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Biomedical subjects

W M Herrmann

Publications and source records attributed to W M Herrmann.

At least 19 recordsLinked to original sources

Moving from the question of efficacy to the question of therapeutic relevance: an exploratory reanalysis of a controlled clinical study of 130 inpatients with dementia syndrome taking piracetam.

The authors reanalyzed previously published data from a prospectively randomized, placebo-controlled, double-blind phase-III study of 130 inpatients with dementia syndrome. The patients in the study had been diagnosed as having suffered from organic brain syndrome (ICD 290), which is the core syndrome of dementia (so-called dementia syndrome) for at least two years. They were treated with piracetam for three months at a dose level of 4,800 mg/d. These data were reexamined in order both to survey the extent of drug-related improvement and response rates when assessed at different levels and to investigate the comparability of efficacy in subgroups suffering from either senile dementia of the Alzheimer type or multi-infarct dementia. Three scales were used for the assessment of efficacy. They were the CGI, or Clinical Global Impression, completed by the physicians; the SCAG, or Sandoz Clinical Assessment Geriatric, used by clinical psychologists; and the BGP, or Beurteilungsskala für Geriatrische Patienten (Evaluation Scale for Geriatric Patients), employed by the nursing staff. The Syndrome-Kurztest (SKT) and Benton tests served to measure performance. The items and subscores of the SCAG and the SKT were highly intercorrelated at baseline, forming a common factor fairly independent of the information gained by BGP. This suggests that merely using different kinds of information-gathering methods, i.e., clinical scales and performance tests, completed by different groups of observers, does not automatically result in nonredundant comprehensive information. When using the most conservative response criterion of individual improvement, i.e., at least one baseline standard deviation, treatment with piracetam showed statistically significant (pe less than .001) explorative response rates of 50% and above in three out of four target variables, as compared to the 0 to 6% obtained with placebo. CGI was used as descriptive variable. Again, using this response criterion from a separate analysis of diagnostic subgroups, as matched by the median of the patients' Hachinski Ischemic Scale scores, it does not appear that piracetam's efficacy for patients with senile dementia of the Alzheimer type (SDAT) varies with its efficacy for patients with multi-infarct dementia (MID).

Aged

Therapeutic efficacy of pyritinol in patients with senile dementia of the Alzheimer type (SDAT) and multi-infarct dementia (MID).

This trial was performed to investigate the efficacy of pyritinol in the treatment of senile dementia. Initially, a total of 183 inpatients were screened for eligibility. Of 164 patients who met the inclusion criteria, 156 completed the trial. Allocation of the patients to the Senile Dementia of the Alzheimer Type group or the Multi-Infarct Dementia group was based on the Hachinski Ischemic Score, computed tomography scans and electroencephalographic (EEG) findings. In a 12-week double-blind treatment phase either 200 mg pyritinol dihydrochloride-monohydrate or placebo was given 3 times daily. Confirmatory statistics included item 2 of the Clinical Global Impression, the total score of the Short Cognitive Performance Test (Syndrom Kurz Test) and the factor 'cognitive disturbances' of the Sandoz Clinical Assessment Geriatric scale. In addition, data on tolerance, of EEG brain mapping and of a responder analysis were evaluated based on descriptive statistics. The therapeutic efficacy of pyritinol was clearly demonstrated by confirmatory analysis as the drug was statistically significantly superior to placebo in all 3 target variables. The clinical relevance of the outcome was underlined by the analysis of the descriptive variables and by the convergence found at the different observation levels. The EEG mapping demonstrated significant differences between placebo and pyritinol, with the latter decreasing slow and increasing fast alpha and beta activity, which reflects improvement of vigilance. Based on the results of this trial, it can be accepted that the therapeutic effect of pyritinol is superior to placebo in patients with mild to moderate dementia of both degenerative and vascular etiology.

Aged

Intensity dependence of auditory evoked N1/P2 component and personality.

