Dose Of Flumazenil Research Articles

Individual differences in aggressive responding to intravenous flumazenil administration in adult male parolees

Nonhuman and human studies have shown that benzodiazepine (BZD) receptor agonists can modify aggressive behaviour. However, it is unknown whether flumazenil, a BZD receptor antagonist, enhances or inhibits aggressive behaviour. The present study was designed to investigate the effects of acute administrations of flumazenil on aggressive responding in adult humans. Six adult males with histories of childhood conduct disorder (DSM IV R) participated in experimental sessions. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP; Cherek 1992), which provided subjects with aggressive and monetary-reinforced response options. Acute doses of flumazenil (2 and 3mg) did not produce statistically significant changes in either monetary-reinforced responding or aggressive responding. The analysis of individual subjects data revealed that aggressive responses varied across subjects. The results are discussed in terms of individual differences based on the previous history of BZD abuse. Additional laboratory research is needed to better clarify the behavioural mechanisms by which BZD receptor antagonists modify human aggressive responding.

Comparison of the behavioral effects of bretazenil and flumazenil in triazolam-dependent and non-dependent baboons

Behavioral effects of the benzodiazepine receptor partial agonist bretazenil were compared with those of the benzodiazepine receptor antagonist flumazenil under conditions in which three baboons received continuous intragastric (i.g.) infusion of vehicle and then continuous i.g. infusion of triazolam (1.0 mg/kg/day). In each condition, acute doses of flumazenil (0.01–3.2 mg/kg) and bretazenil (0.01–10.0 mg/kg) were administered every 2 weeks (beginning after 30 days of treatment in the triazolam-dependent condition). Food pellets were available during daily 20-h sessions. Following test injections, 60-min behavioral observations were conducted followed by a fine motor assessment. During chronic vehicle administration, neither drug produced changes in observed behaviors. Bretazenil increased pellets earned and time to complete the fine-motor task (10.0 mg/kg dose). During chronic triazolam dosing, both bretazenil and flumazenil precipitated benzodiazepine withdrawal syndromes, characterized by vomiting, tremors/jerks, and a decrease in pellets earned. Thus, bretazenil can function as an antagonist under conditions of benzodiazepine physical dependence.

Plasma pharmacokinetics of [11C]‐flumazenil and its major metabolite [11C]‐flumazenil ‘acid’

[11C]‐Flumazenil is a radiopharmaceutical that can be used to quantify benzodiazepine receptor concentrations and drug binding in the human brain using positron emission tomography (PET). In PET studies, arterial blood sampling is required to correct for labelled metabolites in plasma. The metabolite corrected arterial plasma curve of [11C]‐flumazenil is used as the input function for the receptor pharmacokinetic model in clinical PET studies.The main metabolic pathway for flumazenil is conversion to flumazenil ‘acid’ by hepatic carboxylesterases. Interestingly, carboxylesterases are also involved in the bioconversion of other ester‐type drugs such as cocaine, acetylsalicylic acid and many cholesterol synthesis inhibitors. Thus far, little is known about (genetic) differences in carboxylesterase activities. In principle, flumazenil may serve as a marker substrate for carboxylesterase phenotyping and predict metabolism for these kinds of drugs.The aim was to study interindividual differences in flumazenil clearance and flumazenil ‘acid’ formation in healthy volunteers and CNS patients.Healthy volunteers and CNS patients (n=25) participating in different PET protocols were included. During PET scanning, arterial blood samples were collected for ex vivo counting and metabolite analysis at 7 time‐points. The plasma samples were analysed by reversed phase h.p.l.c. with radioactivity detection, as previously described [1]. The data were fitted by a commercially available and previously validated pharmacokinetic computer program (MW\Pharm, MediWare BV, Groningen, The Netherlands).The total body clearance (CL), volume of distribution (Vd) and the elimination rate constant (k10) were calculated for flumazenil pharmacokinetics.Parent flumazenil clearance from the plasma compartment was best fitted with a 2‐compartment model (r2>0.98). The plasma clearance ranged from 48–139 l h−1. The flumazenil ‘acid' curve was fitted by an extravascular, 1‐compartment model (r2>0.98). The rate constant of metabolite formation (km) ranged from 2.4–24 h−1, indicating pronounced interindividual differences in flumazenil ‘acid' formation. The total body clearance of this tracer dose of flumazenil is in the range of earlier reported pharmacological doses ([2]; Table 1). The estimated hepatic extraction ratio (EH) was 0.6–0.8 (assuming a hepatic blood flow of 60–90 l h−1). The rate of flumazenil ‘acid' formation correlated with the clearance of flumazenil, suggesting a major role of hepatic carboxylesterases in flumazenil clearance. Pharmacokinetics of parent [11C]‐flumazenil. Tracer dose Pharmacological dose Range Mean Clearance (l h−1) 48–139 76 ± 23 30–78 Vd (l kg−1) n.d. 0.78 (n.d.) 0.6–1.1 k 10 (h−1) 1.7–25 4.6 ± 4.6 n.d. EH 0.6–0.8 n.d. 0.6 The plasma pharmacokinetics of [11C]‐flumazenil show pronounced interindividual variation. The relative high hepatic extraction ratio implicates that the formation of flumazenil ‘acid' depends on the functional status of liver cells (carboxylesterase activity) and also on hepatic blood flow. Input curves of [11C]‐flumazenil should be corrected for labelled metabolites on an individual basis. Interindividual differences in flumazenil handling may reflect the variation in drug metabolism of ester‐type drugs.

