title: Bosentan therapy for pulmonary arterial hypertension.
abstract: BACKGROUND
  Endothelin-1 is a potent vasoconstrictor and smooth-muscle mitogen. In a preliminary study, the orally administered dual endothelin-receptor antagonist bosentan improved exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary arterial hypertension. The present trial investigated the effect of bosentan on exercise capacity in a larger number of patients and compared two doses.
  
  
  METHODS
  In this double-blind, placebo-controlled study, we randomly assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 62.5 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks. The primary end point was the degree of change in exercise capacity. Secondary end points included the change in the Borg dyspnea index, the change in the World Health Organization (WHO) functional class, and the time to clinical worsening.
  
  
  RESULTS
  At week 16, patients treated with bosentan had an improved six-minute walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95 percent confidence interval, 21 to 67; P<0.001). Bosentan also improved the Borg dyspnea index and WHO functional class and increased the time to clinical worsening.
  
  
  CONCLUSIONS
  The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California at San Diego, La Jolla 92037-1330, USA. ljrubin@ucsd.edu
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Rubin
authors.forename: David B
authors.initials: DB
authors.lastname: Badesch
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galie
authors.forename: Carol M
authors.initials: CM
authors.lastname: Black
authors.forename: Anne
authors.initials: A
authors.lastname: Keogh
authors.forename: Tomas
authors.initials: T
authors.lastname: Pulido
authors.forename: Adaani
authors.initials: A
authors.lastname: Frost
authors.forename: Sebastien
authors.initials: S
authors.lastname: Roux
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leconte
authors.forename: Michael
authors.initials: M
authors.lastname: Landzberg
authors.forename: Gerald
authors.initials: G
authors.lastname: Simonneau
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077300:Bosentan; D002648:Child; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000145:classification / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008099:Liver / Q000187:drug effects; D008180:Lupus Erythematosus, Systemic / Q000150:complications; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000150:complications; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016138:Walking
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan