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antifibrotic drug

Chengguo Wei, Li Li, Madhav C Menon, Weijia Zhang, Jia Fu, Brian Kidd, Karen L Keung, Christopher Woytovich, Ilana Greene, Wenzhen Xiao, Fadi Salem, Zhengzi Yi, John Cijiang He, Joel T Dudley, Barbara Murphy
Renal fibrosis is the common pathway of progression for patients with CKD and chronic renal allograft injury (CAI), but the underlying mechanisms remain obscure. We performed a meta-analysis in human kidney biopsy specimens with CAI, incorporating data available publicly and from our Genomics of Chronic Renal Allograft Rejection study. We identified an Src family tyrosine kinase, hematopoietic cell kinase (Hck), as upregulated in allografts in CAI. Querying the Kinase Inhibitor Resource database revealed that dasatinib, a Food and Drug Administration-approved drug, potently binds Hck with high selectivity...
December 7, 2016: Journal of the American Society of Nephrology: JASN
Chrysovalantis Voutouri, Christiana Polydorou, Panagiotis Papageorgis, Vasiliki Gkretsi, Triantafyllos Stylianopoulos
Despite the important role that mechanical forces play in tumor growth and therapy, the contribution of swelling to tumor mechanopathology remains unexplored. Tumors rich in hyaluronan exhibit a highly negative fixed charge density. Repulsive forces among these negative charges as well as swelling of cancer cells due to regulation of intracellular tonicity can cause tumor swelling and development of stress that might compress blood vessels, compromising tumor perfusion and drug delivery. Here, we designed an experimental strategy, using four orthotopic tumor models, to measure swelling stress and related swelling to extracellular matrix components, hyaluronan and collagen, as well as to tumor perfusion...
November 21, 2016: Neoplasia: An International Journal for Oncology Research
Isabelle Delanote, Wim A Wuyts, Jonas Yserbyt, Eric K Verbeken, Geert M Verleden, Robin Vos
BACKGROUND: Following recent approval of pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF), questions arise about the use of these antifibrotics in patients awaiting lung transplantation (LTx). METHODS: Safety and efficacy of antifibrotic drugs in IPF patients undergoing LTx were investigated in a single-centre retrospective cohort analysis. RESULTS: A total of nine patients, receiving antifibrotic therapy for 419 ± 315 days until subsequent LTx, were included...
November 18, 2016: BMC Pulmonary Medicine
A M Jacko, L Nan, S Li, J Tan, J Zhao, D J Kass, Y Zhao
The transforming growth factor β-1 (TGFβ-1) signaling pathway plays a central role in the pathogenesis of pulmonary fibrosis. Two TGFβ-1 receptors, TβRI and TβRII, mediate this pathway. TβRI protein stability, as mediated by the ubiquitin/de-ubiquitination system, has been well studied; however, the molecular regulation of TβRII still remains unclear. Here we reveal that a de-ubiquitinating enzyme, USP11, promotes TGFβ-1 signaling through de-ubiquitination and stabilization of TβRII. We elucidate the role that mitoxantrone (MTX), an USP11 inhibitor, has in the attenuation of TGFβ-1 signaling...
November 17, 2016: Cell Death & Disease
Gi-Su Oh, Su-Bin Lee, Anjani Karna, Hyung-Jin Kim, AiHua Shen, Arpana Pandit, SeungHoon Lee, Sei-Hoon Yang, Hong-Seob So
BACKGROUND: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet...
October 2016: Tuberculosis and Respiratory Diseases
Peter Sandner, Peter Berger, Christoph Zenzmaier
Fibrotic diseases cause high rates of morbidity and mortality, and their incidence increases with age. Despite intense research and development efforts, effective and well-tolerated antifibrotic treatments are scarce. Transforming growth factor-β signaling, which is widely considered the most important profibrotic factor, causes a pro-oxidant shift in redox homeostasis and a concomitant decrease in nitric oxide (NO) signaling. The NO/cyclic guanosine monophosphate (cGMP) signaling cascade plays a pivotal role in the regulation of cell and organ function in whole-body hemostasis...
October 27, 2016: Gerontology
Zhanna Kobalava
The burden of cardiovascular diseases (CVD) in general and heart failure (HF) in particular continues to increase worldwide. CVD are major contributors to death and morbidity and recognized as important drivers of healthcare expenditure. Chronic overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in human hypertension and HF pathophysiology. RAAS is fundamental in the overall regulation of cardiovascular homeostasis through the actions of hormones, which regulate vascular tone, and specifically blood pressure through vasoconstriction and renal sodium and water retention...
September 2016: Journal of Hypertension
Raktim Kumar Ghosh, Kinjal Banerjee, Ramyashree Tummala, Somedeb Ball, Keyvan Ravakhah, Anjan Gupta
Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising health care costs and one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy but eventually found to have a number of other physiological actions, not only in pregnancy, but also in non-pregnant women and men...
October 11, 2016: Cardiovascular Therapeutics
Bintou A Ahidjo, Mariama C Maiga, Elizabeth A Ihms, Mamoudou Maiga, Alvaro A Ordonez, Laurene S Cheung, Sarah Beck, Bruno B Andrade, Sanjay Jain, William R Bishai
Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response...
September 8, 2016: JCI Insight
Y Ghebre, G Raghu
Proton pump inhibitors (PPIs) are structurally composed of benzimidazole core; a pharmacologically common scaffold that makes up nearly one quarter of the hundred most selling drugs including anticancer, opioid, antihistaminic and antihelmintic drugs. In medicinal chemistry, benzimidazoles are coined as privileged scaffolds due to their ability to recognize and bind diverse biological targets. In this regard, PPIs have been linked to other extra-intestinal functions including direct modulation of airway epithelial, vascular endothelial and immune cells...
