S-Nitrosothiol-Based Rinse/Aerosol Solutions for Treatment/Prevention of Rhinosinusitis (Phase II)

用于治疗/预防鼻窦炎的 S-亚硝基硫醇冲洗/气雾剂溶液（第二阶段）

• 批准号: 9408559
• 负责人: JOAN A KEISER
• 金额: $ 85.82万
• 依托单位: NOTA LABORATORIES, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408559
• 关键词: Adult; Aerosols; Affect; Aluminum; Animal Experiments; Animals; Antibiotics; Antimicrobial Effect; Antiviral Agents; Ascorbic Acid; Bacteria; Bacterial Counts; Bicarbonates; Blood; Blood Circulation; Cell Line; Cells; Clinical Trials; Common Cold; Data; Detection; Direct Costs; Disease; Dose; Edetic Acid; Effectiveness; Epithelial Cells; Exhalation; Exhibits; Expert Opinion; Film; Flushing; Formulation; Frequencies; Funding; Generations; Glutathione; Healthcare; Histologic; Hour; Human; IL8 gene; In Vitro; Individual; Isotonic Exercise; Laboratories; Laboratory Animal Medicine; Literature; Measures; Michigan; Microbe; Microbial Biofilms; Modeling; Monitor; Mucociliary Clearance; Mucous Membrane; Nitric Oxide; Nose; Oryctolagus cuniculus; Patients; Pennsylvania; Pharmaceutical Preparations; Phase; Plasticizers; Polymers; Population; Powder dose form; Prevention; Process; Productivity; Pseudomonas aeruginosa; Reducing Agents; Research; Risk; Role; S-Nitrosoglutathione; S-Nitrosothiols; Saline; Sinus; Small Business Innovation Research Grant; Specialist; Staphylococcus aureus; Surface; Technology; Test Result; Testing; Time; Toxic effect; Universities; Visit; Water; antimicrobial; antimicrobial drug; ascorbate; base; chronic rhinosinusitis; cost; cytokine; economic impact; effective therapy; experimental study; human subject; improved; in vivo; innovative technologies; microbial; natural antimicrobial; phase 1 study; phase 3 study; pre-clinical; prevent; product development; reconstitution; rhinosinusitis; treatment duration

Abstract: Chronic rhinosinusitis (CRS) is estimated to affect 13% of the US population, with annual health care direct costs of nearly $10 billion per year, yet there are few effective therapies for CRS. Detection of Staphylococcus aureus and/or Pseudomonas aeruginosa biofilm in the sinus mucosa is associated with severe CRS presentation. Healthy cells that line the nasal passages normally emit significant levels of nitric oxide (NO), a potent and natural antimicrobial molecule that stimulates mucociliary clearance and reduces bacterial biofilm formation. Reduced levels of NO in the exhaled nasal breath of CRS patients suggest that boosting local NO concentrations within the sinuses may be quite beneficial. In Phase I of this project, NOTA Laboratories, LLC, clearly demonstrated that a naturally occurring and inexpensive NO releasing agent, S-nitrosoglutathione (GSNO), can be incorporated into a typical saline/bicarbonate sinus rinse solution and generate adequate levels of NO to significantly reduce levels of live bacteria counts for two biofilm forming CRS microbes (S. aureus and P. aeruginosa). In these experiments, the bacterial biofilms were grown on the surface of human upper airway epithelial cells. We further demonstrated that the levels of GSNO and concomitant NO released do not harm the underlying human cells, as assessed by monitoring the levels of a toxicity-associated cytokine (IL-8). In addition, NOTA demonstrated that the release rates of NO from GSNO can be enhanced by the presence of ascorbate (Asc; vitamin C) and that the resulting powder formulations of GSNO/Asc can be stored for more than 6 months (at 37 °C) while retaining >80% of their NO release capability. Via Phase II SBIR funding, NOTA will: 1) Further optimize the concentration of the GSNO/Asc mixture within an isotonic NaCl/NaHCO3/EDTA solution and frequency of application for the in vitro disruption of S. aureus and P. aeruginosa biofilms formed on human upper airway epithelial cells over 3 d test periods; 2) Explore a commercial packaging process (in polymer film lined aluminum pouches) and test the resulting 1-year stability of a dry packaged GSNO/Asc/NaCl/NaHCO3/EDTA mixed powder that will be reconstituted in plastic sinus flush bottles with 240 mL of pure water immediately before use by patients; 3) Conduct animal studies in rabbits to determine if NOTA's reconstituted RSNO/Asc/NaCl/NaHCO3/EDTA formulation, given as an aerosol spray twice daily over a 7 d period, significantly decreases bacterial counts in the sinus cavities of infected rabbits (with CRS) vs. controls (only NaCl/NaHCO3/EDTA); and 4) Begin the regulatory process by obtaining expert assessments of the role of the FDA in approval of the new GSNO formulations as a potential over-the-counter product for the CRS market. The completion of these efforts during Phase II will enable NOTA to plan the first human subject clinical trials at the University of Michigan Sinus Center as part of Phase III studies.

