Traditional Glucocorticoids Research Articles

Association between Diabetes and Rheumatoid Arthritis: A Systematic Literature Review

Objective: To examine the risk of diabetes mellitus (DM) in patients with rheumatoid arthritis (RA) and whether the risk is related to conventional risk factors, RA disease activity, and treatment. Methods: A systematic literature review (SLR) query was conducted using specified MeSH terms, searching PubMed and EMBASE databases from inception to March 2020. Both cohort or case-control design studies assessing the incidence or prevalence of DM in RA patients were included. Results: Of the 1948 articles, 43 peer-reviewed observational studies were selected. A high degree of heterogeneity in study design and reporting was observed, precluding final conclusions. Based on the studies included, it was observed that DM prevalence ranged between 1% and 20% in RA patients, which was similar to controls (1–29%). The cumulative incidence of DM in RA patients ranged between 1.3% and 11.7% over different time frames. DM incidence rates in patients with RA per 1000 person-years ranged from 5.2 to 16.7. RA patients may be at higher risk of DM, particularly among those receiving glucocorticoids (GC), while patients on hydroxychloroquine and biological disease-modifying anti-rheumatic treatments (DMARDs) may be at lower risk. Conclusion: DM incidence may be increased in patients with RA as a result of more concomitant traditional risk factors and GC exposure. It is unclear whether biologics may have a true protective effect or provide a GC-sparing effect. High-quality studies in large cohorts of RA patients with appropriate adjustment for covariates are warranted to fully investigate the interplay between DM and RA.

Efficacy and safety of tocilizumab in Behçet's syndrome with refractory arterial lesions: a single-centre observational cohort study in China.

ObjectiveThe aim of this observational cohort study was to assess the effectiveness and safety of the IL-6-receptor inhibitor tocilizumab (TCZ) in Behçet’s syndrome (BS) with refractory arterial involvement.MethodsTen patients admitted to the Rheumatology and Immunology Department of Peking University People’s Hospital between January 2014 and December 2019 were enrolled. The enrolled patients met the BS international criteria and exhibited severe arterial impairments. Refractory arterio-BS was diagnosed based on objective vascular symptoms unexplainable by other known illnesses, and resistance to traditional immunosuppressants and glucocorticoids after 12 weeks. Patients received 8 mg/kg TCZ infusions every 4 weeks for ≥24 weeks, with simultaneous continuation of immunosuppressants and glucocorticoids. Clinical and imaging data were assessed before and after TCZ treatment.ResultsThe enrolled patients were men aged 44.3 (10.5) years; the median disease duration was 186.5 (45.7) months, and the average age of arterial impairment onset was 38.7 (12.9) years. The following trends were observed: improvement and maintenance of symptoms after the 26.8 (7.2)-month follow-up, n = 9; complete remission, n = 6; partial response, n = 3; immunosuppressant dose reduction, n = 4; radiologic improvement of arterial lesions, n = 4; and TCZ discontinuation owing to enlarged abdominal aortic aneurysm relapse, n = 1. The average daily glucocorticoid dose reduced from 54.5 (20.6) to 8.3 (3.6) mg/d (P < 0.001), while the median ESR and CRP values reduced from 50 (2–82) mm/h and 32.9 (2.1–62.3) mg/dl to 4 (1–10) mm/h and 2.9 (0.2–12.1) mg/dl, respectively (P < 0.001). No TCZ-associated side effects were noted.ConclusionTCZ proved to be safe and effective for refractory arterial lesions in BS, with a steroid- and immunosuppressant-sparing benefit.

Role of Autophagy and Apoptosis in Acute Lymphoblastic Leukemia.

