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Michael J Lewis - One of the best experts on this subject based on the ideXlab platform.
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Interactions of Ro15-4513, Ro15-1788 (Flumazenil) and ethanol on measures of exploration and locomotion in rats
Psychopharmacology, 1994Co-Authors: Harry L. June, Michael J LewisAbstract:The present study investigated the role of the GABA_A-benzodiazepine (BDZ) receptor complex in mediating ethanol (ETOH)-induced increases in exploration (head-dipping) and locomotion of rats in a holeboard test. Male Sprague-Dawley rats were selected based on low basal exploratory rates to increase the likelihood that ETOH would increase these behaviors. The effects of the BDZ partial inverse agonist, Ro15-4513 (2.5 mg/kg), and the BDZ receptor antagonist, Ro15-1788 (Flumazenil) (8.0 mg/kg), alone, and in combination with ETOH (0.25, 0.50 and 0.75 g/kg, IP) were investigated. The 0.25 and 0.50 g/kg doses of ETOH markedly increased both exploration and locomotion in low exploratory rats. The ETOH-induced increases were prevented by Ro15-4513 on both measures at a dose that produced no observable intrinsic action; however, this apparent lack of intrinsic activity on exploration may have been related to the low basal rates of responding in the subjects. The BDZ antagonist, Flumazenil, completely reversed the antagonistic action produced by Ro15-4513 of the ETOH-induced stimulant effects on locomotion, however, Flumazenil exerted only a marginal statistically significant effect on Ro15-4513's actions on head-dipping. When Flumazenil was given alone, it increased head-dipping, but was without effect on locomotion. Flumazenil did not affect ETOH-induced increases in locomotion; however, ETOH and Flumazenil appeared to show agonistic effects on exlporation. The different effects exerted by Flumazenil alone, and in combination with ETOH on head-dipping and locomotion suggest that the actions of Flumazenil on these behaviors are mediated through separate mechanisms. The research further suggests that both the anxiolytic and locomotor activational effects of ETOH are mediated through the GABA_A-BDZ receptor complex.
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Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (Flumazenil)
Psychopharmacology, 1994Co-Authors: Harry L. June, Roger W. Hughes, Holly L. Spurlock, Michael J LewisAbstract:Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (Flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of Flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When Flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of Flumazenil (16.0 mg/kg). Neither Ro15-4513 nor Flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with Flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and Flumazenil attenuate ETOH self-administration in non-food or water deprived rats. These studies suggest that the suppressant effects of Ro15-4513 and Flumazenil on ETOH self-administration are associated with actions at the BDZ site of the GABA_A receptor complex. These data are discussed in relation to the possible mechanism(s) by which Ro-15-4513 and Flumazenil exert their antagonism on ETOH self-administration.
Lisa R. Gerak - One of the best experts on this subject based on the ideXlab platform.
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Quantitative pharmacological analyses of the interaction between Flumazenil and midazolam in monkeys discriminating midazolam: Determination of the functional half life of Flumazenil.
European journal of pharmacology, 2013Co-Authors: Claudio Zanettini, Lisa R. GerakAbstract:The duration of action of a drug is commonly estimated using plasma concentration, which is not always practical to obtain or an accurate estimate of functional half life. For example, Flumazenil is used clinically to reverse the effects of benzodiazepines like midazolam; however, its elimination can be altered by other drugs, including some benzodiazepines, thereby altering its half life. This study used Schild analyses to characterize antagonism of midazolam by Flumazenil and determine the functional half life of Flumazenil. Four monkeys discriminated 0.178mg/kg midazolam while responding under a fixed-ratio 10 schedule of stimulus-shock termination; Flumazenil was given at various times before determination of a midazolam dose-effect curve. There was a time-related decrease in the magnitude of shift of the midazolam dose-effect curve as the interval between Flumazenil and midazolam increased. The potency of Flumazenil, estimated by apparent pA2 values (95% CI), was 7.30 (7.12, 7.49), 7.17 (7.03, 7.31), 6.91 (6.72, 7.10) and 6.80 (6.67, 6.92) at 15, 30, 60 and 120min after Flumazenil administration, respectively. The functional half life of Flumazenil, derived from potency estimates, was 57±13min. Thus, increasing the interval between Flumazenil and midazolam causes orderly decreases in Flumazenil potency; however, across a broad range of conditions, the qualitative nature of the interaction does not change, as indicated by slopes of Schild plots at all time points that are not different from unity. Differences in potency of Flumazenil are therefore due to elimination of Flumazenil and not due to pharmacodynamic changes over time.
