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Inflammopharmacology Dec 2022Pirfenidone (PFN) is an anti-fibrotic drug with significant anti-inflammatory property used for treatment of fibrotic conditions such as idiopathic pulmonary fibrosis... (Review)
Review
Pirfenidone (PFN) is an anti-fibrotic drug with significant anti-inflammatory property used for treatment of fibrotic conditions such as idiopathic pulmonary fibrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to the more severe critical stage of pulmonary fibrosis commonly named post-Covid-19 pulmonary fibrosis which needs an urgent address and proper management. Therefore, the objective of the present study was to highlight the potential role of PFN in the management of post-Covid-19 pulmonary fibrosis. The precise mechanism of post-Covid-19 pulmonary fibrosis is related to the activation of transforming growth factor beta (TGF-β1), which activates the release of extracellular proteins, fibroblast proliferation, fibroblast migration and myofibroblast conversion. PFN inhibits accumulation and recruitment of inflammatory cells, fibroblast proliferation, deposition of extracellular matrix in response to TGFβ1 and other pro-inflammatory cytokines. In addition, PFN suppresses furin (TGFβ1 convertase activator) a protein effector involved in the entry of SARS-CoV-2 and activation of TGFβ1, and thus PFN reduces the pathogenesis of SARS-CoV-2. Besides, PFN modulates signaling pathways such as Wingless/Int (Wnt/β-catenin), Yes-Associated Protein (YAP)/Transcription Co-Activator PDZ Binding Motif (TAZ) and Hippo Signaling Pathways that are involved in the pathogenesis of post-Covid-19 pulmonary fibrosis. In conclusion, the anti-inflammatory and anti-fibrotic properties of PFN may attenuate post-Covid-19 pulmonary fibrosis.
Topics: Humans; Pulmonary Fibrosis; Goals; SARS-CoV-2; Fibrosis; Acute Lung Injury; Respiratory Distress Syndrome; COVID-19 Drug Treatment
PubMed: 36044102
DOI: 10.1007/s10787-022-01027-6 -
Frontiers in Pharmacology 2021Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only...
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a K3.1 ion channel blocker. Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC ( = 32). Nintedanib ( = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,-4,-13,-14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and -13. Senicapoc ( = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the K3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.
PubMed: 34712131
DOI: 10.3389/fphar.2021.679388 -
Bone Marrow Transplantation Aug 2022Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive... (Randomized Controlled Trial)
Randomized Controlled Trial
Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive airway fibrosis leads to a 5-year survival of 40%. Treatment options for BOS are limited. A single arm, 52-week, Phase I study of pirfenidone was conducted. The primary outcome was tolerability defined as maintaining the recommended dose of pirfenidone (2403 mg/day) without a dose reduction totaling more than 21 days, due to adverse events (AEs) or severe AEs (SAEs). Secondary outcomes included pulmonary function tests (PFTs) and patient reported outcomes (PROs). Among 22 participants treated for 1 year, 13 (59%) tolerated the recommended dose, with an average daily tolerated dose of 2325.6 mg/day. Twenty-two SAEs were observed, with 90.9% related to infections, none were attributed to pirfenidone. There was an increase in the average percent predicted forced expiratory volume in 1 s (FEV%) of 7 percentage points annually and improvements in PROs related to symptoms of cGVHD. In this Phase I study, treatment with pirfenidone was safe. The stabilization in PFTs and improvements in PROs suggest the potential of pirfenidone for BOS treatment and support the value of a randomized controlled trial to evaluate the efficacy of pirfenidone in BOS after HCT. The study is registered in ClinicalTrials.gov (NCT03315741).
