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Electroencephalogram Effect Measures and Relationships Between Pharmacokinetics and Pharmacodynamics of Centrally Acting Drugs

  • Review Article
  • Pharmacokinetic-Pharmacodynamic Relationships
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Summary

Electroencephalogram (EEG) effect parameters may be useful in pharmacokinetic-pharmacodynamic modelling studies of drug effects on the central nervous system (CNS). Effect parameters derived from a quantitative analysis of the EEG appear to be perfectly suited to characterise the relationships between pharmacokinetics and pharmacodynamics of benzodiazepines and intravenous anaesthetics. EEG parameters represent many of the characteristics of ideal pharmacodynamic measures, being continuous, objective, sensitive and reproducible. These features provide the opportunity to derive concentration-effect relationships for these drugs in individuals, which yield important quantitative information on the potency and intrinsic efficacy of these drugs. The EEG techniques presented can be used to study the influences of factors such as age, disease, chronic drug use and drug interactions on the concentration-effect relationships of psychotropic drugs.

An important issue is the choice of the EEG parameter to characterise the CNS effects of the compounds. More attention must be paid to evaluating the relevance of EEG parameters to the pharmacological effects of the drugs. Knowledge of the relationship between EEG effect parameters and clinical effects of drugs under different physiological and pathophysiological conditions is crucial to determining the value of EEG parameters in drug effect monitoring.

Pharmacodynamic parameters derived from the concentration-EEG effect relationship may be correlated to pharmacodynamic parameters obtained from other in vitro and in vivo effect measurements. These comparisons revealed that changes in the amplitudes in the β frequency band of EEG signals is a relevant measure of pharmacological effect intensity of benzodiazepines, which reflects their affinity and intrinsic efficacy at the central γ-aminobutyric acid (GABA) benzodiazepine receptor complex. The exact EEG correlates of the anxiolytic, anticonvulsant, sedative and hypnotic actions of benzodiazepines have not yet clearly been elucidated. For intravenous anaesthetics, close correlations between the potency determined with EEG measurements and clinical measures of anaesthetic depth have been established, suggesting that, in principle, EEG parameters can adequately reflect depth of anaesthesia. However, more study is required to further substantiate these findings.

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References

  • Arbilla S, Depoortere H, George P, Langer SZ. Pharmacological profile of the imidazopyridine zolpidem at benzodiazepines receptors and electrocorticogram in rats. Naunyn-Schmiede-berg’s Archives of Pharmacology 330: 248–251, 1985

    CAS  Google Scholar 

  • Arden JR, Holley FO, Stanski DR, Ebling WF. Dose potency comparison of thiopental and etomidate. Anesthesiology 63: A286, 1985

    Google Scholar 

  • Arden JR, Holley FO, Stanski DR. Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response. Anesthesiology 65: 19–27, 1986

    PubMed  CAS  Google Scholar 

  • Becker KE. Plasma levels of thiopental necessary for anesthesia. Anesthesiology 49: 192–196, 1978

    PubMed  Google Scholar 

  • Belzung C, Misslin R, Vogel E. Anxiogenic effects of a benzodiazepine receptor partial inverse agonist, Ro 19-4603, in a light/dark choice situation. Pharmacology Biochemistry and Behavior 36: 593–596, 1990

    CAS  Google Scholar 

  • Bennet DA. Pharmacology of the pyrazolo-type compounds: agonist, antagonist and inverse agonist actions. Physiology and Behavior 41: 241–245, 1987

    Google Scholar 

  • Berger H. Uber das Elektroenkephalogramm des Menschen III. Mitteilung Archiv der Psychiatrie und Nervenkrankheiten 94: 16–60, 1931

    Google Scholar 

  • Berger H. Uber das Elektroenkephalogramm des Menschen VIII. Mitteilung Archiv der Psychiatrie und Nervenkrankheiten 101: 452–469, 1933

    Google Scholar 

  • Bolander HG, Wahlström G. Age related changes in CNS sensitivity to hexobarbital and thiopental in the rat. Archives Internationales de Pharmacodynamie et de Thérapie 267: 213–223, 1984

    PubMed  CAS  Google Scholar 

  • Bolander HG, Wahlström G, Norberg L. Reevaluation of potency and pharmacokinetic properties of some lipid-soluble barbiturates with an EEG-threshold method. Acta Pharmacologica Toxicologica 54: 33–40, 1984

