Novel Therapies in Idiopathic Pulmonary Fibrosis

描述（由申请人提供）： 特发性肺纤维化（IPF）患者的生存期短，生活质量差，并且几乎普遍存在疾病的自发进展。 我们建议与志同道合的机构合作，加快对治疗方案的研究步伐，以延长这些患者的生存期，提高生活质量和增加功能能力。 本提案的总体目标是在多中心临床研究网络中评价一种多种药物（N-乙酰半胱氨酸[NAC]、克拉霉素和普伐他汀）和一种新型疗法（前列腺素12 [PG 12]、前列环素或其类似物）治疗IPF的疗效。 我们的主要终点将是确定这些方法中的一种或两种是否延迟至死亡或FVC下降的时间。 我们的次要终点将是确定这些方法是否改善生活质量，增加功能状态或延迟肺功能丧失。 探索性终点将确定在这些治疗中计划外门诊访视或住院的减少，并有利地改变疾病活动的拟定生物标志物。 我们的假设是NAC、克拉霉素和副伐他汀将对疾病活动的三个部位（异常肺泡上皮、淋巴浆细胞性炎症和间质肌成纤维细胞的持续存在）具有有利的生物学和临床作用。 我们假设PG 12将阻断成纤维细胞向肌成纤维细胞的分化，从而延迟或阻止纤维化的进展。 次要目的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用作生物测定以监测生物疾病活性。 我们的假设是BAL液中的活性TGF-β是这种活性的原因，并且可以通过PG 12治疗有利地改变。 (End摘要）

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)