melasma

黄褐斑
  • 文章类型: Journal Article
    背景:深色皮肤个体(DSI)的黄褐斑和炎症后色素沉着的发生率很高。使用带有矿物过滤器的防晒霜对于预防和治疗至关重要。我们的目标是确定皮肤科医生和皮肤科居民在DSI防晒霜处方中的偏好。
    方法:对2022年3月31日在西班牙举行的在线光保护活动的参与者进行的匿名调查。
    结果:66.6%(221/332)的参与者回答了该调查:159名皮肤科医生(71.9%)和62名皮肤科居民(28.1%)。受访者报告建议使用防晒霜的中位数为DSI的80%[四分位距(IQR),50-90].医生报告处方有色防晒霜的中位数百分比为60%(IQR,25-90)的DSI伴痤疮;中位数百分比为90%(IQR,58-99)的DSI与黄褐斑。对具有黑斑病的DSI规定最多的光保护剂是具有抗氧化剂的有机广谱防晒剂:102/220(46.4%)和矿物广谱防晒剂(具有氧化铁):45/220(20.4%)。在有黄褐斑或其他色素性疾病的DSI中,防晒剂最优选的特征如下:防晒系数≥30:217/221(98.2%),UVA保护:214/221(96.8%),伪装颜色:150/220(68.2%)和矿物过滤器,如二氧化钛和氧化锌:151/220(68.6%)或氧化铁:131/220(59.5%)。
    结论:在线调查,潜在的包含偏差。
    结论:受访者报告为大多数DSI开防晒霜,和有色防晒霜,适用于大多数患有色素失调的DSI。然而,DSI最常用的防晒霜是含有抗氧化剂的有机广谱防晒霜.
    BACKGROUND: Dark-skinned individuals (DSI) present high rates of melasma and post-inflammatory hyperpigmentation. The use of sunscreens with mineral filters is essential for prevention and treatment. Our objective was to determine the preferences of dermatologists and dermatology residents in the prescription of sunscreens for DSI.
    METHODS: An anonymous survey of attendees at an online photoprotection event held on March 31, 2022, in Spain.
    RESULTS: The survey was answered by 66.6% (221/332) of the attendees: 159 dermatologists (71.9%) and 62 dermatology residents (28.1%). Respondents reported recommending the use of sunscreen to a median of 80% of DSI [interquartile range (IQR), 50-90]. Physicians reported prescribing tinted sunscreens to a median percentage of 60% (IQR, 25-90) of DSI with acne; and to a median percentage of 90% (IQR, 58-99) of DSI with melasma. The most prescribed photoprotectors to DSI with melasma were organic broad-spectrum sunscreens with antioxidants: 102/220 (46.4%) and mineral broad-spectrum sunscreens (with iron oxides): 45/220 (20.4%). In DSI with melasma or other pigmentary disorders, the most preferred features of sunscreens were as follows: sun protection factor ≥ 30: 217/221 (98.2%), UVA protection: 214/221 (96.8%), color for camouflage: 150/220 (68.2%) and mineral filters such as titanium dioxide and zinc oxide: 151/220 (68.6%) or iron oxides: 131/220 (59.5%).
    CONCLUSIONS: Online survey, potential inclusion bias.
    CONCLUSIONS: Respondents reported to prescribe sunscreens to the majority of DSI, and tinted sunscreens for the majority of DSI with pigmentary disorders. However, the most frequently recommended sunscreens for DSI were organic broad-spectrum sunscreens with antioxidants.
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  • 文章类型: Journal Article
    背景:甲咪唑,口服抗甲状腺药物,最近因其局部应用于治疗黄褐斑时的皮肤增亮效果而受到关注。本研究旨在开发,优化,并表征了甲咪唑微乳作为一种新型的,局部黄褐斑治疗的安全方法。
    方法:我们通过混合适量的表面活性剂(Tween80和Span20)制备了含有3%甲咪唑的微乳液制剂,丙二醇助表面活性剂,和油相(油酸-transcutolp,比例为1:10)。然后我们评估液滴大小,稳定性,粘度,和使用大鼠皮肤模型的皮肤渗透。
    结果:微乳液的液滴尺寸范围为7.06至28.13nm,粘度在120和254厘泊之间。我们的分析确定了液滴大小,粘度,和膜释放作为重要的独立变量。我们确定了最佳配方通过大鼠皮肤的渗透性参数,包括稳态渗透率(Jss),渗透系数(p),滞后时间(Tlag),和表观扩散系数(Dapp)。
    结论:我们发现微乳液的特性,物理化学性质,和体外释放取决于表面活性剂与辅助表面活性剂的比例,含水量,和含油量。我们开发了具有高表面活性剂与辅助表面活性剂比率和低水和油百分比的最佳配方。该配方显示出最终产品的商业化和制造潜力。
    BACKGROUND: Methimazole, an oral antithyroid drug, has recently gained attention for its skin-brightening effects when applied topically to treat melasma. This study aims to develop, optimize, and characterize a methimazole microemulsion as a novel, safe approach for local melasma treatment.