Modification of the Effects of Benzodiazepines on the Exploratory Behaviors of Mice on a Hole-Board by Diabetes

The effect of diabetes on the emotional behavior of mice was examined using an automatic hole-board apparatus. Changes in the emotional state of mice were evaluated in terms of changes in exploratory activity; i.e., total locomotor activity, numbers and duration of rearing and head-dipping, and latency to the first head-dipping. The number and duration of head-dipping in diabetic mice were less than those in non-diabetic mice. Diazepam (0.1-0.56 mg/kg, i.p.) dose-dependently increased the number and duration of head-dipping at doses that did not produce sedation in both diabetic and non-diabetic mice. In contrast, methyl-beta-carboline-3-carboxylate (1 and 2 mg/kg, i.p.) decreased the number and duration of head-dipping in non-diabetic mice, but not in diabetic mice. The number and duration of head-dipping in diabetic mice were increased by treatment with flumazenil (0.1 and 0.3 mg/kg, i.v.). These doses of flumazenil did not affect the number or duration of head-dipping in non-diabetic mice. The present data indicate that diabetic mice exhibited anxiety in the hole-board test and that a benzodiazepine receptor antagonist affected the attenuated number and duration of head-dipping in diabetic mice. The heightened anxiety in diabetic mice may be due to the dysfunction of the benzodiazepine receptor and/or of central inhibitory systems.

Flumazenil in children after esophagogastroduodenoscopy

OBJECTIVE: Our aim was to evaluate if the routine use of the benzodiazepine antagonist flumazenil would shorten postprocedure recovery times after esophagogastroduodenoscopy in pediatric patients receiving standard intravenous conscious sedation with the benzodiazepine diazepam in combination with meperidine. METHODS: Upper endoscopy was performed using intravenous conscious sedation with standardized doses of diazepam and meperidine on 29 children, age range 6–18 yr. Patients were randomized in a double-blind fashion to receive either intravenous normal saline (placebo) or 0.01 mg/kg (maximum, 1.0 mg) flumazenil within 5 min of procedure completion. Evaluation of the degree of sedation using a modified Observer’s Assessment of Alertness/Sedation Scale was performed presedation, immediately before reversal solution administration, and serially over 60 min after reversal solution injection. RESULTS: Fifteen patients received flumazenil and 14 received placebo; patient group composition did not vary significantly in age and weight. Fifty-four percent of flumazenil patients and 30% of control patients achieved full alertness within 10 min of reversal solution injection. However, this difference between groups was not significant ( p > 0.45). Resedation or side effects directly attributable to flumazenil were not observed. CONCLUSIONS: A single postsedation dose of flumazenil is well-tolerated in children >6 yr old. However, its routine use after esophagogastroduodenoscopy is of questionable benefit in shortening recovery time in this age group.

