Journal articles on the topic 'Glucocorticoids – Therapeutic use'
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Grbovic, Leposava, and Miroslav Radenkovic. "Therapeutic use of glucocorticoids and immunosuppressive agents." Srpski arhiv za celokupno lekarstvo 133, Suppl. 1 (2005): 67–73. http://dx.doi.org/10.2298/sarh05s1067g.
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Pharmacotherapy of autoimmune thyroid disease (AITD) is complex. Apart from the replacement hormone therapy, antithyroid agents, beta adrenoceptor blockers and other drugs, in regard to the present symptoms, it also includes the administration of glucocorticoids and immunosuppressive agents. Physiological actions of glucocorticoids are significant in number, well known and described in details. The most prominent pharmacological properties of glucocorticoids, that are important for their clinical use, are antiinflammatory and immunosuppressive actions. In this article, the most notable clinical pharmacology aspects of glucocorticoids have been presented, including the basic principles of their therapeutic use, as well as the most important indications with the examples of dosing regiments (rheumatic disorders, renal diseases, allergic reactions, bronchial asthma, gastrointestinal inflammatory diseases, thrombocytopenia, organ transplantation, and Graves? ophthalmopathy). In addition, adverse and toxic effects of glucocorticoids as well as their interactions with other drugs have been described. Immunosuppressive agents have important role in treatment of immune disorders, including the reduction of immune response in autoimmune diseases and organ transplantation. Apart from glucocorticoids, immunosuppressive agents consist of calcineurin inhibitors (cyclosporine, tacrolimus), antiproliferative and antimetabolic agents (sirolimus, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide), monoclonal antibodies: anti-CD3 antibody (muromonab-CD3), anti- CD25 antibody (daclizumab), anti-TNF-alpha antibody (infliximab). In this part, the most updated facts about mechanism of action, rational therapeutic use, as well as adverse and toxic effects of immunosuppressive agents have been reviewed.
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Ouanes, S. "Glucocorticoid-based therapeutic options for PTSD." European Psychiatry 33, S1 (March 2016): S215. http://dx.doi.org/10.1016/j.eurpsy.2016.01.521.
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IntroductionPTSD has been associated with HPA axis alterations, mainly consisting of reduced cortisol levels, elevated CRH and enhanced glucocorticoid receptor responsiveness. These findings led to the emergence of glucocorticoid-based therapeutic options for PTSD.ObjectiveTo outline the different glucocorticoid-based interventions for PTSD either for prophylactic or for curative treatment.MethodsA systematic review was performed. The Medline database was searched using the following keywords: ‘PTSD’, ‘treatment’, ‘Glucocorticoids’, ‘hydrocortisone’.ResultsGlucocorticoid-based therapeutic for PTSD comprise preventive and curative interventions. Preventive interventions mainly consist of administering one single bolus of hydrocortisone shortly following the exposure to a traumatic event. Evidence comes from six published trials, all positive. Curative interventions include: prescribing hydrocortisone over short periods of time to treat PTSD symptoms, using Glucocorticoids to augment psychotherapy (in particular exposure therapy) for PTSD and using Mifepristone, a glucocorticoid receptor antagonist. Moreover, novel glucocorticoid receptor modulators are currently being developed and tested on animal models as a potential curative treatment for PTSD.ConclusionsUse of hydrocortisone in preventing PTSD might be tempting, as is the use of hydrocortisone or Glucocorticoid receptors antagonists/modulators in treating PTSD. Yet, it should be emphasized that these interventions are not mainstream yet. They rather reflect a revolutionary new direction.Disclosure of interestThe author has not supplied his/her declaration of competing interest.
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Kamada, Alan K. "Therapeutic Controversies in the Treatment of Asthma." Annals of Pharmacotherapy 28, no. 7-8 (July 1994): 904–14. http://dx.doi.org/10.1177/106002809402800716.
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OBJECTIVE: To introduce readers to the current controversial topics in the area of asthma therapy. Background is provided such that clinicians are aware of these issues and can make rational decisions. DATA SOURCES: Pertinent articles were individually identified and reviewed from each journal. STUDY SELECTION: Relevant studies, determined by topic and other specific criteria, e.g., testing methodology, were included. DATA SYNTHESIS: Further investigation is required in the areas discussed. Systemic effects, specifically growth suppression (in children), adrenal suppression, and osteoporosis, have been demonstrated with high-dose inhaled glucocorticoids; however, the clinical relevance of such intravenous glucocorticoid formulations via nebulizer have not been demonstrated. Likewise, data on the equivalence of the inhaled glucocorticoids, with regard to efficacy and potential systemic effects, and the differences between metered-dose inhalers and dry powder inhalers, with regard to aerosol characteristics and drug delivery, are unclear. Theophylline, when used with inhaled β-adrenergic agonists and systemic glucocorticoids for the treatment of acute asthma, as not been shown to provide clear benefit and may result in increased adverse effects. The use of regular (vs. “as needed” or prn) inhaled β-adrenergic agonists, although shown in two studies to be detrimental to the control of asthma and result in an increased risk of death or near death caused by asthma, has not been conclusively demonstrated to be harmful. CONCLUSIONS: Monitoring for adverse effects and the use of techniques to minimize systemic absorption (spacers and mouth rinsing) are recommended when high-dose inhaled glucocorticoid therapy is used. Intranasal and intravenous glucocorticoid products are not recommended for administration via nebulizer because of safety concerns. Until further data are available, inhaled glucocorticoids are thought to be equivalent on a μg-per-μg basis rather than an actuation-per-actuation basis. Theophylline is no longer recommended for treatment of acute exacerbations in nonhospitalized patients not already receiving the medication, and the link between deterioration of asthma control (and the risk for death) and regular inhaled beta-adrenergic agonists appears weak.
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Hughes, David, Nicole Vlahovich, Marijke Welvaert, Nicolin Tee, Peter Harcourt, Susan White, Alan Vernec, Ken Fitch, and Gordon Waddington. "Glucocorticoid prescribing habits of sports medicine physicians working in high-performance sport: a 30-nation survey." British Journal of Sports Medicine 54, no. 7 (February 5, 2020): 402–7. http://dx.doi.org/10.1136/bjsports-2019-101175.
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ObjectivesGlucocorticoids are commonly prescribed in medicine. When administered via certain routes, glucocorticoids are prohibited for incompetition use by WADA. The glucocorticoid prescribing habits of sports medicine doctors have not been reported.MethodsAn online survey was distributed internationally to physicians working in high-performance sports. The survey queried the doctors about their use of glucocorticoids with athletes and their understanding of WADA’s regulations regarding glucocorticoid use in competition.Results603 sports medicine doctors from 30 different countries participated. The majority (>85%) routinely injected glucocorticoids and/or prescribed glucocorticoids by other routes. There were substantial differences in the common routes of injection as well as types of glucocorticoid used among the physicians from various countries. A relatively small percentage of sports doctors (<25%) accurately identified which routes of glucocorticoid administration are prohibited in competition by WADA. There was a great variation in how long before competition the use of glucocorticoids would cause the doctor to consider applying for a therapeutic use exemption (TUE). A better understanding of the clearance rates of glucocorticoids from athletes’ bodies would greatly aid sports medicine doctors’ decisions on how and when to apply for a TUE. A small number of doctors had observed side effects of glucocorticoid administration, with the majority of side effects being minor in nature.ConclusionGlucocorticoids are widely prescribed by sports physicians. There is a need to better educate sports physicians on the current WADA regulations in relation to glucocorticoid administration.
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López, Francisco J., Robert J. Ardecky, Bruce Bebo, Khalid Benbatoul, Louise De Grandpre, Sha Liu, Mark D. Leibowitz, et al. "LGD-5552, an Antiinflammatory Glucocorticoid Receptor Ligand with Reduced Side Effects, in Vivo." Endocrinology 149, no. 5 (January 24, 2008): 2080–89. http://dx.doi.org/10.1210/en.2007-1353.
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Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.
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Otlewska, Anna, Grzegorz Szpotowicz, and Agnieszka Otlewska. "Effects of glucocorticoids on the skin." Pediatria i Medycyna Rodzinna 16, no. 3 (October 30, 2020): 257–60. http://dx.doi.org/10.15557/pimr.2020.0047.
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Glucocorticoids are widely used in the treatment of many diseases. They have multiple therapeutic applications mainly because of their anti-inflammatory, immunosuppressive and antiproliferative activity. Glucocorticoids are broadly used in the therapy of dermatological diseases. Various routes of glucocorticoids administration are known. In the treatment of skin disorders, glucocorticoids are often administered topically. It must be noted that glucocorticoid-induced complications may occur not only as a result of systemic treatment, but also topical application of glucocorticoids to the skin. Commonly reported cutaneous adverse effects resulting from glucocorticoid therapy include changes in facial appearance – rounded appearance of the face, redness, development of stretch marks, difficulty in wound healing, and easy bruising. It needs to be highlighted that glucocorticoids also affect metabolism, water and electrolyte balance, and bones. Therefore, in addition to dermatological disorders, they may also cause many other types of complications. As a result, a degree of caution is advised in the use of drugs of this class. In order to reduce the risk of adverse effects, glucocorticoids should be used at the smallest effective dose for the shortest possible time.
