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Lewis J. Rubin - One of the best experts on this subject based on the ideXlab platform.
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Endothelin Receptor Antagonists for the treatment of pulmonary artery hypertension
Life Sciences, 2012Co-Authors: Lewis J. RubinAbstract:Abstract Aims The demonstration that Endothelin production is upregulated in pulmonary artery hypertension (PAH) served as the rationale for developing Endothelin-Receptor Antagonists (ERAs) as a treatment for PAH. This article reviews the primary studies demonstrating efficacy of ERAs in PAH. Main methods Multicenter, placebo-controlled trials and open-label extension studies. Key findings Two orally active ERAs are currently approved for the treatment of PAH — the dual Receptor antagonist bosentan, and the more selective ETA Receptor antagonist ambrisentan-based on multicenter randomized clinical trials demonstrating efficacy and safety. Long-term experience with both agents supports maintenance of therapeutic effects in most patients. Adverse effects, including altered liver function and edema may occur and require careful monitoring. Significance Despite failure to demonstrate efficacy of ERAs in other cardiopulmonary conditions, ERAs have a major role in the treatment algorithm for PAH.
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clinical trials with Endothelin Receptor Antagonists what went wrong and where can we improve
Life Sciences, 2012Co-Authors: Donald E. Kohan, Lewis J. Rubin, John G F Cleland, Dan Theodorescu, Matthias BartonAbstract:In the early 1990s, within three years of cloning of Endothelin Receptors, orally active Endothelin Receptor Antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.
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Endothelin Receptor Antagonists in pulmonary arterial hypertension.
Journal of the American College of Cardiology, 2004Co-Authors: Richard N. Channick, Olivier Sitbon, Robyn J. Barst, Alessandra Manes, Lewis J. RubinAbstract:Endothelin Receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that Endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral Endothelin Receptor Antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-Receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective Endothelin Receptor-A Antagonists sitaxsentan and ambrisentan are currently undergoing investigation.
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Endothelin in health and disease Endothelin Receptor Antagonists in the management of pulmonary artery hypertension
Journal of Cardiovascular Pharmacology and Therapeutics, 2002Co-Authors: Nick H Kim, Lewis J. RubinAbstract:Endothelin (ET) has been identified as playing a fundamental role in many disease processes. Therapeutic efforts at interrupting ET's pathologic effects have focused on Endothelin Receptor Antagonists (ERAs), of which two, bosentan and sitaxsentan, have been evaluated for the treatment of both primary and secondary pulmonary arterial hypertension (PAH). We discuss the multiple actions of ET, its role in various disease states, and the effects of ET Receptor stimulation and blockade. Current classification and management of PAH are reviewed, along with the promise of greatly improved treatment generated by recent and ongoing clinical trials using ERAs.
Matthias Barton - One of the best experts on this subject based on the ideXlab platform.
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clinical trials with Endothelin Receptor Antagonists what went wrong and where can we improve
Life Sciences, 2012Co-Authors: Donald E. Kohan, Lewis J. Rubin, John G F Cleland, Dan Theodorescu, Matthias BartonAbstract:In the early 1990s, within three years of cloning of Endothelin Receptors, orally active Endothelin Receptor Antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.
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Endothelin Receptor Antagonists in Cardiovascular Medicine: Challenges and Opportunities
Translational Vascular Medicine, 2011Co-Authors: Matthias BartonAbstract:The discovery of the release of endothelium-derived vasoconstriction led to studies identifying the endothelium-derived peptide Endothelin and its Receptors. In the early 1990s, Endothelin Receptor Antagonists (ERAs) were developed and preclinical and clinical studies initiated. Despite strong experimental evidence for a role of Endothelin-1, the predominant member of the Endothelin peptide family, in cardiovascular physiology and disease, the vast majority of clinical studies in cardiovascular medicine using Endothelin Receptor Antagonists (ERAs) were negative partly because study design and/or patient selection were frequently inadequate. This chapter provides an overview of the Endothelin system as well as preclinical data of ERA studies obtained in disease models of arterial hypertension, atherosclerosis, coronary artery disease, pulmonary hypertension, heart failure, renal disease, and allograft rejection following cardiac transplantation. Results and developments in ERA clinical trials in cardiovascular medicine will be discussed also covering reasons for failed ERA trials and discontinuation of clinical drug development of numerous ERAs.
