Perspectives of topical formulations for melasma.

Melasma is acquired hyperpigmentation that mainly affects the face, can cause negative changes in self-esteem, and mostly affects women. Treatment is difficult, and different drugs can be used in mono or combination therapy. In this article, we present a brief overview of melasma, how to evaluate it, and a synthesis of the most commonly used topical therapies and their indications, including sunscreens, pharmacological agents, and plant extracts. Hydroquinone (4%) in monotherapy or combined with corticosteroids (dexamethasone and fluocinolone acetonide) and retinoids (tretinoin); arbutin (1%); methimazole (5%); kojic (2%), azelaic (20%), and tranexamic (5%) acids are the pharmacological agents that stand out. Correct application of these substances determines a variable improvement in melasma but often causes adverse reactions such as erythema, itching, and burning at the application site. Vitamin C can contribute to the reduction of melasma and have little or no adverse effects while sunscreens are normally used as coadjuvant therapies. In conclusion, we have compiled specific topical therapies for treating melasma and discussed those that are the most used currently. We consider it important that prescribers and researchers evaluate the best cost-benefit ratio of topical therapeutic options and develop new formulations, enabling efficacy in the treatment with safety and comfort during application, through the reduction of adverse effects.

Understanding Melasma-How Can Pharmacology and Cosmetology Procedures and Prevention Help to Achieve Optimal Treatment Results? A Narrative Review.

Melasma is a chronic skin condition that involves the overproduction of melanin in areas exposed to ultraviolet radiation. Melasma treatment is long-term and complicated with recurrence and resistance to treatment. The pathogenesis of melasma is highly complex with multiple pathologies occurring outside of the skin pigment cells. It includes photoaging, excessive melanogenesis, an increased number of mast cells, increased vascularization, and basement membrane damage. In addition, skin lesions related to melasma and their surrounding skin have nearly 300 genes differentially expressed from healthy skin. Traditionally, melasma was treated with topical agents, including hydroquinone, tretinoin, glucocorticosteroids and various formulations; however, the current approach includes the topical application of a variety of substances, chemical peels, laser and light treatments, mesotherapy, microneedling and/or the use of systemic therapy. The treatment plan for patients with melasma begins with the elimination of risk factors, strict protection against ultraviolet radiation, and the topical use of lightening agents. Hyperpigmentation treatment alone can be ineffective unless combined with regenerative methods and photoprotection. In this review, we show that in-depth knowledge associated with proper communication and the establishment of a relationship with the patient help to achieve good adherence and compliance in this long-term, time-consuming and difficult procedure.

Topical Cyperus rotundus essential oil for treatment of axillary hyperpigmentation: a randomized, double-blind, active- and placebo-controlled study.

BACKGROUND: The oil of the grass Cyperus rotundus (purple nutsedge) is an effective and safe treatment option for a variety of conditions. It has anti-inflammatory and antipigmenting properties. There have been no clinical trials comparing topical C. rotundus oil with skin-lightening treatments for axillary hyperpigmentation. AIM: To assess the efficacy of C. rotundus essential oil (CREO) in treating axillary hyperpigmentation, and compare with another active treatment hydroquinone (HQ) and a placebo (cold cream) in this study. METHODS: The study included 153 participants, who were assigned to one of three study groups: CREO, HQ group or placebo group. A tri-stimulus colorimeter was used to assess pigmentation and erythema. Two independent experts completed the Physician Global Assessment, and the patients completed a self-assessment questionnaire. RESULTS: CREO had significantly (P < 0.001) better depigmenting effects than HQ. CREO and HQ did not differ significantly in terms of depigmentation effects (P > 0.05); however, there were statistically significant differences in anti-inflammatory effects and decrease in hair growth (P < 0.05) in favour of CREO. CONCLUSIONS: CREO is a cost-effective and safe treatment for axillary hyperpigmentation.

Fractional erbium:YAG laser (2940 nm) plus topical hydroquinone compared to intradermal tranexamic acid plus topical hydroquinone for the treatment of refractory melasma: a randomized controlled trial.

