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T Duka

Publications and source records attributed to T Duka.

At least 37 records · Page 2Linked to original sources
PubMed1998

Discriminative stimulus properties of low doses of ethanol in humans.

Discriminative stimulus properties of low doses of ethanol were evaluated in humans using established behavioural drug discrimination procedures. Twenty-five moderate drinkers (12 females and 13 males) were trained to discriminate placebo from 0.2 g/kg ethanol in 200 ml tonic water mixed with Tabasco sauce and drunk in portions of 50 ml every 15 s. Seventeen of the subjects (ten females and seven males) were able to reach criterion performance (at least 80% correct responses). Generalisation responding across ethanol doses of 0 (placebo), 0.025, 0.05, 0.1 and 0.2 g/kg was examined the day after training using a procedure in which subjects reported the extent to which the test stimulus resembled the training dose. At the end of each generalisation session, self ratings of mood changes, physiological responses and performance in a working memory and a time estimation task were evaluated. Subjects were able to distinguish the three higher doses of ethanol from placebo. Self ratings indicated that subjects' ability to distinguish ethanol from placebo was related, at the highest dose, to change of taste, but to feelings of light-headedness at the lower doses. Ethanol administration influenced skin conductance measurements but there was no relationship found between changes in skin conductance and the ethanol discriminative stimulus. These data suggest a difference in the nature of the discriminative stimulus of ethanol between high (training) and low (generalising) doses as indicated in the subjective reports.

Adolescent↗
PubMed1998

Alcohol choice and outcome expectancies in social drinkers.

Eighteen male social drinkers underwent four training sessions during which they ingested two colour-coded drinks (red or blue, balanced for drink type); one containing alcohol (aliquots of 0.1 g/kg) and the other placebo (aliquots of orangeade). Following the training sessions, subjects were presented with both drinks, and instructed to choose the drink they felt like consuming and to indicate their preference for their chosen drink over the other drink. In addition, they were instructed to consume the first drink but that all subsequent drinks (total of six drinks), offered at 10-min intervals, were optional. A number of trait characteristics were assessed including alcohol outcome expectancies, drinking habits and personality traits. The acute effects of alcohol on mood was also evaluated by comparing subjective ratings following alcohol and placebo during the training sessions. Of the 18 subjects, 12 chose alcohol at least once ('samplers'), whereas six never chose alcohol ('non-samplers'). Over the three sessions, however, alcohol and placebo were chosen equally. When alcohol was chosen, subjects drank significantly more than when placebo was chosen, which may be consistent with a priming effect of drinking alcohol. The amount of alcohol drunk was seen to correlate with the alcohol expectancy factor 'sociability'. Subjective reports of feeling 'alert', 'clear-headed', 'quick-witted', and 'attentive' all showed a main effect of choosing behaviour (i.e. 'samplers'/'non-samplers'). Further analysis indicated that this effect was due to 'samplers' reporting increased subjective ratings of these mood states following the ingestion of alcohol compared to 'non-samplers'. These increased subjective ratings were also positively correlated with the amount of alcohol consumed by the subjects during the choice procedure. No other relationships were found between the amount of alcohol consumed and any of the other state or trait measures. These data suggest that social drinkers who sample alcohol in a laboratory setting can be primed by alcohol to consume more. The results also indicated that the amount drunk was related to the degree to which subjects expected alcohol to increase sociability and to reports of subjective stimulant effects of alcohol (e.g., 'alert', 'clear-headed', 'quick-witted', and 'attentive').

Adult↗
PubMed1998

Discriminative stimulus properties of nicotine at low doses: the effects of caffeine preload.

Discriminative stimulus properties of low nicotine doses administered in the form of chewing gum in combination with caffeine have been evaluated in humans, using established behavioural drug discrimination procedures. Twenty-one smokers who were also regular coffee drinkers were trained to discriminate 0 versus 1 mg nicotine chewing gum. Twenty subjects (11 men and nine women) were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 0.25, 0.5 and 1 mg was then examined. Subjects were randomly allocated to receive either 50 mg caffeine or placebo before testing. Nicotine-appropriate responding was linearly related to dose, demonstrating that smokers can accurately discriminate nicotine from placebo and between relatively small doses of nicotine. Nicotine-appropriate responding was high at the 0 mg nicotine dose in the caffeine group demonstrating a partial generalization. Subjective effects assessed concurrently with behavioural discrimination revealed that nicotine discrimination was guided by the interoceptive cues of 'sensations in mouth', 'taste', 'heart rate', 'stimulated', 'alert' 'jittery' and 'nausea'. Caffeine increased self-ratings of 'stimulated' and 'alert' (at the 0 mg nicotine dose) and 'jittery' at the 0.5 and 1.0 mg nicotine dose. Relationships between nicotine-appropriate responding and subjective feelings induced by caffeine suggested that feelings of 'stimulated' and 'alert' were guiding discrimination behaviour. These data are discussed in terms of interoceptive nicotine cues and their importance at different doses and after caffeine preload.