    METHODS: We prepared microemulsion formulations containing 3% methimazole by combining appropriate amounts of surfactants (Tween 80 and Span 20), propylene glycol cosurfactant, and an oil phase (oleic acid-transcutol p at a 1:10 ratio). We then assessed droplet size, stability, viscosity, and skin permeation using rat skin models.
    RESULTS: The microemulsions\' droplet sizes ranged from 7.06 to 28.13 nm, with viscosities between 120 and 254 centipoises. Our analysis identified droplet size, viscosity, and membrane release as significant independent variables. We determined the permeability parameters of the optimal formulation through rat skin, including steady-state permeability rate (Jss), permeability coefficient (p), lag time (Tlag), and apparent diffusion coefficient (Dapp).
    CONCLUSIONS: We found that the microemulsions\' characteristics, physicochemical properties, and in vitro release depended on the surfactant-to-cosurfactant ratio, water content, and oil content. We developed an optimal formulation with a high surfactant-to-cosurfactant ratio and low water and oil percentages. This formulation shows potential for commercialization and manufacturing of final products.
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  • 文章类型: Letter
    暂无摘要。
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  • 文章类型: Journal Article
    黄褐斑,一种普遍的色素性疾病,其特点是病因复杂,复发倾向,和对治疗的抵抗力。然而,目前还没有通过文献计量学和可视化研究黄褐斑。本研究基于WebofScienceCoreCollection(WOSCC)的2,709种出版物分析了该领域的热点和趋势。我们使用Citespace软件对不同国家/地区进行了文献计量分析,机构,作者,和关键词。还使用VoSviewer分析了参考文献。结果表明,自2014年以来,与黄褐斑有关的出版物有所增加。根据对协同网络图的分析,美国,埃及知识库,BenjakulSoottawat是贡献最大的国家,机构,和作者,分别。参考文献和关键词分析已将黄褐斑的发病机制和治疗确定为近年来的流行话题。如何寻找新的治疗方案和更有效的治疗药物是未来的研究趋势。这是首次对黄褐斑相关文献进行文献计量和可视化分析,探讨研究热点和趋势。
    Melasma, a prevalent pigmentary disorder, is characterized by its complex etiology, propensity for recurrence, and resistance to treatment. However, there is currently no research on melasma through bibliometrics and visualisation. This study analyses the hotspots and trends in the field based on 2,709 publications from the Web of Science Core Collection (WOSCC). We carried out bibliometric analyses using Citespace software for different countries/regions, institutions, authors, and keywords. References were also analysed using VoSviewer. The results indicate that overall, there has been an increase in publications related to melasma since 2014. According to the analysis of the collaborative network diagram, the United States, Egyptian Knowledge Bank, and Benjakul Soottawat are the most contributing countries, institutions, and authors, respectively. Reference and keyword analyses have identified the pathogenesis and treatment of melasma as a prevalent topic in recent years. And how to find new treatment options and more effective therapeutic drugs is a future research trend. This is the first bibliometric and visual analysis of melasma-related literature to explore research hotspots and trends.
