Summary
The receptor to which benzodiazepine hypnosedatives and anticonvulsants bind was discovered and characterized in the late 1970s. Agonists and inverse agonists that act at various sites within the receptor complex have been identified. In addition, antagonists of the benzodiazepine receptor have been synthesised. At present, flumazenil is the only agent of this class that is available clinically.
Flumazenil has well documented benefits in the treatment of hepatic encephalopathy and benzodiazepine overdose. The drug has also been studied as a potential treatment for neuropsychiatric illnesses in which dysfunction of the γ-aminobutyric acid (GABA)ergic system is implicated as a causal factor. Potential therapeutic benefits are suggested in benzodiazepine tolerance and withdrawal, benzodiazepine-related amnesia, epilepsy, sleep disorders, cognitive disorders and idiopathic recurrent stupor. In contrast, no clear benefits have been found in alcoholism, anxiety and movement disorders. Flumazenil induces few adverse effects, and so represents a promising tool for pharmacological investigations of the GABAergic system and for imaging of the benzodiazepine receptor. As an imaging agent it has been used for quantification of the receptor, and as a neuronal marker in epilepsy and cerebral ischaemia.
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References
Squires RF, Braestrup C. Benzodiazepine receptors in rat brain. Nature 1977; 266: 732–4
Mohler H, Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science 1977; 198: 849–51
Dunn SMJ, Bateson AN, Martin IL. Molecular biology of the GABAA receptor. Int Rev Neurobiol 1994; 36: 51–96
Tallman J. Subunit composition affects agonist/antagonist actions at GABAa/benzodiazepine receptors. Neuropsychopharmacology 1994; 10Suppl.: 586S
Tallman JF, Gallager DW. The GABA-ergic system: a locus of benzodiazepine action. Annu Rev Neurosci 1985; 8: 21–44
Luddens H, Wisden W. Function and pharmacology of multiple GABAA receptor subunits. Tends Pharmacol Sci 1991; 12: 49–51
Luddens H, Pritchett D, Kohler M, et al. Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 1990; 346: 648–51
Pritchett D, Luddens H, Seeburg P. Type I and type II GABAAbenzodiazepine receptors produced in transfected cells. Science 1989; 245: 1389–92
Pritchett D, Seeburg P. Gamma-aminobutyric acid A receptor α5-subunit creates novel type II benzodiazepine receptor pharmacology. J Neurochem 1990; 54: 1802–4
Guidotti A, Forchetti C, Corda M, et al. Isolation, characterization and purification to homogeneity of an endogenous polypeptide with agonist action on benzodiazepine receptors. Proc Natl Acad Sci USA 1983; 80: 3531–5
Hunkeler W, Mohler H, Pieri L, et al. Selective antagonists of benzodiazepine. Nature 1981; 290: 514–6
Hoffman RS, Goldfrank LR. The poisoned patient with altered consciousness. JAMA 1995; 274: 562–9
Mullen K, Basile A. Benzodiazepine-receptor antagonists and hepatic encephalopathy: where do we stand? Gastroenterology 1993; 105: 937–40
Jones E, Basile A, Mullen K, et al. Flumazenil: potential implications for hepatic encephalopathy. Pharmacol Ther 1990; 45: 331–43
Higgit A, Lader M, Fonagy P. The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacology 1986; 89: 395–403
Schopf J, Laurian S, Le P, et al. Intrinsic activity of the benzodiazepine antagonist Ro 15-1788 in man: an electrophysiological investigation. Pharmacopsychiatry 1984; 17: 79–83
Laurian S, Gaillard J, Schopf J. Effects of a benzodiazepine antagonist on the diazepam-induced electrical brain activity modifications. Neuropsychobiology 1984; 11: 55–8