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Ponticelli, Claudio, and Francesco Locatelli. "Glucocorticoids in the Treatment of Glomerular Diseases." Clinical Journal of the American Society of Nephrology 13, no. 5 (February 23, 2018): 815–22. http://dx.doi.org/10.2215/cjn.12991117.
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Glucocorticoids exert anti-inflammatory and immunosuppressive activities by genomic and nongenomic effects. The classic genomic effects are mediated by cytosolic glucocorticoid receptors that can upregulate the expression of anti-inflammatory proteins in the nucleus (transactivation) or repress the translocation of proinflammatory transcription factors from the cytosol into the nucleus (transrepression). The nongenomic effects are probably mediated by membrane glucocorticoid receptors. Glucocorticoid receptors are expressed also in podocytes and experimental data suggest that glucocorticoids may protect from podocyte injury. Glucocorticoids have a low therapeutic index and may exert a number of time-dependent and dose-dependent side effects. Measures to prevent or attenuate side effects include single-morning administration of short-acting glucocorticoids, dietetic counseling, increasing physical activity, frequent monitoring, and adapting the doses to the clinical conditions of the patient. Synthetic glucocorticoids, either given alone or in combination with other immunosuppressive drugs, are still the cornerstone therapy in multiple glomerular disorders. However, glucocorticoids are of little benefit in C3 glomerulopathy and may be potentially deleterious in patients with maladaptive focal glomerulosclerosis. Their efficacy depends not only on the type and severity of glomerular disease, but also on the timeliness of administration, the dosage, and the duration of treatment. Whereas an excessive use of glucocorticoids can be responsible for severe toxicity, too low a dosage and too short duration of glucocorticoid treatment can result in false steroid resistance.
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van der Goes, Marlies C., Johannes W. G. Jacobs, and Johannes W. J. Bijlsma. "Rediscovering the therapeutic use of glucocorticoids in rheumatoid arthritis." Current Opinion in Rheumatology 28, no. 3 (May 2016): 289–96. http://dx.doi.org/10.1097/bor.0000000000000278.
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Ruiz-Irastorza, Guillermo, Amaia Ugarte, Ioana Ruiz-Arruza, and Munther Khamashta. "Seventy years after Hench’s Nobel prize: revisiting the use of glucocorticoids in systemic lupus erythematosus." Lupus 29, no. 10 (June 15, 2020): 1155–67. http://dx.doi.org/10.1177/0961203320930099.
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In 1950, Hench, Kendall and Reichstein were awarded with the Nobel Prize in Physiology and Medicine for the isolation and first therapeutic use of glucocorticoids. Since then, they have become one of the main agents in the treatment of systemic lupus erythematosus (SLE). The use of high-dose oral glucocorticoids (usually 1 mg/kg/day of prednisone equivalent) have become the rule for treating moderate to severe lupus activity. In addition, tapering schemes have not been well defined, all this leading to prolonged exposures to potentially damaging amounts of glucocorticoids. Several studies have shown that glucocorticoids are a major cause of toxicity in SLE in a dose-dependent manner, with prolonged doses greater than 7.5 mg/day being associated with damage accrual. Thus, there is an urgent need for different therapeutic schedules that can achieve a rapid and durable control of lupus activity while reducing the many unwanted effects of glucocorticoids. Recent data show that pulses of methyl-prednisolone are an effective first-line therapy to treat lupus flares (not only severe ones) without major short or long-term toxicity and allowing a reduction in oral prednisone doses. Universal use of hydroxychloroquine – always recommended, infrequently accomplished – and early therapy with immunosuppressive drugs also help control SLE and reduce prednisone load. Results from observational studies confirm the more rapid achievement of remission and the reduction of long-term damage using these combination schedules with reduced prednisone doses. Seventy years after their first therapeutic use, we are learning to use glucocorticoids in a more efficient and safe manner.
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Sjögren, Sara E., and Johan Flygare. "Progress towards Mechanism-Based Treatment for Diamond-Blackfan Anemia." Scientific World Journal 2012 (2012): 1–8. http://dx.doi.org/10.1100/2012/184362.
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Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplastic anemia, characterized by macrocytic anemia, reticulocytopenia, and severely reduced numbers of erythroid precursors in the bone marrow. For more than fifty years, glucocorticoids have remained the main option for pharmacological treatment of DBA. While continuous glucocorticoid administration increases hemoglobin levels in a majority of DBA patients, it also causes severe side effects. There is therefore a great need for more specific and effective treatments to boost or replace the use of glucocorticoids. Over the years, many alternative therapies have been tried out, but most of them have shown to be ineffective. Here we review previous and current attempts to develop such alternative therapies for DBA. We further discuss how emerging knowledge regarding the pathological mechanism in DBA and the therapeutic mechanism of glucocorticoids treatment may reveal novel drug targets for DBA treatment.
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Ballard, Philip L., and Roberta A. Ballard. "Scientific basis and therapeutic regimens for use of antenatal glucocorticoids." American Journal of Obstetrics and Gynecology 173, no. 1 (July 1995): 254–62. http://dx.doi.org/10.1016/0002-9378(95)90210-4.
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Drake, Amanda J., Justin I. Tang, and Moffat J. Nyirenda. "Mechanisms underlying the role of glucocorticoids in the early life programming of adult disease." Clinical Science 113, no. 5 (August 1, 2007): 219–32. http://dx.doi.org/10.1042/cs20070107.
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Compelling epidemiological evidence suggests that exposure to an adverse intrauterine environment, manifested by low-birth weight, is associated with cardiometabolic and behavioural disorders in adulthood. These observations have led to the concept of ‘fetal programming’. The molecular mechanisms that underlie this relationship remain unclear, but are being extensively investigated using a number of experimental models. One major hypothesis for early life physiological programming implicates fetal overexposure to stress (glucocorticoid) hormones. Several animal studies have shown that prenatal glucocorticoid excess, either from endogenous overproduction with maternal stress or through exogenous administration to the mother or fetus, reduces birth weight and causes lifelong hypertension, hyperglycaemia and behavioural abnormality in the offspring. Intriguingly, these effects are transmitted across generations without further exposure to glucocorticoids, which suggests an epigenetic mechanism. These animal observations could have huge implications if extrapolated to humans, where glucocorticoids have extensive therapeutic use in obstetric and neonatal practice.
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Spahn, Joseph D., and Alan K. Kamada. "Special Considerations in the Use of Glucocorticoids in Children." Pediatrics In Review 16, no. 7 (July 1, 1995): 266–72. http://dx.doi.org/10.1542/pir.16.7.266.
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GCs are used commonly for the treatment of various inflammatory and autoimmune diseases. Although potent and generally effective, they are not without risks for producing serious adverse effects, especially when used in high doses for prolonged periods of time. Thus, the clinician must balance the therapeutic effects of GCs with their risks for adverse effects; using the lowest possible effective GC doses as well as maximizing other therapeutic modalities are means by which this goal can be achieved. Early recognition and appropriate management are other methods to minimize GC-induced adverse effects. Maximization of therapy, early recognition, and appropriate management of adverse effects can minimize the potential severe complications of GC therapy.
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Meagher, L. C., J. M. Cousin, J. R. Seckl, and C. Haslett. "Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes." Journal of Immunology 156, no. 11 (June 1, 1996): 4422–28. http://dx.doi.org/10.4049/jimmunol.156.11.4422.
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Abstract Eosinophils and neutrophils are closely related, terminally differentiated cells that in vitro undergo constitutive cell death by apoptosis. The onset of apoptosis in both cell types can be delayed by hemopoietins and inflammatory mediators. Although there have been a number of reports demonstrating that glucocorticoids (in particular dexamethasone) antagonize the eosinophil life-prolonging effects of hemopoietins, direct effects of dexamethasone on eosinophil apoptosis have not been documented. In this study we examined the direct effects of glucocorticoids on eosinophil and neutrophil apoptosis in light of their common therapeutic use as anti-inflammatory and anti-allergic/hypereosinophilic agents. We found that treatment with dexamethasone induced eosinophil apoptosis. In contrast, dexamethasone was a potent inhibitor of neutrophil apoptosis. The effect of dexamethasone on both cell types was mediated through the glucocorticoid receptor, i.e., it was abolished by the glucocorticoid receptor antagonist RU38486. This is the first description of an agent that promotes eosinophil apoptosis while inhibiting neutrophil apoptosis, and thus presents a novel approach to the study of control of apoptosis in these closely related cell types as well as increases our understanding of the clinical action of glucocorticoids in inflammation.
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Quaia, Michele, Paola Zancai, Roberta Cariati, Silvana Rizzo, Mauro Boiocchi, and Riccardo Dolcetti. "Glucocorticoids promote the proliferation and antagonize the retinoic acid–mediated growth suppression of Epstein-Barr virus–immortalized B lymphocytes." Blood 96, no. 2 (July 15, 2000): 711–18. http://dx.doi.org/10.1182/blood.v96.2.711.