September 2016: QJM: Monthly Journal of the Association of Physicians
Zhanna Kobalava
The burden of cardiovascular diseases (CVD) in general and heart failure (HF) in particular continues to increase worldwide. CVD are major contributors to death and morbidity and recognized as important drivers of healthcare expenditure. Chronic overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in human hypertension and HF pathophysiology. RAAS is fundamental in the overall regulation of cardiovascular homeostasis through the actions of hormones, which regulate vascular tone, and specifically blood pressure through vasoconstriction and renal sodium and water retention...
September 2016: Journal of Hypertension
Vishal K Rajput, Alison MacKinnon, Santanu Mandal, Patrick Collins, Helen Blanchard, Hakon Leffler, Tariq Sethi, Hans Schambye, Balaram Mukhopadhyay, Ulf J Nilsson
Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3-O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target...
September 8, 2016: Journal of Medicinal Chemistry
Seo-Hee Jung, Dan-Bi Sung, Cho-Hee Park, Won-Suk Kim
A new and mild synthetic approach for the N-arylation of 2-pyridones with diaryliodonium salts has been developed. Most reactions proceed readily at room temperature in the presence of 10 mol % of copper chloride. As a result, a wide range of N-arylpyridine-2-ones were synthesized in yields of 23% to 99%. With this method, an antifibrotic drug, Pirfenidone, was successfully synthesized in 99% yield within 30 min at room temperature.
September 2, 2016: Journal of Organic Chemistry
Marcela Janka-Zires, Paloma Almeda-Valdes, Ana Cecilia Uribe-Wiechers, Sonia Citlali Juárez-Comboni, Joel López-Gutiérrez, Jarod Jazek Escobar-Jiménez, Francisco J Gómez-Pérez
Only 30 percent of chronic diabetic foot ulcers heal after 20 weeks of standard treatment. Pirfenidone is a drug with biological, anti-inflammatory, and antifibrotic effects. The aim of this study was to evaluate the effect of topical pirfenidone added to conventional treatment in noninfected chronic diabetic foot ulcers. This was a randomized crossover study. Group 1 received topical pirfenidone plus conventional treatment for 8 weeks; after this period, they were switched to receive conventional treatment only for 8 more weeks...
2016: Journal of Diabetes Research
George A Margaritopoulos, Eirini Vasarmidi, Katerina M Antoniou
The landscape of idiopathic pulmonary fibrosis (IPF) has changed. The significant progress regarding our knowledge on the pathogenesis of the disease together with the experience achieved after a series of negative trials has led to the development of two drugs for the treatment of IPF. Both pirfenidone and nintedanib can slow significantly the rate of disease progression. They are safe with side effects that can be either prevented by close collaboration between health care professionals and patients or treated successfully when they occur, rarely leading to treatment discontinuation...
2016: Core Evidence
Sabbir Khan, Kailash Ahirwar, Gopabandhu Jena
Tissue injuries and pathological insults produce oxidative stress, genetic and epigenetic alterations, which lead to an imbalance between pro- and anti-fibrotic molecules, and subsequent accumulation of extracellular matrix, thereby fibrosis. Various molecular pathways play a critical role in fibroblasts activation, which promotes the extracellular matrix production and accumulation. Recent reports highlighted that histone deacetylases (HDACs) are upregulated in various fibrotic disorders and play a central role in fibrosis, while HDAC inhibitors exert antifibrotic effects...
August 2016: Epigenomics
Elisabeth G D Stribos, Jan-Luuk Hillebrands, Peter Olinga, Henricus A M Mutsaers
Chronic kidney disease (CKD) is associated with renal fibrosis, a pathological process that is characterized by excessive accumulation of extracellular matrix proteins resulting in loss of organ architecture and function. Currently, renal transplantation and dialysis are the sole treatment options for advanced CKD, yet these therapies have limited impact on fibrogenesis. Even though antifibrotic therapies are being developed, the search for effective antifibrotic drugs is being hampered by the lack of appropriate cell and animal models to study renal fibrosis...
June 30, 2016: European Journal of Pharmacology
Marlies Wijsenbeek, Mirjam van Manen, Francesco Bonella
PURPOSE OF REVIEW: In a chronic, progressive and ultimately fatal disease like idiopathic pulmonary fibrosis (IPF), the maintenance of patients' quality of life should be regarded as a major aim of treatment. Although better knowledge and two antifibrotic drugs are now available in IPF, the individual response to treatment and its acceptance remain poorly explored. This review summarizes recent advances in research on patient-reported outcomes and their measures, indispensable instruments to investigate how patients feel and function, and how the disease impacts their lives...
September 2016: Current Opinion in Pulmonary Medicine
LuAnn Sabounjian, Philip Graham, Lijun Wu, Virginia Braman, Changfu Cheng, Julie Liu, James Shipley, Joel Neutel, Michael Dao
The prevalence of chronic kidney disease (CKD) related to type 2 diabetes is increasing worldwide. In addition to standard of care, treatment with anti-inflammatory and antifibrotic agents such as CTP-499, a novel oral, multisubtype selective inhibitor of phosphodiesterases, may be important in CKD treatment. A phase 1b randomized, double-blind, placebo-controlled clinical trial of CTP-499 in CKD patients (25 active, 8 placebo) with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m(2) was conducted to assess safety and tolerability...
July 2016: Clinical Pharmacology in Drug Development
Cécile Daccord, Toby M Maher
Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable...
2016: F1000Research
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