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    BIOMARKERS FOR CARDIOVASCULAR SIDE-EFFECTS INDUCED BY COX-2 INHIBITORY COMPOUNDS
    1.
    发明公开
    BIOMARKERS FOR CARDIOVASCULAR SIDE-EFFECTS INDUCED BY COX-2 INHIBITORY COMPOUNDS 有权
    BIOMARKERFÜRDURCH COX-2-INHIBITORVERBINDUNGEN INDUZIERTEKARDIOVASKULÄRENEBENWIRKUNGEN

    公开(公告)号：EP1910825A2

    公开(公告)日：2008-04-16

    申请号：EP06710533.8

    申请日：2006-03-10

    申请人： Novartis AG ,  NOVARTIS-PHARMA GMBH

    发明人： FIRAT, Hueseyin ,  BOISCLAIR, Julie ,  GRENET, Olivier ,  PERENTES, Elias ,  SCHUMACHER, Martin, M.

    IPC分类号： G01N33/53 ,  A61K45/06 ,  C12Q1/68

    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 INF³ 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 INF³ 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： 分析了用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）激活的基因表达变化，血细胞与EC的相互作用，INF 3途径的活化以及促炎细胞因子和化学引诱物的释放。 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INF3诱导蛋白的水平升高。 通过血清和血浆中的ELISA证实CXCL10趋化因子的表达增加。 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。 这些数据连同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。

    MARKER GENES FOR DETERMINING RENAL TOXICITY
    2.
    发明公开
    MARKER GENES FOR DETERMINING RENAL TOXICITY 审中-公开
    标记基因检测肾毒性的

    公开(公告)号：EP1521847A2

    公开(公告)日：2005-04-13

    申请号：EP03762612.4

    申请日：2003-07-03

    申请人： Novartis AG ,  Novartis Pharma GmbH

    发明人： CHIBOUT, Salah-Dine ,  GRENET, Olivier ,  IMBERT, Georges ,  KEHREN, Jeanne ,  STÄDTLER. Frank ,  WOLFGANG, Curt, Douglas

    IPC分类号： C12Q1/68

    CPC分类号： C12Q1/6883 ,  C12Q2600/158

    摘要： Methods are disclosed for fast and accurate readout of kidney toxicity before it occurs and before it is demonstrated by histopathology examination. Ultimately this approach shall allow earlier compound selection. The twelve genes identified, namely Calbindin-D28k, KIM-1, OPN, EGF, Clusterin, VEGF, OAT-K1, Aldolase A, Aldolase B, Podocin, Alpha-2u and C4, were grouped and ultimately can be assessed in the form of a kit using PCR, a high throughput technology, in order to characterize and rank new compounds according to their anticipated general kidney toxicity. Also disclosed are methods for identifying agents useful in the treatment of kidney disease, methods for monitoring the efficacy of a treatment for kidney disease and kidney-specific vectors including the sequences of the disclosed genes, and a method for identifying a candidate gene associated with a biological process including kidney function.