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T Duka

Publications and source records attributed to T Duka.

At least 55 records · Page 3Linked to original sources
PubMed1988

[Benzodiazepine antagonism by RO 15-1788: psychometric, hormonal and biophysical parameters].

Ro 15-1788, a selective benzodiazepine (BZD) antagonist, is known to precipitate withdrawal reactions in BZD-pretreated animals. We examined whether a high dose of Ro 15-1788 can precipitate withdrawal reactions relating to behavior and changes in the stress-hormone plasma levels after acute BZD treatment in man. On two consecutive days, 15 min and 24 h respectively after a single treatment with either lormetazepam (0.06 mg/kg: LMZ group), flunitrazepam (0.03 mg/kg: FNZ group) or placebo (PLA group), 18 healthy volunteers received two injections of Ro 15-1788 (0.01 mg/kg). Behavioral responses (mood changes, anxiety), cortisol and prolactin plasma levels, and physiological parameters were examined. In all groups there were only slight changes in the circulation parameters. Minor anxiety reactions were seen after Ro 15-1788, which occurred the 1st day in the PLA group and the 2nd day in the BZD groups. Depression was noted especially in the FNZ group after both injections of Ro 15-1788. The physiological morning decrease in cortisol plasma level was influenced on the 1st day in the LMZ group (2 volunteers showed high plasma levels) and the 2nd day in the FNZ group: a slight increase of cortisol plasma level was measured after the 2nd injection of Ro 15-1788. Prolactin plasma levels arose immediately after LMZ injection and continued to increase after Ro 15-1788 injection. No increase in prolactin plasma levels was found in the other groups or in the LMZ group after the 2nd challenge by Ro 15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Human studies on the benzodiazepine receptor antagonist beta-carboline ZK 93,426: preliminary observations on psychotropic activity.

The beta-carboline ZK 93,426, a benzodiazepine receptor antagonist, was administered intravenously to human volunteers at two different doses (0.01 mg/kg, 0.04 mg/kg) according to a double-blind, placebo controlled design. Vital functions (i.e. blood pressure, heart rate, ECG, EEG), peripheral (finger) skin temperature and performance in psychometric tests for psychotropic and cognitive effects were evaluated. Blood samples were collected in addition and certain pharmacokinetic parameters were estimated. ZK 93,426 in both doses was well tolerated and exhibited no side effects. A decrease in peripheral skin temperature and heart rate was observed. In a general estimation of behavioural changes, volunteers experienced a stimulant and activating effect of the drug. An improvement in performance was observed in two cognitive tasks, the "logical reasoning task" and "pictures differences task" which estimated concentration and attention, respectively. No effects were found in time estimation. Plasma levels 5 min after intravenous administration of ZK 93 426 were 16 +/- 10 ng/ml and 52 +/- 31 ng/ml for 0.01 mg/kg and 0.04 mg/kg, respectively. Total clearance was calculated as 46 +/- 22 ml/min/kg (0.04 mg/kg).

Adolescent↗
PubMed1987

Amnestic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15-1788.

A combined visual (pictures) and auditory (word lists) memory test developed to trace the course of information processing under pharmacological or other influences was validated in a group of 20 subjects (control group) and then applied to determine the amnesic effects of lormetazepam and the reversal of these effects by the benzodiazepine antagonist Ro 15-1788. Three groups of n = 10 subjects received either 0.02 mg/kg IV lormetazepam (groups B and C) or placebo (group A) followed 14 min later by 0.03 mg/kg IV Ro 15-1788 (groups A and C) or placebo (group B). The time course of memory performance in the three groups was investigated and compared across three consecutive 14-min phases: before (phase 1) and after (phase 2) the first intravenous administration, and after the second treatment (phase 3). Results were also compared with those of 20 subjects from a drug-free control group in order to verify the memory test. Lormetazepam clearly impaired immediate and delayed free recall as well as recognition in both visual and auditory tasks. These effects were completely reversed by Ro 15-1788, which alone had no clear effect on memory performance in this study. Psychometric scales indicated concomitant sedation and impaired concentration after lormetazepam alone. Interestingly, lormetazepam retrogradely enhanced performance in the visual test of delayed free recall. The impaired acquisition of new information after the administration of lormetazepam may be associated with an improvement of the consolidation process of information acquired before drug treatment.

Adult↗
PubMed1987

Influence of the histaminergic system on opiate-induced neurosecretion and behaviour.

The influence of the histaminergic system on fentanyl (Fe)-induced growth hormone (GH) and prolactin (PRL) release as well as on Fe-induced increase of noradrenaline (NA) plasma levels has been studied in male volunteers. These volunteers received, according to a randomized block design, different pretreatments: the H1-antagonist dimethindene (Di) (0.1 mg/kg i.v.), or the H2-antagonist cimetidine (Ci)(5 mg/kg i.v.), or a combination of dimethindene and cimetidine (Di + Ci), or saline. The PRL increase caused by Fe (0.2 mg/70 kg) was not altered by pretreatment with the H1-antagonist Di, the H2-antagonist Ci, or the combination of both. The increase of NA plasma levels after Fe also was not modified by the histamine antagonists. In contrast, the maximum GH increase after Fe was blunted by the combination of Ci and Di, but not by either Ci or Di alone. These results suggest an involvement of the histaminergic system in opiate-induced GH-release.

Adult↗
PubMed1987

Clinical perspectives of beta-carbolines from first studies in humans.

First results from studies in healthy subjects with the beta-carbolines ZK 91 296, ZK 95 962 and ZK 93 426 are reviewed. ZK 91 296 and ZK 95 962, characterized as partial benzodiazepine agonists in preclinical research, were unable to induce some typical benzodiazepine effects like sedation when administered intravenously in high doses. ZK 95 962, reported to be effective in photoepileptic patients, was able to reverse lormetazepam-induced sleep as documented by EEG-parameters. The benzodiazepine receptor antagonist ZK 93 426 dose-dependently elicited alertness, restlessness and mild apprehension--symptoms opposite those known for the benzodiazepines. The activating effect of ZK 93 426 was confirmed by the results from e.g., self-rating scales and the logical reasoning test. In another placebo-controlled study comparing the effects of ZK 93 426 alone and in combination with lormetazepam vigilosomnograms obtained after ZK 93 426 alone clearly confirmed the activating effect. In combination with lormetazepam ZK 93 426 was able to reverse the benzodiazepine induced sleep. The attenuation of benzodiazepine effects was also evident from multiple sleep latency tests. Our results support findings from animal experiments which classify these beta-carbolines as benzodiazepine receptor ligands with partial agonist and antagonist properties. beta-Carbolines may prove to be beneficial drugs in the treatment of anxiety, convulsions and diseases with an impairment of cognitive functions as well as in the reversal of unwanted benzodiazepine effects.

Anti-Anxiety Agents↗
PubMed1986

Changes in noradrenaline plasma levels and behavioural responses induced by benzodiazepine agonists with the benzodiazepine antagonist Ro 15-1788.

Noradrenaline (NA) plasma levels were examined in 18 healthy volunteers on 2 consecutive days after a single treatment with either lormetazepam (0.06 mg/kg) (LMZ group), flunitrazepam (0.03 mg/kg) (FNZ group) or placebo (PLA group) in combination with the benzodiazepine (BZ) antagonist Ro 15-1788 (0.1 mg/kg). Behavioural responses (mood changes, anxiety) were also investigated in parallel. Both BZ decreased NA plasma levels to 50% of the basal values 10 min after the injection; administration of Ro 15-1788 15 min later reinstated NA plasma levels to basal values. A second administration of Ro 15-1788 (0.1 mg/kg) 24 h after BZ or PLA treatment increased NA plasma levels, estimated 10 min after the injection in both the LMZ- and the FNZ groups, but not in the PLA group. Behavioural responses measured under the same treatment also indicated minor anxiety responses followed by mood impairment. These data suggest that a stressful situation may be precipitated by the antagonist Ro 15-1788 24 h after a single BZ treatment, which resembles a withdrawal response, and increases NA plasma levels.

Adult↗
PubMed1986

Potentiation of the propunishment, but not the convulsant action of the beta-carboline DMCM by naltrexone.

The ability of naltrexone (NTX) to potentiate the propunishment and convulsant properties of DMCM, a benzodiazepine receptor inverse agonist, was studied in mice. Doses (0.39 and 1.56 mg/kg) of DMCM which were below the threshold for propunishment effects showed a marked ability to enhance the suppressive effects of punishment on locomotor activity in the presence of naltrexone (0.5 or 2.5 mg/kg IP), higher doses of DMCM and NTX (3.13 mg/kg and 10 mg/kg, respectively) had a depressant effect of their own on both punished and unpunished locomotor activity. DMCM given alone induced clonic convulsions (ED50: 5.7 mg/kg IP) but this activity was not changed in the presence of naltrexone. These results suggest an interaction of BZ receptors and opioid systems in the control of anxiety.

