生物活性

• 描述Pirfenidone is mainly used in treatment for idiopathic pulmonary fibrosis based on its inhibition on production of growth factors, such as TGFβ. Over-expression of TGF-β in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including idiopathic pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease and asthma^[1]. Pirfenidone can inhibit TGFβ expression or TGFβ-induced fibrogenesis by blocking nuclear translocation of Smads^[2]. Treatment of pirfenidone at concentration of 0.3 mg/ml can decrease the expression level of TGF-β1, 2, 3 in HTF cells^[2]. Pretreatment with pirfenidone at concentration 0.5 mg/ml for 1h can inhibit TGFβ-induced nuclear localization of the Smads in ARPE-19 cells, but has little effect on p-smad2/3. In the presence of pirfenidone at concentration 0.5 mg/ml for 1h with TGFβ (10 ng/ml) for an additional 48 h, cell migration and expression of extracellular matrix induced by TGFβ, including collagen type I and fibronectin, can be inhibited in ARPE-19 cells^[3]. Oral administration of pirfenidone, 300 mg/kg, daily for 4 weeks, can attenuates bleomycin-induced pulmonary fibrosis in mice^[4]. Increased expression levels of TGF-β1, TNF-a and PDGF of idiopathic pulmonary fibrosis rat models can be converted to almost normal when the rats treated with 100 mg/kg pirfenidone once daily on day 15, 30 and 45^[5]. Pirfenidone can attenuate the EMT process induced not only by exogenous TGF-β1 but also by paracrine TGF-β produced from NSCLC cells^[6]. Up to now, pirfenidone treatment of idiopathic pulmonary fibrosis is approved by FDA (see https://www.fda.gov/).
• 作用机制Pirfenidone can inhibit TGFβ expression or TGFβ-induced fibrogenesis by blocking nuclear translocation of Smads. But the mechanism for the process is unknown.

• 动物研究
  剂量	Mice[7] (p.o.): 200 mg/kg; rat[8] (p.o.): min = 50 mg/kg, max = 1000 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[9] Dose 100 mg/kg Administration p.o. Cmax 21.0 ± 6.6 μg/ml T1/2 2.9 ± 0.5 h F 0.771 Tmax 0.12 ± 0.09 h AUC 36.0 ± 6.4 μg·h/ml MRT 2.9 ± 0.6 h

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01695408	-	-	Recruiting	April 2020	Germany ... more >> Institute for Clinical Pharmacology, Medical Faculty, Technical University Active, not recruiting Dresden, Germany, 01307 Klinik für Pneumologie, Medizinische Hochschule Hannover Recruiting Hannover, Germany Contact: Antje Prasse, MD    +49511 532 ext 3934    pneumologie@mh-hannover.de    Principal Investigator: Antje Prasse, MD          Pneumologie und Beatmungsmedizin, Thoraxklinik,Universitätsklinikum Recruiting Heidelberg, Germany, 69126 Contact: Michael Kreuter, MD    +496221396 ext 1214    michael.kreuter@thoraxklinik-heidelberg.de    Principal Investigator: Michael Kreuter, MD          Abteilung für Pneumologie Department Innere Medizin, Neurologie und Dermatologie Universitätsklinikum Leipzig AöR Recruiting Leipzig, Germany Contact: Hubert Wirtz, MD       hubert.wirtz@medizin.uni-leipzig.de    Principal Investigator: Hubert Wirtz, MD          V. Med. Clinic, Ludwig-Maximilians-Unviversity Recruiting München, Germany Contact: Jürgen Behr, MD Collapse <<
  NCT03104322	Idiopathic Pulmonary Fibrosis	Not Applicable	Completed	-	Ireland ... more >> Dept. of Respiratory Medicine Galway, Ireland Collapse <<
  NCT02135380	Idiopathic Pulmonary Fibrosis	Phase 1 Phase 2	Unknown	-	India ... more >> Kasiak Research Pvt Ltd Recruiting Thane, Maharashtra, India, 400 610 Contact: Dr. Pankaj A Thakur, PhD    +91-(022)-411 73463 ext 463    pankaj.thakur@kasiakresearch.com    Contact: Sainyukta S Medhekar, MSc    +91-(022)-411 73463 ext 463    sainyukta.medhekar@kasiakresearch.com    Principal Investigator: Dr.Pratibha Singhal, M.B.B.S.M.D.          Principal Investigator: Dr. Ashok Mahashur, M.B.B.S.M.D.          Principal Investigator: Dr. Sujeet Rajan, M.B.B.S.M.D.          Principal Investigator: Dr. Karthik Shah, M.B.B.S.M.D. Collapse <<

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• 参考文献

• [1] Lachapelle P, Li M, et al. Safer approaches to therapeutic modulation of TGF-β signaling for respiratory disease. Pharmacol Ther. 2018 Jul;187:98-113.

  [2] Lin X, Yu M, et al. Effects of pirfenidone on proliferation, migration, and collagen contraction of human Tenon's fibroblasts in vitro. Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3763-70.

  [3] Choi K, Lee K, et al. Pirfenidone inhibits transforming growth factor-β1-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19. Mol Vis. 2012;18:1010-20. Epub 2012 Apr 21.

  [4] Liu Y, Lu F, et al. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium. BMC Pulm Med. 2017 Apr 18;17(1):63.

  [5] Yu W, Guo F, et al. Effects and mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models. Pharm Biol. 2017 Dec;55(1):450-455.

  [6] Fujiwara A, Shintani Y, et al. Pirfenidone plays a biphasic role in inhibition of epithelial-mesenchymal transition in non-small cell lung cancer. Lung Cancer. 2017 Apr;106:8-16.

  [7] Li C, Rezov V, et al. Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo. Sci Rep. 2018 Jul 3;8(1):10070.

  [8] Pirfenidone

  [9] Pharmacokinetics of pirfenidone

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