title: Modelling acute tolerance to the EEG effect of two benzodiazepines.
abstract: OBJECTIVE
  We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791.
  
  
  METHODS
  Nine young (24-28 years) and nine elderly (67-81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml-1 min-1 for midazolam, 3 and 1.5 ng ml-1 min-1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum.
  
  
  RESULTS
  The concentration-effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3-91.6%) and 37% (5.3-69.5%); Ro 48-6791, 22% (-2.8% to 44.6%) and 43% (3.4-82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results.
  
  
  CONCLUSIONS
  Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.
authors.affiliation: Department of Anaesthesiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. harald.ihmsen@kfa.imed.uni-erlangen.de
authors.forename: Harald
authors.initials: H
authors.lastname: Ihmsen
authors.forename: Sven
authors.initials: S
authors.lastname: Albrecht
authors.forename: Werner
authors.initials: W
authors.lastname: Hering
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schüttler
authors.forename: Helmut
authors.initials: H
authors.lastname: Schwilden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001569:Benzodiazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004351:Drug Resistance; D004569:Electroencephalography / Q000187:drug effects*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D006993:Hypnotics and Sedatives; C107068:Ro 48-6792; D001569:Benzodiazepines; D008874:Midazolam