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Continuous monitoring of anti-fibrinolytic therapy in cardiovascular surgery

心血管手术中抗纤溶治疗的持续监测

基本信息

批准号：
7806354
负责人：
FRANCIS G SPINALE
金额：
$ 11.75万
依托单位：
MICRO VIDE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7806354
关键词：
Address Adult Adverse effects Adverse event Algorithms Animal Model Animal Testing Antifibrinolytic Agents Aprotinin Biochemical Biological Blood Clot Blood Platelets Blood Transfusion Blood coagulation Calibration Cardiac Cardiac Surgery procedures Cardiopulmonary Bypass Cardiovascular Surgical Procedures Cardiovascular system Catheters Child Clinical Coagulation Process Companions Coupled Detection Development Diagnostic Dose Effectiveness Environment Equilibrium FDA approved Family Fiber Fibrin Fibrinogen Fibrinolysis Fluorescence Fluorogenic Substrate Future Generic Drugs Goals Hemorrhage Hemostatic Agents In Vitro Intensive Care Units Label Legal patent Marketing Measurement Measures Methods Microdialysis Microfluidics Monitor Morbidity - disease rate Operative Surgical Procedures Outcome Pathway interactions Patients Peptide Hydrolases Perioperative Pharmaceutical Preparations Plasma Proteins Plasmin Plasminogen Plasminogen Activator Postoperative Period Process Program Development Prospective Studies Protocols documentation Recovery Regimen Reporting Reproducibility Risk Risk Factors Sensitivity and Specificity Serine Protease Serine Proteinase Inhibitors Serious Adverse Event Simulate Site Structure System Technology Technology Transfer Testing Therapeutic Thrombolytic Therapy Time United States Validation Weight Withdrawal base blood product digital enzyme activity enzyme pathway improved inhibitor/antagonist interstitial lysine analog mortality operation prevent protein structure prototype public health relevance research clinical testing response subcutaneous technology development

项目摘要

DESCRIPTION (provided by applicant): A major cause of morbidity and mortality in cardiovascular surgery is excessive bleeding post- operatively, which is commonly managed by pharmacologically modifying clot degradation (fibrinolysis), through inhibition of plasmin activity (PLact). However, the only FDA approved and most commonly used inhibitor of PLact in cardiovascular surgery, while effective in reducing post-operative bleeding, was associated with extravascular effects and ultimately led to FDA withdrawal. The likely mechanisms for these adverse events include highly variable dosing regimens and inhibition of enzyme pathways other than PLact (off target effects). As a consequence, a significant void in approaches for haemostatic control following cardiovascular surgery has developed. Presently, a class of pharmacological compounds called lysine analogues is being used clinically in an "off label" status to modify PLact in the context of cardiovascular surgery. The effective dosing strategy of these lysine analogues to selectively modify PLact is unknown, and therefore clinical dosing algorithms for these compounds remain empirical. The technology and product to be developed in this application directly addresses this problematic issue and clinical need by providing a means to continuously monitor PLact during and following cardiovascular surgery. Through the use of microdialysis and microfluidics, the specific aims of this development project are (1) to complete calibration studies of a prototype and validated method to specifically and continuously measure PLact following administration of a prototypical lysine analogue; (2) to complete and construct a refined prototype that can be easily used in the setting of cardiovascular surgery; (3) to demonstrate the application and utility of this validated prototype in a large animal model of cardiopulmonary bypass. The outcomes from the technology refinement and animal testing will be a complete system that can be easily deployed in the cardiovascular surgical setting for continuously monitoring PLact. The clinical benefit from this project will be a means to individualize dosing strategies of antifibrinolytics such as lysine analogues and thereby maximizing haemostatic control and minimizing off target effects. The marketing/technology transfer benefit is a companion diagnostic that can be easily coupled to existing and future pharmacological compounds targeting the fibrinolytic cascade in cardiovascular surgery. PUBLIC HEALTH RELEVANCE: In the United States alone, almost 2 million adults and children require open heart surgery. While the overall outcomes from these cardiac surgical procedures is excellent, one of the factors that can cause a difficult early recovery from cardiac surgery is excessive bleeding in the early post-surgical period. Bleeding in the post cardiac surgical period can require blood transfusions, administration of factors that can enhance blood clotting, and may even require re-operation. Since blood transfusions and blood product administration is associated with a set of intrinsic risks and complications, is costly, and can be in short supply, alternative strategies to improve blood clotting following cardiac surgery have been pursued. One of these strategies is to prevent the breakdown of a blood clot following cardiac surgery by inhibiting the activity of an enzyme called plasmin. However, up to now, it has not been possible to directly and continuously measure plasmin activity in the cardiac surgery setting and in the intensive care unit. The technology and product to be developed in this application directly addresses this problematic issue and clinical need by providing a means to continuously monitor plasmin activity during and following cardiac surgery. The clinical benefit from this project will be to provide a means to individualize dosing strategies of drugs currently used to reduce blood loss following cardiac surgery. As a consequence, millions of patients that may be at risk for significant post-surgical bleeding will directly benefit from the development of this technology.

描述（由申请人提供）：