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（由申请人提供）：自发性脑出血 (sICH) 是最致命的中风亚型，尽管它是导致显着发病率和死亡率的原因，但目前尚无针对 sICH 的有效治疗方法显示其与 30 天死亡率相关。导致血肿扩大的持续脑出血在症状出现后的前 3 小时内最高，约 40% 的患者可能会在 3 至 3 小时内持续出现这种情况。发病后 24 小时，预防 sICH 中的血肿扩大一直是一个有吸引力的治疗目标，Jy 博士（共同研究员）和他的团队研究红细胞衍生微粒 (RMP) 作为止血剂已有十多年了。 RMP 有潜力用作 sICH 的治疗剂，因为它们部分通过与血小板相互作用和增强接触途径的激活来促进活动性出血部位的凝血。该项目的目标是。（R21 阶段）确定高压挤出法制备的 RMP 的纯度、稳定性、体外功效和药代动力学，（R33 阶段）确定 RMP 在减少血肿体积以及改善神经功能和预后方面的功效。最终目标是将这些发现转化为临床实践，以降低 sICH 的发病率，我们发现 sICH 后 RMP 治疗将抑制血肿生长并改善。初步结果支持这一假设，即在胶原酶诱导的 sICH 模型中进行 24 小时测量时，RMP 治疗（胶原酶注射后 1 小时）可有效防止血肿生长。这些目标是： R21 相：目标 1：表征 RMP 的纯度、体外凝固活性和稳定性（保质期）。 RMP 在大鼠中的生物分布。目标 3：确定 RMP 在大鼠实验性 sICH 后预防血肿生长的最佳治疗剂量。目标 4：确定 RMP 给药的最佳（和最大）治疗时间窗。目标 5：验证 RMP 治疗在患病自发性高血压大鼠中的疗效，该大鼠更接近地模拟人类 sICH 在本提案中，将通过检查血肿体积来评估 RMP 的疗效。（短期实验）或梗塞体积（长期实验）（主要结果），以及长期神经功能和死亡率（次要结果）根据初步结果，我们相信 RMP 治疗也将减轻血肿的生长。在我们的动物模型中改善 sICH 后的神经系统结果，所获得的结果将提供临床前证据，证明 RMP 在降低 sICH 后血肿生长方面的功效，并且还将为后续的动物研究和最终的人体研究提供数据。