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Biomedical subjects

K Wiedemann

Publications and source records attributed to K Wiedemann.

At least 73 records · Page 4Linked to original sources
PubMed1994

Endocrine characterization of the new dopamine autoreceptor agonist roxindole.

Roxindole (5-Hydroxy-3-(4-phenyl-1,2,3,6-tetrahydropyridil-(1)-butyl)-indol) is a newly developed compound with a high dopamine autoreceptor agonistic potency at D2 receptors. Evaluation of roxindole for clinical purposes in psychiatric patients revealed that the substance has contrary to expectation merely negligible antipsychotic but considerable antidepressive effects. Interestingly it is nearly devoid of any side effects. To further characterize the endocrine effects, 1 mg roxindole was applied at 09:00 to 6 male volunteers and the effects compared to placebo. From 08:00 to 13:00 blood samples were drawn every 30 min. No effect on adrenocorticotropin and cortisol secretion was observed, neither mean plasma concentrations nor area values differed significantly. 90 min after roxindole administration an enhanced release of growth hormone could be observed, comparison of mean hormonal concentration revealed statistical significance (p < 0.05). Also the area values differed significantly (roxindole vs. placebo mean +/- SD 18.1 +/- 17.1 vs. 7.7 +/- 8.0 micrograms x h/l; p < 0.05). After roxindole also a pronounced reduction of prolactin plasma levels from 5.3 +/- 1.4 micrograms/l to 1.1 +/- 0.4 microgram/l within 150 min could be observed. Mean plasma concentrations (p < 0.05) and area values differed significantly (roxindole vs. placebo mean +/- SD 14.8 +/- 13.5 vs. 34.4 +/- 18.1; p < 0.05). Roxindole had no effect on blood pressure parameters and heart rate. The major findings of the present exploratory study are, that roxindole has potent effects on the facilitation of growth hormone secretion and the inhibition of prolactin release. Both findings are complementary and point also to interesting postsynaptic dopamine receptor agonistic effects.

Adrenocorticotropic Hormone↗
PubMed1994

Effects of pulsatile cortisol infusion on sleep-EEG and nocturnal growth hormone release in healthy men.

This study investigates the short-term effects of pulsatile cortisol administrations upon sleep electroencephalogram (EEG) and spontaneous release of growth hormone (GH) in humans. Ten young healthy male volunteers received intravenous injections of either placebo or cortisol every 60 min between 17.00 hours and 06.00 hours (1 mg kg-1 BW with a loading dose of 20% starting at 17.00 hours, followed by a dose of 6% every hour until 06.00 hours). The amount of rapid eye-movement (REM) sleep was significantly reduced (placebo: 19.9 +/- 1.8; cortisol: 12.2 +/- 1.5%; P < 0.05), whereas the time spent in slow-wave sleep (SWS) was significantly increased (placebo: 9.4 +/- 1.6; cortisol: 13.9 +/- 1.9%; P < 0.05). The SWS-promoting effect was most prominent during the first hours of sleep, but tended to persist also during the second half of the night. The pulsatile cortisol administration augmented the total amount of plasma GH concentrations (mean area under the time course curve, AUC, placebo: 3.2 +/- 0.5; cortisol: 4.4 +/- 0.6 [ng x 1000 x ml min-1]; P < 0.05) due to an increase of GH release before sleep onset, and during the second half of the night, while the GH surge at sleep onset remained unchanged. Our data are in accordance with the hypotheses that cortisol-induced changes of both sleep-EEG and GH secretion involve a common mechanism that includes activation of the hypothalamic-somatotrophic (growth hormone releasing hormone-growth hormone) system.

Journal Article↗
PubMed1994

Sleep endocrine effects of antigluco- and antimineralocorticoids in healthy males.

