title: Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure.
abstract: BACKGROUND
  Increased gamma-aminobutyric acid (GABA) neurotransmission has been implicated in the pathogenesis of hepatic encephalopathy. The mechanism by which GABA-ergic activity is increased in hepatic failure is unclear, but recent studies in animals with encephalopathy due to fulminant hepatic failure suggest that GABA-ergic neurotransmission may be increased by the presence of elevated concentrations of benzodiazepine agonists such as diazepam and N-desmethyldiazepam.
  
  
  RESULTS
  Samples of frontal cortex were obtained at autopsy from 11 patients with hepatic encephalopathy who died of acetaminophen-induced fulminant hepatic failure and 8 patients who died of cardiovascular disease or trauma. None of the 19 patients had received benzodiazepines while hospitalized. Chromatographic analyses of extracts of these samples revealed 4 to 19 peaks representing substances that inhibited the binding of a radiolabeled imidazobenzodiazepine ([3H]flumazenil) to its receptors. Several of these peaks had retention times corresponding to those of known 1,4-benzodiazepines. Ultraviolet- and mass-spectroscopic analysis confirmed that two of these peaks represented diazepam and N-desmethyldiazepam. The patients who died of fulminant hepatic failure could be divided into two groups: six who had had significantly elevated brain concentrations (2-fold to 10-fold higher than normal) of substances inhibiting the binding of [3H]flumazenil and five who had normal concentrations.
  
  
  CONCLUSIONS
  Brain concentrations of substances inhibiting the binding of [3H]flumazenil to its receptors are increased in some patients with hepatic encephalopathy due to fulminant hepatic failure. The origin of these substances is unknown, but these findings provide a rational basis for trials of benzodiazepine-receptor antagonists in the management of this disorder.
authors.affiliation: Laboratory of Neuroscience, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: A S
authors.initials: AS
authors.lastname: Basile
authors.forename: R D
authors.initials: RD
authors.lastname: Hughes
authors.forename: P M
authors.initials: PM
authors.lastname: Harrison
authors.forename: Y
authors.initials: Y
authors.lastname: Murata
authors.forename: L
authors.initials: L
authors.lastname: Pannell
authors.forename: E A
authors.initials: EA
authors.lastname: Jones
authors.forename: R
authors.initials: R
authors.lastname: Williams
authors.forename: P
authors.initials: P
authors.lastname: Skolnick
mesh_terms: D000328:Adult; D000368:Aged; D001569:Benzodiazepines / Q000032:analysis*; D001923:Brain Chemistry; D002845:Chromatography; D003975:Diazepam / Q000032:analysis; D005442:Flumazenil / Q000378:metabolism; D005625:Frontal Lobe / Q000737:chemistry; D006501:Hepatic Encephalopathy / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D013058:Mass Spectrometry; D008875:Middle Aged; D003708:Nordazepam / Q000032:analysis; D011963:Receptors, GABA-A / Q000187:drug effects; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D003708:Nordazepam; D003975:Diazepam