OBJECTIVES: Melasma is a chronic acquired condition characterized by grayish-brown macules and patches with a distinct border on the face. Although various treatments methods have been suggested for treating melasma, none has been completely successful. The aim of the study was to compare the efficiency of erbium: yttrium-aluminum-garnet (Er:YAG) laser and 4% hydroquinone (HQ) with the effects of intradermal tranexamic acid (TA) and 4% HQ for the treatment of refractory melasma. METHODS: The study included 31 female patients with refractory melasma. The left or right side of the patient's face was chosen randomly to receive laser therapy with topical HQ on the one side (i.e. the laser side) and intradermal injection of TA plus topical HQ on the other side (i.e. the mesotherapy side). Digital photography was performed at baseline, at the end of the treatment, and three months after the treatment as follow-up. Two independent dermatologists evaluated the modified Melasma Area and Severity Index (mMASI) score according to the pictures. Overall, 27 patients completed the study and went through the clinical evaluation. RESULTS: Treatment using HQ in combination with either Er:YAG laser therapy or intradermal injection of TA significantly improved the hemi-mMASI and resulted in higher patient satisfaction. While the improvement was not significantly different between the two regiments after the treatment and upon follow up and both were equally efficient in the treatment of refractory melasma (p = 1.308), recurrence rate was higher after treatment with Er:YAG laser than TA (12% vs 34%). CONCLUSION: This study confirmed the comparable efficacy of TA plus topical HQ versus Er:YAG laser plus topical HQ for the treatment of refractory melasma. Both groups improved significantly and no subject left the treatment because of adverse effects. TRIAL REGISTRATION NUMBER: IRCT20191011045057N1.

Antioxidant Combo Therapy Protects White Matter After Traumatic Brain Injury.

Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.

Efficacy of 577 nm pro-yellow laser in the treatment of melasma: a prospective split-face study.

We aimed to study the effectiveness of 577 nm pro-yellow laser in the treatment of melasma. A total of 82 patients with melasma were included in this comparative study. A detailed medical history, examination, and calculation of Melasma Area and Severity Index were done for all patients. All participants were treated with topical sunscreen and hydroquinone 4% cream on both sides of the face. In addition, the left side of the face was subjected to a single pass of 577-nm pro-yellow laser at a monthly interval for three sessions. Follow up was done by comparing the Melasma area and severity index at 0, 3 and 6 months. At baseline, there is no significant difference in the Melasma area and severity index score between both sides of the face. At 3 months, MASI score was statistically significantly decreased on both sides of the face compared to pretreatment (P < .05). At 6 months, the mean MASI score at the laser-treated side was statistically significantly decreased compared to the non-laser-treated side (P < .05). we concluded that the addition of 577 nm pro-yellow laser in the treatment of melasma leads to maintain the improvement and reduction of the recurrence rate.

What's New in Pigmentary Disorders.

Pigmentary disorders are common and can be very distressing to patients. There is a need for better, standardized therapies. The authors review the most recent data for topical, systemic, light, and laser treatments for vitiligo, melasma, and postinflammatory hyperpigmentation. There is a paucity of large-scale, well-designed, randomized, controlled trials for these treatments. Treatment options are often drawn from smaller trials and case series. The treatments described in this article are promising candidates for larger follow-up studies.

Complications and posttreatment care following invasive laser skin resurfacing: A review.

OBJECTIVE: Laser skin resurfacing (LSR) has been used for facial rejuvenation for the last 20 years. Posttreatment care after LSR is essential to decrease the risk of complications. Currently, no unified standards or criteria exist for invasive LSR posttreatment care. We aimed to identify the optimal wound care timing and choice of specific local, systemic, and general medical measures required to decrease complications. METHODS: We performed a systematic search of the PubMed/MEDLINE electronic databases and included only articles written and published in the English language, with no restrictions on the publication time (year). RESULTS: The search yielded 316 potentially relevant articles, 133 of which met our review criteria. Most of the studies on this topic have focused on wound care during the early stage, typically the first 2 weeks. Closed dressings may offer a more ideal, moist wound environment. The use of medications must be judicious. The ongoing emergence of new methods and products warrants evaluation in future large clinical trials. SUMMARY: Familiarity with the complications following invasive LSR and the provision of optimal, effective, and timely posttreatment care may substantially decrease the risks associated with the treatment modality.

Effects of a fractional picosecond 1,064 nm laser for the treatment of dermal and mixed type melasma.

