SURFACE-ACTIVE ANTITHROMBOTIC AGENTS FOR PROSTHESES

用于假体的表面活性抗血栓剂

• 批准号: 3336773
• 负责人: ANDREW LASSLO
• 金额: $ 15.64万
• 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 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3336773
• 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.

这些努力的重点仍然主要是帮助那些 特别是易患血栓栓塞并发症，因为它们 血液暴露于生物材料（植入的假体装置、肾 透析、血氧饱和度、心导管插入术等）。 我们寻求 继续我们的探索性工作，设计、综合和评估 能够增强人血小板完整性的化合物 防止生物动力学影响引发血小板聚集。 的 一系列结构差异有助于血小板的鉴定 具有上级或优选生物分布的聚集抑制剂， 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给予这些药物 已经有几十年了 加强血小板聚集抑制 具有适当增强界面的组分的特定功能 活动，我们已经开发了专门知识，以“微调”分子构型 对血小板功能的最佳效果。 一名美国患者和一名外国患者 此外，还有两项美国专利和十项外国专利， 我们的几个系列的化合物之前没有与 抗血小板活性。 在确定了我们先前报道的化合物的有效性之后， 它们的内在细胞毒性、急性致死性和体内活性（在 狗将被研究。 药代动力学和生物利用度评价 将对各系列中最有希望的同系物进行检测。 这些化合物的影响之间的显着关系， 聚合物诱导的血小板聚集及其抑制作用 ADP和凝血酶刺激的血小板聚集将进一步增加。 研究了 与拉里·V·麦金太尔博士合作，在赖斯 大学，他们的影响将研究对人体血液动力学 胶原、生物材料对血小板粘附和血栓生长的影响 和相关的聚合物。 在其他研究中，重点将放在评估 我们的化合物对人体血小板中5-羟色胺的摄入和释放， 我将奋进将这些发现与血小板间的转运联系起来 质膜和细胞器膜的颗粒，储存这些 内源性因子 我们的化合物对血小板因子3的影响 将评估其可用性，以及它们对血小板因子4的影响。 也将被审查。