Background:Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by an excessive number of immature lymphocytes, including immature precursors of both B- and T cells. ALL affects children more often than adults. Immature lymphocytes lead to arrested differentiation and proliferation of cells. Its conventional treatments involve medication with dexamethasone, vincristine, and other anticancer drugs. Although the current first-line drugs can achieve effective treatment, they still cannot prevent the recurrence of some patients with ALL. Treatments have high risk of recurrence especially after the first remission. Currently, novel therapies to treat ALL are in need. Autophagy and apoptosis play important roles in regulating cancer development. Autophagy involves degradation of proteins and organelles, and apoptosis leads to cell death. These phenomena are crucial in cancer progression. Past studies reported that many potential anticancer agents regulate intracellular signaling pathways.Methods:The authors discuss the recent research findings on the role of autophagy and apoptosis in ALL.Results:The autophagy and apoptosis are widely used in the treatment of ALL. Most studies showed that many agents regulate autophagy and apoptosis in ALL cell models, clinical trials, and ALL animal models.Conclusions:In summary, activating autophagy and apoptosis pathways are the main strategies for ALL treatments. For ALL, combining new drugs with traditional chemotherapy and glucocorticoids treatments can achieve the greatest therapeutic effect by activating autophagy and apoptosis.

Short-term efficacy and safety of rhTPO combined with traditional monotherapy regimen for the treatment of ITP: a Meta-analysis

Objective To evaluate the short-term efficacy and safety of recombinant human thrombopoietin(rhTPO) combined with glucocorticoid or danazol regimen and traditional monotherapy regimen in the treatment of idiopathic thrombocytopenic purpura(ITP). Methods All the randomized controlled trial(RCT) about short-term efficacy and safety of combined rhTPO regimen with hormone or danazol regimen and traditional monotherapy regimen in the treatment of ITP were electronically collected by searching databases, including PubMed, Wanfang database, VIP database, China National Knowledge Infrastructure (CNKI), China Biology Medicine disc(CBMdisc). Retrieval time is up to September 2017.Independent search of the literature by two trained researchers, excluding articles that were not available and of non-compliant quality, and using the Jadad scale for literature quality scoring.Then, Meta-analysis of the efficacy and safety of rhTPO combined with traditional glucocorticoids or danazol and traditional monotherapy regimenin the treatment of ITP were preformed by using R software. Results A total of 10 RCTs involving 625 ITP patients were included by tracking the literatures and follow-up to relevant references with full text. Among them, there were 319 patients in the experimental group and 306 patients in the control group. Ten RCTs in 10 articles have lower Jadad scores which are low quality RCTs. The Meta-analysis of the short-term efficacy and adverse effects of 10 studies on ITP in the study were as follows. ①Comparison of significant efficiency rate: 7 RCTs of 420 ITP patients from 7 studies were found to have relatively high heterogeneity (I2=62.3%, P=0.01). There was significant difference in significant efficiency rate between experimental group and the control group by the random effects model of Meta-analysis(OR=2.95, 95% CI: 1.37-6.37, P=0.06). After removing factor of high-dose dexamethasone interference, 5 RCTs involving 287 ITP patients had mild heterogeneity (I2=45%, P=0.12), and Meta-analysis using a fixed-effect model showed that the significant efficiency rate of the experimental group was higher than that of the control group, and the difference was statistically significant (OR=5.28, 95% CI: 2.95-9.44, P<0.000 1). ②Comparison of good efficiency rate: Six RCTs involving 358 patients with ITP had mild heterogeneity (I2=38%, P=0.15). Meta-analysis showed that there was no statistically significant difference in good efficiency rate between the experimental group and the control group by the fixed-effect model(OR=1.30, 95%CI: 0.82-2.07, P=0.27). ③Comparison of total effective rate: The heterogeneity between the 9 RCTs included in the 563 patients with ITP was low (I2=0%, P=0.65). The Meta-analysis using the fixed-effect model showed that the total effective rate of the test group was higher than that of the control group (OR=3.79, 95% CI: 2.50-5.73, P<0.01). ④Comparison of incidence of adverse reactions showed there was no significant difference in the incidence of adverse reactions between the experimental group and the control group (OR=3.56, 95% CI: 0.85-14.95, P=0.08) among 4 RCTs. Conclusions Compared with traditional monotherapy regimen, rhTPO combined with glucocorticoid or danazol regimen can improve significant efficiency rate and the total effective rate of ITP patients, but there were no significant differences in good efficiency rate and incidence of adverse reaction. Key words: Thrombocytopenia; Thrombopoietin; Glucocorticoids; Danazol; Meta-analysis

The 70th anniversary of glucocorticoids in rheumatic diseases: the second youth of an old friend.