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Abstract Glucocorticoids are able to release Epstein-Barr virus–immortalized (EBV-immortalized) lymphoblastoid B cell lines (LCLs) from the persistent growth arrest induced in these cells by retinoic acid (RA). Moreover, physiologic concentrations of glucocorticoids efficiently antagonized LCL growth inhibition induced by 13-cis-RA; 9-cis-RA; all-trans-RA; and Ro 40-6055, an RA receptor (RAR) selective agonist. RAR expression levels, however, were not affected by glucocorticoids. Glucocorticoids, but not other steroid hormones, directly promote LCL proliferation, a phenomenon that was mainly mediated by down-regulation of the cyclin-dependent kinase (CDK) inhibitor p27Kip-1. Moreover, glucocorticoids contrasted the up-regulation of p27Kip-1, which was underlying the RA-induced LCL growth arrest, thereby indicating that glucocorticoids and RA signalings probably converge on p27Kip-1. Both antagonism of RA-mediated growth inhibition and promotion of LCL proliferation were efficiently reversed by the glucocorticoid receptor (GR) antagonist RU486, indicating that all of these effects were mediated by GR. Of note, RU486 also proved to be effective in vivo and, in mice, was able to significantly inhibit the growth of untreated LCLs as well as LCLs growth-arrested by RA in vitro. These findings provide a rational background to further evaluate the possible role of glucocorticoids in the pathogenesis of EBV-related lymphoproliferations of immunosuppressed patients. Moreover, GR antagonists deserve further consideration for their possible efficacy in the management of these disorders, and the use of schedules, including both RA and a GR antagonist, may allow a more thorough evaluation of the therapeutic potential of RA in this setting.
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Quaia, Michele, Paola Zancai, Roberta Cariati, Silvana Rizzo, Mauro Boiocchi, and Riccardo Dolcetti. "Glucocorticoids promote the proliferation and antagonize the retinoic acid–mediated growth suppression of Epstein-Barr virus–immortalized B lymphocytes." Blood 96, no. 2 (July 15, 2000): 711–18. http://dx.doi.org/10.1182/blood.v96.2.711.014k02_711_718.
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Glucocorticoids are able to release Epstein-Barr virus–immortalized (EBV-immortalized) lymphoblastoid B cell lines (LCLs) from the persistent growth arrest induced in these cells by retinoic acid (RA). Moreover, physiologic concentrations of glucocorticoids efficiently antagonized LCL growth inhibition induced by 13-cis-RA; 9-cis-RA; all-trans-RA; and Ro 40-6055, an RA receptor (RAR) selective agonist. RAR expression levels, however, were not affected by glucocorticoids. Glucocorticoids, but not other steroid hormones, directly promote LCL proliferation, a phenomenon that was mainly mediated by down-regulation of the cyclin-dependent kinase (CDK) inhibitor p27Kip-1. Moreover, glucocorticoids contrasted the up-regulation of p27Kip-1, which was underlying the RA-induced LCL growth arrest, thereby indicating that glucocorticoids and RA signalings probably converge on p27Kip-1. Both antagonism of RA-mediated growth inhibition and promotion of LCL proliferation were efficiently reversed by the glucocorticoid receptor (GR) antagonist RU486, indicating that all of these effects were mediated by GR. Of note, RU486 also proved to be effective in vivo and, in mice, was able to significantly inhibit the growth of untreated LCLs as well as LCLs growth-arrested by RA in vitro. These findings provide a rational background to further evaluate the possible role of glucocorticoids in the pathogenesis of EBV-related lymphoproliferations of immunosuppressed patients. Moreover, GR antagonists deserve further consideration for their possible efficacy in the management of these disorders, and the use of schedules, including both RA and a GR antagonist, may allow a more thorough evaluation of the therapeutic potential of RA in this setting.
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Burt, Morton G., Gudmundur Johannsson, A. Margot Umpleby, Donald J. Chisholm, and Ken K. Y. Ho. "Impact of Acute and Chronic Low-Dose Glucocorticoids on Protein Metabolism." Journal of Clinical Endocrinology & Metabolism 92, no. 10 (October 1, 2007): 3923–29. http://dx.doi.org/10.1210/jc.2007-0951.
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Abstract Context: High-dose glucocorticoids cause acute protein loss by increasing protein breakdown and oxidation. Whether lower glucocorticoid doses, typical of therapeutic use, induce sustained catabolism has not been studied. Objective: Our objective was to assess the effect of acute and chronic therapeutic glucocorticoid doses on protein metabolism. Design and Setting: We conducted an open longitudinal and a cross-sectional study at a clinical research facility. Patients and Intervention: Ten healthy subjects were studied before and after a short course of prednisolone (5 and 10 mg/d sequentially for 7 d each). Twelve subjects with inactive polymyalgia rheumatica receiving chronic (>12 months) prednisone (mean = 5.0 ± 0.8 mg/d) were compared with 12 age- and gender-matched normal subjects. Main Outcome Measure: Whole-body protein metabolism was assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance (leucine Ra, an index of protein breakdown), leucine oxidation (Lox, index of protein oxidation) and leucine incorporation into protein (LIP, index of protein synthesis) were estimated. Results: Prednisolone induced an acute significant increase in Lox (P = 0.008) and a fall in LIP (P = 0.08) but did not affect leucine Ra. There was no significant difference between the effects of the 5- and 10-mg prednisolone doses on leucine metabolism. In subjects receiving chronic prednisone therapy, leucine Ra, Lox, and LIP were not significantly different from normal subjects. Conclusion: Glucocorticoids stimulate protein oxidation after acute but not chronic administration. This time-related change suggests that glucocorticoid-induced stimulation of protein oxidation does not persist but that a metabolic adaptation occurs to limit protein loss.
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Grigorieva, D. D., E. M. Zhidkova, E. S. Lylova, D. V. Demina, K. I. Kirsanov, G. A. Belitsky, M. G. Yakubovskaya, and E. A. Lesovaya. "Inhibition of glucocorticoid-induced REDD1 expression by rapamycin in breast cancer cells." Advances in Molecular Oncology 9, no. 1 (March 18, 2022): 42–47. http://dx.doi.org/10.17650/2313-805x-2022-9-1-42-47.
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Introduction. Glucocorticoids are often used in combination therapy for breast cancer as an adjuvant to increase therapeutic effects of the main cytotoxic drug and to reduce side effects of chemotherapy. However, glucocorticoids can cause serious complications and trigger tumor progression. In the last decade, it was found that side effects from glucocorticoids are mediated by an increase in REDD1 gene expression. Using this knowledge, we have developed a new chemotherapeutic strategy for blood cancers aimed at reducing adverse events from glucocorticoids. Successful experiments with a combination of glucocorticoids and REDD1 expression inhibitors on the models of blood tumors allowed us to use this regimen for the treatment of certain subtypes of breast cancer.Objective: to optimize the algorithm of breast cancer cell treatment with a combination of glucocorticoids and REDD1 expression inhibitors on the example of rapamycin.Materials and methods. We used the MCF-7 and MDA-MB-231 breast cancer cell lines. The antiproliferative activity was estimated by direct cell count; REDD1 expression was measured using western blotting and quantitative polymerase chain reaction.Results. We found that rapamycin can inhibit both baseline and glucocorticoids induced REDD1 expression in the cells of luminal and triple negative breast cancer. The drug demonstrated lower ability to inhibit the viability of breast cancer cells than that of leukemia and lymphoma cells.Conclusion. Inhibited proliferation of breast cancer cells after their incubation with rapamycin and dexamethasone, as well as the ability of rapamycin to reduce basal and glucocorticoid-induced REDD1 expression in breast cancer cells suggest the importance of studies analyzing the impact of combinations that include glucocorticoids and REDD1 expression inhibitors from the class of PI3K/Akt/mTOR signaling pathway modulators (phosphoinositide-3-kinase/α-serine-threonine kinase/mammalian rapamycin target) on breast cancer cells.
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Dressler, J., F. Grünwald, B. Leisner, E. Moser, Chr Reiners, H. Schicha, P. Schneider, O. Schober, and M. Dietlein. "Guideline for radioiodine therapy for benign thyroid diseases (version 3)." Nuklearmedizin 43, no. 06 (2004): 217–20. http://dx.doi.org/10.1055/s-0038-1623919.
