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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 -
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 -
PloS One 2015Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. In the last decades pirfenidone an anti-inflammatory and anti-fibrotic agent has shown... (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. In the last decades pirfenidone an anti-inflammatory and anti-fibrotic agent has shown benefit in inhibit collagen production and has also demonstrated benefit in decline progression in IPF in physiological outcomes as Forced vital capacity (FVC), in clinical outcomes such as progression free survival (PFS) and a benefit in mortality but no in clinically relevant outcomes as exacerbations or worsening of IPF.
METHODS
We conducted a systematic review to evaluate the effectiveness of physiological and clinical outcomes of pirfenidone compared to placebo in IPF. We performed a search with no language restriction. Two researchers performed literature search, quality assessment, data extraction and analysis. And was performed a summary of findings table following the GRADE approach.
RESULTS
We included 5 RCTs (Randomized controlled trials) in analysis. The meta-analysis resulted in a decrease in all cause-mortality (RR 0.52 IC 0.32-0.88) and IPF related mortality (RR 0.32 IC 0.14-0.75); other outcomes evaluated were worsening of IPF (RR 0.64 IC 0.50-0.83) and acute exacerbation (RR: 0.72 IC 0.30-1.66 respectively). Also there was a decrease in the risk of progression (RR of PFS: 0.82 IC 0.73–0.92) compared to placebo. Conclusions: We observed significant differences in physiologic and clinically relevant outcomes such as reduction in all-cause mortality, IPF related mortality, worsening of IPF and improvement of PFS. So pirfenidone treatment should be considered not only for its benefits in pulmonary function tests but also by its clinically relevant outcomes [corrected].
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Pulmonary Fibrosis; Pyridones
PubMed: 26308723
DOI: 10.1371/journal.pone.0136160 -
Clinical Medicine (London, England) Dec 2014Idiopathic pulmonary fibrosis (IPF) is a devastating condition with a poor prognosis and few treatment options. However, recent research into this condition has led to... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a devastating condition with a poor prognosis and few treatment options. However, recent research into this condition has led to considerable insights into the pathophysiology of the disease, resulting in the identification of potential biomarkers to aid diagnosis and stratification of patients and the development of novel therapies. In this review we will discuss the recent developments in this field and review how this knowledge has been translated into clinical trials and a paradigm shift in our approach to patients with IPF.
Topics: Biomarkers; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones
PubMed: 25468919
DOI: 10.7861/clinmedicine.14-6-s45 -
JCI Insight Jan 2022Despite decades of research, there is no specific therapy for acute pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an...
Despite decades of research, there is no specific therapy for acute pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an antiinflammatory and antifibrotic agent that is approved by the FDA for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (e.g., after initiation of injury), even when administered at the peak of injury, reduces severity of local and systemic injury and inflammation in multiple models of AP. In vitro evaluation suggests that pirfenidone decreases cytokine release from acini and macrophages and disrupts acinar-macrophage crosstalk. Therapeutic pirfenidone treatment increases IL-10 secretion from macrophages preceding changes in histology and modulates the immune phenotype of inflammatory cells with decreased levels of inflammatory cytokines. Antibody-mediated IL-10 depletion, use of IL-10-KO mice, and macrophage depletion experiments confirmed the role of IL-10 and macrophages in its mechanism of action, as pirfenidone was unable to reduce severity of AP in these scenarios. Since pirfenidone is FDA approved for IPF, a trial evaluating the efficacy of pirfenidone in patients with moderate to severe AP can be initiated expeditiously.
Topics: Acinar Cells; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Cytokines; Disease Models, Animal; Fibrosis; Interleukin-10; Macrophages; Mice; Pancreas; Pancreatitis; Paracrine Communication; Pyridones; Signal Transduction
PubMed: 34847076
DOI: 10.1172/jci.insight.141108 -
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 -
Scientific Reports Nov 2022Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs for the treatment of IPF and are now the standard of care. This is a significant step in slowing down the progression of the disease. However, the drugs are unable to stop or reverse established fibrosis. Several retrospective clinical studies indicate that proton pump inhibitors (PPIs; FDA-approved to treat gastroesophageal reflux) are associated with favorable outcomes in patients with IPF, and emerging preclinical studies report that PPIs possess antifibrotic activity. In this study, we evaluated the antifibrotic efficacy of the PPI esomeprazole when combined with pirfenidone in vitro and in vivo. In cell culture studies of IPF lung fibroblasts, we assessed the effect of the combination on several fibrosis-related biological processes including TGFβ-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGFβ-induced lung fibrosis to evaluate the antifibrotic efficacy of esomeprazole/pirfenidone combination. We also performed computational studies to understand the molecular mechanisms by which esomeprazole and/or pirfenidone regulate lung fibrosis. We found that esomeprazole significantly enhanced the anti-proliferative effect of pirfenidone and favorably modulated TGFβ-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGFβ in comparison to pirfenidone monotherapy. In addition, our animal study demonstrated that the combination therapy effectively inhibited the differentiation of lung fibroblasts into alpha smooth muscle actin (αSMA)-expressing myofibroblasts to attenuate the progression of lung fibrosis. Finally, our bioinformatics study of cells treated with esomeprazole or pirfenidone revealed that the drugs target several extracellular matrix (ECM) related pathways with esomeprazole preferentially targeting collagen family members while pirfenidone targets the keratins. In conclusion, our cell biological, computational, and in vivo studies show that the PPI esomeprazole enhances the antifibrotic efficacy of pirfenidone through complementary molecular mechanisms. This data supports the initiation of prospective clinical studies aimed at repurposing PPIs for the treatment of IPF and other fibrotic lung diseases where pirfenidone is prescribed.
