Efficacy and safety of liposome‐encapsulated 4‐n‐butylresorcinol 0.1% cream for the treatment of melasma: A randomized controlled split‐face trial

Melasma is an acquired pigmentary disorder that most commonly occurs in women of child‐bearing age. Melasma is therapeutically challenging, and most commercially available hypopigmenting agents include tyrosinase inhibitors, which regulate the rate‐limiting step of melanogenesis. 4‐n‐Butylresorcinol has received considerable attention as a novel hypopigmenting agent in the last 15 years because it has an inhibitory effect against tyrosinase and tyrosinase‐related protein‐1. However, the hypopigmenting effect of 4‐n‐butylresorcinol in human subjects has only been shown in a few studies. Liposome encapsulation is known to improve stabilization and enhance penetration of the product. Therefore, this study was conducted to evaluate the hypopigmenting efficacy and safety of liposome‐encapsulated 4‐n‐butylresorcinol 0.1% cream in patients with melasma. This was a randomized, double‐blind, vehicle‐controlled and split‐face comparison study. Twenty‐three patients with a clinical diagnosis of melasma were included. 4‐n‐Butylresorcinol 0.1% cream or vehicle was applied to each side of the face twice daily for 8 weeks. Clinical and photographic evaluations, Mexameter measurements and assessment of patient satisfaction and side‐effects were performed at baseline, 4 and 8 weeks. All subjects completed the study. Mexameter measurements demonstrated that the melanin index of the 4‐n‐butylresorcinol‐treated side showed a significant decrease when compared with the vehicle‐treated side after 8 weeks (P = 0.043). No adverse reactions were observed throughout the study. Subjectively, 4‐n‐butylresorcinol was considered to be efficacious in more than 60% of the patients after 8 weeks of treatment. In conclusion, liposome‐encapsulated 4‐n‐butylresorcinol 0.1% cream was well tolerated and showed significant higher efficacy than vehicle alone for the treatment of melasma.     

Treatment monitoring of 5‐fluorouracil 0.5%/salicylic acid 10% lesion‐directed therapy for actinic keratosis using dermoscopy and in‐vivo reflectance confocal microscopy

Recently, 5‐fluorouracil 0.5%/salicylic acid 10% (5‐FU/SA) topical solution has been included in the National Italian portfolio for lesion‐directed treatment of grade I/II actinic keratosis (AKs) located on the face or scalp. To describe the utility of dermoscopy and RCM in treatment response monitoring of a series of AKs treated with 5‐FU/SA as lesion‐directed therapy. Consecutive patients were prospectively treated for a maximum of 12 weeks with 5‐FU/SA for AKs located on the face or scalp. Clinical, dermoscopic, and confocal images of one index AK were acquired at each visit and pre‐specified criteria were evaluated. Clinical, dermoscopic, and confocal responses were evaluated at last follow‐up visit. Fourteen patients were enrolled, of which five were treated for 12 weeks, seven for 8, and two for 4 weeks. At a median follow up of 30 weeks, 64.3% (9/14) index AKs achieved complete clinical, 50% (7/14) complete dermoscopic and 42.9% (6/14) complete confocal clearance. Local skin reaction was mild and significantly decreased during therapy administration. Although the small number of cases, our study underlines the utility of both dermoscopy and in‐vivo RCM in 5‐FU/SA treatment response monitoring for AKs located on the face or scalp.     

Prospective,open‐label,rater‐blinded and self‐controlled pilot study of the treatment of proliferating superficial infantile hemangiomas with 0.5% topical timolol cream versus 595‐nm pulsed dye laser