Lupolover Y, Safran A, Desangles D, et al. Evaluation of visual function in healthy subjects after administration of Ro 15-1788. Eur J Clin Pharmacol 1984; 27: 505–7
Darragh A, Lambe R, O’Boyle C, et al. Absence of central effect in man of the benzodiazepine antagonist Ro 15-1788. Psychopharmacology 1983; 80: 192–5
Abi-Dargham A, Laruelle M, Seibyl J, et al. SPECT measurement of benzodiazepine receptors in human brain with [123I]iomazenil: kinetic and equilibrium paradigms. J Nucl Med 1994; 35: 228–38
Enrich H, Sonderegger P, Mai N. Action of the benzodiazepine antagonist Ro 15-1788 in humans after sleep withdrawal. Neurosci Lett 1984; 47: 369–73
Savic I, Widen L, Stone-Elander S. Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 1991; 337: 133–7
Cone A, Stott S. Flumazenil. Br J Hosp Med 1994; 51: 346–8
Breimer LT, Hennis PJ, Burm AG, et al. Pharmacokinetics and EEG effects of flumazenil in volunteers. Clin Pharmacokinet 1991; 20: 491–6
Amrein R, Hetzel W. Pharmacology of Dormicum (midazolam) and Anexate (flumazenil). Acta Anaesthesiol Scand 1990; 34Suppl. 92: 6–15
Roncari G, Timm U, Zell M, et al. Flumazenil kinetics in the elderly. Eur J Clin Pharmacol 1993; 45: 585–7
Tefakis-Karavokiros K, Tsipis G. Flumazenil: a benzodiazepine antagonist. Ann Pharmacother 1990; 24: 976–81
Longmire A, Seger D. Topics in clinical pharmacology: flumazenil, a benzodiazepine antagonist. Am J Med Sci 1993; 306: 49–52
Brogden R, Goa K. Flumazenil: a reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991; 42: 1061–89
Griffiths RR, Evans SM, Guarino JJ, et al. Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: antagonism and precipitated withdrawal. Am Soc Pharmacol Exp Ther 1993; 265: 1163–74
Bassett M, Mullen K, Skolnick P, et al. Amelioration of hepatic encephalopathy by pharmacological antagonism of the GABAabenzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. Gastroenterology 1987; 93: 1069–77
Gammal S, Basile A, Geller D, et al. Reversal of the behavioral and electrophysiological abnormalities of an animal model of hepatic encephalopathy by benzodiazepine receptor ligands. Hepatology 1990; 11: 371–8
Bosman D, van den Buijs C, de Haan J, et al. The effects of the benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat. Gastroenterology 1991; 101: 772–81
Sterling R, Shiffman M, Schubert M. Flumazenil for hepatic coma: the elusive wake-up call? Gastroenterology 1994; 107: 1204–5
Winkler E, Almog S, Krigr D, et al. Use of flumazenil in the diagnosis and treatment of patients with coma of unknown etiology. Crit Care Med 1993; 21: 538–42
Hojer J, Baehrendtz S, Matell G, et al. Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind, randomised controlled study. BMJ 1990; 301: 1308–11
Lheureux P, Vrankx M, Askenasi R. Administration of flumazenil. Ann Emerg Med 1991; 20: 592–3
Birch B. Cardiac arrest associated with flumazenil. BMJ 1992; 305: 180–1
Hodgkinson D, Driscoll P. Diagnostic utility of flumazenil in coma with suspected poisoning [letter]. BMJ 1991; 302: 238
LaFleche F, Milzman D. Flumazenil and coma [letter], Ann Emerg Med 1991; 20: 1397
Ghoneim M. The reversal of benzodiazepine-induced amnesia by flumazenil: a review. Curr Ther Res 1992; 52: 757–67
Wesensten N, Balkin T, Davis H, et al. Reversal of triazolamand zolpidem-induced memory impairment by flumazenil. Psychopharmacology 1995; 121:242–9
Birch B, Anson K, Clifford E, et al. Day-case surgery: enhanced recovery with flumazenil. J R Soc Med 1990; 83: 436–8
