Biomedical subjects
E Rüther
Publications and source records attributed to E Rüther.
The metabolic fate of infused L-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites.
L-Tryptophan (Trp) was widely used as a natural tool for the support of serotonin-mediated brain functions and as a challenge probe for the assessment of serotonin-mediated neuroendocrine responses. The metabolic fate of the administered Trp and the kinetics of the accumulation of Trp metabolites in the circulation, however, have never thoroughly been investigated. This study describes the time- and dose-dependent alterations in the plasma levels of various Trp metabolites and large neutral amino acids after the infusion of Trp to healthy young men (1, 3 and 5 g; placebo-controlled, double-blind, cross-over study during day- and night-time). The major Trp metabolites (kynurenine, indole acetic acid and indole lactic acid) in plasma increased dose-dependently but rather slowly after Trp administration to reach their maximal plasma levels (up to 10-fold after the 5 g dose) at about 3 h p.i., and remained at an elevated level (about 5-fold) for up to 8 h. N-acetyl-Trp and 5-hydroxy-Trp rose rapidly and massively after Trp infusions, at the 5 g dose more than 200- and 20-fold, respectively, and declined rapidly to about 5-fold baseline levels within 2 h. Whole blood serotonin levels were almost unaffected by the Trp infusions. A rather slow increase of 5-hydroxyindole acetic acid was seen, reaching maximum values (3-fold at the 5 g dose) at about 2 h after the infusion of Trp. Additionally, a dose-dependent rise of circulating melatonin was observed after L-Trp infusions. The administration of L-Trp caused a depletion of the concentrations of the other large neutral amino acids and a dose dependent decrease of the ratio between plasma tyrosine and the sum of the plasma concentrations of the other large neutral amino acids. Apparently, none of the existing pathways of peripheral Trp metabolism is saturated by its substrate, Trp in men. At least some of the central effects reported after L-Trp administration may be mediated by the Trp-stimulated formation of neuroactive metabolites or by the decreased availability of tyrosine for catecholamine synthesis.
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.
Assessment of intracranial hemodynamics in sleep apnea syndrome.
BACKGROUND AND PURPOSE: Sleep apnea syndrome may lead to changes in cerebral hemodynamics due to altered alveolar ventilation. We investigated the dynamics of CO2- and blood pressure-regulated alterations of cerebral blood flow velocities during apneic episodes and evaluated CO2 reactivity during different sleep stages. METHODS: A computer-assisted pulsed Doppler system (2 MHz) was used for continuous overnight recordings of middle cerebral artery flow patterns together with simultaneous polysomnography, continuous blood pressure recordings, and measurements of end-expiratory CO2 in six patients with sleep apnea syndrome. RESULTS: Increases in mean flow velocity of 19-219% and in blood pressure of 12.5-83.1% could be observed during the apneic episodes, with maximum increases during rapid eye movement (REM) sleep. CO2 reactivity was in the normal range (4.4 +/- 1.2%) in the waking state and was markedly increased during sleep stages 1 and 2 (p less than 0.005 compared with awake). The greatest increase was found during REM sleep, with a rise of up to three times the waking value (p less than 0.0001 compared with sleep stage 2). CONCLUSIONS: The changes of mean flow velocity could be interpreted as reactive adaptation processes because of CO2 and blood pressure increases corresponding to apnea. The increased CO2 reactivity during sleep may indicate a "hypersensitivity" of intracranial vascular CO2 or pH receptors and a disturbance of central catecholaminergic and cholinergic systems. The pronounced velocity changes during apneic episodes and the concomitant alterations of vessel wall tension might lead to microangiopathies and macroangiopathies due to chronic strain on the brain vessels.
Life-threatening allergic reaction to clozapine.
Clozapine, an 'atypical' antipsychotic drug, rarely induces allergic complications, which usually present as cutaneous reactions. We report the case of a 69-year-old woman, suffering from chronic schizophrenia, who developed an allergic asthmatic reaction following clozapine therapy. Intensive-care treatment was necessary. The reaction could be repeated by further exposure to the drug. Skin tests for hypersensitivity were negative.
[Somnambulism and pavor nocturnus--review and case report].