Impact of flumazenil on recovery after outpatient endoscopy: a placebo-controlled trial

Background: Flumazenil is an imidazobenzodiazepine that blocks the central effects of benzodiazepines by competitive interaction at the receptor level. In this study we assessed the impact of flumazenil use on postsedation observation time in outpatients undergoing endoscopy. Methods: Sixty outpatients received midazolam for conscious sedation and were randomized after endoscopy to receive intravenous flumazenil (0.1 mg/mL) or placebo until awake or a total of 10 mL was given. All patients were assessed using various psychomotor and cognitive tests at baseline and at 5, 15, 30, 45 and 60 minutes after flumazenil or placebo was administered. Results: The two groups were similar in age, gender, midazolam dose (mg/kg), vital signs, and baseline parameters. The average dose of flumazenil given was 0.41 mg. Sedation scores returned to presedation levels earlier in the flumazenil group, with significant differences compared to placebo at 5 minutes (84.6% vs. 24.2%), 15 minutes (88.5% vs. 57.6%) and 30 minutes (96.2% vs. 66.7%). Other parameters tested were not significantly different for patients receiving placebo compared to those given flumazenil. Sedation scores returned to baseline earlier than other psychomotor and cognitive tests in both groups. Flumazenil reduced the mean observation time from 23.5 minutes to 8.3 minutes ( p < 0.0005), a difference of 15.2 minutes (64.7%) based on sedation score. Conclusions: Flumazenil significantly reduces postsedation observation time. Actual cost savings will vary depending on staff and facility capacity, patient volume, flumazenil cost, and unit cost of observation time. (Gastrointest Endosc 1999;49:573-9.)

Diazepam-Treated Female Rats: Flumazenil- and PK 11195-Induced Withdrawal in the Hippocampus CA1

Six female rats had a loading dose of 180 mg of diazepam (DZ) contained in two Silastic capsules implanted in their backs. Thereafter, a single 90-mg capsule was implanted weekly for 4 weeks prior to weekly microinjections of 1 μl of flumazenil (6.25, 12.5, or 25 μg) and PK 11195 (3.125, 6.25, or 12.5 μg) or vehicle into the CA1. Three control rats had empty capsules implanted but received only the high dose of flumazenil after 5 weeks. The time of DZ exposure spanned 8 weeks. Mean steady-state plasma levels of DZ were 1.06 ± 0.11, and the mean total (DZ + metabolites) was 2.46 μg/ml ± 0.37. Flumazenil elicited a dose-related precipitated withdrawal score (PAS) in DZ-treated rats (but not in controls) characterized by dose-related increases in convulsive (twitches and jerks), motor and autonomic signs, dose-related increases in the percent of total power in the low frequency (1–4 Hz), and decreases in the high-frequency (18–26 Hz) bands of the EEG recorded from the dentate and the amygdala. PK 11195 produced a dose-related increase in the 4–12 Hz band of the EEG recorded from the CA1, whereas the PAS was mild and not dose-related. However, the 6.25 and 12.5-μg doses elicited a significant PAS that tended to increase with dose. These data indicate that chronic DZ produces dependence, and that in the CA1 it involves the participation of central and possibly peripheral benzodiazepine (BZ) receptors located within this structure.