    CAS  Google Scholar 

  • Braestrup C, Nielsen M, Honoré T. Benzodiazepines receptor ligands with positive and negative efficacy. In Mandel P & DeFeudis FV (Eds) CNS receptors — from molecular pharmacology to behavior, pp. 237–245, Raven Press, New York, 1983

    Google Scholar 

  • Breimer DD, Van Rossum JM. Pharmacokinetics of (+)-, (−)-, and (±)-hexobarbitone in man after oral administration. Journal of Pharmacy and Pharmacology 25: 762–763, 1973

    PubMed  CAS  Google Scholar 

  • Breimer DD, Van Rossum JM. Pharmacokinetics of the enantiomers of hexobarbital studied in the same rat and in the same isolated perfused rat liver. European Journal of Pharmacology 26: 321–330, 1974

    PubMed  CAS  Google Scholar 

  • Breimer LTM, Hennis PJ, Burm AGL, Danhof M, Bovill JG, et al. Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers: pharmacokinetic/pharmacodynamic modelling. Clinical Pharmacokinetics 18: 245–253, 1990

    PubMed  CAS  Google Scholar 

  • Breimer LTM, Burm AGL, Danhof M, Hennis PJ, Vletter AA, et al. Pharmacokinetic-pharmacodynamic modelling of the interaction between flumazenil and midazolam in volunteers with aperiodic EEG analysis. Clinical Pharmacokinetics 20: 497–508, 1991

    PubMed  CAS  Google Scholar 

  • Brown CR, Sarnquist FH, Canup CA, Pedley TA. Clinical electroencephalographic, and pharmacokinetic studies of a water soluble benzodiazepine, midazolam maleate. Anesthesiology 50: 467–470, 1979

    PubMed  CAS  Google Scholar 

  • Buch H, Knabe J, Buzello W, Rummel W. Stereospecificity of anaesthetic activity, distribution, inactivation and protein binding of the optical antipodes of 2 N-methylated barbiturates. Journal of Pharmacology and Experimental Therapeutics 175: 709–716, 1970

    PubMed  CAS  Google Scholar 

  • Bührer M, Maitre PO, Crevoisier C, Stanski DR. Pharmacodynamics of benzodiazepines II: pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam. Clinical Pharmacology and Therapeutics 48: 555–567, 1990a

    PubMed  Google Scholar 

  • Bührer M, Maitre PO, Hung O, Stanski DR. Pharmacodynamics of benzodiazepines I: choosing an EEG parameter to measure the CNS effect of midazolam. Clinical Pharmacology and Therapeutics 48: 544–554, 1990b

    PubMed  Google Scholar 

  • Buschbaum, MS, Hazlett E, Sicotte N, Stein M, Wu J, et al. Topographic EEG changes with benzodiazepine administrationin generalised anxiety disorder. Biological Psychiatry 20: 832–842, 1985

    Google Scholar 

  • Crevoisier Ch, Ziegler WH, Eckert M, Heizmann P. Relationship between plasma concentration and effect of midazolam after oral and intravenous administration. British Journal of Clinical Pharmacology 16: 51S–61S, 1983

    PubMed  Google Scholar 

  • Depoortere H. A comparative EEG study of some benzodiazepine (BZD) and non-BZD sedative or hypnotic drugs. Pharmacopsychiatry 18: 17–19, 1985

    Google Scholar 

  • Depoortere H, Decobert M, Granger P, Riou-Merle F. Hypnotics: clinical value of pharmaco-EEG methods. Nueropsychobiology 16: 157–162, 1986a

    CAS  Google Scholar 

  • Depoortere H, Decobert M, Honore L. Drug effects on the EEG of various species of laboratory animals. Neuropsychobiology 9: 244–249, 1983

    PubMed  CAS  Google Scholar 

  • Depoortere H, Decobert M, Riou-Merle F, Granger P. Pharmaco-EEG profile of zolpidem: an imidazopyridine hypnotic agent. In Sauvanet et al. (Eds) Imidazopyridines in sleep disorders, pp. 81–96, Raven Press, New York, 1988

    Google Scholar 

  • Depoortere H, Granger P. Differentiation of EEG sleep stages in the rat and the cat by automatic analysis. In Kubicki S & Herrmann WM (Eds) Methods of sleep research, pp. 37–45, Gustav Fischer, Stuttgart, 1985

    Google Scholar 

  • Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, et al. Zolpidem, a novel nonbenzodiazepine hypnotic I: neuropharmacological and behavioural effects. Journal of Pharmacology and Experimental Therapeutics 237: 649–658, 1986b

    PubMed  CAS  Google Scholar 

  • Dingemanse J, Danhof M, Breimer DD. Pharmacokinetic-pharmacodynamic modelling of CNS drug effects: an overview. Pharmacology and Therapeutics 38: 1–52, 1988

    PubMed  CAS  Google Scholar 

  • Dumermuth G, Molinari L. Spectral analysis of the EEG: some fundamentals revisited and some open problems. Neuropsychobiology 17: 85–99, 1987

    PubMed  CAS  Google Scholar 

  • Duncan JS. Antiepileptic drugs and the electroencephalogram. Epilepsia 28: 259–266, 1987

    PubMed  CAS  Google Scholar 

  • Ebling WF, Danhof M, Stanski DR. Pharmacodynamic characterization of the electroencephalographic effects of thiopental in rats. Journal of Pharmacokinetics and Biopharmaceutics 19: 123–143, 1991

    PubMed  CAS  Google Scholar 

  • Fischer RS. Animal model of the epilepsies. Brain Research Reviews 14: 245–278, 1989

    Google Scholar 

  • Fink M, Irwin P. Pharmacoelectroencephalographic study of brotizolam, a novel hypnotic. Clinical Pharmacology and Therapeutics 30: 336–342, 1981

    PubMed  CAS  Google Scholar 

  • Fink M, Irwin P, Weinfeld RE, Schwartz MA, Conney AH. Blood levels and electroencephalographic effects of diazepam and bromazepam. Clinical Pharmacology and Therapeutics 20: 184–191, 1976

    PubMed  CAS  Google Scholar 

  • Frost Jr JD. Mimetic techniques. In Gevins AS & Rémond A (Eds) Methods of analysis of brain electrical and magnetic signals. EEG handbook (revised series), Vol. 1, pp. 195–209, El-sevier, Amsterdam, 1987

    Google Scholar 

  • Gardner CR. Functional in vivo correlates of the benzodiazepine agonist-inverse agonist continuum. Progress in Neurobiology 31: 425–476, 1988

    PubMed  CAS  Google Scholar 

  • Gardner CR, James V. Activity of some benzodiazepine receptor ligands with reduced sedative and muscle relaxant properties on stress-induced electrocorticogram arousal in sleeping rats. Journal of Pharmacological Methods 18: 47–54, 1987

    PubMed  CAS  Google Scholar 

  • Gevins AS, Rémond A. Methods of analysis of brain electrical and magnetic signals. EEG handbook (revised series), Vol I, Elsevier, Amsterdam, 1987

    Google Scholar 

  • Ghoneim MM, Yamada T. Etomidate: a clinical and electroenchalographic comparison with thiopental. Anesthesia and Analgesia 56: 479–485, 1977

    PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Ehrenberg BL, Gunderman J, Locniskar A, Scavone JM, et al. Pharmacokinetic and electrocephalographic study of intravenous diazepam, midazolam and placebo. Clinical Pharmacology and Therapeutics 45: 356–365, 1989a

    PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Ehrenberg BL, Gunderman J, Scavone JM, Tai NT, et al. Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous diazepam. Journal of Pharmacology and Experimental Therapeutics 250: 134–140, 1989b

    PubMed  CAS  Google Scholar 

  • Gregory TK, Pettus DC. An electroencephalographic processing algorithm specifically intended for analysis of cerebral electrical activity. Journal of Clinical Monitoring 2: 190–197, 1986

    PubMed  CAS  Google Scholar 

  • Haefely W. The pharmacological profile of two benzodiazepine partial agonists: Ro 16-6028 and Ro 17-1812. Clinical Neuropharmacology 7 (Suppl.): 670–671, 1984

    Google Scholar 

  • Haefely W. Partial agonists of the benzodiazepine receptor: from animal data to results in patients. In Biggi G & Costa E (Eds) Chloride channels and their modulation by neurotransmitters and drugs, pp. 275–292, Raven Press, New York, 1988

    Google Scholar 

  • Haefely WE. Pharmacology of the benzodiazepine receptor. European Archives of Psychiatry and Neurological Sciences 238: 294–301, 1989

    PubMed  CAS  Google Scholar 

  • Haefely W, Kyburz E, Gerecke M, Möhler H. Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure activity relationships of their agonists and antagonists. Adverse Drug Research 14: 165–322, 1985

    CAS  Google Scholar 

  • Haefely W, Martin JR, Schoch P. Novel anxiolytics that act as partial agonists at benzodiazepine receptor. Trends in Pharmacological Sciences 11: 452–456, 1990

    PubMed  Google Scholar 

  • Herrmann WM. Development and critical evaluation of an objective procedure for the electroencephalographic classification of psychotropic drug. In Herrmann WM (Ed.) Electroencephalography in drug research, pp. 249–351, Gustav Fischer, Stuttgart, 1982

    Google Scholar 

  • Herrmann, WM, Irrgang U. An absolute must in clinico-pharmacological research: pharmaco-electrocephalography, its possibilities and limitations. Pharmacopsychiatry 16: 134–142, 1983

    CAS  Google Scholar 

  • Herrmann WM, Schaerer E. Pharmaco-EEG: computer EEG analysis to describe the projection of drug effects on a functional cerebral level in humans. In Lopes et al. (Eds) Clinical applications of computer analysis of EEG and other neurophysiological signals. EEG handbook (revised series), Vol. 2, pp. 385–445, Elsevier, Amsterdam, 1986

    Google Scholar 

  • Holford NGH, Sheiner LB. Kinetics of pharmacologic response. Pharmacology and Therapeutics 16: 143–166, 1982

    PubMed  CAS  Google Scholar 

  • Homer TD, Stanski DR. The effect of increasing age on thiopental disposition and anesthetic requirement. Anesthesiology 62: 714–724, 1985

    PubMed  CAS  Google Scholar 

  • Huang L–Y, Barker JL. Pentobarbital: stereospecific actions (+) and (−) isomers revealed on cultured mammalian neurons. Science 207: 195–197, 1980

    PubMed  CAS  Google Scholar 

  • Hudson RJ, Stanski DR, Saidman LJ, Meathe E. A model for studying depth of anesthesia and acute tolerance to thiopental. Anesthesiology 59: 301–308, 1983

    PubMed  CAS  Google Scholar 

  • Hung OR, Vravel JR, Shafer SL, Stanski DR. Use of EEG as a measure of thiopental anesthetic depth. Anesthesiology 73: A391, 1990

    Google Scholar 

  • Itil TM. Digital computer analyzed EEG in psychiatry and psychopharmacology. In Dolce G & Künkel H (Eds) CEAN computerized EEG analysis, pp. 289–308, Gustav Fischer Verlag, Stuttgart, 1947a

    Google Scholar 

  • Itil TM. Quantitative pharmaco-electroencephalography: use of computerized cerebral biotentials in psychotropic drug research. In Itil TM (Ed.) Modern problems in pharmacopsychiatry, Vol. 8: Psychotropic drugs and the human EEG, pp. 43–75, Karger, Basel, 1974b

    Google Scholar 

  • Itil TM. The discovery of psychotropic drugs by computer-analyzed cerebral bioelectrical potential (CEEG). Drug Development Research 1: 373–407, 1981

    CAS  Google Scholar 

  • Itil TM, Hugue M. Computer EEG profiles of anxiolytics (quantitative pharmaco-EEG in the development of new anxiolytics). In Fielding S & Harbans L (Eds) Industrial pharmacology-anxiolytics, Vol. 3, pp. 281–316, Futura Publishing Company, New York, 1979

    Google Scholar 

  • Itil TM, Menoh GN, Itil KZ. Computer EEG drug data base in psychopharmacology and in drug development. Psychopharmacology Bulletin 18: 165–172, 1982

    PubMed  CAS  Google Scholar 

  • Itil TM, Polvan N, Hsu W. Clinical and EEG effects of GB-94, a tetracyclic antidepressant (EEG model in discovery of a new psychotropic drug). Current Therapeutic Research 14: 395–413, 1972

    PubMed  CAS  Google Scholar 

  • Itil TM, Shapiro D, Itil KZ, Eralp E, Bergamo M, Mucci A. Discrimination of mode of action of anxiolytics using an integrated computer data bank and dynamic brain mapping (CNS effects of diazepam and lorazepam). International Clinical Psychopharmacology 4: 273–282, 1989

    PubMed  CAS  Google Scholar 

  • Jaward S, Oxley J, Wilson J, Richens A. A pharmacodynamic evaluation of midazolam as an antiepileptic compound. Journal of Neurology, Neurosurgery and Psychiatry 49: 1050–1054, 1986

