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

描述(由申请人提供)： 囊性纤维化是以慢性细菌性呼吸道感染为特征的渐进性破坏，占该病死亡率的95%。囊性纤维化跨膜电导调节氯离子通道的破坏是由于慢性阻塞性肺疾病患者的基因突变所致，导致液体和电解质在呼吸道上皮细胞的转运改变，导致粘液纤毛清除受损，从而导致慢性呼吸道感染。呼吸道疾病的急性和慢性方面都使用抗生素和旨在优化粘液纤毛清除的治疗方法进行治疗。CF患者的估计中位生存期仍然很低，为36.8年。因此，迫切需要更有效的新疗法。人类呼吸道内有一层薄薄的液体，即呼吸道表面液体(ASL)，其中含有许多在先天免疫中起重要作用的抗菌肽。ASL的抗菌活性对NaCI(盐)敏感。降低ASL中的盐浓度，提高其抗菌活性，为预防呼吸道感染提供了一种新的机制。木糖醇是一种5碳糖，可以在不为细菌提供碳源的情况下降低ASL盐的浓度。木糖醇已被证明可以预防龋齿的进展，并降低急性中耳炎的发生率。这些研究提出了一种耐人寻味的可能性：吸入木糖醇可以增强呼吸道抗菌防御，从而减少呼吸道定植和恶化。在我们的第一阶段安全性研究中，健康志愿者和患有CF的稳定受试者对单剂等渗木糖醇和高渗木糖醇耐受性良好。在2周内，2种动物在良好的实验室做法下进行了研究，比格犬和大鼠对吸入木糖醇的耐受性良好。在这一应用中，我们建议进行第二阶段试验，以测试吸入木糖醇对CF患者的安全性和有效性。在一项辅助研究中，我们将评估吸入木糖醇对我们最近建立的猪CF模型的呼吸道定植和炎症的影响。如果这些研究成功，吸入木糖醇有望成为治疗非慢性支气管炎、慢性支气管炎和呼吸机相关性肺炎等多种慢性支气管炎的廉价而有效的干预手段。相关性：囊性纤维化是高加索人最常见的遗传性肺部疾病。反复的呼吸道感染导致了该病95%的死亡和短寿命。该项目正在测试一种名为木糖醇的新制剂的有效性，这种制剂有可能减少肺部细菌的生长。将木糖醇作为雾化器注入肺部可能是预防肺部感染的一种简单而安全的方法。(摘要结束)

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)