Effect of morphine on the electroencephalogram and other physiological and other physiological and behavioral parameters.

A double-blind, crossover, placebo-controlled study was carried out in 10 healthy male volunteers to investigate the effects of subcutaneously administered single doses of 4 and 8 mg morphine and 2.5 and 5 mg of a new centrally acting analgesic with a benzomorphane structure. After an adaptation session, each subject received all five treatments in a random sequence at intervals of 1 week. Quantified EEG, cardiovascular and behavioral parameters, quantitative respiratory measurements, body temperature, symptom reports, pain threshold estimates, and blood drug assays were used to assess the effects of the drugs. The measurement battery was completed before injection and after 30, 60, 120, 240 and 360 min. In addition, EEG, blood samples and respiratory signals were also taken during/after the first 5, 10, 15, 20 and 25 min. As the new compound did not show any obvious advantages over morphine, only the results with the latter substance are reported here. As the main effects of morphine on the EEG a dose-dependent slowing and monorhythmization of alpha and an increase of the average frequency of fast beta activity were observed. Slow EEG waves tended to decrease. Heart rate and body temperature decreased, whereas there was no discernible effect on blood pressure. Subjects reported feelings of drowsiness, muzziness, lethargy and mental slowness. The pain threshold increased. All these effects had a maximum between min 120 and 240, although the highest blood levels of the parent drug were measured 10-25 min after drug administration. An explanation for this delay might be that the pharmacological effects are due not to free morphine but to one of its metabolites.

Quantitative pharmaco-electroencephalographic differentiation between the CNS effects of bromocriptine and imipramine, drugs with qualitatively different antidepressant properties.

Two double-blind, placebo-controlled studies were carried out at two different centers using the same protocol. Eight young healthy male volunteers were recruited for each of the studies, which were both undertaken to investigate the effect of single doses of 0.6, 1.25 and 2.5 mg bromocriptine (Parlodel) in comparison with 25 and 50 mg imipramine (Tofranil) on the electroencephalogram (EEG), subjective mental and emotional states, blood pressure, heart rate, and plasma prolactin levels. Side effects were also noted. The changes in the resting EEG power spectrum after imipramine were an increase in slow wave and fast beta activity and a decrease in alpha activity. At the same time imipramine depressed subjective mental and emotional states. Bromocriptine slowed the alpha activity of the resting EEG power spectrum, depressed subjective mental and emotional states, lowered blood pressure, and reduced prolactin secretion.

Investigation of the effect of fluperlapine on the EEG in schizophrenic patients.

The investigations of the EEG during an open study with the antipsychotic drug fluperlapine in acute schizophrenic patients are reported. Due to ethical and practical considerations some of the common pharmaco-electroencephalographic procedures as well as placebo controlled study designs could not be applied in these patients. To overcome at least partly these limitations, intraindividual as well as interindividual correlations were used. They were computed between plasma concentrations of unchanged fluperlapine as well as its metabolite N-oxide fluperlapine, on one hand, and EEG variables, on the other. The intraindividual correlations can be computed either on the first day of the active treatment over various time points of that day (acute effects) or across several appointed treatment days always taking values at the same time during these days (chronic effects). The intraindividual correlations of a set of subjects were submitted to a sign test to obtain an overall result for the relation between the EEG and blood plasma levels of the drug. In this way an acute and a chronic effect of fluperlapine on the EEG could be shown consisting mainly of an increase in slow waves, a decrease in the alpha-activity and a tendency of beta-activity to decrease. A comparison of the correlations between the plasma levels of fluperlapine and the EEG variables with the correlations between the plasma levels of N-oxide fluperlapine and the EEG gives rise to the hypothesis that unchanged fluperlapine has a stronger effect on the EEG than its metabolite.

[Magnetic resonance tomography and safety. Electroencephalographic and neuropsychologic findings before and after MR studies of the brain]. / Magnetresonanztomographie und Sicherheit. Elektroenzephalographische und neuropsychologische Befunde vor und nach MR-Untersuchungen des Gehirns.

The influence of MR on the EEG and neuropsychological functions was investigated. An EEG was done in 8 of 20 patients before and after 0.5 Tesla MRI. Computerized EEG analysis showed no significant differences in respect of the dominant frequency and the power spectrum. The memory functions of 12 patients were investigated by clinically proven neuropsychological tests before and after MRI (0.5 and 1.5 tesla). The results demonstrated no measurable influence of MRI on cognitive functions.

Some correlations in geriatric patients between EEG parameters and clinical status as evaluated using the observer-rated SCAG rating scale. A retrospective study.

