ZZ-3K3A-201: Safety evaluation of 3K3A-APC in ischemic stroke

ZZ-3K3A-201：3K3A-APC在缺血性中风中的安全性评价

基本信息

批准号：
8760276
负责人：
Patrick D Lyden
金额：
$ 243.98万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8760276
关键词：
Active Sites Acute Adult Adverse effects Americas Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Anticoagulants Biological Markers Biology Blood Blood - brain barrier anatomy Blood Vessels Brain Cause of Death Cell Death Process Cells Chronic Clinical Data Collaborations Cytoprotection Data Development Dose Dose-Limiting Drug Kinetics Endothelial Cells Endothelium Engineering Ensure Evaluation Experimental Models Factor Va Female Guidelines Heart Hemorrhage Hospitals Hour Human Human Volunteers In Vitro Intravenous Ischemia Ischemic Stroke Kidney Laboratories Liver Lung Lytic Magnetic Resonance Imaging Maximum Tolerated Dose Mediating Membrane Methods Microglia Mutate National Institute of Neurological Disorders and Stroke Neuraxis Neuroglia Neurons Neuroprotective Agents PAR-1 Receptor Patients Peptide Hydrolases Pharmaceutical Preparations Phase I Clinical Trials Phase II Clinical Trials Pre-Clinical Model Primates Program Development Property Proteins Reading Recombinants Recommendation Research Infrastructure Rodent Safety Signal Pathway Signal Transduction Stroke Structure of thyroid parafollicular cell System Testing Thrombolytic Therapy Time Toxic effect Toxicology Variant activated Protein C acute stroke aged base blind cell type central nervous system injury clinical efficacy clinically relevant cofactor design disability effective therapy experience improved injured mutant neurobehavioral neurovascular unit novel pre-clinical public health relevance receptor stroke therapy success thrombolysis

项目摘要

DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability in America, and one of the leading causes of death in the world. If patients arrive at a hospital within 3 hours of their stroke beginning, thrombolytic therapy can be very effective. Only 40 to 50% of patients respond to lytic treatment, however, creating a priority to develop new, effective treatments for stroke. The brain consists of multiple cell types: neurons, glia, and endothelial cells, among others; during stroke, the brain loses 1.2 million neurons per minute. In the past, candidate stroke treatments that failed to benefit patients were targeted only at neurons. We now propose to test a new drug that powerfully protects neurons, glia, and endothelial cells, together known as the neurovascular unit. This drug, 3K3A-APC, acts on cells partly via the PAR-1 receptor to induce protection by several mechanisms. Multiple laboratories- using neurobehavioral and histomorphometric endpoints in several animal models-have shown the drug powerfully reduces the effects of experimental stroke, even when administered up to 4 hours after the stroke begins. In human volunteers, only mild and moderate side effects were detected at clinically relevant doses. We now propose to test 3K3A-APC-for the first time-in stroke patients who arrive at the hospital very early and receive thrombolytic treatment. Very low doses will be tried at first, and then progressively higher doses will be tried. Ultimately, we wil determine the maximum tolerated dose (MTD), that is, the largest drug dose that can be given without causing severe side effects. By the end of this study, we hope to determine a dose that is safe and well tolerated by patients suffering acute stroke. Should this study succeed, the next step would be a much larger study to test for possible benefit of 3K3A-APC in stroke patients.

描述（由申请人提供）：中风是美国成人残疾的主要原因，也是世界上导致死亡的主要原因之一。如果患者在中风发生后 3 小时内到达医院，溶栓治疗可能非常有效。然而，只有 40% 至 50% 的患者对溶解治疗有反应，因此开发新的、有效的中风治疗方法成为当务之急。大脑由多种细胞类型组成：神经元、神经胶质细胞和内皮细胞等；中风期间，大脑每分钟损失 120 万个神经元。过去，未能使患者受益的候选中风治疗方法仅针对神经元。我们现在建议测试一种新药，它可以有效保护神经元、神经胶质细胞和内皮细胞（统称为神经血管单元）。这种药物 3K3A-APC 部分通过 PAR-1 受体作用于细胞，通过多种机制诱导保护。多个实验室在几种动物模型中使用神经行为和组织形态学终点表明，即使在中风开始后 4 小时内服用，该药物也能有效降低实验性中风的影响。在人类志愿者中，在临床相关剂量下仅检测到轻度和中度副作用。我们现在建议首次在很早到达医院并接受溶栓治疗的中风患者中测试3K3A-APC。首先尝试非常低的剂量，然后逐渐尝试更高的剂量。最终，我们将确定最大耐受剂量（MTD），即在不引起严重副作用的情况下可以给予的最大药物剂量。在这项研究结束时，我们希望确定急性中风患者安全且耐受性好的剂量。如果这项研究成功，下一步将进行更大规模的研究，以测试 3K3A-APC 对中风患者的可能益处。