Nintedanib in IPF: Post hoc Analysis of the Italian FIBRONET Observational Study.

BACKGROUND: The FIBRONET study was an observational study of patients with idiopathic pulmonary fibrosis (IPF) in Italy. OBJECTIVES: In this post hoc descriptive analysis, we describe changes in lung function, anxiety/depression, coughing, exacerbations, and adverse events (AEs) in patients receiving nintedanib treatment. METHODS: Patients with IPF from 20 centers in Italy, aged ≥40 years who received nintedanib for ≥7 months, were followed up for 12 months from study enrollment, attending clinic visits every 3 months. Outcomes included change in forced vital capacity (FVC)% predicted from baseline to 12 months, anxiety/depression measured by the Hospital Anxiety and Depression Scale (HADS), and the proportion of patients with cough, AEs, and exacerbations. RESULTS: In total, 52 patients received nintedanib (mean duration of 11.6 months). Ten patients had dose reductions from 150 mg to 100 mg twice daily, due to AEs. FVC% predicted was unchanged in the overall nintedanib population (78.7% at baseline; 79.8% at 12 months) and those with a reduced dose (77.7% at baseline; 81.0% at 12 months). HADS score was low at baseline and throughout the study. The proportion of patients with cough decreased from 50.0% to 21.2% over 12 months. Two patients experienced exacerbations, 2 patients discontinued treatment, and 27 (51.9%) reported AEs. The most common AE was diarrhea (34.6%). CONCLUSIONS: In patients with IPF who received nintedanib in the FIBRONET study, FVC% predicted was stable over 12 months, and the proportion of patients with cough decreased. The safety profile was consistent with the known safety profile for nintedanib in IPF.

Effects of ambrisentan in a patient affected by combined pulmonary fibrosis and emphysema and by severe pulmonary hypertension: clinical, functional, and biomolecular findings.

Combined pulmonary fibrosis and emphysema (CPFE) is a computed tomography (CT)-defined syndrome of combined pulmonary fibrosis and emphysema, characterized by subnormal spirometry, impairment of gas exchange, and high prevalence of pulmonary hypertension. Although endothelin-1 (ET-1) plays an important role in the development of lung fibrosis as well as in pulmonary hypertension, no ET-1-targeted therapy is currently recommended. Here we report a case of CPFE successfully treated with ambrisentan, an endothelin-A receptor antagonist, and also discuss the biologic mechanisms underlying the observed therapeutic effects. A 79-year-old man with chronic obstructive pulmonary disease (COPD) was referred to our respiratory unit as an outpatient for dyspnea. Clinical, radiologic, and laboratory findings suggested a diagnosis of chronic hypoxemic, type 1 respiratory failure, due to combined pulmonary fibrosis and emphysema, complicated by severe, precapillary pulmonary hypertension. Pharmacologic treatment with ambrisentan induced an initial improvement in clinical symptoms that proved to be very relevant 9 months later. In order to investigate the biologic mechanisms underlying the clinical effects of ambrisentan, we performed an "in vitro" study on primary cultures of fibrotic human lung fibroblasts, as well as on human umbilical vein endothelial cells, incubated for 24 and 48 h with ET-1, in the absence or presence of an overnight treatment with ambrisentan. ET-1 significantly increased cell proliferation and mitogen-activated protein kinase activation (P < 0.01). These effects were significantly (P < 0.01) inhibited by ambrisentan in both cell cultures. In conclusion, we hypothesize that the clinical benefits induced by ambrisentan in this patient with CPFE can be attributed to its vasodilator and anti-proliferative actions, exerted on pulmonary the vascular bed and lung fibroblasts.