In a retrospective analysis, correlations were sought between pretreatment electroencephalographic and clinical data obtained in 18 therapeutic studies conducted in elderly patients according to almost identical protocols. Power spectrum analysis was applied to the EEG tracings, while clinical status was observer-rated using the Sandoz clinical assessment - geriatric (SCAG) scale. The study population comprised a total of 286 patients between the ages of 51 and 97 years (median age 70 years), 162 of whom were male (median age 68 years) and 124 female (median age 73 years). A 2-week washout period and several 'adaptation recordings' preceded the pretreatment EEGs used in this analysis. These tracings were recorded under resting conditions between 8 and 10 a.m. and were followed by an assessment of clinical status. Spearman rank correlations with 4 EEG parameters--total slow waves, alpha and beta waves, and dominant alpha frequency--were computed for all 18 SCAG items and for 'overall impression of patient' as well as for 5 SCAG factors. All 96 - (19 + 5) X 4 - correlation coefficients were formally tested for statistical significance at the nominal level of alpha = 0.05. In this analysis, 9 of the 18 items, 'overall impression' and two of the factors ('apathy' and 'somatic dysfunction') showed nominally significant correlations with at least 1 of the 4 EEG variables. As expected, a positive correlation was found between percentage slow-wave activity and degree of clinical impairment. In addition correlations were identified between clinical data and alpha and beta activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of the central effects of the asthma prophylactic ketotifen, the bronchodilator theophylline, and both in combination: an application of quantitative electroencephalography to the study of drug interactions.

Ketotifen (Zaditen) is a new, orally active benzocycloheptathiophene derivative for use in the prophylaxis of asthma. Besides possessing anti-allergic properties, it also has H1-receptor mediated antihistaminic activity. Drugs which block H1-receptors are known to have some sedative properties. On the other hand the bronchodilator theophylline is a CNS stimulant. We investigated whether these side-effects could be reduced by concomitant administration. In a balanced-sequence crossover study, 12 healthy males received placebo, 1 mg ketotifen + 300 mg theophylline, 1 mg ketotifen + 600 mg theophylline, and each drug separately at 1-week intervals. Quantified electroencephalograms, cardiovascular and behavioral measurements, symptom reports, and blood drug assays were used to assess the drug interaction. Results showed EEG and behavioral effects with both ketotifen and theophylline alone which were less evident with the drugs in combination. Blood drug levels were not altered by combined drug administration. These findings suggest a mutual attenuation of the CNS effects of ketotifen and theophylline at therapeutic doses and encourage their combined use in asthma therapy. The combined effect may be optimized by modifying formulations or timing. The applicability of quantitative EEG to such problems is well demonstrated.

Electroencephalographic and psychometric assessment of the CNS effects of single doses of guanfacine hydrochloride (Estulic) and clonidine (Catapres).

A double-blind, placebo-controlled study was carried out in 10 young healthy volunteers to investigate the effects of single doses of 1 and 2 mg guanfacine hydrochloride (Estulic) and 0.15 and 0.3 mg clonidine (Catapres) on the electroencephalogram (EEG), subjective mental and emotional state, blood pressure and heart rate. These doses are considered to be equipotent with regard to their antihypertensive effects, as shown in long-term therapeutic trials. Each subject received all five treatments in random sequence at intervals of 1 week. The EEG tracings were evaluated quantitatively by spectral analysis. Procedures were carried out before and at 1, 2, 4, 6 and 8 h after drug administration. After clonidine the EEG showed increased slow-wave activity and decreased alpha activity, these effects being dose-dependent. They were of the sedative type and did not clearly indicate specific psychotropic properties. The subjective mental and emotional state questionnaire indicated a decrease of alertness, extroversion, concentration and mood (in that order), changes which paralleled the EEG changes. The changes observed after guanfacine were qualitatively similar to those after clonidine, but were of considerably lower intensity. Our data suggest that guanfacine has less central nervous system-depressant activity than clonidine.

Pharmaco-EEG studies with fluperlapine.

In the first of 2 studies, the effects of 3-fluoro-6-(4-methyl-piperazinyl)- 11H -dibenz[b,e]azepine ( fluperlapine , NB 106-689) 5 and 10 mg, clozapine 5 and 10 mg, and placebo on the EEG and on subjective mental and emotional state were investigated in 8 healthy male volunteers. The study was carried out as a double-blind within-subject comparison, with randomized sequence of treatments. Quantitative spectral analysis of the EEG revealed that changes after fluperlapine were strikingly similar to those after clozapine, i.e. an increase in delta and theta and a decrease in alpha activity. These changes were associated with a reduction in self-rated "wakefulness" and are evidence of a sedative effect. The drugs' effects differed only in the magnitude of the increase in beta activity in the 20-40 cps frequency band (beta 2), which was greater after fluperlapine than after clozapine. Since increased beta 2 activity has been reported with tricyclic antidepressants, it is suggested that fluperlapine , besides possessing neuroleptic properties, might also have some properties of a (sedative) antidepressants. It is estimated from the EEG findings that, at equal doses, fluperlapine (capsules) has approximately one half of the sedative potency of clozapine (tablets). A second study in schizophrenic patients revealed strong correlations between EEG effects and blood levels of unchanged fluperlapine during long-term treatment.

