Novel Therapies in Idiopathic Pulmonary Fibrosis

描述(由申请人提供)： 特发性肺纤维化(IPF)患者生存时间短，生活质量差，疾病的自发性进展几乎是普遍的。我们建议与志同道合的机构合作，加快对治疗方案的调查步伐，以延长这些患者的生存期，改善生活质量，并增加功能能力。 这项建议的总体目标是在多中心临床研究网络中评估一种多药(N-乙酰半胱氨酸[NAC]、克拉霉素和普伐他汀)和一种新疗法(前列腺素12[PG12]、前列环素或其类似物)治疗IPF的疗效。我们的主要目的将是确定这两种方法中的一种或两种方法是否会延缓FVC的死亡或下降时间。我们的次要目标将是确定这些方法是改善生活质量，增加功能状态，还是延缓肺功能的丧失。探索性终点将是在这些治疗中确定计划外就诊或住院的减少，并有利地改变所提出的疾病活动的生物标志物。我们的假设是，NAC、克拉霉素和帕伐他汀对疾病活动性、肺泡上皮异常、淋巴浆细胞性炎症和间质肌成纤维细胞持续存在这三个部位具有良好的生物学和临床效果。我们假设PG12将阻止成纤维细胞向肌成纤维细胞的分化，从而延缓或阻止纤维化的进展。 第二个目标将是确定支气管肺泡灌洗液将成纤维细胞转化为肌成纤维细胞的能力是否可以用作监测生物疾病活动的生物测定。我们的假设是，BAL液中活跃的转化生长因子-β是这种活性的原因，并且可以被PG12治疗有利地改变。(摘要结束)

DESCRIPTION (provided by applicant): The survival of patients with idiopathic pulmonary fibrosis (IPF) is short, their quality of life is poor, and spontaneous progression of their disease is almost universal. We propose to collaborate with like-minded institutions to increase the pace of investigation into treatment options with a goal of prolonging survival, improving quality of life, and increasing functional capacity in these patients. The overall objective in this proposal is to evaluate, in a multicentered clinical research network, the efficacy of one multi-drug (N-acetyl cysteine [NAC], clarithromycin, and pravastatin) and a novel therapy (prostaglandin 12 [PG12], prostacyclin or its analogues) in the treatment of IPF. Our primary endpoint will be to determine if one or both of these approaches delays the time to death or decline in FVC. Our secondary endpoints will be to determine if these approaches improve quality of life, increase functional status, or delay loss of lung function. Exploratory endpoints will be to determine in these therapies decrease in unplanned clinic visits or hospitalizations and favorably alter proposed biologic markers of disease activity. Our hypothesis is that NAC, clarithromycin, and paravastatin will have favorable biologic and clinical effects on three sites of disease activity, abnormal alveolar epithelium, lymphoplasmacytic inflammation, and persistence of interstitial myofibroblasts. We hypothesize that PG12 will block the differentiation of fibroblasts into myofibroblasts thereby delaying or preventing the progression of fibrosis. A secondary objective will be to determine if the ability of bronchoalveolar lavage fluid to convert fibroblasts to myofibroblasts can be used as a bioassay to monitor biologic disease activity. Our hypothesis is that active TGF-beta in BAL fluid is responsible for this activity and can be favorably altered by PG12 therapy. (End of Abstract)