A comparison of the antifibrillatory effect of midazolam and flunitrazepam in acute myocardial ischaemia in the dog

Summary

A study was carried out using a model of myocardial ischaemia in the dog after ligation of the left coronary artery to determine the effects of the benzodiazepines, flunitrazepam and midazolam, on the ventricular fibrillation threshold. The fibrillation threshold was measured twice within 15?min and 8?min after ligation. Fifteen minutes after the onset ofischaemic heart attack, 1.2?mg midazolam/kg or 0.25?mg flunitrazepam and midazolam, on the ventricular fibrillation threshold. The fibrillation threshold was measured twice within 15?min and 8?min after ligation. Fifteen minutes after the onset ofischaemic heart attack, 1.2?mg midazolam/kg or 0.25?mg of ischaemia. Their effects on haemodynamics were negligible. It is suggested that both benzodiazepines can be used for increasing electrical stability of the heart in patients with acute myocardial infarction and to inhibit the psychic stress response. Because of its short biological half-life and water solubility, allowing painless intravenous administration, midazolam offers a more flexible approach to pharmacotherapy immediately after acute heart attack according to the patient's current clinical status.     

Flunitrazepam in terminal care

Flunitrazepam is a benzodiazepine of long half-life with sedative, anxiolytic, muscle relaxant and anticonvulsant properties. It has proved effective in controlling terminal agitation, confusion, restlessness, dystonia and fitting in adults and can be given by subcutaneous infusion in combination with other drugs. Its use in children during their terminal illness is described. Good symptom control without excessive sedation was achieved over the 24 h prior to death.     

Social isolation does not alter brain regional benzodiazepine binding site numbers,affinity and coupling in the rat

Male Sprague-Dawley rats were differentially housed for 21 days immediately after weaning. Isolated animals showed a selective suppression of exploration of the light side of a two compartment box; spending significantly less time in the light, and making fewer transitions between the light and dark compartments compared to socially reared controls. However, both basal and GABA-stimulated [³H] flunitrazepam binding was unaltered in the frontal cortex, hippocampus, amygdala and cerebellum following social isolation. These results are discussed in relation to other studies on central benzodiazepine receptor changes following a variety of experimental stressors.     

Acute tolerance from benzodiazepine night sedation

The hypothesis that benzodiazepine night sedation causes acute tolerance to benzodiazepine sedation given the following morning was examined in six volunteers in a double blind, randomised, crossover study. Before each of three study days, subjects received midazolam 15 mg or flunitrazepam 2 mg or placebo as oral night sedation. They were then given intravenous midazolam 5 mg the following morning and the resulting sedative effects examined, using an observers sedation scale and a psychomotor test battery (critical flicker fusion frequency, digit-symbol substitution, reflex time, tapping test and a visual analogue sedation scale). Although a consistent pattern emerged with the greatest degree of sedation following the placebo night sedation and the least degree of sedation following the midazolam, with flunitrazepam intermediate, no statistically significant differences were present between the three treatment groups. The results indicate that single use of benzodiazepine night sedation is not an important influence on benzodiazepine requirements for intravenous sedation.     

Heterogeneous distribution of benzodiazepine receptors in the human striatum: a quantitative autoradiographic study comparing the pattern of receptor labelling with the distribution of acetylcholinesterase staining

The distribution of benzodiazepine receptors in the human striatum was studied by quantitative autoradiography following in vitro labelling of cryostat sections with [3H]flunitrazepam, and the pattern of receptor-labelling was compared to the distribution of acetylcholinesterase (AChE) staining in adjacent sections. A heterogeneous pattern of benzodiazepine receptors was found in all regions of the striatum. The highest densities of receptors were seen in the ventral striatum (nucleus accumbens and olfactory tubercle), where very dense receptor patches aligned with both AChE-poor and AChE-rich regions. The dorsal striatum (caudate nucleus and putamen) contained lower concentrations of benzodiazepine receptors, but dense receptor patches were still evident (especially in the caudate nucleus) and these aligned with AChE-poor striosomes.     

