Pirfenidone effectively reverses experimental liver fibrosis

García, L. Sarmiento; Hernández, Ivan; Sandoval, Ana; Salazar, Andrea; García-Benavides, Leonel; Vera, José; Grijalva, Guillermo; Muriel, Pablo; Margolin, Solomon B.; Armendáriz‐Borunda, Juan

doi:10.1016/s0168-8278(02)00272-6

Cited by 147 publications

(114 citation statements)

References 22 publications

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“…Our case had acute liver failure consistent with fatal DILI. Severe or fatal DILI is rare but may constitute up to 15% of ALF cases 3, 5. Also, it is the most common etiology of ALF in the United States and Europe 8…”

Section: Discussionmentioning

confidence: 99%

“…Initially used as an antihelminthic and antipyretic, it is currently approved as an antifibrotic drug for use in patients with IPF. It has also been shown to reduce liver fibrosis in animal models and improve fibrosis in patients with chronic hepatitis C 3, 4, 11. In large randomized control trials, hepatotoxicity has been reported in about 4% of patients, with mild to moderate asymptomatic serum aminotransferase elevations requiring termination of the drug in up to 1% of cases 11.…”

Section: Discussionmentioning

confidence: 99%

“…Pirfenidone is an anti‐inflammatory and antifibrotic drug used for the treatment of idiopathic pulmonary fibrosis (IPF) 2. It has been shown to reduce liver fibrosis 3, 4. Hepatotoxicity with its use is rare and manifests as a mild rise in aminotransferases.…”

Section: Introductionmentioning

confidence: 99%

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Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

Verma

Kumar

Mitra

et al. 2017

Hepatology Communications

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Idiosyncratic drug‐induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant‐free survival. Pirfenidone is an anti‐inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini‐review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77‐year‐old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long‐term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI‐ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI‐ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone‐related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142–147)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

Verma

Kumar

Mitra

et al. 2017

Hepatology Communications

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“…The PAI-1 role in liver fibrogenesis was demonstrated in a rat model where antifibrotic drug (interferon (IFN)-α 2a) led to reduced collagen and PAI-1 production and subsequently amelioration of the cirrhosis 68 . Abdominal adhesions formation after hepatectomy is influenced by natural killer (NK) cells and their production of IFN-γ, which seems to be the key regulator of this process through the balance of PAI-1/t-PA levels.…”

Section: Pulmonary Fibrosis Involves Alveolar Epithelial Injurymentioning

confidence: 99%

Mechanisms of plasminogen activator inhibitor 1 action in stromal remodeling and related diseases

et al. 2017

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Plasminogen activator inhibitor type 1 (PAI-1) is the main physiologic inhibitor of fibrinolysis. However, it is also involved in many physiological processes such as extracellular matrix (ECM) proteolysis and remodeling, cell adhesion, motility, and apoptosis, angiogenesis, etc. The aim of the study was to summarize current knowledge and gain insights into the mechanisms of PAI-1 action in the processes of stromal remodeling and diseases with considerable matrix pathologies (atherosclerosis, tissue fibrosis, cancer metastasis, pregnancy related complications, etc). As a component of an early cellular response to injury, PAI-1 reacts with membrane surface proteins and participates in the initiation of intracellular signaling, specifically cytoskeletal reorganization and motility. Complexity of ECM homeostasis resides in varying relation of the plasminogen system components and other matrix constituents. Inflammatory mediators (transforming growth factor-β and interferon-γ) and hormones (angiotensin II) are in the close interdependent relation with PAI-1. Also, special attention is devoted to the role of increased PAI-1 concentrations due to the common 4G/5G polymorphism. Some of the novel mechanisms of ECM modification consider PAI-1 dependent stabilization of urokinase mediated cell adhesion, control of the vascular endothelial cadherin trafficking and interaction with endothelial cells proteasome, its relation to matrix metalloproteinase 2 and osteopontin, and oxidative inhibition by myeloperoxidase. Targeting and/or alteration of PAI-1 functions might bring benefit to the future therapeutic approaches in diseases where ECM undergoes substantial remodeling.

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“…PFD also decreased TGFβ and collagen type I mRNA expression in this model (14,15). In cirrhotic rats, PFD (500 mg.kg.day) reduced serum aminotransferase and alkaline phosphate levels as well as liver hydroxyproline content and fibrosis index scores (15,16). Pirfenidone has the demonstrated effect of reducing fibrosis and the markers of extracellular matrix deposition in varied in vivo models.…”

Section: Anti-inflammatory Actionsmentioning

confidence: 99%

Pirfenidone: Anti-fibrotic agent with a potential therapeutic role in the management of transplantation patients

Dosanjh

2006

European Journal of Pharmacology

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Pirfenidone effectively reverses experimental liver fibrosis

Cited by 147 publications

References 22 publications

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

Mechanisms of plasminogen activator inhibitor 1 action in stromal remodeling and related diseases

Pirfenidone: Anti-fibrotic agent with a potential therapeutic role in the management of transplantation patients

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