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At least 1,063 records · Page 59Linked to original sources
PubMed2000

Postsynaptic receptor occupancy during evoked transmission at striatal GABAergic synapses in vitro.

The effect of benzodiazepines (BZs) on GABA(A)-ergic synaptic responses depends on the control receptor occupancy: the BZ-induced enhancement of receptor affinity can lead to greater peak amplitudes of quantal responses only when, under normal conditions, receptors are not fully saturated at peak. Based on this fact, receptor occupancy at the peak of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) has been assessed in various mammalian neuronal preparations. To use the same principle with compound (or multiquantal), action potential-evoked IPSCs, complications introduced by quantal asynchrony in conjunction with the BZ-induced increase in the decay time of the quantal responses have to be overcome. We used a simple analytic convolution model to calculate expected changes in the rise time and amplitude of postsynaptic currents when the decay time constant, but not the peak amplitude, of the underlying quantal responses is increased, this being the expected BZ effect at saturated synapses. Predictions obtained were compared with the effect of the BZ flunitrazepam on IPSCs recorded in paired pre- and postsynaptic whole cell voltage-clamp experiments on striatal neurons in cell culture. In 22 pairs, flunitrazepam (500 nM) reliably prolonged the decay of IPSCs (49 +/- 19%, mean +/- SE) and in 18 of 22 cases produced an enhancement in their peak amplitude that varied markedly between 3 and 77% of control (26.0 +/- 5.3%). The corresponding change in rise time, however (+0.38 +/- 0.11 ms, range -0.8 to +1.3 ms) was far smaller than calculated for the observed changes in peak amplitude assuming fixed quantal size. Because therefore an increase in quantal size is required to explain our findings, postsynaptic GABA(A) receptors were most likely not saturated during impulse-evoked transmission at these unitary connections. The peak amplitudes of miniature IPSCs in these neurons were also increased by flunitrazepam (500 nM, +26.8 +/- 6.6%), and their decay time constant was increased by 26.3 +/- 7.3%. Using these values in our model led to a slight overestimate of the change in compound IPSC amplitude (+28 to +30%).

Animals↗
PubMed1993

A quantitative autoradiographic study of GABAA and benzodiazepine receptors in the brain of the frog, Rana esculenta.

Specific binding sites for GABAA and benzodiazepines were detected in the brain of the frog Rana esculenta after the in vitro incubation of tissue sections with their respective specific agonists [3H] muscimol and [3H] flunitrazepam. Conditions for the binding assay were optimized and as a result binding was saturable and specific. Quantitative autoradiographic receptor measurements in the different brain sections showed that elevated levels of [3H] muscimol binding sites were found in the two layers of the cerebellum (periventricular and external) with the highest binding densities being detected in the periventricular layer. Relatively high densities of [3H] muscimol binding sites were also observed in the torus semicircularis of the mesencephalon and in the thalamic nucleus rotundus and posterolateral nucleus, plus the mitral cell layer of the olfactory bulb, the amygdala pars lateralis and the striatum of the telencephalon. Intermediate to low binding levels were obtained in the remaining brain areas such as the external layer of the optic tectum, the dorsomedial and dorsolateral anterior thalamic nuclei, the medial and lateral pallium, the medial septal nucleus, the preoptic nucleus, the dorsal and ventral infundibular nuclei of the hypothalamus and the interpeduncular nucleus. Autoradiographic evaluation of benzodiazepine receptors revealed that binding levels of [3H] flunitrazepam were overall lower than those of the GABAA sites. In fact the highest [3H] flunitrazepam binding levels were observed in the striatum, external layer of the optic tectum and the torus semicircularis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Effects of hypnotics on memory.

The influence on memory of 7.5 mg zopiclone, given in single and repeated doses was compared with that of 2 mg flunitrazepam, 5 mg nitrazepam and placebo. Compared with placebo, all three drugs induced some impairment of memory especially after the first day of administration. Effects were more pronounced for the two benzodiazepines and more marked for flunitrazepam. There was one report of an anterograde amnestic episode after flunitrazepam.

Adult↗
PubMedDate not supplied

Cerebellar grafts partially reverse amino acid receptor changes observed in the cerebellum of mice with hereditary ataxia: quantitative autoradiographic studies.