BACKGROUND: Picosecond laser is a novel modality for pigmented skin disorders with extremely short pulse duration. Little is known about the effects of the picosecond laser in melasma. OBJECTIVE: This study aimed to investigate the efficacy of fractional picosecond 1,064 nm laser in melasma treatment. STUDY DESIGN: A prospective, randomized, assessor-blinded, intra-individual split face comparative study. METHODS: Female subjects with melasma were enrolled and received fractional picosecond 1,064 nm laser plus 4% hydroquinone cream on one randomly assigned side of the face; the results were compared to the use of hydroquinone cream only on the contralateral side. The modified melasma area severity index (mMASI) score, melanin index by Mexameter MX18®, participant satisfaction score by quartile rating scale, and the quality of life by the dermatology life quality index (DLQI) were evaluated over 12 weeks. RESULTS: Thirty female subjects completed the protocol. The mean (± standard deviation, SD) mMASI score at the 12-week visit was significantly reduced in the picosecond laser-treated areas compared to controls (3.52 ± 1.4 and 4.18 ± 2.03 respectively; p = 0.035). No differences were observed in the mean Mexameter melanin index, participant satisfaction score, and DLQI score. The observed adverse effects included transient mild erythema and mild skin desquamation. CONCLUSION: The addition of fractional picosecond 1,064 nm laser to 4% hydroquinone was effective and significantly better than 4% hydroquinone alone for the treatment of melasma.

Depigmentation Therapies for Vitiligo.

The general goals of medical management of vitiligo are to repigment vitiliginous areas of skin and to stabilize the progression of depigmentation. However, for some patients with vitiligo affecting extensive body surface areas who are unresponsive to repigmentation therapies, depigmentation of the remaining normal skin may be a better choice. Candidates for depigmentation therapy should be carefully screened and patient education is essential. Permanent topical therapies used for depigmentation include monobenzyl ether of hydroquinone, 4-methoxyphenol, and 88% phenol. Physical modalities, such as cryotherapy and lasers, are also being used successfully.

A pilot study for triple combination therapy with a low-fluence 1064 nm Q-switched Nd:YAG laser, hydroquinone cream and oral tranexamic acid for recalcitrant Riehl's Melanosis.

BACKGROUND: Riehl's melanosis presents as a diffuse gray-brown to black hyperpigmentation around face. The treatment of this disease is challenging and quite limited despite patients' excessive psychological stresses. OBJECTIVE: In this prospective pilot study, we evaluated the efficacy and safety for a novel combination therapy based on low-fluence Q-switched 1064 nm Nd:YAG laser, hydroquinone cream and oral tranexamic acid for recalcitrant Riehl's melanosis. METHODS: Totally eight patients with Riehl's melanosis who had failed improvements previously received multiple sessions (10-18 times) of combination treatment regimen. The primary endpoint was clinical score by the physician and the secondary endpoints were clinical score by the patients, instrumental analysis using melanin and erythema values, and histopathological score. RESULTS: Among eight patients, three received "Almost clear" grade, the other five patients received "Marked improvement" grade at final visits. No serious adverse events and post-treatment downtime was observed. Mean Melanin and Erythema Indexes also showed significant decreases compared with baseline. Histopathologic examination confirmed a significantly greater reduction of melanin content in melanophages. CONCLUSION: This combination method can be a viable option for Asian patients having Riehl's melanosis with high risk of post-inflammatory hyperpigmentation, maintaining low-dose laser irradiation.

The Effect of Topical Use of Petroselinum Crispum (Parsley) Versus That of Hydroquinone Cream on Reduction of Epidermal Melasma: A Randomized Clinical Trial.

Melasma disfigures the skin and thus influences people's self-image and self-concept. Therefore, melasma influences emotional and psychosocial health in addition to physical health. This clinical trial was performed to assess the effect of the topical use of Petroselinum crispum (parsley) on reduction of the severity of epidermal melasma.

Natural Cosmeceutical Ingredients for Hyperpigmentation.

As Dermatologists caring for patients with hyperpigmentation problems, we are always looking for more alternative therapies. Hydroquinone (HQ) is still the standard of care. However, traditional depigmenting agents such as HQ and corticosteroids, although highly effective, can raise safety concerns including exogenous ochronosis, atrophy, carcinogenesis and local and systemic untoward effects with long term use. Therefore, we need to investigate non-prescription natural alternatives. This manuscript presents many of the natural ingredients found in cosmeceuticals for the treatment of hyperpigmentation and their mechanisms of action. It will also describe the melanocyte activation pathways and how each of these ingredients interferes with it.

Triple combination as adjuvant to cryotherapy in the treatment of solar lentigines: investigator-blinded, randomized clinical trial.

