Flumazenil

11C-flumazenil is commonly labeled at the A7-me 1 11 yl position by N-methylation with 11 C-iodomethane, which is prepared from 11C-C02, and using the freshly prepared Grignard reagent, methylmagnesium bromide (Maziere et al, 1984). The specific activity is very important for this product and therefore is purified by HPLC to give an optimum value between 0.5 and 2Ci/Vmol (18.5-74GI k]/i imol). It remains stable for up to 3 h at room temperature at pH 7.0. The molecular structure of 11C-fumazenil is shown in Fig. 8.2b. 

Since it is a benzodiazepine receptor ligand, 11C-flumazenil is primarily used for the neuroreceptor characterization in humans. 

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Midazolam and diazepam decrease arterial pressure without a change ia heart rate. Like thiopeatoae, midazolam is a respiratory depressant. Advantages of midazolam are its amnestic effect, coupled with less postoperative depression (102). A reversal agent for the benzodiazepiaes has also become available. Flumazenil [78755-81-4] C25H24FN2O2, (5) displaces the beazodiazepiaes from their receptor but has Httie demoastrable activity of its owa (103,104). 

Combinations of barbiturates and benzodiazepine tranquilizers or even antihistaminergics having sedative properties are sometimes used. Furthermore, infusion of anesthetics can be used to provide long-term anesthesia for intensive care medicine. The antagonist flumazenil (18) is available to reverse the effects of anesthetics of the benzodiazepine class. 

The most important fluorinated benzodiazepine, flurazepam (21) has found considerable use (and abuse) as a hypnotic [I4 Flumazenil (22) is a fast-acting antidote in the treatment of benzodiazepine intoxication and m the reversal of the CNS effects of benzodiazepines dunng anesthesia [f<5,19]... 

Although flumazenil binds with high affinity to the benzodiazepine site of GABAa receptors, it has practically no action when given alone. However, flumazenil competitively blocks the action of benzodiazepine site agonists. Flumazenil can be used to terminate the action of benzodiazepines, e.g., after a benzodiazepine overdose. It may also serve as a diagnostic tool in this regard. 

The definition of desired therapeutic and side effects in the case of the benzodiazepines very much depends on the clinical problem in question. The sedative and hypnotic actions are desired effects in the treatment of insomnia, but undesired effects in the treatment of anxiety disorders. Effects that are usually undesired include daytime drowsiness, potentiation of the sedative effects of ethanol, and anterograde amnesia. They are mediated via the benzodiazepine site of GABAa receptors, since they can be antagonized with flumazenil. 

Although rare, benzodiazepine toxicity may occur from an overdose of the drug. Benzodiazepine toxicity causes sedation, respiratory depression, and coma. Flumazenil (Romazicon) is an antidote (antagonist) for benzodiazepine toxicity and acts to reverse die sedation, respiratory depression, and coma within 6 to 10 minutes after intravenous administration. The dosage is individualized based on the patient s response, widi most patients responding to doses of 0.6 to 1 mg. However, die drug s action is short, and additional doses may be needed. Adverse reactions of flumazenil include agitation, confusion, seizures, and in some cases, symptoms of benzodiazepine withdrawal. Adverse reactions of flumazenil related to the symptoms of benzodiazepine withdrawal are relieved by die administration of die benzodiazepine. 

C3H5NO 109-90-0) see Alfentanil Cabergoline ethyl isocyanatoaeetate (C5H7NO3 2949-22-6) see Flumazenil ethyl isonicotinate... 

CH2FI 373-53-5) see Fluticasone propionate 5-fluoroisatoic anhydride (C8H4FNO3 321-69-7) see Flumazenil... 

C3H7NO2 107-97-1) see Flumazenil methylglyoxal diethyl acetal (C7H14O2 5774-26-5) see Betacarotene... 

CfiH3N02S 874-84-0) see Temocapril 2-nitro 5-fluorobenzoic acid (C7H4FNO4 320-98-9) see Flumazenil... 

Brogden RN, Goa KL Flumazenil a preliminary review of its benzodiazepine antagonist properties, intrinsic activity and therapeutic use. Drugs 35 448 67, 1988... 

Buldakova S, Weiss M Electrophysiological evidence for agonist properties of flumazenil, a benzodiazepine receptor antagonist, in rat hippocampus slices. J Neurol Sci 149 121-126, 1997... 

Gerra G, Zaimovic A, Giusti F, et al Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal a randomized, placebo-controlled... 

Mintzer MZ, Stoller KB, Griffiths RR A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users. Psychopharmacology (Berl) 147 200-209, 1999... 

Nutt DJ, Glue P, Lawson C, et al Flumazenil provocation of panic attacks evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 47 917-923, 1990... 

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

The first antagonist to be developed was the (imidazo)benzodiazepine, flumazenil. This compound blocks the actions of both agonists and inverse agonists in vitro. It will... 

Evidence for the false transmitter theory as the cause of encephalopathy is demonstrated by the fact that administration of flumazenil (a benzodiazepine antagonist) has resulted in functional improvement. Unfortunately, long-term benefit has not been shown, and since flumazenil can only be administered par-enterally, it is not an appropriate choice for long-term therapy. 

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