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Sample records for topical glucocorticoid budesonide

  1. Tachyphylaxis to topical glucocorticoids; what is the evidence?

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    Taheri, Arash; Cantrell, Jacob; Feldman, Steven R.

    2013-01-01

    Background: Common belief holds that as topical glucocorticoids are used over time the less effective they become, a phenomenon called tolerance or tachyphylaxis. Objective: To determine what evidence supports the concept of tachyphylaxis to glucocorticoids. Methods: We searched Medline and Google Scholar for articles on tachyphylaxis to glucocorticoids published through October 2012. Results: Rapid tolerance, tac...

  2. Use of topical glucocorticoids: a population-based cohort study.

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    El-Khoury, M; Thay, R; N'Diaye, M; Fardet, L

    2017-06-01

    Little is known about the prescriptions of topical glucocorticoids in the general population. To report an overall picture of topical glucocorticoid prescriptions in France. This study used the Echantillon Généraliste de Bénéficiaires (EGB) database, a 1/97th random sampling of the French population covered by the main national healthcare insurance system (approximately 90% of the whole population). All patients prescribed topical glucocorticoids over a 5-year period (1 January 2011 to 31 December 2015) were identified using a specific code list for topical glucocorticoids. Over the 5-year study period, 662 531 individuals were recorded for at least 1 day in the EGB. Among them, 220 345 (33.3%) were prescribed at least once topical glucocorticoid. The prevalence of topical glucocorticoid prescription increased regularly from 2011 (11.7%) to 2015 (12.5%). A total of 922 026 tubes of topical glucocorticoids were dispensed, mainly high-potency glucocorticoids, and were mainly prescribed by general practitioners (73.1%). A total of 1713 (0.8%) patients were prescribed at least 24 tubes over a calendar year. These patients were more frequently men (P glucocorticoids. The 124 844 tubes prescribed to these patients had stronger potency than those prescribed to the overall population (P glucocorticoids at least once each year. Most prescriptions are issued by general practitioners, dermatologists being the prescribers in less than one-quarter of cases. © 2017 European Academy of Dermatology and Venereology.

  3. Budesonide multi-matrix system formulation for treating ulcerative colitis.

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    Prantera, Cosimo; Scribano, Maria Lia

    2014-04-01

    Budesonide is a corticosteroid characterized by high topical activity and low systemic effect associated with fewer glucocorticoid-related adverse events than conventional steroids. Differently from Crohn's disease, no evidence suggests that oral budesonide is effective for the induction of remission of ulcerative colitis (UC). Budesonide multi-matrix (MMX) system is a new oral preparation that, by employing a MMX, provides the release of the drug throughout the entire colon. Its efficacy in inducing UC remission, at a dose of 9 mg, is based on some recent trials. However, in two studies the absolute differences between budesonide MMX and placebo were much lower than the rate of success reported in previous trials with mesalazines. In addition, the therapeutic advantage of budesonide MMX 9 mg over 5-aminosalicylic acid (5-ASA) showed by one study, and the advantage of budesonide MMX over budesonide reported in the other study, was only 5.8 and 4.8%, respectively. The evidence supporting the use of budesonide MMX at a dose of 6 mg for maintenance is weak. Therefore, the effective dosage should be 9 mg also in maintenance, but not for > 4 - 6 months, because a prolonged treatment has showed to increase the rate of side effects.

  4. Topical therapy with high-volume budesonide nasal irrigations in difficult-to-treat chronic rhinosinusitis.

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    Kosugi, Eduardo Macoto; Moussalem, Guilherme Figner; Simões, Juliana Caminha; Souza, Rafael de Paula e Silva Felici de; Chen, Vitor Guo; Saraceni Neto, Paulo; Mendes Neto, José Arruda

    2016-01-01

    Chronic rhinosinusitis (CRS) is termed difficult-to-treat when patients do not reach acceptable level of control despite adequate surgery, intranasal corticosteroid treatment and up to 2 short courses of systemic antibiotics or corticosteroids in the preceding year. Recently, high-volume corticosteroid nasal irrigations have been recommended for CRS treatment. To assess high-volume budesonide nasal irrigations for difficult-to-treat CRS. Prospective uncontrolled intervention trial. Participants were assessed before- and 3 months after nasal irrigation with 1mg of budesonide in 500 mL of saline solution daily for 2 days. Subjective (satisfactory clinical improvement) and objective (SNOT-22 questionnaire and Lund-Kennedy endoscopic scores) assessments were performed. Sixteen patients were included, and 13 (81.3%) described satisfactory clinical improvement. SNOT-22 mean scores (50.2-29.6; p=0.006) and Lund-Kennedy mean scores (8.8-5.1; p=0.01) improved significantly. Individually, 75% of patients improved SNOT-22 scores, and 75% improved Lund-Kennedy scores after high volume budesonide nasal irrigations. High-volume corticosteroid nasal irrigations are a good option in difficult-to-treat CRS control of disease, reaching 81.3% success control and significant improvement of SNOT-22 and Lund-Kennedy scores. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  5. Active eosinophilic esophagitis is associated with impaired elimination of budesonide by cytochrome P450 3A enzymes.

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    Dilger, Karin; Lopez-Lazaro, Luis; Marx, Claudia; Bussmann, Christian; Straumann, Alex

    2013-01-01

    Topically administered glucocorticoids such as budesonide have the potential of being established as first-line medical treatment of eosinophilic esophagitis (EoE). Safety of budesonide is based on high elimination by cytochrome P450 3A (CYP3A) enzymes. We aimed to investigate systemic absorption and elimination of a new budesonide formulation in patients with active EoE in comparison with healthy controls. After single and multiple doses of orodispersible budesonide (4 mg/day) the parent drug, its CYP3A-dependent metabolites, and endogenous cortisol were determined in 12 adult patients with active EoE and 12 healthy controls. An approved ileal-release formulation of budesonide was taken for reference. Molar ratios of metabolite formation in plasma were used as indices of CYP3A metabolic function. CYP3A-dependent metabolite formation was significantly reduced in patients with active EoE as compared to healthy controls. Impaired biotransformation was reflected by a significantly higher extent of budesonide absorption and elongated elimination half-life in EoE patients. Comparison of morning serum cortisol levels at baseline with those after 1 week of treatment with budesonide revealed a significant decrease in EoE patients but not in healthy subjects. Active EoE is associated with reduced elimination of budesonide via CYP3A, the major subfamily of drug-metabolizing enzymes in humans. Copyright © 2013 S. Karger AG, Basel.

  6. Iatrogenic Cushing's Syndrome Due to Topical Ocular Glucocorticoid Treatment.

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    Fukuhara, Daisuke; Takiura, Toshihiko; Keino, Hiroshi; Okada, Annabelle A; Yan, Kunimasa

    2017-02-01

    Iatrogenic Cushing's syndrome (CS) is a severe adverse effect of systemic glucocorticoid (GC) therapy in children, but is extremely rare in the setting of topical ocular GC therapy. In this article, we report the case of a 9-year-old girl suffering from idiopathic uveitis who developed CS due to topical ocular GC treatment. She was referred to the ophthalmology department with a complaint of painful eyes, at which time she was diagnosed with bilateral iridocyclitis and started on a treatment of betamethasone sodium phosphate eye drops. Six months after the initiation of topical ocular GC treatment, she was referred to our pediatric department with stunted growth, truncal obesity, purple skin striate, buffalo hump, and moon face. Because her serum cortisol and plasma adrenocorticotropic hormone levels were undetectable, she was diagnosed with iatrogenic CS. After the doses of topical ocular GC were reduced, the clinical symptoms of CS were improved. The fact that the amount of topical ocular GC with our patient was apparently less than that of similar previous cases tempted us to perform genetic analysis of her NR3C1 gene. We found that our patient had a single heterozygous nucleotide substitution in the 3' untranslated region of the NR3C1 gene, which may explain why she developed CS. However, additional investigations are required to determine if our findings can be extrapolated to other patients. In conclusion, clinicians should be aware that even extremely low doses of topical ocular steroid therapy can cause iatrogenic CS. Copyright © 2017 by the American Academy of Pediatrics.

  7. REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids.

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    Baida, Gleb; Bhalla, Pankaj; Kirsanov, Kirill; Lesovaya, Ekaterina; Yakubovskaya, Marianna; Yuen, Kit; Guo, Shuchi; Lavker, Robert M; Readhead, Ben; Dudley, Joel T; Budunova, Irina

    2015-01-01

    Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress-inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down-regulation of genes involved in anti-inflammatory glucocorticoid response was strikingly similar in wild-type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid-dependent and glucocorticoid-independent atrophy. Importantly, the lack of REDD1 did not diminish the anti-inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid-based therapies. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  8. Topical glucocorticoid has no antinociceptive or anti-inflammatory effect in thermal injury

    DEFF Research Database (Denmark)

    Pedersen, J L; Møiniche, S; Kehlet, H

    1994-01-01

    We have studied the antinociceptive and anti-inflammatory effects of topical glucocorticoids in human thermal injury. The right and left legs of 12 healthy volunteers were allocated randomly to be treated with either 0.05% clobetasol propionate cream or placebo in a double-blind trial. Thermal...... injury caused a decrease in HPDT, HPT and MPDT, an increase in EI and development of mechanical, secondary hyperalgesia. Clobetasol propionate had no effect on any of the nociceptive or inflammatory variables studied....

  9. Adrenal function in asthmatic children treated with inhaled budesonide

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    Bisgaard, H; Pedersen, S; Damkjaer Nielsen, M

    1991-01-01

    The effect of the inhaled topical steroid budesonide on adrenal function was evaluated in 33 children (aged 7-15 years) with moderate bronchial asthma. The trial was designed as a prospective single-blind study of the effect of budesonide in daily doses of 200 microgram through 400 microgram to 8...

  10. Iatrogenic Cushing's syndrome related to the interaction between oral budesonide with fluvoxamine: a case report.

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    Martin, C S; Blaga, C; Lambrescu, I M; Fierbințeanu-Braticevici, C; Fica, S

    2015-08-06

    Budesonide, an oral glucocorticoid indicated for the treatment of Crohn's disease, rarely interferes with the hypothalamic-pituitary-adrenal axis because more than 80% of it is metabolized by cytochrome P450 enzymes. A 33-year-old female patient diagnosed with Crohn's disease, treated with oral budesonide, was admitted for Cushingoid symptoms and signs. The onset coincided with the use of fluvoxamine, a serotonin reuptake inhibitor and also a potent inhibitor of cytochrome P450 enzymes that presumably led to budesonide accumulation. Practitioners should take into consideration the possibility of iatrogenic Cushing's syndrome caused by the association of oral budesonide with a P450 cytochrome inhibitor. © 2015 John Wiley & Sons Ltd.

  11. In vivo characterization of structural changes after topical application of glucocorticoids in healthy human skin

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    Jung, Sora; Lademann, Jürgen; Darvin, Maxim E.; Richter, Claudia; Pedersen, Claus Bang; Richter, Heike; Schanzer, Sabine; Kottner, Jan; Blume-Peytavi, Ulrike; Røpke, Mads Almose

    2017-07-01

    Topical glucocorticoids (GC) are known to induce changes in human skin with the potential to develop skin atrophy. Here, atrophogenic effects and subsequent structural changes in the skin after topical application of GC were investigated in vivo. Sixteen healthy volunteers were topically treated daily on the forearms with clobetasol propionate, betamethasone dipropionate, and the petrolatum vehicle for 4 weeks. All treated skin areas and a nontreated control area were examined by ultrasound, optical coherence tomography, confocal laser scanning microscopy, multiphoton tomography (MPT), and resonance Raman spectroscopy at baseline 1 day after last application and 1 week after last application. Investigated parameters included stratum corneum thickness, epidermal, and full skin thickness, keratinocyte size and density, keratinocyte nucleus-to-cytoplasm ratio, skin surface classification, relative collagen and elastin signal intensity, second-harmonic generation-to-autofluorescence aging index of dermis (SAAID), and the antioxidant status of the skin. A reduction in epidermal and dermal skin thickness was observed in GC treated as well as in vehicle-treated and untreated skin areas on the volar forearm. MPT analysis showed an increased epidermal cell density and reduced cell size and nucleus-to-cytoplasm ratio and a significant increase of SAAID after GC treatment indicating a restructuring or compression of collagen fibers clinically being observed as atrophic changes.

  12. Budesonide Oral Inhalation

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    ... if they get worse.Budesonide helps to prevent asthma attacks (sudden episodes of shortness of breath, wheezing, and coughing) but will not stop an asthma attack that has already started. Your doctor will prescribe ...

  13. Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review.

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    Dahl, J B; Nielsen, R V; Wetterslev, J; Nikolajsen, L; Hamunen, K; Kontinen, V K; Hansen, M S; Kjer, J J; Mathiesen, O

    2014-11-01

    In contemporary post-operative pain management, patients are most often treated with combinations of non-opioid analgesics, to enhance pain relief and to reduce opioid requirements and opioid-related adverse effects. A diversity of combinations is currently employed in clinical practice, and no well-documented 'gold standards' exist. The aim of the present topical, narrative review is to provide an update of the evidence for post-operative analgesic efficacy with the most commonly used, systemic non-opioid drugs, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs)/COX-2 antagonists, glucocorticoids, gabapentinoids, and combinations of these. The review is based on data from previous systematic reviews with meta-analyses, investigating effects of non-opioid analgesics on pain, opioid-requirements, and opioid-related adverse effects. Paracetamol, NSAIDs, COX-2 antagonists, and gabapentin reduced 24 h post-operative morphine requirements with 6.3 (95% confidence interval: 3.7 to 9.0) mg, 10.2 (8.7, 11.7) mg, 10.9 (9.1, 12.8) mg, and ≥ 13 mg, respectively, when administered as monotherapy. The opioid-sparing effect of glucocorticoids was less convincing, 2.33 (0.26, 4.39) mg morphine/24 h. Trials of pregabalin > 300 mg/day indicated a morphine-sparing effect of 13.4 (4, 22.8) mg morphine/24 h. Notably, though, the available evidence for additive or synergistic effects of most combination regimens was sparse or lacking. Paracetamol, NSAIDs, selective COX-2 antagonists, and gabapentin all seem to have well-documented, clinically relevant analgesic properties. The analgesic effects of glucocorticoids and pregabalin await further clarification. Combination regimens are sparsely documented and should be further investigated in future studies. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  14. Topical glucocorticoids and the skin-mechanisms of action: an update

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    A. Ahluwalia

    1998-01-01

    Full Text Available The topical glucocorticoids (GCs represent the treatment of choice for many types of inflammatory dermatoses. Despite the extensive use of this class of drugs as first line therapy the mechanism of their action is uncertain. It is clear that the multiplicity of actions of the topical GCs is an important facet of their scope in the treatment of dermal disorders. The aim of this update is to review past and current theories regarding how these agents might work. Current understanding of the molecular mechanism s of GC action has advanced significantly over the past decade with the realisation that multiple systems are responsible for transduction of GC effects at a molecular level. The two primary modes of action are via interaction directly with DNA or indirectly through modulation of specific transcription factors: the endpoint in both cases being modulation of specific protein synthesis. Both of these mechanisms will be discussed. In particular this review will concentrate on the possibility that a GC-inducible protein, termed lipocortin 1, may have a significant role to play in the anti-inflammatory actions of these drugs. Additionally it has become apparent that several inflammatory enzymes induced in inflamm ation are sites of inhibitory action of the GCs, and the possibility that this occurs in the skin will be discussed paying particular attention to the inducible phospholipase A2, nitric oxide synthase and cyclooxygenase systems.

  15. The Use of Budesonide in the Treatment of Autoimmune Hepatitis in Canada

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    Iman Zandieh

    2008-01-01

    Full Text Available BACKGROUND: Autoimmune hepatitis (AIH is a chronic inflammatory disease that is successfully treated with prednisone and/or azathioprine immunosuppressive therapy in 70% to 80% of patients. The remaining patients are intolerant or refractory to these standard medications. Budesonide, a synthetic glucocorticoid, undergoes a high degree of first-pass metabolism, reducing its systemic bioavailability, and has a 15-fold greater affinity for the glucocorticoid receptor than prednisolone. Budesonide may be a potentially useful systemic steroid-sparing immunosuppressive agent in the treatment of AIH.

  16. Adverse effects of perioperative paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review

    DEFF Research Database (Denmark)

    Mathiesen, O; Wetterslev, J; Kontinen, V K

    2014-01-01

    with the most common perioperative non-opioid analgesics: paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCCs), gabapentinoids and their combinations. The review is based on data from systematic reviews with meta-analyses of analgesic efficacy and/or adverse effects...... of perioperative non-opioid analgesics, and randomised trials and cohort/retrospective studies. Generally, data on AE are sparse and related to the immediate post-operative period. For paracetamol, the incidence of AEs appears trivial. Data are inconclusive regarding an association of NSAIDs with mortality...

  17. Long-term safety and efficacy of budesonide nasal aerosol in perennial rhinitis. A 12-month multicentre study.

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    Lindqvist, N; Balle, V H; Karma, P; Kärjä, J; Lindström, D; Mäkinen, J; Pukander, J; Ruoppi, P; Suonpää, J; Ostlund, W

    1986-04-01

    A long-term safety study of intranasally administered budesonide, a topical glucocorticoid, has been performed. 104 patients with perennial rhinitis, allergic or non-allergic, participated in a multicentre study in seven ENT-clinics utilising an identical protocol. A budesonide dosage of 400 micrograms/day was used as starting dose, but the patients were at liberty to reduce the daily dose to 200 micrograms. The patients were observed at intervals up to 12 months. At the entry and follow-up visits the following parameters were recorded: rhinoscopic findings, nasal symptom scores, blood chemistry, hematology, urinalysis and determination of plasma cortisol levels before and after stimulation with ACTH (Synacthen). Nasal biopsies taken from 50 of the patients at the beginning and completion of the study were examined in a blinded way by an independent pathologist. The analysis revealed no histopathological changes of the nasal mucosa. At rhinoscopy no signs of atrophy or candida were reported. Lividity of the nasal mucosa was significantly reduced during the trial, which was also the case for nasal congestion and secretion. All nasal symptom parameters assessed by the patients were significantly reduced from baseline during the follow-up period. No clinically significant changes in the hematological and blood chemistry parameters were observed. Plasma cortisol analysis before and after challenge with ACTH revealed no influence on the hypothalamic pituitary adrenal axis. No tachyphylaxis was observed; on the contrary, there was a clear tendency for reduction of the daily dose of budesonide necessary to keep the patients symptom-free.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Two-week inhalation of budesonide increases muscle Na,K ATPase content but not endurance in response to terbutaline in men

    DEFF Research Database (Denmark)

    Nielsen, Morten Hostrup; Onslev, Johan; Jessen, Søren Kaare

    2017-01-01

    While chronic systemic administration of glucocorticoids increases muscle Na+ ,K+ ATPase content, such effect is unexplored after therapeutic inhalation. We investigated the effect of therapeutic inhalation of the glucocorticoid budesonide on Na+ ,K+ ATPase content of skeletal muscle in men. Ten...... healthy trained subjects, aged 23 ± 4 years (mean ± 95% CI), participated in the study. Before and after 2 weeks of daily inhalation of budesonide (1.6 mg/day), a biopsy was taken from the vastus lateralis muscle for measurement of Na+ ,K+ ATPase content and blood samples were drawn for determination...... of plasma budesonide, cortisol, and K+ . Subjects' performance during cycling to fatigue at 90% of incremental peak power output (iPPO) was measured in response to 4 mg inhaled terbutaline to maximally stimulate Na+ ,K+ ATPase activity. Plasma concentrations of budesonide rose to 5.0 ± 1.6 n...

  19. Two-week inhalation of budesonide increases muscle Na,K ATPase content but not endurance in response to terbutaline in men

    DEFF Research Database (Denmark)

    Hostrup, M.; Jessen, S.; Onslev, J.

    2017-01-01

    While chronic systemic administration of glucocorticoids increases muscle Na+,K+ ATPase content, such effect is unexplored after therapeutic inhalation. We investigated the effect of therapeutic inhalation of the glucocorticoid budesonide on Na+,K+ ATPase content of skeletal muscle in men. Ten...... healthy trained subjects, aged 23 ± 4 years (mean ± 95% CI), participated in the study. Before and after 2 weeks of daily inhalation of budesonide (1.6 mg/day), a biopsy was taken from the vastus lateralis muscle for measurement of Na+,K+ ATPase content and blood samples were drawn for determination...... of plasma budesonide, cortisol, and K+. Subjects' performance during cycling to fatigue at 90% of incremental peak power output (iPPO) was measured in response to 4 mg inhaled terbutaline to maximally stimulate Na+,K+ ATPase activity. Plasma concentrations of budesonide rose to 5.0 ± 1.6 n...

  20. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking

    NARCIS (Netherlands)

    Pauwels, RA; Lofdahl, CG; Laitinen, LA; Schouten, JP; Postma, DS; Pride, NB; Ohlsson, SV

    1999-01-01

    Background and Methods Although patients with chronic obstructive pulmonary disease (COPD) should stop smoking, some do not. In a double-blind, pla cebo-controlled study, we evaluated the effect of the inhaled glucocorticoid budesonide in subjects with mild COPD who continued smoking. After a

  1. Efficacy and safety of budesonide/formeterol combination therapy in asthma patients.

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    Jakopović, Marko; Pavicić, Fadila; Redzepi, Gzim; Plestina, Sanja; Janković, Mateja; Franić, Zrinka; Samija, Mirko; Samarzija, Miroslav

    2009-06-01

    Budesonide/formoterol as single inhaler was developed for treating asthma patients who are not adequately controlled on glucocorticoides alone. The aim of this study was to evaluate efficacy, safety and patient/physician satisfaction of budesonide/formoterol therapy.Total of 268 asthma patients (120 men, mean age 38.8 +/- 37.2 years, and 148 women, mean age 42.2 +/- 32 years) were included in the study. All patients received budesonide/formoterol bid (640 mcg of budesonide and 18 mcg of formoterol daily) during run-in period for three weeks. Patients were followed during 14 weeks at 5 visits. At each visit lung function (FEV1 and PEF) was measured,presence of side affects was recorded and questionnaire was given to patients and physicians to estimate the level of satisfaction with budesonide/formoterol therapy (1 very unsatisfied to 5 very satisfied). Significant improvement was noticed in FEV1, from 76.25% of predicted value to 86.94% (p < 0.01); and in PEF from 380.84 L/min to 442.29 L/min (p < 0.01) in all patients. At the end of the study patients' satisfaction with budesonide/formeterol therapy was significantly improved comparing with satisfaction with previously taken therapy, in average grade, from 2.94 to 4.56 (p < 0.01), and similar results were noticed with physicians' satisfaction, from 2.60 to 4.41 (p < 0.01). Budesonide/formoterol in single inhaler, significantly improved lung function in patients with asthma.

  2. Budesonide-induced periorificial dermatitis presenting as chalazion and blepharitis.

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    Henningsen, Emil; Bygum, Anette

    2011-01-01

    We report a case of periorificial dermatitis caused by suboptimal inhalation of budesonide for asthma. The initial skin lesions presented in the eye surroundings, leading to diagnostic difficulties and treatment of presumed chalazion and staphylococcal folliculitis. After several months, the patient developed perioral papules and pustules and was diagnosed with periorificial dermatitis. He was efficiently treated with topical metronidazole and oral erythromycin. © 2011 Wiley Periodicals, Inc.

  3. Budesonide added to modified porcine surfactant Curosurf may additionally improve the lung functions in meconium aspiration syndrome.

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    Mikolka, P; Mokrá, D; Kopincová, J; Tomčíková-Mikušiaková, L; Calkovská, A

    2013-01-01

    Severe meconium aspiration syndrome (MAS) in newborns is often treated by exogenous surfactant. Because its efficacy is reduced by meconium-induced inflammation, glucocorticoid budesonide was added into surfactant preparation Curosurf to enhance efficacy of the surfactant therapy in experimental model of MAS. Oxygen-ventilated rabbits were intratracheally given meconium (25 mg/ml, 4 ml/kg) to induce respiratory failure. Thirty minutes later, animals were treated by intratracheal budesonide (0.25 mg/kg) or surfactant lung lavage (10 ml/kg, 5 mg phospholipids/ml) repeated twice, followed by undiluted Curosurf (100 mg phospholipids/kg) or by the above mentioned surfactant treatment with the last surfactant dose fortified with budesonide (0.25 mg/kg) or were untreated. Animals were ventilated for additional 5 hours and respiratory parameters were measured regularly. After sacrificing animals, wet-dry lung weight ratio was evaluated and plasma levels of interleukins (IL)-1beta, -6, -8, and TNF-alpha were measured by ELISA method. Efficacy of the given therapies to enhance lung functions and to diminish lung edema formation and inflammation increased from budesonide-only and surfactant-only therapy to surfactant+budesonide therapy. Combined therapy improved gas exchange from 30 min of administration, and showed a longer-lasting effect than surfactant-only therapy. In conclusions, budesonide additionally improved the effects of exogenous surfactant in experimental MAS.

  4. Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2

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    Wang X

    2013-08-01

    Full Text Available Xingqi Wang,1 Amy Nelson,1 Zachary M Weiler,1 Amol Patil,1 Tadashi Sato,1 Nobuhiro Kanaji,1 Masanori Nakanishi,1 Joel Michalski,1 Maha Farid,1 Hesham Basma,1 Tricia D LeVan,1 Anna Miller-Larsson,2 Elisabet Wieslander,2 Kai-Christian Muller,3 Olaf Holz,3 Helgo Magnussen,3 Klaus F Rabe,3 Xiangde Liu,1 Stephen I Rennard1 1Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 2AstraZeneca R&D Molndal, Molndal, Sweden; 3Hospital Grosshansdorf, Center for Pneumology and Thoracic Surgery, Grosshansdorf, Germany Objective and design: Reduced expression of histone deacetylase 2 (HDAC2 in alveolar macrophages and epithelial cells may account for reduced response of chronic obstructive pulmonary disease (COPD patients to glucocorticoids. HDAC2 expression and its role in mediating glucocorticoid effects on fibroblast functions, however, has not been fully studied. This study was designed to investigate whether HDAC2 mediates glucocorticoid effects on release of inflammatory cytokines and matrix metalloproteinases (MMPs from human lung fibroblasts. Methods: Human lung fibroblasts (HFL-1 cells were stimulated with interleukin (IL-1β plus tumor necrosis factor (TNF-α in the presence or absence of the glucocorticoid budesonide. Cytokines (IL-6 and IL-8 were quantified by enzyme linked immunosorbent assay (ELISA and MMPs (MMP-1 and MMP-3 by immunoblotting in culture medium. The role of HDAC2 was investigated using a pharmacologic inhibitor as well as a small interfering ribonucleic acid (siRNA targeting HDAC2. Results: We have demonstrated that budesonide concentration-dependently (10-10–10-7 M inhibited IL-6, IL-8, MMP-1, and MMP-3 release by HFL-1 cells in response to IL-1β plus TNF-a. While an HDAC inhibitor significantly blocked the inhibitory effect of budesonide on human bronchial epithelial cells (HBECs and monocytes (THP-1 cells, it did not block the inhibitory

  5. Effect of budesonide and azelastine on histamine signaling regulation in human nasal epithelial cells.

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    Liu, Shao-Cheng; Lin, Chun-Shu; Chen, Shyi-Gen; Chu, Yueng-Hsiang; Lee, Fei-Peng; Lu, Hsuan-Hsuan; Wang, Hsing-Won

    2017-02-01

    Both glucocorticoids and H1-antihistamines are widely used on patients with airway diseases. However, their direct effects on airway epithelial cells are not fully explored. Therefore, we use the primary culture of human nasal epithelial cells (HNEpC) to delineate in vitro mucosal responses to above two drugs. HNEpC cells were cultured with/without budesonide and azelastine. The growth rate at each group was recorded and measured as population double time (PDT). The histamine1-receptor (H1R), muscarinic1-receptor (M1R) and M3R were measured using immunocytochemistry and western blotting after 7-days treatment. Then, we used histamine and methacholine to stimulate the mucus secretion from HNEpC and observed the MUC5AC expression in culture supernatants. Concentration-dependent treatment-induced inhibition of HNEpC growth rate was observed. Cells incubated with azelastine proliferated significantly slower than that with budesonide and the combined use of those drugs led to significant PDT prolong. The immunocytochemistry showed the H1R, M1R and M3R were obviously located in the cell membrane without apparent difference after treatment. However, western blotting showed that budesonide can significantly up-regulate the H1R, M1R and M3R level while azelastine had opposite effects. Histamine and methacholine stimulated MUC5AC secretion was greater in cells treated with budesonide but was lesser in those treated with azelastine, as compared to controls. Our data suggest that both budesonide and azelastine can significantly inhibit HNEpC proliferation, and therefore, be helpful in against airway remodeling. Long-term use of budesonide might amplify histamine signaling and result in airway hyperreactivity to stimulants by enhancing H1R, M1R and M3R expression while azelastine can oppose this effect. Therefore, combined use of those two drugs in patients with chronic inflammatory airway diseases may be an ideal option.

  6. Treatment of postoperative tracheal granulation tissue with inhaled budesonide in congenital tracheal stenosis.

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    Yokoi, Akiko; Nakao, Makoto; Bitoh, Yuko; Arai, Hiroshi; Oshima, Yoshihiro; Nishijima, Eiji

    2014-02-01

    Tracheal obstruction by granulation tissue can compromise the postoperative course in congenital tracheal stenosis (CTS). Balloon dilatation and stenting may be required. Budesonide is a corticosteroid with topical anti-inflammatory effects. In 2008, we used inhaled budesonide for treatment of postoperative granulation tissue for the first time in CTS, resulting in significant improvement. The aim of this study was to evaluate the efficacy of inhaled budesonide for treatment of postoperative granulation tissue in CTS. Retrospective chart review was conducted. From 2004 through 2011, we performed 39 tracheoplasties. Forced stenting ± balloon dilatation (S/B) was required when airway obstruction with tissue granulation was life-threatening. We compared the requirement for S/B between the early group without budesonide (2004-Nov. 2008, Early) and the late group with budesonide (Dec. 2008-2011, Late). Statistical analysis was performed using Fisher's Exact test. Eleven of 22 in Early and 8 of 17 in Late were successfully extubated, never having had life-threatening tissue granulation. The remaining patients in each group (11 in Early and 9 in Late) required tracheostomies due to postoperative complication. Ten in Early and 5 in Late with tracheostomies developed granulation tissue. Of these patients, the 10 in Early required S/B, while none of the 5 in Late required S/B (P=.0003). Bronchoscopy demonstrated significant regression of granulation tissue in all cases treated with inhaled budesonide. Inhaled budesonide is effective for treatment of tracheal granulation tissue in patients with tracheostomies after repair of CTS. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Lung inflammatory and oxidative alterations after exogenous surfactant therapy fortified with budesonide in rabbit model of meconium aspiration syndrome.

    Science.gov (United States)

    Mikolka, P; Kopincová, J; Košútová, P; Čierny, D; Čalkovská, A; Mokrá, D

    2016-12-22

    Meconium aspiration syndrome (MAS) triggers inflammatory and oxidative pathways which can inactivate both pulmonary surfactant and therapeutically given exogenous surfactant. Glucocorticoid budesonide added to exogenous surfactant can inhibit inflammation and thereby enhance treatment efficacy. Neonatal meconium (25 mg/ml, 4 ml/kg) was administered intratracheally (i.t.) to rabbits. When the MAS model was prepared, animals were treated with budesonide i.t. (Pulmicort, 0.25 mg/kg, M+B); with surfactant lung lavage (Curosurf®, 10 ml/kg, 5 mg phospholipids/ml, M+S) followed by undiluted Curosurf® i.t. (100 mg phospholipids/kg); with combination of budesonide and surfactant (M+S+B); or were untreated (M); or served as controls with saline i.t. instead of meconium (C). Animals were oxygen-ventilated for additional 5 h. Cell counts in the blood and bronchoalveolar lavage fluid (BAL), lung edema formation (wet/dry weight ratio), oxidative damage of lipids/ proteins and inflammatory expression profiles (IL-2, IL-6, IL-13, TNF-alpha) in the lung homogenate and plasma were determined. Combined surfactant+budesonide therapy was the most effective in reduction of neutrophil counts in BAL, oxidative damage, levels and mRNA expression of cytokines in the lung, and lung edema formation compared to untreated animals. Curosurf fortified with budesonide mitigated lung inflammation and oxidative modifications what indicate the perspectives of this treatment combination for MAS therapy.

  8. Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.

    Science.gov (United States)

    Straumann, Alex; Conus, Sebastien; Degen, Lukas; Frei, Cornelia; Bussmann, Christian; Beglinger, Christoph; Schoepfer, Alain; Simon, Hans-Uwe

    2011-05-01

    Topical corticosteroids are effective in inducing clinical and histologic remission in patients with eosinophilic esophagitis (EoE). However, the best long-term management strategy for this chronic inflammatory disease has not been determined. In a randomized, double-blind, placebo-controlled, 50-week trial, we evaluated in 28 patients the efficacy of twice-daily swallowed budesonide (0.25 mg each) to maintain quiescent EoE in remission. Pretreatment and posttreatment activity was assessed clinically, endoscopically, histologically, immunohistologically, and by endosonography. The primary end point was the therapy's ability to maintain EoE in histologic remission. Secondary end points were efficacy in symptom control, prevention of tissue remodeling, and safety. In patients given low-dose budesonide, the load of esophageal eosinophils increased from 0.4 to 31.8 eosinophils/high-power field (P = .017). In patients given placebo, the load increased from 0.7 to 65.0 eosinophils/high-power field (P = .0001); this increase was significantly greater than in patients given budesonide (P = .024). The symptom scores developed in a similar manner in the 2 groups. Budesonide, but not placebo, reduced noneosinophilic markers of inflammation, epithelial cell apoptosis, and remodeling events. Compared with control individuals, patients had significantly thickened esophageal walls, based on endosonography (3.05 vs 2.18 mm; P < .0001). Budesonide therapy was associated with a significant reduction in mucosal thickness (0.75-0.45 mm; P = .025), but epithelial thickness remained stable (261.22 vs 277.23 μm; P = .576). No serious adverse events occurred. Low-dose budesonide is more effective than placebo in maintaining EoE in histologic and clinical remission. Signs of esophageal remodeling showed a trend toward normalization. Long-term administration of topical corticosteroids was well tolerated without induction of epithelial atrophy. Copyright © 2011 AGA Institute. Published by

  9. Glucocorticoids decrease Treg cell numbers in lungs of allergic mice.

    Science.gov (United States)

    Olsen, P C; Kitoko, J Z; Ferreira, T P; de-Azevedo, C T; Arantes, A C; Martins, Μ A

    2015-01-15

    Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Budesonide

    Science.gov (United States)

    ... blood sugar) or glaucoma, or if you have tuberculosis, high blood pressure, osteoporosis (a condition in which the bones become thin and weak and break easily), stomach ulcer, cataracts, or liver disease.tell your doctor if you are pregnant, think you may be pregnant, or plan to ...

  11. Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.

    Science.gov (United States)

    Straumann, Alex; Conus, Sebastien; Degen, Lukas; Felder, Stephanie; Kummer, Mirjam; Engel, Hansjürg; Bussmann, Christian; Beglinger, Christoph; Schoepfer, Alain; Simon, Hans-Uwe

    2010-11-01

    Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus characterized by dense tissue eosinophilia; it is refractory to proton pump inhibitor therapy. EoE affects all age groups but most frequently individuals between 20 and 50 years of age. Topical corticosteroids are effective in pediatric patients with EoE, but no controlled studies of corticosteroids have been reported in adult patients. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effect of oral budesonide (1 mg twice daily for 15 days) in adolescent and adult patients with active EoE. Pretreatment and posttreatment disease activity was assessed clinically, endoscopically, and histologically. The primary end point was reduced mean numbers of eosinophils in the esophageal epithelium (number per high-power field [hpf] = esophageal eosinophil load). Esophageal biopsy and blood samples were analyzed using immunofluorescence and immunoassays, respectively, for biomarkers of inflammation and treatment response. A 15-day course of therapy significantly decreased the number of eosinophils in the esophageal epithelium in patients given budesonide (from 68.2 to 5.5 eosinophils/hpf; P < .0001) but not in the placebo group (from 62.3 to 56.5 eosinophils/hpf; P = .48). Dysphagia scores significantly improved among patients given budesonide compared with those given placebo (5.61 vs 2.22; P < .0001). White exudates and red furrows were reversed in patients given budesonide, based on endoscopy examination. Budesonide, but not placebo, also reduced apoptosis of epithelial cells and molecular remodeling events in the esophagus; no serious adverse events were observed. A 15-day course of treatment with budesonide is well tolerated and highly effective in inducing a histologic and clinical remission in adolescent and adult patients with active EoE. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  12. BUDESONIDE TREATMENT IN CHILDREN PRESCHOOL AGE

    Directory of Open Access Journals (Sweden)

    E.A. Vishneva

    2010-01-01

    Full Text Available Bronchial asthma remains disease with wide prevalence in children different age. Inhalation corticosteroids are medications of first line of therapy in children. The article describes the ways of treatment with budesonide (Pulmicort in children preschool age. The data from different studies prove the effectiveness and safety of treatment with as turbuhaler, as nebulizer form of this drug. Key words: children, bronchial asthma, inhalational corticosteroids, budesonide.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2010;9(1:76-80

  13. Minimization of Local and Systemic Adverse Effects of Topical Glucocorticoids by Nanoencapsulation: In Vivo Safety of Hydrocortisone-Hydroxytyrosol Loaded Chitosan Nanoparticles.

    Science.gov (United States)

    Siddique, Muhammad Irfan; Katas, Haliza; Amin, Mohd Cairul Iqbal Mohd; Ng, Shiow-Fern; Zulfakar, Mohd Hanif; Buang, Fhataheya; Jamil, Adawiyah

    2015-12-01

    Hydrocortisone (HC) is a topical glucocorticoid for the treatment of atopic dermatitis (AD); the local as well as systemic side effects limit its use. Hydroxytyrosol (HT) is a polyphenol present in olive oil that has strong antimicrobial and antioxidant activities. HC-HT coloaded chitosan nanoparticles (HC-HT CSNPs) were therefore developed to improve the efficacy against AD. In this study, HC-HT CSNPs of 235 ± 9 nm in size and with zeta potential +39.2 ± 1.6 mV were incorporated into aqueous cream (vehicle) and investigated for acute dermal toxicity, dermal irritation, and repeated dose toxicity using albino Wistar rats. HC-HT CSNPs exhibited LD50 > 125 mg/body surface area of active, which is 100-fold higher than the normal human dose of HC. Compared with the commercial formulation, 0.5 g of HC-HT CSNPs did not cause skin irritation, as measured by Tewameter®, Mexameter®, and as observed visually. Moreover, no-observed-adverse-effect level was observed with respect to body weight, organ weight, feed consumption, blood hematological and biochemical, urinalysis, and histopathological parameters at a dose of 1000 mg/body surface area per day of HC-HT CSNPs for 28 days. This in vivo study demonstrated that nanoencapsulation significantly reduced the toxic effects of HC and this should allow further clinical investigations. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  14. Iatrogenic Cushing's syndrome due to coadministration of ritonavir and inhaled budesonide in an asthmatic human immunodeficiency virus infected patient.

    Science.gov (United States)

    Kedem, Eynat; Shahar, Eduardo; Hassoun, Gamal; Pollack, Shimon

    2010-09-01

    Iatrogenic Cushing's syndrome (CS) is caused by exposure to glucocorticoids and may be promoted by interaction with additional drugs. It is well known in asthmatic human immunodeficiency virus (HIV)-infected patients treated with inhaled fluticasone with ritonavir-containing antiretroviral regimen (cART). The authors present an asthmatic HIV-infected Ethiopian woman, treated with fluticasone/salmeterol, commencing cART with tenofovir, emtricitabine, and lopinavir/ritonavir. During 7 months she gained 9 kg and hyperpigmentation, mild edema, marked abdominal striae, and increase in blood pressure were noted. Plasma am and urine free cortisol levels confirmed CS diagnosis and fluticasone was discontinued. Complete resolution of CS occurred within 2 months. However, frequent asthma symptoms required resumption of inhaled corticosteroid (ICS) treatment, and budesonide/formeterol was prescribed. Soon reemergence of symptomatic CS was noted. Ritonavir dose was halved, but CS symptoms continued to develop. Budesonide was stopped and montelukast initiated. Resolution of cushingoid symptoms was observed within weeks. Corticosteroids are metabolized by cytochrome P450 3A4 (CYP3A4). Fluticasone has the longest glucocorticoid receptor-binding half-life and is 300 times more lipophilic than budesonide. Inhaled fluticasone possesses a high suppression rate of hypothalamic-pituitary-adrenal axis. Ritonavir, a potent CYP3A4 inhibitor, may inhibit corticosteroid degradation and increase its accumulation. Inhaled budesonide is less likely to cause adrenal suppression. Diagnosing Cushing's syndrome presents a clinical challenge due to similarities with clinical manifestations and side effects related to cART. In patients treated with inhaled or intranasal corticosteroids together with cART there may be a higher incidence of iatrogenic CS. CS should be looked for, and management considered carefully.

  15. Iatrogenic cushing syndrome secondary to a probable interaction between voriconazole and budesonide.

    Science.gov (United States)

    Jones, Whitney; Chastain, Cody A; Wright, Patty W

    2014-07-01

    Oral budesonide is commonly used for the management of Crohn's disease given its high affinity for glucocorticoid receptors and low systemic activity due to extensive first-pass metabolism through hepatic cytochrome P450 (CYP) 3A4. Voriconazole, a second-generation triazole antifungal agent, is both a substrate and potent inhibitor of CYP isoenzymes, specifically CYP2C19, CYP2C9, and CYP3A4; thus, the potential for drug-drug interactions with voriconazole is high. To our knowledge, drug-drug interactions between voriconazole and corticosteroids have not been specifically reported in the literature. We describe a 48-year-old woman who was receiving oral budesonide 9 mg/day for the management of Crohn's disease and was diagnosed with fluconazole-resistant Candida albicans esophagitis; oral voriconazole 200 mg every 12 hours for 3 weeks was prescribed for treatment. Because the patient experienced recurrent symptoms of dysphagia, a second 3-week course of voriconazole therapy was taken. Seven weeks after originally being prescribed voriconazole, she came to her primary care clinic with elevated blood pressure, lower extremity edema, and weight gain; she was prescribed a diuretic and evaluated for renal dysfunction. At a follow-up visit 6 weeks later with her specialty clinic, the patient's blood pressure was elevated, and her physical examination was notable for moon facies, posterior cervical fat pad prominence, and lower extremity pitting edema. Iatrogenic Cushing syndrome due to a drug-drug interaction between voriconazole and budesonide was suspected, and voriconazole was discontinued. Budesonide was continued as previously prescribed for her Crohn's disease. On reevaluation 2 months later, the patient's Cushingoid features had markedly regressed. To our knowledge, this is the first published case report of iatrogenic Cushing syndrome due to a probable interaction between voriconazole and oral budesonide. In patients presenting with Cushingoid features who

  16. Budesonide-Related Iatrogenic Cushing's Syndrome in Microscopic Colitis.

    Science.gov (United States)

    Tripathi, Kartikeya; Dunzendorfer, Thomas

    2017-01-01

    Budesonide is the treatment of choice for microscopic colitis because of its excellent risk to benefit ratio. It is a potent, well-absorbed corticosteroid, but because of a high rate of first-pass metabolism in the liver, its systemic bioavailability is low. It has fewer corticosteroid-related adverse effects than prednisone, and adrenal suppression is considered to be rare. We present a middle-aged woman with lymphocytic colitis whose symptoms responded to budesonide but developed budesonide-related iatrogenic Cushing's syndrome. Withdrawal of budesonide led to restoration of normal pituitary-adrenal responsiveness but at the price of recurrent diarrhea due to re-emergence of lymphocytic colitis.

  17. Nasal inhalation of budesonide from a spacer in children with perennial rhinitis and asthma

    DEFF Research Database (Denmark)

    Pedersen, W; Hjuler, Inga Merete; Bisgaard, H

    1998-01-01

    The standard treatment of allergic rhinitis and asthma consists of topical corticosteroids administered intranasally and inhaled through the mouth. Although this therapy is highly effective, and side-effects are few and mild, it may be possible further to improve the therapeutic index and patient...... compliance with the treatment. In the present study, we evaluated a nasal inhalation system used for the simultaneous treatment of rhinitis and asthma. In principle, it results in an airway deposition of the corticosteroid similar to that of inhaled allergens. Twenty-four children with perennial rhinitis...... and asthma inhaled budesonide through the nose from a pressurized aerosol, attached to a spacer device, in a double-blind, placebo-controlled, crossover study. Compared with placebo, budesonide treatment resulted in a significant reduction of nasal symptoms (Pasthma symptoms (P

  18. Improved efficiency of budesonide nebulization using surface-active agents

    NARCIS (Netherlands)

    Heijstra, M. P.; Schaefer, N. C.; Duiverman, E. J.; LeSouef, P. N.; Devadason, S. G.

    2006-01-01

    Our aim was to improve the efficiency of nebulised budesonide using surface-active agents. Cationic, anionic, and nonionic detergents were added to commercial budesonide suspension, and the particle size distribution during nebulization was measured using both cascade impaction and laser

  19. An inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti- and proinflammatory effector genes.

    Science.gov (United States)

    Leigh, Richard; Mostafa, Mahmoud M; King, Elizabeth M; Rider, Christopher F; Shah, Suharsh; Dumonceaux, Curtis; Traves, Suzanne L; McWhae, Andrew; Kolisnik, Tyler; Kooi, Cora; Slater, Donna M; Kelly, Margaret M; Bieda, Mark; Miller-Larsson, Anna; Newton, Robert

    2016-08-01

    Although inhaled glucocorticoids, or corticosteroids (ICS), are generally effective in asthma, understanding their anti-inflammatory actions in vivo remains incomplete. To characterize glucocorticoid-induced modulation of gene expression in the human airways, we performed a randomized placebo-controlled crossover study in healthy male volunteers. Six hours after placebo or budesonide inhalation, whole blood, bronchial brushings, and endobronchial biopsies were collected. Microarray analysis of biopsy RNA, using stringent (≥2-fold, 5% false discovery rate) or less stringent (≥1.25-fold, P  ≤   0.05) criteria, identified 46 and 588 budesonide-induced genes, respectively. Approximately two third of these genes are transcriptional regulators (KLF9, PER1, TSC22D3, ZBTB16), receptors (CD163, CNR1, CXCR4, LIFR, TLR2), or signaling genes (DUSP1, NFKBIA, RGS1, RGS2, ZFP36). Listed genes were qPCR verified. Expression of anti-inflammatory and other potentially beneficial genes is therefore confirmed and consistent with gene ontology (GO) terms for negative regulation of transcription and gene expression. However, GO terms for transcription, signaling, metabolism, proliferation, inflammatory responses, and cell movement were also associated with the budesonide-induced genes. The most enriched functional cluster indicates positive regulation of proliferation, locomotion, movement, and migration. Moreover, comparison with the budesonide-induced expression profile in primary human airway epithelial cells shows considerable cell type specificity. In conclusion, increased expression of multiple genes, including the transcriptional repressor, ZBTB16, that reduce inflammatory signaling and gene expression, occurs in the airways and blood and may contribute to the therapeutic efficacy of ICS. This provides a previously lacking insight into the in vivo effects of ICS and should promote strategies to improve glucocorticoid efficacy in inflammatory diseases.

  20. Two-week inhalation of budesonide increases muscle Na,K ATPase content but not endurance in response to terbutaline in men.

    Science.gov (United States)

    Hostrup, M; Jessen, S; Onslev, J; Clausen, T; Porsbjerg, C

    2017-07-01

    While chronic systemic administration of glucocorticoids increases muscle Na + ,K + ATPase content, such effect is unexplored after therapeutic inhalation. We investigated the effect of therapeutic inhalation of the glucocorticoid budesonide on Na + ,K + ATPase content of skeletal muscle in men. Ten healthy trained subjects, aged 23 ± 4 years (mean ± 95% CI), participated in the study. Before and after 2 weeks of daily inhalation of budesonide (1.6 mg/day), a biopsy was taken from the vastus lateralis muscle for measurement of Na + ,K + ATPase content and blood samples were drawn for determination of plasma budesonide, cortisol, and K + . Subjects' performance during cycling to fatigue at 90% of incremental peak power output (iPPO) was measured in response to 4 mg inhaled terbutaline to maximally stimulate Na + ,K + ATPase activity. Plasma concentrations of budesonide rose to 5.0 ± 1.6 nM with the intervention, whereas no changes were observed in plasma cortisol. Muscle Na + ,K + ATPase content increased (P ≤ 0.01) by 46 ± 34 pmol/(g wet wt) (17% increase) with the intervention. Cycling performance at 90% of iPPO did not change (P = 0.21) with the intervention (203 vs 214 s) in response to terbutaline. The present observations show that therapeutic inhalation of glucocorticoids increases muscle Na + ,K + ATPase content, but does not enhance high-intensity cycling endurance in response to terbutaline. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Iatrogenic Cushing syndrome in patients receiving inhaled budesonide and itraconazole or ritonavir: two cases and literature review.

    Science.gov (United States)

    Blondin, Marie-Christine; Beauregard, Hugues; Serri, Omar

    2013-01-01

    To present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole. We present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options. A 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 μg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 μg/dL. A cosyntropin stimulation test showed values of serum cortisol of Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir.

  2. Budesonide and phenethyl isothiocyanate attenuate DNA damage in bronchoalveolar lavage cells of mice exposed to environmental cigarette smoke.

    Science.gov (United States)

    Micale, Rosanna T; D'Agostini, Francesco; Steele, Vernon E; La Maestra, Sebastiano; De Flora, Silvio

    2008-12-01

    Chemoprevention by dietary and pharmacological means provides a strategy for attenuating the health risks resulting from cigarette smoking and in particular from passive exposure to environmental cigarette smoke (ECS). We evaluated the ability of the glucocorticoid budesonide and of the natural agent phenethyl isothiocyanate (PEITC) to affect DNA damage in bronchoalveolar lavage (BAL) cells of CD-1 mice exposed to ECS, starting within 12 h after birth and continuing until the end of the experiment. After weanling, based on a preliminary subchronic toxicity study, groups of mice received daily either budesonide (24 mg/kg diet) or PEITC (1,000 mg/kg diet). After 2 weeks of treatment, all mice were sacrificed and subjected to BAL, mainly recovering pulmonary alveolar macrophages. Evaluation of single-cell DNA strand breaks was made by using the alkaline-halo test, a modification of the comet assay. The analysis of 481 BAL cells yielded the following results (expressed as nuclear spread factor): (a) Sham-exposed mice: mean 0.84 (lower-upper 95% confidence intervals 0.74-0.94); (b) ECS-exposed mice: 2.77 (2.46-3.09); (c) ECS-exposed mice treated with PEITC: 1.15 (1.05-1.26); (d) ECS-exposed mice treated with budesonide: 1.37 (1.25-1.49). Thus, exposure to ECS resulted in a significant increase of DNA damage as compared with sham, and both PEITC and budesonide significantly attenuated this damage. In conclusion, the analysis of sentinel cells collected by BAL, a semi-invasive technique that is commonly used in humans for diagnostic purposes, showed that the investigated chemopreventive agents are able to revert the DNA damage produced by passive exposure to cigarette smoke.

  3. Improved efficiency of budesonide nebulization using surface-active agents.

    Science.gov (United States)

    Bouwman, A M; Heijstra, M P; Schaefer, N C; Duiverman, E J; Lesouëf, P N; Devadason, S G

    2006-01-01

    Our aim was to improve the efficiency of nebulised budesonide using surface-active agents. Cationic, anionic, and nonionic detergents were added to commercial budesonide suspension, and the particle size distribution during nebulization was measured using both cascade impaction and laser diffraction. Our results showed that the emitted dose was increased after addition of cationic (p < 0.001) and nonionic detergents (p < 0.01) compared with the commercial formulation alone. The respirable fraction was increased for all detergent formulations (p < 0.001) compared with the commercial formulation. We concluded that cationic and nonionic detergent increased the total output of budesonide from the Sidestream. All detergent formulations increased the respirable fraction of nebulized budesonide.

  4. Budesonide-induced periorificial dermatitis presenting as chalazion and blepharitis

    DEFF Research Database (Denmark)

    Henningsen, Emil; Bygum, Anette

    2011-01-01

    We report a case of periorificial dermatitis caused by suboptimal inhalation of budesonide for asthma. The initial skin lesions presented in the eye surroundings, leading to diagnostic difficulties and treatment of presumed chalazion and staphylococcal folliculitis. After several months, the pati......We report a case of periorificial dermatitis caused by suboptimal inhalation of budesonide for asthma. The initial skin lesions presented in the eye surroundings, leading to diagnostic difficulties and treatment of presumed chalazion and staphylococcal folliculitis. After several months...

  5. Development of budesonide nanocluster dry powder aerosols: preformulation.

    Science.gov (United States)

    El-Gendy, Nashwa; Selvam, Parthiban; Soni, Pravin; Berkland, Cory

    2012-09-01

    Wet milling was previously demonstrated as a simple process for producing agglomerates of budesonide nanoparticles (also known as NanoClusters) for use in dry powder aerosol formulation. The resulting budesonide NanoCluster powders exhibited a large emitted fraction and a high fine particle fraction (FPF) from a Monodose® dry powder inhaler. In this work, excipients were added premilling or postmilling and the performance of budesonide NanoCluster dry powders was investigated. Sodium chloride, Pluronic®, or ethanol was added prior to milling due to their ability to modify surface tension or ionic strength and thereby affect the attrition/agglomeration process. Lactose or l-leucine was added after milling because these are known to modify powder flow and dispersion. The chemical stability of budesonide was maintained in all cases, but the physical aerosol properties changed substantially with the addition of excipients. In all cases, the addition of excipients led to an increase in the size of the budesonide NanoClusters and tended to reduce the emitted fraction and FPF. Titrating excipients may provide a means to discretely modify the aerosol properties of budesonide NanoClusters but did not match the performance of excipient-free NanoCluster powder. Copyright © 2012 Wiley Periodicals, Inc.

  6. The Skeletal Effects of Inhaled Glucocorticoids.

    Science.gov (United States)

    Sutter, Stephanie A; Stein, Emily M

    2016-06-01

    The skeletal effects of inhaled glucocorticoids are poorly understood. Children with asthma treated with inhaled glucocorticoids have lower growth velocity, bone density, and adult height. Studies of adults with asthma have reported variable effects on BMD, although prospective studies have demonstrated bone loss after initiation of inhaled glucocorticoids in premenopausal women. There is a dose-response relationship between inhaled glucocorticoids and fracture risk in asthmatics; the risk of vertebral and non-vertebral fractures is greater in subjects treated with the highest doses in the majority of studies. Patients with COPD have lower BMD and higher fracture rates compared to controls, however, the majority of studies have not found an additional detrimental effect of inhaled glucocorticoids on bone. While the evidence is not conclusive, it supports using the lowest possible dose of inhaled glucocorticoids to treat patients with asthma and COPD and highlights the need for further research on this topic.

  7. Complete mucosal healing of distal lesions induced by twice-daily budesonide 2-mg foam promoted clinical remission of mild-to-moderate ulcerative colitis with distal active inflammation: double-blind, randomized study.

    Science.gov (United States)

    Naganuma, Makoto; Aoyama, Nobuo; Tada, Tomohiro; Kobayashi, Kiyonori; Hirai, Fumihito; Watanabe, Kenji; Watanabe, Mamoru; Hibi, Toshifumi

    2017-08-04

    Budesonide foam is used for the topical treatment of distal ulcerative colitis. This phase III study was performed to confirm mucosal healing and other therapeutic effects of twice-daily budesonide 2-mg foam in patients with mild-to-moderate ulcerative colitis including left-sided colitis and pancolitis. This was a multicenter, randomized, placebo-controlled, double-blind trial. A total of 126 patients with mild-to-moderate ulcerative colitis with active inflammation in the distal colon were randomized to two groups receiving twice-daily budesonide 2 mg/25 ml foam or placebo foam. The primary endpoint was the percentage of complete mucosal healing of distal lesions (endoscopic subscore of 0) at week 6. Some patients continued the treatment through week 12. Drug efficacy and safety were evaluated. The percentages of both complete mucosal healing of distal lesions and clinical remission were significantly improved in the budesonide as compared with the placebo group (p = 0.0003 and p = 0.0035). Subgroup analysis showed similar efficacy of budesonide foam for complete mucosal healing of distal lesions and clinical remission regardless of disease type. The clinical remission percentage tended to be higher in patients achieving complete mucosal healing of distal lesions than in other patients. There were no safety concerns with budesonide foam. This study confirmed for the first time complete mucosal healing with twice-daily budesonide 2-mg foam in mild-to-moderate ulcerative colitis with distal active inflammation. The results also indicated that complete mucosal healing of distal lesions by budesonide foam promotes clinical remission of ulcerative colitis. Clinical trial registration no.: Japic CTI-142704.

  8. Functionalized mesoporous silica nanoparticles for oral delivery of budesonide

    Energy Technology Data Exchange (ETDEWEB)

    Yoncheva, K., E-mail: krassi.yoncheva@gmail.com [Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia (Bulgaria); Popova, M. [Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia (Bulgaria); Szegedi, A.; Mihaly, J. [Institute of Nanochemistry and Catalysis, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út. 59-67, 1025 Budapest (Hungary); Tzankov, B.; Lambov, N.; Konstantinov, S.; Tzankova, V. [Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia (Bulgaria); Pessina, F.; Valoti, M. [Dipartimento di Scienze della Vita, Universita di Siena, via Aldo Moro 2, Siena (Italy)

    2014-03-15

    Non-functionalized and amino-functionalized mesoporous silica nanoparticle were loaded with anti-inflammatory drug budesonide and additionally post-coated with bioadhesive polymer (carbopol). TEM images showed spherical shape of the nanoparticles and slightly higher polydispersity after coating with carbopol. Nitrogen physisorption and thermogravimetic analysis revealed that more efficient loading and incorporation into the pores of nanoparticles was achieved with the amino-functionalized silica carrier. Infrared spectra indicated that the post-coating of these nanoparticles with carbopol led to the formation of bond between amino groups of the functionalized carrier and carboxyl groups of carbopol. The combination of amino-functionalization of the carrier with the post-coating of the nanoparticles sustained budesonide release. Further, an in vitro model of inflammatory bowel disease showed that the cytoprotective effect of budesonide loaded in the post-coated silica nanoparticles on damaged HT-29 cells was more pronounced compared to the cytoprotection obtained with pure budesonide. -- Graphical abstract: Silica mesoporous MCM-41 particles were amino-functionalized, loaded with budesonide and post-coated with bioadhesive polymer (carbopol) in order to achieve prolonged residence of anti-inflammatory drug in GIT. Highlights: • Higher drug loading in amino-functionalized mesoporous silica. • Amino-functionalization and post-coating of the nanoparticles sustained drug release. • Achievement of higher cytoprotective effect with drug loaded into the nanoparticles.

  9. Budesonide Versus Acetazolamide for Prevention of Acute Mountain Sickness.

    Science.gov (United States)

    Lipman, Grant S; Pomeranz, David; Burns, Patrick; Phillips, Caleb; Cheffers, Mary; Evans, Kristina; Jurkiewicz, Carrie; Juul, Nick; Hackett, Peter

    2018-02-01

    Inhaled budesonide has been suggested as a novel prevention for acute mountain sickness. However, efficacy has not been compared with the standard acute mountain sickness prevention medication acetazolamide. This double-blind, randomized, placebo-controlled trial compared inhaled budesonide versus oral acetazolamide versus placebo, starting the morning of ascent from 1240 m (4100 ft) to 3810 m (12,570 ft) over 4 hours. The primary outcome was acute mountain sickness incidence (headache and Lake Louise Questionnaire ≥3 and another symptom). A total of 103 participants were enrolled and completed the study; 33 (32%) received budesonide, 35 (34%) acetazolamide, and 35 (34%) placebo. Demographics were not different between the groups (P > .09). Acute mountain sickness prevalence was 73%, with severe acute mountain sickness of 47%. Fewer participants in the acetazolamide group (n = 15, 43%) developed acute mountain sickness compared with both budesonide (n = 24, 73%) (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.3-10.1) and placebo (n = 22, 63%) (OR 0.5, 95% CI 0.2-1.2). Severe acute mountain sickness was reduced with acetazolamide (n = 11, 31%) compared with both budesonide (n = 18, 55%) (OR 2.6, 95% CI 1-7.2) and placebo (n = 19, 54%) (OR 0.4, 95% CI 0.1-1), with a number needed to treat of 4. Budesonide was ineffective for the prevention of acute mountain sickness, and acetazolamide was preventive of severe acute mountain sickness taken just before rapid ascent. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Primary generalized glucocorticoid resistance and hypersensitivity.

