title: Effects of Sapropterin on Portal and Systemic Hemodynamics in Patients With Cirrhosis and Portal Hypertension: A Bicentric Double-Blind Placebo-Controlled Study.
abstract: OBJECTIVE
  Tetrahydrobiopterin (BH4), a cofactor of nitric oxide synthase, might have a role in the treatment of portal hypertension (PHT) as its administration improves endothelial nitric oxide generation and hepatic endothelial dysfunction, and reduces portal pressure in experimental models of cirrhosis. Sapropterin is an oral synthetic analogue of BH4 recently approved for the treatment of phenylketonuria. This study evaluated the safety and effects of sapropterin on hepatic and systemic hemodynamics in patients with cirrhosis and PHT.
  
  
  METHODS
  Forty patients with cirrhosis and PHT (hepatic venous pressure gradient (HVPG) ≥10 mm Hg) were randomly allocated to receive sapropterin (n=19) for 2 weeks (5 mg/kg/day increased to 10 at day 8) or placebo (n=21) in a double-blind multicenter clinical trial. Randomization was stratified according to concomitant treatment with β-adrenergic blockers. We studied at baseline and post-treatment splanchnic (HVPG and hepatic blood flow (HBF)) and systemic hemodynamics, endothelial dysfunction and oxidative stress markers (von Willebrand factor and malondialdehyde), liver function tests, and safety variables.
  
  
  RESULTS
  HVPG was not modified by either sapropterin (16.0±4.4 vs. 15.8±4.7 mm Hg) or placebo (16.0±4.6 vs. 15.5±4.9 mm Hg). HBF, systemic hemodynamics, endothelial dysfunction markers, and liver function tests remained unchanged. Sapropterin was well tolerated (no patient required dose adjustment or withdrawal), and adverse events were mild and similar between groups.
  
  
  CONCLUSIONS
  Sapropterin, an oral synthetic analogue of BH4, at the used dose did not reduce portal pressure in patients with cirrhosis. Sapropterin was safe and no serious adverse effects or deleterious systemic hemodynamic effects were observed.
authors.affiliation: 1] Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain [2] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Reverter
authors.affiliation: 1] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain [2] Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Mesonero
authors.affiliation: 1] Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain [2] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Seijo
authors.affiliation: 1] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain [2] Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martínez
authors.affiliation: 1] Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain [2] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
authors.affiliation: 1] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain [2] Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Peñas
authors.affiliation: 1] Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain [2] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Berzigotti
authors.affiliation: 1] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain [2] Department of Biochemistry and Molecular Genetics, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Deulofeu
authors.affiliation: 1] Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain [2] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Bosch
authors.affiliation: 1] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain [2] Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, Madrid, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Albillos
authors.affiliation: 1] Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain [2] Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: García-Pagán
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006785:Hospitals, University; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology*; D008102:Liver Circulation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011168:Portal System / Q000187:drug effects*; D011446:Prospective Studies; D013030:Spain
chemical_list: D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin