Psychopharmacology

, Volume 114, Issue 1, pp 138–146 | Cite as

EEG profile of intravenous zolpidem in healthy volunteers

  • A. Patat
  • S. Trocherie
  • J. J. Thebault
  • P. Rosenzweig
  • C. Dubruc
  • G. Bianchetti
  • L. A. Court
  • P. L. Morselli
Original Investigations
Received:
Revised:

Abstract

Zolpidem is an imidazopyridine which binds specifically to the ω1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h post-dosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3–4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2 h), clearance and volume of distribution did not change according to the dose or the route of administration. Tmax was 1 h after the oral administration. The absolute bioavailability was about 70%. In conclusion, EEG induced changes and score of SSS were in good correlation with what has been observed with insomniac patients: zolpidem has a rapid onset and a short duration of action.

Key words

Zolpidem EEG Non benzodiazepine hypnotic Clinical pharmacology Healthy volunteers Psychopharmacology 
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Arbilla S, Depoortere H, George P, Langer SZ (1985) Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats. Arch of Pharmacol 330:248–251Google Scholar
  2. Arbilla S, Allen J, Wick A et al. (1986) High affinity (3H) zolpidem binding in the rat brain: an imidazopyridine with agonist properties at central benzodiazepine receptors. Eur J Pharmacol 130:257–263Google Scholar
  3. Balkin TJ, O'Donnell VM, Wesensten N, McCann U, Belenky G (1992) Comparison of the daytime sleep and performance effects of zolpidem versus triazolam. Psychopharmacology 107:83–86Google Scholar
  4. Benavides J, Peny B, Dubois A, Perrault G, Morel E (1988) In vivo interaction of zolpidem with central benzodiazepine (BZD) binding sites (as labeled by [3H]Ro 15-1788) in the mouse brain. Preferential affinity of zolpidem for the ω1 (BZD1) subtype. J Pharmacol Exp Ther 245:1033–1041Google Scholar
  5. Bensimon G, Foret J, Warot D, Lacomblez L, Thiercelin JF et al. (1990) Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo. Br J Clin Pharmacol 30:463–469Google Scholar
  6. Bianchetti G, Dubruc C, Thiercelin JP, Bercoff E et al. (1988) Clinical pharmacokinetics of zolpidem in various physiological and pathological conditions. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 155–163Google Scholar
  7. Biggio G, Concas A, Corda MG, Serra M (1989) Enhancement of GABAergic transmission by zolpidem an imidazopyridine with preferential affinity for type I benzodiazepine receptors. Eur J Pharmacol 161:173–180Google Scholar
  8. Blois R, Gaillard JM (1988) The effects of zolpidem on characteristics of normal human sleep. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 375–376Google Scholar
  9. Borbely AA, Mattmann P, Loepfe M, Strauch I, Lehmann D (1985) Effect of benzodiazepine hypnotics on all-night sleep EEG spectra. Hum Neurobiol 4:189–194Google Scholar
  10. Borbely AA, Youmbi-Balderer G, Jaggi-Schwarz K (1988) Zolpidem (10 mg and 20 mg): hypnotic action and residual effects after a single bedtime dose. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 205–210Google Scholar
  11. Breimer LTM, Hennis PJ, Burm AGL, Danhof M, Bovill JG et al. (1990) Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers. Pharmacokinetic/pharmacodynamic modelling. Clin Pharmacokinet 18:245–253Google Scholar
  12. Brunner DP, Dijk DJ, Munch M, Borbely AA (1991) Effect of zolpidem on sleep and sleep EEG spectra in healthy young men. Psychopharmacology, 104:1–5Google Scholar
  13. Crevoisier C, Ziegler WH, Eckert M, Heizmann P (1983) Relationship between plasma concentration and effect of midazolam after oral and intravenous administration. Br J Clin Pharmacol 16:51S-61SGoogle Scholar
  14. Crowe McCann C, Quera-Salva MA, Boudet J, Frisk M, Barthouil P, Borderies P, Meyer P (1993) Effect of zolpidem during sleep on ventilation and cardiovascular variables in normal subjects. Fundam Clin Pharmacol 7:305–310Google Scholar
  15. Dennis T, Dubois A, Benavides J, Scatton B et al. (1988) Distribution of central ω1 (benzodiazepine1) and ω2 (benzodiazepine2) receptor subtypes in the monkey and human brain. An autoradiographic study with [3H] flunitrazepam and the ω1 selective ligand [3H] zolpidem. J Pharmacol Exp Ther 247:309–322Google Scholar
