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 investigator's 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.     

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.     

Phase 2a,randomized, double‐blind,placebo‐controlled,multicenter, parallel‐group study of a H4R‐antagonist (JNJ‐39758979) in Japanese adults with moderate atopic dermatitis

This trial was conducted to evaluate the safety and efficacy of the H₄R‐antagonist JNJ‐39758979 in adult Japanese patients with moderate atopic dermatitis (AD). Eligible patients were randomly assigned to JNJ‐39758979 300 mg, 100 mg or placebo once daily for 6 weeks in this phase 2a, double‐blind, multicenter, placebo‐controlled study. Primary efficacy was assessed via week‐6 Eczema Area and Severity Index (EASI) scores. Secondary efficacy assessments included Investigator's Global Assessment (IGA) and patient‐reported outcome (PRO) pruritus assessments (Pruritus Categorical Response Scale [PCRS], Pruritus Numeric Rating Scales [PNRS], Pruritus Interference Numeric Rating Scale [PINRS] and Subject's Global Impressions of Change in Pruritus [SGICP]). Eighty‐eight of 105 planned patients were randomized before the study was stopped and unblinded for safety reasons. The study did not meet the primary end‐point. However, numerical improvements (i.e. decreases) in median EASI were observed with JNJ‐39758979 100 mg (?3.7) and 300 mg (?3.0) versus placebo (?1.3) at week 6. Nominally significant improvements across PRO PCRS, PNRS and SGICP assessments were consistently observed, particularly with JNJ‐39758979 300 mg. Safety, including adverse events (AE), was comparable between JNJ‐39758979 and placebo with the exception of two patients (both receiving JNJ‐39758979 300 mg) with serious AE of neutropenia, leading to premature study discontinuation. No deaths were reported. Except for neutropenia, no clinically relevant changes in laboratory values were observed. Although not conclusive, findings suggest H₄R‐antagonism may be beneficial for AD, particularly in controlling pruritus. JNJ‐39758979 appears to be associated with drug‐induced agranulocytosis, likely an off‐target effect.     

Efficacy and safety of topical OPA‐15406, a new phosphodiesterase 4 inhibitor,in Japanese patients with atopic dermatitis for 8 weeks: A phase 2, randomized,double‐blind,placebo‐controlled study

The efficacy and safety of topical OPA‐15406, a new phosphodiesterase 4 inhibitor, were examined in Japanese patients aged 15–70 years with atopic dermatitis in a phase 2, randomized, double‐blind, vehicle‐controlled study. Two hundred patients were randomized to three treatment groups at a 1:1:1 ratio to receive OPA‐15406 0.3%, OPA‐15406 1% or vehicle ointment twice daily for 8 weeks. The OPA‐15406 1% group was superior to the vehicle group in terms of the incidence of success based on the Investigator Global Assessment score at week 4 (P = 0.0328), which was the primary end‐point, while the OPA‐15406 0.3% group showed a trend toward improvement in the primary end‐point. The mean Eczema Area and Severity Index total score and subscale (erythema, induration/papulation, excoriation and lichenification) scores, the Visual Analog Scale pruritus score and the Patient‐Oriented Eczema Measure score were significantly improved and the percentage of affected body surface area was significantly decreased in both OPA‐15406 groups relative to the vehicle group as early as week 1, and the improved scores and decreased percentages were generally maintained until week 8. No deaths or serious treatment‐emergent adverse events occurred in the OPA‐15406 treatment groups. Treatment‐emergent adverse events frequently observed across treatment groups were worsening of atopic dermatitis, viral upper respiratory tract infection and pruritus, all of which were mild or moderate in severity in the OPA‐15406 groups. OPA‐15406 1% ointment showed favorable efficacy and safety profiles, indicating a promising treatment option for patients with atopic dermatitis.     