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SummaryThe version 3 of the guideline for radioiodine therapy for benign thyroid diseases presents first of all a revision of the version 2. The chapter indication for radioiodine therapy, surgical treatment or antithyroid drugs bases on an interdisciplinary consensus. The manifold criteria for decision making consider the entity of thyroid disease (autonomy, Graves’ disease, goitre, goitre recurrence), the thyroid volume, suspicion of malignancy, cystic nodules, risk of surgery and co-morbidity, history of subtotal thyroidectomy, persistent or recurrent thyrotoxicosis caused by Graves’ disease including known risk factors for relapse, compression of the trachea caused by goitre, requirement of direct therapeutic effect as well as the patient’s preference. Because often some of these criteria are relevant, the guideline offers the necessary flexibility for individual decisions. Further topics are patients’ preparation, counseling, dosage concepts, procedural details, results, side effects and follow-up care. The prophylactic use of glucocorticoids during radioiodine therapy in patients without preexisting ophthalmopathy as well as dosage and duration of glucocorticoid medication in patients with preexisting ophthalmopathy need to be clarified in further studies. The pragmatic recommendations for the combined use of radioiodine and glucocorticoids remained unchanged in the 3rd version.
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Rustecka, Agnieszka, Maria Węgrzynek, Agata Tomaszewska, and Bolesław Kalicki. "The role of glucocorticoids in the treatment of acute anaphylactic reaction." Pediatria i Medycyna Rodzinna 17, no. 3 (September 30, 2021): 256–60. http://dx.doi.org/10.15557/pimr.2021.0040.
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Food allergy is a growing health problem, which is particularly common among the youngest children. Anaphylaxis, which is defined as a sudden-onset and potentially fatal response to an allergen, is an indication for urgent treatment. Although intramuscular epinephrine is the treatment of choice, all therapeutic algorithms also recommend glucocorticoids. They play an important role in reducing the risk of late allergic reaction, and, due to their non-genomic effects, are also increasingly often mentioned in the context of early response to shock. This effect is directly proportional to the dose of the drug, and a reduced duration of the symptoms of anaphylactic shock is achieved with the use of high doses of glucocorticoids. The paper presents a case of a 3-month-old girl with an anaphylactic reaction after consuming a modified milk preparation. After systemic administration of glucocorticoids, a satisfactory therapeutic effect was observed in the child.
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Božić, Ksenija. "Significance of glucocorticoid dose adjustment in rheumatoid arthritis." Galenika Medical Journal 1, no. 2 (2022): 81–84. http://dx.doi.org/10.5937/galmed2202081b.
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For almost seven decades, glucocorticoids have been used to treat patients with rheumatoid arthritis. To this day, they remain an important part of the therapeutic approach in the treatment of those patients. Although their use is widespread due to well-known efficiency, their side effects are numerous. Therefore, there is no consensus on the dosage, the route of administration and the exact length of administration. According to modern international recommendations for the treatment of patients with early rheumatoid arthritis, the use of glucocorticoids is justified in the initial phase with conventionally synthetic drugs that change the course of the disease or in the period of overcoming their change, and in the lowest possible dose. In everyday clinical practice, it is suggested to determine the dose and duration of use based on the benefit/harm ratio for each patient before introducing glucocorticoids into therapy.
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Alexaki, Vasileia Ismini, and Holger Henneicke. "The Role of Glucocorticoids in the Management of COVID-19." Hormone and Metabolic Research 53, no. 01 (November 18, 2020): 9–15. http://dx.doi.org/10.1055/a-1300-2550.
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AbstractCoronavirus disease 2019 (COVID-19), caused by an infection with the novel coronavirus SARS-CoV-2, has resulted in a global pandemic and poses an emergency to public health systems worldwide. COVID-19 is highly infectious and is characterized by an acute respiratory illness that varies from mild flu-like symptoms to the life-threatening acute respiratory distress syndrome (ARDS). As such, there is an urgent need for the development of new therapeutic strategies, which combat the high mortality in severely ill COVID-19 patients. Glucocorticoids are a frontline treatment for a diverse range of inflammatory diseases. Due to their immunosuppressive functions, the use of glucocorticoids in the treatment of COVID-19 patients was initially regarded with caution. However, recent studies concluded that the initiation of systemic glucocorticoids in patients suffering from severe and critical COVID-19 is associated with lower mortality. Herein we review the anti-inflammatory effects of glucocorticoids and discuss emerging issues in their clinical use in the context of COVID-19.
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Buyse, Gunnar M., Nuri Gueven, and Craig M. McDonald. "Idebenone as a Novel Therapeutic Approach for Duchenne Muscular Dystrophy." European Neurological Review 10, no. 2 (2015): 189. http://dx.doi.org/10.17925/enr.2015.10.02.189.
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Progressive loss of pulmonary function leads to early morbidity and mortality in Duchenne muscular dystrophy (DMD) due to both expiratory impairment with ineffective airway clearance, and inspiratory impairment leading to nocturnal and daytime hypoventilation and respiratory failure. Glucocorticoid steroids have become a mainstay of DMD therapy with well-documented efficacy on muscle strength and respiratory function. However, the side-effect profile restricts their long-term use, particularly in non-ambulant patients. Idebenone improves secondary mitochondrial dysfunction caused by dystrophin deficiency, intracellular calcium accumulation and increased reactive oxygen species (ROS). Idebenone-mediated improved bioenergetics leads to enhanced adenosine triphosphate (ATP) production and reduced ROS. Based on this rationale, idebenone has been investigated clinically for efficacy on reducing respiratory function decline in exploratory phase II (DELPHI) and confirmatory phase III (DELOS) trials. Idebenone significantly reduced the loss of respiratory function in 8–18-year-old DMD patients who were not using concomitant glucocorticoids. These results indicate that idebenone can modify the natural course of respiratory disease progression in DMD, which is relevant in clinical practice where loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD.
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Zhao, Qingchun, Junbo Yang, Yongmei Sheng, Min Zhuang, and Min Qi. "Study on the Therapeutic Effect of Azithromycin Combined with Glucocorticoid on Pulmonary Function and Inflammatory Response in Children with Pneumonia." Journal of Healthcare Engineering 2022 (March 27, 2022): 1–7. http://dx.doi.org/10.1155/2022/5288148.
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Objective. The objective is to explore the efficacy of azithromycin combined with glucocorticoids in the treatment of children with pneumonia and its effect on the inflammatory response. Methods. A total of 86 children with pneumonia were divided into the experimental group (EG) and the control group (CG). Both groups received conventional treatment, the CG was treated with azithromycin and the EG was additionally treated with glucocorticoid methylprednisolone. The therapeutic effect, disappearance time of clinical symptoms, pulmonary function, inflammatory factors, immune function, quality of life, and adverse reactions were measured in the two groups. Results. After treatment, compared with CG, the total effective rate was significantly elevated, the disappearance time of various clinical symptoms was earlier, and various pulmonary function indexes were increased in the EG. The interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C reactive protein (CRP), and CD8+ levels were reduced, and CD3+ and CD4+ levels were increased in the EG. The quality-of-life scores were upregulated in the EG. Moreover, there was no significant difference in the incidence of adverse reactions between the two groups. Conclusion. The combined use of azithromycin and glucocorticoids in the treatment of children with Mycoplasma pneumoniae infection has a good curative effect, can significantly improve lung function, restore pulmonary inflammatory indexes to normal, and enhance patients’ immune function and improve their quality of life, with fewer adverse reactions and safety.
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Cicenas, Jonas, Edita Meskinyte-Kausiliene, Vigilijus Jukna, Arnas Rimkus, Jokubas Simkus, and Diana Soderholm. "SGK1 in Cancer: Biomarker and Drug Target." Cancers 14, no. 10 (May 12, 2022): 2385. http://dx.doi.org/10.3390/cancers14102385.
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Serum- and glucocorticoid-regulated kinases (SGKs) are members of the AGC family of serine/threonine kinases, consisting of three isoforms: SGK1, SGK2, and SGK3. SGK1 was initially cloned as a gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells. It is upregulated in some cancers and downregulated in others. SGK1 increases tumor cell survival, adhesiveness, invasiveness, motility, and epithelial to mesenchymal transition. It stimulates tumor growth by mechanisms such as activation of K+ channels and Ca2+ channels, Na+/H+ exchanger, amino acid and glucose transporters, downregulation of Foxo3a and p53, and upregulation of β-catenin and NFκB. This chapter focuses on major aspects of SGK1 involvement in cancer, its use as biomarker as well as potential therapeutic target.
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Neumann, Irmgard. "Immunosuppressive and glucocorticoid therapy for the treatment of ANCA-asssociated vasculitis." Rheumatology 59, Supplement_3 (April 29, 2020): iii60—iii67. http://dx.doi.org/10.1093/rheumatology/keaa035.
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Abstract ANCA-associated vasculitis (AAV) is a systemic, potentially organ and life threatening chronic autoimmune disease. With current management strategies, such as high-dose glucocorticoids in combination with cyclophosphamide or rituximab, outcomes have progressively improved with overall remission rates of 70–90%. However, relapse rates after discontinuation of therapy are consistently high, and treatment-related toxicity, mainly driven by glucocorticoids, still determines morbidity and quality of life. Prevention of relapses while minimizing adverse events is a major goal of long-term treatment, but the optimal duration of maintenance therapy and the role and utility of glucocorticoids in this context remains controversial. This review of induction and maintenance treatment of AAV aims to offer practical advice on immunosuppressive therapies and patient care, addressing individual risk factors and their therapeutic implications. It will discuss benefits and harms of the use of glucocorticoids, particularly focusing on recent advances in steroid sparing concepts.
