Psychological factors have long been assumed to be involved in the pathogenesis of allergic skin diseases. The effects of psychological stress on allergic contact dermatitis (ACD) have been experimentally well investigated; however, the effects of ACD on stress responses are largely unknown. Here, we report that preceding chronic ACD dramatically affects the behavioral and physiological stress responses to social isolation (a psychological stressor). In male BALB/c mice, social isolation combined with long-standing (>2 months) ACD by repeated hapten application caused characteristic symptoms, including chronic dermatitis from persistent self-scratching, behavioral changes related to fear/anxiety, and elevated serum IgE levels. The symptoms were maintained by social isolation alone without further hapten application after the onset, and were improved by resocialization. Treatment with topical corticosteroids exacerbated chronic scratch dermatitis, whereas it was effective for chronic ACD. These results show that the symptoms represent a de novo development of a specific disease state and not a mere exacerbation of a preexisting allergic inflammation. With this experimental protocol, similar results were obtained in several other strains of mice. This murine model provides a tool for investigating the pathogenesis and treatment of allergic skin disease with psychodermatological aspects.
PDE4 inhibitors are expected to be anti-inflammatory agents based on their mechanism of action, but the application of this drug class is limited by a narrow therapeutic window due to adverse effects associated with gastrointestinal function. Difamilast, a novel selective phosphodiesterase 4 (PDE4) inhibitor, demonstrated significant efficacy without adverse reactions such as nausea and diarrhea in patients with atopic dermatitis (AD) and was recently approved in Japan. In this study, we investigated the pharmacological and pharmacokinetic properties of difamilast to provide nonclinical data to help understanding the clinical effects. Difamilast selectively inhibited recombinant human PDE4 activity in assays. The IC 50 of difamilast against PDE4B, a PDE4 subtype that plays an important role in the inflammatory response, was 0.0112 μM, representing a 6.6-fold decrease compared to the IC 50 against PDE4D (0.0738 μM), a subtype that can trigger emesis.Difamilast inhibited TNF-α production in human (IC 50 = 0.0109 μM) and mouse (IC 50 = 0.0035 μM) peripheral blood mononuclear cells and improved skin inflammation in a mouse model of chronic allergic contact dermatitis. These effects of difamilast on TNF-α production and dermatitis were superior to those of other topical PDE4 inhibitors: CP-80633, cipamfylline, and crisaborole. In pharmacokinetic studies using miniature pigs and rats, the concentrations of difamilast in the blood and brain after topical application were not sufficient to support pharmacological activity. This nonclinical study contributes to explain the efficacy and safety of difamilast with a sufficient therapeutic window in the clinical trials.
Significance StatementThis is the first report on the nonclinical pharmacological profile of difamilast ointment, a novel topical PDE4 inhibitor that demonstrated utility in clinical trials in patients with atopic dermatitis.Difamilast, which has high PDE4 selectivity (especially for the PDE4B subtype), ameliorated chronic allergic contact dermatitis in mice after topical application, with a pharmacokinetic profile in animals that suggests few systemic side effects; thus, difamilast is a promising new therapeutic treatment for atopic dermatitis.
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