Development of Fibrin-Specific Nuclear Probe to Reduce LVAD Adverse Events

开发纤维蛋白特异性核探针以减少 LVAD 不良事件

• 批准号: 9607429
• 负责人: James Blackledge
• 金额: $ 76.86万
• 依托单位: CAPELLA IMAGING, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9607429
• 关键词: Acute; Acute Kidney Failure; Adverse event; Analytical Chemistry; Animal Model; Animals; Anticoagulation; Antiplatelet Drugs; Area; Avidity; Benchmarking; Binding; Biological Markers; Biomedical Engineering; Blood flow; Blood specimen; Cannulas; Cardiology; Cessation of life; Chemicals; Chemistry; Clinical; Clinical Management; Collaborations; Complex; Cytolysis; Data; Destinations; Detection; Development; Development Plans; Diagnosis; Doctor of Philosophy; Documentation; Drug Kinetics; Economics; Effectiveness; Event; Fibrin; Gamma Cameras; Gastrointestinal Hemorrhage; Goals; Guidelines; Heart; Heart Transplantation; Heart failure; Hemorrhage; Hospital Costs; Hospitalization; Hospitals; Housing; Human; Image; Impairment; Implant; In Vitro; Incidence; Infection; Intervention; Leadership; Life; Light; Mechanics; Medical; Medicine; National Heart, Lung, and Blood Institute; Neurologic; Nuclear; Operative Surgical Procedures; Orphan Drugs; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevention; Process; Production; Pump; Quality of life; Radiology Specialty; Recurrence; Regulatory Affairs; Research; Research Contracts; Rodent Model; Savings; Serum; Small Business Technology Transfer Research; Splenic Infarction; Suggestion; Support System; Testing; Therapeutic; Thrombosis; Thrombus; Titanium; Toxicology; Translational Research; Transplantation; Urine; Warfarin; aged; analytical method; chemical synthesis; follower of religion Jewish; hospital readmission; improved; innovation; instrument; left ventricular assist device; mid-career faculty; nanomedicine; novel; nuclear imaging; outcome forecast; prevent; product development; professor; programs; prophylactic; prototype; scale up; sex; stability testing

Despite the myriad major advances in cardiology, the prognosis for patients with severe, medically refractive heart failure (HF) is exceedingly poor. Approximately 287,000 deaths occur annually in patients with HF who have endured an impaired quality of life often accompanied by significant economic and personal losses due to recurrent hospitalizations. At least 58,000 of these deaths were directly related to severe heart failure. Because the number of available heart donors (~2,200/year) has not increased over the last decade, there is an enormous and expanding gap between medical need for transplant and the woefully low supply of hearts. Today's axial and centrifugal flow left ventricular assist devices (LVAD) have reduced size and power requirements, allowing LVADs to become a therapeutic options as a bridge-to-transplantation (BTT) and increasingly for destination-therapy (DT). Unfortunately the life-saving benefit of LVADs is offset by potential life-threatening complications and costly hospital readmissions for bleeding, infection, and thrombosis. Prophylactic anticoagulation to prevent intra-pump thrombus with warfarin (in addition to an anti-platelet drug) exacerbates inherent bleeding complications induced by the high shear high blood flow conditions of the pumps. Multicenter efforts to reduce anticoagulation guidelines tripled the incidence of pump thrombotic complications. LDH, a nonspecific marker of RBC lysis, is currently used as the best surrogate indicator for pump thrombosis. But, given clinical results to date, LDH is only an insensitive probably late biomarker of LVAD fibrin accumulation. We have innovated and demonstrated a very high avidity nuclear probe prototype, 99mTc-F4A, in vitro, in excised LVADs operated ex vivo, and in rodent models, which sensitively localizes thrombus accumulation in LVADs. In Phase 1 of this Fast-track proposal the effectiveness of 99mTc-F4A will be demonstrated in a large animal model, calves (70kg), using reimplanted human LVADs (70Kg) and a clinical gamma camera. In Phase 2 the analytical, chemical process, and regulatory development and documentation required to transfer the product candidate (FibroScint) to contract research organizations for GMP toll manufacturing, stability testing, and GLP toxicology will be completed. FibroScint is anticipated to refine and individualize LVAD clinical management to reduce bleeding events, thromboembolic complications and pump exchanges.

尽管心脏病学取得了无数重大进展，但严重的、医学上的 屈光性心力衰竭(HF)是非常糟糕的。每年约有28.7万人死亡 生活质量受损的心力衰竭患者经常伴有明显的 因反复住院造成的经济和个人损失。这些死亡中至少有58,000人是 与严重的心力衰竭直接相关。因为可用的心脏捐赠者的数量(约2,200/年) 在过去的十年里没有增加，在医疗需求之间存在着巨大的且不断扩大的差距 移植和可悲的低心脏供应。 今天的轴向和离心流左心室辅助装置(LVAD)已经缩小了体积和 电力需求，使LVAD成为治疗选择，作为移植的桥梁 (Btt)，并越来越多地用于目的地治疗(Dt)。不幸的是，LVAD的救命益处是 被潜在的危及生命的并发症和因出血、感染、 和血栓形成。预防性抗凝预防华法林内泵内血栓(此外 到抗血小板药物)加剧高切高引起的固有出血并发症 泵的血液流动状况。减少抗凝指南的多中心努力使 泵血栓并发症的发生率。乳酸脱氢酶是一种红细胞溶解的非特异性标志物，目前正在使用 作为泵血栓形成的最佳替代指标。但是，根据迄今的临床结果，LDH只是一种 不敏感，可能是LVAD纤维蛋白积聚的晚期生物标志物。 我们创新并展示了一种非常高亲和力的核探测器原型99mTC-F4A，在 在体外，在体外操作的切除的LVAD中，在啮齿动物模型中，敏感地定位血栓 在左心室反搏中的累积。在此快速通道提案的第一阶段中，99mTc-F4A的有效性将为 在一个大型动物模型小牛(70公斤)中演示了，使用重新植入的人左心室(70公斤)和 临床伽马相机。在第二阶段，分析、化学流程和法规的开发以及 将候选产品(FibroScint)转移到合同研究所需的文档 GMP收费制造、稳定性测试和GLP毒理学的组织将完成。 FibroScint预计将改进和个性化LVAD临床管理，以减少 出血事件、血栓栓塞症并发症和换泵。