    Science.gov (United States)

    Charmandari, Evangelia

    2011-01-01

    The human glucocorticoid receptor (hGR) is a ubiquitously expressed intracellular, ligand-dependent transcription factor, which mediates the action of glucocorticoids and influences physiological functions essential for life. Alterations in the molecular mechanisms of hGR action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms and clinical aspects of primary generalized glucocorticoid resistance (PGGR) and hypersensitivity (PGGH). A systematic review of the published, peer-reviewed medical literature (PubMed: 1975 through May 2011) was conducted to identify original articles and reviews on this topic. Evidence synthesis was relied upon the experience of a number of experts in the field, including our extensive personal experience. The molecular basis of PGGR and PGGH has been ascribed to mutations in the hGR gene, which alter tissue sensitivity to glucocorticoids. The stochastic nature of glucocorticoid signaling pathways in association with the variable effect that hGR gene mutations/polymorphisms might have on glucocorticoid signal transduction indicates that alterations in hGR action may have important implications for many critical biological processes, such as the behavioral and physiological responses to stress, the immune and inflammatory reaction, as well as growth and reproduction. Copyright © 2011 S. Karger AG, Basel.

  11. Rectal budesonide and mesalamine formulations in active ulcerative proctosigmoiditis: efficacy, tolerance, and treatment approach

    Directory of Open Access Journals (Sweden)

    Christophi GP

    2016-05-01

    Full Text Available George P Christophi, Arvind Rengarajan, Matthew A Ciorba Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA Abstract: Ulcerative colitis (UC is an immune-mediated disease of the colon that is characterized by diffuse and continuous inflammation contiguous from the rectum. Half of UC patients have inflammation limited to the distal colon (proctitis or proctosigmoiditis that primarily causes symptoms of bloody diarrhea and urgency. Mild-to-moderate distal UC can be effectively treated with topical formulations (rectal suppositories, enemas, or foam of mesalamine or steroids to reduce mucosal inflammation and alleviate symptoms. Enemas or foam formulations adequately reach up to the splenic flexure, have a minimal side-effect ­profile, and induce remission alone or in combination with systemic immunosuppressive therapy. Herein, we compare the efficacy, cost, patient tolerance, and side-effect profiles of steroid and mesalamine rectal formulations in distal UC. Patients with distal mild-to-moderate UC have a remission rate of approximately 75% (NNT =2 after treatment for 6 weeks with mesalamine enemas. Rectal budesonide foam induces remission in 41.2% of patients with mild-to-moderate active distal UC compared to 24% of patient treated with placebo (NNT =5. However, rectal budesonide has better patient tolerance profile compared to enema formulations. Despite its favorable efficacy, safety, and cost profiles, patients and physicians significantly underuse topical treatments for treating distal colitis. This necessitates improved patient education and physician familiarity regarding the indications, effectiveness, and potential financial and tolerability barriers in using rectal formulations. Keywords: inflammatory bowel disease, treatment cost effectiveness, Crohn’s disease, ulcerative colitis, colon mucosa, proctitis suppositories, topical immunosuppressive therapy

  12. Use of budesonide Turbuhaler in young children suspected of asthma

    DEFF Research Database (Denmark)

    Bisgaard, H; Pedersen, S; Nikander, K

    1994-01-01

    The question addressed in this study was the ability of young children to use a dry-powder inhaler, Turbuhaler. One hundred and sixty five children suspected of asthma, equally distributed in one year age-groups from 6 months to 8 yrs, inhaled from a Pulmicort Turbuhaler, 200 micrograms budesonide...

  13. Budesonide for ulcerative colitis Budesonida en el tratamiento de la colitis ulcerosa

    Directory of Open Access Journals (Sweden)

    I. Marín-Jiménez

    2006-05-01

    Full Text Available In this review, we examined studies published on oral and topical formulations of budesonide (Entocort® and Budenofalk®, in Spain: Entocord® and Intestifalk® for the treatment of ulcerative colitis. This glycocorticosteroid has a potent local action and an important first-pass liver metabolism. It has proven successful over the last years as a controlled-release formulation. It obtained results similar to prednisolone, without the latter's significant suppression of plasma cortisol. Many publications exist on the effects of oral budesonide for the treatment of Crohn's disease (CD. These have led to the registration of this drug for the treatment of CD. Studies on oral formulations of budesonide for the treatment of ulcerative colitis (UC are scarce. After reviewing published evidence, we suggest the conduction of controlled trials for the treatment of UC to obtain evidence-based efficacy and safety results in order to benefit patients with this form of inflammatory bowel disease (IBD.En esta revisión repasamos los estudios publicados hasta la fecha con las formulaciones orales y las preparaciones tópicas rectales de budesonida (Entocort® y Budenofalk®, en España Entocord® e Intestifalk® para el tratamiento de la colitis ulcerosa. Este glucocorticosteroide de una elevada acción tópica y un importante metabolismo de primer paso hepático se ha utilizado en los últimos años como una formulación de liberación controlada, proporcionando resultados similares a la prednisolona pero sin suprimir de forma apreciable los niveles de cortisol plasmático. Aunque se han publicado muchos estudios sobre los efectos de la budesonida oral para el tratamiento de la enfermedad de Crohn, los estudios sobre esta misma forma galénica de administración de budesonida para el tratamiento de los pacientes con colitis ulcerosa son escasos. Después de revisar los trabajos publicados al respecto, se sugiere la necesidad de realizar un estudio controlado

  14. Budesonide nanoparticle agglomerates as dry powder aerosols with rapid dissolution

    Science.gov (United States)

    El-Gendy, Nashwa; Gorman, Eric M.; Munson, Eric J.; Berkland, Cory

    2015-01-01

    Purpose Nanoparticle technology represents an attractive approach for formulating poorly water soluble pulmonary medicines. Unfortunately, nanoparticle suspensions used in nebulizers or metered dose inhalers often suffer from physical instability in the form of uncontrolled agglomeration or Ostwald ripening. In addition, processing such suspensions into dry powders can yield broad particle size distributions. To address these encumbrances, a controlled nanoparticle flocculation process has been developed. Method Nanosuspensions of the poorly water soluble drug budesonide were prepared by dissolving the drug in organic solvent containing surfactants followed by rapid solvent extraction in water. Different surfactants were employed to control the size and surface charge of the precipitated nanoparticles. Nanosuspensions were flocculated using leucine and lyophilized. Results Selected budesonide nanoparticle suspensions exhibited an average particle size ranging from ~160–230 nm, high yield and high drug content. Flocculated nanosuspensions produced micron-sized agglomerates. Freeze-drying the nanoparticle agglomerates yielded dry powders with desirable aerodynamic properties for inhalation therapy. In addition, the dissolution rates of dried nanoparticle agglomerate formulations were significantly faster than that of stock budesonide. Conclusion The results of this study suggest that nanoparticle agglomerates possess the microstructure desired for lung deposition and the nanostructure to facilitate rapid dissolution of poorly water soluble drugs. PMID:19130469

  15. [Nasal budesonide plus zafirlukast vs nasal budesonide plus loratadine-pseudoephedrine for controlling the symptoms of rhinitis and asthma].

    Science.gov (United States)

    Benitez, Hector Hugo Salas; Arvizu, Victor Manuel Almeida; Gutiérrez, Daniel Jijón; Fogelbach, Guillermo Arturo Guidos; Castellanos Olivares, Antonio; Vázquez Nava, Francisco; Velázquez, Héctor Chong; González Pérez, Maria del Carmen; Mora Nieto, Alejandra; Rodríguez, Eduardo Castro

    2005-01-01

    To compare the efficacy of nasal budesonide plus oral zafirlukast against nasal budesonide plus oral loratadine/pseudoephedrine combination in the control of symptoms of rhinitis and asthma. A controlled, clinical, randomized, double blind and crossover study was made in 36 patients with allergic rhinitis and asthma following one of the next treatment regimes: group a) nasal budesonide plus oral zafirlukast twice a day or group b) nasal budesonide plus oral loratadine/pseudoephedrine twice a day, both of them during six weeks, and two weeks of washing and crossover of the treatments during six more weeks. Changes in the rhinitis and asthma symptoms, blood eosinophils, pulmonary function testing, and nasal cytology were evaluated before and after the treatment. 19 patients were assigned to group a, whereas 17 patients to group b. The age ranged between 16 to 45 years, and it predominated the female group, 70 and 89%, respectively (statistically no significant). During the first six weeks of the treatment, V0 to V3, both groups of patients got better nasal symptoms but group a was superior to group b. However, in bronchial symptoms, cough, wheezing and breathlessness, group a showed efficacy in comparison with group b, where no significant improvement was shown. Once the crossover was made, from V5 to V7, there was no difference between both groups. The other evaluated indicators, such as eosinophilia, VEF1 and nasal eosinophils, had a significant improvement before and at the end of the study. The association of a nasal steroid with a leukotriene modifier (zafirlukast) was more effective for controlling nasal symptoms and especially bronchial symptoms than the association of a nasal steroid with antihistamines (loratadine) with pseudoephedrine. Other inflammation indicators, such as eosinophilia and nasal eosinophilia, were diminished; the VEF1 increased significantly in both treatment groups. All the above may be due to the nasal steroid use associated to a

  16. Glucocorticoids as regulatory signals during intrauterine development.

    Science.gov (United States)

    Fowden, Abigail L; Forhead, Alison J

    2015-12-01

    What is the topic of this review? This review discusses the role of the glucocorticoids as regulatory signals during intrauterine development. It examines the functional significance of these hormones as maturational, environmental and programming signals in determining offspring phenotype. What advances does it highlight? It focuses on the extensive nature of the regulatory actions of these hormones. It highlights the emerging data that these actions are mediated, in part, by the placenta, other endocrine systems and epigenetic modifications of the genome. Glucocorticoids are important regulatory signals during intrauterine development. They act as maturational, environmental and programming signals that modify the developing phenotype to optimize offspring viability and fitness. They affect development of a wide range of fetal tissues by inducing changes in cellular expression of structural, transport and signalling proteins, which have widespread functional consequences at the whole organ and systems levels. Glucocorticoids, therefore, activate many of the physiological systems that have little function in utero but are vital at birth to replace the respiratory, nutritive and excretory functions previously carried out by the placenta. However, by switching tissues from accretion to differentiation, early glucocorticoid overexposure in response to adverse conditions can programme fetal development with longer term physiological consequences for the adult offspring, which can extend to the next generation. The developmental effects of the glucocorticoids can be direct on fetal tissues with glucocorticoid receptors or mediated by changes in placental function or other endocrine systems. At the molecular level, glucocorticoids can act directly on gene transcription via their receptors or indirectly by epigenetic modifications of the genome. In this review, we examine the role and functional significance of glucocorticoids as regulatory signals during intrauterine

  17. Glucocorticoids decrease the production of glucagon-like peptide-1 at the transcriptional level in intestinal L-cells.

    Science.gov (United States)

    Sato, Taiki; Hayashi, Hiroto; Hiratsuka, Masahiro; Hirasawa, Noriyasu

    2015-05-05

    Glucocorticoids are widely used as anti-inflammatory or immunosuppressive drugs, but often induce hyperglycemia as a side effect. Glucagon-like peptide-1 (GLP-1) is secreted from intestinal L cells and plays crucial roles in maintaining glucose homeostasis. However, the direct effects of glucocorticoids on the GLP-1 production pathway in L cells remain unclear. We investigated the effects of glucocorticoids on GLP-1 production in vitro and in vivo. In L cell lines, glucocorticoids decreased GLP-1 release and expression of the precursor, proglucagon, at protein and mRNA levels, which were inhibited by mifepristone. The administration of dexamethasone or budesonide to mice significantly decreased the mRNA expression of proglucagon in the ileum and partially decreased glucose-stimulated GLP-1 secretion. Compound A, a dissociated glucocorticoid receptor modulator, did not affect the expression of proglucagon in vitro. These results suggested that glucocorticoids directly reduced GLP-1 production at the transcriptional level in L cells through a glucocorticoid receptor dimerization-dependent mechanism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Immune regulation by glucocorticoids.

    Science.gov (United States)

    Cain, Derek W; Cidlowski, John A

    2017-04-01

    Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.

  19. Risk of pneumonia with budesonide-containing treatments in COPD: an individual patient-level pooled analysis of interventional studies.

    Science.gov (United States)

    Hollis, Sally; Jorup, Carin; Lythgoe, Dan; Martensson, Gunnar; Regnell, Pontus; Eckerwall, Göran

    2017-01-01

    Concerns have been raised that treatment of COPD with inhaled corticosteroids may increase pneumonia risk. Responding to a request from the European Medicines Agency Pharmacovigilance Risk Assessment Committee, a pooled analysis of interventional studies compared pneumonia risk with inhaled budesonide-containing versus non-budesonide-containing treatments and the impact of other clinically relevant factors. AstraZeneca-sponsored, parallel-group, double-blind, randomized controlled trials meeting the following criteria were included: >8 weeks' duration; ≥60 patients with COPD; inhaled budesonide treatment arm (budesonide/formoterol or budesonide); and non-budesonide-containing comparator arm (formoterol or placebo). Primary and secondary outcomes were time to first pneumonia treatment-emergent serious adverse event (TESAE) and treatment-emergent adverse event (TEAEs), respectively, analyzed using Cox regression models stratified by study. Eleven studies were identified; 10,570 out of 10,574 randomized patients receiving ≥1 dose of study treatment were included for safety analysis (budesonide-containing, n=5,750; non-budesonide-containing, n=4,820). Maximum exposure to treatment was 48 months. The overall pooled hazard ratio (HR), comparing budesonide versus non-budesonide-containing treatments, was 1.15 for pneumonia TESAEs (95% confidence interval [CI]: 0.83, 1.57) and 1.13 for pneumonia TEAEs (95% CI: 0.94, 1.36). The annual incidence of pneumonia TESAEs was 1.9% and 1.5% for budesonide-containing and non-budesonide-containing treatments, respectively. Comparing budesonide/formoterol with non-budesonide-containing treatment, the HRs for pneumonia TESAEs and TEAEs were 1.00 (95% CI: 0.69, 1.44) and 1.21 (95% CI: 0.93, 1.57), respectively. For budesonide versus placebo, HRs were 1.57 for pneumonia TESAEs (95% CI: 0.90, 2.74) and 1.07 for pneumonia TEAEs (95% CI: 0.83, 1.38). This pooled analysis found no statistically significant increase in overall risk for

  20. Long-term safety and efficacy of budesonide in the treatment of ulcerative colitis

    Directory of Open Access Journals (Sweden)

    Iborra M

    2014-02-01

    Full Text Available Marisa Iborra,1 Diego Álvarez-Sotomayor,2 Pilar Nos1 1Gastroenterology Unit, Department of Digestive Disease, Centro de investigación biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD, La Fe University and Polytechnic Hospital, Valencia, Spain; 2Gastroenterology Unit, Department of Digestive Disease, La Fe University and Polytechnic Hospital, Valencia, Spain Abstract: Ulcerative colitis (UC is a chronic, relapsing, and remitting inflammatory disease involving the large intestine (colon. Treatment seeks to break recurrent inflammation episodes by inducing and maintaining remission. Historically, oral systemic corticosteroids played an important role in inducing remission of this chronic disease; however, their long-term use is limited and can lead to adverse events. Budesonide is a synthetic steroid with potent local anti-inflammatory effects and low systemic bioavailability due to high first-pass hepatic metabolism. Several studies have demonstrated oral budesonide's usefulness in treating active mild to moderate ileocecal Crohn's disease and microscopic colitis and in an enema formulation for left sided UC. However, there is limited information regarding oral budesonide's efficacy in UC. A novel oral budesonide formulation using a multimatrix system (budesonide-MMX to extend drug release throughout the colon has been developed recently and seems to be an effective treatment in active left sided UC patients. This article summarizes budesonide's long-term safety and efficacy in treating UC. Keywords: budesonide, ulcerative colitis, Crohn's disease, safety

  1. Glucocorticoids and chronic inflammation.

    Science.gov (United States)

    Straub, Rainer H; Cutolo, Maurizio

    2016-12-01

    Glucocorticoids are steroid hormones that once bound to their receptor interact with the DNA binding domain. Almost 1000-2000 genes are sensitive to their effects, including immune/inflammatory response genes. However, their role in pathophysiology and therapy is still debated. We performed a literature survey using the key words glucocorticoids, inflammation, autoimmune disease, rheumatology and adrenal glands in order to define important targets for this review on glucocorticoids. Considering endogenous/exogenous glucocorticoids in chronic inflammatory diseases brought up five major points for discussion: inadequately low production of endogenous cortisol relative to systemic inflammation (the disproportion principle); changes of the systemic and local cortisol-to-cortisone shuttle (reactivation and degradation of cortisol); inflammation-induced glucocorticoid resistance; highlights of present glucocorticoid therapy; and the role of circadian rhythms in action of cortisol. Much of this information becomes understandable in the context of neurohormonal energy regulation as recently summarized. The optimization of long-term low-dose glucocorticoid therapy in chronic inflammatory diseases arises from the understanding of the above mentioned aspects. Since glucocorticoid resistance is a consequence of inflammation, adequate anti-inflammatory therapy is mandatory. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Comparing the effects of two inhaled glucocorticoids on allergen-induced bronchoconstriction and markers of systemic effects, a randomised cross-over double-blind study

    Directory of Open Access Journals (Sweden)

    Lötvall Jan

    2011-10-01

    Full Text Available Abstract Background Inhaled glucocorticoids are efficient in protecting against asthma exacerbations, but methods to compare their efficacy vs systemic effects have only been attempted in larger multi-centre studies. The aim of the current study was therefore to directly compare the effects of two separate inhaled glucocorticoids, mometasone and budesonide, to compare the effects on the early and late asthmatic responses to inhaled allergen in patients with mild allergic asthma, and sputum eosinophils, and to relate the clinical positive effects to any systemic effects observed. Methods Twelve patients with documented early and late asthmatic responses (EAR and LAR to inhaled allergen at a screening visit were randomized in a double-blind fashion to treatment with mometasone (200 μg × 2 or 400 μg × 2, budesonide (400 μg × 2 or placebo in a double-blind crossover fashion for a period of seven days. Challenge with the total allergen dose causing both an EAR and LAR was given on the last day of treatment taken in the morning. Lung function was assessed using FEV1, and systemic glucocorticoid activity was quantified using 24 h urinary cortisol. Results Mometasone and budesonide attenuate both EAR and LAR to allergen to a similar degree. No significant dose-related effects on the lung function parameters were observed. Both treatments reduced the relative amount of sputum eosinophils (% after allergen. At the dose of 800 μg daily, mometasone reduced 24 h urinary cortisol by approximately 35%. Both drugs were well tolerated. Conclusions Mometasone and budesonide are equieffective in reducing early and late asthmatic responses induced by inhaled allergen challenge. Mometasone 800 μg given for seven days partially affects the HPA axis.

  3. Glucocorticoids and Cancer

    Science.gov (United States)

    2017-01-01

    Unlike other steroid hormone receptors, the glucocorticoid receptor (GR) is not considered an oncogene. In breast cancer, the estrogen receptor (ER) drives cell growth, proliferation, and metastasis, and the androgen receptor (AR) plays a similar role in prostate cancer. Accordingly, treatment of these diseases has focused on blocking steroid hormone receptor function. In contrast, glucocorticoids (GCs) work through GR to arrest growth and induce apoptosis in lymphoid tissue. Glucocorticoids are amazingly effective in this role, and have been deployed as the cornerstone of lymphoid cancer treatment for decades. Unfortunately, not all patients respond to GCs and dosage is restricted by immediate and long term side effects. In this chapter we review the treatment protocols that employ glucocorticoids as a curative agent, elaborate on what is known about their mechanism of action in these cancers, and also summarize the palliative uses of glucocorticoids for other cancers. PMID:26216001

  4. Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis.

    Science.gov (United States)

    Fitzsimons, Carlos P; Herbert, Joe; Schouten, Marijn; Meijer, Onno C; Lucassen, Paul J; Lightman, Stafford

    2016-04-01

    Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate. Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological conditions in which glucocorticoid oscillations are affected. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Genomic effects of glucocorticoids.

    Science.gov (United States)

    Grbesa, Ivana; Hakim, Ofir

    2017-05-01

    Glucocorticoids and their receptor (GR) have been an important area of research because of their pleiotropic physiological functions and extensive use in the clinic. In addition, the association between GR and glucocorticoids, which is highly specific, leads to rapid nuclear translocation where GR associates with chromatin to regulate gene transcription. This simplified model system has been instrumental for studying the complexity of transcription regulation processes occurring at chromatin. In this review we discuss our current understanding of GR action that has been enhanced by recent developments in genome wide measurements of chromatin accessibility, histone marks, chromatin remodeling and 3D chromatin structure in various cell types responding to glucocorticoids.

  6. Budesonide-Related Iatrogenic Cushing’s Syndrome in Microscopic Colitis

    Science.gov (United States)

    Tripathi, Kartikeya

    2017-01-01

    Budesonide is the treatment of choice for microscopic colitis because of its excellent risk to benefit ratio. It is a potent, well-absorbed corticosteroid, but because of a high rate of first-pass metabolism in the liver, its systemic bioavailability is low. It has fewer corticosteroid-related adverse effects than prednisone, and adrenal suppression is considered to be rare. We present a middle-aged woman with lymphocytic colitis whose symptoms responded to budesonide but developed budesonide-related iatrogenic Cushing’s syndrome. Withdrawal of budesonide led to restoration of normal pituitary-adrenal responsiveness but at the price of recurrent diarrhea due to re-emergence of lymphocytic colitis. PMID:28138449

  7. Production, characterisation, and in vitro nebulisation performance of budesonide-loaded PLA nanoparticles.

    Science.gov (United States)

    Amini, Mohammad Ali; Faramarzi, Mohammad Ali; Gilani, Kambiz; Moazeni, Esmaeil; Esmaeilzadeh-Gharehdaghi, Elina; Amani, Amir

    2014-01-01

    The aim of this study is to prepare a nanosuspension of budesonide for respiratory delivery using nebuliser by optimising its particle size and characterising its in vitro deposition behaviour. PLA (poly lactic acid)-budesonide nanosuspension (BNS) was prepared using high-pressure emulsification/solvent evaporation method. To optimise particle size, different parameters such as PLA concentration, sonication time, and amplitude were investigated. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscope (SEM) analyses were performed to characterise the prepared PLA-budesonide nanoparticles. The in vitro aerodynamic characteristics of the PLA-BNS using a jet nebuliser were estimated and compared with that of commercially available suspension formulation of budesonide. Budesonide-loaded PLA nanoparticles with fine particle size (an average size of 224-360 nm), narrow size distribution, and spherical and smooth surface were prepared. The optimum condition for preparation of fine particle size for aerosolisation was found to be at PLA concentration of 1.2 mg/ml and amplitude of 70 for 75 s sonication time. The in vitro aerosolisation performance of PLA-BNS compared to that of commercial budesonide indicated that it has significantly (p PLA-BNS could be considered as a promising alternative suspension formulation for deep lung delivery of the drug using nebuliser.

  8. Open-Capsule Budesonide for Refractory Celiac Disease.

    Science.gov (United States)

    Mukewar, Saurabh S; Sharma, Ayush; Rubio-Tapia, Alberto; Wu, Tsung-Teh; Jabri, Bana; Murray, Joseph A

    2017-06-01

    Refractory celiac disease (RCD) is a rare condition often associated with poor prognosis. Various immunosuppressive medications (IMs) have been used with modest success. We describe outcomes in patients treated with open-capsule budesonide (OB), including those for whom IM treatment failed. We identified RCD patients treated with OB at Mayo Clinic, Rochester, Minnesota from 2003 to 2015. Demographic, serologic, and clinical variables were analyzed. We identified 57 patients who received OB for suspected RCD. Based on clonal T-cell receptor gamma gene rearrangement or aberrant phenotype of intraepithelial lymphocytes (IELs), 13 patients (23%) were classified as having RCD-2 and 43 (75%) as RCD-1. In one patient (2%) TCR gene rearrangement status was unknown. Most patients were women (69%), mean (s.d.) age was 60.5 (3.5) years and body mass index was 28.4 (4.5) kg/m 2 . The majority had diarrhea (72%), with median of 6 bowel movements per day (range, 4-25). IM treatment (azathioprine, systemic corticosteroids, or regular budesonide) had failed in nearly half. Twenty-four patients (42%) had anemia and 12 (21%) had hypoalbuminemia. All had Marsh 3 lesions on biopsy: 3a (19%), 3b (46%), and 3c (35%). After OB therapy, the majority had clinical (92%) and histologic (89%) improvement. Follow-up biopsy in 7 out of 13 patients with RCD-2 (53%) showed an absence of clonal TCR gamma gene rearrangement/aberrant IEL phenotype previously seen. On follow-up, 2 patients (4%) died of enteropathy-associated T-cell lymphoma. Most patients with RCD show clinical and histopathologic improvement with OB therapy, including those with failure of IMs. OB is a promising therapeutic option for management of RCD.

  9. Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

    International Nuclear Information System (INIS)

    Chen, Jing; Mo, Yiqun; Schlueter, Connie F.; Hoyle, Gary W.

    2013-01-01

    Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury

  10. Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jing; Mo, Yiqun; Schlueter, Connie F.; Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu

    2013-10-15

    Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury.

  11. Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation.

    Science.gov (United States)

    Sarkar, Mrinal K; Kaplan, Nihal; Tsoi, Lam C; Xing, Xianying; Liang, Yun; Swindell, William R; Hoover, Paul; Aravind, Maya; Baida, Gleb; Clark, Matthew; Voorhees, John J; Nair, Rajan P; Elder, James T; Budunova, Irina; Getsios, Spiro; Gudjonsson, Johann E

    2017-07-01

    The factors involved in maintaining a localized inflammatory state in psoriatic skin remain poorly understood. Here, we demonstrate through metabolomic and transcriptomic profiling marked suppression of glucocorticoid biosynthesis in the epidermis of psoriatic skin leading to localized deficiency of cortisol. Utilizing a 3D human epidermis model, we demonstrate that glucocorticoid biosynthesis is suppressed by proinflammatory cytokines and that glucocorticoid deficiency promotes inflammatory responses in keratinocytes. Finally, we show in vitro and in vivo that treatment with topical glucocorticoids leads to rapid restoration of glucocorticoid biosynthesis gene expression coincident with normalization of epidermal differentiation and suppression of inflammatory responses. Taken together, our data suggest that localized glucocorticoid deficiency in psoriatic skin interferes with epidermal differentiation and promotes a sustained and localized inflammatory response. This may shed new light on the mechanism of action of topical steroids, and demonstrates the critical role of endogenous steroid in maintaining both inflammatory and differentiation homeostasis in the epidermis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing.

    Science.gov (United States)

    Goyanes, Alvaro; Chang, Hanah; Sedough, Daniel; Hatton, Grace B; Wang, Jie; Buanz, Asma; Gaisford, Simon; Basit, Abdul W

    2015-12-30

    The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were engineered into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment® (Uceris®) and Entocort®, were also investigated for comparison. Budesonide release from the Entocort® formulation was rapid in conditions of the upper small intestine while release from the Cortiment® product was more delayed and very slow. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release then continued in a sustained manner throughout the distal intestine and colon. This work has demonstrated the potential of combining FDM 3DP with established pharmaceutical processes, including HME and film coating, to fabricate modified release oral dosage forms. Copyright © 2015. Published by Elsevier B.V.

  13. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN)

    DEFF Research Database (Denmark)

    Fellström, Bengt C.; Barratt, Jonathan; Cook, Heather

    2017-01-01

    ·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58–1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group...... of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases...... block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised...

  14. Acute Pathophysiological Effects of Intratracheal Instillation of Budesonide and Exogenous Surfactant in a Neonatal Surfactant-depleted Piglet Model

    Directory of Open Access Journals (Sweden)

    Chia-Feng Yang

    2010-08-01

    Conclusions: Intratracheal instillation of surfactant or surfactant plus budesonide can improve oxygenation and pulmonary histologic outcome in neonatal surfactant-depleted lungs. The additional use of budesonide does not disturb the function of the exogenous surfactant. Intratracheal administration of a corticosteroid combined with surfactant may be an effective method for alleviating local pulmonary inflammation in severe RDS.

  15. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

    DEFF Research Database (Denmark)

    Skov, M; Main, K M; Sillesen, Ida Blok

    2002-01-01

    assessment of this axis and gonadal function in all patients treated with itraconazole in the authors' CF centre. Itraconazole can inhibit CYP3A, thus interfering with synthesis of gluco- and mineralocorticoids, androgens and oestradiol as well as the metabolism of budesonide. The aim of this study...... was to evaluate adrenal and gonadal function in patients treated with itraconazole with or without budesonide. An adrenocorticotrophic hormone (ACTH) test (250 microg tetracosactid) was performed in 25 CF patients treated with both itraconazole and budesonide, and in 12 patients treated with itraconazole alone...... (six patients with CF and six with chronic granulomateous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma-renin, follicle stimulating hormone, luteinising hormone, progesterone, oestradiol, testosterone, serum-inhibin A and B. ACTH tests performed...

  16. Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide.

    Science.gov (United States)

    Dufour, Gilles; Bigazzi, William; Wong, Nelson; Boschini, Frederic; de Tullio, Pascal; Piel, Geraldine; Cataldo, Didier; Evrard, Brigitte

    2015-11-30

    To achieve an efficient lung delivery and efficacy, both active ingredient aerosolisation properties and permeability through the lung need to be optimized. To overcome these challenges, the present studies aim to develop cyclodextrin-based spray-dried microparticles containing a therapeutic corticosteroid (budesonide) that could be used to control airway inflammation associated with asthma. The complexation between budesonide and hydroxypropyl-β-cyclodextrin (HPBCD) has been investigated. Production of inhalation powders was carried out using a bi-fluid nozzle spray dryer and was optimized based on a design of experiments. Spray-dried microparticles display a specific "deflated-ball like shape" associated with an appropriate size for inhalation. Aerodynamic assessment show that the fine particle fraction was increased compared to a classical lactose-based budesonide formulation (44.05 vs 26.24%). Moreover, the budesonide permeability out of the lung was shown to be reduced in the presence of cyclodextrin complexes. The interest of this sustained budesonide release was evaluated in a mouse model of asthma. The anti-inflammatory effect was compared to a non-complexed budesonide formulation at the same concentration and attests the higher anti-inflammatory activity reach with the cyclodextrin-based formulation. This strategy could therefore be of particular interest for improving lung targeting while decreasing systemic side effects associated with high doses of corticosteroids. In conclusion, this works reports that cyclodextrins could be used in powder for inhalation, both for their abilities to improve active ingredient aerosolisation properties and further to their dissolution in lung fluid, to decrease permeability out of the lungs leading to an optimized activity profile. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients

    Directory of Open Access Journals (Sweden)

    Wen-biao ZHAO

    2014-10-01

    Full Text Available Objective To observe the effect of glucocorticoid inhalation on the clinical symptoms and pulmonary fibrosis index in ARDS patients. Methods Fifty-three ARDS patients admitted to ICU of Songjiang District Center Hospital of Shanghai from Dec. 2011 to Jun. 2013 were randomly divided into two groups. Group A (n=29 received conventional therapy, and group B (n=24 was given glucocorticoid inhalation treatment (budesonide, 2 mg, 1/12 h, for 12 days on the basis of the conventional therapy. The oxygenation index, time of extubation, changes in pulmonary fibrosis index, including collagen Ⅰ(Co Ⅰ, Ⅲ procollagen peptide (PⅢP and transforming growth factor (TGF-β1 were compared between the two groups, and the incidence of common adverse reactions were analyzed. Results The oxygenation index of patients in group B was significantly improved on the 15th day compared with group A (P0.05. Conclusion A small dose of glucocorticoids introduced by inhalation can improve the oxygenation index and pulmonary fibrosis level without increasing common adverse reactions, suggesting that the inhalation of corticosteroid may be a clinically safe and effective way in patients with ARDS. DOI: 10.11855/j.issn.0577-7402.2014.09.13

  18. Budesonide/formoterol combination in COPD: a US perspective

    Directory of Open Access Journals (Sweden)

    Amir Sharafkhaneh

    2010-10-01

    Full Text Available Amir Sharafkhaneh1,2, Amarbir S Mattewal1, Vinu M Abraham1, Goutham Dronavalli1, Nicola A Hanania11Section of Pulmonary, Critical Care Medicine and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; 2Section of Pulmonary, Critical Care Medicine and Sleep Medicine, Medical Care Line, Michael E DeBakey VA Medical Center, Houston, Texas, USAAbstract: Chronic obstructive pulmonary disease (COPD is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 µg; Symbicort™, AstraZeneca, Sweden delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD.Keywords: inhaled steroid, bronchodilator, ß2-agonist, lung function, quality of life

  19. Clinical aspects of glucocorticoid sensitivity

    OpenAIRE

    Lamberts, Steven; Huizenga, Nannette; Lange, Pieter; Jong, Frank; Koper, Jan

    1996-01-01

    textabstractRecent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant.' These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even during long-term therapy with a much higher dose. Awareness of this heterogeneity in glu...

  20. Low-dose budesonide treatment reduces severe asthma-related events in patients with infrequent asthma symptoms at baseline

    DEFF Research Database (Denmark)

    Reddel, H. K.; Busse, W. W.; Pedersen, Søren

    2015-01-01

    .0 for Groups 0-1, >1-2, respectively. The rate of severe exacerbations identified by oral/systemic corticosteroid courses was lower for budesonide compared with placebo in all 3 symptom frequency groups (Figure). Patients treated with budesonide experienced significantly greater improvements in symptoms...... and significantly more symptom-free days compared with patients receiving placebo in all symptom frequency groups. CONCLUSIONS: Long-term, once-daily, low-dose budesonide treatment decreases the risk of SAREs and improves asthma symptoms in patients with mild, recent-onset asthma. These beneficial effects were seen...

  1. Evaluation of supercritical fluid engineered budesonide powder for respiratory delivery using nebulisers.

    Science.gov (United States)

    Amani, Amir; Chrystyn, Henry; Clark, Brian J; Abdelrahim, Mohamed E; York, Peter

    2009-12-01

    Currently, suspensions prepared from micronised drug substances are the only delivery system marketed for nebulisation of steroids, and reported inconsistent or low bioavailability arising from their use provides a rationale for researching alternative formulations. Supercritical fluid processing of drug substances to obtain respirable-sized particles has been used over the last decade to formulate dry powder inhalers. We aimed thus to process budesonide powder to improve its deposition characteristics. In an attempt to overcome the limitations of nebuliser suspensions when prepared from micronised drug particles, budesonide powder was processed using a supercritical fluid based process and suspended using Tween 80 as a surfactant to provide an aqueous nebuliser formulation. The in-vitro characteristics of the emitted dose on nebulisation for the prepared suspension were then compared to a commercially available suspension formulation of budesonide using a jet and a vibrating mesh nebuliser. The results showed a significant improvement of the in-vitro deposition properties of the suspension containing supercritical fluid engineered budesonide particles. The results indicated the benefit of such materials compared with traditionally micronised drug powders.

  2. Coated particle assemblies for the concomitant pulmonary administration of budesonide and salbutamol sulphate.

    Science.gov (United States)

    Raula, Janne; Rahikkala, Antti; Halkola, Tuomas; Pessi, Jenni; Peltonen, Leena; Hirvonen, Jouni; Järvinen, Kristiina; Laaksonen, Timo; Kauppinen, Esko I

    2013-01-30

    The aims were to prepare stable and well-dispersible pulmonary fine powders composed of combination drugs with different water solubility, to facilitate concomitant release of corticosteroid budesonide and short acting β-agonist salbutamol sulphate and to improve the dissolution of the budesonide. The budesonide nanosuspensions were prepared by a wet milling which were mixed then with salbutamol sulphate, mannitol (bulking material) and leucine (coating material) for the preparation of micron-sized particles by an aerosol flow reactor wherein leucine formed a rough coating layer on particle surface. The stable and intact particle assemblies showed excellent aerosolization performance. The emitted doses from the inhaler, Easyhaler(®), were ~3 mg/dose with a coefficient variation of 0.1, and the fine particle fractions were ~50%. Complete dissolution of budesonide nanocrystals from the particles took place within 20 min with the same rate as salbutamol sulphate. Combining the two formulation technologies enabled the encapsulation of drugs with different solubility into a single, intact particle. The leucine coating provided excellent aerosolization properties which allowed fine powder delivery from the inhaler without carrier particles. This study showed the feasibility of preparing powders for combination therapy that are utilized, for instance, in inhalation therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma

    DEFF Research Database (Denmark)

    O'Byrne, Paul M; Bisgaard, Hans; Godard, Philippe P

    2005-01-01

    Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever...

  4. Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Psuedomonas aeruginosa infection

    DEFF Research Database (Denmark)

    Bisgaard, H; Pedersen, S S; Nielsen, K G

    1997-01-01

    consisted of budesonide dry powder, 800 microg twice daily, delivered from a Turbuhaler. The study period covered two successive 3-mo intervals between elective courses of intravenous anti-Pseudomonas antibiotics. Fifty-five patients entered the study, with a mean age of 20 yr and a mean FEV1 of 63...

  5. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide

    DEFF Research Database (Denmark)

    Bisgaard, H; Damkjaer Nielsen, M; Andersen, B

    1988-01-01

    The effect of inhaled beclomethasone dipropionate and budesonide on the adrenal function was studied in 30 children (aged 7 to 15 years) with mild bronchial asthma. The trial was designed as a prospective double-blind parallel study of the effect of stepwise increase of either beclomethasone...

  6. Different Nebulized Budesonide Dosing Regimens in a Mouse Model of Chronic Asthma

    Directory of Open Access Journals (Sweden)

    Pınar Uysal

    2016-12-01

    Full Text Available Objective: The aim of this study was to compare the effectiveness of different inhaled steroid regimens on the lungs and their potential side effects on the bone tissues in chronic asthma model. Materials and Methods: Thirty-five specific pathogen-free BALB/c mice were divided into five groups. The mice in all of the study groups except the control group were sensitized with chicken egg albumin. After sensitization, the mice in group 2 were treated with saline modeling twice daily, the mice in group 3 were treated with 250 mcg of nebulized budesonide twice daily, the mice in group 4 were treated with 500 mcg of budesonide once daily, and the mice in group 5 were treated with 1000 mcg of budesonide every other day for the last 14 days of the challenge period. After challenge, the mice were sacrificed and lung and tibia samples were histologically examined. Results: Pulmonary parameters, including subepithelial smooth muscle thickness, goblet cell count, mast cell count and epithelial thickness, were the lowest in group 5 compared to other groups (p0.01. Conclusion: The beneficial effect on lung tissue was highest in the treatment group receiving budesonide every other day (group 5 and no further measureable side effects on bone mineralization were observed in this group compared with the other treatment groups. Every-other-day treatment application seems to be the most effective regimen in chronic asthma model.

  7. EFFECTS OF BUDESONIDE AND BAMBUTEROL ON CIRCADIAN VARIATION OF AIRWAY RESPONSIVENESS AND NOCTURNAL SYMPTOMS OF ASTHMA

    NARCIS (Netherlands)

    WEMPE, JB; TAMMELING, EP; POSTMA, DS; AUFFARTH, B; TEENGS, JP; KOETER, GH

    Effects of the inhaled corticosteroid budesonide and the oral beta-agonist bambuterol on the nocturnal worsening of asthma were studied in patients with allergic asthma with a circadian peak expiratory flow variation greater-than-or-equal-to 15% (group 1, n = 8) and

  8. BLOOD EOSINOPHIL NUMBERS AND ACTIVITY DURING 24 HOURS - EFFECTS OF TREATMENT WITH BUDESONIDE AND BAMBUTEROL

    NARCIS (Netherlands)

    WEMPE, JB; TAMMELING, EP; KOETER, GH; HAKANSSON, L; VENGE, P; POSTMA, DS

    1992-01-01

    The effects of the inhaled corticosteroid budesonide and the oral long-acting beta-agonist bambuterol on circadian variation of blood eosinophil numbers, serum levels of eosinophil cationic protein (ECP), serum eosinophil chemotactic activity (ECA), and serum neutrophil chemotactic activity (NCA)

  9. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists.

    Science.gov (United States)

    Stahn, Cindy; Löwenberg, Mark; Hommes, Daniel W; Buttgereit, Frank

    2007-09-15

    Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGCR); secondary non-genomic effects which are also initiated by the cGCR; membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; non-specific, non-genomic effects caused by interactions with cellular membranes. The classical, genomic mechanism of GC-action can be divided into two processes: "transrepression", which is responsible for a large number of desirable anti-inflammatory and immunomodulating effects, and "transactivation" which is associated with frequently occurring side effects as well as with some immunosuppressive activities [Ehrchen, J., Steinmuller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkotter, C., Roth, J., 2007. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265-1274]. Great efforts have been made to diminish glucocorticoid-induced adverse effects, but the improvement of conventional glucocorticoids has almost reached its limits. As a consequence, new variations of the conventional "good old drugs" are being tested and nitro-steroids and long circulating liposomal glucocorticoids indeed show promising results. Nevertheless, crux of the matter should be the design of qualitatively new drugs, such as selective glucocorticoid receptor agonists (SEGRAs). These innovative steroidal or non-steroidal molecules induce transrepression, while transactivation processes are less affected. First reports on two different GCR ligands, A276575 and ZK216348, show promising results. Here, we review the above-mentioned mechanisms of glucocorticoid action and give particular attention

  10. Glucocorticoids, chronic stress, and obesity

    NARCIS (Netherlands)

    Dallman, Mary F.; Pecoraro, Norman C.; la Fleur, Susanne E.; Warne, James P.; Ginsberg, Abigail B.; Akana, Susan F.; Laugero, Kevin C.; Houshyar, Hani; Strack, Alison M.; Bhatnagar, Seema; Bell, Mary E.

    2006-01-01

    Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a

  11. Clinical aspects of glucocorticoid sensitivity

    NARCIS (Netherlands)

    S.W.J. Lamberts (Steven); N.A.T.M. Huizenga (Nannette); P. de Lange (Pieter); F.H. de Jong (Frank); J.W. Koper (Jan)

    1996-01-01

    textabstractRecent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant.' These abnormalities might explain why some individuals develop

  12. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial

    DEFF Research Database (Denmark)

    Vestbo, Jørgen; Sørensen, T; Lange, Peter

    1999-01-01

    BACKGROUND: Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD...... recruited from the general population by screening. We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD....... was outside the 95% CI. No effect of inhaled budesonide was seen on respiratory symptoms. 316 exacerbations occurred during the study period, 155 in the budesonide group and 161 in the placebo group. Treatment was well tolerated. INTERPRETATION: Inhaled budesonide was of no clinical benefit in COPD patients...

  13. [Clinical efficacy of porcine pulmonary surfactant combined with budesonide suspension intratracheal instillation in the treatment of neonatal meconium aspiration syndrome].

    Science.gov (United States)

    Tan, Xiu-Zhen; Wu, Shi-Guang; Zhang, Jian-Hua; Li, Xiao-Fen; Gao, Ping-Ming; Wang, Yu

    2016-12-01

    To study the clinical efficacy of porcine pulmonary surfactant (PS) combined with budesonide suspension intratracheal instillation in the treatment of neonatal meconium aspiration syndrome (MAS). Seventy neonates with MAS were enrolled for a prospective study. The neonates were randomly assigned to PS alone treatment group and PS+budesonide treatment group (n=35 each). The PS alone treatment group was given PS (100 mg/kg) by intratracheal instillation. The treatment group was given budesonide suspension (0.25 mg/kg) combined with PS (100 mg/kg). The rate of repeated use of PS in the PS+ budesonide group was significantly lower than that in the PS alone group 12 hours after treatment (p<0.05). The improvement of PaO 2 /FiO 2 , TcSaO 2 , PaO 2 , and PaCO 2 in the PS+ budesonide group was significantly greater than that in the PS alone group 6, 12, and 24 hours after treatment (p<0.05). The chest X-ray examination showed that the pulmonary inflammation absorption in the PS+ budesonide group was significantly better than that in the PS alone group 48 hours after treatment (p<0.05). The incidence of complications in the PS+budesonide group was significantly lower than that in the PS alone group (p<0.05), and the average hospitalization duration was significantly shorter than that in the PS alone group (p<0.01). PS combined with budesonide suspension intratracheal instillation for the treatment of neonatal MAS is effective and superior to PS alone treatment.

  14. Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts.

    Science.gov (United States)

    Fehrholz, Markus; Glaser, Kirsten; Speer, Christian P; Seidenspinner, Silvia; Ottensmeier, Barbara; Kunzmann, Steffen

    2017-03-23

    Although caffeine and glucocorticoids are frequently used to treat chronic lung disease in preterm neonates, potential interactions are largely unknown. While anti-inflammatory effects of glucocorticoids are well defined, their impact on airway remodeling is less characterized. Caffeine has been ascribed to positive effects on airway inflammation as well as remodeling. Connective tissue growth factor (CTGF, CCN2) plays a key role in airway remodeling and has been implicated in the pathogenesis of chronic lung diseases such as bronchopulmonary dysplasia (BPD) in preterm infants. The current study addressed the impact of glucocorticoids on the regulation of CTGF in the presence of caffeine using human lung epithelial and fibroblast cells. The human airway epithelial cell line H441 and the fetal lung fibroblast strain IMR-90 were exposed to different glucocorticoids (dexamethasone, budesonide, betamethasone, prednisolone, hydrocortisone) and caffeine. mRNA and protein expression of CTGF, TGF-β1-3, and TNF-α were determined by means of quantitative real-time PCR and immunoblotting. H441 cells were additionally treated with cAMP, the adenylyl cyclase activator forskolin, and the selective phosphodiesterase (PDE)-4 inhibitor cilomilast to mimic caffeine-mediated PDE inhibition. Treatment with different glucocorticoids (1 μM) significantly increased CTGF mRNA levels in H441 (p caffeine (10 mM), both glucocorticoid-induced mRNA and protein expression were significantly reduced in IMR-90 cells (p caffeine alone significantly suppressed basal expression of CTGF mRNA and protein in IMR-90 cells. Caffeine-induced reduction of CTGF mRNA expression seemed to be independent of cAMP levels, adenylyl cyclase activation, or PDE-4 inhibition. While dexamethasone or caffeine treatment did not affect TGF-β1 mRNA in H441 cells, increased expression of TGF-β2 and TGF-β3 mRNA was detected upon exposure to dexamethasone or dexamethasone and caffeine, respectively. Moreover

  15. Glucocorticoids, bone and energy metabolism.

    Science.gov (United States)

    Cooper, Mark S; Seibel, Markus J; Zhou, Hong

    2016-01-01

    Prolonged exposure to excessive levels of endogenous or exogenous glucocorticoids is associated with serious clinical features including altered body composition and the development of insulin resistance, impaired glucose tolerance and diabetes. It had been assumed that these adverse effects were mediated by direct effects of glucocorticoids on tissues such as adipose or liver. Recent studies have however indicated that these effects are, at least in part, mediated through the actions of glucocorticoids on bone and specifically the osteoblast. In mice, targeted abrogation of glucocorticoid signalling in osteoblasts significantly attenuated the changes in body composition and systemic fuel metabolism seen during glucocorticoid treatment. Heterotopic expression of osteocalcin in the liver of normal mice was also able to protect against the metabolic changes induced by glucocorticoids indicating that osteocalcin was the likely factor connecting bone osteoblasts to systemic fuel metabolism. Studies are now needed in humans to determine the extent to which glucocorticoid induced changes in body composition and systemic fuel metabolism are mediated through bone. This article is part of a Special Issue entitled Bone and diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. [Mechanisms of action of glucocorticoids].

    Science.gov (United States)

    Dejean, C; Richard, D

    2013-05-01

    Glucocorticoids exert their actions at nuclear levels through genomic mechanisms including both transcriptional activation (transactivation) and gene expression repression (transrepression). Transactivation mechanisms are mediated by transcription factors, the main one being the activated glucocorticoid receptor (GR). These mechanisms contribute to both powerful therapeutic effects of glucocorticoids on inflammatory and immune diseases, and adverse effects than can be harmful on vital functions. Non-genomic mechanisms, which act faster than genomic ones, have also been explored. They also involve the GR in different membranous and cytosolic sites. The phenomenon of glucocorticoid resistance is also complex and several different mechanisms may mediate this phenomenon. Among them are alterations in number, binding affinity or phosphorylation status of the GR, changes in capacity of cellular apoptosis, polymorphic changes or expression of proteins involved in the genomic actions of glucocorticoids. Finally, some proteins, which mediate glucocorticoid activity could be therapeutic targets for reducing glucocorticoid-induced adverse effects. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  17. Budesonide/formoterol maintenance and reliever therapy versus conventional best practice

    DEFF Research Database (Denmark)

    Demoly, Pascal; Louis, Renaud; Søes-Petersen, Ulrik

    2009-01-01

    Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) reduces asthma exacerbations and symptoms versus fixed-dose regimens plus short-acting beta(2)-agonists (SABA) in double-blind trials. Information is lacking regarding its effectiveness versus conventional best practice (CBP....../formoterol maintenance and reliever therapy (160/4.5microg bid and as needed) or CBP (ICS or ICS/LABA+/-other agents at an approved dose plus as-needed SABA). Overall asthma control was assessed comparing the incidence of exacerbations and levels of asthma control using the asthma control questionnaire (ACQ). Budesonide....../formoterol maintenance and reliever therapy did not significantly reduce time to first severe exacerbation (primary variable) versus CBP (P=0.062). However, patients in this group experienced 15% fewer exacerbations (0.20 versus 0.24/patient/year; P=0.021) and used 27% less ICS (P

  18. The Effects of Inhaled Budesonide on Lung Function in Smokers and Nonsmokers With Mild Persistent Asthma

    DEFF Research Database (Denmark)

    O'Byrne, Paul M; Lamm, Carl Johan; Busse, William W

    2009-01-01

    difference being -83.1 mL (p 5 mL (p = 0.011) in smokers and + 46.5 mL (p = 0.001) in nonsmokers. The corresponding effect......BACKGROUND: Previous studies have suggested reduced benefit from inhaled corticosteroids (ICS) in smoking asthmatics. The objective of this post-hoc study was to study the effects of low dose inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma. METHODS: Adult...

  19. [Glucocorticoids in rheumatology].

    Science.gov (United States)

    Dziurla, R; Buttgereit, F

    2008-11-01

    Glucocorticoids (GC) are effective drugs which are often used in rheumatology. However, they have a considerable potential for frequent and sometimes serious side effects that restrict their use. Their mechanisms of action are either receptor dependent (specific) or independent (unspecific) on the genomic as well as the non-genomic level. Many adverse effects are predominantly caused by transactivation while the desired effects are mostly mediated by transrepression. Treatment strategies are sub-classified into low, medium, high, very high dose and pulse therapy based on criteria such as dose, indication, duration of treatment and potential risk of adverse events. The musculoskeletal, gastrointestinal, neuro-endocrino-immunological, opthalmological and neuropsychiatric systems are examples where adverse effects may occur.

  20. In vitro release profiles of PLGA core-shell composite particles loaded with theophylline and budesonide.

    Science.gov (United States)

    Yeh, Hsi-Wei; Chen, Da-Ren

    2017-08-07

    We investigated the effects of drug loading location, matrix material and shell thickness on the in vitro release of combinational drugs from core-shell PLGA (i.e., poly(lactic-co-glycolic acid)) particles. Budesonide and Theophylline were selected as highly hydrophobic and hydrophilic model drugs, respectively. The dual-capillary electrospray (ES) technique, operated at the cone-jet mode, was used to produce samples of drug-loaded core-shell composite particles with selected overall sizes, polymer materials, and shell thicknesses. Theophylline and Budesonide were loaded at different locations in a PLGA composite particle. This study illustrated how the aforementioned factors affect the release rates of Budesonide and Theophylline loaded in core-shell PLGA composites. We further identified that core-shell composite particles with both model drugs loaded in the core and with matrix PLGA polymers of low molecular weights and low LA/GA ratios are the best formulation for the sustained release of highly hydrophilic and hydrophobic active pharmaceutical ingredients from PLGA composite particles. The formulation strategy obtained in this study can be in principle generalized for biopharmaceutical applications in fixed-dose combination therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Impact of glucocorticoid on neurogenesis

    Directory of Open Access Journals (Sweden)

    Haruki Odaka

    2017-01-01

    Full Text Available Neurogenesis is currently an area of great interest in neuroscience. It is closely linked to brain diseases, including mental disorders and neurodevelopmental disease. Both embryonic and adult neurogeneses are influenced by glucocorticoids secreted from the adrenal glands in response to a variety of stressors. Moreover, proliferation/differentiation of the neural stem/progenitor cells (NSPCs is affected by glucocorticoids through intracellular signaling pathways such as phosphoinositide 3-kinase (PI3K/Akt, hedgehog, and Wnt. Our review presents recent evidence of the impact of glucocorticoids on NSPC behaviors and the underlying molecular mechanisms; this provides important information for understanding the pathological role of glucocorticoids on neurogenesis-associated brain diseases.

  2. Locomotor therapy with extended-release crystalline glucocorticoids

    Directory of Open Access Journals (Sweden)

    Vladimir Vasilyevich Badokin

    2013-01-01

    Full Text Available Topical glucocorticoid (GC therapy for locomotor diseases is an extremely important component of a comprehensive program to treat inflammatory and, to a lesser extent, degenerative diseases. It reduces the time of hospitalization by 5—10 days in this category of patients, has a prompt and potent anti-inflammatory effect, and shows predictable efficiency. This therapy shows good tolerability and high safety and prevents serious adverse reactions to GC treatment.

  3. Dose uniformity of budesonide Easyhaler® under simulated real-life conditions and with low inspiration flow rates.

    Science.gov (United States)

    Haikarainen, Jussi; Rytilä, Paula; Roos, Sirkku; Metsärinne, Sirpa; Happonen, Anita

    2017-01-01

    Budesonide Easyhaler® multidose dry powder inhaler is approved for the treatment of asthma. Objectives were to determine the delivered dose (DD) uniformity of budesonide Easyhaler® in simulated real-world conditions and with different inspiration flow rates (IFRs). Three dose delivery studies were performed using 100, 200, and 400 µg/dose strengths of budesonide. Dose uniformity was assessed during in-use periods of 4-6 months after exposure to high temperature (30°C) and humidity (60% relative humidity) and after dropping and vibration testing. The influence of various IFRs (31, 43, and 54 L/min) on the DD was also investigated. Acceptable dose uniformity was declared when mean DD were within 80-120% of expected dose; all data reported descriptively. DD was constant (range: 93-109% of expected dose) at all in-use periods and after exposure to high temperature and humidity for a duration of up to 6 months. DD post-dropping and -vibration were unaffected (range 98-105% of expected dose). Similarly, DD was constant and within 10% of expected dose across all IFRs. Results indicate that budesonide Easyhaler® delivers consistently accurate doses in various real-life conditions. Budesonide Easyhaler® can be expected to consistently deliver a uniform dose and improve asthma control regardless of high temperature and humidity or varying IFR.

  4. Glucocorticoid treatment and impaired mood, memory and metabolism in people with diabetes: the Edinburgh Type 2 Diabetes Study

    Science.gov (United States)

    Reynolds, Rebecca M; Labad, Javier; Sears, Alison V; Williamson, Rachel M; Strachan, Mark W J; Deary, Ian J; Lowe, Gordon D O; Price, Jackie F; Walker, Brian R

    2012-01-01

    Objective Both type 2 diabetes and glucocorticoid therapy are highly prevalent. Although people with type 2 diabetes may be more susceptible to adverse effects of glucocorticoids, and it is recommended that glucocorticoid therapy is avoided for fear of worsening glycaemic control, the extent to which this advice is followed and the consequences when glucocorticoids are prescribed are poorly documented. The aim was to assess the characteristics of people with type 2 diabetes prescribed glucocorticoids in a real-world setting and to quantify resulting adverse effects. Design Cross-sectional cohort study. Methods Cardiometabolic variables, body fat distribution, cognitive function and mood were studied in the 1066 participants of the Edinburgh Type 2 Diabetes Study, of whom 162 (15%) were taking systemic, topical or inhaled glucocorticoids. Results Glucocorticoid therapy was more common in women and in smokers but was not avoided in patients with diabetic complications or cardiovascular risk factors. People taking glucocorticoids were more centrally obese with slightly higher HbA1c and total serum cholesterol but were no more likely to have hepatic steatosis or hypertension. Glucocorticoid treatment was associated with substantially lower mood and greater anxiety. Women taking glucocorticoid therapy were twice as likely to report depressive symptoms compared with those not taking treatment. Glucocorticoid therapy was also associated with poorer cognitive function among those with subclinical atherosclerosis, as indicated by low ankle–brachial pressure index. Conclusions Glucocorticoids are prescribed commonly for people with type 2 diabetes despite being associated with adverse indices of glycaemic control, cardiovascular risk factors, mood and cognitive function. PMID:22408122

  5. [Efficacy of systemic glucocorticoids combined with inhaled steroid on children with acute laryngitis].

    Science.gov (United States)

    Chen, Q P; Zhou, R F; Zhang, Y M; Yang, L

    2018-01-07

    Objective: To evaluate the efficacy of systemic glucocorticoid (steroid) combined with high dose inhaled steroid in the treatment of children with acute laryngitis. Methods: A total of 78 children with acute laryngitis were randomly divided into study group( n =40) and control group( n =38) between November 2016 and April 2017. In addition to routine treatment of anti infection and symptomatic treatment, Dexamethasone injection(0.3-0.5 mg/kg, 1-3 d, according to the patient's condition) was provided to each group. In addition to the treatment mentioned above, the study group were assigned to receive 1.0 mg Budesonide suspension for inhalation, oxygen-driven atomizing inhalation, every/30 minutes, 2 times in a row, after that every 12 hours. The improvement of inspiratory dyspnea, hoarseness, barking cough and wheezing of both groups was evaluated at 30 min, 1 h, 2 h, 6 h, 12 h, 24 h and 72 h after treatment.Sigmaplot 11.5 software was used to analyze the data. Results: No significant difference was detected in terms of inspiratory dyspnea, hoarseness, barking cough or stridor score before treatment between the two groups( P >0.05). Compared with those before treatment, symptoms of inspiratory dyspnea, hoarseness, barking cough and stridor score of both groups improved markedly at 12 h and 24 h after treatment( P dyspnea, hoarseness, barking cough or stridor score at each time point after treatment between the two groups( P >0.05). The effective rate was 92.50% and 92.11% in study group and control group, respectively, and no significant difference was noted ( P >0.05). Conclusion: Compared with single systemic glucocorticoid, systemic glucocorticoids combined with inhaled steroid possessed similar efficacy in treating acute laryngitis and relieving laryngeal obstruction of children.

  6. Progesterone attenuates airway remodeling and glucocorticoid resistance in a murine model of exposing to ozone.

    Science.gov (United States)

    Zhang, Xue; Bao, Wuping; Fei, Xia; Zhang, Yingying; Zhang, Guoqing; Zhou, Xin; Zhang, Min

    2018-03-01

    Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week. The peribronchial collagen deposition was measured. The protein levels of MMP8 and MMP9 in bronchoalveolar lavage fluid (BALF) and lungs were assessed. Western blot analysis was used to detect the levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), a-smooth muscle actin (α-SMA), glycogen synthase kinase-3β (GSK-3β). The expression of VEGF and histone deacetylase 2 (HDAC2) in the lung were determined by Immunohistochemical analyses. We observe that progesterone attenuates the peribronchial collagen deposition, as well as the expression of MMP8, MMP9, HIF-1α, VEGF, α-SMA, and GSK-3β in BALF or lung tissues. Progesterone or BUD monotherapy has no effect on HDAC2 production. Progesterone combines with BUD induce dramatically enhanced effects. Thus, these results demonstrate novel roles of progesterone for the pathogenesis and airway remodeling in COPD. Progesterone plus BUD administration exerts more significant inhibition on airway remodeling with dose-independent. Additionally, progesterone may, to some extent, improve the glucocorticoid insensitivity. Copyright © 2018. Published by Elsevier Ltd.

