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 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.

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 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.

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).

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.

[Improved method for the diagnosis of diabetes mellitus (author's transl)]. / Verbessertes Diagnoseverfahren zur Erkennung des Diabetes mellitus.

Based on a sample of 953 subjects without known metabolic abnormalities and a sample of 186 diabetics a classification rule was developed by a quadratic discriminant analysis. The measurements of blood glucose 1 and 2 h after the oral administration of 100 g oligosaccharids are used to classify the patients into the categories of "healthy", "suspect" and "diabetic". The rates of false positive and false negative classification were estimated from a second sample of 128 non-diabetic and 73 diabetics. By administration of 100 g oligosaccharids these rates were found to be 3.1% and 0%, respectively. An analogous study for the administration of 100 g glucose was based on a different sample of N = 472, 99 diabetics included. Misclassification rates were found to be 1.6% and 2.7%, respectively. For practical application of the rules two-dimensional netplanes are given.

[Influence of vasoactive substances on blood sugar and serum insulin in normal and diabetic carbohydrate metabolism (author's transl)]. / Einfluss gefssaktiver Pharmaka auf den Blutzucker und das Seruminsulin. Akutstudie bei normaler und diabetischer Kohlenhydratstoffwechsellage

The effect of the following vasoactive substances, which are used in the treatment of peripheral arterial occlusive diseases, was investigated in a randomized study in 36 patients with normal and 52 patients with diabetic carbohydrate metabolism by intravenous infusion on the behaviour of blood sugar and serum insulin (IMI) during simultaneous oral glucose tolerance tests (100 g oligosaccharides). The substances used and the doses given were as follows: protein-free calf-blood extract (Actihaemyl, 0,5 ml per kg body weight), bencyclane (Fludilat, 200 mg), naftidrofuryl (Dusodril, 200 mg, pentoxifyllin (Trenal, 200 mg). The results obtained with the simultaneous treatment and oral glucose tolerance test were compared with a second OGTT carried out at an interval of 3-4 days under the same conditions but without administration of the substances (in a cross-over procedure) and the results of these experiments were compared with those obtained from an untreated control group. In subjects with a diabetic metabolic state, Actihaemyl led to a significant reduction of the blood sugar after oral glucose load (p less than 0,05) without producing any change in serum insulin. The same behaviour was exhibited by Fludilat for the total area integral and by Trental for the first 60 min after the oral glucose load. The change in the blood sugar behaviour was only significantly different from the untreated controls with Actihaemyl (p less than 0,05). In subjects with a normal metabolic state neither blood sugar nor serum insulin (IMI) were altered by any of the substances investigated.

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.

Reflections on the topics: EEG frequency bands and regulation of vigilance.

A critical analysis of quantitative pharmaco-electroencephalography begins with parametrization into variables. The determination of frequency bands according to clinical criteria should be reconsidered. Alternatives may be the determination of factor scores or the definition of frequency bands based on factor analysis. If the latter procedure is used, the clinical alpha-band is subdivided into a lower (alpha 1F = 8,5-10.5 HZ) and an upper (alpha 2F = 10.5-12.5 HZ) part. Furthermore parts of the clinical theta-band (and the delta-band are combined into the delta F-band (1.5-6.0 HZ), for awake healthy volunteers with an occipital alpha-rhythm. Existing concepts of vigilance for the awake stages are not contradictory to the following observations: the factor structure of EEG relative power spectrum variables shows a negative correlation of slow alpha-frequencies with those in the delta F- and beta 3F-band. There is also a negative correlation between slow and fast alpha-wave relative power values.

[The mathematical rationale for the clinical EEG-frequency-bands. 1. Factor analysis with EEG-power estimations for determining frequency bands]. / Mathematische Rationale für die klinischen EEG-Frequenzbänder. 1. Faktorenanalyse mit EEG-Powerspektralschätzungen zur Definition von Frequenzbändern.