Vital role of the itch-scratch response in development of spontaneous dermatitis in NC/Nga mice

BACKGROUND: The itch sensation and the resultant response, scratching, are important symptoms of atopic dermatitis (AD) and have a significant impact on the quality of life of affected patients. However, the influence of the itch-scratch response on the pathology of AD has not been precisely elucidated. OBJECTIVES: To investigate the role of scratching behaviour in the development of spontaneous dermatitis using conventionally raised NC/Nga mice (Conv-NC mice), which are known to be an animal model for human AD. METHODS: Capsaicin-sensitive sensory nerves of the mice were ablated by neonatal capsaicin treatment (Cap-NC mice), and the development of spontaneous dermatitis in the Cap-NC mice was compared chronologically with that in Conv-NC mice. RESULTS: Scratching behaviour was almost completely prevented in Cap-NC mice raised for 84 days under conventional conditions, and the development of dermatitis and elevation of the serum IgE level were significantly suppressed. Histological analysis revealed that the numbers of infiltrating eosinophils and mast cells in the lesional skin of Cap-NC mice were lower than those in Conv-NC mice. Immunological studies showed that the capability of spleen T cells to produce both T-helper (Th) 1 (interferon-gamma) and Th2 [interleukin (IL)-5 and IL-13] cytokines was diminished in Cap-NC mice. Furthermore, serum levels of IL-18 were approximately twice higher in Conv-NC mice than in Cap-NC mice. CONCLUSIONS: These observations suggest that scratching behaviour contributes to the development of dermatitis by enhancing various immunological responses in the murine AD model, implying that prevention of the itch sensation and/or itch-associated scratching behaviour is an effective treatment for AD.     

Induction of scratching behaviour and dermatitis in various strains of mice cohabiting with NC/Nga mice with chronic dermatitis

BACKGROUND: NC/Nga (NC) mice with similar pathological and behavioural features as seen in human atopic dermatitis are used as a model of the disease. Under normal circumstances, spontaneous and persistent scratching occurs in NC mice and this can lead to the onset of skin inflammation. OBJECTIVES: We examined the induction of scratching behaviour in NC, BALB/c, ICR and C3H/HeN mice, and of dermatitis in NC and BALB/c mice, by cohabitation with mice with dermatitis. METHODS: NC, BALB/c, ICR and C3H/HeN mice were kept together with NC mice with chronic dermatitis (CNV-NC) for 2 weeks, and the numbers of scratching episodes were counted. NC and BALB/c mice were also kept together with CNV-NC mice for 24 weeks and the skin severity score was assessed. The score was assessed for a further 8 weeks after separation of these mice. RESULTS: The number of scratching episodes in NC, BALB/c, ICR and C3H/HeN mice was increased by cohabitation with CNV-NC mice. Cohabitation with CNV-NC mice led to dermatitis in both NC and BALB/c mice. The number of scratching episodes and the skin severity score in BALB/c mice were about half of those in NC mice. When cohabitation with CNV-NC mice stopped, the number of scratching episodes and the skin severity score decreased in BALB/c mice, but not in NC mice. Changes in the histopathological data of BALB/c mice supported the severity of skin inflammation. CONCLUSIONS: Our study demonstrates that scratching behaviour and dermatitis can be induced in various strains of mice by cohabitation with CNV-NC mice, and that cessation of cohabitation leads to a recovery in BALB/c mice but not in NC mice.     

Involvement of leukotriene B4 in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions

To elucidate the mechanisms of severe itch in atopic dermatitis, we investigated the role of leukotriene B(4) , a potent itch mediator, in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. Topical application of the BLT leukotriene B(4) receptor antagonist ONO-4057 inhibited spontaneous itch-related behaviour. The concentration of leukotriene B(4) was significantly increased in the lesional skin. The expression levels of 5-lipoxygenase were also elevated in the lesional skin, yet present throughout the epidermis of both healthy and lesional skin. These results suggest a role for leukotriene B(4) in chronic dermatitis-related itch. Sphingosylphosphorylcholine (SPC) was increased in the epidermis of the lesional skin. Moreover, intradermal injection of SPC elicited itch-related behaviours in healthy mice. Because SPC induces itch-related responses through the production of leukotriene B(4) in keratinocytes (J Invest Dermatol, 129, 2009, 2854), these results suggest that an increase in SPC induces leukotriene B(4) -mediated itching in chronic dermatitis. BLT1 receptor and 5-lipoxygenase in the skin may be effective pharmacological targets for the treatment of itch in atopic dermatitis.     

