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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.
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PMID:Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. 128 3

Flumazenil is a new drug indicated for the reversal of the sedative effects of benzodiazepines mediated at the benzodiazepine-receptor site. Worldwide sources to date have disclosed 43 cases of seizures related, at least temporally, to the intravenous administration of flumazenil. There was no apparent relationship between the dose of flumazenil and the development of seizures, which occurred at doses ranging from 0.2 to 10.0 mg. The seizures were not considered to be a toxic effect of flumazenil, but many of them probably were due to an unmasking of the anticonvulsant effect of the previously used benzodiazepine or to a severe benzodiazepine-withdrawal syndrome. Eighteen (42%) of the patients had ingested overdoses of cyclic antidepressants, which were considered responsible for the seizures. In addition to patients with concurrent cyclic antidepressant poisoning, high-risk populations include patients who have been treated with benzodiazepines for a seizure disorder or an acute convulsive episode, patients with concurrent major sedative-hypnotic drug withdrawal, patients who have recently been treated with repeated doses of parenteral benzodiazepines, and overdose patients with myoclonic jerking or seizure activity before flumazenil administration. To minimize the likelihood of a seizure, it is recommended that flumazenil not be administered to patients who have used benzodiazepines for the treatment of seizure disorders or to patients who have ingested drugs (eg, cyclic antidepressants, cocaine, lithium, methylxanthines, isoniazid, propoxyphene, monoamine oxidase inhibitors, buproprion HCl, and cyclosporine) that place them at risk for the development of seizures.
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PMID:Flumazenil and seizures: analysis of 43 cases. 161 50

Chronic exposure to ethanol is associated with the development of tolerance to the acute effects of ethanol and a withdrawal syndrome characterized by anxiety and seizure susceptibility. In the present study we examined the ability of flumazenil (Ro15-1788), a benzodiazepine receptor antagonist, to reverse neuronal and behavioral manifestations of ethanol tolerance and dependence. A single injection of flumazenil (10 mg/kg, 14 hr before withdrawal) to mice administered a liquid diet containing ethanol for 10 days, reduced seizure severity during withdrawal from ethanol. Acute tolerance to ethanol-induced hypothermia was not sensitive to flumazenil treatment, but tolerance and diazepam-induced cross-tolerance to the ataxic effects of ethanol were reversed by a single injection of flumazenil given 2 to 26 hr before evaluation of tolerance. At a biochemical level, the ability of benzodiazepine inverse agonists (e.g., Ro15-4513) to reduce the activity of gamma-aminobutyric acid (GABA) receptor-operated chloride channels may represent a neuronal manifestation of ethanol dependence (Buck and Harris, 1990). Flumazenil treatment of ethanol-dependent mice 14 hr before isolation of brain membrane vesicles partially reversed the augmentation of Ro15-4513 inhibition of muscimol-stimulated 36Cl- uptake in vitro. These results demonstrate that brief occupation of benzodiazepine receptors by an antagonist may reset the cellular mechanisms responsible for the development of ethanol tolerance and dependence, and support the hypothesis that increased sensitivity to benzodiazepine inverse agonists is involved in the development of ethanol dependence.
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PMID:Reversal of alcohol dependence and tolerance by a single administration of flumazenil. 164 33

The generalized repetitive fast discharge (GRFD) is an ictal pattern representing the EEG counterpart of tonic seizures occurring mainly in Lennox-Gastaut syndrome (LGS) during slow-wave sleep. The history of terminology, electromorphology, correlations with sleep, ictal clinical correlations and associations with different epileptic syndromes as well as the clinical significance of the pattern is described reviewing the pertinent literature and our own experiences. The physiopathogenesis from both the electrophysiological and pharmacological aspects is discussed in the framework of a concept according to which GRFD is considered as a malignant derivative of an existing slow spike-wave mechanism, due to the permanent or momentary breakdown of the GABA-ergic inhibitory process. In observations performed on some patients we found a paradoxical GRFD-eliciting effect of BDZ drugs and hexobarbiturate after chronic treatment with BDZ agents and/or barbiturate, and a GRFD-blocking effect of Anexate (Flumazenil), a BDZ antagonist on the pattern, appearing either spontaneously in slow-wave sleep or elicited by diazepam or barbiturate. Our findings support the assumption that BDZ (Barbiturate) GABA-Chloride Ionophore Complex plays an important role, both in the development of and possibly in the therapeutic approach to, the GRFD phenomena. Some hypotheses about the role played by the complex based on these observations are put forward.
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PMID:Runs of rapid spikes in sleep: a characteristic EEG expression of generalized malignant epileptic encephalopathies. A conceptual review with new pharmacological data. 166 48