Birch B, Anson K, Kalmanovitch D, et al. Sedation for day-case urology: an assessment of patient recovery profiles after midazolam and flumazenil. Ann R Coll Surg Engl 1991; 73: 373–8
Bigl P, Hess L, Pavek V. Our experience with midazolam and flumazenil in dentistry. Curr Ther Res 1992; 51: 92–6
Allan A, Baier L, Zhang X. Effects of lorazepam tolerance and withdrawal on GABAA receptor-operated chloride channels. J Pharmacol Exp Ther 1992; 261: 395–402
Nutt D, Costello M. Rapid induction of lorazepam dependence and reversal with flumazenil. Life Sci 1988; 43: 1045–53
Gonsalves S, Gallager D. Spontaneous and Ro 15-1788 induced subsensitivity to GABA recognition site following chronic benzodiazepine. Eur J Pharmacol 1985; 110: 163–70
Cittadini A, Lader M. Lack of effect of a small dose of flumazenil in reversing short term tolerance to benzodiazepines in normal subjects. J Psychopharmacol 1991; 5: 220–7
Gerra G, Marcato A, Caccavari R, et al. Effectiveness of flumazenil in the treatment of benzodiazepine withdrawal. Curr Ther Res 1993; 54: 580–7
Lader M, Morton S. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. J Psychopharmacol 1992; 6: 357–63
Baldwin H, Hitchcott P, File S. The use of flumazenil in prevention of diazepam dependence in the rat. Hum Psychopharmacol 1990; 5: 57–61
Gallager D, Heninger K, Heninger G. Periodic benzodiazepine antagonist administration prevents benzodiazepine withdrawal symptoms in primates. Eur J Pharmacol 1986; 132: 31–8
Lamb R, Griffiths R. Effects of repeated Ro 15-1788 administration in benzodiazepine-dependent baboons. Eur J Pharmacol 1985; 110: 257–61
Kang I, Miller L. Decreased GABAA receptor subunit mRNA concentration following lorazepam administration. Br J Pharmacol 1990; 103: 1285–7
Korpi ER. Role of GABA(A) receptors in the actions of alcohol and in alcoholism - recent advances. Alcohol Alcohol 1994; 29: 115–29
Buck K, Hahner L, Sikela J, et al. Chronic ethanol treatment alters brain levels of y-aminobutyric acid A receptor subunit mRNAs: relationship to genetic differences in ethanol withdrawal seizure severity. J Neurochem 1991; 57: 1452–5
Mhatre M, Ticku M. Chronic ethanol administration alters γ-aminobutyric acid A receptor gene expression. Mol Pharmacol 1992; 42: 415–22
Freund G, Ballinger WJ. Decrease of benzodiazepine receptors in frontal cortex of alcoholics. Alcohol 1988; 5: 275–82
Freund G, Ballinger WJ. Loss of muscarinic and benzodiazepine neuroreceptors from hippocampus of alcohol abusers. Alcohol 1989; 6: 23–31
Gerra G, Caccavari R, Volpi R, et al. Effectiveness of flumazenil in the treatment of ethanol withdrawal. Curr Ther Res 1991; 50: 62–6
Clausen T, Wolff J, Carl P, et al. The effect of the benzodiazepine antagonist, flumazenil, on psychometric performance in acute ethanol intoxication in man. Eur J Clin Pharmacol 1990; 38: 233–6
Buck K, Heim H, Harris R. Reversal of alcohol dependence and tolerance by a single administration of flumazenil. J Pharmacol Exp Ther 1991; 257: 984–9
Buck K, Harris R. Benzodiazepine agonist and inverse agonist actions on GABAA receptor operated chloride channels. II: Chronic effects of ethanol. J Pharmacol Exp Ther 1990; 253: 713–9
June H, Greene T, Murphy J, et al. Effects of the benzodiazepine inverse agonist RO 19-4603 alone and in combination with the benzodiazepine receptor antagonists flumazenil, ZK 93426 and CGS 8216, on ethanol intake in alcohol-preferring (P) rats. Brain Res 1996; 734: 19–34
