The phosphodiesterase 4 inhibitor AWD 12-281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytokines in mice

Abstract

The selective phosphodiesterase 4 (PDE4) inhibitor AWD 12-281 is structurally optimized for topical administration. It has potent effects in models of lung inflammation if administered as a dry powder inhalation. It has also demonstrated its anti-inflammatory property in a mouse model of cutaneous inflammation after topical administration. The aim of this study was to evaluate whether AWD 12-281 may be capable of penetrating human skin. Therefore a new guinea-pig model of allergic skin inflammation had to be developed. In ovalbumin-sensitized guinea-pigs, intracutaneous administration of ovalbumin results in a rapid development of allergic skin wheals. Topically administered AWD 12-281 was capable of reducing the development of wheals, indicating that this compound can penetrate the stratum corneum of guinea-pig skin as a predictor of human skin penetration. A secondary aim was the evaluation of a T cell subtype preference of AWD 12-281 since PDE4 inhibitors are said to preferentially inhibit Th2-type cytokines. Therefore, the effects of AWD 12-281 on a broad spectrum of Th1- and Th2-type cytokines were studied in tissue homogenates after allergen challenge in sensitized mice and in supernatants of anti CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs). In both models, AWD 12-281 suppressed both T cell subtype cytokines indicating a broad spectrum activity of AWD 12-281. A further issue was to determine the duration of action and the concentration-response relationship of the topical activity of AWD 12-281 using a model of acute local inflammation--the arachidonic-acid-induced mouse ear oedema. The compound exhibited a dose-dependent effect with a minimally effective concentration of 0.3%; after repeated administration the minimally effective concentration was found to be 0.03%. A single administration of a 3% solution resulted in significant suppression of inflammation even 48 h after treatment. In conclusion, our results indicate that AWD 12-281 is a very promising drug candidate not only for the treatment of lung inflammation using inhalative administration but also for the treatment of atopic dermatitis.