Nobukazu Hayashi

Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: Results of a randomized, vehicle-controlled, multicenter clinical trial

The safety and efficacy of topical E6005, a novel phosphodiesterase 4 inhibitor, in Japanese adults with atopic dermatitis were evaluated. A total of 78 patients were randomized to receive either the 0.2% E6005 ointment or vehicle control (without E6005) at an allocation ratio of 2:1. The randomization phase of 4 weeks was followed by an extension phase of 8 weeks. In the extension phase, all 67 subjects who completed the randomization phase were treated with 0.2% E6005 ointment. The 4‐week application of topical E6005 twice daily was safe and well tolerated. The safety profile for up to 12 weeks was similar to that for the first 4 weeks. No deaths or other serious adverse effects were observed during the entire study period of 12 weeks. Plasma E6005 was undetectable in all subjects at all sampling points while very low plasma concentrations of an E6005 metabolite were detected in 47% of subjects receiving E6005 treatment. At the end of week 4, Eczema Area and Severity Index (EASI), Severity Scoring Atopic Dermatitis (SCORAD)‐objective, SCORAD‐C (visual analog scales for pruritus and sleep loss), itch Behavioral Rating Scale, and the severity of the targeted eczematous lesions in the topical E6005 group showed trends toward improvement compared with those in the vehicle group (not statistically significant). However, the group receiving topical E6005 for 12 weeks showed significant score reductions from baselines for EASI (P = 0.030), SCORAD‐objective (P < 0.001) and SCORAD‐C (P = 0.038). These results further support the development of topical E6005 for the treatment of atopic dermatitis.

A single UVB exposure increases the expression of functional KIT in human melanocytes by up-regulating MITF expression through the phosphorylation of p38/CREB

KIT is an essential receptor that modulates melanocyte function and whose function is disrupted in several pigmentary disorders. However, little is known about the effects of a single UVB exposure on the expression of KIT and two important regulatory transcription factors, MITF and AP-2α, in human melanocytes. We found that a single UVB exposure of human melanocytes induces an early decrease and a subsequent increase in functional KIT expression in concert with up-regulated MITF expression. The increased MITF expression was accompanied by a markedly stimulated and prolonged phosphorylation of p38/CREB. The UVB-stimulated expression of KIT could be completely abolished by a p38 inhibitor, concomitant with a reduced phosphorylation of CREB and a down-regulation of MITF expression. Interestingly, in non-UVB exposed human melanocytes, a MEK inhibitor stimulated the phosphorylation of p38/CREB which was associated with an increased production of MITF and KIT in a pattern similar to that induced by UVB. These findings indicate that UVB stimulates functional KIT expression in human melanocytes via the up-regulation of MITF which is, in turn, due to the activation of p38 and CREB.

Relationship between the severity of acne vulgaris and antimicrobial resistance of bacteria isolated from acne lesions in a hospital in Japan.

Propionibacterium acnes and Staphylococcus epidermidis are normal skin inhabitants that are frequently isolated from lesions caused by acne, and these micro-organisms are considered to contribute to the inflammation of acne. In the present study, we examined the antimicrobial susceptibilities and resistance mechanisms of P. acnes and S. epidermidis isolated from patients with acne vulgaris in a university hospital in Japan from 2009 to 2010. Additionally, we analysed the relationship between the antimicrobial resistance of P. acnes and the severity of acne vulgaris. Some P. acnes strains (18.8 %; 13/69) were resistant to clindamycin. All strains had a mutation in the 23S rRNA gene, except for one strain that expressed erm(X) encoding a 23S rRNA methylase. Tetracycline-resistant P. acnes strains were found to represent 4.3 % (3/69) of the strains, and this resistance was caused by a mutation in the 16S rRNA gene. Furthermore, three strains with reduced susceptibility to nadifloxacin (MIC = 16 µg ml(-1)) were detected. When analysing the correlation between the antimicrobial resistance of P. acnes and S. epidermidis, more than 80 % of the patients who carried clindamycin-resistant P. acnes also carried clindamycin-resistant S. epidermidis. However, no epidemic strain that exhibited antimicrobial resistance was detected in the P. acnes strains when analysed by PFGE. Therefore, our results suggest that the antimicrobial resistance of P. acnes is closely related to antimicrobial therapy. Additionally, those P. acnes strains tended to be frequently found in severe acne patients rather than in mild acne patients. Consequently, the data support a relationship between using antimicrobial agents and the emergence of antimicrobial resistance.

