Pyrazinamide Breath Test for TB

吡嗪酰胺呼气试验检测结核病

• 批准号: 8870819
• 负责人: GRAHAM S TIMMINS
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-05 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870819
• 关键词: Amides; Ammonia; Antimycobacterial Agents; Biochemical; Breath Tests; Breathing; Clinical; Clinical Trials; Data; Detection; Development; Disease Resistance; Drug resistance; Drug-sensitive; Effectiveness; Enzymes; Exhalation; Gases; Human; In Vitro; Inhalators; Label; Lung; Modeling; Mus; Mutation; Mycobacterium tuberculosis; Nebulizer; Oral; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Predisposition; Prodrugs; Production; Pyrazinamide; Pyrazinamide resistance; Reporting; Resistance; Route; Staging; Testing; Time; Translational Research; Tuberculosis; Visit; Work; in vivo; mouse model; mycobacterial; point of care; pre-clinical; public health relevance; pyrazinamide deamidase; pyrazinoic acid; stable isotope

 DESCRIPTION (provided by applicant): Pyrazinamide (PZA) is a critical drug for treating tuberculosis (TB) because of its potent sterilizing activity. PZA is a prodrug, activated by pyrazinamidase to the antimycobacterial product pyrazinoic acid (POA) and ammonia. Resistance against PZA is dominated by mutations in pncA that decrease PZA activation. PZA resistance is becoming of great concern because it is so important in therapy, resistance is increasing and conventional resistance detection is difficult and slow in practice. We propose a rapid, robust, simple and point-of-care (POC) approach that delivers biochemical PZA resistance data during the time of a typical patient-doctor visit. Stable isotope 15N-amide labeled PZA is directly delivered to the lung by inhaler or nebulizer. Mycobacterial pyrazinamidase then converts it to POA and 15N-ammonia that is then exhaled and detected in breath. We will perform in vitro and in vivo studies to characterize and validate this approach.

 描述（由申请人提供）：吡嗪酰胺（PZA）是治疗结核病（TB）的关键药物，因为PZA是一种前药，由吡嗪酰胺酶激活，产生抗分枝杆菌产物吡嗪酸（POA）和氨。 PZA 主要由 pncA 突变控制，降低 PZA 的激活变得越来越重要。之所以引起关注，是因为它在治疗中非常重要，但耐药性不断增加，而传统的耐药性检测在实践中既困难又缓慢，我们提出了一种快速、稳健、简单的即时护理 (POC) 方法，可在此期间提供生化 PZA 耐药性数据。典型的患者-医生就诊过程中，稳定同位素 15N-酰胺标记的 PZA 通过吸入器或雾化器直接输送到肺部，然后将其转化为 POA 和然后呼出并在呼吸中检测到 15N-氨。我们将进行体外和体内研究来表征和验证这种方法。