Topical timolol and 595‐nm pulsed dye laser (PDL) are both widely used in the treatment of superficial infantile hemangiomas (IH). However, to date, there is no reliable study comparing the therapeutic outcomes between the two treatment options. We designed the present study to evaluate and compare the efficacy and safety of timolol cream and PDL in the treatment of superficial proliferating IH. Twenty‐one patients with superficial IH were included in the study. Each lesion was divided into two regions; one part was treated with 0.5% topical timolol cream four times daily, and the other part was treated monthly with PDL. Both treatments were continued for 2–6 months. Five independent and blinded assessors were asked to judge the results in both the topical timolol‐treated and PDL‐treated parts by comparing photographs taken before and after treatment. Both treatments resulted in significant clinical improvements after 3.39 sessions in the 2‐month follow up. The average visual evaluation showed that PDL had significantly better results than topical timolol (6.55 ± 2.26 to 4.98 ± 2.92, P < 0.01). No patients experienced permanent side‐effects during the treatment. Our short‐term study revealed that PDL had better results compared with topical timolol cream application in the treatment of superficial proliferating IH. Further studies with longer follow‐up time and larger sample size are required to validate our findings.     

Basal cell carcinomas treated with 0.5% 5‐fluorouracil and 10% salicylic acid topical solution

Basal cell carcinomas (BCCs) are the most common nonmelanoma skin cancers. Dermoscopy is an indispensable tool to differentiate superficial BCC from other subtypes and between pigmented and not pigmented ones. Although surgery is considered the gold‐standard therapy, new current pharmacological options are available and focus on tumor eradication, increasing cosmetic results and functionality. 5‐fluorouracil (5‐FU) is a cytostatic drug associated with antimetabolite effects and already approved as monotherapy for superficial BCCs treatment. A recent formulation combining of 5‐FU 0.5% with salicylic acid 10% has been indicated for the management of slightly palpable and/or moderately thick hyperkeratotic actinic keratosis of the face, forehead, and balding scalp in immunocompetent adult patients. This formulation has never been used as treatment for superficial BCC. In this article, we reported superficial BCC clinical and dermoscopic outcomes in two patients treated with this new topical agent, to assess its role in treating these lesions and to point out dermoscopy's usefulness in supporting clinical diagnosis and excluding tumor persistence or recurrence.     

Topical 2% ketoconazole cream monotherapy significantly improves adult female acne: A double‐blind,randomized placebo‐controlled trial

The emergence of bacterial resistance is a global crisis. Prolonged use of antibiotics especially in acne is one issue of concern among dermatologists. Ketoconazole (KTZ) cream, a topical antifungal with anti‐inflammatory and antiandrogenic actions, can decrease lipase activity of Cutibacterium acnes in vitro. We evaluated the efficacy and safety of KTZ cream in mild adult female acne (AFA) by conducting a randomized, double‐blind, placebo‐controlled trial using KTZ 2% and placebo cream twice daily for 10 weeks. We assessed the improvement of clinical severity, measured by AFA score graded by investigators and participants, and the change of acne count. Forty‐one participants enrolled in our study. The proportion of participants with acne improvement from baseline (42.9% vs 9.5%, P = 0.015) and the success rate (45.0% vs 14.3%, P = 0.043) in the KTZ group were significantly higher than that of the placebo group. The most common adverse events were dryness and itching. The percentage change of acne count decreased significantly compared with baseline but did not differ statistically between the two groups (P = 0.268). We concluded that the KTZ monotherapy showed a plausible effect in improving AFA with excellent safety profile. It should be considered as a viable option for mild AFA treatment.     

Efficacy of long‐term treatment with efinaconazole 10% solution in patients with onychomycosis,including severe cases: A multicenter,single‐arm study

We evaluated the efficacy of efinaconazole 10% topical solution in long‐term use, for up to 72 weeks, for onychomycosis, including severe cases. Among 605 participants, 219 patients diagnosed as having onychomycosis were evaluated for the efficacy of efinaconazole. The treatment success rate (<10% clinical involvement of the target toenail) at the final assessment time point was 56.6%, the complete cure rate was 31.1% and the mycological cure rate was 61.6%, all of which increased over time, demonstrating that continuous application contributed to the improvement of cure rate. Even in severe cases, reduction of the affected nail area was observed, showing the potential efficacy of the treatment. Responses to a quality of life questionnaire among patients with onychomycosis, OnyCOE‐t, suggested that efinaconazole treatment improved the patients’ quality of life. The incidence of adverse drug reaction in the patients eligible for the assessment was 6.3%, and this developed only in the administration site in all cases. No systemic adverse event was observed. In addition, no increase in the incidence of adverse drug reaction due to long‐term use was found. Efinaconazole therapy was proved to exhibit excellent balance between efficacy and safety, and thus may serve as a useful treatment option for onychomycosis.     