  7. From gastroprotective to ulcerogenic effects of glucocorticoids: role of long-term glucocorticoid action.

    Science.gov (United States)

    Filaretova, Ludmila; Podvigina, Tatiana; Bagaeva, Tatiana; Morozova, Olga

    2014-01-01

    Glucocorticoids may have dual action on the gastric mucosa: gastroprotective and ulcerogenic. In this article, we review the data which suggested that an initial action of endogenous glucocorticoids, including stress-produced ones as well as exogenous glucocorticoids is gastroprotective and consider possible mechanisms of the conversion of physiological gastroprotective action of glucocorticoid hormones to their pathological ulcerogenic effect.

  8. Glucocorticoid programming of neuroimmune function.

    Science.gov (United States)

    Walker, David J; Spencer, Karen A

    2018-01-15

    Throughout life physiological systems strive to maintain homeostasis and these systems are susceptible to exposure to maternal or environmental perturbations, particularly during embryonic development. In some cases, these perturbations may influence genetic and physiological processes that permanently alter the functioning of these physiological systems; a process known as developmental programming. In recent years, the neuroimmune system has garnered attention for its fundamental interactions with key hormonal systems, such as the hypothalamic pituitary adrenal (HPA) axis. The ultimate product of this axis, the glucocorticoid hormones, play a key role in modulating immune responses within the periphery and the CNS as part of the physiological stress response. It is well-established that elevated glucocorticoids induced by developmental stress exert profound short and long-term physiological effects, yet there is relatively little information of how these effects are manifested within the neuroimmune system. Pre and post-natal periods are prime candidates for manipulation in order to uncover the physiological mechanisms that underlie glucocorticoid programming of neuroimmune responses. Understanding the potential programming role of glucocorticoids may be key in uncovering vulnerable windows of CNS susceptibility to stressful experiences during embryonic development and improve our use of glucocorticoids as therapeutics in the treatment of neurodegenerative diseases. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  9. Investigations of Glucocorticoid Action in GN

    NARCIS (Netherlands)

    Kuppe, C.; Roeyen, C. van; Leuchtle, K.; Kabgani, N.; Vogt, M.; Zandvoort, M. Van; Smeets, B.; Floege, J.; Grone, H.J.; Moeller, M.J.

    2017-01-01

    For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR)

  10. Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics

    DEFF Research Database (Denmark)

    Bisgaard, H; Nikander, K; Munch, E

    1998-01-01

    . A consistent trend showed the nebulizer treatment to be at least as efficient as the pMDI plus spacer treatment. In actual fact, the apparent order of effect was: 4 mg nebulized suspension treatment > or = 1 mg nebulized suspension treatment > or = 0.8 mg pMDI with spacer treatment. Plasma budesonide...... and plasma cortisol also exhibited dose-related levels independent of device. The adverse effects reported appeared to be related to the dose rather than delivery device. Accordingly, the effect was related to total mass output, rather than to the small particle fraction of the budesonide aerosol...

  11. Investigation into Alternative Sugars as Potential Carriers for Dry Powder Formulation of Budesonide

    Directory of Open Access Journals (Sweden)

    Ali Nokhodchi

    2011-08-01

    Full Text Available Introduction: Dry powder inhaler (DPI formulations are so far being used for pulmonary drug delivery, mainly for the treatment of asthma and chronic obstructive pulmonary disease (COPD. Currently most of DPI formulations rely on lactose as a carrier in the drug powder blend. However, due to reducing sugar function of lactose which makes it incompatible with some drugs such as budesonide, it is realistic to investigate for alternative sugars that would overcome the concerned drawback but still have the positive aspects of lactose. Methods: The study was conducted by characterizing carriers for their physico-chemical properties and preparing drug/carrier blends with concentration of 5% and 10% drug with the carrier. The mixing uniformity (homogeneity of Budesonide in the blends was analyzed using spectrophotometer. The blend was then filled into NB7/2 Airmax inhaler device and the deposition profiles of the drug were determined using multi stage liquid impinger (MSLI after aerosolization at 4 kPa via the inhaler. The morphology of the carriers conducted using the scanning electron microscope. Results: The results determined that the mean fine particle fraction (FPF of 5% and 10% blends of mannitol was 61%, possibly due to fine elongated particles. Dextrose exhibited excellent flowability. Scanning electron microscope illustrated mannitol with fine elongated particles and dextrose presenting larger and coarse particles. It was found out that type of carriers, particle size distribution, and morphology would influence the FPF of budesonide. Conclusion: It may be concluded that mannitol could be suitable as a carrier on the basis of its pharmaceutical performance and successful achievement of FPF whereas the more hygroscopic sugars such as sorbitol or xylitol showed poor dispersibility leading to lower FPF.

  12. Lack of effect of methotrexate in budesonide-refractory collagenous colitis

    Directory of Open Access Journals (Sweden)

    Münch A

    2013-08-01

    Full Text Available Andreas Münch,1,* Johan Bohr,2,3,* Lina Vigren,4 Curt Tysk,2,3,* Magnus Ström1,* 1Division of Gastroenterology and Hepatology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, 2Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro University, Örebro, 3School of Health and Medical Science, Örebro University, Örebro, 4Division of Gastroenterology, Department of Clinical Science, Lund University, Malmö, Sweden *These authors are members of the Swedish Organization for the study of Inflammatory Bowel Disease (SOIBD, a national organization for gastroenterologists, colorectal surgeons, and basic scientists Background: In most cases, collagenous colitis can be treated effectively with budesonide. However, some patients develop side effects or have chronic symptoms refractory to budesonide. This paper reports an open case series of patients intolerant or refractory to budesonide who were treated with methotrexate (MTX. Methods and patients: Nine patients (seven women with a median (range age of 62 (44–77 years were studied. Bowel movements were registered during 1 week prior to baseline and after 6 and 12 weeks’ treatment, enabling calculation of the mean bowel movements/day. All patients underwent colonoscopy with biopsies before inclusion to confirm diagnosis. Open treatment with MTX was given 15 mg subcutaneously weekly for 6 weeks and was increased to 25 mg for a further 6 weeks if symptoms were unresponsive to the first 6 weeks’ treatment. The endpoint was clinical remission, which was defined as a mean <3 stools/day and mean <1 watery stool/day/week at Week 12. The Short Health Scale was used at baseline and Week 12 to assess health-related quality of life. Results: Five patients fulfilled the treatment according to the protocol and four patients discontinued the study after 3–6 weeks because of adverse events. No patient achieved

  13. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

    NARCIS (Netherlands)

    Stahn, Cindy; Löwenberg, Mark; Hommes, Daniel W.; Buttgereit, Frank

    2007-01-01

    Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused

  14. Tavaborole Topical

    Science.gov (United States)

    Tavaborole topical solution is used to treat fungal toenail infections (infections that may cause nail discoloration, splitting, or pain). Tavaborole topical solution is in a class of medications called antifungals. It works by stopping the growth of nail ...

  15. Efinaconazole Topical

    Science.gov (United States)

    Efinaconazole topical solution is used to treat fungal toenail infections (infections that may cause nail discoloration, splitting, or pain). Efinaconazole topical solution is in a class of medications called antifungals. It works by stopping the growth of nail ...

  16. Health Topics

    Science.gov (United States)

    ... Carpal tunnel syndrome Depression Irritable bowel syndrome Migraine Thyroid disease Urinary tract infections All A-Z health topics ... Carpal tunnel syndrome Depression Irritable bowel syndrome Migraine Thyroid disease Urinary tract infections All A-Z health topics ...

  17. Insight into the molecular mechanisms of glucocorticoid receptor action promotes identification of novel ligands with an improved therapeutic index.

    Science.gov (United States)

    Schäcke, Heike; Rehwinkel, Hartmut; Asadullah, Khusru; Cato, Andrew C B

    2006-08-01

    Glucocorticoids are highly effective in the therapy of inflammatory and autoimmune disorders. Their beneficial action is restricted because of their adverse effects upon prolonged usage. Topical glucocorticoids that act locally have been developed to significantly reduce systemic side effects. Nonetheless, undesirable cutaneous effects such as skin atrophy persist from the use of topical glucocorticoids. There is therefore a high medical need for drugs as effective as glucocorticoids but with a reduced side-effect profile. Glucocorticoids function by binding to and activating the glucocorticoid receptor that positively or negatively regulates the expression of specific genes. Several experiments suggest that the negative regulation of gene expression by the glucocorticoid receptor accounts for its anti-inflammatory action. This occurs through direct or indirect binding of the receptor to transcription factors such as activator protein-1, nuclear factor-kappaB or interferon regulatory factor-3 that are already bound to their regulatory sites. The positive action of the receptor occurs through homodimer binding of the receptor to discrete nucleotide sequences and this possibly contributes to some of the adverse effects of the hormone. Glucocorticoid receptor ligands that promote the negative regulatory action of the receptor with reduced positive regulatory function should therefore show improved therapeutic potential. A complete separation of the positive from the negative regulatory activities of the receptor has so far not been possible because of the interdependent nature of the two regulatory processes. Nevertheless, considerable improvement in the therapeutic action of glucocorticoid receptor ligands is being achieved through the use of key molecular targets for screening novel glucocorticoid receptor ligands.

  18. Glucocorticoids in nephrology II: indications and dosage

    Directory of Open Access Journals (Sweden)

    Jernej Pajek

    2015-05-01

    Full Text Available Present article describes glucocorticoid prescriptions in nephrology and renal transplantation, the dosages in induction and maintenance treatment phases and discontinuation. Key evidence and landmark trials are referenced, to establish the basis for modern glucocorticoid application in specific kidney disease indications. The glucocorticoid regimens in IgA glomerulonephritis, major primary glomerular diseases with nephrotic syndrome, vasculitides and tubulointerstitial nephritis are described. Various schemes for glucocorticoid dosage in lupus nephritis are given. The evolution of glucocorticoid usage in kidney transplantation is delineated and the modern role of these drugs in renal transplantation is defined. There are attempts to replace glucocorticoids with adrenocorticotrophic hormone in some glomerular diseases. Despite being relatively old drugs and having numerous side effects, glucocorticoids still function as major therapeutic agents for specific immunosuppressive treatment in nephrology.

  19. Mechanisms of Glucocorticoid Action During Development.

    Science.gov (United States)

    Busada, Jonathan T; Cidlowski, John A

    2017-01-01

    Glucocorticoids are primary stress hormones produced by the adrenal cortex. The concentration of serum glucocorticoids in the fetus is low throughout most of gestation but surge in the weeks prior to birth. While their most well-known function is to stimulate differentiation and functional development of the lungs, glucocorticoids also play crucial roles in the development of several other organ systems. Mothers at risk of preterm delivery are administered glucocorticoids to accelerate fetal lung development and prevent respiratory distress. Conversely, excessive glucocorticoid signaling is detrimental for fetal development; slowing fetal and placental growth and programming the individual for disease later in adult life. This review explores the mechanisms that control glucocorticoid signaling during pregnancy and provides an overview of the impact of glucocorticoid signaling on fetal development. © 2017 Elsevier Inc. All rights reserved.

  20. Glucocorticoid programming of intrauterine development.

    Science.gov (United States)

    Fowden, A L; Valenzuela, O A; Vaughan, O R; Jellyman, J K; Forhead, A J

    2016-07-01

    Glucocorticoids (GCs) are important environmental and maturational signals during intrauterine development. Toward term, the maturational rise in fetal glucocorticoid receptor concentrations decreases fetal growth and induces differentiation of key tissues essential for neonatal survival. When cortisol levels rise earlier in gestation as a result of suboptimal conditions for fetal growth, the switch from tissue accretion to differentiation is initiated prematurely, which alters the phenotype that develops from the genotype inherited at conception. Although this improves the chances of survival should delivery occur, it also has functional consequences for the offspring long after birth. Glucocorticoids are, therefore, also programming signals that permanently alter tissue structure and function during intrauterine development to optimize offspring fitness. However, if the postnatal environmental conditions differ from those signaled in utero, the phenotypical outcome of early-life glucocorticoid receptor overexposure may become maladaptive and lead to physiological dysfunction in the adult. This review focuses on the role of GCs in developmental programming, primarily in farm species. It examines the factors influencing GC bioavailability in utero and the effects that GCs have on the development of fetal tissues and organ systems, both at term and earlier in gestation. It also discusses the windows of susceptibility to GC overexposure in early life together with the molecular mechanisms and long-term consequences of GC programming with particular emphasis on the cardiovascular, metabolic, and endocrine phenotype of the offspring. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Inhibitory effects of budesonide, desloratadine and dexamethasone on cytokine release from human mast cell line (HMC-1).

    Science.gov (United States)

    Zhao, Y; Leung, P C; Woo, K S; Chen, G G; Wong, Y O; Liu, S X; van Hasselt, C A

    2004-12-01

    To determine the inhibitory potency of budesonide on interleukin (IL)-4, 6 and 8, GM-CSF and TNF-alpha release from the human mast cell line (HMC-1) in comparison with the systemic glucocorticosteroid, dexamethasone, and H(1) antagonist, desloratadine. HMC-1 was stimulated with 25 ng/ml phorbol 12- myristate 13-acetate (PMA) and 2.5 x 10(-7) M ionomycin (A23187) for 6, 12 and 24 h in both the presence and absence of 10(-6)-10(-10) M concentrations of the test drugs. Culture supernatants were collected and assayed by ELISAs. HMC-1 produced substantial amounts of GM-CSF and IL-8 and smaller amounts of TNF-alpha, IL-4 and IL-6 after being stimulated with PMA together with A23187. Budesonide and dexamethasone had potent inhibitory effects and desloratadine had modest inhibitory effects on the release of these cytokines. Budesonide was more potent than dexamethasone at most concentrations and time points. IL-4 was the cytokine which was most susceptible to inhibition by the three tested drugs. The inhibitory effects, in some cases, were time- and concentration-dependent. Budesonide had a potent inhibitory effect on cytokine release from HMC-1. Its potency was greater than that of both dexamethasone and desloratadine.

  2. Iatrogenic Cushing's Syndrome After Topical Steroid Therapy for Psoriasis.

    Science.gov (United States)

    Sahıp, Birsen; Celık, Mehmet; Ayturk, Semra; Kucukarda, Ahmet; Mert, Onur; Dıncer, Nejla; Guldıken, Sıbel; Tugrul, Armagan

    2016-01-01

    Glucocorticoids are used for the treatment of many diseases, such as inflammatory, allergic, autoimmune, and neoplastic diseases. They can be used in the form of topical, oral, inhalable, rectal, and intra-articular agents. Many topical steroid-related iatrogenic Cushing's syndrome cases affecting especially children have been reported in the literature. Topical steroid-related Cushing's syndrome is rarely seen in adults. In this report, we present the case of a 32-year-old male patient with iatrogenic Cushing's syndrome related to long-term clobetasol propionate treatment for psoriasis. In the context of such treatment, the glucocorticoid withdrawal problem has to be overcome. At present there is no consensus on steroid withdrawal. Patients on long-term glucocorticoid treatment must be evaluated for potential adverse effects and withdrawal symptoms by their physician and their endocrinologist.

  3. Mode of Glucocorticoid Actions in Airway Disease

    Directory of Open Access Journals (Sweden)

    Kazuhiro Ito

    2006-01-01

    Full Text Available Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5% of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR, which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.

  4. Does insulin resistance co-exist with glucocorticoid resistance in the metabolic syndrome? Studies comparing skin sensitivity to glucocorticoids in individuals with and without acanthosis nigricans.

    Science.gov (United States)

    Teelucksingh, Surujpal; Jaimungal, Sarada; Pinto Pereira, Lexley; Seemungal, Terence; Nayak, Shivananda

    2012-03-30

    The metabolic syndrome is associated with increased risk for both diabetes and coronary artery disease, which insulin resistance alone does not satisfactorily explain. We propose an additional and complementary underlying mechanism of glucocorticoid resistance. Using acanthosis nigricans (AN) and skin vasoconstrictor (SVC) response to topically applied beclomethasone dipropionate as markers of insulin and glucocorticoid resistance, respectively, we compared anthropometric, biochemical, pro-inflammatory markers and the SVC response in subjects with AN in two studies: STUDY 1 was used to compare subjects with AN (Grade 4, n = 32), with those without AN (n = 68) while STUDY 2 compared these responses among a cross-section of diabetic patients (n = 109) with varying grades of AN (grade 0, n = 30; grade 1, n = 24; grade 2, n = 18; grade 3, n = 25; grade 4, n = 12). In both studies there was an inverse relationship between AN Grade 4 and the SVC response, (P glucocorticoid action in vascular tissue.

  5. Iatrogenic Cushing's Syndrome After Topical Steroid Therapy for Psoriasis

    OpenAIRE

    Sah?p, Birsen; Cel?k, Mehmet; Ayturk, Semra; Kucukarda, Ahmet; Mert, Onur; D?ncer, Nejla; Guld?ken, S?bel; Tugrul, Armagan

    2016-01-01

    Glucocorticoids are used for the treatment of many diseases, such as inflammatory, allergic, autoimmune, and neoplastic diseases. They can be used in the form of topical, oral, inhalable, rectal, and intra-articular agents. Many topical steroid-related iatrogenic Cushing′s syndrome cases affecting especially children have been reported in the literature. Topical steroid-related Cushing′s syndrome is rarely seen in adults. In this report, we present the case of a 32-year-old male patient with ...

  6. New dimension of glucocorticoids in cancer treatment.

    Science.gov (United States)

    Lin, Kai-Ti; Wang, Lu-Hai

    2016-07-01

    Glucocorticoids have been used in clinical oncology for over half a century. The clinical applications of glucocorticoids in oncology are mainly dependent on their pro-apoptotic action to treat lymphoproliferative disorders, and also on alleviating side effects induced by chemotherapy or radiotherapy in non-hematologic cancer types. Researches in the past few years have begun to unveil the profound complexity of glucocorticoids signaling and have contributed remarkably on therapeutic strategies. However, it remains striking and puzzling how glucocorticoids use different mechanisms in different cancer types and different targets to promote or inhibit tumor progression. In this review, we provide an update on glucocorticoids and its receptor, GR-mediated signaling and highlight some of the latest findings on the actions of glucocorticoids signaling during tumor progression and metastasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma

    DEFF Research Database (Denmark)

    Busse, William W; Pedersen, Søren; Pauwels, Romain A

    2008-01-01

    BACKGROUND: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study enrolled 7241 patients aged 5 to 66 years with recent-onset, mild persistent asthma to assess early intervention with the inhaled corticosteroid budesonide on long-term asthma control. OBJECTIVE: The open......-label phase of the START study was included to determine the effect on lung function and asthma control of adding budesonide to the reference group patients who had not initially received inhaled corticosteroids. METHODS: Patients were randomized to double-blind treatment with budesonide, 200 mug (those aged...... asthma therapy for 3 years, after which all patients received 2 years of open-label treatment with budesonide once daily. RESULTS: During the full 5-year study period, postbronchodilator FEV(1) percent predicted decreased, irrespective...

  8. Comparison of the effect of high-dose inhaled budesonide and fluticasone on adrenal function in patients with severe chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Ahmed Fahim

    2012-01-01

    Conclusion: Inhaled budesonide and fluticasone have no significantly different effect on adrenal function in moderate to severe COPD. The adverse event profile of high-dose inhaled steroids should not influence the choice of medication.

  9. Xenobiotics and the Glucocorticoid Receptor.

    Science.gov (United States)

    Gulliver, Linda S M

    2017-03-15

    Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Glucocorticoid control of gene transcription in neural tissue

    NARCIS (Netherlands)

    Morsink, Maarten Christian

    2007-01-01

    Glucocorticoid hormones exert modulatory effects on neural function in a delayed genomic fashion. The two receptor types that can bind glucocorticoids, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), are ligand-inducible transcription factors. Therefore, changes in gene

  11. The effects of glucocorticoids on feeding behavior in rats

    NARCIS (Netherlands)

    la Fleur, Susanne E.

    2006-01-01

    Glucocorticoids have major effects on food intake, however, the underlying mechanisms are poorly understood. This article highlights data on the changes that occur when glucocorticoids are removed by adrenalectomy, and the effects of central and systemic administered glucocorticoids on feeding

  12. THE SURPRISING DUAL ACTION OF GLUCOCORTICOIDS.

    Science.gov (United States)

    Filaretova, Ludmila; Makara, Gábor

    2014-03-30

    Glucocorticoid hormones may have dual action on the stomach: physiological gastroprotective and pathological proulcerogenic one. In physiological conditions, even in acute stress situations, glucocorticoids have an adaptive effect on the stomach and, therefore, are gastroprotective. The findings that we review in this article suggest that glucocorticoids released during acute stress are naturally occurring protective factors that play an important role in maintenance of the gastric mucosal integrity.

  13. Aging, glucocorticoids and developmental programming.

    Science.gov (United States)

    Zambrano, E; Reyes-Castro, L A; Nathanielsz, P W

    2015-06-01

    Glucocorticoids are pleiotropic regulators of multiple cell types with critical roles in physiological systems that change across the life-course. Although glucocorticoids have been associated with aging, available data on the aging trajectory in basal circulating glucocorticoids are conflicting. A literature search reveals sparse life-course data. We evaluated (1) the profile of basal circulating corticosterone across the life-course from weaning (postnatal day-PND 21), young adult PND 110, adult PND 450, mature adult PND 650 to aged phase PND 850 in a well-characterized homogeneous rat colony to determine existence of significant changes in trajectory in the second half of life; (2) sex differences; and (3) whether developmental programming of offspring by exposure to maternal obesity during development alters the later-life circulating corticosterone trajectory. We identified (1) a fall in corticosterone between PND 450 and 650 in both males and females (p age but from higher levels in male and female offspring of obese mothers. In all four groups studied, there was a second half of life fall in corticosterone. Higher corticosterone levels in offspring of obese mothers may play a role in their shorter life-span, but the age-associated fall occurs at a similar time to control offspring. Although even more life-course time-points would be useful, a five life-course time-point analysis provides important new information on normative and programmed aging of circulating corticosterone.

  14. AMPK regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 MAPK.

    Science.gov (United States)

    Nader, Nancy; Ng, Sinnie Sin Man; Lambrou, George I; Pervanidou, Panagiota; Wang, Yonghong; Chrousos, George P; Kino, Tomoshige

    2010-09-01

    Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, whereas AMP-activated protein kinase (AMPK) is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive glucocorticoid-inducible leucine zipper protein, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Because increased action of glucocorticoids is associated with the development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacological interventions to these pathologies.

  15. Long-term side effects of glucocorticoids.

    Science.gov (United States)

    Oray, Merih; Abu Samra, Khawla; Ebrahimiadib, Nazanin; Meese, Halea; Foster, C Stephen

    2016-01-01

    Glucocorticoids represent the standard therapy for reducing inflammation and immune activation in various diseases. However, as with any potent medication, they are not without side effects. Glucocorticoid-associated side effects may involve most major organ systems. Musculoskeletal, gastrointestinal, cardiovascular, endocrine, neuropsychiatric, dermatologic, ocular, and immunologic side effects are all possible. This article analyzes English-language literature and provides an update on the most recent literature regarding side effects of systemic glucocorticoid treatment. The risk/benefit ratio of glucocorticoid therapy can be improved by proper use. Careful monitoring and using appropriate preventive strategies can potentially minimize side effects.

  16. Analysis of the structure and surfactant activity of novel formulations containing exogenous pulmonary surfactant and glucocorticoids.

    Science.gov (United States)

    Cimato, Alejandra; Hoyos Obando, Andres; Facorro, Graciela; Martínez Sarrasague, María

    2016-11-01

    Exogenous pulmonary surfactant (EPS) could be used as carrier of glucocorticoids (GCs) in therapy for respiratory diseases. We formulated novel combination drug products containing bovine EPS and one GC (10wt%): beclomethasone (Be), budesonide (Bu) or fluticasone (Flu), and studied the GCs action on the surface activity and biophysical properties of EPS. Subtype ratio was evaluated by phospholipid determination; surface tension (ST) with a pulsating bubble surfactometer and conformational changes by Electron Spin Resonance (ESR). GCs were incorporated into EPS in more than 80%. None of them generated disaggregation of surfactant, only Bu was found in the light subtype. Bu and Be caused minimal changes in fluidity on polar region of bilayers, but these changes were not enough to inactivate the surfactant. Flu did not significantly alter any biophysical properties or surface activity. These novel combination EPS-GC products might be a promising strategy in the therapy of pulmonary diseases as the incorporation of the GCs tested did not cause detrimental effects on EPS functionality. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells

    NARCIS (Netherlands)

    S.W. Paugh (Steven); E.J. Bonten (Erik J.); D. Savic (Daniel); L.B. Ramsey (Laura B.); W.E. Thierfelder (William E.); P. Gurung (Prajwal); R.K.S. Malireddi (R. K. Subbarao); M. Actis (Marcelo); A. Mayasundari (Anand); J. Min (Jaeki); D.R. Coss (David R.); L.T. Laudermilk (Lucas T.); J.C. Panetta (John); J.R. McCorkle (J. Robert); Y. Fan (Yiping); K.R. Crews (Kristine R.); G. Stocco (Gabriele); M.R. Wilkinson (Mark R.); A.M. Ferreira (Antonio M.); C. Cheng (Cheng); W. Yang (Wenjian); S.E. Karol (Seth E.); C.A. Fernandez (Christian A.); B. Diouf (Barthelemy); C. Smith (Colton); J.K. Hicks (J Kevin); A. Zanut (Alessandra); A. Giordanengo (Audrey); D.J. Crona; J.J. Bianchi (Joy J.); L. Holmfeldt (Linda); C.G. Mullighan (Charles); M.L. den Boer (Monique); R. Pieters (Rob); S. Jeha (Sima); T.L. Dunwell (Thomas L.); F. Latif (Farida); D. Bhojwani (Deepa); W.L. Carroll (William L.); C.-H. Pui (Ching-Hon); R.M. Myers (Richard M.); R.K. Guy (R Kiplin); T.-D. Kanneganti (Thirumala-Devi); M.V. Relling (Mary); W.E. Evans (William)

    2015-01-01

    textabstractGlucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia

  18. Bimatoprost Topical

    Science.gov (United States)

    ... not use a cotton swab or any other brush or applicator to apply topical bimatoprost.To use the solution, follow these steps: Wash your hands and face thoroughly with soap and water. Be sure that ...

  19. Ciclopirox Topical

    Science.gov (United States)

    Ciclopirox topical solution is used along with regular nail trimming to treat fungal infections of the fingernails and toenails (an infection that may cause nail discoloration, splitting and pain). Ciclopirox is in a ...

  20. Thymus as a target tissue of glucocorticoid action: what are the consequences of glucocorticoids thymectomy?

    Science.gov (United States)

    Bjelaković, Gordana; Stojanovic, Ivana; Jevtovic-Stoimenov, Tatjana; Pavlović, Dusica; Kocić, Gordana; Kamenov, Borisav; Saranac, Ljiljana; Nikolić, Jelenka; Bjelaković, Bojko; Sokolović, Dusan; Basić, Jelena

    2009-01-01

    Glucocorticoids represent the most powerful endogenous anti-inflammatory and immunosuppressive effectors, interfering with virtually every step of immunoinflammatory responses. Glucocorticoids are often the most effective therapy in the prevention or suppression of inflammation and other immunologically mediated processes, but their use is limited by systemic side effects induced by the over-production of reactive oxygen species, causing dysregulation of physiological processes. The thymus is an organ with both endocrine and immune functions. Glucocorticoids induce thymocyte apoptosis, causing a profound reduction in thymic mass and volume and inducing hormonal thymectomy. The clinical aspects of glucocorticoid thymectomy are not under enough investigation. These unwanted systemic side effects may be the consequence of prolonged therapeutic application of glucocorticoids and prolonged or chronic activation of the hypothalamic-pituitary adrenal axis, which may lead to increased and prolonged secretion of glucocorticoids. This review will discuss the metabolic effects of glucocorticoids in the context of thymic physiology asthe primary sex hormone-responsive organ.

  1. Advances in Glucocorticoid-induced Osteoporosis

    NARCIS (Netherlands)

    den Uyl, D.; Bultink, I.E.M.; Lems, W.F.

    2011-01-01

    Glucocorticoid-induced osteoporosis (GIOP) is one of the most important side effects of glucocorticoid use, as it leads to an increased risk of fractures. Recently, many published studies have focused on the cellular and molecular mechanisms of bone metabolism, the pathophysiology of GIOP, and the

  2. Glucocorticoid pulsatility : implications for brain functioning

    NARCIS (Netherlands)

    Sarabdjitsingh, Ratna Angela

    2010-01-01

    Pronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body’s major neuroendocrine axes, were already demonstrated several decades ago. Until now, the clinical relevance of the pulsatile nature of glucocorticoids

  3. Central serous chorioretinopathy and glucocorticoids: an update on evidence for association.

    Science.gov (United States)

    Nicholson, Benjamin P; Atchison, Elizabeth; Idris, Amrou Ali; Bakri, Sophie J

    Central serous chorioretinopathy is a common idiopathic retinal disease characterized by central vision loss from serous detachment of the neurosensory retina, serous pigment epithelial detachments, and leakage of fluid through the retinal pigment epithelium into the subretinal space. The concept of an association between exogenous glucocorticoid use and central serous chorioretinopathy is widely accepted among ophthalmologists. Here, we review the evidence for and against such an association. This evidence includes 2 large, case-control studies that found strong associations, and a smaller, population-based study that found no association. We conclude that the preponderance of the literature on this topic supports the existence of an association. Both exogenous and endogenous glucocorticoids have been implicated. Although a mechanism and a causal relationship remain to be established, the association deserves broader recognition among physicians who prescribe glucocorticoids. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Optimal glucocorticoid replacement in adrenal insufficiency.

    Science.gov (United States)

    Øksnes, Marianne; Ross, Richard; Løvås, Kristian

    2015-01-01

    Adrenal insufficiency (glucocorticoid deficiency) comprises a group of rare diseases, including primary adrenal insufficiency, secondary adrenal insufficiency and congenital adrenal hyperplasia. Lifesaving glucocorticoid therapy was introduced over 60 years ago, but since then a number of advances in treatment have taken place. Specifically, little is known about short- and long-term treatment effects, and morbidity and mortality. Over the past decade, systematic cohort and registry studies have described reduced health-related quality of life, an unfavourable metabolic profile and increased mortality in patients with adrenal insufficiency, which may relate to unphysiological glucocorticoid replacement. This has led to the development of new modes of replacement that aim to mimic normal glucocorticoid physiology. Here, evidence for the inadequacy of conventional glucocorticoid therapy and recent developments in treatment are reviewed, with an emphasis on primary adrenal insufficiency. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Exogenous Cushing's syndrome and glucocorticoid withdrawal.

    Science.gov (United States)

    Hopkins, Rachel L; Leinung, Matthew C

    2005-06-01

    Glucocorticoid therapy in various forms is extremely common for a wide range of inflammatory, autoimmune, and neoplastic disorders. It is therefore important for the physician to be aware of the possibility of both iatrogenic and factitious Cushing's syndrome. Although most common with oral therapy, it is also important to be alert to the fact that all forms of glucocorticoid delivery have the potential to cause Cushing's syndrome. Withdrawal from chronic glucocorticoid therapy presents significant challenges. These include the possibility of adrenal insufficiency after discontinuation of steroid therapy, recurrence of underlying disease as the glucocorticoid is being withdrawn, and the possibility of steroid withdrawal symptoms. Nonetheless, with patience and persistence, a reasonable approach to withdrawal of glucocorticoid therapy can be achieved.

  6. Glucocorticoids as mediators of developmental programming effects.

    Science.gov (United States)

    Khulan, Batbayar; Drake, Amanda J

    2012-10-01

    Epidemiological evidence suggests that exposure to an adverse environment in early life is associated with an increased risk of cardio-metabolic and behavioral disorders in adulthood, a phenomenon termed 'early life programming'. One major hypothesis for early life programming is fetal glucocorticoid overexposure. In animal studies, prenatal glucocorticoid excess as a consequence of maternal stress or through exogenous administration to the mother or fetus is associated with programming effects on cardiovascular and metabolic systems and on the brain. These effects can be transmitted to subsequent generations. Studies in humans provide some evidence that prenatal glucocorticoid exposure may exert similar programming effects on glucose/insulin homeostasis, blood pressure and neurodevelopment. The mechanisms by which glucocorticoids mediate these effects are unclear but may include a role for epigenetic modifications. This review discusses the evidence for glucocorticoid programming in animal models and in humans. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Anti-inflammatory glucocorticoids: changing concepts.

    Science.gov (United States)

    Newton, Robert

    2014-02-05

    Despite being the most effective anti-inflammatory treatment for chronic inflammatory diseases, the mechanisms by which glucocorticoids (corticosteroids) effect repression of inflammatory gene expression remain incompletely understood. Direct interaction of the glucocorticoid receptor (NR3C1) with inflammatory transcription factors to repress transcriptional activity, i.e. transrepression, represents one mechanism of action. However, transcriptional activation, or transactivation, by NR3C1 also represents an important mechanism of glucocorticoid action. Glucocorticoids rapidly and profoundly increase expression of multiple genes, many with properties consistent with the repression of inflammatory gene expression. For example: the dual specificity phosphatase, DUSP1, reduces activation of mitogen-activated protein kinases; glucocorticoid-induced leucine zipper (TSC22D3) represses nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) transcriptional responses; inhibitor of κBα (NFKBIA) inhibits NF-κB; tristraprolin (ZFP36) destabilises and translationally represses inflammatory mRNAs; CDKN1C, a cell cycle regulator, may attenuate JUN N-terminal kinase signalling; and regulator of G-protein signalling 2 (RGS2), by reducing signalling from Gαq-linked G protein-coupled receptors (GPCRs), is bronchoprotective. While glucocorticoid-dependent transrepression can co-exist with transactivation, transactivation may account for the greatest level and most potent repression of inflammatory genes. Equally, NR3C1 transactivation is enhanced by β2-adrenoceptor agonists and may explain the enhanced clinical efficacy of β2-adrenoceptor/glucocorticoid combination therapies in asthma and chronic obstructive pulmonary disease. Finally, NR3C1 transactivation is reduced by inflammatory stimuli, including respiratory syncytial virus and human rhinovirus. This provides an explanation for glucocorticoid resistance. Continuing efforts to understand roles for glucocorticoid

  8. Influencia de los glucocorticoides inhalados sobre la densidad mineral ósea y el metabolismo óseo Inhaled glucocorticoids: influence on bone mineral density and bone metabolism

    Directory of Open Access Journals (Sweden)

    Fernando D. Saraví

    2000-04-01

    Full Text Available Los glucocorticoides inhalados (GCI constituyen hoy un tratamiento de primera línea del asma bronquial. Los efectos sistémicos de los GCI, como la supresión del eje hipotalámico- hipofisario-adrenal, son en general menores que los de los glucocorticoides orales. Sin embargo, existe el riesgo de efectos adversos sobre el hueso a largo plazo. El objetivo del presente trabajo fue revisar los datos publicados acerca de los efectos de los GCI sobre los marcadores del metabolismo óseo y la densidad mineral ósea en adultos y en pacientes pediátricos. Aunque los estudios examinados no proporcionan resultados uniformes, en términos generales sugieren que los GCI pueden afectar al metabolismo y a la densidad mineral ósea, en particular 1 cuando se administran a dosis elevadas (más de 400 µg/día en niños y más de 800 µg/día en adultos; 2 en pacientes pediátricos, en los que también pueden afectar al crecimiento en estatura; 3 en pacientes cuya ingesta de calcio y vitamina D es inadecuada, y 4 en mujeres postmenopáusicas sin terapia de reposición hormonal. En general, a dosis terapéuticamente equivalentes, la beclometasona tiene mayor efecto deletéreo sobre el hueso que la budesonida, y esta mayor que la fluticasona. Además de la precaución obvia de utilizar la menor dosis eficaz, se proponen como medidas preventivas: 1 la adecuada instrucción sobre el uso de los aerosoles; 2 el uso de cámaras de inhalación; 3 el enjuague bucal tras la administración de GCI, y 4 ajustes o suplementos dietéticos para asegurar una adecuada ingesta de calcio y vitamina D.Inhaled glucocorticoids (IGs are today the first-line treatment for bronchial asthma. The systemic effects of inhaled glucocorticoids, such as suppressing the hypothalamic-pituitary-adrenal axis, are generally less than those with oral glucocorticoids. However, there is a long-term risk of adverse effects on bone. The objective of this piece was to review the published data on the

  9. Impact of constant and breath-synchronized nebulization on inhaled mass of nebulized budesonide in infants and children

    DEFF Research Database (Denmark)

    Nikander, K; Bisgaard, H

    1999-01-01

    suspension, 0.5 mg mL-1, 2 mL, was used. With 5 min of constant output nebulization, the mean inhaled mass of budesonide in percent of the nominal dose was 11.4% in the youngest children and 14.9% in the 7-year-old children. Expressed in percent of the total output of budesonide, i.e., the amount that left...... the nebulizer as an aerosol, the inhaled mass ranged from 34.6-48.6%. Thus, 51.4-65.4% of the total output was deposited on the expiratory filter. With 5 min of breath-synchronized nebulization, the mean inhaled mass ranged from 10.5-14.9% of the nominal dose. For the youngest patients less than 3-4 years...... of age, it was approximately 80-90% of the total output. For the older patients the inhaled mass was approximately 95% of the total output, i.e., only small amounts of budesonide were deposited on the expiratory filter. For both modes of nebulization the between-subject variation in inhaled mass...

  10. Quality of life assessment in asthmatic patients receiving fluticasone compared with equipotent doses of beclomethasone or budesonide

    Directory of Open Access Journals (Sweden)

    Thomas Sabin

    2005-01-01

    Full Text Available Aims: To assess the quality of life in patients with asthma receiving either fluticasone or other inhaled steroids like beclomethasone or budesonide. To assess the effect of equipotent dosage of inhaled steroids at 3 months duration. Methods: Patients were randomised to receive either fluticasone or beclomethasone/budesonide. After spirometry, St. George′s Respiratory Questionnaire (SGRQ was administered at baseline and at 15 th , 30 th , 45 th , 60 th and 90 th day, to assess improvement in lung function and HRQoL. Results: Out of 96 patients who were enrolled, eighty patients completed three months duration of the study, while sixteen patients dropped out. Forty patients received fluticasone and forty received either beclomethasone or budesonide. No significant difference (p>0.05 was found in the baseline values of St. George′s Respiratory Questionnaire (SGRQ scores and Forced Expiratory Volume at first second (FEV 1 between the two groups. However, significant difference (p< 0.05 was noted between the above two groups, in Quality of Life (QoL but not in pulmonary functions, on 15th day favoring fluticasone. No significant difference (p>0.05 was noted either in QoL or in pulmonary function tests on subsequent follow-ups. Conclusion: Early response in terms of improved QoL was observed in fluticasone treated group in patients with moderate to severe asthma.

  11. Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles

    Directory of Open Access Journals (Sweden)

    Naeem M

    2015-07-01

    Full Text Available Muhammad Naeem, Jiafu Cao, Moonjeong Choi, Woo Seong Kim, Hyung Ryong Moon, Bok Luel Lee, Min-Soo Kim, Yunjin Jung, Jin-Wook Yoo College of Pharmacy, Pusan National University, Busan, South Korea Abstract: Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy. Keywords: azo-polyurethane, methacrylate copolymer, budesonide, colon-targeted nanoparticles, colitis

  12. Assessment of montelukast, doxofylline, and tiotropium with budesonide for the treatment of asthma: which is the best among the second-line treatment? A randomized trial.

    Science.gov (United States)

    Rajanandh, Muhasaparur Ganesan; Nageswari, Arcot D; Ilango, Kaliappan

    2015-02-01

    Data comparing various second-line treatments for asthma with subjective and objective assessment are lacking. This study aimed to compare the efficacy and safety of montelukast, doxofylline, and tiotropium with a low-dose budesonide in patients with mild to moderate persistent asthma. Patients, all of whom were concurrently using inhaled budesonide (400 µg), were treated for 6 months with formoterol (12 µg), montelukast (10 mg), doxofylline (400 mg), or tiotropium (18 µg). Outcomes included forced expiratory volume in 1 second (FEV1), Saint George Respiratory Questionnaire (SGRQ) scores, asthma symptom scores (daytime and nighttime), and assessment of tolerability and rescue medication use. A total of 297 patients completed the study. In all 4 groups, significant improvements were observed in all the outcome measures, with formoterol treatment having greater and earlier improvements than the other 3 second-line controller medications with budesonide. Among the second-line treatments, monteradlukast improved the FEV1 from day 45 (P < 0.01), SGRQ scores from day 30 (P < 0.0001), daytime scores from day 30 (P < 0.05), nighttime scores from day 30 (P < 0.0001), and rescue medication use from day 15 (P < .0001) at a faster rate than doxofylline or tiotropium with budesonide. No patients discontinued the treatment because of adverse reactions. Among the tested second-line treatment regimens, the budesonide/montelukast combination was found to be superior to either the budesonide/doxofylline or budesonide/tiotropium combination in all the outcome measures without adversely affecting the tolerability of the patients. Further clinical studies with blinding techniques are likely to be useful. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

  13. Antenatal glucocorticoid treatment and polymorphisms of the glucocorticoid and mineralocorticoid receptors are associated with IQ and behavior in young adults born very preterm

    NARCIS (Netherlands)

    Voorn, B. van der; Pal, S.M. van der; Rotteveel, J.; Finken, M.J.

    2015-01-01

    Context: Preterm survivors exhibit neurodevelopmental impairments. Whether this association is influenced by antenatal glucocorticoid treatment and glucocorticoid sensitivity is unknown. Objectives: To study the effects of antenatal glucocorticoid treatment and glucocorticoid receptor (GR) and

  14. Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper.

    Science.gov (United States)

    Fan, Huapeng; Kao, Wenping; Yang, Yuan H; Gu, Ran; Harris, James; Fingerle-Rowson, Günter; Bucala, Richard; Ngo, Devi; Beaulieu, Elaine; Morand, Eric F

    2014-08-01

    Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We undertook this study to investigate whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF. GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MKP-1 was studied at the level of expression and function. GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3A. GILZ was shown to regulate the expression of MKP-1 and consequent MAPK phosphorylation and cytokine release. MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity. Copyright © 2014 by the American College of Rheumatology.

  15. Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.

    Science.gov (United States)

    Zhang, Yong; Leung, Donald Y M; Nordeen, Steven K; Goleva, Elena

    2009-09-04

    Although glucocorticoids suppress proliferation of many cell types and are used in the treatment of certain cancers, trials of glucocorticoid therapy in breast cancer have been a disappointment. Another suggestion that estrogens may affect glucocorticoid action is that the course of some inflammatory diseases tends to be more severe and less responsive to corticosteroid treatment in females. To date, the molecular mechanism of cross-talk between estrogens and glucocorticoids is poorly understood. Here we show that, in both MCF-7 and T47D breast cancer cells, estrogen inhibits glucocorticoid induction of the MKP-1 (mitogen-activated protein kinase phosphatase-1) and serum/glucocorticoid-regulated kinase genes. Estrogen did not affect glucocorticoid-induced glucocorticoid receptor (GR) nuclear translocation but reduced ligand-induced GR phosphorylation at Ser-211, which is associated with the active form of GR. We show that estrogen increases expression of protein phosphatase 5 (PP5), which mediates the dephosphorylation of GR at Ser-211. Gene knockdown of PP5 abolished the estrogen-mediated suppression of GR phosphorylation and induction of MKP-1 and serum/glucocorticoid-regulated kinase. More importantly, after PP5 knockdown estrogen-promoted cell proliferation was significantly suppressed by glucocorticoids. This study demonstrates cross-talk between estrogen-induced PP5 and GR action. It also reveals that PP5 inhibition may antagonize estrogen-promoted events in response to corticosteroid therapy.

  16. Diflorasone Topical

    Science.gov (United States)

    ... area, do not use tight-fitting diapers or plastic pants. Such use may increase side effects.Do not apply other skin preparations or products ... doctor.if you are having surgery, including dental surgery, tell the doctor or dentist that you are using betamethasone topical.

  17. Betamethasone Topical

    Science.gov (United States)

    ... area, do not use tight-fitting diapers or plastic pants. Such use may increase side effects.Do not apply other skin preparations or products ... immediately.if you are having surgery, including dental surgery, tell the doctor or dentist that you are using betamethasone topical.

  18. Halcinonide Topical

    Science.gov (United States)

    ... area, do not use tight-fitting diapers or plastic pants. Such use may increase side effects.Do not wrap or bandage the treated area ... doctor.if you are having surgery, including dental surgery, tell the doctor or dentist that you are using halcinonide topical.

  19. Fluocinonide Topical

    Science.gov (United States)

    ... area, do not use tight-fitting diapers or plastic pants. Such use may increase side effects.Do not apply other skin preparations or products ... immediately.if you are having surgery, including dental surgery, tell the doctor or dentist that you are using fluocinonide topical.

  20. Dapsone Topical

    Science.gov (United States)

    ... go away: skin redness or burning skin drying skin oiliness and peeling itching Some side effects can be serious. If you experience any of these symptoms, stop using dapsone and call ... yellow or pale skin Dapsone topical may cause other side effects. Call ...

  1. Mometasone Topical

    Science.gov (United States)

    ... a few drops on the affected areas and massage lightly until it disappears.This medication is only for use on the skin. Do not let mometasone topical get into your eyes or mouth and do not swallow it. Avoid use on the face, in the genital and rectal areas, and in ...

  2. Dynamic regulation of glucocorticoid signalling in health and disease

    OpenAIRE

    Biddie, Simon C.; Conway-Campbell, Becky L.; Lightman, Stafford L.

    2011-01-01

    Activation of the glucocorticoid receptor (GR) by endogenous and synthetic glucocorticoids regulates hundreds of genes to control regulatory networks in development, metabolism, cognition and inflammation. Elucidation of the mechanisms that regulate glucocorticoid action has highlighted the dynamic nature of hormone signalling and provides novel insights into genomic glucocorticoid actions. The major factors that regulate GR function include chromatin structure, epigenetics, genetic variation...

  3. Effects of surfactant/budesonide therapy on oxidative modifications in the lung in experimental meconium-induced lung injury.

    Science.gov (United States)

    Mikolka, P; Kopincova, J; Tomcikova Mikusiakova, L; Kosutova, P; Antosova, M; Calkovska, A; Mokra, D

    2016-02-01

    Meconium aspiration syndrome (MAS) is a serious condition, which can be treated with exogenous surfactant and mechanical ventilation. However, meconium-induced inflammation, lung edema and oxidative damage may inactivate delivered surfactant and thereby reduce effectiveness of the therapy. As we presumed that addition of anti-inflammatory agent into the surfactant may alleviate inflammation and enhance efficiency of the therapy, this study was performed to evaluate effects of surfactant therapy enriched with budesonide versus surfactant-only therapy on markers of oxidative stress in experimental model of MAS. Meconium suspension (25 mg/ml, 4 ml/kg) was instilled into the trachea of young rabbits, whereas one group of animals received saline instead of meconium (C group, n = 6). In meconium-instilled animals, respiratory failure developed within 30 min. Then, meconium-instilled animals were divided into 3 groups according to therapy (n = 6 each): with surfactant therapy (M + S group), with surfactant + budesonide therapy (M + S + B), and without therapy (M group). Surfactant therapy consisted of two bronchoalveolar lavages (BAL) with diluted surfactant (Curosurf, 5 mg phospholipids/ml, 10 ml/kg) followed by undiluted surfactant (100 mg phospholipids/kg), which was in M + S + B group enriched with budesonide (Pulmicort, 0.5 mg/ml). Animals were oxygen-ventilated for additional 5 hours. At the end of experiment, blood sample was taken for differential white blood cell (WBC) count. After euthanizing animals, left lung was saline-lavaged and cell differential in BAL was determined. Oxidative damage, i.e. oxidation of lipids (thiobarbituric acid reactive substance (TBARS) and conjugated dienes) and proteins (dityrosine and lysine-lipoperoxidation products) was estimated in lung homogenate and isolated mitochondria. Total antioxidant capacity was evaluated in lung homogenate and plasma. Meconium instillation increased transmigration of neutrophils and production of free

  4. Glucocorticoids, epigenetic control and stress resilience

    Directory of Open Access Journals (Sweden)

    Johannes M.H.M. Reul

    2015-01-01

    Full Text Available Glucocorticoid hormones play a pivotal role in the response to stressful challenges. The surge in glucocorticoid hormone secretion after stress needs to be tightly controlled with characteristics like peak height, curvature and duration depending on the nature and severity of the challenge. This is important as chronic hyper- or hypo-responses are detrimental to health due to increasing the risk for developing a stress-related mental disorder. Proper glucocorticoid responses to stress are critical for adaptation. Therefore, the tight control of baseline and stress-evoked glucocorticoid secretion are important constituents of an organism's resilience. Here, we address a number of mechanisms that illustrate the multitude and complexity of measures safeguarding the control of glucocorticoid function. These mechanisms include the control of mineralocorticoid (MR and glucocorticoid receptor (GR occupancy and concentration, the dynamic control of free glucocorticoid hormone availability by corticosteroid-binding globulin (CBG, and the control exerted by glucocorticoids at the signaling, epigenetic and genomic level on gene transcriptional responses to stress. We review the beneficial effects of regular exercise on HPA axis and sleep physiology, and cognitive and anxiety-related behavior. Furthermore, we describe that, possibly through changes in the GABAergic system, exercise reduces the impact of stress on a signaling pathway specifically in the dentate gyrus that is strongly implicated in the behavioral response to that stressor. These observations underline the impact of life style on stress resilience. Finally, we address how single nucleotide polymorphisms (SNPs affecting glucocorticoid action can compromise stress resilience, which becomes most apparent under conditions of childhood abuse.

  5. Topical anesthesia

    Science.gov (United States)

    Kumar, Mritunjay; Chawla, Rajiv; Goyal, Manish

    2015-01-01

    Topical anesthetics are being widely used in numerous medical and surgical sub-specialties such as anesthesia, ophthalmology, otorhinolaryngology, dentistry, urology, and aesthetic surgery. They cause superficial loss of pain sensation after direct application. Their delivery and effectiveness can be enhanced by using free bases; by increasing the drug concentration, lowering the melting point; by using physical and chemical permeation enhancers and lipid delivery vesicles. Various topical anesthetic agents available for use are eutectic mixture of local anesthetics, ELA-max, lidocaine, epinephrine, tetracaine, bupivanor, 4% tetracaine, benzocaine, proparacaine, Betacaine-LA, topicaine, lidoderm, S-caine patch™ and local anesthetic peel. While using them, careful attention must be paid to their pharmacology, area and duration of application, age and weight of the patients and possible side-effects. PMID:26702198

  6. Topical anesthesia

    Directory of Open Access Journals (Sweden)

    Mritunjay Kumar

    2015-01-01

    Full Text Available Topical anesthetics are being widely used in numerous medical and surgical sub-specialties such as anesthesia, ophthalmology, otorhinolaryngology, dentistry, urology, and aesthetic surgery. They cause superficial loss of pain sensation after direct application. Their delivery and effectiveness can be enhanced by using free bases; by increasing the drug concentration, lowering the melting point; by using physical and chemical permeation enhancers and lipid delivery vesicles. Various topical anesthetic agents available for use are eutectic mixture of local anesthetics, ELA-max, lidocaine, epinephrine, tetracaine, bupivanor, 4% tetracaine, benzocaine, proparacaine, Betacaine-LA, topicaine, lidoderm, S-caine patch™ and local anesthetic peel. While using them, careful attention must be paid to their pharmacology, area and duration of application, age and weight of the patients and possible side-effects.

  7. Circumvention of glucocorticoid resistance in childhood leukemia.

    Science.gov (United States)

    Haarman, E G; Kaspers, G J L; Pieters, R; Rottier, M M A; Veerman, A J P

    2008-09-01

    In this study, we determined if in vitro resistance to prednisolone and dexamethasone could be circumvented by cortivazol or methylprednisolone, or reversed by meta-iodobenzylguanidine in pediatric lymphoblastic and myeloid leukemia. As there were strong correlations between the LC50 values (drug concentration inducing 50% leukemic cell kill, LCK) of the different glucocorticoids and median prednisolone/methylprednisolone, prednisolone/dexamethasone and prednisolone/cortivazol LC50 ratios did not differ between the leukemia subtypes, we conclude that none of the glucocorticoids had preferential anti-leukemic activity. Meta-iodobenzylguanidine however, partially reversed glucocorticoid resistance in 19% of the lymphoblastic leukemia samples.

  8. Timing of glucocorticoid therapy for liver failure

    Directory of Open Access Journals (Sweden)

    MENG Qinghua

    2017-09-01

    Full Text Available There are still controversies over the use of glucocorticoids in the treatment of liver failure, and current guidelines for liver failure recommend that glucocorticoids should be used with great caution. However, some latest studies have shown that the use of glucocorticoid therapy in the early stage of liver failure can bring more benefits to patients. Age, disease progression rate and severity, and complications of liver failure may affect the treatment outcome. Further studies are still needed for the selection of right patients, drugs and dose, and treatment timing.

  9. Cost Utility Analysis of Topical Steroids Compared With Dietary Elimination for Treatment of Eosinophilic Esophagitis.

    Science.gov (United States)

    Cotton, Cary C; Erim, Daniel; Eluri, Swathi; Palmer, Sarah H; Green, Daniel J; Wolf, W Asher; Runge, Thomas M; Wheeler, Stephanie; Shaheen, Nicholas J; Dellon, Evan S

    2017-06-01

    Topical corticosteroids or dietary elimination are recommended as first-line therapies for eosinophilic esophagitis, but data to directly compare these therapies are scant. We performed a cost utility comparison of topical corticosteroids and the 6-food elimination diet (SFED) in treatment of eosinophilic esophagitis, from the payer perspective. We used a modified Markov model based on current clinical guidelines, in which transition between states depended on histologic response simulated at the individual cohort-member level. Simulation parameters were defined by systematic review and meta-analysis to determine the base-case estimates and bounds of uncertainty for sensitivity analysis. Meta-regression models included adjustment for differences in study and cohort characteristics. In the base-case scenario, topical fluticasone was about as effective as SFED but more expensive at a 5-year time horizon ($9261.58 vs $5719.72 per person). SFED was more effective and less expensive than topical fluticasone and topical budesonide in the base-case scenario. Probabilistic sensitivity analysis revealed little uncertainty in relative treatment effectiveness. There was somewhat greater uncertainty in the relative cost of treatments; most simulations found SFED to be less expensive. In a cost utility analysis comparing topical corticosteroids and SFED for first-line treatment of eosinophilic esophagitis, the therapies were similar in effectiveness. SFED was on average less expensive, and more cost effective in most simulations, than topical budesonide and topical fluticasone, from a payer perspective and not accounting for patient-level costs or quality of life. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  10. Solubility Enhancement of Budesonide and Statistical Optimization of Coating Variables for Targeted Drug Delivery

    Directory of Open Access Journals (Sweden)

    Himanshu Bhatt

    2014-01-01

    Full Text Available The purpose of the research was to present Budesonide (BUD as a novel formulation showing improved aqueous solubility, which may decrease variability in Cmax⁡ and Tmax⁡ found in inflammatory bowel disease (IBD patients, and drug targeting to colon. To improve aqueous solubility, solid dispersion (SD of the BUD with poloxamer 188 was prepared by melting method. Physical characterization of solid dispersion was performed. The SD was used to prepare tablet equivalent to 9 mg of BUD. The tablet was coated with enteric polymers Eudragit S100 and Eudragit L100 to target colon. The ratio of polymers and percentage coating was optimized using statistical design. Variables studied in design were ratio of enteric polymers and the effect of percentage coating on in vitro drug release. Dissolution at different pH showed that drug release in colon could be modified by optimizing the ratio of polymers and percentage coating. The dissolution data showed that the percentage coating and ratio of polymers are very important to get lag time and optimum formulation. The optimized batch from statistical design was kept under accelerated condition for three months. After accelerated stability study, there was no significant change in the drug release.

  11. Nebulised budesonide using a novel device in patients with oral steroid-dependent asthma.

    Science.gov (United States)

    Vogelmeier, Claus; Kardos, Peter; Hofmann, Thomas; Canisius, Sebastian; Scheuch, Gerhard; Muellinger, Bernhard; Nocker, Karlheinz; Menz, Guenter; Rabe, Klaus F

    2015-05-01

    This phase 2/3 randomised, parallel-group, placebo-controlled trial investigated oral corticosteroid (OCS)-sparing efficacy, safety and tolerability of nebulised budesonide (Bud) administered with a novel computer-controlled, compressor-driven inhalation system (AKITA) as add-on therapy to Global Initiative for Asthma step 5. Patients (18-65 years) with OCS-dependent asthma were randomised (2:1:1:1) to receive 18-week, twice-daily, double-blind treatment with AKITA inhaled corticosteroid (AICS)-Bud 1 mg, AICS-Bud 0.5 mg, AICS-placebo or open-label Bud 1 mg administered by conventional nebuliser (CN-Bud). OCS doses were tapered until week 14. 199 patients started treatment. More AICS-Bud 1 mg (80.0%) than placebo-treated (62.5%) patients had daily OCS doses reduced ≥50%, with clinical stability to week 18 (one-sided p=0.02; treatment difference: 17.5% (95% CI 0.1-34.9%), two-sided p=0.04). Mean±sd forced expiratory volume in 1 s improved (from baseline to week 18) for AICS-Bud 1 mg (239±460 mL, pcontrol. Copyright ©ERS 2015.

  12. Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma

    DEFF Research Database (Denmark)

    Jorup, Carin; Lythgoe, Dan; Bisgaard, Hans

    2018-01-01

    Asthma control is often suboptimal in adolescents, but few studies have evaluated asthma treatments in this population.This post hoc analysis assessed the efficacy and safety of budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (MART) for treatment of persistent asthma in adolescent...... s, as-needed medication use and five-item asthma control questionnaire scores.In adolescents (n=1847), BUD/FORM MART was similar to or more effective than comparators across each of the studies in reducing the risk of a first severe exacerbation (hazard ratios (HR) BUD/FORM MART versus comparators 0.......15-1.01; pooled HR 0.49, 95% CI 0.34-0.70), with comparable outcomes to the adult subgroups (n=12 197). Similar treatment benefits for BUD/FORM MART were observed for secondary end-points. As-needed medication use was lower with BUD/FORM MART than comparators, and BUD/FORM as-needed use was lower in adolescents...

  13. Molecular mechanisms of glucocorticoid receptor signaling

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR. Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.

  14. Effects of Glucocorticoids in the Immune System.

    Science.gov (United States)

    Oppong, Emmanuel; Cato, Andrew C B

    2015-01-01

    Glucocorticoids (GCs) are steroid hormones with widespread effects. They control intermediate metabolism by stimulating gluconeogenesis in the liver, mobilize amino acids from extra hepatic tissues, inhibit glucose uptake in muscle and adipose tissue, and stimulate fat breakdown in adipose tissue. They also mediate stress response. They exert potent immune-suppressive and anti-inflammatory effects particularly when administered pharmacologically. Understanding these diverse effects of glucocorticoids requires a detailed knowledge of their mode of action. Research over the years has uncovered several details on the molecular action of this hormone, especially in immune cells. In this chapter, we have summarized the latest findings on the action of glucocorticoids in immune cells with a view of identifying important control points that may be relevant in glucocorticoid therapy.

  15. Glucocorticoids are ineffective in alcoholic hepatitis

    DEFF Research Database (Denmark)

    Christensen, E; Gluud, C

    1995-01-01

    The aim of this study was to perform a meta-analysis of controlled clinical trials of glucocorticoid treatment in clinical alcoholic hepatitis, adjusting for prognostic variables and their possible interaction with therapy, because these trials have given appreciably different results. Weighted...... may be different (beneficial or harmful) in special patient subgroups. These results do not support the routine use of glucocorticoids in patients with alcoholic hepatitis, including those with encephalopathy. Whether other subgroups may benefit needs further investigation using the individual patient...

