Red blood cell microparticles (RMPs) to reduce bleeding following hemorrhagic stroke

红细胞微粒（RMP）可减少出血性中风后的出血

基本信息

批准号：
9414571
负责人：
Kunjan R Dave
金额：
$ 41.26万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9414571
关键词：
Active Sites Address Adverse effects Affect Animal Model Animals Antiplatelet Drugs Biodistribution Blood Cells Blood Coagulation Disorders Blood Platelet Disorders Blood Platelets Bolus Infusion Brain Brain hemorrhage Cerebral hemisphere hemorrhage Cerebrum Clinic Coagulants Coagulation Process Comorbidity Data Defect Disease Dose Drug Kinetics Environment Erythrocytes Goals Growth Guidelines Hematologist Hematoma Hemorrhage Hemostatic Agents Hemostatic function Hour Human Hypertension In Vitro Inbred SHR Rats Industry Infarction Injections Leukocytes Life Measures Mediating Methods Modeling Morbidity - disease rate Nervous System Physiology Neurological outcome Organ Pathway interactions Patients Phase Prevention Production Property Rattus Regimen Research Personnel Risk Factors Savings Scientist Site Stroke Supportive care Survivors Symptoms Testing Therapeutic Therapeutic Agents Time Tissues Training Translating Treatment Efficacy base clinical practice clinically relevant collagenase comparative efficacy cranium disability dosage effective therapy experience experimental study improved interest mortality particle particle therapy pre-clinical preclinical study pressure prevent primary outcome public health relevance recombinant FVIIa response secondary outcome stroke model stroke therapy stroke treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Spontaneous intracerebral hemorrhage (sICH) is the deadliest subtype of stroke. Despite being the cause of significant morbidity and mortality, no effective treatment for sICH exists. Hematoma volume is shown to correlate with the 30-day mortality rate. Continued cerebral bleeding leading to hematoma expansion is highest in the first 3 hours after symptom onset and may continue in ≈40% of patients between 3 and 24 hours after the onset. The prevention of hematoma expansion in sICH has been an attractive therapeutic target. Dr. Jy (Co-investigator) and his group have studied red blood cell-derived micro particles (RMP) as hemostatic agents for over a decade. RMP have the potential to be used as a therapeutic agent in sICH since they promote clotting at sites of active bleeding, in part, by interaction with platelets and by amplifying activation of the contact pathway. The goals of this project are (R21 phase) to establish the purity, stability, in vitro efficacy, and pharmacokinetics of RMP prepared by the high pressure extrusion method, and (R33 phase) to establish the efficacy of RMP in reducing hematoma volume, as well as improving neurological outcome and mortality in clinically relevant sICH animal models. The ultimate goal is to translate these findings to clinical practice in order to reduce morbidity from sICH. We hypothesize that post-sICH RMP treatment will suppress hematoma growth and improve long-term neurological outcome and reduce post-sICH mortality. Preliminary results support this hypothesis in that RMP treatment (1 h post-collagenase injection) effectively prevented hematoma growth when measured at 24 h in a collagenase-induced sICH model. Our specific aims addressing these goals are: R21 phase: Aim 1: To characterize the purity, in vitro coagulant activity and stability (shelf-life) of RMP. Aim 2: To establish the pharmacokinetic profile and bio-distribution of RMP in rats. R33 phase: Aim 3: To determine the optimum therapeutic dose of RMP in preventing hematoma growth following experimental sICH in rats. Aim 4: To determine the optimal (and maximal) therapeutic time window for RMP administration. Aim 5: To validate the efficacy of RMP therapy in in diseased spontaneously hypertensive rats, which simulate human sICH more closely. In this proposal the efficacy of RMP will be evaluated by examining hematoma volume (short-term experiments) or infarct volume (longer-term experiments) (primary outcome), and long-term neurological function and mortality (secondary outcomes). Based on preliminary results we are confident that RMP therapy will mitigate hematoma growth, as well as improve neurological outcome following sICH in our animal model. The results obtained will provide pre-clinical evidence demonstrating the efficacy of RMP in lowering post-sICH hematoma growth, and will also provide data for subsequent animal and, ultimately, human studies.

描述：脑内出血（SICH）是中风的致命亚型。在最初的3个小时中，可能会在ND的40％中持续24小时，预防SICH中的血肿扩张是一个有吸引力的JY博士（共同投资者）。微粒（RMP）作为止血剂十年。，通过高挤压法制备的RMP的稳定性，体外功效和药代动力学，以及（R33期）在减少临床相关的SICH动物模型中，建立RMP。为了减少SICH的练习RMP的活性和稳定性。 RMP给药5：验证RMPY在自发的高血压大鼠中的功效和长期的神经学功能和死亡率。并最终是人类研究。