Rifampin potentiation in NTM

利福平在 NTM 中的增强作用

基本信息

批准号：
9908969
负责人：
GRAHAM S TIMMINS
金额：
$ 20.53万
依托单位：
SPINCEUTICA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-19 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908969
关键词：
Aerosols Affect Age-Years Amikacin Antibiotics Autophagocytosis Bacillus Biological Assay CYP3A4 gene Cell Wall Chemicals Chemosensitization Chronic Clinical Development Disease Dose Drug Interactions Drug Kinetics Drug resistance Ethambutol Granuloma Guidelines High Pressure Liquid Chromatography Human Hydrophobicity In Vitro Industry Standard Infection Inhalation Lung diseases Macrolides Medicine Metabolic Metabolism Modeling Mus Mycobacterium avium Mycobacterium avium Complex Organism Outcome Patients Pharmaceutical Preparations Pharmacodynamics Phase Production Protocols documentation Publishing Rattus Refractory Disease Regimen Reporting Resistance Rifampin Rodent Small Business Technology Transfer Research Sputum Structure of parenchyma of lung Testing Toxic effect Tuberculosis Work amikacin liposome chronic infection course development design dosage drug development improved in vivo isoniazid lung injury mortality mouse model mycolate non-tuberculosis mycobacteria pharmacokinetics and pharmacodynamics programs stable isotope tuberculosis treatment

项目摘要

Non-tuberculous mycobacterial lung disease (NTM-LD) caused by Mycobacterium avium complex is a serious chronic infection causing permanent lung damage, and is difficult to treat, typically requiring 12-24 months of treatment with rifampin, macrolide and ethambutol. We hypothesize that combined deuterated ambroxol and [acyl-13C]INH will allow both pharmacokinetic and pharmacodynamic enhancement of Rif activity against MAC to dramatically improve therapy. To test this hypothesis we propose these aims. Specific Aim 1. Determine the resistance of deuterated ambroxol and controls to Cyp3A4 metabolism using Supersomes. We will use industry standard Corning® Cyp3A4 Supersomes™ to determine resistance of ambroxol-d2 to in vitro metabolism using HPLC, MS and 13C-NMR assays. Specific Aim 2. Quantify rifampin, [acyl-13C]INH and ambroxol-d2 efficacy by combination treatment activity against a clinical isolate of Mycobacterium avium in a chronic mouse aerosol infection model. The model will also evaluate the ability of a combination treatment to penetrate the established granuloma and access the internalized bacilli. At the end of this Phase 1 STTR project we will have determined whether deuteration can solve the Cyp3A4 metabolic liability of Amb, and whether ambroxol-d2 and [acyl-13C]INH, separately and combined can potentiate MAC treatment in in a highly predictive mouse model, setting the stage for Phase 2 proposal.

由分枝杆菌复合物引起的无结核分枝杆菌肺疾病（NTM-LD）是一个严重的慢性感染会导致永久性肺损伤，并且难以治疗，通常需要12-24个月利福平，大环内酯类和乙酰丁醇治疗。我们假设合并的氘化ambroxol和[Acyl-13c] INH将允许两种药代动力学 RIF活性对MAC的药效学增强，以显着改善治疗。到检验这个假设，我们提出了这些目标。具体目的1。确定氘化的ambroxol和对照对CYP3A4代谢的抗性使用超级体。我们将使用行业标准Corning®COP3A4SuperSomes™来确定使用HPLC，MS和13C-NMR测定法对体外代谢进行Ambroxol-D2。特定目的2。量化利福平，[酰基-13c] INH和Ambroxol-d2通过联合处理效率在慢性小鼠气溶胶感染模型中，对鸟分枝杆菌的临床分离物的活性。该模型还将评估联合处理能够穿透已建立的肉芽瘤和访问内在的细菌。在此阶段1 sttr项目的结束时，我们将确定侵占是否可以解决CYP3A4 AMB的代谢责任以及Ambroxol-D2和[Acyl-13c] INH是否分别且合并可以潜在 MAC在高度预测的小鼠模型中进行的MAC处理，为2阶段提案奠定了基础。