Adult↗
PubMed1997

The effects of incentive on antisaccades: is a dopaminergic mechanism involved?

The effect of incentive was investigated upon performance in the antisaccade (AS), memory saccade (MS) and reflexive saccade (RS) task, alone and following performance in tasks of a psychometric battery. Accuracy performance (correct saccades) in the AS and MS task is dependent on two prefrontal functions, the preservation of transient information across short time intervals and the inhibition of prepotent but inappropriate responses, and is impaired in patient populations with known prefrontal dysfunction. It was predicted that, in normal humans, incentive will improve accuracy performance in the AS and MS task, leaving performance in the RS task unaffected (study 1). Saccades were recorded in 24 healthy young male volunteers. Measurements of saccades were performed (in the presence and absence of monetary incentive) alone or following performance on a psychometric test battery that included tasks of working memory, vigilance, attention and psychomotor activity. Incentive increased the number of correct saccades in the AS task and the performance index in the working memory task. No other direct changes were seen in the presence of incentive. The role of dopamine in performance in the AS compared to the RS task was investigated subsequently in study 2. Twenty healthy young male volunteers received levodopa and benserazide (100 and 25 mg, respectively) orally, and 1 and 5 h later measurements of AS and RS were performed. Levodopa significantly decreased the number of correct saccades in the AS task. No other effects were seen. These data, taken together, suggest, first, that the accuracy performance in the AS task is more sensitive than in the MS or RS task, to positive incentive due to monetary reward; and second, that the dopaminergic system may mediate such an effect, because levodopa, a dopaminergic drug, influenced the same performance measurement. The relationship, however, between these two manipulations (incentive and administration of dopaminergic drugs) is not clear, because incentive improved and levodopa impaired performance.

Adult↗
PubMed1996

The effects of a benzodiazepine receptor antagonist beta-carboline ZK-93426 on scopolamine-induced impairment on attention, memory and psychomotor skills.

The effects of a single dose of scopolamine alone and in combination with ZK 93426 (a beta-carboline antagonist at the GABAA/BZ receptor complex with weak inverse agonist activity) were tested in two studies. In one study (study 1) the emphasis of enquiry was on different stages of information processing measured by a psychometric battery; in the second study (study 2) performance at different stages of memory and psychomotor abilities was tested and electroencephalogram recordings and video-tracking were also performed. Each study consisted of two parts, part I in which scopolamine (0.5 mg; 1 ml) or placebo were administered subcutaneously, and part II in which scopolamine (0.5 mg; 1 ml) was administered subcutaneously followed by an intravenous injection of ZK 93426 (0.04 mg; 0.04 ml/kg) or placebo. Thirty-six volunteers, who were randomly allocated to receive one of the two treatments (n = 18 per treatment), participated in each part. In study 1 attention was measured by a continuous attention task and a rapid information processing task, vigilance was measured by a visual vigilance task, and working memory and reasoning were evaluated by a logical reasoning task. A visual memory task was also included to measure acquisition and retention. In study 2 acquisition and short term storage and retrieval were measured by a word lists-Buschke restricted reminding procedure, and retention was tested by delayed recall and recognition. Psychomotor performance was assessed by measuring tapping speed (related to gross motoric abilities) and a pegboard task (related to fine motoric abilities). A task to measure working memory, the Pauli test, was also included. In study 1 scopolamine significantly impaired performance in the attentional and vigilance tasks (P < 0.05), but there was no effect in the logical reasoning task main measurements of time and accuracy. In study 2, scopolamine also impaired performance in the psychomotor tasks (P < 0.05) and the Pauli test. ZK 93426 partially antagonised most of the effects of scopolamine on memory and attention, suggesting that an interaction between the GABA-ergic and cholinergic systems is reflected in measurements of both attention and memory. In general a dissociation was found in the effects of scopolamine on memory, i.e. scopolamine impaired performance during all acquisition measurements but left retention unaffected.

