Dodecafluoropentane emulsion (DDFPe), NanO2™ as Cerebroprotectant in Ischemic Stroke

十二氟戊烷乳液 (DDFPe)、NanO2™ 作为缺血性中风的脑保护剂

• 批准号: 10591442
• 负责人: Evan charles Unger
• 金额: $ 30.14万
• 依托单位: NUVOX PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591442
• 关键词: Acute; Adult; Affect; Alteplase; American; Anesthesia procedures; Animals; Applications Grants; Autopsy; Behavior; Blinded; Blood flow; Body Weight; Brain; Caring; Clinical Trials; Contrast Media; Data; Dependence; Development; Dose; Eligibility Determination; Emulsions; Exhalation; Experimental Designs; Female; Filament; Funding; Half-Life; Hospitals; Hour; Human; Inbred SHR Rats; Injury; Ischemia; Ischemic Stroke; Magnetic Resonance Imaging; Measurement; Measures; Mechanics; Medical; Middle Cerebral Artery Occlusion; Modeling; Nervous System Physiology; Neurologic; Neurons; Obesity; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Oxygen; Patients; Pharmaceutical Preparations; Phase; Phase Ib/II Clinical Trial; Phase Ib/II Trial; Placebo Control; Placebos; Procedures; Production; Protocols documentation; Randomized; Rattus; Reperfusion Therapy; Risk; Rodent; Route; Small Business Innovation Research Grant; Specific qualifier value; Stroke; Stroke Volume; Survival Analysis; Testing; Thinness; Thrombectomy; Time; Tissue Preservation; Tissue Viability; United States National Institutes of Health; Wistar Rats; Zucker Rats; aged; anaerobic glycolysis; cohort; comorbidity; cost; diabetic; diabetic rat; drug testing; experimental study; functional outcomes; hypertensive; improved; improved outcome; male; manufacture; manufacturing scale-up; meetings; mortality; nano; normotensive; perfluoropentane; phase II trial; post stroke; pre-clinical; preservation; programs; scale up; standard of care; stroke model; stroke patient; tissue oxygenation; ultrasound

ABSTRACT / PROJECT SUMMARY Stroke affects more than 795,000 patients per year in the US and kills approximately 40,000. Long-term medical care expense for stroke in the US, costs over $34B per year. Large vessel occlusion (LVO) stroke accounts for almost 40% of ischemic strokes but causes 95% of mortality and 62% of long-term dependence. Mechanical thrombectomy (MT), or a combination of MT and tPA, has emerged as standard of care treatment of LVO stroke. Up to 60% of thrombectomy patients are first evaluated at spoke hospitals and transferred to hub hospitals for MT. `Time is brain' following stroke, the sooner therapy can be instituted, the greater the likelihood of preserving neurological function. A therapy that could be rapidly deployed in all stroke patients to preserve the brain could provide enormous potential benefit to stroke patients. NanO2TM (aka dodecafluoropentane emulsion, DDFPe) significantly decreased stroke volume (SV), by about 85%, and improved neurological assessment score (NAS) in rabbits when administered IV up to 3 hours following stroke and also improved SV and NAS in permanent rat MCAo. In a randomized, placebo-controlled Phase Ib/II clinical trial of acute ischemic stroke, in which patients receive standard reperfusion therapy, NanO2 was safe at all dose levels. The higher doses of NanO2 caused significantly better modified Rankin Scale (mRS) at 30 and 90-days post stroke. Early administration of NanO2 (<5 hours from onset) presented with significantly better NIH Stroke Scale (NIHSS) scores. NanO2 is active at very low doses (e.g. 0.1 to 0.17 mL of 2% w/vol emulsion per kg body weight) and clears via exhalation with a terminal half-life of about 90 minutes in humans. NanO2 was previously tested as an ultrasound contrast agent in 2,230 patients and was considered safe and approvable by the FDA and EMEA. The Specific Aims are 1) to manufacture DDFPe GMP for SPAN studies and to scale-up GMP manufacturing, 2) to test drug in tMCAo models in lean, adult and aged Wistar rats and 3) to perform studies in obese, diabetic Zucker rats and spontaneously hypertensive rats. Expected Outcome: NanO2 will show great efficacy in rodent tMCAo models enabling this drug to be considered as a candidate for entry into clinical trials in ischemic stroke sponsored by StrokeNet.

摘要/项目摘要 在美国，中风每年影响超过795,000名患者，并导致大约40,000人死亡。长期医疗 在美国，中风的护理费用每年超过340亿美元。大血管闭塞(LVO)卒中 几乎40%的缺血性中风，但导致95%的死亡率和62%的长期依赖。机械式 血栓切除术(MT)，或MT和tPA的组合，已成为LVO卒中的标准护理治疗。 多达60%的血栓摘除患者首先在分支医院接受评估，然后转移到中心医院进行治疗 Mt.Mt.中风后“时间就是大脑”，越早开始治疗，保存下来的可能性就越大 神经功能。一种可以在所有中风患者中迅速部署以保护大脑的疗法可能 为中风患者提供巨大的潜在利益。 纳米O2TM(又名十二氟戊烷乳剂，DDFPe)显著降低了每搏量(SV)，降低了约 85%，并改善神经评估评分(NAS)时，兔静脉注射后3小时 并能改善永久性大鼠MCAO的SV和NAS。在随机、安慰剂对照的Ib/II期 急性缺血性卒中的临床试验中，患者接受标准的再灌注治疗，NanO2在 所有剂量水平。较高剂量的纳米O2在30℃和30℃时显著改善了改良朗肯分级(MRS) 中风后90天。早期使用纳米O2(发病后5小时)表现出明显改善的NIH 卒中评分(NIHSS)。纳米O2在非常低的剂量下是活性的(例如，0.1至0.17毫升的2%w/vol乳状液 体重)，并通过呼气清除，在人类体内的终末半衰期约为90分钟。纳米O2是 以前作为超声造影剂在2230名患者中测试，被认为是安全和批准的 FDA和EMEA。具体目标是1)生产用于SPAN研究的DDFPe GMP并扩大规模 GMP制造，2)在瘦身、成年和老年Wistar大鼠的tMCAo模型中测试药物，3)执行 对肥胖、糖尿病Zucker大鼠和自发性高血压大鼠的研究。 预期结果：纳米O2将在啮齿动物tMCAo模型中显示出巨大的疗效，使该药物能够被考虑使用 作为候选进入由StrokeNet赞助的缺血性中风的临床试验。