抽象的： 据估计，慢性鼻塞炎（CRS）会影响美国人口的13％，并具有年度医疗保健 每年的直接成本接近100亿美元，但CRS的有效疗法很少。检测 金黄色葡萄球菌和/或窦粘膜中的铜绿假单胞菌生物膜与 严重的CRS介绍。排列鼻腔通道的健康细胞通常会散发出大量的水平 一氧化氮（NO），一种潜在的和天然的抗菌分子，可刺激粘膜纤毛清除和 减少细菌生物膜的形成。 CRS患者疲惫的鼻呼吸中的NO水平降低 表明提高鼻窦内的局部没有浓度可能是非常有益的。 在该项目的第一阶段，Nota Laboratories，LLC清楚地表明，自然发生并且 廉价的没有释放剂S-硝基谷胱甘肽（GSNO）可以纳入典型 盐水/碳酸氢盐冲洗溶液并产生足够的NO水平，以显着降低 两种形成CRS微生物的生物膜的活细菌水平计数（金黄色葡萄球菌和铜绿假单胞菌）。在 这些实验，细菌生物膜在人上皮上皮的表面生长 细胞。我们进一步证明了GSNO和随之而来的NO释放的水平不会损害 通过监测与毒性相关的细胞因子（IL-8）的水平评估的人类细胞的潜在细胞。 此外，Nota证明了GSNO的NO释放率可以通过 抗坏血酸酯的存在（ASC；维生素C），并且可以是GSNO/ASC的粉末配方 存储超过6个月（在37°C下），同时保留了其无释放能力的80％。 通过II期SBIR资助，NOTA将：1）进一步优化GSNO/ASC混合物的浓度 在等渗NACL/NAHCO3/EDTA解决方案中，以及用于体外破坏的应用频率 金黄色葡萄球菌和铜绿假单胞菌生物膜在3 d测试的人类上皮上皮细胞上形成 时期； 2）探索商业包装过程（在聚合物膜中衬里铝袋）和测试 由干包装的GSNO/ASC/NaHCO3/EDTA混合粉末的1年稳定性 在使用之前，用240毫升的纯净水在塑料窦齐平瓶中重构 患者; 3）对兔子进行动物研究，以确定Nota是否重构 rsno/asc/nacl/nahco3/edta公式，每天两次以气溶胶喷雾剂给出，在7 d期间两次 在感染兔子的鼻窦腔中显着降低了细菌计数（带有CRS）与对照 （只有NACL/NAHCO3/EDTA）; 4）通过获得专家评估开始监管过程 FDA在批准新GSNO公式作为潜在非处方产品的作用 对于CRS市场。在第二阶段完成这些努力的完成将使Nota能够计划第一个 作为第三阶段研究的一部分，密歇根大学鼻窦中心的人类学科临床试验。