Pharmaco-EEG and Psychometric study of the effect of single doses of temazepam and nitrazepam.

A double-blind, daytime, placebo-controlled study was carried out in 12 healthy volunteers to investigate the effects of single doses of 5, 15 and 30 mg temazepam and of 5 and 10 mg nitrazepam on the EEG, psychomotor performance, subjective mental and emotional status, blood pressure and heart rate. Each subject received all 6 treatments in a random sequence at intervals of 1 week. The EEG tracings were evaluated quantitatively by spectral analysis. Psychomotor performance was assessed by means of the tapping test. Subjective mental and emotional status were assessed using the Bond and Lader analogue self-rating scale. Procedures were carried out before and at 1/2, 1, 2, 4, 6, 7, 8 and 9 h after drug administration, with the exception of the tapping test, which was carried out before and, again, after 2 and 7 h. EEG estimates of equipotency, based on magnitude of peak effect, were as follows: 15 mg temazepam approximately 5 mg nitrazepam; and 30 mg temazepam greater than or equal to 10 mg nitrazepam. At these approximately equipotent doses, temazepam had a somewhat earlier onset of action on the EEG, a clearly shorter duration of EEG action, and lesser impairment of psychomotor performance than nitrazepam. Qualitatively, both drugs had similar effects on the subjective mental and emotional states of the subjects. There were no clinically relevant changes in mean or individual sitting and standing blood pressure values. After temazepam, but not after nitrazepam, heart rate increased (maximal mean change 10 bpm) as part of a normal startle response to arousal. The results suggest that temazepam has less hangover potential than nitrazepam.

Correlation between EEG changes indicative of sedation and subjective responses.

The central activity of ketotifen ( Zaditen ), a benzocycloheptathiophene derivative for use in the prophylaxis of asthma, was determined by quantitative pharmaco-EEG in 7 healthy volunteers in a single-blind trial. During the 1st week of the trial, placebo was given twice daily followed by ketotifen 1 mg twice daily for 3 weeks. Placebo was again given for a further week. 15-min resting EEGs were taken immediately before and 3 and 6 h after medication on 8 defined days during the study, and the subjects were asked for side effects. Lead O2-Cz was analyzed by spectral analysis, and the relative power of the delta, theta, and fast and slow alpha bands as well as the dominant alpha frequency were calculated. The mean of each of these parameters was calculated per subject for each of the three measurements on each study day and compared with the baseline by means of one-way analysis of variance. A statistically significant slowing of the dominant alpha frequency, a decrease of the relative power of the fast alpha activity, and an increase of the relative power of the theta rhythm were found. These effects, indicative of a mild sedation, were highest during the 1st week of treatment with ketotifen, with a peak at the 3rd day, and gradually decreased thereafter. In contrast to the sensitive pharmaco-EEG method, none of the subjects complained of sedation or tiredness while taking ketotifen.

Confirmatory and exploratory analysis applied to pharmaco-EEG and related study data: contradiction or useful enrichment?

Besides hypothesis testing, which should be done as sparingly as possible, the measured or observed data should be described as extensively as possible. The traditional reliance on profiles of the mean responses may neglect useful information, and such profiles may also be misleading. With the aid of exploratory data analysis, different aspects of the structure of a data set can be considered. 'Data snooping' may discover coherences, non-trivial structures and peculiarities, which lead to a new hypothesis or to new mathematical-statistical models. It is, in our opinion, a necessity to consider exploratory and confirmatory data analyses in conjunction. This will be illustrated by examples taken from pharmaco-EEG studies.

[On the meaning of psychometrically operationalized therapeutic effects in the treatment of brain insufficiency phenomena caused by old age demonstrated by the "Nürnberger-Alters-Inventar" (author's transl)]. / Uber die Relevanz psychometrisch operationalisierter Therapic-Effekte bei der Behandlung altersbedingter Insuffizienzerscheinungen des Gehirns am Beispiel des Nürnberger-Alters-Inventars.

