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Aerosol spectinamide-1599 therapy against tuberculosis

Aerosol spectinamide-1599 therapy against tuberculosis
壮观酰胺-1599气雾剂治疗结核病
批准号:
9196248
负责人:
Miriam S. Braunstein
金额:
$62.99万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-06-10 至 2021-05-31

项目摘要

项目成果

Miriam S. Braunstein的其他基金

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中文摘要
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英文摘要
Summary The lengthy treatment for tuberculosis (TB) is the primary cause of the emergence of multidrug resistant tuberculosis (MDR-TB), as it frequently results in non-compliance. Current chemotherapy for MDR-TB can last up to two years with multidrug regimens some of which are painful injectable drugs with serious associated toxicity. Eradication and control of TB depends on the development of shorter and more effective treatment regimens with minimal drug associated toxicity. One approach under study in this application is to develop an inhalational TB therapy [to replace injectable drugs] that when administered with oral TB drugs eases and shortens treatment. Aerosolized drug delivery unlike injectable agents is easy to administer and provides high pulmonary concentrations of antibiotics to the local site of infection thereby reducing the systemic level of exposure to the drug. A recently published article in Nature Medicine by the “spectinamide consortium” showed that novel spectinamide analogs have excellent activity against Mycobacterium tuberculosis (Mtb) including MDR and XDR Mtb strains in vitro, as well as in vivo when administered by subcutaneous injection. In the same study, the lead compound spectinamide-1599 demonstrated strong efficacy against pulmonary TB when administered as a liquid formulation directly to the lungs of mice via intrapulmonary aerosol (IPA) delivery. By expanding on our preliminary data in this application Aim 1 will determine the pharmacokinetics (PK) and tissue distribution of spectinamide-1599 after IPA. Aim 2 will determine optimal dose, duration and frequency for treatment with spectinamide-1599 delivered by IPA and Aim3 will optimize a dry powder formulation of spectinamide-1599 to be used as inhalational TB therapy. These studies will be developed as a consortium between experts in the field of TB, inhalational animal models of TB and preclinical studies, pharmacokinetics and pharmacodynamics of TB chemotherapy and aerosol formulations and formulation of dry powders located at Colorado State University, University of Tennessee, Research Triangle Institute and St. Jude Children's Research Hospital. Working all together this consortium of researchers aims to advance research for this drug to the level that inhalational therapy via spectinamide-1599 can be considered a new drug/therapy candidate for TB. Thus, these studies will provide a formulation and inhalational therapy regimen of the spectinamide-1599 with well defined aerodynamic and PK properties and of well characterized in vivo efficacy for future testing in multidrug combination studies and in larger inhalational animal TB models and ultimately in TB patients.
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