Reversal of Midazolam-Induced Laryngospasm With Flumazenil

Midazolam is a commonly used benzodiazepine that is ideal for conscious sedation during a variety of procedures. Laryngospasm is listed by the manufacturer as a rare side effect of midazolam. Flumazenil is a competitive inhibitor of the benzodiazepines that is available for reversal at the end of such a procedure or when too much sedation has been achieved. We present a case of a 61-year-old man who was to undergo conscious sedation before cardioversion. Shortly after receiving midazolam, he developed laryngospasm and resultant respiratory distress; the laryngospasm was reversed by a small dose of flumazenil. The symptoms recurred after approximately 25 minutes and were again reversed with flumazenil. Neither midazolam-induced laryngospasm nor its reversal with flumazenil have previously been reported. A brief discussion regarding laryngospasm and the use of flumazenil are included. [Davis DP, Hamilton RS, Webster TH: Reversal of midazolam-induced laryngospasm with flumazenil. Ann Emerg Med August 1998;32:263-265.]

P1G178 - Effect of low doses of flumazenil (FLZ) on upper airway resistance and work of breathing (WOB) during pure of predominant benzodiazepine (BZD) intoxications

The principles and procedures for the assessment of the safety/risk of chemical used by the relevant WHO and EPA expert groups are outlined. The assessment in terms of acceptable daily intakes (ADIs) and reference doses (RfDs) of 25 pesticides is listed. The pesticides assessed are acephate, alachlor, amitrole, azinphos-methyl, benomyl, biphenthrin, bromophos, chlordane, chlorthalonil, cyhalothrin, DDT, EPTC, ethion, folpet, fosetyl-al, glyphosate, isofenphos, methomyl, methyl mercury, paraquat, phosphamidon, systhane, terbutyn, tribultyltin oxide, and vinclozin. In addition, their critical effects, the no-observed-effect levels and the size of the safety/uncertainty factors used are also listed to illustrate the diversity of the toxic effects and the resulting assessments. Furthermore, the enormous amount of data reviewed and the complex scientific judgement involved are also indicated. Considering the various uncertainties existing, the ADIs and RfDs do not differ appreciably in most instances. However, marked differences exist between the ADIs and RfDs of DDT and chlordane. It is suggested that re-evaluation be done on these, and perhaps other, chemicals.

Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation

Objective: To determine the safety and efficacy of flumazenil when given for reversal of benzodiazepine-induced conscious sedation in children. Design: Multicenter study conducted in emergency departments and pediatric endoscopy, bronchoscopy, or oncology suites. Patients: One hundred seven children (median age, 6 years; range, 1 to 17 years) who received intravenous benzodiazepine for an invasive procedure. Interventions: Flumazenil was given in increments of 0.01 mg/kg (0.2 mg maximum) at 1-minute intervals to a maximum total dose of 0.05 mg/kg (1.0 mg maximum). Measurements: Clinical efficacy was assessed by the Clinical Global Impression Scale and Observer’s Assessment of Alertness/Sedation Scale. The OAA/S, vital signs, lead II electrocardiogram, and clinical assessments were recorded at 0, 10, 30, 60, 90, and 120 minutes after flumazenil was given. Results: All children received midazolam (mean total dose, 0.18 mg/kg) for sedation. One hundred (96%) patients achieved a complete or partial response to flumazenil by 10 minutes after its administration, on the basis of their CGIS scores (the mean dose of flumazenil administered at the time of the first complete response was 0.017 ± 0.010 mg/kg). Seventy-one of 93 (76%) patients with a baseline OAA/S score ≤ 3 (1 = deep sleep, 5 = alert) experienced an increase of ≥ 2 points at 10 minutes after flumazenil administration, and 81 of 93 (87%) had a score of 4 or 5 after flumazenil administration. Seven patients, all within the 1- to 5-year age range, experienced resedation after initially responding to flumazenil. Thirty-seven of 107 patients (35%) experienced a total of 56 adverse events, most of which were considered to be unrelated to flumazenil administration. The most frequently occurring adverse events were abnormal crying, dizziness, nausea, fever, and headache. There were no clinically significant changes in vital signs or ECG tracings. No adverse events resulted in premature termination of drug administration. Conclusions: Flumazenil promptly and effectively reverses the central nervous system depressant effects of midazolam in children undergoing conscious sedation, with no significant adverse effects. Because of the potential for resedation, children who receive flumazenil should be monitored for 1 to 2 hours after its administration. (J Pediatr 1997;131:582-6)