The drug effects of dihydroergotoxine (Hydergin) and piracetam were examined in a sample of 44 old-age home residents, 76 years average age, using performance tests, nurse-ratings for the need of care and self-evaluation measures of the "Nürnberger Alters-Inventar" (NAI). Within a subsample of 18 patients, selected according to certain EEG-criteria, EEG day profiles were assessed. The medication lasted for 6 weeks. 2 mg dihydroergotoxine or 0.8 g piracetam, respectively, were applied three times a day. Initial effects were observed for both medications after 3 weeks in terms of improvements in the cognitive performance, for the activities of daily living and need of care, respectively, and for subjective, physical, functional and social self-evaluations. After 6 weeks, at the end of the study, these effects were confirmed only for dihydroergotoxine, whereas the piracetam subjects could not stabilize these improvements. The psychometric results were corroberated by the EEG-data. Correlations between the independent levels of psychometric assessment did demonstrate the meaning of the performance measures in terms of activities of daily living and subjective well-being.

[Some relationships between occipital E.E.G. activity and age. A spectral analytic study (author's transl)]. / Application de l'analyse spectrale pour l'etude de certaines relations entre l'activité E.E.G. occipitale et l'age.

Experience amassed over many years indicates that the human E.E.G. undergoes characteristic changes with advancing age. To study these phenomena a spectral analytic investigation was carried out. Results obtained from the E.E.G. by spectral analysis (lead O2-CZ, 3-minute resting E.E.G., n = 739, age range 20-95 years) show that a slowing of the dominant occipital alpha frequency occurs increasingly in old age. Slow activities, delta and theta, increase in percentage to the entire spectrum, while at the same time there is a decrease in percentage in alpha and beta activities (statistical evaluation: polynomial regression analysis). Another investigation was carried out in 619 subjects ranging in age between 20 and 95 years, in order to identify the E.E.G. variable most closely correlated with age. All the subjects had a normal alpha E.E.G. and were in a state of physical and mental health normal for their chronological age. Because of the mutual dependency of the E.E.G. parameters and the possible existence of substructures within the data that are not related to age, factor analyses were performed. Three factors account for about 80% of the total variance, on the which can be considered age-related. In this factor the variable age has the highest loading and the dominant (alpha) frequency shows -- negatively correlated with age -- the second highest loading. It is therefore assumed that, among the various E.E.G. variables correlated with age, the slowing of the dominant (alpha) frequency represents the most characteristic symptom of the E.E.G. in senescence.

Electroencephalographic and clinical changes as correlated in geriatric patients treated three months with an ergot alkaloid preparation.

The results of a 3-month trial with an ergot alkaloid preparation (Hydergine) in 16 geriatric patients showed that, in accordance with a previously proposed working hypothesis, the improvement induced by the drug in electroencephalographic age-related changes was accompanied by clinical improvement in patients with similarly age-related mental deterioration.

Pharmaco-electroencephalography: the value of quantified EEG in psychopharmacology.

One of the first routine applications of quantitative EEG analysis was in the field of human psychopharmacology. As early as the 1960's, quantitative techniques, mainly period and amplitude integration analyses or analogue filtering, were successfully applied to EEG data with the aim of quantifying and objectifying changes induced by psychoactive medidation. Thus, step by step, a new research field, pharmacoelectroencephalography, was developed. Many other sophisticated new techniques have been described in great detail from the engineering viewpoint. However, due to the language barriers common between representatives of the various disciplines involved, it is still difficult to view them in context with the experimental design as a whole. Therefore, based on examples taken from our routine work, an attempt is made to give a balanced judgement on the value of such techniques in pharmaco-electroencephalography, and their contribution to the CNS pharmacology.

Slow-drip dibenzepine infusion in depression. Proof of rapid efficacy by quantitative EEG and affect-polarity profile studies.

The efficacy of a new intensive antidepressive treatment procedure--48 h slow drip infusion with 1,440 mg dibenzepine2 and subsequent oral treatment--was investigated in endomorphous (endogenous) depressed patients. In addition to evaluations of alterations in psychopathology by clinicians, time of onset and the extent of the therapeutic effect was determined by the patients themselves using the affect-polarity profile, and by EEG power-spectral density analysis. Clinical improvement started as early as in the 3rd hour of the dibenzepine infusion and was predominantly due to an anxiolytic/sedative drug effect. The thymoleptic effect started at the end of the infusion and increased with progressing oral treatment up to the 3rd week. Neurophysiological changes were ahead of the psychopathological ones, since a statistical decrease in dominant frequency of the EEG occurred 1 h after the start of dibenzepine infusion.

[Spectral-analytical studies of the action of etifoxin on the human EEG]. / Spektralanalytische Untersuchungen zur Wirkung von Etifoxin auf das menschliche EEG

Spectral analysis of EEG in healthy volunteers shows that Etifoxin, the hydrochloride of 6-chloro-4-methyl-4-phenyl-2-ethylamino-4H-3,1-benzoxazine (Hoe 36,801), in an oral dosage of 100 mg has a differential effect in function of the individual alpha organization. This differential effect appearing in the course of the quantitative evaluation can be interpreted, from a morphological point of view, as an expression of various partial phases and patterns of a process leading to reduced vigilance.