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MacLeod, Clare, Patrick W. F. Hadoke, and Mark Nixon. "Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers?" International Journal of Molecular Sciences 22, no. 14 (July 16, 2021): 7622. http://dx.doi.org/10.3390/ijms22147622.
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Glucocorticoids are steroid hormones with key roles in the regulation of many physiological systems including energy homeostasis and immunity. However, chronic glucocorticoid excess, highlighted in Cushing’s syndrome, is established as being associated with increased cardiovascular disease (CVD) risk. Atherosclerosis is the major cause of CVD, leading to complications including coronary artery disease, myocardial infarction and heart failure. While the associations between glucocorticoid excess and increased prevalence of these complications are well established, the mechanisms underlying the role of glucocorticoids in development of atheroma are unclear. This review aims to better understand the importance of glucocorticoids in atherosclerosis and to dissect their cell-specific effects on key processes (e.g., contractility, remodelling and lesion development). Clinical and pre-clinical studies have shown both athero-protective and pro-atherogenic responses to glucocorticoids, effects dependent upon their multifactorial actions. Evidence indicates regulation of glucocorticoid bioavailability at the vasculature is complex, with local delivery, pre-receptor metabolism, and receptor expression contributing to responses linked to vascular remodelling and inflammation. Further investigations are required to clarify the mechanisms through which endogenous, local glucocorticoid action and systemic glucocorticoid treatment promote/inhibit atherosclerosis. This will provide greater insights into the potential benefit of glucocorticoid targeted approaches in the treatment of cardiovascular disease.
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Mitchell, Brett M., and R. Clinton Webb. "Impaired Vasodilation and Nitric Oxide Synthase Activity in Glucocorticoid-Induced Hypertension." Biological Research For Nursing 4, no. 1 (July 2002): 16–21. http://dx.doi.org/10.1177/1099800402004001003.
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Synthetic glucocorticoids are among the most widely prescribed medications by physicians. Although they have a vast array of beneficial effects such as immunosuppression and anti-inflammation, excess glucocorticoids can lead to iatrogenic Cushing’s syndrome, which includes hypertension and cardiovascular disease. The exact mechanism by which glucocorticoids elevate blood pressure is not completely understood, but it appears to be a complex pathology that involves increased responsiveness to vasoconstrictors and decreased vasodilator production. Nitric oxide is a vasodilator that plays a key role in blood pressure regulation, and previous studies have shown that a reduction in nitric oxide production or bioavailability contributes to hypertension. Tetrahydrobiopterin, a necessary cofactor for nitric oxide synthase activity, can affect nitric oxide production and bioavailability, with low levels causing decreased nitric oxide production. However, little is known about the interaction between glucocorticoids and tetrahydrobiopterin levels. In this review, the roles of nitric oxide and tetrahydrobiopterin in the pathogenesis of glucocorticoid hypertension will be discussed. Furthermore, the authors propose that glucocorticoids exert a genomic effect to decrease guanosine triphosphate cyclohydrolase I, the rate-limiting enzyme in the production of tetrahydrobiopterin. In the future, tetrahydrobiopterin supplementation in patients with iatrogenic Cushing’s syndrome may prove to be beneficial and decrease mortality attributed to cardiovascular disease.
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Petersen, Helle Heibroch, Thomas K. Andreassen, Tilman Breiderhoff, Jan Hinrich Bräsen, Herbert Schulz, Volkmar Gross, Hermann-Josef Gröne, Anders Nykjaer, and Thomas E. Willnow. "Hyporesponsiveness to Glucocorticoids in Mice Genetically Deficient for the Corticosteroid Binding Globulin." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7236–45. http://dx.doi.org/10.1128/mcb.00400-06.
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ABSTRACT Corticosteroid binding globulin (CBG) is the carrier for glucocorticoids in plasma. The protein is believed to keep the steroids inactive and to regulate the amount of free hormone acting on target tissues (free hormone hypothesis). Here, we generated a mouse model genetically deficient for CBG to test the contribution of the carrier to glucocorticoid action and adrenocortical stress response. The absence of CBG resulted in a lack of corticosterone binding activity in serum and in an ∼10-fold increase in free corticosterone levels in CBG-null mice, consistent with its role in regulation of circulating free hormone levels. Surprisingly, cbg − / − animals did not exhibit features seen in organisms with enhanced glucocorticoid signaling. Rather, the mice exhibited increased activity of the pituitary axis of hormonal control, normal levels of gluconeogenetic enzymes, and fatigue, as well as an aggravated response to septic shock, indicating an inability to appropriately respond to the excess free corticosterone in the absence of CBG. Thus, our data suggest an active role for CBG in bioavailability, local delivery, and/or cellular signal transduction of glucocorticoids that extends beyond a function as a mere cargo transporter.
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Fowden, A. L., and A. J. Forhead. "Endocrine mechanisms of intrauterine programming." Reproduction 127, no. 5 (May 2004): 515–26. http://dx.doi.org/10.1530/rep.1.00033.
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Epidemiological findings and experimental studies in animals have shown that individual tissues and whole organ systems can be programmedin uteroduring critical periods of development with adverse consequences for their function in later life. Detailed morphometric analyses of the data have shown that certain patterns of intrauterine growth, particularly growth retardation, can be related to specific postnatal outcomes. Since hormones regulate fetal growth and the development of individual fetal tissues, they have a central role in intrauterine programming. Hormones such as insulin, insulin-like growth factors, thyroxine and the glucocorticoids act as nutritional and maturational signals and adapt fetal development to prevailing intrauterine conditions, thereby maximizing the chances of survival bothin uteroand at birth. However, these adaptations may have long-term sequelae. Of the hormones known to control fetal development, it is the glucocorticoids that are most likely to cause tissue programmingin utero. They are growth inhibitory and affect the development of all the tissues and organ systems most at risk of postnatal pathophysiology when fetal growth is impaired. Their concentrationsin uteroare also elevated by all the nutritional and other challenges known to have programming effects. Glucocorticoids act at cellular and molecular levels to alter cell function by changing the expression of receptors, enzymes, ion channels and transporters. They also alter various growth factors, cytoarchitectural proteins, binding proteins and components of the intracellular signalling pathways. Glucocorticoids act, directly, on genes and, indirectly, through changes in the bioavailability of other hormones. These glucocorticoid-induced endocrine changes may be transient or persist into postnatal life with consequences for tissue growth and development both before and after birth. In the long term, prenatal glucocorticoid exposure can permanently reset endocrine systems, such as the somatotrophic and hypothalamic–pituitary–adrenal axes, which, in turn, may contribute to the pathogenesis of adult disease. Endocrine changes may, therefore, be both the cause and the consequence of intrauterine programming.
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WIEDERSBERG, S. "Bioavailability and bioequivalence of topical glucocorticoids." European Journal of Pharmaceutics and Biopharmaceutics 68, no. 3 (March 2008): 453–66. http://dx.doi.org/10.1016/j.ejpb.2007.08.007.
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Freeman, Lisa, Martin Hewison, Susan V. Hughes, Katie N. Evans, Deborah Hardie, Terry K. Means, and Ronjon Chakraverty. "Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells." Blood 106, no. 6 (September 15, 2005): 2042–49. http://dx.doi.org/10.1182/blood-2005-01-0186.
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Abstract Glucocorticoids (GCs) exert powerful anti-inflammatory effects that may relate in part to their ability to restrict the differentiation and function of dendritic cells (DCs). Although these inhibitory effects are dependent upon GCs binding to nuclear glucocorticoid receptors (GRs), fine-tuning of GR signaling is achieved by prereceptor interconversion of cortisol that binds GRs with high affinity and cortisone that does not. We show for the first time that human monocyte-derived DCs are able to generate cortisol as a consequence of up-regulated expression of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Immature DCs demonstrate selective enhancement of 11β-HSD1 reductase activity, leading to increased conversion of inactive cortisone to active cortisol. Enhancement of GC bioavailability is maintained or increased upon terminal differentiation induced by signals associated with innate immune activation. In marked contrast, maturation induced by CD40 ligation leads to a sharp reduction in cortisol generation by DCs. The differentiation of DCs from monocyte precursors is inhibited at physiologic concentrations of inactive cortisone, an effect that requires activity of the 11β-HSD1 enzyme. In conclusion, prereceptor regulation of endogenous GCs appears to be an important determinant of DC function and represents a potential target for therapeutic manipulation.
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Cattaneo, Dario, Norberto Perico, Flavio Gaspari, Eliana Gotti, and Giuseppe Remuzzi. "Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation." Kidney International 62, no. 3 (September 2002): 1060–67. http://dx.doi.org/10.1046/j.1523-1755.2002.00531.x.
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Hu, Aihua, Sumbul Fatma, Jing Cao, Judith S. Grunstein, Gustavo Nino, Yael Grumbach, and Michael M. Grunstein. "Th2 cytokine-induced upregulation of 11β-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 5 (May 2009): L790—L803. http://dx.doi.org/10.1152/ajplung.90572.2008.
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The anti-inflammatory actions of endogenous glucocorticoids (GCs) are regulated by the activities of the GC-activating and -inactivating enzymes, 11β-hydroxysteroid dehydrogenase (11β-HSD)-1 and 11β-HSD2, respectively, that catalyze the interconversion of the inert GC, cortisone, and its bioactive derivative, cortisol. Proinflammatory cytokines regulate 11β-HSD1 expression in various cell types and thereby modulate the bioavailability of cortisol to the glucocorticoid receptor (GR). Since endogenous GCs reportedly attenuate the airway asthmatic response to allergen exposure, we investigated whether airway smooth muscle (ASM) exhibits cytokine-induced changes in 11β-HSD1 expression that enable the ASM to regulate its own bioavailability of GC and, accordingly, the protective effect of GR signaling on airway function under proasthmatic conditions. Human ASM cells exposed to the primary proasthmatic T helper type 2 (Th2) cytokine, IL-13, exhibited upregulated expression of 11β-HSD1, an effect that was attributed to activation of the transcription factor, AP-1, coupled to MAPK signaling via the ERK1/2 and JNK pathways. The induction of 11β-HSD1 expression and its oxoreductase activity by IL-13 (also IL-4) served to amplify the conversion of cortisone to cortisol by the cytokine-exposed ASM and, hence, heighten GR-mediated transcriptional activation. Extended studies demonstrated that this amplified 11β-HSD1-dependent GC activation enabled physiologically relevant concentrations of cortisone to exert enhanced protection of ASM tissues from the proasthmatic effects of IL-13 on ASM constrictor and relaxation responsiveness. Collectively, these novel findings identify a Th2 cytokine-driven homeostatic feedback mechanism in ASM that enhances its responsiveness to endogenous GCs by upregulating 11β-HSD1 activity, thereby curtailing the adverse effects of the proasthmatic cytokine on airway function.
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Kamada, Alan K., Matthew B. Wiener, Nicole M. LaVallee, Maryanne Bartoszek Scott, John C. Seiner, and Stanley J. Szefler. "A Pharmacokinetic Comparison of Two Oral Liquid Glucocorticoid Formulations." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 17, no. 2 (March 4, 1997): 353–56. http://dx.doi.org/10.1002/j.1875-9114.1997.tb03719.x.
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To compare pharmacokinetics of liquid prednisolone and prednisone solutions and to assess relative bioavailability, six healthy adult men were administered 15 mg of each formulation. Blood samples were obtained and assayed for plasma prednisolone concentrations by high‐performance liquid chromatography. Peak concentration was significantly higher with liquid prednisolone (mean ± SD 430.3 ± 62.5 vs 333.0 ± 27.8 ng/ml, p=0.013), with similar times to peak concentration. Prednisolone liquid gave higher concentrations at every time point (statistically significant for all except 0.25 hrs after the dose), resulting in a significantly greater total area under the curve (2029.8 ± 246.9 vs 1633.3 ± 221.1 ng/ml•hour, respectively, p=0.002). Clearance was slower for prednisolone (128.3 ± 15.1 vs 149.1 ± 17.6 ml/min/1.73 m2, p=0.01), and the relative bioavailability of the prednisolone liquid using prednisone liquid as the reference standard was 116 ± 14%. Thus, prednisolone liquid has similar pharmacokinetic characteristics as prednisone liquid, with improved bioavailability.
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Elder, Charlotte J., Ruben Vilela, Trevor N. Johnson, Rosie N. Taylor, E. Helen Kemp, Brian G. Keevil, Alexandra S. Cross, Richard J. Ross, and Neil P. Wright. "Pharmacodynamic studies of nasal tetracosactide with salivary glucocorticoids for a noninvasive Short Synacthen Test." Journal of Clinical Endocrinology & Metabolism 105, no. 8 (June 2, 2020): 2692–703. http://dx.doi.org/10.1210/clinem/dgaa323.
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Abstract Context The Short Synacthen Test (SST) is the gold standard for diagnosing adrenal insufficiency. It requires invasive administration of Synacthen, venous sampling, and is resource-intensive. Objective To develop a nasally administered SST, with salivary glucocorticoids measurement, to assess the adrenal response. Design We conducted 5 studies: 4 open-label, sequence-randomized, crossover, pharmacodynamic studies testing 6 doses/formulations and a repeatability study. Additionally, pharmacokinetic analysis was undertaken using our chosen formulation, 500 µg tetracosactide with mucoadhesive chitosan, Nasacthin003, in our pediatric study. Setting Adult and children’s clinical research facilities. Participants A total of 36 healthy adult males and 24 healthy children. Intervention We administered all 6 nasal formulations using an European regulator endorsed atomization device. The IV comparators were 250 µg or 1 µg SST. Main Outcome Measures We analyzed paired blood and saliva samples for plasma cortisol and salivary cortisol and cortisone. Results The addition of chitosan to tetracosactide and dose escalation increased peak cortisol response (P = 0.01 and 0.001, respectively). The bioavailability of Nasacthin003 was 14.3%. There was no significant difference in plasma cortisol at 60 minutes between 500 µg Nasacthin003 and 250 µg IV Synacthen (P = 0.17). The repeatability coefficient at 60 minutes was 105 nmol/L for IV Synacthen and salivary cortisol and cortisone was 10.3 and 21.1 nmol/L, respectively. The glucocorticoid response in children was indistinguishable from that of adults. Conclusions Nasal administration of Nasacthin003 generates equivalent plasma cortisol values to the 250-µg IV SST and, with measurement at 60 minutes of salivary cortisol or cortisone, provides a noninvasive test for adrenal insufficiency.
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Perogamvros, I., C. Underhill, D. E. Henley, K. D. Hadfield, W. G. Newman, D. W. Ray, S. L. Lightman, G. L. Hammond, and P. J. Trainer. "Novel Corticosteroid-Binding Globulin Variant That Lacks Steroid Binding Activity." Endocrine Reviews 31, no. 4 (August 1, 2010): 607–8. http://dx.doi.org/10.1210/edrv.31.4.9978.
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Abstract Background: Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described. Patients, Methods, and Results: In a 26-yr-old female with hypotension, fatigue, and undetectable serum cortisol at presentation, we have identified a novel homozygous c.776g>t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two β-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband. Conclusion: We describe a novel CBG variant that lacks steroid binding. All mutant homozygotes have very low serum cortisol, but normal free cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency.
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Nakhla, Meranda, Andrew E. Denker, James D. Connor, Thomas O. Carpenter, Philip D. Walson, Arturo G. Porras, Catherine Z. Matthews, et al. "Bioavailability and Short-Term Tolerability of Alendronate in Glucocorticoid-Treated Children." Clinical Therapeutics 33, no. 10 (October 2011): 1516–23. http://dx.doi.org/10.1016/j.clinthera.2011.09.001.
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Edsb�cker, S., K. E. Andersson, and �. Ryrfeldt. "Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man." European Journal of Clinical Pharmacology 29, no. 4 (1985): 477–81. http://dx.doi.org/10.1007/bf00613465.
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Choudhury, Sirazum, Tricia Tan, Katharine Lazarus, and Karim Meeran. "The use of prednisolone versus dual-release hydrocortisone in the treatment of hypoadrenalism." Endocrine Connections 10, no. 2 (February 2021): R66—R76. http://dx.doi.org/10.1530/ec-20-0473.
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The introduction of adrenocortical extract in 1930 improved the life expectancy of hyhpoadrenal patients, with further increases seen after the introduction of cortisone acetate from 1948. Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multidose regimens. There remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with the risk of detrimental excess glucocorticoid exposure at later times in the day. The way forwards will involve replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens. The steroid profile produced by both prednisolone and dual-release hydrocortisone (Plenadren), provide a smoother glucocorticoid profile of cortisol than standard oral multidose regimens of hydrocortisone and cortisone acetate. The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Although there is emerging evidence of both treatments offering better cardiometabolic outcomes than standard glucocorticoid replacement regimens, there is a paucity of evidence involving very low dose prednisolone (2–4 mg daily) compared to the larger doses (~7.5 mg) historically used. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.
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Vermeer, Harry, Brenda I. Hendriks-Stegeman, Bart van der Burg, Sylvia C. van Buul-Offers, and Maarten Jansen. "Glucocorticoid-Induced Increase in Lymphocytic FKBP51 Messenger Ribonucleic Acid Expression: A Potential Marker for Glucocorticoid Sensitivity, Potency, and Bioavailability." Journal of Clinical Endocrinology & Metabolism 88, no. 1 (January 2003): 277–84. http://dx.doi.org/10.1210/jc.2002-020354.
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Paglialunga, Musetta, Sara Flamini, Raffaele Contini, Marta Febo, Erika Ricci, Simona Ronchetti, Oxana Bereshchenko, Graziella Migliorati, Carlo Riccardi, and Stefano Bruscoli. "Anti-Inflammatory Effects of Synthetic Peptides Based on Glucocorticoid-Induced Leucine Zipper (GILZ) Protein for the Treatment of Inflammatory Bowel Diseases (IBDs)." Cells 12, no. 18 (September 16, 2023): 2294. http://dx.doi.org/10.3390/cells12182294.
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Glucocorticoids (GCs) are commonly used to treat autoimmune and inflammatory diseases, but their clinical effects and long-term use can lead to serious side effects. New drugs that can replace GCs are needed. Glucocorticoid-induced leucine zipper (GILZ) is induced by GCs and mediates many of their anti-inflammatory effects, such as inhibiting the pro-inflammatory molecule NF-κB. The GILZ C-terminal domain (PER region) is responsible for GILZ/p65NF-κB interaction and consequent inhibition of its transcriptional activity. A set of five short peptides spanning different parts of the PER region of GILZ protein was designed, and their anti-inflammatory activity was tested, both in vitro and in vivo. We tested the biological activity of GILZ peptides in human lymphocytic and monocytic cell lines to evaluate their inhibitory effect on the NF-κB-dependent expression of pro-inflammatory cytokines. Among the tested peptides, the peptide named PEP-1 demonstrated the highest efficacy in inhibiting cell activation in vitro. Subsequently, PEP-1 was further evaluated in two in vivo experimental colitis models (chemically induced by DNBS administration and spontaneous colitis induced in IL-10 knock-out (KO) mice (to assess its effectiveness in counteracting inflammation. Results show that PEP-1 reduced disease severity in both colitis models associated with reduced NF-κB pro-inflammatory activity in colon lamina propria lymphocytes. This study explored GILZ-based ‘small peptides’ potential efficacy in decreasing lymphocyte activation and inflammation associated with experimental inflammatory bowel diseases (IBDs). Small peptides have several advantages over the entire protein, including higher selectivity, better stability, and bioavailability profile, and are easy to synthesize and cost-effective. Thus, identifying active GILZ peptides could represent a new class of drugs for treating IBD patients.
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Gouveia, Virgínia M., Loris Rizzello, Claudia Nunes, Alessandro Poma, Lorena Ruiz-Perez, António Oliveira, Salette Reis, and Giuseppe Battaglia. "Macrophage Targeting pH Responsive Polymersomes for Glucocorticoid Therapy." Pharmaceutics 11, no. 11 (November 15, 2019): 614. http://dx.doi.org/10.3390/pharmaceutics11110614.
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Glucocorticoid (GC) drugs are the cornerstone therapy used in the treatment of inflammatory diseases. Here, we report pH responsive poly(2-methacryloyloxyethyl phosphorylcholine)–poly(2-(diisopropylamino)ethyl methacrylate) (PMPC–PDPA) polymersomes as a suitable nanoscopic carrier to precisely and controllably deliver GCs within inflamed target cells. The in vitro cellular studies revealed that polymersomes ensure the stability, selectivity and bioavailability of the loaded drug within macrophages. At molecular level, we tested key inflammation-related markers, such as the nuclear factor-κB, tumour necrosis factor-α, interleukin-1β, and interleukin-6. With this, we demonstrated that pH responsive polymersomes are able to enhance the anti-inflammatory effect of loaded GC drug. Overall, we prove the potential of PMPC–PDPA polymersomes to efficiently promote the inflammation shutdown, while reducing the well-known therapeutic limitations in GC-based therapy.
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Mittal, Shweta, Ishita Kathuria, and Meenakshi K. Chauhan. "IN SILICO STUDIES OF PREDNISOLONE ACETATE DERIVATIVES FOR THE TREATMENT OF DRY EYE DISEASE." Journal of Advanced Scientific Research 12, no. 04 Suppl 1 (December 31, 2021): 242–49. http://dx.doi.org/10.55218/jasr.s1202112427.
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An attempt was made to find a potential cure for the dry eye syndrome affecting millions of people around the globe eventually leading to inflammation, blurry vision, irritation, redness, and ocular pains. In this condition, the tears are unable to provide enough lubrication either due to the lack of adequate tears or generation of poor-quality tears. The pressing need to find a cure to this chronic disease led to the search for a potential anti-inflammatory drug with the help of molecular studies. Molecular docking studies were used to find the potential anti-inflammatory drug. The study used the glucocorticoid receptor in the eye (PDB Id: 6DXK) as our target protein and A HJ4 801 as our ligand for the binding studies. The CRESSET Flare software was used for the in-silico studies of 152 derivatives and the target glucocorticoid protein receptor. Further, ADMET screening was performed to evaluate parameters like lipophilicity, polarity, solubility, Lipinski rule, and bioavailability score. Swiss ADME, web-based software was used to perform these studies, and further strengthen our result. Out of 152 compounds that were studied for molecular docking, 18 compounds namely Deprodone propionate, Methylprednisolone aceponate, Prednisolone valerate acetate, Methylprednisolone hemisuccinate, and pred forte, etc. were found to possess a better score than prednisolone acetate. All the molecules were found to have molecular size (less than 500 Da), aqueous solubility (soluble, moderately soluble), lipophilicity scores (less than 5) that serve as a good candidate for ocular permeability. The toxicity studies also showed no ocular irritation or corrosion. The high binding affinity of the target glucocorticoid protein receptor with the ligands can be seen as a potential treatment for dry eye disease. It serves as the basis for introducing better compounds that act as an efficient antiinflammatory agent by inhibiting the glucocorticoid receptor and having a high binding affinity. The ADME studies showed significant bioavailability and permeability across the cornea. The top five molecules pursued properties necessary to be a good candidate for ocular absorption. Screening more compounds from various databases and performing clinical trials can be an effective strategy to further validate the results eventually leading to the discovery of less toxic and efficacious compounds for curing dry eye syndrome.
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Vermeer, H., B. I. Hendriks-Stegeman, C. E. Van Den Brink, P. T. Van Der Saag, B. Van Der Burg, S. C. Van Buul-Offers, and M. Jansen. "A novel specific bioassay for the determination of glucocorticoid bioavailability in human serum." Clinical Endocrinology 59, no. 1 (June 16, 2003): 49–55. http://dx.doi.org/10.1046/j.1365-2265.2003.01793.x.
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Cárdenas, Graciela, Raúl J. Bobes, Gladis Fragoso, Nicolas I. Pérez-Osorio, Marisela Hernández, Alejandro Espinosa, Agnes Fleury, et al. "Pharmacokinetic Study of Intranasal Dexamethasone and Methylprednisolone Compared with Intravenous Administration: Two Open-Label, Single-Dose, Two-Period, Two-Sequence, Cross-Over Study in Healthy Volunteers." Pharmaceutics 15, no. 1 (December 28, 2022): 105. http://dx.doi.org/10.3390/pharmaceutics15010105.
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Dexamethasone (DXM) and methylprednisolone (MEP) are potent glucocorticoids used to control several inflammatory conditions. Evidence of delayed DXM reaching the central nervous system (CNS) as well as tachyphylaxis and systemic, undesirable side effects are the main limitations of peripheral delivery. Intranasal administration offers direct access to the brain as it bypasses the blood–brain barrier. The Mucosal Atomization Device is an optimal tool that can achieve rapid absorption into the CNS and the bloodstream across mucosal membranes. This study was designed to evaluate and compare the bioavailability of DXM and MEP after intranasal versus intravenous administration. Two open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover studies were conducted, which involved healthy male and female adult volunteers. After intranasal administration, DXM and MEP were detected in plasma after the first sampling time. Mean peak concentrations of DXM and MEP were 86.61 ng/mL at 60 min and 843.2 ng/mL at 1.5 h post-administration, respectively. DXM and MEP showed high absolute bioavailability, with values of 80% and 95%, respectively. No adverse effects were observed. DXM and MEP systemic bioavailability by intranasal administration was comparable with the intravenous one, suggesting that the intranasal route can be used as a non-invasive and appropriate alternative for systemic drug delivery.
