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Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal suppression. 5\u03b1\u2010Tetrahydrocorticosterone (5\u03b1THB) is a potential selective anti\u2010inflammatory with reduced metabolic effects. Here, the efficacy and side\u2010effect profile of 5\u03b1THB were compared with hydrocortisone in preclinical models of irritant dermatitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Acute irritant dermatitis was invoked in ear skin of male C57BL\/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5\u03b1THB and hydrocortisone. Side\u2010effects of 5\u03b1THB and hydrocortisone were assessed following chronic topical steroid treatment (28\u2009days) to non\u2010irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5\u03b1THB and hydrocortisone were measured following intravenous and oral administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>5\u03b1THB suppressed ear swelling in mice, with ED<jats:sub>50<\/jats:sub> similar to hydrocortisone (23\u2009\u03bcg vs. 13\u2009\u03bcg). Chronic application of 5\u03b1THB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5\u03b1THB (8\u00d7 ED<jats:sub>50<\/jats:sub>). 5\u03b1THB was rapidly cleared from the systemic circulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Topical 5\u03b1THB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16285","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T12:24:27Z","timestamp":1700655867000},"page":"1256-1267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["5\u03b1\u2010Tetrahydrocorticosterone: A topical anti\u2010inflammatory glucocorticoid with an improved therapeutic index in a murine model of 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