The slope of the amplitude/stimulus intensity function (ASF) of sensory evoked potentials was found to be related to 'action-oriented' personality traits like 'sensation seeking', 'extraversion', and 'impulsivity'. We studied the ASF slope of the auditory evoked N1/P2 component as well as short-term ASF slope changes and their relationship to a German personality inventory (Freiburger Persönlichkeits-Inventar) in 33 healthy subjects. The ASF slope correlated negatively with 'life contentment' and positively with 'stress' in the first run. Stronger associations, however, were noted between slope changes within one test session and personality. Subjects scoring high on the second-order factor 'aggressive excitability' were characterized by a slope decrease from the first to the second run, following a 20-min interval. This finding of personality-dependent test-retest changes of the ASF slope stresses the importance of monitoring the duration of the recording when studying ASF slopes and offers an explanation for inconsistencies in the literature concerning cross-modal correlations in visual and auditory ASF slopes. The hypothesis is proposed that the serotonergic system, which has been related to 'action-oriented' personality, is involved in the modulation of the intensity dependence of the auditory evoked N1/P2 component.

Acoustic Stimulation

Predictive value of pharmaco-electroencephalography in early human-pharmacological evaluations of psychoactive drugs. First example: savoxepine.

The present paper forms the first part of a contribution to a comprehensive critical evaluation of the use of pharmaco-electroencephalography (pharmaco-EEG) as an instrument in the evaluation of pharmacodynamic effects of psychoactive drugs in man and further prediction of therapeutic effects by utilizing partial effects in a clinical pharmacological model situation. The basic principles and the methodological approaches are described first, prior to discussing the possibilities and limitations of the pharmaco-EEG in postulating hypotheses about therapeutic efficacy of psychoactive drugs in man. The discussion rests upon the findings with three selected new psychoactive drugs (savoxepine, levoprotiline and maroxepine), presented in this (Part I) and subsequent (Part II and III) reports. In this report results obtained with savoxepine, a novel tetracyclic compound, are described. Convergent evidence for antipsychotic potential of this drug has emerged from preclinical and pharmaco-EEG studies, subsequently corroborated by the first open trials in patients suffering from acute episodes of schizophrenia. In the pharmaco-EEG study a single dose of 0.5 mg savoxepine was tested in 15 healthy subjects with comparison to chlorpromazine (75 mg) and placebo. The experimental design was a threefold cross-over uncompleted block design with three consecutive trial days one week apart. Pharmaco-EEG was recorded under a high situational level of vigilance before 3 h and 6 h after drug administration. The recording was performed by means of 12 electrodes placed in the frontal, central, parietal and occipital regions. EEG-maps were constructed after power spectral analysis of absolute power changes in predetermined frequency bands within the range 0.5 to 30.0 Hz. The findings indicated EEG effects of savoxepine similar to those of chlorpromazine. In the tested dosage, however, savoxepine showed higher potency, later maximum (6 h) of the effect and lower sedative potential. Clinical trials performed in two centres and in, altogether, 28 acutely psychotic patients indicated antipsychotic activity of the drug in a low range of doses (on average, 0.1 to 0.9 mg/d). Even though the antipsychotic efficacy of savoxepine remains to be confirmed in controlled studies, the results favour the hypothesis that pharmaco-EEG has a value in predicting the quality of action of a new drug in man. Results also favour the complementary use of pharmaco-EEG in human pharmacology testing in order to objectively assess central effects of drugs and rationally estimate the doses for therapeutic trials.

Antipsychotic Agents

Pharmaco-EEG profile of levoprotiline: second example to discuss the predictive value of pharmaco-electroencephalography in early human pharmacological evaluations of psychoactive drugs.

The present paper forms the second part of a critical evaluation of the use of pharmaco-EEG as an instrument for assessing the profile of action of psychoactive drugs in man based on the trial results of three new psychoactive test substances. Part I described the basic principles and methodological approaches and illustrated the value of pharmaco-EEG in framing hypotheses about the therapeutic efficacy of psychotropic drugs by the example of the neuroleptic drug savoxepine. This chapter illustrates the relevance of pharmaco-EEG in the assessment of psychoactive drugs by reference to the test substance levoprotiline. Levoprotiline is the pure R-(-)-enantiomer of the racemic drug oxaprotiline, a successor to the second-generation antidepressant maprotiline. Only the S-(+)-enantiomer of oxaprotiline inhibits the re-uptake of noradrenaline. In view of the absence of any monoamine-uptake inhibiting action of levoprotiline, this drug was assumed to be devoid of an antidepressive action. This assumption, however, was disproved by observations made in clinical studies with depressive patients, in whom levoprotiline did indeed display antidepressive activity. Investigations of levoprotiline in the pharmaco-EEG model--even though being retrospective in the sequence of events--would have been able to produce objective prediction of antidepressive potential in man. The substance was tested by comparison to placebo and to the standard antidepressant imipramine in nine young, healthy male volunteers. The experimental design was a cross-over uncompleted block design with three consecutive trial days one week apart.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Pharmaco-EEG profile of maroxepine: third example to discuss the predictive value of pharmaco-electroencephalography in early human pharmacological evaluations of psychoactive drugs.