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Pensado, Andrea, Anita McGrogan, K. A. Jane White, Annette L. Bunge, Richard H. Guy, and M. Begoña Delgado-Charro. "Assessment of dermal bioavailability: predicting the input function for topical glucocorticoids using stratum corneum sampling." Drug Delivery and Translational Research 12, no. 4 (October 1, 2021): 851–61. http://dx.doi.org/10.1007/s13346-021-01064-8.
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AbstractPredicting the dermal bioavailability of topically delivered drugs is challenging. In this work, minimally invasive stratum corneum (SC) sampling was used to quantify the delivery of betamethasone valerate (BMV) into the viable skin. Betnovate® cream (0.1% w/w BMV) was applied at three doses (2, 5, and 10 mg cm−2) to the ventral forearms of 12 healthy volunteers. The mass of drug in the SC was measured using a validated tape-stripping method (a) after a 4-h “uptake” period, and (b) following a 6-h “clearance” period subsequent to cream removal. Concomitantly, the skin blanching responses to the same doses were assessed with a chromameter over 22 h post-application. BMV uptake into the SC was significantly higher for the 5 mg cm−2 dose compared to those of 2 and 10 mg cm−2. In all cases, ~30% of the drug in the SC at the end of the uptake period was cleared in the subsequent 6 h. From the SC sampling data, the average drug flux into the viable epidermis and its first-order elimination rate constant from the SC were estimated as 4 ng cm−2 h−1 and 0.07 h−1, respectively. In contrast, skin blanching results were highly variable and insensitive to the dose of cream applied. The SC sampling method was able to detect a 50% difference between two applied doses with 80% power; detection of a 20% difference would require a larger sample size. SC sampling enabled quantitative metrics describing corticosteroid delivery to the viable epidermis to be determined. Graphical abstract
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Rohatagi, Shashank, Gerald R. Rhodes, and Philip Chaikin. "Absolute Oral Versus Inhaled Bioavailability: Significance for Inhaled Drugs with Special Reference to Inhaled Glucocorticoids." Journal of Clinical Pharmacology 39, no. 7 (July 1999): 661–63. http://dx.doi.org/10.1177/00912709922008281.
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Koszdin, Kari L., Danny D. Shen, and Christopher M. Bernards. "Spinal Cord Bioavailability of Methylprednisolone after Intravenous and Intrathecal Administration." Anesthesiology 92, no. 1 (January 1, 2000): 156. http://dx.doi.org/10.1097/00000542-200001000-00027.
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Background High-dose intravenously administered methylprednisolone has been shown to improve outcome after spinal cord injury. The resultant glucocorticoid-induced immunosuppression, however, results in multiple complications including sepsis, pneumonia, and wound infection. These complications could be reduced by techniques that increase the spinal bioavailability of intravenously administered methylprednisolone while simultaneously decreasing plasma bioavailability. This study aimed to characterize the spinal and plasma bioavailability of methylprednisolone after intravenous and intrathecal administration and to identify barriers to the distribution of methylprednisolone from plasma into spinal cord. Methods The spinal and plasma pharmacokinetics of intravenous (30-mg/kg bolus dose plus 5.4 mg x kg(-1) x h(-1)) and intrathecal (1-mg/kg bolus dose plus 1 mg x kg(-1) x h(-1)) methylprednisolone infusions were compared in pigs. In addition, wild-type mice and P-glycoprotein knockout mice were used to determine the role of P-glycoprotein in limiting spinal bioavailability of methylprednisolone. Results Despite the greater intravenous dose, concentrations of methylprednisolone in pig spinal cord were far higher and plasma concentrations much lower after intrathecal administration. After intraperitoneal administration in the mouse, the concentrations of methylprednisolone in muscle were not different between mice expressing P-glycoprotein (2.39 +/- 1.79 microg/g) and those lacking P-glycoprotein (2.83 +/- 0.46 microg/g). In contrast, methylprednisolone was undetectable in spinal cords of wild-type mice, whereas concentrations in spinal cords of P-glycoprotein-deficient mice were similar to those in skeletal muscle (2.83 +/- 0.27 microg/g). Conclusions These pig studies demonstrate that the spinal cord bioavailability of methylprednisolone is poor after intravenous administration. The studies in knockout mice suggest that this poor bioavailability results from P-glycoprotein-mediated exclusion of methylprednisolone from the spinal cord.
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Egbuonu, Francis, Farrah A. Antonio, and Mahamood Edavalath. "Effect of Inhaled Corticosteroids on Glycemic Status." Open Respiratory Medicine Journal 8, no. 1 (December 31, 2014): 101–5. http://dx.doi.org/10.2174/1874306401408010101.
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Although the dysglycemic effects of systemic glucocorticoid therapy are well known, the effect of inhaled corticosteroids (ICS) on carbohydrate metabolism is still a subject of debate. The systemic bioavailability of ICS is claimed to be minimal and the side effects negligible. However, some large retrospective cohort studies showed a definite association between ICS use and incident diabetes or worsening glycemic control in pre-existing diabetes. There are no professional-body recommended guidelines on the diagnosis and management of steroid-induced diabetes for the general population. This review aims to evaluate the systemic dysglycemic effect of ICS treatment and to propose a management algorithm.
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Sutariya, Vijaykumar, Jared Tur, Shannon Kelly, Kathleen Halasz, Kalyan C. Chapalamadugu, Rohini Nimbalkar, Yashwant V. Pathak, et al. "Nanodrug delivery platform for glucocorticoid use in skeletal muscle injury." Canadian Journal of Physiology and Pharmacology 96, no. 7 (July 2018): 681–89. http://dx.doi.org/10.1139/cjpp-2017-0795.
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Glucocorticoids are utilized for their anti-inflammatory properties in the skeletal muscle and arthritis. However, the major drawback of use of glucocorticoids is that it leads to senescence and toxicity. Therefore, based on the idea that decreasing particle size allows for increased surface area and bioavailability of the drug, in the present study, we hypothesized that nanodelivery of dexamethasone will offer increased efficacy and decreased toxicity. The dexamethasone-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared using nanoprecipitation method. The morphological characteristics of the nanoparticles were studied under scanning electron microscope. The particle size of nanoparticles was 217.5 ± 19.99 nm with polydispersity index of 0.14 ± 0.07. The nanoparticles encapsulation efficiency was 34.57% ± 1.99% with in vitro drug release profile exhibiting a sustained release pattern over 10 days. We identified improved skeletal muscle myoblast performance with improved closure of the wound along with increased cell viability at 10 nmol/L nano-dexamethasone-PLGA. However, dexamethasone solution (1 μmol/L) was injurious to cells because the migration efficiency was decreased. In addition, the use of dexamethasone nanoparticles decreased lipopolysaccharide-induced lactate dehydrogenase release compared with dexamethasone solution. Taken together, the present study clearly demonstrates that delivery of PLGA-dexamethasone nanoparticles to the skeletal muscle cells is beneficial for treating inflammation and skeletal muscle function.
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Cornejo, Salomon, Kelan Tantisira, Benjamin A. Raby, Scott T. Weiss, and Feige Kaplan. "Nuclear bioavailability of the glucocorticoid receptor in a pediatric asthma cohort with variable corticosteroid responsiveness." Pediatric Research 78, no. 5 (August 13, 2015): 505–12. http://dx.doi.org/10.1038/pr.2015.148.
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Chen, Hsiao-Jou Cortina, Tsz Yip, Johnny K. Lee, Juliani Juliani, Conrad Sernia, Andrew F. Hill, Nickolas A. Lavidis, and Jereme G. Spiers. "Restraint Stress Alters Expression of Glucocorticoid Bioavailability Mediators, Suppresses Nrf2, and Promotes Oxidative Stress in Liver Tissue." Antioxidants 9, no. 9 (September 11, 2020): 853. http://dx.doi.org/10.3390/antiox9090853.