Topics: Animals; Mice; Esomeprazole; Transforming Growth Factor beta; Prospective Studies; Retrospective Studies; Proton Pump Inhibitors; Idiopathic Pulmonary Fibrosis; Disease Models, Animal
PubMed: 36450789
DOI: 10.1038/s41598-022-24985-x -
International Journal of Molecular... May 2023There has been increasing interest in adjunctive use of anti-inflammatory drugs to control periodontitis. This study was performed to examine the effects of pirfenidone...
There has been increasing interest in adjunctive use of anti-inflammatory drugs to control periodontitis. This study was performed to examine the effects of pirfenidone (PFD) on alveolar bone loss in ligature-induced periodontitis in mice and identify the relevant mechanisms. Experimental periodontitis was established by ligating the unilateral maxillary second molar for 7 days in mice (n = 8 per group), and PFD was administered daily via intraperitoneal injection. The micro-computed tomography and histology analyses were performed to determine changes in the alveolar bone following the PFD administration. For in vitro analysis, bone marrow macrophages (BMMs) were isolated from mice and cultured with PFD in the presence of RANKL or LPS. The effectiveness of PFD on osteoclastogenesis, inflammatory cytokine expression, and NF-κB activation was determined with RT-PCR, Western blot, and immunofluorescence analyses. PFD treatment significantly inhibited the ligature-induced alveolar bone loss, with decreases in TRAP-positive osteoclasts and expression of inflammatory cytokines in mice. In cultured BMM cells, PFD also inhibited RANKL-induced osteoclast differentiation and LPS-induced proinflammatory cytokine (IL-1β, IL-6, TNF-a) expression via suppressing the NF-κB signal pathway. These results suggest that PFD can suppress periodontitis progression by inhibiting osteoclastogenesis and inflammatory cytokine production via inhibiting the NF-κB signal pathway, and it may be a promising candidate for controlling periodontitis.
Topics: Mice; Animals; NF-kappa B; Alveolar Bone Loss; X-Ray Microtomography; Lipopolysaccharides; Signal Transduction; Osteoclasts; Periodontitis; Cytokines; RANK Ligand
PubMed: 37240020
DOI: 10.3390/ijms24108682 -
Laboratory Investigation; a Journal of... Sep 2019Nonalcoholic steatohepatitis (NASH) is associated with lipotoxic liver injury, leading to insulin resistance, inflammation, and fibrosis. Despite its increased global...
Nonalcoholic steatohepatitis (NASH) is associated with lipotoxic liver injury, leading to insulin resistance, inflammation, and fibrosis. Despite its increased global incidence, very few promising treatments for NASH are available. Pirfenidone is an antifibrotic agent used to treat pulmonary fibrosis; it suppresses the pulmonary influx of T cells and macrophages. Here, we investigated the effect of pirfenidone in a mouse model of lipotoxicity-induced NASH via a high-cholesterol and high-fat diet. After 12 weeks of feeding, pirfenidone administration attenuated excessive hepatic lipid accumulation and peroxidation by reducing the expression of genes related to lipogenesis and fatty acid synthesis and enhancing the expression of those related to fatty acid oxidation. Flow cytometry indicated that pirfenidone reduced the number of total hepatic macrophages, particularly CD11cCD206(M1)-type macrophages, increased the number of CD11cCD206(M2)-type macrophages, and subsequently reduced T-cell numbers, which helped improve insulin resistance and steatohepatitis. Moreover, pirfenidone downregulated the lipopolysaccharide (LPS)-induced mRNA expression of M1 marker genes and upregulated IL-4-induced M2 marker genes in a dose-dependent manner in RAW264.7 macrophages. Importantly, pirfenidone reversed insulin resistance, hepatic inflammation, and fibrosis in mice with pre-existing NASH. These findings suggest that pirfenidone is a potential candidate for the treatment of NASH.
Topics: Animals; Diet, High-Fat; Disease Models, Animal; Insulin Resistance; Liver; Liver Cirrhosis; Macrophages; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Protective Agents; Pyridones; RAW 264.7 Cells
PubMed: 31019294
DOI: 10.1038/s41374-019-0255-4