Acute-infarct selective cardiac MRI contrast agent

急性梗塞选择性心脏MRI造影剂

• 批准号: 8145695
• 负责人: Akos Varga-Szemes
• 金额: $ 59.05万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145695
• 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). PUBLIC HEALTH RELEVANCE: A significant number of heart patients suffer a second heart attack after the first infarction was treated either by angioplasty or by bypass surgery. It would be important to the cardiologist to be able to distinguish on the MRI image between the old and new infarct. A reliable, noninvasive diagnostic differentiation between acute and older 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 multiple myocardial infarction. MRI contrast agents presently used in the clinic are unable to make such differentiation. 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).

描述（由申请人提供）：该项目的总体目标是证明我们的急性心肌梗死选择性顺磁造影剂钆（ABE-DTTA）在使用对比增强磁共振成像（ceMRI）以可靠的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）通过引起信号超增强来专门突出急性梗死，但与目前使用的造影剂相反，它不会引起4周梗死的超增强。对急性心肌梗死和老年心肌梗死进行可靠的无创诊断鉴别，可用于决定介入心脏科医生或心脏外科医生对心肌梗死患者应以何种顺序重开或分流哪些血管。目前临床上使用的MRI造影剂无法进行这种区分。使用传统的MRI造影剂来突出所有的梗死，然后在适当的最短时间内让造影剂从心肌中清除（30-60分钟），随后使用Gd(ABE- DTTA)，可以阐明哪个梗死区域是由新的急性梗死引起的。通过一期项目犬心肌梗死模型，我们证明了Gd（ABE-DTTA）表现出这种分化的能力具有统计学意义。为了准备商业化，第二阶段的目标是：1)在猪再灌注梗死模型中，研究Gd（ABE-DTTA）对心肌梗死的亲和力消失或衰减的梗死年龄范围。2)在同一动物模型中阐明这一现象的组织学基础。3)测定Gd（ABE-DTTA）在猪亚急性和慢性心肌梗死时的体内心肌组织动力学。4)测定Gd（ABE-DTTA）在猪体内的生物分布动力学及在家兔体内的清除动力学。5)测定小鼠Gd（ABE-DTTA）毒性（LD50）。6)定量比较高剂量Gd（ABE-DTTA）与FDA批准的Gd（DTPA）对肾源性系统性纤维化的影响。