This publication forms the third part of a critical evaluation of pharmaco-EEG applications as an instrument for assessing the profile of action of psychoactive drugs based on the trial results of three new psychoactive test substances: savoxepine, levoprotiline and maroxepine. After the presentation, in Parts I (savoxepine) and II (levoprotiline), of trial substances for which compatible results were obtained in the pharmaco-EEG model and in the clinical studies, a case with discrepant and less predictive results has been presented, and on this basis the limitations of the pharmaco-EEG model in the evaluation of therapeutic efficacy are discussed. The substance examined in this report, the tetracyclic dibenzoxepine derivative, maroxepine, produced prominent central effects in pharmacological studies which pointed to a bipolar profile of action, i.e., the EEG showed similarities both to antidepressants and antipsychotics. The pharmaco-EEG effects of maroxepine were investigated in a randomised, double-blind study in 15 young healthy male subjects and compared with those of placebo and the reference substances, chlorpromazine and imipramine. The experimental design was a cross-over uncompleted block design with five consecutive trial days one week apart. The pharmaco-EEG was recorded from the occipito-temporal and frontocentral regions before, 3 and 6 h after application of 2.5 mg and 5.0 mg maroxepine, 75 mg chlorpromazine, 75 mg imipramine and placebo. The selected target variables for descriptive statistical evaluation were the Spectral Difference Index (SDI), the absolute and relative power values in seven predetermined frequency bands within the range 1.5 to 30.0 Hz, the dominant frequency (6.0 to 18.0 Hz) and the alpha slow-wave index (ASI). The results show that maroxepine has a potent central nervous action and a strong sedative potential. The EEG effects consisted of a shift to the left of the relative power spectrum of the occipital lead, accompanied by an increase in the absolute beta power in the frontocentral region. Discriminative inspection of the profiles of EEG changes, induced by maroxepine and the reference drugs, revealed closer similarity of maroxepine with chlorpromazine than with imipramine. Maroxepine showed vigilance-decreasing features like imipramine. This is one condition to be able to interfere with depressive illness. The underlying hypothesis is that depressive illness is based on affective and vigilance disturbance. Maroxepine furthermore showed the typical neuroleptic-like shift from resting alpha to resting subalpha (theta F band) which we assume related to the anti-productive properties of neuroleptics in schizophrenia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult

Efficacy and clinical relevance of cognition enhancers.

Changes from the end of 4-week placebo (washout) baselines to the end of 3-month therapy with three chemically different cognition enhancers (CEs) [i.e., piracetam, acetyl-L-carnitine, and nimodipine (NIM)], and parallel changes in placebo controls, were compared to determine the influence of the severity of disease at study entry. Four trials published elsewhere, showing significant treatment differences between active drugs and placebo, were selected according to their (a) sharing at least one global measure for treatment outcome and having shown effects on at least one additional scale or test, and (b) presenting an obvious rank order in the severity of disease. Each study was a standard-controlled clinical phase III trial with greater than 100 psychogeriatric in-or outpatients. The patients' symptoms met the criteria for mild to moderate/severe age-related organic brain syndrome, a core syndrome of senile dementia, either from the primary degenerative, mixed, or multi-infarct type. The extent of changes on placebo was clearly influenced by the mean pretreatment severity of disease. On the whole, the improvements on active drugs reached or exceeded the baseline variability of psychogeriatric scales and tests.