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  • 文章类型: Journal Article
    酪氨酸酶(TYR)是存在于多种物种中的含铜金属酶。在人类中,hTYR负责黑色素生成的关键步骤,催化l-酪氨酸氧化为l-DOPA,并进一步催化多巴醌。虽然已经报道了许多TYR抑制剂,多酚化合物倾向于主导文献。然而,这些化合物中的许多,特别是单酚和儿茶酚,已被确定为替代底物,而不是真正的抑制剂,考虑到它们与天然底物的结构相似性。含间苯二酚的化合物已成为应对这一挑战的有希望的候选化合物,间苯二酚中的间二羟基部分显示出对TYR介导的氧化的抗性,同时保留与羟基提供的铜离子的有利相互作用。尽管它们的确切作用机制仍存在争议,间苯二酚衍生物对分离的蘑菇和人TYRs产生了一些最具活性的化合物,以及临床上使用的皮肤美容剂,如芥子醇和硫胺醇,在面部黄褐斑患者中表现出非常有希望的效果。这篇综述概述了含间苯二酚的TYR抑制剂的发展,按脚手架类型分类,从简单的烷基类似物到复杂的合成衍生物。还提出了关于间苯二酚-TYR相互作用的机理见解并进行了辩论。
    Tyrosinases (TYRs) are copper-containing metalloenzymes present in a large diversity of species. In human, hTYR is responsible for pivotal steps in melanogenesis, catalysing the oxidation of l-tyrosine to l-DOPA and further to dopaquinone. While numerous TYR inhibitors have been reported, polyphenolic compounds tend to dominate the literature. However, many of these compounds, particularly monophenols and catechols, have been identified as alternative substrates rather than true inhibitors, given their structural similarity to natural substrates. Resorcinol-containing compounds have emerged as promising candidates to address this challenge, as the meta-dihydroxy moiety in resorcinol demonstrates resistance to TYR-mediated oxidation, while retaining the favourable interactions with copper ions provided by the hydroxy groups. Although their precise mechanism of action remains debated, resorcinol derivatives have yielded some of the most active compounds against isolated mushroom and human TYRs, as well as clinically used dermocosmetic agents like rucinol and thiamidol, which exhibited very promising effects in patients with facial melasma. This review outlines the development of resorcinol-containing TYR inhibitors, categorized by scaffold type, ranging from simple alkyl analogues to intricate synthetic derivatives. Mechanistic insights about the resorcinol-TYR interaction are also presented and debated.
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  • 文章类型: Journal Article
    黄褐斑是一种普遍的皮肤病学挑战,治疗干预有限。富含血小板的血浆(PRP)因其在各种皮肤病学中的潜在益处而被越来越多地研究。本研究旨在系统评价PRP治疗黄褐斑的有效性和安全性。2024年1月,使用PubMed进行了符合系统审查和荟萃分析(PRISMA)指南的首选报告项目的全面搜索,重点研究PRP在黄褐斑中的疗效和安全性。纳入标准为临床试验和对照研究,检查PRP在黄褐斑治疗中的作用,虽然排除包括评论,非英语文章,研究年龄超过10年,在其他人中。其中包括8项研究,大多数针对女性参与者。研究显示出一致的积极成果,PRP是单独使用还是与氢醌和氨甲环酸等治疗协同使用。然而,PRP与其他药物联合使用的阳性研究将无法提供PRP的实际安全性和有效性数据.联合治疗方法通常显示出增强的结果。患者的满意度和黄褐斑面积和严重程度指数(MASI)评分的降低是整个研究的共同发现,强调PRP在黄褐斑管理中的潜力。总之,PRP成为黄褐斑的有希望的治疗干预措施。无论是作为独立治疗还是与既定方法相结合,PRP在黄褐斑的临床管理中具有巨大的潜力,保证进一步扩大试验,以证实其长期疗效和安全性。
    Melasma is a prevalent dermatological challenge with limited therapeutic interventions. Platelet-rich plasma (PRP) has been increasingly explored for its potential benefits in various dermatological conditions. This study aimed to systematically review the efficacy and safety of PRP in the treatment of melasma. A comprehensive search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was executed in January 2024 using PubMed, focusing on studies investigating the efficacy and safety of PRP in melasma. Criteria for inclusion were clinical trials and controlled studies examining PRP\'s role in melasma treatment, while exclusions covered reviews, non-English articles, and studies older than 10 years, among others. Eight studies were included, with the majority targeting female participants. The research displayed consistent positive outcomes, whether PRP was used alone or synergistically with treatments like hydroquinone and tranexamic acid. However, positive studies with the combination of PRP and other drugs will not provide the actual safety and efficacy data of PRP. The combined treatment approaches often showed enhanced results. Satisfaction rates among patients and reductions in the melasma area and severity index (MASI) scores were common findings across the studies, emphasizing the potential of PRP in melasma management. In conclusion, PRP emerges as a promising therapeutic intervention for melasma. Whether as a standalone treatment or combined with established methods, PRP presents significant potential in melasma\'s clinical management, warranting further expansive trials to substantiate its long-term efficacy and safety.
