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: 9410234
• 负责人: James Blackledge
• 金额: $ 15.19万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9410234
• 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; Injectable; 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的重大进展，但严重，医学上的患者的预后 屈光心力衰竭（HF）极为差。每年大约287,000人死亡 HF患者遭受生活质量受损的患者通常伴随着大量 由于住院的复发而导致的经济和个人损失。其中至少有58,000人是 与严重的心力衰竭直接相关。因为可用的心脏捐献者数量（约2200/年） 在过去的十年中，没有增加，医疗需求之间存在巨大的差距 移植和严重的心脏供应。 当今的轴向和离心流左心室辅助设备（LVAD）的尺寸降低，并且 功率要求，允许LVAD成为一种治疗选择作为桥梁转移 （BTT），越来越多地用于目的地治疗（DT）。不幸的是，LVADS的挽救生命的好处是 被潜在威胁生命的并发症和昂贵的医院再入院所抵消，以免出血，感染， 和血栓形成。预防性抗凝治疗可防止与华法林的泵内血栓（此外） 抗血小板药物）加剧了高剪切高的固有出血并发症 泵的血流条件。多中心减少抗凝指南的努力增加了两倍 泵血栓形成并发症的发生率。 LDH目前使用了RBC裂解的非特异性标记 作为泵血栓形成的最佳替代指标。但是，鉴于迄今为止的临床结果，LDH只是一个 LVAD纤维蛋白积累的可能不敏感的生物标志物。 我们已经创新并展示了非常高的核探针原型，即99mtc-f4a， 体外，在切除的LVAD中操作的离体和啮齿动物模型中，该模型敏感地定位了血栓 在LVAD中积累。在此快速提案的第1阶段中，99mtc-f4a的有效性将为 使用重新植入的人LVAD（70kg）和A 临床伽马相机。在第2阶段，分析，化学过程和调节性开发以及 将产品候选者（Fibroscint）转移到合同研究所需的文档 GMP TOLL制造，稳定性测试和GLP毒理学的组织将完成。 预计纤维纤维将完善和个性化LVAD临床管理以减少 出血事件，血栓栓塞并发症和泵交换。 呢