Effect of Sitagliptin on Short-Term Metabolic Dysregulation of Oral Glucocorticoid Therapy - Full Text View - ClinicalTrials.gov
The investigators plan to conduct a prospective, randomized, double-blind, placebo-controlled parallel arm study comparing insulin secretion and insulin resistance in subjects with impaired fasting glucose on oral glucocorticoid therapy + placebo versus subjects on oral glucocorticoid therapy + sitagliptin. For the oral glucocorticoid therapy, we plan to use dexamethasone (dex) 2.5 mg daily. We chose dex for known glycemic effects, improved compliance, and once daily dosing.. Previous studies have shown that in humans, glucocorticoid-induced insulin resistance develops within 4 hours with infused drug at high dose (methylprednisolone 500 mg x single infusion) and does not change with duration of drug therapy of up to 3 months.10 Furthermore, more modest doses over a short duration (dex 2.0 mg orally daily x 2 days) have been shown to decrease insulin-mediated glucose disposal.11 12 Thus, studying acute effects of oral dex at 2.5 mg daily x 7 days should be more than adequate to achieve impaired ...https://clinicaltrials.gov/ct2/show/NCT01488279
Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid...
This study confirms that glucocorticoid therapy is associated with serious infection in older patients with RA. We have replicated previous reports of an increased risk using conventional models of exposure. For example, we have shown in model 1 an OR for current exposure of 1.84 (95% CI 1.64 to 2.06), which compares with previous estimates using the same analysis model of between 1.9 and 2.1.13,-,15 Similarly, our OR for recent exposure (2.26, 95% CI 2.02 to 2.54, model 3) is similar to a previous estimate of 2.56 (95% CI 2.29 to 2.85),16 and for ever exposed our estimate of 1.72 (95% CI 1.53 to 1.94) from model 4 overlaps with a published estimate of 2.2 (95% CI 1.5 to 3.4).12 Furthermore, our dose-specific estimates are also similar to those published analyses that accounted for glucocorticoid doses. In our study, 5 mg PEQ was associated with an OR of 1.4-1.6 (models 6 and 7 in table 2), compared with previous estimates of 1.3-1.5 for 1-5 mg PEQ and 1.5-2.1 for 5-10 mg PEQ.14 15 26 27 More ...http://ard.bmj.com/content/71/7/1128
Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P,0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P,0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on ...http://respiratorydecade.blogspot.com
Pathogenesis, clinical features, and evaluation of glucocorticoid-induced osteoporosis
Chronic glucocorticoid excess, either endogenous (ie, Cushing's syndrome) or exogenous, can lead to osteoporosis and fractures. The pathogenesis, clinical features, and evaluation of glucocorticoid-induced osteoporosis will be reviewed here. The prevhttp://www.uptodate.com/contents/pathogenesis-clinical-features-and-evaluation-of-glucocorticoid-induced-osteoporosis
Protective effect of VK2 on glucocorticoid-treated MC3T3-E1 cells
GC-induced osteoporosis greatly increases the risk of fracture, and pharmacological therapy is recommended as soon as possible and has been studied for many years (27). VK2 has been reported to be a promising therapy for GC-induced osteoporosis (28). Studies have indicated that VK2 inhibits bone loss and increases bone formation in GC-treated rats (25,29). Clinical studies have also reported increased serum levels of carboxylated OCN and lumbar bone mass volume in GC-treated patients (26,30). This study further confirmed the protective effects of VK2 against GC-induced damage in osteoblasts in vitro.. Several studies have indicated that GCs inhibit osteoblast proliferation in vivo (31,32), and VK2 has also been reported to promote osteoblast proliferation (13). In this study, we further confirmed the proliferative-promoting effect of VK2 on GC-treated MC3T3-E1 cells. This effect may be related to growth arrest-specific gene 6 (Gas6), which is a VK-dependent protein that is involved in cell ...https://spandidos-publications.com/ijmm/39/1/160
Anti-inflammatory Actions of Glucocorticoids: Molecular Mechanisms | Clinical Science
1. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. The molecular mechanisms involved in this antiinflammatory action of glucocorticoids is discussed, particularly in asthma, which accounts for the highest clinical use of these agents.. 2. Glucocorticoids bind to glucocorticoid receptors in the cytoplasm which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription. Glucocorticoids may increase the transcription of genes coding for antiinflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist and neutral endopeptidase, but this is unlikely to account for all of the ...http://www.clinsci.org/content/94/6/557
Fracture risk with intermittent high-dose oral glucocorticoid therapy. - Nuffield Department of Orthopaedics, Rheumatology and...
