A decrease in the ceramide content of the stratum corneum is known to cause dry and barrier‐disrupted skin. In this literature review, the clinical usefulness of preparations containing natural or ...synthetic ceramides for water retention and barrier functions was evaluated. The PubMed, Cochrane Library, and Igaku Chuo Zasshi databases were searched using keywords such as “ceramide”, “skincare products”, “barrier + hydration + moisture + skin”, and “randomized trial”. All database searches were conducted in February 2019. Forty‐one reports were selected based on the following criterion: comparative control studies that evaluated the effects of ceramide‐containing formulations based on statistical evidence. Among the 41 reports, 12 were selected using the patient, intervention, comparison, and outcome approach. These 12 reports showed that external ceramide‐containing preparations can improve dry skin and barrier function in patients with atopic dermatitis. However, a double‐blinded comparative study with a large sample size is warranted for appropriate clinical use.
Amenamevir (ASP2151), a novel, non‐nucleoside analog, antiviral drug, inhibits the enzyme activities of helicase and primase, which are essential for replication of herpes viral genomic DNA. In this ...phase 3, randomized, double‐blind, placebo‐controlled, multicenter study, the authors investigated the efficacy and safety of a single patient‐initiated dose of amenamevir to treat recurrent herpes labialis. Adult immunocompetent patients with recurrent herpes labialis who had the experience and ability to recognize prodromal symptoms were randomly assigned to administer amenamevir 1200 mg or placebo as a patient‐initiated therapy within 6 hours after onset of prodromal symptoms. The primary efficacy end point was time to healing of all herpes labialis lesions in the modified intention‐to‐treat population. Secondary efficacy end points were time to crusting of all herpes labialis lesions, time to resolution of pain accompanying herpes labialis, proportion of patients with aborted lesions, and time to resolution of subjective symptoms accompanying herpes labialis. The modified intention‐to‐treat population, which excluded patients with aborted lesions, comprised 298 patients who self‐initiated amenamevir and 307 who took placebo. Amenamevir demonstrated superiority over placebo for the primary end point; the median time to all lesion healing was 5.1 days for amenamevir versus 5.5 days for placebo (hazard ratio, 1.24; 95% confidence interval, 1.06–1.46; p = 0.0085). Time to crusting of all lesions was significantly shorter with amenamevir versus placebo (p = 0.0065); there were no significant between‐group differences in other secondary outcomes. Treatment‐emergent adverse events in both groups were generally mild in severity; there were two moderate events that were judged unrelated to study treatment, and no severe or serious events. In summary, a single patient‐initiated dose of amenamevir 1200 mg taken within 6 hours of prodromal symptom onset significantly shortened the time to all lesion healing of recurrent herpes labialis compared with placebo, with no clinically important safety concerns.
Summary Background Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with ...dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. Methods In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov , number NCT01859988. Findings Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week n=63, 300 mg every 2 weeks n=64, 200 mg every 2 weeks n=61, 300 mg every 4 weeks n=65, 100 mg every 4 weeks n=65; placebo n=61). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (−74% SE 5·16), 300 mg every 2 weeks (−68% 5·12), 200 mg every 2 weeks (−65% 5·19), 300 mg every 4 weeks (−64% 4·94), 100 mg every 4 weeks (−45% 4·99); placebo (−18% 5·20). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). Interpretation Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. Funding Sanofi and Regeneron Pharmaceuticals.
T helper type 2 (Th2) cytokines, IL-4 and IL-13, attenuate the expression of genes that regulate epidermal cellular structures and the barrier function at the terminal stage of keratinocyte ...differentiation. However, whether these Th2 cytokines act at earlier stages remains unknown. We investigated the roles of cytokines in expression levels of mRNAs and/or proteins in primary mouse keratinocytes and human keratinocyte HaCaT cells at earlier stages. We showed that IL-4 downregulated the expression levels of Krt1, Krt10, Dsg1, and Dsc1 via IL-4Rα- and signal transducer and activator of transcription factor 6 (STAT6)-dependent mechanisms in differentiating mouse keratinocytes at early stages. As the expression levels of keratin-1 and -10 in the keratinocytes transiently expressing an active form of STAT6 were not downregulated, STAT6 and other IL-4-induced molecules may synergistically regulate this expression. The restoration of the downregulated expression levels of Krt1 and Krt10 induced by IL-4 with the MEK (mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase kinase) inhibitor U0126 indicated the involvement of the p44/42 MAPK signaling pathway in the attenuated expression. IL-13 also downregulated the expression of the four genes. Furthermore, IL-4 or IL-13 caused the downregulation of these genes in HaCaT cells and promoted the fragmentation of cell sheets with mechanical stress. Our results showed that IL-4 or IL-13 acted on differentiating keratinocytes in vitro at early stages to attenuate the gene expression.