In several mammalian species the responsiveness of brain neurons to corticosteroids is mediated by mineralo- (MR) and glucocorticoid (GR) receptors. These receptors play a key role not only in the endocrine adaptation to stress but also in corticosteroid-induced changes of behavior, including sleep. We further explored the specific physiological role of this binary receptor system in the human brain by studying electroencephalogram (EEG) sleep and changes in plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, and growth hormone from 1800 to 0700 h in a series of investigations in healthy men pretreated the previous evening with the nonselective GR agonist dexamethasone (Dex) and then receiving at 1400 h either placebo, spironolactone (Spi), an MR antagonist, or mifepristone (Mif), a GR antagonist. The Dex-induced suppression of ACTH and cortisol was unaltered after Spi (200 mg) but attenuated by Mif treatment (400 mg). The sleep-associated plasma growth hormone surge was increased by Dex, an effect that remained unchanged by Spi but was reduced by Mif treatment. Pretreatment with Dex did not by itself induce recognizable effects on EEG sleep, but the Dex combination with Spi reduced the amount of rapid-eye-movement (REM) sleep. With Dex plus Mif, both REM sleep and slow wave sleep (SWS) were reduced compared with placebo. The Dex-induced endocrine effects on plasma ACTH, cortisol, and growth hormone concentrations could not be antagonized by Spi, which acts via MRs mainly located in the hippocampus, but were compensated for in part by Mif, which antagonizes GR at the pituitary and in the central nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Influence of endotoxin on nocturnal sleep in humans.

Sleepiness is a common complaint during infectious diseases, but the interaction between sleep and host defense mechanisms has been poorly explored in humans. We therefore studied the effect of endotoxin, a major pathophysiological factor in gram-negative bacterial infections, on sleep and on parameters of the primary host response in men. In a single-blind counterbalanced trial, 15 healthy volunteers received either placebo or Salmonella abortus equi endotoxin (0.4 ng/kg body wt) intravenously on two separate occasions. Nocturnal sleep was recorded, and rectal temperature and the plasma levels of tumor necrosis factor-alpha, interleukin-6, adrenocorticotropic hormone, and cortisol were monitored for 12 h. Endotoxin reduced the relative amounts of wakefulness (P < 0.05) and rapid-eye-movement (REM) sleep (P < 0.05) and increased the relative amount of non-REM sleep (P < 0.01). Electroencephalogram delta power during non-REM sleep, as measured by spectral analysis, was not altered by endotoxin. The endotoxin-induced changes in sleep structure were related temporally and quantitatively to the increases in rectal temperature and to the release of cytokines and neurohormones. It is concluded that cytokines and neurohormones mediate the effects of endotoxin upon sleep. The ensuing increase in non-REM sleep may be part of the adaptive host response to bacterial infections in humans.

Adrenocorticotropic Hormone↗
PubMed1993

Endotoxin- and corticotropin-releasing hormone-induced release of ACTH and cortisol. A comparative study in men.

The present study compares the effects of endotoxin, a key factor in gram-negative bacterial infection, and of corticotropin-releasing hormone (CRH) on ACTH and cortisol secretion in healthy male volunteers in a placebo-controlled design. Endotoxin (isolated from Salmonella abortus equi; 0.4 ng/kg body weight) induced a significantly delayed and prolonged increase of ACTH and cortisol secretion as compared to CRH (100 micrograms), supporting the hypothesis that different intermediate mechanisms are involved (baseline/peak: ACTHEndotoxin vs. ACTHCRH: 140 +/- 40 min vs. 44 +/- 17 min (p < 0.001); CortisolEndotoxin vs. CortisolCRH: 113 +/- 51 min vs. 66 +/- 31 min (p < 0.05); peak/baseline: ACTHEndotoxin vs. ACTHCRH: 244 +/- 79 min vs. 200 +/- 25 min (p < 0.05); CortisolEndotoxin vs. CortisolCRH: 278 +/- 76 min vs. 182 +/- 16 min (p < 0.001)). Activation of the hypothalamo-pituitary-adrenocortical (HPA) system by endotoxin in men is associated with increased interleukin-6 (peak value: 124 +/- 109 pg/ml) and tumor necrosis factor-alpha (peak value: 69 +/- 53 pg/ml) plasma levels which, probably together with locally produced interleukin-1, stimulate the HPA system both at the hypothalamic and (to a lesser degree) at the pituitary site. Provided that strictly controlled laboratory conditions are applied, the endotoxin challenge test presented here may serve as an appropriate and safe tool to explore an individual's capacity for neuroendocrine adaptation to a bacterial stressor, thus providing information complementary to the CRH test.