To evaluate the risk of fracture in patients receiving intermittent therapy with high-dose oral glucocorticoids (GCs).The study group comprised 191,752 patients from the UK General Practice Database who were 40 years of age and older and received therapy with GCs. The followup time period was divided into the categories of 'current' and 'no exposure.' The daily dose and cumulative dose for each time period were determined. Relative risks were estimated using Cox proportional hazards models, adjusted for age, sex, body mass index, smoking, disease history, and drug history. Fractures of the radius/ulna, humerus, rib, femur/hip, pelvis, or vertebrae were included in the evaluation.Patients who intermittently received high-dose GCs (daily dose | or =15 mg) and had no or little previous exposure to GCs (cumulative exposure | or =1 gm) had a small increased risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increasing cumulative exposure. Among patients who ...https://www.ndorms.ox.ac.uk/publications/126241
"Population-based assessment of adverse events associated with long-ter" by Jeffrey R. Curtis, Andrew O. Westfall et al.
OBJECTIVE: The frequency of many adverse events (AEs) associated with low-dose glucocorticoid use is unclear. We sought to determine the prevalence of glucocorticoid-associated AEs in a large US managed care population. METHODS: Using linked administrative and pharmacy claims, adults receiving |or=60 days of glucocorticoids were identified. These individuals were surveyed about glucocorticoid use and symptoms of 8 AEs commonly attributed to glucocorticoid use. RESULTS: Of the 6,517 eligible glucocorticoid users identified, 2,446 (38%) returned the mailed survey. Respondents were 29% men with a mean +/- SD age of 53 +/- 14 years; 79% were white and 13% were African American. Respondents had a mean +/- SD of 7 +/- 3 comorbid conditions and were prescribed a mean +/- SD prednisone-equivalent dosage of 16 +/- 14 mg/day. More than 90% of individuals reported at least 1 AE associated with glucocorticoid use; 55% reported that at least 1 AE was very bothersome. Weight gain was the most common ...http://escholarship.umassmed.edu/qhs_pp/802/
Hypersensitivity reactions to systemic glucocorticoids
Glucocorticoids are prescribed for their immunosuppressive, antiproliferative, anti-inflammatory, and antiallergenic effects and are integral to the management of numerous conditions, including malignancies, transplantation, autoimmune and allergic dhttp://www.uptodate.com/contents/hypersensitivity-reactions-to-systemic-glucocorticoids
We evaluated how maternally administered glucocorticoids would influence fetal lung inflammation caused by chorioamnionitis and whether this interaction affected the inflammation-induced lung maturation. As anticipated, 1 day after treatment, maternal glucocorticoids suppressed IA Endo-induced inflammation in the fetal lung. However, 5 and 15 days after treatment, maternal glucocorticoids paradoxically amplified Endo-induced lung inflammation. Lung inflammation was indicated by increased influx of neutrophils, production of hydrogen peroxide by inflammatory cells, and transcription of proinflammatory cytokines and the acute-phase reactant SAA3. Although exposure to glucocorticoids increased the Endo-induced lung inflammation at 5 and 15 days, the lung maturation induced by either Endo or the combined Endo and glucocorticoid treatment was similar 15 days after exposure. These experiments are the first to show that ...http://ajplung.physiology.org/content/284/4/L633
Elucidating the identity of resistance mechanisms to prednisolone exposure in acute lymphoblastic leukemia cells through...
