bromochloroacetic-acid and tazarotene

Oral retinoids have been widely used in psoriasis, but topical forms have been ineffective or irritating.. Our purpose was to determine the clinical and molecular effects of a new topical retinoid, AGN 190168, on psoriasis.. Seven patients with psoriasis were treated for 2 weeks with topical retinoid and 2 weeks with vehicle. Two control subjects with psoriasis were treated for 2 weeks with vehicle alone. Biopsy specimens from normal skin as well as from untreated and treated psoriatic lesions were compared by immunohistochemical analysis. Differentiation and inflammatory markers were studied.. Clinical improvement was seen in all seven patients after 2 weeks of treatment. Improvement was still present, but not significant, after 2 additional weeks of vehicle application. Histologic examination showed a return to a more normal morphology in four of seven biopsy specimens, which correlated with filaggrin expression. There was a diminution in the precocious expression of keratinocyte transglutaminase, keratin 16, and involucrin, as well as a decrease in epidermal growth factor receptor and in the number of cells expressing intercellular adhesion molecule type 1 and HLA-DR.. Clinical and histologic improvements were seen in psoriasis in association with the topical application of AGN 190168 at 2 weeks, including decreased inflammation and restoration of normal epidermal differentiation. Small patient numbers and the possibility that the changes were related to clinical improvement alone and not the topical agent preclude definitive conclusions.

Topics: Administration, Cutaneous; Adult; Antigens, CD; Biopsy; Cell Adhesion Molecules; Double-Blind Method; Epidermis; ErbB Receptors; Female; Filaggrin Proteins; Follow-Up Studies; HLA-DR Antigens; Humans; Immunohistochemistry; Intercellular Adhesion Molecule-1; Intermediate Filament Proteins; Keratinocytes; Keratins; Male; Nicotinic Acids; Pilot Projects; Prospective Studies; Protein Precursors; Psoriasis; Retinoids; Severity of Illness Index; Skin; Transglutaminases

Retinoids affect keratinocyte differentiation and modulate the expression of many epidermal proteins, among them cellular retinoic acid-binding protein II and the family of cytokeratins. The upregulation of the former protein is a well-known phenomenon, whereas the retinoid-induced regulation of epidermal keratin expression is more complex and only partially understood. We studied the effect of topical retinoids on the expression in healthy skin of cellular retinoic acid-binding protein II, tazarotene-induced genes 1 and 2, several epidermal keratins (K1, K2e, and K10), and two mucous keratins (K4 and K13) known to appear in epidermis under certain abnormal conditions. Reverse transcription-polymerase chain reaction experiments showed that the K4 expression was the one most overtly induced by 2 wk of open treatment with 0.05% of retinoic acid and tazarotene. Using real-time quantitative polymerase chain reaction (TaqMan) and normalization of the mRNA values to beta-actin, the increase in K4 was found to be 100-1000-fold. In comparison, the expression of K13 and cellular retinoic acid-binding protein II was increased 10-50-fold, the K1 and K10 mRNA levels remained unchanged, and the K2e level decreased by a factor of 100-1000. In parallel biopsies, immunohistochemistry showed no change in K1, K2e, or K10 staining, but a strong de novo appearance of K4 in the granular layer after retinoid treatment. In a separate study, occlusive application of 0.025% retinoic acid in four healthy subjects produced a maximal K4 mRNA signal after 48 h and strong K4 staining after 80 h. Finally, a dose-response study showed that the de novo appearance of K4 can be utilized as a sensitive test for retinoid bioactivity in epidermis in vivo.

Topics: Administration, Topical; Adult; Biomarkers; Dose-Response Relationship, Drug; Female; Gene Expression; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Nicotinic Acids; Receptors, Retinoic Acid; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin; Time Factors; Tretinoin; Up-Regulation