Non‐corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis

Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non‐corticosteroid adherence. As such, non‐corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non‐corticosteroid users and 225 with moderate to severe itch who were defined as non‐corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non‐corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non‐corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.     

Toll‐like receptor 4 attenuates a murine model of atopic dermatitis through inhibition of langerin‐positive DCs migration

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that is often associated with skin barrier dysfunction leading to a higher frequency of bacterial and viral skin infections. Toll‐like receptor (TLR) 4 on resident skin cells was involved in sensing pathogens and eliciting pathogen‐specific innate and adaptive immune responses. Previous studies have demonstrated that TLR4 was linked to AD severity in context of pathogen infection. However, the immune regulatory role of TLR4 in AD remains to be defined. We here investigated the immune regulatory function of TLR4 in AD induced by repeated epicutaneous application of a hapten, 2,4‐dinitrochlorobenzene (DNCB). Our results showed that TLR4‐deficient (TLR4^?/?) mice exhibited more severe AD symptoms than WT mice after DNCB challenge. The DNCB‐treated TLR4^?/? mice also displayed higher expression levels of inflammatory cytokines and stronger Th2 response than WT counterparts. Moreover, the skin expression of thymic stromal lymphopoietin (TSLP), an important potential contributor to allergic inflammation, was significantly elevated in TLR4^?/? mice compared with that in WT mice upon DNCB administration. Furthermore, we demonstrated that the migration of langerin‐positive dendritic cells (DCs) into draining lymph nodes was enhanced in TLR4^?/? mice following DNCB challenge, which is partially dependent on the production of pro‐inflammatory cytokine TNF‐α. Together, these results determined that TLR4 affected the hapten‐induced skin inflammation in the absence of exogenous pathogen infection, suggesting that TLR4 not only regulates infection but also may serve as a modulator of the immune response during AD development.     

Topical application of rapamycin ointment ameliorates Dermatophagoides farina body extract‐induced atopic dermatitis in NC/Nga mice

Atopic dermatitis (AD), a chronic inflammatory skin disease characterized by relapsing eczema and intense prurigo, requires effective and safe pharmacological therapy. Recently, rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, has been reported to play a critical role in immune responses and has emerged as an effective immunosuppressive drug. In this study, we assessed whether inhibition of mTOR signalling could suppress dermatitis in mice. Rapamycin was topically applied to inflamed skin in a murine AD model that was developed by repeated topical application of Dermatophagoides farina body (Dfb) extract antigen twice weekly for 7 weeks in NC/Nga mice. The efficacy of topical rapamycin treatment was evaluated immunologically and serologically. Topical application of rapamycin reduced inflammatory cell infiltration in the dermis, alleviated the increase of serum IgE levels and resulted in a significant reduction in clinical skin condition score and marked improvement of histological findings. In addition, increased mTOR phosphorylation in the lesional skin was observed in our murine AD model. Topical application of rapamycin ointment inhibited Dfb antigen‐induced dermatitis in NC/Nga mice, promising a new therapy for atopic dermatitis.     

Deficiency of n‐6 polyunsaturated fatty acids is mainly responsible for atopic dermatitis‐like pruritic skin inflammation in special diet‐fed hairless mice