Flunitrazepam and Its Involvement in Date or Acquaintance Rape

An estimated 1 in 4 women in the United States will be raped in their lifetimes. Approximately 75% of all rapes are date or acquaintance rapes. Recently the illegal use of flunitrazepam (Rohypnol), a benzodiazepine, as a prelude to the assault has been reported. Flunitrazepam readily dissolves, and once in solution, is colorless, odorless, and tasteless. The predominant clinical manifestations are drowsiness, impaired motor skills, and anterograde amnesia. Due to the amnestic effects of flunitrazepam, historical clues of the rape event are difficult to obtain. Patients with a complaint of sexual assault who appear intoxicated or have anterograde amnesia should be suspected of unknowingly ingesting flunitrazepam. In addition to adhering to standard rape protocols, a urine specimen should be analyzed for flunitrazepam metabolites using gas chromatography/mass spectrometry. If the hospital, local, or forensic laboratory is unable to analyze for flunitrazepam, Hoffmann-La Roche Inc., the manufacturer of Rohypnol, should be contacted. Hoffmann—La Roche has a mechanism for definitive testing for flunitrazepam, at no cost, for health care providers, rape treatment centers, and law enforcement agencies. A network of organizations is attempting to reduce the abuse of flunitrazepam in association with date rape.     

Is upregulation of benzodiazepine receptors a compensatory reaction to reduced GABAergic tone in the brain of stressed mice?

Effects of various forms of stress on the GABA_A receptor-chloride ionophore complex in the brain of NMRI mice were investigated. Male albino mice were subjected to stress by placing them on small platforms (SP; 3.5 cm diameter) surrounded by water for 24 h. This experimental model contains several stress factors like rapid eye movement (REM) sleep deprivation, isolation, immobilization, falling into water and soaking. As additional stress control groups we used animals subjected to isolation, large platform (9.0 cm diameter) and repeated swimming stress. SP stress induced an increase in the number of cortical benzodiazepine (BDZ) receptors and a reduction in the GABA-stimulated ³⁶C1^– uptake by brain microsacs, whereas none of these changes could be observed in animals exposed to isolation, swimming or large platform stresses. Furthermore, the amount of GABA-induced stimulation of [³H]flunitrazepam binding was reduced in cortical brain membranes of SP-stressed animals, an effect due to fact that these animals dispayed an increase in the basal [³H]flunitrazepam binding, whereas the absolute level of maximally enhanced BDZ binding in the presence of GABA did not differ from those found in controls. Neither basal [³H]muscimol binding or thiopentone sodium-induced stimulation of [³H]flunitrazepam binding were changed in any group of stressed mice. It is proposed that the observed upregulation in the number (B _max ) of cortical BDZ receptors in SP-stressed mice may represent a compensatory response to a stress-induced attenuation of GABAergic neurotransmission.     

Effect of flunitrazepam on sleep and memory

Flunitrazepam's (FNZ) effect on sleep and memory 1 mg and 2 mg was investigated in 6 healthy volunteers (mean age 21.5 ± 0.8 years) by polysomnography (PSG) and memory testing. A PSG was recorded on each study night. Memory testing was done before sleep (40 min after taking FNZ or placebo), and after waking (560 min after medication). Rapid eye movement (REM) latency was found to be prolonged on the FNZ 2 mg night (FNZ2N) compared to the baseline night (BN). Percentage of stage 2 sleep was increased in the FNZ2N as compared to BN, while REM percentage on both FNZ nights did not significantly differ from BN. The number of total REM and REM density were decreased in the FNZ2N compared to BN. Memory testing showed significant differences between before sleep and after waking on the FNZ2N. There was a significant correlation between the degree of impairment on memory testing and the rate of reduced REM density, but there was no significant correlation between degree of impairment on memory testing and the rate of increased non-REM sleep on the FNZ2N. The results of this study suggest that impairments in memory result from the dose of FNZ, and that there is a possibility of a relationship between memory disturbance and REM sleep suppression caused by this benzodiazepine.     

Ketamine sequelae

The ability of a number of drugs to abolish the emergence delirium and unpleasant dreams which follow anaesthesia induced with 2 mg/kg ketamine was studied. These included three benzodiazepines, droperidol and 'neurolept' combinations and four commonly-used premedicants. When given intravenously 10 min before induction of anaesthesia flunitrazepam and lorazepam gave best results. In a subsequent study, these two benzodiazepines and diazepam were given intravenously 30-40 min before induction of anaesthesia. There was no doubt that 4 mg lorazepam gave the greatest protection and is worthy of further study in this respect.