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Cells Jan 2022Antifibrotic agents have been widely used in patients with idiopathic pulmonary fibrosis (IPF). Long-term continuation of antifibrotic therapy is required for IPF...
Antifibrotic agents have been widely used in patients with idiopathic pulmonary fibrosis (IPF). Long-term continuation of antifibrotic therapy is required for IPF treatment to prevent disease progression. However, antifibrotic treatment has considerable adverse events, and the continuation of treatment is uncertain in many cases. Therefore, we examined and compared the continuity of treatment between pirfenidone and nintedanib in patients with IPF. We retrospectively enrolled 261 consecutive IPF patients who received antifibrotic treatment from six core facilities in Gunma Prefecture from 2009 to 2018. Among them, 77 patients were excluded if the antifibrotic agent was switched or if the observation period was less than a year. In this study, 134 patients treated with pirfenidone and 50 treated with nintedanib were analyzed. There was no significant difference in patient background, discontinuation rate of antifibrotic treatment over time, and survival rate between the two groups. However, the discontinuation rate due to adverse events within one year of antifibrotic treatment was significantly higher in the nintedanib group than in the pirfenidone group (76% vs. 37%, < 0.001). Furthermore, the discontinuation rate due to adverse events in nintedanib was higher than that of pirfenidone treatment throughout the observation period (70.6% vs. 31.2%, = 0.016). The pirfenidone group tended to be discontinued due to acute exacerbation or transfer to another facility. The results of this study suggest that better management of adverse events with nintedanib leads to more continuous treatment that prevents disease progression and acute exacerbations, thus improving prognosis in patients with IPF.
Topics: Antineoplastic Agents; Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Prognosis; Pyridones; Treatment Outcome
PubMed: 35011705
DOI: 10.3390/cells11010143 -
Transplantation Aug 2009We previously showed that pirfenidone, an anti-fibrotic agent, reduces lung allograft injury or rejection. In this study, we tested the hypothesis that pirfenidone has...
BACKGROUND
We previously showed that pirfenidone, an anti-fibrotic agent, reduces lung allograft injury or rejection. In this study, we tested the hypothesis that pirfenidone has immune modulating activities and evaluated its effects on the function of T-cell subsets, which play important roles in allograft rejection.
METHOD
We first evaluated whether pirfenidone alters T-cell proliferation and cytokine release in response to T-cell receptor (TCR) activation, and whether pirfenidone alters regulatory T cells (CD4CD25) suppressive effects using an in vitro assay. Additionally, pirfenidone effects on alloantigen-induced T-cell proliferation in vivo were assessed by adoptive transfer of carboxyfluorescein diacetate succinimidyl ester-labeled T cells across a parent->F1 major histocompatibility complex mismatch, as well as using a murine heterotopic cardiac allograft model (BALB/c->C57BL/6).
RESULTS
Pirfenidone was found to inhibit the responder frequency of TCR-stimulated CD4 cell total proliferation in vitro and in vivo, whereas both CD4 and CD8 proliferation index were reduced by pirfenidone. Additionally, pirfenidone inhibited TCR-induced production of multiple pro-inflammatory cytokines and chemokines. Interestingly, there was no change on transforming growth factor-beta production by purified T cells, and pirfenidone had no effect on the suppressive properties of naturally occurring regulatory T cells. Pirfenidone alone showed a small but significant (P<0.05) effect on the in vivo allogeneic response, whereas the combination of pirfenidone and low dose rapamycin had more remarkable effect in reducing the alloantigen response with prolonged graft survival.
CONCLUSION
Pirfenidone may be an important new agent in transplantation, with particular relevance to combating chronic rejection by inhibiting both fibroproliferative and alloimmune responses.
Topics: Adoptive Transfer; Animals; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Chemokines; Cytokines; Drug Therapy, Combination; Graft Rejection; Heart Transplantation; Histocompatibility; Immunosuppressive Agents; Isoantigens; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pyridones; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Time Factors
PubMed: 19667934
DOI: 10.1097/TP.0b013e3181ae3392 -
Advanced Science (Weinheim,... Jan 2024BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials,...
BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.
Topics: Humans; Liposomes; Cancer-Associated Fibroblasts; Nuclear Proteins; Biomimetics; Cell Line, Tumor; Transcription Factors; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Antineoplastic Agents; Tumor Microenvironment; Bromodomain Containing Proteins; Cell Cycle Proteins
PubMed: 37968249
DOI: 10.1002/advs.202305279 -
BMC Pulmonary Medicine May 2020While antifibrotic drugs significantly decrease lung function decline in idiopathic pulmonary fibrosis (IPF), there is still an unmet need to halt disease progression.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
While antifibrotic drugs significantly decrease lung function decline in idiopathic pulmonary fibrosis (IPF), there is still an unmet need to halt disease progression. Antioxidative therapy with N-acetylcysteine (NAC) is considered a potential additional therapy that can be combined with antifibrotics in some patients in clinical practice. However, data on the efficacy, tolerability, and safety of this combination are scarce. We performed a systematic review and meta-analysis to appraise the safety, tolerability, and efficacy of the combination compared to treatment with pirfenidone alone.
METHODS
We systematically reviewed all the published studies with combined pirfenidone (PFD) and NAC (PFD + NAC) treatment in IPF patients. The primary outcomes referred to decline in pulmonary function tests (PFTs) and the rates of IPF patients with side effects.
RESULTS
In the meta-analysis, 6 studies with 319 total IPF patients were included. The PFD + NAC group was comparable to the PFD alone group in terms of the predicted forced vital capacity (FVC%) and predicted diffusion capacity for carbon monoxide (DLco%) from treatment start to week 24. Side effects and treatment discontinuation rates were also comparable in both groups.
CONCLUSION
This systematic review and meta-analysis suggests that combination with NAC does not alter the efficacy, safety, or tolerability of PFD in comparison to PFD alone in IPF patients.
Topics: Humans; Acetylcysteine; Administration, Inhalation; Anti-Inflammatory Agents, Non-Steroidal; Carbon Monoxide; Drug Therapy, Combination; Free Radical Scavengers; Idiopathic Pulmonary Fibrosis; Pyridones; Randomized Controlled Trials as Topic; Treatment Outcome; Vital Capacity
PubMed: 32380989
DOI: 10.1186/s12890-020-1121-2 -
Pharmaceutical Biology Dec 2017Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic... (Comparative Study)
Comparative Study
CONTEXT
Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown.
OBJECTIVE
This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF.
MATERIALS AND METHODS
Rat IPF model was established by endotracheal injection of 5 mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100 mg/kg once daily), prednisone (H, 5 mg/kg once daily) and acetylcysteine (N, 4 mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay.
RESULTS
After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower (p < 0.05) significance of airsacculitis and fibrosis scores of lung tissues, as well as expression of TGF-β1, TNF-α and PDGF, but the expression of Cav-1 was higher (p < 0.05). Compared with the N group, the fibrosis score was significantly lower and the protein expression of Cav-1 was significantly higher in the P group (p < 0.05). Additionally, the expression of Cav-1 was negatively correlated with the airsacculitis and fibrosis scores (r = -0.506, p < 0.01; r = -0.676, p < 0.01) as well as expression of TGF-β1, TNF-α and PDGF (r = -0.590, p < 0.01; r = -0.530, p < 0.01; r = -0.553, p < 0.01).
DISCUSSION AND CONCLUSION
Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-α, TGF-β1, PDGF.
Topics: Acetylcysteine; Animals; Bleomycin; Blotting, Western; Caveolin 1; Cytoprotection; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Idiopathic Pulmonary Fibrosis; Lung; Male; Platelet-Derived Growth Factor; Prednisone; Protective Agents; Pyridones; Rats, Wistar; Real-Time Polymerase Chain Reaction; Signal Transduction; Time Factors; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha
PubMed: 27937011
DOI: 10.1080/13880209.2016.1247879 -
European Respiratory Review : An... Jun 2011Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal... (Review)
Review
Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-β. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component.
Topics: Administration, Oral; Animals; Cardiomyopathies; Disease Models, Animal; Extracellular Matrix Proteins; Humans; Kidney Diseases; Liver Cirrhosis; Pulmonary Fibrosis; Pyridones; Signal Transduction; Transforming Growth Factor beta
PubMed: 21632796
DOI: 10.1183/09059180.00001111 -
Sarcoidosis, Vasculitis, and Diffuse... 2020Patients with idiopathic pulmonary fibrosis (IPF) often do not tolerate pirfenidone in the recommended dose of 2400 mg/day. The proportion of patients requiring dose... (Comparative Study)
Comparative Study Observational Study
BACKGROUND
Patients with idiopathic pulmonary fibrosis (IPF) often do not tolerate pirfenidone in the recommended dose of 2400 mg/day. The proportion of patients requiring dose reduction and its impact on survival in the real-world remain unclear.
METHODS
Consecutive subjects with IPF were enrolled between March 2017 and June 2019. The maximum tolerated dose of pirfenidone (primary outcome) and adverse drug reactions (ADRs) were recorded. A post hoc logistic regression analysis was performed to evaluate the predictors of drug discontinuation due to ADRs. We also compared survival between the full-dose (2400 mg/day), reduced-dose (< 2400 mg/day), and the no-pirfenidone groups, with age and percentage of the predicted forced vital capacity (%pred FVC) as covariates.
RESULTS
Of the 128 subjects (mean age, 67.4 years; 77.3% men) included, 115 were initiated on pirfenidone. Forty-nine (42.6%) and 51 (44.3%) subjects tolerated the full dose and reduced doses, respectively. Ninety-six (83.5%) subjects developed at least one ADR; anorexia dyspepsia, and nausea being the most common. Twenty-two subjects discontinued the drug; 15 of them due to ADRs. Body mass index < 20 kg/m was the only predictor of drug discontinuation due to ADRs. Among subjects newly initiated on treatment during the study period (n = 80), survival was longer (hazard ratio [interquartile range], 0.19 [0.04-0.96]; p = 0.045) in the full-dose but not the reduced-dose group (p = 0.08) compared with the no-pirfenidone group, after adjusting for covariates.
CONCLUSION
Pirfenidone was tolerated in the full dose in a minority of patients with IPF and appears to improve survival only with the full dose. .
Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Idiopathic Pulmonary Fibrosis; Lung; Male; Maximum Tolerated Dose; Middle Aged; Patient Safety; Prospective Studies; Pyridones; Recovery of Function; Treatment Outcome; Vital Capacity
PubMed: 33093778
DOI: 10.36141/svdld.v37i2.8718 -
Thoracic Cancer Nov 2020Pirfenidone is an antifibrotic agent that is potentially effective for the treatment of idiopathic pulmonary fibrosis (IPF). However, no study has reported on its...
Safety and effectiveness of pirfenidone combined with carboplatin-based chemotherapy in patients with idiopathic pulmonary fibrosis and non-small cell lung cancer: A retrospective cohort study.
BACKGROUND
Pirfenidone is an antifibrotic agent that is potentially effective for the treatment of idiopathic pulmonary fibrosis (IPF). However, no study has reported on its prophylactic value against chemotherapy-associated acute IPF exacerbations when combined with chemotherapy for non-small cell lung cancer (NSCLC). The present study assessed the safety and effectiveness of pirfenidone combined with carboplatin-based chemotherapy or immune checkpoint inhibitors (ICIs) in patients with IPF and NSCLC.
METHODS
A total of 14 patients with IPF and NSCLC who received treatment from 2013 to 2019 were included. Patients were treated with pirfenidone combined with carboplatin and nanoparticle albumin-bound paclitaxel or S-1 as first-line chemotherapy. After confirming disease progression, patients received cytotoxic agents or ICIs, including nivolumab and pembrolizumab. Pirfenidone was continued regardless of chemotherapy changes. Overall survival (OS) and progression-free survival (PFS) for lung cancer and IPF were calculated. Moreover, the cumulative incidence of acute exacerbation of IPF (AE-IPF) within one year was evaluated.
RESULTS
Median PFS for lung cancer was 110 days (95% confidence interval [CI]: 57-199 days), while the median OS was 362 days (95% CI: 220-526 days). Moreover, PFS for IPF was 447 days (95% CI: 286-indeterminate days), and the cumulative incidence of AE-IPF within one year was 18%. Notably, none of the patients developed AE-IPF associated with first-line chemotherapy. Among the included patients, four received ICIs, none of whom developed ICI-associated AE-IPF.
CONCLUSIONS
The present study found that pirfenidone combined with carboplatin-based regimens or ICIs might be safe first-line chemotherapy for patients with IPF and NSCLC.
KEY POINTS
SIGNIFICANT FINDINGS OF THE STUDY: No patients with IPF and NSCLC who received pirfenidone in combination with first-line carboplatin-based chemotherapy or late-line ICIs developed acute IPF exacerbations. What this study adds Pirfenidone might have a prophylactic effect against chemotherapy-associated AE-IPF.
Topics: Aged; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Female; Humans; Idiopathic Pulmonary Fibrosis; Immune Checkpoint Inhibitors; Lung Neoplasms; Male; Middle Aged; Pyridones; Retrospective Studies
PubMed: 32986306
DOI: 10.1111/1759-7714.13675 -
Drugs Mar 2016Idiopathic pulmonary fibrosis (IPF) is an aging-associated, recalcitrant lung disease with historically limited therapeutic options. The recent approval of two drugs,... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is an aging-associated, recalcitrant lung disease with historically limited therapeutic options. The recent approval of two drugs, pirfenidone and nintedanib, by the US Food and Drug Administration in 2014 has heralded a new era in its management. Both drugs have demonstrated efficacy in phase III clinical trials by retarding the rate of progression of IPF; neither drug appears to be able to completely arrest disease progression. Advances in the understanding of IPF pathobiology have led to an unprecedented expansion in the number of potential therapeutic targets. Drugs targeting several of these are under investigation in various stages of clinical development. Here, we provide a brief overview of the drugs that are currently approved and others in phase II clinical trials. Future therapeutic opportunities that target novel pathways, including some that are associated with the biology of aging, are examined. A multi-targeted approach, potentially with combination therapies, and identification of individual patients (or subsets of patients) who may respond more favourably to specific agents are likely to be more effective.
Topics: Aging; Clinical Trials, Phase II as Topic; Drug Approval; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Molecular Targeted Therapy; Pyridones
PubMed: 26729185
DOI: 10.1007/s40265-015-0523-6 -
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