title: Cutaneous pharmacodynamics of a toll-like receptor 7 agonist, 852A, in humans.
abstract: 852A is a specific toll-like receptor 7 (TLR7) agonist. Thirty-two healthy adults (8 subjects per group) received two 1-g topical applications over 400 cm(2), separated by >or= 5 days, of 852A 0.01% followed by vehicle, vehicle followed by 852A 0.1%, 852A 0.3% followed by vehicle, or vehicle followed by 852A 1.0%. Systemic absorption was minimal as 852A was not quantifiable in any serum sample up to 24 hours postadministration and was only quantifiable at 24 hours in the urine of 4 of 8 subjects after application of 852A 1.0%. No systemic adverse events were associated with drug treatment. Gene expression analysis from application site biopsies showed a >or=2-fold increase in expression for 40 genes in at least 2 subjects. CXCL9/MIG (8/32 subjects), CCL2/MCP1 (7/32), and OAS3 (5/32) were most frequently increased, followed by other type I interferon-inducible genes. Cluster analysis of the genes with a >or=2-fold increase did not reveal a definitive pattern with respect to 852A concentration or time of biopsy. Overall, single topical application of 852A up to 1.0% was well tolerated. Data gathered from these subjects are suggestive that 852A can produce increases in local gene expression consistent with TLR7 stimulation.
authors.affiliation: 3M Pharmaceuticals, Department of Pharmacokinetics/Drug Metabolism, 3M Center Bldg 260-3A-05, St. Paul, MN 55144, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Astry
authors.forename: Woubalem
authors.initials: W
authors.lastname: Birmachu
authors.forename: Lester I
authors.initials: LI
authors.lastname: Harrison
authors.forename: Tze-Chiang
authors.initials: TC
authors.lastname: Meng
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D015331:Cohort Studies; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009824:Ointments; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D009824:Ointments; D011804:Quinolines; D012333:RNA, Messenger; D013449:Sulfonamides; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7