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Marius M Hoeper, Vallerie V McLaughlin, Joan Albert Barberá, Adaani E Frost, Hossein-Ardeschir Ghofrani, Andrew J Peacock, Gérald Simonneau, Stephan Rosenkranz, Ronald J Oudiz, R James White, Karen L Miller, Jonathan Langley, Julia H N Harris, Christiana Blair, Lewis J Rubin, Jean-Luc Vachiery
BACKGROUND: In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival. METHODS: We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial...
October 10, 2016: Lancet Respiratory Medicine
Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki
AIM: To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model. METHODS: Fatty liver shionogi (FLS) FLS-ob/ob mice (male, 12 wk old) received ambrisentan (2.5 mg/kg orally per day; n = 8) or water as a control (n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver. RESULTS: In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group (18...
August 8, 2016: World Journal of Hepatology
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
Aryeh Fischer, Christopher P Denton, Marco Matucci-Cerinic, Hunter Gillies, Christiana Blair, James Tislow, Steven D Nathan
OBJECTIVE: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH)...
August 2016: Respiratory Medicine
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
S Orlandini, B Pasquini, C Caprini, M Del Bubba, M Douša, S Pinzauti, S Furlanetto
A capillary electrophoresis method for the simultaneous determination of the enantiomeric purity and of impurities of the chiral drug ambrisentan has been developed following the Quality by Design principles. The selected separation system consisted of a micellar pseudostationary phase made by sodium dodecyl sulphate with the addition of γ-cyclodextrin. The effects of critical process parameters (capillary length, temperature, voltage, borate concentration, pH, sodium dodecyl sulphate concentration, γ-cyclodextrin concentration) on enantioresolution of ambrisentan and analysis time were extensively investigated by multivariate strategies involving a screening phase and Response Surface Methodology...
July 1, 2016: Journal of Chromatography. A
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
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
Jean-Luc Vachiéry, Marius M Hoeper, Andrew J Peacock, Olivier Sitbon, Martino Cheli, Colin Church, Karen M Olsson, Massimiliano Palazzini, Brian Waterhouse, Jonathan Langley, Nazzareno Galié
BACKGROUND: The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN). METHODS: In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled...
May 6, 2016: Journal of Heart and Lung Transplantation
Mengchun Chen, Wenjie Song, Shuanghu Wang, Qiulei Chen, Peipei Pan, Tao Xu, Guoxin Hu, Zhiqiang Zheng
A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for the simultaneous determination of bosentan (BOS), glimepiride (GLP), hydroxyl bosentan (HYBOS) and hydroxyl glimepiride (M1) in rat plasma using one-step protein precipitation was developed and validated. After addition of ambrisentan as an internal standard (IS), protein precipitation by acetonitrile was used in sample preparation. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C18 column (2...
August 2016: Journal of Chromatographic Science
Shao-Jung Hsu, Te-Yueh Lin, Sun-Sang Wang, Chiao-Lin Chuang, Fa-Yauh Lee, Hui-Chun Huang, I-Fang Hsin, Jing-Yi Lee, Han-Chieh Lin, Shou-Dong Lee
BACKGROUND: Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension. DESIGN: This study aimed to survey the influences of ET-1 in cirrhosis-related angiogenesis. Common bile duct ligation was performed on Spraque-Dawley rats to induce cirrhosis. Since the 14th day after the operation, rats randomly received distilled water (DW, control), bosentan [a nonselective ET receptor (ETR) blocker] or ambrisentan (a selective ETA R blocker) for 4 weeks...
June 2016: European Journal of Clinical Investigation
Ari M Cedars, Joshua Saef, Linda R Peterson, Andrew R Coggan, Eric L Novak, Debra Kemp, Philip A Ludbrook
The Fontan operation is a common end point for children born with a single functional ventricle. Fontan patients typically experience physiological deterioration leading to transplant or death in their third or fourth decades of life. This deterioration is partially attributable to progressive increases in pulmonary vascular resistance (PVR) and as such endothelin receptor antagonists, which are known to decrease pulmonary vascular resistance, have been proposed as potentially beneficial in this population...
May 1, 2016: American Journal of Cardiology
Takao Takeuchi, Seiichiro Sakao, Fumiaki Kato, Akira Naito, Takayuki Jujo, Tadashi Yasuda, Nobuhiro Tanabe, Koichiro Tatsumi
RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by obstructive lesions and vasoconstriction of the pulmonary arteries. Early therapeutic interventions with vasodilator drugs are thought to be beneficial in PAH. However, it remains unknown whether the severity of intimal obstruction is associated with increased pulmonary arterial pressure and whether reduction of vasoconstriction in the earlier stage by these drugs has a beneficial effect. Therefore, the aims of this study were to investigate these issues in a rat model of severe PAH...