In the present work, we have set up and propose a rational computational analysis framework, in order to aid the elucidation of the molecular mechanisms of glucocorticoid resistance and specifically whether these are to a larger extent inherent or acquired. To the best of our knowledge, there are no reports trying to analyze systematically the underlying, inherent or acquired molecular mechanisms of GC resistance. The issue whether leukemic cells possess the inherent genetically imprinted resistance mechanisms or it is rather a post effect of evolutionary adoption of originally sensitive cells upon GC treatment is still a controversial one, with potentially significant interest for design of novel therapeutic approaches in cancer treatment. A similar work  reported recently that in ex vivo samples, leukemic cells exhibit an at least in part, intrinsic mechanism of reaction. In another work , it has also been mentioned that glucocorticoids can induce intrinsic mechanisms of ...https://jclinbioinformatics.biomedcentral.com/articles/10.1186/2043-9113-1-36
Chapter 342. Disorders of the Adrenal Cortex | Harrison's Principles of Internal Medicine, 18e | AccessMedicine | McGraw-Hill...
The most important first step in the management of patients with suspected Cushing's syndrome is to establish the correct diagnosis. Most mistakes in clinical management, leading to unnecessary imaging or surgery, are made because the diagnostic protocol is not followed (Fig. 342-9). This protocol requires establishing the diagnosis of Cushing's beyond doubt prior to employing any tests used for the differential diagnosis of the condition. In principle, after excluding exogenous glucocorticoid use as the cause of clinical signs and symptoms, suspected cases should be tested if there are multiple and progressive features of Cushing's, particularly features with a potentially higher discriminatory value. Exclusion of Cushing's is also indicated in patients with incidentally discovered adrenal masses. ...http://accessmedicine.mhmedical.com/content.aspx?bookid=331§ionid=40727147
Predictors for vertebral fractures and fracture threshold in patients using oral glucocorticoids - Nuffield Department of...
A new study reveals that steroid injections used to prevent premature birth might increase future risks of behavioral and emotional problems in the developing children.. Expectant mothers who might give birth prematurely are often treated with an infusion of glucocorticoids. These drugs, wrote Psych Central, are cortisol mimickers; cortisol is a natural hormone. The treatment is meant to assist in the developing baby's lung development; however new concerns have arisen that high glucocorticoids exposure in the womb might lead to dangerous, long-term effects on brain development.. Cortisol is naturally produced in the fetus during later pregnancy stages and works to help the lungs develop appropriately, according to Medical Daily. Premature babies often miss this important development stage, which leads to lung problems and life-threatening breathing issues.. Synthetic glucocorticoids are known to copy the effect of natural cortisol and, when given prior to ...http://www.newsinferno.com/mental-health-risks-tied-to-steroid-injections-meant-to-stop-premature-birth/
Sexually Dimorphic Actions of Glucocorticoids Provide a Link to Inflammatory Diseases with Gender Differences in Prevalence |...
Males and females show differences in the prevalence of many major diseases that have important inflammatory components to their etiology. These gender-specific diseases, which include autoimmune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, are largely considered to reflect the actions of sex hormones on the susceptibility to inflammatory stimuli. However, inflammation reflects a balance between pro- and anti-inflammatory signals, and investigation of gender-specific responses to the latter has been neglected. Glucocorticoids are the primary physiological anti-inflammatory hormones in mammals, and synthetic derivatives of these hormones are prescribed as anti-inflammatory agents, irrespective of patient gender. We explored the possibility that sexually dimorphic actions of glucocorticoid regulation of gene expression may contribute to the dimorphic basis of inflammatory disease by evaluating the rat liver, a classic glucocorticoid-responsive organ. Surprisingly, ...http://stke.sciencemag.org/content/3/143/ra74
Inappropriate use of potent topical glucocorticoids in infants.