Benzodiazepine-Like Substances and Hepatic Encephalopathy

Hepatic encephalopathy is a neuropsychiatric syndrome that can complicate acute and chronic liver disease. Recent research has focused on the role benzodiazepine-like substances play in the pathogenesis of this disorder. It has been proposed that potentiation of the action of the neuroinhibitory transmitter γr-aminobutyric acid (GABA) through the binding of endogenous benzodiazepine agonists to the benzodiazepine receptor binding site accounts for the clinical and biochemical features of this condition.Increased levels of endogenous benzodiazepine-like substances have been noted in animal models of hepatic encephalopathy. In human studies, levels of these substances of up to 10 times those found in the body fluids of nonencephalopathic controls have been reported. The existence of such markedly elevated levels cannot be satisfactorily explained with reference to possible pharmaceutical or dietary origins.Further support for the role of benzodiazepines in the mediation of hepatic encephalopathy comes from the therapeutic effect reported after administration of the benzodiazepine receptor antagonist flumazenil. Improvements in the severity of hepatic encephalopathy have been documented in rats with fulminant hepatic failure given flumazenil, although results have been inconsistent according to the dose of flumazenil used and the procedure employed to induce the encephalopathy. Transient, but distinct, improvements in the grade of hepatic encephalopathy have also been documented in several human studies. In a placebo-controlled study involving patients with mild hepatic encephalopathy, a low dose of flumazenil (0.2 mg/kg) resulted in a significant improvement in reaction time.Research now needs to identify whether the beneficial effect of flumazenil is due to its antagonistic or inverse agonistic properties, and also to clarify the mechanisms by which the differential response to the drug in animal models of fulminant hepatic failure is mediated.

Intrathecally administered flumazenil and PK 11195 precipitate abstinence syndrome in freely moving diazepam dependent rats

The central and peripheral benzodiazepine (BZ) receptor antagonists, flumazenil (FLU) and PK 11195 (PK), administered intrathecally (IT) to diazepam (DZ)-dependent rats produced a precipitated abstinence syndrome. The scores for abstinence increased with increasing dose of FLU but not with increasing dose of PK. Twitches and jerks increased with increased doses of both. Head and body tremors were produced by FLU, but not by PK. Neither FLU nor PK precipitated abstinence in controls. In DZ-dependent rats IT administered FLU and PK did not significantly change the spectral content and the total power of the EEG. The data indicate that an abstinence syndrome is precipitated at the spinal level in DZ-dependent rats and that both central and peripheral BZ receptors are involved.

Intraseptal Flumazenil Enhances, while Diazepam Binding Inhibitor Impairs, Performance in a Working Memory Task

GABAA/benzodiazepine receptors in the medial septum modulate the activity of cholinergic neurons that innervate the hippocampus. Injection of benzodiazepine (BDZ) agonists into the medial septum impairs working memory performance and decreases high-affinity choline transport (HAChT) in the hippocampus. In contrast, intraseptal injection of the BDZ antagonist flumazenil increases HAChT and prevents the memory deficits induced by systemic BDZs. The present studies attempted to further characterize the behavioral effects of medial septal injections of flumazenil to an endogenous negative modulator of the GABAA/BDZ receptor complex, diazepam binding inhibitor (DBI). Male Sprague–Dawley rats were cannulated to study the effects of intraseptal injections of these BDZ ligands on spatial working memory, anxiety-related behaviors in the elevated plus maze, and on general locomotor activity. Intraseptal flumazenil (10 nmol/0.5 μl) produced a delay-dependent enhancement of DNMTS performance after an 8-h, but not a 4-h, delay interval. This promnestic dose of flumazenil had no effect on locomotor activity and did not produce changes in measures of anxiety on the plus maze. Intraseptal injection of DBI had no effect (8 nmol/0.5 μl) or slightly impaired (4 nmol/0.5 μl) DNMTS radial maze performance following an 8-h delay, without producing changes in locomotion or plus maze behavior. These data demonstrate that flumazenil has a unique profile of activity in enhancing working memory following intraseptal injection.

