FDG-PET IMAGING AS A MARKER OF ANTI-INFLAMMATORY DRUG EFFECTS

FDG-PET 成像作为抗炎药物作用的标志

• 批准号: 7603360
• 负责人: Daniel P Schuster
• 金额: $ 1.21万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603360
• 关键词: Adult Respiratory Distress Syndrome; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Clinical; Computer Retrieval of Information on Scientific Projects Database; Cystic Fibrosis; Data; Data Set; Deoxyglucose; Development; Disease; Dose; Endotoxins; Funding; Grant; Harvest; Human; Human Volunteers; Image; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Institution; Invasive; Lead; Lesion; Lilly brand of drotrecogin alfa activated; Liquid substance; Lovastatin; Lung; Lung Inflammation; Lung diseases; Measurement; Measures; Modeling; Numbers; Outcome; Outcome Measure; Oxidoreductase; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Placebo Control; Pneumonia; Preclinical Drug Evaluation; Publishing; Randomized; Rate; Recombinants; Research; Research Personnel; Resources; Role; Screening procedure; Signal Transduction; Source; Surrogate Endpoint; Testing; United States National Institutes of Health; Upper arm; Work; X-Ray Computed Tomography; activated Protein C; airway inflammation; cystic fibrosis patients; density; drotrecogin alfa; drug testing; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose analog; improved; inhibitor/antagonist; neutrophil; novel; prospective; pulmonary function; uptake; volunteer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective of this project is to show that non-invasive imaging with [18F] fluorodeoxyglucose (FDG) and positron emission tomography (PET) can be used to improve the efficiency with which potential new anti-inflammatory drugs are screened for possible use in patients with lung disease characterized by neutrophilic inflammation (e.g., cystic fibrosis (CF), acute respiratory distress syndrome, and others). The project is motivated and quantify inflammatory responses in the lungs. This deficiency seriously hampers the development and testing of novel drugs for these diseases. It is already clear that FDG-PET imaging can detect inflammatory lesions in the lungs. However, as our recently published data show, the signal obtained by FDG-PET imaging is also quantitatively related to the influx of activated neutrophils into the lungs. Recent preliminary data provide additional support for this conclusion. For instance, using CF as a human model of inflammatory lung disease, we found that the pulmonary uptake of [18F]FDG correlates positively with the number of neutrophils present in bronchoalveolar lavage (BAL) fluid, and that the in vitro uptake of another glucose analog, H-deoxyglucose ([18F]DG), is limited to neutrophils harvested from BAL. Of potential clinical importance, the imaging signal was highest in CF patients with the most rapid decline in pulmonary function. In addition, we have recently shown that FDG-PET imaging can quantify focal inflammatory responses to experimentally-induced airway inflammation in normal human volunteers (specifically, after the direct intra-bronchial instillation of low-dose endotoxin). Finally, this clinical work has been supplemented by recent animal studies showing that FDG-PET imaging can quantify the anti-inflammatory effects of novel drugs. The results lead us to propose the hypothesis that FDG-PET imaging will be able to quantify drug-induced suppression of pulmonary inflammation. We plan to support this hypothesis by pursuing the following specific aims: Specific Aim 1. In normal volunteers, demonstrate that the recombinant form of activated protein C (rhAPC, drotrecogin [alpha], Xigris¿), and separately, the hydroxymethylglutaryl co-A reductase inhibitor lovastatin (Mevacor¿), will significantly suppress experimentally-induced focal lung inflammation as measured by FDG-PET imaging. East of the test drugs is commercially available and FDA-approved. The study will be prospective, triple-blinded, randomized, and placebo-controlled. rhAPC has already been shown by other, using fluid obtained via BAL, to reduce lung inflammation in this same model of endotocin-induced inflammation in normal human volunteers. Statin drugs have been shown in animal models, but not yet in humans, to reduce endotoxin-induced airway inflammation. The primary outcome measure will be a quantitative measure of [18F]FDG uptake by the lungs, namely the net uptake rate constant, Ki. Specific Aim 2. Compare anti-inflammatory drug effects on Ki with their effects on alternative measures of lung inflammation. The FDG-PET measurements will be compared with neutrophil concentrations in BAL fluid and with xray computed tomography (CT) measures of inflammation lung density. The study will produce a unique set of data about potential biomarkers of pulmonary inflammatory responses which could prove useful as surrogate end-points in early developmental trials of new anti-inflammatory drugs. Since rhAPC has already been shown to reduce endotoxin-induced inflammation, data from this study will serve as a positive control. The data from the lovastatin arms will serve as a test of a new paradigm for studying anti-inflammatory drugs in patients with lung diseases characterized by neutrophilic inflammation, in which drugs are first screened with FDG-PET imaging in normal human volunteers after bronchial instillation of endotoxin, followed by a similar screening study in a small group of actual patients. Positive results for anti-inflammatory efficacy would provide justification for further testing in large Phase III studies to demonstrate improvements in functional or clinical outcomes. Overall, the proposed studies will help establish the role of FDG-PET imaging as a new and useful biomarker of pulmonary inflammatory responses.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 The overall objective of this project is to show that non-invasive imaging with [18F] fluorodeoxyglucose (FDG) and positive emission tomography (PET) can be used to improve the efficiency with which potential new anti-inflammatory drugs are screened for possible use in patients with lung disease characterised by neutrophilic inflammation (e.g., cystic fibrosis (CF), acute respiratory distress syndrome, and others).该项目是动机的，并量化了肺部的炎症反应。这种缺乏严重阻碍了这些疾病的新药物的开发和测试。 很明显，FDG-PET成像可以检测肺部的炎症性病变。但是，正如我们最近发表的数据所示，通过FDG-PET成像获得的信号也与活化的中性粒细胞在肺中的影响相关。最近的初步数据为此结论提供了更多支持。例如，使用CF作为炎症性肺部疾病的人类模型，我们发现[18F] FDG的肺摄取与支气管肺泡灌洗液（BAL）液中存在的嗜中性粒细胞的数量正相关，并且在另一种葡萄糖类似物，H-Deoxyglucose（h-DeoxyCyopols）的体外摄取的体外摄取量是有限的（18f）[18f] [18f] [18f] d. [18f] dsr。潜在的临床重要性，在肺功能下降最快的CF患者中，成像信号最高。此外，我们最近表明，FDG-PET成像可以量化正常人志愿者中对实验诱导的气道感染的局灶性炎症反应（特别是，在直接支撑低剂量内毒素之后）。最后，最近的动物研究补充了这项临床工作，表明FDG-PET成像可以量化新药物的抗炎作用。 结果使我们提出了以下假设：FDG-PET成像将能够量化药物诱导的肺注射抑制。我们计划通过追求以下特定目的来支持这一假设： 具体目的1。在正常志愿者中，表明活化蛋白C的重组形式（Rhapc，Drotrecogin [alpha]，Xigris¿）和单独的重组形式，羟基甲基戊二酰co-A Co-a可减少抑制剂lovastatin（mevacor），将根据测量抑制型号的焦点，以实验性地抑制了焦点。 测试药物的东部是商业上可用的，并批准了FDA。该研究将是前瞻性，三叶，随机和安慰剂对照的。在正常人类志愿者中，使用通过BAL获得的流体已经显示了RHAPC，它已经使用BAL获得的流体来减少肺部感染。他汀类药物已在动物模型中显示，但尚未在人类中显示，以减少内毒素诱导的气道感染。主要结局度量将是肺对[18F] FDG摄取的定量度量，即净摄取速率常数KI。 具体目的2。比较抗炎药对Ki的影响及其对肺部感染的替代测量的影响。 FDG-PET测量将与BAL流体中的中性粒细胞浓度以及X射线计算机断层扫描（CT）测量的肺部密度进行比较。 该研究将产生有关肺部炎症反应潜在生物标志物的独特数据，这些数据可能被证明是在新的抗炎药的早期发育试验中被证明是替代终点。由于RHAPC已被证明可以减少内毒素诱导的感染，因此该研究的数据将作为阳性对照。 Lovastatin Arm的数据将用于测试以嗜中性炎症为特征的肺部疾病患者研究抗炎药的新范式，在该患者中首先用正常人类志愿者在内托毒素灌注内毒素后，首先将药物用FDG-PET成像筛查，并进行了类似的筛查。抗炎效率的阳性结果将为大型III期研究提供进一步测试的正当结果，以证明功能或临床结果的改善。总体而言，拟议的研究将有助于确定FDG-PET成像作为肺部炎症反应的新生物标志物的作用。