Adult↗
PubMed1995

Effects of ZK 93,426, a beta-carboline benzodiazepine receptor antagonist on night sleep pattern in healthy male volunteers.

The beta-carboline ZK 93,426, a benzodiazepine-antagonist with weak inverse agonist activity, was administered intravenously to human volunteers at a dose of 0.04 mg/kg when they initially reached slow-wave sleep during their night's sleep. Eight subjects, subjected to half a night of sleep withdrawal, took part in the study, which was performed according to a double-blind, placebo-controlled, cross-over design. Sleep parameters as determined by electroencephalography, actometry (wrist actometer) and temperature (rectal thermometer) were monitored for the whole night. Vital functions (blood pressure and heart rate) as well as subjectively experienced effects via visual analogue scales were evaluated and blood samples for hormone plasma level estimation were taken before and after sleep. ZK 93,426 was well tolerated. Sleep parameters were reduced under the influence of the drug indicating a stimulant effect. Slow wave sleep (sleep stages 3 and 4) was significantly reduced in favour of light sleep stages 1 and 2 during the first 30 min after the administration of ZK 93,426 (P = 0.02). In keeping with these findings subjects exhibited a significantly (P < 0.02) elevated number and intensity of movements during the first 90 min after the beta-carboline injection. Effects on self-ratings, in body temperature and on hormonal changes were not found. It is assumed that the benzodiazepine-antagonist ZK 93,426 is able to induce activation and disturb sleep via modulation of GABAergic transmission mainly by benzodiazepine receptor blocking properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Scopolamine and lorazepam exert different patterns of effects in a test battery assessing stages of information processing.

The effects of a single dose of scopolamine (0.5 mg) SC and of lorazepam (2.5 mg) PO were tested in two independent studies for their effects on performance in a psychometric battery which measured functions related to different stages of information processing. Attention and vigilance were measured by a continuous attention task and a vigilance task, respectively. Working memory and reasoning were evaluated by the rapid information processing and logical reasoning task; memory acquisition and storage were measured by pre- and post-drug immediate and delayed recall using visual material. The following pattern of effects was revealed; both scopolamine and lorazepam impaired performance in attentional and vigilance tasks as well as in the rapid information processing task significantly (P < 0.05) when compared with their own placebo; in the logical reasoning task lorazepam significantly prolonged the time required to solve a problem; scopolamine did not have any effect on this task. Scopolamine impaired performance in the immediate recall but left delayed recall unaffected; lorazepam impaired only delayed recall, immediate recall remaining unaffected. These data suggest that scopolamine at this dose impaired mostly attention and early stages of information processes; lorazepam at the dose tested impaired also the later acquisition and encoding aspects of memory.

Adult↗
PubMed1993

Opiates increase plasma catecholamines in humans.

Evidence from animal studies suggests that centrally acting opiates and opioid peptides increase catecholamine (CA) plasma concentrations, reflecting a central activation of sympathetic outflow. We describe here similar opiate actions in humans. Increasing doses of the potent mu opioid receptor agonist fentanyl (FE), 0.1, 0.2, and 0.25 mg/70 kg body weight (bw), induced a significant, dose-dependent increase of noradrenaline (NA) and adrenaline (A) plasma concentrations in healthy male individuals. Whereas NA increased continuously with increasing FE dose, a maximum A response was already reached at the lowest dose. These dose-related NA and A response patterns, showing a higher A sensitivity to opiate receptor stimulation, corresponded closely to those reported from animal studies. Furthermore, comparing the CA releasing potency of 0.2 mg FE/70 kg bw to analgetically equipotent doses of the less selective mu opioid receptor agonist morphine and the kappa agonist/mu antagonist nalbuphine in different groups of male individuals, we found similar effects of these opiates on CA plasma concentrations. These data suggest that the opiate-induced CA release in humans is not only mediated by mu opioid receptors, but may also involve kappa opioid receptor subtypes.

Adult↗
PubMed1993

Human studies on abecarnil a new beta-carboline anxiolytic: safety, tolerability and preliminary pharmacological profile.

1. Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a beta-carboline with high affinity for benzodiazepine receptors, was tested in healthy male subjects; single doses of abecarnil were given in five dosage levels (1 mg, 5 mg, 10 mg, 20 mg, 40 mg) and in a multiple dose study in four dosage levels (15 mg, 30 mg, 60 mg, 90 mg day-1) for 7 days. On two days following multiple dose treatment, placebo was given in single-blind conditions (follow-up). In each dosage level, in both studies drug was given to 10 subjects (7: verum, 3: placebo). 2. Safety and tolerability were evaluated by changes in vital signs, incidence and severity of adverse reactions and biochemical and haematological screening. Drug effects were estimated utilizing a bipolar visual analogue scale (poles: 'sleepy'-'alert') and a psychomotor task, the digit symbol substitution task. The pharmacokinetics of single and multiple doses were also determined in the multiple dose study. 3. Abecarnil was generally well tolerated. In the single dose study the most frequently reported side effects associated with abecarnil at high doses (20 and 40 mg) were dizziness, unsteady gait, and lack of concentration. A decrement in performance on the digit symbol substitution task was also observed in the two high dosage groups 20 mg and 40 mg. Evaluation of visual analogue scale ratings did not reveal a sedative effect even at higher doses. 4. In the multiple dose study the most frequently reported side effects during the treatment period were dizziness, unsteady gait, and lack of concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous, intramuscular, and subcutaneous injection.

The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 micrograms lisuride hydrogen maleate as an aqueous solution. After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml.min-1.kg-1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration. The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.

Adult↗
PubMed1991

Pharmacokinetics and biotransformation of the anxiolytic abecarnil in healthy volunteers.

1. The pharmacokinetics of abecarnil were studied in eight healthy male volunteers using 14C-abecarnil and an h.p.l.c. method for determination of unchanged drug. 2. Abecarnil was rapidly and nearly completely absorbed after an oral dose of 10 mg; bioavailability was 40%. Plasma levels of the unchanged drug declined with a terminal half-life of 4 h. The total clearance of abecarnil was 11 ml/min per kg. 14C-Abecarnil was excreted rapidly and completely. The main route of elimination was in the faeces. 3. Abecarnil was extensively metabolized resulting in ether cleavage at position 6 with subsequent glucuronidation or sulphation and, to a minor extent, in ester cleavage.

Administration, Oral↗
PubMed1990

Pharmacokinetics and acute toleration of the beta-carboline derivative abecarnil in man.

Plasma levels of the beta-carboline, abecarnil (isopropyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido [3,4-b]indole-3- carboxylate, ZK112119) which is presently under development as an anxiolytic, were measured by HPLC with fluorescence detection in six healthy male volunteers given 30 micrograms/kg i.v. and 5 and 10 mg p.o. Following i.v. injection, plasma levels declined biphasically with half-lives of 6 min and 3.4 h. The total clearance was 13 ml/min/kg. After oral administration, maximum concentrations were reached after 2 h. The bioavailability was approximately 60%. The terminal half-life after p.o. administration was 7 h. No clinically relevant changes in ECG, vital signs or standard laboratory measurements occurred. Eight different adverse reactions were noted by the subjects. The most frequently reported side-effects were tiredness, dizziness, unsteady gait and lack of concentration.

Adult↗
PubMed1988

Beta-carbolines as tools in memory research: human data with the beta-carboline ZK 93426.

The discovery of substances which bind with high affinity to benzodiazepine receptors but have no pharmacological effects (antagonists) or effects opposite to those of benzodiazepines (inverse agonists) have introduced a new approach to elucidating mechanisms underlying memory and other cognitive processes. Since benzodiazepines induce anterograde amnesia and sedation, these substances should show an opposite effect and so enhance memory and/or increase vigilance. In the present report we present data obtained in humans with a benzodiazepine receptor antagonist with weak inverse agonist properties, ZK 93426. The drug was given intravenously to human volunteers in double-blind, placebo-controlled designs and performance on several psychometric tests was evaluated. In a general estimation of behavioural changes volunteers experienced a stimulatory, activating effect of the drug. An improvement was observed in two cognitive tasks, the logical reasoning task and the pictures difference task, which estimate concentration and attentional processes respectively. No effects were found in a letter cancellation test or in time estimation. In another study utilizing EEG recording, we demonstrated that ZK 93426 increased wakefulness (vigilance) in healthy subjects during the daytime. The effect of ZK 93426 upon memory processes was also investigated utilizing a visual memory test and word lists. A slight improvement in some memory processes, especially long-term retrieval, was found. The present data suggest that benzodiazepine receptor antagonists with weak inverse intrinsic activity possess some effects opposite to those of benzodiazepines.