BACKGROUND: Post-inflammatory hyperpigmentation is a frequent concern when treating solar lentigines. OBJECTIVES: To assess the safety and efficacy of a triple combination cream with fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05% as adjuvant to cryotherapy in the treatment of solar lentigines in hands dorsum, and in the prevention of post-inflammatory hyperpigmentation after cryotherapy. METHODS: This prospective, randomized, controlled, investigator-blinded, single-centre study enrolled 50 patients. Twenty-five patients received a 2-week daily triple combination cream plus sunscreen pre-treatment and 25 received sunscreen alone. After that, cryotherapy was performed in all patients followed by a 3-week recovery period. After this period, patients received the same initial treatment and were followed up for 8 weeks. Melanin and erythema levels of a target and a control lentigo were objectively measured using a narrowband reflectance spectrophotometer. Lentigines count, colour homogeneity and global improvement were also assessed. RESULTS: The number of solar lentigines reduced in the first 2 weeks only in patients who used the triple combination 25 ± 7 vs. 22 ± 8 (P < 0.0001), and reduced at the end of the study for both groups (P < 0.0001). The melanin levels also reduced in the first 2 weeks only in patients who used the triple combination 297 ± 69 vs. 273 ± 66 (P < 0.0001) and reduced at the end of the study for both groups (P < 0.0001). Erythema and residual blisters from cryotherapy were the reported adverse reactions. CONCLUSION: Triple combination cream can be used to enhance the resolution of solar lentigines, and to significantly reduce melanin levels and lentigines count, improving treatment results. It was well-tolerated and did not increase the occurrence of neither erythema nor other side-effects after the cryotherapy.

A randomized, double-blind, placebo-controlled clinical trial on the efficacy and safety of 3% Rumex occidentalis cream versus 4% hydroquinone cream in the treatment of melasma among Filipinos.

BACKGROUND: Melasma is a commonly acquired hyperpigmentation symmetrically distributed on the face, neck, and arms. The skin-lightening properties of Rumex occidentalis make it a therapeutic alternative to the reference standard treatment of hydroquinone (HQ). OBJECTIVES: This study was conducted to evaluate the safety and efficacy of 3% R. occidentalis cream versus 4% HQ cream in the management of epidermal and mixed melasma. METHODS: This was a randomized, double-blind, placebo-controlled trial. Forty-five subjects with epidermal and mixed melasma were recruited to compare 3% R. occidentalis cream, 4% HQ cream, and placebo cream applied twice daily for eight weeks. Changes in pigmentation were measured every two weeks using the Melasma Area Severity Index (MASI) and a mexameter. Adverse events were noted on every visit. Patient and investigator global evaluations were performed at the end of the study. RESULTS: Overall mean MASI and mexameter readings in the three groups decreased from baseline to week 8. The greatest decline in score from weeks 2 to 6 was achieved by the HQ group, followed by the R. occidentalis group. By week 8, the R. occidentalis group showed a greater mean ± standard deviation decline in MASI and mexameter readings from baseline (MASI: 0.60 ± 0.86; mexameter: 50.56 ± 25.63) than the HQ group (MASI: 0.55 ± 0.62; mexameter: 45.89 ± 47.83). The efficacy of R. occidentalis cream and HQ cream were assessed as similarly favorable by both study subjects and investigators. CONCLUSIONS: Rumex occidentalis 3% cream is a safe and effective skin-lightening agent for melasma and is comparable in efficacy with 4% HQ cream.

Pretreatment with tert-butylhydroquinone attenuates cerebral oxidative stress in mice after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a worldwide health problem, identified as a major cause of death and disability. Increasing evidence has shown that oxidative stress plays an important role in TBI pathogenesis. The antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), is a known mediator in protection against TBI-induced brain damage. The objective of this study was to test whether tert-butylhydroquinone (tBHQ), a novel Nrf2 activator, can protect against TBI-induced oxidative stress. METHODS: Adult male imprinting control region mice were randomly divided into three groups: (1) sham + vehicle group; (2) TBI + vehicle group; and (3) TBI + tBHQ group. Closed-head brain injury was applied using the Feeney weight-drop method. We accessed the neurologic outcome of mice at 24 h after TBI, and subsequently measured protein levels of Nrf2 and the NOX2 subunit of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), the concentration of malondialdehyde, superoxide dismutase activity, and brain edema. RESULT: The NOX2 protein level was increased fivefold in the TBI + vehicle group, whereas pretreatment with tBHQ markedly attenuated the NOX2 protein expression relative to that in the TBI + vehicle group. TBI increased Nrf2 formation by 5% compared with the sham group, whereas treatment with tBHQ further upregulated the Nrf2 protein level by 12% compared with the sham group. The level of the oxidative damage marker malondialdehyde was reduced by 29% in the TBI + tBHQ group compared with the TBI + vehicle group, Moreover, pretreatment with tBHQ significantly increased the antioxidant enzyme superoxide dismutase activity. Administration of tBHQ also significantly decreased TBI-induced brain edema and neurologic deficits. CONCLUSIONS: Pretreatment with tBHQ effectively attenuated markers of cerebral oxidative stress after TBI, thus supporting the testing of tBHQ as a potential neuroprotectant and adjunct therapy for TBI patients.

