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Claudio Corallo, Maurizio Cutolo, Bashar Kahaleh, Gianluca Pecetti, Antonio Montella, Chiara Chirico, Stefano Soldano, Ranuccio Nuti, Nicola Giordano
BACKGROUND: Systemic sclerosis (SSc) is characterized by early vascular abnormalities and subsequent fibroblast activation to myofibroblasts, leading to fibrosis. Recently, endothelial-to-mesenchymal transition (EndoMT), a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype, has been reported in SSc. In the present study, we evaluated the ability of endothelin-1 (ET-1) dual receptor antagonists bosentan (BOS) and macitentan (MAC) to antagonize EndoMT in vitro...
October 6, 2016: Arthritis Research & Therapy
Katarzyna Drozd, Ali Ahmadi, Yupu Deng, Baohua Jiang, Julia Petryk, Stephanie Thorn, Duncan Stewart, Rob Beanlands, Robert A deKemp, Jean N DaSilva, Lisa M Mielniczuk
BACKGROUND: Altered myocardial energy metabolism has been linked to worsening of RV function in pulmonary arterial hypertension (PAH). The aim of this study was to evaluate RV glucose and fatty acid metabolism in vivo in a rat model of PAH using positron emission tomography (PET) and investigate the effects of Macitentan on RV substrate utilization. METHODS: PAH was induced in male Sprague-Dawley rats by a single subcutaneous injection of Sugen 5416 (20 mg/kg) followed by 3 weeks of hypoxia (10% oxygen)...
September 29, 2016: Journal of Nuclear Cardiology: Official Publication of the American Society of Nuclear Cardiology
S Mehta, B K S Sastry, R Souza, A Torbicki, H-A Ghofrani, R N Channick, M Delcroix, T Pulido, G Simonneau, J Wlodarczyk, L J Rubin, P Jansa, E Hunsche, N Galiè, L Perchenet, O Sitbon
BACKGROUND: Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in PAH patients in the SERAPHIN study. The association between baseline HRQoL and long-term outcomes was also investigated. METHODS: Patients were randomized to placebo, macitentan 3 mg or macitentan 10 mg once daily. Patients aged ≥14 years completed the SF-36 questionnaire at baseline, Month 6, Month 12 and end of treatment (EOT)...
September 23, 2016: Chest
David L Prior, Heath Adams, Trevor J Williams
Pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis if not treated. Pharmacological treatment options for PAH have increased significantly over the past 10 years, with availability of intravenous, oral and inhaled drugs targeting the nitric oxide, endothelin and prostacyclin pathways. Treatment with these therapies in specialised pulmonary hypertension centres has resulted in reductions in patient symptoms, disease progression and mortality, and improved exercise capacity. Recognition of chronic thromboembolic pulmonary hypertension is important, as this cause of pulmonary hypertension may be amenable to surgical treatment...
September 19, 2016: Medical Journal of Australia
Gillian M Keating
Macitentan (Opsumit(®)) is an orally active, potent, dual endothelin (ET) receptor antagonist that is indicated for the treatment of pulmonary arterial hypertension (PAH). In the pivotal SERAPHIN trial in patients aged ≥12 years with PAH, the risk of first PAH-related event or all-cause death (primary composite endpoint) was significantly reduced by 45 % with oral macitentan 10 mg once daily versus placebo. Macitentan significantly reduced the risk of the primary composite endpoint across various patient subgroups...
August 31, 2016: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
Martine Clozel
Endothelin receptor antagonists (ERAs) are used for the treatment of pulmonary arterial hypertension (PAH). Macitentan, a dual (ETA+ETB) ERA approved for the long-term treatment of PAH, was discovered through a tailored research program aimed at improving efficacy and safety over the existing ERAs. The goal of improved efficacy was based on the understanding that not only the ETA receptor but also the ETB receptor contributed to the hemodynamic and structural changes induced by endothelin-1 (ET-1) in pathological conditions and on the predefined requirements for optimal tissue penetration and binding kinetics of the antagonist...
