Characterization of Anticoagulant Heparin and Related Polysaccharides

抗凝肝素及相关多糖的表征

基本信息

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
项目类别：
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

项目摘要

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在接受肝素治疗时出现了一系列严重的过敏型事件，引发了全球健康危机。在这场危机发生后的几周内，一个由学术界（包括本提案的共同负责人）、FDA 和行业成员组成的多学科团队在肝素中发现了一种非天然污染物，即过硫酸软骨素 (OSCS)。与不良反应相关的很多。尽管事实上，在过去 20 年中，许多科学研究确定了分析技术，这些技术定义了肝素的分子水平特征，包括成分和序列，但这种关键药剂主要是根据活性进行控制和剂量的，之前这场肝素危机。不幸的是，活性测定无法区分由能够“隐藏在”肝素后面的其他硫酸多糖引起的异质性。因此，这场危机的解决方案强调了纳入更详细的分析表征来监测和控制肝素异质性的重要性，以避免未来出现如此严重的健康危机。在本提案中，我们寻求使用一套完善且可靠的分析和结构功能测定方法从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宏观和微观异质性的结构参数，以便将它们与明确定义的标准进行比较。信息学平台对于快速传播该提案的研究结果以改进当前肝素的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而引发的全球健康危机提高了测量和控制肝素等复杂多糖药物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从结构和功能上定义肝素。