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therapeutic potential of Endothelin Receptor Antagonists for chronic proteinuric renal disease in humans
Biochimica et Biophysica Acta, 2010Co-Authors: Matthias BartonAbstract:article i nfo Keywords: Endothelin Glomerulosclerosis Aging Hypertension Injury Proteinuria Albuminuria Reversal Albuminuria Regression Diabetes and arterial hypertension continue to be the main causes of chronic renal failure in 2010, with a rising prevalence in part due to the worldwide obesity epidemic. Proteinuria is a main feature of chronic renal disease and mediated by defects in the glomerular filtration barrier and is as a good predictor of cardiovascular events. Indeed, chronic renal disease due to glomerulosclerosis is one of the important risk factors for the development of coronary artery disease and stroke. Glomerulosclerosis develops in response to inflammatory activation and increased growth factor production. Preclinical and first preliminary clinical studies provide strong evidence that endogenous Endothelin-1 (ET-1), a 21-amino-acid peptide with strong growth-promoting and vasoconstricting properties, plays a central role in the pathogenesis of proteinuria and glomerulosclerosis via activation of its ETA subtype Receptor involving podocyte injury. These studies have not only shown that Endothelin participates in the disease processes of hypertension and glomerulosclerosis but also that features of chronic renal disease such as proteinuria and glomerulosclerosis are reversible processes. Remarkably, the protective effects of Endothelin Receptors Antagonists (ERAs) are present even on top of concomitant treatments with inhibitors of the renin-angiotensin system. This review discusses current evidence for a role of Endothelin for proteinuric renal disease and podocyte injury in diabetes and arterial hypertension and reviews the current status of Endothelin Receptor Antagonists as a potential new treatment option in renal medicine.
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Anti-Inflammatory Effects of Endothelin Receptor Antagonists and their Importance for Treating Human Disease
2010Co-Authors: Matthias Barton, Philipp C. Nett, Kerstin Amann, Mauro M. TeixeiraAbstract:Endothelin-1 (ET-1) is the main effector peptide of the Endothelin family. Aside from being a potent endogenous vasoconstrictor and mitogen acting through its ETA Receptors, it contributes to the regulation of immune mechanisms, inflammatory cell activation, and release of cytokines. Thereby, Endothelin promo- tes the developement of a number of chronic disease conditions characterized by inflammtory activation, including atherosclerosis and chronic renal failure. Studies using orally active Endothelin Receptor antogonists have shown that the ETA Receptor is mainly responsible for the immunomodulatory actions of Endothelin. This review highlights recent findings in the field showing that the ET system, apart from being a marker and mediator of vascular injury, is directly involved in pathophysiology of these disease processes as an immunomodulatory factor. In this review, we summarize the current understanding of the mechanisms and signal transduction pathways triggered by ET-1 in inflammatory and immunomodulatory processes and discuss the findings of studies evaluating the use of selective and non-selective Endothelin Receptor Antagonists in diseases associated with acute or chronic inflammatory activation, also discussing including the most recent clinical studies in the field using Endothelin Receptor Antagonists.
Suvitesh Luthra - One of the best experts on this subject based on the ideXlab platform.
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Systematic Review of Randomized Controlled Trials of Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension
Lung, 2016Co-Authors: Michael Kuntz, Miguel M. Leiva-juarez, Suvitesh LuthraAbstract: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. Studies that analyzed 6-min walking distance, pulmonary vascular resistance, pulmonary arterial pressure, or WHO functional status were incorporated for analysis. A total of 15 trials and 2 subanalyses were compiled and quality and abovementioned outcomes were compared among studies. Results A constant decrease in pulmonary vascular resistance and pulmonary arterial pressure was globally reported among the different studies, resulting in increased 6-min walking distance and functional status compared to placebo. Conclusions Although this evidence clearly shows the benefit of ERAs, studies, which compare ERAs against one another and with other therapies for progressive PAH, have been lacking. Larger and longer studies are necessary to define the role of ERAs as standalone agents and in combination therapies.
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Systematic Review of Randomized Controlled Trials of Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension.
Lung, 2016Co-Authors: Michael T. Kuntz, Miguel M. Leiva-juarez, Suvitesh LuthraAbstract: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).
David J. Webb - One of the best experts on this subject based on the ideXlab platform.
