公开(公告)号：US20100221186A1

公开(公告)日：2010-09-02

申请号：US12293652

申请日：2006-03-10

申请人： Hueseyin Firat ,  Julie Boisclair ,  Olivier Grenet ,  Perentes Elias ,  Martin M. Schumacher

发明人： Hueseyin Firat ,  Julie Boisclair ,  Olivier Grenet ,  Perentes Elias ,  Martin M. Schumacher

IPC分类号： A61K49/00 ,  C07D231/12 ,  A61K39/00 ,  G01N33/53 ,  C07C63/331 ,  C07D307/46 ,  A61P37/04

CPC分类号： C12Q1/6883 ,  A61K31/00 ,  C12Q2600/106 ,  C12Q2600/142 ,  C12Q2600/158 ,  G01N33/68 ,  G01N2800/328

摘要： Cardiovascular tissue mRNA expression profiles in monkeys treated with coxibs was analyzed. Genomic data indicated that the animals showing vasculitis exhibit a specific mRNA expression pattern. The pattern includes gene expression changes involved in blood and endothelial cell (EC) activation, interaction of blood cells with EC, activation of INFγ pathway, and release of pro-inflammatory cytokines and chemo-attractants. These results provide direct evidence of minimal vasculitis together with corresponding genomic signature and peripheral biomarkers for minimal vasculatis. These results also suggest that treatment might triggers/aggravate a clinically latent cardiovascular disorder in the context of an endothelium tropic viral infection and/or an autoimmune vascular disorder. The histopathological examination revealed marginal vascular changes consistent with the genomic findings. Measurement of soluble proteins present in serum and plasma using a multiplex assay were in line with the genomic results, showing the increased level of INFγ inducible proteins, increased expression of CXCL10 chemokine was confirmed by an ELISA both in serum and plasma. Use of these peripheral biomarkers allows a safe usage of cox-2 inhibitory compounds in clinics and selection of cox-2 inhibitory follow-up compounds with no cardiovascular toxicity. These data together with biochemical and histopathological findings suggest that the specific cox2 inhibitor may exaggerate host immune response during some specific viral infections with endothelial tropism, or subjacent vascular autoimmune disorders.

摘要翻译： 分析用coxibs处理的猴子的心血管组织mRNA表达谱。 基因组数据表明，显示血管炎的动物表现出特异的mRNA表达模式。 该模式包括参与血液和内皮细胞（EC）激活，血细胞与EC的相互作用，INFγ通路的激活和促炎细胞因子和化学引诱物的释放的基因表达变化。 这些结果提供了最小血管炎的直接证据，以及相应的基因组特征和用于最小血管平滑肌的外周生物标志物。 这些结果还表明治疗可能在内皮热带病毒感染和/或自身免疫性血管疾病的背景下触发/加重临床上潜在的心血管疾病。 组织病理学检查发现边缘血管变化与基因组结果一致。 使用多重测定法测定血清和血浆中的可溶性蛋白质与基因组结果一致，显示INFγ诱导型蛋白水平升高，CXCL10趋化因子表达增加通过血清和血浆中的ELISA证实。 使用这些外周生物标志物可以安全使用cox-2抑制性化合物在临床和选择没有心血管毒性的cox-2抑制性后续化合物。 这些数据以及生物化学和组织病理学研究结果表明，特定的cox2抑制剂可能在具有内皮向性或下部血管自身免疫疾病的特定病毒感染期间夸大宿主免疫应答。