Acne management in Japan: study of patient adherence.

Obtaining good adherence to acne therapy is a challenge for all dermatologists. We studied 428 acne patients in Japan to determine the likelihood of good adherence and factors associated with medication-taking. This study utilized a simple validated questionnaire to assess risk of poor adherence; information about patient and treatment characteristics was also collected. There was an overall rate of poor adherence in 76% of subjects. Adherence to topical medication was poor in 52% of those treated with a topical agent only (n = 123). Among those taking combination therapies (n = 275), adherence to the topical portion of therapy was poor in 49% of subjects. The likelihood of poor adherence to oral medication was higher, both when administered alone (n = 30, 93% poor adherence) and when given as part of a combination regimen (n = 275, 86%). Factors with an impact on adherence included satisfaction with treatment (p = 0.023) and the experience of side effects (p = 0.027). Patients who felt they had a good understanding of acne and its treatment were more likely to have good adherence. These data suggest that there is significant room for improvement in acne adherence in Japan, as in other areas of the world, and that improved education may enhance adherence.

Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial.

This exploratory study was designed to evaluate the safety and efficacy profile of the topical phosphodiesterase 4 inhibitor E6005 in Japanese children with mild‐to‐moderate atopic dermatitis. The present randomized, multicenter study included 62 patients who were treated with 0.05% E6005, 0.2% E6005 or vehicle ointment twice daily for 2 weeks. Safety and pharmacokinetics were assessed with a focus on the occurrence of adverse events and the whole blood concentrations of E6005 and its metabolite. Exploratory efficacy evaluations included assessments of lesion severity and pruritus score. The 2‐week application of topical E6005 was safe and well tolerated with no cutaneous adverse events. The whole blood concentration of E6005 was quantified in only one subject receiving 0.2% E6005 treatment, while its major metabolite was undetectable. The 0.2% E6005 group showed a greater decrease in the severity score than the vehicle group (−45.94% vs −32.26%), although this difference was not statistically significant. Similarly, the treatment success rate according to the investigators global assessment of the total application sites was higher in the 0.2% E6005 group than in the vehicle group (34.4% vs 20.0%). Moreover, the 0.2% E6005 group showed a greater decrease in the pruritus score than the vehicle group (−37.5% vs −6.7%) in a predefined subpopulation. The efficacy of 0.05% E6005 treatment was comparable to that of vehicle treatment. These results suggest that topical 0.2% E6005 treatment is safe and effective in children with atopic dermatitis, although further large confirmatory clinical trials are warranted.

Antimicrobial susceptibility and phylogenetic analysis of Propionibacterium acnes isolated from acne patients in Japan between 2013 and 2015

The prevalence of antimicrobial‐resistant Propionibacterium acnes strains isolated from acne patients has been increasing in Japan. Here, to estimate the current resistance rate, we tested antimicrobial susceptibility among P. acnes from acne patients having visited a specialized dermatology clinic between 2013 and 2015. Rates of resistance to macrolides and clindamycin were 44.3 (31/70) and 38.6% (27/70), respectively. erm(X), which confers high‐level clindamycin resistance (minimum inhibitory concentration ≥256 μg/mL), was detected in six isolates, whereas no resistance determinants were identified in eight strains showing high‐level resistance to clindamycin. Using single‐locus sequence typing, the P. acnes isolates were classified into five clades (A, E, F, H and K), with all high‐level clindamycin‐resistant strains lacking known clindamycin resistance determinants being grouped together (in clade F). P. acnes isolates from patients previously treated with macrolides and clindamycin showed a macrolide resistance rate (55.3%) significantly higher than that of those from patients not having received these treatments (21.7%, P < 0.05). Furthermore, strains of clade F, which were very rarely isolated from healthy individuals, were more frequently recovered from patients with severe acne (40.0%) than those with mild acne (23.3%). Our data showed an increase in macrolide‐resistant P. acnes prevalence in Japan due to the use of antimicrobial agents for acne treatment. Furthermore, we identified strains of specific phylogenetic groups frequently associated with severe acne patients.

