SURFACE-ACTIVE ANTITHROMBOTIC AGENTS FOR PROSTHESES

用于假体的表面活性抗血栓剂

• 批准号: 3336766
• 负责人: ANDREW LASSLO
• 金额: $ 12.51万
• 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/3336766
• 关键词: alkanes; antithrombogenic surface; biomaterial interface interaction; biomaterials; cardiovascular prosthesis; cell adhesion; chemical structure function; drug design /synthesis /production; drug metabolism; electrical potential; epinephrine; ethylenediamines; human tissue; implant; ionophores; 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 尤其是容易发生血栓栓塞症并发症，因为它们 血液接触生物材料(植入型假体、肾脏 透析、血液充氧、心导管术等)。我们寻求 继续我们在设计、综合和评估方面的探索工作 能够增强人体血小板膜完整性的化合物 防止可能引发血小板聚集的生物动力学影响。这个 结构多样性的范围有助于识别血小板 具有更好或更好生物分布的聚集抑制剂和 生物转化概况；这一点非常重要，因为 寻求的预防措施的性质可能需要这些药物的管理 几年又几十年。加强抑制血小板聚集的研究 具有适当增强界面的组件的特定功能 活性，我们已经开发出专业知识来“微调”分子构型 以达到对血小板功能的最佳效果。一名美国患者和一名外国患者 已颁发；此外，两项美国专利和十项外国专利 我们的几个系列化合物正在等待研究，这些化合物以前与 抗血小板活性。 在证实了我们之前报道的化合物的有效性后， 其固有的细胞毒性、急性致死性和体内活性(in 狗)将被研究。药代动力学和生物利用度评价 将在各自系列中最有希望的同代者身上表演。 这些化合物对人类健康的影响 聚合物诱导的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 调查过了。与拉里·V·麦金泰尔博士合作，在莱斯 他们将研究它们对人体血液动力学的影响 胶原蛋白生物材料对血小板黏附和血栓生长的影响 和相关聚合物在平行板流室系统中。 在其他研究中，重点将放在评估 我们的化合物对人血小板中5-羟色胺的摄取和释放，我们 将努力将这些发现与通过血小板的转运联系起来 质膜和跨细胞器膜的颗粒 内生性因素。中药复方对血小板因子3的影响 将评估其可用性，以及它们对血小板第4因子的影响 也将接受检查。