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efficacy and the discriminative stimulus effects of negative gabaa modulators or inverse agonists in diazepam treated rhesus monkeys
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Lance R Mcmahon, Lisa R. GerakAbstract:In benzodiazepine (BZ)-dependent animals, the effects of negative GABAA modulators at BZ sites are not clearly related to differences in negative efficacy (i.e., inverse agonist activity). A Flumazenil discriminative stimulus in diazepam (5.6 mg/kg/day)-treated rhesus monkeys was used to test the hypothesis that the effects of negative GABAA modulators at BZ sites do not vary as a function of efficacy in BZ-dependent animals. Negative GABAA modulators varying in efficacy were studied in combination with positive modulators acting at different modulatory sites (BZ, barbiturate, and neuroactive steroid sites). The negative modulators Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4 H -imidazo[1,5-α]-[1,4]benzodiazepine-3-carboxylate) and ethyl β-carboline-3-carboxylate (β-CCE) substituted for the Flumazenil discriminative stimulus. Acute pretreatment with diazepam (3.2 and 10 mg/kg s.c., in addition to 5.6 mg/kg/day p.o.), pentobarbital (3.2 and 10 mg/kg), or pregnanolone (1 and 3.2 mg/kg) attenuated the Flumazenil discriminative stimulus and also attenuated the Flumazenil-like discriminative stimulus effects of Ro 15-4513 and β-CCE. Attenuation of the discriminative stimulus effects of Flumazenil, Ro 15-4513, and β-CCE did not systematically vary as a function of negative efficacy. Compared with their discriminative stimulus effects in untreated monkeys discriminating midazolam, both pregnanolone and pentobarbital were relatively more potent than diazepam in attenuating the discriminative stimulus effects of Flumazenil, Ro 15-4513, and β-CCE in diazepam-treated monkeys. These results show that the discriminative stimulus effects of BZ-site neutral and negative modulators are not different in BZ-dependent animals trained to discriminate Flumazenil, and extend the results of a previous study showing that positive modulators acting at non-BZ sites are especially potent in attenuating the effects of Flumazenil in diazepam-treated monkeys (i.e., diazepam withdrawal).
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Discriminative stimulus effects of Flumazenil in untreated and in diazepam-treated rhesus monkeys.
Psychopharmacology, 1999Co-Authors: Lisa R. GerakAbstract:Rationale: Long-term use of benzodiazepine agonists can have adverse effects (e.g., development of dependence), thereby limiting their clinical usefulness. Objectives: The goal of the current study was to examine the discriminative stimulus effects of Flumazenil in untreated and diazepam-treated monkeys to determine whether this type of procedure could be used to examine benzodiazepine dependence. Methods: Flumazenil (0.32 mg/kg s.c.) was established as a discriminative stimulus in eight monkeys receiving 5.6 mg/kg/day of diazepam (p.o.); four responded under a fixed ratio (FR)5 schedule of stimulus-shock termination (SST) and four responded under a FR5 schedule of food presentation. For comparison, 1.0 mg/kg Flumazenil (s.c.) was established as a discriminative stimulus in four untreated monkeys responding under a FR5 schedule of SST. Results: Flumazenil dose-dependently increased responding on the Flumazenil-appropriate lever in all monkeys. In diazepam-treated monkeys, Ro 15-4513, ethyl beta-carboline-3-carboxylate and bretazenil substituted for Flumazenil with pentylenetetrazole substituting in some monkeys; other drugs failed to substitute for Flumazenil. Acute administration of 10.0 mg/kg diazepam (s.c.) shifted the Flumazenil dose–effect curve threefold to the right of the control dose–effect curve. Temporary suspension of diazepam treatment produced a time-related increase in Flumazenil-lever responding that was reversed by diazepam. In untreated monkeys, midazolam substituted for Flumazenil, with other drugs, including those with primary mechanisms of action at non-γ-aminobutyric acidA receptors, substituting in some monkeys. Ro 15-4513 did not substitute in any untreated monkey. Conclusions: The Flumazenil discriminative stimulus appears to be pharmacologically selective in treated monkeys with only negative and low efficacy positive modulators substituting for Flumazenil; in contrast, a variety of drugs substitute for Flumazenil in untreated monkeys. This apparent difference in selectivity suggests that diazepam treatment modifies the Flumazenil discriminative stimulus perhaps due to the development of dependence.