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Hepatic glutathione synthesis and antioxidant protection are critically important for efficient detoxification processes in response to metabolic challenges. However, this biosynthetic pathway, regulated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), previously demonstrated paradoxical repression following exposure to glucocorticoid stress hormones in cultured hepatic cells. Therefore, the present study used an in vivo model of sub-acute psychological stress to investigate the relationship between hepatic corticosteroid regulation and antioxidant systems. Male Wistar rats were kept under control conditions or subjected to six hours of restraint stress applied for 1 or 3 days (n = 8 per group) after which the liver was isolated for assays of oxidative/nitrosative status and expression of corticosteroid regulatory and Nrf2-antioxidant response element pathway members. A single stress exposure produced a significant increase in the expression of corticosterone reactivator, 11-beta-hydroxysteroid dehydrogenase 1 (11β-Hsd1), while the 11β-Hsd2 isozyme and corticosteroid-binding globulin were down-regulated following stress, indicative of an elevated availability of active corticosterone. Exposure to restraint significantly decreased hepatic concentrations of total cysteine thiols and the antioxidant reduced glutathione on Day 1 and increased 3-nitrotyrosinated and carbonylated proteins on Day 3, suggestive of oxidative/nitrosative stress in the liver following stress exposure. Conversely, there was a sustained down-regulation of Nrf2 mRNA and protein in addition to significant reductions in downstream glutamate-cysteine ligase catalytic subunit (Gclc), the rate-limiting enzyme in glutathione synthesis, on Day 1 and 3 of stress treatment. Interestingly, other antioxidant genes including superoxide dismutase 1 and 2, and glutathione peroxidase 4 were significantly up-regulated following an episode of restraint stress. In conclusion, the results of the present study indicate that increased expression of 11β-Hsd1, indicative of elevated tissue glucocorticoid concentrations, may impair the Nrf2-dependent antioxidant response.
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Zuo, Xu, Xiaoping Guo, Yinuo Gu, Haoyu Zheng, Zhengjie Zhou, Xinlei Wang, Shengyu Jiang, Guoqiang Wang, Caina Xu, and Fang Wang. "Recent Advances in Nanomaterials for Asthma Treatment." International Journal of Molecular Sciences 23, no. 22 (November 20, 2022): 14427. http://dx.doi.org/10.3390/ijms232214427.
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Asthma is a chronic airway inflammatory disease with complex mechanisms, and these patients often encounter difficulties in their treatment course due to the heterogeneity of the disease. Currently, clinical treatments for asthma are mainly based on glucocorticoid-based combination drug therapy; however, glucocorticoid resistance and multiple side effects, as well as the occurrence of poor drug delivery, require the development of more promising treatments. Nanotechnology is an emerging technology that has been extensively researched in the medical field. Several studies have shown that drug delivery systems could significantly improve the targeting, reduce toxicity and improve the bioavailability of drugs. The use of multiple nanoparticle delivery strategies could improve the therapeutic efficacy of drugs compared to traditional delivery methods. Herein, the authors presented the mechanisms of asthma development and current therapeutic methods. Furthermore, the design and synthesis of different types of nanomaterials and micromaterials for asthma therapy are reviewed, including polymetric nanomaterials, solid lipid nanomaterials, cell membranes-based nanomaterials, and metal nanomaterials. Finally, the challenges and future perspectives of these nanomaterials are discussed to provide guidance for further research directions and hopefully promote the clinical application of nanotherapeutics in asthma treatment.
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Blecharz, Kinga G., Malgorzata Burek, Johann Bauersachs, Thomas Thum, Dimitrios Tsikas, Julian Widder, Norbert Roewer, and Carola Y. Förster. "Inhibition of proteasome-mediated glucocorticoid receptor degradation restores nitric oxide bioavailability in myocardial endothelial cellsin vitro." Biology of the Cell 106, no. 7 (May 23, 2014): 219–35. http://dx.doi.org/10.1111/boc.201300083.
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Charmandari, E., A. Johnston, CG Brook, and PC Hindmarsh. "Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency." Journal of Endocrinology 169, no. 1 (April 1, 2001): 65–70. http://dx.doi.org/10.1677/joe.0.1690065.
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The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.
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Längericht, Jan, Irene Krämer, and George J. Kahaly. "Glucocorticoids in Graves’ orbitopathy: mechanisms of action and clinical application." Therapeutic Advances in Endocrinology and Metabolism 11 (January 2020): 204201882095833. http://dx.doi.org/10.1177/2042018820958335.
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Background: Graves’ orbitopathy (GO) is the most frequent extrathyroidal manifestation of the autoimmune Graves’ disease. GO significantly impacts quality of life and has a psycho-social morbidity. Inflammation and swelling of the orbital tissue often leads to proptosis, diplopia, and decrease of visual acuity. Due to the inflammatory background of the disease, glucocorticoids (GC) have been used as a first-line treatment for decades. Methods: PubMed and MeSH database were searched for original articles, clinical trials, reviews, and meta-analyses published between 1 January 2000 and 31 March 2020 and pertaining to both the mechanism of action and immunological effects of GC as well as to the treatment of GO by GC. The publications were evaluated according to their setting and study design. Results: GC act through genomic (trans-activation and trans-repression) and rapid non-genomic mechanisms. GC in general, and the intravenous (IV) administration of GC in particular, markedly decrease the activity and number of the most potent antigen-presenting dendritic cells. According to the internationally acknowledged European Thyroid Association Guidelines for the management of GO, weekly IVGC application over 12 weeks is recommended as first-line treatment for patients with active and severe GO. The daily and cumulative dose should be tailored according to clinical severity, for example, 4.5 g of IV methylprednisolone for the inflammatory component versus 7.5 g in the presence of diplopia and severe proptosis. Fast and significant improvements in orbital symptoms and signs are noted in 65–70% of patients. Long-term experience over decades, and worldwide availability at low cost, underline the clinical and therapeutic relevance of GC. Adverse events are rarely severe, dose-dependent, and usually reversible, hence easy to handle by medical investigators. Oral GC application on a daily basis is characterized by high bioavailability but reduced efficacy and increased toxicity. Conclusion: IVGC still represents the standard of care in active/severe GO. Innovative biologicals, like monoclonal antibodies targeting the thyrotropin/Insulin-like growth factor-1 receptors or pro-inflammatory cytokines (e.g., Interleukin-6) should be compared with standard GC treatment with respect to short- and long-term efficacy, safety, costs, and global availability.
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Dubashynskaya, Natallia V., Anton N. Bokatyi, Andrey S. Trulioff, Artem A. Rubinstein, Igor V. Kudryavtsev, and Yury A. Skorik. "Development and Bioactivity of Zinc Sulfate Cross-Linked Polysaccharide Delivery System of Dexamethasone Phosphate." Pharmaceutics 15, no. 10 (September 28, 2023): 2396. http://dx.doi.org/10.3390/pharmaceutics15102396.
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Improving the biopharmaceutical properties of glucocorticoids (increasing local bioavailability and reducing systemic toxicity) is an important challenge. The aim of this study was to develop a dexamethasone phosphate (DexP) delivery system based on hyaluronic acid (HA) and a water-soluble cationic chitosan derivative, diethylaminoethyl chitosan (DEAECS). The DexP delivery system was a polyelectrolyte complex (PEC) resulting from interpolymer interactions between the HA polyanion and the DEAECS polycation with simultaneous incorporation of zinc ions as a cross-linking agent into the complex. The developed PECs had a hydrodynamic diameter of 244 nm and a ζ-potential of +24.4 mV; the encapsulation efficiency and DexP content were 75.6% and 45.4 μg/mg, respectively. The designed DexP delivery systems were characterized by both excellent mucoadhesion and prolonged drug release (approximately 70% of DexP was released within 10 h). In vitro experiments showed that encapsulation of DexP in polysaccharide nanocarriers did not reduce its anti-inflammatory activity compared to free DexP.
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Ciarambino, Tiziana, Pietro Crispino, Giovanni Minervini, and Mauro Giordano. "Vitamin D: Can Gender Medicine Have a Role?" Biomedicines 11, no. 6 (June 19, 2023): 1762. http://dx.doi.org/10.3390/biomedicines11061762.
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This narrative review aims to shed light on the role of gender differences, on the biological and molecular functions in the main pathological mechanisms that recognize the role of vitamin D. Vitamin D deficiency is widespread worldwide, but it is still very controversial whether the amount of vitamin D taken daily is actually the only problem related to its biological functions. Currently, the plasma concentration of 25-hydroxyvitamin D represents the only indicator of the circulating blood quota. The concept is that the biological function of vitamin D is not only linked to its circulating levels, but it is hypothesized that its biological functions depend, above all, on its total bioavailability. In particular, vitamin D circulates for the most part linked to albumin and vitamin D binding protein (DBP), which depend on various pathological conditions and physiologically, above all, the function of the latter is regulated by estrogens, glucocorticoids, and inflammatory cytokines. During her life, women undergo various changes in the hormonal and sexual sphere concerning menarche, possible pregnancies, and breastfeeding but also the use of contraceptives and, finally, the transition from the period of fertility to menopause. Each of these phases presents specific needs and, consequently, sometimes also specific criticalities. Studies on young women have shown that vitamin D deficiency is present in 58 to 91% of cases. Obesity, metabolic disorders, and variation in estrogen contraction may affect vitamin D deficiency due to the decreased bioavailability from dietary sources due to deposition in body fat compartments.
