Abstract
A phase 1 double blind crossover comparison of a new benzodiazepine antagonist (Ro 15-3505) with Ro 15-1788 and placebo, in the reversal of sedative and psychophysiological effects of single IV doses of flunitrazepam (2 mg), was carried out in 12 normal volunteers. The antagonists were equally effective, leading to full reversal of all effects with a potency ratio of approximately 2.5 mg Ro 15-1788 for 1 mg Ro 15-3505. Inverse agonism, in the form of unpleasant feelings and symptoms, was reported by all subjects following Ro 15-3505 but none after Ro 15-1788. Adaptational phenomena such as acute tolerance and rebound of sedative effects of flunitrazepam were also detected and their potential implications are discussed.
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References
Amrein R, Cano JP, Hartmann D, Ziegler WH, Dubois R (1979) Clinical and psychometric effects of flunitrazepam observed during the day in relation to pharmacokinetic data. In: Priest RG, Pletscher A, Ward J (eds) Sleep research. MTP Press, Lancaster, pp 83–98
Bond AJ, Lader MH (1972) Residual effects of hypnotics. Psychopharmacologia 25:117–132
Bond AJ, Lader MH (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218
Dorrow R, Horowski R, Paschelke G, Amn M, Braestrup C (1983) Severe anxiety induced by FG 7142, a beta-carboline ligand for benzodiazepine receptors. Lancet II:98–99
Ellinwood Jr EH, Linnoila M, Easler ME, Molter DW (1983) Profile of acute tolerance to three sedative anxiolytics. Psychopharmacology 79:137–141
File SE (1985) Tolerance to the behavioral actions of benzodiazepines. Neurosci Biobehav Rev 9:113–121
File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 88:1–11
File SE, Lister RG, Nutt DJ (1982) The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 21:1033–1037
Fink M (1975) Prediction of clinical activity of psychoactive drugs: application of cerebral electrometry in phase-I studies. In: Sudilovsky A, Gershon S, Beer B (eds) Predictability in psychopharmacology: pre-clinical and clinical correlations. Raven Press, New York, pp 65–82
Gath I, Weidenfeld J, Collins GI, Hadad H (1984) Electrophysiological aspects of benzodiazepine antagonists, Ro 15-1788 and Ro 15-3505. Br J Clin Pharmacol 18:541–547
Gentil V (1988) Towards an integrated model for panic disorder. Stress Med 4:131–134
Gentil V, Gorenstein C, Camargo CHP, Singer JM (1989) Effects of flunitrazepam on memory and their reversal by two antagonists. J Clin Psychopharmacol 9:191–197
Good R (1940) Some observations on the psychological aspects of cardiazol therapy. J Ment Sci 86:491–501
Gorenstein C, Gentil V (1983) Residual and acute effects of flurazepam and triazolam in normal subjects. Psychopharmacology 80:376–379
Gorenstein C, Gentil V, Ragazzo PC, Manzano G, Arruda PV, Peres C (1986) On the dose equivalence of flurazepam and triazolam. Brazilian J Med Biol Res 19:173–182
Greenwood MH, Lader MH, Kantamaneni BD, Curzon G (1975) The acute effects of oral (−)-tryptophan in human subjects. Br J Clin Pharmacol 2:165–172
Haefely W (1983) The biological basis of benzodiazepine actions. J Psychoactive Drugs 15:19–39
Haefely W (1985) Pharmacology of benzodiazepine antagonists. Pharmacopsychiatry 18:163–166
Haefely W, Kyburz E, Gerecke N, Mohler H (1985) Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists. In: Testa B (ed) Advances in drug research, vol 14. Academic Press, London, pp 165–322
Higgitt A, Lader M, Fonagy P (1986) The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacology 89:395–403
Hunkeler W, Mohler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516
Kornetsky C, Vates TS, Kessler EK (1959) A comparison of hypnotic and residual psychological effects of a single dose of chlorpromazine and secobarbital in man. J Pharmacol Exp Ther 127:51–54
Lucki I, Rickels K, Geller M (1986) Chronic use of benzodiazepines and psychomotor and cognitive test performance. Psychopharmacology 88:426–433
Mitler MM, Gujavarty KS, Browman CP (1982) Maintenance of wakefulness test: a polysomnographic technique for evaluating treatment efficacy in patients with excessive somnolence. Electroencephalogr Clin Neurophysiol 53:658–661
Rechtschaffen A, Kales A (1968) A manual of standard terminology, techniques and scoring system for sleep stages of human subjects. Public Health Service, US Government Printing Office, Washington DC
Richardson GS, Carskadon MA, Flagg W, Van Den Hoed J, Dement WC, Mitler MM (1978) Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 45:621–627
Schopf J, Laurian S, Le PK, Gaillard JM (1984) Intrinsic activity of the benzodiazepine antagonist Ro 15-1788 in man: an electrophysiological investigation. Pharmacopsychiatry 17:79–83
Singlas E (1979) Pharmacocinetique du flunitrazepam. Nouv Presse Med 8:2519–2523
Wechsler DA (1955) Manual for the Wechsler adult intelligence scale. National Foundation for Educational Research, London
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Gentil, V., Tavares, S., Gorenstein, C. et al. Acute reversal of flunitrazepam effects by Ro 15-1788 and Ro 15-3505: inverse agonism, tolerance, and rebound. Psychopharmacology 100, 54–59 (1990). https://doi.org/10.1007/BF02245790
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DOI: https://doi.org/10.1007/BF02245790