Gesche Jürgens - One of the best experts on this subject based on the ideXlab platform.
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adverse events associated with Flumazenil treatment for the management of suspected benzodiazepine intoxication a systematic review with meta analyses of randomised trials
Basic & Clinical Pharmacology & Toxicology, 2016Co-Authors: Elisabeth Penninga, Morten Baekbo Ladekarl, Niels Graudal, Gesche JürgensAbstract:Flumazenil is used for the reversal of benzodiazepine overdose. Serious adverse events (SAEs) including seizures and cardiac arrhythmias have been reported in patients treated with Flumazenil, and the clinical advantage of Flumazenil treatment has been questioned. The objective was to assess the risk of (S)AEs associated with the use of Flumazenil in patients with impaired consciousness due to known or suspected benzodiazepine overdose. Studies included in the meta-analyses were identified by literature search in Medline, Cochrane Library and Embase using combinations of the words Flumazenil, benzodiazepines, anti-anxiety agents, poisoning, toxicity and overdose. Randomised clinical trials (RCTs) in verified or suspected benzodiazepine overdose patients comparing treatment with Flumazenil versus placebo were included. Pre-defined outcome measures were AEs, SAEs and mortality. Thirteen trials with a total of 994 randomised (990 evaluable) patients were included. AEs were significantly more common in the Flumazenil group (138/498) compared with the placebo group (47/492) (risk ratio: 2.85; 95% confidence interval: 2.11–3.84; p < 0.00001). SAEs were also significantly more common in the Flumazenil group compared with the placebo group (12/498 versus 2/492; risk ratio: 3.81; 95% CI: 1.28–11.39; p = 0.02). The most common AEs in the Flumazenil group were agitation and gastrointestinal symptoms, whereas the most common SAEs were supraventricular arrhythmia and convulsions. No patients died during the blinded phase of the RCTs. The use of Flumazenil in a population admitted at the emergency department with known or suspected benzodiazepine intoxication is associated with a significantly increased risk of (S)AEs compared with placebo. Flumazenil should not be used routinely, and the harms and benefits should be considered carefully in every patient.
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Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication--A Systematic Review with Meta-Analyses of Randomised Trials.
Basic & Clinical Pharmacology & Toxicology, 2015Co-Authors: Elisabeth Penninga, Morten Baekbo Ladekarl, Niels Graudal, Gesche JürgensAbstract:Flumazenil is used for the reversal of benzodiazepine overdose. Serious adverse events (SAEs) including seizures and cardiac arrhythmias have been reported in patients treated with Flumazenil, and the clinical advantage of Flumazenil treatment has been questioned. The objective was to assess the risk of (S)AEs associated with the use of Flumazenil in patients with impaired consciousness due to known or suspected benzodiazepine overdose. Studies included in the meta-analyses were identified by literature search in Medline, Cochrane Library and Embase using combinations of the words Flumazenil, benzodiazepines, anti-anxiety agents, poisoning, toxicity and overdose. Randomised clinical trials (RCTs) in verified or suspected benzodiazepine overdose patients comparing treatment with Flumazenil versus placebo were included. Pre-defined outcome measures were AEs, SAEs and mortality. Thirteen trials with a total of 994 randomised (990 evaluable) patients were included. AEs were significantly more common in the Flumazenil group (138/498) compared with the placebo group (47/492) (risk ratio: 2.85; 95% confidence interval: 2.11–3.84; p
Harry L. June - One of the best experts on this subject based on the ideXlab platform.
