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Respirology (Carlton, Vic.) Apr 2015
Topics: Acetylcysteine; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Pyridones
PubMed: 25678074
DOI: 10.1111/resp.12487 -
Burns & Trauma 2020Keloids are benign fibroproliferative skin lesions that are difficult to treat and become a lifetime predicament for patients. Several treatment modalities have been put...
BACKGROUND
Keloids are benign fibroproliferative skin lesions that are difficult to treat and become a lifetime predicament for patients. Several treatment modalities have been put forth, but as yet no satisfactory approach to the prevention or treatment of keloids has been identified. The process of epithelial-to-mesenchymal transition (EMT) has been implicated in keloid scarring, as keloid keratinocytes display an EMT-like phenotype. This study investigated the potential of pirfenidone, an antifibrotic agent, to counteract EMT-like alterations in keloid keratinocytes, including gene expression, cell migratory and proliferative functions.
METHODS
Normal and keloid keratinocytes were isolated from discarded normal skin tissues and from resected keloid tissues, respectively. Cells were quiesced for 24 h without epidermal growth factor DS-Qi1MCDigital and were exposed to transforming growth factor-beta1 (TGF-β1; 10 ng/mL), with or without pirfenidone (400 μg/mL), for an additional 24 h. The effects of pirfenidone on cytotoxicity, cell migration, cell proliferation, and on expression of genes and proteins involved in EMT were assayed. Statistical significance was determined by two-way ANOVA using Sigma Plot.
RESULTS
We found that pirfenidone did not elicit any cytotoxic effect at concentrations up to 1000 μg/mL. A statistically significant dose-dependent decrease in basal cell proliferation rate was noted in both normal and keloid keratinocytes when exposed to pirfenidone at concentrations ranging from 200 to 1000 μg/mL. Pirfenidone significantly decreased basal cell migration in both normal and keloid keratinocytes, but a significant decrease in TGF-β1-induced cell migration was seen only in keloid keratinocytes. Significant inhibition of the expression of TGF-β1-induced core EMT genes, namely hyaluronan synthase 2, vimentin, cadherin-11, and wingless-type MMTV integration site family, member 5A along with fibronectin-1, was observed in both normal and keloid keratinocytes treated with pirfenidone. In addition, the protein levels of vimentin and fibronectin were significantly reduced by pirfenidone (400 μg/mL) in both normal and keloid keratinocytes.
CONCLUSIONS
For the first time, this study shows the efficacy of pirfenidone in inhibiting the EMT-like phenotype in keratinocytes derived from keloids, suggesting that pirfenidone may counteract a critical contributor of keloid progression and recurrence.
PubMed: 32405508
DOI: 10.1093/burnst/tkz007 -
The European Respiratory Journal Sep 2018Idiopathic pulmonary fibrosis (IPF) is a fatal condition that reduces life expectancy and shows a limited response to available therapies. Pirfenidone has been approved...
Idiopathic pulmonary fibrosis (IPF) is a fatal condition that reduces life expectancy and shows a limited response to available therapies. Pirfenidone has been approved for treatment of IPF, but little is known about the distinct metabolic changes that occur in the lung upon pirfenidone administration.Here, we performed a proof-of-concept study using high-resolution quantitative matrix-assisted laser desorption/ionisation Fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI) to simultaneously detect, visualise and quantify endogenous and exogenous metabolites in lungs of mice subjected to experimental fibrosis and human patients with IPF, and to assess the effect of pirfenidone treatment on metabolite levels.Metabolic pathway analysis and endogenous metabolite quantification revealed that pirfenidone treatment restores redox imbalance and glycolysis in IPF tissues, and downregulates ascorbate and aldarate metabolism, thereby likely contributing to modulation of collagen processing. As such, we detected specific alterations in metabolite pathways in fibrosis and, importantly, metabolic recalibration following pirfenidone treatment.Together, these results highlight the suitability of high-resolution MALDI-FTICR-MSI for deciphering the therapeutic effects of pirfenidone and provide a preliminary analysis of the metabolic changes that occur during pirfenidone treatment These data may therefore contribute to improvement of currently available therapies for IPF.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Idiopathic Pulmonary Fibrosis; Lung; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Proof of Concept Study; Pyridones; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tissue Distribution
PubMed: 30072508
DOI: 10.1183/13993003.02314-2017 -
The European Respiratory Journal Jan 2021A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown.