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  • 文章类型: Journal Article
    背景:痤疮的严重程度和治疗反应,黄褐斑,酒渣鼻可能受到目前尚不清楚的各种内部和外部因素的影响。本研究旨在通过实际病例对照研究为上述条件的影响因素提供证据。
    方法:实施了一项由60个问题组成的在线调查,收集人口统计信息,社会经济学,遗传因素,生活习惯,环境暴露,和皮肤护理行为。然后,我们构造了单变量和多变量逻辑回归。此外,我们分析了暴露与结局之间的剂量-反应关系.
    结果:共有399人,包括94名痤疮患者,107名黄褐斑患者,并纳入91例酒渣鼻患者。痤疮和黄褐斑与屏幕时间呈正相关(痤疮:比值比[OR]:2.24,95%置信区间[CI]:1.25-4.02;黄褐斑:OR:1.59,95%CI:1.09-2.31),而运动对痤疮(OR:0.31,95%CI:0.13-0.77)和黄褐斑(OR:0.42,95%CI:0.22-0.80)均具有剂量反应关系。此外,男性与痤疮风险升高相关(OR:6.62,95%CI:1.01-43.26).年龄(OR:1.15,95%CI:1.07-1.24)和不规则排便(OR:2.99,95%CI:1.11-8.08)是黄褐斑的独立危险因素。酒渣鼻与BMI呈正相关(OR:1.17,95%CI:1.01~1.35)。
    结论:在我们的研究中,我们强调运动是痤疮和黄褐斑的独立保护因素,呈剂量-反应趋势.相反,电子设备的长期使用与痤疮和黄褐斑的高风险独立相关.酒渣鼻,然而,更有可能与BMI有关。
    BACKGROUND: The severity and treatment response of acne, melasma, and rosacea may be influenced by various currently unclear internal and external factors. This study aimed to provide evidence to the influencing factors for the mentioned conditions through a real-world case-control study.
    METHODS: An online survey consisting of 60 questions was implemented, collecting information on demographics, socioeconomics, genetic factors, lifestyle habits, environmental exposures, and skin care behaviors. Then we constructed univariate and multivariate logistic regressions. Furthermore, we analyzed the dose-response relationship between exposure and outcome.
    RESULTS: A total of 399 individuals, including 94 acne patients, 107 melasma patients, and 91 rosacea patients were included. Acne and melasma were positively correlated with screen time (acne: odds ratio [OR]: 2.24, 95% confidence interval [CI]: 1.25-4.02; melasma: OR: 1.59, 95% CI: 1.09-2.31), while exercise exerted a protective effect on both acne (OR: 0.31, 95% CI: 0.13-0.77) and melasma (OR: 0.42, 95% CI: 0.22-0.80) in a dose-response relationship. In addition, males were associated with an elevated risk of acne (OR: 6.62, 95% CI: 1.01-43.26). Aging (OR: 1.15, 95% CI: 1.07-1.24) and irregular bowel movements (OR: 2.99, 95% CI: 1.11-8.08) were independent risk factors for melasma. Rosacea was positively associated with BMI (OR: 1.17, 95% CI: 1.01-1.35).
    CONCLUSIONS: In our study, we highlighted exercise as an independent protective factor for both acne and melasma in a dose-response trend. Inversely, extended use of electronic equipment was independently associated with higher risks of acne and melasma. Rosacea, however, was more likely to be related with BMI.
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  • 文章类型: Journal Article
    对当前可用的黄褐斑治疗的反应,真皮型,特别是,通常是渐进的,可能会导致可能的副作用。
    在这项研究中,我们的目的是评估富含生长因子的血浆(PRGF)和局部4%氢醌(HQ)联合治疗与单独使用局部4%HQ的单药治疗皮肤型黄褐斑的疗效.