  16. Depoortere H, Decobert M, Honore L (1983) Drug effects on the EEG of various species of laboratory animals. Neuropsychiobiology 9:244–249Google Scholar
  17. Depoortere H, Decobert M, Granger P, Riou-Merle F (1984) EEG studies of some benzodiazepine (BZD) and non-BZS anxiolytichypnotic drugs. In: Court L, Trocherie S, Doucet J (eds) Le traitement du signal en électrophysiologie expérimentale et clinique du système nerveux central. CEA, Paris, pp 427–442Google Scholar
  18. Depoortere H, Zivkovic B, Lloyd DG, Sanger DJ, Perrault G (1986) Zolpidem, a novel nonbenzodiazepine hypnotic: neuropharmacoly and behaviourial effects. J Pharmacol Exp Ther 237:649–658Google Scholar
  19. Depoortere H, Decobert M, Riou-Merle F, Granger P (1988) EEG profile of zolpidem: in imidazopyridine hypnotic agent. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines on sleep disorders. Raven Press, New York, pp 81–96Google Scholar
  20. Ellinwood EH, Heatherly DG, Nikkaido AM, Bjornsson TD, Kilts G (1985) Comparative pharmacokinetics and pharmacodynamics of lorazepam, alprazolam and diazepam. Psychopharmacology 86:392–399Google Scholar
  21. Fairweather DB, Kerr JS, Hindmarch I (1992) The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Clin Pharmacol 43:597–601Google Scholar
  22. Fink M (1974) Cerebral electrometry. Quantitative EEG applied to human psychopharmacologiques. In: Dolce G, Kunkel M (eds) CEAN: Computerized EEG analysis. Fisher, Stuttgart, pp 271–288Google Scholar
  23. Fink M (1977) Quantitative EEG analysis and psychopharmacology. In: Remond A (ed) EEG informatics. A didactic review of methods and applications of EEG data processing. Elsevier, Amsterdam, pp 301–318Google Scholar
  24. Fink M (1978) EEG and psychopharmacology. Electroencephalogr Clin Neurophysiol 45:41–46Google Scholar
  25. Fink M (1980) An objective classification of psychoactive drugs. Prog Neurophysiol 45:41–56Google Scholar
  26. Fink M, Irwin P, Weinfeld RE, Scharz MA, Coney AH (1976) Blood levels and electroencephalographic effects of diazepam and bromazepam. Clin Pharmacol Therap 20:184–191Google Scholar
  27. Friedman H, Greenblatt DJ, Peters GR, Metzler CM, Charlton MD, Harmatz JS, Antal EJ, Sanborn EC, Francom SF (1992) Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time. Clin Pharmacol Ther 52:135–150Google Scholar
  28. Garrigou-Gadenne D, Burke JT, Durand A, Depoortere H, Thenot JP, Morselli PL (1989) Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat. J Pharmacol Exp Ther 248[3]: 1283–1288Google Scholar
  29. Goldstein A, Aronow L, Kalman SM (1974) Principles of drug action, the basis of pharmacology, 2nd edn. Wiley, New York, pp 96–104Google Scholar
  30. Greenblatt DJ, Shety VH (1990) Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam and oxazepam. Psycopharmacology 102:373–378Google Scholar
  31. Greenblatt DJ, Ehrenberg BL, Gunderman J et al. (1989a) Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam and placebo. Clin Pharmacol Ther 45:356–65Google Scholar
  32. Greenblatt DJ, Ehrenberg BL, Gunderman J et al. (1989b) Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous diazepam. J Pharmacol Exp Ther 250:134–140Google Scholar
  33. Herrmann WM (1982) Development and critical evaluation of an objective procedure for the electroencephalographic classification of psychotropic drugs. In: Hermann W (ed) EEG in drug Research. Fisher, Stuttgart, pp 249–351Google Scholar
  34. Herrmann WM, Irrgang U (1983) An absolute must in clinicopharmacological research: pharmaco-electroencephalography, its possibilities and limitations. Pharmacopsychiatry 16:134–142Google Scholar
  35. Herrmann WM, Kubicki St, Wober W (1988) Zolpidem: a four week pilot polysomnographic study in patients with chronic sleep disturbances In: Sauvanet JP, Lander SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 261–278Google Scholar
  36. Herrmann WM, Fichte K, Itil TM, Kubicki St (1979) Development of a classification rule for the electroencephalographic classification rule for four clinical therapeutic psychotropic drug classes with EEG power spectrum variables in human volunteers. Pharmacopsychiatry 12:20–34Google Scholar