Hairless mice fed a special diet, HR‐AD, develop atopic dermatitis (AD)‐like skin inflammation with skin barrier defects and itch‐related scratching; however, the ingredient(s) causing the dermatitis remains unclear. In this study, we examined whether deficiency of certain polyunsaturated fatty acids (PUFAs) is involved in HR‐AD‐induced AD. High‐purity PUFAs were given to HR‐AD‐fed mice by dietary supplementation or gavage. Fatty acid levels in the serum and skin were determined by using gas chromatography–mass spectrometry. In serum from HR‐AD‐fed mice, linoleic acid (LA, 18:2n‐6) and α‐linolenic acid (ALA, 18:3n‐3), as well as their metabolites, were markedly decreased. When mice were fed HR‐AD supplemented with LA or ALA in an amount equal to that contained in a normal diet, the development of AD‐like symptoms was completely prevented by supplementation with LA but not with ALA. Relatively high dose of ALA slightly alleviated skin barrier defects, but did neither itch‐related scratching nor skin inflammation. On the other hand, gavage administration of LA metabolites, such as γ‐linolenic acid and arachidonic acid (AA), significantly ameliorated established dermatitis without increasing LA in the serum and skin. Moreover, AA‐induced amelioration of dermatitis was not affected by pharmacological blockade of 5‐lipoxygenase (5‐LOX) and cyclooxygenase (COX), suggesting no involvement of 5‐LOX‐ or COX‐mediated AA metabolites in the amelioration. In conclusion, our results indicate that deficiency of n‐6 PUFAs is mainly responsible for AD‐like symptoms by HR‐AD feeding. Thus, this model could be useful for studying the pathomechanisms associated with deficiency of n‐6 PUFAs in AD.     

A novel JAK inhibitor JTE‐052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents

Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE‐052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE‐052 inhibited the Th1‐, Th2‐ and Th17‐type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE‐052 inhibited skin inflammation in hapten‐induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)‐4 production in skin, and enhanced IgE production in serum. Oral administration of JTE‐052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL‐23. The maximal efficacy of JTE‐052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE‐052 ointment ameliorated hapten‐induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE‐052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE‐052 is a promising candidate as an anti‐inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application.     

Anti‐IL5 decreases the number of eosinophils but not the severity of dermatitis in Sharpin‐deficient mice

Please cite this paper as: Anti‐IL5 decreases the number of eosinophils but not the severity of dermatitis in Sharpin‐deficient mice. Experimental Dermatology 2010; 19: 252–258. Abstract: Sharpin‐deficient (Sharpin^cpdm) mutant mice develop a chronic eosinophilic dermatitis. To determine the efficacy of eosinophil‐depletion in chronic inflammation, Sharpin^cpdm mice were treated with anti‐IL5 antibodies. Mice treated with anti‐IL5 had a 90% reduction of circulating eosinophils and a 50% decrease in cutaneous eosinophils after 10 days compared with sham‐treated littermates. Reducing the number of eosinophils resulted in increased severity of alopecia and erythema and a significant increase in epidermal thickness. Skin homogenates from mice treated with anti‐IL5 had decreased mRNA expression of arylsulfatase B (Arsb), diamine oxidase (amiloride‐binding protein 1, also called histaminase; Abp1) and Il10, which are mediators that eosinophils may release to quench inflammation. Skin homogenates from mice treated with anti‐IL5 also had decreased mRNA expression of Il4, Il5, Ccl11, kit ligand (Kitl) and Tgfa; and increased mRNA expression of Tgfb1, Mmp12 and tenascin C (Tnc). In order to further decrease the accumulation of eosinophils, Sharpin^cpdm mice were crossed with IL5 null mice. Il5^?/?, Sharpin^cpdm/Sharpin^cpdm mice had a 98% reduction of circulating eosinophils and a 95% decrease in cutaneous eosinophils compared with IL5‐sufficient Sharpin^cpdm mice. The severity of the lesions was similar between IL5‐sufficient and IL5‐deficient mice. Double mutant mice had a significant decrease in Abp1, and a significant increase in Tgfb1, Mmp12 and Tnc mRNA compared with controls. These data indicate that eosinophils are not essential for the development of dermatitis in Sharpin^cpdm mice and suggest that eosinophils have both pro‐inflammatory and anti‐inflammatory roles in the skin of these mice.     

Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream,cream vehicle and hydrocortisone 17-butyrate cream for the treatment of atopic dermatitis

BACKGROUND: Therapeutic options to treat atopic dermatitis are limited. Leukocytes from atopic patients have an abnormally high activity of cyclic adenosine monophosphate (AMP)-phosphodiesterase (PDE), which can be normalized in vitro by PDE inhibitors. Cipamfylline is a new potent and selective inhibitor of PDE-4. OBJECTIVES: To compare the efficacy and safety of up to 14 days' topical treatment with cipamfylline (0.15%) cream with vehicle and with hydrocortisone 17-butyrate (0.1%) cream. PATIENTS AND METHODS: International, multicentre, prospective, randomized double-blind, left-right studies of cipamfylline vs. vehicle and cipamfylline vs. hydrocortisone 17-butyrate in adult patients with stable symmetrical atopic dermatitis on the arms. RESULTS: Both cipamfylline and hydrocortisone 17-butyrate reduced the Total Severity Score significantly (P < 0.001). The reduction with cipamfylline was significantly greater than that with vehicle (difference vehicle-cipamfylline 1.67 95% confidence interval (CI) 1.06, 2.28; P < 0.001) and was significantly less than with hydrocortisone 17-butyrate (difference hydrocortisone-cipamfylline -2.10 95% CI -2.93, -1.27; P < 0.001). Investigator and patient assessments of the overall treatment response showed a similar picture. CONCLUSIONS: Cipamfylline cream is significantly more effective than vehicle, but significantly less effective than hydrocortisone 17-butyrate cream in the treatment of atopic dermatitis.     

Dietary deficiencies of unsaturated fatty acids and starch cause atopic dermatitis‐like pruritus in hairless mice

Hairless mice fed with a special diet (named HR‐AD) show atopic dermatitis (AD)‐like pruritic skin inflammation that is almost completely resolved with the supplementation of an unsaturated fatty acid (UFA), the linoleic acid (LA). This suggests that the dietary deficiency of LA is the key cause of this dermatitis. However, because there is no appropriate control diet for HR‐AD, the involvement of other dietary ingredients cannot be ruled out. Furthermore, it has not yet been tested whether only UFA deficiency can cause such AD‐like pruritus. In this study, using semi‐purified custom diets, we attempted to reproduce this syndrome. Four‐week‐old hairless mice were maintained on a widely used standard diet American Institute of Nutrition‐76A (AIN‐76A), its modifications, or HR‐AD. Several modifications of fat and carbohydrate components revealed that dietary deficiency of both UFAs and cornstarch was required to induce severe skin barrier dysfunction as typically occurred in HR‐AD‐fed mice. An UFA‐ and cornstarch‐deficient diet caused severe AD‐like pruritus comparable to HR‐AD, despite weak Th2 immune responses and absence of immunoglobulin E production. On the other hand, a diet lacking UFAs but containing cornstarch significantly alleviated the development of pruritic dermatitis. Furthermore, the supplementation of wheat starch similarly improved skin barrier function. In conclusion, this study showed that a lack of certain starches might also be the cause of diet‐induced AD. Our findings could help to reproduce the diet‐induced AD itch model and also provide evidence that certain starches can have protective and ameliorative effects on AD‐like pruritus.     

Effect of pedunculagin investigated by non‐invasive evaluation on atopic‐like dermatitis in NC/Nga mice

Background/purpose: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder that is becoming increasingly prevalent. Experimental animal models have been an indispensable tool for studying its pathological mechanisms and for in vivo testing of novel therapeutic approaches. AD‐like lesions can be induced experimentally in NC/Nga mice. Pedunculagin, an ellagitannin purified from the Manchurian alder, Alnus hirsuta var. microphylla, Betulaceae, is a novel immunomodulator. To evaluate the effect of pedunculagin for AD‐like lesions in NC/Nga mice, using clinical and non‐invasive methods. Methods: AD‐like lesions were induced in NC/Nga mice using 2,4,6‐trinitrochlorobenzene (TNCB). A cream containing 0.1% or 0.5% pedunculagin was applied to the positive treatment group, and the base cream without pedunculagin was applied to the negative treatment group. The control group did not receive any kind of topical agents. We evaluated the therapeutic efficacy of pedunculagin for AD by statistical evaluation of the clinical severity score using non‐invasive biomedical engineering tools before treatment, and 1 day, 3 days, 1 week, 2 weeks and 4 weeks afterwards. Results: An AD‐like skin rash was successfully induced using TNCB in NC/Nga mice. The group receiving higher concentrations of pedunculagin showed faster and greater improvement. Conclusion: Our results suggest that remedies made from natural materials like pedunculagin are now showing promise for medical applications, and many new studies are expected to explore this potential.     