  16. Perioperative glucocorticoids in hip and knee surgery - benefit vs. harm?

    DEFF Research Database (Denmark)

    Lunn, T H; Kehlet, H

    2013-01-01

    glucocorticoid administration analogous to > 10 mg or ≤ 10 mg dexamethasone, and local glucocorticoid administration. Seventeen studies with data from 1081 patients were included in the final qualitative synthesis. Benefit (of any kind) with glucocorticoid vs. placebo was reported in 15 studies. PONV was reduced...... with systemic glucocorticoid. Pain was reduced with high-dose systemic and local glucocorticoid, but not with low-dose systemic glucocorticoid. Systemic inflammatory markers were reduced with low-dose and high-dose systemic glucocorticoid, and with local glucocorticoid. Functional recovery was improved...... with local glucocorticoid. All studies were small-sized and none sufficiently powered to meaningfully evaluate uncommon adverse events. Most of the local administration studies had poor scientific quality (high risk of bias). Due to clinical heterogeneity and poor scientific quality, no meta...

  17. Glucocorticoids and fetal programming part 2: Mechanisms.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

    The lifelong health of an individual is shaped during critical periods of development. The fetus is particularly susceptible to internal and external stimuli, many of which can alter developmental trajectories and subsequent susceptibility to disease. Glucocorticoids are critical in normal development of the fetus, as they are involved in the growth and maturation of many organ systems. The surge in fetal glucocorticoid levels that occurs in most mammalian species over the last few days of pregnancy is an important developmental switch leading to fundamental changes in gene regulation in many organs, including the brain. These changes are important for the transition to postnatal life. Exposure of the fetus to increased levels of glucocorticoids, resulting from maternal stress or treatment with synthetic glucocorticoids, can lead to long-term 'programming' of hypothalamic-pituitary-adrenal function and behaviours. Glucocorticoids act at multiple levels within the fetal brain. Growing evidence indicates that they can exert powerful effects on the epigenome, including on DNA methylation, histone acetylation and microRNA, to influence gene expression. Such influences probably represent a critical component of the 'programming' process, and might be partly responsible for the transgenerational effects of antenatal glucocorticoid exposure on neurologic, cardiovascular and metabolic function.

  18. The multiple facets of glucocorticoid action in rheumatoid arthritis.

    Science.gov (United States)

    Baschant, Ulrike; Lane, Nancy E; Tuckermann, Jan

    2012-11-01

    Glucocorticoids have potent anti-inflammatory effects and have been used to treat patients with rheumatoid arthritis for more than 60 years. However, severe adverse effects of glucocorticoid treatment, including loss of bone mass and increased risk of fractures, are common. Data from studies of glucocorticoid-mediated gene regulation, which utilized conditional knockout mice in animal models of arthritis or glucocorticoid-induced osteoporosis, have substantially increased our understanding of the mechanisms by which glucocorticoids act via the glucocorticoid receptor. Following glucocorticoid binding, the receptor regulates gene expression either by interacting with DNA-bound transcription factors as a monomer or by binding directly to DNA as a dimer. In contrast to the old hypothesis that transrepression mechanisms involving monomeric glucocorticoid receptor actions were responsible for the anti-inflammatory effects of glucocorticoids, whereas dimeric glucocorticoid receptor binding resulted in adverse effects, data from animal models have shown that the anti-inflammatory and adverse effects of glucocorticoids are mediated by both monomeric and dimeric glucocorticoid receptor binding. This improved knowledge of the molecular mechanisms that underlie the beneficial and adverse effects of glucocorticoid therapy might lead to the development of rationales for novel glucocorticoid receptor ligands that could potentially have anti-inflammatory efficacy without adverse effects on bone.

  19. Comparative Effectiveness of Mesalamine, Sulfasalazine, Corticosteroids, and Budesonide for the Induction of Remission in Crohn's Disease: A Bayesian Network Meta-analysis.

    Science.gov (United States)

    Coward, Stephanie; Kuenzig, M Ellen; Hazlewood, Glen; Clement, Fiona; McBrien, Kerry; Holmes, Rebecca; Panaccione, Remo; Ghosh, Subrata; Seow, Cynthia H; Rezaie, Ali; Kaplan, Gilaad G

    2017-03-01

    Induction treatment of mild-to-moderate Crohn's disease is controversial. To compare the induction of remission between different doses of mesalamine, sulfasalazine, corticosteroids, and budesonide for active Crohn's disease. We identified randomized controlled trials from existing Cochrane reviews and an updated literature search in Medline, EMBASE, and CENTRAL to November 2015. We included randomized controlled trials (n = 22) in adult patients with Crohn's disease that compared budesonide, sulfasalazine, mesalamine, or corticosteroids with placebo or each other, for the induction of remission (8-17 wks). Mesalamine (above and below 2.4 g/d) and budesonide (above and below 6 mg/d) were stratified into low and high doses. Our primary outcome was remission, defined as a Crohn's Disease Activity Index score <150. A Bayesian random-effects network meta-analysis was performed on the proportion in remission. Corticosteroids (odds ratio [OR] = 3.80; 95% credible interval [CrI]: 2.48-5.66), high-dose budesonide (OR = 2.96; 95% CrI: 2.06-4.30), and high-dose mesalamine (OR = 2.29; 95% CrI: 1.58-3.33) were superior to placebo. Corticosteroids were similar to high-dose budesonide (OR = 1.21; 95% CrI: 0.84-1.76), but more effective than high-dose mesalamine (OR = 1.83; 95% CrI: 1.16-2.88). Sulfasalazine was not significantly superior to any therapy including placebo. Randomized controlled trials that use a strict definition of induction of remission and disease severity at enrollment to assess effectiveness in treating mild-to-moderate Crohn's disease are limited. Corticosteroids and high-dose budesonide were effective treatments for inducing remission in mild-to-moderate Crohn's disease. High-dose mesalamine is an option among patients preferring to avoid steroids.

  20. Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations.

    Science.gov (United States)

    Rose, Adam J; Vegiopoulos, Alexandros; Herzig, Stephan

    2010-10-01

    Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids and their cognate, intracellular receptor, the glucocorticoid receptor have been characterized as critical checkpoints in the delicate hormonal control of energy homeostasis in mammals. Whereas physiological levels of glucocorticoids are required for proper metabolic control, aberrant glucocorticoid action has been linked to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Based on its importance for human health, studies of the molecular mechanisms of within the glucocorticoid signaling axis have become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the glucocorticoid receptor pathway has been proven to be of substantial value for the development of novel therapies in the treatment of chronic metabolic disorders. Therefore, this review focuses on the consequences of endogenous and experimental modulation of glucocorticoid receptor expression for metabolic homeostasis and dysregulation, particularly emphasizing tissue-specific contributions of the glucocorticoid pathway to the control of energy metabolism. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Cushing's syndrome with adrenal suppression induced by inhaled budesonide due to a ritonavir drug interaction in a woman with HIV infection.

    Science.gov (United States)

    Yoganathan, K; David, L; Williams, C; Jones, K

    2012-07-01

    A 48-year-old woman with HIV infection developed Cushingoid features while she was taking ritonavir-boosted darunavir. Cushing's syndrome was confirmed due to the drug interaction between ritonavir and budesonide. Diagnosis of iatrogenic Cushing's syndrome in HIV-positive patients who are on ritonavir-boosted protease inhibitors (PIs) presents a clinical challenge due to similar clinical features of lipohypertrophy related to ritonavir-boosted PIs. Although this complication has been widely described with the use of inhaled fluticasone, the interaction with inhaled budesonide at therapeutic dose is not widely recognized.

  2. Cost-effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy in Denmark--cost-effectiveness analysis based on five randomised controlled trials

    DEFF Research Database (Denmark)

    Wickstrøm, Jannie; Dam, Nanna; Malmberg, Irena

    2009-01-01

    . The aim of this study was to determine the cost-effectiveness of the Symbicort SMART regime in Denmark vs higher dose inhaled corticosteroid (ICS) plus reliever medication, similar dose inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) combination therapy plus reliever medication or higher......Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) is an effective asthma-management regime where patients use budesonide/formoterol both as maintenance treatment and as additional doses as needed to improve overall asthma control by reducing symptoms and exacerbations...

  3. Effect of aerosol inhalation of ipratropium bromide combined with budesonide and terbutaline on cytokines in children with bronchopneumonia

    Directory of Open Access Journals (Sweden)

    Xiang-Yu Che

    2016-09-01

    Full Text Available Objective: To explore the clinical efficacy of aerosol inhalation of ipratropium bromide combined with budesonide and terbutaline in the treatment of bronchopneumonia in children and the effect on cytokines. Methods: A total of 70 children with bronchopneumonia who were admitted in our hospital from March, 2015 to March, 2016 were included in the study and randomized into the study group and the control group. The patients in the control group were given anti-infection, oxygen inhalation, cough and asthma relieving, acidosis correcting, mask+oxygen driven aerosol inhalation of budesonide (0.5 mg/time and terbutaline (1.0 mg/time, with an oxygen flow rate of 5-7 L/min, 5-10 min every time, twice a day. On the above basis, the patients in the study group were given additional ipratropium bromide (1.0 mg/time. After 7-day treatment, the efficacy was evaluated. The levels of IL-6, TNF-毩, CRP, and WBC before and after treatment were detected. PEF, FVC, and FEV1 before and after treatment were detected. The improvement of clinical symptoms and signs, and the occurrence of adverse reactions were observed. Results: The levels of IL-6, TNF-毩, CRP, and WBC counting after treatment in the two groups were significantly reduced when compared with before treatment (P0.05. Conclusions: Ipratropium bromide combined with budesonide and terbutaline in the treatment of bronchopneumonia in children can rapidly relieve the symptoms, and improve the cytokine level, without obvious adverse reactions; therefore, it deserves to be widely recommended in the clinic.

  4. The insulin-like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

    DEFF Research Database (Denmark)

    Wolthers, O D; Juul, A; Hansen, M

    1995-01-01

    Serum concentrations of growth hormone-dependent insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP......) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double-blind treatment periods (200 and 800 micrograms) and one open...

  5. Rehydrated sterically stabilized phospholipid nanomicelles of budesonide for nebulization: physicochemical characterization and in vitro, in vivo evaluations

    Directory of Open Access Journals (Sweden)

    Sahib MN

    2011-10-01

    Full Text Available Mohanad Naji Sahib, Yusrida Darwis, Kok Khiang Peh, Shaymaa Abdalwahed Abdulameer, Yvonne Tze Fung TanSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, MalaysiaBackground: Inhaled corticosteroids provide unique systems for local treatment of asthma or chronic obstructive pulmonary disease. However, the use of poorly soluble drugs for nebulization has been inadequate, and many patients rely on large doses to achieve optimal control of their disease. Theoretically, nanotechnology with a sustained-release formulation may provide a favorable therapeutic index. The aim of this study was to determine the feasibility of using sterically stabilized phospholipid nanomicelles of budesonide for pulmonary delivery via nebulization.Methods: PEG5000-DSPE polymeric micelles containing budesonide (BUD-SSMs were prepared by the coprecipitation and reconstitution method, and the physicochemical and pharmacodynamic characteristics of BUD-SSMs were investigated.Results: The optimal concentration of solubilized budesonide at 5 mM PEG5000-DSPE was 605.71 ± 6.38 µg/mL, with a single-sized peak population determined by photon correlation spectroscopy and a particle size distribution of 21.51 ± 1.5 nm. The zeta potential of BUD-SSMs was -28.43 ± 1.98 mV. The percent entrapment efficiency, percent yield, and percent drug loading of the lyophilized formulations were 100.13% ± 1.09%, 97.98% ± 1.95%, and 2.01% ± 0.02%, respectively. Budesonide was found to be amorphous by differential scanning calorimetry, and had no chemical interaction with PEGylated polymer according to Fourier transform infrared spectroscopy. Transmission electron microscopic images of BUD-SSMs revealed spherical nanoparticles. BUD-SSMs exhibited prolonged dissolution behavior compared with Pulmicort Respules® (P , 0.05. Aerodynamic characteristics indicated significantly higher deposition in the lungs compared with Pulmicort Respules®. The mass median aerodynamic, geometric

  6. Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design.

    Science.gov (United States)

    Emami, J; Mohiti, H; Hamishehkar, H; Varshosaz, J

    2015-01-01

    Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7(®) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the

  7. A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.

    Science.gov (United States)

    Miehlke, Stephan; Hruz, Petr; Vieth, Michael; Bussmann, Christian; von Arnim, Ulrike; Bajbouj, Monther; Schlag, Christoph; Madisch, Ahmed; Fibbe, Christiane; Wittenburg, Henning; Allescher, Hans Dieter; Reinshagen, Max; Schubert, Stefan; Tack, Jan; Müller, Michaela; Krummenerl, Patrick; Arts, Joris; Mueller, Ralph; Dilger, Karin; Greinwald, Roland; Straumann, Alex

    2016-03-01

    To investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE). Adults with active EoE (n=76) randomly received 14 days' treatment with either BET 2×1 mg/day (BET1, n=19) or BET 2×2 mg/day (BET2, n=19), or BVS 2×5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm(2 )hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patient's preference for drug formulation. Histological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients. BET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation. NCT02280616; EudraCT number, 2009-016692-29. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  8. Oesophageal lichen planus: the efficacy of topical steroid-based therapies.

    Science.gov (United States)

    Podboy, A; Sunjaya, D; Smyrk, T C; Murray, J A; Binder, M; Katzka, D A; Alexander, J A; Halland, M

    2017-01-01

    Oesophageal lichen planus is an idiopathic inflammatory disorder characterized by significant oesophageal stricturing. Oesophageal lichen planus is a rare, difficult to diagnose, and likely an under recognized disease. As a result, there is no standardized approach to therapy and treatment strategies vary. To examine the utility of topical steroid therapy (fluticasone or budesonide) in the management of oesophageal lichen planus. A retrospective chart review was conducted of patients diagnosed with oesophageal lichen planus who underwent baseline and follow up endoscopy pre and post topical steroid therapy between 1995 and 2016 at Mayo Clinic, Rochester MN. Average time between upper GI endoscopy was 3.2 months (0.7-11.7). Swallowed steroid preparations included fluticasone 880 μg twice daily or budesonide 3 mg twice daily. Patients were reviewed for symptomatic response to therapy using the Dakkak-Bennett dysphagia score (0-4, no dysphagia to total aphagia). Pre- and post-endoscopic findings were assessed. Additional baseline demographic, endoscopic, and histologic data were also obtained. We identified 40 patients who met the inclusion criteria. A significant reduction in median dysphagia score from 1 (0-4) to 0 (0-3) after steroid therapy (P lichen planus. © 2016 John Wiley & Sons Ltd.

  9. NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells

    Science.gov (United States)

    Paugh, Steven W.; Bonten, Erik J.; Savic, Daniel; Ramsey, Laura B.; Thierfelder, William E.; Gurung, Prajwal; Malireddi, R. K. Subbarao; Actis, Marcelo; Mayasundari, Anand; Min, Jaeki; Coss, David R.; Laudermilk, Lucas T.; Panetta, John C.; McCorkle, J. Robert; Fan, Yiping; Crews, Kristine R.; Stocco, Gabriele; Wilkinson, Mark R.; Ferreira, Antonio M.; Cheng, Cheng; Yang, Wenjian; Karol, Seth E.; Fernandez, Christian A.; Diouf, Barthelemy; Smith, Colton; Hicks, J. Kevin; Zanut, Alessandra; Giordanengo, Audrey; Crona, Daniel; Bianchi, Joy J.; Holmfeldt, Linda; Mullighan, Charles G.; den Boer, Monique L.; Pieters, Rob; Jeha, Sima; Dunwell, Thomas L.; Latif, Farida; Bhojwani, Deepa; Carroll, William L.; Pui, Ching-Hon; Myers, Richard M.; Guy, R. Kiplin; Kanneganti, Thirumala-Devi; Relling, Mary V.; Evans, William E.

    2015-01-01

    Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444 newly diagnosed ALL patients, revealing significantly higher expression of caspase 1 (CASP1) and its activator NLRP3 in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of CASP1 and NLRP3 promoters. Over-expression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1 overexpressing ALL. Our findings establish a new mechanism by which the NLRP3/CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on glucocorticoid transcriptional response suggests this mechanism could also modify glucocorticoid effects in other diseases. PMID:25938942

  10. Glucocorticoid Receptors and the Pattern of Steroid Response in ...

    African Journals Online (AJOL)

    CD3+) expression of glucocorticoid receptors (GCR) and the response to glucocorticoid treatment in children with idiopathic nephrotic syndrome (NS). The aim of the current study is to determine whether steroid responsiveness is dependent on ...

  11. Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction.

    Science.gov (United States)

    Whirledge, Shannon; Cidlowski, John A

    2017-06-01

    Glucocorticoids are steroid hormones that regulate diverse cellular functions and are essential to facilitate normal physiology. However, stress-induced levels of glucocorticoids result in several pathologies including profound reproductive dysfunction. Compelling new evidence indicates that glucocorticoids are crucial to the establishment and maintenance of reproductive function. The fertility-promoting or -inhibiting activity of glucocorticoids depends on timing, dose, and glucocorticoid responsiveness within a given tissue, which is mediated by the glucocorticoid receptor (GR). The GR gene and protein are subject to cellular processing, contributing to signaling diversity and providing a mechanism by which both physiological and stress-induced levels of glucocorticoids function in a cell-specific manner. Understanding how glucocorticoids regulate fertility and infertility may lead to novel approaches to the regulation of reproductive function. Published by Elsevier Ltd.

  12. Glucocorticoids and the regulation of memory in health and disease

    NARCIS (Netherlands)

    de Quervain, Dominique J. -F; Aerni, Amanda; Schelling, Gustav; Roozendaal, Benno

    Over the last decades considerable evidence has accumulated indicating that glucocorticoids - stress hormones released from the adrenal cortex - are crucially involved in the regulation of memory. Specifically, glucocorticoids have been shown to enhance memory consolidation of emotionally arousing

  13. Mechanisms of glucocorticoid action and insensitivity in airways disease

    NARCIS (Netherlands)

    Boardman, C.; Chachi, L.; Gavrila, A.; Keenan, C. R.; Perry, M. M.; Xia, Y. C.; Meurs, H.; Sharma, P.

    2014-01-01

    Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate

  14. Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects

    NARCIS (Netherlands)

    Judd, L.L.; Schettler, P.J.; Brown, E.S.; Wolkowitz, O.M.; Sternberg, E.M.; Bender, B.G.; Bulloch, K.; Cidlowski, J.A.; Kloet, E.R. de; Fardet, L.; Joels, M.; Leung, D.Y.; McEwen, B.S.; Roozendaal, B.; Rossum, E.F. van; Ahn, J.; Brown, D.W.; Plitt, A.; Singh, G.

    2014-01-01

    Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as

  15. Investigations of Glucocorticoid Action in GN.

    Science.gov (United States)

    Kuppe, Christoph; van Roeyen, Claudia; Leuchtle, Katja; Kabgani, Nazanin; Vogt, Michael; Van Zandvoort, Marc; Smeets, Bart; Floege, Jürgen; Gröne, Hermann-Josef; Moeller, Marcus J

    2017-05-01

    For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR) specifically in kidney epithelial cells using Pax8-Cre/GR fl/fl mice. Pax8-Cre/GR fl/fl mice did not exhibit an overt spontaneous phenotype. In mice treated with nephrotoxic serum to induce crescentic nephritis (rapidly progressive GN), this genetic inactivation of the GR in kidney epithelial cells exerted renal benefits, including inhibition of albuminuria and cellular crescent formation, similar to the renal benefits observed with high-dose prednisolone in control mice. However, genetic inactivation of the GR in kidney epithelial cells did not induce the immunosuppressive effects observed with prednisolone. In vitro , prednisolone and the pharmacologic GR antagonist mifepristone each acted directly on primary cultures of parietal epithelial cells, inhibiting cellular outgrowth and proliferation. In wild-type mice, pharmacologic treatment with the GR antagonist mifepristone also attenuated disease as effectively as high-dose prednisolone without the systemic immunosuppressive effects. Collectively, these data show that glucocorticoids act directly on activated glomerular parietal epithelial cells in crescentic nephritis. Furthermore, we identified a novel therapeutic approach in crescentic nephritis, that of glucocorticoid antagonism, which was at least as effective as high-dose prednisolone with potentially fewer adverse effects. Copyright © 2017 by the American Society of Nephrology.

  16. Islet-cell dysfunction induced by glucocorticoid treatment

    DEFF Research Database (Denmark)

    van Raalte, Daniël H; Kwa, Kelly A A; van Genugten, Renate E

    2013-01-01

    Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system.......Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system....

  17. Tissue glucocorticoid sensitivity: beyond stochastic regulation on the diverse actions of glucocorticoids.

    Science.gov (United States)

    Kino, T

    2007-06-01

    Glucocorticoids have a broad array of life-sustaining functions, such as for the maintenance of the basal- and stress-related organ homeostasis. They are also frequently used as therapeutic compounds for many pathologic conditions. Thus, changes of tissue sensitivity to glucocorticoids play important roles in the physiologic conditions and are associated with and influence the course of numerous pathologic states. Changes in tissue glucocorticoid sensitivity may present on either side of an optimal range, respectively as glucocorticoid resistance or hypersensitivity, and may be generalized or tissue-specific. Recent insights into the mechanisms of the glucocorticoid receptor (GR) action indicated that the glucocorticoid signaling system is highly stochastic. Indeed, numerous factors contribute to the hormonal action at each step of the GR signaling cascade, such as ligand availability, receptor isoform expression, intracellular circulation, promoter association, attraction of cofactors, and finally clearance of the receptor from the target genes. Importantly, these regulatory mechanisms appear to be functional in tissue-, gene- and cellular biologic state-specific fashions. As an example of such phase-specific factors, we discussed influence of the cyclin-dependent kinase 5 to the GR transcriptional activity, which specifically functions in the central nervous system and may thus play an important role in the regulation of glucocorticoid action in this organ.

  18. Budesonide loaded nanoparticles with pH-sensitive coating for improved mucosal targeting in mouse models of inflammatory bowel diseases.

    Science.gov (United States)

    Ali, H; Weigmann, B; Neurath, M F; Collnot, E M; Windbergs, M; Lehr, C-M

    2014-06-10

    The purpose of this study was to investigate the therapeutic potential of budesonide loaded nanocarriers for the treatment of inflammatory bowel disease (IBD). First, budesonide was encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles by an oil in water (O/W) emulsion technique. A second batch of the same nanoparticles was additionally coated with a pH-sensitive methyl-methacrylate-copolymer. The particle sizes of the plain and the coated PLGA were 200±10.1nm and ~240±14.7nm, respectively. As could be shown in vitro, the pH-sensitive coating prevented premature drug release at acidic pH and only releases the drug at neutral to slightly alkaline pH. The efficacy of both coated and plain nanoparticle formulations was assessed in different acute and chronic colitis mouse models, also in comparison to an aqueous solution of the drug. The dose was always the same (0.168mg/kg). It was found that delivery by coated PLGA nanoparticles alleviated the induced colitis significantly better than by plain PLGA particles, which was already more effective than treatment with the same dose of the free drug. These data further corroborate the potential of polymeric nanocarriers for targeted drug delivery to the inflamed intestinal mucosa, and that this concept can still be further improved regarding the oral route of administration by implementing pH-dependent drug release characteristics. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. The role of early inhaled budesonide therapy in meconium aspiration in term newborns: a randomized control study.

    Science.gov (United States)

    Garg, Neelmani; Choudhary, Mukesh; Sharma, Deepak; Dabi, Dhanraj; Choudhary, Jagveer Singh; Choudhary, Sushil Kumar

    2016-01-01

    To study the clinical spectrum of Meconium aspiration syndrome babies and to find out the efficacy of early nebulized steroids (Budesonide) in the clinical course and outcome (morbidity and mortality) of neonates with meconium aspiration: randomized controlled trial. A total of 78 neonates were included in the study. After randomization, intervention group received nebulization with Budesonide (0.5 mg dissolved in 2.5-ml sterile normal saline within 2 h of birth and second dose was given at 12 h of birth) whereas controls were nebulized with normal saline. All neonates were accessed for serial respiratory distress score (Downe's score), requirement (dependence) of oxygen (in days), duration of neonatal intensive-care unit (NICU) stay, any complication and their final outcome. The mean days of oxygen requirement for the cases and controls were 1.79 and 3.46, respectively (p meconium aspiration results in significant early improvement in general condition (early improvement in respiratory distress and early normalization of Downe's score) of the newborn with lesser oxygen requirement, thus early discharge from NICU but has no impact on final outcome.

  20. Perinatal glucocorticoid treatment and perspectives for antioxidat therapy

    NARCIS (Netherlands)

    Tijsseling, D.|info:eu-repo/dai/nl/338666885

    2014-01-01

    Pre- and postnatal glucocorticoids are a life-saving therapy for prematurely born infants. However, glucocorticoids also trigger unwanted side effects. In part I we investigated the effects of antenatal glucocorticoids on hippocampal development. First in a mice model using a clinically relevant

  1. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

    Magnussen, Helgo; Disse, Bernd; Rodriguez-Roisin, Roberto

    2014-01-01

    exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT...

  2. Clinical trial: Preliminary efficacy and safety study of a new Budesonide-MMX® 9 mg extended-release tablets in patients with active left-sided ulcerative colitis

    NARCIS (Netherlands)

    D'Haens, G. R.; Kovács, A.; Vergauwe, P.; Nagy, F.; Molnár, T.; Bouhnik, Y.; Weiss, W.; Brunner, H.; Lavergne-Slove, A.; Binelli, D.; Di Stefano, A. F. D.; Marteau, P.

    2010-01-01

    Ulcerative colitis (UC) is a chronic inflammatory disease with relapses. Many patients need systemic corticosteroids to induce clinical remission. Efficacy and safety of Budesonide-MMX® 9 mg tablets, a new oral, extended-release formulation, were evaluated in patients suffering from active,

  3. Extrinsic lactose fines improve dry powder inhaler formulation performance of a cohesive batch of budesonide via agglomerate formation and consequential co-deposition.

    Science.gov (United States)

    Kinnunen, Hanne; Hebbink, Gerald; Peters, Harry; Huck, Deborah; Makein, Lisa; Price, Robert

    2015-01-15

    The aim of the study was to investigate how the fine particle content of lactose carriers prepared with different types of lactose fines regulates dry powder inhaler (DPI) formulation performance of a cohesive batch of micronised budesonide. Budesonide formulations (0.8 wt%) were prepared with three different lactose carriers (Lactohale (LH) LH100, 20 wt% LH210 in LH100 and 20 wt% LH300 in LH100). Fine particle fraction of emitted dose (FPFED) and mean mass aerodynamic diameter (MMAD) of budesonide was assessed with a Next Generation Impactor (NGI) using a Cyclohaler at 90 l/min. Morphological and chemical characteristics of particles deposited on Stage 2 were determined using a Malvern Morphologi G3-ID. The results indicate that increasing concentration of lactose fines (agglomerates. Presence of agglomerates on Stage 2 was confirmed by morphological analysis of particles. Raman analysis of material collected on Stage 2 indicated that the more fine lactose particles were available the more agglomerates of budesonide and lactose were delivered to Stage 2. These results suggest drug-fines agglomerate formation is an important mechanism for how lactose fines improve and regulate DPI formulation performance. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Glucocorticoids and fetal programming part 1: Outcomes.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

    Fetal development is a critical period for shaping the lifelong health of an individual. However, the fetus is susceptible to internal and external stimuli that can lead to adverse long-term health consequences. Glucocorticoids are an important developmental switch, driving changes in gene regulation that are necessary for normal growth and maturation. The fetal hypothalamic-pituitary-adrenal (HPA) axis is particularly susceptible to long-term programming by glucocorticoids; these effects can persist throughout the life of an organism. Dysfunction of the HPA axis as a result of fetal programming has been associated with impaired brain growth, altered behaviour and increased susceptibility to chronic disease (such as metabolic and cardiovascular disease). Moreover, the effects of glucocorticoid-mediated programming are evident in subsequent generations, and transmission of these changes can occur through both maternal and paternal lineages.

  5. An Approach to Greater Specificity for Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Carson C. Chow

    2018-03-01

    Full Text Available Glucocorticoid steroids are among the most prescribed drugs each year. Nonetheless, the many undesirable side effects, and lack of selectivity, restrict their greater usage. Research to increase glucocorticoid specificity has spanned many years. These efforts have been hampered by the ability of glucocorticoids to both induce and repress gene transcription and also by the lack of success in defining any predictable properties that control glucocorticoid specificity. Correlations of transcriptional specificity have been observed with changes in steroid structure, receptor and chromatin conformation, DNA sequence for receptor binding, and associated cofactors. However, none of these studies have progressed to the point of being able to offer guidance for increased specificity. We summarize here a mathematical theory that allows a novel and quantifiable approach to increase selectivity. The theory applies to all three major actions of glucocorticoid receptors: induction by agonists, induction by antagonists, and repression by agonists. Simple graphical analysis of competition assays involving any two factors (steroid, chemical, peptide, protein, DNA, etc. yields information (1 about the kinetically described mechanism of action for each factor at that step where the factor acts in the overall reaction sequence and (2 about the relative position of that step where each factor acts. These two pieces of information uniquely provide direction for increasing the specificity of glucocorticoid action. Consideration of all three modes of action indicate that the most promising approach for increased specificity is to vary the concentrations of those cofactors/pharmaceuticals that act closest to the observed end point. The potential for selectivity is even greater when varying cofactors/pharmaceuticals in conjunction with a select class of antagonists.

  6. Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome.

    Science.gov (United States)

    Cuzzoni, Eva; De Iudicibus, Sara; Franca, Raffaella; Stocco, Gabriele; Lucafò, Marianna; Pelin, Marco; Favretto, Diego; Pasini, Andrea; Montini, Giovanni; Decorti, Giuliana

    2015-01-01

    Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in their efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.

  7. Glucocorticoids Recruit Tgfbr3 and Smad1 to Shift Transforming Growth Factor-β Signaling from the Tgfbr1/Smad2/3 Axis to the Acvrl1/Smad1 Axis in Lung Fibroblasts*

    Science.gov (United States)

    Schwartze, Julian T.; Becker, Simone; Sakkas, Elpidoforos; Wujak, Łukasz A.; Niess, Gero; Usemann, Jakob; Reichenberger, Frank; Herold, Susanne; Vadász, István; Mayer, Konstantin; Seeger, Werner; Morty, Rory E.

    2014-01-01

    Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-β is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-β signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-β signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-β receptor Tgfbr3, also called betaglycan. Tgfbr3 was demonstrated to be a “switch” that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-β to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung Tgfbr3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-β signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions. PMID:24347165

  8. Effect of budesonide and cetirizine hydrochloride on neurotrophic factor, airway function and chemokines CCL17 and CCL22 in patients with allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Xiang Xu

    2017-11-01

    Full Text Available Objective: To investigate the effect of budesonide combined with cetirizine hydrochloride on neurotrophic factor, airway function and chemokines CCL17 and CCL12 in patients with allergic rhinitis. Methods: A total of 123 patients with Allergic Rhinitis were randomly divided into three groups, A group treated with budesonide nasal spray, B group treated with cetirizine hydrochloride, C group treated with budesonide combined with cetirizine hydrochloride, then the Neurotrophic factors, airway function indexes and chemokines CCL17 and CCL12 levels in three groups were compared. Results: Before the treatments, the three groups of patients in neurotrophic factor, airway function index and chemokines CCL17, CCL22 have no differences, Compared with before the treatments, after receiving different treatments, the three groups of patients in all indicators were Showed significant differences. In the indexes of neurotrophic factor (NGF, BDNF, NT-3mRNA expression, there was no significant difference between group A and group B, and group C was lower than group A and B. In airway function indexes (FVC, FEV1 and PEF, A group was significantly higher than B group, C group was significantly higher than A group; In the chemokines CCL17 and CCL22 indicators, C group was lower than A group, A group was lower than B group, the difference was significant. Conclusions: Budesonide combined with cetirizine hydrochloride in the treatment of Allergic Rhinitis, can effectively control the patients' neurotrophic factor, pulmonary ventilation and chemokine CC17, CCL22 indicators, the effect is better than Budesonide alone or Cetirizine hydrochloride.

  9. Does insulin resistance co-exist with glucocorticoid resistance in the metabolic syndrome? Studies comparing skin sensitivity to glucocorticoids in individuals with and without acanthosis nigricans

    Directory of Open Access Journals (Sweden)

    Teelucksingh Surujpal

    2012-03-01

    Full Text Available Abstract Background The metabolic syndrome is associated with increased risk for both diabetes and coronary artery disease, which insulin resistance alone does not satisfactorily explain. We propose an additional and complementary underlying mechanism of glucocorticoid resistance. Results Using acanthosis nigricans (AN and skin vasoconstrictor (SVC response to topically applied beclomethasone dipropionate as markers of insulin and glucocorticoid resistance, respectively, we compared anthropometric, biochemical, pro-inflammatory markers and the SVC response in subjects with AN in two studies: STUDY 1 was used to compare subjects with AN (Grade 4, n = 32, with those without AN (n = 68 while STUDY 2 compared these responses among a cross-section of diabetic patients (n = 109 with varying grades of AN (grade 0, n = 30; grade 1, n = 24; grade 2, n = 18; grade 3, n = 25; grade 4, n = 12. Findings In both studies there was an inverse relationship between AN Grade 4 and the SVC response, (P Conclusion An absent SVC response represents a new biomarker for the metabolic syndrome and the exaggerated inflammatory response, which characterizes the metabolic syndrome, may be an outcome of deficient glucocorticoid action in vascular tissue.

  10. Rediscovering the therapeutic use of glucocorticoids in rheumatoid arthritis.

    Science.gov (United States)

    van der Goes, Marlies C; Jacobs, Johannes W G; Bijlsma, Johannes W J

    2016-05-01

    This review will focus on new information obtained on how to apply glucocorticoids in the treatment of rheumatoid arthritis, aiming at an optimal risk-benefit ratio. Moreover, advances in the development of new preparations such as liposomal glucocorticoids will be discussed. In early rheumatoid arthritis, treatment regimens with a disease-modifying drug and initially medium-dose glucocorticoids (>7.5 but ≤30 mg prednisone equivalent) are noninferior compared with regimens with disease-modifying drugs and initially high-dose glucocorticoids (>30 mg prednisone equivalent) and have repeatedly been proven to be more effective than methotrexate monotherapy. Use of glucocorticoids following such a scheme during a period of 6 months to 2 years was not associated with increased mortality, nor with substantial bone loss if bone protective measures had been taken. New drug delivery systems, and in particular long-circulating liposomes, aiming at enhancing the biodistribution and the target site accumulation of glucocorticoids and thereby improving the balance between their efficacy and toxicity, are promising; more results on the effects in rheumatoid arthritis patients are expected to be reported during the years to come. Combination therapy including methotrexate and glucocorticoids should be the initial treatment in patients with early rheumatoid arthritis. Treatment regimens including medium-dose glucocorticoids are noninferior compared with regimens with initially high-dose glucocorticoids. Studies on new glucocorticoid preparations and new drug delivery systems improving the balance between efficacy and toxicity of glucocorticoid therapy are ongoing.

  11. [Management and Treatment of Glucocorticoid-Induced Hyperglycemia].

    Science.gov (United States)

    Paredes, Sílvia; Alves, Marta

    2016-09-01

    Glucocorticoids have been associated to several side effects, specially a diabetogenic action, the most common and representative effect. Glucocorticoid-induced hyperglycemia is a common medical condition, with general associated morbidity and mortality. It was performed a literature review about the management and treatment of glucocorticoid-induced hyperglycemia. Through numerous not quite fully understood mechanics, glucocorticoids promote hyperglycemia in non-diabetic patients and worsen diabetes control in diabetic individuals. Glucocorticoid-induced hyperglycemia presents key patterns, enhanced in the postprandial period and scheduled-dependent. Despite the existence of guidelines for hyperglycemia treatment in non-critic hospitalized and non-hospitalized patients, there are no guidelines respecting glucocorticoid-induced hyperglycemia. Nevertheless, it is known that glucocorticoid-induced hyperglycemia is complex and demanding, requiring a specific approach. Indeed, glucocorticoid-induced hyperglycemia treatment depends on the glucocorticoid used, its dose, frequency and schedule. Furthermore, the scheme of treatment previously used by diabetic individuals also influences the choice of the new scheme. The authors reviewed the glucocorticoid induced-hyperglycemia thematic and propose strategies to approach and treat glucocorticoid induced-hyperglycemia in diabetic and non-diabetic individuals. This review is expected to be useful in different settings and crosswise to all medical specialties.

  12. Mechanisms of glucocorticoid action and insensitivity in airways disease.

    Science.gov (United States)

    Boardman, C; Chachi, L; Gavrila, A; Keenan, C R; Perry, M M; Xia, Y C; Meurs, H; Sharma, P

    2014-12-01

    Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Hormones, stress, and cognition: The effects of glucocorticoids and oxytocin on memory

    Science.gov (United States)

    Wirth, Michelle M.

    2014-01-01

    Hormones have nuanced effects on learning and memory processes. The degree and direction of the effect (e.g., is memory impaired or enhanced?) depends on the dose, type and stage of memory, and type of material being learned, among other factors. This review will focus on two specific topics within the realm of effects of hormones on memory: (1) How glucocorticoids (the output hormones of the hypothalamic-pituitary-adrenal axis) affect long-term memory consolidation, retrieval, and working memory, with a focus on neural mechanisms and effects of emotion; and (2) How oxytocin affects memory, with emphasis on a speculative hypothesis that oxytocin might exert its myriad effects on human social cognition and behavior via impacts on more general cognitive processes. Oxytocin-glucocorticoid interactions will be briefly addressed. These effects of hormones on memory will also be considered from an evolutionary perspective. PMID:25893159

  14. On the retinal toxicity of intraocular glucocorticoids.

    Science.gov (United States)

    Torriglia, Alicia; Valamanesh, Fatemeh; Behar-Cohen, Francine

    2010-12-15

    Corticosteroids are hormones involved in many physiological responses such as stress, immune modulation, protein catabolism and water homeostasis. The subfamily of glucocorticoids is used systemically in the treatment of inflammatory diseases or allergic reactions. In the eye, glucocorticoides are used to treat macular edema, inflammation and neovascularization. The most commonly used glucocorticoid is triamcinolone acetonide (TA). The pharmaceutical formulation of TA is not adapted for intravitreal administration but has been selected by ophthalmologists because its very low intraocular solubility provides sustained effect. Visual benefits of intraocular TA do not clearly correlate with morpho-anatomical improvements, suggesting potential toxicity. We therefore studied, non-common, but deleterious effects of glucocorticoids on the retina. We found that the intravitreal administration of TA is beneficial in the treatment of neovascularization because it triggers cell death of endothelial cells of neovessels by a caspase-independent mechanism. However, this treatment is toxic for the retina because it induces a non-apoptotic, caspase-independent cell death related to paraptosis, mostly in the retinal pigmented epithelium cells and the Müller cells. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Bisphosphonates and glucocorticoid-induced osteoporosis: cons

    NARCIS (Netherlands)

    Lems, W.F.; Saag, K.

    2015-01-01

    During the use of glucocorticoids (GCs), both vertebral and nonvertebral fracture risk are increased, due to the direct and indirect negative effects of GCs on bone, muscles, and the activity of the underlying inflammatory diseases. Inhibition of bone formation and increased apoptosis of osteocytes

  16. Glucocorticoid receptor knockdown and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Hooijdonk, Leonarda Wilhelmina Antonia van

    2010-01-01

    The research in this thesis is aimed at the elucidation of the role of the glucocorticoid receptor (GR) in hippocampal neuroplasticity and functioning. To achieve this, we have developed a novel method to specifically knockdown GR in a discrete cell population of the mouse brain. In this thesis I

  17. Are BDNF and glucocorticoid activities calibrated?

    Science.gov (United States)

    Jeanneteau, Freddy; Chao, Moses V.

    2012-01-01

    One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by enhancing survival, synapse formation and synaptic plasticity. Implementation of ‘BDNF therapies’, however, faces numerous methodological and pharmacokinetic issues. Identifying BDNF mimetics that activate the BDNF receptor or downstream targets of BDNF signaling represent an alternative approach. One mechanism that shows great promise is to study the interplay of BDNF and glucocorticoid hormones, a major class of natural steroid secreted during stress reactions and in synchrony with circadian rhythms. While small amounts of glucocorticoids support normal brain function, excess stimulation by these steroid hormones precipitate stress-related affective disorders. To date, however, because of the paucity of knowledge of underlying cellular mechanisms, deleterious effects of glucocorticoids are not prevented following extreme stress. In the present review, we will discuss the complementary roles share by BDNF and glucocorticoids in synaptic plasticity, and delineate possible signaling mechanisms mediating these effects. PMID:23022538

  18. Glucocorticoid Regulation of the Vitamin D Receptor

    Science.gov (United States)

    Hidalgo, Alejandro A.; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and Dex induce VDR- and glucocorticoid receptor (GR)-mediated transcription respectively, indicating both hormone receptors are active in SCC. Pre-treatment with Dex increases VDR-mediated transcription at the human CYP24A1 promoter. Whereas, pre-treatment with other steroid hormones, including dihydrotestosterone and R1881, has no effect on VDR-mediated transcription. Real-time PCR indicates treatment with Dex increases Vdr transcripts in a time-dependent manner, suggesting Dex may directly regulate expression of Vdr. Numerous putative glucocorticoid response elements (GREs) were found in the Vdr gene. Chromatin immunoprecipitation (ChIP) assay demonstrated GR binding at several putative GREs located within the mouse Vdr gene. However, none of the putative GREs studied increase GR-mediated transcription in luciferase reporter assays. In an attempt to identify the response element responsible for Vdr transcript regulation, future studies will continue to analyze newly identified GREs more distal from the Vdr gene promoter. PMID:20398752

  19. Prepubertal glucocorticoid status and pubertal timing.

    Science.gov (United States)

    Shi, Lijie; Wudy, Stefan A; Buyken, Anette E; Maser-Gluth, Christiane; Hartmann, Michaela F; Remer, Thomas

    2011-06-01

    Whether prepubertal glucocorticoid status impacts on the timing of puberty is not clear. The objective of the study was to examine the relationship between prepubertal glucocorticoid status and early or late pubertal markers, independent of adrenarchal and nutritional status. Prospective cohort study of healthy Caucasian children (n = 111, 56 boys) who provided both 24-h urine samples and weighed dietary records 1 and 2 yr before the start of pubertal growth spurt [age at take-off (ATO)]. Major urinary glucocorticoid and androgen metabolites determined by gas chromatography-mass spectrometry analysis were summed to assess daily overall cortisol (ΣC21) and adrenal androgen secretion; urinary free cortisol and cortisone measured by RIA were summed (UFF+UFE) as an indicator of potentially bioactive free glucocorticoids. The main outcomes included ATO, age at peak height velocity, age at menarche/voice break, ages at Tanner stage 2 for breast (girls) and genital (boys) development, and pubic hair. In girls ΣC21, but not UFF+UFE, was associated with pubertal markers after adjusting for overall adrenal androgen, urinary nitrogen, and body fat. Girls with higher ΣC21 (fourth quartile) reached ATO 0.7 yr (P = 0.01) and menarche 0.9 yr later (P = 0.006) than girls with lower ΣC21 (first quartile). The ΣC21 tended to be also positively associated with age at Tanner stage 2 for breast (P = 0.1), Tanner stage 2 for pubic hair (P = 0.1), and age at peak height velocity (P = 0.06). In boys, neither the ΣC21 nor UFF+UFE was related to pubertal timing. An individually higher prepubertal glucocorticoid secretion level, even in physiological range, appears to delay early and late pubertal timing of healthy girls, particularly their onset of pubertal growth spurt and menarche.

  20. The insulin-like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

    DEFF Research Database (Denmark)

    Wolthers, O D; Juul, A; Hansen, M

    1995-01-01

    Serum concentrations of growth hormone-dependent insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP...... the calculations (p type III collagen. A similar trend was observed in ICTP levels when the 400 micrograms period was excluded from the calculations (p = 0.05; z = -1.9). No other statistically significant variations were seen.......) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double-blind treatment periods (200 and 800 micrograms) and one open...

  1. Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors.

    Science.gov (United States)

    Vincent, Melanie Y; Hussain, Rifat J; Zampi, Michael E; Sheeran, Katherine; Solomon, Matia B; Herman, James P; Khan, Anum; Jacobson, Lauren

    2013-08-07

    The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Systemic glucocorticoids: important issues and practical guidelines for the dermatologist.

    Science.gov (United States)

    Dodiuk-Gad, Roni P; Ish-Shalom, Sophia; Shear, Neil H

    2015-06-01

    The potent anti-inflammatory and immunosuppressive effects of systemic glucocorticoids have led to their wide use in the treatment of dermatologic diseases. However, glucocorticoids have been designated the "archetypal double-edged sword of medicine" as a result of their various potential adverse side effects. Dermatologists face major challenges in their usage and require knowledge of both the risks related to their usage and strategies with which to manage them. This brief review includes an evidence-based, strategic approach to the general risk management of systemic glucocorticoids with a focus on preventing glucocorticoid-induced osteoporosis (GIOP). We assess which classes of corticosteroid are most likely to provoke allergic cross-reactions and outline the mechanism for glucocorticoid resistance. We examine how glucocorticoids both help and impair normal physiology. Five reactivity groups are defined, based on the structural and clinical characteristics of glucocorticoids. Tests for allergy reactions and mechanisms for glucocorticoid resistance are described. Guidelines for the prevention and treatment of GIOP are introduced. Glucocorticoids play an important teleologic role in maintaining blood glucose levels adequate for brain function by inducing a catabolic state through the production of carbohydrates at the expense of proteins and fat stores. It is hoped that the various recommendations for the protection of patients treated with systemic glucocorticoids will provide physicians with practical guidelines for prescribing. © 2015 The International Society of Dermatology.

  3. Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.

    Directory of Open Access Journals (Sweden)

    Benjamin D Weger

    2016-12-01

    Full Text Available Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.

  4. Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.

    Science.gov (United States)

    Weger, Benjamin D; Weger, Meltem; Görling, Benjamin; Schink, Andrea; Gobet, Cédric; Keime, Céline; Poschet, Gernot; Jost, Bernard; Krone, Nils; Hell, Rüdiger; Gachon, Frédéric; Luy, Burkhard; Dickmeis, Thomas

    2016-12-01

    Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.

  5. A valved holding chamber does not decrease the bronchodilator activity of budesonide-formoterol combination metered dose inhaler.

    Science.gov (United States)

    Mansfield, Lyndon E; Maynes, Ruby

    2013-02-01

    Spacers and valved holding chambers (VHCs) were developed to facilitate using pressurized metered dose inhaler (pMDI) by patients who could not coordinate the actions required for successful pMDI use. There is little in vivo evidence about how VHC may affect the bronchodilation from combination drugs in pMDI. This study was to determine the effect, if any, of VHC on the bronchodilating actions of the pMDI budesonide/formoterol combination. Sixteen adult asthmatic subjects with 15% or greater reversibility of forced expiratory volume in one second (FEV-1), 15 minutes after inhaling 180-360 μg of albuterol, participated. The study had a randomized crossover design with each subject using budesonide-formoterol pMDI as described in the product information one timeand on a second occasion using the pMDI with a VHC. Spirometry and impedance osscilometry were measured at baseline and repeatedly over a 12-hour period. This study was approved by IntegReview Institutional Review Board, Austin, TX, USA. The clinical trial number for this study was NCT 009-15538 (http://www.westernskymed.com). The area under the curve of FEV-1, the FEV-1, and the fraction FEV-1/FVC was similar over the 12-hour time frame with both methods. Resistance was not different at any time point. In both procedures, the onset of bronchodilation occurred rapidly within 3 to 5 minutes. In well-trained asthmatic subjects, both tested methods caused equivalent bronchodilation. This suggests a VHC itself has no deleterious effect on the bronchodilator activity in the combined drug. These results may not apply to patients who have coordination problems with the pMDI and further study is indicated.

  6. Exogenous glucocorticoids and adverse cerebral effects in children.

    Science.gov (United States)

    Damsted, Sara K; Born, A P; Paulson, Olaf B; Uldall, Peter

    2011-11-01

    Glucocorticoids are commonly used in treatment of paediatric diseases, but evidence of associated adverse cerebral effects is accumulating. The various pharmacokinetic profiles of the exogenous glucocorticoids and the changes in pharmacodynamics during childhood, result in different exposure of nervous tissue to exogenous glucocorticoids. Glucocorticoids activate two types of intracellular receptors, the mineralocorticoid receptor and the glucocorticoid receptor. The two receptors differ in cerebral distribution, affinity and effects. Exogenous glucocorticoids favor activation of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported. Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular structures involved in axonal transport, long-term potentiation and neuronal plasticity. Significant maturation of the brain continues throughout childhood and we hypothesize that exposure to exogenous glucocorticoids during preschool and school age causes adverse cerebral effects. It is our opinion that studies of associations between exposure to glucocorticoids during childhood and impaired neurodevelopment are highly relevant. Copyright © 2011 European Paediatric Neurology

  7. Bone safety of low-dose glucocorticoids in rheumatic diseases.

    Science.gov (United States)

    Saag, Kenneth G

    2014-05-01

    Glucocorticoids are widely used internationally for the treatment of inflammatory disease, such as rheumatoid arthritis (RA). Although the benefit of glucocorticoids in RA on both disease activity and severity are well known, there remain unanswered questions about the overall bone safety of chronic low-dose glucocorticoids in RA. Debate exists about the merits of glucocorticoids for bone health on the basis of their benefits in promoting activity and reducing proinflammatory cytokines. Overall current evidence supports the view that bone loss is a disease related both to RA and to glucocorticoid use independently. Calcium and vitamin D, along with prescription antiosteoporosis therapies, particularly bisphosphonates and teriparatide, play an important role in stabilizing bone mineral density and potentially lowering spinal fracture risk at the spine. International guidelines provide pathways for appropriate prevention of glucocorticoid-induced osteoporosis (GIOP). Despite the evidence and these guidelines, many patients do not receive adequate management to prevent GIOP. © 2014 New York Academy of Sciences.

  8. [Dual effects of glucocorticoids on the gastric mucosa].

    Science.gov (United States)

    Podvigina, T T; Filaretova, L P

    2014-01-01

    In this review we systematise and analyze data of literature about the effect of glucocorticoids on the gastric mucosa. There are convincing results that show the adaptive gastoprotective nature of endogenous glucocorticoids, which are produced during acute stress-induced activation of the HPA axis. The role glucocorticoid hormones play in the effect of chronic stress remains little-studied. We have seen that after single administration of glucocorticoids, there can arise gastroprotective and ulcerogenic effects. Although. the question about the effect of therapy using glucocorticoid hormones on gastric ulceration is being debated, the data confirm the ulcerogenic influence that large doses of these hormones have on experimental animals. The initial gastroprotective effect that glucocorticoid hormones have, even after their single administration can be transformed into an ulcerogenic effect with a prolongation of the hormonal action, but not of the hormone dose. We are discussing the possible mechanism behind the transformation.

  9. [Glucocorticoids in neurology: mechanism of action, applications and side effects].

    Science.gov (United States)

    Finsterer, J; Frank, M

    2014-06-01

    Glucocorticoids represent a cornerstone in the therapy for many neurological disorders. Even though their mechanism of action is still not completely understood, synthetic glucocorticoids are given as first line drugs in a number of immunological and non-immunological disorders of the central or peripheral nervous system. For most of these disorders, however, the level of evidence that glucocorticoids are truly effective is still not sufficient. This is why treatment with glucocorticoids cannot be recommended on an evidenced-based level for many of these disorders. Due to the huge number of acute or chronic side effects, it is essential that the effects are documented by more randomised placebo-controlled cross-over trials. Generally, glucocorticoids can no longer be omitted in the treatment of neurological disorders, the indication to apply glucocorticoids, however, needs to be thoroughly balanced in the light of their many side effects. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Molecular dynamics of ultradian glucocorticoid receptor action.

    Science.gov (United States)

    Conway-Campbell, Becky L; Pooley, John R; Hager, Gordon L; Lightman, Stafford L

    2012-01-30

    In recent years it has become evident that glucocorticoid receptor (GR) action in the nucleus is highly dynamic, characterized by a rapid exchange at the chromatin template. This stochastic mode of GR action couples perfectly with a deterministic pulsatile availability of endogenous ligand in vivo. The endogenous glucocorticoid hormone (cortisol in man and corticosterone in rodent) is secreted from the adrenal gland with an ultradian rhythm made up of pulses at approximately hourly intervals. These two components - the rapidly fluctuating ligand and the rapidly exchanging receptor - appear to have evolved to establish and maintain a system that is exquisitely responsive to the physiological demands of the organism. In this review, we discuss recent and innovative work that questions the idea of steady state, static hormone receptor responses, and replaces them with new concepts of stochastic mechanisms and oscillatory activity essential for optimal function in molecular and cellular systems. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  11. Glucocorticoid Availability in Colonic Inflammation of Rat

    Czech Academy of Sciences Publication Activity Database

    Ergang, Peter; Leden, Pavel; Bryndová, Jana; Žbánková, Šárka; Mikšík, Ivan; Kment, M.; Pácha, Jiří

    2008-01-01

    Roč. 53, č. 8 (2008), s. 2160-2167 ISSN 0163-2116 R&D Projects: GA MZd(CZ) NR8576; GA ČR GA305/07/0328 Grant - others:Univerzita Karlova(CZ) 77/2006C Institutional research plan: CEZ:AV0Z50110509 Keywords : glucocorticoids * 11beta hydroxisteroid dehydrogenase 1 Subject RIV: ED - Physiology Impact factor: 1.583, year: 2008

  12. Biochemical endpoints of glucocorticoid hormone action

    Energy Technology Data Exchange (ETDEWEB)

    Young, D.A.; Nicholson, M.L.; Guyette, W.A.; Giddings, S.J.; Mendelsohn, S.L.; Nordeen, S.K.; Lyons, R.T.

    1978-01-01

    Both the rapidly evolving metabolic effects of glucocorticoids and the more slowly developing lethal actions appear to be initiated via the synthesis of new mRNAs and proteins. The chronic suppression of cell growth may be the consequence of suppression of overall rates of protein synthesis (and probably RNA and DNA synthesis as well) that in turn may represent the cellular response to the small changes in ratios of adenine nucleotides that result from the suppression of oxidative ATP production. The inhibition of glucose transport may also play a role here to prevent a compensatory increase in glycolytic ATP production. Some other hormone actions, the decrease in the ability of cells to concentrate AIB and the increase in nuclear fragility are unrelated to, and evolve separately from, the hormonal inhibitions on energy production. Cell killing is not the result of suppression of protein synthesis, nor of hormone-induced increases in calcium uptake. While the mechanisms are unknown, the increase in nuclear fragility appears to be the earliest measure of their operation. In tumor cells resistance to lethal actions of glucocorticoids may emerge via the selection of cells with hardier membranes, that are better able to withstand the intracellular destructive events set in motion by high levels of glucocorticoids.

  13. Bioequivalence of budesonide plus formoterol (BF) Spiromax® and BF Turbohaler® (with and without charcoal block) in healthy volunteers.

    Science.gov (United States)

    Weisfeld, Lori; Shu, Youyi; Shah, Tushar P

    2015-07-01

    Budesonide formoterol (BF) Spiromax® is a breath-actuated dry-powder inhaler designed to deliver similar combinations of budesonide and formoterol as Symbicort® Turbohaler®. We performed two studies to demonstrate pharmacokinetic (PK) equivalence of BF Spiromax with BF Turbohaler. Two single-center, open-label, randomized, 5-period crossover studies were performed. The first study compared BF Spiromax 160/4.5 μg with BF Turbohaler 200/6 μg, while the second study compared BF Spiromax 320/9 μg with BF Turbohaler 400/12 μg. All treatments were administered with and without charcoal. PK parameters were calculated by measuring plasma drug concentrations from blood samples taken pre-dose and up to 24 hours post-dose. In each study, 90 healthy volunteers were randomized. Bioequivalence of BF Spiromax with BF Turbohaler was demonstrated for budesonide and formoterol (AUC0-t and Cmax (90% confidence intervals of the geometric mean between-device ratios for both parameters were within the predefined range of 0.80-1.25 in both studies)). Equivalence was observed without use of charcoal (overall absorption post-inhalation) and with charcoal (pulmonary absorption). There were no major differences between treatments in tmax for either budesonide or formoterol. All study treatments were well tolerated (one treatment-emergent adverse event (TEAE) in the medium-dose study and four TEAEs in the high-dose study). These studies indicate that BF Spiromax (±charcoal block) is bioequivalent to BF Turbohaler with respect to the PK parameters assessed. Single doses of BF Spiromax were well tolerated; the overall safety profile of BF Spiromax and BF Turbohaler was similar.

  14. Dual Role for Glucocorticoids in Cardiomyocyte Hypertrophy and Apoptosis

    Science.gov (United States)

    Ren, Rongqin; Oakley, Robert H.; Cruz-Topete, Diana

    2012-01-01

    Glucocorticoids and their synthetic derivatives are known to alter cardiac function in vivo; however, the nature of these effects and whether glucocorticoids act directly on cardiomyocytes are poorly understood. To explore the role of glucocorticoid signaling in the heart, we used rat embryonic H9C2 cardiomyocytes and primary cardiomyocytes as model systems. Dexamethasone (100 nm) treatment of cardiomyocytes caused a significant increase in cell size and up-regulated the expression of cardiac hypertrophic markers, including atrial natriuretic factor, β-myosin heavy chain, and skeletal muscle α-actin. In contrast, serum deprivation and TNFα exposure triggered cardiomyocyte apoptosis, and these apoptotic effects were inhibited by dexamethasone. Both the hypertrophic and anti-apoptotic actions of glucocorticoids were abolished by the glucocorticoid receptor (GR) antagonist RU486 and by short hairpin RNA-mediated GR depletion. Blocking the activity of the mineralocorticoid receptor had no effect on these glucocorticoid-dependent cardiomyocyte responses. Aldosterone (1 μm) activation of GR also promoted cardiomyocyte hypertrophy and cell survival. To elucidate the mechanism of the dual glucocorticoid actions, a genome-wide microarray was performed on H9C2 cardiomyocytes treated with vehicle or dexamethasone in the absence or presence of serum. Serum dramatically influenced the transcriptome regulated by GR, revealing potential glucocorticoid signaling mediators in both cardiomyocyte hypertrophy and apoptosis. These studies reveal a direct and dynamic role for glucocorticoids and GR signaling in the modulation of cardiomyocyte function. PMID:22989630

  15. Effect of perinatal glucocorticoids on vascular health and disease.

    Science.gov (United States)

    Millage, Aaron R; Latuga, Mariam S; Aschner, Judy L

    2017-01-01

    The benefits of antenatal glucocorticoids are now firmly established in the perinatal management of threatened preterm birth. Postnatal glucocorticoid therapy, however, remains controversial in neonatal medicine, with the need to balance short-term physiological benefits against the potential for long-term adverse consequences. This review focuses on the vascular effects of prenatal and postnatal glucocorticoids, synthesizing data from both experimental animal models and human infants with the goal of better appreciation of the short and long-term effects of these commonly used drugs. Due to their widespread and varied use, improved understanding of the cellular and molecular impact of glucocorticoids is important in guiding current practice and future research.

  16. Glucocorticoid-resistant asthma: more than meets the eye.

    Science.gov (United States)

    Reddy, Divya; Little, Frederic F

    2013-12-01

    For decades glucocorticoids have been considered as the gold standard for the treatment of asthma. We present a case report of typical glucocorticoid-resistant asthma and current consensus in definitions of "severe refractory", "difficult" and "glucocorticoid-resistant" asthma. Full-text papers and abstracts were identified on the basis of a comprehensive literature search primarily in MEDLINE (1966 to June 2012) but also in the Cochrane Central Register of Controlled Trials database. Glucocorticoid-resistant asthmatics are a small subset of patients who pose noteworthy diagnostic challenges while contributing disproportionately to health care costs. Recognition of various asthma phenotypes has aided in characterizing groups with severe asthma and given a better understanding of its pathophysiological process. The molecular mechanism of glucocorticoid action is complicated and several pathways have been identified to explain drug resistance, which in turn is crucial for drug development. Tobacco smoking appears to be the single most important contributor of glucocorticoid resistance. We present the emerging and promising concepts in the management of glucocorticoid-resistant asthma, which mainly include drugs targeting specific molecules, receptors, inflammatory cells or immune processes. The challenges in making a diagnosis of glucocorticoid-resistant asthma may contribute to underestimating its prevalence and impact on patient care. Considerable progress has been made in identifying distinct phenotypes and mechanisms of glucocorticoid resistance; therefore the future of new drug development in management of asthma is promising.