Adrenocorticotropic Hormone↗
PubMed1992

Antiglucocorticoid treatment disrupts endocrine cycle and nocturnal sleep pattern.

Mifepriston (RU 486) is a steroid antagonist which binds with high affinity to glucocorticoid receptors (GR), and also to progesterone receptors. The antiglucocorticoid action of Mifepriston in man has been demonstrated by blockade of the negative feedback action of endogenous cortisol and by antagonism of the effects of exogenously administered dexamethasone. In the present study Mifepriston was administered to a normal male volunteer at 14.00 h and its effects on pituitary-adrenal activity and nocturnal sleep pattern were recorded. Mifepriston caused a large rise in plasma ACTH levels during the morning hours in comparison to untreated male control subjects. Plasma ACTH levels in the Mifepriston treated subject at 7.00 h were threefold greater than in the control subjects (104.4 pg/ml vs. 37.6 +/- 13.9 pg/ml; mean +/- SD). Subsequently the cortisol secretion was enhanced and the rise was advanced by about 60 minutes compared to controls. The main effects of Mifepriston on EEG sleep pattern were a dramatic disruption of sleep quality with a prolonged sleep onset latency, increased nocturnal awakenings and a considerable reduction of both slow wave sleep (SWS) and REM sleep. After Mifepriston, SWS was reduced by about 80% in comparison to placebo, and REM sleep was reduced by more than 50%. While the present data were collected from only a single subject the effects observed were so pronounced that tentative conclusions seem to be justified: The well-established pharmacological properties of Mifepriston as a glucocorticoid antagonist are reflected by its action on sleep physiology since it influences sleep in a direction opposite to that produced by cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1992

Modeling the pharmacokinetics and pharmacodynamics of dexamethasone in depressed patients.

Changes in time course effected by cortisol suppression and the relationship of these changes to the plasma dexamethasone concentration of suppressor and non-suppressor patients are described in this report on a combined pharmacokinetic-pharmacodynamic model. Thirteen depressed patients (8 suppressors and 5 non-suppressors) received an intravenous dose (1.5 mg) of dexamethasone. The drug-induced effect changes are found to lag behind, in time, the plasma drug level changes. To accurately relate the temporal relationship of effect changes to plasma dexamethasone levels, a pharmacodynamic model (sigmoid-Emax) was combined with a pharmacokinetic model that incorporated an effect compartment. The magnitude of the time-lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma dexamethasone levels (t1/2keo). The t1/2keo of the nonsuppressing group was about 50% of that of the suppressing group, indicating that for a given plasma level the onset and termination of effect for the nonsuppressing group is about two times more rapid than for the suppressing group. Moreover, the model can estimate the effect-site concentration that causes one-half of the maximal predicted effect (EC50), a measure of an individual's sensitivity to dexamethasone. The receptor sensitivity (as determined from the EC50 ratio) of the suppressing group was about twice that of the nonsuppressing group.

Depression↗
PubMed1992

Atrial natriuretic factor inhibits the CRH-stimulated secretion of ACTH and cortisol in man.

Corticotrophic secretion of ACTH is stimulated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), and suppressed by glucocorticoids. In vitro and preclinical studies suggest that atrial natriuretic factor (ANF) may be a peptidergic inhibitor of pituitary-adrenocortical activity. The aim of this study was to elucidate a possible role of ANF as a modulator of ACTH release in humans. A bolus injection of 100 micrograms human CRH (hCRH) during a 30 min intravenous infusion of 5 micrograms/min human alpha atrial natriuretic factor (h alpha ANF) was administered at 19:00 to six healthy male volunteers. In comparison to saline, a blunted CRH-stimulated secretion of ACTH (mean maximum plasma level +/- SD 45 min after hCRH: saline 46.2 +/- 14.2 pg/ml, h alpha ANF 34.6 +/- 13.8 pg/ml, p-value = 0.007) and a delayed rise (10 min) in cortisol were detected. The maximum plasma cortisol levels remained nearly unchanged between saline and h alpha ANF administration (mean maximum plasma level +/- SD 60 min after hCRH: saline 182 +/- 26 ng/ml, h alpha ANF 166 +/- 54 ng/ml). No effects of h alpha ANF on basal cortisol levels were observed; in contrast, basal ACTH plasma levels were slightly reduced. Basal blood pressure and heart rate remained unaffected. In the control experiment, infusion of 3 IU AVP in the same experimental paradigm increased basal and stimulated ACTH and cortisol levels significantly in comparison to saline. These observations suggest that intravenously administered haANF inhibits the CRH-stimulated release of ACTH in man.