Topical acidic cream prevents the development of atopic dermatitis‐ and asthma‐like lesions in murine model

Long‐standing or repeated skin barrier damage followed by atopic dermatitis (AD) is the initial step of the atopic march that eventually progresses to respiratory allergies. Maintenance of an acidic pH in the stratum corneum (SC) is an important factor for normal skin barrier function. We performed this study to determine whether an oxazolone (Ox)‐induced AD murine model can develop airway inflammation by topical application and nasal inhalation of a house dust mite, Dermatofagoides pteronyssinus (Dp), which is a novel ‘atopic march animal model’, and whether an acidic SC environment, made by repeated application of acidic cream, can interrupt this atopic march. During repeated treatment with Ox and Dp to make an atopic march murine model, acidic cream (pH 2.8) and neutral cream (pH 7.4) adjusted by citric acid and sodium hydroxide mixed with vehicle were applied twice daily. Repeated treatment with Ox and Dp to hairless mice induced AD‐like skin lesions followed by respiratory allergy, defining it as an atopic march model. Acidic cream inhibited the occurrence of respiratory allergic inflammation as well as AD‐like skin lesions. These results indicate that a novel atopic march animal model can be developed by repeated topical and nasal treatments with house dust mite on Ox‐induced AD mice and that the acidification of SC could be a novel intervention method to block the atopic march.     

Oral supplementation with Lactobacillus rhamnosus CGMCC 1.3724 prevents development of atopic dermatitis in NC/NgaTnd mice possibly by modulating local production of IFN‐γ

Abstract: Prevalence of allergies has increased during the last two decades. Alteration of the gut microbiota composition is thought to play a crucial role in development of atopic diseases. Oral administration of probiotics has been reported to treat and/or prevent symptoms of atopic diseases in infants, but the results are still controversial. We investigated the potential efficacy of dietary interventions by a probiotic strain on prevention and treatment of atopic dermatitis (AD) in a human‐like AD model, NC/NgaTnd mice by perinatal administration. Pregnant NC/NgaTnd mice were orally treated with the probiotic strain Lactobacillus rhamnosus CGMCC 1.3724 (LPR), which was followed by treatment of pups until 12 weeks of age. LPR‐treated mice exhibited significant lower clinical symptoms of dermatitis, reduced scratching frequency, lower levels of plasma total Immunoglobulin E and higher levels of interferon‐γ in skin biopsies, compared with untreated mice. The protective effect was also observed when mice started to be treated at weaning time (5 weeks of age) even with limited supplementation period of 2 weeks. However, treatment of mice with the probiotic starting 1 week after the onset of the disease (8 weeks of age) had limited effects. The usefulness of LPR for primary prevention of AD was supported.     

Coping as mediator of the relationship between stress and itch in patients with atopic dermatitis: a regression and mediation analysis

Even though it has been shown that stress and itch are associated in patients with atopic dermatitis (AD), it remains unclear whether this relationship occurs due to certain coping strategies being activated under stress. Therefore, this study investigates the role of coping as possible mediating factor between stress and itch in 31 patients with AD. Coping and itch were assessed by self‐reported measures, while stress was measured both by a validated questionnaire and by a physiological stress marker, the postawakening cortisol. Using a regression and a mediation analysis, this study showed a relationship between perceived stress and itch (corrected R² = 0.21), which was fully mediated by negative itch‐related cognitions. 62.3% of the variance of itch intensity could be explained by negative itch‐related cognitions. This finding helps to explain the positive effects of cognitive restructuring in the treatment of chronic itch.