Managing Idiopathic Pulmonary Fibrosis: Which Drug for Which Patient?

Hayton, Conal; Chaudhuri, Nazia

doi:10.1007/s40266-017-0488-0

Cited by 12 publications

(12 citation statements)

References 34 publications

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“…It predominantly affects individuals aged 60 to 75 years old, with a median survival of 3–5 years after diagnosis, which is akin to many aggressive cancers [ 1 , 2 ]. Although pirfenidone (Esbriet ® ) and nintedanib (Ofev ® ) have recently been approved as IPF therapies, with indication of manageable side effect profiles, both drugs only slow down the progression of the disease [ 3 – 5 ]. Therefore, there is no curative treatment other than lung transplantation.…”

Section: Introductionmentioning

confidence: 99%

“…At present, the FDA approved drugs nintedanib (Ofev ® ) and pirfenidone (Esbriet ® ) are widely used for IPF therapy [ 5 , 21 ]. Nintedanib is a receptor tyrosine kinase inhibitor of platelet-derived growth factor receptor (PDGFR)-, vascular endothelial growth factor receptor (VEGFR)- and fibroblast growth factor receptor (FGFR) signaling, which have been shown to critically regulate myofibroblast transformation and collagen production under fibrotic conditions, through subsequent signaling via the ERK, MAPK and the PI3K/Akt pathways [ 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

et al. 2018

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. Pirfenidone is the first antifibrotic agent to be approved for IPF-treatment as it is able to slow down disease progression. However, there is no curative treatment other than lung transplantation. Because epigenetic alterations are associated with IPF, histone deacetylase (HDAC)-inhibitors have recently been proven to attenuate fibrotic remodeling in vitro and in vivo. This study compared the effects of pirfenidone with the pan-HDAC-inhibitor panobinostat/LBH589, a FDA-approved drug for the treatment of multiple myeloma, head-to-head on survival, fibrotic activity and proliferation of primary IPF-fibroblasts in vitro.MethodsPrimary fibroblasts from six IPF-patients were incubated for 24h with vehicle (0.25% DMSO), panobinostat (LBH589, 85 nM) or pirfenidone (2.7 mM), followed by assessment of proliferation and expression analyses for profibrotic and anti-apoptosis genes, as well as for ER stress and apoptosis-markers. In addition, the expression status of all HDAC enzymes was examined.ResultsTreatment of IPF-fibroblasts with panobinostat or pirfenidone resulted in a downregulated expression of various extracellular matrix (ECM)-associated genes, as compared to vehicle-treated cells. In agreement, both drugs decreased protein level of phosphorylated (p)-STAT3, a transcription factor mediating profibrotic responses, in treated IPF-fibroblasts. Further, an increase in histone acetylation was observed in response to both treatments, but was much more pronounced and excessive in panobinostat-treated IPF-fibroblasts. Panobinostat, but not pirfenidone, led to a significant suppression of proliferation in IPF-fibroblasts, as indicated by WST1- and BrdU assay and markedly diminished levels of cyclin-D1 and p-histone H3. Furthermore, panobinostat-treatment enhanced α-tubulin-acetylation, decreased the expression of survival-related genes Bcl-XL and BIRC5/survivin, and was associated with induction of ER stress and apoptosis in IPF-fibroblasts. In contrast, pirfenidone-treatment maintained Bcl-XL expression, and was neither associated with ER stress-induction nor any apoptotic signaling. Pirfenidone also led to increased expression of HDAC6 and sirtuin-2, and enhanced α-tubulin-deacetylation. But in line with its ability to increase histone acetylation, pirfenidone reduced the expression of HDAC enzymes HDAC1, -2 and -9.ConclusionsWe conclude that, beside other antifibrotic mechanisms, pirfenidone reduces profibrotic signaling also through STAT3 inactivation and weak epigenetic alterations in IPF-fibroblasts, and permits survival of (altered) fibroblasts. The pan-HDAC-inhibitor panobinostat reduces profibrotic phenotypes while inducing cell cycle arrest and apoptosis in IPF-fibroblasts, thus indicating more efficiency than pirfenidone in inactivating IPF-fibroblasts. We therefore believe that HDAC-inhibitors such as panobinostat can present a novel therapeutic strategy for IPF.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

et al. 2018

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“…One of the last substances of note is pirfenidone, a pyridine molecule used as an antifibrotic agent [ 147 , 148 ] in the treatment of pulmonary fibrosis [ 148 ]. Studies about pirfenidone and UFs demonstrated that pirfenidone was an effective inhibitor of myometrial and UF cell proliferation, and that it reduced ECM mRNA levels [ 147 ].…”

Section: Discussionmentioning

confidence: 99%

Alternative Oral Agents in Prophylaxis and Therapy of Uterine Fibroids—An Up-to-Date Review

Ciebiera

Łukaszuk

Męczekalski

et al. 2017

IJMS

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Uterine fibroids (UFs) are the most common tumors of the female genital tract. The effect of UFs on the quality of life and the overall cost of treatment are significant issues worldwide. Tumor size and location are the two specific factors which influence the occurrence of symptoms, the need for, and method of, treatment (some tumors require surgery while some can be treated with selected drugs). Primary prevention and treatment of early UF disease are worthy goals that might have a great impact on health care systems. Several treatments and prophylactic methods can be used in this endeavor. This publication presents current data about lesser-known substances which may have a beneficial effect on the treatment or prophylaxis of UFs and can be administered orally, serving as an alternative to (or complement of) surgery or selective progesterone receptor modulators (SPRMs). Early prevention and treatment of UFs in women from high-risk groups should be our priority. Innovative forms of UF management are under intensive investigation and may be promising options in the near future. Many of them evaluated vitamin D, paricalcitol, epigallocatechin gallate (EGCG), elagolix, aromatase inhibitors (AIs), and cabergoline and deemed them to be safe and effective. The next step in such projects should be properly constructed randomized control trials (RCTs), carried out by successive phases.

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“…Meta-analysis indicates similar efficacy between both antifibrotics [ 133 , 134 ]. Treatment decisions are generally driven by tolerance to side effect profiles [ 135 ]. Adverse events were common in all the major anti-fibrotic studies with discontinuation rates of 11.9% for pirfenidone in the CAPACITY and ASCEND studies and 19.3% for nintedanib in INPULSIS [ 120 , 127 ].…”

Section: Treatmentmentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis (IPF): An Overview

Barratt

Creamer

Hayton

et al. 2018

JCM

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248

201

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Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic, progressive scarring of the lungs and the pathological hallmark of usual interstitial pneumonia. Current paradigms suggest alveolar epithelial cell damage is a key initiating factor. Globally, incidence of the disease is rising, with associated high morbidity, mortality, and economic healthcare burden. Diagnosis relies on a multidisciplinary team approach with exclusion of other causes of interstitial lung disease. Over recent years, two novel antifibrotic therapies, pirfenidone and nintedanib, have been developed, providing treatment options for many patients with IPF, with several other agents in early clinical trials. Current efforts are directed at identifying key biomarkers that may direct more customized patient-centred healthcare to improve outcomes for these patients in the future.

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Managing Idiopathic Pulmonary Fibrosis: Which Drug for Which Patient?

Cited by 12 publications

References 34 publications

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

Alternative Oral Agents in Prophylaxis and Therapy of Uterine Fibroids—An Up-to-Date Review

Idiopathic Pulmonary Fibrosis (IPF): An Overview

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