In order to determine whether the clinically used frequency bands of the EEG can also be obtained by a mathematical system we did a factor analysis with 480 EEG recordings, 5 minutes each, in 60 healthy male volunteers. A power spectrum analysis was done and 57 frequency bands between 1.5 and 30.0 Hz in a half Hz steps were calculated. The factor structure obtained made the following frequency bands (Hz) reasonable: deltaF = 1.5 - 6.0, thetaF = 6.0 - 8.5, alpha1F = 8.5 - 10.5, alpha2F = 10.5 - 12.5, beta1F = 12.5 - 18.5, beta2F = 18.2 - 21.0, beta3F = 21.0 - 30.0. Except for alpha1F all other 6 frequency bands were represented by one general factor with the complexity 1. The variance of the alpha1F band is explained by several of the 6 factors. The clinically known and the by factor analysis obtained frequency bands in the beta-range are similar. The clinically alpha-band is subdivided into two frequency bands alpha1F and alpha2F by the factor analysis. The clinically known border line between delta- and theta-band of 3.5 Hz cannot be found by factor analysis.

[Prolactin and thyrotropin after stimulation by thyrotropin releasing hormone a study under long-term administration of oral contraceptives (author's transl)]. / Die Stimulierbarkeit der Sekretion von Prolaktin und Thyreoidea-stimulierendem Hormon mit Thyreotropin-releasing-Hormon bei Langzeiteinnahme von oralen Kontrazeptiva.

The longtime application of oral contraceptives is assumed to elevate serum prolactin levels under non-stimulated conditions. We therefore examined whether oral contraceptives also will augment prolactin secretion after stimulation, e.g. by thyrotropin releasing hormone (TRH). After TRH stimulation the time sequence of secretion both of prolactin (HPRL) and thyroid stimulating hormone (TSH) was determined. Three groups of women were tested in a non-randomized study: group 1 without any hormonal medication (= controls), group 2 taking an oral contraceptives containing cyproterone acetate, group 3 using an oral contraceptive containing d-norgestrel. HPRL secretion was similar in all three groups, the same held true for TSH. A possible correlation between the secretion of HPRL and TSH was examined in the control group. No such correlation was found. The secretion patterns of both hormones also were different. In addition, the basic levels of both HPRL and TSH did not seem to influence the response after stimulation.

[Serum concentrations of prolactin, growth hormone, and alpha-fetoprotein under long-term administration of an oral contraceptive containing cyproterone acetate (author's transl)]. / Serumkonzentrationen von Prolaktin, Wachstumshormon und Alpha-Fetoprotein bei Langzeiteinnahme eines Cyproteronacetat-haltigen Kontrazeptivums.

Serum prolactin, growth hormone, and alpha-fetoprotein were determined in women taking a new oral contraceptive, consisting of 2 mg cyproterone acetate and 50 microgram of ethinylestradiol. Because these women were suffering from acne vulgaris they were taking this contraceptive containing a gestagen with antiandrogenic activity. Prolatin and growth hormone were determined because both may favour the development and the growth of mammary tumors and because their secretion may be stimulated by estrogenic compounds. Alpha-fetoprotein is a marker of hepatocellular carcinoma, which may be associated with long-term use of oral contraceptives. During one year of treatment with cyproterone acetate and ethinylestradiol there was a continuous rise of serum concentrations of prolactin. However, this rise did not exceed the normal range. In contrast, serum concentrations of growth hormone did not change significantly. Serum alpha-fetoprotein levels remained below the detection limit of the method.

[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).

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.

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)

[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.

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.

[Lormetazepam in preoperative sleeplessness. Dose dependance of the effect and comparison with 100 mg pentobarbital (author's transl)]. / Lormetazepam bei präoperativen Schlafstörungen. Dosisabhängigkeit der Wirkung und Vergleich zu 100 mg Pentobarbital.

Lormetazepam (0.5, 1, 2, 4, 8 mg)--a new benzodiazepine--was tested versus Pentobarbital (100 mg) under double blind conditions on 240 preoperative inpatients for night-time sedative and side effects after acute oral intake. Results are based on p less than 0.05. Additionally p less than 0.125 in binomial-two-sample-tests was accepted. Lormetazepam shows dose dependent increase in hypnotic effects (e.g. reduction in sleep latency and number of awakenings, increase of total sleep duration), and side effects (e.g. dopiness, dizziness), but no relevant change in vital signs. About 0.5 mg of Lormetazepam are equivalent to 100 mg of Pentobarbital. 2 mg of Lormetazepam seem to be the optimum dose regarding the relation between hypnotic and side effects. In the view of anaesthesists Lormetazepam is preferable to Pentobarbital because of more favorable safety aspects.