Topical therapy with glucocorticoids (GCs) is used commonly in chronic dermatoses. Side effects are less common compared to systemic use; however, newer potent preparations may have serious side effects. A potential danger is their inappropriate use.http://www.biomedsearch.com/nih/Inappropriate-use-potent-topical-glucocorticoids/17396439.html
Cortisol and other glucocorticoids are secreted in response to a single stimulator: adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH is itself secreted under control of the hypothalamic peptide corticotropin-releasing hormone (CRH). The central nervous system is thus the commander and chief of glucocorticoid responses, providing an excellent example of close integration between the nervous and endocrine systems. Virtually any type of physical or mental stress results in elevation of cortisol concentrations in blood due to enhanced secretion of CRH in the hypothalamus. This fact sometimes makes it very difficult to assess glucocorticoid levels, particularly in animals. Observing the approach of a phlebotomist, and especially being restrained for blood sampling, is enough stress to artificially elevate cortisol levels several fold! Cortisol secretion is suppressed by classical negative feedback loops. When blood concentrations rise above a certain theshold, cortisol ...http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/adrenal/gluco.html
Rebel Science News: Anesthetics and Glucocorticoids for ALS
Even though many in the ALS money making industry maintain otherwise, there is no question that ALS is an autoimmune disease. This is why my wife and other ALS sufferers have experienced strong improvements after injection with anti-inflammatory drugs. This is not the first time that glucocorticoid drugs have been implicated in spectacular ALS remissions. In 2011, famous ALS patient Ted Harada experienced an amazing recovery after being anesthetized for up to five hours during stem cell treatment and given several anti-inflammatory glucocorticoids to prevent rejection. In June 2013, Ernie Schmid published an ALS remission story in which he explained how he kept his ALS under control with powerful glucocorticoids. There is also the story of US Authors Guild's director Paul Aiken whose ALS went into remission after injections with the glucocorticoid drug Kenalog. Other ALS sufferers have reported strong improvements in their speech and ability to swallow after a visit to the ...http://rebelscience.blogspot.co.il/2014/08/anesthetics-and-glucocorticoids-for-als.html
Citation tools | The Journal of Immunology
Taves, Matthew Donald et al "Paracrine rather than systemic glucocorticoids are biologically active in the thymus." The Journal of Immunology 198.1 Supplement (2017): 202.1. Web. 16 Dec. 2017. ...http://www.jimmunol.org/highwire/citation/341258/download
Proapoptotic Bcl-2 family members provoke cell death by neutralizing their anti-apoptotic relatives, which in turn maintain cell viability by regulating the activation of the cell death effectors, the caspases. In this study we investigate a potential novel splice variant of human BCL2L11/Bim, termed \#8220;Bimbam\#8221;. First evidence for Bimbam was obtained by Affymetrix-based whole genome comparative expression profiling, where a corresponding probe set was found to be induced in 8 of the 13 ALL children and 1 adult during systemic glucocorticoid (GC) monotherapy (Schmidt et al., Blood 107: 2061, 2006). The postulated Bimbam mRNA consists of the 5\#8217; portion of Bim (up to and including the BH3-containing exon 8) and the 3\#8217; portion of Bam, a cDNA originally discovered in a multiple myeloma cDNA library (Claudio et al, 2002). Thus, it encodes a putative protein consisting of the N-terminal region of Bim (including its BH3 domain) and 40 C-terminal amino acids derived from Bam and not ...http://cancerres.aacrjournals.org/content/69/9_Supplement/3264
2464 Glucocorticoids (GCs) are a crucial component in all protocols for the treatment of human lymphoid malignancies, including childhood acute lymphoblastic leukemia (ALL). A central role in GC-mediated apoptosis is played by the proapoptotic BH3-only proteins, most notably Bim, Puma and, to a lesser extent, Noxa. Following exposure to GCs, these genes are upregulated at the mRNA and protein level. Silencing of Bim using siRNA technology correlates with protection from GC induced apoptosis in ALL cell lines. To dissect the molecular mechanisms leading to GC resistance in vivo, we developed a model of childhood ALL, using patient biopsies established as xenografts in immune-deficient (NOD/SCID) mice. Using this model, we demonstrated that resistance is typically associated with failure to induce Bim mRNA and protein in response to GC treatment. Using a methylated DNA immunoprecipitation analysis of the entire Bim CpG island, we found that increased methylation of Bim 5' Untranslated Region ...http://cancerres.aacrjournals.org/content/68/9_Supplement/2464