Amenamevir is a potent helicase–primase inhibitor and a novel class of antiviral agent other than nucleoside compounds, such as aciclovir, valaciclovir and famciclovir. This study is the first ...randomized, double‐blind, valaciclovir‐controlled phase 3 study to evaluate the efficacy and safety of amenamevir in Japanese patients with herpes zoster when treated within 72 h after onset of rash. A total of 751 patients were randomly assigned to receive either amenamevir 400 mg or 200 mg p.o. once daily or valaciclovir 1000 mg three times daily (daily dose, 3000 mg) for 7 days. The primary efficacy end‐point was the proportion of cessation of new lesion formation by day 4 (“day 4 cessation proportion”). The day 4 cessation proportions for amenamevir 400 and 200 mg and valaciclovir were 81.1% (197/243), 69.6% (172/247) and 75.1% (184/245), respectively. Non‐inferiority of amenamevir 400 mg to valaciclovir was confirmed by a closed testing procedure. Days to cessation of new lesion formation, complete crusting, healing, pain resolution and virus disappearance were evaluated as secondary end‐points. No significant differences were observed in any of the treatment groups. Amenamevir 400 and 200 mg were well tolerated as well as valaciclovir. The proportions of patients who experienced drug‐related adverse events were 10.0% (25/249), 10.7% (27/252) and 12.0% (30/249) with amenamevir 400 and 200 mg and valaciclovir, respectively. In conclusion, amenamevir 400 mg appears to be effective and well tolerated for treatment of herpes zoster in immunocompetent Japanese patients.
There have been very few studies on the prevalence and severity of acne scars in Japanese patients. The aim of the present study was to investigate the prevalence of acne scars and their impact on ...the quality of life (QOL) in Japanese acne patients. Acne scars were classified as mini-scars (atrophic scars of ≥0.5 and <2 mm in diameter) atrophic scars (≥2 mm in diameter), and hypertrophic scars. The severity of acne and acne scars were evaluated. The background of patients and their QOL in relation to acne were assessed. Of 240 subjects, 218 (90.8%) had scars. All patients with scars had mini-scars; 61.2% and 14.2% of 240 had atrophic scars and hypertrophic scars, respectively. Severe scarring was found in patients who had experienced severe acne symptoms, although 15.0% of patients with scars had experienced only mild acne symptoms. The total Dermatology Life Quality Index score was significantly higher in patients with scars than in patients without scars (5.9 ± 4.4 vs 4.2 ± 4.1). Almost all the patients had small atrophic scars with a diameter of 0.5 or more and less than 2 mm, which we have termed "mini-scars". Acne scars had a negative impact on patient QOL. Early initiation of treatment is recommended to avoid acne scars.
The Guidelines for the Treatment of Acne Vulgaris of the Japanese Dermatological Association was first published in Japanese in 2008 and revised in 2016 and 2017. These guidelines (GL) indicate the ...standard acne treatments in Japan and address pharmaceutical drugs and treatments applicable or in use in Japan. In these GL, the strength of the recommendation is based on clinical evidences as well as availability in Japanese medical institutions. In the 2016 and 2017 GL, some of the clinical questions were revised, and other questions were added in accordance with approval of topical medicines containing benzoyl peroxide (BPO). Rather than monotherapies of antibiotics, the 2017 GL more strongly recommend combination therapies, especially fixed-dose combination gels including BPO in the aspects of pharmacological actions and compliance in the acute inflammatory phase to achieve earlier and better improvements. The 2017 GL also indicate to limit the antimicrobial treatments for the acute inflammatory phase up to approximately 3 months and recommend BPO, adapalene, and a fixed-dose combination gel of 0.1% adapalene and 2.5% BPO for the maintenance phase to avoid the emergence of antimicrobial-resistant Propionibacterium acnes. The 2017 GL also discuss rosacea, which requires discrimination from acne and a different treatment plan.
PDF
