Nitric Oxide redistribution by a phospholipid nanoparticle colloid to treat septic shock.

通过磷脂纳米粒子胶体重新分布一氧化氮来治疗感染性休克。

基本信息

批准号：
10321061
负责人：
Cuthbert Ormond Simpkins
金额：
$ 25.19万
依托单位：
VIVACELLE BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2023-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321061
关键词：
Address Albumins Allergic Reaction Animal Model Anti-Inflammatory Agents Antibiotic Resistance Antibiotics Area Bacterial Antibiotic Resistance Biological Assay Biological Availability Biological Markers Biophysics Blood Blood Chemical Analysis Blood Pressure Blood Volume Caliber Cardiovascular system Cause of Death Cessation of life Characteristics Clinical Clinical Trials Colloids Dangerousness Data Detection Development Drug Kinetics Embolism Emulsions Ensure Environment Exhalation Extracorporeal Membrane Oxygenation Failure Fatty acid glycerol esters Formulation Functional disorder Future Grant Growth Health Hemorrhage Hemorrhagic Shock Human Hydrophobicity Hypotension Hypovolemia Immunologics Inflammatory Inflammatory Response Infusion procedures Injury to Kidney Intellectual Property International Intervention Lactated Ringer&apos s Solution Legal patent Licensing Licensure Life Liposomes Liquid substance Mass Spectrum Analysis Measures Metabolism Methemoglobin Methods Micelles Mitochondria Modeling Monitor Morbidity - disease rate Nitrates Nitric Oxide Nitric Oxide Synthetase Inhibitor Nitrites Organ Organ failure Outcome Oxygen Pathologic Pathway interactions Perfusion Pharmacologic Substance Phase Phospholipids Physiological Plasma Plasmapheresis Privatization Process Production Prognosis Property Rattus Refractory Renal Replacement Therapy Reperfusion Injury Respiration Rest Resuscitation Safety Saline Sepsis Septic Shock Small Business Innovation Research Grant Sodium Cholate Soybean Oil Spectrophotometry Survival Rate Suspensions Therapeutic Therapeutic Embolization Time Tissues Toxic effect Treatment Cost Treatment outcome Validation Vasoconstrictor Agents Vasodilation Work aqueous autocrine base bile salts biomaterial compatibility blood filtration cecal ligation puncture design efficacy study experimental study health organization improved improved outcome in vivo lung injury mortality nano nanoparticle novel novel strategies novel therapeutics oxygen transport paracrine particle pre-clinical pre-clinical assessment sheep model uptake vasoconstriction

项目摘要

PROJECT SUMMARY Septic shock continues to be a leading cause of morbidity and mortality worldwide. The increasing bacterial antibiotic resistance is forcing the search for new methods to improve prognosis. Traditional resuscitation therapy is not designed to address the physiological mechanisms of septic shock that contribute to hypotension and organ failure. The inflammatory response is a limiting factor even with interventions such as renal replacement therapy and extracorporeal membrane oxygenation. Vivacelle Bio has patented VBI-1, a novel anti-inflammatory suspension of phospholipid nanoparticles designed to modulate the bioavailability of nitric oxide (NO) responsible for excessive vasodilatation, hypotension, or dangerous reperfusion injury that leads to organ failure in septic shock. Preliminary data support the ability of VBI-1 to carry life-sustaining amounts of oxygen and to absorb reversibly and quickly NO. Because of this reversibility, VBI-1 represents a novel approach to the modulation of NO that reduces its bioavailability without stopping its production or its autocrine or paracrine effects. Through its NO uptake and release, VBI-1 acts as a high-capacity NO modulator. At the same time, VBI-1 can carry oxygen and enable oxygen transport during resuscitation therapy. VBI-1 also inhibits the inflammatory response, reducing ischemia-reperfusion injury and organ dysfunction. Also, the small nanoparticle size and high emulsifier content of VBI-1 guarantee longer stability and higher efficacy in raising blood pressure when compared to currently used resuscitation fluids. Finally, VBI-1 is based on non-allergic soybean-oil micelles and liposomes comprised of phospholipid bilayers which make the new formulation highly biocompatible. VBI-1 formulation has been successfully proven to treat hemorrhagic shock with up to 55% replacement of blood volume without evidence of fat emboli, toxicity, or lung injury. In this SBIR grant, Vivacelle Bio will validate VBI-1 as a superior product for intravascular volume replacement compared to current resuscitation fluids, such as albumin or saline, in treating septic shock. To establish the feasibility of this approach, we propose the following two specific aims: 1) demonstrate the efficacy of VBI-1 when used in vivo on a Cecal Ligation Puncture (CLP) rat model of severe septic shock and 2) validate in vivo the NO modulatory effect by measuring NO biomarkers in the same CLP rat model. This work will be preparatory for further studies in Phase II, aimed at optimizing the formulation of VBI-1 and obtaining an FDA licensure for its use as a fluid for reducing the intensity of the inflammatory process in the intravascular space.

项目摘要败血性休克仍然是全球发病率和死亡率的主要原因。细菌的增加抗生素耐药性迫使人们寻找改善预后的新方法。传统复苏治疗并非旨在解决败血性休克的生理机制，这有助于低血压和器官衰竭。即使有干预措施，例如肾脏替代疗法和体外膜氧合。 Vivacelle Bio已获得申请VBI-1，磷脂纳米颗粒的新型抗炎悬浮液旨在调节生物利用度一氧化氮（NO）负责过度血管舒张，低血压或危险再灌注损伤导致败血性休克的器官衰竭。初步数据支持VBI-1携带生命的能力氧气量，可逆，迅速地吸收。由于这种可逆性，VBI-1代表一种新颖的方法调节NO，可以降低其生物利用度，而不会停止其生产或自分泌或旁分泌作用。 VBI-1通过其不吸收和释放，充当大容量否调制器。同时，VBI-1可以携带氧气并在复苏期间启用氧气传输治疗。 VBI-1还抑制炎症反应，减少缺血 - 重新灌注损伤和器官功能障碍。另外，VBI-1的小纳米颗粒尺寸和高乳化剂含量可确保更长的稳定性与当前使用的复苏液相比，升高血压的功效更高。最后， VBI-1基于非过敏性大豆油胶束和脂质体，由磷脂双层组成使新的配方高度生物相容性。 VBI-1配方已成功证明可以治疗出血性休克，最多55％的血容量替代，没有脂肪栓塞，毒性或肺部受伤。在此SBIR赠款中，Vivacelle Bio将验证VBI-1作为血管内体积的卓越产品与当前的复苏液（例如白蛋白或盐水）相比，在治疗败血性休克中的替代品。到确定这种方法的可行性，我们提出以下两个具体目的：1）证明 VBI-1的功效在体内在盲肠结扎刺穿（CLP）大鼠模型的严重败血性休克和 2）通过在同一CLP大鼠模型中测量无生物标志物来验证体内验证无调节效应。这工作将为第二阶段的进一步研究做准备，旨在优化VBI-1和获得FDA许可，以用作降低炎症过程强度的流体血管内空间。