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Chen, Liang, Sun-Li Hu, Jun Xie, De-Yi Yan, She-Ji Weng, Jia-Hao Tang, Bing-Zhang Wang, Zhong-Jie Xie, Zong-Yi Wu, and Lei Yang. "Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts." Oxidative Medicine and Cellular Longevity 2020 (September 25, 2020): 1–14. http://dx.doi.org/10.1155/2020/9102012.
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The widespread use of therapeutic glucocorticoids has increased the frequency of glucocorticoid-induced osteoporosis (GIOP). One of the potential pathological processes of GIOP is an increased level of oxidative stress and mitochondrial dysfunction, which eventually leads to osteoblast apoptosis. Proanthocyanidins (PAC) are plant-derived antioxidants that have therapeutic potential against GIOP. In our study, a low dose of PAC was nontoxic to healthy osteoblasts and restored osteogenic function in dexamethasone- (Dex-) treated osteoblasts by suppressing oxidative stress, mitochondrial dysfunction, and apoptosis. Mechanistically, PAC neutralized Dex-induced damage in the osteoblasts by activating the Nrf2 pathway, since silencing Nrf2 partly eliminated the protective effects of PAC. Furthermore, PAC injection restored bone mass and promoted the expression of Nrf2 in the distal femur of Dex-treated osteoporotic rats. In summary, PAC protect osteoblasts against Dex-induced oxidative stress and mitochondrial dysfunction via the Nrf2 pathway activation and may be a promising drug for treating GIOP.
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Small, Benjamin, Charles E. F. Millard, Edwina P. Kisanga, Andreanna Burman, Anika Anam, Clare Flannery, Ayman Al-Hendy, and Shannon Whirledge. "The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor." Journal of Clinical Endocrinology & Metabolism 105, no. 3 (October 29, 2019): 716–34. http://dx.doi.org/10.1210/clinem/dgz139.
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Abstract Context The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. Objective To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. Design Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. Results Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. Conclusions These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.
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Reichardt, Sybille D., Agathe Amouret, Chiara Muzzi, Sabine Vettorazzi, Jan P. Tuckermann, Fred Lühder, and Holger M. Reichardt. "The Role of Glucocorticoids in Inflammatory Diseases." Cells 10, no. 11 (October 28, 2021): 2921. http://dx.doi.org/10.3390/cells10112921.
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For more than 70 years, glucocorticoids (GCs) have been a powerful and affordable treatment option for inflammatory diseases. However, their benefits do not come without a cost, since GCs also cause side effects. Therefore, strong efforts are being made to improve their therapeutic index. In this review, we illustrate the mechanisms and target cells of GCs in the pathogenesis and treatment of some of the most frequent inflammatory disorders affecting the central nervous system, the gastrointestinal tract, the lung, and the joints, as well as graft-versus-host disease, which often develops after hematopoietic stem cell transplantation. In addition, an overview is provided of novel approaches aimed at improving GC therapy based on chemical modifications or GC delivery using nanoformulations. GCs remain a topic of highly active scientific research despite being one of the oldest class of drugs in medical use.
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Wang, Zijing, Lin Han, and Lisheng Yu. "Effects of surgery and topical medication on eosinophilic granulomatosis with polyangiitis with otitis media and sinusitis: a case report." Journal of International Medical Research 48, no. 4 (April 2020): 030006052092004. http://dx.doi.org/10.1177/0300060520920049.
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Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg–Strauss syndrome, is eosinophil-rich, necrotizing granulomatous inflammation often involving the respiratory tract. Furthermore, EGPA is necrotizing vasculitis that predominantly affects small to medium vessels and is associated with asthma and eosinophilia. Most patients with EGPA have sinusitis and some complain of hearing loss and refractory otitis media with effusion. Systemic use of immunosuppressants and glucocorticoids is currently recommended, despite the inevitable associated side effects. However, systemic treatment is not always effective for nasal and ear symptoms. We report a case of EGPA with refractory otitis media and chronic sinusitis, which were resistant to systemic high-dose steroids and immunosuppressants. However, these symptoms responded well to functional endoscopic sinus surgery and myringotomy and grommet insertion. We also administered budesonide nasal irrigation and glucocorticoid injection by intratympanic and postaural methods in this patient. The therapeutic effect was satisfactory.
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Reik, Andreas, Michael C. Holmes, Yuanyue Zhou, Matthew Mendel, Pei-Qi Liu, Gary Lee, David Paschon, et al. "Targeted Killing of Glioblastoma Multiforme In Vivo by IL-13 Zetakine Redirected CTLs Made Glucocorticoid Resistant with Zinc Finger Nucleases." Blood 110, no. 11 (November 16, 2007): 2597. http://dx.doi.org/10.1182/blood.v110.11.2597.2597.
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Abstract Genetic modification of cytolytic T-lymphocytes (CTL) for enhancing their functional immunobiology is a promising immunotherapeutic approach for the treatment of cancer and infectious disease. CTLs modified to express a chimeric antigen receptor comprising an extracellular IL13 domain and cytoplasmic CD3 domain (IL13-zetakine) can be re-directed both in vitro and in animal models to target glioblastoma multiforme (GBM), which is characterized by high expression of IL13Ralpha2. Patient-derived IL13-zetakine/HyTK expressing CD8+ CTL clones have entered early stage clinical trials. However, their clinical application is frequently limited in this patient population by the pervasive use of dexamethasone, a potent glucocorticoid analogue employed in the management of cerebral edema. Thus iatrogenic dexamethasone-mediated T-cell functional anergy and apoptosis in these patients is a barrier to realizing the full clinical utility of this adoptive therapy strategy. We hypothesized that knocking out the expression of the glucocorticoid receptor would render therapeutic CTLs resistant to the effects of synthetic glucocorticoids, including dexamethasone. We therefore developed engineered zinc finger nucleases (ZFNs) to specifically disrupt the glucocorticoid receptor (GR) locus in the human genome. ZFNs include the cleavage domain of the restriction enzyme FokI linked to an engineered zinc finger DNA-binding domain and can be designed to cleave a predetermined site in the genome. Natural repair of such DNA breaks via the error-prone non-homologous end joining pathway results in the inactivation of the target gene at frequencies which permit the isolation of knock out clones. Employing adenovirally delivered and transiently expressed ZFNs targeting exon 3 of the human GR gene, we isolated IL13-zetakine+ CD8+T-cells containing a biallelically mutated GR locus. These cells were characterized by the absence of full length GR protein, lack of glucocorticoid hormone-induced gene regulation and resistance to glucocorticoid hormone-mediated immunosupression and apoptosis. Importantly, the ZFN-modified, glucocorticoid-resistant CTLs demonstrated zetakine re-directed cytolytic activity and tumor cell specificity in chromium release assays in vitro and in an orthotopic mouse model of GBM in vivo. These results indicate that glucocorticoid-resistant IL13-zetakine targeted CTLs should retain function in cancer patients receiving glucocorticoids. A clinical trial to test this hypothesis is currently under development.
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Alunno, Alessia, Aurélie Najm, Pedro M. Machado, Heidi Bertheussen, Gerd R. Burmester, Francesco Carubbi, Gabriele De Marco, et al. "EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19." Annals of the Rheumatic Diseases 80, no. 6 (February 5, 2021): 698–706. http://dx.doi.org/10.1136/annrheumdis-2020-219724.
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Objectives Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies. Methods PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting. Results Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1–6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7–14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates. Conclusions Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19.
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Loftis, Christine Elizabeth, Emilia Dulgheru, and Adolfo Kaplan. "Rituximab for steroid-resistant organising pneumonia in a woman with rheumatoid arthritis." BMJ Case Reports 15, no. 11 (November 2022): e249912. http://dx.doi.org/10.1136/bcr-2022-249912.
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Organising pneumonia (OP) is a form of interstitial pneumonia characterised by inflammation and scarring leading to obstruction within the small airways and alveoli. Practice guidelines recommend treatment of moderate to severe OP with glucocorticoids; however, there have been cases of steroid-resistant OP successfully treated with rituximab. We describe a case of a woman in her 20s with rheumatoid arthritis who presented with pleuritic chest pain, haemoptysis and dyspnoea on exertion and was diagnosed with OP after multiple radiographic images and biopsies. The patient failed numerous treatment regimens, including corticosteroids, antibiotics and mycophenolate, but was successfully treated with rituximab. This case highlights the importance of identifying new therapeutic agents that will minimise the use of glucocorticoids in the treatment of OP.
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Mitre-Aguilar, Irma B., Daniel Moreno-Mitre, Jorge Melendez-Zajgla, Vilma Maldonado, Nadia J. Jacobo-Herrera, Victoria Ramirez-Gonzalez, and Gretel Mendoza-Almanza. "The Role of Glucocorticoids in Breast Cancer Therapy." Current Oncology 30, no. 1 (December 25, 2022): 298–314. http://dx.doi.org/10.3390/curroncol30010024.