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Bolkenius, Ursula, Daniela Hahn, Axel M. Gressner, Katja Breitkopf, Steven Dooley, and Lucia Wickert. "Glucocorticoids decrease the bioavailability of TGF-β which leads to a reduced TGF-β signaling in hepatic stellate cells." Biochemical and Biophysical Research Communications 325, no. 4 (December 2004): 1264–70. http://dx.doi.org/10.1016/j.bbrc.2004.10.164.
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Serra, Magda F., Amanda C. Cotias, Camila R. R. Pão, Julio B. Daleprane, Patricia B. Jurgilas, Gina C. Couto, Edna A. Anjos-Valotta, et al. "Repeated Allergen Exposure in A/J Mice Causes Steroid-Insensitive Asthma via a Defect in Glucocorticoid Receptor Bioavailability." Journal of Immunology 201, no. 3 (June 18, 2018): 851–60. http://dx.doi.org/10.4049/jimmunol.1700933.
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Clemmons, David R. "40 YEARS OF IGF1: Role of IGF-binding proteins in regulating IGF responses to changes in metabolism." Journal of Molecular Endocrinology 61, no. 1 (July 2018): T139—T169. http://dx.doi.org/10.1530/jme-18-0016.
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The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2. These proteins are present in plasma and extracellular fluids and regulate access of both IGF1 and II to the type I IGF receptor. Additionally, they have functions that are independent of their ability to bind IGFs. Each protein is regulated independently of IGF1 and IGF2, and this provides an important mechanism by which other hormones and physiologic variables can regulate IGF actions indirectly. Several members of the family are sensitive to changes in intermediary metabolism. Specifically the presence of obesity/insulin resistance can significantly alter the expression of these proteins. Similarly changes in nutrition or catabolism can alter their synthesis and degradation. Multiple hormones such as glucocorticoids, androgens, estrogen and insulin regulate IGFBP synthesis and bioavailability. In addition to their ability to regulate IGF access to receptors these proteins can bind to distinct cell surface proteins or proteins in extracellular matrix and several cellular functions are influenced by these interactions. IGFBPs can be transported intracellularly and interact with nuclear proteins to alter cellular physiology. In pathophysiologic states, there is significant dysregulation between the changes in IGFBP synthesis and bioavailability and changes in IGF1 and IGF2. These discordant changes can lead to marked alterations in IGF action. Although binding protein physiology and pathophysiology are complex, experimental results have provided an important avenue for understanding how IGF actions are regulated in a variety of physiologic and pathophysiologic conditions.
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Gonzalez, Daniel, and Hartmut Derendorf. "Ciclesonide in the Management of Asthma." Clinical Medicine. Therapeutics 1 (January 2009): CMT.S2133. http://dx.doi.org/10.4137/cmt.s2133.
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Ciclesonide is a novel inhaled corticosteroid (ICSs) approved in most countries for the management of persistent asthma. Although inhaled corticosteroids are first-line therapy in the treatment of asthma, long term use and high-doses of these products may result in significant side effects. When developing a new ICSs, the goal is to identify a drug with comparable (or superior) efficacy to active comparators, and an improved safety profile. Ciclesonide is a prodrug which is administered through a hydrofluoroalkane-propellant metered dose inhaler (HFA-MDI). Once it reaches the lungs, the parent compound is metabolized by esterases to desisobutyryl ciclesonide (des-CIC), an active metabolite with a 100-fold greater affinity for the glucocorticoid receptor. Ciclesonide has a unique pharmacokinetic-pharmacodynamic profile which confers an improved therapeutic ratio. Several clinical trials have shown that its efficacy is superior to placebo and similar to several active comparators. However, its high pulmonary deposition and on-site activation minimizes the risk for local side effects. Also, its low oral bioavailability, high hepatic clearance, and extensive plasma protein binding, among other factors, decrease the risk for systemic side effects. Doses of ciclesonide as high as 1280 μg/day (ex-actuator) result in minimal hypothalamic-pituitary-adrenal (HPA) axis suppression, a measure commonly used to assess systemic bioavailability for an ICSs. This review will provide a summary of ciclesonide's role in the management of asthma, including a discussion of relevant clinical trials designed to evaluate its efficacy and safety.
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Dubashynskaya, Natallia V., Anton N. Bokatyi, Alexey S. Golovkin, Igor V. Kudryavtsev, Maria K. Serebryakova, Andrey S. Trulioff, Yaroslav A. Dubrovskii, and Yury A. Skorik. "Synthesis and Characterization of Novel Succinyl Chitosan-Dexamethasone Conjugates for Potential Intravitreal Dexamethasone Delivery." International Journal of Molecular Sciences 22, no. 20 (October 11, 2021): 10960. http://dx.doi.org/10.3390/ijms222010960.
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The development of intravitreal glucocorticoid delivery systems is a current global challenge for the treatment of inflammatory diseases of the posterior segment of the eye. The main advantages of these systems are that they can overcome anatomical and physiological ophthalmic barriers and increase local bioavailability while prolonging and controlling drug release over several months to improve the safety and effectiveness of glucocorticoid therapy. One approach to the development of optimal delivery systems for intravitreal injections is the conjugation of low-molecular-weight drugs with natural polymers to prevent their rapid elimination and provide targeted and controlled release. This study focuses on the development of a procedure for a two-step synthesis of dexamethasone (DEX) conjugates based on the natural polysaccharide chitosan (CS). We first used carbodiimide chemistry to conjugate DEX to CS via a succinyl linker, and we then modified the obtained systems with succinic anhydride to impart a negative ζ-potential to the polymer particle surface. The resulting polysaccharide carriers had a degree of substitution with DEX moieties of 2–4%, a DEX content of 50–85 μg/mg, and a degree of succinylation of 64–68%. The size of the obtained particles was 400–1100 nm, and the ζ-potential was −30 to −33 mV. In vitro release studies at pH 7.4 showed slow hydrolysis of the amide and ester bonds in the synthesized systems, with a total release of 8–10% for both DEX and succinyl dexamethasone (SucDEX) after 1 month. The developed conjugates showed a significant anti-inflammatory effect in TNFα-induced and LPS-induced inflammation models, suppressing CD54 expression in THP-1 cells by 2- and 4-fold, respectively. Thus, these novel succinyl chitosan-dexamethasone (SucCS-DEX) conjugates are promising ophthalmic carriers for intravitreal delivery.
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Zandieh, Iman, Darin Krygier, Victor Wong, John Howard, Lawrence Worobetz, Gerald Minuk, Helga Witt-Sullivan, and Eric M. Yoshida. "The Use of Budesonide in the Treatment of Autoimmune Hepatitis in Canada." Canadian Journal of Gastroenterology 22, no. 4 (2008): 388–92. http://dx.doi.org/10.1155/2008/509459.
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BACKGROUND: Autoimmune hepatitis (AIH) is a chronic inflammatory disease that is successfully treated with prednisone and/or azathioprine immunosuppressive therapy in 70% to 80% of patients. The remaining patients are intolerant or refractory to these standard medications. Budesonide, a synthetic glucocorticoid, undergoes a high degree of first-pass metabolism, reducing its systemic bioavailability, and has a 15-fold greater affinity for the glucocorticoid receptor than prednisolone. Budesonide may be a potentially useful systemic steroid-sparing immunosuppressive agent in the treatment of AIH.OBJECTIVE: To review the Canadian experience using budesonide to treat AIH.METHODS: Patients with AIH currently or previously treated with budesonide were identified through the Canadian Association for the Study of the Liver membership. Data were collected regarding their clinical and treatment history.RESULTS: A total of nine patients were identified. All patients were female, with an average age of 39 years (range 12 to 66 years). The indications for budesonide were adverse side effects of prednisone in two patients, noncompliance with prednisone and azathioprine in one patient and intolerance to azathioprine resulting in prednisone dependence in the remaining six patients. Patients were treated in doses ranging from 9 mg daily to 3 mg every other day for 24 weeks to eight years. Seven of nine patients had a complete response, defined as sustained normalization of the aminotransferase levels. The remaining two patients were classified as nonresponders (less than a 50% reduction in pretreatment aminotransferase levels).CONCLUSIONS: In Canada, budesonide has been successfully used in seven of nine patients with autoimmune hepatitis who were either intolerant to prednisone and azathioprine or prednisone-dependent. No adverse effects were reported with budesonide. Budesonide is potentially a valuable treatment option for AIH patients refractory or intolerant to standard therapy, and is deserving of further study.