Propionibacterium acnes is developing gradual increase in resistance to oral tetracyclines

&NA; Propionibacterium acnes is an anaerobic bacterium that causes deep infection in organs and prosthetic joints, in addition to acne vulgaris. Many tetracycline‐resistant P. acnes strains have been isolated because oral tetracyclines are frequently used as an acne treatment against P. acnes. In this study, we found a novel tetracycline resistance mechanism in P. acnes. Three doxycycline‐resistant (MIC: 16 &mgr;g ml−1) strains were isolated from 69 strains in acne patients in Japan between 2010 and 2011. Additionally, six insusceptible strains (MIC: 1‐2 &mgr;g ml−1) that had reduced susceptibility compared to susceptible strains (MIC: ≤0.5 &mgr;g ml−1) were identified. All doxycycline‐resistant strains had a G1036C mutation in the 16S rRNA gene in addition to an amino acid substitution in the ribosomal S10 protein encoded by rpsJ. By contrast, insusceptible strains had an amino acid substitution in the S10 protein but no mutation in the 16S rRNA. When the mutant with decreased susceptibility to doxycycline was obtained in vitro, only the mutated S10 protein was found (MIC: 4 &mgr;g ml−1), not the mutated 16S rRNA gene. This result shows that the S10 protein amino acid substitution contributes to reduced doxycycline susceptibility in P. acnes and suggests that tetracycline resistance is acquired through a 16S rRNA mutation after the S10 protein amino acid substitution causes reduced susceptibility.

Paracrine cytokine mechanisms underlying the hyperpigmentation of seborrheic keratosis in covered skin areas

We previously reported that increased expression of the endothelin (EDN)1/EDNB receptor (EDNBR) as well as the stem cell factor (SCF)/SCF receptor (c‐KIT) linkages is mainly responsible for the activation of melanocytes in the epidermal hyperpigmentation of ultraviolet (UV)‐B melanosis and lentigo senilis (LS). In this study, we characterized seborrheic keratosis (SK) to examine the paracrine cytokine mechanism(s) involved in its epidermal hyperpigmentation by reverse transcription polymerase chain reaction, immunohistochemistry and western blotting analyses. In contrast to our previous study which showed the upregulated expression of EDN1 and EDNBR at the transcriptional and translational levels in the epidermis of SK, we observed unexpectedly that the cytokine SCF and its receptor c‐KIT are not upregulated, but are downregulated at both the gene and protein levels. We established SK cell lines to examine whether SK basaloid cells are less sensitive to SCF‐inducible stimulation than are normal human keratinocytes (NHK). Comparison of the stimulatory effects of interleukin (IL)‐1α or tumor necrosis factor (TNF)‐α on SCF production between SK cells and NHK demonstrated that SK cells do not respond to IL‐1α or TNF‐α to stimulate production of SCF, whereas a significant stimulation of SCF is elicited by those same cytokines in NHK. These finding underscore a role of phenotypic changes in melanogenic cytokine production in the epidermis between SK and LS/UV‐B melanosis.

Multiple basal cell carcinomas in an atomic bomb survivor

A 65-year-old woman with multiple skin nodules visited our hospital in 2008. In 1945, when she was 2 years old, she was exposed to atomic bomb radiation in Hiroshima. She developed thyroid and mammary cancer at the ages of 24 years and 46 years, respectively, and was treated by surgery and radiotherapy. At the age of 64 years, she noticed several nodules on her skin. When she visited our hospital, eight blackish or reddish nodules with diameters of £20 mm were present on her neck, lower back, left axilla and extremities (Fig. 1a–g). The patient showed no other symptoms of basal cell nevus syndrome (BCNS), including multiple odontogenic keratocysts in the mandible. Dermoscopy revealed arborizing vessels, multiple blue–gray globules or leaf-like areas on most of these nodules (Fig. 2). All the tumors were surgically removed. Histological examination revealed that the nodules comprised nests of basaloid cells in a palisading arrangement (Fig. 3); all these nodules were subsequently diagnosed as basal cell carcinoma (BCC). Two more BCCs, one on the thigh and the other on the hip, were discovered and removed during the 2-year follow-up period.