Hart YM, Meinardi H, Sander JWAS, et al. The effect of intravenous flumazenil on interictal electroencephalographic epileptic activity: results of a placebo-controlled study. J Neurol Neurosurg Psychiatry 1991; 54: 305–9
Sharief M, Sander J, Shorvon S. The effect of oral flumazenil on interictal epileptic activity: results of a double-blind, placebo-controlled study. Epilepsy Res 1993; 15: 53–60
Bruguerolle B, Emperaire N. Local anesthetics-induced toxicity may be modified by low doses of flumazenil [letter]. Life Sci 1992; 50: PL 185–8
Spivey W. Flumazenil and seizures: an analysis of 43 cases. Clin Ther 1992; 14: 292–305
Escorihuela R, Fernandez-Teruel A, Zapata A, et al. Flumazenil prevents the anxiolytic effects of diazepam, alprazolam, and adinazolam on the early acquisition of two-way active avoidance. Pharmacol Res 1993; 28: 53–8
Kapczinski F, Curran H, Gray J, et al. Flumazenil has an anxiolytic effect in simulated stress. Psychopharmacology 1994; 114: 187–9
Randall P, Bremner J, Krystal J, et al. Effects of the benzodiazepine antagonist flumazenil in PTSD. Biol Psychiatry 1995; 38: 319–24
Woods S, Charney D, Silver J, et al. Behavioral, biochemical, and cardiovascular responses to the benzodiazepine receptor antagonist flumazenil in panic disorder. Psychiatry Res 1991; 36: 115–27
Nutt D, Glue P, Lawson C, et al. Flumazenil provocation of panic attacks. Arch Gen Psychiatry 1990; 47: 917–25
Ball D, Glue P, Wilson S, et al. Pharmacology of saccadic eye movements in man. 1: Effects of the benzodiazepine receptor ligands midazolam and flumazenil. Psychopharmacology 1991; 105: 361–7
Wilson S, Glue P, Nutt D. Flumazenil and saccadic eye movements in patients with panic disorder and normal controls. Hum Psychopharmacol 1992; 7: 45–50
Steiger A, Guldner J, Lauer C, et al. Flumazenil exerts intrinsic activity on sleep EEG and nocturnal hormone secretion in normal controls. Psychopharmacology 1994; 113: 334–8
Lloyd K, Hornykiewicz O. L-glutamic acid decarboxylase in Parkinson’s disease. Nature 1973; 243: 521–3
Seifritz E, Hemmeter U, Trachsel L, et al. Effects of flumazenil on recovery sleep and hormonal secretion after sleep deprivation in male controls. Psychopharmacology 1995; 120: 449–56
Duka T, Goerke D, Fichte K. Effects of ZK 93426, a B-carboline benzodiazepine receptor antagonist on night sleep pattern in healthy male volunteers. Psychopharmacology 1995; 117: 178–85
Tinuper P, Montagna P, Corelli P, et al. Idiopathic recurring stupor: a case with possible involvement of the gamma-aminobutyric acid (GABA)ergic system. Ann Neurol 1992; 31: 503–6
Rothstein J, Guidotti A, Tinuper P, et al. Endogenous benzodiazepine ligands in idiopathic recurring stupor. Lancet 1992; 340: 1002–4
Trifiletti R, Snowman A, Whitehouse P, et al. Huntington’s disease: increased number and altered regulation of benzodiazepine receptor complexes in frontal cerebral cortex. Neurology 1987; 37: 916–22
McGeer P, McGeer E. Enzymes associated with the metabolism of catecholamines, acetylcholine and GABA in human controls and patients with Parkinson’s disease and Huntington’s chorea. J Neurochem 1976; 26: 65–76
Kulisevsky J, Avila A, Berthier M, et al. Double-blind trial of flumazenil in hemiaballismus. Clin Neuropharmacol 1994; 17: 470–2
Ghoneim M, Mewaldt S. Benzodiazepines and human memory: a review. Anesthesiology 1990; 72: 926–38
Lai H, Kumar B, Forster M. Enhancement of learning and memory in mice by a benzodiazepine antagonist. FASEB J 1988; 2: 2707–11