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Glucocorticoids (GCs) are anti-inflammatory and immunosuppressive steroid molecules secreted by the adrenal gland and regulated by the hypothalamic–pituitary–adrenal (HPA) axis. GCs present a circadian release pattern under normal conditions; they increase their release under stress conditions. Their mechanism of action can be via the receptor-independent or receptor-dependent pathway. The receptor-dependent pathway translocates to the nucleus, where the ligand-receptor complex binds to specific sequences in the DNA to modulate the transcription of specific genes. The glucocorticoid receptor (GR) and its endogenous ligand cortisol (CORT) in humans, and corticosterone in rodents or its exogenous ligand, dexamethasone (DEX), have been extensively studied in breast cancer. Its clinical utility in oncology has mainly focused on using DEX as an antiemetic to prevent chemotherapy-induced nausea and vomiting. In this review, we compile the results reported in the literature in recent years, highlighting current trends and unresolved controversies in this field. Specifically, in breast cancer, GR is considered a marker of poor prognosis, and a therapeutic target for the triple-negative breast cancer (TNBC) subtype, and efforts are being made to develop better GR antagonists with fewer side effects. It is necessary to know the type of breast cancer to differentiate the treatment for estrogen receptor (ER)-positive, ER-negative, and TNBC, to implement therapies that include the use of GCs.
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Vandevyver, Sofie, Lien Dejager, Jan Tuckermann, and Claude Libert. "New Insights into the Anti-inflammatory Mechanisms of Glucocorticoids: An Emerging Role for Glucocorticoid-Receptor-Mediated Transactivation." Endocrinology 154, no. 3 (March 1, 2013): 993–1007. http://dx.doi.org/10.1210/en.2012-2045.
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Abstract Glucocorticoids are anti-inflammatory drugs that are widely used for the treatment of numerous (autoimmune) inflammatory diseases. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor family of transcription factors. Upon ligand binding, the GR translocates to the nucleus, where it acts either as a homodimeric transcription factor that binds glucocorticoid response elements (GREs) in promoter regions of glucocorticoid (GC)-inducible genes, or as a monomeric protein that cooperates with other transcription factors to affect transcription. For decades, it has generally been believed that the undesirable side effects of GC therapy are induced by dimer-mediated transactivation, whereas its beneficial anti-inflammatory effects are mainly due to the monomer-mediated transrepressive actions of GR. Therefore, current research is focused on the development of dissociated compounds that exert only the GR monomer-dependent actions. However, many recent reports undermine this dogma by clearly showing that GR dimer-dependent transactivation is essential in the anti-inflammatory activities of GR. Many of these studies used GRdim/dim mutant mice, which show reduced GR dimerization and hence cannot control inflammation in several disease models. Here, we review the importance of GR dimers in the anti-inflammatory actions of GCs/GR, and hence we question the central dogma. We summarize the contribution of various GR dimer-inducible anti-inflammatory genes and question the use of selective GR agonists as therapeutic agents.
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Floyd, Lauren, Adam Morris, Miland Joshi, and Ajay Dhaygude. "Glucocorticoid Therapy in ANCA Vasculitis: Using the Glucocorticoid Toxicity Index as an Outcome Measure." Kidney360 2, no. 6 (April 20, 2021): 1002–10. http://dx.doi.org/10.34067/kid.0000502021.
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AbstractBackgroundANCA-associated vasculitis (AAV) is an autoimmune disease. Induction remission and maintenance treatment typically includes high-dose, tapering glucocorticoids (GC), in addition to other immunosuppressive medication. The use of theGlucocorticoid Toxicity Index (GTI) provides a global, quantifiable assessment tool in which clinicians can assess GC-associated morbidity. Recent trials in AAV have exposed the need for systemic assessment of GC burden. In this small cohort study, we look to address these issues and the justification of newer GC sparing agents, such as C5a inhibitors.MethodsA retrospective cohort study of 43 patients with biopsy AAV was constructed from a single center between 2012–2016, and followed up for 48 months. The GTI table made up of adverse features was used to quantify patients’ GC toxicity. Electronic patient records were reviewed and scores calculated according to published methods. GTI scores were compared with cumulative steroid doses at separate intervals and incidences of adverse features in relation to the treatment timeline.ResultsThe mean age was 65.9 (±11.06) years and treatment regimens consisted of glucocorticoids alongside cyclophosphamide or rituximab. Our results showed statistical significance in the association of cumulative GC doses and GTI scores (P=0.008; 95% CI, 1.31 to 8.05). Adverse features relating to mood disturbance and GC-induced psychosis occurred early, in contrast to adrenal insufficiency, which typically presented later in the follow-up. Infection-related adverse events were consistent throughout.ConclusionsWe demonstrated that higher cumulative doses of steroids in AAV lead to worse glucocorticoid-related toxicity. Using the GTI creates the potential to individualize and quantify the adverse effects patients experience as a result of GC treatment and permits more patient-centered management. Although glucocorticoids remain the main adjunctive immunosuppression of AAV treatment, the narrow therapeutic window supports the need for GC-sparing treatments.
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Riley, Thomas R., and Michael D. George. "Risk for infections with glucocorticoids and DMARDs in patients with rheumatoid arthritis." RMD Open 7, no. 1 (February 2021): e001235. http://dx.doi.org/10.1136/rmdopen-2020-001235.
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Immunomodulatory therapy for rheumatoid arthritis (RA) carries risk for infectious complications. Understanding the risks of different therapeutic options is essential for making treatment decisions and appropriately monitoring patients. This review examines data on the risks for serious infections and other key infections of interest for the major classes of agents in use for RA: glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologics and Janus kinase (JAK) inhibitors. Conventional synthetic DMARDs have an excellent safety profile with recent data available supporting the relative safety of methotrexate. Tumour necrosis factor (TNF) inhibitors are associated with an increase in the risk of serious infections. Risk with other biological agents and with JAK inhibitors varies somewhat but overall appears similar to that of TNF inhibitors, with JAK inhibitors also associated with a greater risk of herpes zoster. Glucocorticoids have a dose-dependent effect on serious infection risk—at higher doses risk of infection with glucocorticoids is substantially greater than with other immunomodulatory therapies, and even low-dose therapy carries a risk of infection that appears to be similar to that of biological therapies.
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Hua, Charlotte, Frank Buttgereit, and Bernard Combe. "Glucocorticoids in rheumatoid arthritis: current status and future studies." RMD Open 6, no. 1 (January 2020): e000536. http://dx.doi.org/10.1136/rmdopen-2017-000536.
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Since their first use for treating rheumatoid arthritis (RA) in the late 1940s, glucocorticoids (GCs) have been representing a substantial part of the therapeutic arsenal for RA. However, even if GCs are still widely prescribed drugs, their toxicity is discussed controversially, so obtaining consensus on their use in RA is difficult. Hence, the most recent European League Against Rheumatism and American College of Rheumatology recommendations on early arthritis and RA management advocate the use of GCs as adjunct treatment to conventional synthetic disease-modifying antirheumatic drugs, at the lowest dose possible and for the shortest time possible. However, the recommendations remain relatively vague on dose regimens and routes of administration. Here, we describe literature data on which the current recommendations are based as well as data from recent trials published since the drafting of the guidelines. Moreover, we make proposals for daily practice and provide suggestions for studies that could help clarifying the place of GCs in RA management. Indeed, numerous items, including the benefit/risk ratio of low-dose and very low-dose GCs and optimal duration of GCs as bridging therapy, remain on the research agenda, and future studies are needed to guide the next recommendations for RA.
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Tan, Marcus, Thurston Heng, and Anselm Mak. "The Potential Use of Metformin, Dipyridamole, N-Acetylcysteine and Statins as Adjunctive Therapy for Systemic Lupus Erythematosus." Cells 8, no. 4 (April 6, 2019): 323. http://dx.doi.org/10.3390/cells8040323.
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Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune condition that can potentially affect every single organ during the course of the disease, leading to increased morbidity and mortality, and reduced health-related quality of life. While curative treatment is currently non-existent for SLE, therapeutic agents such as glucocorticoids, mycophenolate, azathioprine, cyclosporine, cyclophosphamide and various biologics are the mainstay of treatment based on their immunomodulatory and immunosuppressive properties. As a result of global immunosuppression, the side-effect profile of the current therapeutic approach is unfavourable, with adverse effects including myelosuppression, infection and malignancies. Hydroxychloroquine, one of the very few Food and Drug Administration (FDA)-approved medications for the treatment of SLE, has been shown to offer a number of therapeutic benefits to SLE patients independent of its immunomodulatory effect. As such, it is worth exploring drugs similar to hydroxychloroquine that confer additional clinical benefits unrelated to immunosuppressive mechanisms. Indeed, apart from hydroxychloroquine, a number of studies have explored the use of a few conventionally non-immunosuppressive drugs that are potentially useful in the management of SLE. In this review, non-immunosuppressive therapeutic agents, namely metformin, dipyridamole, N-acetylcysteine and statins, will be critically discussed with regard to their mechanisms of action and efficacy pertaining to their potential therapeutic role in SLE.
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Xie, Yufei, Panagiota Papadopoulou, Björn de Wit, Jan C. d’Engelbronner, Patrick van Hage, Alexander Kros, and Marcel J. M. Schaaf. "Two Types of Liposomal Formulations Improve the Therapeutic Ratio of Prednisolone Phosphate in a Zebrafish Model for Inflammation." Cells 11, no. 4 (February 15, 2022): 671. http://dx.doi.org/10.3390/cells11040671.
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Glucocorticoids (GCs) are effective anti-inflammatory drugs, but their clinical use is limited by their side effects. Using liposomes to target GCs to inflammatory sites is a promising approach to improve their therapeutic ratio. We used zebrafish embryos to visualize the biodistribution of liposomes and to determine the anti-inflammatory and adverse effects of the GC prednisolone phosphate (PLP) encapsulated in these liposomes. Our results showed that PEGylated liposomes remained in circulation for long periods of time, whereas a novel type of liposomes (which we named AmbiMACs) selectively targeted macrophages. Upon laser wounding of the tail, both types of liposomes were shown to accumulate near the wounding site. Encapsulation of PLP in the PEGylated liposomes and AmbiMACs increased its potency to inhibit the inflammatory response. However, encapsulation of PLP in either type of liposome reduced its inhibitory effect on tissue regeneration, and encapsulation in PEGylated liposomes attenuated the activation of glucocorticoid-responsive gene expression throughout the body. Thus, by exploiting the unique possibilities of the zebrafish animal model to study the biodistribution as well as the anti-inflammatory and adverse effects of liposomal formulations of PLP, we showed that PEGylated liposomes and AmbiMACs increase the therapeutic ratio of this GC drug.
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Cassier, Philippe A., Sawsan Abou-Amara-Olivieri, Pascal Artru, Marie-George Lapalus, Jean-Paul Riou, and Catherine Lombard-Bohas. "Mifepristone for ectopic ACTH secretion in metastatic endocrine carcinomas: report of two cases." European Journal of Endocrinology 158, no. 6 (June 2008): 935–38. http://dx.doi.org/10.1530/eje-07-0792.
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Ectopic adrenocorticotropin secretion (EAS) remains a therapeutic challenge whenever the tumor responsible for the syndrome is not amenable to curative resection. Two cases of EAS related to metastatic foregut-derived endocrine carcinomas led us to use mifepristone, an antagonist of both progesterone and glucocorticoids. Mifepristone clearly improved skin lesions and diabetes associated with hypercorticism. The beneficial effect lasted for about 10 months. In both cases, recurrent hypertension and hypokalemia eventually required adrenalectomy.
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Moalli, PA, S. Pillay, D. Weiner, R. Leikin, and ST Rosen. "A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA." Blood 79, no. 1 (January 1, 1992): 213–22. http://dx.doi.org/10.1182/blood.v79.1.213.213.
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Abstract Despite their widespread use, little is known of either the mechanism of action of glucocorticoids in the treatment of multiple myeloma or why patients ultimately become resistant to their therapeutic effects. Here, we address these issues by examining the direct effects of the glucocorticoid dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human multiple myeloma line and compare them with those of its hormone-resistant counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and is lysed by DEX. DEX-induced cytolysis is effectively blocked by the glucocorticoid antagonist, RU 486, indicating the specificity of this response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone, has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at low levels. Interestingly, we have found that two distinct phenotypes emerge from MM.1R with increasing periods of growth in culture. The first or “early” form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5 kb that has a deletion in its 3′ end. With further growth in the presence or absence of selective media, the expression of this transcript is repressed, resulting in the second or “late” phenotype characteristic of MM.1RL. No discernible differences in the organization of the genomic GR sequence in DEX-sensitive and -resistant cells were detectable by Southern analysis, suggesting that no gross deletions, rearrangements, or allelic variations in the genomic sequence account for the resistant phenotypes of MM.1R.
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Moalli, PA, S. Pillay, D. Weiner, R. Leikin, and ST Rosen. "A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNA." Blood 79, no. 1 (January 1, 1992): 213–22. http://dx.doi.org/10.1182/blood.v79.1.213.bloodjournal791213.
Full textAbstract:
Despite their widespread use, little is known of either the mechanism of action of glucocorticoids in the treatment of multiple myeloma or why patients ultimately become resistant to their therapeutic effects. Here, we address these issues by examining the direct effects of the glucocorticoid dexamethasone (DEX) on a hormone-sensitive clone (MM.1S) of a human multiple myeloma line and compare them with those of its hormone-resistant counterpart (MM.1R). MM.1S expresses approximately 50,000 glucocorticoid receptors (GR) per cell, the full-length 7.1-kb GR mRNA at high levels, and is lysed by DEX. DEX-induced cytolysis is effectively blocked by the glucocorticoid antagonist, RU 486, indicating the specificity of this response for the GR. In contrast to MM.1S, MM.1R is not lysed by hormone, has little hormone-binding activity, and expresses the 7.1-kb GR mRNA at low levels. Interestingly, we have found that two distinct phenotypes emerge from MM.1R with increasing periods of growth in culture. The first or “early” form, MM.1Re, expresses high levels of a variant GR mRNA of 5.5 kb that has a deletion in its 3′ end. With further growth in the presence or absence of selective media, the expression of this transcript is repressed, resulting in the second or “late” phenotype characteristic of MM.1RL. No discernible differences in the organization of the genomic GR sequence in DEX-sensitive and -resistant cells were detectable by Southern analysis, suggesting that no gross deletions, rearrangements, or allelic variations in the genomic sequence account for the resistant phenotypes of MM.1R.
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Reik, Andreas, Michael C. Holmes, Fyodor D. Urnov, Yuanyue Zhou, Matthew Mendel, Pei-Qi Liu, Erica Moehle, et al. "“Designer” Cells for Cellular Immunotherapy: Zinc Finger Nuclease (ZFN) Stimulated Targeted Recombination for the Simultaneous Disruption of the Endogenous Glucocorticoid Receptor and Site-Specific Addition of the IL13-Zetakine." Blood 108, no. 11 (November 16, 2006): 3705. http://dx.doi.org/10.1182/blood.v108.11.3705.3705.
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Abstract Immunotherapy utilizing genetically-modified cytolytic T-lymphocytes (CTL) provides a promising therapeutic approach for treating a variety of diseases, including cancer. We have demonstrated that CTLs encoding a chimeric T-cell receptor (IL13-zetakine), consisting of an extracellular IL-13 domain and a cytoplasmic CD3 domain, can be re-directed to target malignant glioma both in vitro and in animal models. This chimera re-targets the antigen-specific effector functions of modified CTLs to recognize glioblastomas due to the high expression of IL13R in these tumors. However, practical application of this approach is limited by the fact that patients undergoing surgical resection of the tumor often require treatment with glucocorticoids to control the resulting inflammation. Such treatment blocks the activity of the re-directed CTL clones and thus inhibits their therapeutic action. To overcome this limitation and render these tumor-specific CTLs resistant to glucocorticoids we have chosen to employ engineered ZFNs to specifically disrupt the endogenous glucocorticoid receptor (GR) gene. Heterodimeric ZFNs, consisting of the cleavage domain of the restriction enzyme FokI linked to engineered zinc finger DNA-binding domains, can be designed to specifically cleave a predetermined site in the genome. We have shown that these ZFN-induced double strand breaks can promote homologous recombination with high efficiency. In the present study we have investigated the use of ZFNs to simultaneously effect functional inactivation of human GR via specifically targeting the integration of the IL13-zetakine expression cassette into the GR locus itself. We can show that GR-specific ZFNs cleave their intended target sequences with high specificity and efficiency - resulting in the disruption of GR and the creation of glucocorticoid resistant cells. Moreover, we can demonstrate that these ZFNs coupled with an appropriate IL13-zetakine containing donor-DNA molecule can stimulate the integration of this chimeric T-cell receptor directly into the GR locus. Thus, this procedure results in the simultaneous knockout of GR and addition of the IL13-zetakine in a genetically defined manner. These data support the notion that ZFN-modified cells can be engineered to express chimeric antigen receptors from a predetermined genomic locus and may provide a general approach to generating effective cellular immunotherapy strategies.
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Ewig, Celeste L. Y., Kai Sang Wong, Pak Hei Chan, Ting Fan Leung, and Yin Ting Cheung. "Chronic Medication Use and Factors Associated With Polypharmacy Among Outpatient Pediatric Patients." Journal of Pediatric Pharmacology and Therapeutics 27, no. 6 (July 1, 2022): 537–44. http://dx.doi.org/10.5863/1551-6776-27.6.537.