  17. Tissue-specific glucocorticoid action: a family affair.

    Science.gov (United States)

    Gross, Katherine L; Cidlowski, John A

    2008-11-01

    Glucocorticoids exert a wide variety of physiological and pathological responses, most of which are mediated by the ubiquitously expressed glucocorticoid receptor (GR). The glucocorticoid response varies among individuals, as well as within tissues from the same individual, and this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of GR. This review focuses on the recent advances in our understanding of prereceptor ligand metabolism, GR subtypes and GR polymorphisms. Furthermore, we evaluate the impact of tissue- and individual-specific diversity in the glucocorticoid pathway on human health and disease.

  18. Dibutyltin disrupts glucocorticoid receptor function and impairs glucocorticoid-induced suppression of cytokine production.

    Directory of Open Access Journals (Sweden)

    Christel Gumy

    Full Text Available BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK and tyrosine-aminotransferase (TAT and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6 and TNF-alpha production in lipopolysaccharide (LPS-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.

  19. Back to basics: the development of a simple, homogenous, two-component dry-powder inhaler formulation for the delivery of budesonide using miscible vinyl polymers.

    Science.gov (United States)

    Buttini, F; Colombo, P; Wenger, M P E; Mesquida, P; Marriott, C; Jones, Stuart A

    2008-03-01

    It was hypothesised that formulating a dry-powder inhaler (DPI) using a refined, smooth grade of lactose, without fines and a polymer coated drug microparticle should produce an homogeneous formulation in which aerosolization behaviour could be modified. Hence, the aim of this study was to develop a simple two component polymer coated-budesonide/lactose blend in which the drug microparticle adhesive forces could be optimised by modifying the drug coating in order to improve aerosolization from a DPI. Budesonide microparticles (1.83 +/- 0.03 microm) were coated with the vinyl polymers by adsorption and then spray-dried. The drug was blended with three different types of lactose, checked for uniformity of mixing and loaded into Pulvinal devices. The median volume particle size of all but one of the polymer coated microparticles remained below 4 microm after spray-drying and the content uniformity for all the blends >96%. Coating the budesonide with 0.01% poly(vinyl alcohol) increased the fine particle fraction (FPF) in the next generation impactor (NGI) from 29.1 +/- 0.7% to 52.8 +/- 1.0% and reduced the force of adhesion from 410 +/- 182 to 241 +/- 82 nN with smooth lactose. This illustrates that vinyl polymers could effectively modify adhesive interactions without the need for ternary components such as fines. (Copyright) 2008 Wiley-Liss, Inc.

  20. [Prophylaxis and therapy of the glucocorticoid-induced osteoporosis - a review of recent guidelines].

    Science.gov (United States)

    Rintelen, Bernhard; Bobacz, Klaus; Höfle, Günter; Peichl, Peter; Rainer, Franz; Weber, Kurt; Gaugg, Markus

    2011-11-01

    Several international guidelines for treatment and prophylaxis of glucocorticoid-induced osteoporosis (GIO) have been published. Consistent with the development of new therapeutic agents, a different approach to treatment can be recognized depending on the year of publication. Also, new insights for the postmenopausal osteoporosis leave their marks on recent guidelines. The working committee on Osteology of the Austrian Society for Rheumatology and Rehabilitation (ÖGR) sifted through actual guidelines and recent literature on the topic to develop recommendations for the prophylaxis and treatment of the GIO.

  1. Molecular mechanisms of glucocorticoid receptor signaling Mecanismos moleculares de señalización del receptor de glucocorticoides

    OpenAIRE

    Marta Labeur; Florian Holsboer

    2010-01-01

    This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR). Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeost...

  2. Glucocorticoids can affect Pseudomonas aeruginosa (ATCC 27853) internalization and intracellular calcium concentration in cystic fibrosis bronchial epithelial cells.

    Science.gov (United States)

    Hussain, Rashida; Shahror, Rami; Karpati, Ferenc; Roomans, Godfried M

    2015-01-01

    Glucocorticoids (GCs) are anti-inflammatory agents, but their use in cystic fibrosis (CF) is controversial. In CF, the early colonization with Pseudomonas aeruginosa is mainly due to nonmucoid strains that can internalize, and induce apoptosis in the epithelial cells. Uptake of P. aeruginosa by the epithelial cells and subsequent apoptosis may prevent colonization of P. aeruginosa in CF airways. In the airway epithelia, several other biological effects, including an anti-secretory role by decreasing intracellular Ca(2+) concentration have been described for this anti-inflammatory drug. However, the effects of GCs on the nonmucoid P. aeruginosa internalization and intracellular Ca(2+) in CF bronchial epithelial cells have not been evaluated. We used cultured human CF bronchial airway epithelial cell (CFBE) monolayers to determine P. aeruginosa internalization, apoptosis, and intracellular Ca(2+)concentration in CF bronchial epithelial cells. Cells were treated with IL-6, IL-8, dexamethasone, betamethasone, or budesonide. GCs in co-treatments with IL-6 reversed the effect of IL-6 by decreasing the internalization of P. aeruginosa in the CFBE cells. GCs decreased the extent of apoptosis in CFBE cells infected with internalized P. aeruginosa, and increased the intracellular Ca(2+) concentration. These findings suggest that if internalization of P. aeruginosa reduces infection, GC therapy would increase the risk of pulmonary infection by decreasing the internalization of P. aeruginosa in CF cells, but GCs may improve airway hydration by increasing the intracellular Ca(2+) concentration. Whether the benefits of GC treatment outweigh the negative effects is questionable, and further clinical studies need to be carried out.

  3. Context Modulates Outcome of Perinatal Glucocorticoid Action in the Brain

    Directory of Open Access Journals (Sweden)

    Edo Ronald ede Kloet

    2014-07-01

    Full Text Available Prematurely born infants may be at risk, because of inadequate maturation of tissues. If there are signs of preterm birth, it has become common practice therefore to treat either antenatally the mother or postnatally the infant with glucocorticoids to accelerate tissue development, particularly of the lung. However, this life-saving early glucocorticoid treatment was found to increase the risk of adverse outcome in later life. In one animal study the authors reported a 25% shorter lifespan of rats treated as newborns with the synthetic glucocorticoid dexamethasone, but sofar this finding has not been replicated. After a brief clinical introduction, we discuss studies in rodents designed to examine how perinatal glucocorticoid action affects the developing brain. It appears that the perinatal action of the glucocorticoid depends on the context and the timing as well as the type of administered steroid. The type of steroid is important because the endogenous glucocorticoids cortisol and corticosterone bind to two distinct receptor populations, i.e. mineralocorticoid (MR and glucocorticoid receptors (GR, while synthetic glucocorticoids predominantly bind to the GR. In addition, if given antenatally hydrocortisone is inactivated in the placenta by 11β-HSD type 2, and dexamethasone is not. With respect to timing, the outcome of glucocorticoid effects is different in early vs late phases of brain development. The context refers to the environmental input that can affect the susceptibility to glucocorticoid action in the newborn rodent brain; early handling of pups and maternal care obliterate effects of postnatal dexamethasone treatment. Context also refers to coping with environmental conditions in later life, for which the individual may have been programmed epigenetically by early life experience. This knowledge of determinants affecting the outcome of perinatal glucocorticoid exposure may have clinical implications for the treatment of

  4. The Regulation of Muscle Mass by Endogenous Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Daniel L Marks

    2015-02-01

    Full Text Available Glucocorticoids are highly conserved fundamental regulators of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, glucocorticoids are released from the adrenal gland, rapidly mobilizing energy from carbohydrate, fat and protein stores. In the case of inflammation, mobilized protein is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilization can lead to a p rofound depletion of energy stores. Skeletal muscle represents the major body store of protein, and can become substantially atrophied under conditions of chronic inflammation. Glucocorticoids elicit the atrophy of muscle by increasing the rate of protein degradation by the ubiquitin-proteasome system and autophagy lysosome system. Protein synthesis is also suppressed at the level of translational initiation, preventing the production of new myofibrillar protein. Glucocorticoids also antagonize the action of anabolic regulators such as insulin further exacerbating the loss of protein and muscle mass. The loss of muscle mass in the context of chronic disease is a key feature of cachexia and contributes substantially to morbidity and mortality. A growing body of evidence demonstrates that glucocorticoid signaling is a common mediator of wasting, irrespective of the underlying initiator or disease state. This review will highlight fundamental mechanisms of glucocorticoid signaling and detail the mechanisms of glucocorticoid-induced muscle atrophy. Additionally, the evidence for glucocorticoids as a driver of muscle wasting in numerous disease states will be discussed. Given the burden of wasting diseases and the nodal nature of glucocorticoid signaling, effective anti-glucocorticoid therapy would be a valuable clinical tool. Therefore, the progress and potential pitfalls in the development of glucocorticoid antagonists for muscle wasting will

  5. Context modulates outcome of perinatal glucocorticoid action in the brain.

    Science.gov (United States)

    de Kloet, E Ronald; Claessens, Sanne E F; Kentrop, Jiska

    2014-01-01

    Prematurely born infants may be at risk, because of inadequate maturation of tissues. If there are signs of preterm birth, it has become common practice therefore to treat either antenatally the mother or postnatally the infant with glucocorticoids to accelerate tissue development, particularly of the lung. However, this life-saving early glucocorticoid treatment was found to increase the risk of adverse outcome in later life. In one animal study, the authors reported a 25% shorter lifespan of rats treated as newborns with the synthetic glucocorticoid dexamethasone, but so far this finding has not been replicated. After a brief clinical introduction, we discuss studies in rodents designed to examine how perinatal glucocorticoid action affects the developing brain. It appears that the perinatal action of the glucocorticoid depends on the context and the timing as well as the type of administered steroid. The type of steroid is important because the endogenous glucocorticoids cortisol and corticosterone bind to two distinct receptor populations, i.e., mineralocorticoid and glucocorticoid receptors (GR), while synthetic glucocorticoids predominantly bind to the GR. In addition, if given antenatally hydrocortisone is inactivated in the placenta by 11β-HSD type 2, and dexamethasone is not. With respect to timing, the outcome of glucocorticoid effects is different in early vs. late phases of brain development. The context refers to the environmental input that can affect the susceptibility to glucocorticoid action in the newborn rodent brain; early handling of pups and maternal care obliterate effects of post-natal dexamethasone treatment. Context also refers to coping with environmental conditions in later life, for which the individual may have been programed epigenetically by early-life experience. This knowledge of determinants affecting the outcome of perinatal glucocorticoid exposure may have clinical implications for the treatment of prematurely born infants.

  6. Systemic activity of inhaled topical steroid in toddlers studied by knemometry

    DEFF Research Database (Denmark)

    Bisgaard, H

    1993-01-01

    The short-term linear growth rate of the lower leg in toddlers was measured and evaluated in order to study the possible effect of inhaled budesonide on this factor in toddlers with mild recurrent wheezing. The short-term linear growth rate of the lower leg was measured weekly using a hand......-held knemometer. Eighteen toddlers aged 13-36 months (mean 27 months) with a history of recurrent wheezing requiring inhaled topical steroids, but without need of regular medication during the months prior to the study, were studied. The children were randomized blindly through three consecutive treatment periods...... of exacerbations and one because of non-compliance. The precision of the measurement procedure was 51 microns/day. The mean growth rate during placebo, low-dose and high-dose steroid treatment was 92 microns/day, 114 microns/day and 46 microns/day respectively. The growth rate during the high-dose treatment...

  7. Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance.

    Science.gov (United States)

    Ramamoorthy, Sivapriya; Cidlowski, John A

    2013-01-01

    Glucocorticoids regulate a variety of physiological processes, and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR), but sensitivity to glucocorticoids varies among individuals, and even within different tissues from the same individual. The molecular basis of this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of the GR. The molecular mechanisms that regulate glucocorticoid action highlight the dynamic nature of hormone signaling and provide novel insights into genomic glucocorticoid actions and glucocorticoid sensitivity. Although glucocorticoids are highly effective for therapeutic purposes, long-term and/or high-dose glucocorticoid administration often leads to reduced glucocorticoid sensitivity or resistance. Here, we summarize our current understanding of the mechanisms that modulate glucocorticoid sensitivity and resistance with a focus on GR-mediated signaling. Copyright © 2013 S. Karger AG, Basel.

  8. Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.

    NARCIS (Netherlands)

    H. Russcher (Henk); P. Smit (Pauline); E.L.T. van den Akker (Erica); E.F.C. van Rossum (Liesbeth); A.O. Brinkmann (Albert); F.H. de Jong (Frank); S.W.J. Lamberts (Steven); J.W. Koper (Jan)

    2005-01-01

    textabstractCONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND

  9. Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands

    NARCIS (Netherlands)

    Löwenberg, Mark; Stahn, Cindy; Hommes, Daniel W.; Buttgereit, Frank

    2008-01-01

    Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant agents. Unfortunately, they also produce serious side effects that limit their usage. This discrepancy is the driving force for the intensive search for novel GC receptor ligands with a better benefit-risk ratio as compared to

  10. Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for colitis therapy

    Directory of Open Access Journals (Sweden)

    Naeem M

    2015-07-01

    Full Text Available Muhammad Naeem,1 Moonjeong Choi,1 Jiafu Cao,1 Yujeong Lee,1 Muhammad Ikram,2 Sik Yoon,2 Jaewon Lee,1 Hyung Ryong Moon,1 Min-Soo Kim,1 Yunjin Jung,1 Jin-Wook Yoo11College of Pharmacy, Pusan National University, Busan, 2Pusan National University School of Medicine, Yangsan, South KoreaAbstract: Single pH-dependent drug delivery systems have been widely used for colon-targeted delivery, but their efficiency is often hampered by the variation in gut pH. To overcome the limitation of single pH-dependent delivery systems, in this study, we developed and evaluated the therapeutic potential of budesonide-loaded dual pH/time-dependent nanoparticles (NPs for the treatment of colitis. Eudragit FS30D was used as a pH-dependent polymer, and Eudragit RS100 as a time-dependent controlled release polymer. Single pH-dependent NPs (pH_NPs, single time-dependent NPs (Time_NPs, and dual pH/time-dependent NPs (pH/Time_NPs were prepared using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these NPs in gastrointestinal (GI tract conditions were investigated. The therapeutic potential and in vivo distribution of the NPs were evaluated in a dextran sulfate sodium (DSS-induced colitis mice model. The pH/Time_NPs prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the mice GI tract demonstrated that pH/Time_NPs were more efficiently delivered to the inflamed colon than pH_NPs were. Compared to the single pH_NPs-treated group, the pH/Time_NPs-treated group showed increased body weight and colon length and markedly decreased disease activity index, colon weight/length ratios, histological damage, and inflammatory cell infiltration in colon tissue. Our results demonstrate that the dual pH/time-dependent NPs are an effective oral colon-targeted delivery system for colitis therapy.Keywords: colon-specific delivery, dual-sensitive delivery

  11. Using fecal glucocorticoids for stress assessment in Mourning Doves

    Science.gov (United States)

    Washburn, Brian E.; Millspaugh, Joshua J.; Schulz, John H.; Jones, Susan B.; Mong, T.

    2003-01-01

    Fecal glucocorticoid assays provide a potentially useful, noninvasive means to study physiological responses of wildlife to various stressors. The objective of our study was to validate a method for measuring glucocorticoid metabolites in Mourning Dove (Zenaida macroura) feces. We validated the assay using standard procedures (e.g., parallelism, recovery of exogenous corticosterone) to demonstrate that the assay accurately and precisely measured glucocorticoid metabolites in Mourning Dove fecal extracts. We conducted adrenocorticotropin (ACTH) challenge experiments to validate the assay's ability to determine biologically important changes in fecal glucocorticoids. Fecal glucocorticoid levels increased significantly approximately 2-3 hr after administration of ACTH at 50 IU per kg body mass to wild Mourning Doves held in captivity. In contrast, fecal glucocorticoid metabolites did not increase in control birds, birds that received saline injections, or a lower dose of ACTH (1 IU per kg body mass). Variation in overall fecal glucocorticoid metabolite levels may have been influenced by season and the length of time birds were held in captivity. Non-invasive fecal glucocorticoid metabolite analyses, in combination with demographic information, may have considerable utility for monitoring the effects of natural and anthropogenic disturbances on Mourning Dove populations.

  12. Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4

    Directory of Open Access Journals (Sweden)

    Shin J. Lee

    2016-07-01

    Conclusions: Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies.

  13. Glucocorticoids and hypothalamo-pituitary-adrenal function : prevention of suppression?

    NARCIS (Netherlands)

    E.N.W. Janssens (Emile )

    1984-01-01

    textabstractThe suppressive effects of prolonged administration of pharmacologic doses of glucocorticoids on the HPA function are wellknown and often represent a major problem in clinical practice: it is unknown after what duration of administration, and for what dosages of glucocorticoids precisely

  14. Primary hypoadrenocorticism in a dog receiving glucocorticoid supplementation

    Science.gov (United States)

    Harris, Paul

    1999-01-01

    A 5-year-old, spayed, female husky-Labrador retriever cross was diagnosed with primary hypoadrenocorticism, an uncommon endocrine disorder caused by a deficiency of glucocorticoid and mineralocorticoid hormones. Subtle clinical signs and previous treatment with exogenous glucocorticoid drugs required an adrenocorticotropic hormone stimulation test to confirm the diagnosis. PMID:10065324

  15. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    NARCIS (Netherlands)

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T.; Van Der Horst, Geertje; Lemhemmer, Daniël; Marijt, Koen A.; Hwang, Ming S.; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M.|info:eu-repo/dai/nl/244207690; Meijer, Onno C.; Culig, Zoran; Van Der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCA). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance.

  16. Genomic and epigenomic mechanisms of glucocorticoids in the brain.

    Science.gov (United States)

    Gray, Jason D; Kogan, Joshua F; Marrocco, Jordan; McEwen, Bruce S

    2017-11-01

    Following the discovery of glucocorticoid receptors in the hippocampus and other brain regions, research has focused on understanding the effects of glucocorticoids in the brain and their role in regulating emotion and cognition. Glucocorticoids are essential for adaptation to stressors (allostasis) and in maladaptation resulting from allostatic load and overload. Allostatic overload, which can occur during chronic stress, can reshape the hypothalamic-pituitary-adrenal axis through epigenetic modification of genes in the hippocampus, hypothalamus and other stress-responsive brain regions. Glucocorticoids exert their effects on the brain through genomic mechanisms that involve both glucocorticoid receptors and mineralocorticoid receptors directly binding to DNA, as well as by non-genomic mechanisms. Furthermore, glucocorticoids synergize both genomically and non-genomically with neurotransmitters, neurotrophic factors, sex hormones and other stress mediators to shape an organism's present and future responses to a stressful environment. Here, we discuss the mechanisms of glucocorticoid action in the brain and review how glucocorticoids interact with stress mediators in the context of allostasis, allostatic load and stress-induced neuroplasticity.

  17. Roles of glucocorticoids in human parturition: a controversial fact?

    Science.gov (United States)

    Li, X Q; Zhu, P; Myatt, L; Sun, K

    2014-05-01

    The pivotal role of glucocorticoids in the initiation of parturition has been very well documented in several domestic mammalian animal species. However the role of glucocorticoids in human parturition remains controversial mainly because of the absence of effect of synthetic glucocorticoids, given to promote fetal organ maturation in pregnant women with threatened preterm delivery, on the length of gestation. This article will review studies of glucocorticoids in human parturition and provide evidence for an important role of glucocorticoids in human parturition as well but a simultaneous high concentration of estrogen within the intrauterine tissues may be necessary for GCs to initiate parturition. The synthetic GCs dexamethasone and betamethasone pass through the placenta intact resulting in potent negative feedback on the fetal HPA axis and diminished production of DHEA from fetal adrenal glands for estrogen synthesis by the placenta. This may negate the effect of systemic administration of GCs on the induction of labor, especially in cases where the myometrium is not yet fully primed by estrogen. Endogenous glucocorticoids are inactivated by the placental 11β-HSD2 thus limiting the negative feedback of maternal cortisol on the fetal HPA axis and allowing the simultaneous rise of cortisol and estrogen levels towards the end of gestation. Therefore, endogenous glucocorticoids, particularly glucocorticoids produced locally in the intrauterine tissues may play an important role in parturition in humans by enhancing prostaglandin production in the fetal membranes and stimulating estrogen and CRH production in the placenta. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Profound postanesthetic hypoglycemia attributable to glucocorticoid deficiency in 2 dogs.

    OpenAIRE

    Lane, I F; Matwichuk, C L; Carpenter, L G; Behrend, E N

    1999-01-01

    Glucocorticoid deficiency was diagnosed as the cause of severe postanesthetic hypoglycemia in 2 dogs. Prior signs of systemic illness were not described in either dog; however, preoperative hematologic findings were consistent with glucocorticoid deficiency. Fasting hypoglycemia is a possible complication of chronic adrenal insufficiency primarily because of impaired gluconeogenesis.

  19. Glucocorticoids facilitate the retention of acquired immobility during forced swimming

    NARCIS (Netherlands)

    Veldhuis, H D; De Korte, C C; De Kloet, E R

    1985-01-01

    The adrenalectomy-induced decrease in the level of immobility during a 5 min retest period in the Porsolt swimming test could be reversed by glucocorticoids administered s.c. 15 min after the initial forced swimming exposure. The synthetic glucocorticoids dexamethasone and RU 28362 were active in

  20. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

    Damsted, Sara K.; Born, A P; Paulson, Olaf B

    2011-01-01

    structures involved in axonal transport, long-term potentiation and neuronal plasticity. Significant maturation of the brain continues throughout childhood and we hypothesize that exposure to exogenous glucocorticoids during preschool and school age causes adverse cerebral effects. It is our opinion...... of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids...... reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported...

  1. The effects of glucocorticoids on feeding behavior in rats.

    Science.gov (United States)

    la Fleur, Susanne E

    2006-08-30

    Glucocorticoids have major effects on food intake, however, the underlying mechanisms are poorly understood. This article highlights data on the changes that occur when glucocorticoids are removed by adrenalectomy, and the effects of central and systemic administered glucocorticoids on feeding behavior in rats. Next, animal data on the interaction of glucocorticoids with insulin on intake of comfort foods are addressed and the hypothesis that glucocorticoids modify feeding behavior, whereas insulin modifies the choice of food is discussed. Finally a view is presented that hormonal and vagal signals generated when (comfort) food is consumed will affect the corticotropin-releasing factor (CRF) brain network important for the response to stress and the regulation of feeding. With a society, where stress is experienced daily and comfort food is found at every street corner, it will be vital to understand the interactions between the systems that react to stress and regulate feeding behavior to fight the obesity epidemic.

  2. Chromatin Architecture Defines the Glucocorticoid Response

    Science.gov (United States)

    Burd, Craig J.; Archer, Trevor K.

    2013-01-01

    The glucocorticoid receptor (GR) functions to regulate a wide group of physiological processes through hormone inducible interaction with genomic loci and subsequent manipulation of the transcriptional output of target genes. Despite expression in a wide variety of tissues, the GR has diverse roles that are regulated tightly in a cell type specific manner. With the advent of whole genome approaches, the details of that diversity and the mechanisms regulating them are beginning to be elucidated. This review aims describe the recent advances detailing the role chromatin structure plays in dictating GR specificity. PMID:23545159

  3. Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Fitzsimons, C.P.; Herbert, J.; Schouten, M.; Meijer, O.C.; Lucassen, P.J.; Lightman, S.

    2016-01-01

    Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free

  4. Topical-steroid-induced iatrogenic Cushing syndrome in the pediatric age group: A rare case report.

    Science.gov (United States)

    Tiwari, Ashish; Goel, Manjusha; Pal, Pankaj; Gohiya, Poorva

    2013-10-01

    Cushing syndrome, a systemic disorder, is the result of abnormally high blood level of cortisol or other glucocorticoids. The most common cause of Cushing syndrome is prolonged exogenous administration of glucocorticoid hormones. Prolonged use of topical corticosteroids, particularly in children, may cause Cushing syndrome and suppression of the hypothalamopituitory-adrenal axis, which is less common than that of oral or parenteral route. However, iatrogenic Cushing syndrome in the infantile age group due to topical steroid is very rare and only a few patients have been reported to date in the literature. Here we report a case of iatrogenic Cushing syndrome due to topical steroid application in a 5-month-old female child admitted to the hospital for repeated episodes of fever and cough.

  5. Novel Budesonide Particles for Dry Powder Inhalation Prepared Using a Microfluidic Reactor Coupled With Ultrasonic Spray Freeze Drying.

    Science.gov (United States)

    Saboti, Denis; Maver, Uroš; Chan, Hak-Kim; Planinšek, Odon

    2017-07-01

    Budesonide (BDS) is a potent active pharmaceutical ingredient, often administered using respiratory devices such as metered dose inhalers, nebulizers, and dry powder inhalers. Inhalable drug particles are conventionally produced by crystallization followed by milling. This approach tends to generate partially amorphous materials that require post-processing to improve the formulations' stability. Other methods involve homogenization or precipitation and often require the use of stabilizers, mostly surfactants. The purpose of this study was therefore to develop a novel method for preparation of fine BDS particles using a microfluidic reactor coupled with ultrasonic spray freeze drying, and hence avoiding the need of additional homogenization or stabilizer use. A T-junction microfluidic reactor was employed to produce particle suspension (using an ethanol-water, methanol-water, and an acetone-water system), which was directly fed into an ultrasonic atomization probe, followed by direct feeding to liquid nitrogen. Freeze drying was the final preparation step. The result was fine crystalline BDS powders which, when blended with lactose and dispersed in an Aerolizer at 100 L/min, generated fine particle fraction in the range 47.6% ± 2.8% to 54.9% ± 1.8%, thus exhibiting a good aerosol performance. Subsequent sample analysis confirmed the suitability of the developed method to produce inhalable drug particles without additional homogenization or stabilizers. The developed method provides a viable solution for particle isolation in microfluidics in general. Copyright © 2017 American Pharmacists Association®. All rights reserved.

  6. Preparation of budesonide nanosuspensions for pulmonary delivery: Characterization, in vitro release and in vivo lung distribution studies.

    Science.gov (United States)

    Zhang, Yuan; Zhang, Jianhua

    2016-01-01

    The main objective of the present article was to prepare stable and well-dispersible budesonide (BUD) nanosuspensions by microfluidizer method. The morphology, particle size, and zeta potential of formulation were investigated and in vitro release and in vivo lung distribution were evaluated. Characterizations showed that BUD nanosuspensions were spherical in shape with a smooth surface. The measured average particle size was 122.5 ± 6.3 nm, and ζ potential was - 13.6 ± 0.4 mV. In vitro release behavior of three batches BUD nanosuspensions had a good reproduction. The deposition distribution of BUD different formulations was measured using a modified multi-stage liquid collision method. The data showed that BUD nanosuspensions have the most outstanding deposition distribution with fine particle ratio 82.2%. Compared with normal particle and micronized particles, nanosuspensions were easier to be distributed in lung. After inhalation of 1 h, the drug concentration can reach 872.9 ng/g, which was extremely significantly different from normal particles (p < 0.01) and significantly different from micronized particles (p < 0.05).

  7. Spray drying of budesonide, formoterol fumarate and their composites-II. Statistical factorial design and in vitro deposition properties.

    Science.gov (United States)

    Tajber, L; Corrigan, O I; Healy, A M

    2009-02-09

    The aim of this study was to investigate the effect of changing spray drying parameters on the production of a budesonide/formoterol fumarate 100:6 (w/w) composite. The systems were spray dried as solutions from 95% ethanol/5% water (v/v) using a Büchi 191-Mini Spray Dryer. A 2(5-1) factorial design study was undertaken to assess the consequence of altering spray drying processing variables on particle characteristics. The processing parameters that were studied were inlet temperature, spray drier airflow rate, pump rate, aspirator setting and feed concentration. Each batch of the resulting powder was characterised in terms of thermal and micromeritic properties as well as an in vitro deposition by twin impinger analysis. Overall, the parameter that had the greatest influence on each response investigated was production yield - airflow (higher airflow giving greater yields), median particle size - airflow (higher airflow giving smaller particle sizes) and Carr's compressibility index - feed concentration (lower feed concentration giving smaller Carr's indices). A six- to seven-fold difference in respirable fraction can be observed by changing the spray drying process parameters. The co-spray dried composite system which displayed best in vitro deposition characteristics, showed a 2.6-fold increase in respirable fraction in the twin impinger experiments and better dose uniformity compared with the physical mix of micronised powders.

  8. Diclofenac Topical (osteoarthritis pain)

    Science.gov (United States)

    Diclofenac topical gel (Voltaren) is used to relieve pain from osteoarthritis (arthritis caused by a breakdown of ... the knees, ankles, feet, elbows, wrists, and hands. Diclofenac topical liquid (Pennsaid) is used to relieve osteoarthritis ...

  9. Women's Health Topics

    Science.gov (United States)

    ... Information by Audience For Women Women's Health Topics Women's Health Topics Share Tweet Linkedin Pin it More ... State & Local Officials Consumers Health Professionals Science & Research Industry Scroll back to top Popular Content Home Latest ...

  10. Child Development & Behavior Topics

    Science.gov (United States)

    ... Your Child Topics Commentaries Featured Links Contact Us Child Development & Behavior Topics A B C D E F ... Seat Safety Carbon Monoxide Chewing Tobacco Child Care Child Development Milestones Child Development, What Do Grown-Ups Know ...

  11. Glucocorticoid-induced osteoporosis: 2013 update

    Directory of Open Access Journals (Sweden)

    M. Mazzantini

    2014-07-01

    Full Text Available Glucocorticoids are the most common cause of secondary osteoporosis leading to the so-called glucocorticoidinduced osteoporosis (GIO. A treatment with 10 mg/d of prednisone or equivalent for more than 3 months leads to a 7-fold increase in hip fractures and a 17-fold increase in vertebral fractures. The difference between bone quantity and quality in GIO makes bone mineral density measurements inadequate to detect patients at risk of fracture. The adverse effects of glucocorticoids on the skeleton derive from a direct impact on bone cells with a severe impairment of mechanical competence. Crucial to prevention of GIO is early timing of intervention. The World Health Organization has adopted a fracture prevention algorithm (FRAX intended to estimate fracture risk in GIO. The American College of Rhematology modified its prevention and treatment guidelines taking into account the individual risk of fracture calculated in GIO on the basis of the FRAX algorithm. Recently, also a joint Guideline Working Group of the International Osteoporosis Foundation (IOF and the European Calcified Tissue Society (ECTS published a framework for the development of national guidelines for the management of GIO. Bisphosphonates are the first-line drugs to treat GIO; teriparatide counteracts several fundamental pathophysiologic aspects of GIO; denosumab is useful in patients with renal failure and in potentially pregnant young women. Vertebroplasty and kyphoplasty may be less beneficial in GIO than in primary involutional osteoporosis.

  12. Exploring the Molecular Mechanisms of Glucocorticoid Receptor Action from Sensitivity to Resistance

    OpenAIRE

    Ramamoorthy, Sivapriya; Cidlowski, John A.

    2013-01-01

    Glucocorticoids regulate a variety of physiological processes, and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR), but sensitivity to glucocorticoids varies among individuals, and even within different tissues from the same individual. The molecular basis of this phenomenon can be partially explained through understanding the process of generating bioavailab...

  13. Freshman Health Topics

    Science.gov (United States)

    Hovde, Karen

    2011-01-01

    This article examines a cluster of health topics that are frequently selected by students in lower division classes. Topics address issues relating to addictive substances, including alcohol and tobacco, eating disorders, obesity, and dieting. Analysis of the topics examines their interrelationships and organization in the reference literature.…

  14. Treatment with Glucocorticoids or Calcineurin Inhibitors in Primary FSGS.

    Science.gov (United States)

    Laurin, Louis-Philippe; Gasim, Adil M; Poulton, Caroline J; Hogan, Susan L; Jennette, J Charles; Falk, Ronald J; Foster, Bethany J; Nachman, Patrick H

    2016-03-07

    In primary FSGS, calcineurin inhibitors have primarily been studied in patients deemed resistant to glucocorticoid therapy. Few data are available about their use early in the treatment of FSGS. We sought to estimate the association between choice of therapy and ESRD in primary FSGS. We used an inception cohort of patients diagnosed with primary FSGS by kidney biopsy between 1980 and 2012. Factors associated with initiation of therapy were identified using logistic regression. Time-dependent Cox models were performed to compare time to ESRD between different therapies. In total, 458 patients were studied (173 treated with glucocorticoids alone, 90 treated with calcineurin inhibitors with or without glucocorticoids, 12 treated with other agents, and 183 not treated with immunosuppressives). Tip lesion variant, absence of severe renal dysfunction (eGFR≥30 ml/min per 1.73 m(2)), and hypoalbuminemia were associated with a higher likelihood of exposure to any immunosuppressive therapy. Only tip lesion was associated with initiation of glucocorticoids alone over calcineurin inhibitors. With adjusted Cox regression, immunosuppressive therapy with glucocorticoids and/or calcineurin inhibitors was associated with better renal survival than no immunosuppression (hazard ratio, 0.49; 95% confidence interval, 0.28 to 0.86). Calcineurin inhibitors with or without glucocorticoids were not significantly associated with a lower likelihood of ESRD compared with glucocorticoids alone (hazard ratio, 0.42; 95% confidence interval, 0.15 to 1.18). The use of immunosuppressive therapy with calcineurin inhibitors and/or glucocorticoids as part of the early immunosuppressive regimen in primary FSGS was associated with improved renal outcome, but the superiority of calcineurin inhibitors over glucocorticoids alone remained unproven. Copyright © 2016 by the American Society of Nephrology.

  15. The Effect of Glucocorticoid and Glucocorticoid Receptor Interactions on Brain, Spinal Cord, and Glial Cell Plasticity

    Directory of Open Access Journals (Sweden)

    Kathryn M. Madalena

    2017-01-01

    Full Text Available Stress, injury, and disease trigger glucocorticoid (GC elevation. Elevated GCs bind to the ubiquitously expressed glucocorticoid receptor (GR. While GRs are in every cell in the nervous system, the expression level varies, suggesting that diverse cell types react differently to GR activation. Stress/GCs induce structural plasticity in neurons, Schwann cells, microglia, oligodendrocytes, and astrocytes as well as affect neurotransmission by changing the release and reuptake of glutamate. While general nervous system plasticity is essential for adaptation and learning and memory, stress-induced plasticity is often maladaptive and contributes to neuropsychiatric disorders and neuropathic pain. In this brief review, we describe the evidence that stress/GCs activate GR to promote cell type-specific changes in cellular plasticity throughout the nervous system.

  16. Addison disease in patients treated with glucocorticoid therapy.

    LENUS (Irish Health Repository)

    Cronin, C C

    2012-02-03

    Acute adrenal crisis in patients with unrecognized chronic adrenocortical failure is difficult to diagnose and potentially fatal. We describe 2 patients with acute adrenal crisis whose diagnoses were hindered because of concomitant glucocorticoid treatment. Acute adrenal insufficiency is primarily a state of mineralocorticoid deficiency. Prednisolone and prednisone, the most frequently prescribed anti-inflammatory corticosteroid agents, have minimal mineralocorticoid activity. Several conditions that may be treated with pharmacological glucocorticoids are associated with an increased risk of Addison disease. An acute adrenal crisis, against which concurrent glucocorticoid therapy does not confer adequate protection, may develop in such patients.

  17. Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration.

    Science.gov (United States)

    Starkman, Monica N

    2013-09-01

    This article reviews the neuropsychiatric presentations elicited by spontaneous hypercortisolism and exogenous supraphysiologic glucocorticoids. Patients with Cushing disease and syndrome develop a depressive syndrome: irritable and depressed mood, decreased libido, disrupted sleep and cognitive decrements. Exogenous short-term glucocorticoid administration may elicit a hypomanic syndrome with mood, sleep and cognitive disruptions. Treatment options are discussed. Brain imaging and neuropsychological studies indicate elevated cortisol and other glucocorticoids are especially deleterious to hippocampus and frontal lobe. The research findings also shed light on neuropsychiatric abnormalities in conditions that have substantial subgroups exhibiting elevated and dysregulated cortisol: aging, major depressive disorder and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Glucocorticoids and prostate cancer treatment: friend or foe?

    Science.gov (United States)

    Montgomery, Bruce; Cheng, Heather H; Drechsler, James; Mostaghel, Elahe A

    2014-01-01

    Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of defining their contribution to the biology of prostate cancer. PMID:24625881

  19. The Effects of Budesonid that Added to Tiotropium Therapy on Health Related Quality of Life, Exercise Capacity and Pulmonary Functions in COPD Patients

    Directory of Open Access Journals (Sweden)

    Bahar Arslan

    2015-12-01

    Full Text Available Objective: The aim of this study was to evaluate the effects of adding inhaled budesonide to the tiotropium treatment on the pulmonary function tests, health-related quality of life and exercise capacity of patients with chronic obstructive pulmonary disease (COPD. Methods: Forty study subjects with COPD were randomized to two groups. The patients in the first group was treated with 1x1 18 mcg of Tiotropium and the patients in the second group was treated with the combination of tiotropium (18 mcg 1x1 and budesonide (400 mcg 2x1 for three months. Pulmonary function tests, six minute walk test, body mass index and Saint George Respiratory Questionnaire (SGRQ scores were recorded both at the beginning and 3 months later and the results at the begining and third month were compared with each other. There were no statistically significant difference in all basline parameters between the two groups. Results: At the end of the study, no statistically significant differences were obtained between two groups in terms of pulmonary function tests (p>0.05. Significant improvements were observed on the parameters of walking distance (p=0.023 and SGRQ scores (symptom score: p<0.001, activity score: p=0.001, impact score: p=0.003 and total score: p<0.001 in Group 2 when compared with Group 1. Conclusion: These results show that, in patients with COPD, tiotropium/budesonide combination is more effective than alone tiotropium inhalation in quality of life and exercise performance. But this combination is not more effective in improving lung functions.

  20. Effect of budesonide inhalation combined with azithromycin on pulmonary function, serum inflammatory factors and immune function of children with mycoplasma pneumonia

    Directory of Open Access Journals (Sweden)

    Yi-Lin Tan

    2016-11-01

    Full Text Available Objective: To observe the effect of budesonide inhalation combined with azithromycin on pulmonary function ,serum inflammatory factors and immune function of children with mycoplasma pneumonia. Methods: A total of 128 cases of children with MPP were selected from June 2014 to May 2016 and were randomly divided into observation group (68 cases and control group (60 cases.The control group were treated with azithromycin while the observation group were given both budesonide aerosol inhalation and azithromycin therapy. After two weeks, observe two groups of lung function index (FVC, FEV1, PEV and PEF25, the serum levels of inflammatory factors (TNF-α, IL-2, IL-6, INF-γ and the immune function (IgM, IgG, IgA. Results: After treatment, the level of FEV1, FVC, PEV and PEF25 of the two group were increased compared with before (P<0.05, and the FEV1, FVC, PEV and PEF25 of observation group after treatment were respectively significantly higher than the control group (P<0.05. TNFα, IL-2, IL-6 and INF-γ in both groups were decreased compared with before (P<0.05, and the TNFα, IL-2, IL-6 and INF-γ of observation group after treatment were significantly lower than the control group (P<0.05. IgM and IgA were decreased while the IgG was increased (P<0.05, the observation group was significantly lower than control group (P<0.05. Conclusion: Budesonide aerosol inhalation in combination with azithromycin can significantly improve lung function, inhibit inflammation and regulate immune function strongly than that of azithromycin alone in treatment of children MPP.

  1. Skin and glucocorticoids: effects of local skin glucocorticoid impairment on skin homeostasis.

    Science.gov (United States)

    Nikolakis, Georgios; Zouboulis, Christos C

    2014-11-01

    The role of skin as a de novo source of glucocorticoids and the importance of cutaneous glucocorticoidogenesis as a homeostatic mechanism in human skin is highlighted by Slominski et al. in a recently published issue. Impairment of glucocorticoidogenesis through noxious stimuli, such as UVB, can explain pathophysiology of skin diseases (e.g. rosacea). In addition to keratinocytes, melanocytes and fibroblasts, cutaneous adnexes also play a significant role as targets and sources of glucocorticoids, because they express most of the enzymes required for steroidogenesis. Glucocorticoids are also involved in the pathogenesis of acne lesions, affecting sebum production in vivo and in vitro. Certain steroidogenic enzymes, such as 11β-hydroxysteroid dehydrogenase, are upregulated in acne lesions. On this background, the paper by Slominski et al. provides further insights into dermatoendocrinology, with emphasis on the importance of an impairment of the skin's own hypothalamic-pituitary-adrenal-like axis in the pathophysiology of several skin diseases. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Opposite effects of serum- and glucocorticoid-regulated kinase-1 and glucocorticoids on POMC transcription and ACTH release.

    Science.gov (United States)

    Reiter, Marie Helene; Vila, Greisa; Knosp, Engelbert; Baumgartner-Parzer, Sabina M; Wagner, Ludwig; Stalla, Günter K; Luger, Anton

    2011-08-01

    Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a glucocorticoid early-response gene; its function, however, has been elucidated mainly in the context of mineralocorticoid signaling. Here, we investigate the expression and function of SGK1 in the pituitary gland, one of the primary glucocorticoid targets. SGK1 is expressed in the human pituitary gland and colocalizes to ACTH. The AtT-20 murine corticotroph cell line was used for functional experiments. Glucocorticoids upregulated SGK1 mRNA and protein levels, parallel to decreasing proopiomelanocortin (POMC) transcription and ACTH release. Dexamethasone-induced changes in SGK1 protein were abolished by the steroid receptor antagonist RU-486 and reduced by the inhibition of PI 3-kinase with LY-294002. SGK1 overexpression increased CREB- and activator protein-1-dependent transcription, POMC transcription, and ACTH secretion but did not influence intracellular cAMP levels. SGK1 overexpression and corticotropin-releasing hormone had additive effects on POMC promoter activity but not on ACTH secretion. SGK1 knockdown by RNA interference decreased POMC promoter activity, demonstrating the importance of SGK1 for basal POMC signaling. In summary, SGK1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however, its effects on POMC transcription are antagonistic to the classical inhibitory glucocorticoid action, suggesting a cell-regulated counterregulatory mechanism to potentially detrimental glucocorticoid effects.

  3. Deposition of intranasal glucocorticoids--preliminary study.

    Science.gov (United States)

    Rapiejko, Piotr; Sosnowski, Tomasz R; Sova, Jarosław; Jurkiewicz, Dariusz

    2015-01-01

    Intranasal glucocorticoids are the treatment of choice in the therapy of rhinitis. The differences in efficiency of particular medications proven by therapeutic index may result from differences in composition of particular formulations as well as from diverse deposition in nasal cavities. Intranasal formulations of glucocorticoids differ in volume of a single dose in addition to variety in density, viscosity and dispenser nozzle structure. The aim of this report was to analyze the deposition of most often used intranasal glucocorticoids in the nasal cavity and assessment of the usefulness of a nose model from a 3D printer reflecting anatomical features of a concrete patient. Three newest and most often used in Poland intranasal glucocorticoids were chosen to analysis; mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF). Droplet size distribution obtained from the tested formulations was determined by use of a laser aerosol spectrometer Spraytec (Malvern Instruments, UK). The model of the nasal cavity was obtained using a 3D printer. The printout was based upon a tridimensional reconstruction of nasal cavity created on the basis of digital processing of computed tomography of paranasal sinuses. The deposition of examined medications was established by a method of visualization combined with image analysis using commercial substance which colored itself intensively under the influence of water being the dominant ingredient of all tested preparations. On the basis of obtained results regions of dominating deposition of droplets of intranasal medication on the wall and septum of the nasal cavity were compared. Droplet size of aerosol of tested intranasal medications typically lies within the range of 25-150 µm. All tested medications deposited mainly on the anterior part of inferior turbinate. FP preparation deposited also on the anterior part of the middle nasal turbinate, marginally embracing a fragment of the central part of this

  4. Nasal inhalation of budesonide from a spacer in children with perennial rhinitis and asthma

    DEFF Research Database (Denmark)

    Pedersen, W; Hjuler, Inga Merete; Bisgaard, H

    1998-01-01

    The standard treatment of allergic rhinitis and asthma consists of topical corticosteroids administered intranasally and inhaled through the mouth. Although this therapy is highly effective, and side-effects are few and mild, it may be possible further to improve the therapeutic index and patient...... compliance with the treatment. In the present study, we evaluated a nasal inhalation system used for the simultaneous treatment of rhinitis and asthma. In principle, it results in an airway deposition of the corticosteroid similar to that of inhaled allergens. Twenty-four children with perennial rhinitis...... and effective treatment for both rhinitis and asthma in children, but it is an open question whether the nasal inhalation system can improve the ratio of antirhinitis/antiasthma effects to side-effects....

  5. Glucocorticoid programming of the mesopontine cholinergic system

    Directory of Open Access Journals (Sweden)

    Sónia eBorges

    2013-12-01

    Full Text Available Stress perception, response, adaptation and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programming intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to glucocorticoids (iuGC present hyperanxiety, increased fear behaviour and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT and pedunculopontine tegmental nucleus (PPT, in the initiation of 22kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individuals stress vulnerability threshold.

  6. Current topics in autoimmune hepatitis.

    Science.gov (United States)

    Muratori, Luigi; Muratori, Paolo; Granito, Alessandro; Pappas, Giorgios; Cassani, Fabio; Lenzi, Marco

    2010-11-01

    Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis. Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  7. Glucocorticoids in nephrology I: pharmacology and side effects

    Directory of Open Access Journals (Sweden)

    Jernej Pajek

    2015-05-01

    Full Text Available Glucocorticoids have been used in clinical medicine since 1940s. Despite the time-long use they are still a subject of active ongoing research. We describe the mode of action, pharmacology and side effects to enable proper prescription of these drugs. Glucocorticoids exert genomic and non-genomic effects, the latter become important at higher doses. The nomenclature of dosage ranges and the principles of dosage adjustments are given. Glucocortioid use is associated with frequent and important side effects in numerous organ systems. Prophylactic treatments for osteoporosis and infections are described. The suppression of hypothalamic-hypophyseal hormonal axis determines the need for gradual glucocorticoid withdrawal and supplementation after discontinuation. Finally, glucocorticoid withdrawal syndrome is described.

  8. Effects of suspension on tissue levels of glucocorticoid receptors

    Science.gov (United States)

    Steffen, J. M.

    1984-01-01

    Differential muscle responses can be simulated by hypokinetic/hypodynamic (H/H) suspension of rats with complete unloading of the hindlimb muscles. Since mechanism(s) underlying these atrophic effects were not clearly elucidated, experiments were initiated to investigate a possible role for glucocorticoids in the physiological and biochemical responses to H/H. The principal objective was to assess the potential for alterations in peripheral responsiveness to glucocorticoids in response to H/H. Studies have initially focused on the determination of tissue levels of glucocorticoid receptors as one index of hormonal sensitivity at the cellular level. Four hindlimb muscles (soleus, gastrocnemius, plantaris and EDL), previously demonstrated to exhibit differential responses to H/H, were investigated. Receptor levels in other glucocorticoid sensitive tissues (heart, liver, and kidney) were determined. Male rats (180-200g) were suspended for 7 or 14 days, sacrificed by cervical dislocation, and the tissues excised.

  9. Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn

    NARCIS (Netherlands)

    Lowenberg, M; Tuynman, J; Bilderbeek, J; Gaber, T; Buttgereit, F; van Deventer, S; Peppelenbosch, M; Hommes, D

    2005-01-01

    Glucocorticoids (GCs) are effective immunosuppressive agents and mediate well-defined transcriptional effects via GC receptors. There is increasing evidence that GCs also initiate rapid nongenomic signaling events. Using activated human CD4(+) lymphocytes and a peptide array containing 1176

  10. Glucocorticoids induce autophagy in rat bone marrow mesenchymal stem cells

    DEFF Research Database (Denmark)

    Wang, L.; Fan, J.; Lin, Y. S.

    2015-01-01

    and their responses to diverse stimuli, however, the role of autophagy in glucocorticoidinduced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy...

  11. Comparison of two methods for glucocorticoid evaluation in maned wolves

    Directory of Open Access Journals (Sweden)

    Angélica S Vasconcellos

    2011-12-01

    Full Text Available Analysis of faecal glucocorticoid metabolites provides a powerful noninvasive tool for monitoring adrenocortical activity in wild animals. However, differences regarding the metabolism and excretion of these substances make a validation for each species and sex investigated obligatory. Although maned wolves (Chrysocyon brachyurus are the biggest canids in South America, their behaviour and physiology are poorly known and they are at risk in the wild. Two methods for measuring glucocorticoid metabolites in maned wolves were validated: a radio- and an enzyme immunoassay. An ACTH challenge was used to demonstrate that changes in adrenal function are reflected in faecal glucocorticoid metabolites. Our results suggest that both methods enable a reliable assessment of stress hormones in maned wolves avoiding short-term rises in glucocorticoid concentrations due to handling and restraint. These methods can be used as a valuable tool in studies of stress and conservation in this wild species.

  12. The emerging importance of ultradian glucocorticoid rhythms within metabolic pathology.

    Science.gov (United States)

    Flynn, Benjamin P; Conway-Campbell, Becky L; Lightman, Stafford L

    2018-04-04

    Glucocorticoid (GC) hormones play significant roles within homeostasis and the chrono-dynamics of their regulatory role has become increasingly recognised within dysregulated GC pathology, particularly with metabolic phenotypes. Within this article, we will discuss the relevance of the ultradian homeostatic rhythm, how its dysregulation effects glucocorticoid receptor and RNA polymeraseII recruitment and may play a significant role within aberrant metabolic action. Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

  13. The relevance of glucocorticoid receptor in early stress

    OpenAIRE

    Rodríguez Fernández, Jorge Mario; Hospital Universitario San Ignacio; García Acero, Mary; Hospital Universitario San Ignacio

    2010-01-01

    Previous studies have shown how Hypothalamic-Pituitary-adrenal Axis dysfunction is related to early life stress; several works show that Hypothalamic-Pituitary-adrenal Axishyperactivity increases production of ACTH and glucocorticoids, indicating a pathophysiological key factor in stress related diseases like depression.This review will discuss results of some epigenetical studies linking early life stress, decreased production of the glucocorticoid receptor and Hypothalamic-Pituitary-adrenal...

  14. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

    Damsted, Sara K.; Born, A P; Paulson, Olaf B

    2011-01-01

    reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported....... Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular...

  15. Glucocorticoid-Induced Avascular Bone Necrosis: Diagnosis and Management

    Science.gov (United States)

    Chan, KL; Mok, CC

    2012-01-01

    Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty. PMID:23115605

  16. Antenatal glucocorticoids: where are we after forty years?

    Science.gov (United States)

    McKinlay, C J D; Dalziel, S R; Harding, J E

    2015-04-01

    Since their introduction more than forty years ago, antenatal glucocorticoids have become a cornerstone in the management of preterm birth and have been responsible for substantial reductions in neonatal mortality and morbidity. Clinical trials conducted over the past decade have shown that these benefits may be increased further through administration of repeat doses of antenatal glucocorticoids in women at ongoing risk of preterm and in those undergoing elective cesarean at term. At the same time, a growing body of experimental animal evidence and observational data in humans has linked fetal overexposure to maternal glucocorticoids with increased risk of cardiovascular, metabolic and other disorders in later life. Despite these concerns, and somewhat surprisingly, there has been little evidence to date from randomized trials of longer-term harm from clinical doses of synthetic glucocorticoids. However, with wider clinical application of antenatal glucocorticoid therapy there has been greater need to consider the potential for later adverse effects. This paper reviews current evidence for the short- and long-term health effects of antenatal glucocorticoids and discusses the apparent discrepancy between data from randomized clinical trials and other studies.

  17. Molecular mechanisms of glucocorticoid action in mast cells.

    Science.gov (United States)

    Oppong, Emmanuel; Flink, Nesrin; Cato, Andrew C B

    2013-11-05

    Glucocorticoids are compounds that have successfully been used over the years in the treatment of inflammatory disorders. They are known to exhibit their effects through the glucocorticoid receptor (GR) that acts to downregulate the action of proinflammatory transcription factors such as AP-1 and NF-κB. The GR also exerts anti-inflammatory effects through activation of distinct genes. In addition to their anti-inflammatory actions, glucocorticoids are also potent antiallergic compounds that are widely used in conditions such as asthma and anaphylaxis. Nevertheless the mechanism of action of this hormone in these disorders is not known. In this article, we have reviewed reports on the effects of glucocorticoids in mast cells, one of the important immune cells in allergy. Building on the knowledge of the molecular action of glucocorticoids and the GR in the treatment of inflammation in other cell types, we have made suggestions as to the likely mechanisms of action of glucocorticoids in mast cells. We have further identified some important questions and research directions that need to be addressed in future studies to improve the treatment of allergic disorders. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. Mechanisms of Brain Glucocorticoid Resistance in Stress-Induced Psychopathologies.

    Science.gov (United States)

    Merkulov, V M; Merkulova, T I; Bondar, N P

    2017-03-01

    Exposure to stress activates the hypothalamic-pituitary-adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stress- and GR-induced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.

  19. Glucocorticoid inhibition of cellular proliferation in rat hepatoma cell lines

    International Nuclear Information System (INIS)

    Cook, P.W.

    1987-01-01

    Glucocorticoids were shown to inhibit the growth rate of Fu5 rat hepatoma cells cultured in the presence or absence of serum and thus, induced a more stringent dependence on serum for growth in this cell line. Fu5 cells, made quiescent at low cell density by continuous exposure to glucocorticoid in the absence of serum, were induced with serum and insulin, which subsequently caused a rapid reinitiation of cellular proliferation. Analysis of total RNA isolated from hormone treated Fu5 cells undergoing serum/insulin induction of DNA synthesis revealed a sequential expression of cellular proto-oncogene products in the absence of any immediate changes in intracellular Ca ++ levels. Introduction of functional glucocorticoid receptor genes into both classes of dexamethasone resistant variants restored glucocorticoid responsiveness and suppression of cell growth. The BDS1 rat hepatoma cell line, an Fu5 derived subclone hypersensitive to the antiprofliferation effects of glucocorticoid, was observed to externalize a glucocorticoid suppressible mitogen (GSM) activity capable of mimicking EGF and insulin induced stimulation of [ 3 H]thymidine incorporation into serum starved, competant Balb/c 3T3 cells

  20. [Glucocorticoid and Bone. The effect of glucocorticoid and PTH in osteoblast apoptosis and differentiation via interleukin 11 expression].

    Science.gov (United States)

    Endo, Itsuro

    2014-09-01

    Intermittent PTH administration stimulates bone formation and counteracts the inhibition of bone formation by glucocorticoid excess. We have previously demonstrated that PTH enhances interleukin (IL) -11 gene transcription by a rapid induction of delta-fosB expression and Smad1/5 phosphorylation. On the other hand, glucocorticoid can suppress osteoblast differentiation and enhance apoptosis of osteoblast cells via down-regulation of IL-11 expression. PTH could reverse glucocorticoid-induced these damage of osteoblast via stimulation of IL-11 expression. Our data also suggested that IL-11 mediates stimulatory and inhibitory signals of osteoblast differentiation by affecting Wnt signaling. These data demonstrates that PTH and glucocorticoid may regulate osteoblast differentiation and apoptosis via their effect on IL-11 expression.

  1. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants

    Science.gov (United States)

    Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoi...

  2. Syntacticized topics in Kurmuk

    DEFF Research Database (Denmark)

    Andersen, Torben

    2015-01-01

    This article argues that Kurmuk, a little-described Western Nilotic language, is characterized by a syntacticized topic whose grammatical relation is variable. In this language, declarative clauses have as topic an obligatory preverbal NP which is either a subject, an object or an adjunct. The gr...

  3. Systematic review of the clinical effect of glucocorticoids on nonhematologic malignancy

    Directory of Open Access Journals (Sweden)

    Keith Bruce D

    2008-03-01

    Full Text Available Abstract Background Glucocorticoids are often used in the treatment of nonhematologic malignancy. This review summarizes the clinical evidence of the effect of glucocorticoid therapy on nonhematologic malignancy. Methods A systematic review of clinical studies of glucocorticoid therapy in patients with nonhematologic malignancy was undertaken. Only studies having endpoints of tumor response or tumor control or survival were included. PubMed, EMBASE, the Cochrane Register/Databases, conference proceedings (ASCO, AACR, ASTRO/ASTR, ESMO, ECCO and other resources were used. Data was extracted using a standard form. There was quality assessment of each study. There was a narrative synthesis of information, with presentation of results in tables. Where appropriate, meta-analyses were performed using data from published reports and a fixed effect model. Results Fifty four randomized controlled trials (RCTs, one meta-analysis, four phase l/ll trials and four case series met the eligibility criteria. Clinical trials of glucocorticoid monotherapy in breast and prostate cancer showed modest response rates. In advanced breast cancer meta-analyses, the addition of glucocorticoids to either chemotherapy or other endocrine therapy resulted in increased response rate, but not increased survival. In GI cancer, there was one RCT each of glucocorticoids vs. supportive care and chemotherapy +/- glucocorticoids; glucocorticoid effect was neutral. The only RCT found of chemotherapy +/- glucocorticoids, in which the glucocorticoid arm did worse, was in lung cancer. In glucocorticoid monotherapy, meta-analysis found that continuous high dose glucocorticoids had a detrimental effect on survival. The only other evidence, for a detrimental effect of glucocorticoid monotherapy, was in one of the two trials in lung cancer. Conclusion Glucocorticoid monotherapy has some benefit in breast and prostate cancer. In advanced breast cancer, the addition of glucocorticoids to other

  4. A structural explanation of the effects of dissociated glucocorticoids on glucocorticoid receptor transactivation.

    Science.gov (United States)

    Dezitter, Xavier; Fagart, Jérôme; Taront, Solenne; Fay, Michel; Masselot, Bernadette; Hétuin, Dominique; Formstecher, Pierre; Rafestin-Oblin, Marie-Edith; Idziorek, Thierry

    2014-02-01

    There is a therapeutic need for glucocorticoid receptor (GR) ligands that distinguish between the transrepression and transactivation activity of the GR, the later thought to be responsible for side effects. These ligands are known as "dissociated glucocorticoids" (dGCs). The first published dGCs, RU24782 (9α-fluoro-11β-hydroxy-16α-methylpregna-21-thiomethyl-1,4-diene-3,20-dione) and RU24858 (9α-fluoro-11β-hydroxy-16α-methylpregna-21-cyanide-1,4-diene-3,20-dione), do not have the 17α-hydroxyl group that characterizes dexamethasone (Dex; 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione), and they differ from one another by having C21-thiomethyl and C21-cyanide moieties, respectively. Our aim was therefore to establish the structural basis of their activity. Both RU24782 and RU24858 induced a transactivation activity highly dependent on the GR expression level but always lower than dexamethasone. They also display less ability than dexamethasone to trigger steroid receptor coactivator 1 (SRC-1) recruitment and histone H3 acetylation. Docking studies, validated by mutagenesis experiments, revealed that dGCs are not anchored by Gln642, in contrast to Dex, which is hydrogen bonded to this residue via its 17α-hydroxyl group. This contact is essential for SRC-1 recruitment and subsequent dexamethasone-induced GR transactivation, but not transrepression. The ability of dGCs to make contacts with Ile747, for both RU24858 and RU24782 and with Asn564 for RU24858 are not strong enough to maintain GR in a conformation able to efficiently recruit SRC-1, unless SRC-1 is overexpressed. Overall, our findings provide some structural guidelines for the synthesis of potential new dissociated glucocorticoids with a better therapeutic ratio.

