Inhaled Caprazamycin for Tuberculolsis Therapy

描述(申请人提供)：结核病仍然是一种严重的全球传染病，每年造成至少200万人死亡。可以说，耐多药结核病的发病率构成了21世纪最重大的公共卫生威胁。CPZEN-45是卡普扎霉素的一种衍生物，已被结核病治疗界的领导人确定为具有巨大的疾病治疗潜力。在过去的30年里，开发的新药很少，而且还没有一种上市。CPZEN-45按常规给药途径生物利用度较低。此前，我们已经证明了几种药物在雾化吸入肺部后具有活性的潜力。非常低的剂量(几十个5g/kg)给豚鼠肺部，可显著减少细菌的负担。这种方法将在不增加毒性的情况下补充药物组合的护理标准。卷曲霉素的给药剂量更高(mg/kg)，而且比肌注给药更有效。这种药物有可能在目前的耐多药结核病治疗标准中补充或取代卷曲霉素IM(基于达到全身最低抑菌浓度)。据推测，将卡普扎霉素衍生物(CPZEN-45)直接局部注射到受感染的豚鼠肺部将导致足够高的局部浓度，从而迅速消除细菌种群，并有可能对肺部进行消毒。证明这一效应的意义可能是通过增加目前的治疗方法来缩短治愈耐药结核病所需的化疗持续时间。CPZEN喷雾干燥制剂将制备成适合气雾剂输送的颗粒尺寸。(A)吸入CPZEN的药代动力学和药效学将在小剂量感染的豚鼠模型中进行评估。了解(A)喷雾剂给药后药物的分布(局部和全身)以及(B)其对减少代表局部和全身区域的不同器官中细菌负担的影响，是提出人类应用的先决条件。

DESCRIPTION (provided by applicant): Tuberculosis remains a serious global infectious disease responsible for at least 2 million deaths per year. The incidence of multiple drug resistant tuberculosis arguably poses the most significant public health threat for the twenty first century. CPZEN-45 is a derivative of caprazamycin which has been identified by leaders in the tuberculosis treatment community as having great potential for disease therapy. There have been very few new drugs developed in the last 30 years and none have yet come to market. CPZEN-45 is poorly bioavailable by the conventional routes of administration. Previously, we have demonstrated the potential for several drugs to be active following aerosol administration to the lungs. Very low doses (tens of 5g/kg) delivered to the lungs of guinea pigs resulted in a significant reduction in the burden of bacteria. This approach would supplement the standard of care for drug combinations without increasing toxicity. Capreomycin has been delivered in higher doses (mg/kg) and is more potent than delivered by the IM route. This drug has the potential to supplement or replace (based on achieving systemic MIC levels) capreomycin IM in the current standard of care for MDR-TB. It is postulated that direct, topical delivery of the caprazamycin derivative (CPZEN-45) to the lungs of infected guinea pigs will result in sufficiently high local concentrations to quickly eradicate bacterial populations and potentially sterilize the lungs. The implications of demonstrating this effect may be to reduce the duration of chemotherapy necessary to achieve a cure in drug resistant tuberculosis by ADDING to the current therapy. Spray dried CPZEN formulations will be prepared in particle sizes suitable for aerosol delivery. (a) Pharmacokinetics and (b) pharmacodynamics of inhaled CPZEN will be assessed in the low dose infected guinea pig model. Understanding (a) the distribution (local and systemic) of drug following aerosol administration and (b) its effect on reducing the burden of bacteria in various organs representing local and systemic regions is a prerequisite for proposing a human application.