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

• 批准号: 9378567
• 负责人: Kunjan R Dave
• 金额: $ 42.21万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378567
• 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; Injection of therapeutic agent; 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 therapy; stroke treatment; therapeutic target

 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（由适用提供）：自发性脑内出血（SICH）是中风的最致命的亚型。尽管是发病率明显和死亡率的原因，但对SICH的有效治疗尚无。血肿的体积显示与30天的死亡率相关。症状发作后的前3小时，导致血肿膨胀的持续脑出血最高，并且在发作后3至24小时之间可能会持续约40％的患者。 SICH中预防血肿的扩张一直是吸引治疗靶标。 JY博士（共同入选者）及其小组研究了红细胞衍生的微粒（RMP）作为止血剂，已有十多年了。 RMP有可能在SICH中用作治疗剂，因为它们通过与血小板的相互作用并扩增接触途径的激活来促进活跃出血部位的衣服。该项目的目标是（R21阶段），以建立通过高压扩展方法制备的RMP的纯度，稳定性，体外效率和药代动力学，以及（R33阶段），以确定RMP在减少血肿量的效率，以及改善临床上相关的Sich Sich Animal Modely的神经学结果和死亡率。最终目标是将这些发现转化为临床实践，以减少SICH的发病率。我们假设薄荷后的RMP治疗将抑制血肿的生长并改善长期神经系统效果并降低后疗法死亡率。初步结果支持这一假设，因为在胶原酶诱导的SICH模型中，在24小时测量时，有效地防止了RMP治疗（1小时后注射酶后注射）。我们针对这些目标的具体目的是：R21阶段：目标1：表征RMP的纯度，体外凝血活性和稳定性（保质期）。目标2：建立大鼠RMP的药代动力学概况和生物分布。 R33阶段：目标3：确定RMP的最佳治疗剂量在大鼠实验sich后防止血肿生长。目标4：确定RMP给药的最佳（和最大）治疗时间窗口。目标5：验证在否认的赞助高血压大鼠中验证RMP疗法的效率，从而更加仔细地模拟人类的SICH。在该提案中，RMP的效率将通过检查血肿量（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）来评估。基于初步结果，我们相信RMP疗法将减轻血肿的生长，并在我们的动物模型中改善神经系统效果。获得的结果将提供临床前的证据，证明RMP在降低后血肿的生长中的效率，还将为随后的动物以及最终的人类研究提供数据。