Topics: Bronchiolitis Obliterans; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lung; Pyridones
PubMed: 35641662
DOI: 10.1038/s41409-022-01716-4 -
Presse Medicale (Paris, France : 1983) Jun 2020Idiopathic pulmonary fibrosis (IPF) is a chronic and devastating disease of unknown etiology, characterized by irreversible morphological changes, ultimately leading to... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a chronic and devastating disease of unknown etiology, characterized by irreversible morphological changes, ultimately leading to lung fibrosis and death. In recent years, significant progress has been achieved in understanding the pathogenesis of IPF. Moreover, we assisted to the conceptual change of the pathogenic hypothesis that currently considers IPF as a primarily fibrotic driven disease. However, despite the undeniable progress, the diagnosis of IPF remains still very complex requiring the presence of a team of experts to achieve the highest level of diagnostic confidence. The advent of antifibrotics has radically changed the treatment landscape of IPF and new promising drugs are currently under evaluation. Furthermore, a more extensive use of non-pharmacological treatments has also to be encouraged in all patients both to reduce symptoms and improve quality of life.
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antibodies; Connective Tissue Growth Factor; Drug Therapy, Combination; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Integrins; Leukotriene Antagonists; Lung Transplantation; Microbiota; Middle Aged; Multimorbidity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Protein Kinase Inhibitors; Pyridones; Serum Amyloid P-Component
PubMed: 32437841
DOI: 10.1016/j.lpm.2020.104025 -
Cureus Sep 2022Background After a diagnosis of two to five years, the survival length for pulmonary fibrosis (PF) is considered to be medium. The primary objective of PF treatment is...
Background After a diagnosis of two to five years, the survival length for pulmonary fibrosis (PF) is considered to be medium. The primary objective of PF treatment is to stabilize or minimize the pace of progression of the illness. The treatment of PF by nintedanib and pirfenidone was a breakthrough. In a group of coronavirus disease 2019 (COVID-19)-induced PF patients, we examined the efficacy of pirfenidone and nintedanib. Methodology From May 2021 to April 2022, 5,000 patients receiving antifibrotic treatment with pirfenidone or nintedanib (mean age of 78.3 ± 23.8) for PF were identified. Their clinical and functional information was retrospectively examined at zero, six, and twelve months of therapy. Results The average age of patients receiving nintedanib was greater than the average age of the pirfenidone group (p < 0.0001). Exertional dyspnea and dry cough, with no distinction between the two groups, were the most prevalent symptoms of the illness (p < 0.05). No significant changes between patients on pirfenidone and nintedanib were seen in forced vital capacity, forced expiratory volume in one second, total lung capacity, and diffusing capacity for carbon monoxide at zero or six months (p > 0.05). After one year, lung function measures were similar to the baseline in individuals treated with pirfenidone and nintedanib. This study highlights the appearance of both antifibrotic medicines as promising treatment options for functional stability in COVID-19-induced PF patients. Conclusions The patients affected by COVID-19 and undergoing fibrinolytic therapy may be well treated by any of the drugs with a significant improvement.
PubMed: 36299940
DOI: 10.7759/cureus.29435 -
Scientific Reports Mar 2022Left ventricular (LV) remodeling after myocardial infarction (MI) is promoted by an intense fibrotic response, which could be targeted by the anti-fibrotic drug...
Left ventricular (LV) remodeling after myocardial infarction (MI) is promoted by an intense fibrotic response, which could be targeted by the anti-fibrotic drug pirfenidone. We explored the relationship between protein modulation by pirfenidone and post-MI remodeling, based on molecular information and transcriptomic data from a swine model of MI. We identified 6 causative motives of post-MI remodeling (cardiomyocyte cell death, impaired myocyte contractility, extracellular matrix remodeling and fibrosis, hypertrophy, renin-angiotensin-aldosterone system activation, and inflammation), 4 pirfenidone targets and 21 bioflags (indirect effectors). Pirfenidone had a more widespread action than gold-standard drugs, encompassing all 6 motives, with prominent effects on p38γ-MAPK12, the TGFβ1-SMAD2/3 pathway and other effector proteins such as matrix metalloproteases 2 and 14, PDGFA/B, and IGF1. A bioinformatic approach allowed to identify several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodeling, and suggests additional effects over guideline-recommended therapies.