December 2016: Histology and Histopathology
Yukihiro Imajo, Nobuyasu Komasawa, Yusuke Kusaka, Haruki Kido, Toshiaki Minami
Pulmonary arterial hypertension (PAH) is a known risk factor of perioperative complications, but the risks for non-cardiac operations have not yet been examined sufficiently. We report a case of a right lower lobectomy in a patient with PAH. A 73-year-old woman with Sjögren's syndrome was scheduled for right lowr lobectomy for primary lung cancer under general anesthesia. She was diagnosed with symptomatic PAH (estimated mean pulmonary arterial pressure, 40 mmHg) and medicated with ambrisentan. After induction of general anesthesia with propofol and fentanyl, a pulmonary artery catheter was placed to measure pulmonary artery pressure...
February 2016: Masui. the Japanese Journal of Anesthesiology
Olivier Sitbon, Caroline Sattler, Laurent Bertoletti, Laurent Savale, Vincent Cottin, Xavier Jaïs, Pascal De Groote, Ari Chaouat, Céline Chabannes, Emmanuel Bergot, Hélène Bouvaist, Claire Dauphin, Arnaud Bourdin, Fabrice Bauer, David Montani, Marc Humbert, Gérald Simonneau
Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8)...
June 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Anthony P Davenport, Kelly A Hyndman, Neeraj Dhaun, Christopher Southan, Donald E Kohan, Jennifer S Pollock, David M Pollock, David J Webb, Janet J Maguire
The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action...
April 2016: Pharmacological Reviews
Guillermo Pousada, Adolfo Baloira, Olalla Castro-Añón, Diana Valverde
BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare and progressive disease that can be inherited as autosomal dominant form. The BMPR2, ACVRL1 and ENG genes are main genes involved in the pathology. PAH associated to human immunodeficiency virus (HIV) is another rare disease with a low incidence, prevalence and survival. The main objective of this analysis was to study the clinical and molecular characteristics of PAH associated to HIV patients. PATIENTS: We present 4 cases of HIV patients who developed PAH and have been treated with ambrisentan...
April 15, 2016: Medicina Clínica
Bram Rochwerg, Binod Neupane, Yuan Zhang, Carlos Cuello Garcia, Ganesh Raghu, Luca Richeldi, Jan Brozek, Joseph Beyene, Holger Schünemann
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with high morbidity and mortality. Effective treatments for IPF are limited. Several recent studies have investigated novel therapeutic agents for IPF, but very few have addressed their comparative benefits and harms. METHODS: We performed a Bayesian network meta-analysis (NMA) to assess the effects of different treatments for IPF on mortality and serious adverse events (SAEs)...
2016: BMC Medicine
Shinya Fukumoto, Kaname Saida, Hiroki Sakai, Hiroshi Ueno, Hidetomo Iwano, Tsuyoshi Uchide
AIMS: Hemangiosarcoma (HSA) that originates from vascular endothelial cells is the most common splenic malignant neoplasm in dogs, as it accounts for approximately 20% of all canine soft tissue sarcomas. In this study, inhibitory effects of endothelin receptor antagonists on the growth of HSA cells were examined using cell lines established from canine HSA. MAIN METHODS: The preproendothelin-1 (PPET-1), endothelin type A receptor (ETA) and endothelin type B receptor (ETB) mRNA expression levels in HSA cell lines (n=5) were analyzed quantitatively by real-time RT-PCR...
August 15, 2016: Life Sciences
Kevin Liou, Nigel Jepson, Nicolas Buckley, Vivien Chen, Shane Thomas, Elizabeth Anne Russell, Sze-Yuan Ooi
PURPOSE: Peri-procedural myocardial infarction (PMI) occurs in a small but significant portion of patients undergoing percutaneous intervention (PCI). The underlying mechanisms are complex and may include neurohormonal activation and release of vasoactive substances resulting in disruption of the coronary microcirculation. Endothelin in particular has been found in abundance in atherosclerotic plaques and in systemic circulation following PCI, and may be a potential culprit for PMI through its action on microvascular vasoconstriction, and platelet and neutrophil activation...
April 2016: Cardiovascular Drugs and Therapy
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