Inhibition of Cardiac Device Induced Cellular Dysfunction in Pigs

抑制猪心脏装置引起的细胞功能障碍

基本信息

批准号：
8321993
负责人：
Rekha Bansal
金额：
$ 69.14万
依托单位：
NOVELMED THERAPEUTICS, INC.
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：
2010-08-17 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321993
关键词：
Acute Address Adverse reactions Affinity Alveolar Anaphylatoxins Animal Model Anterior Descending Coronary Artery Arteries Binding Biocompatible Materials Blood Blood Circulation Blood Platelets Blood flow Blood specimen Businesses Bypass Cardiac Cardiac Output Cardiac Surgery procedures Cardiopulmonary Bypass Cardiovascular system Chest Clinical Clinical Chemistry Clinical Trials Complement Complement 3a Complement 5a Coronary Coronary artery Data Defense Mechanisms Development Devices Dose Drug Kinetics Elastases Enzymes Evaluation Event FDA approved Family suidae Fostering Functional disorder Funding Heart Heart failure Hemorrhage Histology Hour Human In Vitro Infarction Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intellectual Property Irrigation Ischemia Kidney Lead Left Liver Lung Measures Medical Modeling Monkeys Monoclonal Antibodies Multiple Organ Failure Mus One-Step dentin bonding system Operative Surgical Procedures Organ Oryctolagus cuniculus Outcome Measure Outcome Study Pathway interactions Patients Perfusion Peroxides Pharmacodynamics Phase Pichia Plasma Platelet Activation Procedures Process Production Properdin Pulmonary Edema Reaction Reperfusion Injury Reperfusion Therapy Rivers Safety Spleen Staging Sternotomy Stroke Volume Surface Testing Therapeutic Thrombocytopenia Thrombosis Toxic effect Trauma Whole Blood base cross reactivity cytokine human tissue immunogenicity in vitro Assay in vivo in vivo Model lung injury meetings member monocyte neutralizing antibody neutralizing monoclonal antibodies neutrophil nonhuman primate novel phase 1 study preclinical efficacy preclinical study prevent prophylactic public health relevance response serological marker time interval

项目摘要

DESCRIPTION (provided by applicant): Artificial surfaces of cardiac devices induce cellular activation and platelet dysfunction in patients undergoing bypass procedure. While other pathways may be activated during this process, alternative pathway (AP) activation appears to be one of the important mechanisms for cellular activation and platelet dysfunction in the whole blood model of biomaterial surface-induced activation. Our hypothesis is based on the ex vivo whole blood circulation model demonstrating near complete inhibition of cellular activation, platelet dysfunction, and release of inflammatory mediators by a target-specific mAb. We would like to extend these novel findings utilizing a pig model of cardiopulmonary bypass with an induced occlusion of the descending coronary artery to mimic the clinical setting. During and following circulation through the CPB, high circulating levels of anaphylatoxins, C3a and C5a, and activated neutrophils, monocytes, and platelets are expected. As a result, activated neutrophils and monocytes release inflammatory mediators that cause organ damage and activated platelets become dysfunctional. These events can cause thrombosis, thrombocytopenia, and severe bleeding complications. NovelMed intends to test a target-specific and highly selective monoclonal antibody that blocks AP activation, cellular activation, platelet dysfunction, and blood loss in a pig model of cardiopulmonary bypass. Collective effects of these inflammatory events on multiple organ failure will be evaluated in this proposal using the proposed pig cardiopulmonary bypass model. Proof of concept in a well-accepted pig model of occlusion with CPB is a critical step for furthering the development of NovelMed's lead biologic and moving it towards clinical use. PUBLIC HEALTH RELEVANCE: Billions of dollars are spent annually to prevent systemic inflammatory response in cardiac patients undergoing cardiac procedures with cardiopulmonary bypass to correct partial or complete occlusion of the coronary artery. Cardiac failure can occur if the coronary descending artery is completely occluded. There is currently no approved prophylactic therapeutic for CPB-associated inflammatory responses. When the blood flow in the occluded, ischemia reperfusion injury can exacerbate the response. There is no approved therapeutic for IRI or for CPB associated inflammatory response. NovelMed intends to develop YalcioMab as a treatment to prevent complications that occur as a result of AP activation in the pig model of ischemia with cardiopulmonary bypass.

描述（由申请人提供）：心脏器件的人造表面诱导搭桥手术患者的细胞激活和血小板功能障碍。尽管在此过程中可能会激活其他途径，但在生物材料表面诱导的整个血液模型中，替代途径（AP）激活似乎是细胞激活和血小板功能障碍的重要机制之一。我们的假设基于离体全血环循环模型，表明细胞活化，血小板功能障碍以及通过靶标特异性mAB释放炎症介质的释放。我们想利用心肺旁路的猪模型来扩展这些新发现，并引起降冠状动脉的阻塞，以模仿临床环境。在通过CPB的循环过程中，预计高循环水平的过敏毒素，C3A和C5A，以及活化的中性粒细胞，单核细胞和血小板。结果，激活的中性粒细胞和单核细胞释放炎症介质，导致器官损伤，活化的血小板发生功能失调。这些事件会导致血栓形成，血小板减少症和严重的出血并发症。新颖的人打算测试目标特异性且高度选择性的单克隆抗体，该抗体阻止了心肺旁路猪模型中AP激活，细胞激活，血小板功能障碍和失血。这些炎症事件对多器官故障的集体影响将在本提案中使用拟议的猪心肺旁路模型评估。 CPB闭塞猪模型中的概念证明是促进新颖的铅生物学发展并将其转向临床使用的关键步骤。公共卫生相关性：每年花费数十亿美元，以防止接受心肺旁路心脏手术的心脏炎症患者的全身性炎症反应，以纠正冠状动脉的部分或完全阻塞。如果冠状动脉下动脉完全遮住，可能会发生心脏衰竭。目前尚无针对CPB相关炎症反应的批准的预防治疗。当被阻塞的血液流动时，缺血再灌注损伤会加剧反应。 IRI或CPB相关的炎症反应没有批准的治疗性。新颖的人打算开发YALCIOMAB作为一种治疗方法，以防止与心肺旁路的缺血模型中AP激活有关的并发症。