Topics: Animals; Computational Biology; Fibrosis; Myocardial Infarction; Myocardium; Pyridones; Swine; Ventricular Function, Left; Ventricular Remodeling
PubMed: 35304529
DOI: 10.1038/s41598-022-08523-3 -
The Annals of Pharmacotherapy Jun 2021The comparative efficacy of pirfenidone, nintedanib, and pamrevlumab in slowing the rate of forced vital capacity (FVC) decline and mortality in patients with idiopathic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The comparative efficacy of pirfenidone, nintedanib, and pamrevlumab in slowing the rate of forced vital capacity (FVC) decline and mortality in patients with idiopathic pulmonary fibrosis (IPF) is unknown.
OBJECTIVE
To perform a systematic review and meta-analysis (MA) of these drugs for IPF.
METHODS
We searched CENTRAL, PubMed, EMBASE, ClincalTrials.gov, and the World Health Organization's registry databases up to March 2020. Phase II/III randomized controlled trials in adults with IPF were eligible. The random-effect model was implemented calculating the effect size and respective 95% CI as Cohen's for change from baseline FVC (in percentage predicted and liters) and odds ratio (OR) for 10% reduction in FVC and all-cause mortality (ACM).
RESULTS
Six studies were included in the MA. For change from baseline in percentage predicted FVC, the MA indicated that the 3 drugs were more effective than placebo (pirfenidone: =3.30%, 95% CI=2.15-4.45; nintedanib: =3.15%, 95% CI=2.35-3.95; pamrevlumab: =4.30%, 95% CI=0.45-8.15). These results are superimposable to those relating to change from baseline FVC in liters (pirfenidone: =0.09L, 95% CI=0.04-0.14; nintedanib: =0.13L, 95% CI=0.10-0.16; pamrevlumab: =0.20L, 95% CI=0.05-0.35). Each drug had a positive effect on 10% reduction in FVC (pirfenidone: OR=0.57, 95% CI=0.45-0.74; nintedanib: OR=0.66, 95% CI=0.51-0.85; pamrevlumab: OR=0.24, 95% CI=0.08-0.73), but only pirfenidone showed an effect on ACM (OR=0.50; 95% CI=0.31-0.83).
CONCLUSION AND RELEVANCE
This MA provided encouraging results on pamrevlumab efficacy in slowing the decline in FVC compared with pirfenidone and nintedanib. Actually, in phase 3, it could become a potential IPF treatment.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones; Treatment Outcome
PubMed: 33054319
DOI: 10.1177/1060028020964451 -
International Journal of Clinical and... 2022Traumatic brain injury (TBI) continues to be a significant public healthcare concern. Neuroinflammation that occurs in the secondary phase of TBI leads to cognitive and...
Traumatic brain injury (TBI) continues to be a significant public healthcare concern. Neuroinflammation that occurs in the secondary phase of TBI leads to cognitive and physical dysfunction. A number of therapeutic modalities have been evaluated in an attempt to find a suitable treatment. The only drug approved for the treatment of idiopathic pulmonary fibrosis, pirfenidone, has been evaluated for its antifibrotic, anti-inflammatory, and anti-oxidant properties for various disorders, but this is the first study to examine its effects in an experimental TBI model. Twenty-four Wistar rats were randomly divided into three groups: control, trauma, and pirfenidone. The two latter groups underwent experimental diffuse cortical injury mimicking TBI. Neurological assessment was performed using the Garcia test, histological analysis was performed to examine neuroprotective and anti-inflammatory effects, and biochemical analyses of neuron-specific enolase (NSE), S-100B, caspase-3, and thiobarbituric acid reactive substances were performed. The pirfenidone group had a better Garcia test score (P=0.001), an increased anti-inflammatory effect (P<0.001), and an enhanced neuroprotective effect (P=0.007) along with decreased NSE, S100B, and TBARS levels compared to the trauma group. However, pirfenidone did not show a beneficial effect on caspase-3 levels. Pirfenidone may help decrease mortality and morbidity rates after TBI through its anti-inflammatory and antioxidant effects.