Adrenocorticotropic Hormone↗
PubMed1992

Brofaromine in panic disorder: a pilot study with a new reversible inhibitor of monoamine oxidase-A.

The therapeutic efficacy of brofaromine--a new reversible and short acting MAO-A inhibitor--was evaluated in 14 inpatients with a panic disorder. In an open trial, the patients were treated with placebo during the first week and with 150 mg brofaromine per day during the following four weeks. In all patients a distinct improvement in both anxiety and depressive symptoms was observed under the active drug. Treatment outcome was the same in patients with and without a concomitant major depressive episode. No side-effects of any note were reported. Our findings suggest that the MAO-A inhibitor brofaromine is an effective drug in the treatment of anxiety disorders.

Adult↗
PubMed1992

Effects of growth hormone-releasing hormone and somatostatin on sleep EEG and nocturnal hormone secretion in male controls.

When applied centrally to animals, growth hormone-releasing hormone (GHRH) stimulates slow-wave sleep (SWS), whereas somatostatin (SRIF) increases REM sleep. We investigated whether these peptides also affect the sleep EEG in humans when given intravenously by comparing polysomnographically the effects of four boluses of (1) placebo, (2) 50 micrograms GHRH or (3) 50 micrograms SRIF administered at 22.00, 23.00, 24.00 and 1.00 h to 7 male controls. In addition, we collected blood samples through a long catheter every 20 min from 22.00 to 7.00 h and measured plasma cortisol and growth hormone (GH) levels. In comparison with SRIF and placebo, GHRH produced a significant increase in plasma GH concentration throughout the night (mean +/- SD: 10.8 +/- 2.0 ng/ml after GHRH; 3.0 +/- 1.7 ng/ml after SRIF and 3.2 +/- 2.0 ng/ml after placebo). SRIF failed to substantially attenuate the nocturnal GH release. Nocturnal cortisol secretion was blunted after GHRH but remained unaffected by SRIF (61.4 +/- 12.9 ng/ml after placebo; 46.6 +/- 19.7 ng/ml after GHRH and 70.8 +/- 12.6 ng/ml after SRIF). Quantitative sleep EEG staging showed a significant increase in SWS after GHRH administration but no change after SRIF (percent spent in SWS per night: 14.0 +/- 5.6 after placebo, 20.2 +/- 6.6 after GHRH and 15.1 +/- 8.2 after SRIF). Application of SRIF was accompanied by a trend toward increased REM density. The effects of episodic GHRH administration upon SWS, GH and cortisol secretion were opposite to those previously reported for corticotropin-releasing hormone, which supports the view that neuroregulation of human sleep involves an interaction of central GHRH and corticotropin-releasing hormone.

Adult↗
PubMed1991

Savoxepine: invalidation of an "atypical" neuroleptic response pattern predicted by animal models in an open clinical trial with schizophrenic patients.

The new tetracyclic compound savoxepine exhibits potent antidopaminergic effects with preferential activity in the hippocampus as compared to striatum in rat brain. As a result of behavioural animal models and regional differences in dopamine receptor binding characteristics, it has been suggested to possess an "atypical" neuroleptic response pattern. In an open clinical trial, savoxepine was administered to 12 in-patients suffering from paranoid schizophrenia and schizophreniform disorder (DSM-III). Eight patients were treated with a stable dose of 0.5 mg per day throughout the study, while in the remaining patients higher doses up to 20 mg/day were administered. Mean total BPRS scores and subscores demonstrated a moderate improvement of mainly positive schizophrenic symptoms. In contrast to animal test results, savoxepine in a broad dose range produced typical untoward extrapyramidal symptoms in the majority of patients. Our results indicate that savoxepine may not possess the expected "atypical" neuroleptic response pattern, and that the predictive validity of the animal models in question used to separate antipsychotic effects from extrapyramidal reactions may be ill-founded.

Adult↗