title: Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study.
abstract: OBJECTIVE
  Confirm in patients with cirrhosis and gastrointestinal bleeding the safety of ornithine phenylacetate (OP) and assess the pharmacokinetic profile of OP and its effects on plasma ammonia.
  
  
  BACKGROUND
  OP is a drug that has shown experimentally to decrease hyperammonemia and improve hepatic encephalopathy. OP is safe in healthy subjects and in stable patients with cirrhosis, but there are no data in decompensated cirrhosis.
  
  
  METHODS
  We performed a study to assess safety and tolerance of OP in cirrhotic patients after an episode of upper gastrointestinal bleeding.Ten patients were included within 24 hours of an upper gastrointestinal bleeding. OP was administered as a continuous infusion up to a maximum of 10 g/24 h (0.42 g/h) for 5 days. The infusion was started at 33% of the target dose and increased at 12-hour intervals achieving target dose at 24 hours. Ammonia was also assessed in control group of 10 patients.
  
  
  RESULTS
  No severe adverse events were observed. Mild adverse events were reported in 4 patients. Plasma ammonia (baseline: 80±43 μmol/L) showed a progressive drop between baseline and 36 hours (42±15 μmol/L), 72 hours (44±15 μmol/L), 96 hours (40±24 μmol/L), and 120 hours (33±14 μmol/L). Plasma ammonia at 24 hours was significantly higher in the control group. Plasma glutamine showed a significant decrease (-37% at day 5) and its excretion in urine as phenylacetylglutamine, a progressive rise (52±35 mmol at day 5).
  
  
  CONCLUSIONS
  OP is a safe and well-tolerated drug in decompensated cirrhotics that may decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine.
authors.affiliation: *Liver Unit, Hospital Vall d'Hebron †Department of Medicine, Universitat Autònoma de Barcelona ‡Laboratori de Metabolopaties, Hospital Universitari Vall d'Hebron §UCICAC, Vall Hebron Institut of Research ∥Pharmacy, Hospital Vall Hebron #Liver Unit, Hospital Sant Pau, Barcelona ¶CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Ventura-Cots
authors.forename: José A
authors.initials: JA
authors.lastname: Arranz
authors.forename: Macarena
authors.initials: M
authors.lastname: Simón-Talero
authors.forename: Maria
authors.initials: M
authors.lastname: Torrens
authors.forename: Albert
authors.initials: A
authors.lastname: Blanco
authors.forename: Encarnació
authors.initials: E
authors.lastname: Riudor
authors.forename: Inma
authors.initials: I
authors.lastname: Fuentes
authors.forename: Pilar
authors.initials: P
authors.lastname: Suñé
authors.forename: German
authors.initials: G
authors.lastname: Soriano
authors.forename: Juan
authors.initials: J
authors.lastname: Córdoba
mesh_terms: D000368:Aged; D000641:Ammonia / Q000097:blood*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006471:Gastrointestinal Hemorrhage / Q000209:etiology*; D005973:Glutamine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D006801:Humans; D007262:Infusions, Intravenous; D008103:Liver Cirrhosis / Q000150:complications / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009952:Ornithine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D005973:Glutamine; D000641:Ammonia; C003089:phenylacetylglutamine; C572232:ornithine phenylacetate; D009952:Ornithine