NEW DIRECTION FOR EXTRACORPORPOREAL HEPARIN REMOVAL

体外肝素清除的新方向

• 批准号: 6139144
• 负责人: VICTOR C YANG
• 金额: $ 20.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6139144
• 关键词: affinity chromatography; anticoagulants; biomaterial development /preparation; biomedical equipment development; biosensor device; blood filtration; clinical biomedical equipment; disease /disorder model; dogs; drug adverse effect; drug screening /evaluation; extracorporeal circulation; gel filtration chromatography; heart /lung bypass; hemodialysis; heparin; intravenous administration; laboratory mouse; laboratory rat; molecular weight; pharmacokinetics; protamines

DESCRIPTION (Investigators' abstract): Heparin employed in the nearly 15 million extracorporeal procedures performed annually often leads to a high incidence (8-33%) of bleeding complications. Protamine employed in heparin reversal, however, can cause serious and at times fatal cardiovascular responses. Indeed, the combined use of heparin and protamine has been considered a major cause of morbidity and mortality for patients undergoing cardiovascular surgery. We previously proposed an approach which would simultaneously prevent both heparin and protamine induced complications. The approach consists of placing a blood filter device containing immobilized protamine (termed "protamine filter") at the distal end of an extracorporeal device. The project received a FIRST Award in 1987, followed by a highly merited 5 year competing renewal (Percentile: 6.9%) in 1993 to further continue our pursuit in this area. During this past grant period (1993-96), remarkable progress has been achieved; as reflected by the publication of 31 manuscripts and 5 patents. A highly effective protamine filter and a sensor-directed bio-feedback heparin-removing system are both established. In addition, a first ever sensor for blood heparin monitoring has been developed and is presently on the market for research uses. After the conclusion of our on-going animal studies (by 1997), every aim proposed in the previous application will be completely achieved. Since all the fundamental research related to this project has been addressed during the two grant periods, we plan in this competing renewal application to shift our long-time research on extracorporeal heparin removal toward a new direction. This new research direction is to develop an intravenous heparin-neutralizing agent which provides all the advantages of protamine and yet lacks its toxic effects. As gathered from the consensus of clinicians routinely engaged in heparin and protamine therapy, this would be the ultimate solution to achieve safe clinical heparin reversal. An explicit review of the mechanisms of heparin neutralization and protamine toxicity suggests that a chain-shortened low molecular weight protamine (LMWP) species, if it can be derived from protamine to contain the intact, arginine-rich heparin-binding domain but not the futile and yet etiologic region in protamine, could simply be this ideal anti-heparin agent. In addition, the LMWP would also be devoid of immunogenicity and antigenicity; both are known to contribute mightily to protamine toxicity. Preliminary studies have yielded promising results to verify our hypotheses. In this application, we plan to build upon these initial findings and follow the precedent methodology in deriving low molecular weight heparins (LMWH) to further develop the LMWP species. These compounds will then be tested in vitro and in vivo of the efficacy and toxicity against both heparin and LMWH.

描述（研究人员摘要）：近 15 项研究中使用的肝素 每年进行数百万次体外手术通常导致高 出血并发症的发生率（8-33%）。 肝素中使用的鱼精蛋白 然而，逆转可能会导致严重的、有时甚至是致命的心血管疾病 回应。 事实上，肝素和鱼精蛋白的联合使用已经 被认为是患者发病和死亡的主要原因 心血管手术。 我们之前提出了一种方法 同时预防肝素和鱼精蛋白引起的并发症。 该方法包括放置一个血液过滤装置，其中包含 固定在鱼精蛋白（称为“鱼精蛋白过滤器”）的远端 体外装置。 该项目于 1987 年获得一等奖，随后 1993 年，通过备受赞誉的 5 年竞争性更新（百分位数：6.9%） 进一步继续我们在这一领域的追求。 在过去的资助期内 （1993-96），取得了显着的进步；正如所反映的 发表论文31篇，授权专利5项。 高效鱼精蛋白 过滤器和传感器引导的生物反馈肝素去除系统都是 已确立的。 此外，首款用于血液肝素监测的传感器 已经开发出来，目前已投放市场用于研究用途。 后 我们正在进行的动物研究的结论（到 1997 年），提出的每一个目标 在前面的应用中就完全实现了。 由于所有的 与该项目相关的基础研究已在 两个资助期，我们计划在这个竞争性更新申请中转移 我们对体外肝素清除的长期研究迈向新的方向 方向。 这个新的研究方向是开发一种静脉注射 肝素中和剂，具有鱼精蛋白的所有优点 但缺乏毒性作用。 根据共识得出 临床医生常规进行肝素和鱼精蛋白治疗，这将是 实现临床安全肝素逆转的最终解决方案。 一个 明确回顾肝素中和和鱼精蛋白的机制 毒性表明链缩短的低分子量鱼精蛋白 (LMWP) 物种，如果它可以从鱼精蛋白中提取以包含完整的， 富含精氨酸的肝素结合域，但不是无用的，但仍是病因学的 鱼精蛋白中的区域，可能就是这种理想的抗肝素剂。 在 此外，LMWP 也将缺乏免疫原性和抗原性； 已知两者都会极大地导致鱼精蛋白毒性。 初步的 研究已经取得了有希望的结果来验证我们的假设。 在这个 应用程序，我们计划以这些初步发现为基础，并遵循 衍生低分子量肝素 (LMWH) 的先例方法 进一步开发LMWP品种。 然后这些化合物将在以下环境中进行测试： 体外和体内对肝素和肝素的功效和毒性 低分子肝素。