Animals↗
PubMed1985

Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788.

Following a single intravenous dose of 0.1 mg/kg, the pharmacokinetics of Ro 15-1788, a specific benzodiazepine antagonist, have been investigated in 20 healthy male volunteers. In random order injection of Ro 15-1788 has been preceded (5 min) by intravenous dosing with 0.06 mg/kg of lormetazepam (n = 6), 0.03 mg/kg of flunitrazepam (n = 8) or placebo (n = 6). The rapid elimination of the antagonist could be characterized by an elimination half-life between 0.9 to 1.4 h and a total plasma clearance of 727 to 1440 ml/min. These single dose studies indicate that the disposition of Ro 15-1788 was not affected by the acute coadministration of both benzodiazepines.

Adolescent↗
PubMed1985

Effects of propofol ('Diprivan') on histamine release, immunoglobulin levels and activation of complement in healthy volunteers.

This randomized study compared the effects of the emulsion formulation of propofol with those of the Cremophor-containing agent Althesin. Plasma histamine concentration, immunoglobulin levels, total complement C3 and complement C3 conversion were measured prior to and following induction of anaesthesia in 32 male volunteers with either 2 mg/kg propofol or 0.05 ml/kg Althesin. In only one volunteer, in the Althesin group, was an increase in plasma histamine to a value greater than 1 ng/ml associated with a relatively large increase over the base line value. Cutaneous signs, such as flushing, did not correlate with the plasma concentrations of histamine. No changes consistent with a propensity to produce anaphylactoid reactions could be seen from measurements of immunoglobulin levels, complement C3 or plasma histamine concentration in the propofol treated subjects.

Adolescent↗
PubMed1984

Dose-dependent influence of fentanyl on prolactin, growth hormone, and mood.

The effect of Fentanyl (FE), an opioid agonist, on neurosecretion and mood was investigated in normal volunteers using doses of 0.1, 0.2, 0.25 mg/70 kg. FE caused a strong dose-dependent increase in prolactin (PRL) secretion in every subject. In contrast, growth hormone (GH) was stimulated significantly at the highest dose only. Additionally, FE induced a significant increase in feeling of wellbeing measured by the Visual Analogue Scale (VAS).

Adult↗
PubMed1981

Selective localization of different types of opiate receptors in hippocampus as revealed by in vitro autoradiography.

The visualization of opiate binding sites within the hippocampus of the rat has been achieved by means of an in vitro autoradiography. In line with the concept of multiple opiate receptors, different opioid agonists revealed a particular distribution pattern. Whereas the selective delta-receptor agonist [3H]D-Ala2,D-Leu5-enkephalin specifically labelled binding sites in the CA2 area, [3H]etorphine grains displayed a uniform dense distribution throughout the pyramidal cell layers from CA1 to CA4.

Animals↗
PubMed1981

A selective distribution pattern of different opiate receptors in certain areas of rat brain as revealed by in vitro autoradiography.

A differential localization of binding sites in the rat brain for [3H]D-Ala2,Leu5-enkephalin ([3H]DADL) and [3H]etorphine ([3H]Eto) was been demonstrated by an in vitro autoradiography technique. Labeling with [3H]DADL was found predominantly in septum and paraventricular nuclei of hypothalamus, whereas [3H]Eto labeling was primarily observed in the periaqueductal gray and several thalamic nuclei. The distinctive patterns of labeling by the two ligands in certain central nervous system structures suggests the existence of specific neuronal pathways which are preferentially labeled with either [3H]DADL or [3H]Eto.

Animals↗
PubMed1981

Naloxone reduces abdominal muscle tone in mice and rats.

The effect of naloxone on muscle tone was investigated in mice and rats at various times after administration. The naloxone effect was also tested in diazepam-pretreated animals. Naloxone was found to display muscle relaxant activity. This effect appeared to be additive to that of diazepam.

Abdominal Muscles↗
PubMed1981

Naloxone blocks the effect of diazepam and meprobamate on conflict behaviour in rats.

The effect of naloxone on the anticonflict action of diazepam was studied in a model involving foot shock-induced suppression of food-rewarded operant behaviour. Both 1 and 10 mg/kg naloxone SC abolished the increase in punished responding produced by diazepam and chlordiazepoxide. Naloxone also blocked the anticonflict effect of meprobamate. These observations are discussed in terms of a possible involvement of endogenous opioid peptides in the anxiolytic effects of tranquillizers.

Animals↗