INFLAMMATION AND DRUG IDIOSYNCRASY

炎症和药物特异性

基本信息

批准号：
7870407
负责人：
Robert Andrew Roth
金额：
$ 25.58万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7870407
关键词：
Address Ancrod Animal Model Animals Appearance Biological Markers Cells Cessation of life Clinical Coagulation Process Contrast Media Critiques Cytokine Activation Data Decision Making Deposition Development Dose Drug Interactions EMSA Early identification Etanercept Evaluation Event Famotidine Fibrin Future Genes Genetic Polymorphism Goals Grant Growth Hemostatic Agents Hemostatic function Heparin Hepatic Hepatocyte Hepatotoxicity Human Hypoxia IL8RB gene Immune Sera In Vitro Individual Inflammation Inflammatory Inflammatory Response Injury Injury to Liver Knockout Mice Knowledge Lead Levaquin Lipopolysaccharides Liver Location Mediator of activation protein Modeling Mus Organ Pathogenesis Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacogenomics Pharmacotherapy Phosphorylation Predisposition Production Progress Reports Proteins Ranitidine Rattus Reaction Research Risk Rodent Role Streptokinase Stress System Testing Text Therapeutic Thromboplastin Time Toxic effect Tumor Necrosis Factor-alpha Up-Regulation Ursidae Family Vascular Endothelial Growth Factors Work base chemokine chemokine receptor cytokine design drug candidate drug development drug mechanism improved in vivo killings neutrophil novel prevent public health relevance receptor response transcription factor trovafloxacin

项目摘要

DESCRIPTION (provided by applicant): Animal models with the potential to enable prediction/early identification of idiosyncratic adverse drug reactions (IADRs) could prevent human suffering and improve decision-making during drug development and the understanding of mechanisms. One mode by which IADRs might occur is through interaction of the drug with an inflammatory stress. In support of this hypothesis, a modest inflammatory episode caused by bacterial lipopolysaccharide (LPS) in animals interacts with drugs that cause IADRs in humans to produce liver injury, whereas drugs without IADR liability in people do not. For example, trovafloxacin (TVX) has caused hepatotoxic IADRs in people, and it interacts with LPS in rodents to cause liver injury. In contrast, levofloxacin, which has not caused human IADRs, shows no hepatotoxic interaction with LPS. In the current granting period, we have not only expanded the number of LPS-drug interaction models in rodents but have also identified tumor necrosis factor-alpha (TNF), neutrophils (PMNs) and the hemostatic system as important mediators in the pathogenesis of hepatocellular injury. Vascular endothelial growth factor (VEGF) can upregulate all of these factors, and recent results suggest its involvement in the liver injury. Accordingly, the overall hypothesis to be tested during the next granting period is that enhanced VEGF production during LPS-drug interaction results in liver injury by influencing TNF, PMNs and/or the hemostatic system. A major goal of the proposed research is to elucidate the cascade of events that culminates in liver injury from the interaction of inflammatory stress with IADR-associated drugs. Specific aims are proposed to delineate the time course of VEGF appearance and the effect of VEGF neutralization on other, critical events in the pathogenesis. The relationship of VEGF to the roles of TNF, PMNs and the hemostatic system will be elucidated in vivo to understand the cascade of events that leads to injury from cotreatment with LPS and TVX as a model IADR-causing drug. Egr-1 is a transcription factor that controls expression of VEGF and is selectively upregulated in livers of LPS/drug-treated animals; accordingly, its role in the hepatotoxic cascade will be explored in part by using egr-1 knockout mice. These studies will continue to test a novel hypothesis that could explain a cause of hepatic IADRs and will increase knowledge of mechanisms of drug interactions with inflammatory stress. PUBLIC HEALTH RELEVANCE: Idiosyncratic adverse drug reactions are rare, poorly understood toxic reactions to drugs that often damage the liver and cause human suffering and sometimes death. Recently developed animal models suggest that these reactions sometimes happen when a patient has an inflammatory response during drug therapy, and these models may enable prediction of drugs that are likely to cause such reactions. The proposed research is aimed at understanding the cascade of events that leads to liver toxicity in these models, with the ultimate goal of choosing safer drug candidates and developing strategies to reduce human suffering from idiosyncratic drug reactions.

描述（由申请人提供）：有潜力的动物模型可以预测/早期鉴定特质不良药物反应（IADRS）可以防止人类的痛苦并改善药物开发过程中的决策和对机制的理解。 IADR可能发生的一种模式是通过药物与炎症应激的相互作用。为了支持这一假设，动物中由细菌脂多糖（LPS）引起的适度炎症发作与导致人类IADR的药物相互作用，以引起人类造成肝损伤，而人不承担IAIADR责任的药物。例如，trovafloxacin（TVX）引起了人们的肝毒性IADR，并且它与啮齿动物中的LPS相互作用以引起肝损伤。相比之下，尚未引起人类IADR的左氧氟沙星与LPS没有肝毒性相互作用。在当前的给予期内，我们不仅扩大了啮齿动物中的LPS-rug相互作用模型的数量，而且还确定了肿瘤坏死因子 - α（TNF），中性粒细胞（PMN）和止血系统是肝细胞损伤病原体中重要的介体。血管内皮生长因子（VEGF）可以上调所有这些因素，最近的结果表明其参与了肝损伤。因此，在下一个授予期间要测试的总体假设是，在LPS-Crug相互作用期间，VEGF产生增强会通过影响TNF，PMN和/或止血系统而导致肝损伤。拟议的研究的主要目标是阐明一系列事件，这些事件因炎症应激与IADR相关药物的相互作用而导致肝损伤。提出了具体目的来描述VEGF外观的时间过程以及VEGF中和对发病机理中其他关键事件的影响。 VEGF与TNF，PMNS和止血系统的作用的关系将在体内阐明，以了解导致与LPS和TVX的损伤的事件级联，并作为导致IADR的模型引起的药物。 EGR-1是控制VEGF表达并在LPS/药物治疗动物的肝脏中选择性上调的转录因子。因此，将通过使用EGR-1敲除小鼠在某种程度上探索其在肝毒性级联反应中的作用。这些研究将继续检验一个新的假设，该假设可以解释肝IADR的原因，并将增加对药物相互作用与炎症应激的机制的了解。公共卫生相关性：特殊的不良药物反应很少见，对经常损害肝脏并有时会造成人类痛苦的药物的有毒反应很少见。最近开发的动物模型表明，当患者在药物治疗期间患有炎症反应时，这些反应有时会发生，并且这些模型可以预测可能引起此类反应的药物。拟议的研究旨在了解导致这些模型中肝脏毒性的一系列事件，其最终目的是选择更安全的候选药物并制定策略，以减少人类因特殊药物反应的痛苦。