PubMed: 35145580
DOI: No ID Found -
Pulmonary Pharmacology & Therapeutics Oct 2022While pirfenidone and nintedanib have greatly influenced the treatment of idiopathic pulmonary fibrosis (IPF), both drugs have significant early adverse drug reactions...
INTRODUCTION
While pirfenidone and nintedanib have greatly influenced the treatment of idiopathic pulmonary fibrosis (IPF), both drugs have significant early adverse drug reactions (ADRs) and almost nothing is known of their rare and delayed ADRs. We collected and analyzed pirfenidone- or nintedanib-related ADRs identified in a French rare lung disease center, recorded their profiles and identified potential safety signals.
METHODS
We analyzed the medical records of IPF patients treated with pirfenidone or nintedanib between January 2011 and January 2020 at the Rennes University Hospital to estimate the incidence of serious and non-serious ADRs cases due to each drug and the incidence of ADRs involving the cardiovascular, hepatobiliary, gastro-intestinal, dermatological, and metabolic/nutritional systems.
RESULTS
The 176 patients included 115 (65%) initially treated with pirfenidone and 61 (35%) given nintedanib. ADRs occurred in 78.3% of those given pirfenidone and in 70.5% of those given nintedanib. The incidence of first serious ADRs cases was about 33 per 100 person-years (100 PY) for both drugs; first non-serious pirfenidone ADRs cases were 102 per 100 PY and 130 per 100 PY for nintedanib. The incidence involving each organ system were quite similar, except for the gastro-intestinal and skin disorders. Cardiovascular disorders occurred in about 10 cases per 100 PY in both pirfenidone and nintedanib patients.
DISCUSSION
Most ADRs were consistent with the expected antifibrotic drug safety profiles. As arterial and venous thromboembolic events are rare, it is important to assess the risk associated with using antifibrotics by a dedicated pharmacoepidemiological study.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones; Treatment Outcome
PubMed: 35918026
DOI: 10.1016/j.pupt.2022.102149 -
American Journal of Respiratory Cell... Apr 2020Pirfenidone (PFD) is a pharmacological compound with therapeutic efficacy in idiopathic pulmonary fibrosis. It has been chiefly characterized as an antifibrotic agent,... (Review)
Review
Pirfenidone (PFD) is a pharmacological compound with therapeutic efficacy in idiopathic pulmonary fibrosis. It has been chiefly characterized as an antifibrotic agent, although it was initially developed as an antiinflammatory compound because of its ability to diminish the accumulation of inflammatory cells and cytokines. Despite recent studies that have elucidated key mechanisms, the precise molecular activities of PFD remain incompletely understood. PFD modulates fibrogenic growth factors, thereby attenuating fibroblast proliferation, myofibroblast differentiation, collagen and fibronectin synthesis, and deposition of extracellular matrix. This effect is mediated by suppression of TGF-β1 (transforming growth factor-β1) and other growth factors. Here, we appraise the impact of PFD on TGF-β1 production and its downstream pathways. Accumulating evidence indicates that PFD also downregulates inflammatory pathways and therefore has considerable potential as a viable and innovative antiinflammatory compound. We examine the effects of PFD on inflammatory cells and the production of pro- and antiinflammatory cytokines in the lung. In this context, recent evidence that PFD can target inflammasome pathways and ensuing lung inflammation is highlighted. Finally, the antioxidant properties of PFD, such as its ability to inhibit redox reactions and regulate oxidative stress-related genes and enzymes, are detailed. In summary, this narrative review examines molecular mechanisms underpinning PFD and its recognized benefits in lung fibrosis. We highlight preclinical data that demonstrate the potential of PFD as a nonsteroidal antiinflammatory agent and outline areas for future research.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Fibroblasts; Humans; Lung; Lung Diseases; Oxidative Stress; Pyridones
PubMed: 31967851
DOI: 10.1165/rcmb.2019-0328TR