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)

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)

Scopolamine-induced amnesia in humans: lack of effects of the benzodiazepine receptor antagonist ß-carboline ZK 93426.

It has been suggested from pharmacological studies in animals that ZK 93426 may improve memory and other cognitive processes in humans. Scopolamine has been used to model aspects of memory impairment. To test the effects of ZK 93426 alone and in combination with scopolamine, ZK 93426 (0.04 mg/kg) or vehicle (Intralipid R) was administered intravenously (i.v.) to normal controls, pre-treated with either scopolamine 0.5 mg administered subcutaneously (s.c.) or the same volume of saline. A visual (presentation of pictures) and a verbal (words list) memory test were applied. Both drugs on their own and in combination were found to be safe and well tolerated. ZK 93426 did not antagonize the scopolamine-induced impairment of acquisition of the words list. Scopolamine did not impair delayed recall of visual or verbal material. ZK 93426 alone improved performance in delayed recall of visual material presented after drug application, whereas it impaired performance in delayed recall of visual material presented before drug administration.

Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine.

Rolipram improves signal transmission in central noradrenergic neurones at a pre- and postsynaptic level, and is thus a novel approach in antidepressant therapy. In order to prove efficacy, tolerance, and safety, several controlled studies are underway. Results of a randomized double-blind comparative trial versus imipramine involving 64 in-patients with Major Depressive Disorder (DSM III) in six independent centers will be presented and discussed. The chosen biometric model provided evidence that towards the end of the study imipramine was superior to Rolipram. The particular clinical relevance of this difference is discussed. As regards tolerance, nausea emerged as the typical side-effect of Rolipram, whereas imipramine precipitated mainly anticholinergic side-effects.

Osmolality of nonionic contrast media.

Solutions of different low osmolar contrast media (CM) obviously show clinically relevant differences in the osmolality despite equal iodine concentrations and similar molecular structure. To obtain precise and comparable data, the osmolality of five batches (usually) each of contrast media, iopamidol, iohexol, iopromide, and ioxaglate-all preparations commercially available-were measured by means of the vapor pressure method. The osmolality of the solutions of sodium meglumine ioxaglate with the same iodine concentration is lower than that of the nonionic CM examined. Iopromide showed the lowest osmolality and iohexol the highest value of the nonionic preparations. The differences are statistically significant as a rule. They are attributed to a varying association and hydration of the CM molecules in the solution.

Rolipram versus imipramine in inpatients with major, "minor" or atypical depressive disorder: a double-blind double-dummy study aimed at testing a novel therapeutic approach.

Unlike conventional antidepressants, rolipram stimulates both the presynaptic as well as the postsynaptic component of monoaminergic transmission. Several double-blind comparative trials are on the way to assess the clinical efficacy and safety of this novel compound. The present study was a randomized double-blind double-dummy comparison with imipramine in inpatients with major, "minor" and atypical depressions (DSM III). Results show no relevant differences between rolipram and imipramine regarding efficacy and safety.

[Subjective verbal methods in preoperative measurement of anxiety]. / Subjektiv-verbale Methoden der präoperativen Angstmessung.

The role of preoperative anxiety in perioperative adaptation is viewed in two different ways. Janis suggested that anxiety is a drive that evokes the cognitive work of worrying. Leventhal stresses the importance of coping behavior for adaptation, while anxiety may or may not accompany this coping process. Both theories have empirical support. The aim of this study was to determine whether both theories could show empirical support because the scientists chose different methods: Janis used interviews, Leventhal and Lazarus anxiety scales. The study analyzed the pre- and postoperative emotional reactions of surgical patients with three different methods of anxiety measurement: an anxiety scale, a fear thermometer, and a psychoanalytic interview (Gottschalk-Gleser content analysis method). The different methods were compared and related to the adaptation behavior (Table 3). The data showed a clear interaction between the selected methods and respective theories about the effects of preoperative anxiety on intra- and postoperative adaptation. The anxiety scales showed no correlation with adaptation behavior (blood pressure and heart rate during surgery; postoperative pain medication) and were not related to the anxiety scores obtained from the interview (content analysis). On the other hand, the interview anxiety measurements showed a clear relationship between separation anxiety (and also shame anxiety), physiological excitement during surgery (increase in heart rate), and postoperative medication (increased analgesics and tranquilizers). The patients who worried about the risks of surgery (Verletzungsangst, see Fig. 3) had very good perioperative adjustment, so that the quality of anxiety measured in the interview was very important for the prediction of adaptation.