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Patiño-Rodríguez, Omar, Abraham Escobedo-Moratilla, Rosa María Martínez-Medina, Irma Torres-Roque, Maricela Martínez-Delgado, and José Pérez-Urizar. "Development and Validation of a Sensitive LC-MS/MS Method for Determination of Betamethasone in Human Plasma. Application to a Pharmacokinetic Study of Healthy Mexican Subjects." Current Pharmaceutical Analysis 15, no. 1 (November 28, 2018): 2–8. http://dx.doi.org/10.2174/1573412913666170912111945.
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Background: Synthetic glucocorticoids like Betamethasone (BE) are used in the treatment of inflammatory diseases due to its effective and potent effect. BE is available in three different esters: dipropionate (BD), sodium phosphate (BP), and acetate (BA). BD/BP combined in suspension has antiinflammatory, anti-allergic, and anti-rheumatic effects. The aim of this study was to describe the bioavailability of a single-dose of the injectable formulation of BP/BD in healthy Mexican subjects. Methods: This was a randomized, open-label, longitudinal, not therapeutic, single-dose trial of an intramuscular administration of BD/BP (5 mg/2 mg), in healthy Mexican subjects under fasting condition. Twenty-six healthy Mexicans volunteers of both genders who were between the ages of 18 and 45 were enrolled in the study. Results: From non-compartmental estimation of data, it was observed that the BE highest mean concentration was 15.70 ± 3.93 ng/mL reaching it in 2.83 ± 1.35 h. The values of elimination half-life were 10.89 ± 2.02 h. No clinically significant adverse effects were presented during the study. Conclusion: The reported PK parameters for BE suggest that the BD/BP suspension has a similar release velocity in Mexican healthy subjects compared with previous studies.
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Desantis, Lanna M., Jeff Bowman, Erin Faught, Rudy Boonstra, Mathilakath M. Vijayan, and Gary Burness. "Corticosteroid-binding globulin levels in North American sciurids: implications for the flying squirrel stress axis." Canadian Journal of Zoology 96, no. 10 (October 2018): 1090–96. http://dx.doi.org/10.1139/cjz-2017-0300.
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Corticosteroid-binding globulin (CBG) helps to regulate tissue bioavailability of circulating glucocorticoids (GCs), and in most vertebrates, ≥80%–90% of GCs bind to this protein. New World flying squirrels have higher plasma total cortisol levels (the primary corticosteroid in sciurids) than most vertebrates. Recent research suggests that flying squirrels have either low amounts of CBG or CBG molecules that have a low binding affinity for cortisol, as this taxon appears to exhibit very low proportions of cortisol bound to CBG. To test whether CBG levels have been adjusted over evolutionary time, we assessed the levels of this protein in the plasma of northern (Glaucomys sabrinus (Shaw, 1801)) and southern (Glaucomys volans (Linnaeus, 1758)) flying squirrels using immunoblotting, and compared the relative levels among three phylogenetically related species of sciurids. We also compared the pattern of CBG levels with cortisol levels for the same individuals. Flying squirrels had higher cortisol levels than the other species, but similar levels of CBG to their closest relatives (tree squirrels). We conclude that CBG levels in flying squirrels have not been adjusted over evolutionary time, and thus, the uncoupling of CBG levels from cortisol concentrations may represent an evolutionary modification in the lineage leading to New World flying squirrels.
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Haourigui, M., S. Sakr, M. E. Martin, N. Thobie, A. Girard-Globa, C. Benassayag, and E. A. Nunez. "Postprandial free fatty acids stimulate activity of human corticosteroid binding globulin." American Journal of Physiology-Endocrinology and Metabolism 269, no. 6 (December 1, 1995): E1067—E1075. http://dx.doi.org/10.1152/ajpendo.1995.269.6.e1067.
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The effect of postprandial variation of free fatty acids (FFA) on serum corticosteroid binding globulin (CBG) properties and cortisol (hydrocortisone) concentrations were explored in 11 women (20-30 yr) during 8 h after an oral load of tallow (26% C16:0, 18% C18:0, and 43% C18:1), oleic-sunflower (oleic-SF; 73% C18:1), sunflower (SF; 67% C18:2), and mixed oil (MO; 39% C18:1 and 48% C18:2). Serum FFA increased little after SF and MO but more than doubled in the late postprandial period (6 and 8 h) after oleic-SF (due to monounsaturated FFA) or tallow (due to saturated and monounsaturated FFA). CBG concentrations remained unchanged, but in relation with the postprandial elevation of serum FFA, CBG binding activity was increased after tallow or oleic-SF as a result of a combined two- to threefold increase in affinity constant and a 50% reduction in binding sites. Immunological and in vitro binding studies showed the changes in CBG behavior to be conformational and to be mediated mainly by monounsaturated FFA, especially C18:1. The modifications of CBG properties were associated with sustained high concentrations of cortisol (suppression of midday decrease) 6 and 8 h after tallow or oleic-SF. Thus dietary FFA may have an impact on bioavailability of glucocorticoids.
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Guevara-Gordillo, Willams Andrés, Anthony Josué Coloma-León, Paulo Fernando Telenchana-Chimbo, and Carlos Pérez-Salazar. "Actualización en el manejo de gonartrosis: Revisión bibliográfica." Revista Metropolitana de Ciencias Aplicadas 7, no. 3 (September 8, 2024): 15–25. http://dx.doi.org/10.62452/npqfna86.
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Gonarthrosis is a chronic-degenerative disease that involves the entire joint and its components, mainly affecting the articular cartilage, producing its degeneration and bone hyperplasia. About 50-60% of older adults experience symptoms of OA. The objective of this research is to discover new therapeutic options for gonarthrosis, in addition to expanding knowledge about intra-articular infiltration by describing the substances available for this therapy. An electronic search of scientific articles published from January 2018 to April 2024 was carried out in the PubMed, Scopus, Web of Science and ScieLO databases. Currently there are several options for the treatment of OA, from physiotherapy, pharmacotherapy to surgery. Intra-articular drug administration is a new therapeutic approved by the FDA, among its advantages are local bioavailability, reduced systemic drug exposure, fewer adverse events and reduced costs. Some of the substances used are glucocorticoids, hyaluronic acid, ozone and platelet-rich plasma, which reduce pain and inflammation, increasing the patient's quality of life. It is concluded that botulinum toxin decreases central and peripheral sensitivity, reducing pain in the short term. The use of hyaluronic acid as a vehicle for the application of gold microparticles has decreased symptoms in the short and long term, however, further studies are required to evaluate its effectiveness on the control of other symptoms.
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Gromotowicz-Poplawska, Anna, Piotr Szoka, Agnieszka Zakrzeska, Patrycjusz Kolodziejczyk, Natalia Marcinczyk, Janusz Szemraj, Piotr Tutka, and Ewa Chabielska. "Hyperglycemia Potentiates Prothrombotic Effect of Aldosterone in a Rat Arterial Thrombosis Model." Cells 10, no. 2 (February 22, 2021): 471. http://dx.doi.org/10.3390/cells10020471.
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We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 μg/kg/h) enhanced thrombosis in adrenalectomized rats, while this effect was potentiated in diabetic rats. ALDO shortened bleeding time, increased plasma levels of tissue factor (TF) and plasminogen activator inhibitor, decreased plasma level of nitric oxide (NO) metabolites, and increased oxidative stress. Moreover, 2 h incubation of human umbilical vein endothelial cells (HUVECs) with ALDO (10−7 M) disrupted hemostatic balance in endothelial cells in normoglycemia (glucose 5.5 mM), and this effect was more pronounced in hyperglycemia (glucose 30 mM). We demonstrated that the acute ALDO infusion enhances arterial thrombosis in rats and hyperglycemia potentiates this prothrombotic effect. The mechanism of ALDO action was partially mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors and related to impact of the hormone on primary hemostasis, TF-dependent coagulation cascade, fibrinolysis, NO bioavailability, and oxidative stress balance. Our in vitro study confirmed that ALDO induces prothrombotic phenotype in the endothelium, particularly under hyperglycemic conditions.
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Qin, Zhenmiao, Baohua Li, Qiyi Deng, Yifeng Wen, Shiquan Feng, Chengcheng Duan, Beicheng Zhao, Hailong Li, Yanan Gao, and Junfeng Ban. "Polymer Nanoparticles with 2-HP-β-Cyclodextrin for Enhanced Retention of Uptake into HCE-T Cells." Molecules 29, no. 3 (January 31, 2024): 658. http://dx.doi.org/10.3390/molecules29030658.
