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

摘要/项目总结 在美国，中风每年影响超过795，000名患者，并导致约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）卒中占 几乎40%的缺血性中风，但导致95%的死亡率和62%的长期依赖性。机械 血栓切除术（MT）或MT和tPA的组合已经成为LVO卒中的标准护理治疗。 多达60%的血栓切除术患者首先在分支医院接受评估，然后转移到中心医院， 山“时间就是大脑”中风后，越早开始治疗， 神经功能一种可以在所有中风患者中快速部署以保护大脑的治疗方法， 为中风患者提供了巨大的潜在益处。 NanO 2 TM（又名十二氟戊烷乳剂，DDFPe）显著降低每搏输出量（SV），约 85%，并且当在给药后3小时内IV给药时，兔的神经系统评估评分（NAS）改善 中风，并改善SV和NAS在永久性大鼠MCAo。在一项随机、安慰剂对照的Ib/II期研究中， 急性缺血性中风的临床试验，其中患者接受标准再灌注治疗，NanO 2在 所有剂量水平。较高剂量的NanO 2在30和40 ℃时引起显著更好的改良兰金量表（mRS）， 90-卒中后天数。早期给予NanO 2（发病后<5小时），NIH显著改善 卒中量表（NIHSS）评分。NanO 2在非常低的剂量下具有活性（例如，0.1至0.17 mL的2%w/vol乳液， kg体重），并通过呼气清除，在人体中的终末半衰期约为90分钟。nano 2是 之前在2，230名患者中作为超声造影剂进行了测试，并被认为是安全和可批准的 FDA和EMEA。具体目标是：1）生产用于SPAN研究的DDFPe GMP和放大 GMP生产，2）在瘦型、成年和老年Wistar大鼠的tMCAo模型中检测药物，3）执行 在肥胖、糖尿病Zucker大鼠和自发性高血压大鼠中进行的研究。 预期结果：NanO 2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 作为进入由StrokeNet赞助的缺血性卒中临床试验的候选人。

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.