An ortho-carbonyl substituted hydroquinone derivative is an anticancer agent that acts by inhibiting mitochondrial bioenergetics and by inducing G2/M-phase arrest in mammary adenocarcinoma TA3.

Tumor cells present a known metabolic reprogramming, which makes them more susceptible for a selective cellular death by modifying its mitochondrial bioenergetics. Anticancer action of the antioxidant 9,10-dihydroxy-4,4-dimethyl-5,8-dihydroanthracen-1(4H)-one (HQ) on mouse mammary adenocarcinoma TA3, and its multiresistant variant TA3-MTXR, were evaluated. HQ decreased the viability of both tumor cells, affecting slightly mammary epithelial cells. This hydroquinone blocked the electron flow through the NADH dehydrogenase (Complex I), leading to ADP-stimulated oxygen consumption inhibition, transmembrane potential dissipation and cellular ATP level decrease, without increasing ROS production. Duroquinol, an electron donor at CoQ level, reversed the decrease of cell viability induced by HQ. Additionally, HQ selectively induced G2/M-phase arrest. Taken together, our results suggest that the bioenergetic dysfunction provoked by HQ is implicated in its anticancer action.

Single-session intense pulsed light combined with stable fixed-dose triple combination topical therapy for the treatment of refractory melasma.

The effectiveness of intense pulsed light (IPL) has been reported in adults with melasma, but there is little information about IPL with triple combination topical therapy (TC) and refractory melasma. Sixty-two patients with totally or partially refractory melasma were enrolled in this randomized open-label study. Thirty-one patients were treated with IPL in a single session, bleaching agents and broad-spectrum sunscreens. Thirty-one patients were in the control group, receiving only bleaching agents and broad-spectrum sunscreens. The Melasma Area and Severity Index (MASI) and the investigator's global assessment using a seven-point scale were used to determine the impact and effectiveness of the treatment. The IPL group results based on MASI showed a 49.4% reduction (from 17.6 to 8.9; p < 0.001) after six months and a 44.9% reduction after 12 months (from 17.6 to 9.7; p < 0.001). The investigator's global assessment showed that the difference in the improvement rate between the IPL group and control group was significant (p = 0.002), with a better response in the IPL group. Single session IPL combined with stable fixed-dose triple combination treatment is a safe and effective treatment for refractory mixed and dermal melasma.

Advanced treatment modalities for vitiligo.

BACKGROUND: Vitiligo is an acquired multifocal and polygenic dyschromia that affects 1% to 3% of the world and presents as multiple depigmented macules and patches. Traditionally, the treatment of vitiligo has focused on pharmacologic interventions, but nearly half of all treated patients fail to respond successfully. OBJECTIVE: Several advanced techniques exist that can aid dermatologists in treating vitiligo in patients who do not respond favorably to traditional pharmacologic treatments. These advanced interventions include the use of the 308-nm excimer laser, total body depigmentation therapy with monobenzyl ether of hydroquinone, microdermabrasion, micropigmentation, khellin-UVA therapy, and surgical management using miniature punch grafting, suction blister grafting, and epidermal cultures. MATERIALS AND METHODS: This article reviews the current literature on these advanced treatment modalities for vitiligo and provides a practical guide for application of these techniques. RESULTS AND CONCLUSION: Our ability to treat vitiligo may be imperfect, but through appropriate patient selection and careful application of one or more of these advanced therapies, successful treatment of vitiligo, even in patients refractory to treatment, can be achieved.

Topical treatment of hyperpigmentation disorders.

Hyperpigmentation has traditionally been a relatively difficult condition to treat, especially in darker racial ethnic groups. Multiple topical agents available act upon different steps of the pigmentation pathway. We review these topical agents, their mechanisms of action, and their effectiveness as monotherapy and in combination with other compounds. Ultimately, combination therapy is the most efficacious when considering overall depigmentation as well as treatment time required to achieve clinical improvement.