Iowa Phase II Clinical Trials of Novel Therapies for Lung Diseases (U01

描述（由申请人提供）： 囊性纤维化（CF）的特征是慢性细菌性气道感染伴进行性破坏，导致该病95%的死亡率。由于CF受试者的基因突变导致囊性纤维化跨膜传导调节剂氯离子通道的破坏，导致气道上皮细胞中液体和电解质转运的改变，从而导致粘膜纤毛清除受损，进而导致慢性气道感染。气道疾病的急性和慢性方面都用抗生素和旨在优化粘膜纤毛清除的疗法进行治疗。CF患者的估计中位生存期仍然较低，为36.8年。因此，迫切需要更有效的新疗法。人的呼吸道表面覆盖着一层薄薄的液体，称为气道表面液（ASL），其中含有许多在天然免疫中起重要作用的抗菌肽。ASL的抗菌活性是NaCl（盐）敏感的。降低ASL中的盐浓度，提高其抗微生物活性，并提供预防气道感染的新机制。木糖醇是一种5碳糖，可以降低ASL盐浓度，但不为细菌提供碳源。木糖醇已被证明可以防止龋齿的进展，并降低急性中耳炎的发病率。这些研究提出了一个有趣的可能性：吸入木糖醇可以增强气道抗菌防御，从而减少气道定植和加重。在我们的I期安全性研究中，健康志愿者和稳定的CF受试者对等渗和高渗木糖醇单次给药耐受良好。在根据良好实验室规范进行的2周、2种动物种属研究中，比格犬和大鼠对吸入木糖醇耐受良好。在本申请中，我们提出了II期试验，以测试吸入木糖醇在CF受试者中的安全性和有效性。在一项辅助研究中，我们将在我们最近开发的猪CF模型中评估吸入木糖醇对气道定植和炎症的影响。如果这些研究是成功的，吸入木糖醇有望成为一种廉价和有效的干预，除了CF的几个条件，如非CF支气管扩张，慢性支气管炎和呼吸机相关性肺炎。相关性：囊性纤维化是白种人最常见的遗传性肺病。复发性呼吸道感染导致95%的死亡和短寿命。该项目正在测试一种名为木糖醇的新药物的有效性，该药物有可能减少肺部细菌的生长。将木糖醇作为雾化器吸入肺部可能是预防肺部感染的一种简单而安全的方法。(End摘要）

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is characterized by chronic bacterial airway infection with progressive destruction which contributes to 95% of the mortality from this disease. Disruption of the cystic fibrosis transmembrane conductance regulator chloride channels due to genetic mutations in subjects with CF results in altered fluid and electrolyte transport across the airway epithelium leading to impaired mucociliary clearance which leads to chronic airway infection. Both the acute and chronic aspects of the airway diseased are treated with antibiotics and therapies aimed at optimizing mucociliary clearance. The estimated median survival of CF patients remains low, at 36.8 years. Thus, the need for more effective novel therapies is urgent. Human airways are lined by a thin layer of liquid, airway surface liquid (ASL) that contains many antibacterial peptides which play an important role in innate immunity. The antibacterial activity of ASL is NaCI (salt) sensitive. Lowering the salt concentration in ASL, raises its antimicrobial activity and provide a novel mechanism to prevent airway infection. Xylitol, a 5-carbon sugar, can lower ASL salt concentration without providing a carbon-source for bacteria. Xylitol has been shown to prevent progression of dental caries, and decrease the incidence of acute otitis media. These studies raise an intriguing possibility: inhaled xylitol could enhance airway antibacterial defenses, resulting in a decrease in airway colonization and exacerbations. In our phase 1 safety studies, healthy volunteers and stable subjects with CF tolerated single doses of iso-osmolar and hypertonic xylitol well. In a 2 week, 2 animal species study done under good laboratory practices, beagle dogs and rats tolerated inhaled xylitol well. In this application, we propose phase II trials to test the safety and efficacy of inhaled xylitol in subjects with CF. In an ancillary study, we will evaluate the effect of inhaled xylitol on airway colonization and inflammation in pig CF model that we developed recently. If these studies are successful, inhaled xylitol promises to be a cheap and effective intervention for several conditions in addition to CF, such as non-CF bronchiectasis, chronic bronchitis and ventilator associated pneumonia. RELEVANCE: Cystic fibrosis is the most common genetic lung disease in Caucasians. Recurrent airway infection contribute to 95% of death and short lifespan from this disease. This project is looking to test the effectiveness of a new agent called xylitol that has the potential to decrease bacterial growth in the lungs. Giving xylitol as a nebulizer into the lungs may be a simple and safe way to ward off lung infections. (End of Abstract)