Characterization of Anticoagulant Heparin and Related Polysaccharides

抗凝肝素及相关多糖的表征

• 批准号: 7939713
• 负责人: ROBERT J LINHARDT
• 金额: $ 55.2万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939713
• 关键词: API 2; Academia; Address; Adverse event; Adverse reactions; Allergic; Anticoagulants; Applications Grants; Arts; Biological; Biological Assay; Cardiology; Caring; Cessation of life; Characteristics; Chemical Structure; Chondroitin Sulfates; Clinic; Clinical; Complex; Delaware; Dermatan Sulfate; Development; Digestion; Disaccharides; Dose; Ensure; Event; Family suidae; Fibrinolytic Agents; Foundations; Future; Glycosaminoglycans; Grant; Health; Healthcare Systems; Hematology; Hemodialysis; Hemorrhage; Heparin; Heterogeneity; High Pressure Liquid Chromatography; Home environment; Hospitals; Individual; Industry; Infant formula; Informatics; Ingestion; Inorganic Sulfates; Intestinal Mucosa; Investigation; Kidney Diseases; Mass Spectrum Analysis; Measures; Medical; Medical center; Melamine; Molecular; Monitor; Nature; Nuclear Magnetic Resonance; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Plant Roots; Polysaccharides; Positioning Attribute; Postoperative Period; Preparation; Prevention; Production; Proteins; Public Health; Quality Control; Reaction; Reporting; Serious Adverse Event; Solutions; Source; Structure; Techniques; Technology; Testing; Thinking; Thrombosis; Time; United States; Unspecified or Sulfate Ion Sulfates; Venous Thrombosis; Viral; analytical method; base; cost; design; experience; global health; improved; meetings; member; multidisciplinary; prevent; prophylactic; public health relevance; vigilance

DESCRIPTION (provided by applicant): Heparin is a suflated polysaccharide mixture that is widely used as baseline therapy in a number of clinical situations, especially for preventing thrombosis. While heparin has been administered in the clinic for the past several decades, recently, clusters of serious allergic-type events were reported in patients undergoing hemodialysis who were receiving heparin causing a global health crisis. Within a matter of weeks from the time of this crisis, a multidisciplinary team that comprised of members from academia (including co-PIs of this proposal), FDA and industry identified an unnatural contaminant, over sulfated chondroitin sulfate (OSCS), in the heparin lots associated with the adverse reactions. Despite the fact that, in the last 20 years, a number of scientific studies identified analytical techniques, which have defined molecular level characteristics of heparin, including composition and sequence, this critical pharmaceutical agent was primarily controlled and dosed on the basis of activity, prior to this heparin crisis. Unfortunately, the activity assays have not been able to distinguish the heterogeneity arising from other sulfated polysaccharides that have been able to "hide behind" heparin. The solution to this crisis, therefore emphasizes the importance of incorporating more detailed analytical characterization to monitor and control the heterogeneity in heparins to avoid such a serious health crisis in the future. In this proposal we seek to structurally and functionally define heparin using a set of well developed and robust analytical and structure-function assays. The information on heparin obtained from these assays would enable us to construct filters for monitoring and controlling the quality of heparin. Finally we seek to develop an informatics platform to capture and disseminate the structural parameters that capture the macro- and microheterogeneity of heparin to compare them against well defined standards. The informatics platform would be critical to rapidly disseminate the findings from this proposal to improve current quality control measures for heparin. PUBLIC HEALTH RELEVANCE: The recent global health crisis due to contaminated lots of heparin has elevated the importance of measuring and controlling the structural heterogenetiy of complex polysaccharide drugs like heparin. In this proposal we seek to build on our experience and expertise in employing robust analytical methods to structurally and functionally define heparin.

描述（由申请人提供）： 肝素是一种弹性的多糖混合物，在许多临床情况下被广泛用作基线治疗，尤其是用于预防血栓形成。尽管过去几十年来一直在诊所中施用肝素，但据报道，正在接受肝素造成全球健康危机的血液透析的患者报告了严重的过敏反应事件。从这场危机开始后的几周内，由学术界成员组成的多学科团队（包括该提案的共同提案），FDA和行业确定了与不良反应相关的肝素批次，硫酸盐硫酸盐（OSC），硫酸盐硫酸盐硫酸盐（OSC），是一种不自然的污染物。尽管事实是，在过去的20年中，许多科学研究确定了分析技术，这些分析技术已经定义了肝素的分子水平特征，包括组成和序列，但这种关键的药物主要是基于活性控制并在这种肝素危机之前的活性控制和剂量的。不幸的是，活动分析无法区分其他能够“隐藏在”肝素后面的硫化多糖产生的异质性。因此，解决这一危机的解决方案强调了将更详细的分析表征纳入监测和控制肝素的异质性，以避免将来如此严重的健康危机。在此提案中，我们寻求使用一组良好发达且可靠的分析和结构功能分析在结构和功能上定义肝素。从这些测定中获得的有关肝素的信息将使我们能够构建过滤器，以监视和控制肝素的质量。最终，我们试图开发一个信息平台，以捕获和传播捕获肝素的宏观和微观均匀性的结构参数，以将它们与定义明确的标准进行比较。信息平台对于快速传播该提案的发现至关重要，以改善肝素的当前质量控制措施。 公共卫生相关性： 由于污染了许多肝素的污染，最近的全球健康危机升高了测量和控制复杂多糖药（如肝素）的结构性异质分析的重要性。在这项建议中，我们试图以我们的经验和专业知识来利用强大的分析方法来在结构和功能上定义肝素。