title: A review of pulmonary arterial hypertension: role of ambrisentan.
abstract: Pulmonary arterial hypertension (PAH) is a rare fatal disease. Current disease-specific therapeutic interventions in PAH target 1 of 3 established pathways in disease pathobiology: prostacyclin, nitric oxide, and endothelin-1. Endothelin receptor antagonists (ERAs) act on the endothelin pathway by blocking binding of endothelin-1 to its receptors (endothelin type-A [ET(A)] and/or type-B [ET(B)]) on the surface of endothelial and smooth muscle cells. Ambrisentan is an oral, once-daily, ET(A)-selective ERA in development for the treatment of PAH. In Phase 3 clinical trials in patients with PAH, ambrisentan (2.5-10 mg orally once-daily) improved exercise capacity, Borg dyspnea index, time to clinical worsening, WHO functional class, and quality of life compared with placebo. Ambrisentan provided durable (at least 2 years) improvement in exercise capacity in a Phase 2 long-term extension study. Ambrisentan was well tolerated with a lower incidence and severity of liver function test abnormalities compared with the ET(A)/ET(B) ERA, bosentan, and the ET(A)-selective ERA, sitaxsentan. Ambrisentan does not induce or inhibit P450 enzymes; therefore, ambrisentan is unlikely to affect the pharmacokinetics of P450-metabolized drugs. The demonstration of clinical efficacy, low incidence of acute hepatic toxicity, and low risk of drug-drug interactions support the role of ambrisentan for the treatment of PAH.
authors.affiliation: New York Presbyterian Pulmonary Hypertension Center, Columbia University College of Physicians & Surgeons, 3959 Broadway, BHN 2-255, NewYork, NY 10032, USA. rjb3@columbia.edu
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
mesh_terms: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects; D015444:Exercise / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D010666:Phenylpropionates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017466:Receptors, Endothelin / Q000097:blood; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011724:Pyridazines; D017466:Receptors, Endothelin; C467894:ambrisentan