  5. Corticoterapia: minimizando efeitos colaterais Glucocorticoid therapy: minimizing side effects

    Directory of Open Access Journals (Sweden)

    Carlos Alberto Longui

    2007-11-01

    Full Text Available OBJETIVO: Ressaltar os principais efeitos indesejáveis durante a corticoterapia, o mecanismo de seu desencadeamento e as medidas necessárias para minimizar os efeitos colaterais. FONTES DOS DADOS: Experiência do autor, complementada com trabalhos publicados no MEDLINE. SÍNTESE DOS DADOS: Os princípios para que se minimizem os efeitos indesejáveis da corticoterapia incluem: a indicação rígida em que o uso do glicocorticóide seja essencial; b evitar o uso de glicocorticóides de ação prolongada, preferindo glicocorticóide de ação curta ou intermediária; c reduzir ao m��nimo necessário a duração do tratamento, visto que tratamentos com duração entre 5 e 7 dias apresentam poucos efeitos colaterais e rápida recuperação do eixo hipotalâmico-hipofisário; d preferir glicocorticóides de ação local, como glicocorticóides inalatórios; e associação com outros fármacos, em especial outros antiinflamatórios ou imunossupressores mais específicos, buscando efeitos sinérgicos que permitam evitar o uso de glicocorticóides ou reduzir a dose e o tempo da corticoterapia; f oferecer a menor dose necessária para o efeito desejado, respeitando a sensibilidade de cada indivíduo aos glicocorticóides. CONCLUSÕES: o conhecimento das características farmacológicas e ações biológicas dos glicocorticóides permite a melhor opção terapêutica quanto à indicação, dose, via de administração e duração da corticoterapia.OBJECTIVE:To describe the main undesirable side effects of glucocorticoid therapy, mechanisms of action and the necessary measures to minimize side effects. SOURCES: Author's experience, supplemented with papers published in MEDLINE. SUMMARY OF THE FINDINGS: The principles for minimizing undesirable side effects of glucocorticoid therapy include: a only use glucocorticoids if they are essential; b avoid the use of long-acting glucocorticoids, using short- and intermediate-acting glucocorticoids instead; c

  6. Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor

    Science.gov (United States)

    2014-01-01

    Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor. PMID:25155432

  7. Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor.

    Science.gov (United States)

    Nicolaides, Nicolas C; Charmandari, Evangelia; Chrousos, George P; Kino, Tomoshige

    2014-08-25

    Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor.

  8. Fructose consumption enhances glucocorticoid action in rat visceral adipose tissue.

    Science.gov (United States)

    Bursać, Biljana N; Djordjevic, Ana D; Vasiljević, Ana D; Milutinović, Danijela D Vojnović; Veličković, Nataša A; Nestorović, Nataša M; Matić, Gordana M

    2013-06-01

    The rise in consumption of refined sugars high in fructose appears to be an important factor for the development of obesity and metabolic syndrome. Fructose has been shown to be involved in genesis and progression of the syndrome through deregulation of metabolic pathways in adipose tissue. There is evidence that enhanced glucocorticoid regeneration within adipose tissue, mediated by the enzyme 11beta-hydroxysteroid dehydrogenase Type 1 (11βHSD1), may contribute to adiposity and metabolic disease. 11βHSD1 reductase activity is dependent on NADPH, a cofactor generated by hexose-6-phosphate dehydrogenase (H6PDH). We hypothesized that harmful effects of long-term high fructose consumption could be mediated by alterations in prereceptor glucocorticoid metabolism and glucocorticoid signaling in the adipose tissue of male Wistar rats. We analyzed the effects of 9-week drinking of 10% fructose solution on dyslipidemia, adipose tissue histology and both plasma and tissue corticosterone level. Prereceptor metabolism of glucocorticoids was characterized by determining 11βHSD1 and H6PDH mRNA and protein levels. Glucocorticoid signaling was examined at the level of glucocorticoid receptor (GR) expression and compartmental redistribution, as well as at the level of expression of its target genes (GR, phosphoenolpyruvate carboxyl kinase and hormone-sensitive lipase). Fructose diet led to increased 11βHSD1 and H6PDH expression and elevated corticosterone level within the adipose tissue, which was paralleled with enhanced GR nuclear accumulation. Although the animals did not develop obesity, nonesterified fatty acid and plasma triglyceride levels were elevated, indicating that fructose, through enhanced prereceptor metabolism of glucocorticoids, could set the environment for possible later onset of obesity. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Impact of saline irrigation and topical corticosteroids on the post-surgical sinonasal microbiota

    Science.gov (United States)

    Liu, Cindy M.; Kohanski, Michael A.; Mendiola, Michelle; Soldanova, Katerina; Dwan, Michael G.; Lester, Richard; Nordstrom, Lora; Price, Lance B.; Lane, Andrew P.

    2015-01-01

    Introduction Topical treatments with nasal saline irrigation, topical steroid sprays, or corticosteroid rinses can improve sinonasal symptoms in chronic rhinosinusitis (CRS). However, the impact of these therapies on commensals (Corynebacterium) and on biofilm pathogens associated with CRS (Staphylococcus aureus and Pseudomonas) is not well characterized. Methods Paired nasal and sinus swabs were collected endoscopically from 28 controls and 14 CRS patients with nasal polyposis (CRSwNP) who had not received systemic antibiotics or corticosteroids in the previous eight weeks. Total DNA from swab eluents were extracted and analyzed by 16S rRNA gene-based pyrosequencing. A total 359,077 reads were obtained and classified taxonomically. The association of use of topical therapies with sinonasal microbiota composition was assessed by factor and vector-fitting. The proportional abundances of sinonasal bacteria between topical therapy users and non-users were further compared by two-tailed Kolmogorov-Smirnov test among controls and among CRSwNP participants. Result Nasal saline irrigation, with or without added budesonide, was not associated with significantly distinct sinonasal microbiota composition or significantly decreased Pseudomonas or S. aureus abundances among either controls or CRSwNP participants. Corynebacterium was slightly lower in controls that reported using saline irrigation than those who did not. No significant association was found between nasal saline irrigation and the proportional abundances of Pseudomonas, S. aureus, and Corynebacterium in CRSwNP participants. However, male CRSwNP patients were noted to have significantly higher Corynebacterium proportional abundances than their female counterparts. The use of topical steroid sprays was associated with a distinct microbiota in control subjects, characterized by higher proportional abundances of Dolosigranulum and Simonsiella and a lower proportional abundance of Campylobacter. Conclusion Nasal

  10. Effects of glucocorticoids on human brown adipocytes.

    Science.gov (United States)

    Barclay, Johanna L; Agada, Hadiya; Jang, Christina; Ward, Micheal; Wetzig, Neil; Ho, Ken K Y

    2015-02-01

    Clinical cases of glucocorticoid (GC) excess are characterized by increased fat mass and obesity through the accumulation of white adipocytes. The effects of GCs on growth and function of brown adipose tissue are unknown and may contribute to the negative energy balance observed clinically. This study aims to evaluate the effect of GCs on proliferation, differentiation, and metabolic function of brown adipocytes. Human brown adipocytes sourced from supraclavicular fat biopsies were grown in culture and differentiated to mature adipocytes. Human white adipocytes sourced from subcutaneous abdominal fat biopsies were cultured as controls. Effects of dexamethasone on growth, differentiation (UCP1, CIDEA, and PPARGC1A expression), and function (oxygen consumption rate (OCR)) of brown adipocytes were quantified. Dexamethasone (1 μM) significantly stimulated the proliferation of brown preadipocytes and reduced that of white preadipocytes. During differentiation, dexamethasone (at 0.1, 1, and 10 μM) stimulated the expression of UCP1, CIDEA, and PPARGC1A in a concentration-dependent manner and enhanced by fourfold to sixfold the OCR of brown adipocytes. Isoprenaline (100 nM) significantly increased (Peffects were significantly reduced (Peffects on development and function of brown adipocytes. These findings provide strong evidence for an effect of GCs on the biology of human brown adipose tissue (BAT) and for the involvement of the BAT system in the metabolic manifestation of Cushing's syndrome. © 2015 Society for Endocrinology.

  11. Glucocorticoid regulation of astrocytic fate and function.

    Directory of Open Access Journals (Sweden)

    Shuang Yu

    Full Text Available Glial loss in the hippocampus has been suggested as a factor in the pathogenesis of stress-related brain disorders that are characterized by dysregulated glucocorticoid (GC secretion. However, little is known about the regulation of astrocytic fate by GC. Here, we show that astrocytes derived from the rat hippocampus undergo growth inhibition and display moderate activation of caspase 3 after exposure to GC. Importantly, the latter event, observed both in situ and in primary astrocytic cultures is not followed by either early- or late-stage apoptosis, as monitored by stage I or stage II DNA fragmentation. Thus, unlike hippocampal granule neurons, astrocytes are resistant to GC-induced apoptosis; this resistance is due to lower production of reactive oxygen species (ROS and a greater buffering capacity against the cytotoxic actions of ROS. We also show that GC influence hippocampal cell fate by inducing the expression of astrocyte-derived growth factors implicated in the control of neural precursor cell proliferation. Together, our results suggest that GC instigate a hitherto unknown dialog between astrocytes and neural progenitors, adding a new facet to understanding how GC influence the cytoarchitecture of the hippocampus.

  12. Comparative effectiveness of budesonide/formoterol combination and tiotropium bromide among COPD patients new to these controller treatments

    Directory of Open Access Journals (Sweden)

    Trudo F

    2015-09-01

    Full Text Available Frank Trudo,1 David M Kern,2 Jill R Davis,1 Ozgur Tunceli,2 Siting Zhou,2 Emma L Graham,3 Charlie Strange,4 Setareh A Williams1 1AstraZeneca Pharmaceuticals LP, 2HealthCore, Inc., Wilmington, DE, USA; 3AstraZeneca Pharmaceuticals LP, Alderley Park, Cheshire, UK; 4Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA Background: Inhaled corticosteroid/long-acting β2-agonist combinations and/or long-acting muscarinic antagonists are recommended first-line therapies for preventing chronic obstructive pulmonary disease (COPD exacerbation. Comparative effectiveness of budesonide/formoterol combination (BFC, an inhaled corticosteroid/long-acting β2-agonist combination vs tiotropium (long-acting muscarinic antagonist in the US has not yet been studied.Methods: Using US claims data from the HealthCore Integrated Research Environment, COPD patients (with or without comorbid asthma ≥40 years old initiating BFC or tiotropium between March 1, 2009 and February 28, 2012 and at risk for exacerbation were identified and followed for 12 months. Patients were propensity score matched on demographics and COPD disease severity indicators. The primary outcome was time to first COPD exacerbation. Secondary outcomes included COPD exacerbation rate, health care resource utilization, and costs.Results: The Cox proportional hazards model for time to first exacerbation yielded a hazard ratio (HR of 0.78 (95% CI =[0.70, 0.87], P<0.001, indicating a 22% reduction in risk of COPD exacerbation associated with initiation of BFC versus tiotropium. A post hoc sensitivity analysis found similar effects in those who had a prior asthma diagnosis (HR =0.72 [0.61, 0.86] and those who did not (HR =0.83 [0.72, 0.96]. BFC initiation was associated with lower COPD-related health care resource utilization and costs ($4,084 per patient-year compared with $5,656 for tiotropium patients, P<0.001.Conclusion

  13. Topical Pain Medications

    Science.gov (United States)

    ... skin Learn about the various types of topical pain medications available for pain relief. Can they ease your ... hurt even though you take your usual arthritis pain medication. Reluctant to pop another pill, you might wonder ...

  14. Topics in Nuclear Astrophysics

    International Nuclear Information System (INIS)

    Chung, K.C.

    1982-01-01

    Some topics in nuclear astrophysics are discussed, e.g.: highly evolved stellar cores, stellar evolution (through the temperature analysis of stellar surface), nucleosynthesis and finally the solar neutrino problem. (L.C.) [pt

  15. Metalloproteinases and their inhibitors are influenced by inhalative glucocorticoid therapy in combination with environmental dust reduction in equine recurrent airway obstruction.

    Science.gov (United States)

    Barton, Ann Kristin; Shety, Tarek; Bondzio, Angelika; Einspanier, Ralf; Gehlen, Heidrun

    2016-12-09

    Overexpression of matrix-metalloproteinases (MMPs) has been shown to lead to tissue damage in equine recurrent airway obstruction (RAO), as a misbalance with their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), occurs. This favors irreversible pulmonary fibrosis formation. Increased levels of MMPs, TIMPs or altered ratios between them can be used as biomarkers of respiratory disease. We hypothesized that levels of MMPs, TIMPs and their ratios correlate with improvement in clinical findings and bronchoalveolar lavage fluid (BALF) cytology after 10 days of inhalative glucocorticoid therapy and environmental dust reduction (EDR) and may be used to monitor treatment success. Ten horses with a history of RAO participated in a prospective clinical study. Clinical and cytological scoring was performed before and after inhalative therapy using budesonide (1500 μg BID over 10 days) and EDR (bedding of wood shavings and wet hay as roughage). Gelatin zymography was performed for qualitative and semi-quantitative evaluation of MMP-2 and MMP-9 in BALF supernatant, while fluorimetry was used to evaluate MMP-8 activity. Additionally, specific equine ELISA assays were used for quantitative assessment of MMP-2, MMP-9, TIMP-1 and TIMP-2. A significant reduction in the total and several single parameters of the clinical score were found after 10 days of inhalative therapy and EDR. The concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 (ELISA) as well as their activities (MMP-2 and MMP-9 zymography and MMP-8 fluorimetry) were significantly decreased after therapy. Significant improvements in MMP-8/TIMP-1 and MMP-8/TIMP-2 ratios were also found, differences between other ratios before and after therapy were insignificant. Metalloproteinases and their inhibitors, in particular MMP-9 and TIMP-2, are valuable markers for clinical improvement in RAO.

  16. Topical approaches to cellulite

    OpenAIRE

    ALĞIN YAPAR, Evren

    2017-01-01

    Today, topical application of pharmacologically active chemicals and local application of physical, mechanical and thermal methods are available in order to eliminate cellulite which is an aesthetic problem that affects the majority of women. Many products on natural or synthetic originated anti-cellulite active ingredients have been developed with topical application studies performed on cellulite developed parts. Formulations developed against cellulite are usually in the form of gel...

  17. Topical treatment of melasma

    Directory of Open Access Journals (Sweden)

    Bandyopadhyay Debabrata

    2009-01-01

    Full Text Available Melasma is a common hypermelanotic disorder affecting the face that is associated with considerable psychological impacts. The management of melasma is challenging and requires a long-term treatment plan. In addition to avoidance of aggravating factors like oral pills and ultraviolet exposure, topical therapy has remained the mainstay of treatment. Multiple options for topical treatment are available, of which hydroquinone (HQ is the most commonly prescribed agent. Besides HQ, other topical agents for which varying degrees of evidence for clinical efficacy exist include azelaic acid, kojic acid, retinoids, topical steroids, glycolic acid, mequinol, and arbutin. Topical medications modify various stages of melanogenesis, the most common mode of action being inhibition of the enzyme, tyrosinase. Combination therapy is the preferred mode of treatment for the synergism and reduction of untoward effects. The most popular combination consists of HQ, a topical steroid, and retinoic acid. Prolonged HQ usage may lead to untoward effects like depigmentation and exogenous ochronosis. The search for safer alternatives has given rise to the development of many newer agents, several of them from natural sources. Well-designed controlled clinical trials are needed to clarify their role in the routine management of melasma.

  18. Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations

    DEFF Research Database (Denmark)

    Dahl, J B; Nielsen, R V; Wetterslev, J

    2014-01-01

    , and no well-documented 'gold standards' exist. The aim of the present topical, narrative review is to provide an update of the evidence for post-operative analgesic efficacy with the most commonly used, systemic non-opioid drugs, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs)/COX-2 antagonists......, glucocorticoids, gabapentinoids, and combinations of these. The review is based on data from previous systematic reviews with meta-analyses, investigating effects of non-opioid analgesics on pain, opioid-requirements, and opioid-related adverse effects. Paracetamol, NSAIDs, COX-2 antagonists, and gabapentin....... Trials of pregabalin > 300 mg/day indicated a morphine-sparing effect of 13.4 (4, 22.8) mg morphine/24 h. Notably, though, the available evidence for additive or synergistic effects of most combination regimens was sparse or lacking. Paracetamol, NSAIDs, selective COX-2 antagonists, and gabapentin all...

  19. Treatment of frozen shoulder with subcutaneous TNF-alpha blockade compared with local glucocorticoid injection

    DEFF Research Database (Denmark)

    Schydlowsky, Pierre; Szkudlarek, Marcin; Madsen, Ole Rintek

    2012-01-01

    We compared the effect of subcutaneous adalimumab injections with intraarticular glucocorticoid injections on frozen shoulder of 18 patients with unilateral joint involvement. Ten patients were randomised to subcutaneous injections with adalimumab and eight to intraarticular glucocorticoid inject...

  20. ROLE OF THE ENDOCANNABINOID SYSTEM IN REGULATING GLUCOCORTICOID EFFECTS ON MEMORY FOR EMOTIONAL EXPERIENCES

    NARCIS (Netherlands)

    Atsak, P.; Roozendaal, B.; Campolongo, P.

    2012-01-01

    Glucocorticoids, stress hormones released from the adrenal cortex, have potent modulatory effects on emotional memory. Whereas early studies focused mostly on the detrimental effects of chronic stress and glucocorticoid exposure on cognitive performance and the classic genomic pathways that mediate

  1. Role of the endocannabinoid system in regulating glucocorticoid effects on memory for emotional experiences

    NARCIS (Netherlands)

    Atsak, P.; Roozendaal, B.; Campolongo, P.

    2012-01-01

    Glucocorticoids, stress hormones released from the adrenal cortex, have potent modulatory effects on emotional memory. Whereas early studies focused mostly on the detrimental effects of chronic stress and glucocorticoid exposure on cognitive performance and the classic genomic pathways that mediate

  2. Minireview: glucocorticoids--food intake, abdominal obesity, and wealthy nations in 2004

    NARCIS (Netherlands)

    Dallman, Mary F.; la Fleur, Susanne E.; Pecoraro, Norman C.; Gomez, Francisca; Houshyar, Hani; Akana, Susan F.

    2004-01-01

    Glucocorticoids have a major effect on food intake that is underappreciated, although the effects of glucocorticoids on metabolism and abdominal obesity are quite well understood. Physiologically appropriate concentrations of naturally secreted corticosteroids (cortisol in humans, corticosterone in

  3. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

    NARCIS (Netherlands)

    Atsak, P.; Hauer, D.; Campolongo, P.; Schelling, G.; McGaugh, J.L.; Roozendaal, B.

    2012-01-01

    There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism

  4. Glomerular Glucocorticoid Receptors Expression and Clinicopathological Types of Childhood Nephrotic Syndrome.

    Science.gov (United States)

    Gamal, Yasser; Badawy, Ahlam; Swelam, Salwa; Tawfeek, Mostafa S K; Gad, Eman Fathalla

    2017-02-01

    Glucocorticoids are primary therapy of idiopathic nephrotic syndrome (INS). However, not all children respond to steroid therapy. We assessed glomerular glucocorticoid receptor expression in fifty-one children with INS and its relation to response to steroid therapy and to histopathological type. Clinical, laboratory and glomerular expression of glucocorticoid receptors were compared between groups with different steroid response. Glomerular glucocorticoid expression was slightly higher in controls than in minimal change early responders, which in turn was significantly higher than in minimal change late responders. There was significantly lower glomerular glucocorticoid receptor expression in steroid-resistance compared to early responders, late responders and controls. Glomerular glucocorticoid expression was significantly higher in all minimal change disease (MCD) compared to focal segmental glomerulosclerosis. In INS, response to glucocorticoid is dependent on glomerular expression of receptors and peripheral expression. Evaluation of glomerular glucocorticoid receptor expression at time of diagnosis of NS can predict response to steroid therapy.

  5. Control of cell proliferation in human glioma by glucocorticoids.

    Science.gov (United States)

    Freshney, R I; Sherry, A; Hassanzadah, M; Freshney, M; Crilly, P; Morgan, D

    1980-06-01

    Survival and proliferation of cell cultures from human anaplastic astrocytomas were shown to be enhanced by glucocorticoids with an optimal concentration of approximately 2.5 x 10(-5)M (10 micrograms/ml). The stimulation of proliferation was only observed in a clonal growth assay and was reversed as the size of individual colonies reached approximately 50 cells. Above this size, and in regular monolayer cultures, glucocorticoids were found to inhibit cell proliferation as measured by direct cell counting and incorporation of [3H] thymidine. Cultures grown to maximum cell densities in non-limiting medium conditions reached a lower terminal cell density, and had a reduced labelling index with [3H] thymidine in the presence of glucocorticoids. Although there was little difference between the actions of beta-methasone, dexamethasone and ethyl prednisolone, methyl prednisolone was found to be more effective, both in terms of stimulation of clonal growth and inhibition of growth at high cell densities. There was no evidence of cytotoxicity with glucocorticoids up to 5 x 10(-5)M (20 micrograms/ml) and it is suggested that glucocorticoids act via a normal regulatory process, perhaps enhancing cell-cell recognition.

  6. The role of glucocorticoids in emotional memory reconsolidation.

    Science.gov (United States)

    Meir Drexler, Shira; Wolf, Oliver T

    2017-07-01

    Glucocorticoids are secreted following exposure to stressful events. Their modulating role on memory reconsolidation, a post-retrieval process of re-stabilization, has been investigated only recently, at times with conflicting results. The goal of this review is twofold. First, to establish the modulating role of glucocorticoids on memory reconsolidation. Second, to point the potential factors and confounds that might explain the seemingly paradoxical findings. Here we review recent pharmacological studies, conducted in rodents and humans, which suggest a critical role of glucocorticoids in this post-retrieval process. In particular, the activation of glucocorticoid receptors in the amygdala and hippocampus is suggested to be involved in emotional memories reconsolidation, pointing to a similarity between post-retrieval reconsolidation and initial memory consolidation. In addition, based on the general reconsolidation literature, we suggest several factors that might play a role in determining the direction and strength of the reconsolidation effect following glucocorticoids treatment: memory-related factors, manipulation-related factors, and individual differences. We conclude that only when taking these additional factors into account can the paradox be resolved. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Glucocorticoid hyper- and hypofunction: stress effects on cognition and aggression.

    Science.gov (United States)

    Kim, Jeansok J; Haller, József

    2007-10-01

    It is now well documented that both increased and decreased stress responses can profoundly affect cognition and behavior. This mini review presents possible neural mechanisms subserving stress effects on memory and aggression, particularly focusing on glucocorticoid (GC) hyper- and hypofunction. First, uncontrollable stress impedes hippocampal memory and long-term potentiation (LTP). Because the hippocampus is important for the stability of long-term memory and because LTP has qualities desirable of an information storage mechanism, it has been hypothesized that stress-induced alterations in LTP contribute to memory impairments. Recent evidence suggests a neural-endocrine network comprising amygdala, prefrontal cortex (PFC), and glucocorticoids may be involved in regulating stress effects on hippocampal mnemonic functioning. Second, antisocial aggressiveness correlates with chronically decreased glucocorticoid production, and this condition leads in rats to behavioral-autonomic deficits reminiscent of the human disorder. Glucocorticoid deficiency-induced antisocial aggressiveness results from functional changes in the PFC, medial and central amygdala, and altered serotonin and substance P neurotransmissions. Accordingly, a neurobiological understanding of how stress and glucocorticoid deficiency alter brain, cognition, and behavior is an important challenge facing modern neuroscience with broad implications for individual and social well-being.

  8. Presumed Pseudotumor Cerebri Syndrome After Withdrawal of Inhaled Glucocorticoids.

    Science.gov (United States)

    Kwon, Young Joon; Allen, Julian L; Liu, Grant T; McCormack, Shana E

    2016-06-01

    Pseudotumor cerebri syndrome (PTCS) is characterized by increased intracranial pressure with normal brain parenchyma and cerebrospinal fluid constituents. PTCS after withdrawal of systemic corticosteroids also has been described in children. In contrast, to our knowledge, PTCS after withdrawal of inhaled glucocorticoids has not previously been described. Here we report the case of an 8-year and 6-month-old girl who developed signs and symptoms consistent with PTCS after withdrawal of inhaled glucocorticoids. The patient had excellent adherence to inhaled glucocorticoid therapy for ∼1 year before presentation, after which the therapy was stopped for concern related to poor growth. The withdrawal of inhaled glucocorticoids was associated with the development of severe headaches and diplopia, and further clinical examination led to the patient's diagnosis of likely PTCS. Although its occurrence is likely rare, clinicians caring for the many children receiving inhaled glucocorticoid therapy should be aware of the potential for PTCS after abrupt withdrawal of such treatment, and consider ophthalmology evaluation if patients report suggestive symptoms, such as headaches or vision changes in this context. Copyright © 2016 by the American Academy of Pediatrics.

  9. [Treatment of iatrogenic Cushing syndrome: questions of glucocorticoid withdrawal].

    Science.gov (United States)

    Igaz, Péter; Rácz, Károly; Tóth, Miklós; Gláz, Edit; Tulassay, Zsolt

    2007-02-04

    Iatrogenic Cushing's syndrome is the most common form of hypercortisolism. Glucocorticoids are widely used for the treatment of various diseases, often in high doses that may lead to the development of severe hypercortisolism. Iatrogenic hypercortisolism is unique, as the application of exogenous glucocorticoids leads to the simultaneous presence of symptoms specific for hypercortisolism and the suppression of the endogenous hypothalamic-pituitary-adrenal axis. The principal question of its therapy is related to the problem of glucocorticoid withdrawal. There is considerable interindividual variability in the suppression and recovery of the hypothalamic-pituitary-adrenal axis, therefore, glucocorticoid withdrawal and substitution can only be conducted in a stepwise manner with careful clinical follow-up and regular laboratory examinations regarding endogenous hypothalamic-pituitary-adrenal axis activity. Three major complications which can be associated with glucocorticoid withdrawal are: i. reactivation of the underlying disease, ii. secondary adrenal insufficiency, iii. steroid withdrawal syndrome. Here, the authors summarize the most important aspects of this area based on their clinical experience and the available literature data.

  10. Glucocorticoid influence on prognosis of idiopathic sudden sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Eduardo Amaro Bogaz

    2014-06-01

    Full Text Available INTRODUCTION: Idiopathic Sudden Sensorineural Hearing Loss (ISSHL is defined when a loss of at least 30 dB occurs in over 3 continuous frequencies, in up to 72 hours, of which etiology is not established, despite adequate investigation. Different types of treatment regimens have been proposed, but only glucocorticoids have shown some evidence of benefit in the literature. OBJECTIVE: To analyze whether the type of treatment or time of treatment with glucocorticoids have any influence on hearing recovery in ISSHL. METHODS: Observational retrospective cohort study. One hundred twenty-seven patients with ISSHL, treated at outpatient clinics between the years 2000 and 2010, were studied. We evaluated the prognostic correlation of the type of treatment and time to treatment with glucocorticoids and ISSHL. RESULTS: The absolute hearing gain and the relative hearing gain was as follows: 23.6 dB and 37.2%. Complete recovery was observed in 15.7% of patients, significant recovery in 27.6% and recovery in 57.5%. CONCLUSION: In this study, there was no difference between the use and nonuse of glucocorticoids in hearing improvement. However, when started within seven days after onset, the use of glucocorticoids was a factor of better prognosis.

  11. Rapid central corticosteroid effects: evidence for membrane glucocorticoid receptors in the brain

    OpenAIRE

    Tasker, Jeffrey G.; Shi Di; Malcher-Lopes, Renato

    2005-01-01

    Glucocorticoid secretion occurs in a circadian pattern and in response to stress. Among the broad array of glucocorticoid actions are multiple effects in the brain, including negative feedback regulation of hypothalamic hormone secretion. The negative feedback of glucocorticoids occurs on both rapid and delayed time scales, reflecting different regulatory mechanisms. While the slow glucocorticoid effects are widely held to involve regulation of gene transcription, the rapid effects are too fa...

  12. Adrenal Insufficiency Caused by Locally Applied Glucocorticoids-Myth or Fact?

    Science.gov (United States)

    Borresen, Stina Willemoes; Klose, Marianne; Rasmussen, Ase Krogh; Feldt-Rasmussen, Ulla

    2015-01-01

    Case-reports have made it evident that both inhaled, percutaneous, intranasal, intraarticular and ophthalmic administered glucocorticoids have the potential to cause life threatening adrenal insufficiency. With few and sometimes conflicting data and study methodology the prevalence of adrenal insufficiency secondary to locally applied glucocorticoids is not clear. Adrenal insufficiency can only be correctly evaluated by a stimulation test, and has by this procedure been reported in up to 40-50% of patients treated with high-dose inhaled glucocorticoids. Medium- to low-dose inhaled glucocorticoids have been shown to cause adrenal suppression in 0-16% of patients. Glucocorticoid creams and nasal glucocorticoids can cause adrenal insufficiency, also when used within prescribed doses, but the frequency seems to be less than with inhaled glucocorticoids. Intraarticularly administered glucocorticoids can cause adrenal suppression after a single injection. The systemic effect of locally applied glucocorticoids depends on pharmacokinetic and -dynamic properties of the particular glucocorticoid as well as individual factors. Many of the symptoms in iatrogen adrenal insufficiency are unspecific and often difficult to differentiate from symptoms of underlying disease activity. The condition might therefore be more common than widely believed and underdiagnosed in clinical practice. Potential adrenal insufficiency must therefore always be kept in mind in patients treated with all forms of glucocorticoids. Clinically important points and patient management are discussed on the basis of a case report and review of the literature. More work assessing the prevalence of adrenal insufficiency secondary to locally applied glucocorticoids is urgently needed.

  13. Glucocorticoids exert context-dependent effects on cells of the joint in vitro

    DEFF Research Database (Denmark)

    Madsen, Suzi H; Andreassen, Kim V; Christensen, Søren T

    2011-01-01

    Glucocorticoids are known to attenuate bone formation in vivo leading to decreased bone volume and increased risk of fractures, whereas effects on the joint tissue are less characterized. However, glucocorticoids appear to have a reducing effect on inflammation and pain in osteoarthritis....... This study aimed at characterizing the effect of glucocorticoids on chondrocytes, osteoclasts, and osteoblasts....

  14. Glucocorticoid receptor polymorphism in obesity and glucose homeostasis.

    Science.gov (United States)

    Majer-Łobodzińska, Agnieszka; Adamiec-Mroczek, Joanna

    2017-01-01

    Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level. BclI polymorphism is associated with increased abdominal obesity, hyperinsulinaemia and increased insulin resistance. Another polymorphism, ER22/23EK, in contrast to the others, is associated with relative resistance to glucocoricides actions and more beneficial metabolic profile-lower insulin resistance level, decreased lower cardiovascular risk and subseuent prolongation of life time. More research is still needed to understand the mechanisms behind these associations at the molecular level.

  15. Chronic restraint stress upregulates erythropoiesis through glucocorticoid stimulation.

    Directory of Open Access Journals (Sweden)

    Jeffrey L Voorhees

    Full Text Available In response to elevated glucocorticoid levels, erythroid progenitors rapidly expand to produce large numbers of young erythrocytes. Previous work demonstrates hematopoietic changes in rodents exposed to various physical and psychological stressors, however, the effects of chronic psychological stress on erythropoiesis has not be delineated. We employed laboratory, clinical and genomic analyses of a murine model of chronic restraint stress (RST to examine the influence of psychological stress on erythropoiesis. Mice exposed to RST demonstrated markers of early erythroid expansion involving the glucocorticoid receptor. In addition, these RST-exposed mice had increased numbers of circulating reticulocytes and increased erythropoiesis in primary and secondary erythroid tissues. Mice also showed increases in erythroid progenitor populations and elevated expression of the erythroid transcription factor KLF1 in these cells. Together this work reports some of the first evidence of psychological stress affecting erythroid homeostasis through glucocorticoid stimulation.

  16. [Steroids: The physiologic and pharmacologic effects of glucocorticoids].

    Science.gov (United States)

    Zelena, Dóra; Makara, B Gábor

    2015-08-30

    Glucocorticoids are widely used in medical practice mainly for suppression of the immune system. According to Selye - who named them - the endogenous molecules are very important for the adaptation to challenges, stress. They were synthesized in the 1940s. Since then numerous data have been published about their production (also locally in several organs), transportation (primarily cortisol-binding globulin) and receptors (nuclear and non-genomic effects). Although glucocorticoids are primarily under the control of the hypothalamo-pituitary-adrenocortical axis, several other molecules (especially catecholamines) may also increase their secretion. Their permissive influences are dominant, thereby they are indispensable for the effect of numerous other molecules. Thus, glucocorticoids have very diverse influence from metabolism through cardiovascular effect to bone-metabolism, affecting even the central nervous system. They are also important in metabolic syndrome. Their extensive therapeutic usage are limited by side-effects, which could be diminished - among others - with concomitant usage of the anabolic dehydroepiandrosterone.

  17. [Toward an explanation for the mnemonic effects of glucocorticoids?].

    Science.gov (United States)

    Jeanneteau, Freddy

    2015-04-01

    If the engram of long-term memory is encoded by structural changes of neuronal circuits, they are expected to be present at distant time points after learning, to be specific of circuits activated by learning, and sensitive to behavioral contingencies. In this review we present new concepts that emerged from in vivo imaging studies that tracked the structural bases of the memory trace. A fine balance of spine formation and spine elimination needed for behavioral adaptation to new experience is regulated by glucocorticoids, which are secreted in synchrony with circadian rhythms and in response to stress. Disruption of glucocorticoid oscillations frequently observed in psychiatric disorders like depression and post-traumatic stress produces spine turnover defects and learning disabilities. These new findings provide a new framework for explaining the potent but complex mnemonic effects of glucocorticoids. © 2015 médecine/sciences – Inserm.

  18. Canonical and Noncanonical Mechanisms of Glucocorticoid Stress Hormones Action.

    Science.gov (United States)

    2016-01-01

    Hormones of stress, glucocorticoids, regulate numerous physiological processes and functions. These hormonal effects involve diverse mechanisms of action. Glucocorticoid receptors (GRs) are transcription factors which regulate gene expression by canonical mechanism of the hormone action through interaction with specific nucleotide sequence (GRE) in the regulatory region of the gene. The effects of the canonical mechanism develop for several hours. Non-genomic rapid effects of the hormone emerged in seconds- minuets and supposed to be associated with yet not identified receptor in the plasma membrane. In addition to these slow and rapid hormonal actions, one more slow non-canonical mechanism of glucocorticoid action become increasingly evident. This mechanism is based on protein-protein interactions of GRs with other transcription factors. The main modern concepts of canonical, non-canonical and membrane mechanisms of hormone action are discussed in the review.

  19. Prescription duration and treatment episodes in oral glucocorticoid users

    DEFF Research Database (Denmark)

    Laugesen, Kristina; Støvring, Henrik; Hallas, Jesper

    2017-01-01

    Purpose: Glucocorticoids are widely used medications. In many pharmacoepidemiological studies, duration of individual prescriptions and definition of treatment episodes are important issues. However, many data sources lack this information. We aimed to estimate duration of individual prescriptions...... for oral glucocorticoids and to describe continuous treatment episodes using the parametric waiting time distribution. Methods: We used Danish nationwide registries to identify all prescriptions for oral glucocorticoids during 1996-2014. We applied the parametric waiting time distribution to estimate...... duration of individual prescriptions each year by estimating the 80th, 90th, 95th and 99th percentiles for the interarrival distribution. These corresponded to the time since last prescription during which 80%, 90%, 95% and 99% of users presented a new prescription for redemption. We used the Kaplan...

  20. Osteoporosis secundaria y Osteoporosis inducida por glucocorticoides (OIG

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    Elías Forero Illera

    2006-01-01

    Full Text Available La osteoporosis es un problema de salud pública importante a nivel mundial, y su prevalencia está aumentando. La osteoporosis secundaria se puede producir por varias patologías y el uso de ciertos medicamentos. Los glucocorticoides son un grupo de fármacos usados extensamente en la práctica médica debido a su indiscutible utilidad. La osteoporosis inducida por glucocorticoides es un problema de salud pública. Aunque la patogénesis de la pérdida producida por los glucocorticoides en el hueso no se conoce totalmente, investigaciones recientes han proporcionado nuevas conocimientos en los mecanismos de estos fármacos a nivel celular y molecular. Diversas guías han sido propuestas por diversos grupos para el tratamiento de la OIG; desafortunadamente, las guías del tratamiento no se utilizan adecuadamente en los pacientes.

  1. Glucocorticoid receptors in monocytes in type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Damm, P; Binder, C

    1989-01-01

    Glucocorticoid receptor binding characteristics were investigated in 8 males with poorly controlled Type 1 diabetes mellitus and 14 healthy males. The cell type studied was monocytes, and a method for correction for heterogeneity in glucocorticoid binding in a mononuclear leucocyte population...... was introduced. The number of receptors and the dissociation constant KD were, respectively, 13,699 and 2.93 X 10(-8) mol/l for the control group and 15,788 and 2.75 X 10(-8) mol/l for diabetics (p greater than 0.05). In diabetics, KD correlated negatively with blood glucose (r = 0.762, p less than 0.......05) indicating an increased sensitivity to cortisol at high blood glucose levels. In 6 of the diabetics and 7 of the control group, a simultaneous insulin receptor study was carried out. However, glucocorticoid receptor binding characteristics did not correlate with insulin receptor binding characteristics...

  2. Glucocorticoids, master modulators of the thymic catecholaminergic system?

    Directory of Open Access Journals (Sweden)

    I. Pilipović

    Full Text Available There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg·100 g body weight-1·day-1 for 4 days. The effects of β-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRαβhigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20 = 10.92, P < 0.01; for CD4-CD8+ F (1,20 = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRαβhigh thymocyte ratio (3.41 ± 0.21 in non-adrenalectomized rats vs 2.90 ± 0.31 in adrenalectomized rats, P < 0.05 were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only β-adrenoceptor- but also α-adrenoceptor-mediated modulation of thymopoiesis.

  3. Dose-related patterns of glucocorticoid-induced side effects.

    Science.gov (United States)

    Huscher, D; Thiele, K; Gromnica-Ihle, E; Hein, G; Demary, W; Dreher, R; Zink, A; Buttgereit, F

    2009-07-01

    To identify patterns of self-reported health problems relating to dose and duration of glucocorticoid intake in unselected patients with rheumatoid arthritis from routine practice. Data from 1066 patients were analysed. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing glucocorticoid treatment for more than 6 months and current doses of less than 5, 5-7.5 and over 7.5 mg/day prednisone equivalent were compared with a group without any glucocorticoid treatment for at least 12 months. The frequency of self-reported health problems was lowest in the group without glucocorticoid exposition and increased with dosage. Two distinct dose-related patterns of adverse events were observed. A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of over 7.5 mg/day for glaucoma, depression/listlessness and increase in blood pressure. Dosages of 5 mg/day or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/day). The associations found are in agreement with biological mechanisms and clinical observations. As there is a paucity of real-life data on adverse effects of glucocorticoids prescribed to unselected groups of patients, these data may help the clinician to adapt therapy with glucocorticoids accordingly and improve the benefit-risk ratio.

  4. Budesonida inalatória em crianças com asma aguda Nebulized budesonide to treat acute asthma in children

    Directory of Open Access Journals (Sweden)

    Geórgia K. M. Milani

    2004-04-01

    Full Text Available OBJETIVO: Avaliar a eficácia de budesonida na forma de suspensão, em dose única para inalação, como tratamento adjunto ao b2 inalatório, comparada com dose única de prednisona por via oral, em pacientes com crise aguda de asma. MÉTODO: Estudo prospectivo, randômico, paralelo, duplo-cego, duplo-placebo. Foram selecionadas 49 crianças, com idade entre 2 e 7 anos, em crise aguda de asma, que, após inalação com salbutamol (0,15 mg/kg, foram divididas em três grupos. O grupo I foi tratado com placebo via oral e inalatório; o grupo II, com prednisona via oral (1 mg/kg e placebo inalatório; e o grupo III, budesonida inalatória (2 mg e placebo via oral. As avaliações foram realizadas pela aplicação de um escore clínico e medida da saturação transcutânea da hemoglobina, seqüencialmente até 72 horas. Caso o escore clínico fosse igual ou superior ao da avaliação inicial, e a saturação inferior à primeira avaliação, a inalação com b2 adrenérgico era repetida. RESULTADOS: A melhora do escore clínico foi progressiva a partir de 30 minutos, e não houve diferença significativa nos três grupos estudados. Ocorreu aumento significativo da saturação da hemoglobina em relação ao valor inicial, com 2 horas no grupo prednisona, 4 horas no grupo budesonida e 24 horas no grupo placebo. CONCLUSÃO: O número de inalações com broncodilatador foi semelhante nos três grupos, com uma média de 2,9 no grupo placebo; 2,7 no grupo prednisona; e 2,5 no grupo budesonida. Em geral, as drogas estudadas foram bem toleradas, com efeitos colaterais semelhantes ao placebo. A administração de dose única de budesonida inalatória associada ao salbutamol, na crise moderada de asma, promoveu melhora clínica comparável à da prednisona oral. A recuperação da saturação transcutânea da hemoglobina foi mais rápida com prednisona.OBJECTIVE: To investigate the efficacy of a single dose of inhaled budesonide as compared to oral

  5. Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

    Science.gov (United States)

    Jackson, Daniel J; Bacharier, Leonard B; Mauger, David T; Boehmer, Susan; Beigelman, Avraham; Chmiel, James F; Fitzpatrick, Anne M; Gaffin, Jonathan M; Morgan, Wayne J; Peters, Stephen P; Phipatanakul, Wanda; Sheehan, William J; Cabana, Michael D; Holguin, Fernando; Martinez, Fernando D; Pongracic, Jacqueline A; Baxi, Sachin N; Benson, Mindy; Blake, Kathryn; Covar, Ronina; Gentile, Deborah A; Israel, Elliot; Krishnan, Jerry A; Kumar, Harsha V; Lang, Jason E; Lazarus, Stephen C; Lima, John J; Long, Dayna; Ly, Ngoc; Marbin, Jyothi; Moy, James N; Myers, Ross E; Olin, J Tod; Raissy, Hengameh H; Robison, Rachel G; Ross, Kristie; Sorkness, Christine A; Lemanske, Robert F

    2018-03-08

    Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma

  6. Glucocorticoid-induced myopathy in the intensive care unit

    DEFF Research Database (Denmark)

    Eddelien, Heidi Shil; Hoffmeyer, Henrik Westy; Lund, Eva Charlotte Løbner

    2015-01-01

    Glucocorticoids (GC) are used for intensive care unit (ICU) patients on several indications. We present a patient who was admitted to the ICU due to severe respiratory failure caused by bronchospasm requiring mechanical ventilation and treated with methylprednisolone 240 mg/day in addition...... to antibiotics and bronchiolytics. When the sedation was lifted on day 10, the patient was awake but quadriplegic. Blood samples revealed elevated muscle enzymes, electromyography showed myopathy, and a muscle biopsy was performed. Glucocorticoid-induced myopathy was suspected, GC treatment was tapered...

  7. Heterogeneity in mechanisms influencing glucocorticoid sensitivity: the need for a systems biology approach to treatment of glucocorticoid-resistant inflammation.

    Science.gov (United States)

    Keenan, Christine R; Radojicic, Danica; Li, Meina; Radwan, Asmaa; Stewart, Alastair G

    2015-06-01

    Glucocorticoids (GCs) have impressive anti-inflammatory and immunosuppressive effects and show a diversity of actions across a variety of cell phenotypes. Implicit in efforts to optimize GCs as anti-inflammatory agents for any or all indications is the notion that the relevant mechanism(s) of action of GCs are fully elucidated. However, recent advances in understanding GC signalling mechanisms have revealed remarkable complexity and contextual dependence, calling into question whether the mechanisms of action are sufficiently well-described to embark on optimization. In the current review, we address evidence for differences in the mechanism of action in different cell types and contexts, and discuss contrasts in mechanisms of glucocorticoid insensitivity, with a focus on asthma and Chronic Obstructive Pulmonary Disease (COPD). Given this complexity, we consider the potential breadth of impact and selectivity of strategies directed to reversing the glucocorticoid insensitivity. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Low-dose glucocorticoids in hyperandrogenism Efecto de bajas dosis de glucocorticoides en el hiperandrogenismo

    Directory of Open Access Journals (Sweden)

    Leonardo Rizzo

    2007-06-01

    Full Text Available To investigate the effect of low-doses of glucocorticoids on androgen and cortisol secretion during the course of the day, we evaluated clinical signs of hyperandrogenism and total, free and bioavailable testosterone, SHBG, and cortisol following two different protocols: A fourteen patients received betamethasone 0.6 mg/day (n=8 or methylprednisolone 4 mg/day (n=6, as single daily oral dose at 11.00 PM, during 30 days, B fourteen patients were evaluated under betamethasone 0.3 mg in a single daily dose at 11.00 PM during six months, 11 out of whom were re-evaluated six months later. Twenty eight women with hyperandrogenism were included and seven normal females were used as control. Blood samples were taken in follicular phase at 8 AM and 7 PM to determine SHBG, cortisol, total, free and bioavailable testosterone. In both protocols, a significant morning and evening decrease in cortisol and testosterone (pCon el objetivo de investigar el efecto de bajas dosis de glucocorticoides sobre la secreción de andrógenos y cortisol en el curso del día, evaluamos signos de hiperandrogenismo, testosterona total, libre y biodisponible y cortisol según dos protocolos diferentes: A catorce pacientes recibieron betametasona 0.6 mg/día (n= 8 o metilprednisolona 4 mg/día (n= 6 en dosis única cotidiana, a las 23 h, durante 30 días, B catorce pacientes fueron evaluadas bajo betametasona 0.3 mg en dosis única cotidiana a la 23 h, administrada durante 6 meses; de ellas, 11 pacientes fueron re-evaluadas 6 meses más tarde. Se incluyeron 28 mujeres con hiperandrogenismo y 7 controles normales. Se obtuvieron muestras de sangre en fase folicular a las 08:00 y 9:00 h para determinar SHBG, cortisol, testosterona total, libre y biodisponible. En ambos protocolos se observó una disminución significativa de cortisol y testosterona (p<0.05 a <0.01, más importante con betametasona (p<0.05. En el protocolo B, los niveles matutinos de SHBG aumentaron

  9. Structural variants of glucocorticoid receptor binding sites and different versions of positive glucocorticoid responsive elements: Analysis of GR-TRRD database.

    Science.gov (United States)

    Merkulov, Vasily M; Merkulova, Tatyana I

    2009-05-01

    The GR-TRRD section of the TRRD database contains the presently largest sample of published nucleotide sequences with experimentally confirmed binding to the glucocorticoid hormone receptor (GR). This sample comprises 160 glucocorticoid receptor binding sites (GRbs) from 77 vertebrate glucocorticoid-regulated genes. Analysis of this sample has demonstrated that the structure of only half GRbs (54%) corresponds to the generally accepted organization of glucocorticoid response element (GRE) as an inverted repeat of the TGTTCT hexanucleotide. As many as 40% of GRbs contain only the hexanucleotide, and the majority of such "half-sites" belong to the glucocorticoid-inducible genes. An expansion of the sample allowed the consensus of GRbs organized as an inverted repeat to be determined more precisely. Several possible mechanisms underlying the role of the noncanonical receptor binding sites (hexanucleotide half-sites) in the glucocorticoid induction are proposed based on analysis of the literature data.

  10. Salicylic Acid Topical

    Science.gov (United States)

    ... the package label for more information.Apply a small amount of the salicylic acid product to one or two small areas you want to treat for 3 days ... know that children and teenagers who have chicken pox or the flu should not use topical salicylic ...

  11. Conditionals Are Topics

    Science.gov (United States)

    Haiman, John

    1978-01-01

    A review of analyses of conditionals (in the philosophical literature) and of topics (primarily in linguistics) reveals that their definitions are very similar. This paper justifies the method of basing semantic analysis of a construction on a cross-linguistic examination of its superficial form. (Author/NCR)

  12. Advanced Topics in Aerodynamics

    DEFF Research Database (Denmark)

    Filippone, Antonino

    1999-01-01

    "Advanced Topics in Aerodynamics" is a comprehensive electronic guide to aerodynamics,computational fluid dynamics, aeronautics, aerospace propulsion systems, design and relatedtechnology. We report data, tables, graphics, sketches,examples, results, photos, technical andscientific literature......, for higher education, learning, reference, research and engineering services....

  13. Characters and Topical Diversity

    DEFF Research Database (Denmark)

    Eriksson, Rune

    2014-01-01

    The purpose of this article is to contribute to our understanding of the difference between the bestseller and the non-bestseller in nonfiction. It is noticed that many bestsellers in nonfiction belongs to the sub-genre of creative nonfiction, but also that the topics in this kind of literature i...

  14. Topical immunomodulators in dermatology

    Directory of Open Access Journals (Sweden)

    Khandpur Sujay

    2004-04-01

    Full Text Available Topical immunomodulators are agents that regulate the local immune response of the skin. They are now emerging as the therapy of choice for several immune-mediated dermatoses such as atopic dermatitis, contact allergic dermatitis, alopecia areata, psoriasis, vitiligo, connective tissue disorders such as morphea and lupus erythematosus, disorders of keratinization and several benign and malignant skin tumours, because of their comparable efficacy, ease of application and greater safety than their systemic counterparts. They can be used on a domiciliary basis for longer periods without aggressive monitoring. In this article, we have discussed the mechanism of action, common indications and side-effects of the commonly used topical immunomodulators, excluding topical steroids. Moreover, newer agents, which are still in the experimental stages, have also been described. A MEDLINE search was undertaken using the key words "topical immunomodulators, dermatology" and related articles were also searched. In addition, a manual search for many Indian articles, which are not indexed, was also carried out. Wherever possible, the full article was reviewed. If the full article could not be traced, the abstract was used.

  15. Co-Activation of Glucocorticoid Receptor and Peroxisome Proliferator-Activated Receptor-γ in Murine Skin Prevents Worsening of Atopic March.

    Science.gov (United States)

    Deckers, Julie; Bougarne, Nadia; Mylka, Viacheslav; Desmet, Sofie; Luypaert, Astrid; Devos, Michael; Tanghe, Giel; Van Moorleghem, Justine; Vanheerswynghels, Manon; De Cauwer, Lode; Thommis, Jonathan; Vuylsteke, Marnik; Tavernier, Jan; Lambrecht, Bart N; Hammad, Hamida; De Bosscher, Karolien

    2017-12-27

    Children with atopic dermatitis show an increased risk to develop asthma later in life, a phenomenon referred to as "atopic march," which emphasizes the need for secondary prevention therapies. This study aimed to investigate whether relief of skin inflammation by glucocorticoids and peroxisome proliferator-activated receptor agonists might influence the subsequent development of asthma in a murine model for the atopic march in which mice were repeatedly exposed to house dust mite via the skin, followed by exposure to house dust mite in lungs. To abrogate atopic dermatitis, mice received topical treatment with glucocorticoid receptor/peroxisome proliferator-activated receptor-γ agonists. Nuclear receptor ligand effects were assessed on primary keratinocytes and dendritic cells, as central players in skin inflammation. Prior house dust mite-induced skin inflammation aggravates allergic airway inflammation and induces a mixed T helper type 2/T helper type 17 response in the lungs. Cutaneous combined activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-γ reduced skin inflammation to a higher extent compared to single activation. Additive anti-inflammatory effects were more prominent in dendritic cells, as compared to keratinocytes. Alleviation of allergic skin inflammation by activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-γ appeared insufficient to avoid the allergic immune response in the lungs, but efficiently reduced asthma severity by counteracting the Th17 response. Glucocorticoid receptor/peroxisome proliferator-activated receptor-γ co-activation represents a potent remedy against allergic skin inflammation and worsening of atopic march. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Molecular mechanisms of glucocorticoids action: implications for treatment of rhinosinusitis and nasal polyposis.

    Science.gov (United States)

    Grzanka, Alicja; Misiołek, Maciej; Golusiński, Wojciech; Jarząb, Jerzy

    2011-02-01

    Intra-nasal glucocorticoids are the most effective drugs available for rhinosinusitis and nasal polyposis treatment. Their effectiveness depends on many factors and not all of them have been well recognized so far. The authors present the basic information on molecular mechanisms of glucocorticoid action, direct and indirect effects of glucocorticoids on transcription of genes encoding inflammatory mediators. They focus on recently proved nongenomic mechanisms which appear quickly, from several seconds to minutes after glucocorticoid administration and discuss clinical implications resulting from this knowledge. Discovery of nongenomic glucocorticoid actions allows for better use of these drugs in clinical practice.

  17. Molecular mechanisms of glucocorticoid receptor signaling Mecanismos moleculares de señalización del receptor de glucocorticoides

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR. Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.Esta revisión destaca los más recientes hallazgos sobre los mecanismos moleculares del receptor de glucocorticoides (GR. La mayoría de los efectos de los glucocorticoides son mediados por los GR intracelulares presentes en casi todos los tejidos y controlan la activación transcripcional por mecanismos directos e indirectos. Las respuestas a los glucocorticoides son específicas para cada gen y tejido. Los GR se asocian en forma selectiva con ligandos producidos en la glándula adrenal, corticosteroides, en respuesta a cambios neuroendocrinos. La interacción del ligando con el GR promueve: a la unión del GR a elementos genómicos de respuesta a glucocorticoides, modulando la transcripción; b la interacción de monómeros del GR con otros factores de transcripción activados por otras vías, llevando a la transrepresión. El GR regula un amplio espectro de funciones fisiológicas, incluyendo la

  18. X-ray Crystal Structure of the Novel Enhanced-Affinity Glucocorticoid Agonist Fluticasone Furoate in the Glucocorticoid Receptor−Ligand Binding Domain

    Energy Technology Data Exchange (ETDEWEB)

    Biggadike, Keith; Bledsoe, Randy K.; Hassell, Anne M.; Kirk, Barrie E.; McLay, Iain M.; Shewchuk, Lisa M.; Stewart, Eugene L. (GSKNC); (GSK)

    2008-07-08

    An X-ray crystal structure is reported for the novel enhanced-affinity glucocorticoid agonist fluticasone furoate (FF) in the ligand binding domain of the glucocorticoid receptor. Comparison of this structure with those of dexamethasone and fluticasone propionate shows the 17{alpha} furoate ester to occupy more fully the lipophilic 17{alpha} pocket on the receptor, which may account for the enhanced glucocorticoid receptor binding of FF.

  19. Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy.

    Science.gov (United States)

    Shi, Jun; Wang, Long; Zhang, Hongyang; Jie, Qiang; Li, Xiaojie; Shi, Qiyue; Huang, Qiang; Gao, Bo; Han, Yuehu; Guo, Kai; Liu, Jian; Yang, Liu; Luo, Zhuojing

    2015-10-01

    Whether glucocorticoids directly enhance or interrupt osteoclastogenesis is still a controversial subject. In this study, we ascertained the dose-dependent positive effects of glucocorticoids on osteoclastogenesis in vivo and in vitro as well as investigated the mechanism in vitro. As the dose of glucocorticoids increased, osteoclastogenesis was stimulated at 0.1 μM, a peak was achieved at 1 μM and a corresponding decrease occurred at 10 μM. Reactive oxygen species (ROS), which play a crucial role in osteoclastogenesis, and autophagy flux activity, a cellular recycling process, were consistently up-regulated along with the dose-dependent effects of the glucocorticoids on osteoclast formation and function. N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of the glucocorticoids on autophagy and osteoclastogenesis. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, interrupted osteoclastogenesis stimulation by the glucocorticoids. These results implied that with glucocorticoid administration, ROS and autophagy, as a downstream factor of ROS, played vital roles in osteoclast formation and function. 3-MA administration did not enhance ROS accumulation, so that autophagy had no effect on ROS induced by glucocorticoids. Our investigation demonstrated that glucocorticoids had dose-dependent positive effects on osteoclast formation and function via ROS and autophagy. These results provide support for ROS and autophagy as therapeutic targets in glucocorticoid-related bone loss diseases such as glucocorticoid-induced osteoporosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome.

    Science.gov (United States)

    Agrawal, S; Chanley, M A; Westbrook, D; Nie, X; Kitao, T; Guess, A J; Benndorf, R; Hidalgo, G; Smoyer, W E

    2016-05-04

    Glucocorticoids are the primary therapy for nephrotic syndrome (NS), but have serious side effects and are ineffective in ~20-50% of patients. Thiazolidinediones have recently been suggested to be renoprotective, and to modulate podocyte glucocorticoid-mediated nuclear receptor signaling. We hypothesized that thiazolidinediones could enhance glucocorticoid efficacy in NS. We found that puromycin aminonucleoside-induced proteinuria in rats was significantly reduced by both high-dose glucocorticoids (79%) and pioglitazone (61%), but not low-dose glucocorticoids (25%). Remarkably, pioglitazone + low-dose glucocorticoids also reduced proteinuria (63%) comparably to high-dose glucocorticoids, whereas pioglitazone + high-dose glucocorticoids reduced proteinuria to almost control levels (97%). Molecular analysis revealed that both glucocorticoids and pioglitazone enhanced glomerular synaptopodin and nephrin expression, and reduced COX-2 expression, after injury. Furthermore, the glomerular phosphorylation of glucocorticoid receptor and Akt, but not PPARγ, correlated with treatment-induced reductions in proteinuria. Notably, clinical translation of these findings to a child with refractory NS by the addition of pioglitazone to the treatment correlated with marked reductions in both proteinuria (80%) and overall immunosuppression (64%). These findings together suggest that repurposing pioglitazone could potentially enhance the proteinuria-reducing effects of glucocorticoids during NS treatment.

  1. Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: COPE-ADHF study.

    Science.gov (United States)

    Liu, Chao; Liu, Kunshen

    2014-04-01

    Newly emerging evidence showed that glucocorticoids could potentiate natriuretic peptides' action by increasing the density of natriuretic peptide receptor A, leading to a potent diuresis and a renal function improvement in patients with acute decompensated heart failure (ADHF). Therefore, glucocorticoid therapy may be used in patients with ADHF. One hundred two patients with ADHF were randomized to receive glucocorticoids or standard treatment. Change from baseline in serum creatinine (SCr) at day 7 and cardiovascular death within 30 days were recorded. The study was terminated early because of slow site initiation and patient enrolment. Glucocorticoid therapy seemed to be well tolerated. There was a remarkable SCr reduction after 7 days treatment. The change from baseline in SCr is -0.14 mg/dL in glucocorticoid group versus -0.02 mg/dL in standard treatment group (P glucocorticoid group with odds ratio of 0.26 (3 deaths in glucocorticoid vs. 10 deaths in standard treatment group, P glucocorticoid therapy persisted during the follow-up. Patient-assessed dyspnea and physician-assessed global clinical status were also improved in glucocorticoid group. Limited data indicate that glucocorticoid therapy may be used safely in patients with ADHF in short term. Glucocorticoid therapy did not cause heart failure deterioration. Further investigations are warranted.

  2. Budesonide Nasal Spray

    Science.gov (United States)

    ... doctor if you have chicken pox, measles, or tuberculosis (TB; a type of lung infection), or if you have been around someone who has one of these conditions.tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If ...

  3. Glucocorticoids Sensitize the Innate Immune System through Regulation of the NLRP3 Inflammasome*

    Science.gov (United States)

    Busillo, John M.; Azzam, Kathleen M.; Cidlowski, John A.

    2011-01-01

    Glucocorticoids have long been recognized as powerful anti-inflammatory compounds that are one of the most widely prescribed classes of drugs in the world. However, their role in the regulation of innate immunity is not well understood. We sought to examine the effects of glucocorticoids on the NOD-like receptors (NLRs), a central component of the inflammasome and innate immunity. Surprisingly, we show that glucocorticoids induce both NLRP3 messenger RNA and protein, which is a critical component of the inflammasome. The glucocorticoid-dependent induction of NLRP3 sensitizes the cells to extracellular ATP and significantly enhances the ATP-mediated release of proinflammatory molecules, including mature IL-1β, TNF-α, and IL-6. This effect was specific for glucocorticoids and dependent on the glucocorticoid receptor. These studies demonstrate a novel role for glucocorticoids in sensitizing the initial inflammatory response by the innate immune system. PMID:21940629

  4. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself

    DEFF Research Database (Denmark)

    Dinsen, Stina; Baslund, Bo; Klose, Marianne

    2013-01-01

    Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due...... to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years....... Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor...

  5. Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress

    Science.gov (United States)

    Herman, James P.

