Treatment of NTM Respiratory Infections with Inhaled Drug Delivery

项目概要/摘要（描述） 重要性：非结核分枝杆菌（NTM）呼吸道感染正在增加， 地球仪。在美国，在65岁以上的人群中， 1997 - 2007年间，从20例/100，000显著增加到47例/100，000，其中夏威夷的 最高流行率为396例/100 000。肺NTM是1.4倍更常见， 妇女这些数字可能被低估，因为缺乏强制性报告， 美国对非结核分枝杆菌肺病的治疗对一些人来说是具有挑战性的， 原因包括对现有药物的相对耐药性和 耐受多种药物的长期治疗。唯一具有可靠活性的口服药物 分支杆菌NTM的主要药物是大环内酯类和氯法齐明。者类似为 M.发现氯法齐明与克拉霉素或阿米卡星协同作用， M.氯法齐明是一种有吸引力的药物，用于治疗NTM呼吸道感染 包括m.高口服剂量引起的皮肤和内脏蓄积 会导致严重的毒性。需要高口服剂量以达到有效浓度， 肺吸入剂量的氯法齐明有可能达到立即治疗 吸入低剂量时，肺中的浓度不会产生显著的全身毒性。 初步数据：Aerophase最近证明， 氯法齐明与一种新型的气雾剂药物吸入器可以治疗肺结核呼吸道感染， 全身毒性的副作用。新的氯法齐明制剂和气雾剂装置具有 证明了持续的肺部治疗浓度和气雾剂大小范围， 用氯法齐明靶向整个肺甚至肺泡区域。气相吸入气雾剂 递送方法具有减轻毒性并允许安全的氯法齐明的巨大希望 直接针对感染部位给药。 具体目标：该项目的第一个目标是治疗NTM呼吸道感染， 氯法齐明比口服氯法齐明更有效，吸入剂量低得多。 第二个目的是开发一种具有药物制剂的小型口袋尺寸的计量剂量吸入器， 气雾剂大小和剂量优化，以治疗NTM呼吸道感染。 第三个目的是测试吸入氯法齐明与其他药物组合的体内功效。

Project Summary/Abstract (Description) Significance: Non-tuberculous mycobacteria (NTM) respiratory infections is increasing across the globe. In the US, in those over 65 years-old, annual prevalence of pulmonary NTM disease increased significantly from 20 to 47 cases/100,000 between 1997-2007 with Hawaii having the highest prevalence at 396 cases/100,000. Pulmonary NTM is 1.4 times more common in women. These numbers are likely underestimated because of a lack of mandatory reporting in the U.S. Treatment of non-tuberculous mycobacterial lung disease is challenging for several reasons including the relative resistance to currently available drugs and the difficulty in tolerating prolonged treatment with multiple drugs. The only oral drugs with reliable activity against M. abscessus complex an NTM are the macrolides and clofazimine. Similar to that for M. avium complex, clofazimine was found to synergize with clarithromycin or amikacin against M. abscessus Clofazimine is an attractive agent for treatment of NTM respiratory infections including M. abscessus but cutaneous and internal organ accumulation from high oral doses cause significant toxicity. High oral doses are required to reach effective concentrations in the lungs. Inhaled doses of clofazimine have the potential to reach immediate treatment concentrations in the lungs with inhaled low doses that do not have significant systemic toxicity. Preliminary Data: Aerophase has recently demonstrated that innovative aerosol formulations of clofazimine with a new type of aerosol drug inhaler can treat TB respiratory infections without side effects from systemic toxicity. The new clofazimine formulation and aerosol device has demonstrated sustained pulmonary treatment concentration and an aerosol size range that can target the entire lung with clofazimine even alveolar regions. The Aerophase inhaled aerosol delivery method holds great promise to mitigate toxicity and allow for safe clofazimine administration directly targeted to the site of infection. Specific Aims: The first aim of this project is to treat NTM respiratory infections with inhaled clofazimine much more effectively than oral clofazimine with much lower inhaled dose. The second aim is to develop a small pocket sized metered dose inhaler with drug formulation, aerosol size, and dose optimized to treat NTM respiratory infections. The third aim will test in-vivo efficacy of inhaled clofazimine in combination with other drugs.