Pathophysiology and Treatment of Vasospasm

血管痉挛的病理生理学和治疗

• 批准号: 8158237
• 负责人: Russell Lonser
• 金额: $ 96.08万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8158237
• 关键词: Affect; Cerebrovascular Spasm; Clinical; Continuous Intravenous Infusion; Data; Development; Dose-Limiting; Dyes; Endothelium; Functional disorder; Image; Intracarotid; Intrathecal Space; Nitric Oxide Synthase; Pharmaceutical Preparations; Structure of subarachnoid cistern; Thick; Tunica Adventitia; Vasospasm; base; disability; insight; preclinical study; prevent

Effect of Blood Clot in the Subarachnoid Space For years different drugs have been administered intrathecally/intraventricularly in an attempt to prevent or reverse this vasospasm, but without clinical success. We hypothesized that the presence of blood clot in the subarachnoid space prevents drugs from penetrating into the vicinity of the affected cerebral arteries, limiting or precluding a significant vasoactive drug effect. We examined this hypothesis, in a primate model of subarachnoid hemorrhage injecting dye (for macro-imaging) and contrast (for radiological imaging) into the intrathecal space and evaluating the extent of their distribution to the subarachnoid cisterns. A manuscript summarizing the findings confirming our hypothesis has been submitted. Effect of Nitric Oxide (NO) on Vasospasm For several years we have investigated the mechanism of delayed vasospasm and demonstrated the presence of local NO deficiency from dysfunction of NO synthases within the endothelium and adventitia in a primate model of vasospasm, which was corrected by intracarotid delivery of an NO donor. We also reported that nitrite acts as a local, on-demand NO donor preventing development of vasospasm in a preclinical study in primates. After receiving IRB and FDA approval for a clinical protocol, we have assessed the safety in 12 healthy subjects of a 48-hour continuous intravenous infusion of nitrite establishing a maximal tolerated dose and dose limiting toxicity. The results of this study have been analyzed and a manuscript has been submitted.

血块在亚蛛网膜下腔中的影响 多年来，不同的药物已被静脉内/静脉注射，以防止或扭转这种血管痉挛，但没有临床成功。 我们假设亚蛛网膜下腔中血凝块的存在可防止药物穿透到受影响的大脑动脉附近，从而限制或排除显着的血管活性药物效应。 我们在蛛网膜下腔出血的灵长类动物模型（用于宏观成像）和对比度（用于放射学成像）中，研究了这一假设，并评估了其分布到亚蛛网膜下腔辅助物的程度。 总结了证实我们假设的发现的手稿。 一氧化氮（NO）对血管痉挛的影响 几年来，我们已经研究了血管痉挛延迟的机制，并证明了在血管痉挛的灵长类动物模型中，无合酶功能障碍存在局部无缺陷，该模型通过无含量递送的无供体的肉体骨骼纠正。 我们还报告说，在灵长类动物的临床前研究中，亚硝酸盐充当局部的，按需的无供体，可以防止血管痉挛的发展。 在获得IRB和FDA批准用于临床方案后，我们评估了12个健康受试者的安全性，该受试者的安全性是48小时连续静脉注射亚硝酸盐，以建立最大耐受剂量和剂量限制毒性。 这项研究的结果已经分析，并提交了手稿。