Aerosol spectinamide-1599 therapy against tuberculosis

摘要 结核病的长期治疗是出现多药耐药的主要原因。 结核病(耐多药结核病)，因为它经常导致不遵守规定。目前耐多药结核病的化疗可以持续 长达两年的多药疗法，其中一些是痛苦的注射药物，与严重的 毒性。根除和控制结核病有赖于开发更短和更有效的治疗方法 药物相关毒性最小的治疗方案。此应用程序中正在研究的一种方法是开发一个 吸入性结核病治疗[替代注射药物]，与口服结核病药物一起使用时，缓解和 缩短治疗时间。雾化给药不同于注射剂，易于管理，并提供高 肺部抗生素浓度增加到局部感染部位，从而降低全身感染水平 接触过这种药物。最近发表在《自然医学》杂志上的一篇文章显示， 新的壮观酰胺类似物对结核分枝杆菌(Mtb)有很好的活性，包括 MDR和XDR Mtb菌株在体外，以及通过皮下注射时在体内也是如此。在 同一项研究表明，先导化合物spectinide-1599在以下情况下对肺结核有很强的疗效 作为液体制剂通过肺内气雾剂(IPA)直接给药到小鼠的肺部。 通过扩展我们在此应用中的初步数据，目标1将确定药物动力学(PK)。 IPA后壮观胺-1599的组织分布。目标2将确定最佳剂量、持续时间和 IPA和Aim3提供的SPECTIAME-1599治疗频率将优化干粉 用于吸入性结核病治疗的壮观胺-1599的配方。这些研究将会得到发展 作为结核病领域专家、结核病吸入性动物模型和临床前研究专家的联盟， 结核病化疗和气雾剂制剂的药代动力学和药效学 干粉位于科罗拉多州立大学、田纳西大学、三角研究所和圣彼得堡大学。 裘德儿童研究医院。这个研究人员联盟通力合作，旨在推动 对这种药物的研究达到了通过壮观-1599吸入疗法可以被认为是一种新的 结核病的药物/治疗候选药物。因此，这些研究将提供一种制剂和吸入疗法。 具有明确的空气动力学和PK性质并在体内具有良好表征的spectinamine-1599 未来在多药联合研究和更大的吸入性动物结核病模型和 最终出现在结核病患者身上。

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.