title: Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.
abstract: Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P=0.02), time to first event (hazard ratio [HR]=0.56; P<0.05), as well as total events (35 versus 57; P=0.04), and was associated with fewer HE hospitalizations (13 versus 25; P=0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P<0.01), time to first event (HR=0.29; P<0.01), and total events (7 versus 31; P<0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events.
  
  
  CONCLUSIONS
  GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167).
authors.affiliation: Medical University of SC, Charleston, SC.
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
authors.forename: John M
authors.initials: JM
authors.lastname: Vierling
authors.forename: Parvez
authors.initials: P
authors.lastname: Mantry
authors.forename: Marwan
authors.initials: M
authors.lastname: Ghabril
authors.forename: Robert S
authors.initials: RS
authors.lastname: Brown
authors.forename: Olga
authors.initials: O
authors.lastname: Alexeeva
authors.forename: Igor A
authors.initials: IA
authors.lastname: Zupanets
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grinevich
authors.forename: Andrey
authors.initials: A
authors.lastname: Baranovsky
authors.forename: Larysa
authors.initials: L
authors.lastname: Dudar
authors.forename: Galyna
authors.initials: G
authors.lastname: Fadieienko
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kharchenko
authors.forename: Iryna
authors.initials: I
authors.lastname: Klaryts'ka
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Morozov
authors.forename: Priya
authors.initials: P
authors.lastname: Grewal
authors.forename: Timothy
authors.initials: T
authors.lastname: McCashland
authors.forename: K Gautham
authors.initials: KG
authors.lastname: Reddy
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.forename: Vasyl
authors.initials: V
authors.lastname: Syplyviy
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Bass
authors.forename: Klara
authors.initials: K
authors.lastname: Dickinson
authors.forename: Catherine
authors.initials: C
authors.lastname: Norris
authors.forename: Dion
authors.initials: D
authors.lastname: Coakley
authors.forename: Masoud
authors.initials: M
authors.lastname: Mokhtarani
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Scharschmidt
mesh_terms: D000328:Adult; D000368:Aged; D000641:Ammonia / Q000097:blood / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives / Q000652:urine; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010654:Phenylbutyrates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014508:Urea / Q000652:urine; D055815:Young Adult
chemical_list: D010654:Phenylbutyrates; D005973:Glutamine; D000641:Ammonia; D014508:Urea; C003089:phenylacetylglutamine; D005990:Glycerol; C570223:glycerol phenylbutyrate