Acetylcarnitine

The long-term tolerability of bencyclane ('Fludilat') in patients with peripheral occlusive disease: a 48-week prospective double-blind controlled study versus placebo.

In a controlled, multi-centre, double-blind trial, 75 patients with Stage II peripheral occlusive disease (Fontaine IIa) were treated with either 200 mg bencyclane twice daily or placebo over a period of 12 months. Undesired drug effects and concomitant phenomena were documented, and efficacy was evaluated. Bencyclane caused a slight, clinically negligible decrease in blood pressure. The pulse rate remained mostly unchanged, ECG and laboratory parameters showed no changes which would indicate a specific effect of the test substance. In the context of the generally low incidence of concomitant effects, patients in the bencyclane group mentioned symptoms such as insomnia, depressive mood, sweating and reduced motoricity more often than those in the placebo group. These symptoms are regarded as signs of the central nervous actions of the drug. The parameters used to assess the efficacy, i.e. the pain-free walking distance estimated by the patients and the physician's global judgment based on Ratschow's test, the palpability of the pedal pulse, the walking range and the patients' subjective statements about the incidence of chill, formication, and pain in the legs, showed a constant and statistically significant superiority of bencyclane over placebo.

Arterial Occlusive Diseases

Effect of lithium on the dynamics of electroencephalographic vigilance in healthy subjects.

Eleven healthy male volunteers had EEG recordings before lithium, after 10 days of lithium administration and 2 weeks after discontinuation of lithium. As postulated from previous investigations the typical lithium effect on the dynamics of electroencephalographic vigilance proved to consist of: (1) a decrease of non-alpha segments, i.e., an increase of alpha continuity or an enhancement of alpha activity; (2) an increase of the anterior/posterior ratio of absolute alpha power (AQ); (3) a decrease of the dynamic variability of this alpha anteriorization (CV-AQ). In addition the decrease of dynamic variability of alpha anteriorization was found to be associated with an increase in the amplitude of P1/N1 components of auditory evoked potentials.

Adult

Event-related potentials and the prediction of differential drug response in psychiatry.

Differences in physiological trait or state characteristics of the organism are ultimately responsible for the wide range of interindividual variability in the clinical response to psychoactive drugs. Event-related potentials (ERPs) appear especially valuable in assessing these physiological characteristics, and might therefore be useful as predictors of the individual drug response. Seven criteria for the selection of potential predictor variables are presented. A review of the literature reveals consistent, prospective and cross-validated results concerning the prediction of the clinical response to psychostimulants in hyperkinetic children. Consistent findings have also been reported concerning the relationship between ERPs and the antidepressive as well as prophylactic effects of lithium. Relating to other aspects of drug therapy in psychiatry, there have been isolated studies describing ERP differences between responders and nonresponders. It is concluded that the use of ERPs in the prediction of differential drug response is a promising research strategy, deserving more attention. Its relevance will be seen not only in its practical value for therapeutic decisions, but also in the clarification of therapeutic mechanisms.

Evoked Potentials

Pharmaco-electroencephalographic and clinical effects of the cholinergic substance--acetyl-L-carnitine--in patients with organic brain syndrome.

In two double-blind, placebo-controlled clinical studies of the nootropic compound acetyl-L-carnitine on the electroencephalogram (EEG) and impaired brain functions of elderly outpatients with mild to moderate cognitive decline of the organic brain syndrome, statistically significant effects could be detected after eight weeks (on the EEG), and after 12 weeks of treatment (on the physician's clinical global impression and the patient-rated level of activities of daily living). Side-effects of acetyl-L-carnitine were generally minor and overall rare. Longer treatment periods and further specifications with regard to the aetiopathology and degree of cognitive impairment are recommended for further clinical studies of this promising compound.

Acetylcarnitine

[Comparison of the action of 2 effective analgesics. Experimental study: tramadol versus tilidine/naloxone].

In the present study involving healthy test subjects, tilidin/naloxone (Valoron N; VAL) proved to have an analgesic effect roughly twice as pronounced as that of tramadol (TRA). Moreover, the analgesic effect of VAL showed a significantly more rapid onset than did that of TRA. This finding reflects the difference in rate of action of the active substances. In accordance with these findings, VAL is thus the most powerful analgesic presently available on the German market on simple prescription.

