Astry Calvin, Birmachu Woubalem, Harrison Lester I, Meng Tze-Chiang
3M Pharmaceuticals, Department of Pharmacokinetics/Drug Metabolism, 3M Center Bldg 260-3A-05, St. Paul, MN 55144, USA.
J Clin Pharmacol. 2008 Jun;48(6):755-62. doi: 10.1177/0091270008314466. Epub 2008 Apr 9.
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.
852A是一种特异性Toll样受体7（TLR7）激动剂。32名健康成年人（每组8名受试者）接受了两次在400平方厘米区域上的1克局部应用，间隔≥5天，分别是先使用0.01%的852A，后使用赋形剂；先使用赋形剂，后使用0.1%的852A；先使用0.3%的852A，后使用赋形剂；或者先使用赋形剂，后使用1.0%的852A。全身吸收极少，因为在给药后24小时内，任何血清样本中均无法检测到852A，仅在8名受试者中的4名在应用1.0%的852A后24小时的尿液中可检测到。药物治疗未出现全身不良事件。应用部位活检的基因表达分析显示，至少2名受试者中有40个基因的表达增加了≥2倍。CXCL9/MIG（8/32名受试者）、CCL2/MCP1（7/32）和OAS3（5/32）增加最为频繁，其次是其他I型干扰素诱导基因。对表达增加≥2倍的基因进行聚类分析，未发现与852A浓度或活检时间相关的明确模式。总体而言，单次局部应用高达1.0%的852A耐受性良好。从这些受试者收集的数据表明，852A可导致与TLR7刺激一致的局部基因表达增加。