Prather P, Forster M, Lai H. Learning and memory-enhancing effects of Ro 15-4513: a comparison with flumazenil. Neuropharmacology 1992; 31: 299–306
Duka T, Ott H, Rohloff A, et al. The effects of a benzodiazepine receptor antagonist (β-carboline ZK-93426 on scopolamine-induced impairment on attention, memory and psychomotor skills. Psychopharmacology 1996; 123: 361–73
Imperato A, Dazzi L, Obinu M, et al. Inhibition of hippocampal acetylcholine release by benzodiazepines: antagonism by flumazenil. Eur J Pharmacol 1993; 238: 135–7
Sarter M, Bruno J, Dudchenko P. Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplification. Psychopharmacology 1990; 101: 1–17
Kapczinski F, Sherman D, Williams R, et al. Differential effects of flumazenil in alcoholic and nonalcoholic cirrhotic patients. Psychopharmacology 1995; 120: 220–6
Zacny J, Yajnik S, Coalson D, et al. Flumazenil may attenuate some subjective effects of nitrous oxide in humans: a preliminary report. Pharmacol Biochem Behav 1995; 51: 815–9
Bradwejn J, Koszycki D, Couetoux du Tertre A, et al. Effects of flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in healthy volunteers. Psychopharmacology 1994; 114: 257–61
Unseld E, Ziegler G, Gemeinhardt A, et al. Possible interaction of fluoroquinolones with the benzodiazepine-GABAa-receptor complex. Br J Clin Pharmacol 1990; 30: 63–70
Samson Y, Hantraye P, Baron JC, et al. Kinetics and displacement of [11C] Ro 15-1788, a benzodiazepine antagonist, studied in human brain in vivo by positron tomography. Eur J Pharmacol 1985; 110: 247–51
Maziere M, Hantraye P, Prenant C, et al. Synthesis of ethyl 8-fluoro-5,6-dihydro-5-[1lC]methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (Ro 15-1788-11C): a specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography. Int J Appl Radiat Isot 1984; 35: 973–6
Hantraye P, Kaijima M, Prenant C, et al. Central type benzodiazepine binding sites: a position emission tomography study in the baboon’s brain. Neurosci Lett 1984; 48: 115–20
Shinotoh H, Iyo M, Yamada T, et al. Detection of benzodiazepine receptor occupancy in the human brain by positron emission tomography. Psychopharmacology 1989; 99: 202–7
Hantraye P, Chavoix C, Guibert B, et al. Benzodiazepine receptors studied in living primates by positron emission tomography: inverse agonist interactions. Eur J Pharmacol 1987; 138: 239–47
Savic I, Roland P, Sedvall G, et al. In-vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancet 1988; 2: 863–6
Persson A, Ehling E, Erikson L, et al. Imaging of [11C]-labelled Ro 15-1788 to benzodiazepine receptors in the human brain by positron emission tomography. J Psychiatr Res 1985; 19: 609–22
Beer H-F, Blauenstein PA, Hasler PH, et al. In vitro and in vivo evaluation of iodine-123 Ro 16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors. J Nucl Med 1990; 31: 1007–14
Iyo M, Itoh T, Yamasaki T, et al. Quantitative in vivo analysis of benzodiazepine binding sites in the human brain using positron emission tomography. Neuropharmacology 1991; 30: 207–15
Abi-Dargham A, Gandelman M, Zoghbi SS, et al. Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine- 123-iomazenil. J Nucl Med 1995; 36: 167–75
Pappata S, Samson Y, Chavoix C, et al. Regional specific binding of [11C]Ro 15-1788 to central type benzodiazepine receptors in human brain: quantitative evaluation by PET. J Cereb Blood Flow Metab 1988; 8: 304–13
Koeppe RA, Holthoff VA, Frey KA, et al. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 1991; 11: 735–44
Holthoff VA, Koeppe RA, Frey KA, et al. Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil. J Cereb Blood Flow Metab 1991; 11: 745–52
