 4% 1 FA 0.01% 8 wk Significantly more patients (28.6%) in R1 cleared completely (P\ .001). Significantly more patients (77%) R1 experienced complete/near- complete clearing (P\ .001). AzA Lowe et al (1998)46 R, DB, PG 52 45 AzA 20% Vehicle 24 wk R1: treatment response in 55% of patients.R1 = 25 R1 = 21 R2: treatment response in 12.5%. R2 = 27 R2 = 24 Continued VOLUME 55, NUMBER 6 1052 Gupta et al treatment of melasma, it is recommended that the HQ preparations be applied uniformly and twice daily to the affected area. It has been recommended that if no improvement is evident after an initial discontinued27; however, in some cases it can take as long as 6 months for a change to appear. Safety and tolerability. The most frequently observed reactions are mild skin irritation and sen- Verallo- Rowell et al (1989)29 R, DB 155 132 AzA 20% HQ 2% 24 wk R1: 56.9% achieved good overall improvement; 16.9% excellent; 23% fair. R1 = 77 R1 = 65 R2: 17.9% good; 1.5% excellent; 50.8% fair; 29.8% treatment failures. R2 = 78 R2 = 67 R1 differed significantly from R2 (P\ .001). Balina et al (1991)47 R, DB 329 243 AzA 20% HQ 4% 24 wk R1: 64.8% good/ excellent overall result; 7.4% treatment failures. R1 = 164 R1 = 122 R2: 72.5% good/ excellent; 8.3% failures. R2 = 165 R2 = 121 No significant difference between R1 and R2. Kakita et al (1998)48 R, DB, PG 65 59 AzA 20% 1 HQ 4% 24 wk R1 and R2 produced equivalent overall improvement scores; no significant difference. R1 = 31 R1 = 29 GA 15%-20% GA vehicle R2 = 34 R2 = 30 KA Garcia et al (1996)50 R, O, SF 39 39 KA 1 HQ 1 3 mo 51% Had equal reduction with both regimens. GA GA 28% Had more reduction with R1. 21% Had more reduction with R2. R1 and R2 not significantly different (P[ .05). Lim (1999)49 R, DB, R/L 43 40 KA 2% 1 HQ 2% 1 12 wk R1: more than half clearance in 60% of cases. HQ 2% 1 GA 10% R2: more than half clearance in 47.5% of cases. GA 10% Improvement not statistically different (P = .9). AzA, Azelaic acid; C, completed; DB, double-blind; E, enrolled; FA, flucinolone acetonide; GA, glycolic acid; HQ, hydroquinone; KA, kojic acid; O, open; PG, parallel group; R, randomized; R1, regimen 1; R2, regimen 2; R/L, right/left comparison; SB, single-blind; SF, split-face; SWC, skin- whitening complex. *The study enrolled 70 patients with various pigmentary disorders, only 50 possessed melasma. Table II. Cont’d No. of patients Treatment Study Design E C 2 months of use, then the drug should be R1 R2 Duration Results J AM ACAD DERMATOL DECEMBER 2006 sitization, characterized by itching, burning, stinging, et al SF showed significant1 GA peel 30% 1 and allergic dermatitis, and have been reported to occur more frequently with 4% than 2% concentra- tions. Chronic use of high concentrations of HQ ($5%) have been reported to produce ochronosis and colloid milium.27 In the study by Amer and Metwalli,24 local irrita- tion was noted in most patients, but exogenous ochronosis was not observed. The randomized, controlled study by Haddad et al25 reported that the incidence of side effects was greater among the HQ group than the SWC group, where 25% of the HQ group reported an itchy eruption. This was not statistically significant from the SWC group, which had no reports of side effects. Bentley-Phillips and Bayles28 conducted a 6-year investigation designed to assess the safety of HQ in an optimal concentration. Through the use of open and closed patch testing of 840 volunteers (resulting in 7000 test areas) they determined that HQ is a suitable for use in cosmetics, provided that the content is kept below a certain limit. HQ 3% concen- tration was determined to be the optimal strength. Interestingly, their impr
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