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Triamcinolone acetonide (TA), a medium-potency synthetic glucocorticoid, is primarily employed to treat posterior ocular diseases using vitreous injection. This study aimed to design novel ocular nanoformulation drug delivery systems using PLGA carriers to overcome the ocular drug delivery barrier and facilitate effective delivery into the ocular tissues after topical administration. The surface of the PLGA nanodelivery system was made hydrophilic (2-HP-β-CD) through an emulsified solvent volatilization method, followed by system characterization. The mechanism of cellular uptake across the corneal epithelial cell barrier used rhodamine B (Rh-B) to prepare fluorescent probes for delivery systems. The triamcinolone acetonide (TA)-loaded nanodelivery system was validated by in vitro release behavior, isolated corneal permeability, and in vivo atrial hydrodynamics. The results indicated that the fluorescent probes, viz., the Rh-B-(2-HP-β-CD)/PLGA NPs and the drug-loaded TA-(2-HP-β-CD)/PLGA NPs, were within 200 nm in size. Moreover, the system was homogeneous and stable. The in vitro transport mechanism across the epithelial barrier showed that the uptake of nanoparticles was time-dependent and that NPs were actively transported across the epithelial barrier. The in vitro release behavior of the TA-loaded nanodelivery systems revealed that (2-HP-β-CD)/PLGA nanoparticles could prolong the drug release time to up to three times longer than the suspensions. The isolated corneal permeability demonstrated that TA-(2-HP-β-CD)/PLGA NPs could extend the precorneal retention time and boost corneal permeability. Thus, they increased the cumulative release per unit area 7.99-fold at 8 h compared to the suspension. The pharmacokinetics within the aqueous humor showed that (2-HP-β-CD)/PLGA nanoparticles could elevate the bioavailability of the drug, and its Cmax was 51.91 times higher than that of the triamcinolone acetonide aqueous solution. Therefore, (2-HP-β-CD)/PLGA NPs can potentially elevate transmembrane uptake, promote corneal permeability, and improve the bioavailability of drugs inside the aqueous humor. This study provides a foundation for future research on transocular barrier nanoformulations for non-invasive drug delivery.
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Shamsher, Ehtesham, Reas S. Khan, Benjamin M. Davis, Kimberly Dine, Vy Luong, M. Francesca Cordeiro, and Kenneth S. Shindler. "Intranasal Resveratrol Nanoparticles Enhance Neuroprotection in a Model of Multiple Sclerosis." International Journal of Molecular Sciences 25, no. 7 (April 5, 2024): 4047. http://dx.doi.org/10.3390/ijms25074047.
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Purpose: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice. Methods: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival. Results: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves. Conclusions: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids.
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Forhead, A. J., and A. L. Fowden. "Thyroid hormones in fetal growth and prepartum maturation." Journal of Endocrinology 221, no. 3 (March 19, 2014): R87—R103. http://dx.doi.org/10.1530/joe-14-0025.
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The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailabilityin uterodepends on development of the fetal hypothalamic–pituitary–thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4and T3concentrations are also affected by gestational age, nutritional and endocrine conditionsin utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating theprepartummaturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4and T3bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.
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Mattos, Gabriele E., Jan-Michael Heinzmann, Stefanie Norkowski, Jean-Christophe Helbling, Amandine M. Minni, Marie-Pierre Moisan, and Chadi Touma. "Corticosteroid-binding globulin contributes to the neuroendocrine phenotype of mice selected for extremes in stress reactivity." Journal of Endocrinology 219, no. 3 (September 17, 2013): 217–29. http://dx.doi.org/10.1530/joe-13-0255.
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Increasing evidence indicates an important role of steroid-binding proteins in endocrine functions, including hypothalamic–pituitary–adrenal (HPA) axis activity and regulation, as they influence bioavailability, local delivery, and cellular signal transduction of steroid hormones. In the plasma, glucocorticoids (GCs) are mainly bound to the corticosteroid-binding globulin (CBG) and to a lesser extend to albumin. Plasma CBG levels are therefore involved in the adaptive stress response, as they determine the concentration of free, biologically active GCs. In this study, we investigated whether male mice with a genetic predisposition for high-reactivity (HR), intermediate-reactivity (IR), or low-reactivity (LR) stress-induced corticosterone (CORT) secretion present different levels of free CORT and CORT-binding proteins, basally and in response to stressors of different intensity. Our results suggest a fine control interaction between plasma CBG expression and stress-induced CORT release. Although plasma CBG levels, and therefore CBG binding capacity, were higher in HR animals, CORT secretion overloaded the CBG buffering function in response to stressors, resulting in clearly higher free CORT levels in HR compared with IR and LR mice (HR>IR>LR), resembling the pattern of total CORT increase in all three lines. Both stressors, restraint or forced swimming, did not evoke fast CBG release from the liver into the bloodstream and therefore CBG binding capacity was not altered in our three mouse lines. Thus, we confirm CBG functions in maintaining a dynamic equilibrium between CBG-bound and unbound CORT, but could not verify its role in delaying the rise of plasma free CORT immediately after stress exposure.
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Valente, Filippo, Edi Simoni, Erica Gentilin, Alessandro Martini, Elisabetta Zanoletti, Gino Marioni, Piero Nicolai, and Laura Astolfi. "Liquid Crystalline Nanoparticles Conjugated with Dexamethasone Prevent Cisplatin Ototoxicity In Vitro." International Journal of Molecular Sciences 23, no. 23 (November 28, 2022): 14881. http://dx.doi.org/10.3390/ijms232314881.
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The conjugation of drugs with nanoparticles represents an innovative approach for controlled and targeted administration of therapeutic agents. Nanoparticle-based systems have been tested for the inner ear therapy, increasing the drug diffusion and being detected in all parts of the cochlea when locally applied near the round window. In this study, glycerol monooleate liquid crystalline NanoParticles were conjugated with Dexamethasone (NPD), a hydrophobic drug already used for inner ear treatments but defective in solubility and bioavailability. NPD has been tested in vitro in the cell line OC-k3, a model of sensory cells of the inner ear, and the therapeutic efficacy has been evaluated against cisplatin, a chemotherapeutic compound known to induce ototoxicity. After comparing the physical chemical characteristics of NPD to the equivalent naïve nanoparticles, an initial investigation was carried out into the nanoparticle’s uptake in OC-k3 cells, which takes place within a few hours of treatment without causing toxic damage up to a concentration of 50 µg/mL. The NPD delivered the dexamethasone inside the cells at a significantly increased rate compared to the equivalent free drug administration, increasing the half-life of the therapeutic compound within the cell. Concerning the co-treatment with cisplatin, the NPD significantly lowered the cisplatin cytotoxicity after 48 h of administration, preventing cell apoptosis. To confirm this result, also cell morphology, cell cycle and glucocorticoids receptor expression were investigated. In conclusion, the NPD system has thus preliminarily shown the potential to improve the therapeutic efficacy of treatments delivered in the inner ear and prevent drug-induced ototoxicity.
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Campieri, M., A. Ferguson, W. Doe, T. Persson, and L.-G. Nilsson. "Oral budesonide is as effective as oral prednisolone in active Crohn’s disease." Gut 41, no. 2 (August 1, 1997): 209–14. http://dx.doi.org/10.1136/gut.41.2.209.
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Background—The use of corticosteroids in active Crohn’s disease often becomes limited by side effects. Budesonide is a potent corticosteroid with low systemic bioavailability due to an extensive first pass liver metabolism.Aims—To compare the efficacy and safety of two dosage regimens of budesonide and prednisolone in patients with active Crohn’s disease affecting the ileum and/or the ascending colon.Patients and methods—One hundred and seventy eight patients were randomised to receive budesonide controlled ileal release (CIR) capsules 9 mg once daily or 4.5 mg twice daily, or prednisolone tablets 40 mg once daily. The treatment period was 12 weeks. The primary efficacy variable was clinical remission, defined as a Crohn’s Disease Activity Index (CDAI) of 150 or less.Results—After eight weeks of treatment, remission occurred in 60% of patients receiving budesonide once daily or prednisolone and in 42% of those receiving budesonide twice daily (p=0.062). The presence of glucocorticoid associated side effects was similar in all groups; however, moon face was more common in the prednisolone group (p=0.0005). The highest frequency of impaired adrenal function, as measured by a short ACTH test, was found in the prednisolone group (p=0.0023).Conclusions—Budesonide CIR, administered at 9 mg once daily or 4.5 mg twice daily, is comparable to prednisolone in inducing remission in active Crohn’s disease. The single dose administration is as promptly effective as prednisolone and represents a simpler and safer therapeutic approach, with a considerable reduction in side effects.