title: First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension.
abstract: BACKGROUND
  New oral substances such as beraprost, bosentan and sildenafil have proven effective in different forms of pulmonary arterial hypertension (PAH), both alone and in combination with standard treatment such as intravenous and inhaled prostacyclins. However, there are few reports so far on the effect of a combination of exclusively oral substances. In this paper, we present our initial findings of treatment using a combination of these oral substances in a heterogeneous group of patients with different forms of PAH.
  
  
  METHODS
  Eleven patients with a median age of 12.9 years (5.5-54.7 years) with both idiopathic PAH and forms associated with congenital cardiac defects (PAH-CHD) with a mean pulmonary arterial pressure > 25 mmHg were enrolled in an observational, open-label, prospective, single-centre study. Either combination treatment with bosentan and sildenafil was started initially, or an existing bosentan treatment was complemented with sildenafil given as an add-on therapy. Mean doses given were 2.3 +/- 0.6 mg kg(-1) for bosentan and 2.1 +/- 0.9 mg kg(-1) for sildenafil. Clinical status, exercise capacity, and haemodynamics were assessed at baseline and at the end of the observation period after a mean follow-up time of 1.1 years (0.5-2.5 years).
  
  
  RESULTS
  No major side effects regarding liver function and blood pressure regulation were noted. One patient died of sudden death elsewhere. Most patients were in New York Heart Association (NYHA) functional class III. Clinical improvement was about one NYHA class (mean 2.8 +/- 0.4-1.6 +/- 0.8, P = 0.001), which was associated with an increase of transcutaneous oxygen saturation (89.9 +/- 9.9-92.3 +/- 7.1%; P = 0.037), maximum oxygen uptake (18.1 +/- 6.8-22.8 +/- 10.4 mL kg(-1) x min; P = 0.043), and 6-minute walking distance (351 +/- 58-451 +/- 119 m; P = 0.039). Mean pulmonary arterial pressure measured invasively decreased (62 +/- 12-46 +/- 18 mmHg; P = 0.041).
  
  
  CONCLUSIONS
  In our patient group, a combination of oral bosentan and sildenafil proved to be safe and effective. Clearly, randomized, double-blind, placebo-controlled studies are warranted to define the role and type of combination therapies in PAH.
authors.affiliation: Klinik für angeborene Herzfehler/Kinderkardiologie, Deutsches Herzzentrum Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Lunze
authors.forename: N
authors.initials: N
authors.lastname: Gilbert
authors.forename: S
authors.initials: S
authors.lastname: Mebus
authors.forename: O
authors.initials: O
authors.lastname: Miera
authors.forename: W
authors.initials: W
authors.lastname: Fehske
authors.forename: F
authors.initials: F
authors.lastname: Uhlemann
authors.forename: E G
authors.initials: EG
authors.lastname: Mühler
authors.forename: P
authors.initials: P
authors.lastname: Ewert
authors.forename: P E
authors.initials: PE
authors.lastname: Lange
authors.forename: F
authors.initials: F
authors.lastname: Berger
authors.forename: I
authors.initials: I
authors.lastname: Schulze-Neick
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D005080:Exercise Test / Q000379:methods; D006330:Heart Defects, Congenital / Q000150:complications / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011446:Prospective Studies; D011687:Purines; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage*; D013450:Sulfones; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D000077300:Bosentan