Clinical Trials as Topic

Influence of cilazapril on memory functions and sleep behaviour in comparison with metoprolol and placebo in healthy subjects.

1. In a controlled, randomized, double-blind study the influence of cilazapril and metoprolol on learning and memory functions and on sleep behaviour was investigated in healthy young volunteers under steady-state conditions. Twenty-three subjects were given either 2.5 mg cilazapril, 200 mg metoprolol, or placebo for 14 days in a latin square design separated by washout periods of 7 days. 2. To test memory functions different modalities--verbal, visual, numerical associative and two dimensional spatial memory were tested for recent anterograde recall, both short-term (less than 10 s) and middle-term (up to 15 min) were selected. The test had a content similar to that used in daily life situations. The sleep behaviour was tested both by objective (all night sleep EEG) and subjective measures. 3. Neither antihypertensive drug had an observable influence on memory performance at the dosages used under steady-state conditions. However, sleep was disturbed during metoprolol, while cilazapril could not be differentiated from placebo. The effects of metoprolol on sleep behaviour were observed in the objective and subjective measures. There was more frequent awakening during the night with the subjective complaint of difficulties in sleeping through. 4. From this study it is concluded that cilazapril has no major effect on memory functions and sleep behaviour. This is only true for the dosages given and under steady-state conditions.

Adult

Psychostimulants, analeptics, nootropics: an attempt to differentiate and assess drugs designed for the treatment of impaired brain functions.

The common characteristic properties of psychostimulants, analeptics, and nootropics are excitatory and disinhibitory effects on the central nervous system. The differences lie in the type of excitatory effect. Psychostimulants produce a general, yet nonphysiologic, activation with subsequent sedation. They generally act in a destabilising manner, disturbing the homoeostatic functions of centrally regulated reactions. Nootropics produce a physiological activation of disturbed or reduced adaptation functions. They have a stabilising effect, increasing the homoeostatic functions of the centrally regulated reactions that have become susceptible to disturbances. Analeptics differ from psychostimulants and nootropics. The effects of neuronal excitation or disinhibition are mainly restricted to the respiratory and circulatory systems. In high dosages they produce convulsions and corresponding motor reactions. No conclusive evidence for a general efficacy in the treatment of organic mental disorders has been furnished for any of the three drug classes. Yet there is sufficient proof that nootropics, unlike psychostimulants and analeptics, can produce therapeutic results in at least some patients, even if it is not yet clear under what conditions they can be meaningfully applied. There is a fundamental difference between the three groups with regard to the potential for abuse. While tolerance and extreme physiological dependence can occur rapidly under treatment with psychostimulants, such risks are not a typical feature of nootropics or analeptics.

Animals

On the distribution of REM and NREM sleep under two benzodiazepines with comparable receptor affinity but different kinetic properties.

Two clinical-pharmacological investigations were performed to give a retrospective and explorative record, based on electroencephalographic parameters, of spindle density and REM distribution in the first and second halves of the night under a short-acting (triazolam) and medium-acting (lormetazepam) benzodiazepine. A further aim was to determine whether a suitable dose of a short-acting benzodiazepine could lead to a REM suppression in the first sleep cycles and a REM compensation in later sleep cycles on the same night. Since sleep spindles are increased and rapid eye movements reduced under benzodiazepines, the two phenomena were respectively taken as indicators of drug effects on NREM and REM sleep. According to the receptor affinity of the two substances, dosages of triazolam and lormetazepam ought to be equieffective in a ratio of about 1:2. Yet clinical experience has shown that a ratio of 1:4 (0.5 mg triazolam vs. 2 mg lormetazepam) gives the doses that are equieffective and which are widely used in clinical practice. The changes in the number of sleep spindles and rapid eye movements documented the different kinetic properties of the two substances. Even after clinically equieffective doses, the changes in the parameters were less marked under lormetazepam than under triazolam. This suggests that the two benzodiazepines different effects on spindle and REM distribution were not attributable to their kinetics, but that pharmacodynamic aspects must also be considered, even if this does not fit in with the prevalent picture of the benzodiazepines mechanisms of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent