353 Mouse model of cutaneous adverse effects: Validation with human topical therapies

Abstract

The discovery of novel topical drugs would benefit from an in vivo screening model to predict unwanted cutaneous effects. With this aim, we established a subacute mouse model and validated it with five approved topical formulations which show cutaneous side effects. Formulations tested were Clovate®-clobetasol cream, Dermosa hidrocortisona®-hydrocortisone cream, Zorac®-tazarotene, Efudix®-5-fluorouracil and Picato®-ingenol mebutate. Mice received a topical application of the test product on dorsal skin once daily for 4 days except for Efudix® (10 applications) and Picato® (single dose). On day 5, skin punch biopsies were taken, weighted and analysed histologically. Additional parameters were also recorded such as macroscopic images, transepidermal water loss (TEWL), body weight and blood cell count. Corticosteroid formulations induced skin atrophy in mice manifested as an increase in TEWL, a punch weight decrease, and epidermis and follicular atrophy. These effects were more severe with Clovate® than with Dermosa hidrocortisona®, in agreement with the distinct corticosteroid potencies. In contrast, Zorac®-treated skin showed signs of irritation accompanied by skin weight increase, epidermal hyperplasia and a dermal neutrophilic infiltrate. Mice treated with Efudix® showed mainly inflammatory epidermal lesions and necrosis and follicular atrophy whereas a single dose of Picato® induced an intense dermal inflammatory neutrophilic infiltrate and epidermal necrosis. Systemic alterations were also observed in treated mice. This mouse model reveals the skin alterations observed in humans for five approved topical therapies. These include the adverse effects reported for corticosteroids and tazarotene, as well as those driving the therapeutic responses in actinic keratosis treatments. As the model is aimed at revealing exclusively cutaneous effects, dose adjustments may be required to minimise systemic involvement. This model may provide a rapid screening assay to detect major local adverse effects induced by new chemical entities.