Inhalable Gallium Nitrate Anti-Infective Powder for CF

CF用可吸入硝酸镓抗感染粉

• 批准号: 7746952
• 负责人: Vu L. Truong
• 金额: $ 30万
• 依托单位: ARIDIS PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746952
• 关键词: Acute; Aerosols; Alginates; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Biodistribution; Biological Availability; Bolus Infusion; Breathing; Burkholderia cepacia; Chronic; Clinical; Communities; Coupled; Cystic Fibrosis; DNA biosynthesis; Data; Data Protection; Dependency; Development; Devices; Disease; Dose; Drug Formulations; Drug resistance; Effectiveness; Electron Transport; Engineering; Excipients; Exhibits; Frequencies; Gallium; Gallium Nitrate; Goals; Gram-Positive Bacteria; Growth; Host Defense Mechanism; Hour; Immune; In Vitro; Infection; Inhalation Therapy; Inhalators; Injection of therapeutic agent; Insufflation; Iron; Lead; Life; Life Expectancy; Liposomes; Liquid substance; Lung; Mediating; Microbial Biofilms; Modeling; Mus; Nose; Nosocomial Infections; Oral; Organism; Oxidative Stress; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Phase; Pneumonia; Polysaccharides; Population; Powder dose form; Preclinical Testing; Process; Property; Pseudomonas aeruginosa; Resistance; Respiratory Failure; Respiratory physiology; Route; Site; Sputum; Staphylococcus aureus; Surface; System; Temperature; Testing; Time; Tobramycin; Treatment Efficacy; Treatment Failure; Ventilator; Wild Type Mouse; Work; airway inflammation; antimicrobial; bacterial resistance; bactericide; combat; compliance behavior; cystic fibrosis patients; design; drug candidate; improved; in vivo; in vivo Model; killings; meetings; methicillin resistant Staphylococcus aureus; mouse model; mucoid; novel; particle; pathogen; physical property; pre-clinical; prophylactic; public health relevance; research clinical testing; residence; solid state

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is an autosomal recessive disorder, which leads to the abnormal composition and physical properties of airway secretions in CF patients. Additionally, the lungs of CF patients are particularly susceptible to chronic bacterial infections with >80% of CF patients becoming chronically infected by 18 years of life with mucoid forms of Pseudomonas aeruginosa that over-produce the surface polysaccharide alginate. The long term goal of this project (which is outside the scope of this application) is to investigate the use of gallium nitrate as an anti-infective to treat chronic P. aeruginosa lung infections in CF patients. The major hypothesis to be tested is whether gallium nitrate can be used to reduce P. aeruginosa lung infections and result in improvement in lung function. One key observation of P. aeruginosa infections in CF is that the patients ultimately succumb to bacterial infections despite being on a regiment of antibiotics. It is believed that bacterial resistance is a major reason for treatment failure, allowing the organism to escape elimination by acquired host immune defenses and underlies the progressive decline in lung function. Gallium nitrate was found to be bactericidal in vitro against both Gram- and Gram+ bacteria, particularly against bacteria that are found to chronically colonize the lungs of CF patients, such as P. aeruginosa, Burkholderia cepacia and methycillin-resistant Staphylococcus aureus (MRSA). Galllium was protective against mucoid strains of P. aeruginosa isolated from patients with nosocomial infections. Preliminary data indicate that gallium is effective against bacterial resistant Pa strains as well as recent strains isolated from fresh sputum. In this application, we propose further preclinical development of gallium nitrate and testing the protective activities against acute P. aeruginosa pulmonary infection in wild- type (WT) mice. We will first develop an optimal aerosol formulation using a spray drying process, characterize the aerosol properties, and confirm that lead formulations can be efficiently delivered from conventional, commercially available inhalers. We will perform preclinical testing of optimized aerosol formulation in a mouse inhalation model to assess its residence time and biodistribution, followed by determination of the minimal protective dose in a bacterial challenge study. PUBLIC HEALTH RELEVANCE: The studies proposed in this application are designed to further development of a new anti-infective candidate gallium nitrate to treat chronic Pseudomonas aeruginosa lung infections of CF patients. At present, 80-95% of CF patients ultimately succumb to respiratory failure due to chronic P. aeruginosa infection and airway inflammation.

描述（申请人提供）：囊性纤维化（CF）是一种常染色体隐性遗传疾病，导致CF患者气道分泌物的组成和物理性质异常。此外，CF患者的肺特别易受慢性细菌感染，其中>80%的CF患者在18岁时被粘液形式的铜绿假单胞菌慢性感染，所述粘液形式过度产生表面多糖藻酸盐。本项目的长期目标（超出本申请范围）是研究硝酸镓作为抗感染药治疗CF患者慢性铜绿假单胞菌肺部感染的用途。待检验的主要假设是硝酸镓是否可用于减少铜绿假单胞菌肺部感染并改善肺功能。CF中铜绿假单胞菌感染的一个关键观察结果是，尽管使用了一组抗生素，患者最终还是死于细菌感染。据信，细菌耐药性是治疗失败的主要原因，使生物体逃避获得性宿主免疫防御的消除，并成为肺功能进行性下降的基础。发现硝酸镓在体外对革兰氏和革兰氏+细菌都具有杀菌作用，特别是对发现长期定殖于CF患者肺部的细菌，如铜绿假单胞菌、洋葱伯克霍尔德氏菌和耐甲氧西林金黄色葡萄球菌（MRSA）。五倍子对从医院感染患者中分离的铜绿假单胞菌粘液株具有保护作用。初步数据表明，镓对细菌耐药性Pa菌株以及从新鲜痰中分离的最近菌株有效。在本申请中，我们提出了硝酸镓的进一步临床前开发，并在野生型（WT）小鼠中测试针对急性铜绿假单胞菌肺部感染的保护活性。我们将首先使用喷雾干燥工艺开发一种最佳的气雾剂制剂，表征气雾剂的特性，并确认铅制剂可以有效地从传统的市售吸入器中递送。我们将在小鼠吸入模型中对优化的气雾剂制剂进行临床前试验，以评估其停留时间和生物分布，然后在细菌挑战研究中确定最小保护剂量。公共卫生相关性：本申请中提出的研究旨在进一步开发新的抗感染候选硝酸镓，以治疗CF患者的慢性铜绿假单胞菌肺部感染。目前，80-95%的CF患者最终死于慢性铜绿假单胞菌感染和气道炎症引起的呼吸衰竭。