    这是一个单盲,随机化,20例皮肤型黄褐斑女性患者的分面临床试验。要求患者在夜间在面部两侧局部施用4%HQ,持续6个月。在每个参与者中,我们随机选择一侧面部接受3次PRGF的每月皮内注射.使用半黄褐斑面积和严重程度指数(MASI)评分评估治疗效果,医师全球评估(PGA),和患者全球评估(PtGA)。
    两组均显示治疗过程中半MASI评分的显着改善。在联合治疗和单一治疗组中,研究结束时的平均改善百分比为40.38±6.04%和33.42±3.23%。分别为(P=0.31)。在联合治疗和单一治疗组中,PGA在25%和5%的患者中显示出黄褐斑的显着改善,分别为(P=0.31)。PtGA在联合治疗组中15%的患者中显示出较高的满意度(与单药治疗组为0%(P=0.05)。
    两个治疗组在hemi-MASI和PGA评分方面的差异无统计学意义;然而,与单独使用局部HQ相比,患者对PRGF和外用4%HQ的组合表现出更高的满意度.因此,PRGF和外用4%HQ联合治疗可被认为是一种安全的替代治疗方法,并有望为皮肤型黄褐斑的未来治疗方案的开发提供依据.
    UNASSIGNED: Response to the current available treatments of melasma, dermal type, in particular, is usually gradual and can result in possible side effects.
    UNASSIGNED: In this study, we aim to evaluate the efficacy of the combination of plasma rich in growth factors (PRGF) and topical 4% hydroquinone (HQ) in comparison with monotherapy using topical 4% HQ alone in the treatment of dermal type of melasma.
    UNASSIGNED: This is a single-blinded, randomized, split-face clinical trial on twenty female patients with dermal type of melasma. Patients were asked to apply topical 4% HQ on both sides of their face at night for 6 months. In each participant, one side of the face was randomly chosen to receive monthly intradermal injections of PRGF for 3 sessions. Efficacy of the treatment was assessed using hemi melasma area and severity index (MASI) score, physician\'s global assessment (PGA), and patients\' global assessment (PtGA).
    UNASSIGNED: Both groups revealed significant improvement in hemi-MASI score during the treatment course. Mean percentage of improvement at the end of study was 40.38 ± 6.04% and 33.42 ± 3.23% in the combination therapy and monotherapy groups, respectively (P = 0.31). PGA demonstrated excellent-to-marked improvement in melasma in 25% and 5% of patients in the combination therapy and monotherapy groups, respectively (P = 0.31). PtGA showed high levels of satisfaction in 15% of patients in the combination therapy group (vs. 0% in the monotherapy group) (P = 0.05).
    UNASSIGNED: Differences between the two treatment groups in terms of hemi-MASI and PGA scores were not statistically significant; however, patients demonstrated higher satisfaction with combination of PRGF and topical 4% HQ compared with topical HQ alone. Thereby, combination of PRGF and topical 4% HQ can be suggested as a safe alternative therapeutic approach and may hold promise in the development of future therapeutic options for dermal type of melasma.
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  • 文章类型: Journal Article
    背景:黄褐斑的治疗具有挑战性,突出了常规疗法的不足之处和高复发风险。整合微针用于与氨甲环酸(TA)的装置辅助药物递送,因其黑色素合成抑制而被认可,提出了一种新颖的方法,值得进一步研究,以充分评估其在增强黄褐斑治疗功效方面的潜力。
    方法:50名中度至重度黄褐斑患者参加了这项随机结局评估盲法对照试验。患者被随机分为两个主要组。A组在交替的夜晚在一个半面接受改良的Kligman配方,持续2个月(A1),并在另一个半面以1个月的间隔(A2)接受3次微针治疗,其中10%的局部TA。B组在面部两侧使用相同的改良Kligman配方,一侧额外接受三个阶段的4%TA(B1)和10%TA(B2)的另一侧。主要结果为6个月随访期间改良黄褐斑面积和严重程度指数(mMASI)和视觉模拟评分(VAS)变化百分比。记录不良事件,包括炎症后色素沉着过度(PIH)和治疗耐受性。
    结果:与基线相比,A1、B1和B2在最后一次会议后立即降低的平均mMASI更高(56.84%,50.88%,55.87%,分别)比A2下降了13.16%。在所有组停止治疗后,功效显著下降。A1、B1和B2组的疗效相当,4%或10%TA的微针结合局部改良的Kligman配方被证明对PIH风险较低的患者更有效。总的来说,22%的患者报告PIH,特别是在A2组(28%的半面),其发生与在温暖的季节和较深的皮肤光型中的治疗显着相关。在任何患者中均未观察到其他不良事件。B1组和B2组患者满意度最高,其中约72%报告“优秀”满意度。在A2组中观察到最低的耐久性率(16%),而在B2组中观察到最高的耐久性率(72%),与A1和B1组相当。所有组的治疗耐受性报告为100%。
    结论:发现改良的Kligman配方优于单独的微针疗法-TA。然而,通过最佳的患者选择,特别是针对那些在低风险的PIH与较轻的皮肤照型和安排治疗在阳光较少的季节,与常规局部治疗相比,将微针与4%或10%TA和改良的Kligman配方相结合,显着提高了疗效和满意度。
    BACKGROUND: The challenging management of melasma highlights the inadequacies of conventional therapies and their high risk of recurrence. Integrating microneedling for device-assisted drug delivery with tranexamic acid (TA), recognized for its melanin synthesis inhibition, presents a novel approach that warrants further investigation to fully assess its potential in enhancing melasma treatment efficacy.
