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* Laval Hospital Research Center, Quebec Heart and Lung Institute, Department of Medicine, Laval University, Sainte-Foy, Quebec, Canada G1V 4G5; IPS Pharma Inc., Sherbrooke, Quebec, Canada J1H 5N4; Clinical Pharmacology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland EH16 4TJ, United Kingdom; and Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132
To whom requests for reprints should be addressed at 1 Centre de recherche de l’Hôpital Laval, Institut de cardiologie et de pneumologie, 2725 Chemin Ste-Foy, Ste-Foy, QC, Canada G1V 4G5. E-mail: bruno.battistini{at}med.ulaval.ca.
Since its initial characterization in 1988, over 18,236 papers, including 2,485 reviews, have been published in the endothelin (ET) field. Over this period, several generations of selective and mixed (dual) ET receptor antagonists (ERAs), from peptidic backbones to orally active potent (subnanomolar) small molecular compounds, have been developed. These agents have been studied in many experimental animal models of various pathological conditions (cardiovascular, respiratory, and neuro-immunological). Continued basic research has led to a better understanding of the complex interactions between the ET axis and other biologic systems in human pathophysiology. The first clinical trial involved patients with idiopathic pulmonary arterial hypertension and led to approval of bosentan (Tracleer) for use in the United States and Europe in 2002. Since then, bosentan, the only currently approved dual (mixed) ERA, has been used in numerous other clinical trials. In addition, more selective ETA receptor antagonists (ambrisentan, atrasentan, avosentan, clazosentan, darusentan, and sitaxsentan) are undergoing clinical trials. Here we outline the ERAs undergoing development and summarize the standing of completed and ongoing trials at the time of the Ninth International Conference on Endothelin and even thereafter. This review is intended to provide a useful reference for those interested in the current state of clinical trials involving ERAs, and to identify lessons that might apply to the design of future trials.
Key Words: endothelin • receptor antagonist • ERA • clinical trials
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