METHODS
This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide ( ) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability.
RESULTS
81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in , 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups.
CONCLUSIONS
Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.
Topics: Acetylcysteine; Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Pulmonary Fibrosis; Japan; Pyridones; Treatment Outcome; Vital Capacity
PubMed: 32703779
DOI: 10.1183/13993003.00348-2020 -
International Journal of Medical... 2015Pirfenidone (PFD) is a non-peptide synthetic molecule issued as a broad-spectrum anti-fibrotic drug with the ability to decrease TGF-β1, TNF-α, PDGF and COL1A1... (Review)
Review
Pirfenidone (PFD) is a non-peptide synthetic molecule issued as a broad-spectrum anti-fibrotic drug with the ability to decrease TGF-β1, TNF-α, PDGF and COL1A1 expression, which is highly related to prevent or remove excessive deposition of scar tissue in several organs. Basic and clinical evidence suggests that PFD may safely slow or inhibit the progressive fibrosis swelling after tissue injuries. Furthermore, a number of evidence suggests that this molecule will have positive effects in the treatment of other inflammatory diseases. This review contains current research in which PFD has been used as the treatment of several diseases, and focus mainly in the outcomes related to improve inflammation and fibrogenesis. Therefore, the main goal of this review is to focus on the novel findings of PFD efficacy rather than deepen in the chemical aspects of the molecule.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Eye; Fibrosis; Humans; Kidney; Liver Cirrhosis; Myocardium; Pulmonary Fibrosis; Pyridones
PubMed: 26640402
DOI: 10.7150/ijms.11579 -
The American Journal of Managed Care Jul 2019Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive-fibrosing interstitial lung disease of unknown origin that affects 3 million people worldwide and imparts... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive-fibrosing interstitial lung disease of unknown origin that affects 3 million people worldwide and imparts substantial burdens to patients, their families, and the healthcare system. The IPF disease course is highly variable and presents several diagnostic and management-related challenges. Two therapies, nintedanib and pirfenidone, are FDA approved and are recommended by clinical practice guidelines for the treatment of IPF. Although neither of these treatments is curative, both slow disease progression and impact survival of patients with IPF. To ensure optimal management, this supplement will provide an overview of the epidemiology, pathophysiology, and diagnosis of IPF, along with management-based considerations including evidence-based guideline recommendations, in-depth reviews of nintedanib and pirfenidone, and outcomes from other completed clinical trials.
Topics: Age Distribution; Aging; Antineoplastic Agents; Chronic Disease; Comorbidity; Disease Progression; Health Expenditures; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Patient Education as Topic; Practice Guidelines as Topic; Pyridones; Sex Distribution
PubMed: 31419091
DOI: No ID Found -
PharmacoEconomics Jun 2019The National Institute for Health and Care Excellence (NICE) published guidance on the use of pirfenidone (Esbriet, Roche) for the treatment of mild to moderate... (Review)
Review
The National Institute for Health and Care Excellence (NICE) published guidance on the use of pirfenidone (Esbriet, Roche) for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in 2013. NICE decided to review existing guidance following publication of an additional clinical trial, and invited the manufacturer of pirfenidone to submit evidence of its clinical and cost effectiveness for the treatment of mild to moderate IPF when compared with best supportive care (BSC) or nintedanib; nintedanib was a comparator only for moderate IPF. An independent Evidence Review Group (ERG) critiqued the company submission and this paper summarises their report and subsequent NICE guidance. The key clinical effectiveness evidence was based on three randomised controlled trials (RCTs) and an open-label extension study. Supportive data were provided from two additional RCTs conducted in Japan, while one additional open-label study was included for safety outcomes. Meta-analysis of the three key RCTs found pirfenidone to be effective at reducing disease progression compared with placebo, but statistically significant differences were not identified in all of the RCTs. A statistically significant reduction in all-cause mortality was only demonstrated when pooling data across studies. The treatment effects of pirfenidone and nintedanib were broadly similar, based on an indirect comparison using network meta-analysis, although they have slightly different adverse event profiles. There remains considerable uncertainty in the cost-effectiveness estimates for pirfenidone versus BSC, particularly due to uncertainty regarding the duration of treatment effect and the method used to implement the stopping rule within the economic model.