We used quantitative autoradiography of [3H]CNQX (200 nM), [3H]muscimol (13 nM), and [3H]flunitrazepam (10 nM) binding to study the distribution of non-NMDA and GABA(A) receptors in the cerebellum of pcd mutant mice with unilateral cerebellar grafts. Nonspecific binding was determined by incubation with 1 mM Glu, 200 microM GABA, or 1 microM clonazepam, respectively. Saturation parameters were defined in wild-type and mutant cerebella. In mutants, non-NMDA receptors were reduced by 38% in the molecular layer and by 47% in the granule cell layer. The reduction of non-NMDA receptors in the pcd cerebellar cortex supports their localization on Purkinje cells. [3H]CNQX binding sites were visualized at higher density in grafts that had migrated to the cerebellar cortex of the hosts (4.1 and 11.0 pmol/mg protein, respectively, at 23 and 37 days after grafting) than in grafts arrested intraparenchymally (2.6 and 6.2 pmol/mg protein, respectively, at 23 and 37 days after grafting). The pattern of expression of non-NMDA receptors in cortical vs. parenchymal grafts suggests a possible regulation of their levels by transacting elements from host parallel fibers. GABA(A) binding levels in the grafts for both ligands used were similar to normal molecular layer. Binding was increased in the deep cerebellar nuclei of pcd mutants: the increase in [3H]muscimol binding over normal was 215% and the increase in [3H]flunitrazepam binding was 89%. Such increases in the pcd deep cerebellar nuclei may reflect a denervation-induced supersensitivity subsequent to the loss of Purkinje axon terminal innervation. In the deep nuclei of pcd mutants with unilateral cerebellar grafts, [3H]muscimol binding was 31% lower in the grafted side than in the contralateral nongrafted side at 37 days after transplantation; [3H]flunitrazepam binding was also lower in the grafted side by 15% compared to the nongrafted side. Such changes in GABA(A) receptors suggest a significant, albeit partial, normalizing trend of cerebellar grafts on the state of postsynaptic supersensitive receptors in the host cerebellar nuclei.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Does choice of the anesthetic influence renal function during infrarenal aortic surgery?

Reconstructive infrarenal aortic surgery is associated with impairment of renal function owing to vasoconstriction during and after aortic cross-clamping. To assess the influence of anesthetic technique on renal hemodynamics during aortic surgery, 34 patients received one of four anesthetics: isoflurane (n = 10), halothane (n = 9), droperidol (n = 8), and flunitrazepam (n = 7). Supplemental anesthesia consisted of midazolam, fentanyl, nitrous oxide in oxygen (50%), and pancuronium. Before aortic cross-clamping, effective renal plasma flow (ERPF) (131iodohippuran clearance) and glomerular filtration rate (GFR) (99technetium-DTPA clearance) were low in the halothane and flunitrazepam groups (118.4 +/- 25.6 and 170 +/- 35 mL/min for ERPF; 19.7 +/- 5.2 and 26.9 +/- 5.8 mL/min for GFR, respectively) and better preserved in the isoflurane group (253.4 +/- 51.5 and 44.9 +/- 8.4 mL/min, respectively; P less than 0.05 between isoflurane and halothane groups) or in the droperidol group as regards GFR (75.4 +/- 9.4 mL/min, P less than 0.05). During clamping, both renal variables were not markedly affected in any group except in the droperidol group in whom GFR significantly decreased from preclamp value. The GFR was then significantly higher in the isoflurane group (49.5 +/- 9.2 mL/min) than in the halothane and flunitrazepam groups (14.8 +/- 3.7 and 26.5 +/- 10.1 mL/min, respectively; P less than 0.05). After aortic declamping, ERPF and GFR increased markedly in the halothane group, and there was no significant difference between the groups. These results suggest that renal hemodynamics are less altered with droperidol-fentanyl anesthesia during abdominal surgery but not during aortic cross-clamping.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Nocturnal enhancement of plasma melatonin could be suppressed by benzodiazepines in humans.

