Exploring the use of a hydroxypyridinone decorporation agent for the removal of toxic residual gadolinium from MRI contrast agent administration

探索使用羟基吡啶酮脱色剂去除 MRI 造影剂给药中有毒残留的钆

• 批准号: 9387827
• 负责人: Rebecca J Abergel
• 金额: $ 26.3万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387827
• 关键词: Actinoid Series Elements; Address; Affinity; Animal Model; Animals; Biodistribution; Blood - brain barrier anatomy; Bone Tissue; Brain; Chelating Agents; Chelation Therapy; Clinical; Clinical Pharmacology; Clinical Research; Complex; Contrast Media; Data; Deposition; Development; Dose; Elements; Ensure; Excision; Excretory function; Fluoride Ion; Fluorine; Formulation; Future; Gadolinium; Goals; Health; Heavy Metals; Human; Image; Injectable; Inorganic Chemistry; Investigational Drugs; Laboratories; Lead; Ligands; Magnetic Resonance Imaging; Medical; Metabolism; Metals; Modeling; Mus; Neptunium; Nuclear; Oral; Patient Agents; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plutonium; Program Development; Prophylactic treatment; Radioactive; Radiobiology; Radioisotopes; Radiolabeled; Regimen; Renal function; Research; Research Project Grants; Residual state; Safety; Series; Spectrum Analysis; Testing; Therapeutic; Thermodynamics; Tissues; Toxic effect; United States Food and Drug Administration; Uranium; absorption; animal rule; base; clinical toxicology; design; imaging agent; imaging study; in vivo; mouse model; pre-clinical; preclinical development; prevent; programs; prophylactic

Project Summary/Abstract Gadolinium-based contrast agents have been widely used in clinical magnetic resonance imaging studies. However, despite their exceptional safety reputation, serious toxicity issues associated with the use of these agents have emerged in the last several years, with studies demonstrating the release of gadolinium (Gd) and subsequent deposition in bone tissue and in the brain in patients with normal renal function and intact blood-brain barriers. The only practical therapy to reduce the health consequences of gadolinium deposition is treatment with chelating agents that form excretable complexes, although gadolinium, like other heavy metals, is among the most intractable elements to decorporate. Over the past three decades, the Lawrence Berkeley National Laboratory has dedicated a research program to the development of oral therapeutics for actinide decorporation, leading to the emergence of the active pharmaceutical ingredient 3,4,3-LI(1,2-HOPO) as an exceptional candidate for actinide sequestration. Initially driven by the civilian need for post-exposure medical countermeasures against nuclear threats, the development of 3,4,3-LI(1,2-HOPO) followed a program that references the Animal Rule approval path established by the U.S. Food and Drug Administration, and focused on pre- clinical pharmacology and toxicology, formulation optimization, as well as controlled efficacy for the removal of injected threat radioisotopes (plutonium, americium, curium, uranium or neptunium). In addition, the oral formulation of 3,4,3-LI(1,2-HOPO) makes it the first oral and indisputably most efficacious therapeutic actinide decorporation product. The Investigational New Drug (IND, 112,264) status was obtained in August 2014 for this drug product. However, while the preclinical development program has focused on demonstrating the outstanding decorporation efficacy of 3,4,3-LI(1,2-HOPO) in vivo for radioactive actinides exclusively, recent solution thermodynamic studies have confirmed its extremely high affinity for other f-elements, including Gd. In the proposed research project, we will explore the potential 3,4,3-LI(1,2-HOPO) as a Gd decorporation agent that may be used in anticipation of, during, or after administration of Gd-based contrast agents. Animal studies using established models will be performed to adequately characterize the efficacy profile of 3,4,3-LI(1,2-HOPO) for eliminating deposited Gd or for preventing deposition, without altering the potency of the contrast agent for imaging. The data gathered through this program will benefit from and be added to the body of data already available for the IND-approved product, which may then lead to an enlarged indication and prospects of clinical studies and use in the very near future.

项目摘要/摘要 基于Gadolinium的对比剂已广泛用于临床磁共振中 成像研究。但是，尽管他们的安全声誉很高，但严重的毒性问题 在过去的几年中，与这些代理的使用有关 证明了do释放（GD）的释放，并在骨组织和随后的沉积中释放 肾功能正常和完整血脑屏障的患者的大脑。唯一的实用 减少Gadolinium沉积的健康后果的治疗是螯合治疗 虽然与其他重金属一样，虽然Gadolinium在 装饰最棘手的元素。在过去的三十年中，劳伦斯 伯克利国家实验室已专门针对口腔发展的研究计划 肌动剂装饰的治疗剂，导致活跃药物的出现 成分3,4,3-LI（1,2-HOPO）作为肌动蛋白隔离的特殊候选者。最初 由平民对暴露后医疗对抗核威胁的对策的驱动， 3,4,3-LI（1,2-Hopo）的开发遵循了一个参考动物规则的程序 美国食品和药物管理局建立的批准路径，专注于 临床药理学和毒理学，配方优化以及控制疗效 去除注射威胁的放射性同位素（p prutonium，umium，curium，铀或 镎）。此外，3,4,3-Li（1,2-Hopo）的口服配方使其成为第一个口头 无可争议的最有效的治疗性acttinide装饰产品。调查 该药物于2014年8月获得新药（IND，112,264）状态。然而， 而临床前开发计划的重点是展示出色的 3,4,3-Li（1,2-Hopo）在体内的装饰功效专门用于放射性actiDIDES，最近 溶液热力学研究已经证实了其对其他F元素的极高亲和力， 包括GD。在拟议的研究项目中，我们将探索潜在的3,4,3-LI（1,2-Hopo） 作为GD装饰剂，可以用于预期，期间或之后 基于GD的对比剂。使用已建立模型的动物研究将进行 充分表征了3,4,3-LI（1,2-HOPO）的功效概况，以消除沉积的GD 或防止沉积，而不会改变对比剂的成像的效力。这 通过此程序收集的数据将受益并已添加到数据体中 可用于订婚产品，然后可能导致扩大的指示和 在不久的将来的临床研究和使用的前景。