    2015-01-01

    Environmental stimuli that signal real or potential threats to homeostasis lead to glucocorticoid secretion by the hypothalamic-pituitary-adrenocortical (HPA) axis. Glucocorticoids promote energy redistribution and are critical for survival and adaptation. This adaptation requires the integration of multiple systems and engages key limbic-neuroendocrine circuits. Consequently, glucocorticoids have profound effects on synaptic physiology, circuit regulation of stress responsiveness, and, ultimately, behavior. While glucocorticoids initiate adaptive processes that generate energy for coping, prolonged or inappropriate glucocorticoid secretion becomes deleterious. Inappropriate processing of stressful information may lead to energetic drive that does not match environmental demand, resulting in risk factors for pathology. Thus, dysregulation of the HPA axis may promote stress-related illnesses (e.g. depression, PTSD). This review summarizes the latest developments in central glucocorticoid actions on synaptic, neuroendocrine, and behavioral regulation. Additionally, these findings will be discussed in terms of the energetic integration of stress and the importance of context-specific regulation of glucocorticoids. PMID:24361584

  6. Glucocorticoid-induced osteoporosis – a disorder of mesenchymal stromal cells?

    Directory of Open Access Journals (Sweden)

    Mark Stuart Cooper

    2011-08-01

    Full Text Available Glucocorticoids are a class of steroid hormones that are essential to life but cause serious harm in excess. The main clinical features of glucocorticoid excess are due to adverse effects on cells and tissues that arise from a common developmental precursor – the mesenchymal stromal cell (MSC; sometimes referred to as the mesenchymal stem cell. Interestingly glucocorticoids appear essential for the differentiation of cells and tissues that arise from MSCs. High levels of glucocorticoids are used in tissue engineering strategies to enhance the formation of tissues such as bone, cartilage and muscle. This article discusses the paradox that glucocorticoids both enhance and impair MSC development and function. It will describe how endogenous glucocorticoids are likely to be important in these processes in vivo and will discuss the implications for therapies aimed at reducing the damage associated with the use of therapeutic glucocorticoids.

  7. PREFACE: CEWQO Topical Issue CEWQO Topical Issue

    Science.gov (United States)

    Bozic, Mirjana; Man'ko, Margarita

    2009-09-01

    This topical issue of Physica Scripta collects selected peer-reviewed contributions based on invited and contributed talks and posters presented at the 15th Central European Workshop on Quantum Optics (CEWQO) which took place in Belgrade 29 May-3 June 2008 (http://cewqo08.phy.bg.ac.yu). On behalf of the whole community took place in Belgrade 29 May-3 June 2008 (http://cewqo08.phy.bg.ac.yu, cewqo08.phy.bg.ac.yu). On behalf of the whole community of the workshop, we thank the referees for their careful reading and useful suggestions which helped to improve all of the submitted papers. A brief description of CEWQO The Central European Workshop on Quantum Optics is a series of conferences started informally in Budapest in 1992. Sometimes small events transform into important conferences, as in the case of CEWQO. Professor Jozsef Janszky, from the Research Institute of Solid State Physics and Optics, is the founder of this series. Margarita Man'ko obtained the following information from Jozsef Janszky during her visit to Budapest, within the framework of cooperation between the Russian and Hungarian Academies of Sciences in 2005. He organized a small workshop on quantum optics in Budapest in 1992 with John Klauder as a main speaker. Then, bearing in mind that a year before Janszky himself was invited by Vladimir Buzek to give a seminar on the same topic in Bratislava, he decided to assign the name 'Central European Workshop on Quantum Optics', considering the seminar in Bratislava to be the first workshop and the one in Budapest the second. The third formal workshop took place in Bratislava in 1993 organized by Vladimir Buzek, then in 1994 (Budapest, by Jozsef Janszky), 1995 and 1996 (Budmerice, Slovakia, by Vladimir Buzek), 1997 (Prague, by Igor Jex), 1999 (Olomouc, Czech Republic, by Zdenek Hradil), 2000 (Balatonfüred, Hungary, by Jozsef Janszky ), 2001 (Prague, by Igor Jex), 2002 (Szeged, Hungary, by Mihaly Benedict), 2003 (Rostock,Germany, by Werner Vogel and

  8. Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

    Science.gov (United States)

    Paolino, Sabrina; Cutolo, Maurizio; Pizzorni, Carmen

    2017-01-01

    Morning symptoms of rheumatoid arthritis (RA) are linked to circadian increase of night inflammation, supported by inadequate cortisol secretion in active disease. Therefore, exogenous glucocorticoid administration in RA is recommended by EULAR and ACR from the beginning of the diagnosis, since may partially act like a "replacement therapy". In addition, the prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective when exogenous glucocorticoid administration is managed with a night-time-release formulation. Despite a considerably higher cost than conventional prednisone (immediate release), chronotherapy with night-time-release prednisone has been recognized a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic disease-modifying antirheumatic drugs (DMARDs). Interestingly, since different cell populations involved in the inflammatory process are particularly activated during the night (i.e. monocytes, macrophages), other therapeutical approaches used in RA, such as conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs) should follow the same concepts of glucocorticoid chronotherapy. Therefore, bedtime methotrexate chronotherapy was found to better manage RA symptoms, and several available NSAIDs (i.e. indomethacin, aceclofenac, ketoprofen, flurbiprofen, lornoxicam) have been recently modified in their formulation, in order to obtain more focused night action.

  9. the effect of early administration of glucocorticoids on learning and ...

    African Journals Online (AJOL)

    Daniel Owu

    was observed that the animals in the treatment group preferred to return to the start arm or explore the other arm. This is indicative of impaired spatial memory. Steroids administered postnatally may have transient retarding effect on learning and memory functions. Keywords: Glucocorticoids, learning, memory, brain, rat.

  10. Calycosin regulates glucocorticoid-induced apoptosis via Nrf2/ARE ...

    African Journals Online (AJOL)

    Calycosin regulates glucocorticoid-induced apoptosis via Nrf2/ARE signaling in MC3T3-E1 cells. ... If you would like more information about how to print, save, and work with PDFs, Highwire Press provides a helpful Frequently Asked Questions about PDFs. Alternatively, you can download the PDF file directly to your ...

  11. Uso de glucocorticoides en enfermedades alérgicas

    Directory of Open Access Journals (Sweden)

    M Rodríguez-González

    2017-01-01

    Full Text Available Los glucocorticoides son análogos sintéticos de las hormonas adrenocorticales, de uso común, de gran utilidad en la práctica clínica del pediatra y se consideran la piedra angular del tratamiento farmacológico de enfermedades alérgicas.

  12. Glucocorticoids, the etiology of obesity and the metabolic syndrome

    NARCIS (Netherlands)

    Dallman, Mary F.; Akana, Susan F.; Pecoraro, Norman C.; Warne, James P.; la Fleur, Susanne E.; Foster, Michelle T.

    2007-01-01

    In mammals, glucocorticoid actions appear to have evolved to maintain and enhance energy stores to be used for life-saving gluconeogenesis. They act on the brain to stimulate search behaviors, palatable feeding and emotionally relevant memories, and they act on the body to mobilize stored peripheral

  13. Brief report: Glucocorticoid receptor polymorphism affects transrepression but not transactivation

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica); H. Russcher (Henk); E.F.C. van Rossum (Liesbeth); A.O. Brinkmann (Albert); F.H. de Jong (Frank); A.C.S. Hokken-Koelega (Anita); H.A.P. Pols (Huib); J.W. Koper (Jan); S.W.J. Lamberts (Steven)

    2006-01-01

    textabstractContext: Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC

  14. Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

    Directory of Open Access Journals (Sweden)

    Sabrina Paolino

    2017-08-01

    Full Text Available Morning symptoms of rheumatoid arthritis (RA are linked to circadian increase of night inflammation, supported by inadequate cortisol secretion in active disease. Therefore, exogenous glucocorticoid administration in RA is recommended by EULAR and ACR from the beginning of the diagnosis, since may partially act like a “replacement therapy”. In addition, the prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective when exogenous glucocorticoid administration is managed with a night-time-release formulation. Despite a considerably higher cost than conventional prednisone (immediate release, chronotherapy with night-time-release prednisone has been recognized a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic disease-modifying antirheumatic drugs (DMARDs. Interestingly, since different cell populations involved in the inflammatory process are particularly activated during the night (i.e. monocytes, macrophages, other therapeutical approaches used in RA, such as conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs should follow the same concepts of glucocorticoid chronotherapy. Therefore, bedtime methotrexate chronotherapy was found to better manage RA symptoms, and several available NSAIDs (i.e. indomethacin, aceclofenac, ketoprofen, flurbiprofen, lornoxicam have been recently modified in their formulation, in order to obtain more focused night action.

  15. Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis

    NARCIS (Netherlands)

    Banciu, M.

    2007-01-01

    Glucocorticoids (GC) have inhibitory actions on solid tumor growth due to suppressive effects on tumor angiogenesis and inflammation. When evaluating the preclinical studies on solid tumor growth inhibition, it appears that GC-induced antitumor effects are achieved by using substantially higher

  16. Optimized glucocorticoid therapy: teaching old drugs new tricks.

    Science.gov (United States)

    Strehl, Cindy; Buttgereit, Frank

    2013-11-05

    Glucocorticoids (GCs) are commonly used in the treatment of a wide range of rheumatic and other inflammatory diseases. They exert their potent anti-inflammatory and immunosuppressive effects primarily via so called genomic mechanisms, mediated by the cytosolic glucocorticoid receptor (cGR). This mechanism of GC action can be divided into the transactivation and the transrepression processes. However, also rapid effects of GCs exist which are mediated by specific and unspecific non-genomic mechanisms. A clinical relevance of this mode of GC action is assumed for effects mediated by membrane-bound glucocorticoid receptors, but detailed knowledge on the underlying mechanisms is still missing. Great efforts have been made in the past to diminish GC-induced adverse effects, thus improving the benefit/risk ratio of the drugs. Besides approaches to improve the treatment with conventional glucocorticoids currently available to clinicians, new innovative GCs or GC receptor ligands are also being developed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  17. Glucocorticoid Receptor Variants Modulate the Sensitivity to Cortisol

    NARCIS (Netherlands)

    H. Russcher (Henk)

    2006-01-01

    textabstractSynthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this

  18. The effect of early administration of glucocorticoids on learning and ...

    African Journals Online (AJOL)

    It has been observed that steroids administered postnatally may have transient retarding effect on learning and memory functions, and that animal age and sex may modify such effects. This study aims to illustrate the effect of early administration of glucocorticoids on learning and spatial memory. Wistar rat pups were ...

  19. Impact of Preterm Birth on Glucocorticoid Variability in Human Milk.

    Science.gov (United States)

    Pundir, Shikha; Mitchell, Cameron J; Thorstensen, Eric B; Wall, Clare R; Perrella, Sharon L; Geddes, Donna T; Cameron-Smith, David

    2018-02-01

    Preterm birth is a stressful event for both the mother and infant. Whereas the initiation of breastfeeding is important for preterm infant health, little is known of the glucocorticoid hormones (cortisol and cortisone) in human milk following preterm birth. Research aim: The aim of this study was to investigate the relationship between human milk glucocorticoid concentrations and preterm birth. Human milk was sampled weekly for up to 6 weeks from 22 women who delivered a preterm infant at 28 to 32 weeks' gestation. Human milk was analyzed for total and free cortisol and cortisone concentrations using liquid chromatography-tandem mass spectrometry. Milk sampled from mothers of preterm infants had more cortisone than cortisol ( p hormones ( p = .001, r = .85). The cortisone was significantly higher in the milk of mothers who delivered infants after 30 weeks compared with those who delivered before 30 weeks of gestation ( p = .02). Glucocorticoid concentrations did not change over the sampling time (weeks 1 to 6 postpartum) and did not differ by infant gender. Glucocorticoids were present in all milk samples following preterm birth. Cortisone concentration tended to be higher in those who delivered after 30 weeks' gestation but did not increase further over the weeks following birth.

  20. Glucocorticoids and inhibition of bone formation induced by skeletal unloading

    Energy Technology Data Exchange (ETDEWEB)

    Halloran, B.P.; Bikle, D.D.; Cone, C.M.; Morey-Holton, E. (Univ. of California, San Francisco (USA) Veterans Administration Medical Center, San Francisco, CA (USA) NASA-Ames Research Center, Moffett Field, CA (USA))

    1988-12-01

    Skeletal unloading or loss of normal weight bearing in the growing animal inhibits bone formation and reduces bone calcium. To determine whether the inhibition of bone formation induced by skeletal unloading is a consequence of an increase in plasma glucocorticoids and/or an increase in bone sensitivity to glucocorticoids, the authors measured plasma corticosterone throughout the day in unloaded and normally loaded rats (hindlimb elevation model) and examined the effect of adrenalectomy on the response of bone to skeletal unloading. Plasma corticosterone levels were similar in normally loaded and unloaded rats at all times. Skeletal unloading in sham-adrenalectomized animals reduced tibial and vertebral calcium by 11.5 and 11.1%, respectively, and in adrenalectomized animals by 15.3 and 20.3%, respectively. Uptake of {sup 45}Ca and ({sup 3}H)proline in the tibia was reduced by 8 and 14%, respectively, in the sham-adrenalectomized animals and by 13 and 19% in the adrenalectomized animals. Bone formation and apposition rates were reduced to the same level in sham- and adrenalectomized animals. These results suggest that the inhibition of bone formation induced by skeletal unloading is not a consequence of increased plasma glucocorticoids or an increase in bone sensitivity to the glucocorticoids but, rather, point to a local mediator in bone that senses mechanical load and transmits that information to the bone-forming cells directly.

  1. Glucocorticoid Treatment in Childhood Nephrotic Syndrome : weighting the cornerstone

    NARCIS (Netherlands)

    N. Teeninga (Nynke)

    2013-01-01

    textabstractUnderstanding which factors influence relapse patterns in childhood nephrotic syndrome is clinically very relevant and could aid in developing new treatment strategies. Clinicians are continuously challenged to reduce relapse rates and at the same time to avoid glucocorticoid toxicity.

  2. Adrenocorticotropic Hormone Secreting Pheochromocytoma Underlying Glucocorticoid Induced Pheochromocytoma Crisis

    Directory of Open Access Journals (Sweden)

    Gil A. Geva

    2018-01-01

    Full Text Available Context. Pheochromocytomas are hormone secreting tumors of the medulla of the adrenal glands found in 0.1–0.5% of patients with hypertension. The vast majority of pheochromocytomas secrete catecholamines, but they have been occasionally shown to also secrete interleukins, calcitonin, testosterone, and in rare cases adrenocorticotropic hormone. Pheochromocytoma crisis is a life threatening event in which high levels of catecholamines cause a systemic reaction leading to organ failure. Case Description. A 70-year-old man was admitted with acute myocardial ischemia following glucocorticoid administration as part of an endocrine workup for an adrenal mass. Cardiac catheterization disclosed patent coronary arteries and he was discharged. A year later he returned with similar angina-like chest pain. During hospitalization, he suffered additional events of chest pain, shortness of breath, and palpitations following administration of glucocorticoids as preparation for intravenous contrast administration. Throughout his admission, the patient demonstrated both signs of Cushing’s syndrome and high catecholamine levels. Following stabilization of vital parameters and serum electrolytes, the adrenal mass was resected surgically and was found to harbor an adrenocorticotropic hormone secreting pheochromocytoma. This is the first documented case of adrenocorticotropic hormone secreting pheochromocytoma complicated by glucocorticoid induced pheochromocytoma crisis. Conclusion. Care should be taken when administering high doses of glucocorticoids to patients with suspected pheochromocytoma, even in a patient with concomitant Cushing’s syndrome.

  3. The Glucocorticoid Receptor Controls Hepatic Dyslipidemia through Hes1

    NARCIS (Netherlands)

    Lemke, U.; Krones-Herzig, A.; Berriel Diaz, M.; Narvekar, P.; Ziegler, A.; Vegiopoulos, A.; Cato, A.C.B.; Bohl, S.; Klingmüller, U.; Screaton, R.A.; Müller-Decker, K.; Kersten, A.H.; Herzig, S.

    2008-01-01

    Aberrant accumulation of lipids in the liver (¿fatty liver¿ or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of

  4. Glucocorticoid receptor effects on the immune system and infl ammation

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica)

    2008-01-01

    textabstractThomas Addison’s discovery in the mid-1800s that the adrenal cortex was essential for survival preceded by nearly a century the demonstration that this gland produced at least two distinct hormones, each essential for normal life. How glucocorticoids sustained life remained a mystery for

  5. Topics in industrial mathematics

    International Nuclear Information System (INIS)

    Vatsya, S.R.

    1992-01-01

    Mathematical methods are widely used to solve practical problems arising in modern industry. This article outlines some of the topics relevant to AECL programmes. This covers the applications of transmission and neutron transport tomography to determine density distributions in rocks and two phase flow situations. Another example covered is the use of variational methods to solve the problems of aerosol migration and control theory. (author). 7 refs

  6. Evaluating Glucocorticoid Administration on Biomechanical Properties of Rats’ Tibial Diaphysis

    Science.gov (United States)

    Freidouni, Mohammadjavad; Nejati, Hossein; Salimi, Maryam; Bayat, Mohammad; Amini, Abdollah; Noruzian, Mohsen; Asgharie, Mohammad Ali; Rezaian, Milad

    2015-01-01

    Background: Osteoporosis is a disease, which causes bone loss and fractures. Although glucocorticoids effectively suppress inflammation, their chronic use is accompanied by bone loss with a tendency toward secondary osteoporosis. Objectives: This study took into consideration the importance of cortical bone in the entire bone's mechanical competence. Hence, the aim of this study was to assess the effects of different protocols of glucocorticoid administration on the biomechanical properties of tibial bone diaphysis in rats compared to control and low-level laser-treated rats. Materials and Methods: This experimental study was conducted at Shahid Beheshti University of Medical Sciences, Tehran, Iran. We used systematic random sampling to divide 40 adult male rats into 8 groups with 5 rats in each group. Groups were as follows: 1) control, 2) dexamethasone (7 mg/week), 3) dexamethasone (0.7 mg/week), 4) methylprednisolone (7 mg/kg/week), 5) methylprednisolone (5 mg/kg twice weekly), 6) dexamethasone (7 mg/kg three times per week), 7) dexamethasone (0.7 mg/kg thrice per week), and 8) low-level laser-treated rats. The study periods were 4-7 weeks. At the end of the treatment periods, we examined the mechanical properties of tibial bone diaphysis. Data were analyzed by statistical analyses. Results: Glucocorticoid-treated rats showed weight loss and considerable mortality (21%). The biomechanical properties (maximum force) of glucocorticoid-treated rats in groups 4 (62 ± 2.9), 6 (63 ± 5.1), and 7 (60 ± 5.3) were comparable with the control (46 ± 1.5) and low-level laser-treated (57 ± 3.2) rats. Conclusions: In contrast to the findings in humans and certain other species, glucocorticoid administration caused anabolic effect on the cortical bone of tibia diaphysis bone in rats. PMID:26019900

  7. Preadmission Use of Glucocorticoids and 30-Day Mortality After Stroke.

    Science.gov (United States)

    Sundbøll, Jens; Horváth-Puhó, Erzsébet; Schmidt, Morten; Dekkers, Olaf M; Christiansen, Christian F; Pedersen, Lars; Bøtker, Hans Erik; Sørensen, Henrik T

    2016-03-01

    The prognostic impact of glucocorticoids on stroke mortality remains uncertain. We, therefore, examined whether preadmission use of glucocorticoids is associated with short-term mortality after ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). We conducted a nationwide population-based cohort study using medical registries in Denmark. We identified all patients with a first-time inpatient diagnosis of stroke between 2004 and 2012. We categorized glucocorticoid use as current use (last prescription redemption ≤90 days before admission), former use, and nonuse. Current use was further classified as new or long-term use. We used Cox regression to compute 30-day mortality rate ratios with 95% confidence intervals (CIs), controlling for confounders. We identified 100 042 patients with a first-time stroke. Of these, 83 735 patients had ischemic stroke, 11 779 had ICH, and 4528 had SAH. Absolute mortality risk was higher for current users compared with nonusers for ischemic stroke (19.5% versus 10.2%), ICH (46.5% versus 34.4%), and SAH (35.0% versus 23.2%). For ischemic stroke, the adjusted 30-day mortality rate ratio was increased among current users compared with nonusers (1.58, 95% CI: 1.46-1.71), driven by the effect of glucocorticoids among new users (1.80, 95% CI: 1.62-1.99). Current users had a more modest increase in the adjusted 30-day mortality rate ratio for hemorrhagic stroke (1.26, 95% CI: 1.09-1.45 for ICH and 1.40, 95% CI: 1.01-1.93 for SAH) compared with nonusers. Former use was not substantially associated with mortality. Preadmission use of glucocorticoids was associated with increased 30-day mortality among patients with ischemic stroke, ICH, and SAH. © 2016 American Heart Association, Inc.

  8. FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.

    Science.gov (United States)

    Malyukova, A; Brown, S; Papa, R; O'Brien, R; Giles, J; Trahair, T N; Dalla Pozza, L; Sutton, R; Liu, T; Haber, M; Norris, M D; Lock, R B; Sangfelt, O; Marshall, G M

    2013-04-01

    Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.

  9. Topic Visualization and Survival Analysis

    OpenAIRE

    Wang, Ping Jr

    2017-01-01

    Latent semantic structure in a text collection is called a topic. In this thesis, we aim to visualize topics in the scientific literature and detect active or inactive research areas based on their lifetime. Topics were extracted from over 1 million abstracts from the arXiv.org database using Latent Dirichlet Allocation (LDA). Hellinger distance measures similarity between two topics. Topics are determined to be relevant if their pairwise distances are smaller than the threshold of Hellinger ...

  10. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor.

    Science.gov (United States)

    Psarra, Anna-Maria G; Sekeris, Constantine E

    2011-10-01

    Glucocorticoids are major regulators of a plethora of cellular functions, acting on target cells through glucocorticoid receptors (GR) and modulation of gene transcription, among other mechanisms. One main site of action of glucocorticoids is the hepatocyte, which responds to the hormonal stimulus with induction of several proteins among them enzymes of oxidative phosphorylation (OXPHOS), both nuclearly and mitochondrially encoded. The induction of OXPHOS is regarded as a result of a nuclear action of the receptor on the respective nuclear genes and on genes encoding mitochondrial transcription factors. The presence of GR in mitochondria and of sequences in the mitochondrial genome similar to glucocorticoid responsive elements, suggested a direct action of GR on mitochondrial transcription. We demonstrate in HepG2 hepatocarcinoma cells specific binding of GR to the regulatory D-loop region of the mitochondrial genome and show that dexamethasone induces the mitochondrial transcription factors A, B1, and B2, the mitochondrial ribosomal RNA, and several mitochondrially encoded OXPHOS genes. Applying α-amanitin, the specific inhibitor of DNA-dependent RNA polymerase II, the dexamethasone-induced transcription of the mitochondrial genes can still proceeds, whereas the DEX effect on transcription of the mitochondrial transcription factors is suppressed. Moreover, HepG2 cells overexpressing mitochondrial targeted GR showed increased RNA synthesis, cytrochrome oxidase subunit I protein expression, and mitochondrial ATP production. We conclude that glucocorticoids can stimulate directly mitochondrial transcription by the mitochondrially localized GR, affecting OXPHOS enzyme biosynthesis. This takes place in addition to their action on mitochondrial genes by way of induction of the nuclearly encoded mitochondrial transcription factors. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Rapid Nongenomic Glucocorticoid Actions in Male Mouse Hypothalamic Neuroendocrine Cells Are Dependent on the Nuclear Glucocorticoid Receptor

    Science.gov (United States)

    Nahar, Jebun; Haam, Juhee; Chen, Chun; Jiang, Zhiying; Glatzer, Nicholas R.; Muglia, Louis J.; Dohanich, Gary P.; Herman, James P.

    2015-01-01

    Corticosteroids act classically via cognate nuclear receptors to regulate gene transcription; however, increasing evidence supports rapid, nontranscriptional corticosteroid actions via activation of membrane receptors. Using whole-cell patch clamp recordings in hypothalamic slices from male mouse genetic models, we tested for nongenomic glucocorticoid actions at glutamate and gamma aminobutyric acid (GABA) synapses in hypothalamic neuroendocrine cells, and for their dependence on the nuclear glucocorticoid receptor (GR). In enhanced green fluorescent protein-expressing CRH neurons of the paraventricular nucleus (PVN) and in magnocellular neurons of the PVN and supraoptic nucleus (SON), dexamethasone activated postsynaptic membrane-associated receptors and G protein signaling to elicit a rapid suppression of excitatory postsynaptic inputs, which was blocked by genetic deletion of type I cannabinoid receptors and a type I cannabinoid receptor antagonist. In magnocellular neurons, dexamethasone also elicited a rapid nitric oxide-dependent increase in inhibitory postsynaptic inputs. These data indicate a rapid, synapse-specific glucocorticoid-induced retrograde endocannabinoid signaling at glutamate synapses and nitric oxide signaling at GABA synapses. Unexpectedly, the rapid glucocorticoid effects on both excitatory and inhibitory synaptic transmission were lost with conditional deletion of GR in the PVN and SON in slices from a single minded-1-cre-directed conditional GR knockout mouse. Thus, the nongenomic glucocorticoid actions at glutamate and GABA synapses on PVN and SON neuroendocrine cells are dependent on the nuclear GR. The nuclear GR, therefore, is responsible for transducing the rapid steroid response at the membrane, or is either a critical component in the signaling cascade or regulates a critical component of the signaling cascade of a distinct membrane GR. PMID:26061727

  12. Topics in Nonlinear Dynamics

    DEFF Research Database (Denmark)

    Mosekilde, Erik

    Through a significant number of detailed and realistic examples this book illustrates how the insights gained over the past couple of decades in the fields of nonlinear dynamics and chaos theory can be applied in practice. Aomng the topics considered are microbiological reaction systems, ecological...... food-web systems, nephron pressure and flow regulation, pulsatile secretion of hormones, thermostatically controlled radiator systems, post-stall maneuvering of aircrafts, transfer electron devices for microwave generation, economic long waves, human decision making behavior, and pattern formation...... in chemical reaction-diffusion systems....

  13. Topics in CP violation

    Energy Technology Data Exchange (ETDEWEB)

    Quinn, H.R.

    1993-02-01

    Given the varied backgrounds of the members of this audience this talk will be a grab bag of topics related to the general theme of CP Violation. I do not have time to dwell in detail on any of them. First, for the astronomers and astrophysicists among you, I want to begin by reviewing the experimental status of evidence for CP violation in particle processes. There is only one system where this has been observed, and that is in the decays of neutral K mesons.

  14. Topics in Operator Theory

    CERN Document Server

    Ball, Joseph A; Helton, JWilliam; Rodman, Leiba; Spitkovsky, Iiya

    2010-01-01

    This is the first volume of a collection of original and review articles on recent advances and new directions in a multifaceted and interconnected area of mathematics and its applications. It encompasses many topics in theoretical developments in operator theory and its diverse applications in applied mathematics, physics, engineering, and other disciplines. The purpose is to bring in one volume many important original results of cutting edge research as well as authoritative review of recent achievements, challenges, and future directions in the area of operator theory and its applications.

  15. REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes.

    Science.gov (United States)

    Wolff, Nicholas C; McKay, Renée M; Brugarolas, James

    2014-06-01

    Glucocorticoids induce apoptosis in lymphocytes and are commonly used to treat hematologic malignancies. However, they are also associated with significant adverse effects and their molecular mechanism of action is not fully understood. Glucocorticoid treatment induces expression of the mTORC1 inhibitor Regulated in Development and DNA Damage Response 1 (REDD1), also known as DNA-Damage Inducible Transcript 4 (DDIT4), and mTORC1 inhibition may distinguish glucocorticoid-sensitive from glucocorticoid-resistant acute lymphoblastic leukemia (ALL). Interestingly, REDD1 induction was impaired in glucocorticoid-resistant ALL cells and inhibition of mTORC1 using rapamycin restored glucocorticoid sensitivity. These data suggest that REDD1 may be essential for the response of ALL cells to glucocorticoids. To further investigate the role of REDD1, we evaluated the effects of glucocorticoids on primary thymocytes from wild-type and REDD1-deficient mice. Glucocorticoid-mediated apoptosis was blocked by a glucocorticoid receptor antagonist and by an inhibitor of transcription, which interfered with REDD1 induction and mTORC1 inhibition. However, REDD1 ablation had no effect on glucocorticoid-induced mTORC1 inhibition and apoptosis in thymocytes ex vivo. Overall, these data not only demonstrate the contextual differences of downstream signaling following glucocorticoid treatment but also provide a better mechanistic understanding of the role of REDD1. These molecular findings underlying glucocorticoid action and the role of REDD1 are fundamental for the design of novel, more efficacious, and less toxic analogs. Mol Cancer Res; 12(6); 867-77. ©2014 AACR. ©2014 American Association for Cancer Research.

  16. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

    Science.gov (United States)

    Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

    1991-10-01

    Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

  17. Topics on continua

    CERN Document Server

    Macias, Sergio

    2005-01-01

    Specialized as it might be, continuum theory is one of the most intriguing areas in mathematics. However, despite being popular journal fare, few books have thoroughly explored this interesting aspect of topology. In Topics on Continua, Sergio Macías, one of the field's leading scholars, presents four of his favorite continuum topics: inverse limits, Jones's set function T, homogenous continua, and n-fold hyperspaces, and in doing so, presents the most complete set of theorems and proofs ever contained in a single topology volume. Many of the results presented have previously appeared only in research papers, and some appear here for the first time. After building the requisite background and exploring the inverse limits of continua, the discussions focus on Professor Jones''s set function T and continua for which T is continuous. An introduction to topological groups and group actions lead to a proof of Effros''s Theorem, followed by a presentation of two decomposition theorems. The author then offers an...

  18. Topic and Topic-Comment Constructions in Mandarin Chinese.

    Science.gov (United States)

    Shi, Dingxu

    2000-01-01

    Attempts to provide a precise definition for topic and to derive most of the properties of topic from this definition. The main assumption is that the topic-comment construction is a syntactic device employed to fulfill certain discourse functions. (Author/VWL)

  19. The glucocorticoid/aggression relationship in animals and humans: an analysis sensitive to behavioral characteristics, glucocorticoid secretion patterns, and neural mechanisms.

    Science.gov (United States)

    Haller, József

    2014-01-01

    Glucocorticoids control a wide array of biological processes from glucose homeostasis to neuronal function. The mechanisms mediating their effects are similarly varied and include rapid and transient nongenomic effects on calcium trafficking, various neurotransmitter receptors, and other membrane/cytoplasmic proteins, as well as slowly developing but durable genomic effects that are mediated by a large number of glucocorticoid-sensitive genes that are affected after variable lag-times. Given this complexity, we suggest that the aggression/glucocorticoid relationship cannot be reduced to the simple "stimulation/inhibition" question. Here, we review the effects of glucocorticoids on aggression by taking into account the complexities of glucocorticoid actions. Acute and chronic effects were differentiated because these are mediated by different mechanisms. The effects of chronic increases and decreases in glucocorticoid production were discussed separately, because the activation of mechanisms that are not normally activated and the loss of normal functions should not be confounded. Findings in healthy/normal subjects and those obtained in subjects that show abnormal forms of behavior or psychopathologies were also differentiated, because the effects of glucocorticoids are indirect, and largely depend on the properties of neurons they act upon, which are altered in subjects with psychopathologies. In addition, the conditions of glucocorticoid measurements were also thoroughly evaluated. Although the role of glucocorticoids in aggression is perceived as controversial by many investigators, a detailed analysis that is sensitive to glucocorticoid and behavioral measure as well as to the mediating mechanism suggests that this role is rather clear-cut; moreover, there is a marked similarity between animal and human findings.

  20. [The Influence of Glucocorticoids on the Healing Processes in the Gastric Mucosa].

    Science.gov (United States)

    Podvigina, T T; Filaretova, L P

    2016-01-01

    In this review, we analyzed the data of literature about the glucocorticoid influences on the gastric erosion and ulcer healing. The data show that multiple injections of glucocorticoids at pharmacological doses delay gastric erosion and ulcer healing. However, according to experimental results endogenic glucocorticoids, on the contrary, play significant role in maintenance of gastric mucosal integrity. Thus, glucocorticoids may have dual effect on healing of gastric injury: contribute to healing process or delay them. The initial glucocorticoid action is physiological and consists in a participation in healing processes what is considered as component gastroprotective action of these hormones. During a long-lasting action of glucocorticoids, the physiological effect can be transformed into pathological one, delaying erosion and ulcer healing, and this contributes to the ulcerogenic action of glucocorticods.

  1. Adrenal Insufficiency Caused by Locally Applied Glucocorticoids-Myth or Fact?

    DEFF Research Database (Denmark)

    Dinsen, Stina; Klose, Marianne; Rasmussen, Åse Krogh

    2015-01-01

    can cause adrenal suppression after a single injection. The systemic effect of locally applied glucocorticoids depends on pharmacokinetic and -dynamic properties of the particular glucocorticoid as well as individual factors. Many of the symptoms in iatrogen adrenal insufficiency are unspecific......Case-reports have made it evident that both inhaled, percutaneous, intranasal, intraarticular and ophthalmic administered glucocorticoids have the potential to cause life threatening adrenal insufficiency. With few and sometimes conflicting data and study methodology the prevalence of adrenal...... insufficiency secondary to locally applied glucocorticoids is not clear. Adrenal insufficiency can only be correctly evaluated by a stimulation test, and has by this procedure been reported in up to 40-50% of patients treated with high-dose inhaled glucocorticoids. Medium- to low-dose inhaled glucocorticoids...

  2. Primary generalized familial and sporadic glucocorticoid resistance (Chrousos syndrome) and hypersensitivity.

    Science.gov (United States)

    Charmandari, Evangelia; Kino, Tomoshige; Chrousos, George P

    2013-01-01

    Familial or sporadic primary generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Primary generalized glucocorticoid hypersensitivity (PGGH) represents the mirror image of the former, and is characterized by generalized, partial, target-tissue hypersensitivity to glucocorticoids, and compensatory hypoactivation of the HPA axis. The molecular basis of both conditions has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair the molecular mechanisms of hGR action and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms and clinical aspects of Chrousos syndrome and PGGH. Copyright © 2013 S. Karger AG, Basel.

  3. The transcriptomics of glucocorticoid receptor signaling in developing zebrafish.

    Directory of Open Access Journals (Sweden)

    Dinushan Nesan

    Full Text Available Cortisol is the primary corticosteroid in teleosts that is released in response to stressor activation of the hypothalamus-pituitary-interrenal axis. The target tissue action of this hormone is primarily mediated by the intracellular glucocorticoid receptor (GR, a ligand-bound transcription factor. In developing zebrafish (Danio rerio embryos, GR transcripts and cortisol are maternally deposited into the oocyte prior to fertilization and influence early embryogenesis. To better understand of the molecular mechanisms involved, we investigated changes in the developmental transcriptome prior to hatch, in response to morpholino oligonucleotide knockdown of GR using the Agilent zebrafish microarray platform. A total of 1313 and 836 mRNA transcripts were significantly changed at 24 and 36 hours post fertilization (hpf, respectively. Functional analysis revealed numerous developmental processes under GR regulation, including neurogenesis, eye development, skeletal and cardiac muscle formation. Together, this study underscores a critical role for glucocorticoid signaling in programming molecular events essential for zebrafish development.

  4. Effects of Glucocorticoids on Apoptosis and Clearance of Apoptotic Cells

    Directory of Open Access Journals (Sweden)

    Aisleen McColl

    2007-01-01

    Full Text Available The glucocorticoid (GC drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed.

  5. Glucocorticoid receptor action in metabolic and neuronal function.

    Science.gov (United States)

    Garabedian, Michael J; Harris, Charles A; Jeanneteau, Freddy

    2017-01-01

    Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture-based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this "brain-fat axis" will enable a more complete understanding of metabolic diseases and inform new ways to target them.

  6. Topical Acne Treatments and Pregnancy

    Science.gov (United States)

    Topical Acne Treatments and Pregnancy In every pregnancy, a woman starts out with a 3-5% chance of having ... This sheet talks about whether exposure to topical acne treatments may increase the risk for birth defects ...

  7. Topics in orbit equivalence

    CERN Document Server

    Kechris, Alexander S

    2004-01-01

    This volume provides a self-contained introduction to some topics in orbit equivalence theory, a branch of ergodic theory. The first two chapters focus on hyperfiniteness and amenability. Included here are proofs of Dye's theorem that probability measure-preserving, ergodic actions of the integers are orbit equivalent and of the theorem of Connes-Feldman-Weiss identifying amenability and hyperfiniteness for non-singular equivalence relations. The presentation here is often influenced by descriptive set theory, and Borel and generic analogs of various results are discussed. The final chapter is a detailed account of Gaboriau's recent results on the theory of costs for equivalence relations and groups and its applications to proving rigidity theorems for actions of free groups.

  8. Topics in atomic physics

    CERN Document Server

    Burkhardt, Charles E

    2006-01-01

    The study of atomic physics propelled us into the quantum age in the early twentieth century and carried us into the twenty-first century with a wealth of new and, in some cases, unexplained phenomena. Topics in Atomic Physics provides a foundation for students to begin research in modern atomic physics. It can also serve as a reference because it contains material that is not easily located in other sources. A distinguishing feature is the thorough exposition of the quantum mechanical hydrogen atom using both the traditional formulation and an alternative treatment not usually found in textbooks. The alternative treatment exploits the preeminent nature of the pure Coulomb potential and places the Lenz vector operator on an equal footing with other operators corresponding to classically conserved quantities. A number of difficult to find proofs and derivations are included as is development of operator formalism that permits facile solution of the Stark effect in hydrogen. Discussion of the classical hydrogen...

  9. Topics in mathematical biology

    CERN Document Server

    Hadeler, Karl Peter

    2017-01-01

    This book analyzes the impact of quiescent phases on biological models. Quiescence arises, for example, when moving individuals stop moving, hunting predators take a rest, infected individuals are isolated, or cells enter the quiescent compartment of the cell cycle. In the first chapter of Topics in Mathematical Biology general principles about coupled and quiescent systems are derived, including results on shrinking periodic orbits and stabilization of oscillations via quiescence. In subsequent chapters classical biological models are presented in detail and challenged by the introduction of quiescence. These models include delay equations, demographic models, age structured models, Lotka-Volterra systems, replicator systems, genetic models, game theory, Nash equilibria, evolutionary stable strategies, ecological models, epidemiological models, random walks and reaction-diffusion models. In each case we find new and interesting results such as stability of fixed points and/or periodic orbits, excitability...

  10. Is There a Renaissance of Glucocorticoids in Rheumatoid Arthritis?

    Science.gov (United States)

    Kirwan, J R; Gunasekera, Wma

    2017-10-01

    The first therapeutic use of glucocorticoids was in a patient with severe rheumatoid arthritis and the symptomatic benefit was astounding. Adverse effects from increasingly large doses led to them being overshadowed, dismissed as inappropriate treatment, and ignored for 20 years - but in the last 2 decades, the accumulating evidence and clinical practice suggest there is a justified renaissance in their use as a first-line treatment. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  11. Synthetic Glucocorticoids and Early Variations of Blood Pressure: A Population-Based Cohort Study.

    Science.gov (United States)

    Fardet, Laurence; Nazareth, Irwin; Petersen, Irene

    2015-07-01

    Endogenous glucocorticoids are known to increase blood pressure, but very little is known about the early effects of synthetic glucocorticoids (eg, prednisone, dexamethasone) on blood pressure. To assess longitudinal variations of blood pressure before and after initiation of systemic glucocorticoid therapy. Adult patients prescribed synthetic glucocorticoid therapy for at least 3 months and registered between 2004 and 2012 in The Health Improvement Network (THIN) primary care database. Systolic and diastolic blood pressure as measured in primary care. Among the 16,351 patients prescribed antihypertensive drug within the year before glucocorticoid initiation (women, 57.1%; age [mean ± SD], 72.0 ± 11.4 y), the mean (SD) blood pressure within the year before glucocorticoid initiation was 140 (18)/78 (9) mm Hg. It was 139 (19)/77 (11), 139 (19)/77 (10), and 139 (19)/77 (11) mm Hg during the first, second, and third months of exposure, respectively. We did not find any evidence of the effects of glucocorticoids on blood pressure in these patients. Among the 6914 patients not prescribed antihypertensive drug within the year before glucocorticoid initiation (women, 64.9%; age, 60.0 ± 17.8 y), the figures were 133 (17)/78 (10), 135 (20)/79 (11), 133 (19)/78 (11), and 133 (19)/78 (11) mm Hg before exposure and during the first, second, and third months of exposure, respectively. In this group of patients, glucocorticoid exposure was associated with a slight (glucocorticoid initiation. Prednisone/prednisolone use was associated with a higher risk of extreme increase in systolic blood pressure than the other synthetic glucocorticoids (odds ratio, 4.9 [95% confidence interval, 1.9-12.6]; P = .001). Contrary to what is usually thought, the increase of blood pressure during the first months of exposure to synthetic glucocorticoids seems clinically nonsignificant.

  12. Glucocorticoids and Preterm Hypoxic-Ischemic Brain Injury: The Good and the Bad

    Directory of Open Access Journals (Sweden)

    Laura Bennet

    2012-01-01

    Full Text Available Fetuses at risk of premature delivery are now routinely exposed to maternal treatment with synthetic glucocorticoids. In randomized clinical trials, these substantially reduce acute neonatal systemic morbidity, and mortality, after premature birth and reduce intraventricular hemorrhage. However, the overall neurodevelopmental impact is surprisingly unclear; worryingly, postnatal glucocorticoids are consistently associated with impaired brain development. We review the clinical and experimental evidence on how glucocorticoids may affect the developing brain and highlight the need for systematic research.

  13. Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing’s syndrome: cohort study

    OpenAIRE

    Fardet, Laurence; Petersen, Irene; Nazareth, Irwin

    2012-01-01

    Objective To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing’s syndrome during treatment with glucocorticoids. Design Cohort study. Setting 424 UK general practices contributing to The Health Improvement Network database. Participants People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome (n=547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatroge...

  14. Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

    OpenAIRE

    Prigent, Hélène; Maxime, Virginie; Annane, Djillali

    2004-01-01

    This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoi...

  15. Antenatal glucocorticoids and neonatal inflammation-associated proteins.

    Science.gov (United States)

    Faden, Maheer; Holm, Mari; Allred, Elizabeth; Fichorova, Raina; Dammann, Olaf; Leviton, Alan

    2016-12-01

    To date, studies of the relationship between antenatal glucocorticoids (AGC) and neonatal inflammation in preterm newborns have been largely limited to umbilical cord blood specimens. To explore the association between exposure to antenatal glucocorticoids and concentrations of inflammation-related proteins in whole blood collected from very preterm newborns at multiple times during the first postnatal month. We measured the protein concentrations on postnatal day 1 (N=1118), day 7 (N=1138), day 14 (N=1030), day 21 (N=936) and day 28 (N=877) from infants born before the 28th week of gestation and explored the relationship between antenatal steroid receipt and protein concentrations in the highest and lowest quartiles. The creation of multinomial logistic regression models (adjusted for potential confounders) allowed us calculate odds ratios and 95% confidence intervals. Twenty of 420 assessments [21 (proteins)×2 (exposure levels: partial and full)×2 (quartile levels: top and bottom)×5 (days)] were statistically significant without any cohesive pattern. Among infants born before 28 weeks of gestational age, neither full, nor partial courses of antenatal glucocorticoids have a sustained anti-inflammatory effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.

    Science.gov (United States)

    Gibbs, Julie; Ince, Louise; Matthews, Laura; Mei, Junjie; Bell, Thomas; Yang, Nan; Saer, Ben; Begley, Nicola; Poolman, Toryn; Pariollaud, Marie; Farrow, Stuart; DeMayo, Francesco; Hussell, Tracy; Worthen, G Scott; Ray, David; Loudon, Andrew

    2014-08-01

    The circadian system is an important regulator of immune function. Human inflammatory lung diseases frequently show time-of-day variation in symptom severity and lung function, but the mechanisms and cell types underlying these effects remain unclear. We show that pulmonary antibacterial responses are modulated by a circadian clock within epithelial club (Clara) cells. These drive circadian neutrophil recruitment to the lung via the chemokine CXCL5. Genetic ablation of the clock gene Bmal1 (also called Arntl or MOP3) in bronchiolar cells disrupts rhythmic Cxcl5 expression, resulting in exaggerated inflammatory responses to lipopolysaccharide and an impaired host response to Streptococcus pneumoniae infection. Adrenalectomy blocks rhythmic inflammatory responses and the circadian regulation of CXCL5, suggesting a key role for the adrenal axis in driving CXCL5 expression and pulmonary neutrophil recruitment. Glucocorticoid receptor occupancy at the Cxcl5 locus shows circadian oscillations, but this is disrupted in mice with bronchiole-specific ablation of Bmal1, leading to enhanced CXCL5 expression despite normal corticosteroid secretion. The therapeutic effects of the synthetic glucocorticoid dexamethasone depend on intact clock function in the airway. We now define a regulatory mechanism that links the circadian clock and glucocorticoid hormones to control both time-of-day variation and the magnitude of pulmonary inflammation and responses to bacterial infection.

  17. Effects of glucocorticoids on glioma cells in culture. Minireview on cancer research.

    Science.gov (United States)

    Freshney, R I

    1984-01-01

    In vitro studies have shown that glucocorticoids have a cytostatic effect on glioma cells at high cell densities but enhance cell survival and proliferation at low cell densities. The cytostatic effect is not cytotoxic and may be mediated via a membrane modification altering cell-cell interaction. Cell interaction is also implicated in differentiation in glial cells and the inducing effect of glucocorticoids may be mediated in part by their effect on cell interaction. Induction of differentiation by glucocorticoids is accompanied by a reduction in malignancy-associated properties and the possibility has emerged that glucocorticoids may be an essential component in attempts to modify the malignant behaviour of glioma cells.

  18. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M

    Science.gov (United States)

    Miyata, Masanori; Lee, Ji-Yun; Susuki-Miyata, Seiko; Wang, Wenzhuo Y.; Xu, Haidong; Kai, Hirofumi; Kobayashi, Koichi S.; Flavell, Richard A.; Li, Jian-Dong

    2015-01-01

    Glucocorticoids are among the most commonly used anti-inflammatory agents. Despite the enormous efforts in elucidating the glucocorticoid-mediated anti-inflammatory actions, how glucocorticoids tightly control overactive inflammatory response is not fully understood. Here we show that glucocorticoids suppress bacteria-induced inflammation by enhancing IRAK-M, a central negative regulator of Toll-like receptor signalling. The ability of glucocorticoids to suppress pulmonary inflammation induced by non-typeable Haemophilus influenzae is significantly attenuated in IRAK-M-deficient mice. Glucocorticoids improve the survival rate after a lethal non-typeable Haemophilus influenzae infection in wild-type mice, but not in IRAK-M-deficient mice. Moreover, we show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter. Together, our studies unveil a mechanism by which glucocorticoids tightly control the inflammatory response and host defense via the induction of IRAK-M and may lead to further development of anti-inflammatory therapeutic strategies. PMID:25585690

  19. The permissive role of glucocorticoids in neuroinflammatory priming: mechanisms and insights.

    Science.gov (United States)

    Frank, Matthew G; Watkins, Linda R; Maier, Steven F

    2015-08-01

    Glucocorticoids have been universally regarded as anti-inflammatory; however, a considerable number of studies now demonstrate that under some conditions, glucocorticoids are capable of potentiating neuroinflammatory processes (i.e. priming), a permissive function of glucocorticoids. The present review addresses recent evidence that provides insight into the mechanism(s) of glucocorticoid-induced neuroinflammatory priming. Glucocorticoids have been found to prime inflammasomes [i.e. nucleotide-binding domain, leucine-rich repeat, pyrin domain containing proteins-3 (NLRP3)], which are intracellular multiprotein complexes that mediate proinflammatory processes. Inflammasomes are activated by products of stressed or damaged cells. Interestingly, these products (damage-associated molecular patterns) are induced by stress and mediate stress-induced neuroinflammatory priming. In light of these findings, we propose a model of glucocorticoid-induced neuroinflammatory priming whereby stress and glucocorticoids induce cellular damage/stress in the brain, the products of which prime the NLRP3 inflammasome. Thus, glucocorticoid-induced priming of the NLRP3 inflammasome may mediate the potentiated neuroinflammatory response to a subsequent proinflammatory immune challenge. We propose that during a flight-or-flight response, available energy stores should be diverted to defensive behaviours, and it might be after the emergency is over that resources should be shifted to recuperation and host defense against infection. This is the scenario that would be promoted by elevated glucocorticoids reducing ongoing inflammation while simultaneously priming the NLRP3 inflammasome.

  20. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M.

    Science.gov (United States)

    Miyata, Masanori; Lee, Ji-Yun; Susuki-Miyata, Seiko; Wang, Wenzhuo Y; Xu, Haidong; Kai, Hirofumi; Kobayashi, Koichi S; Flavell, Richard A; Li, Jian-Dong

    2015-01-14

    Glucocorticoids are among the most commonly used anti-inflammatory agents. Despite the enormous efforts in elucidating the glucocorticoid-mediated anti-inflammatory actions, how glucocorticoids tightly control overactive inflammatory response is not fully understood. Here we show that glucocorticoids suppress bacteria-induced inflammation by enhancing IRAK-M, a central negative regulator of Toll-like receptor signalling. The ability of glucocorticoids to suppress pulmonary inflammation induced by non-typeable Haemophilus influenzae is significantly attenuated in IRAK-M-deficient mice. Glucocorticoids improve the survival rate after a lethal non-typeable Haemophilus influenzae infection in wild-type mice, but not in IRAK-M-deficient mice. Moreover, we show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter. Together, our studies unveil a mechanism by which glucocorticoids tightly control the inflammatory response and host defense via the induction of IRAK-M and may lead to further development of anti-inflammatory therapeutic strategies.

  1. Antenatal endogenous and exogenous glucocorticoids and their impact on immune ontogeny and long-term immunity.

    Science.gov (United States)

    Solano, María Emilia; Holmes, Megan C; Mittelstadt, Paul R; Chapman, Karen E; Tolosa, Eva

    2016-11-01

    Endogenous levels of glucocorticoids rise during pregnancy to warrant development and maturation of the fetal organs close to birth. However, during most of the gestation, the fetus is protected from excessive biologically active endogenous glucocorticoids by placental and fetal expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Maternal stress, which may overwhelm placental 11β-HSD2 activity with high glucocorticoid levels, or administration of synthetic glucocorticoids to improve the survival chances of the premature newborn, are associated to postnatal increased risk for immune diseases. Fetal exposure to excessive glucocorticoids may underlie this altered postnatal immunity. Here, we revise the role that placental and fetal 11β-HSD2, fetal glucocorticoid exposure, and programming of the offspring's the hypothalamic-pituitary-adrenal (HPA) axis play on concerted steps in immune fetal development. We could identify gaps in knowledge about glucocorticoid-induced programming of immune diseases. Finally, based on current evidence about glucocorticoid and HPA axis-mediated immune regulation, we hypothesize on mechanisms that could drive the enhanced risk for atopies, infections, and type I diabetes in offspring that were prenatally exposed to glucocorticoids.

  2. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids.

    Science.gov (United States)

    Cruz-Topete, Diana; Cidlowski, John A

    2015-01-01

    Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940s, glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies. © 2014 S. Karger AG, Basel.

  3. Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain.

    Science.gov (United States)

    Moisan, M P; Minni, A M; Dominguez, G; Helbling, J C; Foury, A; Henkous, N; Dorey, R; Béracochéa, D

    2014-03-01

    Corticosteroid binding globulin (CBG) is a glycoprotein synthesized in liver and secreted in the blood where it binds with a high affinity but low capacity glucocorticoid hormones, cortisol in humans and corticosterone in laboratory rodents. In mammals, 95% of circulating glucocorticoids are bound to either CBG (80%) or albumin (15%) and only the 5% free fraction is able to enter the brain. During stress, the concentration of glucocorticoids rises significantly and the free fraction increases even more because CBG becomes saturated. However, glucocorticoids unbound to CBG are cleared from the blood more quickly. Our studies on mice totally devoid of CBG (Cbg k.o.) showed that during stress these mutant mice display a lower rise of glucocorticoids than the wild-type controls associated with altered emotional reactivity. These data suggested that CBG played a role in the fast actions of glucocorticoids on behavior. Further analyses demonstrated that stress-induced memory retrieval impairment, an example of the fast action of glucocorticoids on the brain is abolished in the Cbg k.o. mice. This effect of stress on memory retrieval could be restored in the Cbg k.o. mice by infusing corticosterone directly in the hippocampus. The mechanisms explaining these effects involved an increased clearance but no difference in corticosterone production. Thus, CBG seems to have an important role in maintaining in blood a glucocorticoid pool that will be able to access the brain for the fast effects of glucocorticoids. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. HES1 Is a Master Regulator of Glucocorticoid Receptor-Dependent Gene Expression

    Science.gov (United States)

    Revollo, Javier R.; Oakley, Robert H.; Lu, Nick Z.; Kadmiel, Mahita; Gandhavadi, Maheer; Cidlowski, John A.

    2014-01-01

    Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of glucocorticoids are mediated by glucocorticoid receptor-dependent regulation of nearly 25% of the genome. We now establish a genome wide molecular link between HES1 and glucocorticoid receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This glucocorticoid-dependent repression of HES1 was necessary for the glucocorticoid receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded glucocorticoid receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper glucocorticoid signaling. PMID:24300895

  5. One Hormone Two Actions: Anti- and Pro-inflammatory Effects of Glucocorticoids

    Science.gov (United States)

    Cruz-Topete, Diana; Cidlowski, John A.

    2014-01-01

    Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940’s, glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies. PMID:25227506

  6. The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases

    Science.gov (United States)

    Petta, Ioanna; Dejager, Lien; Ballegeer, Marlies; Lievens, Sam; Tavernier, Jan; Libert, Claude

    2016-01-01

    SUMMARY Glucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases. PMID:27169854

  7. The effect of ethanol on the formation and physico-chemical properties of particles generated from budesonide solution-based pressurized metered-dose inhalers.

    Science.gov (United States)

    Zhu, Bing; Traini, Daniela; Chan, Hak-Kim; Young, Paul M

    2013-11-01

    The aerosol performance of budesonide solution-based pressurized metered-dose inhalers (HFA 134a), with various amounts of ethanol (5-30%, w/w) as co-solvents, was evaluated using impaction and laser diffraction techniques. With the increase of ethanol concentration in a formulation, the mass median aerodynamic diameter was increased and the fine particle fraction showed a significant decline. Although data obtained from laser diffraction oversized that of the impaction measurements, good correlations were established between the two sets of data. Particles emitted from all the five formulations in this study were amorphous, with two different types of morphology - the majority had a smooth surface with a solid core and the others were internally porous with coral-like surface morphology. The addition of ethanol in the formulation decreased the percentage of such irregular-shape particles from 52% to 2.5% approximately, when the ethanol concentration was increased from 5% to 30%, respectively. A hypothesis regarding the possible particle formation mechanisms was also established. Due to the difference of droplet composition from the designed formulation during the atomization process, the two types of particle may have gone through distinct drying processes: both droplets will have a very short period of co-evaporation, droplets with less ethanol may be dried during such period; while the droplets containing more ethanol will undergo an extra condensation stage before the final particle formation.

  8. Superconcentration and related topics

    CERN Document Server

    Chatterjee, Sourav

    2014-01-01

    A certain curious feature of random objects, introduced by the author as “super concentration,” and two related topics, “chaos” and “multiple valleys,” are highlighted in this book. Although super concentration has established itself as a recognized feature in a number of areas of probability theory in the last twenty years (under a variety of names), the author was the first to discover and explore its connections with chaos and multiple valleys. He achieves a substantial degree of simplification and clarity in the presentation of these findings by using the spectral approach. Understanding the fluctuations of random objects is one of the major goals of probability theory and a whole subfield of probability and analysis, called concentration of measure, is devoted to understanding these fluctuations. This subfield offers a range of tools for computing upper bounds on the orders of fluctuations of very complicated random variables. Usually, concentration of measure is useful when more direct prob...

  9. Topics in statistical mechanics

    International Nuclear Information System (INIS)

    Elser, V.

    1984-05-01

    This thesis deals with four independent topics in statistical mechanics: (1) the dimer problem is solved exactly for a hexagonal lattice with general boundary using a known generating function from the theory of partitions. It is shown that the leading term in the entropy depends on the shape of the boundary; (2) continuum models of percolation and self-avoiding walks are introduced with the property that their series expansions are sums over linear graphs with intrinsic combinatorial weights and explicit dimension dependence; (3) a constrained SOS model is used to describe the edge of a simple cubic crystal. Low and high temperature results are derived as well as the detailed behavior near the crystal facet; (4) the microscopic model of the lambda-transition involving atomic permutation cycles is reexamined. In particular, a new derivation of the two-component field theory model of the critical behavior is presented. Results for a lattice model originally proposed by Kikuchi are extended with a high temperature series expansion and Monte Carlo simulation. 30 references

  10. Advanced verification topics

    CERN Document Server

    Bhattacharya, Bishnupriya; Hall, Gary; Heaton, Nick; Kashai, Yaron; Khan Neyaz; Kirshenbaum, Zeev; Shneydor, Efrat

    2011-01-01

    The Accellera Universal Verification Methodology (UVM) standard is architected to scale, but verification is growing and in more than just the digital design dimension. It is growing in the SoC dimension to include low-power and mixed-signal and the system integration dimension to include multi-language support and acceleration. These items and others all contribute to the quality of the SOC so the Metric-Driven Verification (MDV) methodology is needed to unify it all into a coherent verification plan. This book is for verification engineers and managers familiar with the UVM and the benefits it brings to digital verification but who also need to tackle specialized tasks. It is also written for the SoC project manager that is tasked with building an efficient worldwide team. While the task continues to become more complex, Advanced Verification Topics describes methodologies outside of the Accellera UVM standard, but that build on it, to provide a way for SoC teams to stay productive and profitable.

  11. Topics in inflationary cosmology

    International Nuclear Information System (INIS)

    Kahn, R.N.

    1985-01-01

    This thesis examines several topics in the theory of inflationary cosmology. It first proves the existence of Hawking Radiation during the slow-rolling period of a new inflationary universe. It then derives and somewhat extends Bardeen's gauge invariant formalism for calculating the growth of linear gravitational perturbations in a Friedmann-Robertson-Walker cosmological background. This formalism is then applied, first to several new inflationary universe models all of which show a Zel'dovich spectrum of fluctuations, but with amplitude sigma(100 4 ) above observational limits. The general formalism is next applied to models that exhibit primordial inflation. Fluctuations in these models also exhibit a Zel'dovich spectrum here with an acceptable amplitude. Finally the thesis presents the results of new, numerical calculations. A classical, (2 + 1) dimensional computer model is developed that includes a Higgs field (which drives inflation) along with enough auxiliary fields to generate dynamically not only a thermal bath, but also the fluctuations that naturally accompany that bath. The thesis ends with a discussion of future prospects

  12. Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient.

    Science.gov (United States)

    Main, K M; Skov, M; Sillesen, I B; Dige-Petersen, H; Müller, J; Koch, C; Lanng, S

    2002-01-01

    Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more widespread in chronic lung diseases. A considerable number of patients is concomitantly treated with topical or systemic glucocorticoids for anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such as CYP3A isoforms, they may compromise the metabolic clearance of glucocorticoids, thereby causing serious adverse effects. A patient with cystic fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term treatment with daily doses of 800 mg itraconazole and 1,600 microg budesonide. The patient experienced symptoms of striae, moon-face, increased facial hair growth, mood swings, headaches, weight gain, irregular menstruation despite oral contraceptives and increasing insulin requirement for diabetes mellitus. Endocrine investigations revealed total suppression of spontaneous and stimulated plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an improvement in clinical symptoms and recovery of the pituitary-adrenal axis after 3 mo. This observation suggests that the metabolic clearance of buDesonide was compromised by itraconazole's inhibition of cytochrome P450 enzymes, especially the CYP3A isoforms, causing an elevation in systemic budesonide concentration. This provoked a complete suppression of the endogenous adrenal function, as well as iatrogenic Cushing's syndrome. Patients on combination therapy of itraconazole and budesonide inhalation should be monitored regularly for adrenal insufficiency. This may be the first indicator of increased systemic exogenous steroid concentration, before clinical signs of Cushing's syndrome emerge.