    Google Scholar 

  • Klotz U, Ziegler G, Ludwig L, Reimann IW. Pharmacodynamic interaction between midaxolam and a specific benzodiazepine antagonist in humans. Journal of Clinical Pharmacology 25: 400–406, 1985

    PubMed  CAS  Google Scholar 

  • Koopmans R, Dingemanse J, Danhof M, Horsten GPM, van Boxtel CJ. Pharmacokinetic-pharmacodynamic modeling of midazolam effects on the human central nervous system. Clinical Pharmacology and Therapeutics 44: 14–22, 1988

    PubMed  CAS  Google Scholar 

  • Krijzer FNCM, van der Molen R. Classification of psychotropic drugs by rat EEG analysis: the anxiolytic profile in comparison to the antidepressant and neuroleptic profile. Neuropsychobiology 18: 51–56, 1987

    PubMed  CAS  Google Scholar 

  • Kroboth PD, Smith RB, Erb RJ. Tolerance to alprazolam after intravenous bolus and continuous infusion: psychomotor and EEG effects. Clinical Pharmacology and Therapeutics 43: 270–277, 1988

    PubMed  CAS  Google Scholar 

  • Krubicki ST, Herrmann WM, Ott H, Höller L. On the evaluation of hypnotic drugs with EEG and psychological testing. In Herrmann WM. (Ed.), Electroencephalography in drug research, pp. 577–583, Gustav Fischer, Stuttgart, 1982

    Google Scholar 

  • Kurowski M, Ott H, Herrmann WM. Relationship between EEG dynamics and pharmacokinetics of the benzodiazepine lormetazepam. Pharmacopsychiatry 15: 77–83, 1982

    CAS  Google Scholar 

  • Langer SZ, Arbill S, Tan S, Lloyd KG, George P, et al. Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs. Pharmacopsychiatry (Suppl. 3) 23: 103–107, 1990

    PubMed  Google Scholar 

  • Laurian S, Gaillard JM, Le PK, Schöpf J. Effects of a benzodiazepine antagonist on the diazepam-induced electrical brain activity modifications. Neuropsychobiology 11: 55–58, 1984

    PubMed  CAS  Google Scholar 

  • Lauven PM, Schwilden H, Stoeckel H. Threshold hypnotic concentration of methohexitone. European Journal of Clinical Pharmacoloy 33: 261–265, 1987

    CAS  Google Scholar 

  • Levy G. Pharmacokinetic and pharmacodynamic considerations in therapeutic drug concentration monitoring. In Breimer DD & Speiser P (Eds) Topics in pharmaceutical sciences, pp. 43–50, Elsevier, Amsterdam, 1983

    Google Scholar 

  • Levy WJ. Intraoperative EEG patterns: implications for EEG monitoring. Anesthesiology 60: 430–434, 1984

    PubMed  CAS  Google Scholar 

  • Leysen JE, Gommeren W, Niemegeers CJE. #H-Sufentanil, a superior ligand for μ opiate receptors: binding properties and regional distribution in rat brain and spinal cord. European Journal of Pharmacology 87: 209–225, 1983

    PubMed  CAS  Google Scholar 

  • Longo VG, Massotti M, DeMedici D, Valerio A. Modifications of brain electrical activity after activation of benzodiazepine receptor types in rats and rabbits. Pharmacology Biochemistry and Behavior 29: 785–790 1988

    CAS  Google Scholar 

  • Löscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs?: a proposal based on experimental and clinical considerations. Epilepsy Research 2: 145–181, 1988

    PubMed  Google Scholar 

  • Mandema JW, Danhof M. Pharmacokinetic-pharmacodynamic modelling of the central nervous system effects of heptabarbital using aperiodic EEG analysis. Journal of Pharmacokinetics of Biopharmaceutics 18: 459–481, 1990

    CAS  Google Scholar 

  • Mandema JW, Kuck M, Danhof M. Differences in intrinsic efficacy of benzodiazepines are reflected in their concentration-EEG effect relationship. British Journal of Pharmacology 105: 164–170, 1992a

    PubMed  CAS  Google Scholar 

  • Mandema JW, Kuck M, Danhof M. In vivo modelling of the pharmacodynamic interaction between benzodiazepines which differ in intrinsic efficacy. Journal of Pharmacology and Experimental Therapeutics 261: 56–61, 1992b

    PubMed  CAS  Google Scholar 

  • Mandema JW, Sansom LN, Dios-Vièitez MC, Hollander-Jansen M, Danhof M. Pharmacokinetic-pharmacodynamic modeling of the electroencephalographic effects of benzodiazepines: correlation with receptor binding and anticonvulsant activity. Journal of Pharmacology and Experimental Therapeutics 257: 472–478, 1991a