Topics: Cost-Benefit Analysis; Humans; Idiopathic Pulmonary Fibrosis; Network Meta-Analysis; Pyridones; Randomized Controlled Trials as Topic; Referral and Consultation
PubMed: 30345464
DOI: 10.1007/s40273-018-0727-1 -
BMJ Open Dec 2021Idiopathic pulmonary fibrosis (IPF) has been defined as a distinctive type of chronic fibrotic disease, characterised by a progressive decline in lung function and a... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Idiopathic pulmonary fibrosis (IPF) has been defined as a distinctive type of chronic fibrotic disease, characterised by a progressive decline in lung function and a common histological pattern of interstitial pneumonia. To analyse the efficacy and safety of pirfenidone in the treatment of IPF, a systematic review and meta-analysis was performed.
DESIGN
This is a meta-analysis study.
PARTICIPANTS
Patients were diagnosed as IPF.
INTERVENTIONS
Use of pirfenidone.
PRIMARY AND SECONDARY OUTCOME
Progression-free survival (PFS), acute exacerbation and worsening of IPF and Impact on adverse events.
MEASURES
The inverse variance method for the random-effects model was used to summarise the dichotomous outcomes, risk ratios and 95% CIs.
RESULTS
A total of 9 randomised controlled trials with 1011 participants receiving pirfenidone and 912 controls receiving placebo were summarised. The pooled result suggested a statistically significant difference inall-cause mortality after pirfenidone use, with a summarised relative ratio of 0.51 (p<0.01). Longer PFS was observed in patients receiving pirfenidone compared with those who were given placebo (p<0.01). The IPF groups presented a high incidence of adverse events with a pooled relative ratio of 3.89 (p<0.01).
CONCLUSIONS
Pirfenidone can provide survival benefit for patients with IPF. Pirfenidone treatment was also associated with a longer PFS, a lower incidence of acute exacerbation and worsening of IPF.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Progression-Free Survival; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome; Vital Capacity
PubMed: 34972762
DOI: 10.1136/bmjopen-2021-050004 -
Journal of Internal Medicine Feb 2017Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease occurring in adults. In the last decade, the results of a number of clinical trials based on the... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease occurring in adults. In the last decade, the results of a number of clinical trials based on the updated disease classification have been published. The registration of pirfenidone and nintedanib, the first two pharmacological treatment options approved for IPF, marks a new chapter in the management of patients with this disease. Other nonpharmacological treatments such as lung transplantation, rehabilitation and palliation have also been shown to be beneficial for these patients. In this review, past and present management is discussed based on a comprehensive literature search. A treatment algorithm is presented based on available evidence and our overall clinical experience. In addition, unmet needs with regard to treatment are highlighted and discussed. We describe the development of various treatment options for IPF from the first consensus to recent guidelines based on evidence from large-scale, multinational, randomized clinical trials, which have led to registration of the first drugs for IPF.
Topics: Algorithms; Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones
PubMed: 27862475
DOI: 10.1111/joim.12571 -
The European Respiratory Journal May 2015A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone.
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Japan; Male; Middle Aged; Patient Safety; Pyridones; Treatment Outcome; Vital Capacity
PubMed: 25504994
DOI: 10.1183/09031936.00198013