Primary cutaneous diffuse large B‐cell lymphoma,leg‐type,treated with a modified R‐CHOP immunochemotherapy – diagnostic and therapeutic challenges

Background: Primary cutaneous diffuse large B‐cell lymphoma (PCLBCL) represents a rare subtype among primary cutaneous B‐cell lymphoma exhibiting a characteristic genetic background, an aggressive clinical course and a high relapse rate under different therapeutic regimen. Therefore, PCLBCL has a rather restricted prognosis. Patients and methods: Four patients with PCLBCL were treated at our institution with age‐ and toxicity‐adapted first‐line immunochemotherapy with rituximab and modified CHOP (cyclophosphamid, vincristin, liposomal doxorubicin, prednisolon). On relapse, the same regimen with R‐CHOP or different antineoplastic strategies (radiation, polychemotherapy, immunotherapy, stem cell transplantation) were applied. Toxicity, clinical response and overall survival was documented. Results: Under this regimen, clinical response to modified R‐CHOP was achieved in all patients with tolerable toxicity – however, being characterized by a rapid disease progression with inconsistent response towards the subsequent therapeutic armentarium and unsecure impact on overall survival. Conclusions: So far, it is still unknown, if an extensive multimodal therapy for PBLBCL improves overall survival. Immunochemotherapy with R‐CHOP currently represents the most effective treatment.     

A liposome‐based formulation containing equol,dihomo‐γ‐linolenic acid and propionyl‐l‐carnitine to prevent and treat hair loss: A prospective investigation

Hair loss is a common aesthetic disorder that can be triggered by genetic, inflammatory, hormonal, and environmental factors acting on hair follicles and their life cycle. There are several types of hair loss that differ in causes, symptoms, and spatial and temporal progression. Androgenic alopecia, a common form of hair loss, is the consequence of a decreased microcirculation of the scalp as well as the toxic action of elevated dihydrotestosterone levels on the hair bulbs. In the present study, the lotions TRINOV Lozione Anticaduta Uomo and TRINOV Lozione Anticaduta Donna, containing dihomo‐γ‐linolenic acid (DGLA), S‐equol, and propionyl‐l ‐carnitine, were tested on 30 men and 30 women (mean age of men was 46.6 ± 6.4 years; mean age of women was 49.5 ± 9.0) with signs of androgenic alopecia, respectively. DGLA is a precursor of the prostaglandin PGE1, which acts by improving microcirculation; S‐equol inhibits 5α‐reductases, thus preventing the transformation of testosterone into dihydrotestosterone; and propionyl‐l ‐carnitine promotes lipid metabolism, stimulating energy production. These three molecules are loaded into liposomes for their effective transdermal delivery. Daily topical applications of the lotions resulted in a hair count that significantly increased for women and marginally increased for men after 6 months of treatment. Furthermore, significant increase in anagen hair and a significant decrease in telogen hair were observed starting from 3 months in male and 1 month in female patients. Thus, the formulations under investigation were effective in attenuating androgenic alopecia‐related hair loss in men and women.     

In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT)

Tyrosinase is a key enzyme that catalyses the initial rate‐limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT) had the greatest inhibitory effect and potency as the IC₅₀ value of 5‐HMT was lower than that of kojic acid, widely‐known tyrosinase inhibitor. Based on in silico docking simulation, 5‐HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5‐HMT topical treatment significantly reduced UVB‐induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5‐HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis.     