    PubMed  CAS  Google Scholar 

  • Mandema JW, Tuk B, van Steveninck AL, Breimer DD, Cohen AF, et al. Pharmacokinetic-pharnacodynamic modelling of the CNS effects of midazolam and its main metabolite a-hydroxymidazolam in healthy volunteers. Clinical Pharmacology and Therapeutics, in press, 1992c

    Google Scholar 

  • Mandema JW, Tukker E, Danhof M. Pharmacokinetic-pharnacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration. British Journal of Pharmacology 102: 663–668, 1991b

    PubMed  CAS  Google Scholar 

  • Mandema JW, Tukker E, Danhof M. In vivo characterization of the pharmacodynamic interaction of abenzodiazepine agonist and antagonist: midazolam and flumazenil. Journal of Pharmacology and Experimental Therapeutics 260: 36–44, 1991c

    Google Scholar 

  • Mandema JW, Veng-Pedersen P, Danhof M. Estimation of amobarbital plasma-effect site equilibration kinetics: relevance of poly-exponential conductance functions. Journal of Pharmacokinetics and Biopharmaceutics 19: 617–634, 1991d

    PubMed  CAS  Google Scholar 

  • Mariott M, Ongini E. Differential effects of benzodiazepines on EEG activity and hypnogenic mechanism of the brain stem in cats. Archives of Internal Pharmacodynamics 264: 203–219, 1983

    Google Scholar 

  • Martin JR, Pieri L, Bonetti EP, Schaffner R, Burkard WP, et al. Ro 16-6028: a novel anxiolytic acting as a partial agonist at the benzodiazepine receptor. Pharmacopsychiatry 21: 360–363, 1988

    PubMed  CAS  Google Scholar 

  • Matejcek M. Vigilance and the EEG: psychological physiological and pharmacological aspects. In Herrmann WM (Ed.) Electroencephalography in drug research, pp. 405–508, Gustav Fischer, Stuttgart, 1982

    Google Scholar 

  • Matejcek M, Neff G, Abt K, Wehrli W. Pharmaco-EEG and psychometric study of the effect of single doses of temazepam and nitrazepam. Neuropsychobiology 9: 52–65, 1983

    PubMed  CAS  Google Scholar 

  • Meuldermans WEG, Hurkmans RMA, Heykants JJP. Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Archives of Internal Pharmacodynamics 257: 4–19, 1982

    CAS  Google Scholar 

  • Micheletti Ge, Vergnes M, Marescaux C, Reis J, Depaulis A, et al. Antiepileptic drug evaluation in a new animal model: spontaneous petit mal epilepsy in the rat. Arzneimittel-Forschung/ Drug Research 35: 483–485, 1985

    CAS  Google Scholar 

  • Mönier H, Okada T. The benzodiazepine receptor in normal and pathological human brain. British Journal of Psychiatry 133: 261–268, 1978

    Google Scholar 

  • Moller A, Jensen LH, Skrumsager B, Blatt-Lyon B, Pedersen B, et al. Inhibition of photosensitive seizures in man by the β-carboline, ZK 95962, a selective benzodiazepine receptor agonist. Epilepsy Research 5: 155–159, 1990

    PubMed  CAS  Google Scholar 

  • Morón MA, Stevens CW, Yaksh TL. The antiseizure activity of dihydropyridine calcium channel antagonists in the conscious rat. Journal of Pharmacology and Experimental Therapeutics 252: 1150–1155, 1990

    PubMed  Google Scholar 

  • Ongini E, Parravicini L, Bamonte F, Guzzon V, Iorio LC, et al. Pharmacological studies with quazepam, a new benzodiazepine hypnotic. Arzneimittel-Forschung/Drug Research 32: 1456–1462, 1982

    CAS  Google Scholar 

  • Ongini E, Barzaghi C, Marzanatti M. Intrinsic and antagonistic effects of β-carboline FG 7142 on behavioural and EEG actions of benzodiazepines and pentobarbital in cats. European Journal of Pharmacology 95: 125–129, 1983

    PubMed  CAS  Google Scholar 

  • Persson MP, Nilsson A, Hartvig P. Relation of sedation and amnesia to plasma concentrations of midazolam in surgical patients. Clinical Pharmacology and Therapeutics 43: 324–331, 1988