Plasma melatonin levels were determined every 20 and 30 min for 24 hours on the last day of repeated oral administrations (1 or 2 mg a day for 8 or 9 days) of a benzodiazepine derivative (450191-s), which is known to be metabolized to active benzodiazepines after administration. In one of the two subjects, the nocturnal enhancement of plasma melatonin which was obvious on a control day with placebo was diminished almost completely. In the other subject, observed were not only the diminishment of its nocturnal enhancement but also its increase during the daytime almost to the nocturnal levels on a control day, which may indicate a rebound increase in melatonin synthesis or a shift in its day-night rhythmicity. Such suppressing effects of benzodiazepines on the nocturnal plasma melatonin levels were also examined in the case of a single administration of 2 mg of 450191-s or flunitrazepam in the second series of experiments. Even a single flunitrazepam seemed to have lowered nocturnal plasma melatonin levels, which then recovered to the usual levels following the administration of 5 mg of a benzodiazepine antagonist, Ro 15-1788, given 6 hours after the flunitrazepam. However, single 450191-s did not show any remarkable effects. Thus, it has been suggested that benzodiazepines could suppress the nocturnal levels of plasma melatonin or shift its day-night rhythmicity at least when administered repeatedly. The possible action site of benzodiazepines may be the central nervous system, since melatonin synthesis has been though to be under strongly regulated by the central nervous pathway from the retina to the pineal body. Therefore, these effects of benzodiazepines may provide a method for investigating the physiological role of melatonin and its day-night rhythmicity as well as to further clarify the system regulating melatonin synthesis in humans.

Adult↗
PubMed2005

Possibilities and problems with identification and determination of "new" hypnotics.

Authors discuss problems with identification and determination of flunitrazepam and zolpidem in biological material (BM). Over the recent years, these two structurally different substances have become the most frequently used as well as abused hypnotic drugs. This study presents applicability of immunochemical methods in the screening of flunitrazepam, one of the most commonly prescribed drugs among the benzodiazepines. Herein described techniques, a liquid-liquid (L-L) extraction, solid phase extraction (SPE) and the so-called "freeze out" method are used for isolation of the above mentioned compounds from BM. Besides the thin layer chromatography (TLC) and gas chromatography - mass spectrometry (GC-MS) applied in qualitative analysis, the study also describes a gas chromatography with electron capture detector (GC-ECD) and gas chromatography with nitrogen phosphorus detector (GC-NPD) optimized for the determination of flunitrazepam and zolpidem in blood (serum). Successful analyses of these two substances are of major importance, especially in interpreting the results of forensic toxicological examinations.

Chromatography, Gas↗
PubMed2001

Synergistic protection of allopregnanolone and phenobarbital against maximal electroshock seizures in mice.

AIM: To examine the interactions of allopregnanolone and phenobarbital for the protection against seizures. METHODS: The protective activity of allopregnanolone and/or phenobarbital against seizures was studied in the C57 mice, using the maximal electroshock seizure (MES) test. The modulations by allopregnanolone and/or phenobarbital at the GABA(A) receptor were also characterized using the [3H]flunitrazepam binding in the membrane preparation of mouse cerebral cortex. RESULTS: Pretreatment with phenobarbital produced a dose-dependent protective effect against seizures. The ED50 value of phenobarbital was 2.61 (95 % confidence limits: 1.59 - 4.26) mg . kg-1. Likewise, the ED50 value of allopregnanolone was 0.11 (0.06 - 0.18) mg . kg-1. The combination of allopregnanolone and phenobarbital (1:20) resulted in an ED50 value of 0.73 (0.44 - 1.21) mg . kg-1 with the Q value smaller than 1. In measuring the enhancement of [3H]flunitrazepam binding, we found that the pattern for the concentration-effect curves of phenobarbital with or without allopregnanolone was consistent with that of the theoretical curves of functional synergism. CONCLUSION: There was a synergism between allopregnanolone and phenobarbital for the protective activity against seizures. Also there was a functional synergism between these two agents for the enhancement of [3H]flunitrazepam binding to the GABAA receptor complex in the brain.

Animals↗
PubMed1992

Functional alterations in cerebral GABAA receptor complex associated with formation of alcohol dependence: analysis using GABA-dependent 36Cl- influx into neuronal membrane vesicles.

