Acute-infarct selective cardiac MRI contrast agent

急性梗塞选择性心脏MRI造影剂

• 批准号: 8287126
• 负责人: Akos Varga-Szemes
• 金额: $ 44.05万
• 依托单位: ELGAVISH PARAMAGNETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287126
• 关键词: Acute; Acute myocardial infarction; Affinity; Age; Angioplasty; Animal Model; Animals; Area; Biodistribution; Biological Assay; Blood specimen; Body Weight; Bolus Infusion; Bypass; Canis familiaris; Cardiac; Characteristics; Chest; Chronic; Clinic; Contrast Media; Control Groups; Data; Decision Making; Development; Diagnostic; Dose; Drug Kinetics; Evolution; FDA approved; Family suidae; Feces; Female; Fibrosis; Fluorescence; Gadolinium; Gadolinium DTPA; Generations; Goals; Half-Life; Healed; Heart; Hour; Image; Image Enhancement; Infarction; Injection of therapeutic agent; Intravenous Bolus; Investigation; Kidney; Kinetics; Lethal Dose 50; Liver; Magnetic Resonance Imaging; Metabolic; Methods; Modeling; Morbidity - disease rate; Motor; Mus; Myocardial Infarction; Myocardial tissue; Myocardium; Old Myocardial Infarction; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Patients; Phase; Plasma; Preparation; Progress Reports; Protocols documentation; Rattus; Recovery; Regression Analysis; Reperfusion Therapy; Rest; Route; Saline; Sampling; Scanning; Signal Transduction; Site; Skin; Slice; Specific qualifier value; Spleen; Staining method; Stains; Structure; Subgroup; Surgeon; Tail; Testing; Time; TimeLine; Tissues; Toxic effect; Urine; Veins; analog; base; bone; commercialization; gadolinium oxide; healing; in vivo; intravenous administration; intravenous injection; male; mortality; public health relevance; relating to nervous system; software development

DESCRIPTION (provided by applicant): The overall goal of this project is to demonstrate the ability of our acute-myocardial-infarct- selective paramagnetic contrast agent, Gadolinium(ABE-DTTA), to differentiate between acute and chronic infarcts in a reliable manner using contrast-enhanced magnetic resonance imaging (ceMRI). In our Phase I data we have shown that Gd(ABE-DTTA) exclusively highlights acute infarcts by causing signal hyper-enhancement, but contrary to presently used contrast agents, it does not cause hyper-enhancement in 4-week old infarcts. A reliable noninvasive diagnostic differentiation between acute and older myocardial infarcts could be used to make decisions about which vessels and in what order should be reopened or bypassed by an interventional cardiologist or a cardiac surgeon in a patient with myocardial infarction. MRI contrast agents presently used in the clinic are unable to make such differentiation. Using a conventional MRI contrast agent to highlight all infarcts, followed by an appropriate minimum time period to allow for this agent to clear from the heart muscle (30-60 minutes), and subsequently using Gd(ABE- DTTA), one would elucidate which infarct area is due to a new, acute infarction. Using a canine model of myocardial infarction in the Phase I project we proved with statistical significance the ability of Gd(ABE-DTTA) to show such differentiation. In preparation for commercialization, the objectives of Phase II are: 1) Investigation of the infarct age time frame for the disappearance or the decay of the affinity of Gd(ABE-DTTA) to the myocardial infarct in the pig model of reperfused infarct. 2) Elucidation of the histological basis of this phenomenon in the same animal model. 3) Determination of the in vivo myocardial tissue kinetics of Gd(ABE-DTTA) accumulation into subacute versus chronic myocardial infarct in pigs. 4) Determination of the kinetics of biodistribution of Gd(ABE-DTTA) in pigs and its clearance kinetics in rabbits. 5) Determination of Gd(ABE-DTTA) toxicity (LD50) in mice.6) Quantitative comparison of the effect of high dose of Gd(ABE-DTTA) on Nephrogenic Systemic Fibrosis to that of FDA approved Gd(DTPA).

描述（由申请人提供）：本项目的总体目标是证明我们的急性心肌梗死选择性顺磁性造影剂钆（ABE-DTTA）使用对比增强磁共振成像（ceMRI）以可靠方式区分急性和慢性梗死的能力。在我们的I期数据中，我们已经表明Gd（ABE-DTTA）通过引起信号过度增强而专门突出急性梗死，但与目前使用的造影剂相反，它不会引起4周龄梗死的过度增强。急性心肌梗死和陈旧性心肌梗死之间可靠的非侵入性诊断区分可用于决定哪些血管和以何种顺序应该由介入心脏病专家或心脏外科医生在心肌梗死患者中重新开放或旁路。目前临床上使用的MRI造影剂不能进行这种区分。使用常规MRI造影剂来突出显示所有梗塞，随后是适当的最短时间段以允许该试剂从心肌中清除（30-60分钟），并且随后使用Gd（ABE-DTTA），将阐明哪个梗塞区域是由于新的急性梗塞。在I期项目中使用犬心肌梗死模型，我们证明了Gd（ABE-DTTA）显示这种分化的能力具有统计学意义。在商业化的准备中，II期的目标是：1）在再灌注梗塞的猪模型中研究Gd（ABE-DTTA）对心肌梗塞的亲和力消失或衰减的梗塞年龄时间范围。2)在同一动物模型中阐明这种现象的组织学基础。3)测定Gd（ABE-DTTA）蓄积至猪亚急性与慢性心肌梗死的体内心肌组织动力学。4)Gd（ABE-DTTA）在猪体内的生物分布动力学和在兔体内的清除动力学的测定。5)Gd（ABE-DTTA）在小鼠中的毒性（LD 50）的测定。6）高剂量Gd（ABE-DTTA）与FDA批准的Gd（DTPA）对肾源性系统性纤维化的作用的定量比较。