title: Ambrisentan therapy for pulmonary arterial hypertension.
abstract: OBJECTIVE
  The purpose of this study was to examine the efficacy and safety of four doses of ambrisentan, an oral endothelin type A receptor-selective antagonist, in patients with pulmonary arterial hypertension (PAH).
  
  
  BACKGROUND
  Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options. Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH.
  
  
  METHODS
  In this double-blind, dose-ranging study, 64 patients with idiopathic PAH or PAH associated with collagen vascular disease, anorexigen use, or human immunodeficiency virus infection were randomized to receive 1, 2.5, 5, or 10 mg of ambrisentan once daily for 12 weeks followed by 12 weeks of open-label ambrisentan. The primary end point was an improvement from baseline in 6-min walk distance (6MWD); secondary end points included Borg dyspnea index, World Health Organization (WHO) functional class, a subject global assessment, and cardiopulmonary hemodynamics.
  
  
  RESULTS
  At 12 weeks, ambrisentan increased 6MWD (+36.1 m, p < 0.0001) with similar and statistically significant increases for each dose group (range, +33.9 to +38.1 m). Improvements were also observed in Borg dyspnea index, WHO functional class, subject global assessment, mean pulmonary arterial pressure (-5.2 mm Hg, p < 0.0001), and cardiac index (+0.33 l/min/m2, p < 0.0008). Adverse events were mild and unrelated to dose, including the incidence of elevated serum aminotransferase concentrations >3 times the upper limit of normal (3.1%).
  
  
  CONCLUSIONS
  Ambrisentan appears to improve exercise capacity, symptoms, and hemodynamics in patients with PAH. The incidence and severity of liver enzyme abnormalities appear to be low.
authors.affiliation: University of Bologna, Bologna, Italy. n.galie@bo.nettuno.it
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galié
authors.forename: David
authors.initials: D
authors.lastname: Badesch
authors.forename: Ronald
authors.initials: R
authors.lastname: Oudiz
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Michael D
authors.initials: MD
authors.lastname: McGoon
authors.forename: Anne M
authors.initials: AM
authors.lastname: Keogh
authors.forename: Adaani E
authors.initials: AE
authors.lastname: Frost
authors.forename: Diane
authors.initials: D
authors.lastname: Zwicke
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.forename: Shelley
authors.initials: S
authors.lastname: Shapiro
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Rubin
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010666:Phenylpropionates / Q000008:administration & dosage* / Q000009:adverse effects; D011336:Probability; D011724:Pyridazines; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D010666:Phenylpropionates; D011724:Pyridazines; C467894:ambrisentan