    PubMed  CAS  Google Scholar 

  • Petersen EN, Jensen LH, Drejer J, Honorè T. New perspectives in benzodiazepine receptor pharmacology. Pharmacopsychiatry 19: 4–6, 1986

    CAS  Google Scholar 

  • Pieri L. Ro 19-4603: a benzodiazepine receptor partial inverse agonist with prolonged proconvulsant action in rodents. British Journal of Pharmacology 95: 477P, 1988

    Google Scholar 

  • Pole P, Laurent J–P, Scherschlicht R, Haefely W. Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Naunyn-Schmiedeberg’s Archives of Pharmacology 316: 317–325, 1981

    Google Scholar 

  • Saletu B, Grünberger J, Linzmayer. Quantitative pharmaco-EEG and performance after administration of brotizolam to healthy volunteers. British Journal of Clinical Pharmacology 16: 33S–45S, 1983

    Google Scholar 

  • Saletu B, Grünberger J, Linzmayer. Pharmacokinetic and dynamic studies with a new anxiolytic imidazo-pyridine alpidem utilizing pharmaco-EEG and psychometry. International Clinical Psychopharmacology 1: 145–164, 1986a

    PubMed  CAS  Google Scholar 

  • Saletu B, Grünberger J, Sieghard W. Pharmaco-EEG, behaviourial methods and blood levels in the comparison of temazepam and flunitrazepam. Acta Psychiatrica Scandinavica 74 (Suppl. 332): 67–94, 1986b

    Google Scholar 

  • Schüttler J, Schwilden H, Stoeckel H. Pharmacokinetic-dynamic modeling of diprivan. Anesthesiology 65: A549, 1986

    Google Scholar 

  • Schüttler J, Stanski DR, White PF, Trevor AJ, Horai Y, et al. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. Journal of Pharmacokinetics and Biopharmaceutics 15: 241–253, 1987

    PubMed  Google Scholar 

  • Schuttler J, Sloeckel H, Schwilden H. Pharmacokinetic and pharmacodynamic modelling of propofol (diprivan) in volunteers and surgical patients. Postgraduate Medical Journal 61: 53–54, 1985b

    PubMed  Google Scholar 

  • Schwilden H, Schüttler J, Stoeckel H. Quantitaten of the EEG and pharmacodynamic modelling of hypnotic drugs: etomidate as an example. European Journal of Anaesthesiology 2: 121–131, 1985

    PubMed  CAS  Google Scholar 

  • Schwilden H, Schüttler J, Stoeckel H. Closed-loop feedback control of methohexital anesthesia by quantitative EEG analysis in humans. Anesthesiology 67: 341–347, 1987

    PubMed  CAS  Google Scholar 

  • Schwilden H, Stoeckel H. The derivation of EEG parameters for modelling and control of anaesthetic drug effect. In Stoeckel H (Ed.) Quantitation, modelling and control in anaesthesia, pp. 196–210, Thieme, Stuttgart, 1985

    Google Scholar 

  • Schwilden H, Stoeckel H. Quantitative EEG analysis during anaesthesia with isoflurane in nitrous oxide at 1.3 and 1.5 MAC British Journal of Anaesthesia 59: 738–745, 1987

    CAS  Google Scholar 

  • Schwilden H, Stoeckel H, Schüttler J. Closed-loop feedback control of propofol anaesthesia by quantitative EEG analysis in humans. British Journal of Anaesthesia 62: 290–296, 1989

    PubMed  CAS  Google Scholar 

  • Scott JS, Cooke JE, Stanski DR. Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sulfentanil. Anesthesiology 74: 34–42, 1991

    PubMed  CAS  Google Scholar 

  • Scott JS, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 62: 234–241, 1985

    PubMed  CAS  Google Scholar 

  • Scott JS, Stanski DR. Decreased fentanyl and alfentanil dose requirements with age: a simultaneous pharmacokinetic and pharmacodynamic evaluation. Journal of Pharmacology and Experimental Therapeutics 240: 159–166, 1987

    PubMed  CAS  Google Scholar 

  • Sieghart W. Several new benzodiazepines selectively interact with a benzodiazepine receptor subtype. Neuroscience Letters 38: 73–78, 1983

    PubMed  CAS  Google Scholar 

  • Stanski DR, Hudson RJ, Homer TD, Saidman LJ, Meathe E. Pharmacodynamic modeling of thiopental anesthesia. Journal of Pharmacokinetics and Biopharmacuetics 12: 223–240, 1984