Anterograde and retrograde amnesia after lormetazepam and flunitrazepam.

In a pharmacopsychological study, memory impairments after single oral doses of benzodiazepines or placebo were investigated in 40 healthy men aged 20-40 years. The study was designed as a double-blind and placebo-controlled trial. Four independent groups of 10 subjects randomly received either 1 mg lormetazepam, 2 mg lormetazepam, 2 mg flunitrazepam, or placebo. The tests consisted of word lists, picture tests, and syllable pairs (consonant-vowel-consonant trigrams). Tests were performed before drug ingestion, and 1, 2, 3, and 5 h after application. Different test versions were used on each occasion. The target variables were immediate recall (after presentation and a 10-s distraction task) and delayed recall and recognition (after 30 min). Recognition was also tested after 24 h for all five versions. A distinction must be made between anterograde amnesic effects and retrograde amnesic effects. The greatest anterograde memory impairments were observed after 2 mg flunitrazepam (p less than 0.05). Lormetazepam 2 mg produced less marked impairments than flunitrazepam. Results after 1 mg lormetazepam did not differ from those after placebo. Performance in the memory tests was better under benzodiazepines than under placebo as regards material learned before drug ingestion, i.e. the benzodiazepines had not negative retrograde amnestic effects, but rather "promnesic" effects. The results suggest that the extent of the benzodiazepines' amnesic effects--both negative (anterograde) and positive (retrograde)--depends on the dosage and type of substance.

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.

Alcohol interaction of lormetazepam, mepindolol sulphate and diazepam measured by performance on the driving simulator.

Sixteen healthy volunteers of a mean age of means = 26.4 years took part in a driving simulator test in an eightfold crossover study under double-blind conditions. The additional influence of alcohol was tested acutely after a single administration of 2 mg lormetazepam, a new, highly effective derivative from the benzodiazepine class, 10 mg mepindolol sulphate, a new betablocker without sedating properties, and 10 mg diazepam. All drugs were compared with placebo and the test was performed 1, 2 and 3 hours after oral intake. The aim was to investigate particularly the risks relevant in road traffic caused by simultaneous intake of these substances with alcohol. For this purpose, besides the driving simulator, an accurate reaction test ( WDG ) and self-rating scales were used, the latter in order to assess subjective stress and anxiety levels. Lormetazepam, due to its strong sedating property, showed a reduction in driving performance and an increase in reaction time and pulse rate as compared with placebo, and these effects were highly potentiated by alcohol. Mepindolol sulphate expectedly reduced pulse rate when compared with placebo, otherwise there were no significant differences. Diazepam, when compared with placebo, like lormetazepam caused a reduction in driving performance and reaction capacity and an increase in pulse rate, but intensity and duration of this effect were less than with lormetazepam and did not reach statistical significance. No significant potentiating effects were observed after the additional application of alcohol.

Study with lormetazepam as a hypnotic in general practice.

Due to the increasing pressure to investigate new drugs under conditions met with in practice, Lormetazepam (0.5 mg) was investigated in nine general practices under the direction and collaboration of a psychiatrist used to investigations with psychopharmaceuticals. The results of a double-blind study, carried out in comparison to triazolam (0.5 mg), in a total of 94 ambulatory patients are presented.

[Drug therapy of sleep disorders in shift workers]. / Probleme der medikamentösen Behandlung von Schlafstörungen bei Schichtarbeitern.