The effect of alcohol dependence induced by ethanol inhalation on GABA-dependent 36Cl- influx into membrane vesicles prepared from the mouse brain has been examined. Ethanol, flunitrazepam and salsolinol induced a significant facilitation of the GABA-dependent 36Cl- influx into membrane vesicles obtained from the normal mouse brain. Ethanol inhalation induced the facilitation of GABA-dependent 36Cl- influx at 3-12 hr after the initiation of inhalation, but this facilitation returned to a normal level within 12 hr. In membrane vesicles obtained from the brain of an alcohol-dependent mouse at 7 days after the initiation of ethanol inhalation, not only was there a significant decrease of the GABA-dependent 36Cl- influx but there occurred also the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx. This decrease in GABA-dependent 36Cl- influx was found to be recovered within 8 hr after the withdrawal of ethanol inhalation. On the other hand, behavioural withdrawal signs such as tonic-clonic convulsions with grimaces and heads thrown back appeared at 8 hr after the withdrawal of ethanol inhalation and continued for 8-16 hr. These results suggest that the observed functional deteriorations at cerebral GABAA receptors such as the decrease of GABA-dependent 36Cl- influx and the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx may contribute to the preparation of the exhibition of ethanol withdrawal signs and/or the establishment of functional tolerance to alcohol, but are not directly related to the exhibition of alcohol withdrawal signs.

Administration, Inhalation↗
PubMed1991

Pharmacologic characterization of GABAA/benzodiazepine receptor in rat hippocampus during aging.

We have characterized the pharmacologic properties of the gamma-aminobutyric acid (GABAA)/benzodiazepine receptor complex in hippocampal membranes from 3-month- and 24-month-old Wistar rats. No major changes were found in [3H]flunitrazepam or [3H]muscimol binding parameters. Neither the dissociation constant(s) nor the Bmax for either ligand seemed to be modified during aging in hippocampus. Furthermore, the allosteric interaction between the barbiturates binding site and the GABA binding site, determined by pentobarbital stimulation of [3H] muscimol binding, remained unaltered. However, there was a significant increase with aging in the efficacy of the GABA-enhancement of [3H]flunitrazepam binding. On the other hand, we have also detected a significant increase in the proportion of type I benzodiazepine receptor in 24-month-old hippocampal membranes. We propose that the age-related increase in the efficacy of GABA-enhancement of [3H]flunitrazepam binding could be correlated with the increase in the proportion of type I benzodiazepine receptor. Based on these results it is tempting to speculate that the age-dependent modifications on the GABAA/benzodiazepine receptor might reflect an age-dependent neuronal degeneration of the hippocampus or the hippocampal formation.

Aging↗
PubMed1990

Chronic agonist exposure induces down-regulation and allosteric uncoupling of the gamma-aminobutyric acid/benzodiazepine receptor complex.

Using [3H]flunitrazepam as a probe for the benzodiazepine-sensitive modulator site located on the gamma-aminobutyric acid (GABA)A receptor complex, we have investigated the cellular regulation of the GABAA receptor in neuronal cultures derived from embryonic chick brain. Treatment of cultures with 1 mM GABA for 48 hr causes a reversible 35% decrease in the number of [3H]flunitrazepam binding sites with no change in affinity. The EC50 for chronic GABA-induced down-regulation is 94 microM and the half-time is 25 hr. The effect of GABA is blocked by SR-95531, a GABAA receptor antagonist, and mimicked by muscimol but not baclofen. Consistent with the decrease in [3H]flunitrazepam binding, chronic GABA exposure causes a 43% decrease in the binding of [35S]t-butylbicyclophosphorothionate, a ligand for the receptor-associated chloride ionophore. In addition to chronic GABA-induced down-regulation, allosteric interactions between GABA and benzodiazepine recognition sites are uncoupled by 34%. The half-time and pharmacology for chronic GABA-induced uncoupling is indistinguishable from that for GABA-induced down-regulation, consistent with the hypothesis that the action of GABA at a common site induces both down-regulation and uncoupling.

Allosteric Regulation↗
PubMed1990

Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol.

Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,4]-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter [3H]SR 95531 ([2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide] binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter [3H]Ro15-4513 or [3H]flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[Solubilization of the central benzodiazepine receptor and study of its interaction with nicotinamide].

It was shown that nicotinamide and NAD inhibit the specific binding of [3H]flunitrazepam to benzdiazepine receptors without causing a direct influence of gamma-aminobutyric acid (GABA) receptors. The GABA-benzdiazepine complex was separated by solubilization with 0.5% lubrol PX. The solubilized preparations contain the binding sites for [3H]flunitrazepam alone (Kd = 5.9 nm). The Kd value for the membrane-bound benzdiazepine receptor is 2.9 nM. NAD inhibited the specific binding of [3H]flunitrazepam to the solubilized membrane preparation when used at concentrations by several orders of magnitude lower than that of nicotinamide. Using gel filtration on Sepharose 6B-CL, the molecular mass of the soluble benzdiazepine receptor protein was determined.

Animals↗
PubMed1989

[Inhibition of neutrophil function by solvent of injectable sedatives--effects of propylene glycol, ethanol and benzyl alcohol].

Propylene glycol, ethanol and benzyl alcohol are usually included in the injection solutions of diazepam, flunitrazepam and others as solvents and/or pain relief agents. It was reported that diazepam and flunitrazepam inhibited oxidative burst of human neutrophils to produce O2-, H2O2 and other active oxygen species. However, the present study revealed that the solvents had far more potent inhibitory effects in this regard than diazepam and flunitrazepam themselves. The solvents reversibly inhibited phagocytosis and O2- production by neutrophils, and they were stimulated by both soluble stimulants, phorbol myristate acetate or laurate, and a particulate stimulant, serum opsonized zymosan, in a dose-dependent manner. Benzyl alcohol, which had the most potent effect among the solvents, appeared to inhibit the O2- generating enzyme NADPH oxidase directly, rather than by affecting intracellular calcium mobilization. Thus one should keep in mind such unexpected effects of the solvents included in solutions for injection.

Benzyl Alcohol↗
PubMed1988

In vivo interaction of zolpidem with central benzodiazepine (BZD) binding sites (as labeled by [3H]Ro 15-1788) in the mouse brain. Preferential affinity of zolpidem for the omega 1 (BZD1) subtype.

Zolpidem is a novel hypnotic drug which possesses preferential affinity, under in vitro conditions, for the omega 1 (BZD1) subtype of BZD binding sites. In the present study the in vivo interaction of zolpidem with mouse brain BZD binding sites, as labeled by i.v. injection of [3H]Ro 15-1788, has been investigated. Intraperitoneal administration of zolpidem (30 min before sacrifice) decreased in a dose-dependent manner, the retention of [3H]Ro 15-1788 in the cerebral cortex (ED50 = 8.9 mg/kg i.p.); the inhibition by zolpidem was maximal (70%) at 5 to 10 min postinjection and of only 10% 1 hr later. These kinetics are in agreement with its short lasting hypnotic properties. CGS 9896, CL 218,872 and flunitrazepam also prevented the cortical accumulation of [3H]Ro 15-1788 with ED50 values of 12.5, 24 and 0.17 mg/kg i.p., respectively. Zolpidem, like flunitrazepam, diminishes exploratory activity and possesses anticonvulsant and myorelaxant effects in the mouse. However, in contrast to flunitrazepam, the sedative action of zolpidem can be evidenced at a much lower recognition site occupancy (35%) than that needed for myorelaxant or anticonvulsant effects (50-56%). The regional selectivity of zolpidem as an inhibitor of [3H]Ro 15-1788 in vitro and in vivo binding in the mouse brain has been assessed by quantitative autoradiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Quantitative autoradiography of major neurotransmitter receptors in the monkey striate and extrastriate cortex.

In vitro autoradiography was used to determine the binding properties and distribution of 9 major neurotransmitter receptors and their subtypes in the striate (area 17 of Brodmann) and extrastriate (areas 18 and 19) cortex of 1 infant and 3 adult rhesus monkeys. Differences in total labeling and nonspecific labeling, as well as Kd and Bmax values, were determined for all cortical layers and sublayers in both cytoarchitectonic areas by Scatchard analysis of autoradiograms. Area 17 differed from area 18 in the laminar pattern and density of virtually every ligand examined, i.e., 3H-clonidine, 3H-prazosin, 125I-iodopindolol, 3H-quinuclidinyl benzilate, 3H-5-hydroxytryptamine, 3H-ketanserin, 3H-muscimol, 3H-flunitrazepam, and 3H-spiperone. Kd and Bmax values for each ligand were remarkably consistent across the 3 adult monkeys analyzed quantitatively. Particularly dramatic contrasts were observed with clonidine, 5-hydroxytryptamine, and ketanserin, which have high affinity for alpha 2-adrenergic, 5-HT1-, and 5-HT2-receptors, respectively. The differences in distribution of these ligands, especially clonidine and 5-hydroxytryptamine, correlated well with specific laminae and hence exhibited distinctly different patterns in areas 17 and 18. Other ligands, such as flunitrazepam and quinuclidinyl benzilate that bind to GABAergic and cholinergic receptors, were visually less discriminating both among layers and between regions. However, layer for layer, the Bmax values for quinuclidinyl benzilate were higher in area 17 than 18, indicating the subtle differences between areas may be revealed only by quantitative measures. Some ligands were particularly dense in layer I (iodopindolol in areas 17 and 18; 5-hydroxytryptamine in area 18), and others subdivided cortical layers that are otherwise cytoarchitectonically uniform (e.g., flunitrazepam and clonidine in layer VI of area 17), indicating that areal differences in ligand binding are not a simple read-out of cell-packing density but most likely reflect a genuine difference related to the neurotransmitters of intrinsic and extrinsic afferents in each area. The presence of binding sites in every layer of both areas for all ligands examined indicates that their distribution across laminae is quantitative and not all-or-none. No layer contained less than 50% of binding sites present in any other layer. These findings reveal that visual cortical areas differ in density and lamination of neurotransmitter receptors and presumably in their sensitivity to circulating levels of endogenous neurotransmitters and pharmacologically active compounds.

Animals↗
PubMed1986

Effects of brotizolam and other diazepines on respiration.

The inhibitory influence on respiratory functions is clinically an important attribute of the diazepine drugs. This unwanted side effect is frequently observed with intravenous administration in anesthesiology. It is difficult to demonstrate when taken orally, however, of equal clinical relevance, e.g. in elderly people, in patients with obstructive airways diseases, and eventually also in healthy subjects, when diazepine are given for sleep improvement. In the present study, three diazepines, brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin), triazolam and flunitrazepam, which can be used as soporifics, are investigated comparatively in respect to their effect on respiration in anesthetized cats, using intravenous administration. For all three drugs, a marked toxic interaction was found with chloralose/urethane anesthesia, and noticeably less distinctive with pentobarbital anesthesia. This toxicity increased in quantity with the sequence brotizolam less than triazolam less than flunitrazepam. After repeated injections of equal or increasing doses, a pronounced tachyphylaxia was noted, whereby the tolerance against the toxic actions on respiration commenced already after the first injection. In case of flunitrazepam, however, was this tachyphylaxia clearly less prominent. Recently, similar results with diazepines were reported by several other authors. The various effects of diazepines on respiration and their conceivable mechanism of action are briefly discussed, and the relevance of the results in this context is evaluated.

Anesthesia↗
PubMedDate not supplied

[Neurotropic effects of tranquilizers administered intrathecally].

The effects of intrathecally administered benzodiazepines diazepam, flurazepam and flunitrazepam on the pain thresholds in rats were studied by using chronically implanted catheters. Despite benzodiazepine-induced marked muscle relaxation and sedative effect, benzodiazepines produced no significant changes in the thresholds during tests of tail flick and paw compression whereas morphine was effective in both tests. Experiments with 14C-diazepam and 3H-flunitrazepam showed that after intrathecal administration these substances rapidly enter the brain. It was found that 10-15 minutes after intrathecal administration 3H-flunitrazepam concentration in the frontal parts of the brain is 1/4 of its concentration in the lumbar spinal cord. The data suggest that these benzodiazepines possess no antinociceptive activity at intrathecal administration to rats and that way of administration fails to prevent their action on the brain.

Analgesics↗