Delforge J, Pappata S, Millet P, et al. Quantification of benzodiazepine receptors in human brain using PET, [C-ll]flumazenil, and a single-experiment protocol. J Cereb Blood Flow Metab 1995; 15: 284–300
Price JC, Mayberg HS, Dannals RF, et al. Measurement of benzodiazepine receptor number and affinity in humans using tracer kinetic modeling, positron emission tomography, and [11C]-flumazenil. J Cereb Blood Flow Metab 1993; 13: 656–67
Lassen NA, Bartenstein PA, Lammertsma AA, et al. Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET: application of the steady-state principle. J Cereb Blood Flow Metab 1995; 15: 152–65
Onishi Y, Yonekura Y, Mukai T, et al. Simple quantification of benzodiazepine receptor binding and ligand transport using iodine-123-iomazenil and two SPECT scans. J Nucl Med 1995; 36: 1201–10
Abadie P, Baron JC, Bisserbe JC, et al. Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography. Eur J Pharmacol 1992; 213: 107–15
Delforge J, Syrota A, Bottlaender M, et al. Modeling analysis of [llCJflumazenil kinetics studied by PET: application to a critical study of the equilibrium approaches. J Cereb Blood Flow Metab 1993; 13: 454–68
Brouillet E, Chavoix C, Khalili-Varasten M, et al. Quantitative evaluation of benzodiazepine receptors in live Papio Anubis baboons using positron emission tomography. Mol Pharmacol 1990; 38: 445–51
Laruelle M, Baldwin RM, Rattner Z, et al. SPECT quantification of [l23I]iomazenil binding to benzodiazepine receptors in nonhuman primates. I: Kinetic modeling of single bolus experiments. J Cereb Blood Flow Metab 1994; 14: 439–52
Laruelle M, Abi-Dargham A, Al-Tikriti MS, et al. SPECT quantification of [l23I]iomazenil binding to benzodiazepine receptors in nonhuman primates. II: equilibrium analysis of constant infusion experiments and correlation with in vitro parameters. J Cereb Blood Flow Metab 1994; 14: 453–65
Baldwin RM, Horti AG, Bremner JD, et al. Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-1lC]iomazenil. Nucl Med Biol 1995; 22: 659–65
Westera G, Buck A, Burger C, et al. Carbon-11 and iodine-123 labelled iomazenil: a direct PET-SPET comparison. Eur J Nucl Med 1996; 23:5–12
Pauli S, Liljequist S, Farde L, et al. PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil. Psychopharmacology 1992; 107: 180–5
Litton J-E, Neiman J, Pauli S, et al. PET analysis of [1lC]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls. Psychiatry Res Neuroimaging 1992; 50: 1–13
Farde L, Pauli S, Litton JE, et al. PET-determination of benzodiazepine receptor binding in studies on alcoholism: toward a molecular basis of alcohol use and abuse. Basel: Birk Hauser Verlag, 1994: 143–53
Gilman S, Koeppe RA, Adams K, et al. Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics. Ann Neurol 1996; 40: 163–71
Abi-Dargham A, Krystal J, Webb E, et al. SPECT imaging of benzodiazepine receptors in alcoholics and healthy controls [abstract]. Alcohol Clin Exp Res 1995; 19: 10A
Savic I, Thorell JO, Roland P. [1lCJflumazenil positron emission tomography visualizes frontal epileptogenic regions. Epilepsia 1995; 36: 1225–32
Henry TR, Frey KA, Sackellares JC, et al. In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy. Neurology 1993; 43: 1998–2006
Prevett MC, Lammertsma AA, Brooks DJ, et al. Benzodiazepine-GABAA receptor binding during absence seizures. Epilepsia 1995; 36: 592–9
Prevett MC, Lammertsma AA, Brooks DJ, et al. Benzodiazepine-GABAA receptors in idiopathic generalized epilepsy measured with [1lC]flumazenil and positron emission tomography. Epilepsia 1995; 36: 113–21