Effects of majonoside-R2 on pentobarbital sleep and gastric lesion in psychologically stressed mice

The effects of Vietnamese ginseng (VG) and its major constituent majonoside-R2 on pentobarbital-induced sleep and gastric lesion in psychologically stressed mice were examined. Psychological stress exposure for 30 min significantly decreased the duration of pentobarbital (50 mg/kg, IP)-induced sleep in mice. VG extract (50 mg/kg, PO), VG saponin (25 mg/kg, PO), and majonoside-R2 (3.1–12.5 mg/kg, PO and IP) had no effect on pentobarbital sleep in unstressed control mice, but these drugs significantly recovered pentobarbital sleep decreased by psychological stress to the level of unstressed control animals. On the other hand, Panax ginseng (PG) extract (50–100 mg/kg, PO) failed to affect pentobarbital sleep in psychologically stressed mice. The effect of majonoside-R2 on psychological stress-induced decrease in the hypnotic activity of pentobarbital was significantly blocked by flumazenil (1 mg/kg, IV), a selective benzodiazepine antagonist. Diazepam (0.1 mg/kg, IP) significantly prolonged pentobarbital sleep in unstressed and psychologically stressed groups, and the effect of diazepam was significantly attenuated by the same dose of flumazenil. Naloxone (0.5–5 mg/kg, IP), an opioid antagonist, had no effect on pentobarbital sleep in unstressed or psychologically stressed animals. Psychological stress exposure for 16 h caused gastric lesion in mice. VG extract (25–50 mg/kg, PO) and majonoside-R2 (6.2–12.5 mg/kg, PO), as well as diazepam and naloxone, produced the protective action on gastric lesion in psychologically stressed mice. These results suggest that VG and its major constituent majonoside-R2 have the protective effects on the psychological stress-induced pathophysiological changes and that benzodiazepine receptors are partly implicated in the effects of majonoside-R2.

Reversal of conscious sedation by flumazenil: current status and future prospects

Flumazenil is safe and highly effective at reversing both benzodiazepine-induced sedation and amnesia. Bolus intravenous injection is the most appropriate technique when the goal is to fully reverse conscious sedation. Currently, the proven effective dose of flumazenil is 0.5 mg. For practical purposes, in this clinical setting, true resedation does not occur, and if the appropriate type and dose of agonist have been used, residual sedation is not a clinical problem. Concerns over acute anxiety reactions and precipitation of acute withdrawal syndrome in chronic benzodiazepine users remain theoretical and unsubstantiated by human data. Further clinical studies are required to determine whether the clinical practice of using flumazenil could include this group of patients. Depression of ventilatory responsiveness induced by benzodiazepines can be reversed effectively and promptly by flumazenil. Flumazenil must be immediately available as an emergency drug in any area where benzodiazepines are used. The clinical and economic benefits of elective and routine use of flumazenil have been demonstrated, but yet to gain widespread acceptance.

Interaction between flumazenil and the anesthetic effects of hexobarbital in the rat

Interaction between flumazenil, a substance regarded mainly as a benzodiazepine antagonist, and an intravenous anesthetic barbiturate, hexobarbital, was investigated by using an electroencephalography threshold test in male rats. Flumazenil 10 mg/kg given as pretreatment reduced the threshold dose of hexobarbital approximately 20% indicating a synergistic interaction. Similar effects were obtained with the agonists, diazepam 20 mg/kg and lorazepam 2 mg/kg. Dose-response curve for flumazenil (2.5–10 mg/kg) was determined with the same technique and hexobarbital concentrations were analysed in serum and several brain regions at the threshold by high pressure liquid chromatography. Flumazenil 10 mg/kg pretreated group showed a different pattern of distribution of hexobarbital into the tested brain regions indicating a pharmacokinetic interaction. Low concentrations of hexobarbital in the brainstem which were negatively correlated with the dose of flumazenil indicate a pharmacodynamic interaction which could be due to a partial agonistic intrinsic activity of flumazenil, usually seen at much higher doses.