  37. Hoddes E, Zarcone V, Smythe H, Philips R, Dement WC (1973) Stanford Sleepiness Scale. Quantification of sleepiness: a new approach. Psychophysiology 10:431–436Google Scholar
  38. Itil TM (1974) Quantitative pharmaco electroencephalography. In: Itil T (ed) Psychotropic drugs and the human EEG. Karger, Basel, pp 43–75Google Scholar
  39. Itil TM (1978) Effects of psychotropic drugs in qualitatively and quantitatively analyzed human EEG. In: Clark WG, del Guilduice J (eds) Principles of psychopharmacology, 2nd edn, Academic Press, New York, pp 261–277Google Scholar
  40. Itil TM, Huque M (1979) Computer EEG profiles of anxiolytics (quantitative EEG in the development of new anxiolytics). In: Fielding S, Lal H (eds) Industrial pharmacology-anxiolytics, Vol. 3, Futura, Mt Kisco, New York, pp 281–316Google Scholar
  41. Itil TM, Shapiro DM, Herrmann WM et al. (1979) HZI system for EEG parametrization and classification of psychotropic drugs. Pharmacopsychiatry 12:4–19Google Scholar
  42. Itil TM, Menon GN, Itil KZ (1982) Computer EEG drug data base in psychopharmacology and in drug development. Psychopharmacol Bull 18[4]: 165–172Google Scholar
  43. Itil TM, Shrivastava RK, Collins DM, Michael ST, Dayican G, Itil KZ (1983) A double-blind study comparing the efficacy and safety of a single bedtime dose of halazepam with clorazepate and placebo in anxious outpatients. Cur Therap Res 34[3]: 441–452Google Scholar
  44. Johnson LC, Spinweber CL, Seidel WF, Dement WC (1983) Sleep spindle and delta changes during chronic use of a short acting and a long acting benzodiazepine hypnotic. Electroencephalogr. Clin Neurophysiol 55:662–667Google Scholar
  45. Kanno O, Watanabe H, Ichikawa I, Iyo R, Suzuki M, Nakagome K, Takazawa S, Kazamatsuri H (1991) Effects of zolpidem and triazolam on all night sleep EEG of normal volunteers. Biol Psychiatry 29:305SGoogle Scholar
  46. Koopsmans R, Dingemanse J, Danhof M, Horsten GPM, Van Boxtel CJ (1988) Pharmacokinetic-pharmacodynamic modeling of midazolam effects on the human central nervous system. Clin Pharmacol 44:14–22Google Scholar
  47. Kryger MH, Steljes D, Pouliot Z, Neufeld H, Odynski T (1991) Subjective versus objective evaluation of hypnotic efficacy: experience with zolpidem. Sleep 14[5]: 399–407Google Scholar
  48. Lader M (1991) Rebound insomnia and newer hypnotics. Psychopharmacology 108:248–255Google Scholar
  49. Langer SZ, Arbilla S, Scatton B, Niddam R, Dubois A (1988) Receptors in the mechanism of action of zolpidem. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 55–70Google Scholar
  50. Langtry D, Benfield P (1990) Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 40[2]: 291–313Google Scholar
  51. Lund R, Ruther E, Wober W, Hippins H (1988) Effects of zolpidem (10 and 20 mg), lormetazepam, triazolam and placebo on night sleep and residual effects during the day. Receptors involved in the mechanism of action of zolpidem. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders, Raven Press, New York, pp 193–203Google Scholar
  52. Mandema JW, Danhof M (1992) Electroencephalogram effect measures and relationships between pharmacokinetics and pharmacodynamics of centrally acting drugs. Clin Pharmacokinet 23[3]:191–215Google Scholar
  53. Matejcek M (1979) Pharmaco-electroencephalography: the value of quantified EEG in psychopharmacology. Pharmacopsychiatry 12:126–136Google Scholar
  54. Mereu G, Carcangiu G, Concas A, Passino N, Biggio G (1990) Reduction of reticulate neuronal activity by zolpidem and alpidem, two imidazopyridines with high affinity for type I benzodiazepine receptors. Eur J Pharmacol 179[3]: 339–346Google Scholar
  55. Merlotti L, Roehrs T, Koshorek G, Zorick F, Lamphere J et al. (1989) The dose effects of zolpidem on the sleep of healthy normals. J Clin Psychopharmacol 9:9–14Google Scholar
  56. Monti JM (1989) Effect of zolpidem on sleep in insomniac patients. Eur J Clin Pharmacol 36:461–466Google Scholar
  57. Morselli PL, Larribaud J, Guillet Ph, Thiercelin JF, Barthelet G et al. (1988) Daytime residual effects of zolpidem: a review of available data. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 183–191Google Scholar
  58. Nicholson AN, Pascoe PA (1986) Hypnotic activity of an imidazopyridine (zolpidem). Br J Clin Pharmacol 21:205–211Google Scholar
