New treatment directions for IPF: current status of ongoing and upcoming clinical trials

Montorsi, Francesco; Varone, Francesco; Leone, Paolo Maria; Mari, Pier‐Valerio; Panico, Loredana; Berardini, Ludovica; Richeldi, Luca

doi:10.1080/17476348.2017.1335601

Cited by 14 publications

(15 citation statements)

References 111 publications

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“…The discovery of effective pharmacotherapies strongly encouraged the research for new drugs, and many different molecules are currently investigated in the context of phase I and phase II clinical trials [ 162 ]. Further researches are also focused on combination trials with the existing antifibrotic agents [ 163 ] and their use in progressive fibrosing pneumonias other than IPF. Nevertheless, patients with IPF daily struggle against a variety of symptoms like chronic cough and shortness of breath, and are frequently affected by several comorbidities that should be systematically identified and addressed.…”

Section: Discussionmentioning

confidence: 99%

Idiopathic pulmonary fibrosis: pathogenesis and management

et al. 2018

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open.Main bodyOver the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy.Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities.ConclusionsBuilding on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

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Section: Discussionmentioning

confidence: 99%

Idiopathic pulmonary fibrosis: pathogenesis and management

et al. 2018

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“…Pirfenidone is a pyridine molecule whose exact target is still unknown, which demonstrated pleiotropic anti‐fibrotic, anti‐inflammatory, and anti‐oxidant properties in pre‐clinical models . Several molecules are now facing phase I and II studies, and various combination regimens are currently being tested for the treatment of IPF . Notably, one of these studies is exploring the efficacy on quality of life of a combination of nintedanib and sildenafil in advanced IPF patients (NCT02802345).…”

Section: Idiopathic Pulmonary Fibrosismentioning

confidence: 99%

“…35 Several molecules are now facing phase I and II studies, and various combination regimens are currently being tested for the treatment of IPF. 36 Notably, one of these studies is exploring the efficacy on quality of life of a combination of nintedanib and sildenafil in advanced IPF patients (NCT02802345). Sildenafil is a selective inhibitor of phosphodiesterase type 5 that acts as a vasodilator of pulmonary vessels, and is currently used in pulmonary arterial hypertension.…”

Section: Pulmonary Fibrosis Ipf Systemic Inflammationmentioning

confidence: 99%

Treating heart failure with preserved ejection fraction: learning from pulmonary fibrosis

Graziani

Varone

Crea

et al. 2018

European J of Heart Fail

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Heart failure with preserved ejection fraction (HFpEF) has a poor prognosis, and an effective treatment is currently lacking. Increasing evidence suggests a prevailing pathogenic role of cardiac fibrosis in HFpEF, which generates the possibility of a mechanistic overlap with pulmonary fibrosis. Indeed, cardiac and pulmonary fibrosis share some characteristics and molecular pathways, such as that of transforming growth factor-β. If pulmonary and cardiac fibrosis share common pathways, we can hypothesize a beneficial effect of anti-fibrotic drugs used in idiopathic pulmonary fibrosis on cardiac outcomes. Of note, pirfenidone has been tested in animal models of cardiac fibrosis and was found to be effective in reducing ventricular remodelling. Yet, no results are hitherto available for humans. In this review article, we discuss the potential benefit of anti-fibrotic treatment in HFpEF. In particular, we propose to reappraise safety data collected in placebo-controlled trials of anti-fibrotic drugs in idiopathic pulmonary fibrosis, to explore the hypothesis that these might reduce cardiac fibrosis.

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“…Additionally, they are not equally effective in all patients and it is still not clear which patient would benefit best from what drug. Consequently, there is an urgent need for additional effective therapy options (6).…”

Section: Introductionmentioning

confidence: 99%

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

Boots

Veith

Albrecht

et al. 2019

Preprint

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Background Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal disease of unknown etiology. Current treatment comprises two FDA-approved drugs that can slow down yet not stop or reverse the disease. As IPF pathology is associated with an altered redox balance, adding a redox modulating component to current therapy might exert beneficial effects. Quercetin is a dietary antioxidant with strong redox modulating capacities suggested to exert part of its antioxidative effects via activation of the redox-sensitive transcription factor Nrf2. Therefore, the aim of the present study was to investigate if quercetin can exert anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance. Methods Homozygous Nrf2 deficient mice and their wildtype littermates were fed a control diet without or with 800 mg/kg quercetin from 7 days prior to a single 1 µg/2µl per g BW bleomycin challenge until they were sacrificed 14 days afterwards. Lung tissue and plasma were collected to determine markers of fibrosis (expression of extracellular matrix genes and histopathology), inflammation (pulmonary gene expression and plasma levels of Tumor Necrosis Factor-α (TNFα) and Keratinocyte Chemoattrachtant (KC)), and redox balance (pulmonary gene expression of antioxidants and malondialdehyde-dG (MDA)- DNA adducts). Results Mice fed the enriched diet had significantly enhanced plasma and pulmonary quercetin levels (11.08 ± 0.73 µM versus 7.05 ± 0.2 µM) combined with increased pulmonary expression of Nrf2 and Nrf2-responsive genes compared to mice fed the control diet. Upon bleomycin treatment, quercetin-fed mice displayed reduced expression of collagen (COL1A2) and fibronectin (FN1) and a tendency of reduced inflammatory lesions (2.8 ± 0.7 versus 1.9 ± 0.8). These beneficial effects were accompanied by reduced pulmonary gene expression of TNFα and KC, but not their plasma levels, and enhanced Nrf2-induced pulmonary antioxidant defences. In Nrf2 deficient mice, no effect of the dietary antioxidant on either histology or inflammatory lesions was observed. Conclusion Quercetin exerts anti-fibrogenic and anti-inflammatory effects on bleomycin-induced pulmonary damage in mice possibly through modulation of the redox balance by inducing Nrf2. However, quercetin could not rescue the bleomycin-induced pulmonary damage indicating that quercetin alone cannot ameliorate the progression of IPF.

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New treatment directions for IPF: current status of ongoing and upcoming clinical trials

Cited by 14 publications

References 111 publications

Idiopathic pulmonary fibrosis: pathogenesis and management

Idiopathic pulmonary fibrosis: pathogenesis and management

Treating heart failure with preserved ejection fraction: learning from pulmonary fibrosis

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

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