  13. Glucocorticoids exert context-dependent effects on cells of the joint in vitro.

    Science.gov (United States)

    Madsen, Suzi H; Andreassen, Kim V; Christensen, Søren T; Karsdal, Morten A; Sverdrup, Francis M; Bay-Jensen, Anne-Christine; Henriksen, Kim

    2011-12-11

    Glucocorticoids are known to attenuate bone formation in vivo leading to decreased bone volume and increased risk of fractures, whereas effects on the joint tissue are less characterized. However, glucocorticoids appear to have a reducing effect on inflammation and pain in osteoarthritis. This study aimed at characterizing the effect of glucocorticoids on chondrocytes, osteoclasts, and osteoblasts. We used four model systems to investigate how glucocorticoids affect the cells of the joint; two intact tissues (femoral head- and cartilage-explants), and two separate cell cultures of osteoblasts (2T3-pre-osteoblasts) and osteoclasts (CD14(+)-monocytes). The model systems were cultured in the presence of two glucocorticoids; prednisolone or dexamethasone. To induce anabolic and catabolic conditions, cultures were activated by insulin-like growth factor I/bone morphogenetic protein 2 and oncostatin M/tumor necrosis factor-α, respectively. Histology and markers of bone- and cartilage-turnover were used to evaluate effects of glucocorticoid treatment. Prednisolone treatment decreased collagen type-II degradation in immature cartilage, whereas glucocorticoids did not affect collagen type-II in mature cartilage. Glucocorticoids had an anti-catabolic effect on catabolic-activated cartilage from a bovine stifle joint and murine femoral heads. Glucocorticoids decreased viability of all bone cells, leading to a reduction in osteoclastogenesis and bone resorption; however, bone morphogenetic protein 2-stimulated osteoblasts increased bone formation, as opposed to non-stimulated osteoblasts. Using highly robust in vitro models of bone and cartilage turnover, we suggest that effects of glucocorticoids highly depend on the activation and differential stage of the cell targeted in the joint. Present data indicated that glucocorticoid treatment may be beneficial for articular cartilage, although detrimental effects on bone should be taken into account. Copyright © 2011 Elsevier Inc

  14. BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

    Science.gov (United States)

    Banuelos, J.; Shin, S.; Cao, Y.; Bochner, B. S.; Morales-Nebreda, L.; Budinger, G. R. S.; Zhou, L.; Li, S.; Xin, J.; Lingen, M. W.; Dong, C.; Schleimer, R. P.; Lu, N. Z.

    2016-01-01

    Background Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis. Methods Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo. Results Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids. Conclusion Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma. PMID:26752231

  15. Transcriptional regulation of human dual specificity protein phosphatase 1 (DUSP1) gene by glucocorticoids.

    Science.gov (United States)

    Shipp, Lauren E; Lee, Joyce V; Yu, Chi-Yi; Pufall, Miles; Zhang, Pili; Scott, Donald K; Wang, Jen-Chywan

    2010-10-29

    Glucocorticoids are potent anti-inflammatory agents commonly used to treat inflammatory diseases. They convey signals through the intracellular glucocorticoid receptor (GR), which upon binding to ligands, associates with genomic glucocorticoid response elements (GREs) to regulate transcription of associated genes. One mechanism by which glucocorticoids inhibit inflammation is through induction of the dual specificity phosphatase-1 (DUSP1, a.k.a. mitogen-activated protein kinase phosphatase-1, MKP-1) gene. We found that glucocorticoids rapidly increased transcription of DUSP1 within 10 minutes in A549 human lung adenocarcinoma cells. Using chromatin immunoprecipitation (ChIP) scanning, we located a GR binding region between -1421 and -1118 upstream of the DUSP1 transcription start site. This region is active in a reporter system, and mutagenesis analyses identified a functional GRE located between -1337 and -1323. We found that glucocorticoids increased DNase I hypersensitivity, reduced nucleosome density, and increased histone H3 and H4 acetylation within genomic regions surrounding the GRE. ChIP experiments showed that p300 was recruited to the DUSP1 GRE, and RNA interference experiments demonstrated that reduction of p300 decreased glucocorticoid-stimulated DUSP1 gene expression and histone H3 hyperacetylation. Furthermore, overexpression of p300 potentiated glucocorticoid-stimulated activity of a reporter gene containing the DUSP1 GRE, and this coactivation effect was compromised when the histone acetyltransferase domain was mutated. ChIP-reChIP experiments using GR followed by p300 antibodies showed significant enrichment of the DUSP1 GRE upon glucocorticoid treatment, suggesting that GR and p300 are in the same protein complex recruited to the DUSP1 GRE. Our studies identified a functional GRE for the DUSP1 gene. Moreover, the transcriptional activation of DUSP1 by glucocorticoids requires p300 and a rapid modification of the chromatin structure surrounding

  16. Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling.

    Science.gov (United States)

    Pansters, N A; Langen, R C; Wouters, E F; Schols, A M

    2013-05-01

    Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.

  17. Discovering health topics in social media using topic models.

    Directory of Open Access Journals (Sweden)

    Michael J Paul

    Full Text Available By aggregating self-reported health statuses across millions of users, we seek to characterize the variety of health information discussed in Twitter. We describe a topic modeling framework for discovering health topics in Twitter, a social media website. This is an exploratory approach with the goal of understanding what health topics are commonly discussed in social media. This paper describes in detail a statistical topic model created for this purpose, the Ailment Topic Aspect Model (ATAM, as well as our system for filtering general Twitter data based on health keywords and supervised classification. We show how ATAM and other topic models can automatically infer health topics in 144 million Twitter messages from 2011 to 2013. ATAM discovered 13 coherent clusters of Twitter messages, some of which correlate with seasonal influenza (r = 0.689 and allergies (r = 0.810 temporal surveillance data, as well as exercise (r =  .534 and obesity (r =  -.631 related geographic survey data in the United States. These results demonstrate that it is possible to automatically discover topics that attain statistically significant correlations with ground truth data, despite using minimal human supervision and no historical data to train the model, in contrast to prior work. Additionally, these results demonstrate that a single general-purpose model can identify many different health topics in social media.

  18. Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

    NARCIS (Netherlands)

    Roozendaal, Benno; McReynolds, Jayme R.; Van der Zee, Eddy A.; Lee, Sangkwan; McGaugh, James L.; McIntyre, Christa K.

    2009-01-01

    Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing

  19. Glucocorticoid administration for Graves' hyperthyroidism treated by radioiodine. A questionnaire survey among members of the European Thyroid Association

    NARCIS (Netherlands)

    Lazarus, J. H.; Bartalena, L.; Marcocci, C.; Kahaly, G. J.; Krassas, G.; Wiersinga, W. M.; Baldeschi, L.; Boboridis, K.; Boschi, A.; Currò, N.; Daumerie, C.; Dickinson, A. J.; Eckstein, A.; Kendall-Taylor, P.; Lane, C. M.; Ludgate, M. E.; Mann, K.; Marinò, M.; Mourits, M. P.; Nardi, M.; Neoh, C.; Orgiazzi, J.; Pearce, S.; Perros, P.; Pinchera, A.; Pitz, S.; Salvi, M.; Sivelli, P.; Stahl, M.; von Arx, G.

    2010-01-01

    Background: Glucocorticoid prophylaxis is required in some instances after radioiodine (RAI) treatment for Graves' hyperthyroidism to prevent progression of Graves' orbitopathy (GO). However, no randomized clinical trial has been performed to ascertain the optimum glucocorticoid therapy. Aim and

  20. The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension

    OpenAIRE

    Goodwin, Julie E.; Zhang, Junhui; Velazquez, Heino; Geller, David S.

    2010-01-01

    Glucocorticoids are used as a treatment for a variety of conditions and hypertension is a well-recognized side effect of their use. The mechanism of glucocorticoid-induced hypertension is incompletely understood and has traditionally been attributed to promiscuous activation of the mineralocorticoid receptor by cortisol. Multiple lines of evidence, however, point to the glucocorticoid receptor as an important mediator as well. We have developed a mouse model of glucocorticoid-induced hyperten...

  1. Topics in Bethe Ansatz

    Science.gov (United States)

    Wang, Chunguang

    Integrable quantum spin chains have close connections to integrable quantum field. theories, modern condensed matter physics, string and Yang-Mills theories. Bethe. ansatz is one of the most important approaches for solving quantum integrable spin. chains. At the heart of the algebraic structure of integrable quantum spin chains is. the quantum Yang-Baxter equation and the boundary Yang-Baxter equation. This. thesis focuses on four topics in Bethe ansatz. The Bethe equations for the isotropic periodic spin-1/2 Heisenberg chain with N. sites have solutions containing ±i/2 that are singular: both the corresponding energy and the algebraic Bethe ansatz vector are divergent. Such solutions must be carefully regularized. We consider a regularization involving a parameter that can be. determined using a generalization of the Bethe equations. These generalized Bethe. equations provide a practical way of determining which singular solutions correspond. to eigenvectors of the model. The Bethe equations for the periodic XXX and XXZ spin chains admit singular. solutions, for which the corresponding eigenvalues and eigenvectors are ill-defined. We use a twist regularization to derive conditions for such singular solutions to bephysical, in which case they correspond to genuine eigenvalues and eigenvectors of. the Hamiltonian. We analyze the ground state of the open spin-1/2 isotropic quantum spin chain. with a non-diagonal boundary term using a recently proposed Bethe ansatz solution. As the coefficient of the non-diagonal boundary term tends to zero, the Bethe roots. split evenly into two sets: those that remain finite, and those that become infinite. We. argue that the former satisfy conventional Bethe equations, while the latter satisfy a. generalization of the Richardson-Gaudin equations. We derive an expression for the. leading correction to the boundary energy in terms of the boundary parameters. We argue that the Hamiltonians for A(2) 2n open quantum spin chains

  2. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress.

    NARCIS (Netherlands)

    Oomen, C.A.; Mayer, J.L.; de Kloet, E.R.; Joëls, M.; Lucassen, P.J.

    2007-01-01

    In rodents, stress suppresses adult neurogenesis. This is thought to involve activation of glucocorticoid receptors in the brain. In the present study, we therefore questioned whether glucocorticoid receptor blockade by mifepristone can normalize the effects of chronic stress on adult neurogenesis.

  3. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

    NARCIS (Netherlands)

    S.W.J. Lamberts (Steven); E.F.C. van Rossum (Liesbeth)

    2004-01-01

    textabstractMost actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding

  4. Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions

    NARCIS (Netherlands)

    Bultink, I.E.M.; Baden, M.; Lems, W.F.

    2013-01-01

    Introduction: Glucocorticoid-induced osteoporosis (GIOP) is one of the most devastating side-effects of glucocorticoid (GC) use, as it is associated with an increased fracture risk. The importance of GIOP as a health problem is underlined by the frequent use of GC treatment in patients with various

  5. Heritable variation in circulating glucocorticoids and endocrine flexibility in a free-living songbird.

    Science.gov (United States)

    Stedman, J M; Hallinger, K K; Winkler, D W; Vitousek, M N

    2017-09-01

    Phenotypic flexibility is a central way that organisms cope with challenging and changing environments. As endocrine signals mediate many phenotypic traits, heritable variation in hormone levels, or their context-dependent flexibility, could present an important target for selection. Several studies have estimated the heritability of circulating glucocorticoid levels under acute stress conditions, but little is known about the potential for either baseline hormone levels or rapid endocrine flexibility to evolve. Here, we assessed the potential for selection to operate on the elevation (circulating hormone levels) and flexibility of glucocorticoid reaction norms to acute restraint stress. Multivariate animal models revealed low but significant heritability in baseline (h 2  = 0.13-0.14) and stress-induced glucocorticoids (h 2  = 0.18), and moderate heritability in glucocorticoid flexibility in response to acute stress (h 2  = 0.38) in free-living juvenile tree swallows (Tachycineta bicolor; n = 408). Baseline glucocorticoids were not genetically correlated with either stress-induced glucocorticoids or glucocorticoid flexibility. These findings indicate that baseline glucocorticoids and the acute stress response are distinct traits that can be independently shaped by selection. Microevolutionary changes that influence the expression or flexibility of these endocrine mediators of phenotype may be an important way that populations adapt to changing environments and novel threats. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  6. Glucocorticoids Enhance Taste Aversion Memory via Actions in the Insular Cortex and Basolateral Amygdala

    Science.gov (United States)

    Miranda, Maria Isabel; Quirarte, Gina L.; Rodriguez-Garcia, Gabriela; McGaugh, James L.; Roozendaal, Benno

    2008-01-01

    It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function.…

  7. Bone metabolism in patients with systemic lupus erythematosus. Effect of disease activity and glucocorticoid treatment

    DEFF Research Database (Denmark)

    Hansen, M; Halberg, P; Kollerup, G

    1998-01-01

    and in the distal forearm. A weak correlation was found between the BMD of the femoral neck and the total consumption of glucocorticoids. Apart from this finding the BMD was uninfluenced by treatment with glucocorticoids and cyclophosphamide. No significant changes of BMD were found during the follow-up period...

  8. Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance.

    Science.gov (United States)

    Nicolaides, Nicolas; Lamprokostopoulou, Agaristi; Sertedaki, Amalia; Charmandari, Evangelia

    2016-01-01

    Primary Generalized Glucocorticoid Resistance is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Primary Generalized Glucocorticoid Resistance, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1 gene, and we discuss the diagnostic approach and therapeutic management of the condition. When the condition is suspected, we recommend sequencing analysis of the NR3C1 gene as well as of other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next-generation sequencing will undoubtedly uncover novel hGR partners or cofactors.

  9. Use of systemic glucocorticoids and the risk of major osteoporotic fractures in patients with sarcoidosis

    NARCIS (Netherlands)

    Oshagbemi, Olorunfemi A; Driessen, J H M; Pieffers, A.; Wouters, E F M; Geusens, P.; Vestergaard, P.; van den Bergh, J; Franssen, F M E; de Vries, F

    2017-01-01

    This study revealed the risk of major osteoporotic fracture in patients with sarcoidosis exposed to glucocorticoids. Current use of glucocorticoids was associated with a risk of fracture, with no difference between patients with and without sarcoidosis. Sarcoidosis per se was not associated with an

  10. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy

    DEFF Research Database (Denmark)

    Marcocci, Claudio; Watt, Torquil; Altea, Maria Antonietta

    2012-01-01

    The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO).......The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO)....

  11. Allelic polymorphism of glucocorticoid receptor NR3C1 (GR: from molecular biology to clinical implications

    Directory of Open Access Journals (Sweden)

    Orlovsky M. A.

    2012-09-01

    Full Text Available Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is focused on the molecular biology and clinical implications of glucocorticoid receptor gene polymorphism.

  12. Long-term effects of perinatal glucocorticoid treatment on the heart

    NARCIS (Netherlands)

    Vries, W.B. de

    2006-01-01

    Long-term effects of perinatal glucocorticoid treatment on the heart Chronic lung disease in the extremely preterm baby is still a major complication in neonatal intensive care medicine. Perinatal (ante- and neonatal) glucocorticoids are widely used to prevent severe infant respiratory syndrome and

  13. Instructions for producing a mouse model of glucocorticoid-induced osteoporosis

    DEFF Research Database (Denmark)

    Thiele, S.; Baschant, U.; Rauch, A.

    2014-01-01

    Glucocorticoids are effective drugs used for the treatment of inflammatory diseases such as rheumatoid arthritis or asthma. Furthermore, they regulate various physiological processes, including bone remodeling. However, long-term high- and even low-dose glucocorticoid use is associated with a com...

  14. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor

    DEFF Research Database (Denmark)

    Presman, Diego M; Ogara, M Florencia; Stortz, Martín

    2014-01-01

    Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation wi...

  15. Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors.

    Science.gov (United States)

    Lehrner, Amy; Bierer, Linda M; Passarelli, Vincent; Pratchett, Laura C; Flory, Janine D; Bader, Heather N; Harris, Iris R; Bedi, Aarti; Daskalakis, Nikolaos P; Makotkine, Iouri; Yehuda, Rachel

    2014-02-01

    Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation. Published by Elsevier Ltd.

  16. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2016-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5b. GRANT NUMBER...receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor

  17. Expression and function of nuclear receptor coregulators in brain : understanding the cell-specific effects of glucocorticoids

    NARCIS (Netherlands)

    Laan, Siem van der

    2008-01-01

    Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding

  18. Genetic and in vivo determinants of glucocorticoid sensitivity in relation to clinical outcome of childhood nephrotic syndrome

    NARCIS (Netherlands)

    Teeninga, N.; van Holthe, J.E.; van den Akker, E.L.T.; Kersten, M.C.; Boersma, E.; Krabbe, H.G.; Knoers, N.V.A.M.; van der Heijden, A.J.; Koper, J.W.; Nauta, J.

    2014-01-01

    Following initial glucocorticoid treatment, the clinical course in children with nephrotic syndrome is highly variable. Intrinsic sensitivity to glucocorticoids might be a determinant of this variability. Functional polymorphisms of the glucocorticoid receptor gene NR3C1 have been associated with

  19. Kinetics of glucocorticoid exposure in developing zebrafish: A tracer study.

    Science.gov (United States)

    Steenbergen, Peter Johannes; Bardine, Nabila; Sharif, Faiza

    2017-09-01

    In the current study the dynamics of glucocorticoid uptake by zebrafish chorionated embryos from the surrounding medium were studied, using 2.5 μM cortisol or dexamethasone solutions complemented with their tritiated variant. We measured the uptake of radioactive cortisol by embryos during a 1 h submersion. Interestingly, the signal in chorionated embryos was 85% (exposure: 1-2 hpf) or 78% (exposure: 48-49 hpf) of the signal present in an equal volume medium. By comparing embryos measured without chorion, we found that 18-20% of the radioactivity present in chorionated embryos is actually bound to the chorion or located in the perivitelline space. Consequently, embryonic tissue contains radioactivity levels of 60% of a similar volume of medium after 1 h incubation. During early developmental stages (1-48 hpf) exposure of more than 24 h in cortisol was needed to achieve radioactivity levels similar to an equal volume of medium within the embryonic tissue and more than 48 h for dexamethasone. In glucocorticoid-free medium, radioactivity dropped rapidly below 10% for both glucocorticoids, suggesting that the major portion of the embryonic radioactivity was a result of simple diffusion. During later developmental stages (48-96 hpf) initial uptake dynamics were similar, but showed a decrease of tissue radioactivity to 20% of an equal volume of medium after hatching, probably due to development and activation of the hypothalamic pituitary interrenal axis. Uptake is dependent on the developmental stage of the embryo. Furthermore, the presence of the chorion during exposure should be taken into account even when small lipophilic molecules are being tested. Copyright © 2017. Published by Elsevier Ltd.

  20. Impact of Stress and Glucocorticoids on Schema-Based Learning.

    Science.gov (United States)

    Kluen, Lisa Marieke; Nixon, Patricia; Agorastos, Agorastos; Wiedemann, Klaus; Schwabe, Lars

    2017-05-01

    Pre-existing knowledge, a 'schema', facilitates the encoding, consolidation, and retrieval of schema-relevant information. Such schema-based memory is key to every form of education and provides intriguing insights into the integration of new information and prior knowledge. Stress is known to have a critical impact on memory processes, mainly through the action of glucocorticoids and catecholamines. However, whether stress and these major stress mediators affect schema-based learning is completely unknown. To address this question, we performed two experiments, in which participants acquired a schema on day 1 and learned schema-related as well as schema-unrelated information on day 2. In the first experiment, participants underwent a stress or control manipulation either immediately or about 25 min before schema-based memory testing. The second experiment tested whether glucocorticoid and/or noradrenergic activation is sufficient to modulate schema-based memory. To this end, participants received orally a placebo, hydrocortisone, the α2-adrenoceptor-antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs, before completing the schema-based memory test. Our data indicate that stress, irrespective of the exact timing of the stress exposure, impaired schema-based learning, while leaving learning of schema-unrelated information intact. A very similar effect was obtained after hydrocortisone, but not yohimbine, administration. These data show that stress disrupts participants' ability to benefit from prior knowledge during learning and that glucocorticoid activation is sufficient to produce this effect. Our findings provide novel insights into the impact of stress and stress hormones on the dynamics of human memory and have important practical implications, specifically for educational contexts.

  1. Different response to glucocorticoid therapy in autoimmune diseases of CNS

    Directory of Open Access Journals (Sweden)

    Stanojević Željka

    2016-01-01

    Full Text Available Th17 cells and interleukin (IL-17, their signature cytokine, have the main role in the pathogenesis of autoimmune diseases of the central nervous system such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE. The effect of glucocorticoids (GC on expression and production of IL-17 has not been thoroughly tested yet. Also, the site of action of GC is not precisely defined. This paper presents the main results of the Doctoral thesis devoted to studies of GC on the production of IL-17 in the model of EAE, induced in susceptible laboratory animals. Methylprednisolone (MP, a synthetic glucocorticoid, inhibit in vitro production of IL-17 in mitogen-stimulated lymph node cells (LNC as well as in myelin basic protein (MBP-stimulated draining LNC in dose- dependent manner. However, under the same conditions inhibitory effect of the MP on production and expression of the genes for IFN-γ, a cytokine that TH1 cells generate, is significantly more pronounced. Interestingly, when we analyzed effects of MP applied in vivo in EAE, the same phenomenon was observed: the proportion of IFN-γ producing, but not all of IL-17 cells were reduced in cells isolated from MP treated rats in comparison to control rats which indicates that MP achieves its effects not only in the peripheral lymphoid tissues, but also in target tissue. Different sensitivities of Th1 and Th17 cells that are major cellular sources of IFN-γ or IL-17 in the effect of the GC has been observed in other animal models and in human disease. Understanding the molecular mechanisms underlying the relative resistance of Th17 cells on the operation of GC is very important for the development of new strategies in the treatment of those forms of autoimmune and chronic diseases that are resistant to the effect of glucocorticoids.

  2. Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci

    Directory of Open Access Journals (Sweden)

    Alasdair W. Jubb

    2017-12-01

    Full Text Available Glucocorticoids act by binding to the glucocorticoid receptor (GR, which binds to specific motifs within enhancers of target genes to activate transcription. Previous studies have suggested that GRs can promote interactions between gene promoters and distal elements within target loci. In contrast, we demonstrate here that glucocorticoid addition to mouse bone-marrow-derived macrophages produces very rapid chromatin unfolding detectable by fluorescence in situ hybridization (FISH at loci associated with GR binding. Rapid chromatin decompaction was generally not dependent on transcription at those loci that are known to be inducible in both mouse and human macrophages and was sustained for up to 5 days following ligand removal. Chromatin decompaction was not dependent upon persistent GR binding, which decayed fully after 24 hr. We suggest that sustained large-scale chromatin reorganization forms an important part of the response to glucocorticoid and might contribute to glucocorticoid sensitivity and resistance.

  3. The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone

    DEFF Research Database (Denmark)

    Ding, Ming; Danielsen, Carl C; Overgaard, Søren

    2010-01-01

    The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone – Validation of large animal model for tissue engineering and biomaterial research Ming Ding,1* Carl Christian Danielsen,2 Søren Overgaard1 1Orthopaedic Research Laboratory...... by glucocorticoid treatment and the changes in properties of cancellous bone were comparable with those observed in humans after long-term glucocorticoid treatment. However, the influence on cortical bone has not been thoroughly elucidated. This study aimed to investigate the influence of glucocorticoid on sheep...... cortical bone after long-term treatment. Specifically, we quantify the microarchitecture, mechanical properties, collagen and mineral quality of sheep cortical bone. We hypothesized that glucocorticoid treatment also had significant influences on cortical bone that might increase risk of fracture...

  4. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle

    DEFF Research Database (Denmark)

    Søe, Kent; Delaissé, Jean-Marie

    2010-01-01

    that glucocorticoids deeply modify this resorptive behavior. First, glucocorticoids gradually induce excavations with a trenchlike morphology while reducing the time-dependent increase in excavation numbers. This indicates that glucocorticoids make osteoclasts elongate the excavations they initiated rather than...... migrating to a new resorption site, as in control conditions. Second, the round excavations in control conditions contain undegraded demineralized collagen as repeatedly reported earlier, whereas the excavations with a trenchlike morphology generated under glucocorticoid exposure appear devoid of leftovers...... of demineralized collagen. This indicates that collagenolysis proceeds generally at a lower rate than demineralization under control conditions, whereas collagenolysis rates are increased up to the level of demineralization rates in the presence of glucocorticoids. Taking these observations together leads...

  5. When and for how long should glucocorticoids be used in rheumatoid arthritis? International guidelines and recommendations.

    Science.gov (United States)

    Gaujoux-Viala, Cécile; Gossec, Laure

    2014-05-01

    Glucocorticoids are widely used in rheumatoid arthritis (RA); however, their effectiveness and safety is still a subject of debate. In particular, when to introduce glucocorticoids, but also when and how to taper them, are important questions for clinicians. In this paper, we will discuss the place of glucocorticoids in the European League Against Rheumatism (EULAR) recommendations for the management of RA and review the literature that was the basis for these recommendations. The recommendations cover the introduction of glucocorticoids (and for whom they are recommended), doses and duration of treatment, and tapering strategies. Items still on the research agenda include more data on safety, particularly for long-term use, and small doses of glucocorticoids. © 2014 New York Academy of Sciences.

  6. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore.

    Science.gov (United States)

    Busillo, John M; Cidlowski, John A

    2013-03-01

    Glucocorticoids are essential for maintaining homeostasis and regulate a wide variety of physiological processes. Therapeutically, synthetic glucocorticoids are widely prescribed for the treatment of inflammation, autoimmune disorders, and malignancies of lymphoid origin. In this review we examine emerging evidence highlighting both proinflammatory and anti-inflammatory actions of glucocorticoids on both the innate and adaptive immune systems. We incorporate these findings into the more traditional anti-inflammatory role attributed to glucocorticoids, and propose how the two seemingly disparate processes seamlessly work together to resolve cellular responses to inflammatory stimuli. These ideas provide a framework by which glucocorticoids ready and reinforce the innate immune system, and repress the adaptive immune system, to help to resolve inflammation and restore homeostasis. Published by Elsevier Ltd.

  7. Glucocorticoid treatment earlier in childhood and adolescence show dose-response associations with diurnal cortisol levels

    DEFF Research Database (Denmark)

    Vestergaard, Martin; Holm, Sara K; Uldall, Peter

    2017-01-01

    Heightened levels of glucocorticoids in children and adolescents have previously been linked to prolonged changes in the diurnal regulation of the stress-hormone cortisol, a glucocorticoid regulated by the hypothalamic-pituitary-adrenal-axis (HPA-axis). To address this question, we examined...... the salivary cortisol awakening response (CAR) and daily cortisol output in 36 children and adolescents (25 girls/11 boys) aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder and 36 healthy controls. Patients and controls did not significantly differ in the CAR...... patients showed a positive linear relationship with the mean daily glucocorticoid doses administered during treatment. The observed dose-response associations suggest that glucocorticoid therapy during childhood and adolescence might trigger long-term changes in HPA-axis regulation, which may differ...

  8. Behavioral neuroadaptation to alcohol : from glucocorticoids to histone acetylation

    Directory of Open Access Journals (Sweden)

    Daniel Beracochea

    2016-10-01

    Full Text Available A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic-pituitary-adrenal (HPA axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit including the prefrontal cortex, the hippocampus and the amygdala. These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally amygdala hyperactivity coupled with a hypofunction of the prefrontal cortex and the hippocampus. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately, leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcohol-induced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as CREB (cAMP response element binding protein and chromatin remodeling due to post-translational modifications of histone proteins. We describe the role of prefrontal-hippocampus-amygdala circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region-specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes on how persistently increased glucocorticoid levels in prefrontal cortex may be involved in

  9. Glucocorticoids Inhibit Wound Healing: Novel Mechanism of Action.

    Science.gov (United States)

    Slominski, Andrzej T; Zmijewski, Michal A

    2017-05-01

    Jozic et al. describe mechanisms of glucocorticoid (GC) downregulation of wound healing by interaction with the membrane bound GC receptor, followed by stimulation of β-catenin and c-myc pathways. Targeting the membrane bound GC receptor or the recently discovered interaction of GC with mineralocorticoid receptors may counteract negative effects of GC on the skin barrier and potentially could serve as a remedy for age-related skin atrophy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Hypersensitivity Reactions from Excipients in Systemic Glucocorticoid Formulations

    DEFF Research Database (Denmark)

    Calogiuri, Gianfranco; Garvey, Lene H; Romita, Paolo

    2016-01-01

    Glucocorticoids are the most widely used drugs for the treatment of hypersensitivity, however these drugs themselves and the excipients contained in commercial corticosteroid formulations are able to induce severe immediate-type hypersensitivity reactions. Reactions involving excipients have been...... confirmed to be IgE mediated by the demonstration of specific-IgE to excipients such as carboxymethylcellulose and lactose. In case of hypersensitivity reactions to corticosteroid preparations, a complete allergy work-up with skin tests and/or challenge tests should include testing excipients as well...

  11. Glucocorticoid resistance as a major drive in sepsis pathology.

    Science.gov (United States)

    Dendoncker, Karen; Libert, Claude

    2017-06-01

    Sepsis is an acute systemic inflammatory disease. Glucocorticoids (GCs), which function by binding to the GC receptor GR have very powerful anti-inflammatory activities, yet they are hardly useful in sepsis. We can thus consider sepsis as a GC resistant disease. We here review the literature which has investigated this GC resistance, and summarize the mechanisms of GC resistance that have been observed in other diseases and in experimental models. We also discuss the importance of GC resistance in sepsis, in terms of the contribution of this phenomenon to the pathogenesis of sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Glucocorticoids enhance stability of human growth hormone mRNA.

    OpenAIRE

    Paek, I; Axel, R

    1987-01-01

    We have studied the control of expression of the human growth hormone (hGH) gene introduced into the chromosomes of mouse fibroblasts. Cell lines transformed with the hGH gene expressed low levels of intact hGH mRNA and secreted hGH protein into the medium. Although the level of expression of hGH mRNA was low, the gene remained responsive to induction by glucocorticoid hormones. To localize the sequences responsible for induction and to determine the mechanism by which these cis-acting sequen...

  13. Antenatal glucocorticoid treatment and polymorphisms of the glucocorticoid and mineralocorticoid receptors are associated with IQ and behavior in young adults born very preterm.

    Science.gov (United States)

    van der Voorn, Bibian; Wit, Jan M; van der Pal, Sylvia M; Rotteveel, Joost; Finken, Martijn J J

    2015-02-01

    Preterm survivors exhibit neurodevelopmental impairments. Whether this association is influenced by antenatal glucocorticoid treatment and glucocorticoid sensitivity is unknown. This study aimed to study the effects of antenatal glucocorticoid treatment and glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) polymorphisms on behavior and intelligence quotient (IQ). This study was part of the 19-year follow-up of the Project On Preterm and Small-for-gestational-age birth cohort. Multicenter study. Three hundred forty-four 19-year-olds born very preterm (gestational age IQ (digital Multicultural Capacity Test-intermediate level). Data were analyzed by linear regression and presented as regression coefficient (95% confidence interval [CI]). Sex ratio, GR (R23K; N363S) and MR (-2G/C; I180V) genotypes were equally distributed between treated and nontreated subjects. Independent of treatment, R23K carriers had improved IQ scores (β 9.3; 95% CI, 3.4 to 15.1) and a tendency toward more favorable total problem behavior scores (β -8.5; 95% CI, -17.3 to 0.2) ; -2G/C CC carriers had poorer IQ scores (β -6.2; 95% CI, -10.5 to -1.9); I180V carriers had more favorable internalizing behavior scores (β -2.0; 95% CI, -3.9 to -0.1). Antenatal glucocorticoid treatment was associated with more unfavorable behavior scores, especially internalizing behavior (β 2.4; 95% CI, 0.3 to 4.5). Interaction between GR and MR polymorphisms and antenatal glucocorticoid treatment was observed, with poorer IQ scores for exposed N363S carriers; poorer intellectual subdomain scores for exposed I180V-carriers; more favorable total problem behavior scores for exposed R23K carriers. Genetic variations in glucocorticoid sensitivity and antenatal glucocorticoid treatment are associated with IQ and behavior in young adult preterm survivors.

  14. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis.

    Science.gov (United States)

    Hardy, Rowan; Juarez, Maria; Naylor, Amy; Tu, Jinwen; Rabbitt, Elizabeth H; Filer, Andrew; Stewart, Paul M; Buckley, Christopher D; Raza, Karim; Cooper, Mark S

    2012-10-18

    Inflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis. We examined expression and regulation of DKK1 in primary cultures of human synovial fibroblasts isolated from patients with inflammatory arthritis. The effect of TNFα, IL-1β and glucocorticoids on DKK1 mRNA and protein expression was examined by real-time PCR and ELISA. The ability of inflammatory cytokine-induced expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to sensitise fibroblasts to endogenous glucocorticoids was explored. Global expression of Wnt signalling and target genes in response to TNFα and glucocorticoids was assessed using a custom array. DKK1 expression in human synovial fibroblasts was directly regulated by glucocorticoids but not proinflammatory cytokines. Glucocorticoids, but not TNFα, regulated expression of multiple Wnt agonists and antagonists in favour of inhibition of Wnt signalling. However, TNFα and IL-1β indirectly stimulated DKK1 production through increased expression of 11β-HSD1. These results demonstrate that in rheumatoid arthritis synovial fibroblasts, DKK1 expression is directly regulated by glucocorticoids rather than TNFα. Consequently, the links between synovial inflammation, altered Wnt signalling and bone remodelling are not direct but are dependent on local activation of endogenous glucocorticoids.

  15. Transforming growth factor-β impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line.

    Science.gov (United States)

    Salem, S; Harris, T; Mok, J S L; Li, M Y S; Keenan, C R; Schuliga, M J; Stewart, A G

    2012-08-01

    The lung adenocarcinoma cell line, A549, undergoes epithelial-mesenchymal cell transition (EMT) in response to TGF-β. Glucocorticoids do not prevent the EMT response, but TGF-β induced resistance to the cytokine-regulatory action of glucocorticoids. We sought to characterize the impairment of glucocorticoid response in A549 cells. A549 cells were exposed to TGF-β for up to 96 h before glucocorticoid treatment and challenge with IL-1α to assess glucocorticoid regulation of IL-6 and CXCL8 production. Nuclear localization of the glucocorticoid receptor α (GRα) was ascertained by immunofluorescence and Western blotting. Transactivation of the glucocorticoid response element (GRE) was measured with a transfected GRE-secreted human placental alkaline phosphatase reporter. TGF-β (40-400 pM) reduced the maximum inhibitory effect of dexamethasone on IL-1α-induced IL-6 and CXCL8 production. The impaired glucocorticoid response was detected with 4 h of TGF-β (40 pM) exposure (and 4 h IL-1α to induce CXCL8 expression) and therefore was not secondary to EMT, a process that requires longer incubation periods and higher concentrations of TGF-β. TGF-β also impaired dexamethasone regulation of granulocyte-macrophage colony-stimulating factor in thrombin-stimulated BEAS-2B epithelial cells. Impaired regulation of CXCL8 was associated with markedly reduced GRE transactivation and reduced induction of mRNA for IκBα, the glucocorticoid-inducible leucine zipper and the epithelial sodium channel (SCNN1A). The expression, cellular levels and nuclear localization of GRα were reduced by TGF-β. We have identified mechanisms underlying the impairment of responses to glucocorticoids by TGF-β in the A549 and BEAS-2B cell lines. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  16. Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus.

    Science.gov (United States)

    Mifsud, Karen R; Reul, Johannes M H M

    2016-10-04

    A stressful event results in secretion of glucocorticoid hormones, which bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the hippocampus to regulate cognitive and affective responses to the challenge. MRs are already highly occupied by low glucocorticoid levels under baseline conditions, whereas GRs only become substantially occupied by stress- or circadian-driven glucocorticoid levels. Currently, however, the binding of MRs and GRs to glucocorticoid-responsive elements (GREs) within hippocampal glucocorticoid target genes under such physiological conditions in vivo is unknown. We found that forced swim (FS) stress evoked increased hippocampal RNA expression levels of the glucocorticoid-responsive genes FK506-binding protein 5 (Fkbp5), Period 1 (Per1), and serum- and glucocorticoid-inducible kinase 1 (Sgk1). Chromatin immunoprecipitation (ChIP) analysis showed that this stressor caused substantial gene-dependent increases in GR binding and surprisingly, also MR binding to GREs within these genes. Different acute challenges, including novelty, restraint, and FS stress, produced distinct glucocorticoid responses but resulted in largely similar MR and GR binding to GREs. Sequential and tandem ChIP analyses showed that, after FS stress, MRs and GRs bind concomitantly to the same GRE sites within Fkbp5 and Per1 but not Sgk1 Thus, after stress, MRs and GRs seem to bind to GREs as homo- and/or heterodimers in a gene-dependent manner. MR binding to GREs at baseline seems to be restricted, whereas after stress, GR binding may facilitate cobinding of MR. This study reveals that the interaction of MRs and GRs with GREs within the genome constitutes an additional level of complexity in hippocampal glucocorticoid action beyond expectancies based on ligand-receptor interactions.

  17. Novel aspects of hypothalamic-pituitary-adrenal axis regulation and glucocorticoid actions

    Science.gov (United States)

    Uchoa, Ernane Torres; Aguilera, Greti; Herman, James P.; Fiedler, Jenny L.; Deak, Terrence; Cordeiro de Sousa, Maria Bernardete

    2014-01-01

    Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to rhythmic and episodic release of adrenal glucocorticoids is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, glucocorticoids regulate behavior, metabolic, cardiovascular, immune, and neuroendocrine activities. In contrast to chronic elevated levels, circadian and acute stress-induced increases in glucocorticoids are necessary for hippocampal neuronal survival and memory acquisition and consolidation, through inhibiting apoptosis, facilitating glutamate transmission and inducing immediate early genes and spine formation. In addition to its metabolic actions leading to increasing energy availability, glucocorticoids have profound effects on feeding behavior, mainly through modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that in addition to the recognized immune suppressive actions of glucocorticoids by counteracting adrenergic proinflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative feedback by glucocorticoids involves multiple mechanisms leading to limiting HPA axis activation and preventing deleterious effects of excessive glucocorticoid production. Adequate glucocorticoid secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin releasing hormone (CRH) and vasopressin secretion, the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving non-genomic actions of glucocorticoids, mediate immediate inhibition of hypothalamic CRH and ACTH secretion, while intermediate and delayed mechanisms mediated by genomic actions involve modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily

  18. Topics of Evolutionary Computation 2001

    DEFF Research Database (Denmark)

    Ursem, Rasmus Kjær

    This booklet contains the student reports from the course: Topics of Evolutionary Computation, Fall 2001, given by Thiemo Krink, Rene Thomsen and Rasmus K. Ursem......This booklet contains the student reports from the course: Topics of Evolutionary Computation, Fall 2001, given by Thiemo Krink, Rene Thomsen and Rasmus K. Ursem...

  19. Selective ATP-Binding Cassette Subfamily C Gene Expression and Proinflammatory Mediators Released by BEAS-2B after PM2.5, Budesonide, and Cotreated Exposures

    Directory of Open Access Journals (Sweden)

    Jarline Encarnación-Medina

    2017-01-01

    Full Text Available ATP-binding cassette subfamily C (ABCC genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM2.5 and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1–4 gene expression changes and proinflammatory cytokine (IL-6, IL-8 release in human bronchial epithelial cells (BEAS-2B exposed to PM2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients, and a cotreatment (Co-T: PM2.5 and BUD. A real-time PCR assay shows that ABCC1 was upregulated in BEAS-2B exposed after 6 and 7 hr to PM2.5 extract or BUD but downregulated after 6 hr of the Co-T. ABCC3 was downregulated after 6 hr of BUD and upregulated after 6 hr of the Co-T exposures. ABCC4 was upregulated after 5 hr of PM2.5 extract, BUD, and the Co-T exposures. The cytokine assay revealed an increase in IL-6 release by BEAS-2B exposed after 5 hr to PM2.5 extract, BUD, and the Co-T. At 7 hr, the Co-T decreases IL-6 release and IL-8 at 6 hr. In conclusion, the cotreatment showed an opposite effect on exposed BEAS-2B as compared with BUD. The results suggest an interference of the BUD therapeutic potential by PM2.5.

  20. Topic modelling in the information warfare domain

    CSIR Research Space (South Africa)

    De Waal, A

    2013-11-01

    Full Text Available In this paper the authors provide context to Topic Modelling as an Information Warfare technique. Topic modelling is a technique that discovers latent topics in unstructured and unlabelled collection of documents. The topic structure can be searched...

  1. Safety and tolerability of high doses of glucocorticoides

    Directory of Open Access Journals (Sweden)

    Rakić Branislava D.

    2016-01-01

    Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

  2. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    International Nuclear Information System (INIS)

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-01

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K i = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  3. An epistatic ratchet constrains the direction of glucocorticoid receptor evolution

    Energy Technology Data Exchange (ETDEWEB)

    Bridgham, Jamie T.; Ortlund, Eric A.; Thornton, Joseph W.; (Emory-MED); (Oregon)

    2010-10-28

    The extent to which evolution is reversible has long fascinated biologists. Most previous work on the reversibility of morphological and life-history evolution has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters. Further, despite theoretical work on the factors that could contribute to irreversibility, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution.

  4. Glucocorticoids modulate human brown adipose tissue thermogenesis in vivo.

    Science.gov (United States)

    Scotney, Hannah; Symonds, Michael E; Law, James; Budge, Helen; Sharkey, Don; Manolopoulos, Konstantinos N

    2017-05-01

    Brown adipose tissue (BAT) is a thermogenic organ with substantial metabolic capacity and has important roles in the maintenance of body weight and metabolism. Regulation of BAT is primarily mediated through the β-adrenoceptor (β-AR) pathway. The in vivo endocrine regulation of this pathway in humans is unknown. The objective of our study was to assess the in vivo BAT temperature responses to acute glucocorticoid administration. We studied 8 healthy male volunteers, not pre-selected for BAT presence or activity and without prior BAT cold-activation, on two occasions, following an infusion with hydrocortisone (0.2mg.kg -1 .min -1 for 14h) and saline, respectively. Infusions were given in a randomized double-blind order. They underwent assessment of supraclavicular BAT temperature using infrared thermography following a mixed meal, and during β-AR stimulation with isoprenaline (25ng.kg fat-free mass -1 .min -1 for 60min) in the fasting state. During hydrocortisone infusion, BAT temperature increased both under fasting basal conditions and during β-AR stimulation. We observed a BAT temperature threshold, which was not exceeded despite maximal β-AR activation. We conclude that BAT thermogenesis is present in humans under near-normal conditions. Glucocorticoids modulate BAT function, representing important physiological endocrine regulation of body temperature at times of acute stress. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

    Energy Technology Data Exchange (ETDEWEB)

    Aguilar, David; Strom, Joshua; Chen, Qin M., E-mail: qchen@email.arizona.edu

    2014-04-01

    Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found Glucocorticoid-Induced Leucine Zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. - Highlights: • Corticosteroids act as a cytoprotective agent in cardiomyocytes • Corticosteroids induce GILZ expression in cardiomyocytes • Elevated GILZ results in resistance against apoptosis induced by doxorubicin • GILZ induces Bcl-xL protein without inducing Bcl-xL mRNA.

  6. Glucocorticoid augmentation of prolonged exposure therapy: rationale and case report

    Directory of Open Access Journals (Sweden)

    Laura Pratchett

    2010-12-01

    Full Text Available Rationale: Prolonged exposure (PE therapy has been found to reduce symptoms of posttraumatic stress disorder (PTSD; however, it is difficult for many patients to engage fully in the obligatory retelling of their traumatic experiences. This problem is compounded by the fact that habituation and cognitive restructuring – the main mechanisms through which PE is hypothesized to work – are not instantaneous processes, and often require several weeks before the distress associated with imaginal exposure abates. Case reports: Two cases are described that respectively illustrate the use of hydrocortisone and placebo, in combination with PE, for the treatment of combat-related PTSD. Based on known effects of glucocorticoids on learning and memory performance, we hypothesized that augmentation with hydrocortisone would improve the therapeutic effects of PE by hastening “new” learning and facilitating decreases in the emotional impact of fear memories during the course of treatment. The veteran receiving hydrocortisone augmentation of PE displayed an accelerated and ultimately greater decline in PTSD symptoms than the veteran receiving placebo. Conclusions: While no general conclusion can be derived from comparison of two patients, the findings are consistent with the rationale for augmentation. These case reports support the potential for an appropriately designed and powered clinical trial to examine the efficacy of glucocorticoids in augmenting the effects of psychotherapy for PTSD.

  7. Serum cholesterol selectively regulates glucocorticoid sensitivity through activation of JNK.

    Science.gov (United States)

    Yang, Nan; Caratti, Giorgio; Ince, Louise M; Poolman, Toryn M; Trebble, Peter J; Holt, Cathy M; Ray, David W; Matthews, Laura C

    2014-11-01

    Glucocorticoids (Gc) are potent anti-inflammatory agents with wide clinical application. We have previously shown that increased serum concentration significantly attenuates regulation of a simple Gc-responsive reporter. We now find that glucocorticoid receptor (GR) regulation of some endogenous transactivated but not transrepressed genes is impaired, suggesting template specificity. Serum did not directly affect GR expression, activity or trafficking, implicating GR crosstalk with other signalling pathways. Indeed, a JNK inhibitor completely abolished the serum effect. We identified the Gc modulating serum component as cholesterol. Cholesterol loading mimicked the serum effect, which was readily reversed by JNK inhibition. Chelation of serum cholesterol with methyl-β-cyclodextrin or inhibition of cellular cholesterol synthesis with simvastatin potentiated the Gc response. To explore the effect in vivo we used ApoE(-/-) mice, a model of hypercholesterolaemia. Consistent with our in vitro studies, we find no impact of elevated cholesterol on the expression of GR, or on the hypothalamic-pituitary-adrenal axis, measured by dexamethasone suppression test. Instead we find selective Gc resistance on some hepatic target genes in ApoE(-/-) mice. Therefore, we have discovered an unexpected role for cholesterol as a selective modulator of Gc action in vivo. Taken together these findings reveal a new environmental constraint on Gc action with relevance to both inflammation and cancer. © 2014 The authors.

  8. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  9. Glucocorticoid regulation of transcription at an amplified, episomal promoter

    Energy Technology Data Exchange (ETDEWEB)

    Ostrowski, M.C.; Richard-Foy, H.; Wolford, R.G.; Berard, D.S.; Hager, G.L.

    1983-11-01

    The mouse mammary tumor virus long terminal repeat (MMTV LTR) has been introduced into cultured murine cells, using the 69% transforming fragment of bovine papiloma virus type 1 (BVP). Transformed cells contain up to 200 copies of the chimeric molecules per diploid genome. The restriction endonuclease map of the acquired recombinants, as well as the physical structure of the DNA, indicates that the LTR-BVP molecules present in these cells occur exclusively as unintegrated, extrachromosomal episome. When a 72-base pair direct repeat ''enhancer'' element (derived from the Harvey sarcoma retrovirus) was included in the MMTV LTR-BPV chimeric plasmids, DNA acquired through transfection, with a single exception, was integrated or rearranged or both. Two approaches showed that the MMTV LTR present in the episomal state was capable of supporting glucocorticoid hormone-regulated transcription. The authors have therefore demonstrated the hormone response for the first time in a totally defined primary sequence environment. Significant differences both in the basal level of MMTV-initiated transcription and in the extend of glucocorticoid induction were observed in individual cell lines with similar episomal copy numbers. These phenotypic variations suggest that epigenetic structure is an important component of the mechanism of regulation.

  10. Mental Mechanisms for Topics Identification

    Directory of Open Access Journals (Sweden)

    Louis Massey

    2014-01-01

    Full Text Available Topics identification (TI is the process that consists in determining the main themes present in natural language documents. The current TI modeling paradigm aims at acquiring semantic information from statistic properties of large text datasets. We investigate the mental mechanisms responsible for the identification of topics in a single document given existing knowledge. Our main hypothesis is that topics are the result of accumulated neural activation of loosely organized information stored in long-term memory (LTM. We experimentally tested our hypothesis with a computational model that simulates LTM activation. The model assumes activation decay as an unavoidable phenomenon originating from the bioelectric nature of neural systems. Since decay should negatively affect the quality of topics, the model predicts the presence of short-term memory (STM to keep the focus of attention on a few words, with the expected outcome of restoring quality to a baseline level. Our experiments measured topics quality of over 300 documents with various decay rates and STM capacity. Our results showed that accumulated activation of loosely organized information was an effective mental computational commodity to identify topics. It was furthermore confirmed that rapid decay is detrimental to topics quality but that limited capacity STM restores quality to a baseline level, even exceeding it slightly.

  11. A Study of Topic and Topic Change in Conversational Threads

    Science.gov (United States)

    2009-09-01

    ture or content of a relationship changes. The ability to detect topic change would support investigations of sexual predators, where a conversation...often starts out platonic and then turns sexual [21], as well as investigations into the techniques of recruitment for criminal or religious activity. If...conditions such as Autism or Attention Deficit Disorder be detected via long term studies of topics in individuals’ personal communications? 62 CHAPTER 6

  12. Cell-specific expression of the glucocorticoid receptor within granular convoluted tubules of the rat submaxillary gland

    Energy Technology Data Exchange (ETDEWEB)

    Antakly, T.; Zhang, C.X.; Sarrieau, A.; Raquidan, D. (McGill Univ., Montreal, Quebec (Canada))

    1991-01-01

    The submaxillary gland, a heterogeneous tissue composed essentially of two functionally distinct cell types (tubular epithelial and acinar), offers an interesting system in which to study the mechanisms of steroid-dependent growth and differentiation. One cell type, the granular convoluted tubular (GCT) cell, secretes a large number of physiologically important polypeptides, including epidermal and nerve growth factors. Two steroids, androgens and glucocorticoids, greatly influence the growth, differentiation, and secretory activity of GCT cells. Because glucocorticoids can partially mimic or potentiate androgen effects, it has been thought that glucocorticoids act via androgen receptors. Since the presence of glucocorticoid receptors is a prerequisite for glucocorticoid action, we have investigated the presence and cellular distribution of glucocorticoid receptors within the rat submaxillary gland. Binding experiments using (3H)dexamethasone revealed the presence of high affinity binding sites in rat submaxillary tissue homogenates. Most of these sites were specifically competed by dexamethasone, corticosterone, and a pure glucocorticoid agonist RU 28362. Neither testosterone nor dihydrotestosterone competed for glucocorticoid binding. The cellular distribution of glucocorticoid receptors within the submaxillary gland was investigated by immunocytochemistry, using two highly specific glucocorticoid receptor antibodies. The receptor was localized in the GCT cells, but not in the acinar cells of rat and mouse submaxillary tissue sections. In GCT cells, the glucocorticoid receptor colocalized with several secretory polypeptides, including epidermal growth factor, nerve growth factor, alpha 2u-globulin, and atrial natriuretic factor.

  13. Long-term safety, efficacy, and patient acceptability of teriparatide in the management of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    Dore RK

    2013-05-01

    Full Text Available Robin K DoreDavid Geffen School of Medicine, University of California, Los Angeles, CA, USAAbstract: Glucocorticoids are commonly prescribed medications to treat multiple diseases across many medical specialties. One of the most common yet largely unappreciated side effect of glucocorticoid use is increased risk of fracture. Many different therapies are indicated to prevent and treat this condition; many guidelines exist that suggest appropriate use of both glucocorticoids and the medications approved to prevent this common side effect of glucocorticoid therapy. Nevertheless, 30%–50% of patients on long-term glucocorticoid therapy sustain a fracture. Teriparatide, recombinant human parathyroid hormone (1–34, is a daily self-injectable therapy for 24 months approved for use in patients taking long-term glucocorticoids. Teriparatide has been shown to increase bone mineral density and reduce vertebral fracture risk in glucocorticoid-treated patients. Glucocorticoids have many adverse effects on bone that teriparatide has been shown to prevent or negate. Given the fact that preventive therapy for glucocorticoid-induced osteoporosis is often not prescribed, one wonders whether a daily self-injectable therapy for this condition would be prescribed by physicians and accepted by patients. This article reviews the epidemiology, pathophysiology, treatment, guidelines, and persistence data (when available for patients with glucocorticoid-induced osteoporosis treated with teriparatide.Keywords: glucocorticoid-induced osteoporosis, teriparatide, anabolic, PTH, parathyroid hormone

  14. Cell-specific expression of the glucocorticoid receptor within granular convoluted tubules of the rat submaxillary gland

    International Nuclear Information System (INIS)

    Antakly, T.; Zhang, C.X.; Sarrieau, A.; Raquidan, D.

    1991-01-01

    The submaxillary gland, a heterogeneous tissue composed essentially of two functionally distinct cell types (tubular epithelial and acinar), offers an interesting system in which to study the mechanisms of steroid-dependent growth and differentiation. One cell type, the granular convoluted tubular (GCT) cell, secretes a large number of physiologically important polypeptides, including epidermal and nerve growth factors. Two steroids, androgens and glucocorticoids, greatly influence the growth, differentiation, and secretory activity of GCT cells. Because glucocorticoids can partially mimic or potentiate androgen effects, it has been thought that glucocorticoids act via androgen receptors. Since the presence of glucocorticoid receptors is a prerequisite for glucocorticoid action, we have investigated the presence and cellular distribution of glucocorticoid receptors within the rat submaxillary gland. Binding experiments using [3H]dexamethasone revealed the presence of high affinity binding sites in rat submaxillary tissue homogenates. Most of these sites were specifically competed by dexamethasone, corticosterone, and a pure glucocorticoid agonist RU 28362. Neither testosterone nor dihydrotestosterone competed for glucocorticoid binding. The cellular distribution of glucocorticoid receptors within the submaxillary gland was investigated by immunocytochemistry, using two highly specific glucocorticoid receptor antibodies. The receptor was localized in the GCT cells, but not in the acinar cells of rat and mouse submaxillary tissue sections. In GCT cells, the glucocorticoid receptor colocalized with several secretory polypeptides, including epidermal growth factor, nerve growth factor, alpha 2u-globulin, and atrial natriuretic factor

  15. Topical steroid-damaged skin

    Directory of Open Access Journals (Sweden)

    Anil Abraham

    2014-01-01

    Full Text Available Topical steroids, commonly used for a wide range of skin disorders, are associated with side effects both systemic and cutaneous. This article aims at bringing awareness among practitioners, about the cutaneous side effects of easily available, over the counter, topical steroids. This makes it important for us as dermatologists to weigh the usefulness of topical steroids versus their side effects, and to make an informed decision regarding their use in each individual based on other factors such as age, site involved and type of skin disorder.

  16. Topics in lightwave transmission systems

    CERN Document Server

    Li, Tingye

    1991-01-01

    Topics in Lightwave Transmission Systems is a second volume of a treatise on optical fiber communications that is devoted to the science, engineering, and application of information transmission via optical fibers. The first volume, published in 1985, dealt exclusively with fiber fabrication. The present volume contains topics that pertain to subsystems and systems. The book contains five chapters and begins with discussions of transmitters and receivers, which are basic to systems now operating in the field. Subsequent chapters cover topics relating to coherent systems: frequency and phase m

  17. Radioreceptor assay for evaluation of the plasma glucocorticoid activity of natural and synthetic steroids in man

    International Nuclear Information System (INIS)

    Ballard, P.L.; Carter, J.P.; Graham, B.S.; Baxter, J.D.

    1975-01-01

    An assay for plasma glucocorticoid activity has been developed using specific glucocorticoid receptors. Unlike other assays for cortisol and certain synthetic corticosteroids, this radioreceptor assay measures the glucocorticoid activity of all natural and synthetic steroids. Steroids extracted from as little as 0.05 ml of plasma are incubated with 3 H-dexamethasone and cytosol receptors from cultured rat hepatoma cells. From 0.5 to 50 ng of cortisol are accurately detected. Glucocorticoid activities of adult plasmas determined by the assay correlate closely with corticoid levels obtained in the CBG-isotope and fluorometric assays. Other steroids are measured in proportion to both concentration and potency as glucocorticoids. Relative activities include: cortisol 100, dexamethasone 940, prednisolone 230, prednisone 3, estradiol 1 and androstenedione 1. A similar ranking of steroids was found using receptors from a human source (fetal lung). The assay has been useful in detecting glucocorticoid activity in unidentified medications and in measuring plasma glucocorticoid levels after administration of synthetic corticosteroids. (auth)

  18. Glucocorticoids and renal Na+ transport: implications for hypertension and salt sensitivity

    Science.gov (United States)

    Hunter, Robert W; Ivy, Jessica R; Bailey, Matthew A

    2014-01-01

    The clinical manifestations of glucocorticoid excess include central obesity, hyperglycaemia, dyslipidaemia, electrolyte abnormalities and hypertension. A century on from Cushing's original case study, these cardinal features are prevalent in industrialized nations. Hypertension is the major modifiable risk factor for cardiovascular and renal disease and reflects underlying abnormalities of Na+ homeostasis. Aldosterone is a master regulator of renal Na+ transport but here we argue that glucocorticoids are also influential, particularly during moderate excess. The hypothalamic–pituitary–adrenal axis can affect renal Na+ homeostasis on multiple levels, systemically by increasing mineralocorticoid synthesis and locally by actions on both the mineralocorticoid and glucocorticoid receptors, both of which are expressed in the kidney. The kidney also expresses both of the 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes. The intrarenal generation of active glucocorticoid by 11βHSD1 stimulates Na+ reabsorption; failure to downregulate the enzyme during adaption to high dietary salt causes salt-sensitive hypertension. The deactivation of glucocorticoid by 11βHSD2 underpins the regulatory dominance for Na+ transport of mineralocorticoids and defines the ‘aldosterone-sensitive distal nephron’. In summary, glucocorticoids can stimulate renal transport processes conventionally attributed to the renin–angiotensin–aldosterone system. Importantly, Na+ and volume homeostasis do not exert negative feedback on the hypothalamic–pituitary–adrenal axis. These actions are therefore clinically relevant and may contribute to the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels, such as the metabolic syndrome and chronic stress. PMID:24535442

  19. "Official View" on Glucocorticoids in Rheumatoid Arthritis: A Systematic Review of International Guidelines and Consensus Statements.

    Science.gov (United States)

    Palmowski, Yannick; Buttgereit, Thomas; Dejaco, Christian; Bijlsma, Johannes W; Matteson, Eric L; Voshaar, Marieke; Boers, Maarten; Buttgereit, Frank

    2017-08-01

    To describe the perception of the current role of systemic glucocorticoids in the management of rheumatoid arthritis (RA) by examining their importance and the current level of evidence in recent guidelines, and to identify open questions to be addressed in future guidelines and research projects. We conducted a systematic literature review using the databases Ovid Embase, PubMed Medline, and Cochrane Library for guidelines on the pharmacologic treatment of RA. Retrieved articles were evaluated regarding their quality using the Appraisal of Guidelines for Research and Evaluation II tool and scrutinized for all relevant information concerning the use of glucocorticoids. All guidelines agree that glucocorticoids, especially if given at low doses and for a short duration, are an appropriate option in the treatment of RA. However, many recommendations remain vague, as reliable and detailed evidence is scarce. Important aspects of glucocorticoid therapy are partially or completely neglected, and the existing nomenclature is not used uniformly. Quality evaluation revealed flaws in many articles, concerning not only glucocorticoid-specific recommendations but also guideline quality in general. Current recommendations for use of glucocorticoids in the management of RA are suboptimal. More rigorous evaluation of doses, timing, and duration of their use is needed. Existing nomenclature on glucocorticoid therapy should be used uniformly. © 2016, American College of Rheumatology.

  20. A Role for Glucocorticoids in Stress-Impaired Reproduction: Beyond the Hypothalamus and Pituitary

    Science.gov (United States)

    Whirledge, Shannon

    2013-01-01

    In addition to the well-characterized role of the sex steroid receptors in regulating fertility and reproduction, reproductive events are also mediated by the hypothalamic-pituitary-adrenal axis in response to an individual's environment. Glucocorticoid secretion in response to stress contributes to the well-characterized suppression of the hypothalamic-pituitary-gonadal axis through central actions in the hypothalamus and pituitary. However, both animal and in vitro studies indicate that other components of the reproductive system are also regulated by glucocorticoids. Furthermore, in the absence of stress, it appears that homeostatic glucocorticoid signaling plays a significant role in reproduction and fertility in all tissues comprising the hypothalamic-pituitary-gonadal axis. Indeed, as central regulators of the immune response, glucocorticoids are uniquely poised to integrate an individual's infectious, inflammatory, stress, nutritional, and metabolic status through glucocorticoid receptor signaling in target tissues. Endocrine signaling between tissues regulating the immune and stress response and those determining reproductive status provides an evolutionary advantage, facilitating the trade-off between reproductive investment and offspring fitness. This review focuses on the actions of glucocorticoids in tissues important for fertility and reproduction, highlighting recent studies that show glucocorticoid signaling plays a significant role throughout the hypothalamic-pituitary-gonadal axis and characterizing these effects as permissive or inhibitory in terms of facilitating reproductive success. PMID:24064362