title: A pilot pharmacokinetic-pharmacodynamic study of benzodiazepine antagonism by flumazenil and aminophylline.
abstract: OBJECTIVE
  To develop a pharmacokinetic-pharmacodynamic model using quantitative electroencephalographic (EEG) analysis to compare two separate benzodiazepine antagonists and generate data concerning response variability.
  
  
  METHODS
  A pilot study using a randomized, blinded, crossover design.
  
  
  METHODS
  The Neurology Laboratory at the Akron City Hospital campus of SUMMA Health System.
  
  
  METHODS
  Four healthy volunteers completed the protocol.
  
  
  METHODS
  Subjects received midazolam 0.1-0.2 mg/kg by intravenous bolus on 3 study days, separated by a minimum washout period of 1 week. Subjects participated in an initial open-label response phase followed by a randomized, crossover trial of each benzodiazepine antagonist.
  
  
  RESULTS
  Venous blood samples were obtained to characterize the pharmacokinetics of all study compounds. The EEG parameter of total number of waves/second (recorded from FP1-F3 and FP2-F4 electrodes) in the frequency of 12-30 Hz was used to quantify effect. Flumazenil appeared to prolong the elimination half-life of midazolam significantly (p < 0.05). Theophylline (aminophylline) also appeared to prolong the half-life of flumazenil (p < 0.05). Despite considerable variability, flumazenil resulted in reversal of sedation at concentrations achieved by routine dosing. Resedation was apparent for all subjects following flumazenil reversal. Only partial reversal of sedation by theophylline was achieved by an aminophylline dose of 1-2 mg/kg.
  
  
  CONCLUSIONS
  Flumazenil was consistently effective in reversing sedation by midazolam at routinely recommended dosing. Further investigation of aminophylline as a reversal agent should use an estimated dose of 6-8 mg/kg aminophylline. To achieve adequate reversal, some patients may require aminophylline dosages that exceed safe clinical administration.
authors.affiliation: Department of Pharmacy, SUMMA Health System, Akron, Ohio, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Bonfiglio
authors.forename: L E
authors.initials: LE
authors.lastname: Fisher-Katz
authors.forename: L M
authors.initials: LM
authors.lastname: Saltis
authors.forename: S M
authors.initials: SM
authors.lastname: Traeger
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
authors.forename: N A
authors.initials: NA
authors.lastname: Nackes
authors.forename: T A
authors.initials: TA
authors.lastname: Perkins
mesh_terms: D000328:Adult; D000628:Aminophylline / Q000494:pharmacology*; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D018592:Cross-Over Studies; D004336:Drug Antagonism; D004569:Electroencephalography / Q000187:drug effects*; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D010726:Phosphodiesterase Inhibitors; D000628:Aminophylline; D005442:Flumazenil; D008874:Midazolam