Pirfenidone: a novel antifibrotic agent with implications for the treatment of obliterative bronchiolitis

Dosanjh, Amrita; Wan, Bing; Throndset, William; Sherwood, Sylvia; Morris, Randall E.

doi:10.1016/s0041-1345(98)00478-3

Cited by 22 publications

(10 citation statements)

References 4 publications

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“…In the murine endotoxin shock model and a murine macrophage cell line , pirfenidone potently inhibited the production of proinflammatory cytokines such as TNF-α, which mediates the enhanced fibroblast proliferative response, and enhanced the production of antiinflammatory cytokines like interleukin-10. In an in vitro study using NHLF, this drug was also effective in inhibiting cell proliferation (Dosanjh et al, 1998). Together, these findings indicated the strong potential of pirfenidone as a novel, broadspectrum anti-fibrotic agent.…”

Section: Discussionmentioning

confidence: 79%

Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts

Nakayama¹,

Mukae²,

Sakamoto³

et al. 2008

Life Sciences

145

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Section: Discussionmentioning

confidence: 79%

Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts

Nakayama¹,

Mukae²,

Sakamoto³

et al. 2008

Life Sciences

145

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“…Furthermore, treatment with PD and spironolactone was found to reverse the cardiac and renal fibrosis in streptozotocin-diabetic rats [6] and prevented dimethylnitrosamine-induced hepatic fibrosis in rats [7]. In vitro studies have demonstrated the ability of this compound to decrease proliferation of human lung fibroblasts supporting the possible uses of the compound in the treatment of obliterative bronchiolitis, a major complication of lung transplantation [8]. PD also has been shown to have beneficial effects in humans at varying stages of IPF [9], and chronic, progressive multiple sclerosis [10].…”

Section: Introductionmentioning

confidence: 88%

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration

Giri

Wang

Xie

et al. 2002

Biopharm & Drug Disp

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The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring (14)C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and V(d(ss)) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [(14)C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.

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“…In vitro studies have shown that pirfenidone inhibits proliferation and/or activation of a wide range of cell types including human lung fibroblasts [18], human myometrial and leiomyoma cells [19], human Tenon's fibroblasts [20], human T cells [21], rat hepatic stellate cells [22], and rat renal fibroblasts [23]. In addition, pirfenidone modulates a variety of cytokines, and it has been shown that it decreases levels of intercellular adhesion molecule-1 in cultured human synovial fibroblasts [24], inhibits heat shock protein 47 expression in human lung fibroblasts [25], downregulates TGF-β in human Tenon's fibroblasts [20], and suppresses translation of TNF-α in a murine macrophage-like cell line [26].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

et al. 2011

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Cardiac fibroblasts (CFs) are the primary cell type responsible for cardiac fibrosis during pathological myocardial remodeling. Several studies have illustrated that pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) attenuates cardiac fibrosis in different animal models. However, the effects of pirfenidone on cardiac fibroblast behavior have not been examined. In this study, we investigated whether pirfenidone directly modulates cardiac fibroblast behavior that is important in myocardial remodeling such as proliferation, myofibroblast differentiation, migration and cytokine secretion. Fibroblasts were isolated from neonatal rat hearts and bioassays were performed to determine the effects of pirfenidone on fibroblast function. We demonstrated that treatment of CFs with pirfenidone resulted in decreased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen contractility. Boyden chamber assay illustrated that pirfenidone inhibited fibroblast migration ability, probably by decreasing the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1. Furthermore, pirfenidone attenuated the synthesis and secretion of transforming growth factor-β1 but elevated that of interleukin-10. These direct and pleiotropic effects of pirfenidone on cardiac fibroblasts point to its potential use in the treatment of adverse myocardial remodeling.

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Pirfenidone: a novel antifibrotic agent with implications for the treatment of obliterative bronchiolitis

Cited by 22 publications

References 4 publications

Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts

Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration

In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

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