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      Nintedanib Treatment for Idiopathic Pulmonary Fibrosis Patients Who Have Been Switched from Pirfenidone Therapy: A Retrospective Case Series Study

      brief-report

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          Abstract

          Background: The efficacy and effectiveness of nintedanib as a first-line therapy in idiopathic pulmonary fibrosis (IPF) patients have been demonstrated by clinical trials and real-life studies. Our aim was to examine the safety profile and effectiveness of nintedanib when it is utilized as a second-line treatment in subjects who have discontinued pirfenidone. Methods: The medical charts of 12 patients who were switched from pirfenidone to nintedanib were examined retrospectively. The drug’s safety was defined by the number of adverse events (AEs) that were reported; disease progression was evaluated based on the patient’s vital status and changes in forced vital capacity (FVC) at 12-month follow-up. Results: The numbers of patients experiencing AEs and of the AEs per patient in our study group didn’t significantly differ with respect to a group of 56 individuals who were taking nintedanib as a first-line therapy during the study period (5/12 vs. 22/56; p = 0.9999, and 0.00 (0.00–1.00) vs. 0.00 (0.00–3.00); p = 0.517, respectively). Two out of the 3 patients who had been switched to nintedanib due to a rapid disease progression showed stabilized FVC values. Conclusions: Nintedanib was found to have an acceptable safety profile in the majority of the IPF patients switched from pirfenidone. Prospective studies are warranted to determine if the drug can effectively delay disease progression in these patients.

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          BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.

          Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.
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            Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study

            Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause characterised by progressive fibrotic formation in lung tissue. We hypothesise that disrupted metabolic pathways in IPF contribute to disease pathogenesis. Methods Metabolomics of human IPF was performed using mass spectroscopy (IPF lung=8; donor lung=8). Gene expression of key metabolic enzymes was measured using microarrays. Of the 108 metabolites whose levels were found altered, 48 were significantly increased, whereas 60 were significantly decreased in IPF samples compared with normal controls. Results Specific metabolic pathways mediating the IPF remodelling were found with a downregulated sphingolipid metabolic pathway but an upregulated arginine pathway in IPF. In addition, disrupted glycolysis, mitochondrial beta-oxidation and tricarboxylic acid cycle, altered bile acid, haem and glutamate/aspartate metabolism were found in IPF samples compared with control. Conclusions Our results show alterations in metabolic pathways for energy consumption during lung structural remodelling, which may contribute to IPF pathogenesis. We believe that this is the first report of simultaneously and systemically measuring changes of metabolites involving nine metabolic pathways in human severe IPF lungs. The measurement of the metabolites may serve in the future diagnosis and prognosis of IPF.
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              Real-World Experience with Nintedanib in Patients with Idiopathic Pulmonary Fibrosis

              Background Nintedanib, an oral tyrosine kinase inhibitor, has been shown to slow down the progression of idiopathic pulmonary fibrosis (IPF) in two randomised placebo-controlled trials by reducing the annual decline in forced vital capacity (FVC). However, real-world experience is limited. Objective To assess the efficacy and safety of nintedanib in a large cohort of patients treated at a tertiary referral site for interstitial lung diseases. Methods The records of patients with a confirmed diagnosis of IPF were reviewed. Full medical history, pulmonary function, and adverse events (AEs) were recorded from each clinic visit. Disease progression was defined as a reduction in FVC ≥5% and/or in diffusing capacity of the lung for carbon monoxide ≥15% according to recent publications. Only patients with a treatment duration ≥3 months were included in the efficacy evaluation. Results A total of 64 patients were treated. Mean ± standard deviation (SD) FVC was 71 ± 21% predicted, and the mean time from diagnosis to initiation of nintedanib treatment was 23.8 months. Nearly half of patients ( n = 30, 47%) had received prior pirfenidone treatment. The mean duration of follow-up was 11 months. At 6 months following initiation of nintedanib, 67% of the patients were stable. The mean ± SD change in percent predicted FVC from baseline was 0.2 ± 7.8% at 3 months, −1.3 ± 7.9% at 6 months, and −2.1 ± 9% at 9 months. Diarrhoea was the most common AE experienced by 33% of patients and was generally manageable. Conclusion The results from this real-world clinical setting support findings from previously conducted clinical trials and show that nintedanib is effective for the management of IPF and is associated with disease stabilisation. Nintedanib is generally well tolerated.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                04 February 2020
                February 2020
                : 9
                : 2
                : 422
                Affiliations
                [1 ]Respiratory Pathophysiology Unit, Department of Cardiological, Thoracic and Vascular Sciences, University of Padova, 35128 Padova, Italy; beatrice.molena@ 123456unipd.it (B.M.); fausto.braccioni@ 123456aopd.veneto.it (F.B.); andi.sukthi@ 123456aopd.veneto.it (A.S.)
                [2 ]Pneumology Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; francesco.salton@ 123456asuits.sanita.fvg.it (F.S.); marialaura.gr@ 123456libero.it (M.L.G.); marco.confalonieri@ 123456asuits.sanita.fvg.it (M.C.)
                [3 ]Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; cristianturato@ 123456gmail.com
                [4 ]Pneumology Unit, Arco General Hospital, APSS Trento, 38062 Arco, Italy; valeria.frassani@ 123456apss.tn.it
                [5 ]Pneumology Unit, Trento General Hospital, Trento, APSS Trento, 38121 Trento, Italy; dino.sella@ 123456apss.tn.it
                [6 ]Pulmonology Unit, AS Bolzano, 39100 Bolzano, Italy; paolo.pretto@ 123456asbz.it
                Author notes
                [* ]Correspondence: andrea.vianello@ 123456aopd.veneto.it ; Tel.: +39-049-8218587; Fax: +39-049-8218590
                Author information
                https://orcid.org/0000-0002-8790-6029
                https://orcid.org/0000-0001-7086-0792
                Article
                jcm-09-00422
                10.3390/jcm9020422
                7074103
                32033147
                a48f68d6-869a-4186-9fc1-3a6427a1fe68
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 January 2020
                : 03 February 2020
                Categories
                Brief Report

                idiopathic pulmonary fibrosis,pirfenidone,nintedanib,adverse event,forced vital capacity

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