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.

由鸟分枝杆菌复合体引起的非结核分枝杆菌肺病（NTM-LD）是一种严重的疾病慢性感染会导致永久性肺损伤，并且很难治疗，通常需要 12-24 个月的治疗用利福平、大环内酯和乙胺丁醇治疗。我们已经发现，氘代氨溴索和 [acyl-13C]INH 的组合将允许药代动力学增强 Rif 抗 MAC 活性的药效学，可显着改善治疗效果。检验这个假设，我们提出这些目标。具体目标 1. 确定氘代氨溴索和对照对 Cyp3A4 代谢的耐药性我们将使用行业标准 Corning® Cyp3A4 Supersomes™ 来确定使用 HPLC、MS 和 13C-NMR 检测评估氨溴索-d2 的体外代谢。具体目标 2. 通过联合治疗量化利福平、[acyl-13C]INH 和氨溴索-d2 的疗效在慢性小鼠气溶胶感染模型中对鸟分枝杆菌临床分离株的活性。该模型还将评估联合治疗穿透已建立的肉芽肿的能力，以及进入内化杆菌。在第一阶段 STTR 项目结束时，我们将确定氘化是否可以解决 Cyp3A4 Amb 的代谢能力，以及氨溴索-d2 和 [acyl-13C]INH 单独和组合是否可以增强在高度预测的小鼠模型中进行 MAC 治疗，为第二阶段提案奠定了基础。