L. T.M. Breimer
Leiden University
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Clinical Pharmacokinectics | 1990
L. T.M. Breimer; Pim J. Hennis; Anton G. L. Burm; Meindert Danhof; James G. Bovill; Joh. Spierdijk; Arie A. Vletter
SummaryThe effects of midazolam on the EEG were related to plasma midazolam concentrations in 8 healthy male volunteers in order to develop a pharmacokinetic-pharmacodynamic model. The EEG parameters were derived by aperiodic analysis.The EEG was recorded between Fp1-M1 and FP2-M2. Following a 15-minute baseline EEG registration, midazolam 15mg was given intravenously over 5 minutes. Venous blood samples were taken until 8 hours after the start of the infusion. Within 2 to 4 minutes of starting the infusion all subjects became asleep, with loss of eyelid reflex. The most obvious EEG changes, in the β frequency range (12 to 30Hz), were observed within 2 minutes of the start of drug administration. Seven subjects awoke 60 to 70 minutes after the start of the infusion and 1 awoke after 45 minutes.The EEG parameter that best characterised the effect of midazolam was the total number of waves per second in the frequency range 12 to 30Hz (TNW12–30). This was used as the effect parameter in the pharmacokinetic-pharmacodynamic modelling. The plasma concentration-time data were characterised by a triexponential function for all subjects. To allow for a possible delay between plasma midazolam concentration and EEG effect, a hypothetical effect compartment was included in the pharmacokinetic-pharmacodynamic model. A sigmoid maximum effect (Emax) model was used to characterise the effect compartment midazolam concentration-TNW2–30 data. The plasma drug concentration corresponding to half the maximum increase in TNW12–30 (EC50) was 290 ± 98 μg/L. The half-life reflecting equilibration between plasma concentration and effect (t 00BDkeo) was estimated by a nonparametnc method and was 1.7 ± 0.7 minutes (mean ± SD).The concentration at which the volunteers awoke was 131 ± 14 Mg/L. The EEG had returned to the baseline value 3 hours after the start of the infusion; at this time the plasma midazolam concentration was 60 ± 9 μg/L.The conclusion is reached that, in volunteers, the effect of midazolam on the EEG can be quantified and adequately described with a sigmoid Emax model. TNW12–30, a parameter derived from aperiodic analysis of the EEG, is a suitable, and possibly superior, alternative to psychomotor tests for the assessment of the central nervous system effects of this drug.
Clinical Pharmacokinectics | 1991
L. T.M. Breimer; Anton G. L. Burm; Meindert Danhof; Pim J. Hennis; Arie A. Vletter; Jan-Willem H. de Voogt; J. Spierdijk; James G. Bovill
SummaryThe CNS effects resulting from the combined administration of midazolam and flumazenil were studied in 8 healthy volunteers to develop a model of the pharmacokinetic-pharmacodynamic interaction. Electroencephalograms (EEG) were recorded between Fp1-M1 and FP2-M2. The EEG parameter total number of waves between 12 and 30Hz (TNW12–30) derived by aperiodic analysis was used to quantify the effect. Following a 15 min baseline EEG recording, infusion of placebo or flumazenil was started. Infusion regimens for flumazenil were designed so that ‘steady-state’ concentrations of 10 and 20 µg/L were obtained. Doses of midazolam 15, 30 and 60mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 µg/L (session B) or 20 µg/L (session C), respectively. Venous blood samples were taken until 8h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (Emax) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (Cem) [Cem/Kp] and TNW 12–30.Within 2 to 5 min of starting the midazolam infusion all subjects fell asleep, with loss of eyelid reflex. They awoke between 25 and 82 min later in all 3 sessions. The mean (± SD) plasma drug concentrations of midazolam corresponding to half the maximum increase in TNW 12–30 (EC50) were 276 ± 64, 624 ± 187 and 1086 ± 379 µg/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t½ke0), estimated by a nonparametric method, were 2.2 ± 1.2, 3.3 ± 3.3 and 2.9 ± 1.2 min for the 3 different sessions. Emax and N were not affected by flumazenil. In each subject the plot of the average measured steady-state plasma flumazenil concentration versus the EC50 of midazolam showed a linear relationship. The plasma concentration of flumazenil that doubled the EC50 of midazolam (Cf,2) was 6.5 ± 1.0 µg/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.
Clinical Pharmacokinectics | 1991
L. T.M. Breimer; Pim J. Hennis; Anton G. L. Burm; Meindert Danhof; James G. Bovill; J. Spierdijk; Arie A. Vletter
SummaryThe effect of intravenous flumazenil 10mg on the electroencephalogram (EEG) was investigated in 7 volunteers in a placebo-controlled, randomised, double-blind, crossover study. The EEG was recorded between Fp2-M1 and FP2-M2 and analysed using an aperiodic analysis technique. Two volunteers were excluded from the study because of significant asymmetry between baseline EEG recordings of the left and right hemisphere; in the remainder there were no changes in the β-frequency range (12 to 30Hz) or in other ranges of the EEG during or after flumazenil or placebo administration, with regard to the parameters total number of waves per second or total amplitude per second. There were no changes in heart rate, respiratory rate or blood pressure after administration of flumazenil or placebo. Three volunteers reported feelings of ‘pressure to move’ during the initial 2 min of the flumazenil infusion.The pharmacokinetics of flumazenil were investigated in the same volunteers. Flumazenil 10mg was administered intravenously over 10 min; the data from 1 volunteer were excluded from this analysis because of blood sampling problems. The plasma concentration-time data of the remaining 6 volunteers were characterised by a biexponential function. The pharmacokinetic parameters were (mean ± SD): initial volume of distribution, 16 ± 5.7L; volume of distribution at steady-state, 64.8 ± 12.5L; total body clearance, 53.8 ± 1.2 L/h; distribution half-life, 4.1 ± 1.3 min; and elimination half-life, 70.2 ± 9.9 min.The authors conclude that flumazenil has no significant EEG effects. The rapid distribution and elimination of flumazenil may explain its previously reported short duration of action after intravenous anaesthesia with high doses of midazolam.
Journal of Chromatography B: Biomedical Sciences and Applications | 1990
Arie A. Vletter; Anton G. L. Burm; L. T.M. Breimer; Joh. Spierdijk
Anesthesiology | 1989
L. T.M. Breimer; Pim J. Hennis; James G. Bovill; Anton G. L. Burm; Arie A. Vletter
Anesthesiology | 1987
L. T.M. Breimer; Pim J. Hennis; Joh. Spierdijk; James G. Bovill
Anesthesiology | 1989
L. T.M. Breimer; Pim J. Hennis; Meindert Danhof; James G. Bovill; Joh. Spierdijk
European Journal of Pharmacology | 1990
L. T.M. Breimer; Anton G. L. Burm; Pim J. Hennis; Meindert Danhof; Arie A. Vletter; James G. Bovill; Joh Spierdijk
Anesthesiology | 1990
L. T.M. Breimer; Anton G. L. Burm; Meindert Danhof; Pim J. Hennis; Joh. Spierdijk
Anesthesiology | 1990
L. T.M. Breimer; A. G. L. Burrn; Pim J. Hennis; Meindert Danhof; James G. Bovill