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dorado opportunity postponed lessons from studies of Endothelin Receptor Antagonists in treatment resistant hypertension
Hypertension, 2010Co-Authors: David J. WebbAbstract:Treatment-resistant hypertension (TRH) describes a situation where blood pressure (BP) remains above target in spite of the concurrent use of 3 antihypertensive agents of different classes, with 1 of the agents a diuretic, and all ideally given at an optimized dose. TRH is a common clinical problem, perhaps occurring in 20% to 30% of participants in hypertension trials, and is likely to become increasingly common in the future because BP targets are reducing, and older age and obesity are 2 of the strongest risk factors for its occurrence.1 A number of interventions have been shown to reduce BP substantially in patients with TRH, and, with its growing prevalence and the excellent cost-effectiveness of current first-line treatments, it is increasingly becoming a valuable indication in its own right for newly licensed medicines. One such intervention that has shown promise in this indication is the use of Endothelin Receptor Antagonists (ETRAs). In a major study (DORADO) published last year,2 the ETRA darusentan, at doses of 50, 100, and 300 mg daily, was studied in 379 patients with TRH using a randomized, double-blind, placebo-controlled design. Comorbidities in these patients included type 2 diabetes mellitus and chronic kidney disease. Reduction in the coprimary end points of seated systolic and diastolic BPs at week 14 of treatment were 17/10, 18/10, and 18/11 mm Hg with increasing doses of darusentan but significantly less with placebo at only 9/5 …
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Endothelin Receptor Antagonists
Drugs in R & D, 1999Co-Authors: Jane Goddard, David J. WebbAbstract:Since its discovery in 1988, Endothelin (ET) has been widely implicated in the pathophysiology of cardiovascular disease. ET Antagonists have favourable effects in experimental models of these conditions and have proved useful in elucidating the role of the ET system. Orally acting ET Antagonists appear very promising in clinical trials, particularly in patients with chronic heart failure and hypertension, but more information on the roles of the ET Receptor subtypes in health and disease is required so that an informed choice can be made between the use of Endothelin-A (ET-A) Receptor-selective and nonselective Receptor Antagonists.
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The Clinical Potential of Endothelin Receptor Antagonists in Cardiovascular Medicine
Drugs, 1996Co-Authors: Charles J. Ferro, David J. WebbAbstract:The Endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, Endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two Endothelin Receptor subtypes have so far been cloned in mammalian species; ET_A and ET_B. Both Receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of Endothelin. The ETB Receptor is also found on vascular endothelial cells and mediates Endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the Endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that Endothelin regulates vascular tone and blood pressure, and studies to support the development of Endothelin Receptor Antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud’s disease. There are now a number of selective ET_A and combined ET_A/B Receptor Antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin Receptor Antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.
Olivier Sitbon - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension
American Journal of Cardiovascular Drugs, 2015Co-Authors: Marie-camille Chaumais, Marc Humbert, Laurent Savale, Xavier Jaïs, David Montani, Gérald Simonneau, Christophe Guignabert, Athénaïs Boucly, Olivier SitbonAbstract:Pulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Vascular endothelial cells mainly produce and secrete Endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug, and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. We outline the current understanding of not only the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH but also the clinical pharmacology of Endothelin Receptor Antagonists (ERA) used in the treatment of PAH.
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Endothelin Receptor Antagonists for the treatment of pulmonary arterial hypertension.
Expert Opinion on Pharmacotherapy, 2011Co-Authors: Dermot S. O'callaghan, Marc Humbert, Laurent Savale, Azzedine Yaici, Delphine Natali, Xavier Jaïs, Florence Parent, David Montani, Gérald Simonneau, Olivier SitbonAbstract:Introduction: Endothelin is a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). Its effects are mediated through the activation of two associated Receptor subtypes, termed A and B. Therapeutic strategies that modulate the activity of Endothelin are, therefore, of interest to improve the functional status of patients with PAH. Areas covered: The rationale for the use of Endothelin Receptor Antagonists as a therapeutic class in PAH and pertinent data from important clinical studies are presented in this review. Areas for future research are also suggested. Expert opinion: The availability of the Endothelin Receptor antagonist class of agents represents a significant addition to the therapeutic armamentarium which is available for the treatment of PAH. Comparative studies are warranted to establish whether selective Endothelin-A Receptor antagonism is more advantageous than dual Receptor antagonism. Future studies of Endothelin Receptor Antagonists will increasingly focus on the p...
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Endothelin Receptor Antagonists in pulmonary arterial hypertension.
Journal of the American College of Cardiology, 2004Co-Authors: Richard N. Channick, Olivier Sitbon, Robyn J. Barst, Alessandra Manes, Lewis J. RubinAbstract:Endothelin Receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that Endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral Endothelin Receptor Antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-Receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective Endothelin Receptor-A Antagonists sitaxsentan and ambrisentan are currently undergoing investigation.