    CAS  Google Scholar 

  • Stanski DR, Maitre PO. Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age revisited. Anesthesiology 72: 412–422, 1990

    PubMed  CAS  Google Scholar 

  • Stone DJ, DiFazio CA. Anesthetic action of opiates: correlations of lipid solubility and spectral edge. Anesthesia and Analgesia 67: 663–666, 1988

    PubMed  CAS  Google Scholar 

  • Streitberg B, Röhmel J, Herrmann WM, Kubicki S. COMSTAT rule for vigilance classification based on spontaneous EEG activity. Neuropsychiobiology 17: 105–117, 1987

    CAS  Google Scholar 

  • Swerdlow BN, Holley FO, Maitre PO, Stanski DR. Chronic alcohol intake does not change thiopental anesthetic requirement, pharmacokinetics or pharmacodynamics. Anesthesiology 72: 455–461, 1990

    PubMed  CAS  Google Scholar 

  • Swerdlow BN, Holley FO. Intravenous anaesthetic agents. Pharmacokinetic-pharmacodynamic relationships. Clinical Pharmacokinetics 12: 79–110, 1987

    PubMed  CAS  Google Scholar 

  • Ticku MK, Rastogi SK, Thyagarajan R. Separate site(s) of action of optical isomers of l-methyl-5-phenyl-5-propylbarbituric acid with opposite pharmacological activities at the GABA receptor complex. European Journal of Pharmacology 112: 1–9, 1985

    PubMed  CAS  Google Scholar 

  • Van der Graaf M, Vermeulen NPE, Joeres RP, Breimer DD. Disposition of hexobarbital enantiomers in the rat. Drug Metabolism and Disposition 11: 489–493, 1983

    Google Scholar 

  • Veselis RA, Reinsel R, Alagesan R, Heino R, Bedford RF. The EEG as a monitor of midazolam amnesia: changes in power and topography as a function of amnesic state. Anesthesiology 74: 866–874, 1991

    PubMed  CAS  Google Scholar 

  • Wahlström G. Estimation of brain sensitivity to hexobarbiton (Enhexymal NFN) in rats by an EEG threshold. Acta Pharmacology and Toxicology 24: 404–418, 1966

    Google Scholar 

  • Wahlström G. Hexobarbitone sleeping time in rats following doses with similar EEG changes. Acta Pharmacology and Toxicology 24: 419–434, 1966b

    Google Scholar 

  • Wamsley JK, Golden JS, Yamamura HI, Barnett A. Autoradiographic demonstration of the selectivity of two l-N-trifluoroethyl benzodiazepines for the BZS-1 receptors in the rat brain. Pharmacology Biochemistry and Behaviour 23: 973–978, 1985

    CAS  Google Scholar 

  • Wauquier A, De Ryck M, Van den Broeck W, Van Loon J, Melis W, et al. Relationships between quantitative EEG measures and pharmacodynamics of alfentanil in dogs. Electrocephalography and Clinical Neurophysiology 69: 550–560, 1988

    CAS  Google Scholar 

  • Winters WD. A review of the continuum of drug induced states of excitation and depression. Progress in Drug Research 26: 225–258, 1982

    PubMed  CAS  Google Scholar 

  • White PF, Schüttler J, Shafer A, Stanski DR, Horia Y, et al. comparative pharmacology of the ketamine isomers. British Journal of Anaesthesia 57: 197–203, 1985

    PubMed  CAS  Google Scholar 

  • Yakushiji T, Fukuda T, Oyama Y, Akaike N. Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones. British Journal of Pharmacology 98: 735–740, 1989

    PubMed  CAS  Google Scholar 

  • Zivkovic BM, Morel E, Joly D, Perrault GH, Sanger DJ, et al. Pharmacological and behavioral profile of alpidem as an anxiolytic. Pharmacopsychiatry 23 (Suppl. 3): 108–113, 1990

    PubMed  Google Scholar 

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  1. Center for Bio-Pharmaceutical Sciences, Division of Pharmacology, University of Leiden, Leiden, The Netherlands

    Jaap W. Mandema &  Meindert Danhof

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  1. Jaap W. Mandema
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Mandema, J.W., Danhof, M. Electroencephalogram Effect Measures and Relationships Between Pharmacokinetics and Pharmacodynamics of Centrally Acting Drugs. Clin. Pharmacokinet. 23, 191–215 (1992). https://doi.org/10.2165/00003088-199223030-00003

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