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Interactions of Ro15-4513, Ro15-1788 (Flumazenil) and ethanol on measures of exploration and locomotion in rats
Psychopharmacology, 1994Co-Authors: Harry L. June, Michael J LewisAbstract:The present study investigated the role of the GABA_A-benzodiazepine (BDZ) receptor complex in mediating ethanol (ETOH)-induced increases in exploration (head-dipping) and locomotion of rats in a holeboard test. Male Sprague-Dawley rats were selected based on low basal exploratory rates to increase the likelihood that ETOH would increase these behaviors. The effects of the BDZ partial inverse agonist, Ro15-4513 (2.5 mg/kg), and the BDZ receptor antagonist, Ro15-1788 (Flumazenil) (8.0 mg/kg), alone, and in combination with ETOH (0.25, 0.50 and 0.75 g/kg, IP) were investigated. The 0.25 and 0.50 g/kg doses of ETOH markedly increased both exploration and locomotion in low exploratory rats. The ETOH-induced increases were prevented by Ro15-4513 on both measures at a dose that produced no observable intrinsic action; however, this apparent lack of intrinsic activity on exploration may have been related to the low basal rates of responding in the subjects. The BDZ antagonist, Flumazenil, completely reversed the antagonistic action produced by Ro15-4513 of the ETOH-induced stimulant effects on locomotion, however, Flumazenil exerted only a marginal statistically significant effect on Ro15-4513's actions on head-dipping. When Flumazenil was given alone, it increased head-dipping, but was without effect on locomotion. Flumazenil did not affect ETOH-induced increases in locomotion; however, ETOH and Flumazenil appeared to show agonistic effects on exlporation. The different effects exerted by Flumazenil alone, and in combination with ETOH on head-dipping and locomotion suggest that the actions of Flumazenil on these behaviors are mediated through separate mechanisms. The research further suggests that both the anxiolytic and locomotor activational effects of ETOH are mediated through the GABA_A-BDZ receptor complex.
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Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (Flumazenil)
Psychopharmacology, 1994Co-Authors: Harry L. June, Roger W. Hughes, Holly L. Spurlock, Michael J LewisAbstract:Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (Flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of Flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When Flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of Flumazenil (16.0 mg/kg). Neither Ro15-4513 nor Flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with Flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and Flumazenil attenuate ETOH self-administration in non-food or water deprived rats. These studies suggest that the suppressant effects of Ro15-4513 and Flumazenil on ETOH self-administration are associated with actions at the BDZ site of the GABA_A receptor complex. These data are discussed in relation to the possible mechanism(s) by which Ro-15-4513 and Flumazenil exert their antagonism on ETOH self-administration.
Valery Rudick - One of the best experts on this subject based on the ideXlab platform.
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A Risk-Benefit Assessment of Flumazenil in the Management of Benzodiazepine Overdose
Drug Safety, 1997Co-Authors: Avi A Weinbroum, Oded Szold, Ron Flaishon, Patrick Sorkine, Valery RudickAbstract:The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to an increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of Flumazenil 0.1 to 0.3mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous Flumazenil 10 to 20 µg/kg is effective in neonates and small children. Intramuscular, oral (20 to 25mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2mg bolus, ≈1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to Flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable. The use of Flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While Flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate or carbamazepine or whose ECG shows abnormalities typical of those seen after overdose with tricyclic antidepressants (TCAs); the use of Flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia. Flumazenil per se does not induce adverse effects. Coma reversal by Flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with Flumazenil; these symptoms are avoidable by utilising slow Flumazenil dose titration.
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A Risk-Benefit Assessment of Flumazenil in the Management of Benzodiazepine Overdose
Drug safety, 1997Co-Authors: Avi A Weinbroum, Oded Szold, Ron Flaishon, Patrick Sorkine, Valery RudickAbstract:The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of Flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous Flumazenil 10 to 20 micrograms/kg is effective in neonates and small children. Intramuscular, oral (20 to 25 mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2 mg bolus, approximately equal to 1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to Flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable. The use of Flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While Flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate to carbamazepine or whose ECG shows abnormalities typical to those seen after overdose with tricyclic antidepressants (TCAs); the use of Flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia. Flumazenil per se does not induce adverse effects. Coma reversal by Flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with Flumazenil; these symptoms are avoidable by utilising slow Flumazenil dose titration.