Kuwert T, Stodieck SR, Puskas C, et al. Reduced GABAA receptor density contralateral to a potentially, epileptogenic MRI abnormality in a patient with complex partial seizures. Eur J Nucl Med 1996; 23: 95–8
Sjoholm H, Rosen I, Elmqvist D. Role of I-123-iomazenil SPECT imaging in drug resistant epilepsy with complex partial seizures. Acta Neurol Scand 1995; 92: 41–8
Staedt J, Stoppe G, Kogler A, et al. Changes of central benzodiazepine receptor density in the course of anticonvulsant treatment in temporal lobe epilepsy. Seizure 1995; 4: 49–52
Gilman S, Koeppe RA, Junck L, et al. Benzodiazepine receptor binding in cerebellar degenerations studied with positron emission tomography. Ann Neurol 1995; 38: 176–85
Holthoff VA, Koeppe RA, Frey KA, et al. Positron emission tomography measures of benzodiazepine receptors in Huntington’s disease. Ann Neurol 1993; 34: 76–81
Meyer M, Koeppe RA, Frey KA, et al. Positron emission tomography measures of benzodiazepine binding in Alzheimer’s disease. Arch Neurol 1995; 52: 314–7
Sette G, Baron JC, Young AR, et al. In vivo mapping of brain benzodiazepine receptor changes by positron emission tomography after focal ischemia in the anesthetized baboon. Stroke 1993; 24: 2046–57
Hatazawa J, Satoh T, Shimosegawa E, et al. Evaluation of cerebral infarction with iodine 123-iomazenil SPECT. J Nucl Med 1995; 36: 2154–61
Hatazawa J, Shimosegawa E, Satoh T, et al. Central benzodiazepine receptor distribution after subcortical hemorrhage evaluated by means of [123I]iomazenil and SPECT. Stroke 1995; 26: 2267–71
Schlegel S, Steinert H, Bockisch A, et al. Decreased benzodiazepine receptor binding in panic disorder measured by iomazenil-SPECT: a preliminary report. Eur Arch Psychiatry Clin Neurosci 1994; 244: 49–51
Kuikka JT, Pitkanen A, Lepola U, et al. Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun 1995; 16: 273–80
Videbaek C, Friberg L, Holm S, et al. Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with the single photon emission computer tomography tracer [123I]iomazenil. Eur J Pharmacol 1993; 249: 43–51
Sybirska E, Seibyl JP, Bremner JD, et al. [123I]iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain. Neuropharmacology 1993; 32: 671–80
Schmid L, Bottlaender M, Fuseau C, et al. Zolpidem displays heterogeneity in its binding to the nonhuman primate benzodiazepine receptor in vivo. J Neurochem 1995; 65: 1880–6
Bottlaender M, Brouillet E, Varastet M, et al. In vivo high intrinsic efficacy of triazolam: a positron emission tomography study in nonhuman primates. J Neurochem 1994; 62: 1102–11
Ochs MW, Tucker MR, Owsley TG, et al. The effectiveness of flumazenil in reversing the sedation and amnesia produced by intravenous midazolam. J Oral Maxillofac Surg 1990; 48: 240–5
Hart Y, Sander J, Meinardi H, et al. Flumazenil as an anti-epileptic agent [letter]. Lancet 1991; 337: 744
Nave R, Herer P, Lavie P. The intrinsic effects of sarmazenil on sleep propensity and performance level of sleep-deprived subjects. Psychopharmacology 1994; 115: 366–70
Glue P, Nutt D. Benzodiazepine receptor sensitivity in panic disorder [letter]. Lancet 1991; 337: 563
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Abi-Dargham, A., Charney, D.S. & Krystal, J.H. Benzodiazepine Receptor Antagonists. CNS Drugs 8, 244–256 (1997). https://doi.org/10.2165/00023210-199708030-00007
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DOI: https://doi.org/10.2165/00023210-199708030-00007