Benzodiazepine withdrawal, spontaneous or precipitated by the receptor antagonist, flumazenil, produces anxiety that can be measured in animal models. Benzodiazepine inverse agonists also cause anxiety. Their convulsive effects increase after chronic agonist treatment, but they become anxiolytic. Decreases in GABAA receptor sensitivity occur after chronic benzodiazepine treatment. Flumazenil, given 24h prior to the measurements, prevented both the sensitivity changes and benzodiazepine tolerance in vivo. The anxiety and decreases in seizure threshold during withdrawal were also prevented. It has been suggested that flumazenil causes a prolonged 'resetting' of the benzodiazepine receptor complex. Acute flumazenil decreased anxiety-related behaviour during ethanol withdrawal. Concurrent chronic treatment with verapamil completely prevented anxiety following chronic benzodiazepine treatment.
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PMID:The benzodiazepines: anxiolytic and withdrawal effects. 167 9

We have developed a model of benzodiazepine-type physical dependence in which mice were injected subcutaneously with the test compound on a fixed schedule (0800 and 1600 for 3 days, the PM dose = AM dose x 2). If tolerated, then a starting dose of 150 mg/kg/day was generally used initially and the dose was lowered to 15 and 1.5 mg/kg/day in subsequent assays if the higher doses were active in the test. Twenty-four hours after the last dose, the mice received an intravenous injection of flumazenil (2.5 mg/kg), and 5 min later they were tested for electroshock seizure thresholds by an up-down titration method. Flumazenil-precipitated withdrawal was manifested by a lowering of the mA seizure threshold. We have found that compounds with benzodiazepine agonist properties significantly lower these thresholds in a dose-related fashion. For example, the following compounds (lowest effective mg/kg/day dose) were active in this regard, chlordiazepoxide (150), diazepam (15), flurazepam (15), alprazolam (15), triazolam (15), midazolam (15), zopiclone (150), Ro 16-6028 (150), and Ro 17-1812 (150). In contrast, zolpidem (150), tracazolate (15), and CL 218872 (15) did not cause physical dependence by this criterion. This rapid and simple screening test may be readily used to predict the physical-dependence-inducing properties of compounds that act at the benzodiazepine receptor.
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PMID:A rapid screening method for the assessment of benzodiazepine receptor-related physical dependence in mice. Evaluation of benzodiazepine-related agonists and partial agonists. 168 Nov 36

Alprazolam (48 mg/kg/day) administered orally to dogs 4 times a day in equally divided doses produced physical dependence. This dependence was revealed by a precipitated abstinence syndrome which occurred after either oral administration of flumazenil (6, 18 and 36 mg/kg) or intravenous administration of a liposomal suspension of flumazenil. Flumazenil alone (18, 36 and 72 mg/kg) produced no significant signs of precipitated abstinence in naive dogs. This precipitated abstinence syndrome in alprazolam-dependent dogs was characterized by both clonic and tonic-clonic seizures. Other signs of precipitated abstinence which comprise the NPAS score were less intense in the alprazolam-dependent than in diazepam-dependent dogs. Alprazolam is extensively metabolized in the dog and does not accumulate whereas its predominant metabolite, alpha hydroxyalprazolam, does accumulate. The data suggest that alpha hydroxyalprazolam plays a role in the dependence-producing properties of alprazolam in the dog as revealed by the precipitated abstinence syndrome.
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PMID:Dependence-producing properties of alprazolam in the dog. 211 Oct 29

The anticonvulsive properties of a new compound: F1933 (Dulozafone) were investigated in the amygdala kindling model and compared with those of diazepam. Both drugs protected fully kindled rats against generalized seizures but failed to suppress partial ictal events (amygdala afterdischarges and limbic seizures). The anticonvulsive action of F1933, administered at the ED100, was nearly reversed by the specific antagonist of benzodiazepines receptors; R015-1788 (Flumazenil), suggesting that the effect of F1933 is mediated by this receptor. These results also emphasize the usefulness of kindling to test antiepileptic drugs and to confirm their supposed profile of action.
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PMID:Anticonvulsive properties of F1933 (dulozafone) on kindled seizures in the rat. 211 9

Flumazenil (Lanexat) is the first specific benzodiazepine-antagonist for clinical use. In several controlled investigations, a significant rapidly commencing antagonistic effect on the central effects of benzodiazepines has been demonstrated. Flumazenil possesses only slight side effects which may easily be treated. The immediate indications for employing flumazenil are reversal of the sedation caused by benzodiazepines in outpatients and treatment of cases of poisoning. In addition, flumazenil could be employed to reverse sedation produced by benzodiazepines during general anaesthesia and prolonged sedation in intensive care units. The following should be observed on employing flumazenil: 1. Flumazenil should be administered by slow meticulous titration. 2. The relatively short half-life of flumazenil provides the possibility for partial return of CNS depression. 3. In cases of mixed poisoning, flumazenil may unmask the effects of possible seizure-producing drugs. 4. Care should be employed in using flumazenil in chronic benzodiazepine abusers.
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PMID:[Flumazenil. A specific benzodiazepine antagonist]. 250 84

1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors.
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PMID:Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants. 257 61


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