Mirtazapine decreases stimulatory effects of reboxetine on cortisol, adrenocorticotropin and prolactin secretion in healthy male subjects

Reboxetine is a selective noradrenaline reuptake inhibitor, whereas mirtazapine acts as an antagonist at noradrenergic alpha(2), serotonin (5-HT2), 5-HT3 and histamine H-1 receptors. In a former study we could demonstrate an inhibitory impact of mirtazapine on cortisol secretion. In the present investigation, the influence of combined administration of 15 mg mirtazapine and 4 mg reboxetine on the cortisol ( COR), adrenocorticotropin ( ACTH), growth hormone (GH), and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to reboxetine alone ( 4 mg). In a randomized order, the subjects received reboxetine ( 4 mg) alone or the combination of reboxetine ( 4 mg) and mirtazapine ( 15 mg) at 8: 00 a. m. on two different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to the administration of single reboxetine or the combination ( reboxetine and mirtazapine), at time of administration, and during the time of 5 h thereafter in periods of 30 min. Serum concentrations of COR, GH, and PRL as well as plasma levels of ACTH were determined in each blood sample by means of double antibody RIA, fluoroimmunoassay and chemiluminescence immunometric assay methods. The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. For statistical evaluation, the Wilcoxon signed-ranks test was performed. There was a pronounced stimulation of COR, ACTH, GH, and PRL concentrations after single administration of reboxetine. When reboxetine was given in combination with mirtazapine, a significant reduction of the COR, ACTH, and PRL stimulation was observed whereas GH secretion patterns remained unchanged, compared to single administration of reboxetine. Apparently, the stimulatory effects of reboxetine on pituitary hormone secretion via noradrenergic mechanisms are counteracted in part by the alpha(2)-blocking properties of mirtazapine and its inhibitory influence on cortisol secretion. Copyright (C) 2004 S. Karger AG, Basel

Polymer compositions suitable for use in enriched oxygen atmospheres

Three organic polymer systems are based on copolymer of chlorotrifluoroethylene, ethylene, and tin-based flame retardants. Fourth system is copolymer of chlorotrifluorethylene and tetrafluoroethylene. This system contains no stabilizers of flame retardant additives

Influence of mirtazapine on salivary cortisol in depressed patients

Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin but acts as an antagonist at presynaptic alpha(2)-receptors, at postsynaptic 5-HT2 and 5-HT3 receptors, and at histaminergic H1 receptors. Furthermore, mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on salivary cortisol secretion was investigated in 12 patients (4 men, 8 women) suffering from major depression according to DSM-IV criteria. Patients were treated with mirtazapine for 3 weeks, receiving 15 mg mirtazapine on day 0, 30 mg on day 1 and 45 mg per day from day 2 up to the end of the study (day 21). Response to mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary cortisol concentrations were measured before treatment (day -1), at the beginning of treatment (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 08.00 until 20.00 h. The area under the curve values served as parameter for the salivary cortisol secretion. Following analysis of variance with a repeated measures design, tests with contrasts revealed a significant reduction of cortisol concentrations already after 1 day of mirtazapine treatment that was comparable in responders and nonresponders. In addition to new pharmacological approaches such as CRH1 receptor antagonists, mirtazapine therefore appears to be an effective strategy to decrease hypercortisolism and restore HPA system dysregulation in depression. However, the importance of the acute inhibitory effects of mirtazapine on cortisol secretion for its antidepressant efficacy has to be further clarified. Copyright (C) 2003 S. Karger AG, Basel

grain prices, borders and nationalism in the Habsburg economy before the First World War

This paper explores the pre-First World War Austro-Hungarian economy as a prominent case where growing conflict between various ethnic and national groups within an empire might have contributed to the emergence of internal borders and even its eventual dissolution. To this end we adopt an Engel-and- Rogers–type approach to examine on an annual basis the extent of co-movements in grain prices across a sample of ten regional capital cities in the empire and over the period 1877-1910. There are two key findings. First, the political borders that emerged from 1918 onwards became visible in the price dynamics of grain markets already 20 years before the Great War. Second, this effect of a “border before a border” can be explained by the extent of language heterogeneity across the various parts of the Habsburg Empire. These results raise several important questions about both the forces that shaped pre-war market integration as well as the economic costs of breaking up the Habsburg customs union after 1918

Endocrinological effects of high-dose Hypericum perforatum extract WS 5570 in healthy subjects