An assessment of resedation following flumazenil-induced antagonism of intravenous midazolam: comparison of psychomotor and amnesic recovery with a non-sedated reference group

The specific benzodiazepine antagonist flumazenil can enhance patient recovery following local anaesthetic day-case surgery performed under sedation. However, in view of its short elimination half-life, concerns have been expressed about the risk of resedation following its use. An open, randomised, parallel group study was designed to explore this question. Eighty-five patients were studied. Group A (n=43) patients underwent local anaesthetic cystoscopy with intravenous (i.v.) midazolam sedation. Following cystoscopy, and 30 min after the injection of midazolam, a bolus dose of flumazenil (0.5 mg i.v.) was given. Group B (n=42) patients underwent no operation and received no drugs but, in all other respects, were treated in an identical fashion to patients in group A. Tests of psychomotor function and memory were administered at baseline and again at 0.5, 1, 2, 3 and 4 h (or equivalent times for group B patients) following the injection of flumazenil. The test results showed no evidence of resedation, but there was evidence of incomplete reversal, as shown by significant differences in critical flicker fusion and delayed word recall at the 0.5-h test point. Group B patients showed no evidence of practice effects but did demonstrate an impairment in test performance possibly related to motivational factors. In conclusion, this study provides no evidence of resedation when using flumazenil to reverse the acute effects of midazolam. Incomplete reversal of amnesia need not delay patient discharge but has important implications with respect to the timing and nature of information imparted to patients prior to their release from hospital.

Differential acute psychomotor and cognitive effects of diazepam on long-term benzodiazepine users

The aim of this study is to determine whether long-term use (5-20 years) of therapeutic doses of diazepam (5-20 mg/day) in anxious patients (n = 28) is associated with tolerance to its psychomotor and cognitive effects. Patients were tested at baseline, before and after a 10 mg oral dose of diazepam during chronic use, and at 3 weeks and 10 months after benzodiazepine (BZ) discontinuation. The effects of a single i.v. dose of flumazenil (1 mg administered 5 days before baseline) on reversing tolerance were also assessed. No acute effect of diazepam was observed on the psychomotor performance of patients both under BZ treatment and after short- and long-term discontinuation, suggesting persistence of tolerance. In contrast, acute effects of diazepam were observed in memory measures at all times. Given subjects' very prolonged BZ use, it is possible to predict that tolerance to the memory effects never fully develops. Flumazenil administration did not reverse tolerance. This suggests that neuroadaptative mechanisms, other than benzodiazepine receptor set-point shift, occur after long-term use.

Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (flumazenil)

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlordiazepoxide, but not bretazenil, produces acute dependence, as evidenced by disruptions in schedule-controlled behavior

The purpose of the present study was to determine whether the full benzodiazepine (BDZ) agonist chlordiazepoxide (CDAP) and the partial BDZ agonist bretazenil would produce acute dependence in rats, as evidenced by disruptions in fixed-interval responding during precipitated abstinence withdrawal. Doses of CDAP and bretazenil administered acutely were 10, 75, 100 and mg/kg; flumazenil (1–56 mg/kg) was administered 1, 2, 4, or 18 h later. Withdrawal, defined as a significant decrease in fixed-interval responding, was only seen when a high dose of flumazenil was administered 18 h after 100 mg/kg of CDAP. These results support those of others (5) who found that high (75–450 mg/kg) doses of CDAP were required to produce acute physical dependence. That bretazenil did not produce acute physical dependence supports the findings of other (20,23) who report that chronic administration of bretazenil does not result in physical dependence.