The hypnotic action of a soporific may be of limited use in populations who live in contradiction to their "internal biological clock". In order to test the assumption 60 nurses who had a disturbance in their sleep-waking rhythm due to shift work participated in an one-week double blind study. Nurses were randomly assigned to receive either lormetazepam 1 mg (Noctamid) or placebo (n = 30 per group). In the nurses with disturbance of falling asleep, a normalization of the duration of falling asleep occurred in 15 of 17 cases under lormetazepam as compared to ten of 17 under placebo. In the nurses who slept too little the length of the sleeping time normalized in 15 of 16 cases under lormetazepam as compared to the nine of 16 under placebo. With simultaneous consideration of the duration of falling asleep, total duration of sleep and depth of sleep, a distinction was made between "normalization in all three parameters", "normalization in one or two parameters, but no deterioration in any parameter" and "no normalization" for evaluation of the therapy comparison. The action of lormetazepam was shown in higher improvement rates (p less than 0,05). Neurophysiological and social medical implications are being discussed.

Evaluating mepindolol in a test model of examination anxiety in students.

The effect of a single dose of beta-blocker (5 or 10 mg mepindolol) during a written examination was investigated in two double-blind studies (N : 49 and 55 students, respectively). The question was whether the beta-blocker would in comparison to placebo diminish examination anxiety and improve the performance of highly complex tasks, while leaving the performance of less complex tasks unchanged. A reduction in examination anxiety after beta-blocker intake could not be demonstrated with a multi-level test model (which included the parameters self-rated anxiety, motor behaviour, task performance and physiology), although pulse rates were lowered significantly. An improvement in performance could not be observed, while - by the same token - the performance was not impaired by the beta-blocker. A hypothesis according to which a beta-blocker has an anxiolytic effect and improves performance, dependent on the level of habitual examination anxiety, was tested post hoc, but could not be confirmed. Ten of the subjects treated with 10 mg mepindolol, complained of different side effects, including dizziness, fatigue and headache.

[The antagonistic effect of physostigmine on sedation by lormetazepam (author's transl)]. / Die antagonistische Wirkung von Physostigmin auf die Sedierung durch Lormetazepam.

The purpose of this study was to determine the arousal effect of physostigmine after lormetazepam sedation on the human EEG. 12 male volunteers received 2 mg/kg bm lormetazepam and 30 minutes later physostigmine 2 mg preceded by atropine 1 mg. Generally an arousal effect of physostigmine could be clinically observed and more objectively demonstrated by reduced sleep stages in the vigilosomnogram (p less than 0.05). 2 volunteers did not fall asleep. 9 volunteers were awake 5-12 minutes after termination of physostigmine injection. 1 volunteer did not show any effect. Resedation and parasympathetic side effects did not occur. In earlier studies deep sleep stages after lormetazepam 1 or 2 mg/70 kg bm lasted 70 to 120 minutes. Physostigmine is recommended to counteract undesirable benzodiazepine induced sedation.

[Lormetazepam in the treatment of sleep disorders in a medical practice; double-blind test on 100 patients (author's transl)]. / Lormetazepam bei der Behandlung von Schlafstörungen in der internistischen Praxis. Doppelblindprüfung an 100 Patienten.

Lormetazepam (1 mg) and diazepam (5 mg) were compared in a double-blind study of 100 patients with sleep disorders associated with a medical illness. Assignment to one of two treatment groups was at random. Lormetazepam had a greater hypnotic effect than diazepam in all significant variables (P less than 0.05). There was no hangover effect or other side effects with lormetazepam, which was thus superior to diazepam also in this respect (P less than 0.05).

Comparative efficacy of lormetazepam (Noctamid) and diazepam (Valium) in 100 out-patients with insomnia.

Lormetazepam (Noctamid) at a dosage of 1 mg was compared with diazepam (Valium) at a dosage of 5 mg in a 7-day double-blind study. The study involved fifty patients in the lormetazepam group and fifty patients in the diazepam group. All the patients were suffering from sleep disorders as a concomitant symptom of general diseases. Lormatazepam was significantly better than diazepam in the: -Reduction of the time taken to fall asleep (p less than 0.05) -Prolongation of the duration of uninterrupted sleep (p less than 0.05) -Reduction of the frequency of awakening (p less than 0.05). Lormetazepam displayed no hang-over effects or other side-effects and, in this respect too, was significantly superior to diazepam (p less than 0.05).