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）： 肝素是一种硫酸化多糖混合物，在许多临床情况下广泛用作基线治疗，特别是用于预防血栓形成。虽然过去几十年来临床上一直使用肝素，但最近，接受血液透析的患者报告了一系列严重过敏性事件，导致全球健康危机。在这场危机发生后的几周内，一个由学术界（包括本提案的共同PI）、FDA和行业成员组成的多学科团队在与不良反应相关的肝素批次中发现了一种非天然污染物，即过度硫酸化硫酸软骨素（OSCS）。尽管在过去的20年中，许多科学研究确定了分析技术，这些技术已经定义了肝素的分子水平特征，包括组成和序列，但在肝素危机之前，这种关键药剂主要是根据活性进行控制和给药的。不幸的是，活性测定不能区分由能够“隐藏在”肝素后面的其他硫酸化多糖引起的异质性。因此，这一危机的解决方案强调了纳入更详细的分析表征以监测和控制肝素异质性的重要性，以避免未来发生如此严重的健康危机。在本提案中，我们试图使用一套完善的和强大的分析和结构功能测定来定义肝素的结构和功能。从这些测定中获得的肝素信息将使我们能够构建用于监测和控制肝素质量的过滤器。最后，我们寻求开发一个信息学平台来捕获和传播捕获肝素的宏观和微观异质性的结构参数，以将它们与明确定义的标准进行比较。信息平台对于快速传播本提案的结果以改善肝素的当前质量控制措施至关重要。 公共卫生相关性： 最近由于大量肝素污染引起的全球健康危机已经提高了测量和控制复杂多糖药物如肝素的结构异质性的重要性。在本提案中，我们寻求利用我们的经验和专业知识，采用稳健的分析方法来定义肝素的结构和功能。