A case of night terror with sleepwalking in an adult patient is described. Sleep polygraphic data are presented. The literature related to sleepwalking, night terror and its treatment is reviewed. The psychopathologic patterns of sleepwalking and night terror are illustrated and the differentiations of parasomnias and epileptic seizures discussed. The clinical applications of these findings are described and practical recommendations made for the management of NON-REM parasomnia.
Problems in performing a double-blind multicenter study using a hypnotic in private practice.
1. The procedure described--the immediate data transfer and entry system (ITES)--is suitable to improve the quality of data collected in multicentre studies in private practice. 2. The results of the study show that regarding influence on sleep quality and daytime well-being the non-benzodiazepine Z is significantly superior to placebo and slightly superior to the benzodiazepines F and T. 3. The advantage of Z treatment is the better daytime well-being after taking the hypnotic for sleep induction the night before. 4. This study shows that a quality standard equal to that in clinical practice may be achieved in private practice.
Changes in heart rate during obstructive sleep apnoea.
The mechanisms behind the decrease in heart rate during apnoeas in patients with obstructive sleep apnoea (OSA) are little known. Recent findings in animal experiments indicate that stimulation of the upper airway activates postinspiratory and cardiac vagal neurones in the medullary respiratory centre, causing alterations in heart rate and respiratory rhythm. Since OSA leads to a collapse of the airway and consequent stimulation of upper airway receptors, we studied the interrelations between heart rate and respiratory rhythm during apnoea and during negative intrathoracic pressure generated by the Mueller manoeuvre (MM). Fifteen patients with OSA (apnoea hypopnoea index (AHI) 45 +/- 28.h-1) were studied by polysomnography, during a MM and a Valsalva manoeuvre, each of 15 s duration. The heart rate decrease (delta HRA) and the increase in total respiratory cycle duration (TOT) were evaluated during apnoea in non-rapid eye movement (REM) sleep. Patients with OSA demonstrated a decrease in heart rate during apnoea (-14.4 +/- 9.0 beats.min-1), and during MM (-11.5 +/- 13.5 in OSA vs 3.1 +/- 7.8 beats.min-1 in a control group). TOT increased during apnoea (4.6 +/- 3.1 s). There was a significant correlation between delta HRA and AHI (r = -0.64) as well as between delta HRA and increase in TOT (r = 0.62). These findings indicate that upper airway obstruction may cause an activation of receptors at the site of airway collapse or distortion leading to changes in heart rate and respiratory rhythm.
Benzodiazepine dependence: detoxification under standardized conditions.
In an analysis of the withdrawal syndrome of 12 patients dependent on benzodiazepines (BZD), important factors such as underlying psychiatric disease, precipitating life events, complaints leading to BZD use, and also positive and negative psychological and social consequences, duration of intake, dose and type of BZD dependence are discussed. Withdrawal was completed under standardized inpatient conditions reducing the BZD dose to 50% of the previous dose once every 5 days and maintaining control through regular measurements of the BZD urine concentrations. The course of the somatic, psychological and perceptual withdrawal phenomena was documented according to Lader's BZD withdrawal symptom checklist (Lader, M. (1983) J. Clin. Psychiatry 44, 121-127). The reduction scheme proved to be safe and efficient; no major withdrawal syndromes developed. Abstinence phenomena largely disappeared within 10 days of discontinuation.
[Recommendations for diagnosis, therapy and long-term management of patients with sleep apnea].
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Endocrine response of prolactin, cortisol, and growth hormone to low dose intravenous L-tryptophan in healthy subjects during day and night.
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[Central nervous system side effects of different antibacterial substances].
This review concerns central nervous system side effects of different antibacterial agents. Special attention is focussed on the new quinolone derivatives, penicillins and cephalosporins. As far as possible, mechanisms of action are discussed as well as therapeutic regimens.
[30 years experience with haloperidol].
Haloperidol, a butyrophenone derivative, was first used 30 years ago and has since become one the most frequently prescribed neuroleptics, employed in the treatment of numerous psychiatric and neurological syndromes. It has a very good antipsychotic effect; its sedative effects are moderate compared against weakly potent neuroleptics, and its vegetative side effects are only slight. In a review of the literature, the data found during the past 30 years are commented upon, such as data on pharmacodynamics, pharmacokinetics, indications, undesirable effects, interactions, dosage, contraindications and precautionary measures - all of them having implications on research on neuroleptics as a whole.
