fluticasone and Dermatitis--Irritant

We used a new technique to evaluate and compare cutaneous irritation from various topical medications. Twenty participants with corticosteroid-responsive dermatoses were enrolled. Three target areas of unaffected skin were abraded. A negative control (petrolatum ointment), a positive control (an over-the-counter [OTC] anti-itch preparation containing benzyl alcohol), and a test product (fluticasone propionate lotion 0.05%) were each applied to separate targetareas on the legs. Participants rated the irritation of each target area using a 10-point scale (1 [no symptoms] to 10 [intolerable burning/ stinging requiring removal of the medication]). The mean irritation scores for petrolatum ointment, the OTC anti-itch preparation, and fluticasone propionate lotion 0.05% were 1.20, 6.15, and 2.05, respectively. The difference in irritation between the OTC anti-itch preparation and fluticasone propionate lotion 0.05% was highly significant (P < .0001). The difference in irritation between the OTC anti-itch preparation and petrolatum ointment also was highly significant (P < .0001). The difference in irritation between fluticasone propionate lotion 0.05% and petrolatum ointment also was statistically significant (P = .0104). Irritation scores were then standardized on a 10-point scale, with the irritation score of the negative control given a value of 1.00 and the irritation score of the positive control given a value of 10.00. The standardized irritation score of the test product, fluticasone propionate lotion 0.05%, was calculated to be 2.55. Our assay was able to detect and quantify even minimal cutaneous irritation secondary to application of topical medications.

Topics: Administration, Cutaneous; Androstadienes; Dermatitis, Irritant; Dermatologic Agents; Dosage Forms; Fluticasone; Humans; Reproducibility of Results; Severity of Illness Index; Skin Irritancy Tests

Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti-inflammatory activity.. The pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling.. GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV-driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid-regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase-mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation, GW870086 showed comparable anti-inflammatory efficacy to FP.. GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.

Topics: Alveolitis, Extrinsic Allergic; Androstadienes; Animals; Anti-Inflammatory Agents; Cell Line; Cyclooxygenase 2; Cytokines; Dermatitis, Irritant; Drug Design; Enzyme Induction; Fluticasone; Gene Expression Regulation; Humans; Lung; Mice; Mice, Inbred BALB C; Organ Specificity; Promoter Regions, Genetic; Respiratory Mucosa; Skin; Species Specificity; Steroids; Tight Junctions