Malcolm Johnson *
* Malcolm Johnson, PhD – Din International Medical Affairs, Respiratory, GlaxoWellcome Research and Development, Middlesex, United Kingdom
Abstract
Fluticasone propionate (FP) is a trifluorinated glucocorticoid based on the androstane nucleus. It was selected for development form structure-activity relationships (topical anti-inflammatory, cutaneous vasoconstriction, and hypothalamic-pituitary-adrenal axis suppression) of a seris of 17 carcothioates. FP is a 3-, 300- and 1000-fold more lipophilic than beclomethasone dipropionate, budesonide, and triamcinolone acetonide, respectively. FP has an absolute affinity (KD) for the glucocorticoid receptor of 0,5 nmol/L and a relative receptor affinity 1,5-fold higher than beclomethasone-17-monopropionate (17-BMP) and mometasone furoate, 3-fold higher than budesonide, and 2O-fold higher than flunisolide and triamcinolone acetonide. The rate of association of FP with the receptor is faster and the rate of dissociation slower than other corticosteroids. The resulting half-life of the FP active steroid-receptor complex is> 10 hours, compared with approximately 5, 7.5, and 4 hours for budesonide, 17-BMP and triamcinolone acetonide, respectively. FP has high selectivity for the glucocorticoid receptor, with little or no activity at other steroid receptors. FP is more potent than beclomethasone dipropionate, budesonide, triamcinolone acetonide, and mometasone furoate in inhibiting human T-cell migration and proliferation, inhibiting CD4+ T-cell cytokine and basophil histamine release, attenuating adhesion molecule expression, stimulating inflammatory cell apoptosis, and inducing cellular antiprotease release. In asthma patients, FP decreases the number of CD3+, CD4+, CDS+ and CD25+ Tcells, mast cells, and eosinophils in bronchial biopsies, in addtion to suppressing CD1a-denddritic and lgE+ cells and HLA-DR. FP, therefore, has a good pharmacologic profile for a topical steroid with increased intrinsic glucocorticoid potency and potent anti-inflammatory activity. (J. Allergy Clin. lmmunol. 1988; 101: S434 – 9).