Rifampin potentiation in NTM

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 慢性感染导致永久性肺损伤，并且难以治疗，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。 我们假设，联合使用氘代氨溴索和[酰基-13 C]INH将使药代动力学 和药效学增强Rif对MAC的活性以显著改善治疗。到 为了验证这个假设，我们提出了这些目标。 具体目标1。测定氘代氨溴索和对照品对Cyp 3A 4代谢的抗性 使用超体我们将使用行业标准Corning® Cyp 3A 4 Supersomes™来确定 使用HPLC、MS和13 C-NMR测定法进行氨溴索-d2体外代谢。 具体目标2。定量利福平、[酰基-13 C]INH和氨溴索-d2联合治疗的疗效 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形成的肉芽肿的能力， 获取内化的杆菌 在第一阶段STTR项目结束时，我们将确定氘代是否可以解决Cyp 3A 4问题。 Amb的代谢倾向，以及氨溴索-d2和[酰基-13 C]INH单独或联合使用是否可以增强 MAC治疗在高度预测性小鼠模型中进行，为第2阶段提案奠定了基础。

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.