Seventy years ago, the first administration of cortisone in a patient with RA marked a milestone in the treatment of inflammatory diseases. However, the initial enthusiasm rapidly vanished as the administration of high doses for lengthy periods revealed worrisome adverse effects. It has taken several decades to overcome the (sometimes excessive) mistrust and to achieve a more differentiated evaluation of the benefit-risk profile and the adequate usage of glucocorticoids (GCs). Today, GCs remain indispensable for the treatment of many inflammatory conditions and their usefulness in RA as a disease-modifying low-dose co-medication is widely acknowledged. Recent studies show promising results concerning both traditional GCs and new formulations. Still, decades of relatively little scientific attention have resulted in a continuing lack of detailed evidence. Hence there is an ongoing need for further research regarding mechanisms of GC actions, the further optimization of treatment parameters for traditional GCs and new formulations.

Issue Highlights-May 2018 (94B3).

Issue Highlights-May 2018 (94B3).

Selective glucocorticoid receptor modulation inhibits cytokine responses in a canine model of mild endotoxemia

Selective glucocorticoid receptor modulators (GRMs) promise to reduce adverse events of glucocorticoids while maintaining anti-inflammatory potency. The present study tested the anti-inflammatory activity of two novel non-steroidal GRMs (GRM1: BI 607812 BS, GRM2: BI 653048 BS*H3PO4) in comparison to prednisolone in a canine model of low dose endotoxemia. This study compared the anti-inflammatory and pharmacokinetic profile of escalating daily oral doses of GRM1 (1, 2.5, 5 and 10mg/kg) and GRM2 (0.1, 0.25 and 1mg/kg) with prednisolone (0.25 and 0.5mg/kg) and placebo after intravenous infusion of endotoxin (0.1μg/kg) to Beagle dogs. This was followed by a 14-day evaluation study of safety and pharmacokinetics. Endotoxin challenge increased TNF-α ∼2000-fold and interleukin-6 (IL-6) 100-fold. Prednisolone and both GRMs suppressed peak TNF-α and IL-6 by 71–82% as compared with placebo. The highest doses of GRM1 and GRM2 reduced the mean body temperature increase by ∼30%. The endotoxin-induced rise in plasma cortisol was strongly suppressed in all treatment groups. Pharmacokinetics of both GRMs were non-linear. Adverse effects of endotoxemia such as vomiting were mitigated by GRM2 and prednisolone, indicating an antiemetic effect. During the 14-day treatment period, the adverse event profile of both GRMs appeared to be similar to prednisolone. Both GRMs had anti-inflammatory effects comparable to prednisolone and showed good safety profiles. Compounds targeting the glucocorticoid receptor selectively may provide an alternative to traditional glucocorticoids in the treatment of inflammatory disease.

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

Evaluation of Biological Activity and Computer-Aided Design of New Soft Glucocorticoids.

Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.

Topical drug treatment of infantile hemangioma

Infantile hemangioma (IH) is the most common benign soft tissue tumor in infants. The safety and efficacy of propranolol are superior to those of traditional glucocorticoids for the treatment of IH, but oral propranolol can cause systemic complications. Recently, topical beta-blockers have become a new research hotspot in the treatment of IH, including 0.5% timolol ophthalmic solution, 0.1% timolol gel-forming solution, nano-propranolol-dispersed hydrogel, etc. In addition, topical 5% imiquimod ointment, local injections and combined lasers at different wavelengths all can be alternative therapies for IH. This review summarizes topical drug treatment of IH. Key words: Hemangioma; Infant; External application drugs; Laser therapy; Treatment outcome

Inhibitory Effects of Resveratrol on Airway Remodeling by Transforming Growth Factor-β/Smad Signaling Pathway in Chronic Asthma Model.