Peeling with 70% glicolic acid followed by 5% 5‐fluorouracil as well as 5% 5‐fluorouracil cream are effective methods for the treatment of actinic keratoses on upper limbs: A randomized clinical trial

The 5% 5‐fluorouracil (5‐FU) cream, considered the gold standard topical treatment, and peeling using 70% glycolic acid (GA) followed by 5% 5‐FU are methods for the treatment of actinic keratoses (AKs). However, the comparison of these two treatments had not yet been described and therefore was the objective of this study. A randomized clinical trial, intrapatient study in which 17 patients received a type of treatment in the right and left upper limb with 5% 5‐FU cream (twice daily) or a peeling application of 70% GA (every 15 days) followed by 5% 5‐FU cream. There was a significant reduction of 75% and 85.71% in the mean number of AK lesions and of 74.5% and 85.71% in the size of lesions on the upper limbs of patients treated with peeling and 5% 5‐FU cream (P‐value ≤.001), respectively. Neither treatment was superior to the other since there was no significant difference (P‐value ≥.05) between the treatments, both at the post‐intervention period as well as when comparing the difference between the pre and post‐intervention periods. The peeling with 70% GA followed by 5% 5‐FU as well as 5% 5‐FU cream are effective methods for the treatment of AKs on upper limbs.     

Effectiveness and safety of a prevention‐of‐flare‐progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis

Objective This study was performed to investigate the efficacy and safety of a prevention‐of‐flare‐progression strategy with pimecrolimus cream 1% in children and adolescents with atopic dermatitis (AD). Methods A 26‐week multi‐centre, randomized, double‐blind, vehicle‐controlled study was conducted in 521 patients aged 2–17 years, with a history of mild or moderate AD, who were clear/almost clear of disease before randomization to pimecrolimus cream 1% (n = 256) or vehicle cream (n = 265). Twice‐daily treatment with study medication was started at the first signs and/or symptoms of recurring AD. If, despite the application of study medication for at least 3 days, AD worsened (as confirmed by the investigator), treatment with a moderately potent topical corticosteroid (TCS) was allowed in both groups. The primary efficacy end point was the number of days on study without TCS use for a flare. Results The mean number of TCS‐free days was significantly higher (P < 0.0001) in the pimecrolimus cream 1% group (160.2 days) than in the control group (137.7 days). On average, patients on pimecrolimus cream 1% experienced 50% fewer flares requiring TCSs (0.84) than patients on vehicle cream (1.68) (P < 0.0001). Patients on pimecrolimus cream 1% also had fewer unscheduled visits (87) than patients on vehicle cream (246). Conclusions In children and adolescents with a history of mild or moderate AD but free/almost free of signs or symptoms of the disease, early treatment of subsequent AD exacerbations with pimecrolimus cream 1% prevented progression to flares requiring TCS, leading to fewer unscheduled visits and reducing corticosteroid exposure.     

Galectin‐7, induced by cis‐urocanic acid and ultraviolet B irradiation,down‐modulates cytokine production by T lymphocytes

Urocanic acid (UCA) is an epidermal chromophore that undergoes trans to cis isomerization after UVB irradiation. cis‐UCA is a potent inhibitor of cutaneous acquired immunity. The aim of this study was to explore the genes, which are upregulated by cis‐UCA in normal human epidermal keratinocytes (NHEK) and investigated its role in vitro using human T‐lymphocyte cell line, Jurkat cells. DNA microarray analysis and real‐time PCR investigation revealed that cis‐UCA, not trans‐UCA, increased the expression of a gene encoding a β‐galactoside‐binding lectin, galectin‐7, LGALS7B. Immunohistochemical study demonstrated that galectin‐7 was highly expressed in the epidermis in the patients with actinic keratosis. Galectin‐7 administration upregulated apoptosis and inhibited the expression of interleukin‐2 (IL2) and interferon‐γ (IFNG) mRNA in Jurkat cells. Taken together, galectin‐7 may play important roles in downregulating the functions of T lymphocytes after UVB irradiation and can be developed into novel immunosuppressive therapies for inflammatory skin diseases.