August 17, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Michael Kuntz, Miguel M Leiva-Juarez, Suvitesh Luthra
BACKGROUND: There are currently three Food and Drug Administration approved endothelin receptor antagonists (ERAs): bosentan, ambrisentan, and macitentan. There is a growing body of evidence that demonstrates the beneficial effects of ERAs in patients with pulmonary arterial hypertension (PAH). OBJECTIVES: To compare the available evidence from randomized clinical trials for specific outcomes of different endothelin antagonists for the treatment of PAH. METHODS: A multi-database search of randomized controlled trials up to March 15, 2016 was conducted for those that would measure functional parameters of patients with PAH treated with ERA monotherapy versus placebo...
October 2016: Lung
Udhay Krishnan, Evelyn M Horn
In recent years, there have been major changes in the landscape of pulmonary arterial hypertension therapy with the introduction of novel agents and innovative treatment strategies for this progressive disease. The aim of this review is to discuss the evolution in trial design in this field and highlight the salient features of recently published studies. We also summarize our approach to therapy selection in this chronic disease and identify areas for future exploration. The therapeutic armamentarium now includes 13 approved therapies...
September 2016: Current Atherosclerosis Reports
S N Avdeev
Pulmonary arterial hypertension (PAH) is a clinical group of severe and rare diseases with similar morphological, hemodynamic, and therapeutic characteristics. One of the novel drugs to treat PAH is macitentan, a new double endothelin ETA and ETB receptor antagonist that is characterized by special physicochemical properties, ensuring the penetration of the drug into tissues and its improved receptor-binding properties. The SERAPHIN trial has demonstrated that therapy with macitentan 10 mg versus placebo statistically significantly reduces the risk of poor outcomes and death by 45%...
2016: Terapevticheskiĭ Arkhiv
Yuichi Tamura, Richard N Channick
PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) was previously considered a uniformly fatal disease, with patients succumbing to right heart failure and death at an average of 3 years after diagnosis. The past 20 years, however, have seen the development of numerous targeted therapies that have changed the natural history of PAH. As more pharmacologic agents have been approved and utilized, further advances in the design of and endpoints for clinical trials. This study will review some of these notable developments...
September 2016: Current Opinion in Pulmonary Medicine
Jürgen Knobloch, Sarah Derya Yanik, Sandra Körber, Erich Stoelben, David Jungck, Andrea Koch
UNLABELLED: Pathological proliferation of human airway smooth muscle cells (HASMCs) causes hyperplasia in chronic lung diseases. Signaling pathways that link airway inflammation to HASMC proliferation might provide therapeutic targets for the prevention of airway remodeling and chronic lung diseases. Endothelin-1 (ET-1) signals via endothelin-A- and B-receptors (ETAR, ETBR) to perpetuate HASMC-associated and TNFα-dependent inflammatory processes. HYPOTHESIS: endothelin receptor antagonists (ERAs) suppress HASMC proliferation induced by inflammatory cytokines...
September 15, 2016: Biochemical Pharmacology
Michele Correale, Stefano Zicchino, Ilenia Monaco, Natale Daniele Brunetti, Matteo Di Biase
No abstract text is available yet for this article.
October 1, 2016: International Journal of Cardiology
Christoph Boss, Martin H Bolli, John Gatfield
The endothelin peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular smooth muscle cells, the endothelin-B (ETB)-receptor is also found in endothelial cells, fibroblasts, and neuronal cells. Activation of the endothelin system plays a driving role in several chronic cardiovascular diseases and several endothelin receptor antagonists (ERAs) (bosentan (6), ambrisentan (83) and macitentan (43)) have successfully been introduced as oral treatments for the life threatening condition of pulmonary arterial hypertension (PAH)...