PurposeAsthma is a chronic airway disease characterized by airway remodeling, leading to a progressive decline in lung function. Therapeutic agents that attenuate airway remodeling can complement the limited effects of traditional glucocorticoids. In this study, we investigated the effect of resveratrol on allergic airway inflammation and remodeling in a murine model of chronic bronchial asthma.MethodsPeribronchial smooth muscle thickening that developed in mice challenged with a 3-month repeated exposure to ovalbumin (OVA) was used to study airway remodeling. Oral resveratrol was administered daily during the OVA challenge. The expression of TGF-β1/Smad signaling proteins and downstream mesenchymal markers in the presence or absence of resveratrol was examined in bronchial epithelial cells.ResultsOVA sensitization and chronic challenge increased airway hyperresponsiveness, inflammation, goblet cell hyperplasia, α-smooth muscle actin (SMA), and collagen deposition. Resveratrol effectively suppressed OVA-induced airway inflammation and remodeling. The expression of TGF-β1/phosphorylated Smad2/3 was increased in the lung tissues of OVA-challenged mice but effectively inhibited by resveratrol. In bronchial epithelial cells, the TGF-β1-induced expression of the mesenchymal markers snail, slug, vimentin, and α-SMA was suppressed by resveratrol treatment.ConclusionsResveratrol effectively ameliorated both airway inflammation and airway structural changes in a mouse model of bronchial asthma. These effects were mediated by decreased TGF-β1 expression, in turn suppressing TGF-β1/Smad signaling and the epithelial-mesenchymal transition process. Our results demonstrate the potential benefits of resveratrol for the treatment of airway remodeling associated with bronchial asthma.

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis

To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA). We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences. The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional. This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA). We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences. The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional. This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis.

Multiple sclerosis is a chronic disease of the central nervous system characterized by an autoimmune inflammatory reaction that leads to axonal demyelination and tissue damage. Glucocorticoids, such as prednisolone, are effective in the treatment of multiple sclerosis in large part due to their ability to inhibit pro-inflammatory pathways (e.g., NFκB). However, despite their effectiveness, long-term treatment is limited by adverse side effects. VBP15 is a recently described compound synthesized based on the lazeroid steroidal backbone that shows activity in acute and chronic inflammatory conditions, yet displays a much-reduced side effect profile compared to traditional glucocorticoids. The purpose of this study was to determine the effectiveness of VBP15 in inhibiting inflammation and disease progression in experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of multiple sclerosis. Our data show that VBP15 is effective at reducing both disease onset and severity. In parallel studies, we observed that VBP15 was able to inhibit the production of NFκB-regulated pro-inflammatory transcripts in human macrophages. Furthermore, treatment with prednisolone-but not VBP15-increased expression of genes associated with bone loss and muscle atrophy, suggesting lack of side effects of VBP15. These findings suggest that VBP15 may represent a potentially safer alternative to traditional glucocorticoids in the treatment of multiple sclerosis and other inflammatory diseases.

The application of chromatography techniques for the purification process optimization of amide of hydrocortisone-derived cortienic acid and ethyl ester of L-glycine

Soft ('antedrug') glucocorticoids are pharmacologically active compounds which are biotransformed in a predictable and controllable way to inactive and non-toxic metabolites. Amides of cortienic acids (17(-carboxamide derivatives of glucocorticoids) are potential soft drugs with fewer side effects than traditional glucocorticoids. The purification of 17(- carboxamide derivatives of hydrocortisone was explained using the amide of hydrocortisonederived cortienic acid and ethyl ester of L-glycine as an example and performed by use of column chromatography and preparative thin-layer chromatography (TLC). The optimization of purification process was performed employing analytical TLC and reversed-phase highperformance liquid chromatography (RP-HPLC). The mobile phase that enables best chromatographic separation of the amide from impurities on TLC plate (chloroform-methanol (95:5 V/V)) was selected and modified (reduction of polarity and addition of glacial acetic acid) to be used for the column chromatography and preparative TLC purification. It was confirmed by use of RP-HPLC that purification procedures applied in this study resulted in pure (96.2 %) amide.

VBP15, a Glucocorticoid Analogue, Is Effective at Reducing Allergic Lung Inflammation in Mice

Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation—NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone–but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.

Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases

Glucocorticoids (GCs) have been prescribed to treat a variety of diseases, including inflammatory myopathies and Duchenne muscular dystrophy for over 50 years. However, their prescription remains controversial due to the significant side effects associated with the chronic treatment. It is a common belief that the clinical efficacy of GCs is due to their transrepression of pro-inflammatory genes through inhibition of inflammatory transcription factors (i.e. NF-κB, AP-1) whereas the adverse side effects are attributed to the glucocorticoid receptor (GR)-mediated transcription of target genes (transactivation). The past decade has seen an increased interest in the development of GR modulators that maintain the effective anti-inflammatory properties but lack the GR-dependent transcriptional response as a safe alternative to traditional GCs. Many of these analogues or "dissociative" compounds show potential promise in in vitro studies but fail to reach human clinical trials. In this review, we discuss molecular effects of currently prescribed GCs on skeletal muscle and also discuss the current state of development of GC analogues as alternative therapeutics for inflammatory muscle diseases.

Anti‐inflammatory mechanisms of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts

AbstractPurpose Mapracorat (BOL‐303242‐X; ZK 245186) is a selective glucocorticoid receptor agonist (SEGRA), under clinical evaluation for the treatment of inflammatory eye and skin diseases. It is structurally distinct from glucocorticoids and NSAIDs. Data suggest an improved side effect profile of this compound compared to traditional glucocorticoids. This study was to determine its anti‐inflammatory mechanisms.Methods Primary human conjunctival fibroblasts (HConF)were challenged with IL‐1ß and Luminex technology or ELISA was used to determine the effect of mapracorat on IL‐1ß‐induced cytokine, prostaglandin E2 (PGE2) and matrix metalloproteinase (MMP) release in the presence or absence of mifepristone (RU‐486), a glucocorticoid receptor antagonist. The effect of mapracorat on IL‐1ß‐induced cyclooxygenase‐2 (COX‐2) expression was assessed by Western blotting. Dexamethasone was used as the control.Results IL‐1ß induced release of multiple cytokines, including IL‐6, IL‐8 and monocyte chemotactic protein‐1 (MCP‐1), and of PGE2 and MMPs (MMP‐1 and MMP‐3), as well as the expression of COX‐2. Mapracorat inhibited cytokine, PGE2 and MMP release as well as COX‐2 expression in a dose‐dependent manner with comparable effectiveness as dexamethasone. The inhibition of cytokine and PGE2 release was fully or partially reversed by mifepristone.Conclusion Mapracorat acts as a potent anti‐inflammatory agent in HConF by inhibiting multiple intracellular mediators. The fact that mapracorat is effective on inhibiting PGE2 pathway suggests that it may reduce post‐surgery pain. Clinical significance of these findings needs further investigation. Commercial interest

Ocular Pharmacokinetics of Mapracorat, a Novel, Selective Glucocorticoid Receptor Agonist, in Rabbits and Monkeys

Mapracorat is a selective glucocorticoid receptor agonist in development for the treatment of a variety of ocular diseases. The purpose of this investigation was to evaluate the ocular pharmacokinetics of mapracorat after topical dosing over a range of dose levels in rabbits and monkeys. Mapracorat was administered over a range of doses from 0.01 to 3000 μg/eye (rabbit) or 50 to 3000 μg/eye (monkey). All animals received a single instillation, and monkeys also received repeated (three times per day for 4 days) instillations. At predetermined intervals through at least 24 h after dosing, ocular tissues and plasma were collected and analyzed for mapracorat by liquid chromatography-tandem mass spectrometry. Mapracorat was rapidly absorbed and widely distributed into ocular tissues after topical ocular administration, with measurable levels sustained through ≥24 h. In both species, mapracorat concentrations were highest in tears followed by conjunctiva and cornea, with lower levels observed in iris/ciliary body and aqueous humor. Mapracorat concentrations in conjunctiva, cornea, and iris/ciliary body increased linearly with increasing dose levels. Ocular exposure was higher after repeated dosing to monkeys than after a single dose. Systemic exposure to mapracorat was low after a single administration, with an average maximal concentration of ≤2.0 ng/ml at the highest dose tested (3000 μg/eye). In comparison with the traditional glucocorticoids, dexamethasone (0.1%) and prednisolone acetate (1%), mapracorat (3%) demonstrated similar or higher levels in ocular tissues with lower systemic exposure. The favorable pharmacokinetic profile of mapracorat supports further clinical investigation and suggests that a convenient daily dosing regimen may be efficacious for this novel ophthalmic anti-inflammatory therapy.