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OBJECTIVE This study aimed to determine the prevalence and predictors of chronic polypharmacy among pediatric patients in an outpatient setting. METHODS We conducted a review of medications dispensed to patients from an outpatient pediatric facility during a 12-month period. Patients who received chronic medications (≥30 days' supply), which contained at least 1 active pharmaceutical ingredient were included in the study. Descriptive analysis was used to determine prevalence of polypharmacy while predictive factors for polypharmacy were evaluated using logistic regression. RESULTS Our study included 3920 patients (median age, 9.9 years; IQR, 9.4) and 16,401 medications. The median number of chronic medications used among our study cohort was 2.0 (IQR, 1) with polypharmacy identified in 309 (7.9%) patients. Predictors for polypharmacy were age and the use of certain therapeutic class of medications. Patients 12 to <19 years old (OR, 6.95; 95% CI, 4.1–10.1) were more likely to require ≥5 concurrent medications compared with patients younger than 2 years of age. Use of calcium supplements (OR, 21.2; 95% CI, 11.3–39.6), Vitamin D analogues (OR, 14.3; 95% CI, 8.0–25.8), and systemic glucocorticoids (OR, 18.8; 95% CI, 10.7–33.2) were also highly associated with polypharmacy. CONCLUSIONS Adolescents and children with chronic medical conditions who require prolonged systemic glucocorticoids, calcium, and Vitamin D supplements are at higher risk of incurring long-term polypharmacy. This subgroup of pediatric patients may be more vulnerable to the occurrence of negative outcomes resulting from the use of multiple chronic medications.
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Morrison-Nozik, Alexander, Priti Anand, Han Zhu, Qiming Duan, Mohamad Sabeh, Domenick A. Prosdocimo, Madeleine E. Lemieux, et al. "Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program." Proceedings of the National Academy of Sciences 112, no. 49 (November 23, 2015): E6780—E6789. http://dx.doi.org/10.1073/pnas.1512968112.
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Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC–KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.
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Rabelo, Patrícia Novais, Paula Novais Rabelo, Allyne Fernanda de Paula, Samuel Amanso da Conceição, Daniela Pultrini Pereira de Oliveira Viggiano, Daniela Espíndola Antunes, Estela Muszkat Jatene, Sílvia Leda França Moura de Paula, Monike Lourenço Dias, and Maria Aparecida Lopes Reis. "Propylthiouracil-induced agranulocytosis as a rare complication of antithyroid drugs in a patient with Graves’ disease." Revista da Associação Médica Brasileira 65, no. 6 (June 2019): 755–60. http://dx.doi.org/10.1590/1806-9282.65.6.755.
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SUMMARY INTRODUCTION: Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism. Antithyroid drugs (ATDs) are available as therapy. Agranulocytosis is a rare but potentially fatal complication of this therapy. In this study, we report agranulocytosis induced by propylthiouracil (PTU) in a patient with GD and the difficulties of clinical management. CASE: RNBA, male, 30 years old, with GD, treated with propylthiouracil (PTU). He progressed with pharyngotonsillitis. Then, PTU was suspended and antibiotic, filgrastim, propranolol, and prednisone were initiated. Due to the decompensation of hyperthyroidism, lithium carbonate, dexamethasone, and Lugol's solution were introduced. Total thyroidectomy (TT) was performed with satisfactory postoperative progression. DISCUSSION: We describe here the case of a young male patient with GD. For the treatment of hyperthyroidism, thioamides are effective options. Agranulocytosis induced by ATDs is a rare complication defined as the occurrence of a granulocyte count <500/mm3 after the use of ATDs. PTU was suspended, and filgrastim and antibiotics were prescribed. Radioiodine (RAI) or surgery are therapeutic alternatives. Due to problems with ATD use, a total thyroidectomy was proposed. The preoperative preparation was performed with beta-blocker, glucocorticoid, lithium carbonate, and Lugol solution. Cholestyramine is also an option for controlling hyperthyroidism. TT was performed without postoperative complications. CONCLUSION: Thionamide-induced agranulocytosis is a rare complication. With a contraindication to ATDs, RAI and surgery are definitive therapeutic options in GD. Beta-blockers, glucocorticoids, lithium carbonate, iodine, and cholestyramine may be an adjunctive therapy for hyperthyroidism.
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Shen, Yuqi, Jingyuan Xie, Li Lin, Xiao Li, Pingyan Shen, Xiaoxia Pan, Hong Ren, and Nan Chen. "Combination Cyclophosphamide/Glucocorticoids Provide Better Tolerability and Outcomes versus Glucocorticoids Alone in Patients with Sjogren’s Associated Chronic Interstitial Nephritis." American Journal of Nephrology 46, no. 6 (2017): 473–80. http://dx.doi.org/10.1159/000484903.
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Background: Steroid therapy has become an effective option for patients with primary Sjogren’s syndrome with tubulointerstitial nephritis (TIN), while the use of cytotoxic agents is still debated. Our study aimed to compare the clinical outcomes of patients treated with cyclophosphamide (CTX) combined with glucocorticoids with those of patients treated with glucocorticoids alone. Methods: All patients with primary Sjogren’s syndrome with chronic TIN admitted to the Division of Nephrology, Ruijin Hospital, from January 1, 2002, to April 30, 2016, and treated with steroids alone or combined with CTX were included. The immunological prognosis, improvements of renal function, and acquired tubular defects of the patients were retrospectively compared between the 2 therapeutic groups. Results: A total of 70 cases were included. Of these, 36 were diagnosed by renal biopsy. A total of 56 patients were treated with glucocorticoids alone, while 14 patients received glucocorticoids combined with CTX. There were no significant differences in clinical characteristics and laboratory parameters between the 2 therapeutic groups at baseline. Compared with patients in the steroid group, patients in the CTX group showed better estimated glomerular filtration rate (eGFR) improvement (21.35 ± 19.63 vs. 2.72 ± 19.11 mL/min/1.73 m2, p = 0.006) but a similar decline in immunoglobulin G (IgG; 450 [interquartile range, IQR 910] vs.176 [IQR 1,910] mg/dL, p = 0.93) at 12 months of follow-up. CTX therapy was associated with better eGFR improvement (β = 12.96 [2.95–22.97]) even after adjusting for dry mouth, anti-Sjögren’s-syndrome-related antigen A and anti-Sjögren’s-syndrome-related antigen B positivity, hemoglobin, initial steroid dose, and baseline eGFR by linear regression analyses. Subgroup analyses revealed that the beneficial effects of CTX therapy on renal function were only observed in patients with baseline IgG ≥1,560 mg/dL or eGFR <90 mL/min/1.73 m2. The urine α1-microglobulin improvement was better in the CTX group than in the steroid group at 12 months of follow-up (β = 1.29, 95% CI 0.56–2.02, p = 0.001). Conclusions: CTX therapy is suggested for primary Sjogren’s syndrome patients with chronic TIN, especially those with higher IgG levels and abnormal renal function at baseline.
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Kamiyama, Koki, Naoyuki Matsuda, Seiji Yamamoto, Ken-ichi Takano, Yasuo Takano, Hiromi Yamazaki, Shun-ichiro Kageyama, et al. "Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 6 (December 2008): L998—L1006. http://dx.doi.org/10.1152/ajplung.00459.2007.
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The use of glucocorticoids for treatment of sepsis has waxed and waned during the past several decades, and recent randomized controlled trials have evoked a reassessment of this therapy. Most glucocorticoid actions are mediated by its specific intracellular receptors (GRs). Thus we initially evaluated whether sepsis and high-dose corticosteroid therapy can regulate guinea pig pulmonary expression of GRs: active receptor, GRα, and dominant negative receptor, GRβ. Sepsis induction by LPS injection (300 μg/kg ip) decreased mRNA and protein levels of GRα and increased protein expression of GRβ in lungs. High-dose methylprednisolone (40 mg/kg ip), administered simultaneously with LPS, markedly potentiated the decrease in GRα expression but slightly affected the increase in GRβ expression. Consequently, this led to a significant reduction in GRα nuclear translocation. Nevertheless, methylprednisolone treatment strongly eliminated LPS induction of NF-κB activity, as determined by NF-κB nuclear translocation and by gel mobility shift assays. Furthermore, the LPS-induced increase in inflammatory cells in bronchoalveolar lavage fluid was blunted by administration of the corticosteroid. On the other hand, immunofluorescent staining for cleaved caspase-3 showed a marked increase in this proapoptotic marker in lung sections, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) represented an enhanced appearance of cell apoptosis in lungs and spleen when methylprednisolone was given together with LPS. Cell apoptosis is now considered to play a role in the pathogenesis of septic syndrome. We thus suggest that the action of glucocorticoids at high doses to accelerate sepsis-induced cell apoptosis may overwhelm their therapeutic advantages in septic shock.
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Alunno, Alessia, Aurélie Najm, Pedro M. Machado, Heidi Bertheussen, Gerd-Rüdiger R. Burmester, Francesco Carubbi, Gabriele De Marco, et al. "2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19." Annals of the Rheumatic Diseases 81, no. 1 (October 7, 2021): 34–40. http://dx.doi.org/10.1136/annrheumdis-2021-221366.
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ObjectivesTo update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19.MethodsAccording to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting.ResultsWe updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapyConclusionsGrowing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.