August 1, 2016: Bioorganic & Medicinal Chemistry Letters
Thomas J Monaco, Carlos D Davila
Pulmonary arterial hypertension is a progressive, debilitating disease caused by a dysregulation of the pulmonary vascular tone that inevitably leads to right heart failure and death without treatment. Until relatively recently, the treatment options for those afflicted by pulmonary arterial hypertension were limited; today, a greater understanding of the pathophysiology behind this disease has led to several evidence-based therapies that can improve pulmonary function and quality of life for these patients...
2016: Drug Design, Development and Therapy
Nobuhiro Tahara, Hiroaki Dobashi, Keiichi Fukuda, Masanori Funauchi, Masaru Hatano, Satoshi Ikeda, Shuji Joho, Yasuki Kihara, Takeshi Kimura, Takahisa Kondo, Masakazu Matsushita, Tohru Minamino, Norifumi Nakanishi, Yukio Ozaki, Tsutomu Saji, Satoshi Sakai, Nobuhiro Tanabe, Hiroshi Watanabe, Hidehiro Yamada, Koichiro Yoshioka, Shigetake Sasayama
BACKGROUND: Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS: Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24...
May 25, 2016: Circulation Journal: Official Journal of the Japanese Circulation Society
Dinesh Khanna, Christopher P Denton, Peter A Merkel, Thomas Krieg, Franck-Olivier Le Brun, Angelina Marr, Kelly Papadakis, Janet Pope, Marco Matucci-Cerinic, Daniel E Furst
IMPORTANCE: Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. OBJECTIVE: To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014...
May 10, 2016: JAMA: the Journal of the American Medical Association
Carmen Pizarro, Julia Meyer Zur Heide Genannt Meyer-Arend, Robert Schueler, Christoph Hammerstingl, Izabela Tuleta, Georg Nickenig, Dirk Skowasch
No abstract text is available yet for this article.
July 1, 2016: International Journal of Cardiology
Nancy S Saad, Kyle Floyd, Amany A E Ahmed, Peter J Mohler, Paul M L Janssen, Mohammad T Elnakish
Multikinase inhibitors (e.g. Sorafenib), phosphodiesterase-5 inhibitors (e.g. Tadalafil), and endothelin-1 receptor blockers (e.g. Macitentan) exert influential protection in a variety of animal models of cardiomyopathy; however, their effects on thyroxin-induced cardiomyopathy have never been investigated. The goal of the present study was to assess the functional impact of these drugs on thyroxin-induced hemodynamic changes, cardiac hypertrophy and associated altered responses of the contractile myocardium both in-vivo at the whole heart level and ex-vivo at the cardiac tissue level...
2016: PloS One
Ho Jeong Lee, Masaki Hanibuchi, Sun-Jin Kim, Hyunkyung Yu, Mark Seungwook Kim, Junqin He, Robert R Langley, François Lehembre, Urs Regenass, Isaiah J Fidler
BACKGROUND: We recently demonstrated that brain endothelial cells and astrocytes protect cancer cells from chemotherapy through an endothelin-dependent signaling mechanism. Here, we evaluated the efficacy of macitentan, a dual endothelin receptor (ETAR and ETBR) antagonist, in the treatment of experimental breast and lung cancer brain metastases. METHODS: The effect of macitentan on astrocyte- and brain endothelial cell-mediated chemoprotective properties was measured in cytotoxic assays...
April 2016: Neuro-oncology
Martin Houde, Louisane Desbiens, Adel Schwertani, Gunnar Pejler, Marc Iglarz, Pedro D'Orléans-Juste
AIMS: To determine the impact of mixed endothelin receptor antagonist and mouse mast cell protease-4 (mMCP-4) in the development of atherosclerosis in the mouse model. MATERIALS AND METHODS: Apolipoprotein E (ApoE) KO mice were crossed with mMCP-4 KO mice to generate ApoE/mMCP-4 double KO mice. Atherosclerosis was induced with a normal- or high-fat diet for 12, 27 or 52weeks. Macitentan (30mg/kg/day), a dual ETA/ETB receptor antagonist, was given orally for 6weeks (27week protocol)...
August 15, 2016: Life Sciences
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