SURFACE-ACTIVE ANTITHROMBOTIC AGENTS FOR PROSTHESES

用于假体的表面活性抗血栓剂

• 批准号: 3336772
• 负责人: ANDREW LASSLO
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3336772
• 关键词: alkanes; antithrombogenic surface; biomaterial interface interaction; biomaterials; cardiovascular prosthesis; cell adhesion; chemical structure function; collagen; dogs; drug design /synthesis /production; drug metabolism; electrical potential; epinephrine; ethylenediamines; human tissue; implant; ionophores; laboratory mouse; membrane lipids; pharmacokinetics; phase contrast microscopy; phospholipids; piperazines; piperidine; platelet aggregation; platelet aggregation inhibitors; platelet factor 4; polymers; radiotracer; serotonin; stereochemistry; thrombin; tissue /cell culture

The thrust of these efforts remains directed principally at aiding those especially predisposed to thromboembolic complications because of their blood's exposure to biomaterials (implanted prosthetic devices, renal dialysis, blood oxytenation, cardiac catheterization, etc.). We seek to continue our exploratory work on the design, synthesis and evaluation of compounds capable of reinforcing the integrity of human blood platelets against biodynamic impacts which could trigger platelet aggregation. The range of structural diversities facilitates identification of platelet aggregation inhibitors with superior or preferable biodistribution and biotransformation profiles; this is of prominent importance since the nature of prophylaxis sought may require the administration of these agents for years and decades. Undergirding platelet aggregation-inhibitory specific functions with components enhancing appropriately interfacial activity,we have developed expertise to "fine-tune" molecular configuration for optimal effect on platelet function. One U.S. and one foreign patient have been issued; in addition, two American and ten foreign patents are pending on several series of our compounds previously not associated with antiplatelet activity. Having established the effectiveness of our previously reported compounds, their intrinsic cellular toxicity, acute lethality and in vivo activity (in dogs) will be studied. Pharmacokinetic and bioavailability evaluations will be performed on the most promising congeners of the respective series. The striking relationships between the influence of these compounds on polymer-induced platelet cluster formation and their inhibitory action in ADP- and thrombin-stimulated blood platelet aggregation will be further investigated. In cooperation with Doctor Larry V. McIntire, at Rice University, their impact will be studied on the kinetics of human blood platelet adhesion and thrombus growth effected by collagen, biomaterials and related polymers in a parallel plate flow chamber system. Among other studies, emphasis will be placed on evaluating the effect of our compounds on serotonin intake and release in human platelets, and we will endeavor to relate these findings to transport across the platelet plasma membrane and across organelle membranes of granules which store this endogenous agent. The effect of our compounds on platelet factor 3 availability will be evaluated, and their influence on platelet factor 4 will be also examined.

这些努力的主旨仍然主要是帮助那些 特别容易发生血栓栓塞并发症，因为 血液接触生物材料（植入假体装置、肾 透析、血液氧合、心导管插入术等）。 我们力求 继续我们在设计、合成和评估方面的探索性工作 能够增强人类血小板完整性的化合物 防止可能引发血小板聚集的生物动力学影响。 这 一系列结构多样性有利于血小板的识别 具有优异或更好的生物分布的聚集抑制剂和 生物转化概况；这是非常重要的，因为 寻求预防的性质可能需要使用这些药物 多年来和几十年。 抑制血小板聚集 具有适当增强界面的组件的特定功能 活动，我们开发了“微调”分子构型的专业知识 对血小板功能产生最佳效果。 一名美国患者和一名外国患者 已发出；此外，还拥有两项美国专利和十项外国专利 之前与我们无关的几个系列化合物正在等待研究 抗血小板活性。 确定了我们之前报道的化合物的有效性后， 它们的内在细胞毒性、急性致死率和体内活性（在 狗）将被研究。 药代动力学和生物利用度评估 将对各个系列中最有前途的同系物进行测试。 这些化合物的影响之间的显着关系 聚合物诱导血小板簇形成及其抑制作用 ADP 和凝血酶刺激的血小板聚集将进一步 调查了。 与莱斯大学的 Larry V. McIntire 博士合作 大学将研究它们对人体血液动力学的影响 胶原蛋白、生物材料影响血小板粘附和血栓生长 以及平行板流动室系统中的相关聚合物。 在其他研究中，重点将放在评估效果 我们的化合物对人体血小板中血清素的摄入和释放的影响，并且我们 将努力将这些发现与血小板转运联系起来 质膜和跨细胞器膜的颗粒储存这种物质 内源性因子。 我们的化合物对血小板因子 3 的影响 将评估可用性及其对血小板因子 4 的影响 也将受到审查。