Pharmacologic Suppression of Reperfusion Injury Following Endovascular Thrombectomy In Stroke.

中风血管内血栓切除术后再灌注损伤的药物抑制。

• 批准号: 10006866
• 负责人: DAVID WARNER
• 金额: $ 22.78万
• 依托单位: BIOMIMETIX JV, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006866
• 关键词: Abate; Adverse effects; Advocate; Alteplase; Apoptosis; Apoptotic; Arterial Fatty Streak; BMX gene; Basic Science; Biological Assay; Biological Markers; Biology; Brain; Brain Injuries; Catheters; Cause of Death; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Cognitive; Collaborations; Consult; Data; Dose; Female; Filament; Foundations; Functional disorder; Glioma; Histologic; Hour; Human; Inbred SHR Rats; Infarction; Inflammation; Inflammatory; Infusion procedures; Intervention; Intracarotid; Intracarotid Infusion; Ischemia; Ischemic Penumbra; Ischemic Stroke; Italy; Laboratories; Laboratory Finding; Laboratory Research; Lead; Legal patent; Lesion; MAPK phosphatase; Maintenance; Malignant Neoplasms; Manganese; Measures; Mechanics; Mediating; Metabolic syndrome; Metabolism; Methods; Middle Cerebral Artery Occlusion; Modeling; Monitor; NF-kappa B; Nervous System Physiology; Neurologic; Neurology; Nitrogen; Normal tissue morphology; Outcome; Outcome Measure; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Pilot Projects; Porphyrins; Procedures; Protocols documentation; Radiation Protection; Radiation therapy; Rattus; Recovery; Reducing Agents; Regulation; Reperfusion Injury; Reperfusion Therapy; Safety; Series; Small Business Technology Transfer Research; Standardization; Stroke; Symptoms; Technology; Therapeutic; Therapeutic Index; Thrombectomy; Thromboembolism; Thrombus; Tissues; Toxicology; Transcriptional Activation; Translating; United States; Universities; Validation; Wistar Rats; Work; aged; base; blood-brain barrier disruption; brain tissue; cohort; comorbidity; design; disability; drug development; drug efficacy; functional outcomes; improved; improved outcome; in vitro activity; in vivo; male; multidisciplinary; neuroprotection; nitrosative stress; novel; object recognition; organ injury; pre-clinical; preclinical efficacy; response; response to brain injury; restoration; scale up; screening; stroke model; stroke patient; stroke therapy; subcutaneous; thrombolysis; transcription factor; treatment duration

Ischemic stroke is a leading cause of death and disability in the United States. This often is attributable to thrombus formation at an atherosclerotic plaque or thromboembolism. Patients who present within 4.5 hours of symptom onset are eligible for thrombolysis with tissue plasminogen activator (tPA). This serves <5% of victims. Recently, major advance has been made with proven efficacy from endovascular mechanical thrombectomy in combination with tPA. Despite this, <50% of treated patients have a good recovery. Basic and clinical science indicate that abrupt restoration of oxygen delivery to ischemic tissue causes reperfusion injury that amplifies/propagates adverse cascades initiated by the initial ischemic insult. There has been widespread call for pharmacologic intervention to mitigate reperfusion injury. The mechanistic basis for reperfusion injury is diverse, but fundamentally associated with rapid onset dysfunction of intracellular mechanisms responsible for regulation of oxygen metabolism. This leads to oxidative stress, inflammation, apoptosis, blood-brain barrier disruption and tissue damage. We are working closely with chemists who have synthesized manganese porphyrins (MnP). MnP have been highly characterized and serve as potent catalytic oxidoreductants. MnP have extraordinary efficacy to favorably modulate redox-mediated activation of transcription factors (e.g., NF-kB, Nrf2) and MAPK and phosphatases. MnP also serve as potent catalytic reductants of reactive oxygen/nitrogen species. We have repeatedly shown enduring improvement in experimental stroke long-term outcome after therapeutic MnP dosing. The lead MnP, BMX-001, now in human trials as a radioprotectant for normal tissue in the context of radiotherapy for brain malignancy, has achieved GMP synthesis, scale-up technology, and requisite preclinical toxicological screening. Based on highly encouraging pilot data, we propose BMX-001, given at endovascular thrombectomy reperfusion onset, as an adjunct pharmaceutical to optimize endovascular thrombectomy outcome. In Phase 1, we will define optimal dosing and maximal ischemia duration before reperfusion and treatment onset that retains efficacy, measure long-term functional outcome in aged, metabolic syndrome, and spontaneously hypertensive rats, define interactions with tPA activity, and obtain independent laboratory efficacy validation. A Clinical Trial Consulting Team, consisting of independent stroke experts, will work in collaboration with Biomimetix to monitor go/no-go end-points and develop protocols for human dose-escalation trials.

缺血性中风是美国死亡和残疾的主要原因。这往往是 可归因于动脉粥样硬化斑块处的血栓形成或血栓栓塞。患者 在症状发作后4.5小时内出现的患者有资格接受组织溶栓治疗。 纤溶酶原激活物（tPA）。这为<5%的受害者提供服务。最近，主要进展是 经血管内机械血栓切除术证实有效， tPA。尽管如此，<50%的治疗患者恢复良好。基础和临床科学 表明向缺血组织输送氧气突然恢复引起再灌注损伤 其放大/传播由初始缺血性损伤引发的不利级联。一直 人们普遍呼吁药物干预以减轻再灌注损伤。的 再灌注损伤的机制基础是多种多样的，但从根本上与快速 负责调节氧代谢的细胞内机制的发作功能障碍。 这导致氧化应激、炎症、细胞凋亡、血脑屏障破坏和组织损伤。 损害我们正与合成锰卟啉的化学家密切合作 （MNP）。MnP已被高度表征并用作有效的催化氧化还原剂。MNP 对有利地调节氧化还原介导的转录激活具有非凡的功效 因素（例如，NF-kB、Nrf 2）和MAPK以及磷酸酶。MnP还可以作为有效的催化剂， 活性氧/氮物质的还原剂。我们一再证明， 治疗性MnP给药后实验性中风长期结局的改善。率先 MnP，BMX-001，现在在人体试验中作为正常组织的辐射防护剂， 放射治疗脑恶性肿瘤，已实现GMP合成，放大技术， 必要的临床前毒理学筛选。基于令人鼓舞的试点数据，我们建议 BMX-001，在血管内血栓切除术再灌注开始时给予，作为辅助治疗 优化血管内血栓切除术结局的药物。在第一阶段，我们将定义 再灌注和治疗开始前的最佳剂量和最大缺血持续时间， 保持疗效，测量老年人的长期功能结局，代谢综合征， 自发性高血压大鼠，定义与tPA活性的相互作用，并获得独立的 实验室功效验证。一个临床试验咨询团队，由独立的中风 专家将与Biomimetix合作，监测进行/不进行终点并开发 人体剂量递增试验的方案。