The influence of intravenous L-tryptophan on plasma melatonin and sleep in men.
The sleep-inducing mechanisms of L-Tryptophan (L-Trp) are generally thought to be mediated by a central serotonergic activation. Evidence is presented that some effects of L-Trp on sleep may be mediated by melatonin, a Trp-metabolite with sedative properties. Trp effects on vigilance, sleep, and plasma-melatonin concentrations were measured after double-blind application of 0, 1, 3, and 5 g L-Trp in nine and five healthy probands during daytime and nighttime, respectively. A significant sleep-inducing effect was observed after L-Trp administration during daytime and nighttime. The infusions of L-Trp caused a massive elevation of plasma melatonin levels. This effect was significant both during the night and the day, indicating that the increment of circulating melatonin may be of extrapineal origin.
[ST segmental changes and arrhythmias in obstructive sleep apnea].
Patients with obstructive sleep apnea show a fall in arterial oxygen saturation during apneas. Whether this is causing myocardial ischemia and consecutively ST segment depressions in the electrocardiogram is not known. Therefore 15 consecutive patients (53 +/- 8 years, apnea index 45 +/- 28, minimal oxygen saturation 71 +/- 14%) with OSA were studied by Holter electrocardiogram and polysomnography. History and exercise testing gave no evidence of coronary heart disease. Three patients had ventricular arrhythmias Lown IVA and 10 had Lown I or III. Three patients showed unspecific negative T waves or ST segment elevations. In no patient significant ST segment depression was found. It is concluded that OSA does not lead to ischemic ST segment depression in the absence of coronary heart disease. The cause of ventricular arrhythmias in OSA seems not be related to myocardial ischemia.
[Unwanted effects of psychotropic drugs--selected results from a 10-year multicenter project monitoring drugs in psychiatry].
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Adverse effects of clozapine.
Adverse effects related to clozapine were assessed within a post-marketing drug surveillance program, the AMUP study, in two university psychiatric departments. In a randomly selected sample of patients (intensive drug monitoring) ADRs of any type were observed in 76% of clozapine-treated inpatients. Sedation, hypersalivation, increase in transaminases, and EEG changes were most frequently observed, but only rarely required changes in therapy. In 8.1% of 959 patients exposed to clozapine in the total inpatient population of the participating hospitals ADR led to withdrawal of clozapine; in 3.9% reactions judged as severe and potentially life-threatening occurred. Among these latter toxic delirium prevailed. In addition, four cases of severe cardiovascular and respiratory dysregulation were observed with the combination of clozapine and benzodiazepines. These cases and one case of sudden death under clozapine and haloperidol treatment are presented in some detail. The results obtained for clozapine are compared to data from this drug surveillance program for other neuroleptics.
Tolerability of long term clozapine treatment.
Tolerability of long term clozapine treatment (7-8 years) was investigated in 27 female patients (age 34-77 years). Diagnosis according to ICD 9 was schizophrenia in 21 patients, severe psychomotor agitation with mental deficiency in 4 patients and an "endogenous" depression in 2 patients. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The duration of the disorder was 10-36 years, duration of hospitalisation 10-36 years. At the day of investigation the total dose of clozapine ranged from 52-826 g, the average total dose being 385 g. The daily dose of clozapine ranged from 75 to 600 mg, the average daily dose being 225 mg. Only 2 patients were treated exclusively with clozapine, the other 25 patients were also receiving other neuroleptics. Seventy eight per cent of the investigated patients complained about hypersalivation and 63% showed overweight. In 37% of the patients the EEG demonstrated abnormalities. Mild parkinsonism was reported in 15% and akathisia in 11% of the patients, all these patients being on combined treatment. Clozapine did not induce tardive dysakinesia (TD) in any of the patients within a treatment period of 7-8 years. It is concluded that a potential benefit of clozapine includes a low incidence of neurological side effects even after long term administration.