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      Role and New Insights of Pirfenidone in Fibrotic Diseases

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          Abstract

          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.

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          Most cited references49

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          Therapy for fibrotic diseases: nearing the starting line.

          Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common feature of chronic tissue injury. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the more common fibrotic diseases, which in aggregate represent a huge unmet clinical need. New appreciation of the common features of fibrosis that are conserved among tissues has led to a clearer understanding of how epithelial injury provokes dysregulation of cell differentiation, signaling, and protein secretion. At the same time, discovery of tissue-specific features of fibrogenesis, combined with insights about genetic regulation of fibrosis, has laid the groundwork for biomarker discovery and validation, and the rational identification of mechanism-based antifibrotic drugs. Together, these advances herald an era of sustained focus on translating the biology of fibrosis into meaningful improvements in quality and length of life in patients with chronic fibrosing diseases.
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            Recent advancement of molecular mechanisms of liver fibrosis.

            Liver fibrosis occurs in response to any etiology of chronic liver injury including hepatitis B and C, alcohol consumption, fatty liver disease, cholestasis, and autoimmune hepatitis. Hepatic stellate cells (HSCs) are the primary source of activated myofibroblasts that produce extracellular matrix (ECM) in the liver. Various inflammatory and fibrogenic pathways contribute to the activation of HSCs. Recent studies also discovered that liver fibrosis is reversible and activated HSCs can revert to quiescent HSCs when causative agents are removed. Although the basic research for liver fibrosis has progressed remarkably, sensitive and specific biomarkers as non-invasive diagnostic tools, and effective anti-fibrotic agents have not been developed yet. This review highlights the recent advances in cellular and molecular mechanisms of liver fibrosis, especially focusing on origin of myofibroblasts, inflammatory signaling, autophagy, cellular senescence, HSC inactivation, angiogenesis, and reversibility of liver fibrosis. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
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              Pirfenidone for diabetic nephropathy.

              Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.
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                Author and article information

                Journal
                Int J Med Sci
                Int J Med Sci
                ijms
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                1449-1907
                2015
                14 October 2015
                : 12
                : 11
                : 840-847
                Affiliations
                1. Institute for Molecular Biology and Gene Therapy, Department of Molecular Biology and Genomics, University of Guadalajara, Sierra Mojada St. 950, Guadalajara (44280), Mexico.
                2. Departamento de Ciencias de la Salud, CUValles, University of Guadalajara, Guadalajara - Ameca km. 45.5, Ameca (46600), Mexico.
                Author notes
                ✉ Corresponding author: armdbo@ 123456gmail.com

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijmsv12p0840
                10.7150/ijms.11579
                4643073
                26640402
                b0e08988-8488-48c5-aca8-d941dc804a38
                © 2015 Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.
                History
                : 12 January 2015
                : 16 July 2015
                Categories
                Review

                Medicine
                pirfenidone,fibrosis,inflammation,idiopathic pulmonary fibrosis
                Medicine
                pirfenidone, fibrosis, inflammation, idiopathic pulmonary fibrosis

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