    METHODS: Fifty moderate to severe melasma patients participated in this randomized outcome-assessor-blinded controlled trial. Patients were randomly allocated into two main groups. Group A received a modified Kligman formula on one hemi-face on alternate nights for 2 months (A1) and three sessions of microneedling with 10% topical TA on the other hemi-face at 1-month intervals (A2). Group B used the same modified Kligman formula on both sides of the face, with one side additionally receiving three sessions of microneedling with 4% TA (B1) and the opposite side with 10% TA (B2). Primary outcomes were % Modified Melasma Area and Severity Index (mMASI) and % visual analogue scale (VAS) change during 6 month follow-up. Adverse events including post-inflammatory hyperpigmentation (PIH) and treatment tolerability were recorded.
    RESULTS: Compared to baseline, the mean mMASI reduction immediately after the final session was higher in A1, B1, and B2 (56.84%, 50.88%, and 55.87%, respectively) than in A2, which saw only a 13.16% reduction. Efficacy notably declined after the cessation of treatment across all groups. While the efficacy within groups A1, B1, and B2 was comparable, microneedling with 4% or 10% TA combined with the topical modified Kligman formula proved more potent in patients at a lower risk of PIH. Overall, 22% of patients reported PIH, particularly in the A2 group (28% of hemi-faces), with its occurrence significantly associated with treatment during warmer seasons and in darker skin phototypes. Other adverse events were not observed in any patient. Patient satisfaction was highest in groups B1 and B2, where approximately 72% reported \'excellent\' satisfaction. The lowest durability rate (16%) was observed in group A2, while the highest (72%) was seen in group B2, comparable with groups A1 and B1. Treatment tolerability was reported 100% in all groups.
    CONCLUSIONS: It was found that the modified Kligman formula outperformed microneedling-TA alone. However, with optimal patient selection, particularly targeting those at lower risk for PIH with lighter skin phototypes and scheduling treatments during less-sunny seasons, combining microneedling with 4% or 10% TA and the modified Kligman formula significantly enhanced efficacy and satisfaction rates compared to conventional topical treatment.
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  • 文章类型: Editorial
    色素和毛发疾病具有显著的美容和心理影响。在八月份的《华尔街日报》上,我们重点介绍了反射共聚焦显微镜在诊断和监测黄褐斑患者治疗反应中的应用。我们还将讨论涉及口服褪黑激素以及谷胱甘肽和白藜芦醇联合治疗黄褐斑的新治疗方法。此外,口服低剂量米诺地尔治疗脱发的革命将受到关注,包括在媒体关注的情况下,人们对口服米诺地尔处方的兴趣与日俱增。
    Pigmentary and hair disorders have a significant cosmetic and psychological impact. In the August issue of the Journal, we highlight the use of reflectance confocal microscopy in diagnosing and monitoring treatment responses in patients with melasma. We will also discuss new therapeutic approaches involving oral melatonin and a combination of glutathione and resveratrol for melasma. Additionally, the ongoing revolution in alopecia treatment with oral low-dose minoxidil will be spotlighted, including the circumstances under which media attention has contributed to the growing interest in oral minoxidil prescriptions.
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