  59. Niddam R, Dubois A, Scatton B, Arbilla S, Langer SZ (1987) Autoradiographic localization of [3H] zolpidem binding sites in the rats CNS: comparison with the distribution of [3H] flunitrazepam binding sites. J Neurochem 49:890–899Google Scholar
  60. Oswald I, Adam K (1988) A new look at short-acting hypnotics. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 351–361Google Scholar
  61. Palminteri R, Narbonne G (1988) Safety profile of zolpidem. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 351–361Google Scholar
  62. Patat A, Klein MJ, Hucher M, Granier J (1990) Computer-analysed EEG and psychometric assessment of two new non-benzodiazepine tranquillizers in healthy volunteers. Hum Psychopharmacol 5:123–131Google Scholar
  63. Pidoux B, Etevenon P, Campistron D, Peron-Magnan P, Verdeaux G, Deniker P (1983) Aspects topographiques des rythmes rapides médicamenteux en topo-encephalographie quantitative. Revue EEG Neurophysiol Clin 13:35–41Google Scholar
  64. Pritchett DB, Seeburg PH (1990) γ-Aminobutyric acidA receptor alpha-5 subunit creates novel type II benzodiazepine receptor pharmacology. J Neurochem 54:1802–1804Google Scholar
  65. Puia G, Vicini S, Seeburg PH, Costa E (1991) Influence of recombinant GABAA receptor subunit composition on the allosteric modulators of GABA-gated Cl-currents. Mol Pharmacol 39:691–696Google Scholar
  66. Saletu B (1987) The use EEG in drug profiling. In: Hindmarch I, Stonier PD (eds) Human Psychopharmacology: measures and methods, Vol. 1. Wiley, Chichester, pp 173–200Google Scholar
  67. Saletu B, Grunberg J, Linzmayer L (1983) Quantitative EEG and performance after administration of brotizolam to healthy volunteers. Br J Clin Pharmacol 16:33s-44sGoogle Scholar
  68. Saletu B, Grunberger J, Linzmayer L (1986) Pharmacokinetic and dynamic with a new anxiolytic imidazopyridine alpidem utilizing EEG and psychometry. Int Clin Psychopharmacol 1:145–164Google Scholar
  69. Sanger DJ, Zivkovic B (1987) Investigation of the development of tolerance of the actions of zolpidem and midazolam. Neuropharmacology 26:1513–1518Google Scholar
  70. Sanger DJ, Zivkovic B (1988) Further behaviourial evidence for the selective sedative action of zolpidem. Neuropharmacology 27:1125–1130Google Scholar
  71. Scharf MB, Mayleben DW, Kaffeman M, Krall R, Ochs R (1991) Dose response effects of zolpidem in normal geriatric subjects. J Clin Psychiatry 52[2]: 77683Google Scholar
  72. Streiberg B, Rohmel J, Herrmann WM, Kubicki S (1987) Rule for vigilance classification based on spontaneous EEG activity. Neuropsychiobiology 17:105–117Google Scholar
  73. Thenot JP, Herrmann P, Durand A, Burke JT et al. (1988) Pharmacokinetics and metabolism of zolpidem in various animal species and in humans. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 139–153Google Scholar
  74. Thiercelin JJ, Trocherie S, Thebault JJ, Larribaud J, Thibout E (1984) The contribution of quantitative electroencephalography to the study of a new hypnotic: zolpidem. In: Court L, Trocherie S, Doucet J (eds) Le traitement du signal en électrophysiologie expérimentale et clinique du système nerveux central. CEA, Paris, pp 581–586Google Scholar
  75. Trachsel L, Dijk DJ, Brunner DP, Klene C, Borbely AA (1990) Effect of zopiclone and midazolam on sleep and EEG spectra in a phase-advanced sleep schedule. Neuropsychopharmacology 3:11–18Google Scholar
  76. Vogel G, Scharf M, Walsh J, Roth T (1989) Effects of chronically administered zolpidem on the sleep of healthy insomniacs. Sleep Res 18:80Google Scholar
  77. Wheatley D (1988) Zolpidem and placebo: a study in general practice in patients suffering from insomnia. In: Sauvanet JP, Lander SZ, Morselli PL (eds) Imidazopyridines in sleep disorders. Raven Press, New York, pp 305–316Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • A. Patat
    • 1
  • S. Trocherie
    • 3
  • J. J. Thebault
    • 2
  • P. Rosenzweig
    • 1
  • C. Dubruc
    • 1
  • G. Bianchetti
    • 1
  • L. A. Court
    • 3
  • P. L. Morselli
    • 1
  1. 1.Synthélabo Recherche (L.E.R.S.)Bagneux CedexFrance
  2. 2.ASTER, Hôpital Cognacq-JayParisFrance
  3. 3.CEA/DSV/DPTE/SSAFontenay-aux-Roses CedexFrance

Personalised recommendations