In this single-blind study, the effects of acute oral administration of high-dose Hypericum perforatum extract WS 5570 on the cortisol ( COR), adrenocorticotropic hormone ( ACTH), growth hormone (GH), and prolactin (PRL) secretions were examined in 12 healthy male volunteers. In a randomized order, the subjects received placebo or WS 5570 at several dosages (600, 900, and 1,200 mg) at 08.00 h on 4 different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to administration of placebo or WS 5570 ( 600, 900, or 1,200 mg), at the time of administration, and during 5 h thereafter at intervals of 30 min. The serum concentrations of COR, GH, and PRL as well as the plasma levels of ACTH were determined in each blood sample by means of double antibody radioimmunoassay, fluoroimmunoassay, and chemiluminescence immunometric assay methods. The area under the curve value was used as parameter for COR, ACTH, GH, and PRL responses. Repeated-measures Anova revealed a significant stimulatory effect of WS 5570 on the ACTH secretion, whereas COR and PRL secretions were not significantly influenced. Moreover, there was a stimulatory peak of GH release 240 min after challenge with WS 5570 in some but not all volunteers, without reaching statistical significance in comparison with placebo. Mean arterial blood pressure and heart rate remained unchanged after administration of WS 5570. Apparently, WS 5570 at the dosages given in this study inconsistently causes endocrinological effects in healthy subjects by influencing central neurotransmitters. Copyright (C) 2004 S. Karger AG, Basel

Impact of Gene-Gender Effects of Adrenergic Polymorphisms on Hypothalamic-Pituitary-Adrenal Axis Activity in Depressed Patients

Objective: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. Methods: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of alpha 2-adrenoceptor (ADRA2A -1291C -> G) and the beta 2-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. Results: Male ADRA2A -1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. Conclusions: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders. Copyright (c) 2008 S. Karger AG, Base

Neuroactive steroids in depression and anxiety disorders: Clinical studies

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3 alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium of 3 alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3 alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone. The modulation of GABA(A) receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds. Copyright (c) 2006 S. Karger AG, Basel

FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner

TNF receptor–associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-κB (RANK). This event is central to normal osteoclastogenesis. We discovered that TRAF6 also interacts with FHL2 (four and a half LIM domain 2), a LIM domain–only protein that functions as a transcriptional coactivator or corepressor in a cell-type–specific manner. FHL2 mRNA and protein are undetectable in marrow macrophages and increase pari passu with osteoclast differentiation in vitro. FHL2 inhibits TRAF6-induced NF-κB activity in wild-type osteoclast precursors and, in keeping with its role as a suppressor of TRAF6-mediated RANK signaling, TRAF6/RANK association is enhanced in FHL2(–/–) osteoclasts. FHL2 overexpression delays RANK ligand–induced (RANKL-induced) osteoclast formation and cytoskeletal organization. Interestingly, osteoclast-residing FHL2 is not detectable in naive wild-type mice, in vivo, but is abundant in those treated with RANKL and following induction of inflammatory arthritis. Reflecting increased RANKL sensitivity, osteoclasts generated from FHL2(–/–) mice reach maturation and optimally organize their cytoskeleton earlier than their wild-type counterparts. As a consequence, FHL2(–/–) osteoclasts are hyperresorptive, and mice lacking the protein undergo enhanced RANKL and inflammatory arthritis–stimulated bone loss. FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Regulation of Human Bone Marrow Stromal Cell Proliferation and Differentiation Capacity by Glucocorticoid Receptor and AP-1 Crosstalk

Although marrow adipocytes and osteoblasts derive from a common bone marrow stromal cells (BMSCs), the mechanisms that underlie osteoporosis-associated bone loss and marrow adipogenesis during prolonged steroid treatment are unclear. We show in human BMSCs (hBMSCs) that glucocorticoid receptor (GR) signaling in response to high concentrations of glucocorticoid (GC) supports adipogenesis but inhibits osteogenesis by reducing c-Jun expression and hBMSC proliferation. Conversely, significantly lower concentrations of GC, which permit hBMSC proliferation, are necessary for normal bone mineralization. In contrast, platelet-derived growth factor (PDGF) signaling increases both JNK/c-Jun activity and hBMSC expansion, favoring osteogenic differentiation instead of adipogenesis. Indeed, PDGF antagonizes the proadipogenic qualities of GC/GR signaling. Thus our results reveal a novel c-Jun-centered regulatory network of signaling pathways in differentiating hBMSCs that controls the proliferation-dependent balance between osteogenesis and adipogenesis