Anticonvulsants↗
PubMed1988

Benzodiazepine receptor ligands: tools for memory research in clinical pharmacology.

In order to study the time course of amnesic effects of the benzodiazepine hypnotic lormetazepam, and their reversal by the benzodiazepine antagonist Ro 15-1788, a combined visual and auditory memory test was developed, which was designed to allow repeated assessments. Immediate recall as well as delayed free recall and recognition (1 h after drug) were investigated before and after intravenous lormetazepam (0.02 mg/kg) followed 15 min later by intravenous Ro 15-1788 (0.03 mg/kg) or placebo. A third group received placebo followed by Ro 15-1788. Results are based on ten subjects per treatment group and are compared with an age-matched control population (n = 20) without treatment. Immediate and delayed recall as well as recognition in both visual and auditory tests were impaired abruptly after intravenous lormetazepam. These effects were reversed instantaneously after Ro 15-1788, which had no marked effect on these parameters when given alone. Ratings by visual analog scales (1 h after drug administration) indicated concomitant sedation and impaired concentration after lormetazepam, which was attenuated by Ro 15-1788. By itself, Ro 15-1788 had no effect on these measures. Interestingly, the performance in delayed free recall of the visual memory test was significantly enhanced in the lormetazepam group prior to administration. Our results suggest that impaired acquisition of new information after lormetazepam is benzodiazepine receptor mediated and may be associated with a drug-induced enhancement of retrieval of information acquired before lormetazepam administration.

Anti-Anxiety Agents↗
PubMed1988

Human studies on the benzodiazepine receptor antagonist beta-carboline ZK 93 426: antagonism of lormetazepam's psychotropic effects.

The effects of lormetazepam (0.03 mg/kg IV) a benzodiazepine (BZ) derivative in combination with ZK 93 426 (0.04 mg/kg IV) a beta-carboline, benzodiazepine receptor antagonist were evaluated in humans. Independently, the effects of ZK 93 426 on its own were investigated. A psychometric test battery to evaluate sedation (visual analog scales (VAS), anxiolysis (state-trait-anxiety inventory scale (STAIG X1) and cognitive functions [logical reasoning test (LR), letter detection test (LD)] was applied before and several hours after initiation of treatment. Multiple sleep latency test (MSLT), which measures day time sleepiness, was also applied. Vigilosomnograms analysed from standard EEG recordings were evaluated shortly before and for 1 h after treatment. Treatment started with an intravenous injection of either lormetazepam (LMZ) or placebo (PLA), which was followed 30 min later by administration of either ZK 93 426 or placebo; thus four treatment groups were created (PLA + PLA, LMZ + PLA, LMZ + ZK 93 426 and PLA + ZK 93 426). ZK 93 426 antagonized the sedative and hypnotic effect of LMZ as estimated by MSLT and vigilosomnograms, respectively. Impairment of cognitive functions (LR and LD) induced by LMZ was also antagonized by ZK 93 426. ZK 93 426 had no effect on the changes in the time estimation seen in the LMZ group. Furthermore, ZK 93 426 on its own increased vigilance (alertness) as measured by the vigilosomnogram. A competitive antagonism at the benzodiazepine binding site between ZK 93 426 and LMZ is suggested by their combination effects; the intrinsic activity of ZK 93 426 seems to be due to its weak partial inverse agonist component.

Adult↗
PubMed1988

Human studies on the mu opiate receptor agonist fentanyl: neuroendocrine and behavioral responses.

The neuroendocrine and behavioral responses to the potent mu opiate receptor agonist Fentanyl (FE) have been systematically investigated in healthy male volunteers. These volunteers received, according to a randomized block design, different doses of FE: 0.1 mg/70 kg (n = 11), 0.2 mg/70 kg (n = 11), 0.25 mg/70 kg (n = 8), and saline (n = 11). FE induced a pronounced dose-dependent increase of plasma prolactin concentrations, which was significant at the lowest dose. In contrast, growth hormone was significantly stimulated by the highest FE dose only. Moreover, FE induced a maximum reduction of plasma cortisol concentrations at the lowest dose (0.1 mg/70 kg). In parallel, marked euphoric responses were also observed at this lowest FE dose. These results suggest a mu specific influence on all neuroendocrine and behavioral parameters investigated. Different responses of these parameters to different doses of FE, however, suggest a differential modulation of these parameters by the mu receptor agonist FE.

Adult↗