The major new finding of this study is that prenatal exposure to excess T causes mild hypertension in adult female sheep. Exposure to excess T during the prenatal period in sheep recapitulates many of the components of PCOS (36), a disease also characterized by a clustering of cardiovascular risk factors (8). Although the model has been exploited extensively to understand the developmental origin of neuroendocrine and ovarian dysfunction, as well as insulin resistance, the cardiovascular consequences have not been explored.. Interestingly, the magnitude of the hypertension resulting from prenatal T excess was similar to what has been previously reported for fetal programming with dexamethasone in sheep (10, 11). Phenotypically, intrauterine programming by T shares many features with prenatal glucocorticoid excess, including intrauterine growth retardation, insulin resistance, and hypertension (26). The intrauterine programming effects of glucocorticoids on adult cardiovascular function have ...http://ajpendo.physiology.org/content/292/6/E1837
Molecular Vision: Alteration of TLR3 pathways by glucocorticoids may be responsible for immunosusceptibility of human corneal...
Our results showed that poly(I:C), a TLR3 agonist, up-regulated the production of inflammatory cytokines/chemokines such as MIP1-α, MIP1-β, RANTES, IL-6, and IL-8, by activating NFκB. Incubation of HCECs with poly(I:C) also activated IRF3 followed by IFN-β production. The up-regulated expression of TLR 3 by poly(I:C) indicates that the TLR3/TRIF signaling pathways were most likely activated by poly(I:C) in HCECs. This is consistent with previous reports [1,15-17]. The cytokines and chemokines investigated are known to have powerful effects in recruiting immune cells and stimulating the maturation of dendritic cells [29-31]. Therefore, we suggest that corneal epithelial cells, when the TLR3s are activated de novo, are able to recruit and activate immune cells against viral infections. Our results showed that DEX and CsA inhibit the poly(I:C)-induced NFκB activation and the subsequent production of inflammatory cytokines/chemokines. Earlier studies have shown that the concentration of ...http://www.molvis.org/molvis/v15/a98/
Phase II Study Evaluating the Safety and Efficacy of GSK315234A in Patients With Rheumatoid Arthritis - Full Text View -...
Those subjects on other oral anti-rheumatic therapies, which may include Non Steroidal Anti Inflammatory Drugs (NSAIDs), COX-2 inhibitors, oral glucocorticoids e.g. prednisolone (£10mg/day) must be on stable dosing regimens for at least 4 weeks prior to screening and be willing to remain on this regime throughout the study. Subjects receiving intramuscular glucocorticoids e.g methylprednisolone (£120 mg/month) must be on a stable dosing regimen for at least 3 months prior to screening and be willing to remain on this regimen throughout the study ...https://clinicaltrials.gov/ct2/show/NCT00674635
Glucocorticoid Levels in Blood - Help!
Robert Passey wrote: , , I am currently studying the effect of glucocorticoids on expression of , a murine cytokine gene. , , Can anybody out there either tell me (or indicate a good reference , where I can find out) the normal and stressed physiological , concentrations and the pharmacological concentrations of , hydrocotisone, vitamin D3, and estradiol, and the pharmacological , conc. of dexamethasone in either human or murine blood? Do I also need , to factor in bioavailability? , , I would really appreciate help on this as it's right outside my field , (molecular genetics) and I can't find any reliable texts. , , Many thanks, , , Robert Passey. Hi Robert. I think you may be able to find some hints from a text called 'PsychoImmunology' edited by Alan Husband - it is all about neuroendocrine interaction with the immune system. I know there is a copy of it in Sydney Uni's medical library. Good luck! Aleta Knowles ...http://www.bio.net/bionet/mm/immuno/1996-October/008862.html