title: Effects of intravenous temazepam. I. Saccadic eye movements and electroencephalogram after fast and slow infusion to pseudo steady state.
abstract: OBJECTIVE
  To study the pharmacodynamic effects of intravenous temazepam after different infusion rates to pseudo steady-state concentrations.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled crossover study in an academic department of clinical pharmacology. Subjects were nine healthy volunteers. A computerized infusion pump was used to obtain target plasma concentrations of temazepam after 30 or 120 minutes and to maintain these levels for 2 hours. A vehicle infusion, similar to the 30-minute (fast) infusion was used as a placebo control. Infusion schedules were based on data obtained from individual subjects after infusion of 0.4 mg/kg temazepam in 30 minutes. Target plasma concentrations were chosen to induce subhypnotic effects and averaged (+/- SD) 597 +/- 123 ng/ml. Venous plasma concentrations of temazepam were measured by HPLC. Free fractions of temazepam were assessed at the start of the pseudo steady-state concentration intervals. Electroencephalogram alpha and beta amplitudes, saccadic peak velocity, and saccadic latency were used as pharmacodynamic parameters.
  
  
  RESULTS
  The rate of change of plasma concentrations averaged 21 +/- 4 ng/ml.min-1 during fast infusion and 5 +/- 1 ng/ml.min-1 during slow infusion of temazepam. Average pseudo steady-state concentrations were 639 +/- 132 ng/ml after fast infusion and 629 +/- 133 ng/ml after slow infusion. At the onset of pseudo steady-state concentration intervals the average free fractions of temazepam were 44% (95% confidence interval, 19% to 61%) lower for slow than for fast infusions. Compared with the slow infusion, electroencephalogram beta amplitudes were significantly larger during the first 30 minutes of pseudo steady-state concentration after fast infusion of temazepam. No significant differences were found for the other parameters. There was a slight decline of temazepam effects during the pseudo steady-state concentration intervals for all parameters after the fast infusion and for saccadic peak velocity and saccadic latency after the slow infusion.
  
  
  CONCLUSIONS
  The pharmacodynamic effects of intravenous temazepam may depend partly on the rate of administration. Differences in pharmacodynamic effects after fast and slow infusions could be caused by changes in protein binding over time.
authors.affiliation: Center for Human Drug Research, University Hospital Leiden, The Netherlands.
authors.forename: A L
authors.initials: AL
authors.lastname: van Steveninck
authors.forename: H C
authors.initials: HC
authors.lastname: Schoemaker
authors.forename: J
authors.initials: J
authors.lastname: den Hartigh
authors.forename: J
authors.initials: J
authors.lastname: Rijnkels
authors.forename: M S
authors.initials: MS
authors.lastname: Pieters
authors.forename: D D
authors.initials: DD
authors.lastname: Breimer
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
mesh_terms: D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D012016:Reference Values; D012438:Saccades / Q000187:drug effects*; D013693:Temazepam / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D013693:Temazepam